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Addition of 1,3-disubstituted 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides to 3-thiazolines via a modified Pudovik reaction

Harald Gröger, Ion Neda, Reinhard Schmutzler and Jürgen Martens*

Fachbereich Chemie, Universität Oldenburg, PO Box 2503, D-26111 Oldenburg, Germany
Institut für Anorganische und Analytische Chemie der Technischen Universität, PO Box 3329, D-38023 Braunschweig, Germany


The addition of 1,3-disubstituted 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides 2 to 3-thiazolines 1 furnished the 2-oxo-2-thiazolidin-4-yl-2,3-dihydro-1H-benzo[1,3,2]diazaphosphinin-4-ones 3 via a modified Pudovik reaction. The use of different kinds of compounds 2 allowed some investigations of diastereoselectivity. Thereby, the acyclic N-substitutent on the nitrogen atom of the phosphorus diamide component is the dominant factor in stereocontrol. According to the experimental results a mechanistic discussion, including a postulated transition state, which leads to the major diastereomer, was carried out.

The reaction between N-substituted anthranilamides and phosphorus trichloride to produce 1,3-disubstituted 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides 2 was investigated by Coppola [1]. The chemistry of the phosphorus atom of this ring system has been studied in a number of cases [2-6]. In addition, alkylated 5,6-benzo[1,3,2]diazaphosphorinan-4-one derivatives show biological activity. In parallel, the importance of the thiazolidine system giving rise to biologically and medically interesting compounds, e.g. insecticides [7], HIV protease [8] and others is well known. Pursuing our investigations into the reactivity of the C=N bond towards P(:O)H-derivatives [6,9-12], in this communication for the first time we report the addition of 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides 2 to heterocyclic imines, namely several 3-thiazolines 1, forming the corresponding a-aminophosphonic acid derivatives 3. To the best of our knowledge only the thermally induced addition of 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide 2a to triazine as methylimine synthon was described [6], whereas no general method for addition of this kind of P(:O)H-derivative to imines has been developed until now. Furthermore, the incorporation of this kind of phosphoryl group into the thiazolidine structure may lead to significant biological activities.

In search of a general synthetic method several published strategies, well known for the addition of (RO)2P(:O)H-derivatives to carbonyl and imine compounds were employed [13-17]. But thermal activation as well as phosphorylation of 3-thiazolines using silylphosphite esters {N,N'-anthranilamide}POSiMe3 - generated in situ - are limited in their utility because of incomplete reactions. The same drawback was found using boron trifluoride-activated 3-thiazolines in the addition reaction with 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides 2 at room temperature.

Scheme 1 Addition of 5,6-benzo-1,3,2-diazaphosphorinan-4-one 2-oxides 2 to 3-thiazolines 1

Encouraged by the earlier success of Spilling [17-19] in applying phosphorus acid diamide anions in the asymmetric addition to the C=O-bond, we now successfully applied this stereoselective modified Pudovik-method to imines, namely 3-thiazolines 1. Thereby, in our study the 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide anions were used as a potential phosphorylating agent in the stereoselective reaction with 3-thiazolines [20]. Thus, 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide 2 was treated with the strong base LDA in THF solution at -50 oC to give the corresponding acid anion. Addition of boron trifluoride-activated 3-thiazoline 1 to the solution of the anion followed by refluxing the reaction mixture for 4 h resulted in the formation of the desired products 3 in satisfactory to good yield in the range of 39 to 69% (Table 1). Compared with their monocyclic analogues the 3-thiazolines with spiro structure - except in the case of 3f - gave the corresponding phosphonic acid derivatives 3b, 3c and 3e in higher yields. All the new compounds 3a-f were characterized by IR, 1H, 13C, 31P NMR and MS. In analogy to similar a-amino position P-substituted 3-thiazolidine structures [10,21] the 13C NMR spectra show a characteristic coupling 1J (C,P) with values between 115 and 117 Hz. The 31P NMR spectra exhibit the two singlets of the diastereomers ranging from 23.55 to 24.95 ppm.

Table 1 2-Oxo-2-thiazolidin-4-yl-2,3-dihydro-1H-benzo[1,3,2]diazaphosphinin-4-ones 3a-e
3 R1 R2 R3 R4 R5 Yield (%) dra
3a CH3 CH3 CH3 CH3 CH3 53 50:50
3b CH3 CH3 CH3-(CH2)4-69 50:50
3c CH3 -(CH2)5--(CH2)5-64 50:50
3dC2H5Cl CH3 CH3CH3CH35362:38
3e C2H5Cl CH3 CH3-(CH2)4-60 58:42
3f C2H5Cl -(CH2)5-CH3CH33961:39
a dr = diastereomeric ratio, determined from the 31P NMR spectra of the crude products.

The modified Pudovik reaction of 2 with 3-thiazolines 1 allowed some investigation of diastereoselectivity. The diastereomeric ratios (dr) were determined by integration of the 31P NMR spectra of the crude products (NMR spectra were recorded in CDCl3). The stereoselectivity of the reaction seems to be independent of the nature of the 3-thiazoline substituents. Using 1,3-dimethyl-5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide 2a as a phosphorylating component we obtained the products 3a-c with diastereomeric ratios dr = 50:50.

In addition, the results demonstrate that the (asymmetric) ring system in 2 has no influence on the stereospecific addition to 3-thiazolines. However, 3d-f have been obtained with some diastereoselectivity (see Table 1). Consequently, the diastereoselectivity of the reaction depends on steric (and chemical) properties of the substituents at the N atoms of the corresponding 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide. The 2-chloroethyl substituent, instead of the methyl group as substituent R1, changed the diastereoselectivity from dr = 50:50 to dr = 62:38, as shown in Table 1. Thus, the acyclic substituent on the nitrogen atom of the phosphorous diamide component is the dominant factor in stereocontrol. A further enhancement of the stereodirecting effect might be achieved using sterically more complicated N-substituents.

A study of the stereochemical mechanistic course of the described modified Pudovik reaction could be done in case of 3e regarding the X-ray spectroscopic data [22] of the major diastereomer in 3e (which was found to be the (SP*;RC*)-configuration) in connection with a transition state structure postulated by Volkmann [23] for the addition of lithiated C-nucleophiles to the boron trifluoride activated C=N double bond of 3-thiazolines. Thereby, a five-membered, heterocyclic, N,B,P-containing transition state should occur as shown in Scheme 3 in the case of the major diastereomer.

Scheme 3 Postulated transition state leading to the major diastereomer of 3e (here the transition state of only one of the two enantiomers of the major diastereomer is described)

Herein, the bulkier 2-chloroethyl group at N-3 was found in a less sterically hindered position (and more distant from the methyl groups at (thiazoline-) C-2 than the corresponding acyclic N-substituted methyl group at N-1.

This postulated transition state - leading to the major diastereomer - shows a pro(SP*;RC*)-configuration in corresponding with the (by X-ray spectroscopy observed) (SP*;RC*)-configuration in the resulting major diastereomer of 3e[22]. Thereby, a (via the Tripos force-field modelled) 3D-structure of this major diastereomer of 3e with the (SP*;RC*)-configuration is showed below in Scheme 4 [24].

Scheme 4 3D-structure of the major diastereomer of 3e (here the 3D-structure of only one of the two enantiomers of the major diastereomer is described; the 3D-modelling was carried out with the force-field program Tripos 5.2 [24]; in addition the colours of the atoms are explained in ref. 24)

In contrast to the observed diastereoselectivity in case of 3e-f the lack of diastereoselectivity in case of 3a-c can thus be explained by energetically similar transition states in the formation of the two possible diastereomers resulting from a similar sterically influence of the corresponding acyclic N-attached methyl groups.

In conclusion, we have uncovered a new route to the P-alkylated 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide adducts of imines, namely 3-thiazolines 3, via a modified Pudovik reaction. We are actively pursuing the extension of this kind of synthesis to further 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxide and heterocyclic imine systems.


This research was supported, in part, by the Fonds der Chemischen Industrie and Degussa AG. The authors would also like to thank T. Ries for experimental assistance and J. Eilers for helpful discussions about how to create WWW pages. Furthermore, we thank the Heinz Neumüller Stiftung for supporting the PhD thesis (H.G.).


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11 Gröger, H.; Tehranfar, D.; Martens, J.; Goerlich, J. R.; Thönnessen, H.; Jones, P. G.; Schmutzler, R. in preparation.

12 Goerlich, J. R. Ph.D. thesis, Technische Universität Braunschweig, 1994.

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20 General procedure for the addition of 5,6-benzo[1,3,2]diazaphosphorinan-4-one 2-oxides 2 to 3-thiazolines 1: At -50 oC lithium diisopropylamide (2 mmol; 10%; in hexane) was added to a solution of 5,6-benzo[1,3,2]diazaphosphorinan-4-on 2-oxide in abs. THF (25 ml) via a syringe under an atmosphere of argon. The resulting solution was maintained at -50 oC for 30 min, and then the boron trifluoride activated 3-thiazoline solution (3 mmol, dissolved in 10 ml abs. THF) was added at this temperature. After stirrring for 3 h at -50 oC the reaction mixture was allowed to warm to room temp. To complete the reaction the mixture was refluxed for 4 h, cooled to room temp. and hydrolysed with water (10 ml). After addition of MTBE (10 ml) the organic layer was separated, washed with water (2 x 10 ml), dried (MgSO4) and concentrated in vacuo to give the crude product. The crude products are solids or oils which crystallized at room temp.

21 Manikowski, M.; Gröger, H.; Martens, J. Electronic Conference on Trends in Organic Chemistry, (ECTOC-1), Eds. H. S. Rzepa and J. M. Goodman (CD-ROM), Royal Society of Chemistry publications, 1995. see also

22 In parallel, we reported about the MPLC-chromatographical isolation and the corresponding X-ray crystallographical data of the major diastereomer of 3e: Gröger, H.; Wilken, J.; Martens, J., Neda, I.; Pinchuk, V.; Thönnessen, H.; Jones, P. G.; Schmutzler, R. Z. Naturforsch. Teil B, 1996, 51, in press.

23 Meltz, C. N.; Volkmann, R. A. Tetrahedron Lett., 1985, 24, 4503.

24 The calculation of the 3D-structure of the major diastereomer of 3e was performed with the Tripos 5.2 force-field of the program SYBYL, Version 6.2. SYBYL is a registered trademark of Tripos, Inc. Thereby, the colours of the atoms are chosen as follows: C: grey; O: red, N: blue; P: orange; S: yellow; Cl: green.