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Synlett 2008(14): 2142-2146  
DOI: 10.1055/s-2008-1072789
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Bispyrrolidines by Radical Cyclisation of Diallylamines Using Phosphorus Hydrides

Andrew F. Parsons*, Anthony Wright
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax: +44(1904)432516; e-Mail: afp2@york.ac.uk;
Further Information

Publication History

Received 6 March 2008
Publication Date:
07 May 2008 (online)

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Abstract

Sequential radical addition-cyclisation reactions of diallylamines using either hypophosphorous acid or a bisphosphinothioate are shown to afford bispyrrolidines in good to excellent yields.

Key words

addition reactions - cyclisations - phosphorus - radical reactions

7

All new compounds gave spectroscopic data and high-resolution mass spectrometric data consistent with their assigned structure.

8

Bis({4-methyl-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)phosphinic Acid (8a)
A boiling solution of N,N-diallyl-4-methylbenzenesulfon-
amide (2a, 0.613 g, 2.439 mmol) and hypophosphorous acid (0.070 g, 1.061 mmol), in anhyd THF (5 mL) was treated with AIBN (4 × 0.087 g, 4 × 0.531 mmol) over 36 h. After cooling to r.t., brine (20 mL) was added and the mixture extracted with CH2Cl2 (3 × 20 mL). The combined layers were dried (MgSO4), concentrated (under reduced pressure), and column chromatography [SiO2, PE-EtOAc (4:6) to EtOAc-MeOH (1:1)] gave phosphinic acid 8a (0.495 g, 82%) as an inseparable mixture of isomers, with a cis/trans ratio of 2.2:1 (from the ¹H NMR spectrum); white solid; mp 118-127 ˚C. IR (CH2Cl2): νmax = 3541, 3058, 2964, 2882, 1598, 1479, 1454, 1406, 1384, 1337, 1160, 1093, 1044, 955 cm-¹.
cis-Diastereomers: ¹H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 4 H, 4 × SCCH, arom), 7.43-7.38 (m, 4 H, 4 × CHCCH3, arom), 3.52 (dd, J = 9.5, 7.5 Hz, 2 H, 2 × CH aHbCHCH2P), 3.36-3.26 (m, 2 H, 2 × CH3CHCH aHb), 3.08-2.95 (m, 4 H, 2 × CHa H bNCHa H bCHCH2P), 2.50-2.30 (m, 2 H, 2 × CHCH2P), 2.43, 2.42 (2 × br s, 6 H, 2 × ArCH 3), 2.30-2.11 (m, 2 H, 2 × CH3CH), 1.47 (dq, J = 15.0, 4.5 Hz, 2 H, 2 × CH aHbP), 1.37-1.10 (m, 2 H, 2 × CHa H bP), 0.68, 0.65 (d and dd, J = 7.0 Hz and 7.0, 2.5 Hz, 6 H, 2 × CH 3CH). ¹³C NMR (100 MHz, CDCl3): δ = 145.0, 144.9 (2 × SCCH, arom), 135.2, 135.1 (2 × CHCCH3, arom), 130.8 (4 × CHCCH3), 128.7, 128.6 (4 × SCCH, arom), 55.6 (2 × CH3CHCH2), 53.0, 52.7 (br s and d, ³ J CP = 5.5 Hz, 2 × CH2CHCH2P), 37.9-37.4 (m, 2 × CHCH2P), 37.7, 37.2 (2 × d, ³ J CP = 12.0, 10.5 Hz, 2 × CH3 CH), 30.3 (br d, ¹ J CP = 89.5 Hz, 2 × CH2P), 21.5 (2 × ArCH3), 13.7, 13.6 (2 × CH3CH).
trans-Diastereomers: ¹H NMR (400 MHz, CDCl3): δ = 3.81-3.70 (m, 2 H, 2 × CH aHbCHCH2P), 3.52-3.43 (m, 2 H, 2 × CH3CHCH aHb), 3.08-2.90 (m, 2 H, 2 × CHa H bCHCH2P), 2.73 (br t, J = 9.5 Hz, 2 H, 2 × CH3CHCHa H b), 1.72-1.05 (m, 8 H, 2 × CHCHCH 2P), 0.91, 0.87 (d and dd, J = 6.5 Hz and 8.0, 6.5 Hz, 6 H, 2 × CH 3CH). ¹³C NMR (100 MHz, CDCl3): δ = 55.7-55.2 (m, 2 × CH3CHCH2), 55.3-54.9 (2 × CH2CHCH2P), 41.9-41.3 (m, 2 × CH3 CHCH), 31.7 (br d, ¹ J CP = 90.5 Hz, 2 × CH2P), 15.9, 15.8 (2 × CH3CH). ³¹P NMR (162 MHz; CDCl3): δ = 39.6. ESI-MS: m/z (%) = 316 (100), 567 (92) [M - H+]. ESI-HRMS: m/z calcd for C26H37N2O6PS2: 567.1758; found: 567.1752.

11

In the absence of AIBN or Et3B, pyrrolidine products were formed in low yields after extended reaction times. For example, heating 2a (1 equiv) with H3PO2 (4.3 equiv) in degassed dioxane for 3 d, followed by esterification, gave a 4.7:1 mixture of 9 and 10, respectively, in a combined yield of only 34%.

15

Bond-dissociation energies based on DFT calculations (B3LYP functional, 6-13G(d,p) basis set, calculations performed using Gaussian03) for PhP(S)(OEt)H and PhP(O)(OEt)H are around 316 and 345 kJ mol-¹, respectively. McGrady, J. E.; Pantazis, D. unpublished results.

16

O -(3-{[({4-Methyl-1-[(4-methylphenyl)sulfonyl]-3-pyr-rolidinyl}methyl)(phenyl)phosphorothioyl]oxy}prop-yl){4-methyl-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl(phenyl)phosphinothioate (16a) A boiling solution of N,N-diallyl-4-methylbenzene sulfonamide (2a, 0.372 g, 1.479 mmol) and O-(3-{[phen-
yl(thioxo)phosphoranyl]oxy}propyl)phenylphosphinothioate (14, 0.264 g, 0.741 mmol) in anhyd THF (15 mL) was treated portionwise with AIBN (4 × 0.024 g, 4 × 0.148 mmol) over 36 h. After cooling to r.t., 1 M aq NaOH (20 mL) was added and the mixture extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried (MgSO4), concentrated (under reduced pressure), and column chromatography [SiO2, CH2Cl2-EtOAc (97:3)] gave bispyrrolidine 16a (0.477 g, 75%) as an inseparable mixture of isomers, with a cis/trans ratio of 2.5:1 (from the ¹H NMR spectrum); white solid; mp 61-66 ˚C. IR (CHCl3): νmax = 3022, 2967, 2892, 2433, 2401, 2255, 1965, 1919, 1822, 1598, 1479, 1437, 1400, 1385, 1342, 1305, 1289, 1216, 1160, 1109, 1095, 1041, 1017, 968 cm-¹.
cis-Diastereomers: ¹H NMR (400 MHz, CDCl3): δ = 7.89-7.75 (m, 4 H, 4 × PCCH, arom), 7.72-7.66 and 7.62-7.56 (2 × m, 4 H, 4 × SCCH, arom), 7.59-7.51 (m, 2 H, 2 × PCCHCHCH, arom), 7.55-7.41 (m, 4 H, 2 × PCCHCH, arom), 7.35-7.26 (m, 4 H, 4 × SCCHCH, arom), 4.20-4.04 and 3.75-3.58 (2 × m, 4 H, POCH 2CH2CH 2), 3.25 (dd, J = 9.5, 6.5 Hz, 2 H, 2 × CH3CHCH aHbN), 3.17 (br t, J = 9.0 Hz, 2 H, 2 × NCH aHbCHCH2P), 3.04-2.94 (m, 2 H, 2 × CH3CHCHa H bN), 2.80-2.67 (m, 2 H, NCHa H bCHCH2P), 2.56-2.35 (m, 2 H, 2 × CHCH2P), 2.44, 2.42 (2 × s, 6 H, 2 × ArCH 3), 2.30-1.96 (m, 2 H, 2 × CH3CH), 2.05-1.65 (m, 4 H, 2 × CH 2P), 1.97-1.78 (m, 2 H, POCH2CH 2), 0.74, 0.70 (2 × d, J = 7.0, 7.0 Hz) and 0.65-0.59 (m, 6 H, 2 × CH 3CH). ¹³C NMR (100 MHz, CDCl3): δ = 143.2 (2 × SCCH, arom), 133.8-131.6 (m, 2 × PCCH, 2 × SCCHCHCCH3, arom), 132.5-132.2 (m, 2 × PCCHCHCH, arom), 131.3-129.0 (m, 4 × PCCH, arom), 129.6, 129.5 (4 × SCCHCH, arom), 128.8-128.4 (4 × PCCHCH, arom), 127.3, 127.2 (4 × SCCH, arom), 60.9-60.2 (m, 2 × POCH2), 54.1, 53.9 (2 × CH3CHCH2N), 51.2, 50.9 (2 × d, ³ J CP = 5.5, 8.5 Hz, 2 × CH2CHCH2P), 36.3 (s) and 36.0-35.8 (m) (2 × CHCH2P), 35.7, 35.6 (2 × d, ³ J CP = 10.5, 10.5 Hz, 2 × CH3 CH), 34.5, 34.3 (2 × d, ¹ J CP = 79.5, 80.0 Hz, 2 × CH2P), 31.1-30.7 (m, POCH2 CH2), 21.4, 21.4 (2 × ArCH3), 13.2, 13.1 (2 × CH3CH).
trans-Diastereomers: ¹H NMR (400 MHz; CDCl3): δ = 3.82-3.68 (m, 2 H, 2 × NCH aHbCHCH2P), 3.56-3.35 (m, 4 H, 2 × CH3CH aHbNCHa H bCHCH2P), 0.91-0.85 and 0.81-0.76 (2 × m, 6 H, 2 × CH3CH). ¹³C NMR (100 MHz; CDCl3): δ = 53.6-53.3 (m, 2 × CH3CHCH2), 53.4-53.0 (m, 2 × CH2CHCH2P), 40.3-40.1 and 40.0-39.8 (2 × m, 2 × CHCH2P), 40.0-39.6 (m, 2 × CH3 CH), 38.9-37.5 (m, 2 × CH2P), 15.6, 15.3 (2 × CH3CH). HRMS-FAB: m/z calcd for C41H52N2O6P2S4: 859.2256; found: 859.2264.