Synthesis and structural characterisation of amides from picolinic acid and pyridine-2,6-dicarboxylic acid.

Transcription

1 Supporting Information for Synthesis and structural characterisation of amides from picolinic acid and pyridine-2,6-dicarboxylic acid. Prarthana Devi, Sarah M. Barry, Kate M. Houlihan, Michael J. Murphy, Peter Turner, Paul Jensen and Peter J. Rutledge * School of Chemistry F11, The University of Sydney, NSW 2006, Australia. * peter.rutledge@sydney.edu.au; tel: ; fax: Current address: Department of Chemistry, Faculty of Natural & Mathematical Sciences, King s College London, London, U.K. Contents 1. General Experimental S1 2. Spectroscopic Data for N-Methyl-N-phenylpicolinamide 5a S2 3. Crystallographic Experimental Details for Compounds 5b, 5c, 6b, 6c, 7a and 7c S2 4. References S H and 13 C NMR spectra for compounds 5a c, 6a c, 7a c, and 8a b S8 1. General Experimental All reaction solvents were distilled prior to use. Dry solvents were used where stated below. Methanol (MeOH) and acetonitrile (MeCN) were refluxed over CaH 2 and distilled under nitrogen immediately before use. Where stated below solvents were degassed using three freeze/thaw cycles. All reagents were obtained from chemical suppliers and used as received unless otherwise stated. N-Ethylaniline and N- methylaniline were distilled under vacuum from CaH 2 and stored under inert atmosphere over solid KOH. All alkenes used in turnover experiments were distilled over CaH 2 and stored over 4Å molecular sieves. Thin layer chromatography (TLC) was carried out on aluminium backed silica plates coated with Merck silica gel 60F254. TLC plates were viewed under ultra violet light (254 nm) or by staining with ammonium molybdate solution (10%w/v in 2 M sulphuric acid), ninhydrin (0.3% w/v in n BuOH:AcOH 97:3) for visualising amines or Goofy s stain (0.01% Phosphomolybdic acid, 0.001% ceric sulphate, H 2 O:H 2 SO 4 :EtOH 20:1:40) followed by heating. Retention factors are quoted to the nearest Flash column chromatography was carried out using Ajax Finechem silica gel mesh (40 63 microns). S1

2 Melting points were measured on a GallenKamp melting point apparatus. Infrared spectra were recorded on a Shimadzu FTIR8400S with Shimadzu IRSolution 1.04 software. Nuclear magnetic resonance spectra were recorded on Bruker Avance 200 MHz and Bruker Avance 400 MHz spectrometers. Variable temperature 1 H NMR was carried out on a Bruker Avance 400 MHz at the University of Sydney by Dr Ian Luck. Carbon spectra assignments are supported by DEPT editing where necessary. Low resolution mass spectrometry was carried out on a Finnigan LCQ MS Detector at the University of Sydney. High resolution mass spectrometry (HRMS) was carried out on a Bruker Apex II FTICR Electrospray. Mass spectra were recorded by Dr Keith Fisher. 2. Spectroscopic Data for N-Methyl-N-phenylpicolinamide 5a This compound was prepared from picolinic acid 3 (1.0 g, 8.2 mmol) and N-methylaniline (1.66 ml, 16,2 mmol) using thionyl chloride (Procedure 1), and isolated as a white crystalline solid (0.60 g, 35 %); R f 0.20 (petroleum benzine/ ethyl acetate, 1:1); ν max (CHCl 3, cm -1 ): 3087 (w), 2943 (w), 1660 (s), 1309(s); δ H (400 MHz, (CD 3 ) 2 CO) 3.43 (3H, s, NCH 3 ), (6H, m, NC 6 H 5, 1 pyr-ch), 7.50 (1H, d, J = 7.5 Hz, 1 pyr-ch), 7.72 (1H, t, J = 7.5, 1 pyr-ch), 8.27 (1H, bs, 1 pyr-ch); δ C (100 MHz, (CD 3 ) 2 CO) 37.0, 123.3, 123.7, 126.1, 126.8, 128.7, 136.2, 144.7, 148.0, 155.1, ; m/z (ES+): 213 (16 %, [MH] + ), 235 (25 %, [MNa] + ), 447 (100 %, [2MNa] + ); HRMS (ES+): C 13 H 12 N 2 ONa + ([M+Na] + ) requires , found Data in agreement with literature Crystallographic Details for Compounds 5b, 5c, 6b, 6c, 7a and 7c Full supplementary crystallographic data for this paper can be obtained free of charge from The Cambridge Crystallographic Data Centre via under CCDC (for 5b), (for 5c), (for 6b), (for 6c), (for 7a) and (for 7c). N-Ethyl-N-phenylpicolinamide 5b A colourless prismatic crystal was attached with Exxon Paratone N to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A Bruker SMART 1000 X-ray diffractometer employing graphite monochromated Mo(K radiation generated from a fine-focus sealed tube was used for the data collection. Cell constants were obtained from a least squares refinement against 6006 reflections located between 5 and Data were collected at 150(2) Kelvin with scans to The data integration and reduction were undertaken with SAINT and XPREP, 2 and subsequent computations were carried out with the X-Seed graphical user interface. 3 The intensities of 147 standard S2

3 reflections recollected at the end of the experiment did not change significantly during the data collection. An empirical absorption correction determined with SADABS was applied to the data. 4 The structure was solved in the space group P21/n (#14) by direct methods with SHELXS-97, and extended and refined with SHELXL The non-hydrogen atoms in the asymmetric unit were modelled with anisotropic displacement parameters. A riding atom model with group displacement parameters was used for the hydrogen atoms. Summary Crystallographic Data: Formula C 14 H 14 N 2 O, M , Monoclinic, space group P2 1 /n(#14), a (8), b (13), c (9) Å, (2), V (19) Å 3, D c g cm -3, Z 4, crystal size 0.47 by 0.30 by 0.28 mm, colourless prisms, temperature 150(2) Kelvin, (MoK ) Å, (MoK ) mm -1, T(SADABS) min,max 0.934, 0.978, 2 max 56.66, hkl range , , , N 11006, N ind 2874(R merge ), N obs 2513(I > 2 (I)), N var 155, residuals R1(F) , wr2(f 2 ) , GoF(all) 1.046, min,max , e - Å -3. (R1 = F o F c / F o for F o > 2 (F o ); wr2 = ( w(f 2 o F 2 c ) 2 / (wf 2 c ) 2 ) 1/2 all reflections; w=1/[ 2 (F 2 o )+(0.0475P) P] where P=(F 2 o +2F 2 c )/3) N,N-Diphenylpicolinamide 5c A pale yellow prism-like crystal was attached with Exxon Paratone N, to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A SuperNova (Dual Source) X-ray diffractometer equipped with an Atlas detector and employing mirror monochromated Cu (Kα) radiation from a micro-source was used for the data collection. Cell constants were obtained from a least squares refinement against reflections located between and Data were collected at 150 Kelvin with scans to The data processing was undertaken with CrysAlis Pro 6 and subsequent computations were carried out with WinGX 7 and ShelXle. 8 A multi-scan absorption correction was applied to the data. 6 The structure was solved in the space group Pbca (#61) by direct methods with SHELXS-97, 5 and refined with SHELXL The non-hydrogen atoms in the asymmetric unit were modelled with anisotropic displacement parameters. A riding atom model with group displacement parameters was used for the hydrogen atoms. Summary Crystallographic Data: Formula C 18 H 14 N 2 O, M , orthorhombic, space group Pbca (#61), a (2), b (10), c (2) Å, V (5) Å 3, D c g cm -3, Z 8, crystal size 0.05 by 0.03 by 0.02 mm, colour pale yellow, habit prism, temperature 150(2) Kelvin, (CuK ) Å, (CuK ) mm -1, T min,max , , 2 max , hkl range , , , N 22802, N ind 2902(R merge ), N obs 2475(I > 2 (I)), N var 190, residuals * R1(F) , wr2(f 2 ) , GoF(all) 1.213, min,max , e - Å -3. (R1 = F o - F c / F o for F o > 2 (F o ); wr2 = ( w(f 2 o F 2 c ) 2 / (wf 2 c ) 2 ) 1/2 all reflections; w=1/[ 2 ( 2 Fo )+(0.0371P) P] where P=(F 2 o +2F 2 c )/3) S3

4 4-Chloro-N-ethyl-N-phenylpicolinamide 6b A pale yellow prism-like crystal was attached with Exxon Paratone N, to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A SuperNova (Dual Source) X-ray diffractometer equipped with an Atlas detector and employing mirror monochromated Cu (Kα) radiation from a micro-source was used for the data collection cell constants were obtained from a least squares refinement against 7167 reflections located between and Data were collected at 150 Kelvin with scans to The data processing was undertaken with CrysAlis Pro 6 and subsequent computations were carried out with WinGX 7 and ShelXle. 8 A multi-scan absorption correction was applied to the data. 6 The structure was solved in the space group P (#2) by direct methods with SHELXS-97, 5 and refined with SHELXL The non-hydrogen atoms in the asymmetric unit were modelled with anisotropic displacement parameters. A riding atom model with group displacement parameters was used for the hydrogen atoms. Summary Crystallographic Data: Formula C 14 H 13 ClN 2 O, M , triclinic, space group P (#2), a (4), b (5), c (4) Å, (4), (4), (4), V (5) Å 3, D c g cm -3, Z 2, crystal size 0.07 by 0.06 by 0.05 mm, colour yellow, habit prismatic, temperature 150(2) Kelvin, (CuK ) Å, (CuK ) mm -1, T min,max , , 2 max , hkl range , , , N 10970, N ind 2655(R merge ), N obs 2507(I > 2 (I)), N var 163, residuals R1(F) , wr2(f 2 ) , GoF(all) 1.064, min,max , e - Å -3. (R1 = F o F c / F o for F o > 2 (F o ); wr2 = ( w(f 2 o F 2 c ) 2 / (wf 2 c ) 2 ) 1/2 all reflections; w=1/[ 2 (F 2 o )+(0.0428P) P] where P=(F 2 o +2F 2 c )/3). 4-Chloro-N,N-diphenylpicolinamide 6c A colourless rod-like crystal was attached with Exxon Paratone N, to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A SuperNova (Dual Source) X-ray diffractometer equipped with an Atlas detector and employing mirror monochromated Cu (Kα) radiation from a micro-source was used for the data collection cell constants were obtained from a least squares refinement against reflections located between 7.26 and Data were collected at 150 Kelvin with scans to The data processing was undertaken with CrysAlis Pro 6 and subsequent computations were carried out with WinGX 7 and ShelXle. 8 A multi-scan absorption correction was applied to the data. 6 The structure was solved in the space group I (#82) by direct methods with SHELXS-97, 5 and refined with SHELXL The non-hydrogen atoms in the asymmetric unit were modelled with anisotropic displacement parameters. A riding atom model with group S4

5 displacement parameters was used for the hydrogen atoms. The absolute structure was established with the Flack parameter 9-12 refining to 0.000(12). Summary Crystallographic Data: Formula C 18 H 13 ClN 2 O, M , tetragonal, space group I (#82), a (10), b (10), c (10) Å, V (6) Å 3, D c g cm -3, Z 8, crystal size 0.11 by by mm, colour colourless, habit rod, temperature 150(2) Kelvin, (CuK ) Å, (CuK ) mm -1, T min,max , , 2 max , hkl range , , -6 6, N 33711, N ind 3221(R merge ), N obs 3124(I > 2 (I)), N var 200, residuals R1(F) , wr2(f 2 ) , GoF(all) 0.966, min,max , e - Å -3. (R1 = F o F c / F o for F o > 2 (F o ); wr2 = ( w(f 2 o F 2 c ) 2 / (wf 2 c ) 2 ) 1/2 all reflections; w=1/[ 2 (F 2 o )+(0.1000P) P] where P=(F 2 o +2F 2 c )/3) N 2, N 6 -Dimethyl-N 2, N 6 -diphenylpyridine-2,6-dicarboxamide 7a A pale yellow prism-like crystal was attached with Exxon Paratone N, to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A SuperNova (Dual Source) X-ray diffractometer equipped with an Atlas detector and employing mirror monochromated Cu (Kα) radiation from a micro-source was used for the data collection cell constants were obtained from a least squares refinement against 2271 reflections located between and Data were collected at 150 Kelvin with scans to The data processing was undertaken with CrysAlis Pro 6 and subsequent computations were carried out with WinGX 7 and ShelXle. 8 A multi-scan absorption correction was applied to the data. 6 The structure was solved in the space group Pbca (#61) by direct methods with SHELXS-97, 5 and refined with SHELXL The non-hydrogen atoms in the asymmetric unit were modelled with anisotropic displacement parameters. A riding atom model with group displacement parameters was used for the hydrogen atoms. Summary Crystallographic Data: Formula C 21 H 19 N 3 O 2, M , orthorhombic, space group Pbca(#61), a (4), b (11), c (2) Å, V (4) Å 3, D c g cm -3, Z 8, crystal size by by mm, colour colourless, habit prism, temperature 150(2) Kelvin, (CuK ) Å, (CuK ) mm -1, T min,max , , 2 max , hkl range , , , N 28963, N ind 3602(R merge ), N obs 3464(I > 2 (I)), N var 237, residuals R1(F) , wr2(f 2 ) , GoF(all) 1.002, min,max , e - Å -3. (R1 = F o F c / F o for F o > 2 (F o ); wr2 = ( w(f 2 o F 2 c ) 2 / (wf 2 c ) 2 ) 1/2 all reflections; w=1/[ 2 (F 2 o )+(0.0700P) P] where P=(F 2 o +2F 2 c )/3) S5

6 N 2,N 2,N 6,N 6 -Tetraphenylpyridine-2,6-dicarboxamide 7c A colourless prism like crystal was attached with Exxon Paratone N, to a short length of fibre supported on a thin piece of copper wire inserted in a copper mounting pin, and mounted on an APEXII-FR591 diffractometer employing mirror monochromated MoK radiation generated from a rotating anode. Cell constants were obtained from a least squares refinement against reflections located between 6.20 and Data were collected at 150(2) Kelvin with + scans to The data integration and reduction were undertaken with SAINT and XPREP. 2 An empirical absorption correction determined with SADABS 4 was applied to the data. The structure was solved in the space group P (#2) by direct methods with SIR97, 13 and extended and refined with SHELXL The atoms in the asymmetric unit were modelled with anisotropic displacement parameters. No hydrogen atoms were included in the model. Summary Crystallographic Data: Formula C 31 H 23 N 3 O 2, M , triclinic, space group P (#2), a (5), b (10), c (12) Å, (4), (3), (3), V (3) Å 3, D c g cm -3, Z 4, crystal size by by mm, colour colourless, habit prism, temperature 150(2) Kelvin, (MoK ) Å, (MoK ) mm -1, T(SADABS) min,max 0.878, 1.000, 2 max 52.75, hkl range , , , N 84637, N ind 10008(R merge ), N obs 7101(I > 2 (I)), N var 649, residuals R1(F) , wr2(f 2 ) , GoF(all) 1.111, min,max , e - Å -3. (R1 = F o F c / F o for F o > 2 (F o ); wr2 = ( w(f o 2 F c 2 ) 2 / (wf c 2 ) 2 ) 1/2 all reflections; w=1/[ 2 (F o 2 )+(0.0500P) P] where P=(F o 2 +2F c 2 )/3) 4. References 1 Okamoto, I., et al. Acid-induced conformational alteration of cis-preferential aromatic amides bearing N-methyl-N-(2-pyridyl) moiety. Tetrahedron 67, (2011). 2 Bruker. (Bruker Analytical X-ray Instruments Inc, Madison, Wisconsin, USA., 1995). 3 Barbour, L.J. X-Seed - A software tool for supramolecular crystallography. J. Supramol. Chem. 1, (2001). 4 Sheldrick, G.M. (University of Göttingen, Göttingen, Germany, 1996). 5 Sheldrick, G.M. (University of Göttingen, Göttingen, Germany, 1998). 6 Agilent Technologies (Yarnton, Oxfordshire, UK, 2013). 7 Farrugia, L. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 32, (1999). S6

7 8 Hübschle, C.B. & Sheldrick, G.M.D., B. ShelXle: graphical user interface for SHELXL. J. Appl. Cryst. 44, (2011). 9 Flack, H.D. On enantiomorph-polarity estimation. Acta Crystallogr., Sect. A: Found. Crystallogr. 39, (1983). 10 Bernardinelli, G. & Flack, H.D. Least-squares absolute-structure refinement practical experience and ancillary calculations. Acta Crystallogr., Sect. A: Found. Crystallogr. 41, (1985). 11 Flack, H.D. & Bernardinelli, G. Absolute structure and absolute configuration. Acta Crystallogr., Sect. A: Found. Crystallogr. 55, (1999). 12 Flack, H.D. & Bernardinelli, G. Reporting and evaluating absolute-structure and absoluteconfiguration determinations. J. Appl. Crystallogr. 33, (2000). 13 Altomare, A., et al. SIR97: a new tool for crystal structure determination and refinement. J. Appl. Cryst. 32, (1999). 14 Sheldrick, G.M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr 64, (2008). S7

8 5. 1 H and 13 C NMR spectra 1 H NMR (400MHz, CD 3 COCD 3 ) of N-methyl-N-phenylpicolinamide 5a S8

9 13 C NMR (100MHz, CD 3COCD3) of N-methyl-N-phenylpicolinamide 5a ppm S

10 1 H NMR (400MHz, CD 3COCD3) of N-ethyl-N-phenylpicolinamide 5b ppm S

11 13 C NMR (100MHz, CD 3COCD3) of N-ethyl-N-phenylpicolinamide 5b ppm S

12 1 H NMR (400MHz, CD 3 COCD 3 ) of N, N-diphenylpicolinamide 5c S12

13 13 C NMR (100MHz, CD 3 COCD 3 ) of N, N-diphenylpicolinamide 5c ppm S13

14 1 H NMR (400MHz, CD 3COCD3) of 4-chloro-N-methyl-N-phenylpicolinamide 6a ppm S

15 13 C NMR (100MHz, CD 3 COCD 3 ) of 4-chloro-N-methyl-N-phenylpicolinamide 6a S15

16 1 H NMR (400MHz, CD 3COCD3) of 4-chloro-N-ethyl-N-phenylpicolinamide 6b ppm S

17 13 C NMR (100MHz, CD 3 COCD 3 ) of 4-chloro-N-ethyl-N-phenylpicolinamide 6b ppm S17

18 1 H NMR (400MHz, CD 3COCD3) of 4-chloro-N, N-diphenylpicolinamide 6c ppm S

19 31 C NMR (100MHz, CD 3 COCD 3 ) of 4-chloro-N, N-diphenylpicolinamide 6c ppm S19

20 1 H NMR (400MHz, CD 3 COCD 3 ) of N 2, N 6 -dimethyl-n 2, N 6 -diphenylpyridine-2, 6-dicarboxamide 7a S20

21 13 C NMR (100MHz, CD 3 COCD 3 ) of N 2, N 6 -dimethyl-n 2, N 6 -diphenylpyridine-2, 6-dicarboxamide 7a ppm S21

22 1 H NMR (400MHz, CD 3 COCD 3 ) of N 2, N 6 -diethyl-n 2, N 6 -diphenylpyridine-2, 6-dicarboxamide 7b ppm S22

23 13 C NMR (400MHz, CD 3 COCD 3 ) of N 2, N 6 -diethyl-n 2, N 6 -diphenylpyridine-2, 6-dicarboxamide 7b ppm S23

24 1 H NMR (400MHz, CD 3COCD3) of N 2, N 2, N 6, N 6 -tetraphenylpyridine-2,6-dicarboxamide 7c ppm S

25 13 C NMR (100MHz, CD 3 COCD 3 ) of N 2, N 2, N 6, N 6 -tetraphenylpyridine-2,6-dicarboxamide 7c ppm S25

26 1 H NMR (300 MHz, CDCl 3 ) of Pyridine-2,6-dicarboxylic acid bis(l-valinyl-s-benzyl-l-cysteine methyl ester)carboxamide 8a S26

27 13 C NMR (75.4 MHz, CDCl 3 ) of Pyridine-2,6-dicarboxylic acid bis(l-valinyl-s-benzyl-l-cysteine methyl ester)carboxamide 8a S27

28 1 H NMR (300 MHz, CDCl 3 ) of Pyridine-2,6-dicarboxylic acid bis(s-benzyl-l-cysteinyl-l-valine methyl ester)carboxamide 8b S28

29 13 C NMR (75.4 MHz, CDCl 3 ) of Pyridine-2,6-dicarboxylic acid bis(s-benzyl-l-cysteinyl-l-valine methyl ester)carboxamide 8b S29