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Spectral Assignments and Reference DataReceived: 31 May 2007 Revised: 4 October 2007 Accepted: 26 October 2007 Published online in Wiley Interscience: 19 December 2007

(www.interscience.com) DOI 10.1002/mrc.2156

13C NMR studies of heterocyclic naphtho- andanthraquinones. Deshielding effect on thecarbonyl carbon with methyl substitutionCristian Salas, Veronica Armstrong, Claudio Lopez and Ricardo A. Tapia∗

13C chemical shift assignment of several methyl substituted heterocyclic naphtho- and anthraquinones, includingdihydronaphthofuranquinones, azaanthraquinones, benzopyrroloquinolinediones and benzothiophenoquinolinediones, aredescribed. A deshielding effect due to a methyl group was observed over the neighbouring carbonyl carbon, in every casestudied. 13C assignments were based on 2D experiments. Copyright c© 2007 John Wiley & Sons, Ltd.

Keywords: 13C NMR; heterocycles; naphthofuranquinones; azaanthraquinones; benzopyrroloquinones; benzothiophenoquinones;methyl substitution

Introduction

Heterocyclic 1,4-benzo- and 1,4-naphthoquinones as well as 5,10-anthraquinones containing oxygen and nitrogen atoms have beenreported to exhibit a broad range of bioactivities.[1 – 6]

Complete 13C NMR studies have been published for methylsubstituted anthraquinones: the deshielding experienced bythe carbonyl carbon because of methyl substitution has beenreported[7] and explained as reduced contributions of the enolateresonance structure to the overall electronic distribution becauseof peri interactions hindering co-planarity of the carbonyl groupwith the aromatic system.[8] Despite these studies, there is noevidence in the literature, according to our knowledge, of thiseffect being used for structure assignment.

Moreover, influence of methyl substitution on chemical shifts(13C) has not been studied, until now, in heterocyclic quinoniccompounds.

Several 13C NMR spectra have been described and completelyassigned for various oxygen and nitrogen derivatives,[9,10] never-theless, the methyl deshielding effect has received little attention.Although, for cleistopholine (5) the more deshielded carbonylresonance was attributed to C-10; this could be determined[9]

because of an NOE interaction between C-5 and the protons of theC-4 methyl. Amazingly, no similar interactions were evident in thecompounds studied by us.

Prompted by the interesting biological behaviour of theseclasses of compounds, we have performed regio- and stereoselec-tive syntheses of heterocyclic azaanthraquinones, and naphthofu-ranquinones derivatives, through Diels–Alder cycloadducts.[11,12]

Therefore, we describe in this paper the 13C NMR assignmentsfor ten methyl substituted heterocyclic quinones. In every case, adownfield shift is observed for one of the carbonyl carbons, whencompared to the same heterocycle in the absence of the methylsubstitution. These sets of data might serve as reference for futureassignments of structurally related substances.

Results and Discussion

The chemical structures and the numbering system of dihydron-aphthofurandiones (1–4) are presented in Fig. 1. 13C NMR dataand assignments for quinones (1–4) are listed in Table 1.

The effect exerted over the carbonyl shift, by the oxygen atomin the heterocycle is well observed in the unsubstituted analogue(1) and in the symmetrical compound (2) (δ 182.4 and 183.0,respectively for C-4; δ 178.2 and 178.7 for C-9). An influence ofthe methyl substitution is evidenced by 2.9 ppm deshielding forC-4 carbonyl in the 5-methyl derivative (3) in relation to C-4 inthe unsubstituted naphthofuranquinone (1). Moreover, C-9 in the8-methyl derivative (4) appears 2.4 ppm downfield with respect toC-4 in the same compound (4), in spite of the oxygen influence.

The chemical structures and the numbering system of azaan-thraquinones (5–13) are presented in Fig. 2. 13C NMR data andassignments for quinones (6–13) are listed in Table 2.

For the azaanthraquinones series, the effects observed are quitesimilar to those previously discussed for dihydronaphthofuran-diones. The influence exerted by the nitrogen atom is evidencedin the unsubstituted compound (6) and the chemical shift of C-5 isdownfield related to that of C-10. In the 6-methyl derivative (7), C-5appears 1.7 ppm downfield with respect to C-5 in (6). Moreover,the chemical shifts of C-5 and C-10 in the 9-methyl derivative (8)are almost the same, in spite of the influence of the nitrogen.The 1-aza-4-methylanthraquinone (cleistopholine, 5) represents adifferent example, previously characterised.[9] Thus, the carbonylcarbon shift enabled the unambiguous assignment of the methylposition in the three regioisomers (5, 7 and 8).

In the case of the more substituted azaanthraquinones (9)and (10), the same chemical shift inversion is observed for C-5and C-10, as a result of the methyl influence. In the 6-methyl

∗ Correspondence to: Ricardo A. Tapia, Facultad de Química, Pontificia Universi-dad Catolica de Chile, Casilla 306, Santiago22, Chile. E-mail: rtapia@uc.cl

Facultad de Química, Pontificia Universidad Catolica de Chile, Casilla 306,Santiago22, Chile

Magn. Reson. Chem. 2008; 46: 191–194 Copyright c© 2007 John Wiley & Sons, Ltd.

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Figure 1. Structures and numbering of dihydronaphthofurandiones (1–4).

Table 1. 13C NMR chemical shifts (δ, ppm) of dihydronaphthofuran-diones (1–4)a

C 1 2 3 4

2 91.8 91.8 91.6 91.7

3 40.0 40.1 40.5 39.9

3a 123.4 122.9 124.8 121.5

4 182.4 183.0 185.3 180.14a 131.5 131.6 133.2 128.9

5 125.9 127.2 140.8 124.8

6 134.1 143.9 138.9 133.2

7 132.8 142.3 131.9 137.0

8 126.2 127.4 125.4 141.7

8a 133.0 129.5 130.2 134.8

9 178.2 178.7 178.5 182.59a 158.7 158.9 157.4 159.7

10 28.3 28.4 28.4 29.7

11 28.3 28.4 28.4 29.7

a Signal assignments based on 2D experiments.

derivative (10), C-5 is 2.2 ppm downfield with respect to C-10 inthe same compound, which is consistent with the effect exertedby the nitrogen atom, in spite of possible influence from otherheteroatoms present. The chemical shifts of C-5 and C-10 (δ 182.2and 182.6, respectively) in the 9-methyl derivative (9) are almostthe same, reproducing the same pattern observed between (7)and ( 8).

The methyl-deshielding effect is observed even in more complexheterocyclic quinones, such as pyrrole and thiophene derivatives(11–13). The chemical shift of C-5 in the 6-methyl derivativeof benzopyrroloquinolinedione (12) is 2.2 ppm downfield withrespect to that of C-10 in the same compound, which isconsistent with the effect exerted by the nitrogen of thequinolinedione system. The chemical shift of C-10 in the 9-methyl derivative (11) is 1.0 ppm downfield with respect to thatof C-5 in the same compound; the more deshielded carbonylresonance corresponding to the opposite of what is expectedfrom the quinolinedione nitrogen influence. The same behaviouris exhibited by the carbonyl carbons of (13), where C-10 appears3.3 ppm downfield with respect to C-5 in the same compound.

From preliminary DFT calculations performed with the GAUS-SIAN 03 package programmes, at the B3LYP level of theory with the6–31G basis set, geometries have been optimised, confirming thatthe minimum energy conformations of some of these compoundsare flat. Results of NBO calculations and electrostatic potentialsuggest that the presence of methyl displaces the electronic den-sity towards the carbonyl carbon in the opposite position, thusdeshielding the carbonyl in ortho position.

Experimental

Compounds

The syntheses of dihydronaphthofurandiones (1–4) were per-formed through Diels–Alder reactions as described previously.[11]

The azaanthraquinones (6–8) were obtained by reaction ofquinoline-5,8-diones with the appropriate diene following aknown procedure[13]; spectral characteristics for all three com-pounds are in full accordance with those previously described[13];nevertheless, 13C NMR data has not been reported before. Adetailed experimental procedure for the preparation of benzopy-rroloquinolinediones (11) and (12) has been presented recently.[12]

Azaanthraquinones (9) and (10) were prepared through thefollowing procedure (Scheme 1): AgO (180 mg) and HNO3 (6 N,530 µl) were added to a solution of 4-chloro-3-(2-chloroethyl)-5,8-dimethoxy-2-methylquinoline (14)[12] (0.3 mmol in 15 ml CH3CN).After 5 min stirring at room temperature, water (four times theinitial volume) was poured into the reaction mixture. Extractionwith CHCl3 and drying with sulphate were carried out on the crudesolution to which piperylene (penta-1,3-diene, 20 µl) was added.The mixture was kept overnight in a sealed tube at 90 ◦C. Aftercooling, 1,8-diazabicycloundec-7-ene (5 drops) was added and themixture was stirred at room temperature for 4 hours. The solventwas removed and the regioisomers were separated. A yellowcrystalline solid was identified as (9) (36% yield), mp147–149 ◦C,1H NMR (200 MHz, CDCl3): δ 2.84 (s, 3H, CH3); 2.09 (s, 3H, CH3); 3.49(t, 2H, ArCH2, J = 7.5 Hz); 3.80 (t, 2H, CH2Cl, J = 7.5 Hz); 7.59 (d,1H, H-Ar, J = 7.7 Hz); 7.67 (t, 1H, H-Ar, J = 7.7 Hz); 8.15 (d, 1H,H-Ar, J = 7.7 Hz). Isomer (10) was isolated in 22% yield as a yellowcrystalline solid, mp 145–147 ◦C, 1H NMR (200 MHz, CDCl3): δ 2.77(s, 3H, CH3); 2.88 (s, 3H, CH3); 3.47 (t, 2H, ArCH2, J = 7.5 Hz); 3.79

Table 2. 13C NMR chemical shifts (δ, ppm) of azaanthraquinones(6–13)a

C 6 7 8 9 10 11 12 13

2 155.1 154.7 155.1 144.3 144.1 158.7 158.2 159.9

3 127.9 127.9 127.5 136.2 136.6 129.8 130.0 139.4

4 135.5 135.0 135.2 164.4 163.9 117.5 120.6 144.4

4a 130.6 131.6 127.9 124.8 127.6 135.3 134.5 125.7

5 182.6 184.3 183.2 182.2 184.0 183.6 185.4 182.65a 132.7 130.5 133.3 135.5 132.3 135.8 135.4 135.1

6 127.3 142.3 126.0 126.1 141.2 133.1 139.9 127.2

7 134.6 138.6 139.7 138.5 138.5 125.4 137.6 134.0

8 134.8 133.6 138.7 137.9 133.0 137.9 132.9 138.7

9 127.9 126.8 142.9 142.1 125.9 142.2 126.3 142.5

9a 133.5 134.9 127.9 130.2 134.0 130.9 132.8 130.5

10 181.5 182.1 183.3 182.6 181.8 184.6 183.2 185.9

a Signal assignments based on 2D experiments.

www.interscience.wiley.com/journal/mrc Copyright c© 2007 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2008; 46: 191–194

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Spectral Assignments and Reference Data

Figure 2. Structures and numbering of azaanthraquinones (6–13).

(t, 2H, CH2Cl, J = 7.5 Hz); 7.59 (d, 1H, H-Ar, J = 7.7 Hz); 7.63 (t, 1H,H-Ar, J = 7.6 Hz); 8.15 (d, 1H, H-Ar, J = 7.6 Hz).

Thiophenequinone (13) was obtained as the only isomer,trough Diels–Alder reaction, according to the following procedure(Scheme 1): thiourea (1.2 mmol) was added to a solution of (14)(1 mmol) in ethanol (40 ml) and heated to reflux for 2 h. Aftervacuum removal of the solvent, the residue was dissolved inwater and treated with 5% NaHCO3 solution; the solid formedwas filtered and crystallised. The white solid was identified as 2,3-dihydro-6,9-dimethoxy-4-methylthiene[3,2c]quinoline (86%), mp205–207 ◦C (from CH3CN), 1H NMR (200 MHz, CDCl3): δ 2.64 (s, 3H,CH3); 3.37 (s, 4H, CH2 –CH2); 3.90 (s, 3H, OCH3); 3.99 (s, 3H, OCH3);6.64 (d, 1H, H-Ar, J = 8.5 Hz); 6.83 (d, 1H, H-Ar, J = 8.5 Hz). Pd-C10% (20–30 mg) was added to the previously prepared dihydro

Scheme 1. Synthetic route for (9), (10) and (13).

dimethoxy-thienequinoline (0.8 mmol) in mesitylene (2 ml). Themixture was kept in a sealed tube at 190 ◦C overnight. After coolingand removing the Pd-C and solvent, the crude was purified bycolumn chromatography, with CH2Cl2 elution at first; and thenwith increasing polarity gradient using AcOEt; to yield 38% of awhite solid identified as (16), mp 168–170 ◦C, 1H NMR (200 MHz,CDCl3): δ 3.05 (s, 3H, CH3); 4.08 (s, 3H, O–CH3); 4.10 (s, 3H, O–CH3);6.91 (d, 1H, H-Ar, J 8.6 Hz); 7.00 (d, 1H, H-Ar, J 8.6 Hz); 7.65 (s, 2H,

CH-), 13C-NMR (50 MHz; CDCl3): δ 24.0 (c); 55.9 (c); 56.2 (c); 104.4(d); 106.1 (d); 116.7 (s); 122.2 (d); 128.1 (d); 133.2 (s); 135.7 (s); 141.1(s); 148.2 (s); 149.5 (s); 15.,4 (s). The procedures to afford (13) from(16) were identical to those described above to obtain (15), (9)and (10). Thiophenequinone (13) was obtained as a yellow solid.mp. 180 ◦C d., 1H-NMR (200 MHz; CDCl3): δ 2.92 (s, 3 H, CH3); 3.07(s, 3H, CH3); 7.59 (bd, 1H, H-Ar); 7.63 (d, H, CH, J = 5.5 Hz); 7.67 (t,1H, H-Ar, J = 7.6 Hz); 7.93 (d, 1H, CH-S, J = 5.5); 8.34 (dd, 1H, H-Ar,J = 7.6, J = 1.6 Hz).

NMR measurements

1H and 13C NMR spectra were recorded on a Bruker AC-200Poperating at a frequency of 200 MHz (1H) and 50 MHz (13C).All measurements were carried out at a probe temperature of300 K in 5-mm NMR tubes, using solutions at concentrations of10–30 mg/ml in CDCl3. Chemical shifts are expressed in ppm,downfield relative to TMS (δ scale). 1H NMR spectra were recordedwith a spectral width of 4 kHz and 30◦ pulse; the acquisitiontime was 4 s and relax delay 0.5 s. 13C NMR data were obtainedusing spectral width of 25 kHz, 30◦ pulse and 2.20 s acquisitiontime, 1000–3000 scan with 32K complex data points. Exponentialmultiplication was applied before Fourier transformation in bothcases.

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Carbon multiplicity was established by a DEPT pulse sequenceand signals were assigned based on 2D experiments. All two-dimension spectra were acquired with a Bruker AVANCE 400Spectrometer equipped with a Bruker inverse 5-mm Z gradientprobe. The HMBC spectra were obtained using the inv4gplrndqfpulse sequence in the Bruker software. The spectra widths were5340 Hz (F2) and 30000 Hz (F1) and the delay D2 and D6 were 3.45and 65 ms, respectively. Data were processed using sine windowin F2 and F1.

Acknowledgements

Authors are grateful to FONDECYT (Research Grant 1020874) forfinancial support.

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www.interscience.wiley.com/journal/mrc Copyright c© 2007 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2008; 46: 191–194