Deuterium isotope effects on 13C and 15N chemical shifts of intramolecularly hydrogen-bonded enaminocarbonyl derivatives of Meldrum’s and Tetronic acid

Journal of Molecular Structure 976 (2010) 377–391

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Deuterium isotope effects on 13C and 15N chemical shifts of intramolecularly hydrogen-bonded enaminocarbonyl derivatives of Meldrum’s and Tetronic acid Saif Ullah, Wei Zhang, Poul Erik Hansen * Department of Science, Systems and Models, Roskilde University, P.O. Box 260, DK-4000 Roskilde, Denmark

a r t i c l e

i n f o

Article history: Received 10 February 2010 Received in revised form 19 March 2010 Accepted 20 March 2010 Available online 25 March 2010 In honour of Professor Austin Barnes on his 65th birthday. Keywords: Deuterium isotope effects Enaminocarbonyl Meldrum’s acid Tetronic acids DFT calculations RAHB

a b s t r a c t Secondary deuterium isotope effects on 13C and 15N nuclear shieldings in a series of cyclic enamino-diesters and enamino-esters and acyclic enaminones and enamino-esters have been examined and analysed using NMR and DFT (B3LYP/6-31G(d,p)) methods. One-dimensional and two-dimensional NMR spectra of enaminocarbonyl and their deuterated analogues were recorded in CDCl3 and CD2Cl2 at variable temperatures and assigned. 1JNH coupling constants for the derivatives of Meldrum’s and tetronic acids reveal that they exist at the NH-form. It was demonstrated that deuterium isotope effects, for the hydrogen bonded compounds, due to the deuterium substitution at the nitrogen nucleus lead to large one-bond isotope effects at nitrogen, 1 15 D N(D), and two-bond isotope effects on carbon nuclei, 2DC(ND), respectively. A linear correlations exist between 2DC(ND) and 1D15N(D) whereas the correlation with dNH is divided into two. A good agreement between the experimentally observed 2DC(ND) and calculated dr13C/dRNH was obtained. A very good correlation between calculated NH bond lengths and observed NH chemical shifts is found. The observed isotope effects are shown to depend strongly on Resonance Assisted Hydrogen bonding. Ó 2010 Elsevier B.V. All rights reserved.

1. Introduction A key feature of molecular structure is hydrogen bonds which have been studied both theoretically and experimentally over the years. Characterization of hydrogen-bonded systems is an important feature in both organic and biological molecules and it is therefore of importance to explore the strength and geometry of hydrogen bonding [1–5]. Looking at deuterium isotope effects on chemical shifts, intramolecular hydrogen bonded compounds can be divided into compounds with localized hydrogen bond and non-localized hydrogen bond (equilibrium cases or part of a tautomeric system). A localized hydrogen bond and non-localized hydrogen bond can be differentiated by measuring deuterium isotope effects on the carbon atom directly attached to the proton donor functional group. For the localized hydrogen bond cases the 2 DC(D) is not influenced by the temperature, in contrast to nonlocalized hydrogen bond which indicates temperature sensitive deuterium isotope effect values [8]. The 2DC(D) values reported for localized hydrogen bond lies only in the positive range 0.1 ppm to 0.5 ppm, while for non-localized hydrogen bond case high positive values observed, in the range 0.5 ppm to 0.7 ppm (symmetric double-minimum proton potential), high positive values 0.7–2.3 ppm and negative values 0.3 to

* Corresponding author. Tel.: +45 46 742432; fax: +45 46 743011. E-mail address: [email protected] (P.E. Hansen). 0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2010.03.059

0.8 ppm (asymmetric). Hydrogen bond can be further subdivided into those with resonance assisted hydrogen bond (RAHB) (Scheme 1) and those with non-resonance assisted (non-RAHB) hydrogen bonds [1,2,6,7]. RAHB systems can be recognized using PCA analysis [8]. Non-RAHB systems are found, e.g. in protonated DMAN’s [9] and in Mannich bases [10] but these show usually smaller values for deuterium isotope effects [9]. Deuterium isotope effects on chemical shifts can be primary, pD or secondary sD. The primary deuterium isotope effect is defined as pD1H(D) = d(H)  d(D) and the secondary isotope effects on 13C chemical shifts as follows: nD13C(OD) = d13C (OH)  d13C(OD), where n is the number of bonds between the site of deuteration and the ob15 1 15 served nuclei, while on N it is D N(D) = 15 15 d N(H)  d N(D) [7]. Various structural factors such as conjugation, torsional angle, hybridization, and resonance might affect the sign and magnitude of isotope effects [8,9]. In order to investigate the strength and geometry of hydrogen bonds, isotopic substitution is potentially very useful. Secondary deuterium isotope effect (DIE) on 13C chemical shifts, nD13C (OD), have been studied extensively in intramolecular hydrogen-bonded systems and ascribed qualitatively to the hydrogen bond strength [4,8–25]. Deuterium isotope effects on 1D15N(D) chemical shifts have not been studied as frequently, since indirect detection via long-range couplings is often necessary due to the very long relation times of the deuteriated nitrogen, but one advantage to be considered for the observation of 15N nucleus is its large chemical shift range

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Scheme 1. RAHB.

[4,18,22,26–36]. The important parameters which directly tell about the strength and structure of hydrogen bond are donor– acceptor distance, bond order, 2DC(ND) or 2DC(OD) and 1D15N(D) [37]. With the development of fast, efficient computers and commercial software in recent years, theoretical calculations have shown great promise to calculate structures of hydrogen-bonded systems [20,23,38–40], chemical shifts calculations (nuclear shieldings) [38,41–48] and deuterium isotope effects on nuclear shieldings [38,45,48]. The two-bond deuterium isotope effects on 13C and 15 N chemical shifts at the neighbouring atom can be approximated using the Jameson formula [49]:

r  r ¼

X

ðdr=dr XH Þe ½hDrXH i  hDr XD i where X ¼ C; N

ð1Þ

‘‘Enaminocarbonyl” are a group of organic compounds bearing an amino entity linked through a C@C to a keto group or keto-ester group forming the conjugated system ANAC@CACOA or ANAC@CACO2A, having the ambident nucleophilicity of enaminocarbonyl and ambident electrophilicity of enones, belong to a class of versatile intermediates for the synthesis of various pharmaceutical and bioactive heterocyclic compounds, natural products and numerous products of medicinal interest [50–52]. Accordingly, a number of important medicinal agents contain enaminocarbonyl as common pharmacophores and have demonstrated a wide range of potential therapeutic utility including anti-inflammatory [53], anticonvulsant [54,55], antibacterial [53,56] and antitumour agents [53,57]. In spite of their biological importance, the synthesis of enaminocarbonyl, especially cyclic ones, (Scheme 2) has gained little attention so far. In the present work we have synthesized a number of enaminocarbonyl derived from Meldrum’s acid and Tetronic acid and they are investigated by means of deuterium isotope effects on 13C and 15N chemical shifts combined with theoretical (DFT type) of structures and NMR properties. The main objective of the present study is to evaluate the sensitivity of the NAH  O@C type of intramolecular hydrogen bonding by measuring deuterium isotope effects on chemical shifts,

Scheme 2. Possible tautomers of enaminocarbonyl (derivatives of tetronic acids). Two sets of signals were detected by the ‘external’ equilibrium (a, b to c, d) but no separate signals were seen by ‘internal’ equilibria (a–b and c–d) because the equilibrium is too fast on the NMR time scale at 298 K or non-existing and structure of six-membered cyclic enaminocarbonyl (derivatives of Meldrum’s acid).

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especially for 1D15N(D) which is a sensitive gauge to hydrogen bonding, as it has been shown that compounds lacking NAH protons could be deprived of their activity [58]. A further aim is to

379

investigate deuterium isotope effect on 13C and 15N chemical shifts and to show how 2DC(ND) and 1D15N(D) relate to structural parameters. In addition, DFT calculations are used to obtain struc-

Scheme 3. a and b Experimentally observed deuterium isotope effects in CD2Cl2 on 13C chemical shifts. 1H NH chemical shifts are given in italics. Superscript letters: a298 K; b 220 K.

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Scheme 3 (continued)

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Scheme 4. General structure for the enaminocarbonyl 13_Z–19_Z taken from Ref. [4]. Only the Z forms are shown, but compounds 16 and 18 are also found in solution as E isomers.

tural parameters, to calculate nuclear shieldings and isotope effects. All compounds are presented in Schemes 3 and 4. 2. Results The 1H, 13C and 15N signal assignments were performed by the combined use of one-dimensional and two-dimensional heteronuclear correlation experiments, chemical shifts and coupling constants to 15N. The 1H, 13C and 15N NMR assignments are collected in the experimental section. 2.1. NMR assignments 2.1.1. 2,2-Dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6dione (1_15N) The main problem is the assignment of C-4, C-6 and C-9 as they have rather similar 13C chemical shifts (see experimental). C-9 can be assigned based on the one-bond CAN coupling constant of 14.8 Hz (see Fig. 1). The two carbonyl carbons C-4 and C-6 can be distinguished based on a three-bond CAN coupling of 1.8 Hz. This is to C-6 as the coupling geometry in this case is trans. The main difference between compound 1 and compounds 2–7 is an extra ester functional group in the latter (see Scheme 3). C-4 and C-6 can be assigned in analogy with 1, whereas C-24 is assigned based on the HMBC correlation to CH2-16 and CH2-25 (see Fig. 2). The same approach was adopted to assign compounds 9–12 (see Fig. 4). 2.1.2. 3-(1-Methylamino-ethylidene)-furan-2,4-dione (8_15N) The 1H, 13C and 15N NMR assignments including chemical shifts and coupling constants for approximately 70% deuteriated sample

Fig. 2. Chemical structure, atom numbering scheme and long range interactions observed for 2.

1

H–13C

of compound 8_15N was completed on the basis of J-values, collected in the experimental section and depicted in Fig. 3. The 1H NMR spectra show two sets of resonance signals including the NH proton. The 1H chemical shifts of the NH proton were assigned on the basis of the nature of the acceptor group, as the C@O group is a stronger acceptor group than COOR [4], the NH proton of tautomer-b having a keto acceptor group will be at a higher frequency. Therefore, the downfield shifted NH resonance signal at 11.04 ppm was attributed to tautomer-b and the upfield resonance signal at 10.09 ppm to tautomer-d, both of the NH resonances are rather broad. The proton NMR spectrum recorded in CDCl3 at 298 K was analysed by taking into account the maximum number of peak pairs using the line shape analysis algorithm (Levenberg–Marquardt fit) available in Mestre-C [59] and the determined average ratio b/d was found to be 1.45. Again, the main difficulty lies in the assignment of the C-9 and the two carbonyl groups. The C-6 carbonyl groups can due to their high chemical shifts be distinguished from C-4 and C-9. C-9 can be assigned due to the one-bond coupling constant to 15N. C-4 is then assigned by default. To assign the C-9 pair one can use the 3J(C,N) coupling to assign the one belonging to the b-tautomer and for the two C-4 carbons the one belonging to the d-tautomer shows a 3 J(C,N) coupling. For derivatives like 11 the situation is like that described above for 1 and 2. 2.2. Structural assignments Compounds like 1 and 2 have previously in a single case been reported [60]. However, in this case they were described as tautomeric systems between an enaminone as seen in Scheme 2 and an enolimine. This is not the case as demonstrated for 1_15N as the 1 J(N,H) coupling constant is 90.6 Hz. This clearly demonstrates only a single form, the enaminone one. For compounds 8–12 two tautomers are found (Scheme 3). This corresponds to the parent tetronic acids [24]. From NMR spectra the b/d ratios could be determined as: 1.45; 1.33; 1.92; 1.46 and 2.18, respectively. 2.3. Deuterium Isotope Effects

1

15

Fig. 1. Chemical structure, atom numbering scheme and long range H– N and 13 C–15N interactions observed for 1_15N.

Deuterium isotope effects on 13C chemical shifts were determined for compounds with deuterium substitution of the NH proton involved in an intramolecular hydrogen bond. The solvent used

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Fig. 3. 8_15N Chemical structure, atom numbering scheme and long range 1H–15N and

13

C–15N interactions observed for tautomers b and tautomer-d.

Fig. 4. Compound 11. Chemical structure, atom numbering scheme and long range 1H–13C interactions observed for tautomers b and tautomer-d.

is CD2Cl2 and the data at two different temperatures are given in Scheme 3. The isotope effects for enamino-diesters and enaminoesters (derivatives of Meldrum’s acid and tetronic acid) could be observed at ambient temperature. The values of 1D15N(D), 2 DC(ND) and dNH for compounds 13_Z to 19_Z are taken from Ref. [4] and the compounds are presented in Scheme 4. 2.3.1. 2DC-9(ND) The 2DC(ND) isotope effects on 13C chemical shielding are larger for ketone acceptors (C@O) as compared to esters (COOR). The graph in Fig. 5 shows a displacement between the two types of enaminocarbonyl (acyclic and cyclic) is possibly caused by the fact that the cyclic compounds have two mesomerically electron withdrawing substituents. There are no clear-cut temperature variations observed for all the compounds given in Scheme 3 as the cyclic enamino-diesters 1, 2, 5 and cyclic enamino-esters 9_b to 12_b show a decreasing 2DC-9(ND) isotope effect with decreasing temperature, whereas compounds 3–4, 6–7, 8_b and 8_d to 12_d show a slightly increasing tendency. 2.3.2. nDC(ND) The 4DC(ND) deuterium isotope effects observed at the carbonyl carbon (C@O) in the studied enamino-esters are larger than enaminones, but vary in an irregular way (Scheme 3).

Fig. 5. Plot of experimentally observed 2DC(ND)Obs vs. dNHObs for acyclic and cyclic enaminocarbonyl. Cyclic enaminocarbonyl from this work; acyclic from Ref. [4].

The 4DC-4(ND) isotope effects at the C@O carbon increases with decreasing temperature for all the cyclic enamino-diesters except 1, whereas the isotope effect for all the cyclic enaminones motif (4DC-6(ND)) and enamino-esters motif (4DC-4(ND)) decrease with decreasing temperature. Deuteriation at the NH position also led to long range isotope effect at 13C chemical shifts up to six bonds on

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both side of nitrogen nucleus ranging from 0.005 ppm to 0.019 ppm as also found earlier for Meldrum’s and barbituric acids [61]. A steric effect (twist) was found for the structure of 4 containing tert-butyl moiety leading to different isotope effects. 2.3.3. 1D15N(D) Deuterium isotope effects on 15N chemical shifts were measured from a one-tube experiment for 1_15N and 8_15N (both 15 N-enriched) in CDCl3 solution at 298 K, and summarized in Figs. 6 and 7. A linear dependence was observed between 1D15N(D)Obs vs. dNHObs and d15NObs vs.1JNH coupling constants (plot not shown). One-bond deuterium isotope effect on 15N chemical shifts can be measured from the HMBC spectra of partially deuteriation at the NAH hydrogen site: 1D15N(D) = d15N(H)  d15N(D). A value of 1.16 ppm for the deuterium isotope effect of 1_15N was measured from the centre of the NH resonance to the centre of ND resonance in the F1 dimension, using the correlations between H-16 to NAH and NAD, respectively or to H-10. It can be seen from Fig. 7 that 2 DC(ND) and 1D15N(D) correlate to a reasonable degree.

3. Theoretical work 3.1. Calculated dr13C/dRNH

mentally observed 2DC(ND)Obs for both acyclic and cyclic enaminocarbonyl shows a good correlation (Fig. 8).

3.2. Structures For derivatives of Meldrum’s acid only the NH-form is predicted. In all but 4 a hydrogen bonded form is found. The NAH bond lengths are given in Table 1 and so are the N  O distances. For 4 a twisted forms are arrived at as seen in Fig. 9a and b. The twisted form in Fig. 9b is at higher energy (6.96 kcal/mol) as compared to the structure in Fig. 9a.

3.3. Calculated RNAH The signals of the NH  O protons (dNH) involved in intramolecular hydrogen bond appear in the range 6.33–11.78 ppm. A plot of calculated RNAH bond lengths in Å vs. experimentally observed dNH in ppm gives a linear relationship and is shown in Fig. 10. A plot of 1D15N(D)Obs vs. calculated RNAH bond lengths again shows a split in correlations (Fig. 11) (see also Figs. 5 and 6). In the plots are included data (acyclic enaminones and enamino-esters) from Ref. [4]. 3.4. Calculated 1H,

13

C and

15

N chemical shifts

13

The two-bond deuterium isotope effects on C nuclear shielding, dr13C/dRNH, was calculated using the above mentioned geometries simply by shortening the NAH bond 0.01 Å, recalculating the nuclear shieldings and finally, subtracted the optimized nuclear shieldings on 13C nucleus from the nuclear shielding of reduced NAH bond lengths. The plot of calculated dr13C/dRNH vs. experi-

The Density Functional Theory (DFT) calculations of all the compounds in Scheme 3 were performed to determine the 1H, 13C and 15 N chemical shifts. Then, a simple averaging is done for equivalent protons. A linear regression fit of all the predicted 1H and 13C nuclear shieldings vs. experimental values are given in the following plots (Figs. 12–14).

4. Coupling constants

Fig. 6. Plot of experimentally observed 1D15N(D)Obs vs. dNHObs for cyclic enaminocarbonyl from this work; acyclic enaminocarbonyl from Ref. [4].

Fig. 7. Plot of 2DC(ND)Obs vs. 1D15N(D)Obs.

As already mentioned 1JNH spin–spin coupling constants can be used to determine the presence of either a single form or a tautomeric equilibrium. The values of the NH coupling constant are known to be dependent on several factors like hybridization, charge density, hydrogen bonding and polarity of the NAH bond [62,63]. 1JNH for a hydrogen bonded situation varies from 87 up to 95 Hz [63,64]. In this work, we have synthesized two 15N-enriched model compounds (Figs. 1 and 3), 1_15N (enamino-diester) and 8_15N (enamino-ester). Other coupling constants obtained from the 15N enriched derivatives are seen in Fig. 15. Especially the three-bond 3JCN coupling turned out to be useful as they depend on geometry (see previously).

Fig. 8. Plot of experimentally observed two-bond deuterium isotope effect on 13C chemical shifts vs. calculated change in nuclear shieldings for acyclic and cyclic enaminocarbonyl.

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Table 1 Deuterium isotope effects in various enaminocarbonyl (measured at 298 K in CD2Cl2 unless otherwise stated), d13CObs, 2D13CObs, calculated dr13C/dRNH, 1D15NObs, dNHObs, calculated bond lengths (Å), RNAH, calculated distances RO  N (Å) and energies (kcal/mol). Comp. 1 2 3 4 5 6 7 8_b 8_d 9_b 9_d 10_b 10_d 11_b 11_d 12_b 12_d 13_Zc 14_Zc 15_Zc 16_Zc 16_Ec 17_Zc 18_Zc 18_Ec 19_Zc a b c d

d13CObs (ppm) 174.8 174 178.3 166.7 170.8 173.4 173.7 172.1 171.2 175.7 175.1 175.8 175.3 176 175.5 176.1 175.6 n.m. 148.3 n.m. 151.5 147.3 161.5 152.2 148.5 163

2

D13CObs (ppm)

0.168 0.159 0.162 0.079 0.149 0.174 0.168 0.175 0.158 0.168 0.135 0.166 0.135 0.167 0.137 0.16 0.134 0.241 0.235 0.244 0.272 0.104 0.259 0.183 0.095 0.165

dr13C/dRNHd (ppm) 0.167 0.173 0.144 0.062 0.142 0.165 0.147 0.185 0.139 0.174 0.137 0.171 0.148 0.169 0.149 0.161 0.144 0.269 0.274 0.238 0.293 0.121 0.292 0.176 0.113 0.142

1

D15NObs (ppm) a

1.16 n.m.b n.m. n.m. n.m. n.m. n.m. 1.02a 0.91a n.m. n.m. n.m. n.m. n.m. n.m. n.m. n.m. 1.25 1.3 1.18 1.33 0.84 1.44 0.93 0.69 0.97

dNHObs (ppm)

Calc. RN–Hd (Å)

Calc. RO  Nd (Å)

Energiesd (kcal/mol)

11.32 11.7 11.68 6.33 11.43 11.78 11.72 11.05 10.09 11.32 10.38 11.33 10.44 11.3 10.49 11.25 10.46 10.15 10.2 9.7 9.7 4.45 10.8 7.3 4.6 8.2

1.0278 1.03 1.0311 1.0142 1.0296 1.0299 1.0288 1.0265 1.0249 1.0293 1.0276 1.0293 1.0272 1.0293 1.0276 1.029 1.0267 1.0233 1.024 1.0235 1.0253 1.0095 1.0297 1.0187 1.0073 1.0194

2.6053 2.6105 2.6027 2.86 2.639 2.5921 2.6026 2.7297 2.7342 2.7697 2.7125 2.7691 2.7085 2.7671 2.7057 2.7684 2.7132 2.6876 2.6781 2.6656 2.6263 – 2.6515 2.6946 – 2.7074

443330.06 610988.66 635659.34 684997.71 859628.83 780649.23 803176.47 346774.31 346774.44 539103.82 539103.04 563779.68 563779.04 588454.71 588454.20 684097.09 684096.23 278545.00 327887.18 278540.78 278542.74 278534.04 278548.31 301081.14 301072.73 301083.47

Obtained for 15N enriched sample. Not measured. 2 13 D CObs, 1D15NObs and dNHObs for 13_Z to 19_Z are taken from Ref. [4]. Geometries for all the enaminocarbonyl were optimized at the B3LYP level of theory and using a 6-31G(d,p) basis set.

Fig. 9. (a) Calculated structure of 4 (twisted) and (b) calculated structure of 4 (twisted).

Fig. 10. Calculated RNAH bond length values plotted against the experimentally observed dNHObs.

Fig. 11. Calculated RNAH bond length values plotted against the experimentally observed 1D15N(D)Obs.

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OH groups intramolecularly hydrogen bonded to carbonyl groups of nitro substituted o-hydroxy acylaromatics [66]. 5.1. Coupling constants

Fig. 12. Relationships between the experimental and B3LYP/6-31G(d,p) 1H nuclear shieldings of all the compounds given in Scheme 3. All NAH protons are at the top, aromatic protons in the middle and non-aromatic protons at the bottom.

d15N for the cyclic compounds correlate with 1JNH (plot now shown). d15N increases with decreasing 1JNH coupling constant. A decrease in 1JNH can either be ascribed to more positive charge on nitrogen [33] or to a decrease of the NAH bond order. In the present case a partial positive charge will build up as a function of conjugation with both of the C@OX groups. From the very limited data set it seems like the C@OX group involved in hydrogen bonding is the determining one as seen from the finding that 1 JNH for 8_d is larger than for 8_b as the conjugation is to an ester in 8_b rather than to a carbonyl group (the Mulliken charges confirm the less positive charge on 8_d). 5.2. Isotope effect on

Fig. 13. The linear regression between the experimental and B3LYP/6-31G(d,p) 13C nuclear shieldings of all the compounds given in Scheme 3.

15

N nuclear shieldings vs. observed

15

N chemical shifts.

A value of 13.8 Hz was obtained for 1J(N, D) coupling constant for 1_15N. For 8_15N both couplings were 14.1 Hz. In both cases broad line widths prevented a very accurate determination.

5. Discussion The DFT calculations give access to NAH bond lengths and Mulliken charges in addition to NMR parameters. The plot of calculated NAH bond lengths vs. observed NH chemical shifts show as seen in Fig. 10 a very good correlation. For intermolecular hydrogenbonded systems Limbach et al. have also observed a correlation between NH chemical shifts but in that case to a function of valence bond order and limiting chemical shifts [65]. A correlation of dNHObs vs. Mulliken charges is seen in Fig. 16. One outliner is for the twisted compound 4. The correlation indicates that the NH chemical shift to a large extent is governed by the charge. A similar finding was made for OH chemical shifts of

C chemical shifts

The secondary isotope effects on 13C chemical shifts due to the deuterium substitution at the NAH site clearly reflect the strength of the hydrogen bond [22,67]. Inspection of Table 1 gives a comparison for selected enaminocarbonyl. The 2DC(ND) of the enaminodiesters are larger than for enamino-esters, an indication of stronger hydrogen bond in the diester compounds. A plot of RN  O vs. 2 DC(ND) (Fig. 17) shows that hydrogen bonding to a ketone moiety gives a larger 2DC(ND) for the same N  O distance. NH chemical shifts are also expected to reflect the hydrogen bond strength [7]. Nevertheless, a plot of 2DC(ND) vs. dNHObs results in separate lines for the cyclic and the linear compounds. The former having an extra carbonyl or ester group in conjugation with the NH group and thereby leading to a larger positive charge. This extra positive charge is apparently influence the NH chemical shift more than it influences 2DC(ND). 5.3. Isotope effect on

Fig. 14. Plot of calculated

13

15

N chemical shifts

The 15N chemical shifts and one-bond deuterium isotope effects on nitrogen nuclear shieldings are known to be very useful tools in the investigation of NH  O (N  HO) hydrogen-bonded systems [67–69]. Simple amines and amides in general show 1D15N(D) isotope effects of the order of 0.65 ppm [27]. An interesting finding is that for intermolecular hydrogen-bonded systems as seen, e.g. in proteins 1 15 D N(D) decrease with shortening of the N  O@C distance [67] whereas for enaminones and esters 1D15N(D) increases with increasing hydrogen bond strength [4]. The present study was undertaken to investigate this phenomenon further. As seen in Fig. 6 1D15N(D) correlates with dNHObs but on separate correlation lines for cyclic and non-cyclic compounds. 1D15N(D) is like 2 DC(ND) a gauge for hydrogen bond strength. 1D15N(D)Obs also correlates to some degree to d15NObs (Fig. 18). Like 1JNH 1D15N(D) depends on the charge. The less positive charge on nitrogen the larger the isotope effect [70]. In addition, the potential will be more asymmetric for the stronger hydrogen bonded compounds, thereby explaining the larger one-bond isotope effects. 5.4. 1H,

13

C and

15

N chemical shifts

Experimental and predicted chemical shifts for both 1H, 13C and N nuclei are presented in Figs. 12–14. All the figures reveal good correlation coefficients. Data points for 4 are less good possibly indicating that the single conformation shown in Fig. 9a is not the only populated one.

15

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Fig. 15. Coupling constants.

5.5. Calculations

Fig. 16. Plot of Mulliken charges on NH vs. dNHObs.

Fig. 17. 2DC(ND) plotted vs. N  O distance.

The DFT calculations provide geometries, nuclear shieldings and changes in nuclear shieldings. The two latter properties could be proportional [49]. This is clearly not the case for 13C or for 15N as seen from Figs. 18 and 19. According to Eq. (1) the 2DC(ND) can be calculated by knowing dr13C/dRNH as well as [hDrXHi  hDrXDi]. A plot of dr13C/dRNH vs. d13CObs shows a very good correlation (Fig. 8). This is rather unusual as for o-hydroxyacylaromatics it was found that dr13C/dROH was rather invariant, whereas [hDrXHi  hDrXDi] was the determining factor [38]. For calculated r15N a correlation is found to the NAH bond length (Fig. 20). It can be summarized that 15N chemical shifts can be calculated well in RAHB systems.

Fig. 18. Plot of 1D15N(D) vs. d15NObs.

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tance of conjugation and resonance. The importance of resonance is also supported by the correlation between Mulliken charges and observed NH chemical shifts (Fig. 16). Such a trend was seen very clearly in o-hydroxynitroacyl aromatics [66]. The N  O distance is not very important but again seems to depend more on the type of acceptor than the N  O distance (Fig. 17). The acceptor is important for the resonance. Finally, if the acceptor was not acting in a RAHB way it would give rise to a decrease in 1D15N(D) with decreasing N  O distance as seen in proteins [67] and ammonium ions [34]. 6. Conclusions Fig. 19. Plot of 2DC(ND) vs. observed carbon chemical shifts (C-9 or C-1).

Fig. 20. Plot of calculated NAH bond lengths vs. calculated

15

N nuclear shieldings.

Intramolecular hydrogen bonded and non-hydrogen bonded acyclic and cyclic enaminocarbonyl can be characterized by means of secondary deuterium isotope effects on 13C as well as on 15N chemical shifts. The strength of intramolecular hydrogen bond can be estimated by 2DC(ND), 1D15N(D) and dNH. However, the two former correlate but not in a simple way with dNH. All the structures of enaminocarbonyl including dr13C/dRNH, RNAH bond lengths and chemical shifts are calculated theoretically to a good accuracy using DFT methods. A very good correlation is found between calculated NAH bond lengths and NH chemical shifts. Resonance Assisted Hydrogen Bonding is found to be important for explaining the isotope effects. For sterically hindered compounds like 4, a twist in the bond angle around the six-membered hydrogen bond system is observed. 7. Experimental 7.1. Chemicals Compounds Glycine ethyl ester hydrochloride, L-Phenylalanine ethyl ester hydrochloride, L-Tyrosine methyl ester hydrochloride, Methylmagnesium bromide solution 3.0 M in diethyl ether, Methylamine hydrochloride, Methylamine–15N hydrochloride 98 atom% 15N were purchased from Aldrich Chemicals, Weinheim, Germany, Tetrahydrofuran–2,4-dione from TCI Europe nv, Belgium. All organic solvents were of analytical grade and used as received. 7.2. Synthesis of Enaminocarbonyl (cyclic-esters)

Fig. 21. Plot of observed NH chemical shifts vs. calculated ones.

A plot of the observed NH chemical shift vs. the calculated ones shows as seen in Fig. 21 a rather good correlation for the Z-type enaminocarbonyl, whereas the E-type fall off the line. This could indicate that solvent effects are important for the experimental NH chemical shifts. 5.6. Resonance Assisted Hydrogen Bonding It has recently been claimed that RAHB plays very little role for the NMR properties [71,72]. 1D15N(D) are markedly larger for the Z-derivative than for the E-derivative (Table 1). In addition 1 15 D N(D) is larger for ketones as acceptors than for esters as acceptors (Table 1). This supports that Resonance Assisted hydrogen bonding is important in the Z-isomer. In the present study we also find that the NH chemical shift is proportional to the NAH bond length both for E- and Z-derivatives (Fig. 10) illustrating the impor-

The synthesis of acyl Meldrum’s acid [73], acyltetronic acids [24] and 5-(bis(methylthio)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione and 3-(bis(methylthio)methylene)furan-2,4-dione [74] was accomplished according to the literature methods. The synthesis of all cyclic enaminocarbonyl is done by following the representative procedures below. 7.2.1. Representative procedure (1) The title compounds were prepared according to the literature method [75]. To a well stirred solution of 5-(bis(methylthio)methylene)-2,2dimethyl-1,3-dioxane-4,6-dione (2.5 mmol) in dry tetrahydrofuran (5 ml) or 3-(bis(methylthio)methylene)furan-2,4-dione (5 mmol) in dry tetrahydrofuran (5 ml) at 4 °C was added a solution of Grignard reagent (7.5 mmol) in diethyl ether drop wise over a period of 10 min under nitrogen environment and the resulting mixture was stirred at room temperature for further one hour. Amine salts (4%, 10 ml) were added to the reaction mixture and the solution was stirred for additional 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3  10 ml). The combined organic layer and extracts were washed

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with water (3  30 ml), dried over MgSO4, filtered and solvent was evaporated under reduced pressure. The residue of 2a, 6 and 7) was chromatographed on silica gel (Sigma–Aldrich, 200–400 mesh, 60A) using chloroform–acetone (90:10 v/v) as eluent. The raw product was recrystallised from tetrahydrofuran–petroleum ether to yield pure product. 7.2.2. Representative procedure (2) To a stirred solution of aminoester hydrochloride (5 mmol) in dry toluene (15 ml) at 0 °C under nitrogen supply, triethylamine (5 mmol) was added drop wise over a period of 15 min. Then Meldrum’s acid derivatives (5 mmol) were added to the solution and the mixture was stirred at reflux for 3 h. The cooled solution was filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel (Sigma–Aldrich, 200–400 mesh, 60A) using chloroform–acetone (90:10 v/v) as eluent. The solvent was evaporated from the pooled fractions and recrystallised from chloroform–petroleum ether to afford pure product. 7.2.3. Representative procedure (3) To a stirred solution of aminoester hydrochloride (4 mmol) in dry toluene (15 ml) at 0 °C under nitrogen supply, triethylamine (4 mmol) was added drop wise over a period of 15 min. Then tetronic acid derivatives (4 mmol) were added to the solution and the mixture was stirred at reflux for 3 h. The cooled solution was filtered and hexane was added to force crystallisation. The solvent was filtered and residue was recrystallised from diethylether– dichloromethane–n-hexane to afford pure product. 7.2.3.1. 2,2-dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6dione (1). The compound was prepared by following the representative procedure 1. Yield 0.46 g (93%), white crystals; mp 116– 117 °C. 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (s, NH), 3.14 (d, J = 5.1 Hz, H16), 2.63 (s, H10), 1.69 (s, H7-8); 13C NMR (CDCl3, 75 MHz) d (ppm) 174.8 (C9), 167.4 (C4), 163.2 (C6), 102.5 (C2), 84.6 (C5), 30.6 (C16), 26.4 (C7-8), 17.5 (C10); IR (KBr) mmax 3224, 3155, 3099, 2993, 2945, 1709, 1659, 1578, 1266, 1067 cm1;MS (ESI+) for C9H13NO4 (MNa+) 221.9. Elemental analysis: calc. for C9H13NO4: C, 54.26; H, 6.58; N, 7.03. Found: C, 54.03; H, 6.53; N, 7.04. 7.2.3.2. 2,2-dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6dione (1_15N). The title compound (15N labelled) was prepared by following the representative procedure 1. Yield 0.46 g (93%), white crystals; 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (dq, 1J = 90.6 Hz, NH), 3.14 (dd, 3J = 5.1 Hz, H16), 2.63 (d, 3J = 2.7 Hz, H10), 1.69 (s, H7-8); 13C NMR (CDCl3, 75 MHz) d (ppm) 174.872, 174.678 (CAN, 1J = 14.8 Hz) (C9), 167.398 (C4), 163.204, 163.180 (CAN, 3 J = 1.8 Hz) (C6), 102.435 (C2), 84.599, 84.607 (CAN, 2J = 0.5 Hz) (C5), 30.653, 30.508 (CAN, 1J = 10.9 Hz) (C16), 26.366 (C7-8), 17.525 (C10). 15N NMR (60 MHz; CDCl3) d (ppm) 245.5 (N1AH), 246.66 (N1AD). 7.2.3.3. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethylamino)acetate (2). The title compound was prepared by following the representative procedure 2 and 1. Yield 0.54 g (40%) with procedure 2 and 0.62 g (91%) with procedure 1, white crystals; mp 104–105 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.70 (s, NH), 4.30 (q, J = 7.2 Hz, H25), 4.22 (d, J = 5.4 Hz, H16), 2.60 (s, H10), 1.69 (s, H7-8), 1.33 (t, J = 7.2 Hz, H26); 13C NMR (CDCl3, 75 MHz) d (ppm) 174.0 (C9), 167.3 (C24), 167.1 (C4), 163.0 (C6), 102.6 (C2), 85.74 (C5), 62.4 (C25), 45.3 (C16), 26.5 (C7-8), 18.2 (C26), 14.1 (C10); IR (KBr) mmax 3239, 3185, 3103, 2997, 2939, 2909, 2873, 1740, 1713, 1656, 1611, 1228, 1019 cm1; MS (ESI+) for C12H17NO6 (MNa+) 293.8. Elemental analysis: calc. for C12H17NO6: C, 53.13; H, 6.32; N, 5.16. Found: C, 53.09; H, 6.35; N, 5.10.

7.2.3.4. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)propylamino)acetate (3). The title compound was prepared by following the representative procedure 2. Yield 0.53 g (37%), white crystals; mp 104–105 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.68 (s, NH), 4.30 (q, J = 7.2 Hz, H25), 4.24 (d, J = 5.4 Hz, H16), 3.03 (q, J = 7.5 Hz, H10), 1.69 (s, H7-8), 1.33 (t, J = 7.2 Hz, H26), 1.25 (t, J = 7.5 Hz, H11); 13C NMR (CDCl3, 75 MHz) d (ppm) 178.3 (C9), 167.6 (C24), 167.5 (C4), 162.5 (C6), 102.6 (C2), 84.8 (C5), 62.5 (C25), 44.8 (C16), 26.6 (C7-8), 23.9 (C10), 14.2 (C26), 11.6 (C11); IR (KBr) mmax 3172, 2991, 2944, 2924, 2883, 1746, 1703, 1665, 1583, 1225, 1015 cm1; MS (ESI+) for C13H19NO6 (MNa+) 309.9. Elemental analysis: calc. for C13H19NO6: C, 54.73; H, 6.71; N, 4.91. Found: C, 54.47; H, 6.73; N, 4.91. 7.2.3.5. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)2,2-dimethylpropylamino)acetate (4). The title compound was prepared by following the representative procedure 2. Yield 0.47 g (30%), yellow oil; 1H NMR (CDCl3, 300 MHz) d (ppm): 6.33 (s, NH), 4.22 (q, J = 7.2 Hz, H25), 4.02 (d, J = 5.1 Hz, H16), 1.29 (t, J = 7.2 Hz, H26), 1.24 (s, H11-12-13), 1.23 (s, H7-8); 13C NMR (CDCl3, 75 MHz) d (ppm) 184.2 (C6), 178.9 (C9), 170.4 (C24), 169.6 (C4), 101.5 (C2), 78.0 (C5), 61.5 (C25), 41.6 (C16), 38.7 (C10) 27.4 (C11-12-13), 26.5 (C7-8), 14.1 (C26); IR (KBr) mmax 2928, 2855, 1740, 1663, 1602, 1515, 1466, 1377, 1353 cm1; MS (ESI+) for C15H23NO6 (MNa+) 336.30. 7.2.3.6. Ethyl 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(4nitrophenyl)methylamino)acetate (5). The title compound was prepared by following the representative procedure 2. Yield 0.66 g (35%), white crystals; mp 134–135 °C 1H NMR (CDCl3, 300 MHz) d (ppm): 11.43 (s, NH), 8.37 (d, J = 9.0 Hz, ArH), 7.42 (d, J = 9.0 Hz, ArH), 4.20 (q, J = 7.2 Hz, H25), 3.82 (d, J = 6.0 Hz, H16), 1.74 (s, H7-8), 1.25 (t, J = 7.2 Hz, H26); 13C NMR (CDCl3, 75 MHz) d (ppm) 170.8 (C9), 167.3 (C4), 166.7 (C24), 161.4 (C6), 148.6 (C10), 139.1 (CAr), 127.7 (CAr), 124.3 (CAr), 103.7 (C2), 86.8 (C5), 62.5 (C25), 46.2 (C16), 26.8 (C7-8) 14.0 (C26); IR (KBr) mmax 3163, 3088, 2987, 2943, 2856, 1750, 1721, 1660, 1603, 1249, 1022 cm1; MS (ESI+) for C17H18N2O8 (MNa+) 400.9; found 309.9. Elemental analysis: calc. for C17H18N2O8: C, 53.97; H, 4.80; N, 7.40. Found: C, 54.62; H, 5.01; N, 7.17. 7.2.3.7. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethylamino)-3-phenylpropanoate (6). The title compound was prepared by following the representative procedure 2 and 1. Yield 0.61 g (34%) with procedure 2 and 0.77 g (85%) with procedure 1, yellow viscous oil; 1H NMR (CDCl3, 300 MHz) d (ppm): 11.78 (d, J = 8.4 Hz NH), 7.18–7.34 (ArH, 5H), 4.57 (ddd, J = 4.8 Hz, H16), 4.25 (q, J = 7.2 Hz, H25), 3.30 (dd, J = 13.8 Hz, H17), 3.10 (dd, J = 13.8 Hz, H17), 2.28 (s, H10), 1.67 (s, H7-8), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d (ppm) 173.4 (C9), 169.3 (C4), 167.1 (C25), 163.0 (C6), 134.8 (CAr), 129.4 (CAr), 129.0 (CAr), 127.8 (CAr), 102.5 (C2), 85.6 (C5), 62.4 (C25), 58.5 (C16), 39.5 (C17), 26.5 (C7-8) 17.6 (C10), 14.1 (C26); IR (KBr) mmax 2927, 2855, 1741, 1710, 1660, 1588, 1270, 1022 cm1; MS (ESI+) for C19H23NO6 (MNa+) 383.8. 7.2.3.8. Methyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethylamino)-3-(4-hydroxyphenyl)propanoate (7). The title compound was prepared by following the representative procedure 2 and 1. Yield 0.60 g (33%) with procedure 2 and 0.73 g (80%) with procedure 1, yellow viscous oil; 1H NMR (CDCl3, 300 MHz) d (ppm): 11.72 (d, J = 8.7 Hz, NH), 7.02 (d, J = 8.4 Hz, ArH), 6.78 (d, J = 8.7 Hz, ArH), 6.47 (s, OH), 4.57 (dt, J = 4.5 Hz, H16), 3.81 (s, H25), 3.24 (dd, J = 14.1 Hz, H17), 3.03 (dd, J = 14.1 Hz, H17), 2.29 (s, H10), 1.65 (s, H7–8); 13C NMR (CDCl3, 75 MHz) d (ppm) 173.7 (C9), 169.9 (C4), 167.3 (C24), 163.4 (C6),

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156.0 (CAr), 130.5 (CAr), 125.8 (CAr), 116.0 (CAr), 102.8 (C2), 85.4 (C5), 58.6 (C16), 53.1 (C25), 38.6 (C17), 26.4 (C7-8) 17.8 (C10); IR (KBr) mmax 3620, 2927, 2855, 1748, 1709, 1660, 1589, 1518, 1271, 1018 cm1; MS (ESI+) for C18H21NO7 (MNa+) 385.8. 7.2.3.9. 3-(1-methylamino)ethylidene)furan-2,4(5H)-dione (8). The title compound was prepared by following the representative procedure 1. Yield 0.35 g (45%), yellow crystals; mp 106–107 °C. 1H NMR (CDCl3, 300 MHz) d (ppm): 11.04 (s, 0.66NH_b), 10.09 (s, 0.34NH_d), 4.42 (s, H2_b), 4.41 (s, H2_d), 3.16 (d, J = 5.4 Hz, H16_b), 3.14 (d, J = 5.1 Hz, H16_d), 2.61 (s, H10_d), 2.56 (s, H10_b); 13C NMR (CDCl3, 75 MHz) d (ppm) 197.2 (C6b), 193.5 (C6d), 176.4 (C4d), 172.4 (C4b), 172.1 (C9b), 171.2 (C9d), 92.1 (C5b), 90.6 (C5d), 72.1 (C2d), 70.0 (C2b), 30.1 (C16b), 29.8 (C16d), 14.2 (C10d), 13.9 (C10b); IR (KBr) mmax 3216, 2980, 2945, 2926, 1727, 1651, 1504, 1254, 1228, 1022 cm1; MS (ESI+) for C7H9NO3 (MNa+) 178.0. Elemental analysis: calc. for C7H9NO3: C, 54.19; H, 5.85; N, 9.03. Found: C, 53.70; H, 5.80; N, 8.67. 7.2.3.10. 3-(1-methylamino)ethylidene)furan-2,4(5H)-dione (8_15N). The title compound (15N labelled) was prepared by following the representative procedure 1. Yield 0.35 g (45%), 1H NMR (CDCl3, 300 MHz) d (ppm): 11.04 (dq, 1J = 91.8 Hz, 0.66NH_b), 10.09 (dq, 1J = 92.4 Hz, 0.34NH_d), 4.42 (s, H2_b), 4.41 (s, H2_d), 3.16 (dd, 3J = 4.5 Hz, H16_b), 3.14 (dd, 3J = 4.2 Hz, H16_d), 2.61 (d, 3J = 2.7 Hz, H10_d), 2.56 (d, 3J = 2.7 Hz, H10_b); 13 C NMR (CDCl3, 75 MHz) d (ppm) 197.197 (C6b), 193.553, 193.533 (CAN, 3J = 1.5 Hz) (C6d), 176.408 (C4d), 172.448, 172.411 (CAN, 3J = 2.8 Hz) (C4b), 172.175, 171.978 (CAN, 1 J = 14.8 Hz) (C9b), 171.268, 171.064 (CAN, 1J = 15.3 Hz) (C9d), 92.056 (C5b), 90.624 (C5d), 72.129 (C2d), 69.980 (C2b), 30.180, 30.035 (CAN, 1J = 10.9 Hz) (C16b), 29.904, 29.761(CAN, 1 J = 10.7 Hz) (C16d), 14.231 (C10d), 13.853 (C10b). 15N NMR (60 MHz; CDCl3) d (ppm) 239.8 (N10 AH, tautomer-d), 240.71 (N10 AD, tautomer-d), 241.2 (N1AH, tautomer-b), 242.22 (N1AD, tautomer-b). 7.2.3.11. Ethyl 2-(1-(2,4-dioxo-dihydrofuran(5H)-3-ylidene)propylamino)acetate (9). The title compound was prepared by following the representative procedure 3. Yield 0.87 g (90%), white crystals; mp 120–121 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (s, 0.77NH_b), 10.38 (s, 0.23NH_d), 4.45 (s, H2_b), 4.42 (s, H2_d), 4.31 (q, J = 7.2 Hz, H25_b), 4.30 (q, J = 7.2 Hz, H25_d), 4.27 (d, J = 5.7 Hz, H16_b), 4.26 (d, J = 6.0 Hz, H16_d), 2.98 (q, J = 7.8 Hz, H10_b), 2.94 (q, J = 7.5 Hz, H10_d), 1.34 (t, J = 7.2 Hz, H26_b), 1.33 (t, J = 7.2 Hz, H26_d), 1.25 (t, J = 7.5 Hz, H11_b), 1.23 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d (ppm) 197.8 (C6b), 193.0 (C6d), 176.1 (C9b), 175.7 (C9d), 175.1 (C4d), 171.5 (C4b), 167.2 (C24d), 167.1 (C24b), 91.6 (C5b), 90.4 (C5d), 72.1 (C2d), 70.2 (C2b), 62.6 (C25b), 62.5 (C25d), 44.3 (C16b), 44.0 (C16d), 21.4 (C10d), 21.1 (C10b), 14.1 (C26d), 14.1 (C26b), 11.4 (C11b), 11.3 (C11d); IR (KBr) mmax 3453, 3355, 3196, 3130, 2988, 2939, 1732, 1710, 1673, 1667, 1599, 1227, 1200, 1014 cm1; MS (ESI+) for C11H15NO5 (MNa+) 264.1. Elemental analysis: calc. for C11H15NO5: C, 54.76; H, 6.27; N, 5.81. Found: C, 54.65; H, 6.28; N, 5.80. 7.2.3.12. Ethyl 2-(1-(5-methyl-2,4-dioxo-dihydrofuran(5H)-3-ylidene)propylamino)acetate (10). The title compound was prepared by following the representative procedure 3. Yield 0.89 g (87%), white crystals; mp 117–118 °C. 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (s, 0.67NH_b), 10.43 (s, 0.33NH_d), 4.58 (q, J = 6.9 Hz, 2H_b), 4.43 (q, J = 6.9 Hz, H2_d), 4.32 (q, J = 7.2 Hz, H25_b), 4.30 (q, J = 7.2 Hz, H25_d), 4.25 (d, J = 5.7 Hz, H16_b), 4.24 (d, J = 6.0 Hz, H16_d), 2.96 (q, J = 7.8 Hz, H10_b), 2.92 (q, J = 7.5 Hz, H10_d), 1.45 (d, J = 6.9 Hz, H7_b), 1.44 (d, J = 6.9 Hz,

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H7_d), 1.34 (t, J = 7.2 Hz, H26_b), 1.33 (t, J = 7.2 Hz, H26_d), 1.25 (t, J = 7.5 Hz, H11_b), 1.22 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d (ppm) 200.6 (C6b), 195.9 (C6d), 175.8 (C9b), 175.3 (C9d), 175.2 (C4d), 170.8 (C4b), 167.2 (C24d), 167.1 (C24b), 91.0 (C5b), 90.0 (C5d), 79.4 (C2d), 77.3 (C2b), 62.6 (C25b), 62.5 (C25d), 44.3 (C16b), 44.0 (C16d), 21.3 (C10d), 21.1 (C10b), 17.1 (C7b), 17.1 (C7d), 14.1 (C26b), 14.1 (C26d), 11.4 (C11b), 11.3 (C11d); IR (KBr) mmax 3190, 3051, 2978, 2934, 2872, 1728, 1651, 1603, 1513, 1248, 1240, 1027 cm1; MS (ESI+) for C12H17NO5 (MNa+) 278.2. Anal. Calc. for C12H17NO5: C, 56.46; H, 6.71; N, 5.49. Found: C, 56.97; H, 6.90; N, 5.35. 7.2.3.13. Ethyl 2-(1-(5,5-dimethyl-2,4-dioxo-dihydrofuran(5H)-3-ylidene)propylamino)acetate (11). The title compound was prepared by following the representative procedure 3. Yield 1.08 g (85%), white crystals; mp 66 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.30 (s, 0.72NH_b), 10.49 (s, 0.28NH_d), 4.32 (q, J = 6.9 Hz, H25_b), 4.30 (q, J = 6.9 Hz, H25_d), 4.27 (d, J = 5.7 Hz, H16_b), 4.26 (d, J = 6.0 Hz, H16_d), 2.97 (q, J = 7.8 Hz, H10_b), 2.96 (q, J = 7.5 Hz, H10_d), 1.43 (s, H7-8_b), 1.41 (s, H7-8_d), 1.34 (t, J = 7.2 Hz, H26_b), 1.33 (t, J = 7.2 Hz, H26_d), 1.26 (t, J = 7.5 Hz, H11_b), 1.22 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d (ppm) 202.7 (C6b), 198.1 (C6d), 176.0 (C9b), 175.5 (C9d), 174.4 (C4d), 170.0 (C4b), 167.3 (C24d), 167.2 (C24b), 89.9 (C5b), 89.8 (C5d), 85.7 (C2d), 83.4 (C2b), 62.6 (C25b), 62.5 (C25d), 44.3 (C16b), 44.0 (C16d), 23.9 (C7-8b), 23.8 (C7-8d), 21.2 (C10b), 21.1 (C10d), 14.1 (C26b), 14.1 (C26d), 11.5 (C11b), 11.4 (C11d); IR (KBr) mmax 3211, 3144, 3108, 2983, 2941, 2909, 2878, 1747, 1744, 1740, 1737, 1671, 1643, 1614, 1611, 1607, 1215, 1203, 1010 cm1; MS (ESI+) for C13H19NO5 (MNa+) 292.1. Elemental analysis: calc. for C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C, 58.01; H, 7.11; N, 5.27. 7.2.3.14. Ethyl 2-(1-(2,4-dioxo-5-phenyl-dihydrofuran(5H)-3-ylidene)propylamino)acetate (12). The title compound was prepared by following the representative procedure 3. Yield 0.64 g (80%), white crystals; mp 66 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.25 (s, 0.61NH_b), 10.46 (s, 0.39NH_d), 7.28–7.44 (m, ArH), 5.46 (s, H2_b), 5.40 (s, H2_d), 4.28 (q, J = 6.9 Hz, H25_b), 4.25 (q, J = 6.9 Hz, H25_d), 4.21 (d, J = 5.7 Hz, H16_b), 4.20 (d, J = 6.0 Hz, H16_d), 2.96 (q, J = 7.8 Hz, H10_b), 2.94 (q, J = 7.5 Hz, H10_d), 1.32 (t, J = 7.2 Hz, H26_b), 1.30 (t, J = 7.2 Hz, H26_d), 1.25 (t, J = 7.5 Hz, H11_b), 1.17 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d (ppm) 197.4 (C6b), 192.7 (C6d), 176.1 (C9b), 175.7 (C9d), 175.4 (C4d), 170.8 (C4b), 167.1 (C24d), 167.0 (C24b), 135.0 (CAr), 128.6 (CAr), 128.5 (CAr), 125.8 (CAr), 90.1 (C5b), 90.0 (C5d), 83.3 (C2d), 81.5 (C2b), 62.6 (C25), 62.6 (C25), 44.3 (C16b), 44.1 (C16d), 21.4 (C10d), 21.3 (C10b), 14.0 (C26), 14.0 (C26), 11.4 (C11b), 11.3 (C11d); IR (KBr) mmax 3204, 3062, 3037, 2983, 2946, 1732, 1643, 1603, 1512, 1252, 1233, 1019 cm1; MS (ESI+) for C17H19NO5 (MNa+) 340.1. Elemental analysis: calc. for C13H17NO5: C, 64.34; H, 6.04; N, 4.41. Found: C, 64.31; H, 6.11; N, 4.44. 7.3. Instrumentation 7.3.1. NMR NMR spectra were recorded on a Varian Mercury 300 or an Unity-Inova 600 spectrometer with operating frequency at 300 or 600 MHz (5 mm triple-resonance gradient probe) for 1H, 75 or 150 MHz for 13C and 60 MHz (1H 600 MHz) for 15N. 2D experiments were run by using the standard Varian software. TMS was used as an internal standard both for 1H and 13C spectra while for 15N the data were referenced to formamide as external standard. These values are converted to nitromethane as reference subtracting 269.7 ppm. The spectra for a range of samples were recorded between 223 and 298 K. Deuterium Isotope Effects on

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C and 15N chemical shifts were measured in one-tube experiments. Mestrec software was used in order to process and analysed NMR data [59]. The compounds enaminocarbonyl were dissolved in CDCl3, while deuteriation for low temperature work was done by dissolution of the compounds in CD2Cl2 and D2O (50:50), stirred for 5–10 min, separating the organic layer and this was dried over anhydrous sodium sulphate overnight. Samples of 60 mg of 2, 60 mg of 11, 52 mg of 1_15N (15N labelled) and 22 mg of 8_15N (15N labelled) were dissolved in 650 ll of CDCl3. 1D 1H and 2D 1 H–13C HSQC, HMBC; 2D 1H–15N HMQC, HMBC spectra were recorded at 25 °C. For 1H–13C HSQC and HMBC, an acquisition time of 0.4 s, 8 K data points with a spectral window of 10,000 Hz in the F2 (1H) dimension and 256 data points with a spectral window of 35,000 Hz in the F1 (13C) dimension, a 2.0 s relaxation delay and 288 transient per increment were recorded. The tau delay in HMBC was 0.063 s. For 1H–15N HMQC and HMBC, an acquisition time of 0.2 s, 4 K data points with a spectral window of 10,000 Hz in the F2 (1H) dimension and 512 data points with a spectral window of 1200 Hz in the F1 (15N) dimension, a 2.6 s relaxation delay and 32 transient per increment were recorded. The tau delay in HMBC was 0.1 s. 7.3.2. IR Infrared spectra were recorded on a Perkin Elmer FTIR 2000 spectrometer in KBr or CHCl3, respectively. 7.3.3. LC–MS LC–MS measurements were performed on HPLC instrument (a TSP Spectra system and equipped with an AS3000 auto sampler, P4000 gradient pump, and a UV 6000 LP diode array detector) and mass detector (LCQ-Deca ion trap instrument from ThermoFinnigan equipped with an electrospray ionization interface (ESI) run in the positive mode). 7.3.4. Melting points Melting points were determined on a Buchi-510 equipped with Mettler TM-15 counter and are uncorrected. 7.4. Computational work All the theoretical calculations were carried out using the Gaussian 03 code [41] and the molecular geometries were fully optimized using the B3LYP variant of the Density Functional Theory (DFT) [76,77] with the 6-31G(d,p) basis set. The NMR nuclear shieldings were calculated with the same level of theory and basis set using the GIAO method [42,78]. The obtained nuclear shieldings are converted in chemical shifts by comparison with calculated values of tetramethylsilane. Acknowledgements The authors express their thanks to R. Buch for recording NMR spectra. Thanks are also due to Associate Professor Fritz Duus and Dr. Fadhil S. Kamounah for their helpful discussions and to Jan Phillipp Hofmann for providing tetronic acids and for initial calculations. References [1] G. Gilli, F. Bellucci, V. Ferretti, V. Bertolasi, J. Am. Chem. Soc. 111 (1989) 1023. [2] G. Gilli, V. Bertolasi, in: Z. Rappoport (Ed.), The Chemistry of Enols, vol. 13, Wiley, Chichester, 1990, p. 713 (Chapter 13). [3] P. Gilli, V. Ferretti, V. Bertolasi, G. Gilli, Adv. Mol. Struct. Res. 2 (1996) 67. [4] P.E. Hansen, R. Kawecki, A. Krowczynski, L. Kozerski, Acta Chem. Scand. 44 (1990) 826. [5] S. Scheiner, Hydrogen Bonding: A Theoretical Perspective, Oxford, New York, 1997.

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