Synthesis of [(thiazol-2-ylamino)-methylene]bisphosphonic acids

Article abstract of DOI:10.1007/s10593-011-0884-z

A method for the synthesis of [(thiazol-2-ylamino)methylene]bisphosphonic acids from (aminomethylene)-bisphosphonic acid through 3-N-unsubstituted (thioureidomethylene)bisphosphonic acid was proposed.

Full text of DOI:10.1007/s10593-011-0884-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 9, December, 2011 (Russian Original Vol. 47, No. 9, September, 2011)
SYNTHESIS OF [(THIAZOL-2-YLAMINO)-
METHYLENE]BISPHOSPHONIC ACIDS
A. L. Chuiko1**, L. P. Filonenko1, and M. O. Lozinskii1*
A method for the synthesis of [(thiazol-2-ylamino)methylene]bisphosphonic acids from (aminomethylene)-
bisphosphonic acid through 3-N-unsubstituted (thioureidomethylene)bisphosphonic acid was proposed.
Keywords: bisphosphonate, thiazole, cyclization.
Among bisphosphonate derivatives containing heterocycles biologically active compounds are found
[1-3]. We have synthesized a series of 3-substituted (thiazol-2-ylaminomethylene)bisphosphonates [4, 5] with
phytotoxic activity by the condensation of (thioureidomethylene)bisphosphonic acids with halo ketones.
Biological activity has also been found for tetraesters of [(thiazol-2-yl)aminomethylene]bisphosphonic acids
unsubstituted at the position N-3 synthesized by the condensation of aminothiazoles with triethyl orthoformate
[7].
In the present work, we attempted to extend our method for the Hantzsch condensation to the synthesis
of [(thiazolylamino)methylene]bisphosphonic acids unsubstituted at position N-3. (Thioureidomethylene)bis-
phosphonic acid 1 required for this reaction was synthesized by the acid-catalyzed decomposition of [(tert-
butylthioureido)methylene]bisphosphonic acid 2, which we obtained previously as the disodium salt from
(aminomethylene)bisphosphonic acid 3 [8]. Since acid 2 is unstable in the free state, it was used in situ without
separation from the reaction mixture. Acid 2 decomposes in hydrochloric acid with loss of the tert-butyl residue
to give (thioureidomethylene)bisphosphonic acid 1. This reaction proceeds under milder conditions than the
decomposition described for tert-butylthiourea [9], which was carried out by heating in concentrated hydro-
chloric acid at reflux. However, the decomposition of acid 2 proceeds with formation of (aminomethylene)bis-
phosphonic acid 3 as a side product. The optimal conditions for the formation of desired acid 1 according to the
31P NMR spectrum of the reaction mixture are obtained using 10% hydrochloric acid at 90°C. Under these
conditions, the decomposition of acid 2 requires 10 min and leads to a mixture consisting of 83% of the desired
acid 1 and 17% of the by-product acid 3. An attempt to use concentrated hydrochloric acid led to a mixture
of not readily identifiable side products. Acid 1 precipitated from the mixture as fine-crystalline mono-
(triethylammonium) salt 4, which is stable and can be stored under ordinary conditions without decomposition.
_______
*Deceased.
**To whom correspondence should be addressed, e-mail: chuikoal@yahoo.com.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1381-1384, September, 2011.
Original article submitted May 12, 2011.
0009-3122/11/4709-1137©2011 Springer Science+Business Media, Inc.
1137

S
PO3H2
PO3H2
S
PO3H2
N PO3H2
PO3H2
PO3H2
HCl
t-BuNCS,
Et3N
t-Bu
3
+
H2N
N
H
N
H2N
H
H
3
2
1
R
S
PO3H2
PO3H2· Et3N
Hal
O
–HHal · Et3N
PO3H2
S
Et3N
+
N
H
H2N
N
H
R
R1
R1
PO3H2
N
4
5a–l
a–j R = H, a R1 = Me, b R1 = Et, c R1 = COOH, d R1 = CH2COOMe, e R1 = Ph, f R1 = 4-ClC6H4,
g R1 = 4-MeC6H4, h R1 = 3,4-(HO)2C6H3, i R1 = 2,4-Cl2C6H3, j R1 = -naphthyl;
k R = R1 = Me; l R = COOMe, R1 = Me; Нal = Br or Cl
1
The H NMR spectra of salt 4 show two sets of signals corresponding to two isomers (21 and 79% in
DMSO-d6). Such (E)-(Z) isomerism related to the hindered rotation about the C(S)–N bonds due to their partial
double bond character is described in our previous work for (N-3)-substituted analogs of compound 4 [5].
TABLE 1. Characteristics of Products 4 and 5a-l
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С* Yield, %
C
H
N
4
C2H8N2O6P2S·
·C6H15N
27.18
27.35
6.68
6.60
11.8
12.0
120
51
5a
C5H10N2O6P2S
C6H12N2O6P2S
C5H8N2O8P2S
20.65
20.84
3.45
3.50
9.58
9.72
>215
>190
>246
>245
>260
>260
>240
>210
>265
>225
>223
>200
40
79
75
63
96
69
68
40
54
62
79
58
5b
23.54
23.85
4.29
4.00
8.81
9.27
5c
19.19
18.88
2.86
2.53
8.55
8.81
5d
C7H12N2O8P2S
C10H12N2O6P2S
C10H11ClN2O6P2S
C11H14N2O6P2S
C10H12N2O8P2S
C10H10Cl2N2O6P2S
C14H14N2O6P2S
C6H12N2O6P2S
C7H12N2O8P2S
24.46
24.29
3.59
3.49
8.14
8.09
5e
34.50
34.30
3.58
3.45
8.16
8.00
5f
30.98
31.22
3.15
2.88
6.99
7.28
5g
36.60
36.27
3.68
3.87
7.80
7.69
5h
31.18
31.42
3.32
3.16
7.12
7.33
5i
28.55
28.66
2.59
2.40
6.73
6.68
5j
41.70
42.01
3.77
3.53
7.15
7.00
5k
5l
23.45
23.75
4.06
4.00
9.49
9.27
24.22
24.29
3.62
3.49
8.06
8.09
_______
* All obtained compounds decompose upon melting.
1138

1
TABLE 2. H NMR Spectra of [(Thiazol-2-ylamino)methylene]bisphospho-
nic Acids 5a-l
Chemical shifts, δ, ppm (J, Hz)*
Com-
pound
CH(PO3H2)2 (1H, t)
R, R1
5a
5b
3.83 (J = 17.9)
4.64 (J = 21.5)
2.03 (3Н, s, СН3); 6.04 (1H, s, H-5 thiazole)
1.15 (3Н, t, J = 7.2, СН2СН3); 3.05 (2Н, m, J = 7.2, СН2СН3);
7.45 (1H, s, H-5 thiazole)
5c
5d
5e
5f
3.98 (J = 18.0)
3.71 (J = 18.9)
4.24 (J = 18.9)
4.79 (J = 21.5)
6.94 (1H, s, H-5 thiazole)
3.43 (2Н, s, СН2); 3.60 (3Н, s, СН3); 6.24 (1H, s, H-5 thiazole)
7.20–7.83 (5H, m, H Ar); 6.97 (1H, s, H-5 thiazole)
7.13 (1H, s, H-5 thiazole); 7.44 (2H, d, J = 8.2, H Ar);
7.85 (2H, d, J = 8.2, H Ar)
5g
5h
5i
4.69 (J = 21.2)
4.06 (br.)
2.31 (3Н, s, СН3); 7.00 (1H, s, H-5 thiazole);
7.20 (2H, d, J = 8.2, H Ar); 7.70 (2H, d, J = 8.2, H Ar)
6.56 (1H, s, H-5 thiazole); 6.66 (1H, d, J = 8.0, H Ar);
7.02 (1H, dd, J = 8.0, J = 1.7, H Ar); 7.37 (1H, d, J = 1.7, H Ar)
4.06 (J = 18.6)
7.09 (1H, s, H-5 thiazole); 7.46 (1H, d, J = 8.6, H Ar);
7.62 (1H, s, H Ar); 7.96 (1H, d, J = 8.6, H Ar)
5j
3.02 (J = 18.9)
3.46 (J = 18.3)
4.72 (br.)
6.78–7.59 (7Н, m, H Ar); 6.32 (1H, s, H-5 thiazole)
1.87 (3Н, s, СН3); 2.02 (3Н, s, СН3)
5k
5l*2
2.41 (3Н, s, СН3); 4.72 (3Н, с, СН3)
5l
4.14 (br.)
2.33 (3Н, s, СН3); 4.14 (3Н, s, ОСН3)
_______
*The 1H NMR spectra for compounds 5a,c-e,h,i,k,l were taken in
DMSO-d6 + 2.5% Et3N, the spectra for compounds 5b,f,g were taken in DMSO-d6,
and the spectrum for 5j was taken in D2O + Na2CO3 (added until dissolution).
*2The 1H NMR spectrum was taken in DMSO-d6.
Salt 4 readily reacts with halo ketones in ethanolic solution to give rapidly crystallizing
[(thiazol-2-ylamino)methylene]bisphosphonic acids 5a-l.
Acids 5 are colorless, high-melting compounds, which decompose upon heating, have low solubility in
DMSO, and are virtually insoluble in water, acetone, and alcohols. On the other hand, these acids readily
dissolve in water in the presence of various bases or in DMSO with added triethylamine to give salts.
Thus, we have developed a method for the synthesis of (thioureidomethylene)bisphosphonic acid
unsubstituted at position N-3 and for the conversion of this compound into [(thiazol-2-ylamino)-
methylene]bisphosphonic acid.
EXPERIMENTAL
The 1H NMR spectra were taken on a Varian VXR-300 spectrometer at 300 MHz with TMS as internal
standard for the DMSO-d6 solutions. The chemical shifts for the solutions in D2O are given relative to TMS as
external standard.
Triethylammonium Salt of (Thioureidomethylene)bisphosphonic Acid (4) [8]. t-BuNCS (3 ml,
25 mmol) was added to a solution of (aminomethylene)bisphosphonic acid (3) (3.82 g, 20 mmol) in a mixture of
methanol (50 ml), water (10 ml), and triethylamine (15 ml, 108 mmol) and left for 24 h at 60°C (heating the
mixture to reflux leads to decomposition of the product). The mixture was evaporated under reduced pressure at
1139

30°C to give a thick residue, which was dissolved in 60 ml water. The side products were extracted with ether
(320 ml) and the solution was decolorized using activated carbon. Concentrated hydrochloric acid (10 ml) was
added to the aqueous phase and heated for 10 min at 90°C. The mixture was evaporated in vacuum at 30°C to
leave a thick residue, which was dissolved in 30 ml 2-propanol and left to crystallize for one week at 0°C. The
colorless precipitate was filtered off and washed with 2-propanol. Salt 4, which readily dissolves in water, was
1
dried in vacuum at 30°C. H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.17 (9H, t, J = 7.3, 3CH2CH3); 3.06
2
3
2
3
(6H, q, J = 7.3, 3CH2CH3); 3.99 (0.21H, td, JP−H = 18.8, J = 8.4) and 5.07 (0.79H, td, JP−H = 20.5, J = 9.8,
CH); 6.14 (0.21H, m) and 8.84 (0.79H, m, NH); 7.32 (1H, br. s, NH); 9.94 (1H, s, NH).
[(Thiazol-2-ylamino)methylene]bisphosphonic Acids 5a-l (General Method). Corresponding chloro
(for compounds 5c,d,h,i,k,l) or bromo ketone (6-7 mmol) was added to a solution of compound 4 (1.76 g,
5 mmol) in methanol (10 ml) and heated under reflux for 10 min. The reaction mixture was cooled and 1 ml
concentrated hydrobromic acid was added. The mixture was left at 0°C for 12 h for crystallization. The
precipitate was filtered off, washed with methanol, and dried in the air.
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