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Synlett 2021; 32(19): 1969-1973
DOI: 10.1055/s-0040-1720888
letter

Pyrroloimidazolediones Derived from Aminomalonates and Benzaldehydes

Lewis O’Shaughnessy
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Charles Hutchinson
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Adam Waldron
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Kirsten E. Christensen
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Mark G. Moloney∗
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
b   Oxford Suzhou Centre for Advanced Research, Building A, 388 Ruo Shui Road, Suzhou Industrial Park, Jiangsu, 215123, P. R. of China
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Abstract

Bicyclic lactams can be prepared from diethyl aminomalonate and substituted benzaldehydes by formation of a dimerised imidazolidine cycloadduct followed by a Dieckmann ring closure. The resulting N,N-heterocycles are metal-chelating but show no antibacterial activity.


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Key words

amino acids - heterocycles - cyclization - lactams - ­Dieckmann reaction

We have shown that l-serine, l-cysteine, l-allothreonine, and l-threonine methyl esters 1a–d can be converted into the corresponding O,N- or S,N-hemiaminal ethers or thio ethers 2a–d by condensation with aldehydes, and that these, in turn, can be converted into the tetramates 3a–d by a highly chemo- and enantioselective Dieckmann cyclisation (Scheme [1]).[1] [2] Whereas oxazolidines and thiazolidines are stable,[3] the possibility of forming the analogous tetramate with an embedded imidazolidine was less certain, especially given the greater basicity of the nitrogen atoms and consequent potential for acid-mediated decomposition. The successful synthesis of tetramates incorporating such an N,N-heterocycle system is reported here. Application of the analogous process for the preparation of 2 (X = NR) would require β-aminoalanine, but since this is not readily available, an alternative strategy was required. Fortuitously, while investigating some earlier reported work,[4] we found that the reaction of diethyl aminomalonate (4) and benzaldehyde did not give diethyl (benzylideneamino)malonate (5, Ar = Ph) as expected but instead gave imidazolidine 6a,[5] whose cis-diaryl arrangement was confirmed by NOE analysis and single-crystal X-ray analysis (see Figure [1] below).[6] Such imidazolidines had previously been reported to form under similar reaction conditions as a result of rapid dipolar cycloaddition reactions of the intermediate aryl imine 5 (Scheme [1]).[7] [8]

Zoom Image
Scheme 1

Because 6a was effectively a derivative of the required β-aminoalanine, we used p-tolualdehyde, p-anisaldehyde, and p-nitrobenzaldehyde in the same procedure, all of which resulted in recovery of the desired imidazolidine products 6b–d, respectively, in similar yields of up to 79% (Table [1]). Compounds 6b and 6d had been previously reported, but compound 6c was novel.[8] [9] Preservation of similar proton chemical-shift values across the series of imidazolidine products suggested that these all possessed the same cis-orientation of the aryl groups, and this was confirmed by NOESY analysis of later tetramate products.

Table 1 Imidazolidine Compounds 6 and 7

δH (ppm)

δC (ppm)

Imidazolidine

Yield (%)

H2

H1′

H5

HN

C2

C1′

C5

6a

79

5.28

4.07

5.63

3.65

78.36

62.21

67.64

6b

68

5.21

4.03

5.51

3.51

77.67

61.95

67.07

6c

53

5.23

4.05

5.55

3.55

78.08

62.09

67.41

6d

63

5.41

3.99

5.72

3.55

77.74

62.09

67.33

7

50

5.45

4.03

5.49

3.51

77.23

61.39

68.09

Attempts were made to apply the reaction to two aldehydes of different reactivity, with the intention of obtaining differently substituted systems (Scheme [2]); for example, reaction of diethyl aminomalonate (1.0 equiv) with benzaldehyde (0.5 equiv) or p-anisaldehyde (0.5 equiv) did not give the desired mixed imidazolidine products, but instead gave only the imidazolidine 6b. A similar reaction using isobutyraldehyde (0.5 equiv) gave the same outcome, which is consistent with the absence of alkyl aldehyde-derived ­imidazolidines prepared by this methodology in reported work.[7] [8] However, reactions of p-anisaldehyde (0.5 equiv) and p-nitrobenzaldehyde (0.5 equiv) with diethyl amino­malonate (1.0 equiv) did give the desired imidazolidine 7 as the major product (50% yield), although this was accompanied by the imidazolidine 6b. Clean NMR spectra showing sharp singlets for key characteristic peaks, indicated that a single structural isomer was formed, assigned as indicated in Table [1]. The regiochemistry and cis-diaryl relationship were later confirmed by analysis of downstream products (see below).

Zoom Image
Scheme 2

When the imidazolidine 6a was refluxed in CH2Cl2 with excess ethyl 3-chloro-3-oxopropanoate, pyridine and 0.1 equivalents of DMAP,[2] the desired acylated product 8a could be isolated in high yield (Table [2]); this product was characterised in the 1H NMR spectrum by a pair of doublets at δ = 2.56 and 2.92 ppm for the new malonyl CH2 group.[5] Application of these reaction conditions to p-methoxy and p-methylimidazolidines 6b and 6c, respectively, was also successful, resulting in the isolable products 8b and 8c; these both displayed a characteristic pair of doublets in the 1H NMR at δ = 2.57 and 2.93 ppm and at δ = 2.56 and 2.93 ppm respectively. However, attempts to acylate the p-nitro compound 6d and the mixed p-nitro p-methoxy imidazolidine 7 did not give clean products 8d and 9; although low-resolution mass spectrometry showed the expected molecular mass ions for the acylated materials, the NMR peaks were low and broadened. These compounds were instead used in crude form.

Table 2 Acylated Intermediates 8 and 9

δH (ppm)

δC (ppm)

Acylated intermediate

Yield (%)

H2

H1′

H5

C2

C3′

C5

8a

86

6.25

4.06

5.04

78.06

61.82

70.10

8b

70

6.24

4.06

4.89

77.33

61.37

69.67

8c

55

6.23

4.05

4.94

77.43

60.91

70.07

8d

crude

–

–

–

–

–

–

9

crude

–

–

–

–

–

–
Zoom Image
Figure 1 ORTEP representation of 6a and NOE interactions for 6a, 10 and 11

Cyclisation of these derivatives was attempted by using standard procedures for Dieckmann cyclisation,[2] [10] which successfully gave the desired N,N-tetramate products 10 (Scheme [2]), albeit in low yields. This outcome appeared to result from the difficulty of extraction of the product from the aqueous phase during the workup, rather than poor conversion of the starting material, because TLC analysis showed full consumption of 8a over the course of the reaction. It was also noted that during column chromatography on silica, the desired product was very immobile and required a highly polar mobile phase of 10% methanol in ethyl acetate for elution. Moreover, following column chromatography, it was observed that 1H NMR peaks were broad until the product was washed with 2 M aq HCl, suggesting that the α,α,α-tricarbonyl substructure was chelating metal ions.[11] This has previously been observed with other tetramic acid derivatives, which have proven to be nonselective but efficient chelators of a variety of metal ions.[12] [13] Also worthy of note was the fact that although most of the characteristic protons appeared as sharp clear singlets, no 1H NMR signal was observed for the α,α,α-tricarbonyl proton H-7, and the absence of an OH signal implied a high proportion of enolisation.[14] Moreover, it is likely that these products exist in a zwitterionic form of type A (Scheme [1]), which would be highly polar and harder to extract from the aqueous phase, as observed during workup.[15] The other acylated intermediates 8b–d and 9 all showed the same immobility on silica gel, the same peak broadening in 1H NMR spectra before washing with HCl, and the same absence of the H-7 peak in their NMR spectra. Whereas most of the yields were good, that of the p-nitro p-methoxy tetramate product 11 was poor (8%), more probably as a result of poor recovery rather than of poor conversion; once again, TLC showed that all the starting material was consumed over the course of the reaction. NOESY analysis was used to confirm the cis-orientation of the aryl groups for all the products 10b–d, and, for compound 11, also allowed assignment of the relative positions of the p-methoxy and p-nitro aryl groups. NOE interactions between H-2, H-3′, and H-4 were seen for all the tetramate products and, for compound 11, H-4 only showed interactions with aromatic protons from the p-methoxybenzyl group and H-2 showed interactions only with aromatic protons on the p-nitrobenzyl substituent (Figure [1]). The relative configuration of 10a was tentatively assigned as all- cis because, by calculation, the indicated structure was more stable than the alternative epimer; this assignment could not be substantiated by NOE or X-ray crystal structure analysis. The chemoselectivity and stereoselectivity of this outcome most likely arises as a result of thermodynamic control of the reaction, leading to the most stable outcome, a phenomenon that has been previously reported.[16]

Over time, it was found that tetramates 10c and 10d in solution in CDCl3 decayed by complete decarboxylation at the C-7 position, resulting in the products 10e and 10f (Table [3]). When a solution of p-nitro p-methoxy derivative 11 in CDCl3 was heated to approximately 50 °C for 24 hours, complete decarboxylation to 12 occurred; monitoring by NMR spectroscopy showed complete conversion after about 12 hours.

Table 3 Tetramate-Containing Products 10–12

δH (ppm)

δC (ppm)

Tetramate

Yield (%)

H1

H1′

H3

C1

C1′

C4

10a

 35

6.37

4.34

4.95

74.93

63.92

69.50

10b

 41

6.24

4.28

4.83

74.78

62.22

68.39

10c

 62

6.26

4.31

4.88

74.71

63.57

69.82

10d

 26

6.38

4.30

5.07

73.33

63.29

69.30

10f

100

6.58

4.42

5.16

75.81

65.68

68.30

11

  8

6.38

4.32

4.88

74.78

63.69

68.39

12

100

6.60

4.39

4.95

75.56

65.50

69.94

Of interest was further investigation of the metal-chelating character of tetramates 10 and 12, as this is a characteristic that is of some chemical and biological interest.[12] [17] As noted above, after purification by silica-gel column chromatography, the final tetramate products displayed broadened peaks in their 1H NMR spectra until they were washed with 2 M HCl. This was once again thought to be caused by the formation of chelates with metal ions present in the silica gel. Bicyclic N,O-tetramic acid derivatives that also possess a similar tricarbonyl motif have previously been reported to display nonselective chelation and to bind metal ions including Fe(III), Al(III), Cu(II), Mg(II), Ca(II), and Zn(II).[12] [13] To test whether the N,N-tetramate derivatives behaved similarly, CH2Cl2 solutions of both 10a and 10b were treated with 1 M aqueous MgCl2, Fe(SO4), or Ca(NO3)2 solution and the mixtures were stirred for one hour. The organic phases were separated, the solvent was evaporated, and NMR spectra were recorded of the residues. The 1H NMR spectra of the Ca2+ and Mg2+ samples [Supporting Information (SI), Figure S1] showed a noticeable broadening, similar to that observed during the original preparation of the tetramate products before they were washed with 2 M HCl. This suggests that these compounds are readily capable of forming chelates with both Ca2+ and Mg2+ ions, and especially during column chromatography on silica, for which metal impurities have been reported.[18] The Fe2+ experiment gave a deep-red coloured solution and its NMR spectrum showed paramagnetic broadening (SI, Figure S1).[19]

The five different N,N-tetramates 10a, 11, 10b, 10c, and 10d showed no activity against Staphylococcus aureus or Escherichia coli, in keeping with other unsubstituted tetramates, as reported earlier.[20]

In conclusion, we have shown that the efficient and rapid preparation of bicyclic N,N-tetramates from diethyl aminomalonate and a range of aromatic aldehydes is possible in three steps and in reasonable yields. The products have been shown to reversibly form chelates with both Ca2+ and Mg2+ ions present as impurities in the silica gel used for column chromatography.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1720888.
  • Supporting Information

  • References and Notes

  • 2 Andrews MD, Brewster AG, Crapnell KM, Ibbett AJ, Jones T, Moloney MG, Prout K, Watkin D. J. Chem. Soc., Perkin Trans. 1 1998; 223
  • 5 Diethyl (±)-(2R ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-2,5-diphenylimidazolidine-4,4-dicarboxylate (6a); Typical Procedure Diethyl aminomalonate (1000 mg, 5.71 mmol), benzaldehyde (606 mg, 5.71 mmol, 1.0 equiv), and MgSO4 were added to dry CH2Cl2 (20 mL), and the mixture was refluxed for 16 h. The mixture was then filtered and the solvent was evaporated to yield a crude product that was purified by column chromatography [silica gel, EtOAc–PE (10 to 40%)] to give colourless crystals; yield: 1192.4 mg (79%); mp 109–110 °C; Rf = 0.733 (30% EtOAc). IR: 1741, 1725, 1169 cm–1. 1H NMR (200 MHz, CDCl3, TMS): δ = 0.78 (t, J = 7.1, 3 H, CH3CH2), 1.05 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.12 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2), 3.30 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 3.65 (d, J = 10.0 Hz, 1 H, NH), 3.79 (m, 5 H, CH2 CH3), 4.07 [s, 1 H, CH(N)(CO2Et)2], 4.27 (dq, J = 10.7, 7.1 Hz, 1 H, CH2 CH3), 4.45 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 5.28 [d, J = 10.0 Hz, 1 H, (N)CH(N)(Ph)], 5.63 [s, 1 H, CHPh(N)(C)], 7.44 (m, 10 H, aromatic). 13C (400 MHz, CDCl3, TMS): δ = 13.33, 13.73, 13.85, 13.99 (CH3), 61.11, 61.11, 62.11, 62.18 (CH2CH3), 62.21 [CH(N)(CO2Et)2], 67.64 [CH(N)(Ph)(C)], 77.11 [C(N)(C)(CO2Et)2], 78.36 [CH(N)2(Ph)], 127.85, 127.98, 128.51, 128.59, 129.27 (H–C Ar), 137.99, 138.88 (C–C Ar), 166.59, 166.77, 168.32, 169.59 (C=O). HRMS (ESI+): m/z [M + H]+ calcd for C28H35N2O8; 527.23829; found: 527.23847. Diethyl (±)-(2S ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-3-(3-ethoxy-3-oxopropanoyl)-2,5-diphenylimidazolidine-4,4-dicarboxylate (8a); Typical Procedure Diester 6a (285.0 mg, 0.542 mmol) was dissolved in CH2Cl2 (20 mL) together with pyridine (85.4 mg, 1.08 mmol, 2.0 equiv) and DMAP (6.6 mg, 0.054 mmol, 0.1 equiv). The mixture was stirred and cooled to 0 °C, and a solution of ethyl 3-chloro-3-oxopropanoate (163.1 mg, 1.084 mmol, 2.0 equiv) in CH2Cl2 (5 mL) was added dropwise. The mixture was stirred for a further 15 minutes at 0 °C then refluxed for 16 h. The resulting mixture was diluted with CH2Cl2 (30 mL), washed successively with sat. aq NH4Cl, 10% aq NaHCO3, and brine. The organic layers were dried (MgSO4), combined, and evaporated under vacuum to yield a crude product that was purified by column chromatography (silica gel, 20% EtOAc–PE) to give a pale oil; yield: 302 mg (87%). Rf = 0.269 (50% EtOAc–PE). IR: 2981.33, 1736.66, 1668.24, 1235.45, 155.15, 1030.11, 700.24 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.92 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.05–1.12 (2 × t, J = 7.2 Hz, 6 H, CH3 CH2), 1.20 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.38 (t, J = 7.1 Hz, 3 H, CH3 CH2), 2.56 [d, J = 15.7 Hz, 1 H, C(O)CH2 C(O)], 2.92 [d, J = 15.6 Hz, 1 H, C(O)CH2C(O)], 3.41 (m, 1 H, CH3 CH2 ), 3.65 (dq, J = 10.8, 7.2 Hz, 1 H, CH3 CH2 ), 3.76 (dq, J = 13.5, 6.8 Hz, 2 H, CH3 CH2 ), 3.87 (dq, J = 13.5, 6.8 Hz, 2 H, CH3CH2), 4.05 (q, J = 6.9 Hz, 2 H, CH3 CH2 malonate), 4.06 [s, 1 H, CH(CO2Et)2(N)], 4.37, (m, 2 H, CH3 CH2 ), 5.04 [s, 1 H, CH(Ph)(N)(C)], 6.25 [s, 1 H, CH(Ph)(N)2], 7.31–7.86 (m, 10 H, CHAr). 13C (400 MHz, CDCl3, TMS): δ = 13.46, 13.72, 13.80, 14.03 (CH3CH2), 42.93 [CH2(CO2Et)(CON)], 61.17, 61.45, 61.54, 62.37 (CH3 CH2), 61.82 [CH(CO2Et)2(N)], 70.10 [CH(Ph)(N)(C)], 78.06 [CH(Ph)(N)2], 128.21 (C–CAr), 128.66, 128.87, 130.28 (H–CAr), 165.63, 165.73, 166.22, 166.36 [C(O)OEt]. HRMS (ESI+): m/z [M + H]+ calcd for C33H41N2O11: 641.27049; found: 641.26913. Diethyl (±)-(1S *,3S *)-2-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-5,7-dioxo-1,3-diphenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-6,7a(5H)-dicarboxylate (10a); Typical Procedure Diester 8a (1195 mg, 1.86 mmol) was dissolved in dry THF (50 mL) with KOt-Bu (220.0 mg, 1.05 equiv, 1.96 mmol), and the mixture was refluxed for 16 h. The mixture was then concentrated and the residue was redissolved in Et2O (50 mL) and extracted with H2O (2 × 50 mL). The aqueous phase was acidified with 2 M aq HCl to pH 2 and extracted with EtOAc (3 × 100 mL). The organic phases were combined, dried (MgSO4), and concentrated to yield a crude product that was then purified by column chromatography (silica gel, 50% EtOAc–PE to 10% MeOH–EtOAc). The resulting product was washed twice with 2 M aq HCl and once with sat. aq NH4Cl to yield the pure product as colourless crystals; yield: 388.9 mg (35%); mp 93 °C; 388.9; Rf  = 0.706 (10% MeOH–EtOAc). IR: 2984, 2361, 1733, 1243, 1186, 1029 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.67 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 0.97 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 1.13 (t, J = 7.2 Hz, 3 H, CH2 CH3 ), 1.43 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 3.55 (3 H, m, 3 H, CH2 CH3), 3.67 (dd, J = 10.8, 7.1 Hz,1 H, CH2 CH3), 3.73 (m, 1 H, CH2 CH3), 3.97 (m, 2 H, CH2 CH3), 4.34 [s, 1 H, CH(CO2Et)2(N)], 4.42 (q, J = 6.7 Hz, 2 H, CH2 CH3), 4.95 [s, 1 H, CHPh(N)(C)], 6.37 [s, 1 H, CHPh(N)2], 7.17–7.77 (m, 10 H, HCAr). 13C (400 MHz, CDCl3, TMS): δ = 113.16, 13.46, 13.83, 14.20 (CH3CH2), 61.65, 61.81, 61.96, 62.06 (CH3 CH2), 63.92 [CH(CO2Et)2(N)], 69.50 [CHPh(N)(C)], 74.93 [CHPh(N)2], 127.27, 127.49, 127.83, 127.96, 128.45, 128.57, 128.92 (CAR), 134.55 [C(CO2Et)(N)(CO)(C)], 165.79 (C=O). HRMS (ESI–): m/z [M – H]– calcd for C31H33N2O10: 593.21407; found: 593.21393.
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Corresponding Author

The Department of Chemistry, Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA
UK   

Publication History

Received: 09 August 2021

Accepted after revision: 03 September 2021

Article published online:
28 September 2021

© 2021. Thieme. All rights reserved

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  • References and Notes

  • 2 Andrews MD, Brewster AG, Crapnell KM, Ibbett AJ, Jones T, Moloney MG, Prout K, Watkin D. J. Chem. Soc., Perkin Trans. 1 1998; 223
  • 5 Diethyl (±)-(2R ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-2,5-diphenylimidazolidine-4,4-dicarboxylate (6a); Typical Procedure Diethyl aminomalonate (1000 mg, 5.71 mmol), benzaldehyde (606 mg, 5.71 mmol, 1.0 equiv), and MgSO4 were added to dry CH2Cl2 (20 mL), and the mixture was refluxed for 16 h. The mixture was then filtered and the solvent was evaporated to yield a crude product that was purified by column chromatography [silica gel, EtOAc–PE (10 to 40%)] to give colourless crystals; yield: 1192.4 mg (79%); mp 109–110 °C; Rf = 0.733 (30% EtOAc). IR: 1741, 1725, 1169 cm–1. 1H NMR (200 MHz, CDCl3, TMS): δ = 0.78 (t, J = 7.1, 3 H, CH3CH2), 1.05 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.12 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2), 3.30 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 3.65 (d, J = 10.0 Hz, 1 H, NH), 3.79 (m, 5 H, CH2 CH3), 4.07 [s, 1 H, CH(N)(CO2Et)2], 4.27 (dq, J = 10.7, 7.1 Hz, 1 H, CH2 CH3), 4.45 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 5.28 [d, J = 10.0 Hz, 1 H, (N)CH(N)(Ph)], 5.63 [s, 1 H, CHPh(N)(C)], 7.44 (m, 10 H, aromatic). 13C (400 MHz, CDCl3, TMS): δ = 13.33, 13.73, 13.85, 13.99 (CH3), 61.11, 61.11, 62.11, 62.18 (CH2CH3), 62.21 [CH(N)(CO2Et)2], 67.64 [CH(N)(Ph)(C)], 77.11 [C(N)(C)(CO2Et)2], 78.36 [CH(N)2(Ph)], 127.85, 127.98, 128.51, 128.59, 129.27 (H–C Ar), 137.99, 138.88 (C–C Ar), 166.59, 166.77, 168.32, 169.59 (C=O). HRMS (ESI+): m/z [M + H]+ calcd for C28H35N2O8; 527.23829; found: 527.23847. Diethyl (±)-(2S ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-3-(3-ethoxy-3-oxopropanoyl)-2,5-diphenylimidazolidine-4,4-dicarboxylate (8a); Typical Procedure Diester 6a (285.0 mg, 0.542 mmol) was dissolved in CH2Cl2 (20 mL) together with pyridine (85.4 mg, 1.08 mmol, 2.0 equiv) and DMAP (6.6 mg, 0.054 mmol, 0.1 equiv). The mixture was stirred and cooled to 0 °C, and a solution of ethyl 3-chloro-3-oxopropanoate (163.1 mg, 1.084 mmol, 2.0 equiv) in CH2Cl2 (5 mL) was added dropwise. The mixture was stirred for a further 15 minutes at 0 °C then refluxed for 16 h. The resulting mixture was diluted with CH2Cl2 (30 mL), washed successively with sat. aq NH4Cl, 10% aq NaHCO3, and brine. The organic layers were dried (MgSO4), combined, and evaporated under vacuum to yield a crude product that was purified by column chromatography (silica gel, 20% EtOAc–PE) to give a pale oil; yield: 302 mg (87%). Rf = 0.269 (50% EtOAc–PE). IR: 2981.33, 1736.66, 1668.24, 1235.45, 155.15, 1030.11, 700.24 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.92 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.05–1.12 (2 × t, J = 7.2 Hz, 6 H, CH3 CH2), 1.20 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.38 (t, J = 7.1 Hz, 3 H, CH3 CH2), 2.56 [d, J = 15.7 Hz, 1 H, C(O)CH2 C(O)], 2.92 [d, J = 15.6 Hz, 1 H, C(O)CH2C(O)], 3.41 (m, 1 H, CH3 CH2 ), 3.65 (dq, J = 10.8, 7.2 Hz, 1 H, CH3 CH2 ), 3.76 (dq, J = 13.5, 6.8 Hz, 2 H, CH3 CH2 ), 3.87 (dq, J = 13.5, 6.8 Hz, 2 H, CH3CH2), 4.05 (q, J = 6.9 Hz, 2 H, CH3 CH2 malonate), 4.06 [s, 1 H, CH(CO2Et)2(N)], 4.37, (m, 2 H, CH3 CH2 ), 5.04 [s, 1 H, CH(Ph)(N)(C)], 6.25 [s, 1 H, CH(Ph)(N)2], 7.31–7.86 (m, 10 H, CHAr). 13C (400 MHz, CDCl3, TMS): δ = 13.46, 13.72, 13.80, 14.03 (CH3CH2), 42.93 [CH2(CO2Et)(CON)], 61.17, 61.45, 61.54, 62.37 (CH3 CH2), 61.82 [CH(CO2Et)2(N)], 70.10 [CH(Ph)(N)(C)], 78.06 [CH(Ph)(N)2], 128.21 (C–CAr), 128.66, 128.87, 130.28 (H–CAr), 165.63, 165.73, 166.22, 166.36 [C(O)OEt]. HRMS (ESI+): m/z [M + H]+ calcd for C33H41N2O11: 641.27049; found: 641.26913. Diethyl (±)-(1S *,3S *)-2-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-5,7-dioxo-1,3-diphenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-6,7a(5H)-dicarboxylate (10a); Typical Procedure Diester 8a (1195 mg, 1.86 mmol) was dissolved in dry THF (50 mL) with KOt-Bu (220.0 mg, 1.05 equiv, 1.96 mmol), and the mixture was refluxed for 16 h. The mixture was then concentrated and the residue was redissolved in Et2O (50 mL) and extracted with H2O (2 × 50 mL). The aqueous phase was acidified with 2 M aq HCl to pH 2 and extracted with EtOAc (3 × 100 mL). The organic phases were combined, dried (MgSO4), and concentrated to yield a crude product that was then purified by column chromatography (silica gel, 50% EtOAc–PE to 10% MeOH–EtOAc). The resulting product was washed twice with 2 M aq HCl and once with sat. aq NH4Cl to yield the pure product as colourless crystals; yield: 388.9 mg (35%); mp 93 °C; 388.9; Rf  = 0.706 (10% MeOH–EtOAc). IR: 2984, 2361, 1733, 1243, 1186, 1029 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.67 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 0.97 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 1.13 (t, J = 7.2 Hz, 3 H, CH2 CH3 ), 1.43 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 3.55 (3 H, m, 3 H, CH2 CH3), 3.67 (dd, J = 10.8, 7.1 Hz,1 H, CH2 CH3), 3.73 (m, 1 H, CH2 CH3), 3.97 (m, 2 H, CH2 CH3), 4.34 [s, 1 H, CH(CO2Et)2(N)], 4.42 (q, J = 6.7 Hz, 2 H, CH2 CH3), 4.95 [s, 1 H, CHPh(N)(C)], 6.37 [s, 1 H, CHPh(N)2], 7.17–7.77 (m, 10 H, HCAr). 13C (400 MHz, CDCl3, TMS): δ = 113.16, 13.46, 13.83, 14.20 (CH3CH2), 61.65, 61.81, 61.96, 62.06 (CH3 CH2), 63.92 [CH(CO2Et)2(N)], 69.50 [CHPh(N)(C)], 74.93 [CHPh(N)2], 127.27, 127.49, 127.83, 127.96, 128.45, 128.57, 128.92 (CAR), 134.55 [C(CO2Et)(N)(CO)(C)], 165.79 (C=O). HRMS (ESI–): m/z [M – H]– calcd for C31H33N2O10: 593.21407; found: 593.21393.
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Scheme 1
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Scheme 2
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Figure 1 ORTEP representation of 6a and NOE interactions for 6a, 10 and 11