Green syntheses of potentially bioactive α-hydroxyphosphonates and related derivatives

Figures & data

Scheme 1. Green synthesis of α-hydroxyphosphonates.

Table 1. Experimental details for the preparation of α-hydroxyphosphonates (1 and 2).

Entry	R	Y^1	Y^2	Y^3	Time [min]	Yield [%]	Product
1	Me	H	H	H	10	95	1a
2	Me	Cl	H	H	10	90	1b
3	Me	NO2	H	H	5	95	1c
4	Me	H	H	NO2	5	95	1d
5^a	Me	Me	H	H	30	89	1e
6^b	Me	OMe	OMe	H	120	86	1f
7	Et	H	H	H	60	78	2a
8	Et	Cl	H	H	70	79	2b
9	Et	NO2	H	H	45	88	2c

^a In this case 0.2 equiv. of triethylamine was used.

^b In this case 0.3 equiv. of triethylamine was used.

Scheme 2. The reaction of acetophenones and dimethyl phosphite to afford 3.

Scheme 3. Phosphinoylation of 1-hydroxy-1-arylmethylphosphonates 1.

Table 2. Experimental details for the preparation of α-phosphoryloxyphosphonates (4).

Entry	Y^1, Y^2	Y^3	Time [h]	Yield [%]	Product
1	Ph	H	48	57	4Aa
2		H	24	59	4Ba
3		H	24	59	4Ba
4	Ph	Me	48	49	4Ab
5		Me	24	46	4Bb
6		Me	24	50	4Bb
7	Ph	Cl	48	61	4Ac
8		Cl	24	54	4Bc
9		Cl	24	51	4Bc
10	Ph	NO2	48	70	4Ad
11		NO2	24	72	4Bd
12		NO2	24	80	4Bd

Scheme 4. Nucleophilic substitution of diethyl α-hydroxy-benzyl-phosphonates (2) by primary amines.

Table 3. Experimental details for the preparation of α-aminophosphonates (5).

Entry	Y^1	Y^2	Time (min)	Yield (%)	Product
1	H	^nPr	10	78	5aA
2	H	^nBu	15	86	5aB
3	H	^cHex	10	84	5aC
4	Cl	^nPr	15	60	5bA
5	Cl	^nBu	20	50	5bB
6^a	Cl	^cHex	30	54	5bC
7	Me	^nPr	15	72	5dA
8	Me	^nBu	30	66	5dB
9	Me	^cHex	30	70	5dC
10	MeO	^nPr	15	58	5eA
11	MeO	^nBu	15	79	5eB
12	MeO	^cHex	30	73	5eC

^a In this case, only 2 equiv. of the amine was used.

Scheme 5. Nucleophilic substitution of 3 by n-butylamine.

Scheme 6. The green synthesis of α-hydroxyphosphonic acids 8.

Table 4. Experimental details for the preparation of α-hydroxyphosphonic acids.

Entry	Y		Time [min]	Product	Yield [%]
1	H		15	8a	80
2	2-Cl		10	8b	85
3	3-Cl		5	8c	76
4	4-Cl		7	8d	88
5	3-Me		9	8e	77
6	4-Me		9	8f	90
7	2-MeO		5	8g	72