The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine- 2,5-diones

Tetrahedron 61 (2005) 8722–8739

The synthetic versatility of alkoxycarbonyl- and

hydroxymethyl-piperazine-2,5-diones

*

Christina L.L. Chai, John A. Elix and Paul B. Huleatt

Department of Chemistry, The Faculties, Australian National University, Canberra, ACT 0200, Australia

Received 25 March 2005; revised 8 June 2005; accepted 23 June 2005

Available online 26 July 2005

Abstract—Alkoxycarbonylpiperazine-2,5-diones are versatile precursors for the a-functionalisation of piperazine-2,5-diones. The

alkoxycarbonyl group activates the a-carbon position to alkylation reactions and this provides a mild and selective method for the

extension of the carbon framework of piperazine-2,5-diones. In addition, the alkoxycarbonyl group can be converted to the carboxy group,

which in turn can be ‘deleted’ or manipulated for the installation of carbon and/or heteroatom substituents where desired, the latter via

N-acyliminium chemistry. We also demonstrate that hydroxymethylpiperazine-2,5-diones complement carboxypiperazinediones as

precursors for the generation of N-acyliminium ions.

1. Introduction

polar and steric effects while the latter is more suitable

for the synthesis of bicyclic frameworks. Due to the

limitations of the aforementioned methodologies, we

sought to develop complementary synthetic routes for

the C-functionalisation of piperazinediones. In addition

we also recognized the need to be able to install

heteroatom functionalities on the a-carbon positions of

the piperazine-2,5-dione ring as this substitution is

present in numerous bioactive piperazine-2,5-diones.

These heteroatom functionalised piperazine-2,5-diones can

also serve as radical or cationic precursors in subsequent

chemical transformations.

The ubiquity of the piperazine-2,5-dione motif in a number

of biologically active natural products¹has encouraged

research into the development of methods for the selective

functionalisation of piperazine-2,5-diones. Although piper-

azine-2,5-diones are cyclic dipeptides and can formally be

synthesized from the condensation of the requisite a-amino

acids,²in practice complex piperazine-2,5-diones are

accessed by the functionalisation of readily available

piperazine-2,5-dione precursors.³This approach has the

advantage of enabling the assembly of the carbon and

heteroatom framework of piperazine-2,5-diones without the

need to develop individual strategies for the synthesis of

the requisite a-amino acids.

Our plan involved the use of an alkoxycarbonyl group

as a ‘traceless’ substituent on the piperazine-2,5-dione

ring. The choice of the alkoxycarbonyl group was

expected to enhance the reactivity of the a-carbon

center of the piperazine-2,5-dione ring towards alky-

lation reactions. In addition, we envisage that the

alkoxycarbonyl group can be converted to the carboxy

group, which in turn can be ‘deleted’ or manipulated for

the installation of carbon and/or heteroatom substituents

where desired.

The existing methods for C-functionalisation are limited in

scope due to the necessity of using strong bases in cases

where the generation of the enolate of the piperazinedione is

required.⁴Regioselectivity is also a problem with unsym-

metrical piperazine-2,5-diones. Other methods for

C-functionalisation of piperazinediones include using

radical addition chemistry⁵and Diels–Alder reactions.⁶

The former relies on the ability to synthesise suitable

radical precursors and/or substrates and is sensitive to

Following on from our previous communication,⁷the

studies reported herein detail the synthetic utility of

alkoxycarbonyl piperazine-2,5-diones in the functionalisa-

tion of the piperazine-2,5-dione nucleus. In the course of our

studies we also discovered that the readily accessible

hydroxymethylpiperazine-2,5-diones complement the

chemistry of alkoxycarbonyl derivatives.

Keywords: N-Acyliminium ions; Alkylations; Amino acids and derivatives;

Trapping reactions.

Corresponding author at present address: Institute of Chemical and

Engineering Sciences, 1 Pesek Road, Jurong Island, Singapore 627833.

Tel.: C65 6796 3902; fax: C65 6316 6184;

*

e-mail: christina_chai@ices.a-star.edu.sg

doi:10.1016/j.tet.2005.06.084

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8723

2. Results and discussion

acid 1a by numerous modiﬁcations to the work-up

procedure were unsuccessful and sufﬁcient quantities of

the acid 1a could not be obtained. Consequently, a milder

method of generating the acid 1a was desired. We envisaged

that the acid 1a may be attainable via hydrogenolysis of the

benzyl ester 3a. Thus, ester 2 was successfully transester-

iﬁed with benzyl alcohol and the desired benzyl ester 3a was

obtained in good yield.

2.1. Synthesis of alkoxycarbonyl- and carboxy-piper-

azine-2,5-diones

In order to examine the effects of various substitution

patterns on the chemistry of carboxy piperazine-2,5-diones,

the acids 1a–c derived from the esters of types 2 and 3, were

targeted.

Subsequent hydrogenolysis of the ester 3a using 10%

palladium on carbon under a hydrogen atmosphere

proceeded smoothly and the desired acid 1a was obtained

in excellent yield. Premature decarboxylation of the acid 1a

was suppressed and sarcosine anhydride was only observed

as a minor byproduct.

Our initial work was directed towards the synthesis of the

target, acid 1a. A three step synthesis of diethyl N-

methylaminomalonate (6) was carried out using modiﬁ-

cation of literature procedures.^8–10Diethyl malonate was

readily converted to diethyl a-bromomalonate 4 in 70%

yield using bromine in carbon tetrachloride.⁸However,

when the bromide 4 was treated with N-methylbenzylamine

using conditions reported in the literature,^9,10only diethyl

malonate was recovered. After much experimentation, the

synthesis of the desired diethyl N-methylbenzylaminoma-

lonate (5) was achieved by treatment of the bromide 4 with

N-methylbenzylamine in chloroform at reﬂux. Hydrogeno-

lytic cleavage of the benzyl group from amine 5 then cleanly

afforded diethyl N-methylaminomalonate (6) in 95% yield.

With the aminomalonate 6 in hand, DCC mediated coupling

of the amine with CBZ-sarcosine afforded the dipeptide 7 in

good yield. Hydrogenolytic cleavage of the CBZ protecting

group from the dipeptide 7, followed by thermally promoted

cyclisation of the deprotected dipeptide afforded the

a-ethoxycarbonyl piperazinedione 2 (see Scheme 1).

From the studies above it is evident that the benzyloxy-

carbonyl piperazine-2,5-diones of type 3 are suitable

precursors to the corresponding acids. With this in mind, a

synthetic route to the esters was undertaken. The synthesis

of dibenzyl aminomalonate (8) was carried out following

literature procedures¹²starting from dibenzyl malonate.

Peptide coupling of dibenzyl aminomalonate (8) with BOC-

sarcosine, deprotection of the resultant dipeptide 9 and

subsequent cyclisation gave the piperazinedione 3c in good

yields. N-acetylation of piperazinedione 3c using acetic

anhydride and DMAP under standard conditions gave the

corresponding ester 3b (see Scheme 2).

With the two esters 3b and 3c in hand, the target acids 1b

and 1c were accessed via hydrogenolysis. When the

N-acetyl ester 3b was treated with hydrogen and 10%

palladium on carbon, as described above, a 2:1 mixture of

the desired acid 1b and 1-acetyl-4-methylpiperazine-2,5-

dione was formed (Scheme 3). Unfortunately, this mixture

could not be separated because of the instability of the acid

1b and in subsequent experiments this mixture of

compounds was utilised without puriﬁcation.

With the a-ethoxycarbonyl piperazinedione 2 in hand,

saponiﬁcation of the ethyl ester moiety using potassium

hydroxide in aqueous ethanol was carried out as reported in

the literature.¹¹Disappointingly, we were unable to

achieve the smooth conversion of the ester 2 to the acid

1a. Approximately 70% of the material recovered from

the reaction was identiﬁed as sarcosine anhydride, clearly

resulting from the premature decarboxylation of the acid 1a.

Our attempts to minimise the premature decarboxylation of

When the free amido ester 3c was reacted under similar

conditions only the desired acid 1c was obtained. The

greater stability of the acid 1c as compared with the acid 1b

maybe due to the relief of steric strain upon decarboxylation

of acid 1b. Since analogous steric effects are not present in

Scheme 1.

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C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

Scheme 2.

related to subtle conformational effects associated with the

substitution pattern of the piperazinedione ring.

Alkylation of piperazinedione 3c with one equivalent of

NaH yielded a mixture of products comprising the

a-methylated ester 10c as the major component and equal

amounts of the trimethyl compound 10a and the starting

material 3c (Scheme 4). Thus the use of NaH as base does

not discriminate between C- and N-alkylation. With excess

NaH and MeI, complete conversion of piperazine-2,5-dione

3c and 10c to the trimethyl compound 10a was observed.

Scheme 3.

1c, the latter is relatively stable. Whilst the acid 1c showed

greater stability than 1b, it was highly insoluble in organic

solvents including dichloromethane and chloroform and

only showed appreciable solubility in more polar solvents

such as methanol and DMSO.

When the ester 3c was reacted with one equivalent of

potassium carbonate and excess methyl iodide, a-methyl

piperazinedione 10c was formed exclusively and in

excellent yields. The excellent regioselectivity observed in

the alkylation of piperazinedione 3c is general for a number

of alkyl halides studied. Scheme 5 summarises the range of

alkyl substituents that can be selectively installed at the

a-carbon position of piperazinedione 3c under these mild

alkylation conditions.

2.2. Extension of the carbon framework of

alkoxycarbonyl piperazine-2,5-diones

The a-alkylation reactions of piperazine-2,5-diones are

usually accomplished using strong bases such as n-butyl

lithium or sodamide.⁴In our studies, the a-methylation of

piperazinedione 3a was effected in excellent yields using

NaH and MeI. This is due to the presence of the activating

alkoxycarbonyl group at the a-carbon center of the

piperazine-2,5-dione ring. When the N-acetyl ester 3b was

reacted with NaH and MeI under similar conditions, only

unreacted starting material was recovered. The failure of

this system to undergo a-alkylation is surprising and may be

Surprisingly when dimethyl sulfate was used as the

alkylating agent instead of MeI, only ester 3a was obtained

(Scheme 5). Thus the choice of alkylating agents provides

complementary routes to the a-methylated derivative 10c as

well as to the N-methylated piperazine-2,5-dione 3a.

Scheme 4.

Scheme 5.

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8725

synthesis of conformationally constrained a-amino acid

derivatives such as that derived from pipecolic acid and

baikiain.¹³Two approaches are possible for the synthesis of

these fused ring systems, both of which involve a sequence

of N- and C-alkylation reactions. In the ﬁrst approach

(Scheme 7), allylation of 3c afforded the 3,4-diallyl

piperazinedione 13 in moderate yield. The fused six-

membered ring of the baikiain derivative 14 was then

formed efﬁciently via a ring closing metathesis reaction

using either Grubb’s type I or type II catalysts. Hydro-

genolysis of the benzylic ester 14 is accompanied by the

concomitant reduction of the alkene to give the carboxylic

acid 15. Finally, the known pipecolic acid derivative 16¹⁴

was prepared via the quantitative thermal decarboxylation

of the acid 15.

Scheme 6.

The potential of this selective alkylation methodology is

highlighted when sequential C- and N-functionalisation steps

are carried out. For example, ester 3c can be selectively C-

benzylated to give piperazinedione 10e. This compound is

then readily N-methylated with methyl iodide and sodium

hydride in DMF to yield the N-methylated, C-benzylated

piperazinedione 11 in 85% yield. Alternatively, by simply

changing the sequence of addition of the alkylating agents, the

ester 3c can be C-methylated and subsequently N-benzylated

to afford piperazinedione 12 (Scheme 6).

The second approach, outlined in Scheme 8, to the pipecolic

acid derivative 16 is more direct. When the key precursor 3c

was treated with 2 equiv of sodium hydride and 1 equiv of

1,4-dibromobutane the desired ester 17 was obtained in

moderate yield. The identity of the ester 17 was conﬁrmed

by quantitative conversion to piperazinedione 16 using the

standard decarboxylation conditions.

Similarly the ﬁve membered ring analogue of 16 was also be

synthesized in this manner using 1,3-dibromopropane as the

alkylating agent (Scheme 8). The piperazine-2,5-dione

formed was subsequently converted to the known derivative

19¹⁴via ester cleavage and decarboxylation.

The methodology to selectively install C-alkyl functionality

onto the piperazinedione ring can also be used for the

synthesis of piperazinedione 10b. As previously outlined in

Scheme 4, the synthesis of piperazinedione 10b could not be

achieved via a-methylation of the N-acetyl piperazinedione

3b. However, with the C-methylated piperazinedione 10c in

hand, N-acetylation was readily achieved using acetic anhydride

and DMAP to afford piperazinedione 10b (Scheme 6).

This study into the functionalisation of ester 3c resulted in

the development of a versatile synthetic route to piper-

azinediones with varying N- and a-substitution patterns.

Our subsequent studies focussed on sequential decarbox-

ylation oxidation nucleophilic addition (DONA) reactions

of carboxy piperazine-2,5-diones. We envisaged that in

conjunction with the mild, efﬁcient and selective alkylation

procedures described above, the DONA protocol could lead

to piperazinediones with greater functional diversity.

2.3. Applications to the synthesis of ring fused

piperazinediones

The methodology described above can be applied to the

Scheme 7.

Scheme 8.

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2.4. Decarboxylation oxidation nucleophilic addition

reactions (DONA) of carboxy piperazine-2,5-diones

ion 21b will also be destabilised by electronic effects and

would be expected to be more reactive with nucleophiles.

In contrast to the N-methyl carboxylic acid 1a, which

showed poor solubility in dichloromethane, the N-acetyl

acid 1b was very soluble in chlorinated solvents. Thus,

when the acid 1b was treated with DIB and I₂in the absence

and in the presence of methanol, respectively, the a-acetoxy

piperazinedione 22c and the a-methoxy piperazinedione

22d were obtained in excellent yields.

In 1999, Suarez et al. reported the synthesis of

a-functionalised pyrrolidines from proline derivatives, in

the presence of iodine and diacetoxyiodobenzene (DIB).¹⁵

The transformation is believed to occur via the intermediacy

of the N-acyliminium ion. Although the synthetic potential

of acyl iminium ion chemistry has long been recognized,¹⁶

the study by Suarez provides a mild and efﬁcient method for

the generation and trapping of N-acyl iminium ion species.

These experiments indicate that under these conditions, the

acid 1b appears to have similar reactivity to the acid 1a

despite the expected disparity in the ease of generation and

stability of the reactive N-acyliminium ion intermediates,

21a and 21b. This result is noteworthy as N-acyliminium

ions such as 21b have not been available for synthetic

purposes prior to this work.¹⁶

This methodology offered an attractive means for preparing

a-functionalised piperazinediones from the corresponding

acids. Thus treatment of acid 1a with 1 equiv of

diacetoxyiodobenzene (DIB) and 0.5 equiv iodine gave

the a-acetoxy derivative 22a. The mechanism, as outlined in

Scheme 9, is likely to proceed through the intermediacy of

the carboxy radical which then undergoes rapid decarbox-

ylation to the a-carbon centred radical 20. DIB mediated

one electron oxidation of this radical species would give the

N-acyliminium ion intermediate 21a. In the absence of an

added nucleophile, the acetate ions (or acetic acid) would

add to the N-acyliminium ion 21a to yield the a-acetoxy

piperazinedione 22a. The simplicity and versatility of this

sequence is demonstrated when the acid 1a was treated with

DIB and iodine in the manner described above and methanol

was added as an external nucleophile. This resulted in the

efﬁcient conversion of the acid 1a into the corresponding

a-methoxy product 22b, a compound which displayed

spectroscopic data identical to that reported in the

literature.¹⁷

In contrast to the N-acetyl acid 1b, the free amido acid 1c

was sparingly soluble in solvents suitable for use in the

DONA reaction, namely dichloromethane and acetonitrile.

As a result, when the acid 1c was subjected to the DONA

protocol outlined previously no reaction was observed and

in all cases the starting material was recovered

quantitatively.

2.5. DONA reactions of a,a-disubstituted piperazine-2,5-

diones

The effect of an a-substituent on the formation and

reactivity of the N-acyliminium ion intermediates generated

using the DONA strategy was examined using the a-methyl

acid 23a obtained from the hydrogenolysis of the

corresponding ester 10a. It is interesting to note that in

contrast to the acid 1a, no premature decarboxylation of the

acid 23a was detected. This suggests that the a-substituted

acid 23a is more stable than the unsubstituted acid, 1a,

presumably because the presence of the a-methyl sub-

stituent hinders the ability of the acid 23a to adopt the planar

six-membered ring transition state required for the

decarboxylation to occur.

The successful use of the acid 1a as a substrate for such

DONA reactions prompted us to assess the relative

reactivity of the acids 1b and 1c. In view of the proposed

mechanism of the reaction, it is evident that the ease of

generation as well as the stability of the N-acyliminium ion

may be strongly inﬂuenced by electronic and/or steric

effects. For example, the generation of the N-acyliminium

ion 21b may be more difﬁcult than 21a and 21c as the

radical intermediate derived from acid 1b would be

expected to be more difﬁcult to oxidise to the highly

electron deﬁcient species 21b. If formed, the N-acyliminium

Treatment of the a-methyl carboxylic acid 23a with DIB

and iodine in the presence of either acetic acid or methanol

Scheme 9.

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8727

Scheme 10.

gave rise to the a-acetoxy (24a) and the a-methoxy (25)

piperazinediones, respectively in yields comparable to those

obtained for acids 1a and 1b. Similarly, conversion of the

acid 23b (which was obtained from the ester 11) to the

corresponding a-acetoxy compound 24b was also achieved

(Scheme 10).

afforded the desired 3-allyl-1,4-dimethylpiperazine-2,5-

dione (26) in 68% yield (Scheme 11).

Similarly when 2-methoxynaphthalene was used as the

carbon nucleophile in the presence of boron triﬂuoride

diethyl etherate, Friedel–Crafts alkylation of the intermedi-

ate 21a occurred to yield the a-aryl piperazinedione 27 in

81% yield (Scheme 11).

The synthetic sequence described above led to piperazine-

dione derivatives which cannot be readily accessed using

other synthetic methods. Studies carried out within our

group have established that selective heteroatom

a-functionalisation of piperazinediones can be difﬁcult in

some cases.¹⁸For example, the a-methoxy compound 25

cannot be prepared by the established protocols for the

a-functionalisation of piperazinediones. 3-Bromo-1,3,4-

trimethylpiperazine-2,5-dione cannot be accessed through

established methods as radical bromination of 1,3,4-

trimethylpiperazine-2,5-dione with NBS leads to exclusive

formation of the regioisomer, 6-bromo-1,3,4-trimethylpipe-

razine-2,5-dione.^18bThis in turn means that the formation of

the a-methoxy compound 25, via nucleophilic displacement

of the bromide, cannot be obtained by this route.

In contrast to the stability of the a-acetoxy and a-methoxy

compounds, 22a and 22b, respectively, the C-methyl

piperazinediones 24a and 25, were unstable. Upon standing,

these piperazinediones are converted to the methylidene

piperazinedione 28a. Although Schmidt et al. have reported

the synthesis of methylidene piperazinediones from

a-methyl-a-hydroxypiperazinediones under acidic con-

ditions,²⁰there is no literature precedence for a conversion

of this type under neutral conditions. This elimination

process probably proceeds through the intermediacy of an

a-carbocation/N-acyliminium ion intermediate 29a as out-

lined in Scheme 12.

Due to the competing elimination process, efﬁcient C-

allylation of the N-acyliminium ion 29a (generated from

a-methoxy piperazinedione 25) was difﬁcult to achieve.

Treatment of the piperazinedione 25 with boron triﬂuoride

diethyl etherate and allyltrimethylsilane gave a 1:1 mixture

of the desired product 30 and the methylidene piperazine-

dione 28a. The formation of the desired product 30 was

favoured when 10 equiv of allyltrimethylsilane was used.

Using these optimised conditions, the conversion of the

a-methoxy piperazinedione 25 to the a-allyl piperazine-

dione 30 was achieved in 66% yield.

2.6. Carbon–carbon bond forming reactions via

N-acyliminium ions derived from piperazine-2,5-diones

In order to increase the repertoire of synthetic transform-

ations that can be achieved with N-acyliminium ions

generated from piperazinedione precursors, carbon–carbon

bond forming reactions were investigated. The use of such

N-acyliminium ions as glycine cation equivalents in carbon

chain extension reactions has been reported.¹⁹Our initial

studies focussed on the use of 3-methoxy-1,4-dimethylpi-

perazine-2,5-dione (22b) as an N-acyliminium ion precursor.

Thus, treatment of piperazinedione 22b with boron triﬂuoride

diethyl etherate in the presence of allyltrimethylsilane

The conversion of the N-acyliminium ion 29a to the

methylidene piperazinedione 28a can be exploited for the

synthesis of a variety of alkylidene piperazinediones

Scheme 11.

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C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

Scheme 12.

including natural products. For example, dehydrophenyla-

histin contains a Z-benzylidene piperazinedione moiety.²¹

Thus, to demonstrate the generality of the elimination

process, a conversion of the piperazinedione 24b to the

benzylidene piperazinedione 28b was attempted. Treatment

of the a-acetoxypiperazinedione 24b with boron triﬂuoride

diethyl etherate afforded the benzylidene piperazinedione

28b as a single stereoisomer in 76% yield. The stereo-

chemistry of the product was assigned as (Z) by comparison

of the ¹H NMR data observed for piperazinedione 28b with

data reported in the literature.²²It is likely that formation of

the E-isomer is disfavoured due to steric interaction between

the phenyl ring and the carbonyl group of the piperazine-

dione ring.

envisaged that such a modiﬁed DONA protocol could be

applied to serine derived piperazinediones in which the

a-hydroxymethyl moiety could be employed as a latent

functionality for the N-acyliminium ion in the same manner

as the carboxylic acid group in the previous study. This is an

attractive alternative as the serine based piperazinediones

are readily accessible using peptide coupling procedures.

For example as outlined in Scheme 13, the dipeptide 31 can

be readily converted to piperazinedione 32 using the

standard two step hydrogenolysis/thermal cyclisation

protocol. More efﬁcient conversion was achieved using

catalytic transfer hydrogenolysis conditions. Using 10%

palladium on carbon and cyclohexene in methanol at reﬂux,

cleavage of the CBZ protecting group was followed by the

in situ cyclisation of the free amine to afford the

piperazinedione 32 in 85% yield.²⁴The piperazinedione

32 was only sparingly soluble in most organic solvents,

however, protection of the hydroxy functionality as a silyl

ether afforded the readily soluble piperazinedione 33.

Piperazinedione 33 is a key synthetic intermediate that

can be selectively N-alkylated with a wide variety of alkyl

halides in a combinatorial fashion. In this study, the

N-methyl 34a and N-p-methoxybenzyl 34b derivatives

were targeted. Treatment of piperazinedione 33 with sodium

hydride and either methyl iodide or p-methoxybenzyl

chloride afforded piperazinediones 34a and 34b, respect-

ively. Acidic cleavage of the t-butyldimethylsilyl group

2.7. Alternative piperazine-2,5-dione precursors for

modiﬁed DONA type reactions: the use of

hydroxymethylpiperazinediones

In order to extend the utility of the DONA methodology, we

sought to examine alternative substrates for the DONA type

reactions. The work of Suarez et al. on the synthesis of

a-aryl amino acids from serine derivatives provided the

impetus for our studies.²³In that study Suarez et al.

demonstrated that the hydroxylmethyl moiety can act as a

latent functionality for the N-acyliminium ion via a

sequence of radical deformylation and oxidation steps. We

Scheme 13.

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8729

Scheme 14.

then yielded the piperazinediones 35a and 35b in excellent

yield.

or to TMS. ¹³C spectra were appropriately referenced to

either CDCl₃(77.0 ppm), CD₃OD (49.0 ppm), (CD₃)₂SO

(39.5 ppm). Infrared spectra were recorded on a Perkin

Elmer 1800 or a Shimadzu FTIR-8400 Fourier Transform

Infrared Spectrometer. Samples were analysed as KBr discs

(for solids) or as thin liquid ﬁlms (for oils and liquids) on

NaCl plates. Low and high resolution mass spectra were

recorded on a VG Micromas 7070F double focussing mass

spectrometer using positive ion electron impact techniques.

Melting points are uncorrected and were recorded on a

Leica Galen III microscope. Flash chromatography utilised

Merck silica gel 60 (200–400 mesh ASTM) and analytical

reagent (AR) grade solvents as indicated. Unless stated

otherwise, reagents were purchased from Aldrich, Merck,

Fluka, AJAX or BDH Chemicals. All solvents were of AR

grade, puriﬁed by literature procedures²⁵and where

appropriate, stored over molecular sieves. All reactions

were carried out under an atmosphere of dry, oxygen-free

nitrogen unless otherwise speciﬁed. Reactions which

involved moisture sensitive compounds were carried out

using oven-dried or ﬂame-dried apparatus with dry solvents.

Our initial work in the study focussed on the DONA

reactions of piperazinedione 32. A suspension of the

hydroxymethyl piperazinedione 32 in dichloromethane

was treated with iodine and DIB, followed by addition of

excess methanol to give the desired a-methoxy piperazine-

dione 36 in a moderate yield of 44%.

In contrast to the solubility and stability complications

encountered with the carboxylic acid 1a, the N-methylated

serine derived piperazinedione 35a was stable and readily

soluble in dichloromethane. Furthermore, using the standard

DONA reaction conditions, complete conversion of the

alcohol 35a to the a-acetoxy compound 22a was achieved

(Scheme 14). Similarly, the N-p-methoxybenzyl compound

35b underwent the modiﬁed DONA reaction to give the

a-acetoxy compound 37 in excellent yield.

3. Conclusion

4.2. Syntheses of alkoxycarbonyl- and carboxy-piper-

azine-2,5-diones

Our studies have demonstrated that carboxy- and hydro-

xymethyl-piperazinediones are complementary precursors

for the generation of N-acyliminium ions. The carboxy

piperazinediones potentially suffer from problems with

premature decarboxylation and lack of solubility in the

solvents typically used in these reactions. On the other

hand, the carboxy piperazinediones (with the exception of

the N-acetylated systems) allow for mild C-alkylation

reactions by activating the a-carbon positions of the

piperazine-2,5-dione. By contrast the hydroxymethyl pipe-

razinediones are readily accessible from commercially

available serine and derivatives, have a much better

solubility proﬁle in organic solvents but cannot be

C-functionalised under mild conditions.

4.2.1. Ethyl N-[N-benzyloxycarbonylsarcosyl]-2-ethoxy-

carbonylsarcosinate (7). To a stirred solution of CBZ-

sarcosine (5.58 g, 25.0 mmol) in DMF (60 mL) at 0 8C was

added DCC (5.21 g, 25.0 mmol) and HOBt (3.38 g,

25.0 mmol). The resultant reaction mixture was stirred at

0 8C for 2 h and ﬁltered to remove the DCU byproduct. To

the ﬁltrate was added a solution of diethyl (N-methylami-

no)malonate (6)^8–10(4.73 g, 25.0 mmol) in DMF (20 mL).

The reaction mixture was allowed to warm to room

temperature and stirred for a further 16 h. After this time,

the reaction mixture was ﬁltered and the solvent was

removed in vacuo. The residue was taken up in ethyl acetate

(100 mL) and washed successively with saturated sodium

carbonate solution (50 mL) and water (50 mL). The organic

phase was separated, dried over magnesium sulfate and the

solvent was removed in vacuo to give the crude product.

Puriﬁcation via ﬂash column chromatography (7:3, ethyl

acetate–petroleum spirit, R_f: 0.58) afforded the title

compound 7 as a thick, clear oil (8.06 g, 81%). n_maxﬁlm/

cm^K12981 m, 2938 m, 1740 vs, 1709 vs, 1675 vs, 1478 m,

1456 m, 1399 m, 1368 m, 1308 s, 1233 s, 1180 s, 1154 s,

1113 m, 1034 m. d_H(300 MHz, CDCl₃) 1.30 (m, 6H, 2!

CO₂CH₂CH₃), 2.99 (s, 3H, NCH₃), 3.04, 3.09 (rotamers 2!

s, 3H, NCH₃), 4.14–4.25 (m, 6H, 2!CO₂CH₂CH₃and

CH₂C(O)NCH₃), 5.11, 5.14 (rotamers 2!s, 2H, CH₂Ar),

5.92 (s, 1H, CH(CO₂Et)₂), 7.30–7.36 (m, 5H, C₆H₅). d_C

4. Experimental

4.1. General

¹H and ¹³C NMR spectra were recorded on a Varian Gemini

II NMR spectrometer at 300 and 75.4 MHz, respectively.

CDCl₃was used as the solvent unless otherwise indicated.

The chemical shifts (d) are reported as the shift in ppm from

tetramethylsilane (TMS, 0.00 ppm). ¹H spectra were

appropriately referenced to either the CHCl₃singlet

(7.26 ppm), CHD₂OD quintet (3.31 ppm), CHD₂S(O)CD₃

quintet (2.50 ppm), CHD₂(CD₃)NC(O)D quintet (2.90 ppm)

8730

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

(75 MHz, CDCl₃) 13.7 (2!CO₂CH₂CH₃), 32.3 (NCH₃),

35.0, 35.7 (rotamers CBZ-NCH₃), 50.0, 50.2 (rotamers

CH₂C(O)NCH₃), 59.9, 59.9 (rotamers CH(CO₂Et)₂), 61.8

(2!CO₂CH₂CH₃), 66.9, 67.1 (rotamers CH₂Ar), 127.3,

127.4, 127.5, 127.6, 128.1, 128.1 (rotamers aromatic CH),

136.3 (2!quaternary aromatic C), 155.9, 156.5 (rotamers

(300 MHz, CDCl₃) 2.91 (s, 3H, NCH₃), 2.97 (s, 3H, NCH₃),

3.82 (d, 1H, J_ABZ17 Hz, ring CH_aH_b), 4.13 (d, 1H, J_AB

Z

17 Hz, ring CH_aH_b), 4.60 (s, 1H, ring CH), 5.12 (d, 1H,

J_ABZ12 Hz, benzyl CH_aH_b), 5.29 (d, 1H, J_ABZ12 Hz,

benzyl CH_aH_b), 7.35 (m, 5H, aromatic C₆H₅). d_C(75 MHz,

CDCl₃) 32.7 (NCH₃), 33.6 (NCH₃), 51.5 (ring CH₂), 65.8

(ring CH), 68.2 (benzyl CH₂), 128.0 (2!aromatic CH),

128.5 (3!aromatic CH), 134.4 (quaternary aromatic C),

159.8 (C(O)), 164.4 (C(O)), 166.2 (C(O)). m/z (EI)

276.1105 (M^C%. C₁₄H₁₆N₂O₄requires 276.1110), 232

(17%), 185 ([MKC₇H₇]^C, 6%), 141 ([MKCO₂Bn]^C,

95%), 113 (80%), 91 ([C₇H₇]^C, 100%).

C(O)), 165.9 (C(O)), 168.9 (C(O)). m/z (EI) 394.1741 (M^C%

.

C₁₉H₂₆N₂O₇requires 394.1740), 349 ([MKOEt]^C, 5%), 259

([MKCbz]^C, 10%), 188 (15%), 116 (33%), 91 ([C₇H₇]^C,

100%).

4.2.2. 3-Ethoxycarbonyl-1,4-dimethylpiperazine-2,5-

dione (2). A solution of ethyl N-[N-benzyloxycarbonylsar-

cosyl]-2-ethoxycarbonylsarcosinate (7) (4.14 g, 10.4 mmol)

in degassed methanol (100 mL) was stirred in the presence

of 10% palladium on carbon (450 mg) under an atmosphere

of hydrogen for 16 h. The reaction mixture was ﬁltered

through celite and the solvent evaporated under reduced

pressure. The oily residue was taken up in toluene (50 mL)

and the resultant solution was heated at reﬂux for 48 h. After

this time the solvent was removed in vacuo and the crude

product was recrystallised from ethyl acetate/petroleum

spirit affording 3-ethoxycarbonyl-1,4-dimethylpiperazine-

2,5-dione (2) as colourless crystals (1.99 g, 89%). The

product may also be puriﬁed by column chromatography

(5:1, ethyl acetate–methanol, R_f: 0.48). Mp 66–68 8C. n_max

KBr/cm^K12980 m, 2941 m, 1738 vs, 1678 vs, 1479 s, 1404

s, 1323 m, 1229 s, 1196 s, 1045 s, 746 w, 648 w. d_H

(300 MHz, CDCl₃) 1.31 (t, 3H, JZ6 Hz, CO₂CH₂CH₃),

4.2.4. 3-Carboxyl-1,4-dimethylpiperazine-2,5-dione (1a).

To a solution of 3-benzyloxycarbonyl-1,4-dimethylpiper-

azine-2,5-dione (3a) (920 mg, 3.33 mmol) in degassed

methanol (20 mL) was added 10% palladium on carbon

(80 mg). The reaction mixture was then stirred under a

hydrogen atmosphere for 1 h after which time it was ﬁltered

through a bed of celite. The ﬁltrate was reduced in vacuo

and following co-evaporation with chloroform (3!5 mL),

the acid (1a) was obtained as an unstable colourless solid

(552 mg, w90%) which was contaminated with a small

amount of sarcosine anhydride. d_H(300 MHz, CD₃OD) 2.97

(s, 3H, NCH₃), 3.00 (s, 3H, NCH₃), 3.97 (d, 1H, JZ18 Hz,

ring CH_aH_b), 4.20 (d, 1H, JZ18 Hz, ring CH_aH_b), 4.73 (s,

1H, ring CH).

2.94 (s, 3H, NCH₃), 2.98 (s, 3H, NCH₃), 3.84 (d, 1H, J_AB

Z

4.2.5. Benzyl N-[N-t-butoxycarbonylsarcosyl]-2-benzyl-

oxycarbonylglycinate (9). To a solution of N-t-butoxy-

carbonylsarcosine (227 mg, 1.20 mmol) in DMF (10 mL) at

0 8C was added DCC (248 mg, 1.20 mmol) and HOBt

(163 mg, 1.21 mmol). The resultant reaction mixture was

stirred at 0 8C for 2 h and ﬁltered to remove the DCU

byproduct. To the ﬁltrate was added a solution of dibenzyl

aminomalonate (8) (360 mg, 1.20 mmol) in DMF (5 mL).

The reaction mixture was warmed to room temperature and

stirred for a further 16 h. After this time, the reaction

mixture was ﬁltered and the solvent was removed in vacuo

to give a viscous, pale yellow oil. The residue was taken up

in chloroform (20 mL) and washed with saturated sodium

carbonate solution (10 mL) and water (10 mL). The organic

phase was separated, dried over magnesium sulfate and the

solvent was removed in vacuo to give the crude product as a

clear oil. Puriﬁcation via ﬂash column chromatography (4:1,

ethyl acetate–petroleum spirit, R_f: 0.55) afforded the title

compound 9 as a clear and colourless oil which solidiﬁed

upon prolonged standing (547 mg, 97%). Mp 82–84 8C.

(Found: C, 63.9; H, 6.7; N, 5.7. C₂₅H₃₀N₂O₇requires C,

63.8; H, 6.4; N, 5.95%); n_maxKBr/cm^K13239 s, 3054 w,

2976 m, 1765 vs, 1743 vs, 1708 vs, 1678 vs, 1550 s, 1456 s,

1396 s, 1329 s, 1217 s, 1143, 743 s, 698 s. d_H(300 MHz,

CDCl₃) 1.46 (s, 9H, (CH₃)₃C), 2.91 (s, 3H, NCH₃), 3.93 (bs,

2H, NCH₂C(O)), 5.15 (d, 2H, J_ABZ12 Hz, 2!CH_aH_bPh),

5.21 (d, 2H, J_ABZ12 Hz, 2!CH_aH_bPh), 5.29 (d, 1H, JZ

7 Hz, NHCHC(O)), 7.24–7.33 (m, 11H, NH and 2!C₆H₅).

d_C(75 MHz, CDCl₃) 28.0 (3!(CH₃)₃C), 35.4 (NCH₃), 52–

53 (rotamers CH₂C(O)NH), 56.0 (CH(CO₂Bn)₂), 68.0 (2!

CH₂Ph), 80.6 (C(CH₃)₃), 128.0 (4!aromatic CH), 128.4

(6!aromatic CH), 134.4 (2!quaternary aromatic C), 165.6

17 Hz, ring CH_aH_b), 4.18 (d, 1H, J_ABZ17 Hz, ring CH_aH_b),

4.28 (m, 2H, CO₂CH₂CH₃), 4.55 (s, 1H, CHCO₂Et). d_C

(75 MHz, CDCl₃) 13.9 (CO₂CH₂CH₃), 32.7 (NCH₃), 33.7

(NCH₃), 51.5 (ring CH₂), 62.9 (CO₂CH₂CH₃), 65.9

(CHCO₂Et), 160.0 (C(O)), 164.5 (C(O)), 166.3 (C(O)).

m/z (EI) 214.0953 (M^C%. C₉H₁₄N₂O₄requires 214.0954),

171 (12%), 141 ([MKCO₂Et]^C, 67%), 113 (100%).

4.2.3. 3-Benzyloxycarbonyl-1,4-dimethylpiperazine-2,5-

dione (3a). Method A.

A

stirred solution of

3-ethoxycarbonyl-1,4-dimethylpiperazine-2,5-dione (2)

(203 mg, 0.95 mmol) in benzyl alcohol (2 mL) was heated

at 180 8C for 16 h. The solvent was then removed by

distillation and the residue puriﬁed by column chromatog-

raphy (ethyl acetate, R_f: 0.45) to afford 3-benzyloxycarbonyl-

1,4-dimethylpiperazine-2,5-dione (3a) as a colourless solid

(207 mg, 79%).

Method B. To a stirred solution of 3-benzyloxycarbonyl-1-

methylpiperazine-2,5-dione (3c) (978 mg, 3.7 mmol) in

acetone (20 mL) was added anhydrous K₂CO₃(1.031 g,

7.46 mmol) and dimethyl sulfate (1.4 mL, 14.9 mmol). The

reaction mixture was heated at reﬂux under nitrogen for

48 h. After this time the inorganic salts were ﬁltered off and

the ﬁltrate was concentrated under reduced pressure.

Trituration with ether (10 mL) followed by ﬁltration

afforded 3-benzyloxycarbonyl-1,4-dimethylpiperazine-2,5-

dione (3a) as a colourless solid (909 mg, 89%). If necessary

the product may be puriﬁed by column chromatography

(ethyl acetate, R_f: K0.45). Mp 110–112 8C. (Found: C 60.6;

H, 6.0; N, 10.1. C₁₄H₁₆N₂O₄requires C, 60.9; H, 5.8; N,

10.1%); n_maxKBr/cm^K13449 w, 3039 w, 2969 w, 1740 vs,

1700 vs, 1696 vs, 1405 s, 1278 s, 1189 s, 1035 m, 739 m. d_H

(3!C(O)), 169.2 (carbamate C(O)). m/z (EI) 470.2050 (M^C%

C₂₅H₃₀N₂O₇requires 470.2053), 414 (MHKC(CH₃)₃]^C,

.

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8731

16%), 371 ([MKBocC2]^C, 17%), 279 ([MKBoc–C₇H₇]^C,

(C(O)), 171.3 (ester C(O)). m/z (EI) 304.1059 (M^C%

.

21%), 91 ([C₇H₇]^C, 100%).

C₁₅H₁₆N₂O₅requires 304.1059), 262 ([MHKAc]^C, 15%),

213 ([MKC₇H₇]^C, 25%), 170 ([MHKCO₂Bn]^C, 20%),

127 ([MHKCO₂Bn-Ac]^C, 42%), 91 (C₇H^C₇, 100%).

4.2.6. 3-Benzyloxycarbonyl-1-methylpiperazine-2,5-

dione (3c). To a solution of benzyl N-[N-t-butoxycarbo-

nylsarcosyl]-2-benzyloxycarbonylglycinate (9) (8.24 g,

17.5 mmol) in chloroform (125 mL) at 0 8C was added

TFA (10 mL). The resultant solution was stirred for 16 h at

room temperature. After this time the solvent and excess

TFA were removed in vacuo. The resulting residue was

taken up in chloroform (100 mL) and washed with saturated

sodium bicarbonate solution (50 mL). The separated

organic phase was dried (MgSO₄) and concentrated in

vacuo. The residue was then taken up in toluene (125 mL)

and heated at reﬂux for 24 h. The product crystallised from

solution upon cooling and was collected by ﬁltration. The

ﬁltrate was evaporated and further product was obtained

from the residue via chromatographic puriﬁcation (5:1,

ethyl acetate–methanol, R_f: 0.58). Using a combination of

these puriﬁcation methods, the title compound was obtained

as a colourless crystalline solid (4.59 g, 82%). Mp 119–

120 8C. (Found C, 59.6; H, 5.4; N, 10.6. C₁₃H₁₄N₂O₄

requires C, 59.5; H, 5.4; N, 10.7%). n_maxKBr/cm^K13338 s,

3069 w, 3016 w, 1742 vs, 1702 vs, 1670 vs, 1457 s, 1248 s,

1180 s, 1040 m, 945 m, 718 m, 700 s. d_H(300 MHz, CDCl₃)

2.97 (s, 3H, NCH₃), 3.80 (d, 1H, J_ABZ18 Hz, ring CH_aH_b),

4.12 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.70 (d, 1H, JZ

4 Hz, NHCHC(O)), 5.19 (d, 1H, J_ABZ12 Hz, benzyl

CH_aH_b), 5.27 (d, 1H, J_ABZ12 Hz, benzyl CH_aH_b), 6.80

(bs, 1H, NH), 7.35 (s, 5H, Aromatic C₆H₅). d_C(75 MHz,

CDCl₃) 34.1 (NCH₃), 51.4 (ring CH₂), 59.2 (NHCHC(O)),

68.3 (CH₂Ph), 128.2 (2!aromatic CH), 128.6 (3!aromatic

CH), 134.6 (quaternary aromatic CH), 160.2 (C(O)), 166.6

(C(O)), 167.1 (C(O)). m/z (EI) 262.0953 (M^C. C₁₃H₁₄N₂O₄

requires 262.0954), 218 (21%), 171 ([MKC₇H₇]^C, 18%),

143 (19%), 127 ([MKCO₂Bn]^C, 23%), 99 (26%), 91

(C₇H^C₇, 100%).

4.2.8. 4-Acetyl-3-carboxyl-1-methylpiperazine-2,5-dione

(1b). To a solution of 4-acetyl-3-benzyloxycarbonyl-1-

methylpiperazine-2,5-dione (3b) (241 mg, 0.79 mmol) in

degassed methanol (20 mL) was added 10% palladium on

carbon (20 mg). The reaction mixture was then stirred under

a hydrogen atmosphere for 1 h after which time it was

ﬁltered through a bed of celite. The ﬁltrate was reduced in

vacuo and following co-evaporation with chloroform (3!

5 mL), the acid (1b) (w112 mg, 66%) was obtained as an

unstable colourless oil which also contained 1-acetyl-4-

methylpiperazine-2,5-dione (w45 mg, 33%).

d_H(300 MHz, CDCl₃) 2.54 (s, 3H, NC(O)CH₃), 2.97 (s, 3H,

NCH₃), 3.89 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.36 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 5.58 (s, 1H, ring CH).

4.3. 3-Carboxyl-1-methylpiperazine-2,5-dione (1c)

To a solution of 3-benzyloxycarbonyl-1-methylpiperazine-

2,5-dione (3c) (710 mg, 2.71 mmol) in degassed methanol

(30 mL) was added 10% palladium on carbon (100 mg). The

reaction mixture was then stirred under a hydrogen

atmosphere for 1 h after which time it was ﬁltered through

a bed of celite. The ﬁltrate was reduced in vacuo and

following co-evaporation with chloroform (5!10 mL), the

acid (1c) was obtained as a colourless gum (468 mg, 100%).

d_H(300 MHz, CD₃OD) 3.01 (s, 3H, NCH₃), 3.94 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 4.21 (d, 1H, J_ABZ18 Hz, ring

CH_aH_b), 4.62 (s, 1H, CHCO₂H). d_C(75 MHz, CD₃OD) 34.3

(NCH₃), 52.3 (CH₂), 60.2 (CHCO₂H), 163.1 (C(O)), 168.9

(C(O)), 170.0 (C(O)).

4.4. Syntheses of N- and/or C-functionalised piperazine-

2,5-diones from alkoxycarbonyl piperazinedione

precursors

4.2.7. 4-Acetyl-3-benzyloxycarbonyl-1-methylpipera-

zine-2,5-dione (3b). To

a

stirred solution of

3-benzyloxycarbonyl-1-methylpiperazine-2,5-dione (3c)

(646 mg, 2.46 mmol) in dichloromethane (10 mL) was

added DMAP (331 mg, 2.71 mmol) and acetic anhydride

(0.26 mL, 2.76 mmol). The resultant solution was stirred

under nitrogen until TLC analysis of the reaction mixture

showed complete consumption of starting material (typi-

cally 2 h). After this time the solvent was removed in vacuo

and the residue was puriﬁed via column chromatography

(4:1, ethyl acetate–petroleum spirit, R_f: 0.49). The title

compound was obtained as a colourless oil (682 mg, 91%)

which solidiﬁed upon standing. Mp 100–101 8C. (Found C,

59.2; H, 5.4; N, 9.1. C₁₅H₁₆N₂O₅requires C, 59.2; H, 5.3; N,

9.2%). n_maxKBr/cm^K13439 w, 2996 w, 1730 vs, 1711 vs,

1676 vs, 1383 s, 1232 s, 1189 s, 998 m, 761 m. d_H

(300 MHz, CDCl₃) 2.59 (s, 3H, NC(O)CH₃), 2.98 (s, 3H,

NCH₃), 3.86 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.23 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 5.22 (d, 1H, J_ABZ12 Hz, benzyl

CH_aH_b), 5.29 (d, 1H, J_ABZ12 Hz, benzyl CH_aH_b), 5.68 (s,

1H, CHCO₂Bn), 7.34 (m, 5H, aromatic C₆H₅). d_C(75 MHz,

CDCl₃) 26.6 (NC(O)CH₃), 33.8 (NCH₃), 53.2 (ring CH₂),

59.8 (CHCO₂Bn), 68.4 (benzyl CH₂), 127.8 (2!aromatic

CH), 128.5 (aromatic CH), 128.6 (2!aromatic CH), 134.6

(quaternary aromatic C), 159.8 (C(O)), 165.7 (C(O)), 165.9

4.4.1. 3-Benzyloxycarbonyl-1,3,4-trimethylpiperazine-2,

5-dione (10a). Method A. To

a

solution of

3-benzyloxycarbonyl-1,4-dimethylpiperazine-2,5-dione

(3a) (552 mg, 2.00 mmol) in DMF (10 mL) at 0 8C under

nitrogen was added sodium hydride (160 mg, 4.00 mmol,

60% in parafﬁn) and methyl iodide (2 mL, excess). The

resultant solution was stirred under a nitrogen atmosphere

for 24 h and after this time the solvent was removed under

reduced pressure. The residue was taken up in chloroform

(20 mL) and washed with water (5 mL), brine (5 mL) and

dried (MgSO₄). The solvent was removed in vacuo and the

crude product was puriﬁed by column chromatography

(ethyl acetate, R_f: 0.47) giving (10a) as a clear and

colourless oil which solidiﬁed upon prolonged standing

(533 mg, 92%).

Method B. The title compound was prepared, as described in

Method A, from 3-benzyloxycarbonyl-1-methylpiperazine-

2,5-dione (3c) (820 mg, 3.13 mmol) in DMF (10 mL), with

sodium hydride (276 mg, 6.89 mmol, 60% in parafﬁn) and

methyl iodide (2 mL, excess). The title compound was

8732

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

obtained as a clear and colourless oil which solidiﬁed upon

prolonged standing (754 mg, 83%).

For 10c and 10e, the resulting solid was triturated with ether

and the solid was further puriﬁed (if necessary) via

recrystallisation from the mixed solvent of ethyl acetate/

petroleum spirits. For 10d and 10f, the residue obtained was

puriﬁed by column chromatography.

Mp 86–88 8C. (Found C, 61.7; H, 6.3; N, 9.5. C₁₅H₁₈N₂O₄

requires C, 62.1; H, 6.3; N, 9.7%). n_maxKBr/cm^K13451 w,

3000 w, 2943 w, 1746 vs, 1664 vs, 1458 m, 1403 m, 1262 s,

1128 m, 769 m, 710 m. d_H(300 MHz, CDCl₃) 1.79 (s, 3H,

C–CH₃), 2.81 (s, 3H, NCH₃), 2.96 (s, 3H, NCH₃), 3.93 (d,

1H, J_ABZ18 Hz, ring CH_aH_b), 4.00 (d, 1H, J_ABZ18 Hz,

ring CH_aH_b), 5.16 (d, 1H, J_ABZ12 Hz, benzyl CH_aH_b), 5.24

(d, 1H, J_ABZ12 Hz, benzyl CH_aH_b), 7.28–7.35 (m, 5H,

aromatic C₆H₅). d_C(75 MHz, CDCl₃) 20.1 (a-CH₃), 29.1

(NCH₃), 33.6 (NCH₃), 50.9 (ring CH₂), 67.6 (quaternary C–

CH₃), 67.7 (benzyl CH₂), 127.7 (2!aromatic CH), 128.1

(aromatic CH), 128.2 (2!aromatic CH), 134.5 (quaternary

aromatic C), 163.0 (C(O)), 163.6 (C(O)), 167.6 (C(O)). m/z

(EI) 290.1264 (M^C%. C₁₅H₁₈N₂O₄requires 290.1267), 155

([MKCO₂Bn]^C, 100%), 127 (82%), 91 ([C₇H₇]^C, 60%).

4.5.1. 3-Benzyloxycarbonyl-1,3-dimethylpiperazine-2,5-

dione (10c). The title compound 10c was synthesised from

3c following the general procedure above. Compound 10c is

a colourless solid which was obtained in quantitative yield.

Mp 142–143 8C. (Found C, 60.6; H, 5.9; N, 10.0.

C₁₄H₁₆N₂O₄requires C, 60.9; H, 5.8; N, 10.1%). n_max

KBr/cm^K13179 w, 3100 w, 2950 w, 1719 vs, 1675 vs, 1448

m, 1414 m, 1239 vs, 1120 m, 920 w, 761 m, 704 m. d_H

(300 MHz, CDCl₃) 1.73 (s, 3H, C–CH₃), 2.95 (s, 3H,

NCH₃), 3.78 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.02 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 5.19 (m, 2H, benzyl CH₂), 6.97

(bs, 1H, NH), 7.32 (m, 5H, aromatic C₆H₅). d_C(75 MHz,

CDCl₃) 21.3 (C–CH₃), 34.3 (NCH₃), 52.1 (ring CH₂), 62.6

(quaternary ring C), 68.0 (benzyl CH₂), 127.7 (2!aromatic

CH), 128.4 (aromatic CH), 128.5 (2!aromatic CH), 134.7

(quaternary aromatic C), 163.7 (C(O)), 167.1 (C(O)), 169.0

(C(O)). m/z (EI) 276.1109 (M^C%. C₁₄H₁₆N₂O₄requires

276.1110), 232 (3%), 185 ([MKC₇H₇]^C, 5%), 141 ([MK

CO₂Bn]^C, 100%), 113 (58%), 91 ([C₇H₇]^C, 87%).

4.4.2. 4-Acetyl-3-benzyloxycarbonyl-1,3-dimethylpiper-

a

azine-2,5-dione (10b). To

stirred solution of

3-benzyloxycarbonyl-1,3-methylpiperazine-2,5-dione (10c)

(140 mg, 0.51 mmol) in dichloromethane (10 mL) was

added DMAP (63 mg, 0.52 mmol) and acetic anhydride

(0.05 mL, 0.530 mmol). The resultant solution was stirred

under nitrogen until TLC analysis of the reaction mixture

showed complete consumption of starting material (typi-

cally 2 h). After this time the solvent was removed in vacuo

and the residue was puriﬁed via column chromatography

(4:1, ethyl acetate–petroleum spirit, R_f: 0.44). The title

compound was obtained as a colourless oil (140 mg, 87%).

d_H(300 MHz, CDCl₃) 1.82 (s, 3H, C–CH₃), 2.47 (s, 3H,

NC(O)CH₃), 3.00 (s, 3H, NCH₃), 4.05 (d, 1H, J_ABZ18 Hz,

ring CH_aH_b), 4.18 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 5.12

(d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 5.16 (d, 1H, J_ABZ12 Hz,

OCH_aH_bPh), 7.33 (m, 5H, aromatic H). d_C(75 MHz,

CDCl₃) 21.4 (C–CH₃), 27.8 (NC(O)CH₃), 33.8 (NCH₃),

52.1 (ring CH₂), 67.1 (quaternary ring C), 67.9 (OCH₂Ph),

128.3 (2!aromatic CH), 128.3 (aromatic CH), 128.4 (2!

aromatic CH), 135.1 (quaternary aromatic C), 164.3 (C(O)),

165.2 (C(O)), 166.9 (C(O)), 173.4 (C(O)). m/z (EI)

318.1207 (M^C%. C₁₆H₁₈N₂O₅requires 318.1216), 276

([MKAcC1]^C, 12%), 211 (25%), 141 ([MKAc–

CO₂BnC1]^C, 91%), 91 ([C₇H₇]^C, 100%).

4.5.2. 3-Allyl-3-benzyloxycarbonyl-1-methylpiperazine-

2,5-dione (10d). The title compound 10d was synthesized

from 3c following the general procedure outlined.

Compound 10d is a colourless oil which was obtained in

82% yield after column chromatography (ethyl acetate,

R_f:K0.55). n_maxﬁlm/cm^K13237 m, 3089 w, 2932 w, 1746

s, 1696 vs, 1667 vs, 1499 w, 1455 m, 1435 m, 1406 m, 1219

s, 751 m, 698 m. d_H(300 MHz, CDCl₃) 2.78 (m, 1H,

C–CH_aH_bCH]CH₂), 2.95 (s, 3H, NCH₃), 3.06 (m, 1H,

C–CH_aH_bCH]CH₂), 3.79 (d, 1H, J_ABZ18 Hz, ring

CH_aH_b), 4.01 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 5.23 (m,

4H, OCH₂Ph and C–CH₂CH]CH₂), 5.60 (m, 1H, C–

CH₂CH]CH₂), 6.32 (bs, 1H, NH), 7.34 (m, 5H, aromatic

C₆H₅). d_C(75 MHz, CDCl₃) 34.3 (NCH₃), 38.8 (C–

CH₂CH]CH₂), 51.9 (ring CH₂), 65.2 (quaternary ring C),

68.2 (OCH₂Ph), 121.7 (C–CH₂CH]CH₂), 127.8 (2!

aromatic CH), 128.4 (aromatic CH), 128.5 (2!aromatic

CH), 130.3 (C–CH₂CH]CH₂), 134.7 (quaternary aromatic

C), 162.3 (C(O)), 166.5 (C(O)), 168.1 (C(O)). m/z (EI)

302.1266 (M^C%. C₁₆H₁₈N₂O₄requires 302.1267), 167

([MKCO₂Bn]^C, 100%), 139 (35%), 91 ([C₇H₇]^C, 95%).

4.5. General procedure for the selective a-alkylation of

piperazinedione 3c to 10c–10f

4.5.3. 3-Benzyl-3-benzyloxycarbonyl-1-methylpipera-

zine-2,5-dione (10e). The title compound 10e was

synthesized from 3c following the general procedure

outlined. Compound 10e is a colourless solid which was

obtained in quantitative yield. Mp 153–154 8C. (Found C,

68.1; H, 5.9; N, 7.8. C₂₀H₂₀N₂O₄requires C, 68.2; H, 5.7; N,

7.95%). n_maxKBr/cm^K13209 w, 1751 vs, 1696 s, 1661 vs,

1457 m, 1224 s, 735 m, 701 m. d_H(300 MHz, CDCl₃) 2.85

(s, 3H, NCH₃), 3.17 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 3.44

To a stirred solution of 3-benzyloxycarbonyl-1-methylpi-

perazine-2,5-dione (3c) (1 mol equiv, typical scales 0.5–

2 mmol) in acetone (ca. 10 mL per mmol of 3c) was added

anhydrous K₂CO₃(1 mol equiv). For the synthesis of 10c,

10d and 10f, this was followed by the addition of the

appropriate alkyl halide in excess (5 mol equiv) and the

reaction mixture was heated under reﬂux in a sealed tube.

For the synthesis of 10e, 1 mol equiv of the appropriate

alkyl halide was utilized and the reaction mixture was

heated at reﬂux under nitrogen.

(d, 1H, J_ABZ14 Hz, C–CH_aH_bPh), 3.50 (d, 1H, J_AB

Z

14 Hz, C–CH_aH_bPh), 3.71 (d, 1H, J_ABZ18 Hz, ring

CH_aH_b), 5.23 (d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 5.30 (d,

1H, J_ABZ12 Hz, OCH_aH_bPh), 6.32 (bs, 1H, NH), 7.10 (m,

2H, aromatic H), 7.25 (m, 3H, aromatic H), 7.36 (s, 5H,

aromatic H). d (75 MHz, CDCl₃) 34.1 (NCH₃), 41.6

After 24 h of reﬂux, the reaction mixture was cooled and

ﬁltered to remove the inorganic salts. The ﬁltrate was then

concentrated under reduced pressure.

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8733

(C–CH₂Ph), 51.3 (ring CH₂), 66.9 (quaternary ring C), 68.4

(OCH₂Ph), 127.8 (aromatic CH), 128.2 (2!aromatic CH),

128.6 (2!aromatic CH), 128.7 (3!aromatic CH), 130.5

(2!aromatic CH), 133.5 (quaternary aromatic C), 134.8

(quaternary aromatic C), 162.4 (C(O)), 165.8 (C(O)), 168.0

(C(O)). m/z (EI) 352.1423 (M^C%. C₂₀H₂₀N₂O₄requires

352.1423), 217 ([MKCO₂Bn]^C, 86%), 189 (27%), 132

(18%), 91 ([C₇H₇]^C, 100%).

C₂₁H₂₂N₂O₄requires 366.1580), 275 ([MKC₇H₇]^C,

33%), 231 ([MKCO₂Bn]^C, 93%), 203 (26%), 132 (35%),

91 ([C₇H₇]^C, 100%).

4.5.6. 4-Benzyl-3-benzyloxycarbonyl-1,3-dimethylpiper-

azine-2,5-dione (12). To

a

stirred solution of

3-benzyloxycarbonyl-1,3-dimethylpiperazine 2,5-dione

(10c) (174 mg, 0.63 mmol) in DMF (10 mL) at 0 8C under

nitrogen was added sodium hydride (27 mg, 0.68 mmol,

60% in parafﬁn) and benzyl bromide (0.1 mL, 0.84 mmol).

The reaction mixture was stirred under a nitrogen

atmosphere for 24 h and after this time the solvent was

removed under reduced pressure. The residue was taken up

in chloroform (15 mL) and washed with water (5 mL), brine

(5 mL) and dried (MgSO₄). The solvent was removed in

vacuo and the crude product was puriﬁed by column

chromatography (3:2, ethyl acetate–petroleum spirit, R_f:

0.45) giving 12 as a clear and colourless oil (155 mg, 67%).

d_H(300 MHz, CDCl₃) 1.76 (s, 3H, CCH₃), 2.98 (s, 3H,

NCH₃), 4.01 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.12 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 4.47 (d, 1H, J_ABZ16 Hz,

NCH_aH_bPh), 4.74 (d, 1H, J_ABZ16 Hz, NCH_aH_bPh), 4.82

(d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 5.02 (d, 1H, J_ABZ12 Hz,

OCH_aH_bPh), 7.18–7.37 (m, 10H, Aromatic H). m/z (EI)

366.1581 (M^C%. C₂₁H₂₂N₂O₄requires 366.1580), 304

(15%), 231 ([MKCO₂Bn]^C, 52%), 91 ([C₇H₇]^C, 100%).

4.5.4. 3-Benzyloxycarbonyl-3-ethyl-1-methylpiperazine-

2,5-dione (10f). The title compound 10f was synthesized

from 3c following the general procedure outlined.

Compound 10f is a colourless solid which was obtained in

90% yield after puriﬁcation by ﬂash column chromato-

graphy (ethyl acetate, R_f: 0.53). Mp 122–123 8C. n_maxKBr/

cm^K13209 m, 3101 m, 2978 w, 1730 vs, 1686 vs, 1670 vs,

1415 s, 1217 s, 1188 s, 1179 s, 917 m, 757 m, 748 m, 699 m.

d_H(300 MHz, CDCl₃) 0.91 (t, 3H, JZ7 Hz, C–CH₂CH₃),

1.96 (m, 1H, C–CH_aH_bCH₃), 2.42 (m, 1H, C–CH_aH_bCH₃),

2.95 (s, 3H, NCH₃), 3.81 (d, 1H, J_ABZ18 Hz, ring CH_aH_b),

3.99 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 5.16 (d, 1H, J_AB

Z

12 Hz, benzyl CH_aH_b), 5.22 (d, 1H, J_ABZ12 Hz, benzyl

CH_aH_b), 7.03 (bs, 1H, NH), 7.33 (m, 5H, aromatic C₆H₅). d_C

(75 MHz, CDCl₃) 7.8 (a-CCH₂CH₃), 27.7 (a-CCH₂CH₃),

34.3 (NCH₃), 52.0 (ring CH₂), 66.8 (quaternary ring C),

68.1 (benzyl CH₂), 127.9 (2!aromatic CH), 128.5

(aromatic CH), 128.6 (2!aromatic CH), 134.8 (quaternary

aromatic C), 162.7 (C(O)), 167.1 (C(O)), 168.8 (C(O)). m/z

(EI) 290.1270 (M^C%. C₁₅H₁₈N₂O₄requires 290.1267), 155

([MKCO₂Bn]^C, 100%), 127 ([MHKEt-CO₂Bn]^C, 44%),

91 ([C₇H₇]^C, 70%).

4.6. General procedure for the a,a-dialkylation of

3-benzyloxycarbonyl-1-methylpiperazine-2,5-dione (3c):

conversion of 3c to piperazinediones 13, 17, 18.

To a solution of 3-benzyloxycarbonyl-1-methylpiperazine-

2,5-dione (3c) (1 mol equiv, typical scale ca. 1 mmol) in

DMF (15 mL/mmol) at 0 8C under nitrogen was added

sodium hydride (2 mol equiv, 60% in parafﬁn) and the

appropriate alkyl halide. For the synthesis of piperazine-

dione 13, excess allyl iodide was added (5 mol equiv) while

for the synthesis of piperazinediones 17 and 18, 1 mol equiv

of the appropriate dibromoalkane was utilized. The resultant

solution was stirred under a nitrogen atmosphere for 24 h

and after this time the solvent was removed under reduced

pressure. The residue was taken up in chloroform and

washed with water, brine and dried (MgSO₄). The solvent

was removed in vacuo and the crude product was puriﬁed by

column chromatography.

4.5.5. 3-Benzyl-3-benzyloxycarbonyl-1,4-dimethylpiper-

azine-2,5-dione (11). To a stirred solution of 3-benzyl-3-

benzyloxycarbonyl-1-methylpiperazine-2,5-dione (10e)

(449 mg, 1.27 mmol) in DMF (15 mL) at 0 8C under

nitrogen was added sodium hydride (51 mg, 1.275 mmol,

60% in parafﬁn) and methyl iodide (0.8 mL, 12.74 mmol).

The reaction mixture was stirred under a nitrogen

atmosphere for 24 h and after this time the solvent was

removed under reduced pressure. The residue was taken up

in chloroform (25 mL) and washed with water (10 mL),

brine (10 mL) and dried (MgSO₄). The solvent was removed

in vacuo and the crude product was puriﬁed by column

chromatography (3:2, ethyl acetate–petroleum spirit, R_f:

0.49) giving 11 as a clear and colourless oil which solidiﬁed

upon standing (398 mg, 85%). Mp 96–97 8C. (Found C,

68.5; H, 6.2; N, 7.5. C₂₁H₂₂N₂O₄requires C, 68.8; H, 6.1; N,

7.7%). n_maxKBr/cm^K13037 w, 2945 w, 1755 s, 1672 s,

1399 m, 1224 m, 1043 m, 745 m. d_H(300 MHz, CDCl₃)

2.27 (d, 1H, J_ABZ17 Hz, ring CH_aH_b), 2.70 (s, 3H, NCH₃),

2.82 (s, 3H, NCH₃), 3.24 (d, 1H, J_ABZ14 Hz, C–CH_aH_bPh),

4.6.1. 3,4-Diallyl-3-benzyloxycarbonyl-1-methylpipera-

zine-2,5-dione (13). The title compound 13 was obtained

as a clear and colourless oil in 66% yield after puriﬁcation

by column chromatography (4:1, ethyl acetate–petroleum

spirit, R_f: 0.51). n_maxﬁlm/cm^K13089 w, 2934 w, 1751 vs,

1667 vs, 1455 s, 1407 s, 1340 m, 1275 s, 1224 s, 929 m, 755

m, 699 m. d_H(300 MHz, CDCl₃) 2.88 (dd, 1H, ²JZ15 Hz,

³JZ7 Hz, C–CH_aH_bCH]CH₂), 2.95 (s, 3H, NCH₃), 3.21

3.40 (d, 1H, J_ABZ17 Hz, ring CH_aH_b), 3.62 (d, 1H, J_AB

Z

14 Hz, C–CH_aH_bPh), 5.15 (d, 1H, J_ABZ12 Hz, OCH_aH_b-

Ph), 5.39 (d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 7.03 (m, 2H,

aromatic H), 7.27 (m, 4H, aromatic H), 7.36 (m, 4H,

aromatic H). d_C(75 MHz, CDCl₃) 30.0 (NCH₃), 33.2

(NCH₃), 38.9 (C–CH₂Ph), 50.2 (ring CH₂), 68.3 (OCH₂Ph),

72.9 (quaternary ring C), 127.9 (aromatic CH), 128.5 (2!

aromatic CH), 128.6 (2!aromatic CH), 128.7 (3!aromatic

CH), 129.9 (2!aromatic CH), 133.7 (quaternary aromatic

C), 134.7 (quaternary aromatic C), 163.0 (C(O)), 163.4

2

3

(dd, 1H, JZ15 Hz, JZ7 Hz, C–CH_aH_bCH]CH₂), 3.74

2

3

(dd, 1H, JZ15 Hz, JZ7 Hz, NCH_aH_bCH]CH₂), 3.97–

4.05 (m, 3H, ring CH₂& NCH_aH_bCH]CH₂), 5.05–5.25 (m,

6H, benzyl CH₂, C–CH₂CH]CH₂& NCH₂CH]CH₂), 5.55

(m, 1H, C–CH₂CH]CH₂), 5.76 (m, 1H, NCH₂CH]CH₂),

7.33 (m, 5H, Aromatic C₆H₅). d_C(75 MHz, CDCl₃) 33.4

(NCH₃), 37.0 (C–CH₂CH]CH₂), 46.5 (NCH₂CH]CH₂),

50.9 (ring CH₂), 67.7 (quaternary ring C), 71.0 (OCH₂Ph),

118.1 (allyl CH₂CH]CH₂), 121.0 (allyl CH₂CH]CH₂),

(C(O)), 167.2 (C(O)). m/z (EI) 366.1577 (M^C%

.

8734

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

127.9 (2!aromatic CH), 128.3 (3!aromatic CH), 129.7

(allyl CH₂CH]CH₂), 131.9 (allyl CH₂CH]CH₂), 134.4

(quaternary aromatic C), 162.5 (C(O)), 163.3 (C(O)), 167.3

(C(O)). m/z (EI) 342.1583 (M^C%. C₁₉H₂₂N₂O₄requires

342.1580), 292 (28%), 251 ([MKC₇H₇]^C, 40%), 207

([MKCO₂Bn]^C, 100%), 91 ([C₇H₇]^C, 42%).

m, 1247 s, 1195 s, 754 m, 699 m. d_H(300 MHz, CDCl₃) 2.48

2

(dm, 1H, JZ18 Hz, 9-CH_aH_b), 2.96 (s, 3H, NCH₃), 3.40

2

3

(dd, 1H, JZ18 Hz, JZ6 Hz, 9-CH_aH_b), 3.56 (dm, 1H,

²JZ19 Hz, 6-CH_aH_b), 3.92 (d, 1H, J_ABZ18 Hz, 3-CH_aH_b),

2

4.05 (d, 1H, J_ABZ18 Hz, 3-CH_aH_b), 4.37 (dm, 1H, JZ

19 Hz, ³JZ4 Hz, 6-CH_aH_b), 5.15 (d, 1H, J_ABZ12 Hz,

OCH_aH_bPh), 5.22 (d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 5.62–

5.58 (m, 1H, 7 or 8-CH), 5.81–5.88 (m, 1H, 7 or 8-CH),

7.25–7.35 (m, 5H, C₆H₅). d_C(75 MHz, CDCl₃) 31.4

(9-CH₂), 33.4 (NCH₃), 41.9 (6-CH₂), 51.1 (3-CH₂), 65.9

(9a-C), 68.3 (OCH₂Ph), 121.9 (7 or 8-CH), 122.6 (7 or

8-CH), 127.8 (2!aromatic CH), 128.4 (aromatic CH),

128.5 (2!aromatic CH), 134.7 (quaternary aromatic C);

162.1 (C(O)), 164.5 (C(O)), 167.4 (C(O)). m/z (EI)

315.1351 ([MH]^C), C₁₇H₁₉N₂O₄([MH]^C) requires

315.1345), 223 ([MKBn]^C, 19%), 195 (18%), 179 ([MK

CO₂Bn]^C, 100%), 151 (41%), 91 ([C₇H₇]^C, 59%).

4.6.2. 9a-Benzyloxycarbonyl-2-methyl-1,4-dioxo-octahy-

dropyrido[1,2-a]pyrazine (17). The title compound 17 was

obtained as a solid in 67% yield after puriﬁcation by column

chromatography (ethyl acetate, R_f: 0.51), followed by

trituration with ether. Mp 107–109 8C. (Found C, 64.5; H,

6.5; N, 8.7. C₁₇H₂₀N₂O₄requires C, 64.5; H, 6.4; N, 8.9%).

n_maxKBr/cm^K12949 w, 2856 w, 1751 s, 1665 s, 1427 m,

1209 m, 1122 m, 761 m, 706 w. d_H(300 MHz, CDCl₃) 1.30–

1.55 (m, 2H, 7-CH_aH_band 8-CH_aH_b), 1.60–1.70 (m, 2H,

9-CH_aH_band 7-CH_aH_b), 1.79–1.83 (m, 1H, 8-CH_aH_b),

2.35–2.46 (m, 1H, 6-CH_aH_b), 2.91–2.97 (m, 1H, 9-CH_aH_b),

2.92 (s, 3H, NCH₃), 3.84 (d, 1H, J_ABZ17 Hz, 3-CH_aH_b),

4.6.5. 2-Methyl-hexahydropyrido[1,2-a]pyrazine-1,4-

dione (16). To a solution of 9a-benzyloxycarbonyl-2-

methyl-1,4-dioxo-1,2,3,4,6,9-hexahydropyrido[1,2-a]pyr-

azine (14) (43 mg, 0.14 mmol) or 9a-benzyloxycarbonyl-2-

methyl-1,4-dioxo-octahydropyrido [1,2-a]pyrazine (17) in

degassed methanol (10 mL) was added 10% palladium on

carbon (5 mg). The reaction mixture was then stirred under

a hydrogen atmosphere for 1 h after which time it was

ﬁltered through a bed of celite. The ﬁltrate was concentrated

in vacuo and suspended in toluene (25 mL). The reaction

mixture was then heated at reﬂux for 24 h, following which

the solvent was removed in vacuo to give the title compound

16 (25 mg, 100%) as a colourless oil which solidiﬁed upon

standing. The physical data for 16 is consistent with that

previously reported, although the NMR data has not been

reported previously.¹⁴Mp 85–86 (lit.: 84–86 8C).¹⁴d_H

(300 MHz, CDCl₃) 1.35–1.80 (m, 4H, 7-CH₂, 8-CH₂), 1.97

(m, 1H, 9-CH_aH_b), 2.34 (m, 1H, 9-CH_aH_b), 2.49 (dt, 1H,

6-CH_aH_b), 2.94 (s, 3H, NCH₃), 3.80 (dm, 1H, 9a-CH), 3.91

(d, 1H, J_ABZ18 Hz, 3-CH_aH_b), 3.99 (d, 1H, J_ABZ18 Hz,

3-CH_aH_b), 4.64 (dm, 1H, JZ13 Hz, 6-CH_aH_b). d_C(75 MHz,

CDCl₃) 24.3 (8-CH₂), 24.5 (7-CH₂), 31.3 (9-CH₂), 33.3

(NCH₃), 42.4 (6-CH), 51.2 (3-CH₂), 59.1 (9a-CH), 161.3

(C(O), 165.4 (C(O). m/z (EI) 182.1056 (M^C%. C₉H₁₄N₂O₂

requires 182.1055), 153 (40%), 125 (38%), 97 (70%), 151

(41%), 83 (100%).

2

3.98 (d, 1H, J_ABZ17 Hz, 3-CH_aH_b), 4.48 (dm, 1H, JZ

12 Hz, 6-CH_aH_b), 5.16 (d, 1H, J_ABZ12 Hz, OCH_aH_bPh),

5.27 (d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 7.26–7.39 (m, 5H,

5!aromatic CH). d_C(75 MHz, CDCl₃) 20.4 (8-CH₂), 22.8

(7-CH₂), 31.0 (9-CH₂), 33.5 (NCH₃), 40.2 (6-CH₂), 50.8

(3-CH₂), 67.1 (9a-C), 67.7 (OCH₂Ph), 127.5 (2!aromatic

CH), 128.1 (aromatic CH), 128.2 (2!aromatic CH), 134.5

(quaternary aromatic C), 162.1 (C(O)), 164.7 (C(O)), 167.2

(C(O)). m/z (EI) 316.1425 (M^C%. C₁₇H₂₀N₂O₄requires

316.1423), 181 ([MKCO₂Bn]^C, 100%), 153 (43%), 91

([C₇H₇]^C, 23%).

4.6.3. 8a-Benzyloxycarbonyl-2-methyl-1,4-dioxo-hexa-

hydropyrrolo[1,2-a]pyrazine (18). The title compound

18 was obtained as a colourless oil in 69% yield after

puriﬁcation by column chromatography (ethyl acetate). n_max

ﬁlm/cm^K12955 w, 1740 s, 1682 vs, 1445 m, 1213 m, 700 w.

d_H(300 MHz, CDCl₃) 1.70–2.00 (m, 2H, 7-CH₂), 2.25–2.37

(m, 1H, 8-CH_aH_b), 2.67–2.75 (m, 1H, 8-CH_aH_b), 2.92 (s,

3H, NCH₃), 3.50–3.70 (m, 2H, 6-CH₂), 3.69 (d, 1H, J_AB

Z

17 Hz, 3-CH_aH_b), 4.07 (d, 1H, J_ABZ17 Hz, 3-CH_aH_b), 5.16

(d, 1H, J_ABZ12 Hz, OCH_aH_bPh), 5.23 (d, 1H, J_ABZ12 Hz,

OCH_aH_bPh), 7.26–7.33 (m, 5H, 5!aromatic CH). d_C

(75 MHz, CDCl₃) 20.8 (7-CH₂), 32.7 (8-CH₂), 33.6

(NCH₃), 44.9 (6-CH₂), 53.1 (3-CH₂), 67.7 (OCH₂Ph),

70.7 (8a-C), 127.4 (2!aromatic CH), 128.1 (1!aromatic

CH), 128.2 (2!aromatic CH), 134.4 (quaternary aromatic

4.6.6. 2-Methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-

dione (19). To a stirred solution of 8a-benzyloxycarbonyl-

2-methyl-1,4-dioxo-hexahydropyrrolo[1,2-a]pyrazine (18)

(197 mg, 1.17 mmol) in degassed methanol (10 mL) was

added 10% palladium on carbon (5 mg). The reaction

mixture was then stirred under a hydrogen atmosphere for

1 h after which time it was ﬁltered through a bed of celite.

The ﬁltrate was reduced in vacuo and suspended in toluene

(25 mL). The reaction mixture was then heated at reﬂux for

24 h. After this time the solvent was removed in vacuo

giving the title compound 19 (197 mg, 100%) as a

colourless oil. The NMR data has not been reported

previously.¹⁴d_H(300 MHz, CDCl₃) 1.81–2.05 (m, 3H,

7-CH₂and 8-CH_aH_b), 2.31–2.43 (m, 1H, 8-CH_aH_b), 2.97(s,

C), 163.1 (C(O)), 163.4 (C(O)). m/z (EI) 302.1270 (M^C%

.

C₁₆H₁₈N₂O₄requires 302.1267), 226 (20%), 167 ([MK

CO₂Bn]^C, 100%), 139 (72%), 108 (65%), 91 ([C₇H₇]^C,

43%), 79 (65%).

4.6.4. 9a-Benzyloxycarbonyl-2-methyl-1,4-dioxo-1,2,3,4,

6,9-hexahydropyrido[1,2-a]pyrazine (14). To a solution

of 3,4-diallyl-3-benzyloxycarbonyl-1-methylpiperazine-

2,5-dione (13) (81 mg, 0.24 mmol) in dichloromethane

(3 mL) was added benzylidene-bis(tricyclohexylpho-

sphine)-dichlororuthenium (8 mg, w10% w/w). The

reaction mixture was stirred under nitrogen for 16 h

following which the solvent was removed in vacuo. The

residue was puriﬁed via column chromatography (4:1, ethyl

acetate–petroleum spirit) to give the title compound 14

(61 mg, 82%) as a clear and colourless oil. n_maxcm^K13034

w, 2938 w, 1754 vs, 1732 s, 1673 vs, 1499 m, 1428 s, 1330

3H, NCH₃), 3.51–3.63 (m, 2H, 6-CH₂), 3.78 (d, 1H, J_AB

Z

17 Hz, 3-CH_aH_b), 4.06 (bt, 1H, JZ7 Hz, 8a-CH), 4.16 (d,

1H, J_ABZ17 Hz, 3-CH_aH_b). d_C(75 MHz, CDCl₃) 19.6

(7-CH₂), 28.4 (8-CH₂), 33.0 (NCH₃), 44.8 (6-CH₂), 53.0

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8735

(3-CH₂), 58.4 (8a-C), 162.2 (C(O)), 166.8 (C(O)). m/z (EI)

168.0897 (M^C%. C₈H₁₂N₂O₂requires 168.0899), 83 (71%),

42 (100%).

using the general procedure outlined above for the DONA

reactions. No external nucleophile was added. The residue

obtained was puriﬁed by column chromatography (ethyl

acetate, R_f: 0.45) to afford 3-acetoxy-4-acetyl-1-methylpi-

perazine-2,5-dione (22c) as a colourless solid (98 mg, 82%).

Mp 156–157 8C. d_H(300 MHz, CDCl₃) 2.08 (s, 3H,

OC(O)CH₃), 2.54 (s, 3H, NC(O)CH₃), 2.99 (s, 3H,

NCH₃), 4.00 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.42 (d,

1H, J_ABZ18 Hz, ring CH_aH_b), 6.89 (s, 1H, CHOAc). d_C

(75 MHz, CDCl₃) 20.6 (OC(O)CH₃), 26.7 (NC(O)CH₃),

33.3 (NCH₃), 53.1 (ring CH₂), 73.6 (CHOAc), 161.4 (C(O)),

166.4 (C(O)), 168.6 (C(O)), 170.4 (C(O)). m/z (EI)

229.0825 ([MH]^C, C₉H₁₃N₂O₅requires 229.0824), 168

([MHKAcOH]^C, 33%), 126 ([MKAc–AcOH]^C, 100%),

115 (36%), 99 (34%).

4.7. DONA reactions of carboxypiperazine-2,5-diones

General procedure for the DONA reactions of carboxypi-

perazine-2,5-diones. To a stirred solution of the appropriate

carboxy piperazine-2,5-dione (1 mol equiv) in dichloro-

methane (ca. 7.5 mL/mmol of carboxypiperazinedione) was

added iodine (0.5 mol equiv) and diacetoxyiodobenzene

(1 mol equiv). In reactions where external nucleophiles

were added, the reaction mixture was stirred for 1 min (for

22a and 22b) or 10 min (for 22d, 24a, 25) before the

addition of the appropriate additive. For the acetoxy

compounds, excess glacial acetic acid (typically 0.4 mL/

mmol of carboxypiperazinedione) is added while for

methoxy derivatives, excess methanol (typically 2.2 mL/

mmol of carboxypiperazinedione) is added.

4.7.4. 4-Acetyl-1-methyl-3-methoxypiperazine-2,5-dione

(22d). The title compound 22d was synthesized from

4-acetyl-3-carboxyl-1-methylpiperazine-2,5-dione (1b)

with methanol as additive, using the general procedure

outlined above for the DONA reactions. The residue was

puriﬁed by column chromatography (ethyl acetate, R_f: 0.57)

to give 4-acetyl-1-methyl-3-methoxypiperazine-2,5-dione

(22d) as a colourless solid (74 mg, 78%). Mp 89–91 8C. d_H

(300 MHz, CDCl₃) 2.57 (s, 3H, NC(O)CH₃), 3.01 (s, 3H,

NCH₃), 3.50 (s, 3H, OCH₃), 3.84 (d, 1H, J_ABZ18 Hz, ring

CH_aH_b), 4.44 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 5.80 (s, 1H,

CHOCH₃). d_C(75 MHz, CDCl₃) 26.6 (NC(O)CH₃), 33.1

(NCH₃), 52.9 (CH₂), 57.9 (OCH₃), 81.5 (CHOCH₃), 163.0

(C(O)), 167.2 (C(O)), 171.6 (C(O)). m/z (EI) 201.0876

([MH]^C. C₈H₁₃N₂O₄requires 201.0875), 145 ([MHK

OMe]^C, 46%), 128 (31%), 55 (86%).

Stirring under a nitrogen atmosphere was continued for 16 h

following which time the reaction mixture was washed with

a saturated solution of sodium thiosulfate, dried (MgSO₄)

and the solvent removed under reduced pressure.

4.7.1. 3-Acetoxy-1,4-dimethylpiperazine-2,5-dione (22a).

The title compound 22a was synthesized from 3-carboxy-

1,4-dimethylpiperazine-2,5-dione (1a) with acetic acid as

additive, using the general procedure outlined above for the

DONA reactions. 3-Acetoxy-1,4-dimethylpiperazine-2,5-

dione (22a) was puriﬁed by column chromatography (5:1,

ethyl acetate–methanol, R_f:K0.42) and was isolated as a

colourless oil which crystallised upon standing (83%). The

title compound has also been prepared from (S)-hydro-

xymethyl-1,4-dimethylpiperazine-2,5-dione (35a) using the

procedure described above (86% yield). Mp 92–94 8C. n_max

KBr/cm^K13429 w, 2981 w, 2935 w, 1757 vs, 1692 vs, 1487

m, 1399 s, 1331 m, 1205 s, 1011 s, 946 s, 750 w. d_H

(300 MHz, CDCl₃) 2.11 (s, 3H, OC(O)CH₃), 2.99 (s, 3H,

NCH₃), 3.01 (s, 3H, NCH₃), 3.89 (d, 1H, J_ABZ18 Hz, ring

CH_aH_b), 4.21 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 6.03 (s, 1H,

CHOAc). d_C(75 MHz, CDCl₃) 20.2 (OC(O)CH₃), 31.7

(NCH₃), 33.0 (NCH₃), 51.0 (ring CH₂), 79.4 (CHOAc),

160.5 (C(O)), 165.1 (C(O)), 169.4 (C(O)). m/z (EI)

201.0874 ([MH]^C. C₈H₁₃N₂O₄requires 201.0875), 157

(36%), 142 ([MHKOAc]^C, 100%), 113 (65%).

4.7.5. 3-Carboxyl-1,3,4-trimethylpiperazine-2,5-dione

(23a). To a solution of 3-benzyloxycarbonyl-1,3,4-tri-

methylpiperazine-2,5-dione (10a) (503 mg, 1.73 mmol) in

degassed methanol (10 mL) was added 10% palladium on

carbon (40 mg). The reaction mixture was stirred under a

hydrogen atmosphere for 1 h. The reaction mixture was then

ﬁltered through a bed of celite. The ﬁltrate was reduced in

vacuo and following co-evaporation with chloroform (3!

5 mL), the acid (23a) was obtained as a colourless solid

(346 mg, 100%). The acid is unstable and was used without

puriﬁcation. d_H(300 MHz, CD₃OD) 1.74 (s, 3H, a-CH₃),

2.91 (s, 3H, NCH₃), 2.98 (s, 3H, NCH₃), 4.11 (s, 2H, ring

CH₂). d_C(75 MHz, CD₃OD) 20.6 (a-CH₃), 30.1 (NCH₃),

34.3 (NCH₃), 52.0 (ring CH₂), 69.3 (quaternary a-CCH₃),

165.8 (C(O)), 166.5 (C(O)), 170.7 (CO₂H). m/z (EI)

200.0799 (M^C%. C₈H₁₂N₂O₄requires 200.0797), 156

([MKCO₂]^C, 100%), 141 ([MKCH₃–CO₂]^C, 30%), 127

(47%), 113 (85%).

4.7.2. 3-Methoxy-1,4-dimethylpiperazine-2,5-dione

(22b). The title compound 22b was synthesized from

3-carboxy-1,4-dimethylpiperazine-2,5-dione (1a) with

methanol as additive, using the general procedure outlined

above for the DONA reactions. Puriﬁcation by column

chromatography (5:1, ethyl acetate–methanol, R_f: 0.33)

gave 3-methoxy-1,4-dimethylpiperazine-2,5-dione (22b) as

a colourless oil (76%) with physical and spectral properties

consistent with data reported previously.¹⁵d_H(300 MHz,

CDCl₃) 2.94 (s, 3H, NCH₃), 3.00 (s, 3H, NCH₃), 3.44 (s, 3H,

OCH₃), 3.79 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.12 (d, 1H,

J_ABZ18 Hz, ring CH_aH_b), 4.67 (s, 1H, CHOMe).

4.7.6. 3-Acetoxy-1,3,4-trimethylpiperazine-2,5-dione

(24a). The title compound 24a was synthesized from

3-carboxyl-1,3,4-trimethylpiperazine-2,5-dione (23a) with

glacial acetic acid as additive, using the general procedure

outlined above for the DONA reactions. However, in this

case, stirring after addition of all reaction components was

continued for only 6 h before work-up commenced. The

residue obtained from the reaction was puriﬁed by column

chromatography (5:1, ethyl acetate–methanol, R_f: 0.53) to

give the title compound 24a as a thick colourless oil (56 mg,

55%). The compound is unstable and eliminates acetic acid

4.7.3. 3-Acetoxy-4-Acetyl-1-methylpiperazine-2,5-dione

(22c). The title compound 22c was synthesised from

4-acetyl-3-carboxyl-1-methylpiperazine-2,5-dione (1b)

8736

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

to give the known 1,4-dimethyl-3-methylidenepiperazine-

dione²⁶(28a) when stored. d_H(300 MHz, CDCl₃) 1.75 (s,

3H, a-CH₃), 2.03 (s, 3H, C(O)CH₃), 2.91 (s, 6H, 2!NCH₃),

3.93 (d, 1H, JZ18 Hz, ring CH_aH_b), 4.07 (d, 1H, JZ18 Hz,

ring CH_aH_b). d_C(75 MHz, CDCl₃) 20.6 (a-CH₃), 24.4

(NCH₃), 27.2 (NCH₃), 33.7 (C(O)CH₃), 51.8 (ring CH₂),

86.0 (a-COAc), 163.8 (NC(O)), 164.1 (NC(O)), 169.7

(C(O)CH₃).

4.8. Reactions of N-acyliminium ions derived from

piperazine-2,5-diones

4.8.1. 3-Allyl-1,4-dimethylpiperazine-2,5-dione (26). To a

stirred solution of 3-methoxy-1,4-dimethylpiperazine-2,5-

dione (22b) (587 mg, 3.41 mmol) in dichloromethane

(10 mL) at 0 8C was added allyltrimethylsilane (5.5 mL,

35.3 mmol) and boron triﬂuoride diethyl etherate (0.9 mL,

7.06 mmol). The cooling bath was removed, the reaction

mixture was warmed to room temperature and stirring was

continued for a further 24 h. After this time the reaction

mixture was washed with brine (5 mL), the organic phase

was separated, dried and the solvent removed under reduced

pressure. The crude residue was puriﬁed by column

chromatography (5:1, ethyl acetate–methanol, R_f: 0.31) to

give the title compound 26 as a colourless oil which

crystallized upon prolonged standing (422 mg, 68%). Mp

60–62 8C. n_maxKBr/cm^K13447 m, 2923 m, 1651 vs, 1492 s,

1400 s, 1347 s, 1256 m, 1039 m, 946 m. d_H(300 MHz,

CDCl₃) 2.61 (m, 1H, allyl CHCH_aH_bCH]CH₂), 2.72 (m,

1H, allyl CHCH_aH_bCH]CH₂), 2.96 (s, 3H, NCH₃), 2.98 (s,

3H, NCH₃), 3.81 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 3.98 (m,

1H, ring CHCH₂), 4.04 (d, 1H, J_ABZ18 Hz, ring CH_aH_b),

5.15 (bs, 1H, allyl CHCH₂CH]CH_aH_b), 5.20 (d, 1H, JZ

9 Hz, allyl CHCH₂CH]CH_aH_b), 5.68 (m, 1H, allyl

CHCH₂CH]CH₂). d_C(75 MHz, CDCl₃) 32.2 (NCH₃),

33.4 (NCH₃), 36.0 (allyl CHCH₂CH]CH₂), 51.6 (ring

CH₂), 62.2 (ring CH), 121.0 (allyl CHCH₂CH]CH₂), 130.7

(allyl CHCH₂CH]CH₂), 163.8 (C(O)), 165.6 (C(O)). m/z

(EI) 182.1055 (M^C%. C₉H₁₄N₂O₂requires 182.1055), 141

([MKallyl]^C, 100%), 113 (90%).

4.7.7. 3-Acetoxy-3-benzyl-1,4-dimethylpiperazine-2,5-

dione (24b). To a solution of 3-benzyl-3-benzyloxycarbo-

nyl-1,4-dimethylpiperazine-2,5-dione (11) (265 mg,

0.72 mmol) in degassed methanol (20 mL) was added

10% palladium on carbon (20 mg). The reaction mixture

was stirred under a hydrogen atmosphere for 1 h after which

time the reaction mixture was ﬁltered through a bed of

celite. The ﬁltrate was reduced in vacuo and taken up in

dichloromethane (10 mL). DIB (233 mg, 0.72 mmol) and

iodine (92 mg, 0.36 mmol) were added and the reaction

mixture was stirred under nitrogen for 6 h. After this time,

the reaction mixture was washed with saturated sodium

thiosulfate solution (5 mL). The organic phase was

separated, dried and concentrated in vacuo. The oily residue

was puriﬁed via column chromatography (ethyl acetate, R_f:

0.61) to give the title compound 24b as a colourless oil

(155 mg, 74%). n_maxﬁlm/cm^K13476 w, 3027 w, 2943 w,

1751 s, 1676 vs, 1399 m, 1222 s, 1016 m, 745 m, 703 m. d_H

(300 MHz, CDCl₃) 2.15 (s, 3H, OC(O)CH₃), 2.71 (s, 3H,

NCH₃), 2.88 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 3.05 (s, 3H,

NCH₃), 3.24 (d, 1H, J_ABZ13 Hz, a-CCH_aH_bPh), 3.45 (d,

1H, J_ABZ13 Hz, a-CCH_aH_bPh), 3.67 (d, 1H, J_ABZ18 Hz,

ring CH_aH_b), 7.07 (m, 2H, aromatic H), 7.27 (m, 3H,

aromatic H). d_C(75 MHz, CDCl₃) 20.6 (OC(O)CH₃), 27.4

(NCH₃), 33.0 (NCH₃), 41.3 (a-CCH₂Ph), 50.7 (ring CH₂),

88.5 (quaternary ring C), 127.9 (2!aromatic CH), 128.4

(aromatic CH), 129.9 (2!aromatic CH), 131.8 (quaternary

aromatic C), 162.3 (C(O)), 163.3 (C(O)), 168.9 (C(O)). m/z

(EI) 290.1273 (M^C%. C₁₅H₁₈N₂O₄requires 290.1267), 231

([MKOAc]^C, 26%), 199 ([MKC₇H₇]^C, 39%), 157

(100%), 91 ([C₇H₇]^C, 35%).

4.8.2. 3-(2-Methoxynaphthalen-1-yl)-1,4-dimethylpiper-

azine-2,5-dione (27). To a stirred solution of 3-acetoxy-1,4-

dimethylpiperazine-2,5-dione (22a) (181 mg, 0.90 mmol) in

dichloromethane (10 mL) was added 2-methoxynaphthalene

(286 mg, 1.81 mmol) and boron triﬂuoride diethyl etherate

(0.23 mL, 1.81 mmol). The resultant reaction mixture was

stirred under nitrogen for 16 h. After this time, the reaction

mixture was washed with brine (5 mL), dried (MgSO₄) and

the solvent removed in vacuo. The residue was puriﬁed via

column chromatography (5:1, ethyl acetate–methanol, R_f:

0.42) to afford the title compound 27 (218 mg, 81%). Mp

174–175 8C. n_maxKBr/cm^K12939 w, 1655 vs, 1518 m,

1485 m, 1271 s, 1122 m, 1094 m, 1001 m, 806 m, 750 m,

741 m. d_H(300 MHz, CDCl₃) 2.67 (s, 3H, NCH₃), 3.03 (s,

3H, NCH₃), 3.92 (s, 3H, OCH₃), 4.08 (d, 1H, J_ABZ18 Hz,

ring CH_aH_b), 4.19 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 5.95

(bs, 1H, ring CH), 7.27 (d, 1H, JZ8 Hz, aromatic CH), 7.38

(t, 1H, JZ7 Hz, aromatic CH), 7.56 (t, 1H, JZ7 Hz,

aromatic CH), 7.82 (d, 1H, JZ8 Hz, aromatic CH), 7.88 (d,

1H, JZ9 Hz, aromatic CH), 8.08 (bd, 1H, JZ8 Hz,

aromatic CH). d_C(75 MHz, CDCl₃) 31.0 (NCH₃), 33.2

(NCH₃), 51.9 (ring CH₂), 56.5 (OCH₃), 57.0 (ring CH),

112.7 (aromatic CH), 116.8 (quaternary aromatic C), 121.3

(aromatic CH), 123.5 (aromatic CH), 127.6 (aromatic CH),

128.7 (aromatic CH), 128.9 (quaternary aromatic C), 131.0

(aromatic CH), 133.3 (quaternary aromatic C); 155.0

(quaternary aromatic COCH₃), 163.6 (C(O)), 165.0

(C(O)). m/z (EI) 298.1318 (M^C%. C₁₇H₁₈N₂O₃requires

298.1317); 210 (38%); 198 (63%); 183 (30%); 169 (39%);

113 (48%).

4.7.8. 3-Methoxy-1,3,4-trimethylpiperazine-2,5-dione

(25). The title compound 24a was synthesized from

3-carboxyl-1,3,4-trimethylpiperazine-2,5-dione (23a) with

methanol as additive, using the general procedure outlined

above for the DONA reactions. However, in this case,

stirring after addition of all reaction components was

continued for only 6 h before work-up commenced. The

residue obtained after work-up was puriﬁed by column

chromatography (5:1, ethyl acetate–methanol, R_f:K0.35) to

give the title compound 25 as a thick colourless oil (79 mg,

77%). The compound is unstable and eliminates acetic acid

to give the known 1,4-dimethyl-3-methylidenepiperazine-

dione²⁶(28a) when stored. Data for 25: d_H(300 MHz,

CDCl₃) 1.60 (s, 3H, a-CH₃); 2.93 (s, 3H, NCH₃), 3.00 (s, 3H,

NCH₃), 3.09 (s, 3H, OMe), 4.01 (s, 2H, ring CH₂). d_C

(75 MHz, CDCl₃) 24.1 (a-CH₃), 26.6 (NCH₃), 33.6 (NCH₃),

51.2 (ring CH₂), 51.2 (OCH₃), 88.0 (quaternary a-CCH₃),

163.5 (C(O)), 164.0 (C(O)). m/z (EI) 187 ([MC1]^C, 3%);

186.1001 (M^C%. C₈H₁₄N₂O₃requires 186.1004), 171 ([MK

CH₃]^C, 20%), 156 ([MKOCH₃C1]^C, 80%), 127 (100%),

114 (50%), 101 (35%), 87 (30%), 72 (50%).

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8737

4.8.3. (Z)-3-Benzylidene-1,4-dimethylpiperazine-2,5-

(C(O)), 166.6 (C(O)). m/z (EI) 272.1533 (M^C%

.

dione (28b). To a stirred solution of 3-acetoxy-3-benzyl-

1,4-dimethylpiperazine-2,5-dione (24b) (55 mg, 0.19 mmol)

in dichloromethane (5 mL) at 0 8C was added boron

triﬂuoride diethyl etherate (0.03 mL, 0.21 mmol). The

reaction mixture was warmed to room temperature and

stirring was continued for a further 16 h. After this time the

reaction mixture was washed with brine (1 mL), dried and

ﬁltered. The solvent was removed in vacuo to give the crude

product as a yellow oil. The oil was puriﬁed via column

chromatography (ethyl acetate, R_f: 0.5) to afford the title

compound (33 mg, 76%) as a colourless oil with spectro-

scopic properties consistent with the Z-isomer reported

previously.²²

C₁₂H₂₄N₂O₃Si requires 272.1556), 215 ([MKC(CH₃)₃]^C,

100%), 158 ([MKSi(CH₃)₂C(CH₃)₃]^C, 30%), 73 (33%).

4.9.2. (S)-3-(t-Butyldimethylsilanyloxymethyl)-1,4-

dimethylpiperazine-2,5-dione (34a). To a stirred solution

of (S)-3-(t-butyldimethylsilanyloxymethyl)-1-methylpiper-

azine-2,5-dione (33) (1.24 g, 4.56 mmol) in DMF (10 mL)

at 0 8C under nitrogen was added sodium hydride (182 mg,

4.60 mmol, 60% in parafﬁn) and methyl iodide (5 mL,

excess). The resultant solution was stirred under a nitrogen

atmosphere for 24 h and after this time the solvent was

removed under reduced pressure. The residue was taken up

in chloroform (30 mL) and washed with water (10 mL),

brine (10 mL) and dried (MgSO₄). The solvent was removed

in vacuo and the crude product was puriﬁed by column

chromatography (ethyl acetate, R_f: 0.49) giving 34a as a

colourless solid (1.17 g, 90%). Mp 147–149 8C. n_maxKBr/

cm^K12932 w, 2858 m, 1666 s, 1474 m, 1408 m, 1335 m,

1258 m, 1111 m, 837 m, 783 m. d_H(300 MHz, CDCl₃) 0.01

(s, 3H, SiCH₃), 0.02 (s, 3H, SiCH₃), 0.83 (s, 9H, C(CH₃)₃),

2.94 (s, 3H, NCH₃), 2.95 (s, 3H, NCH₃), 3.77 (d, 1H, JZ

4.8.4. 3-Allyl-1,3,4-trimethylpiperazine-2,5-dione (30).

To a solution of 3-methoxy-1,3,4-trimethylpiperazine-2,5-

dione (25) (30 mg, 0.16 mmol) in dichloromethane (1 mL)

at 0 8C was added allyltrimethylsilane (0.26 mL,

1.61 mmol) and boron triﬂuoride diethyl etherate

(0.04 mL, 0.32 mmol). The cooling bath was removed and

the reaction mixture was warmed slowly to room

temperature. Stirring was continued for a further 4 h

following which time the reaction mixture was washed

with brine (1 mL), the organic phase was separated, dried

and concentrated in vacuo. The residue was puriﬁed by

column chromatography (5:1, ethyl acetate–methanol, R_f:

0.46) to give the title compound 30 as a colourless oil

(21 mg, 66%). d_H(300 MHz, CDCl₃) 1.56 (s, 3H, a-CH₃),

2.43 (dd, 1H, JZ14 Hz, 8 Hz, allyl a-CCH_aH_bCH), 2.76

(dd, 1H, JZ14 Hz, 7 Hz, allyl a-CCH_aH_bCH), 2.96 (s, 6H,

2!NCH₃), 3.95 (m, 2H, ring CH₂), 5.09 (m, 1H, allyl

a-CCH₂CHCH_aH_b), 5.13 (m, 1H, allyl a-CCH₂CHCH_aH_b),

5.55 (m, 1H, allyl a -CCH₂CH). d_C(75 MHz, CDCl₃) 24.6

(a-CH₃), 27.8 (NCH₃), 33.8 (NCH₃), 42.0 (allyl CCH₂CH),

51.4 (ring CH₂), 64.5 (quaternary ring carbon), 120.2 (allyl

CCH₂CHCH₂), 131.4 (allyl CCH₂CH), 163.5 (C(O)), 167.7

(C(O)). The by-product 1,4-dimethyl-3-methylidenepiper-

azine-2,5-dione²⁶(28a) (w33%) had spectral properties

consistent with those reported previously.

2

17 Hz, 6-CH_aH_b), 3.84 (bs, 1H, 3-CH), 3.90 (dd, 1H, JZ

3

2

3

10 Hz, JZ2 Hz, CH_aH_bO), 4.04 (dd, 1H, JZ10 Hz, JZ

2 Hz, CH_aH_bO), 3.82 (d, 1H, JZ17 Hz, 6-CH_aH_b). d_C

(75 MHz, CDCl₃) K5.8 (2!Si(CH₃)₂), 18.0 (C(CH₃)₃),

25.5 (3!C(CH₃)₃), 31.6 (NCH₃), 33.2 (NCH₃), 51.8

(6-CH₂), 62.3 (CH₂O), 64.5 (3-CH), 164.7 (C(O)), 165.4

(C(O)). m/z (EI) 286.1710 (M^C%. C₁₃H₂₆N₂O₃Si requires

286.1713); 229 ([MKC(CH₃)₃]^C, 100%); 158 ([MK

Si(CH₃)₂C(CH₃)₃]^C, 30%); 73 (37%).

4.9.3. (S)-3-(t-Butyldimethylsilanyloxymethyl)-4-(p-

methoxybenzyl)-1-methylpiperazine-2,5-dione (34b).

The title compound was prepared from (S)-3-(t-butyldi-

methylsilanyloxymethyl)-1-methylpiperazine-2,5-dione

(33) (2.18 g, 8.00 mmol) as outlined for 34a. In this case

p-methoxybenzyl chloride was used instead of methyl

iodide. The compound was purifed via column chromato-

graphy (ethyl acetate, R_f: 0.53). Piperazinedione 34b was

obtained as a colourless solid (2.26 g, 72%). Mp 94–97 8C.

n_maxKBr/cm^K12932 m, 1666 s, 1647 s, 1512 m, 1466 m,

1331 m, 1246 s, 1115 m. d_H(300 MHz, CDCl₃) 0.00 (s, 3H,

SiCH₃), 0.01 (s, 3H, SiCH₃), 0.85 (s, 9H, C(CH₃)₃), 2.94 (s,

3H, NCH₃), 3.78 (s, 3H, OCH₃), 3.75–3.85 (m, 3H, CH_aH_bO

& 6-CH_aH_b& 3-CH), 3.95–3.98 (m, 1H, CH_aH_bO), 4.00 (d,

1H, J_ABZ15 Hz, NCH_aH_bPh), 4.21 (d, 1H, J_ABZ17 Hz,

6-CH_aH_b), 5.15 (d, 1H, J_ABZ15 Hz, NCH_aH_bPh), 6.83 (d,

2H, JZ9 Hz, 2!aromatic CH), 7.17 (d, 2H, JZ9 Hz, 2!

aromatic CH). d_C(75 MHz, CDCl₃) K5.6 (2!Si(CH₃)₂),

18.1 (C(CH₃)₃), 25.7 (3!C(CH₃)₃), 33.4 (NCH₃), 46.4

(NCH₂Ph), 52.2 (ring CH₂), 55.3 (OCH₃), 61.4 (ring CH),

62.8 (CH₂OSi), 114.3 (2!aromatic CH), 127.5 (quaternary

aromatic), 129.7 (2!aromatic CH), 159.3 (quaternary

aromatic), 164.9 (C(O)), 166.0 (C(O)). m/z (EI) 393

([MH]^C, 1%), 392.2130 (M^C%. C₂₀H₃₂N₂O₄Si requires

392.2131), 335 ([MKC(CH₃)₃]^C, 63%), 121 (57%), 61

(100%).

4.9. Hydroxymethylpiperazinediones as precursors in

modiﬁed DONA reactions

4.9.1. (S)-3-(t-Butyldimethylsilanyloxymethyl)-1-methyl-

piperazine-2,5-dione (33). To a stirred solution of (S)-3-

hydroxymethyl-1-methylpiperazine-2,5-dione (32)²⁴(851 mg,

5.38 mmol) in DMF (15 mL) was added t-butyldimethylsi-

lylchloride (983 mg, 6.52 mmol) and imidazole (888 mg,

13.0 mmol). The reaction mixture was stirred for 1 h and the

solvent was then removed in vacuo. The residue was taken

up in ethyl acetate (20 mL) and washed with water (10 mL).

The organic phase was dried (MgSO₄) and the solvent

removed to afford the title compound 33 as a colourless

solid (1.17 g, 80%). Mp 115–117 8C. n_maxKBr/cm^K13213

w, 2932 w, 1670 s, 1443 m, 1335 m, 1250 m, 1096 m, 837

m, 779 m. d_H(300 MHz, CDCl₃) 0.01 (s, 6H, Si(CH₃)₂),

0.83 (s, 9H, C(CH₃)₃), 2.94 (s, 3H, NCH₃), 3.82 (d, 1H, JZ

17 Hz, 6-CH_aH_b), 3.83–3.87 (m, 1H, CH_aH_bOSi), 3.86 (bs,

1H, 3-CH), 3.93–4.00 (m, 1H, CH_aH_bOSi), 4.02 (d, 1H, JZ

17 Hz, 6-CH_aH_b). d_C(75 MHz, CDCl₃) K5.8 (2!

Si(CH₃)₂), 17.9 (C(CH₃)₃), 25.5 (3!C(CH₃)₃), 33.4

(NCH₃), 51.4 (6-CH₂), 57.3 (3-CH), 65.7 (CH₂O), 164.9

4.9.4. 3-Hydroxymethyl-1,4-dimethylpiperazine-2,5-

dione (35a). 3-(t-Butyldimethylsilanyloxymethyl)-1,4-

dimethylpiperazine-2,5-dione (34a) (620 mg, 2.41 mmol)

was dissolved in acetic acid (6 mL), THF (2 mL) and water

8738

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

(2 mL). The resultant solution was heated at reﬂux for 24 h,

following which the solvent was removed in vacuo. The

residue was puriﬁed via column chromatography (9:1,

chloroform–ethyl acetate, R_f: 0.29) to give 3-hydroxymethyl-

1,4-dimethylpiperazine-2,5-dione (35a) as a colourless solid

(361 mg, 87%). Mp 127–129 8C. (Found C, 48.9; H, 7.3; N,

16.5. C₇H₁₂N₂O₃requires C, 48.8; H, 7.0; N, 16.3%). n_max

KBr/cm^K13379 s, 2992 w, 2816 w, 1672 vs, 1647 vs, 1493

s, 1410 s, 1340 s, 1259 s, 1070 m, 1056 m, 1032 m, 833 w.

d_H(300 MHz, CDCl₃) 2.97 (s, 3H, NCH₃), 3.00 (s, 3H,

NCH₃), 3.17 (bs, 1H, OH), 3.78 (d, 1H, J_ABZ17 Hz,

6-CH_aH_b), 3.85 (bs, 1H, 3-CH), 3.96 (dd, 1H, ²J_ABZ12 Hz,

([MH]^C. C₆H₁₁N₂O₃requires 159.0767), 128 ([MK

OCH₃C1]^C, 71%), 101 (100%), 73 (32%).

4.9.7. 3-Acetoxy-4-(p-methoxybenzyl)-1-methylpipera-

zine-2,5-dione (37). To a solution of 35b (106 mg,

0.38 mmol) in dichloromethane (10 mL) was added iodine

(48 mg, 0.19 mmol) and DIB (125 mg, 0.39 mmol). The

reaction mixture was then stirred under a nitrogen

atmosphere for 16 h. After this time, the reaction mixture

was washed with a saturated solution of sodium thiosulfate

(1 mL), dried (MgSO₄) and the solvent removed under

reduced pressure. The residue was triturated with diethyl

ether and collection of the solid afforded the title compound

37 as a colourless solid (110 mg, 94%). Mp 118–120 8C. d_H

(300 MHz, CDCl₃) 1.98 (s, 3H, OC(O)CH₃), 2.96 (s, 3H,

NCH₃), 3.78 (s, 3H, OCH₃), 3.93 (d, 1H, J_ABZ18 Hz,

6-CH_aH_b), 4.18 (d, 1H, J_ABZ18 Hz, NCH_aH_b), 4.28 (d, 1H,

J_ABZ18 Hz, 6-CH_aH_b), 4.94 (d, 1H, J_ABZ18 Hz, NCH_aH_b),

5.98 (s, 1H, 3-CH), 6.84 (d, 2H, JZ9 Hz, 2!aromatic H),

7.23 (d, 2H, JZ9 Hz, 2!aromatic H). d_C(75 MHz, CDCl₃)

20.5 (OC(O))CH₃), 33.5 (NCH₃), 46.9 (NCH₂), 51.7 (6-CH₂),

55.2 (OCH₃), 77.7 (3-CH), 114.1 (2!aromatic CH), 127.2

(quaternary aromatic C), 130.1 (2!aromatic CH), 159.4

(quaternary aromatic), 161.1 (C(O)), 165.2 (C(O)), 169.7

(C(O)). m/z (EI) 306.1219 (M^C%. C₁₅H₁₈N₂O₅requires

306.1216), 246 ([MKOAcK1]^C, 56%), 147 (39%), 136

(29%), 121 (100%).

2

³JZ3 Hz, CH_aH_bOH), 4.05 (dd, 1H, J_ABZ12 Hz, ³JZ

3 Hz, CH_aH_bOH), 4.16 (d, 1H, J_ABZ17 Hz, 6-CH_aH_b). d_C

(75 MHz, CDCl₃) 31.7 (NCH₃), 33.3 (NCH₃), 51.6 (6-CH₂),

61.2 (CH₂OH), 64.5 (3-CH), 165.2 (C(O)), 165.7 (C(O)). m/

z (EI) 173.0923 ([MH]^C. C₇H₁₃N₂O₃requires173.0926),

142 ([MHKCH₂OH]^C, 100%), 113 (72%), 71 (32%).

4.9.5. 3-Hydroxymethyl-4-(p-methoxybenzyl)-1-methyl-

piperazine-2,5-dione (35b). The title compound was

prepared from (S)-3-(t-butyldimethylsilanyloxymethyl)-4-

(p-methoxybenzyl)-1-methylpiperazine-2,5-dione (34b)

(1.01 g, 2.57 mmol) as outlined for the conversion of 34a

to 35a. The compound was purifed via column chromatog-

raphy (5:1, ethyl acetate–methanol, R_f: 0.39). Piperazine-

dione 35b was obtained as a colourless solid (594 mg, 83%).

Mp 94–97 8C. n_maxKBr/cm^K13368 w, 2936 w, 1666 s,

1647 m, 1512 m, 1246 m. d_H(300 MHz, CDCl₃) 2.97 (s, 3H,

NCH₃), 3.79 (s, 3H, OCH₃), 3.82–3.90 (m, 3H, 6-CH_aH_b,

3-CH, CH_aH_bO), 4.00 (dd, 1H, ²JZ12 Hz, ³JZ3 Hz,

CH_aH_bO), 4.07 (d, 1H, JZ15 Hz, NCH_aH_b), 4.27 (d, 1H,

JZ17 Hz, 6-CH_aH_b), 5.16 (d, 1H, JZ15 Hz, NCH_aH_b),

6.85 (d, 2H, JZ9 Hz, 2!aromatic H), 7.19 (d, 2H, JZ9 Hz,

2!aromatic H). d_C(75 MHz, CDCl₃) 33.5 (NCH₃), 46.4

(NCH₂), 52.1 (6-CH₂), 55.4 (OCH₃), 61.8 (CH₂OH), 114.4

(2!aromatic CH), 127.2 (quaternary aromatic C), 129.8

(2!aromatic CH), 159.5 (quaternary aromatic C), 165.4

Acknowledgements

The authors thank the Australian Research Council (ARC)

for support for this project.

References and notes

(C(O)), 166.2 (C(O)). m/z (EI) 278.1266 (M^C%

.

C₁₄H₁₈N₂O₄requires 278.1267), 248 (26%), 121 (100%).

1. (a) Johne, S.; Groeger, D. Pharmazie 1977, 32, 1–16.

(b) Rajappa, S.; Natekar, M. V. Adv. Heterocycl. Chem.

1993, 57, 187–289. (c) Witiak, D. T.; Wei, Y. Prog. Drug. Res.

1990, 35, 249–363.

4.9.6. 3-Methoxy-1-methylpiperazine-2,5-dione (36). To

a solution of 3-hydroxymethyl-1-methylpiperazine-2,5-

dione (32) (225 mg, 1.42 mmol) in dichloromethane

(10 mL) was added iodine (718 mg, 2.84 mmol) and DIB

(462 mg, 1.43 mmol). The reaction mixture was then stirred

under a nitrogen atmosphere for 16 h. After this time,

methanol (10 mL) was added and the reaction mixture was

stirred for a further 24 h. Then reaction mixture was then

washed with a saturated solution of sodium thiosulfate

(2 mL). The aqueous phase was extracted with dichloro-

methane (5!5 mL). The organic washings were dried

(MgSO₄) and the solvent removed under reduced pressure.

The residue was puriﬁed by column chromatography (5:1,

ethyl acetate–methanol, R_f: 0.35) to afford the title

compound 36 as a colourless solid (99 mg, 44%). Mp

118–120 8C. n_maxKBr/cm^K13267 w, 1682 s, 1655 s, 1477

m, 1327 m, 1072 s, 1018 m. d_H(300 MHz, CDCl₃) 2.99 (s,

3H, NCH₃), 3.45 (s, 3H, OCH₃), 3.78 (d, 1H, J_ABZ18 Hz,

ring CH_aH_b), 4.23 (d, 1H, J_ABZ18 Hz, ring CH_aH_b), 4.74

(d, 1H, JZ4 Hz, ring CH), 7.84 (bs, 1H, NH). d_C(75 MHz,

CDCl₃) 33.7 (NCH₃), 51.3 (ring CH₂), 55.9 (OCH₃), 82.3

(ring CH), 162.4 (C(O)), 167.9 (C(O)). m/z (EI) 159.0767

2. For a recent review, see Fischer, P. M. J. Peptide Sci. 2003, 9,

9–35.

3. For examples, see (a) Hayashi, Y.; Orikasa, S.; Tanaka, K.;

Kanoh, K.; Kiso, Y. J. Org. Chem. 2000, 65, 8402–8405.

(b) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille,

J. K. J. Am. Chem. Soc. 1990, 112, 808–821. (c) Fukuyama, T.;

Nakatsuka, S.; Kishi, Y. Tetrahedron 1981, 37, 2045–2078.

4. For examples, see (a) Bull, S. D.; Davies, S. G.; Epstein, S. W.;

Leech, M. A.; Ouzman, J. V. A. J. Chem. Soc., Perkin Trans. 1

1998, 2321–2330. (b) Bull, S. D.; Davies, S. G.; O’Shea, M. D.

J. Chem. Soc., Perkin Trans. 1 1998, 3657–3658. (c) Oehler,

E.; Poisel, H.; Tataruch, F.; Schmidt, U. Chem. Ber. 1972, 105,

635–641. (d) Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem.

1992, 57, 6532–6536.

5. (a) Chai, C. L. L.; Page, D. M. Tetrahedron Lett. 1993, 34,

4373–4376. (b) Chai, C. L. L.; King, A. R. J. Chem. Soc.,

Perkin Trans. 1 1999, 1173–1182.

6. (a) Burkett, B. A.; Chai, C. L. L. Tetrahedron Lett. 2001, 42,

2239–2242. (b) Chai, C. L. L.; Johnson, R. C.; Koh, J.

Tetrahedron 2002, 58, 975–982.

C. L. L. Chai et al. / Tetrahedron 61 (2005) 8722–8739

8739

7. Chai, C. L. L.; Elix, J. A.; Huleatt, P. B. Tetrahedron Lett.

2003, 44, 263–265.

17. Badran, T. W.; Easton, C. J. Aust. J. Chem. 1990, 43,

1455–1459.

18. For examples, see (a) Badran, T. W.; Chai, C. L. L.; Easton, C.

J.; Harper, J. B.; Page, D. M. Aust. J. Chem. 1995, 48,

1379–1384. (b) Chai, C. L. L.; Hay, D. B.; King, A. R. Aust. J.

Chem. 1996, 49, 605–610.

8. Palmer, C. S.; McWherter, P. W.; Organic Syntheses; Wiley:

New York, 1941; Collect. Vol. I, pp 245–246.

9. Hardegger, E.; Corrodi, H. Helv. Chim. Acta 1956, 39,

980–983.

19. Bull, S. D.; Davies, S. G.; Garner, A. C.; O’Shea, M. D.;

Savory, E. D.; Snow, E. J. J. Chem. Soc., Perkin Trans. 1 2002,

2442–2448.

10. Hino, T.; Sato, T. Chem. Pharm. Bull. 1974, 22, 2866–2874.

11. Hino, T.; Sato, T. Chem. Pharm. Bull. 1976, 24, 285–293.

12. (a) Kissman, H. M.; Witkop, B. J. Am. Chem. Soc. 1953, 75,

1967–1974. (b) Zaugg, H. E.; Freifelder, M.; Glenn, H. J.;

Horrom, B. W.; Stone, G. R.; Vernstein, M. R. J. Am. Chem.

Soc. 1956, 78, 2626–2631.

20. Hausler, J.; Schmidt, U. Chem. Ber. 1974, 107, 2804–2815.

21. (a) Kanoh, K.; Kohno, S.; Katada, J.; Takahashi, J.; Uno, I.;

Hayashi, Y. Bioorg. Med. Chem. Lett. 1999, 7, 1451–1457.

(b) Kanoh, K.; Kohno, S.; Katada, J.; Takahashi, J.; Uno, I.

J. Antibiot. 2002, 55, 1042–1047.

13. For a recent review on conformationally constrained amino

acids, see Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58,

8629–8659.

22. (a) Machin, P. J.; Sammes, P. G. J. Chem. Soc., Perkin Trans. 1

1976, 628–634. (b) Shin, C. G.; Sato, Y.; Hayakawa, M.;

Kondo, M.; Yoshimura, J. Heterocycles 1981, 16, 1573–1578.

23. Boto, A.; Hernandez, R.; Suarez, E. Tetrahedron Lett. 2002,

43, 8269–8272.

14. Mauger, A. B.; Desai, R. B.; Rittner, I.; Rzeszotarski, W. J. J.

Chem. Soc., Perkin Trans. 1 1972, 2146–2148.

15. (a) Boto, A.; Hernandez, R.; Suarez, E. Tetrahedron Lett.

1999, 40, 5945–5948. (b) Boto, A.; Hernandez, R.; Suarez, E.

J. Org. Chem. 2000, 65, 4930–4937. (c) Boto, A.; Hernandez,

R.; Suarez, E. Tetrahedron Lett. 2000, 41, 2899–2902.

16. Speckamp, W. N.; Moolenar, M. J. Tetrahedron 2000, 56,

3817–3856.

24. Falomi, M.; Satta, M.; Conti, S.; Giacomelli, G. Tetrahedron:

Asymmetry 1993, 4, 2389–2398.

25. Armarego, W. L. F.; Chai, C. L. L. Puriﬁcation of Laboratory

Chemicals, 5th ed.; Butterworth: Heinemann, 2003.

26. Chai, C. L. L.; King, A. R. J. Chem. Res. (S) 1997, 382.

Article Doi

The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine- 2,5-diones

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