Phosphorylation of imidazo[2, 1-b]thiazoles with phosphorus(III) halides in the presence of bases

Article abstract of DOI:10.1002/hc.20166

The reaction of phosphorus (III) halides with 6-substituted imidazo[2, 1-b]thiazoles in the presence of bases proceeds regioselectively and affords 5-phosphinoimidazo[2,1-b]thiazoles, useful synthons for the preparation of various P(III) and P(V) derivati

Full text of DOI:10.1002/hc.20166

Heteroatom Chemistry
Volume 16, Number 7, 2005
Phosphorylation of Imidazo[2,1-b]thiazoles
with Phosphorus(III) Halides in the Presence
of Bases
Evgenij V. Zarudnitskii,1 Aleksandr A. Yurchenko,1 Anatolij S.
Merkulov,1 Marina G. Semenova,1 Aleksandr M. Pinchuk,1
and Andrej A. Tolmachev2
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya str.,
5, Kyiv-94, 02094, Ukraine
2National Taras Shevchenko University, Volodymyrskaya str., 62, Kyiv-33, 01033, Ukraine
Received 1 September 2005; revised 5 September 2005
containing phosphorus compounds. The high re-
ABSTRACT: The reaction of phosphorus(III) halides
gioselectivity was also observed on phosphoryla-
with 6-substituted imidazo[2,1-b]thiazoles in the pres-
tion of imidazoles fused to six-membered heterocy-
ence of bases proceeds regioselectively and affords
cles, e.g. 2-substituted imidazo[1,2-a]pyridines, with
5-phosphinoimidazo[2,1-b]thiazoles, useful synthons
phosphorus(III) halides [3]. Now we report on the
for the preparation of various P(III) and P(V)
extension of the reaction to imidazoles fused to
derivatives. 5-Phosphinoimidazo[2,1-b]thiazoles are
five-membered rings, i.e., 6-substituted imidazo[2,1-
selectively alkylated at the phosphorus or heterocyclic
b]thiazoles, the phosphorylated derivatives of which
nitrogen atom, depending on the alkylating agent.
are unknown.
ꢀ
C
2005 Wiley Periodicals, Inc. Heteroatom Chem 16:648–
655, 2005; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20166
RESULTS AND DISCUSSION
The 6-substituted imidazo[2,1-b]thiazoles 1a–c react
regioselectively with P(III) halides in equimolar pro-
portion to give 5-phosphino imidazo[2,1-b]thiazoles
INTRODUCTION
The previously developed new synthetic approach
to C-phosphorylated N-alkylimidazoles and N-
alkylbenzimidazoles through immediate phosphory-
lation of the substrates with phosphorus(III) [1] or
phosphorus(V) [2] halides provided access to key
phosphorus acid halides and dihalides, the valuable
synthons for the preparation of various imidazole-
2–4 (Scheme 1). The structure of the phosphory-
lation products was strictly confirmed by H NMR
spectra showing the absence of the singlet due to the
C(5)–H proton (Table 2).
The phosphorylation rate substantially depends
on the electronic nature of the R substituent and
decreases in the order Me > Ph > Cl. Thus, with a
donor methyl group (R = Me) the phosphorylation
by PCl3 is complete within a few minutes at room
temperature, whereas with R = Ph or R = Cl it takes
a day or a week, respectively. In this connection,
it is worthwhile to use in the last case PBr3 as the
1
∗Phosphorylated Azoles. Part III.
Correspondence to: Aleksandr A. Yurchenko; e-mail:
yurchenko@bpci.kiev.ua.
c
ꢀ
2005 Wiley Periodicals, Inc.
648

Phosphorylation of Imidazo[2,1-b]thiazoles with Phosphorus(III) Halides in the Presence of Bases 649
SCHEME 3
SCHEME 1
lamine and sulfur, the bromophosphines 6a, b are
transformed into thiophosphinates 7a, b.
Dihalogenophosphines 2, 3 are crystalline solids
easily hydrolyzable in moist air. Compounds readily
react with secondary amines to give diaminophos-
phines 8–10. On hydrolysis 2, 3 are transformed into
phosphinic acid 11. By successive treatment with
ethanol and sulfur, dibromophosphine 3a was trans-
formed into thiophosphonates 12 (Scheme 3).
Phosphines 8–10 were oxidized into a series of
phosphorylated imidazo[2,1-b]thiazole derivatives
with P(V) atom 13–18 (Scheme 4).
phosphorylating agent with which the reaction is
completed within 2 h and affords dibromophosphine
3b (δ 31P = 90.92 ppm). The agent Ph2PCl can be used
for the preparation of phosphine 4a, while for syn-
thesis of phosphines 4b, c it is necessary to use more
reactive Ph2PBr.
The influence of the substituent R in the start-
ing compounds 1a–c tells not only about the phos-
phorylation rate but also the number of heterocyclic
residues which can be attached to the phosphorus
atom. Thus, the phosphorylation in the system with
the ratio 1 : PHal3 = 3:1 gives the phosphine 5 if R =
Me, whereas with R = Ph or Cl the end products
are bromobisheteroarylphosphines 6a, b. It is more
convenient to prepare the latter at the 2:1 ratio of
the reagents (Scheme 2). On treatment with diethy-
Phosphines
4,8–10,
like
phosphorylated
imidazo[1,2-a]pyridines [3] and imidazoles [1],
can be selectively alkylated at the phosphorus
or heterocyclic nitrogen atom, depending on the
alkylating agent. The first route is realized on
alkylation with methyl iodide and the molar ratio
of the reagents of 1:1 to give phosphonium salts 19.
With excess of methyl iodide both the phosphorus
and the N(2) atom are methylated to yield salts
20. The alkylation of phosphines 4, 9 through the
second route into the compounds 21 occurs when
Meerwein salts are used as the alkylating agent
(Scheme 5).
The P(V)-substituted imidazo[2,1-b]thiazoles are
alkylated on the nitrogen atom with the formation of
imidazo[2,1-b]thiazolium salts 22 (Scheme 6).
EXPERIMENTAL
All the manipulations with air-sensitive compounds
were performed under dry argon. Solvents were puri-
fied by conventional procedures. Melting points were
SCHEME 2

650 Zarudnitskii et al.
SCHEME 4
determined with an electrothermal capillary melting
point apparatus and were uncorrected.
Synthesis of Dihalogenophosphines 2,3
To a solution of compounds 1 (50 mmol) in pyridine
(50 mL) was added triethylamine (60 mmol), then
phosphorus trichloride or tribromide (50 mmol) was
added dropwise under cooling at such a rate that the
temperature was maintained at about 10˚C, and the
mixture was allowed to warm up to room temper-
ature. After completion of the reaction, the solvent
was evaporated in vacuo and benzene (50 mL) was
added to the residue. The precipitated triethylamine
hydrochloride was filtered off, and the filtrate was
evaporated in vacuo.
The 31P, 1H, 13C NMR spectra were measured on
a spectrometer Varian VXR-300 (121, 300, and 75
MHz, respectively). Chemical shifts are reported rel-
ative to internal tetramethylsilane (1H, 13C) or exter-
nal 85% H3PO4 (31P).
All the analytical, spectral, and other physical
data were collected in Tables 1, 2, and 3.
Synthesis of Phosphines 4
A mixture of compound 1 (20 mmol), triethylamine
(20 mmol), and chloro- or bromodiphenylphosphine
(20 mmol) in pyridine (20 mL) was allowed to stand
for 24 h at room temperature, then the reaction mix-
ture was diluted with benzene (60 mL); the precip-
itated triethylamine hydrochloride was removed by
filtration, the filtrate was evaporated in vacuo, and
SCHEME 5
SCHEME 6

Phosphorylation of Imidazo[2,1-b]thiazoles with Phosphorus(III) Halides in the Presence of Bases 651
TABLE 1 Yields, Analytical Data, and 31P NMR Spectra
Mp ( ◦C)
Found (Calculated)(%)
Yield
(%)
Bp/pressure, ◦C/Torr
(cryst. solvent)
δ
31P(ppm)
(Solvent)
Mol. Formula
N
P
2a
93
100.5–102
137–140/0.14
142–143 (C6H6)
144–146
C6H5Cl2N2PS
120.9 (C6H6)
11.53 (11.72)
12.57 (12.96)
2b
2c
90
87
C11H7Cl N PS
C5H Cl 2N 2PS
122.9 (C6H6)
117.0 (C6H6)
9.21 (9.30)
10.53 (10.80)
10.03 (10.29)
11.51 (11.94)
2
3 2
130/0.09a
3a
4a
92
69
108–109
138–139
135–138/0.01
C11H7Br2N2PS
18H15N2PS
100.9 (C5H5N)
−36.8 (CHCl3)
7.23 (7.18)
8.39 (8.69)
7.99 (7.94)
9.51 (9.61)
C
(n-C8H18
)
4b
4c
5
7a
7b
8
72
70
50
67
64
68
166–167 (C2H5OH)
127–128 (CH3OH)
232–233 (C6H6)
150–151 (CH3COOEt)
174–176 (CH3COOEt)
45–46
C23H17N2PS
C17H12ClN2PS
C18H15N6PS3
−34.3 (C5H5N)
−35.4 (CHCl3)
−86.6 (C5H5N)
33.1 (CHCl3)
25.0 (C6H6)
7.09 (7.29)
7.99 (8.17)
19.07 (18.99)
12.89 (13.12)
15.61 (15.55)
21.64 (21.86)
7.87 (8.06)
8.78 (9.04)
6.75 (7.00)
5.59 (5.80)
6.93 (6.88)
11.86 (12.08)
C26H24N5PS
C14H14Cl N5P3S
2
3
C
10H17N4PS
88.3 (C6H6)
139–142/0.01
150–155/0.04
Oil
101–102 (n-C7H16
157–158
149–151
81–82 (n-C7H
48–50 (n-C7H16
60–62 (n-C6H
152–154
67–68 (n-C7H16
85–87
197–198 (i -C H7OH)
153–155 (CH33COOEt:i -
C3H7OH/1:1)
9a
72
70
84
83
87
64
89
83
87
85
77
73
74
C
C
14H25N4PS
19H27N4PS
82.0 (C5H5N)
82.5 (C5H5N)
83.4 (C6H5CH3)
18.03 (17.93)
15.03 (14.96)
16.28 (16.46)
9.97(9.91)
8.07(8.27)
9b
10
)
C14H21N4O2PS
C H7N2O2PS
C161H9N2O2PS
C15H17N2O2PS2
C10H17N4PS2
C14H25N4PS2
14H21N4O2PS2
C19H27N4PS2
C H Cl2N4PS
10 17
8.89 (9.10)
15.03 (15.32)
11.56 (11.72)
8.62 (8.79)
10.49 (10.74)
9.09 (8.99)
8.11 (8.32)
7.51 (7.62)
9.24 (9.47)
9.87 (10.06)
8.38 (8.51)
11a
11b
12
−3.6 d, J = 562 Hz (CH3OH) 13.71 (13.86)
5.0 d, J = 659 Hz (H2O)
69.3 (C6H6)
10.41 (10.60)
8.03 (7.95)
)
)
)
13a
13b
13c
13d
14
15a
15b
66.7 (CHCl3)
61.6 (CHCl3)
62.1 (C6H6)
58.0 (DMSO)
46.2 (CHCl3)
34.5 (CH3CN)
31.6 (CHCl3)
19.03 (19.43)
16.07 (16.26)
14.91 (15.04)
13.49 (13.78)
16.93 (17.12)
22.51 (22.75)
19.01 (19.25)
16
14
C
)
C10
C14
H
H
ClN5PS
ClN5PS
19
27
16a
16b
16c
84
79
86
109–112 (n-C7H16
99–101 (n-C7H16
117–118 (n-C7H16
)
C20H30N5PS
C21 32N5PS
C22 32N5OPS
8.6 (C6H6)
8.1 (C6H6)
10.8 (C6H6)
17.11 (17.36)
16.69 (16.77)
15.48 (15.72)
7.51 (7.68)
7.31 (7.42)
6.82 6.95)
)
H
H
:
CH3COOEt/1:1)
16d
16e
17a
17b
17c
18
19a
19b
19c
19d
20a
20b
21a
21b
22a
22b
80
89
81
80
78
72
82
80
75
79
52
56
74
61
79
74
186–187 (C6H5CH3)
C20H25N6O4PS
C21 27N6O5PS
14H25N4OPS
C14 21N4O3PS
13H22ClN4OPS
14H26N5PS
C15H28IN4PS
10.3 (C H5CH )
8.1 (C 6H5CH 3)
17.51 (17.64)
16.38 (16.59)
16.87 (17.06)
15.43 (15.72)
15.87 (16.06)
21.08 (21.39)
12.27 (12.33)
11.47 (11.62)
5.86 (6.03)
5.41 (5.32)
9.37 (9.4)
8.64 (8.97)
12.79 (13.08)
6.11 (6.39)
6.41 (6.5)
5.87 (6.11)
9.13 (9.43)
8.39 (8.69)
8.51 (8.88)
9.26 (9.46)
6.54 (6.82)
6.13 (6.42)
6.49 (6.67)
5.91 (5.88)
5.02 (5.19)
4.51 (4.96)
6.99 (7.23)
6.84 (7.07)
7.11 (7.20)
5.71 (5.68)
142–144 (n-C7H16
)
H
6
3
Oil
C
18.4 (CHCl3)
15.9 (CH2Cl2)
15.5 (CHCl3)
30.2 (CHCl3)
43.7 (CH3CN)
42.4 (CH3CN)
7.6 (CHCl3)
12.5 (CHCl3)
39.2 (H2O)
42.7 (CH3CN)
76.6 (CH2Cl2)
−32.5 (C2H5OH)
63.5 (CHCl3)
6.0 (CHCl3)
171–173 (n-C7H16
)
H
Oil
Oil
C
C
180–182 (i -C3H7OH)
225–227 (C2H5OH)
210–121 (CH3OH)
208–209 (CH3CN)
261–262 (CH3CN)
254–256 (CH3CN)
83–85
172–173 (CH3OH)
219–221 (CH3OH)
231–232 (CH3OH)
C15H24IN4O2PS
C19H18IN2PS
C24 20
H
IN2PS
C16 31I2N4PS
H
C16H27I2N4O2PS
C16H30BF4N4PS
C20H20BF4N2PS
C11H20IN4PS2
C21H33IN5PS
12.81 (13.02)
12.91 (12.84)
aSublimation in vacuo.

652 Zarudnitskii et al.
TABLE 2 5-Phosphorylated Imidazo[2,1-b]thiazoles: 1H NMR δ (Multiplicity), J (Hz)
Solvent
2-H
3-H
6-Me(Ph)
2.2(d), 0.9
7.83(m), o-Ph
7.05–7.14(m)
m,p-Ph
Other Signals
2a
2b
C6D6
C6D6
5.73(t), 4.6
5.78(d), 4.4
7.45(dd), 4.6, 1.4
7.47(d), 4.4
2c
3a
C6D6
C6D6
5.60(d), 4.5
5.76(d), 4.6
7.22(d), 4.5
7.70(d), 4.6
7.84(m), o-Ph
7.05–7.14(m),
m,p-Ph
4a
4b
CDCl3
CDCl3
6.54(d), 4.5
6.67(d), 4.5
6.54(s)
2.50(s)
7.25–7.35(m), Ph2P
7.28–7.43(m), Ph2P+6-m,p-Ph
7.90(d), 8.0, o-Ph
7.28–7.43(m),
m,p-Ph+Ph2P
4c
5
7a
CDCl3
CDCl3
CDCl3
6.70(d), 4.5
6.84(d), 4.5
5.67(d), 4.5
6.74(d), 4.5
6.77(s)
8.02(d), 4.5
7.28–7.40(m), Ph2P
2.19(s)
7.15–7.35(m)
2.93(m), PNCH2CH3
0.87(t), 7.0, PNCH2CH3
3.18(m), PNCH2CH3
0.68(t), 6.9, PNCH2CH3
2.47(d), 9.6, PNCH3
3.06(m), PNCH2CH3
1.07(t), 7.0, PNCH2CH3
2.75(m), PNCH2CH3
0.78(t), 7.0, PNCH2CH3
7b
C6D6
7.90(d), 4.5
8
9a
C6D6
CD3CN
6.05(d), 4.5
6.86(d), 4.4
7.09(d), 4.5
7.59(d), 4.4
2.47(s)
2.31(s)
9b
10
C6D6
5.98(d), 6.0
6.98(d), 4.5
7.51(d), 6.0
7.82(d), 4.5
8.04(d), 8.0, o-Ph
7.26(t), 8.0, m-Ph
7.14(t), 8.0, p-Ph
2.40(s)
CD3CN
3.67(m), PNCH2CH2O
3.08(m), PNCH2CH2O
11a
11b
CF3COOD
CF3COOD
7.58(s)
7.60–7.80(m)
+6-Ph
8.45(s)
8.55(d), 4.0
2.81(s)
7.60–7.80(m)+2-H
12
CDCl3
6.93(d), 4.5
8.37(d), 4.5
7.78(m), o-Ph
7.40(m), m,p-Ph
2.57(d), 1.4
3.90(m), POCH2CH3
1.10(t), 7.0, POCH2CH3
2.65(d), 12.8, PNCH3
3.19(m), PNCH2CH3
1.08(t), 7.0, PNCH2CH3
3.57(m), PNCH2CH2O
3.03(m), PNCH2CH2O
2.93(m), PNCH2CH3
0.91(t), 7.0, PNCH2CH3
2.64(d), 10.8, PNCH3
5.96(br.s), PNH2
13a
13b
CDCl3
CDCl3
6.81(d), 4.6
6.80(d), 4.4
8.51(d), 4.6
8.56(d), 4.4
2.55(d), 1.5
13c
13d
CD3CN
7.05(d), 4.5
7.45(d), 4.5
8.42(d), 4.5
7.97(d), 4.5
2.56(d), 1.5
(CD3)2SO
7.51(m), o-Ph
7.40(m), m,p-Ph
2.58(d), 1.5
14
15a
CD3CN
CD3CN
7.43(d), 4.4
7.19(d), 4.4
8.28(d), 4.4
8.03(d), 4.4
2.45(d), 1.5
2.75(d), 11.0, PNCH3
6.99(br.s), PNH2+2-H
3.27(m) PNCH2CH3
1.20(t), 7.0, PNCH2CH3
7.14(t), 7.2, m-Ph
15b
CDCl3
6.99(d), 4.5
+PNH2
8.69(m)
2.53(s)
16a
CDCl3
6.80(d), 4.4
8.69(d), 4.4
2.52(d), 1.4
6.71(m), o,p-Ph
3.17(m), PNCH2CH3
0.98(t), 7.0, PNCH2CH3
7.73(dd), 8.8, 1.1, 3,5-H-Ar
6.71(dd), 8.8, 1.1, 2,6-H-Ar
3.22(m), PNCH2CH3
2.41(s), ArCH3
1.00(t), 7.0, PNCH2CH3
7.81(d), 8.7, 3,5-H-Ar
6.69(d), 8.7, 2,6-H-Ar
3.16(m), PNCH2CH3
2.51(s), Ar-COCH3
16b
16c
(CD3)2CO
CDCl3
7.20(d), 4.4
8.64(d), 4.4
8.59(d), 4.4
2.49(d), 1.5
2.53(d), 1.6
6.83(d), 4.4
1.00(t), 7.0, PNCH2CH3
(Continued)

Phosphorylation of Imidazo[2,1-b]thiazoles with Phosphorus(III) Halides in the Presence of Bases 653
TABLE 2 Continued
Solvent
2-H
3-H
6-Me(Ph)
2.56(d), 1.5
Other Signals
16d
16e
CDCl3
CDCl3
6.89(d), 4.5
8.41(d), 4.5
8.08(d), 8.7, 3,5-H-Ar
6.81(d), 8.7, 2,6-H-Ar
3.63(m), PNCH2CH2O
3.16(m), PNCH2CH2O
7.72(m), 4,6-H-Ar
6.83(m)+3-H-Ar
9.22(d), 4.5
2.55(d), 1.5
6.83(m), 3-H-Ar+2-H
3.95(s), OCH3
3.65(m), PNCH2CH2O
3.18(m), PNCH2CH2O
3.18(m), PNCH2CH3
1.12(t), 7.2, PNCH2CH3
3.66(m), PNCH2CH2O
3.16(m), PNCH2CH2O
3.08(m), PNCH2CH3
1.00(t), 7.0, PNCH2CH3
3.12(m), PNCH2CH3
1.05(t), 7.0, PNCH2CH3
3.21(m), PNCH2CH3
2.27(d), 13.6, PCH3
1.19(t), 7.0, PNCH2CH3
3.74(m), PNCH2CH2O
3.25(m), PNCH2CH2O
2.37(d), 13.8, PCH3
7.70–7.95(m), Ph2P
3.37(d), 13.5, PCH3
7.61–7.83(m), Ph2P
2.97(d), 13.5, PCH3
3.81(s), 7-CH3
17a
17b
17c
18
CDCl3
CDCl3
CDCl3
CDCl3
CD3CN
6.87(d), 4.4
6.84(d), 4.5
8.18(d), 4.4
8.14(d), 4.5
8.19(dd), 4.6, 0.6
8.43(d), 4.4
7.60(d), 4.6
2.52(d), 1.4
2.49(s)
6.84(dd), 4.6, 0.6
6.75(d), 4.4
2.49(d), 1.5
2.46(d), 1.5
19a
7.31(d), 4.6
19b
CD3CN
7.35(d), 4.5
7.86(d), 4.5
7.27(d), 4.3
2.52(s)
19c
19d
20a
CDCl3
CDCl3
D2O
7.12(d), 4.3
6.99(d), 4.2
2.01(d), 1.4
7.18–7.26(m)+3-H
2.51(s)
7.18–7.26(m)
+6-Ph
7.72(dd), 4.3, 0.9
7.86(dd), 4.3, 0.9
3.23(m), PNCH2CH3
2.39(d), 13.5, PCH3
1.13(t), 7.0, PNCH2CH3
3.74(s), 7-CH3
20b
21a
21b
D2O
CDCl3
7.69(d), 4.4
7.59(d), 4.2
7.23(d), 4.1
8.00(d), 4.4
7.89(d), 4.2
7.63(d), 4.1
2.49(s)
2.51(s)
2.56(s)
3.64(m), PNCH2CH2O
3.22(m), PNCH2CH2O
2.43(d), 14.4, PCH3
4.33(q), 7.2, 7-CH2CH3
3.16(m), PNCH2CH3
1.56(t), 7.2, 7-CH2CH3
1.14(t), 7.0, PNCH2CH3
7.36–7.52(m), Ph2P
4.37(q), 7.2, 7-CH2CH3
1.47(t), 7.2, 7-CH2CH3
4.08(s), 7-CH3
(CD3)2SO
22a
22b
CDCl3
7.82(d), 4.5
7.72(d), 4.4
8.68(d), 4.5
9.07(d), 4.4
2.78(s)
2.70(s)
2.74(d), 13.2, PNCH3
7.12(t), 7.7, 3,5-Ph
6.75(m), 2,4,6-Ph
CD3OD
3.94(s), 7-CH3
3.23(m), PNCH2CH3
1.05(t), 7.0, PNCH2CH3
the residue was crystallized from the appropriate
solvent.
and the residue was extracted with hot benzene (3 ×
30 mL). The benzene extract was concentrated in
vacuo to 20 mL, and phosphine 5 precipitated on
cooling was separated and recrystallized.
Tris(6-methylimidazo[2,1-b]thiazol-5-yl)
phosphine 5
To a solution of 1a (15 mmol) in pyridine (15 mL)
were successively added triethylamine (15 mmol)
and phosphorus trichloride (5 mmol). After react-
ing for 24 h, the solution was evaporated to dryness
Synthesis of Thiophosphinates 7
To a solution of compound 1b, c (20 mmol) in pyri-
dine (20 mL) was added triethylamine (20 mmol)

654 Zarudnitskii et al.
TABLE 3 Phosphorylated Imidazo[2,1-b]thiazoles: 13C NMRa δ (Multiplicity), ppm; JPC (Hz)
C2
C3
C5
C6
C7a
6-CH3
Others
4a
111.34 (s)
119.18 (d); 114.08 (d);
1.7 26.6
155.94 (d);
30.0
152.96 (s)
15.14 (d); 8.5
134.83 (d); 6.8, ipso-Ph
132.03 (d); 18.1, o-Ph
128.85 (d); 6.2, m-Ph
128.62 (s), p-Ph
39.23 (d); 5.0,
NCH2CH3
13.38 (d); 3.6,
NCH2CH3
41.43 (d); 4.0,
NCH2CH3
13b 110.85 (s)
19a 116.99 (s)
121.54 (s) 114.37 (d);
162.1
150.92 (d);
13.2
152.43 (d);
12.8
16.01 (s)
16.61 (s)
120.42 (s) 103.32 (d);
162.8
156.51 (d);
13.0
158.00 (d);
17.5
14.40 (d); 2.8,
NCH2CH3
14.50 (d); 91.6, Me-P
21b 118.32 (s)
120.58 (d); 119.57 (d);
145.37 (d);
30.5
149.18 (s)
10.70 (d); 10.7 131.20 (d); 6.2, ipso-Ph
132.31 (d); 19.2, o-Ph
129.62 (d); 6.8, m-Ph
2.8
39.6
129.99 (s), p-Ph
43.40 (s), 7-CH2CH3
13.22 (s), 7-CH2CH3
22a 119.44 (s)
122.48 (s) 117.10 (d);
151.5
142.79 (d);
15.8
149.64 (d);
6.8
12.01 (s)
37.04 (d); 3.4, NCH3
36.27 (s), 7-CH3
aAll the spectra were taken in CDCl3.
and phosphorus tribromide (10 mmol). 31P NMR
spectrum of the reaction mixture showed: δ 31P =
7.85 ppm for 6a after 24 h, or δ 31P = 6.11 ppm for
6b after 72 h. Diethylamine (30 mmol) and, 30 min
later, finely crushed sulfur (10 mmol) were added
and the mixture was stirred for 3 h, then the solvent
was evaporated in vacuo and benzene (40 mL) was
added to the residue. The insoluble salts were filtered
off, the filtrate was evaporated, and the residue was
crystallized.
(20 mmol) and then, in a dropwise fashion, ethanol
(20 mmol). After 0.5 h finely dispersed sulfur
(10 mmol) was added and the mixture was stirred un-
til the agent was completely dissolved. Then the tri-
ethylamine salt was separated, the filtrate was evap-
orated in vacuo, and the residue was crystallized.
Synthesis of Phosphine Sulfides 13
To a solution of aminophosphines 8–10 (10 mmol) in
benzene (10–20 mL) was added finely crushed sulfur
(10 mmol), and the mixture was stirred until sulfur
was completely dissolved. The residue after evapora-
tion of the solvent was recrystallized.
Synthesis of Aminophosphines 8–10
To a stirred solution of phosphines 2, 3 (10 mmol)
in toluene (25 mL) cooled to 5◦C was added drop-
wise a solution of the appropriate secondary amine
(50 mmol) in toluene (15 mL). After reacting for
30 min, the precipitate was filtered off and the fil-
trate was evaporated in vacuo.
Synthesis of Chlorophosphonium Chlorides 14
Hexachloroethane (20 mmol) was dissolved in hex-
ane (20 mL) and added to a solution of aminophos-
phine 8–10 (20 mmol) in benzene (20 mL). After 1 h,
the precipitated product was filtered, washed with
hexane and diethyl ether, and dried in vacuo.
Synthesis of Imidazo[2,1-b]thiazol-5-yl-
phosphinic Acids 11
A solution of phosphines 2 or 3 (10 mmol) in ben-
zene (30 mL) was left for 24 h in an open vessel un-
der ambient atmosphere. The precipitated acid was
separated and recrystallized.
Synthesis of Aminophosphonium Chlorides 15
The appropriate chlorophosphonium chloride 14
(10 mmol) was dissolved in dichloromethane
(20 mL), and ammonia gas was bubbled through the
resulting solution until the precipitation ceased (for
about 30 min). The precipitated ammonium chlo-
ride was separated by filtration, and the residue after
evaporation of the filtrate was crystallized.
Diethyl 6-Phenylimidazo[2,1-b]thiazol-5-
ylthiophosphonate 12
To a solution of phosphine 3a (10 mmol) in ben-
zene (20 mL) was added, at 5–10˚C, triethylamine

Phosphorylation of Imidazo[2,1-b]thiazoles with Phosphorus(III) Halides in the Presence of Bases 655
mixture was heated under reflux for 6–7 h. The
product precipitated on cooling was filtered and
crystallized.
Synthesis of Aryliminophosphoranes 16
To a solution of aminophosphine 8–10 (2 mmol) in
toluene (30 mL) was added aryl azide (2 mmol) and
the mixture was heated under reflux until the evolu-
tion of nitrogen ceased (1–2 h). After removal of the
solvent, the residue was triturated with diethyl ether,
to induce solidification, and recrystallized.
Synthesis of Imidazo[2,1-b]thiazolium
Tetrafluoroborates 21
To a stirred solution of 4 or 8–10 (2 mmol) in
dichloroethane (30 mL) was added dropwise, at
−30◦C, solution of thriethyloxonium tetrafluorobo-
rate (2 mmol) in the same (20 mL). The reaction
mixture was stirred at room temperature for 3 h, af-
ter which the solvent was evaporated. The residue
was washed with diethyl ether until it solidified and
then dried in vacuo. Product 21b was purified by
recrystallization.
Synthesis of Phosphine Oxides 17
The corresponding chlorophosphonium chloride 14
(5 mmol) was dissolved in dichloromethane (10 mL)
and shaken with a saturated aqueous solution of
sodium carbonate. The organic layer was separated,
washed with water, dried over anhydrous sodium
sulfate, and evaporated. The residue was held in
vacuo (oily) or recrystallized (solid).
Synthesis of Imidazo[2,1-b]thiazolium
Iodides 22
Synthesis of Iminophosphorane 18
A solution of aminophosphonium chloride 15b
(5 mmol) in dichloromethane (50 mL) was shaken
with 10% aq. NaOH (30 mL) in a separatory funnel.
The organic layer was separated, dried (Na2SO4) and
evaporated. The oily product was held in vacuo.
A mixture of corresponding substrate 13a or 16a
(5 mmol) and methyl iodide (7 mmol) in benzene
(20 mL) was heated under reflux for 10–16 h. The
product precipitated after cooling was filtered and
crystallized.
Synthesis of Phosphonium Salts 19
REFERENCES
To a solution of phosphine 4 or 8–10 (1 mmol) in
benzene (30 mL) was added methyl iodide (1 mmol)
and the reaction mixture was heated under reflux
for 4–5 h. The precipitated product was filtered and
crystallized.
[1] Tolmachev, A. A.; Yurchenko, A. A.; Merculov, A.
S.; Semenova, M. G.; Zarudnitskii, E. V.; Ivanov,
V. V.; Pinchuk, A. M. Heteroatom Chem 1999, 7,
585–597.
[2] Komarov, I. V.; Kornilov, M. Yu.; Turov, A. V.;
Tolmachev, A. A.; Yurchenko, A. A.; Rusanov,
E. V.; Chernega, A. N. Tetrahedron 1995, 51,
12417–12424.
Synthesis of Compound 20
[3] Tolmachev, A. A.; Yurchenko, A. A.; Kozlov, E. S.;
Merkulov, A. S.; Semenova, M. G.; Pinchuk, A. M.
Heteroatom Chem 1995, 6, 419–432.
To a solution 8–10 (1 mmol) in acetonitrile (30
mL) was added methyl iodide (3 mmol) and the