Chemoselective ring opening of benzoxazaphosphinines

Article abstract of DOI:10.1016/j.tetlet.2008.08.069

Cyclization of 2-[(4-chloroanilino)methyl]phenol (1) with thiophosphoryl chloride afforded 2-chloro-3-(4-chlorophenyl)-3,4-dihydro-2H-1,3,2λ⁵-benzoxazaphosphinine-2-thione (2). Reaction of 2 with various heterocyclic amines (3) in the presence

Full text of DOI:10.1016/j.tetlet.2008.08.069

Tetrahedron Letters 49 (2008) 6337–6340
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Tetrahedron Letters
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Chemoselective ring opening of benzoxazaphosphinines
K. R. Kishore Kumar Reddy, M. Anil Kumar, M. V. Narayana Reddy,
*
C. Devendranath Reddy, C. Suresh Reddy
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclization of 2-[(4-chloroanilino)methyl]phenol (1) with thiophosphoryl chloride afforded 2-chloro-3-
(4-chlorophenyl)-3,4-dihydro-2H-1,3,2k5-benzoxazaphosphinine-2-thione (2). Reaction of 2 with various
heterocyclic amines (3) in the presence of Et3N/NaH gave 3-(4-chlorophenyl)-2-nitrogen heterocyclic
substituted-3,4-dihydro-2H-1,3,2k5-benzoxaza-phosphinine-2-thiones (4). Further reaction of 4 with
the N-sodium salt of amino heterocyclics in the presence of HCl at 50–60 °C opened the benz-
oxazaphosphinine ring chemoselectively at the endocyclic P–O bond and yielded 2-[4-chloro(hetero-
cyclic substituted-phosphorothioyl)anilino]methylphenols 5–13.
Received 19 June 2008
Revised 14 August 2008
Accepted 20 August 2008
Available online 23 August 2008
Keywords:
Benzoxazaphosphinine
Chemoselective
Ring opening
Ó 2008 Elsevier Ltd. All rights reserved.
P–O bond cleavage
1. Introduction
ring opening of benzoxazaphosphorines. This reaction may help
to serve as a probe to understand enzymatic hydrolysis of this
Phosphoramides are used extensively in organic and medicinal
chemistry. Cyclophosphamide containing an oxazaphosphinine is a
proven alkylating antitumour agent against a broad spectrum of
human cancers including slow-growing solid tumours.1,2 The clin-
ical significance and the unique conformational and stereochemi-
cal aspects of oxazaphosphinines have attracted much interest in
drug design and synthesis.3–5 The strong electron donor and Lewis
basicity of phosphoramides has made them useful in catalytic
process.6,7 In phosphoramide boron-complexes, the boron, being
a Lewis acid centre, binds with ketones and controls the stereo-
chemistry in their asymmetric reduction.8
Several phosphorus heterocyclic ring-opening reactions involv-
ing C–P–C, O–P–O and N–P–N were reviewed extensively by Maj-
oral in 1994.9 Acid-catalyzed 1,4-addition- type ring-opening
reactions were used for the polymerization of cyclic phosphorimi-
dates.10,11 Simple hydroxy phosphoramides have been prepared by
reaction of amino alcohols and phosphonates.12,13 A new class of
recoverable and highly stable phosphinamide catalysts for the
asymmetric reduction of ketones was synthesized through oxa-
zaphosphorine ring-opening reactions with alkylmagnesium
bromide.14,15
group of drugs in living matrices.
Herein, we report reaction sequence for the preparation of
different N-ligand-substituted tris-thiophosphoramides, 2-(4-
chloro[substituted-phosphorothioyl]aniline-methyl)phenols 5–13
by acid-catalyzed nucleophilic chemoselective ring opening of
benzoxazaphosphorine derivatives 4a–e (Scheme 1).
Cyclization of 1 with PSCl3 in toluene in presence of triethyl-
amine led to the formation of compound 2. Reaction of 2 with a
heterocyclic amine under the same conditions afforded the corre-
sponding benzoxazphosphorine derivatives 4. Subsequent reaction
of 4 in the same vessel with various amino nucleophiles as their so-
dium salts in the presence of a catalytic amount of conc. HCl9,16 at
50–60 °C chemoselectively opened the benzoxazaphosphorine ring
at the P–O bond with simultaneous formation of a P–N bond with
the second molecule of the sodium salt of the nitrogen nucleophile
(Scheme 2). In the above step, HCl appears to weaken the P–O and
N–Na bonds and helps in cleavage of the cyclic P–O bond and
formation of the P–N and O–H bonds.
It was observed that 4 is also ring opened at the cyclic P–O bond
when reacted with free amines even without HCl as the catalyst at
high temperature. In both cases, the products yield was low, and
the reaction times were long. The reaction solvent seems to be
critical since the same reaction when carried out in acetic acid
returned only starting products (Table 1).
A new route for the synthesis of phosphoramides substituted
with functionalized aromatics and heterocycles at their three dif-
ferent nitrogens was accomplished by acid-catalyzed nucleophilic
All the products were characterized by IR, 1H, 13C and 31P NMR
and mass spectroscopic data.17,18
The appearance of a singlet at d 4.24–4.26 for the two acyclic
methylene protons in compounds 5–13 is in good agreement with
* Corresponding author. Tel.: +91 9849694958; fax: +91 0877 2289555.
E-mail address: csrsvu@gmail.com (C. S. Reddy).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.069

6338
K. R. K. K. Reddy et al. / Tetrahedron Letters 49 (2008) 6337–6340
HR3 3a-e, + NaH
S
S
S
P
HR2 3a-e
O
R2
R3
OH
NH
O
OH
P(S)Cl3
conc. HCl
P R2
P Cl
N
N
Et3N, 40-50 °C
50-60 °C
Et3N, 10-40 °C
Toluene
N
Toluene
Toluene
R1
R1
R1
R1
5-13
1
2
4a-e
R1 = 4-Cl-C6H4-
R2
R3
R2
R3
N
O
10
N
N
N CH3
N
N
N CH3
N
N
O
5
O
N
N
N CH3
11
12
13
6
7
N
N
N
N
N
N
N
O
O
O
N
N
NH
NH
8
9
NH
Scheme 1.
drying with anhydrous MgSO4. The residue was washed with
water and purified by column chromatography using silica gel
as adsorbent and ethyl acetate/hexane (1:5) as the eluent to
yield products 5–13. All the reactions were monitored by TLC,
using the same eluent.
S
P
N
N
H
S
N
H
Na
P
-NaCl
N
N
N
O
Cl
O
2.1. 2-[4-Chloro(dimorpholinophosphorothioyl)-
anilino]methylphenol (entry 1)
Scheme 2.
Solid: mp 172–175 °C; IR (KBr) (mmax cmꢀ1): 3397 (O–H), 959
(P–N), 778 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.09–7.34
(6H, m, Ar-H), 6.56 (2H, d, J = 8.5, Ar-H), 4.25 (2H, s, CH–N–P),
3.63 (8H, m, H-300, 3000, 500 and 5000), 3.21 (8H, m, H-200, 2000, 600 and
the structures of the acyclic compounds when compared to the
appearance of a doublet of doublets for the corresponding chemi-
cally nonequivalent methylene protons (CH-4) in the cyclic struc-
tures 4a–e (Fig. 1).19–21
6000); 13C NMR (100 MHz, CDCl3):
d 149.19, 146.52, 130.51,
129.18, 128.93, 125.25, 122.29, 120.56, 113.82, 66.76, 45.39,
44.30; 31P NMR (121 MHz, CDCl3): d 73.18; LCMS(EI) m/z (%), 470
(40) [(MH+2)+], 468 (100) [MH+], 381 (39) [(MHꢀC4H9NO)+]; Anal.
Calcd for C21H27ClN3O3PS: C, 53.90; H, 5.82; N, 8.98. Found: C,
53.86, H, 5.84; N, 9.01.
The sodium salts of heterocyclic amines in the presence of NaH/
HCl effect chemoselective benzoxazaphosphorine ring opening at
the P–O bond to afford the corresponding hydroxy, N-ligand-
substituted tris-thiophosphoramides in high yields. This procedure
offers a method for the synthesis of tri-nitrogen-substituted chiral
phosphoramides, which can be used as catalyst templates for chiral
organic synthesis.8
2.2. 2-(4-Chloro[(4-methylpiperazino)(morpholino)-
phosphorothioyl]anilinomethyl)phenol (entry 2)
2. General procedure for 2-[4-chloro(substituted-
phosphorothioyl)anilino]methyl phenol synthesis
Solid: mp 168–170 °C; IR (KBr) (mmax cmꢀ1): 3385 (O–H), 915
(P–N), 756 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.06–7.35
(6H, m, Ar-H), 6.41 (2H, d, J = 9.8, Ar-H), 4.26 (2H, s, CH–N–P),
3.43 (12H, br, H-200, 2000,3000, 5000, 600 and 6000), 2.50 (4H, s, H-300 and
500), 2.37 (3H, s, N–CH3); 13C NMR (100 MHz, CDCl3): d 153.79,
148.90, 147.51, 134.98, 130.04, 128.85, 124.07, 121.33, 120.97,
115.37, 61.90, 55.66, 50.26, 46.09, 43.36; 31P NMR (121 MHz,
CDCl3): d 74.65; LCMS(EI) m/z (%): 482 (25) [(M+2)+], 480 (67)
[M+], 478 (88), 440 (71), 419 (76), 393 (19); Anal. Calcd for
A solution of thiophosphoryl chloride (2 mmol) in dry toluene
(20 mL) was added dropwise to a cooled (5–10 °C) solution of 2-
(4-chlorophenylamino)methyl phenol 1 (2 mmol) and triethyl-
amine (4 mmol) in dry toluene (40 mL). After addition, the
reaction temperature was raised to 35–40 °C and the reaction
mixture was stirred for an additional 2 h. The formed 2-chloro-
3-(4-chlorophenyl)-3,4-dihydro-2H-1,3,2k5-benzoxazaphosphi-
nine-2-thione (2) was used in the next step without further
purification.
C22H30ClN4O2PS: C, 54.94; H, 6.29; N, 11.65. Found: C, 54.90; H,
6.31; N, 11.68.
To a cooled (0–5 °C) solution of 2, heterocyclic amines (3a–e,
2 mmol) and triethylamine (2 mmol) in dry toluene were added
dropwise with stirring. The temperature of the reaction mixture
was raised to 40–45 °C and stirring was continued for an addi-
tional 3 h to afford compounds 4a–e. To the stirred solution of
4a–e in the same vessel, the heterocyclic amine as the sodium
salts 3a–e (2 mmol) in dry toluene (20 mL) was added dropwise.
After completion of addition, two drops of 37% HCl were added
at room temperature, and the reaction mixture was stirred at
40–50 °C for 3 h. After filtration, the solvent was removed after
2.3. 2-(4-Chloro[morpholino(piperidino)-
phosphorothioyl]anilinomethyl)phenol (entry 3)
Solid: mp 125–128 °C; IR (KBr) (mmax cmꢀ1): 3396 (O–H), 965
(P–N), 757 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.08–7.39
(6H, m, Ar-H), 6.55 (2H, d, J = 9.0, Ar-H), 4.25 (2H, s, CH–N–P),
3.64 (4H, m, H-300 and 500), 3.49 (4H, m, H-2000 and 6000), 3.24
(4H, m, H-200 and 600), 1.57 (6H, m, H-3000,4000 and 5000); 13C NMR
(100 MHz, CDCl3):
d 152.31, 134.6, 129.30, 129.14, 129.11,

K. R. K. K. Reddy et al. / Tetrahedron Letters 49 (2008) 6337–6340
6339
Table 1
Chemoselective benzoxazaphosphinine ring-opening reactions
Entry
Substrate
Catalyst
Temperature (°C)
Time (h)
Product
Yield (%)
R2
R3
—
>150
60
60
24
15
8
5
5
5
1, 3a
31
44
78
—
HCla
HClb
HClc
N
N
N
N
O
O
O
O
N
N
O
N
1
2
3
4
25
4
3a
3a
3a
3a
3a
—
>150
60
60
20
14
9
6
6
6
18
39
65
HCla
HClb
CH3
3b
3c
HClb
HClb
HCla
60
60
80
8
9
7
8
9
69
63
42
N
N
N
3d
H
N
15
N
N
O
N
5
6
7
8
3a
3e
—
150
60
60
20
14
8
10
10
10
25
41
76
CH3
N
N
N
N
CH3
HCla
HClb
3b
3c
3b
3c
N
N
HClb
HClb
60
60
8
11
12
69
60
N
N
10
3d
3d
H
N
H
N
9
HCla
80
18
13
58
3e
3e
‘—’ without catalyst.
a
Heterocyclic amine with concd HCl.
Heterocyclic amine with NaH and concd HCl.
Acetic acid as solvent.
b
c
2.4. 2-(4-Chloro[1H-1-imidazolyl(morpholino)-
N
phosphorothioyl]anilinomethyl)phenol (entry 4)
O
2
Solid: mp 117–119 °C; IR (KBr) (mmax cmꢀ1): 3387 (O–H), 951
(P–N), 762 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.01–7.44
(9H, m, Ar-H), 6.34 (2H, s, Ar-H), 4.25 (2H, s, CH–N–P), 3.48 (4H,
m, H-300 and 500), 3.25 (4H, m, H-200 and 600); 13C NMR (100 MHz,
CDCl3): d 150.22, 148.87, 144.24, 137.45, 130.06, 129.33, 128.83,
126.72, 125.49, 124.58, 122.69, 120.37, 118.98, 63.14, 49.46,
43.84; 31P NMR (121 MHz, CDCl3): d 70.49; LCMS(EI) m/z (%): 471
(100) [(M+23)+]; Anal. Calcd for C20H22ClN4O2PS: C, 53.51; H,
4.94; N, 12.48. Found: C, 53.49; H, 4.98; N, 12.50.
HO
N
P
S
1
N P
O
H
4
3
N
N
H
Cl
Cl
4a-e
5-13
Figure 1.
2.5. 2-[Anilino(morpholino)phosphorothioyl]-4-
chloroanilinomethyl)phenol (entry 5)
126.21, 126.10, 125.94, 122.38, 123.14, 119.27, 115.27, 66.57,
45.53, 32.49, 45.29, 27.81; 31P NMR (121 MHz, CDCl3): d 75.17;
LCMS(EI) m/z (%): 468 (39) [(MH+2)+], 466 (100) [MH+], 381
(26), 379 (43), 340 (10), 339 (46); Anal. Calcd for
Solid: mp 105–107 °C; IR (KBr) (m
max cmꢀ1): 3370 (O–H), 3301
(N–H), 914 (P–N), 755 cmꢀ1 (P@S); 1H NMR (400 MHz, DMSO-d6):
d 7.08–7.47 (11H, m, Ar-H), 6.49 (2H, d, J = 9.0, Ar-H), 5.62 (1H, s,
Ar-NH) 4.26 (2H, s, CH–N–P), 3.59 (4H, m, H-300 and 500) and 3.25
(4H, m, H-200 and 600); 13C NMR (100 MHz, CDCl3): d 150.28,
C22H29ClN3O2PS: C, 56.71; H, 6.27; N, 9.02. Found: C, 56.68; H,
6.32; N, 9.07.

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K. R. K. K. Reddy et al. / Tetrahedron Letters 49 (2008) 6337–6340
146.49, 137.96, 133.18, 131.28, 130.75, 129.18, 126.18, 126.52,
125.01, 123.91, 122.75, 120.35, 119.65, 66.12, 44.23, 53.04; 31P
NMR (121 MHz, DMSO-d6): d 69.47; LCMS(EI) m/z (%): 476 (16)
[(MH+2)+], 474 (42) [MH+], 429 (37), 400 (42), 350 (100), 305
(46), 249 (39); Anal. Calcd for C23H25ClN3O2PS: C, 58.29; H, 5.32;
N, 8.87. Found: C, 58.24, H, 5.28; N, 8.91.
2.9. 2-[4-Chloro(dianilinophosphorothioyl)anilino]methyl-
phenol (entry 9)
Solid: mp 75–77 °C; IR (KBr) (m
max cmꢀ1): 3349 (O–H), 3321 (N–
H), 967 (P–N), 752 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 6.98–
7.47 (16H, m, Ar-H), 6.48 (2H, s, Ar-H), 4.24 (2H, s, CH–N–P); 13C
NMR (100 MHz, CDCl3): d 151.33, 137.55, 120.53, 129.69, 129.40,
129.36, 129.30, 128.53, 127.20, 127.17, 126.69, 124.45, 120.69,
120.58, 119.18, 43.15; 31P NMR (121 MHz, CDCl3): d 68.97; Anal.
Calcd for C25H23ClN3OPS: C, 62.56, H, 4.83; N, 8.75. Found: C,
62.53, H, 4.87; N, 8.78.
2.6. 2-(4-Chloro[di(4-methylpiperazino)phosphorothioyl]-
anilinomethyl)phenol (entry 6)
Solid: mp 102–103 °C; IR (KBr) (mmax cmꢀ1): 3434 (O–H), 969
(P–N), 784 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.10–7.37
(6H, m, Ar-H), 6.56 (2H, d, J = 8.7, Ar-H), 4.25 (2H, d, J = 4.7, CH–
N–P), 3.24 (8H, m, H-200, 2000, 600 and 6000), 2.45 (8H, m, H-300, 3000, 500
and 5000), 2.28 (6H, s, N–CH3); 13C NMR (100 MHz, CDCl3): d
151.12, 142.08, 129.4, 129.14, 128.36, 126.50, 125.94, 125.90,
123.6, 124.08, 118.83, 118.77, 113.00, 54.22, 53.07, 45.23 44.11;
31P NMR (121 MHz, CDCl3): d 73.24; LCMS(EI) m/z (%): 496
(41)[(MH+2)+], 494 (100) [(MH)+]; Anal. Calcd for C23H33ClN5OPS:
C, 55.92; H, 6.73; N, 14.18. Found: C, 55.87; H, 6.76; N, 14.24.
Acknowledgement
The authors express thanks to UGC (33-299), New Delhi, for
providing financial assistance.
References and notes
1. Colvin, O. M. Curr. Pharm. Design 1999, 5, 555–560.
2. Ludeman, S. M.; Boyd, V. L.; Regan, J. B.; Gallo, L. N.; Zon, G.; Ishii, K. J. Med.
Chem. 1986, 29, 716–727.
3. Martinek, T.; Forro, E.; Gunther, G.; Sillanpaa, R.; Fulop, F. J. Org. Chem. 2000, 65,
316–321.
2.7. 2-[4-Chloro(dipiperidinophosphorothioyl)anilino]-
methylphenol (entry 7)
4. Viljanen, T.; Tahtinen, P.; Pihalaja, K.; Fulop, F. J. Org. Chem. 1998, 63, 618–
627.
5. Kivela, H.; Zalam, Z.; Tahtinen, P.; Sillanpaa, R.; Fulop, F.; Pihalaja, K. Eur. J. Org.
Chem. 2005, 6, 1189–1200.
6. Bentrude, W. G.; Setzer, W. N.; Khan, M.; Sopchik, A. E.; Ramli, E. J. Org. Chem.
1991, 56, 6127–6131.
7. Burns, B.; Gamble, M. P.; Simm, A. R. C.; Studley, J. R.; Alcock, N. W.; Wills, M.
Tetrahedron: Asymmetry 1997, 8, 73–78.
8. Gamble, M. P.; Smith, A. R. C.; Willy, M. J. Org. Chem. 1998, 63, 6068–6071.
9. Caminada, A. M.; Majoral, J. P. Chem. Rev. 1994, 94, 1183–1213.
10. Cabrita, E. J.; Candeias, S. X.; Romos, A. M.; Afonso, C. A. M.; Santos, A. G.
Tetrahedron Lett. 1999, 40, 137–140.
11. Cabrita, E. J.; Afonso, C. A. M.; Santos, A. G. Tetrahedron 2004, 60, 11933–11949.
12. Hulst, R.; Zijlstra, R. W. T.; De Varies, N. K.; Feringa, B. L. Tetrahedron:
Asymmetry 1994, 5, 1701–1710.
13. Hulst, R.; Varies, N. K.; Feringa, B. L. Tetrahedron 1994, 50, 11721–11728.
14. Gamble, M. P.; Studley, J. R.; Wills, M. Tetrahedron Lett. 1996, 37, 2853–
2856.
15. Brown, J. M.; Carey, J. V.; Russell, M. J. H. Tetrahedron 1990, 46, 4877–4886.
16. Kajikawa, S.; Nishino, H.; Kurosawa, K. Tetrahedron Lett. 2001, 42, 3351–3354.
17. Thomas, L. C. Interpretation of the Infrared Spectra of Organophosphorus
Compounds; Heydon & Sons: London, 1974.
Solid: mp 88–91 °C; IR (KBr) (m
max cmꢀ1): 3370 (O–H), 952 (P–
N), 764 cmꢀ1 (P@S); 1H NMR (400 MHz, CDCl3): d 7.04–7.43 (6H,
m, Ar-H), 6.55 (2H, s, Ar-H), 4.25 (2H, s, CH–N–P), 3.15 (8H, br,
H-200, 2000, 600 and 6000), 1.50 (8H, br, H-300, 3000, 500 and 5000); 1.42 (4H,
br, C-400 and 4000); 13C NMR (100 MHz, CDCl3): d 150.97, 150.89,
148.32, 148.24, 145.92, 135.36, 129.68, 125.26, 123.36, 122.33,
122.26, 120.49, 118.22, 118.13, 49.75, 40.01, 34.24, 31.33; 31P
NMR (121 MHz, CDCl3): d 72.36; LCMS(EI) m/z (%): 487 (100)
[(M+23)+], 380 (22), 348 (24), 320 (90), 318 (19), 292 (26); Anal.
Calcd for C23H31ClN3O3PS: C, 59.54; H, 6.73; N, 9.06. Found: C,
59.50; H, 6.78, N, 9.09.
2.8. 2-[4-Chloro(di-1H-1-imidazolylphosphorothioyl)anilino]-
methylphenol (entry 8)
Solid: mp 98–100 °C; IR (KBr) (mmax cmꢀ1): 3346 (O–H), 911
(P–N), 757 cmꢀ1 (P@S); 1H NMR (400 MHz, DMSO-d6): d 6.96–
7.61 (12H, m, Ar-H), 6.53. (2H, d, J = 8.7, Ar-H), 4.24 (2H, s, CH–
N–P); 31P NMR (121 MHz, DMSO-d6): d 69.56; LCMS(EI) m/z (%):
430 (39) [(MꢀH+2)+], 428 (100) [(MꢀH)+]; Anal. Calcd for
18. Babu, Y. H.; Reddy, P. V. G.; Reddy, C. S.; Reddy, C. D.; Devi, P. U. M. J. Heterocycl.
Chem. 2002, 39, 1039–1044.
19. Kiran, Y. B.; Gunasekar, D.; Reddy, C. D.; Reddy, C. S.; Tran, K.; Le, T.; Berlin, K.
D.; Srinivasan, S.; Devi, M. C. Pest Manage. Sci. 2005, 61, 1016–1023.
20. Kiran, Y. B.; Reddy, C. D.; Gunasekar, D.; Raju, C. N.; Barbosa, L. C. A.; Marney, D.
C. O.; Russell, L. J. J. Fire Sci. 2007, 25, 193–215.
C
19H17ClN5OPS: C, 53.09; H, 3.99; N, 16.29. Found: C, 53.06, H
21. Kiran, Y. B.; Kasthuraiah, M.; Raju, C. N.; Gunasekar, D.; Madhubabu, S. V. S.;
Reddy, C. D. Indian J. Chem., Sect. B 2005, 44, 2171.
4.02; N, 16.33.