A Dieckmann cyclization route to piperazine-2,5-diones

Article abstract of DOI:10.1021/jo3007144

Piperazine-2,5-diones are formed by Dieckmann cyclization (NaH, THF) of substructures of the type CH₂-N(R)C(O)CH₂N(R′) CO₂Ph in which the terminal methylene (CH₂) that is adjacent to nitrogen closes onto the carbonyl group of the phenyl carbamate unit at the other end of the chain. R and R′ are alkyl groups, and the terminal methylene is activated by a ketone carbonyl, a nitrile, an ester, or a phosphoryl group. The starting materials are assembled by standard acylation and oxidation processes, starting from a β-(alkylamino)alcohol, an (alkylamino)acetonitrile, an (alkylamino) ester, or an (alkylamino)methyl phosphonate.

Full text of DOI:10.1021/jo3007144

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Article
A Dieckmann cyclization route to piperazine-2,5-diones
Claude Larrivee Aboussafy, and Derrick L. J. Clive
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3007144 • Publication Date (Web): 07 May 2012
Downloaded from http://pubs.acs.org on May 14, 2012
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A Dieckmann cyclization route to piperazine-2,5-diones
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Claude Larrivée Aboussafy and Derrick L. J. Clive*
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Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
*Eꢀmail: derrick.clive@ualberta.ca
ABSTRACT
Piperazineꢀ2,5ꢀdiones are formed by Dieckmann cyclization (NaH, THF) of substructures of the
type CH2ꢀN(R)C(O)CH2N(R')CO2Ph in which the terminal methylene (CH2) that is adjacent to
nitrogen closes onto the carbonyl group of the phenyl carbamate unit at the other end of the
chain. R and R' are alkyl groups and the terminal methylene is activated by a ketone carbonyl, a
nitrile, an ester, or a phosphoryl group. The starting materials are assembled by standard
acylation and oxidation processes, starting from
a
βꢀ(alkylamino)alcohol, an
(alkylamino)acetonitrile, an (alkylamino) ester or an (alkylamino)methyl phosphonate.
INTRODUCTION
During synthetic studies carried out in this laboratory and directed towards the synthesis of the
antitumor antibiotic MPC1001 (1), the lactam carbamate 2 was treated with NaH to produce the
piperazinedione 3 (eq 1).1 In this process, the piperazineꢀ2,5ꢀdione substructure of 3 is being
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constructed by the potentially general sequence 4→5 (eq 2) which resembles the classical
Dieckmann cyclization. Surprisingly, the simple disconnection represented by the conversion of
4 into 5 has not been used before, apart from the example of eq 1.2 In view of the importance of
piperazineꢀ2,5ꢀdiones,3 especially for pharmaceutical products,4 we decided to establish if any
special features inherent in structure 2, especially the restraint of the ketone carbonyl group into
a ring, was a requirement for effective cyclization, and we now report that the process defined by
eq 2 represents a general route to piperazineꢀ2,5ꢀdiones. It allows the preparation of such
compounds bearing a variety of different substituents.5
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RESULTS AND DISCUSSION
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The starting carbamates related to generic structure 4 were easily prepared, often along the lines
summarized in Scheme 1 for a particular example, and Table 1 lists the carbamates we have
made in this way or by equally straightforward routes (which are described in the experimental
section).
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SCHEME 1. Preparation of amide carbamate 6d
TABLE 1. Preparation of substrates for cyclization
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aCorrected for recovered 13b.
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All of the starting amino alcohols (Table 1, first column) are known compounds; those of
entries 1ꢀ5, 9 and 10 were made by the epoxide route (cf Scheme 1). Although compound 10a
(entry 6) could also be prepared in this way, reductive amination (NaBH3CN) of pꢀ
methoxybenzaldehyde gave a better yield. The cyano amine 11a was available in one step from
ClCH2CN and BnNH2, and the amino phosphonate 14a was made from (EtO)2P(O)H and 1,3,5ꢀ
tribenzylꢀ1,3,5ꢀtriazinane.6
Each amino alcohol was acylated on nitrogen using one of the acid chlorides 7, 15 or 16,
which were made by Nꢀacylation (PhOCOCl, or pꢀO2NC6H4OCOCl) of the appropriate amino
acid, followed by treatment with (COCl)2. The resulting hydroxy carbamates were then oxidized
(cf 6c→6d) with PCC or the DessꢀMartin reagent.
When carbamate 6d was heated with NaH (2.05 equiv) in refluxing THF (0.02 M in 6d)
for 15 min, it was converted into the piperazinedione 6g in 67% yield (92% after correction for
recovered 6d). These conditions represent the best results from a brief optimization study in
which we varied, in an empirical manner, the reaction temperature (room temperature and 70
°C), the concentration of the starting carbamate (0.2 M and 0.02 M), the solvent (THF, DMF,
DMSO), and the nature of the base (NaH, tꢀBuOK, DBU, LDA, KHMDS, LiHMDS). The
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related carbamate 6f gave 6g in much lower yield under the same conditions. A similar
comparison was made between 9c and 9e, and once again the phenyl carbamate was far superior.
We did not establish the basis of this result, but speculate that the better leaving group facilitates
the incursion of intermolecular side reactions. Cyclization of 6d did not occur with CF3CO2H
(CH2Cl2) or TsOH (CDCl3). In two cases, (Table 2, entries 8 and 11) the cyclization was done in
the presence of a small amount of tꢀBuOH (0.2 equiv). With this change, the experiment of entry
8 gave a higher yield, and that of entry 11 proceeded more rapidly. This modification was tried
because these two examples were abnormally slow under the usual conditions.
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TABLE 2. Cyclization to piperazine-2,5-dionesa
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aUnless otherwise indicated, reactions were done using the following conditions: NaH (2.05
equiv), 0.02 M in substrate, THF, 70 °C, 15 min. bCorrected for recovered starting material.
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d
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cReaction time = 24 h, trace tꢀBuOH added. Reaction time = 2.5 h. Reaction time = 30 min.
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fReaction time = 4.5 h, trace tꢀBuOH added. gThe material contained a minor byproduct (see
text).
The reaction accommodates different alkyl groups on nitrogen (methyl, benzyl, pꢀ
methoxybenzyl). As indicated in Table 2, we have also investigated a limited number of
activating groups adjacent to the carbon [C(6) in 4] that must be deprotonated to initiate the ring
closure. PhCO and pꢀMeOC6H4CO are satisfactory (entries 1ꢀ5, 9, 10) as are MeCO (entry 6)
and CO2Me (entry 8). Use of a nitrile for activation is also successful (entry 7) as is a
diethoxyphosphoryl group (entry 11).
In the case of entry 9, two chromatogaphically inseparable products (ca 89:11) were
formed and the NMR spectra suggest that they are the expected cis and trans isomers, although
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we were unable to identify which was which. We noted that in the H and C NMR spectra of
the material, the minor signals were very similar to those corresponding to the major isomer, but
slightly displaced.
The phosphonate 14c contained a minor byproduct that could not be separated and, when
we treated the material with pꢀmethoxybenzaldehyde and NaH, the two olefins 14d (50%) and
14d' (15%) (Figure 1) were isolated, suggesting that the minor component of the starting
phosphonate 14c was a positional isomer with the phosphoryl group adjacent to the Nꢀmethyl.
Very few phosphonates of piperazineꢀ2,5ꢀdiones have been reported.7 The stereochemistry of
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14d and 14d' was evident from TROESY (Figure 1) and HMBC NMR experiments, (see
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Supporting Information), but we did not establish the origin of the minor phosphonate that gives
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14d'.
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Figure 1. Structures and TROESY correlations for 14d and 14d'.
In the case of 6d a minor byproduct was sometimes obtained. This material had structure
6h.8 When 6d was treated with NaH in THF under an atmosphere of O2, the same
imidazolidinedione 6h was the exclusive product (56% yield) but when 6g was subjected to the
same conditions we did not detect 6h.
Piperazinediones 10d, 11c, and 12c are crystalline, and single crystal Xꢀray analysis
served to confirm the structures and indicate the shape of the heterocyclic ring (see Supporting
Information for ORTEP diagrams). Both compounds 10d and 12c have a shallow boat
conformation with their respective carbonyl substituents (MeCO and CO2Me) axial, while 11c
has an almost planar heterocyclic ring.
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EXPERIMENTAL SECTION
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General Procedures. Solvents used for chromatography were distilled before use.
Commercial thin layer chromatography (TLC) plates (silica gel, Merck 60F–254) were used.
Silica gel for flash chromatography was Merck type 60 (230ꢀ400 mesh). Dry solvents were
prepared under an inert atmosphere and transferred by syringe. Molecular sieves (3 Å) were
stored at 150 °C for 5 h, and then cooled in a desiccator under N2, before use. The symbols s, d,
t, q used for 13C NMR spectra indicate zero, one, two, or three attached hydrogens, respectively,
the assignments being made by APT spectra. Solutions were evaporated under water pump
vacuum and the residue was kept under oil pump vacuum. High resolution mass spectra were
obtained with an aoTOF mass analyzer fitted with an electrospray source. NMR spectra of
many compounds were run both at room temperature and at a higher temperature (usually at 100
°C) in order to verify the presence of rotamers. Samples for Xꢀray analysis were crystallized as
follows: A portion of the sample was dissolved in the minimum amount of EtOAc at room
temperature and the solution was transferred to a shortened (ca 4 cm) NMR tube. This was
placed inside a sample vial containing hexane and the vial was closed. After several days
crystals suitable for Xꢀray analysis had grown.
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Phenyl
N-{[Benzyl(2-hydroxy-2-phenylethyl)carbamoyl]methyl}-N-methylcarba-
mate (6c). NaHCO3 (185 mg, 2.20 mmol) was added to a stirred and cooled (0 °C) solution of
6b9 (200 mg, 0.881 mmol) in dioxane (3 mL) and water (3 mL). Acid chloride 71 (250 mg, 1.10
mmol) in dry THF (1 mL) was added dropwise over 15 min. The cooling bath was left in place,
but not recharged, and stirring was continued overnight. The THF and dioxane were evaporated
and the aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried
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(Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (2 x 12 cm), using
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30% to 50% EtOAc in hexanes, gave 6c (306 mg, 83%) as a white foam: FTIR (CHCl3, cast)
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3422, 3063, 3030, 2935, 1723, 1650, 1495, 1475, 1453, 1398, 1205 cmꢀ1; H NMR (DMSOꢀd6,
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400 MHz) δ 2.82ꢀ3.02 (four s, 3 H in all), 3.14ꢀ3.31 (m, 1 H), 3.43ꢀ3.56 (m, 1 H), 4.14ꢀ4.24 (m,
1.3 H), 4.40ꢀ4.53 (m, 1.7 H), 4.60ꢀ4.67 (m, 0.3 H), 4.78ꢀ4.87 (m, 1.7 H), 5.50ꢀ5.51 (m, 0.3 H),
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5.75ꢀ5.77 (m, 0.7 H), 7.00ꢀ7.40 (m, 15 H); C NMR (DMSOꢀd6, 125 MHz) δ 35.7 (q), 35.8 (q),
36.1 (q), 36.2 (q), 48.2 (t), 48.4 (t), 50.4 (t), 50.6 (t),50.7 (t), 50.8 (t), 53.4 (t), 53.9 (t), 70.3 (d),
70.8 (d), 121.6 (d), 121.7 (d), 124.9ꢀ129.2 (numerous d), 137.0 (s), 137.7 (s), 143.1 (s), 143.1 (s),
143.4 (s), 151.2 (s), 151.3 (s), 151.4 (s), 154.6 (s), 154.9 (s), 168.0 (s), 168.3 (s), 168.5 (s), 168.7
(s); exact mass (electrospray) m/z calcd for C25H26N2NaO4 (M + Na) 441.1785, found, 441.1787.
Phenyl
N-{[Benzyl(2-oxo-2-phenylethyl)carbamoyl]methyl}-N-methylcarbamate
(6d). PCC (435 mg, 2.02 mmol) was added to a stirred and cooled (0 °C) mixture of 6c (282 mg,
0.674 mmol), AcONa (55 mg, 0.674 mmol) and powdered 3 Å molecular sieves (337 mg, 0.5
g/mmol of 6c) in dry CH2Cl2 (10.8 mL). The mixture was stirred at 0 °C for 15 min, the ice bath
was removed and stirring was continued for 30 min. The mixture was filtered through a pad of
Celite (3.5 x 3.5 cm) and the pad was rinsed with CH2Cl2. Flash chromatography silica gel (6.0
g) was added to the filtrate and the solvent was evaporated at room temperature. The dry residue
was poured onto the top of a chromatography column made up with silica gel (2 x 16 cm) and
hexanes. The column was developed using 40% to 50% EtOAc in hexanes to give 6d (264 mg,
94%) as a white foam: FTIR (CHCl3, cast) 3063, 3029, 2930, 1724, 1699, 1666, 1472, 1450,
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1204 cmꢀ1; H NMR (DMSOꢀd6, 400 MHz) δ 2.89ꢀ3.03 (m, 3 H), 4.09ꢀ4.19 (two s, 1 H), 4.30ꢀ
4.40 (two s, 1 H), 4.55ꢀ4.56 (m, 1 H), 4.66ꢀ4.67 (m, 1 H), 4.82ꢀ4.86 (m, 1 H), 5.01ꢀ5.02 (m, 1
H), 7.02ꢀ7.07 (m, 2 H), 7.18ꢀ7.39 (m, 8 H), 7.51ꢀ7.55 (m, 2 H), 7.62ꢀ7.70 (m, 1 H), 7.95ꢀ7.98 (m,
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2 H); C NMR (DMSOꢀd6, 125 MHz) δ 35.5 (q), 35.7 (q), 36.1 (q), 36.2 (q), 50.0 (t), 50.1 (t),
50.3 (t), 50.4 (t), 50.6 (t), 50.8 (t), 53.0 (t), 53.2 (t), 53.3 (t), 121.6 (d), 121.7 (d), 125.0 (d), 125.1
(d), 125.1 (d), 126.8ꢀ129.2 (numerous d), 129.1 (d), 129.2 (d), 133.5 (s), 133.8 (s), 134.7 (s),
134.9 (s), 136.9 (s), 137.5 (s), 137.5 (s), 151.2 (s), 151.3 (s), 154.5 (s), 154.6 (s), 154.8 (s), 168.2
(s), 168.6 (s), 168.7 (s), 169.1 (s), 193.9 (s), 194.7 (s); exact mass (electrospray) m/z calcd for
C25H24N2NaO4 (M + Na) 439.1628, found, 439.1630.
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3-Benzoyl-4-benzyl-1-methylpiperazine-2,5-dione (6g). NaH (60% w/w dispersion in
mineral oil, 20 mg, 0.492 mmol) was added in one portion to a stirred solution of 6d (100 mg,
0.240 mmol) in dry THF (12 mL). The reaction flask was lowered into a preheated oil bath (70
°C) and the mixture was stirred for 15 min. The mixture was cooled (ice bath) and pH 7 buffer
was added. The aqueous solution was extracted with EtOAc and the combined organic extracts
were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (2 x 10
cm), using 20% to 40% EtOAc in hexanes, gave 6g [47 mg, 67% or 92% after correction for
recovered 6d (36 mg)] as a white foam: FTIR (CHCl3, cast) 3064, 3029, 3008, 2930, 1678,
1596, 1580, 1496, 1466, 1450, 1227 cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.92 (s, 3 H), 3.92 (d, J
= 17.0 Hz, 1 H), 3.96 (d, J = 14.0 Hz, 1 H), 4.36 (d, J = 17.0 Hz, 1 H), 5.07 (d, J = 14.0 Hz, 1 H),
5.53 (s, 1 H), 7.13ꢀ7.17 (m, 3 H), 7.21ꢀ7.26 (m, 2 H), 7.43ꢀ7.49 (m, 2 H), 7.62 (apparent tt, J =
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1.5, 7.5 Hz, 1 H), 8.00ꢀ8.03 (m, 2 H); C NMR (DMSOꢀd6, 125 MHz) δ 34.1 (q), 48.9 (t), 52.6
(t), 65.1 (d), 128.5 (d), 128.9 (d), 129.0 (d), 129.2 (d), 129.9 (d), 134.1 (s), 134.7 (s), 134.7 (d),
160.7 (s), 166.1 (s), 192.6 (s); exact mass (electrospray) m/z calcd for C19H18N2NaO3 (M + Na)
345.1210, found, 345.1209.
3-Benzoyl-4-benzyl-1-methylpiperazine-2,5-dione (6g). NaH (60% w/w dispersion in
mineral oil, 5.3 mg, 0.133 mmol) was added in one portion to a stirred solution of 6f (30 mg,
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0.0650 mmol) in dry THF (3.3 mL). The reaction flask was lowered into a preheated oil bath (70
°C) and the mixture was stirred for 30 min. The mixture was cooled (ice bath) and pH 7 buffer
was added. The aqueous solution was extracted with EtOAc and the combined organic extracts
were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (1 x 10
cm), using 20% to 40% EtOAc in hexanes, gave 6g [5.2 mg, 25% or 33% after correction for
recovered 6f (24.4 mg)] as a white foam.
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3-Benzoyl-1,4-dimethylpiperazine-2,5-dione (8d).10 NaH (60% w/w dispersion in
mineral oil, 5 mg, 0.126 mmol) was added in one portion to a stirred solution of 8c (22 mg,
0.0622 mmol) in dry THF (3.2 mL). The reaction flask was lowered into a preheated oil bath (70
°C) and the mixture was stirred for 15 min. The mixture was cooled (ice bath) and pH 7 buffer
was added. The aqueous solution was extracted with EtOAc and the combined organic extracts
were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (1 x 10
cm), using 60% to 70% EtOAc in hexanes, gave 8d10 [8.8 mg, 58% or 85% after correction for
recovered 8c (6.8 mg)] as a white solid: mp 114ꢀ115 °C, FTIR (CHCl3, cast) 3064, 2930, 1674
cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.88 (s, 3 H), 2.93 (s, 3 H), 3.84 (d, J = 17.5 Hz, 1 H), 4.24
(d, J = 17.5 Hz, 1 H), 5.61 (s, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.66 (apparent tt, J = 1.5, 7.5 Hz, 1
13
H), 8.26ꢀ8.28 (m, 2 H); C NMR (DMSOꢀd6, 125 MHz) δ 33.1 (q), 34.0 (q), 52.2 (t), 68.6 (d),
128.9 (d), 130.2 (d), 134.0 (s), 134.8 (d), 160.5 (s), 166.2 (s), 191.8 (s); exact mass (electrospray)
m/z calcd for C13H15N2O3 (M + H) 247.1077, found, 247.1077.
3-Benzoyl-4-[(4-methoxyphenyl)methyl]-1-methylpiperazine-2,5-dione (9h). NaH
(60% w/w dispersion in mineral oil, 6 mg, 0.138 mmol) was added in one portion to a stirred
solution of 9c (30 mg, 0.0671 mmol) in dry THF (3.4 mL). The reaction flask was lowered into
a preheated oil bath (70 °C) and the mixture was stirred for 15 min. The mixture was cooled (ice
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bath) and pH 7 buffer was added. The aqueous solution was extracted with EtOAc and the
combined organic extracts were dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1 x 10 cm), using 40% EtOAc in hexanes, gave 9h [18.5 mg, 78% or 85%
after correction for recovered 9c (2.4 mg)] as a white foam: FTIR (neat film) 3065, 2934, 2837,
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1676, 1513, 1249 cmꢀ1; H NMR (CDCl3, 500 MHz) δ 2.92 (s, 3 H), 3.73 (s, 3 H), 3.91 (d, J =
17.5 Hz, 1 H), 4.07 (d, J = 14.5 Hz, 1 H), 4.36 (d, J = 17.5 Hz, 1 H), 4.88 (d, J = 14.5 Hz, 1 H),
5.52 (s, 1 H), 6.71ꢀ6.73 (m, part of AA'BB' spin system, 2 H), 7.03ꢀ7.05 (m, part of AA'BB' spin
13
system, 2 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.99ꢀ8.01 (m, 2 H); C NMR
(CDCl3, 125 MHz) δ 33.9 (q), 48.2 (t), 52.5 (t), 55.3 (q), 64.7 (d), 114.3 (d), 126.4 (s), 128.7 (d),
129.8 (d), 130.7 (d), 134.1 (s), 134.5 (d), 159.7 (s), 160.8 (s), 165.9 (s), 192.7 (s); exact mass
(electrospray) m/z calcd for C20H20N2NaO4 (M + Na) 375.1315, found, 375.1309.
3-Acetyl-4-[(4-Methoxyphenyl)methyl]-1-methylpiperazine-2,5-dione (10d).
NaH
(60% w/w dispersion in mineral oil, 31 mg, 0.767 mmol) was added in one portion to a stirred
solution of 10c (144 mg, 0.374 mmol) in dry THF (18 mL). The reaction flask was lowered into
a preheated oil bath (70 °C) and the mixture was stirred for 15 min. The mixture was cooled (ice
bath) and pH 7 buffer was added. The aqueous solution was extracted with EtOAc and the
combined organic extracts were dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (2 x 10 cm), using 40% to 50% EtOAc in hexanes, gave 10d [68.4 mg,
63% or 70% after correction for recovered 10c (14.5 mg)] as pale yellow crystals: mp 112ꢀ114
°C, FTIR (CHCl3, cast) 3007, 2935, 2838, 1732, 1674, 1514, 1464, 1248, 1176 cmꢀ1; H NMR
1
(CDCl3, 500 MHz) δ 2.17 (s, 3 H), 2.93 (s, 3 H), 3.79 (s, 3 H), 3.84 (d, J = 17.5 Hz, 1 H), 4.07
(d, J = 14.5 Hz, 1 H), 4.12 (d, J = 17.5 Hz, 1 H), 4.64 (s, 1 H), 4.85 (d, J = 14.5 Hz, 1 H), 6.83ꢀ
13
6.85 (m part of AA'BB' spin system, 2 H), 7.09ꢀ7.11 (m part of AA'BB' spin system, 2 H); C
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NMR (DMSOꢀd6, 125 MHz) δ 28.0 (q), 33.9 (q), 48.1 (t), 52.1 (t), 55.3 (q), 69.5 (d), 114.4 (d),
126.3 (s), 130.6 (d), 159.8 (s), 160.4 (s), 164.8 (s), 200.4 (s); exact mass (electrospray) m/z calcd
for C15H18N2NaO4 (M + Na) 313.1159, found, 313.1158. Crystals for Xꢀray analysis were
grown from EtOAcꢀhexanes, as described in the General Procedures section.
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Phenyl
N-{[Benzyl(cyanoethyl)carbamoyl]methyl}-N-methylcarbamate
(11b).
NaHCO3 (480 mg, 5.73 mmol) was added to a stirred and cooled (0 °C) solution of 11a11 (335
mg, 2.29 mmol) in dioxane (7 mL) and water (7 mL). Acid chloride 71 (651 mg, 2.86 mmol) in
dry THF (2.5 mL) was added dropwise over 15 min. The cooling bath was left in place, but not
recharged, and stirring was continued overnight. The THF and dioxane were evaporated and the
aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (2 x 12 cm), using
40% to 60% EtOAc in hexanes, gave 11b (689 mg, 89%) as a white foam: FTIR (CHCl3, cast)
3064, 3031, 2941, 1724, 1675, 1496, 1432, 1204 cmꢀ1; H NMR (DMSOꢀd6, 500 MHz) δ 2.93ꢀ
1
3.08 (two s, 3 H), 4.30ꢀ4.48 (m, 3.6 H), 4.59ꢀ4.70 (m, 2.4 H), 7.02ꢀ7.40 (m, 10 H); 13C NMR
(DMSOꢀd6, 125 MHz) δ 34.7 (t), 34.9 (t), 35.3 (t), 35.7 (t), 35.9 (q), 36.2 (q), 50.5 (t), 50.6 (t),
50.8 (t), 116.3 (s), 116.5 (d), 121.6 (d), 121.7 (d), 125.2 (d), 125.2 (d), 126.7 (d), 126.9 (d), 127.5
(d), 127.7 (d), 127.7 (d), 128.4 (d), 128.5 (d), 128.7 (d), 128.8 (d), 129.2 (d), 129.3 (d), 135.7 (d),
136.2 (d), 151.1 (s), 151.1 (s), 154.4 (s), 154.6 (s), 168.7 (s), 169.2 (s); exact mass (electrospray)
m/z calcd for C19H19KN3O3 (M + K) 376.1058, found, 376.1058.
1-Benzyl-4-methyl-3,6-dioxopiperazine-2-carbonitrile (11c).
NaH (60% w/w
dispersion in mineral oil, 23 mg, 0.565 mmol) was added in one portion to a stirred solution of
11b (93 mg, 0.276 mmol) in dry THF (12 mL). The reaction flask was lowered into a preheated
oil bath (70 °C) and the mixture was stirred for 15 min. The mixture was cooled (ice bath) and
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pH 7 buffer was added. The aqueous solution was extracted with EtOAc and the combined
organic extracts were dried (Na2SO4) and evaporated. Flash chromatography of the residue over
silica gel (2 x 8 cm), using 40% to 70% EtOAc in hexanes, gave 11c [28.8 mg, 43% or 54% after
correction for recovered 11b (19.3 mg)] as pale pink crystals: mp 147ꢀ149 °C, FTIR (CHCl3,
cast) 3018, 2932, 1689, 1452, 1266 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 3.04 (s, 3 H), 4.02 (d, J
= 18.0 Hz, 1 H), 4.08 (d, J = 14.5 Hz, 1 H), 4.28 (d, J = 18.0 Hz, 1 H), 4.67 (s, 1 H), 5.40 (d, J =
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14.5 Hz, 1 H), 7.28ꢀ7.39 (m, 5 H); C NMR (CDCl3, 125 MHz) δ 34.3 (q), 48.1 (t), 49.9 (d),
51.5 (t), 113.1 (s), 128.9 (d), 129.1 (d), 129.4 (d), 133.0 (s), 156.9 (s), 162.9 (s); exact mass
(electrospray) m/z calcd for C13H13N3NaO2 (M + Na) 266.0900, found, 266.0899. Crystals for
Xꢀray analysis were grown from EtOAcꢀhexanes, as described in the General Procedures section.
Methyl 2-{N-Methyl-2-[methyl(phenoxycarbonyl)amino]acetamido}acetate (12b).
NaHCO3 (700 mg, 8.37 mmol) was added to a stirred and cooled (0 °C) solution of methyl 2ꢀ
(methylamino)acetate hydrochloride12 (260 mg, 1.86 mmol) in dioxane (6 mL) and water (6 mL).
Acid chloride 71 (530 mg, 2.33 mmol) in dry THF (2 mL) was added dropwise over 15 min. The
cooling bath was left in place, but not recharged, and stirring was continued overnight. The THF
and dioxane were evaporated and the aqueous solution was extracted with CH2Cl2. The
combined organic extracts were dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (2 x 12 cm), using 50% to 100% EtOAc in hexanes, gave 12b (477 mg,
87%) as a white foam: FTIR (CH2Cl2, cast) 2953, 1726, 1667, 1480, 1397, 1206, 1118 cmꢀ1; 1H
NMR (DMSOꢀd6, 400 MHz) δ 2.84ꢀ2.87 (m, 2.6 H), 2.99ꢀ3.02 (m, 3.4 H), 3.61ꢀ3.69 (four s, 3
H), 4.09ꢀ4.13 (m, 1.6 H), 4.21ꢀ4.25 (m, 1.6 H), 4.35 (s, 0.8 H), 7.01ꢀ7.03 (m, 1.15 H), 7.09ꢀ7.11
(m, 0.85 H), 7.16ꢀ7.23 (m, 1 H), 7.33ꢀ7.38 (m, 2 H); 13C NMR (DMSOꢀd6, 125 MHz) δ 34.4 (q),
34.5 (q), 35.0 (q), 35.0 (q), 35.6 (q), 36.0 (q), 49.0 (t), 49.2 (t), 49.7 (t), 50.2 (t), 50.4 (t), 51.7 (q),
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52.0 (q), 121.6 (d), 121.8 (d), 125.0 (d), 125.1 (d), 129.1 (d), 129.2 (d), 151.2 (s), 154.5 (s),
154.7 (s), 168.1 (s), 168.4 (s), 168.6 (s), 169.5 (s), 169.7 (s); exact mass (electrospray) m/z calcd
for C14H19N2O5 (M + H) 295.1288, found, 295.1290.
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Methyl 1,4-Dimethyl-3,6-dioxopiperazine-2-carboxylate (12c).13 NaH (60% w/w
dispersion in mineral oil, 35 mg, 0.865 mmol) was added in one portion to a stirred solution of
12b (124 mg, 0.422 mmol) in dry THF (21 mL) containing tꢀBuOH (8.3 ꢀL, 0.0865 mmol). The
reaction flask was lowered into a preheated oil bath (70 °C) and the mixture was stirred for 24 h.
The mixture was cooled (ice bath) and glacial AcOH (50 ꢀL, 0.865 mmol) was added and the
solvent was evaporated. Flash chromatography of the residue over silica gel (2 x 8 cm), using
80% to 100% EtOAc in hexanes, gave 12c13 (47 mg, 55%) as a white solid: mp 121ꢀ123 °C;
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FTIR (CH2Cl2, cast) 2952, 1740, 1676, 1485, 1405, 1236 cmꢀ1; H NMR (CDCl3, 300 MHz) δ
2.94 (s, 3 H), 2.99 (s, 3 H), 3.83 (s, 3 H), 3.84 (d, J = 17.5 Hz, 1 H), 4.17 (d, J = 17.5 Hz, 1 H),
13
4.58 (s, 1 H); C NMR (DMSOꢀd6, 125 MHz) δ 33.0 (q), 34.0 (q), 51.8 (t), 53.7 (q), 66.0 (d),
160.2 (s), 164.7 (s), 167.0 (s); exact mass (electrospray) m/z calcd for C8H12N2NaO4 (M + Na)
223.0689, found, 223.0685. Crystals for Xꢀray analysis were grown from EtOAcꢀhexanes, as
described in the General Procedures section.
3-Benzoyl-1-benzyl-4-[(4-methoxyphenyl)methyl]-6-methylpiperazine-2,5-dione (9i).
NaH (60% w/w dispersion in mineral oil, 30 mg, 0.745 mmol) was added in one portion to a
stirred solution of 9g (195 mg, 0.363 mmol) in dry THF (18 mL). The reaction flask was
lowered into a preheated oil bath (70 °C) and the mixture was stirred for 2.5 h. The mixture was
cooled (ice bath) and pH 7 buffer was added. The aqueous solution was extracted with EtOAc
and the combined organic extracts were dried (Na2SO4) and evaporated. Flash chromatography
of the residue over silica gel (2 x 8 cm), using 30% to 60% EtOAc in hexanes, gave 9i ( 69 mg,
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74%) as a white foam: [α]D20 ꢀ72.02 (c 1.10, CH2Cl2); FTIR (neat, film) 3064, 3031, 2997, 2939,
2837, 1692, 1667, 1513, 1450, 1305, 1247, 1172 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 1.58 (d, J
= 7.0 Hz, 3 H), 3.74 (m, 3 H), 3.87 (d, J = 15.0 Hz, 1 H), 3.91 (d, J = 15.0 Hz, 1 H), 4.06 (q, J =
7.0 Hz, 1 H), 5.03 (d, J = 15.0 Hz, 1 H), 5.13 (d, J = 15.0 Hz, 1 H), 5.65 (s, 1 H), 6.72ꢀ6.75 (m,
part of AA'BB' spin system, 2 H), 7.00ꢀ7.03 (m, part of AA'BB' spin system, 2 H), 7.18ꢀ7.33 (m,
5 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 8.04ꢀ8.06 (m, 2 H); 13C NMR (DMSOꢀ
d6, 125 MHz) δ 18.5 (q), 47.3 (t), 48.2 (t), 55.3 (q), 55.7 (d), 64.3 (d), 114.2 (d), 114.3 (d), 126.3
(s), 128.1 (d), 128.1 (d), 128.6 (d), 128.7 (d), 128.8 (d), 128.9 (d), 129.9 (d), 130.5 (d), 130.6 (d),
134.3 (s), 134.4 (d), 135.3 (s), 159.6 (s), 160.6 (s), 168.6 (s), 192.6 (s);exact mass (electrospray)
m/z calcd for C27H27N2O4 (M + H) 443.1965, found, 443.1964.
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Phenyl N-({Benzyl([2-(4-methoxyphenyl)-2-oxoethyl]carbamoyl}methyl)-N-methyl-
carbamate (13c). DessꢀMartin periodinane (397 mg, 0.938 mmol) was added to a stirred
solution of 13b (280 mg, 0.626 mmol), in dry CH2Cl2 (13 mL), and stirring was continued for 5
h. Et2O was added and the solution was stirred until cloudy. Aqueous NaOH (2 M) was added
and the mixture was stirred until the phases became clear. The aqueous phase was extracted with
Et2O and the combined organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (2 x 8 cm), using 40% to 60% EtOAc in hexanes,
gave 13c [183 mg, 66% or 92% after correction for recovered 13b (79 mg)] as a white foam:
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FTIR (CHCl3, cast) 3008, 2935, 2838, 1726, 1663, 1514, 1397, 1248, 1205 cmꢀ1; H NMR
(DMSOꢀd6, 400 MHz) δ 2.88ꢀ3.03 (four s, 3 H), 3.82ꢀ3.83 (m, 3 H), 4.07ꢀ4.39 (four s, 2 H),
4.53ꢀ4.65 (two m, 2 H), 4.76ꢀ4.95 (m, 2 H), 7.01ꢀ7.07 (m, 3.5 H), 7.18ꢀ7.39 (m, 9 H), 7.93ꢀ7.97
(m, 1.5 H); 13C NMR (DMSOꢀd6, 125 MHz) δ 36.0 (q), 36.2 (q), 36.6 (q), 36.7 (q), 50.7 (t), 50.8
(t), 51.0 (t), 51.1 (t), 51.2 (t), 53.2 (t), 53.4 (t), 56.0 (q), 56.1 (q), 114.4 (d), 122.1 (d), 122.2 (d),
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125.5 (d), 125.6 (d), 125.7 (d), 127.4ꢀ130.9 (numerous d and one s), 137.4 (s), 137.4 (s), 138.0
(s), 138.0 (s), 151.7 (s), 151.7 (s), 151.7 (s), 151.8 (s), 155.0 (s), 155.0 (s), 155.1 (s), 155.3 (s),
163.8 (s), 164.1 (s), 168.7 (s), 169.1 (s), 169.1 (s), 169.6 (s), 192.8 (s), 193.4 (s), 193.4 (s); exact
mass (electrospray) m/z calcd for C26H26N2NaO5 (M + Na) 469.1734, found, 469.1727.
4-Benzyl-3-[(4-Methoxyphenyl)carbonyl]-1-methylpiperazine-2,5-dione (13d). NaH
(60% w/w dispersion in mineral oil, 22 mg, 0.545 mmol) was added in one portion to a stirred
solution of 13c (118 mg, 0.266 mmol) in dry THF (13.3 mL). The reaction flask was lowered
into a preheated oil bath (70 °C) and the mixture was stirred for 30 min. The mixture was cooled
(ice bath) and pH 7 buffer was added. The aqueous solution was extracted with EtOAc and the
combined organic extracts were dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (2 x 10 cm), using 40% to 50% EtOAc in hexanes, gave 13d [50 mg, 54%
or 70% after correction for recovered 13c (27 mg)] as pale yellow crystals: mp 139ꢀ140 °C,
FTIR (CHCl3, cast) 3333, 3065, 3010, 2936, 2842, 1672, 1598, 1453, 1251, 1170 cmꢀ1; 1H NMR
(CDCl3, 300 MHz) δ 2.91 (s, 3 H), 3.83ꢀ3.93 (m, 5 H), 4.34 (d, J = 17.1 Hz, 1 H), 5.14 (d, J =
14.7 Hz, 1 H), 5.46 (s, 1 H), 6.90ꢀ6.93 (m, part of AA'BB' spin system, 2 H), 7.13ꢀ7.16 (m, 2 H),
7.23ꢀ7.26 (m, 3 H), 8.00ꢀ8.03 (m, part of AA'BB' spin system, 2 H); 13C NMR (CDCl3, 125
MHz) δ 33.9 (q), 48.6 (t), 52.4 (t), 64.7 (q), 114.0 (d), 127.0 (d), 128.2 (s), 128.8 (d), 129.0 (d),
132.4 (d), 134.7 (s), 160.9 (s), 164.8 (s), 166.1 (s), 190.4(s); exact mass (electrospray) m/z calcd
for C20H21N2O4 (M + H) 353.1496, found, 353.1492.
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Phenyl
N-({Benzyl[(diethoxyphosphoryl)methyl]carbamoyl}methyl)-N-methyl-
carbamate (14b). NaHCO3 (267 mg, 3.18 mmol) was added to a stirred and cooled (0 °C)
solution of 14a6 (328 mg, 1.27 mmol) in dioxane (4.5 mL) and water (4.5 mL). Acid chloride 71
(363 mg, 1.59 mmol) in dry THF (2 mL) was added dropwise over 15 min. The cooling bath
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was left in place, but not recharged, and stirring was continued overnight. The THF and dioxane
were evaporated and the aqueous solution was extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica
gel (2 x 12 cm), using 70% to 100% EtOAc in hexanes, gave 14b (448 mg, 84%) as a colorless
oil: FTIR (CH2Cl2, cast) 3064, 3031, 2983, 2933, 1730, 1668, 1453, 1395, 1242, 1206, 1050,
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1025 cmꢀ1; H NMR (DMSOꢀd6, 400 MHz) δ 1.15ꢀ1.25 (m, 6 H), 2.89ꢀ3.05 (four s, 3 H), 3.72ꢀ
3.81 (m, 2 H), 3.98ꢀ4.09 (m, 4 H), 4.25ꢀ4.54 (four s, 2 H), 4.67ꢀ4.73 (m, 2 H), 7.00ꢀ7.04 (m, 1.2
13
H), 7.08ꢀ7.13 (m, 0.8 H), 7.18ꢀ7.40 (m, 8 H); C NMR (DMSOꢀd6, 100 MHz) δ 16.1 (q), 16.1
(q), 16.2 (q), 35.7 (q), 35.7 (q), 36.0 (q), 36.1 (q), 41.0 (t), 42.5 (t), 49.2 (t), 49.5 (t), 49.9 (t), 50.4
(t), 50.5 (t), 50.6 (t), 50.7 (t), 61.7 (t), 61.8 (t), 62.0 (t), 62.1 (t), 121.5 (d), 121.6 (d), 125.0 (d),
125.1 (d), 126.5 (d), 126.7 (d), 127.2 (d), 127.5 (d), 128.4 (d), 128.7 (d), 128.8 (d), 129.1 (d),
129.2 (d), 136.0 (s), 136.6 (s), 151.1 (s), 151.2 (s), 151.3 (s), 154.5 (s), 154.6 (s), 154.8 (s), 167.9
(s), 168.0 (s), 168.3 (s), 168.5 (s); exact mass (electrospray) m/z calcd for C22H29N2NaO6P (M +
Na) 471.1655, found, 471.1648.
Diethyl (1-Benzyl-4-methyl-3,6-dioxopiperazin-2-yl)phosphonate (14c). NaH (60%
w/w dispersion in mineral oil, 67 mg, 1.67 mmol) was added in one portion to a stirred solution
of 14b (340 mg, 0.812 mmol) and tꢀBuOH (16 ꢀL, 0.166 mmol) in dry THF (40 mL). The
reaction flask was lowered into a preheated oil bath (70 °C) and the mixture was stirred for 4.5 h.
The mixture was cooled (ice bath) and pH 7 buffer was added. The aqueous solution was
extracted with EtOAc and the combined organic extracts were dried (Na2SO4) and evaporated.
Flash chromatography of the residue over silica gel (2 x 10 cm), using 0% to 6% MeOH in
EtOAc, gave 14c (126 mg, 44%) as a colorless oil: FTIR (CDCl3, cast) 2982, 2934, 1678, 1452,
1
1254, 1046, 1017 cmꢀ1; H NMR (CDCl3, 500 MHz) (the spectrum showed the presence of a
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byproduct, see text) δ 1.28ꢀ1.41 (m, 6 H), 2.99 (m, 3 H), 3.84 (dd, J = 1.5, 18.0 Hz, 1 H), 4.07 (d,
J = 12 Hz, 1 H), 4.14ꢀ4.27 (m, 5 H), 4.43 (dd, J = 5.0, 18.0 Hz, 1 H), 5.58 (d, J = 14.7 Hz, 1 H),
7.21ꢀ7.36 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 16.4 (q), 16.5 (q), 16.5 (q), 16.5 (q) (the last
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four signals represent coupling of two diastereotopic CH3 groups to P), 34.1 (q), 48.1 (t), 52.4
31
(t), 57.3 (d), 58.4 (d) (the last two signals represent coupling of the CH signal to P), 63.6 (t),
63.7 (t), 64.1 (t), 64.2 (t) (the last four signals represent coupling of two diastereotopic CH2
groups to 31P), 128.3 (d), 128.5 (d), 129.1 (d), 134.8 (s), 161.3 (s), 164.6 (s); exact mass
(electrospray) m/z calcd for C16H23N2NaO5P (M + Na) 377.1237, found, 377.1233.
(3E)-4-Benzyl-3-[(4-methoxyphenyl)methylidene]-1-methylpiperazine-2,5-dione
(14d) and (3E)-1-Benzyl-3-[(4-methoxyphenyl)methylidene]-4-methylpiperazine-2,5-dione
(14d'). A solution of 14c (93 mg, 0.262 mmol) and pꢀanisaldehyde (35 ꢁL, 0.289 mmol) in dry
THF (9.6 mL) was added to a stirred and cooled (0 °C) mixture of NaH (60% w/w dispersion in
mineral oil, 15 mg, 0.385 mmol) in dry THF (5.8 mL). The mixture was stirred for 2 h at 0 °C
and then at room temperature for 1 h. Saturated aqueous NH4Cl (1.7 mL) and water (1.7 mL)
were added. The aqueous solution was extracted with EtOAc and the combined organic extracts
were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel (2 x 10
cm), using 30% to 80% EtOAc in hexanes, gave 14d (44 mg, 50%) as a colorless oil and 14d'
(13 mg, 15 %) as a yellow oil. Compound 14d had: FTIR (CDCl3, cast) 3317, 3063, 3007,
2933, 2837, 1679, 1606, 1512, 1398, 1251 cmꢀ1; H NMR (CDCl3, 500 MHz) δ 3.05 (s, 3 H),
1
3.77 (s, 3 H), 4.19 (s, 2 H), 5.06 (s, 2 H), 6.49 (s, 1 H), 6.79ꢀ6.80 (m, 2 H), 7.26ꢀ7.29 (m, 5 H),
7.32ꢀ7.36 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 33.9 (q), 48.1 (t), 52.2 (t), 55.2 (q), 113.2 (d),
124.8 (d), 126.3 (s), 126.8 (d), 127.5 (d), 128.5 (s), 128.9 (d), 131.2 (d), 135.9 (s), 159.4 (s),
160.0 (s), 163.9 (s); exact mass (electrospray) m/z calcd for C20H20N2NaO3 (M + Na) 359.1366,
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found, 359.1366. Compound 14d' had: FTIR (CHCl3, cast) 3335, 3007, 2933, 2837, 1680,
1607, 1512, 1252, 1178 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 3.29 (s, 3 H), 3.83 (s, 3 H), 3.97 (s,
2 H), 4.65 (s, 2 H), 6.49 (s, 1 H), 6.88ꢀ6.90 (m, 2 H), 7.26ꢀ7.35 (m, 5 H), 7.46ꢀ7.48 (m, 2 H); 13C
NMR (CDCl3, 125 MHz) δ 31.0 (q), 49.4 (t), 49.5 (t), 55.3 (q), 113.4 (d), 123.7 (d), 126.4 (s),
128.1 (d), 128.4 (d), 129.0 (d), 129.6 (s), 131.4 (d), 135.4 (s), 159.5 (s), 159.8 (s), 163.9 (s);
exact mass (electrospray) m/z calcd for C20H21N2O3 (M + H) 337.1547, found, 337.1546.
3-Benzyl-1-methylimidazolidine-2,4-dione (6h).8 O2 was bubbled for 4 min into a
stirred solution of 6d (202 mg, 0.485 mmol) in dry THF (24 mL). NaH (60% w/w dispersion in
mineral oil, 40 mg, 0.994 mmol) was added in one portion and the reaction flask was lowered
into a preheated oil bath (70 °C). The mixture was stirred for 2.5 h under O2 (balloon). The
mixture was cooled (ice bath) and pH 7 buffer was added. The aqueous solution was extracted
with EtOAc and the combined organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 x 10 cm), using 30% to 60% EtOAc in hexanes,
gave 6h (55 mg, 56%) as a white foam: FTIR (CHCl3, cast) 3033, 2918, 1773, 1712, 1485,
1451, 1411 cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.99 (s, 3 H), 3.86 (s, 2 H), 4.65 (s, 2 H), 7.29ꢀ
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7.43 (m, 5 H); C NMR (CDCl3, 125 MHz) δ 29.7 (q), 42.6 (t), 51.8 (t), 128.0 (d), 128.7 (d),
128.8 (d), 136.1 (s), 156.6 (s), 169.5 (s); exact mass (electrospray) m/z calcd for C11H12N2O2 (M
+ H) 205.0972, found, 205.0969.
ACKNOWLEDGMENTS
We thank NSERC for financial support. C.L.A. holds a Queen Elizabeth II Graduate
Scholarship.
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Supporting Information Available: Xꢀray data (cif and ORTEP diagrams) for
compounds 10d, 11c and 12c, experimental procedures, and copies of NMR spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
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