Synthesis Of New alpha-Aminophosphonic Acids Derived From 2H-1,3-Thiazines And 2H-1,4-Benzothiazines

Jens Manikowski, Harald Gröger* and Jürgen Martens

Fachbereich Chemie, Universität Oldenburg, P. O. Box 2503, D-26111 Oldenburg, Federal Republic of Germany, e-mail:

Abstract: Dialkyl phosphite adds to the C=N bond in 2H-1,3-thiazines 4 to give α-aminophosphonic acids 6. Starting from 2H-1,4-benzothiazines 5, the corresponding phosphonic acids 7 were obtained.

The α-aminophosphonic acids and their derivates, defined as phosphorus analogues of amino acids, are of interest because of their applications in pharmacological1-6 and agriculture7-9 areas.

Scheme 1: Familiar α-aminophosphonic acid esters 1-3

In the course of our investigations on the synthesis of 4-thiazolidinyl phosphonates10 1 as intermediates of phosphonic acid analogues of penicillamine we became interested in the chemistry of the familiar six membered heterocyclic compounds.

In this paper we report the first synthesis of the novel racemic 1,3-thiazinan-4-yl-phosphonic acid esters 2 and 2-H-1,4-benzothiazin-3-phosphonic acid esters 3. One standard synthesis of α-aminophosphonic acids involves thermal addition of dialkyl phosphonates to imines11-14. By this way we decided to synthesize the desired compounds 2 and 3 starting from 2H-1,3-thiazines 4 and 2H-1,4-benzothiazines 5.

Results and Discussion

At the first time the 2H-1,3-thiazines 4 were prepared analogue to the modified Asinger-reaction, which is well-known for the preparation of 3-thiazolines15. Therefore, in a multi component one pot reaction 3-chloro-2,2-dimethylpropanal16 is treated with a further carbonyl compound in the presence of sodium hydrogen sulfide and aqueous ammonia as shown in scheme 2.

Scheme 2: One pot synthesis of 2H-1,3-thiazines 4

The 2H-1,4-benzothiazine 5 was prepared according to the procedure described by Shridhar17. The synthesized heterocyclic imines 4a-c and 5 are listed in table 1.

Table 1: 2H-1,3-thiazines 4 and 2H-1,3-benzothiazines 5

   4,5         R1       R2           Yield [%]    
   4a             -(CH2)4-              36       
   4b             -(CH2)5-              37       
    5          --       --           17           

The preparation of the new α-aminophosphonic acid esters follows the synthesis of the analogue thiazolidin-4-yl-phosphonates described earlier11,12. In practice, the synthesis is quite simple, requiring refluxing of a mixture of the cyclic imines 4 and 5 with dialkyl phosphite in ligroine for eighteen hours. After storage at -28[[ring]]C the products crystallized in several days.

Table 2: Dialkyl phosphite adducts 2 and 3

   2,3         R1       R2           R3           Yield [%]    mp           
   2a             -(CH2)4-              CH3      12           61           
   2b             -(CH2)4-             C2H5      31           76-78        
   2c             -(CH2)5-              CH3      47           78-79        
   2d             -(CH2)5-             C2H5      54           84           
   3a          --       --           CH3          40           115-117      
   3b          --       --           C2H5         74           110-111      

[a] uncorrected.

We also investigated the nature of the imine component on the rate of formation. According to their lower stability we obtained the phosphite adducts of 2H-1,3-thiazines in lower yields than 1,3-thiazolines and 2H-1,4-benzothiazines. Generally we received the diethylphosphite adducts with higher yields up to 74% than the dimethylphosphite derivates.

The 13C nmr spectra exhibit characteristic P-C signals seen as a doublet centered between 56.64 ppm and 60.66 ppm with coupling constants ranging from 147.7 Hz to 157.9 Hz. In addition with the observed 1H nmr data they are within the limits of usual values10,18-20 (table 3).

Table 3: 13C and 1H nmr data of 2 and 3

              13C nmr data[a]                  1H nmr data[a]              
  2,3       δ[C-P]       1J(C-P)    δ[CH-P]      2J(H-C-P)    4J(H-C-C-C-P)   
   2a        59.64        156.8     3.14         23.6              9.1        
   2b        56.64        157.8     3.20         23.5              7.8        
   2c        59.86        156.8     2.96         23.9              8.9        
   2d        56.72        157.9     2.79         23.8              7.6        
   3a        60.14        148.4     3.89         12.1               --        
   3b        60.66        147.7     3.88         12.7               --        

[a] δ in ppm; J in Hz.

In contrast to recently synthesized 2H-1,3-thiazine derivatives with a carbon atom instead of the phosphorus atom 21, the proton spectra show an additional coupling of one of the diastereotopic methylene protons at C2. This may be explained by an unusual large long range, w-type coupling between 31P and 1H, which is well known for other systems22-28.

Acknowledgement: This research was supported, in part, by the Fonds der Chemischen Industrie and Degussa AG. The authors would also like to thank R. Irmer and S. Vieth for experimental assistance.

References and Notes:

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