Phosphonodithioformates: Efficient Three-Component Coupling of Dialkyl phosphites, Carbon Disulfide, and Alkyl Halides in the Presence of Cesium Carbonate and Tetrabutylammonium Iodide

Abstract

A mild one-pot, three-component coupling reaction uniting­ a dialkyl phosphite, carbon disulfide (CS₂) and an alkyl halid­e for the mild and efficient synthesis of phosphonodithio­formates using cesium carbonate (Cs₂CO₃) and tetrabutyl­ammonium iodide (TBAI) was developed. Various dialkyl phosphites were examined using a diverse array of alkyl halides, and these improved reaction conditions were found to be highly selective­ producing the title compounds exclusively in moderate to high yields.

alkylations - alkyl halides - cesium carbonate - phosphono­dithioformate - phosphorus

References

For recent leading references, see:

1a Halazy S. Ehrhard A. Eggenspiller A. Berges-Gross V. Danzin C. Tetrahedron  1996,  52:  8619 

1b Kawamoto AM. Campbell MM. J. Chem. Soc. Perkin Trans. 1  1997,  1249 

1c Caplan NA. Pogson CI. Hayes DJ. Blackburn GM. J. Chem. Soc. Perkin Trans. 1  2000,  421 

1d Yokomatsu T. Hayakawa Y. Kihara T. Koyanagi S. Soeda S. Shimeno H. Shibuya S. Bioorg. Med. Chem.  2000,  8:  2571 

2a Levillain J. Masson S. Hudson A. Alberti A. J. Am. Chem. Soc.  1993,  115:  8444 

2b Alberti A. Benaglia M. Della Bona A. Macciantelli D. Luccioni-Heuze B. Masson S. Hudson A. J. Chem. Soc., Perkin Trans. 2  1996,  1057 

2c Alberti A. Benaglia M. Bonora M. Borzatta V. Hudson A. Macciantelli D. Masson S. Polym. Degrad. Stab.  1998,  62:  559 

2d Albert A. Benaglia B. Hapiot P. Hudson A. Le Coustumer G. Macciantelli D. Masson S. J. Chem. Soc., Perkin Trans. 2  2000,  1908 

3a Bulpin A. Masson S. Sene A. Tetrahedron Lett.  1989,  30:  3415 

3b Bulpin A. Masson S. Sene A. Tetrahederon Lett.  1990,  31:  1151 

3c Bulpin A. Masson S. Sene A. J. Org. Chem.  1992,  57:  4507 

3d Masson S. Phosphorus, Sulfur Silicon Relat. Elem.  1994,  95:  127 

4 Laus M. Papa R. Sparnacci K. Alberti A. Benaglia M. Macciantelli D. Macromolecules  2001,  34:  7269 

5a Heuze B. Gasparova R. Heras M. Masson S. Tetrahedron Lett.  2000,  41:  7327 

5b Masson S. Saquet M. Marchand P. Tetrahedron  1998,  54:  1523 

5c Makomo H. Saquet M. Simeon F. Masson S. Aboutjaudet E. Collignon N. Gulea-Purcarescu M. Phosphorus, Sulfur Silicon Relat. Elem.  1996,  110:  445 

5d Mikolajczyk M. Mikina M. Graczyk PP. Balczewski P. Synthesis  1996,  1232 

5e Bulpin A. LeRoy-Gourvennec S. Masson S. Phosphorus, Sulfur Silicon Relat. Elem.  1994,  89:  119 

5f Makomo H. Masson S. Saquet M. Tetrahedron  1994,  50:  10277 

6 Grisley DW. J. Org. Chem.  1961,  2544 

7 Bulpin A. Masson S. Sene A. Tetrahedron Lett.  1989,  30:  3415 

8 Zimin MG. Dvoinishnikova TA. Konovalova IV. Pudovik AN. Zh. Obshch. Khim.  1978,  48:  2790 

9a Blackburn GM. England DA. Kolkmann F. J. Chem. Soc., Chem. Commun.  1981,  930 

9b Blackburn GM. Eckstein F. Kent DE. Perree TD. Nucleosides Nucleotides  1985,  4:  165 

10 For a general overview for the synthesis of phosphono- and phosphinopeptides, see: Kafarski P. Lejczak B. In Aminophosphonic and Aminophosphinic Acids, Chemistry and Biological Activity   Kukhar VP. Hudson HR. Wiley; England: 2000.  p.173-203  ; and references cited therein

11 Cs₂CO₃ offered a higher yield than previously reported, see: Alberti A. Benaglia M. Laus M. Sparnacci K. J. Org. Chem.  2002,  67:  7911 

12 Inverse addition (cesium salt of dialkylphosphite to CS₂) was also tried and did not result in a higher yield. Also, formation of secondary products resulting from the reaction between dialkylphosphite salts with the in situ generated cesium phosphonodithiocarboxylate leading to the expected desulfurization forming methylene diphosphonates did not arise as previously described for sodium salts. See: Masson S. Reviews in Heteroatom Chemistry   Vol. 12:  Oae S. VCH; Weinheim: 1995.  p.69-84  

13

General Experimental Procedure: To a solution of diethyl phosphite 4 (0.12 g, 0.85 mmol, 1 equiv) in anhyd DMF (5 mL) was added Cs₂CO₃ (0.83 g, 2.55 mmol, 3 equiv) and TBAI (0.94 g, 2.55 mmol, 3 equiv) with vigorous stirring for 10 min at r.t. under a N₂ atmosphere. CS₂ (0.15 mL, 2.55 mmol, 3 equiv) was added and the fuchsia colored mixture was stirred for 1 h. After this time period, benzyl bromide (0.30 mL, 2.55 mmol, 3 equiv) was added and stirred for an additional 24 h. The resultant yellow reaction suspension was then poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with water (2 × 30 mL), brine (30 mL), and dried over anhyd Na₂SO₄. Evaporation of the solvent followed by flash chromatography (hexanes-EtOAc, 9:1) afforded benzyl diethoxyphosphoryldithioformate(5) as a dark red oil (0.25 g, 97%).
¹H NMR (270 MHz, CDCl₃): δ = 1.36 (t, J _1,2 = 7.6 Hz, 6 H), 4.26 (m, 4 H), 4.46 (s, 2 H), 7.30 (s, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.20 (d, J _CP = 6.34 Hz), 40.63 (d, J _CP = 2.72 Hz), 64.70 (d, J _CP = 6.94 Hz), 128.00 (s), 128.77 (s), 129.26 (s), 133.53 (s), 228.16 [d, J _CP = 174.54 PC(S)S]; ³¹P NMR (85 MHz, CDCl₃)δ from 30% H₃PO₄-H₂O: -4.57. MS: m/z = 91, 121, 182, 248, 276, 304 (M⁺). Anal. Calcd for C₁₂H₁₇O₃PS₂: C, 47.35; H, 5.63. Found: C, 47.42; H, 5.64.

For reviews on the ‘cesium effect’, see:

14a Ostrowicki A. Vogtle F. In Topics in Current Chemistry   Vol. 161:  Weber E. Vogtle F. Springer Verlag; Heidelberg: 1992.  p.37 

14b Galli C. Org. Prep. Proced. Int.  1992,  24:  287 ; and references therein

14c Blum Z. Acta Chem. Scand.  1989,  43:  248 

15 Formation of ‘naked anions’ by solvation of cesium ions has been previously postulated and studied extensively: Dijstra G. Kruizinga WH. Kellogg RM. J. Org. Chem.  1987,  52:  4230 

For examples of efficient cesium-promoted alkylations, see:

16a Parrish JP. Dueno EE. Kim S.-I. Jung KW. Synth. Commun.  2000,  30:  2687 

16b Salvatore RN. Flanders VL. Ha D. Jung KW. Org. Lett.  2000,  2:  2797 

16c Dueno EE. Chu F. Kim S.-I. Jung KW. Tetrahedron Lett.  1999,  40:  1843 

16d Salvatore RN. Nagle AS. Schmidt SE. Jung KW. Org. Lett.  1999,  1:  1893 

16e Salvatore RN. Shin SI. Nagle AS. Jung KW. J. Org. Chem.  2001,  66:  1035 

16f Salvatore RN. Sahab S. Jung KW. Tetrahedron Lett.  2001,  42:  2055 

16g Salvatore RN. Schmidt SE. Shin SI. Nagle AS. Worrell JH. Jung KW. Tetrahedron Lett.  2000,  41:  9705 

16h Salvatore RN. Ledger JA. Jung KW. Tetrahedron Lett.  2001,  42:  6023 

16i Kim S.-I. Chu F. Dueno EE. Jung KW. J. Org. Chem.  1999,  64:  4578 

16j Salvatore RN. Chu F. Nagle AS. Kapxhiu EA. Cross RM. Jung KW. Tetrahedron  2002,  58:  3329 

16k Salvatore RN. Shin SI. Flanders VL. Jung KW. Tetrahedron Lett.  2001,  42:  1799 

16l Salvatore RN. Nagle AS. Jung KW. J. Org. Chem.  2002,  67:  674 

TBAI is strongly believed to act as a phase-transfer catalyst in the reaction, therefore, facilitating alkylations producing high product yields. For other phase-transfer catalyzed phosphorus alkylations, see:

17a Kem KM. Nguyen NV. Cross DJ. J. Org. Chem.  1981,  46:  5188 

17b Weber WP. Gokel GW. Phase Transfer Catalysts in Organic Synthesis   Springer Verlag; New York: 1977. 

17c Starks CM. Liotta C. Phase Transfer Catalysis: Principles and Techniques   Academic Press; New York: 1978. 

17d However, we cannot rule out an internal Finkelstein-type reaction for the in-situ generation of alkyl iodides from bromides and chlorides, hence improving yields. Although, the use of alkyl iodides directly, without TBAI gave lower product yields. Therefore, we propose TBAI minimizes or prohibits direct alkylation of the phosphite with an alkyl halide presumably enhancing the rate of CS₂ incorporation/and or stabilizing the phosphoryl dithioformate anion through conjugation with the tetrabutylammonium cation. Whereas, the cesium ion tends to weakly coordinate to the conjugate anions, making them more nucleophilic. Prior to addition of the halide, the phosphite and CS₂ were reacted to pre-form the incipient dithioformate anion, which is belived to suppress direct alkylation of the phosphite. For a similar example, see ref. for a mechanistic interpretation and for the use of TBABr and other onium salts in the formation of urethanes: Yoshida M. Hara N. Okuyama S. Chem. Commun.  2000,  151 

18

Since dithioesters are known to be very good thioacylating agents for amines due to the high electrophilicity of the C=S which is activated by the phosphono-substituent (an electron-withdrawing group), amino bromides 13 and 15 were used as the corresponding hydrobromide salts, since a spontaneous intermolecular reaction to give thioamides or cyclization to the phosphonothiazoline can readily occur. Neither the aforementioned thioacylation reaction (which usually occurs with the alkyl group in the phosphono-moiety) or cyclization was seen. Therefore, we wish to strongly emphasize product structures for aminodithioesters from 13 and 15 were isolated and assigned without ambiguity from the exact mass (MS), ¹H, ¹³C, and ³¹P NMR spectroscopy.

19 Nagle AS. Salvatore RN. Chong BD. Jung KW. Tetrahedron Lett.  2000,  41:  3011 

20

¹H NMR, ¹³C NMR, ³¹P NMR and 2D NMR analysis indicate the product as a single diastereomer.

For new biologically active phosphonates, see:

21a Hildebrand R. The Role of Phosphonates in Living Systems   CRC Press; Boca Raton: 1983. 

21b Engel R. Chem. Rev.  1977,  77:  349 

21c Kafarski P. Leczak B. Phosphorus, Sulfur Silicon Relat. Elem.  1991,  63:  193