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Synthesis of γ-keto-substituted phosphinic acids from bis(trimethylsilyl)phosphonite and α,β-unsaturated ketones
Tetrahedron Letters, Vol. 33, No. 6, pp. 813-816, 1992 Printed in Great Britain
0040-4039/92 $3.00 + .00 Pergamon Press plc
Synthesis of T-Keto-substituted Phosphinic Acids from Bis(trimethylsilyl)phosphonite and a,l~-Unsaturated Ketones 1 E. Andrew Boyd 2a and Andrew C. Regan *2b
Chemical Laboratory, The University, Canterbury, Kent CT2 7NH, U.K. Keith James
Pfizer Central Research, Sandwich, Kent CT13 9N J, U.K.
Key Words." Bis(trimethylsilyl)phosphonite (BTSP); Phosphinic Acids; 1,4 Michael-type Addition; Adamantanammonium Phosphinates. Abstract: Mono- and di-substituted phosphinic acids have been synthesised in high yield by
addition of silyl phosphonites to ~,~-unsaturated ketones, and conveniently purified vi___a_atheir adamantanammonium salts.
The realisation of the importance of phosphinic acids in understanding and modulating biological processes has generated interest in novel and more efficient routes for their synthesis.3 We have recently developed a method for the synthesis of mono- and di-substituted phosphinic acids,3 which involves the in-situ generation of bis(trimethylsilyl)phosphonite (BTSP) (2) using trimethylsilylchloride/triethylamine,and subsequent conjugate addition to c~,~-unsaturated esters. This method has the advantage of avoiding purification and handling of the very pyrophoric BTSP; however, a large excess of BTSP must be used if further reaction of the initially formed product is to be avoided. We have also found that the reaction with enolisable cql~-unsaturated ketones under these conditions is unsatisfactory, resulting in complex mixtures and negligible yields of the desired product. This can be rationalised by invoking competitive formation of Danishefsky-type silyloxydienes,4 since an excess of trimethylsilylchloride/triethylamine is present in the reaction mixture. Non-enolisable vinyl ketones reacted satisfactorily. In this Letter, we present a new method which overcomes both of the above limitations. We reasoned that a method was required for in-situ generation of BTSP which avoided the presence of excess base or silylating agent, and thus consequent silyloxydiene formation. This was effectively achieved by heating ammonium phosphinate (1) and hexamethyldisilazane (HMDS) for 1-2 h at 100-110 °C under an inert atmosphere, 5 until all the ammonia by-product had been evolved, and then cooling the flask containing the BTSP to room temperature. Dichloromethane solvent was added, followed by one equivalent of the appropriate unsaturated ketone (3) at 0 °C, and stirred for 2-12 h. Aqueous work-up gave the free mono-substituted phosphinic acids (4) in good yields (Scheme 1). Products with appreciable solubility in water were conveniently isolated by stirring in methanol-tetrahydrofuran, followed by evaporation. The mono-substituted phosphinic acids prepared in this way were oils, which were almost pure after direct isolation. However it was not possible to obtain analytically pure material by conventional methods e.g. distillation or chromatography. After extensive efforts at purification, the most efficient method was 813
814
R1 R 2 W ~ 1.
O ii
,PM%SiO
N2, 110 °C, 1-2 h
oe
O
o
(Me3Si) 2NH
H'~'H
R (3)
+ NH3T
~ HIP HO i~2
CH2C12, 0 °C
NH4~
Rl R ~
2. H30 +
(1)
(4)
(2) Scheme 1.
found to be by formation of adamantanammonium phosphinate salts. This was best effected by a work-up involving stirring the silylated product in a solution of adamantanamine in methanol-tetrahydrofuran, giving white crystalline adamantanammonium phosphinates which could be isolated by filtration, and which were generally analytically pure (Table 1). In line with our earlier work,3 unsaturated esters could also be used as electrophiles under these conditions (results not shown).
Table 1. Preparation of Mono-substituted Phosphinic Acids Unsaturated Ketone (3)
Mono-substituted Phosphinic Acid (4)
Yield (%)a
II
.P
Mono-substituted Yield (%)a Phosphinic Acid (4) O
O
~.~Me
Unsaturated Ketone (3)
A
74
.Me
0
Me , . . r . , ~ Me Me
0
II
,. P~ ~
°"°Me\J e
II
..P_ A
_Et
89
0
O
Et 0
II
H o'C2
91
II
..P~ A t O
87
H . P v ~ " . , ~ Pr OH
o
O
II
0
Me ~
~
0
~-....~ Pr
80
O
O
,..~..~ Et
_Me
HH6"~ "
~5
O II /P~EI H H6 Me ~
87
o ..fo
HoO
80
79
O n-Bu , . . . ~
Me 0
II
H, P,,~',,W Me
H61 8 n-Bu
a. isolated as adamantanammonium salt
77
4-cholesten3-one
Cholestan-3-one5-phosphinic acid
76 b
b. isolated as free phosphinic acid
Di-substituted phosphinic acids (6) could also be formed by adding a second equivalent of HMDS to the reaction mixture, followed by a second Michael acceptor, before work-up (Scheme 2). The second electrophile could be different from the first, and hence both symmetrical and unsymmetrical di-substituted phosphinic acids could be formed in a one-pot reaction. Both unsaturated ketones and esters could be used as
815
electxophiles (Table 2). This is a further improvement on our previous work, 3 where isolation of the intermediate mono-substituted acid was necessary if an unsymmetrical di-substituted phosphinic acid was required. It was not necessary to form adamantanammonium salts of these di-substituted phosphinic acids because they were generally isolated as crystalline solids, which were pure after washing with hexane. In conclusion, methodology has been established to synthesise in high yield a wide variety of monoand di-substituted phosphinic acids in a one-pot reaction, under very mild conditions. R1
R
R
1.
Me3SiO
R ~,-,~ (3)
R
3.
O
CH2C12, 0
O
2. (Me3Si)2NH
R 40Hl~2
4. H30 +
(2)
(6) Scheme 2.
Table 2. Preparation of Di-substituted Phosphinic Acids. First Electrophile (3)
Second Electrophile (5)
Di-substituted Phosphinic Acid (6)
Yielda (%)
O
O
87
n-Pr ~ P " o H O ,/2
n-Pr
n-Pr
O
O Pii
Me v ~ . r l ~ Et O
n-Pr
n-Pr
~ o
~
Et
83
Me O
O
O CO2Et
Et
Me
Me
MeO2C'~
Et .tf,,,'-..,.,f I ~ C O 2 E t O OH
CO2Et
O
MeO2Ct[",--I i ~ C O 2 E t OH
a. isolated as free phosphinic acid
79
77
R1
O
816
Typical Experimental Procedure. 6 1. Mono-substituted phosphinic acids (4) and adamantanammonium salts Ammonium phosphinate7 (2.5 g, 30.1 mmol) and hexamethyldisilazane (4.9 g, 30.1 mmol) were heated together at 100-110 °C under nitrogen8 for 1-2 h in a 100 ml 3-neck flask fitted with a septum and condenser. The system was cooled to 0 °C and dry dichloromethane9 (30 ml) was injected, followed by the unsaturated ketone (31.6 mmol). The reaction was stirred overnight at room temperature, filtered, and the solvent removed to yield an oil. This oil could conveniently be divided to prepare either free phosphinic acids or the adamantanammoniumsalts. Free phosphinic acids (4), were prepared either by washing a solution of the above oil in dichloromethane with 2 M hydrochloric acid, followed by drying and removal of solvent, or by dissolving in methanol-tetrahydrofuran, followed by stirring for 2 h and removal of solvent. Adamantanammonium phosphinates were prepared by addition of a solution of adamantanamine (1.05 eq.) in methanol-tetrahydrofuran (20:80) to a solution of the above oil in tetrahydrofuran at 0 °C. The mixture was stirred at room temperature overnight, and the crystalline product was collected by filtration.
2. Di-substituted phosphinic acids (6). Ammonium phosphinate7 (2.5 g, 30.1 mmol) and hexamethyldisilazane 4.9 g, 30.1 mmol) were heated together at 100-110 °C under nitrogen8 for 1-2 h as above. The system was cooled to 0 °C and dry dichloromethane9 (40 ml) was injected, followed by the appropriate unsaturated ketone or ester (31.6 mmol). The reaction was stirred overnight at room temperature, cooled to 0 °C, and hexamethyldisilazane (4.9 g, 30.1 mmol) was added. After 2 h the appropriate second electrophile was added at 0 °C, and stirred overnight at room temperature. Aqueous acidic work-up with 2 M hydrochloric acid resulted in isolation of the phosphinic acid as a crystalline solid.
Acknowledgements: We should like to thank the SERC and Pfizer Central Research for a CASE award to E.A.B., and the SERC Mass Spectrometry Service at Swansea for mass spectra. REFERENCES AND NOTES. 1. 2.
3. 4. 5. 6. 7.
Taken from: E. Andrew Boyd, Ph.D. Thesis, University of Kent at Canterbury, 1990. (a) Present address: Department of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 2AH, U.K. (b) Present address: Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K. Boyd, E. A.; Corless, M.; James, K.; Regan, A. C. Tetrahedron Lett., 1990, 31, 2933-2936, and references cited therein. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc., 1974, 96, 7807-7808; Danishefsky, S.; Kitahara, T.; Yan C. F.; Morris, J. ibid, 1979, 101, 6996-7000. Issleib, K.; M6gelin, W.; Balszuweit, A. Z. Anorg. Allg. Chem., 1985, 530, 16-28. Satisfactory IR, NMR (tH, 31p, and, usually, 13C), and mass spectra, and elemental analysis and/or accurate mass were obtained for all new compounds. Ammonium phosphinate was conveniently prepared t by carefully adding commercially available phosphinic acid (50 % aqueous solution, also called hypophosphorous acid) to 0.880 aqueous ammonia in equimolar amounts. Rotary evaporation of water was followed by rigorous drying over P205 in vaelto.
8. 9.
Commercial oxygen-free nitrogen was used without further purification. Dichloromethane was freshly distilled under nitrogen from P205 .
(Received in UK 5 November 1991)
0040-4039/92 $3.00 + .00 Pergamon Press plc
Synthesis of T-Keto-substituted Phosphinic Acids from Bis(trimethylsilyl)phosphonite and a,l~-Unsaturated Ketones 1 E. Andrew Boyd 2a and Andrew C. Regan *2b
Chemical Laboratory, The University, Canterbury, Kent CT2 7NH, U.K. Keith James
Pfizer Central Research, Sandwich, Kent CT13 9N J, U.K.
Key Words." Bis(trimethylsilyl)phosphonite (BTSP); Phosphinic Acids; 1,4 Michael-type Addition; Adamantanammonium Phosphinates. Abstract: Mono- and di-substituted phosphinic acids have been synthesised in high yield by
addition of silyl phosphonites to ~,~-unsaturated ketones, and conveniently purified vi___a_atheir adamantanammonium salts.
The realisation of the importance of phosphinic acids in understanding and modulating biological processes has generated interest in novel and more efficient routes for their synthesis.3 We have recently developed a method for the synthesis of mono- and di-substituted phosphinic acids,3 which involves the in-situ generation of bis(trimethylsilyl)phosphonite (BTSP) (2) using trimethylsilylchloride/triethylamine,and subsequent conjugate addition to c~,~-unsaturated esters. This method has the advantage of avoiding purification and handling of the very pyrophoric BTSP; however, a large excess of BTSP must be used if further reaction of the initially formed product is to be avoided. We have also found that the reaction with enolisable cql~-unsaturated ketones under these conditions is unsatisfactory, resulting in complex mixtures and negligible yields of the desired product. This can be rationalised by invoking competitive formation of Danishefsky-type silyloxydienes,4 since an excess of trimethylsilylchloride/triethylamine is present in the reaction mixture. Non-enolisable vinyl ketones reacted satisfactorily. In this Letter, we present a new method which overcomes both of the above limitations. We reasoned that a method was required for in-situ generation of BTSP which avoided the presence of excess base or silylating agent, and thus consequent silyloxydiene formation. This was effectively achieved by heating ammonium phosphinate (1) and hexamethyldisilazane (HMDS) for 1-2 h at 100-110 °C under an inert atmosphere, 5 until all the ammonia by-product had been evolved, and then cooling the flask containing the BTSP to room temperature. Dichloromethane solvent was added, followed by one equivalent of the appropriate unsaturated ketone (3) at 0 °C, and stirred for 2-12 h. Aqueous work-up gave the free mono-substituted phosphinic acids (4) in good yields (Scheme 1). Products with appreciable solubility in water were conveniently isolated by stirring in methanol-tetrahydrofuran, followed by evaporation. The mono-substituted phosphinic acids prepared in this way were oils, which were almost pure after direct isolation. However it was not possible to obtain analytically pure material by conventional methods e.g. distillation or chromatography. After extensive efforts at purification, the most efficient method was 813
814
R1 R 2 W ~ 1.
O ii
,PM%SiO
N2, 110 °C, 1-2 h
oe
O
o
(Me3Si) 2NH
H'~'H
R (3)
+ NH3T
~ HIP HO i~2
CH2C12, 0 °C
NH4~
Rl R ~
2. H30 +
(1)
(4)
(2) Scheme 1.
found to be by formation of adamantanammonium phosphinate salts. This was best effected by a work-up involving stirring the silylated product in a solution of adamantanamine in methanol-tetrahydrofuran, giving white crystalline adamantanammonium phosphinates which could be isolated by filtration, and which were generally analytically pure (Table 1). In line with our earlier work,3 unsaturated esters could also be used as electrophiles under these conditions (results not shown).
Table 1. Preparation of Mono-substituted Phosphinic Acids Unsaturated Ketone (3)
Mono-substituted Phosphinic Acid (4)
Yield (%)a
II
.P
Mono-substituted Yield (%)a Phosphinic Acid (4) O
O
~.~Me
Unsaturated Ketone (3)
A
74
.Me
0
Me , . . r . , ~ Me Me
0
II
,. P~ ~
°"°Me\J e
II
..P_ A
_Et
89
0
O
Et 0
II
H o'C2
91
II
..P~ A t O
87
H . P v ~ " . , ~ Pr OH
o
O
II
0
Me ~
~
0
~-....~ Pr
80
O
O
,..~..~ Et
_Me
HH6"~ "
~5
O II /P~EI H H6 Me ~
87
o ..fo
HoO
80
79
O n-Bu , . . . ~
Me 0
II
H, P,,~',,W Me
H61 8 n-Bu
a. isolated as adamantanammonium salt
77
4-cholesten3-one
Cholestan-3-one5-phosphinic acid
76 b
b. isolated as free phosphinic acid
Di-substituted phosphinic acids (6) could also be formed by adding a second equivalent of HMDS to the reaction mixture, followed by a second Michael acceptor, before work-up (Scheme 2). The second electrophile could be different from the first, and hence both symmetrical and unsymmetrical di-substituted phosphinic acids could be formed in a one-pot reaction. Both unsaturated ketones and esters could be used as
815
electxophiles (Table 2). This is a further improvement on our previous work, 3 where isolation of the intermediate mono-substituted acid was necessary if an unsymmetrical di-substituted phosphinic acid was required. It was not necessary to form adamantanammonium salts of these di-substituted phosphinic acids because they were generally isolated as crystalline solids, which were pure after washing with hexane. In conclusion, methodology has been established to synthesise in high yield a wide variety of monoand di-substituted phosphinic acids in a one-pot reaction, under very mild conditions. R1
R
R
1.
Me3SiO
R ~,-,~ (3)
R
3.
O
CH2C12, 0
O
2. (Me3Si)2NH
R 40Hl~2
4. H30 +
(2)
(6) Scheme 2.
Table 2. Preparation of Di-substituted Phosphinic Acids. First Electrophile (3)
Second Electrophile (5)
Di-substituted Phosphinic Acid (6)
Yielda (%)
O
O
87
n-Pr ~ P " o H O ,/2
n-Pr
n-Pr
O
O Pii
Me v ~ . r l ~ Et O
n-Pr
n-Pr
~ o
~
Et
83
Me O
O
O CO2Et
Et
Me
Me
MeO2C'~
Et .tf,,,'-..,.,f I ~ C O 2 E t O OH
CO2Et
O
MeO2Ct[",--I i ~ C O 2 E t OH
a. isolated as free phosphinic acid
79
77
R1
O
816
Typical Experimental Procedure. 6 1. Mono-substituted phosphinic acids (4) and adamantanammonium salts Ammonium phosphinate7 (2.5 g, 30.1 mmol) and hexamethyldisilazane (4.9 g, 30.1 mmol) were heated together at 100-110 °C under nitrogen8 for 1-2 h in a 100 ml 3-neck flask fitted with a septum and condenser. The system was cooled to 0 °C and dry dichloromethane9 (30 ml) was injected, followed by the unsaturated ketone (31.6 mmol). The reaction was stirred overnight at room temperature, filtered, and the solvent removed to yield an oil. This oil could conveniently be divided to prepare either free phosphinic acids or the adamantanammoniumsalts. Free phosphinic acids (4), were prepared either by washing a solution of the above oil in dichloromethane with 2 M hydrochloric acid, followed by drying and removal of solvent, or by dissolving in methanol-tetrahydrofuran, followed by stirring for 2 h and removal of solvent. Adamantanammonium phosphinates were prepared by addition of a solution of adamantanamine (1.05 eq.) in methanol-tetrahydrofuran (20:80) to a solution of the above oil in tetrahydrofuran at 0 °C. The mixture was stirred at room temperature overnight, and the crystalline product was collected by filtration.
2. Di-substituted phosphinic acids (6). Ammonium phosphinate7 (2.5 g, 30.1 mmol) and hexamethyldisilazane 4.9 g, 30.1 mmol) were heated together at 100-110 °C under nitrogen8 for 1-2 h as above. The system was cooled to 0 °C and dry dichloromethane9 (40 ml) was injected, followed by the appropriate unsaturated ketone or ester (31.6 mmol). The reaction was stirred overnight at room temperature, cooled to 0 °C, and hexamethyldisilazane (4.9 g, 30.1 mmol) was added. After 2 h the appropriate second electrophile was added at 0 °C, and stirred overnight at room temperature. Aqueous acidic work-up with 2 M hydrochloric acid resulted in isolation of the phosphinic acid as a crystalline solid.
Acknowledgements: We should like to thank the SERC and Pfizer Central Research for a CASE award to E.A.B., and the SERC Mass Spectrometry Service at Swansea for mass spectra. REFERENCES AND NOTES. 1. 2.
3. 4. 5. 6. 7.
Taken from: E. Andrew Boyd, Ph.D. Thesis, University of Kent at Canterbury, 1990. (a) Present address: Department of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 2AH, U.K. (b) Present address: Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K. Boyd, E. A.; Corless, M.; James, K.; Regan, A. C. Tetrahedron Lett., 1990, 31, 2933-2936, and references cited therein. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc., 1974, 96, 7807-7808; Danishefsky, S.; Kitahara, T.; Yan C. F.; Morris, J. ibid, 1979, 101, 6996-7000. Issleib, K.; M6gelin, W.; Balszuweit, A. Z. Anorg. Allg. Chem., 1985, 530, 16-28. Satisfactory IR, NMR (tH, 31p, and, usually, 13C), and mass spectra, and elemental analysis and/or accurate mass were obtained for all new compounds. Ammonium phosphinate was conveniently prepared t by carefully adding commercially available phosphinic acid (50 % aqueous solution, also called hypophosphorous acid) to 0.880 aqueous ammonia in equimolar amounts. Rotary evaporation of water was followed by rigorous drying over P205 in vaelto.
8. 9.
Commercial oxygen-free nitrogen was used without further purification. Dichloromethane was freshly distilled under nitrogen from P205 .
(Received in UK 5 November 1991)