Alkylation reactions of phosphachroman-2,4-diones and 4-hydroxy phosphacoumarins

Article abstract of DOI:10.1016/j.bioorg.2006.01.003

Phosphachroman-2,4-dione and 4-alkoxyphosphacoumarin derivatives, phosphonic analogues of chromones and coumarins with potential biological activities, were synthesized in good yields through sequential base-catalyzed intramolecular cyclization of O-alkyl

Full text of DOI:10.1016/j.bioorg.2006.01.003

Bioorganic Chemistry 34 (2006) 105–113
www.elsevier.com/locate/bioorg
Alkylation reactions
of phosphachroman-2,4-diones
and 4-hydroxy phosphacoumarins
a
a
a,
*
Xueshu Li , Yitong Wang , Hua Fu
,
Yuyang Jiang a,b, Yufen Zhao
a
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, PR China
b
Key Laboratory of Chemical Biology, Guangdong Province, Graduate School of Shenzhen, Tsinghua University,
Shenzhen 518057, PR China
Received 21 November 2005
Abstract
Phosphachroman-2,4-dione and 4-alkoxyphosphacoumarin derivatives, phosphonic analogues of
chromones and coumarins with potential biological activities, were synthesized in good yields
through sequential base-catalyzed intramolecular cyclization of O-alkyl-O0-(20-methoxycarbonyl
phenyl)-(substituted) benzyl phosphonates and alkylation. The synthesis sets the stage for an exam-
ination of the biological activities.
ꢀ 2006 Elsevier Inc. All rights reserved.
Keywords: Phosphachroman-2,4-dione; Phosphacoumarin; Intramolecular cyclization; Alkylation
1. Introduction
Chromones and coumarins, two kinds of important natural products with various bio-
logical activities, have attracted great interest in the area of pharmacology [1]. Many chr-
omones and coumarins were synthesized leading to molecules with more potent medicinal
*
Corresponding author. Fax: +86 10 62781695.
E-mail address: fuhua@mail.tsinghua.edu.cn (H. Fu).
0045-2068/$ - see front matter ꢀ 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2006.01.003

106
X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
O
O
R3
R'
R2
R''
C
P
OR1
O
O
O
O
chromone
OR''
phosphachromone
OR3
R'
R2
C
P O
OR1
O
O
O
coumarin
phosphacoumarin
Fig. 1. The structure of chromones, coumarins, and their analogs phosphachromones, phosphacoumarins.
and biological activities [2]. The development of phosphorus chemistry has led to organo-
phosphorus compounds that have applications in the area of pharmacy [3], agriculture [4],
and synthetic chemistry [5]. Phosphonic acids and their derivatives often exhibit similar
biological activity to the natural carboxylic acids and their derivatives [6] because the
former are similar to the tetrahedral intermediates of the latter. Hence, introduction of
the phosphorus atom into coumarins and chromanones to form phosphachromones and
phosphacoumarins (Fig. 1) may result in the development of new molecules with biolog-
ical activities. Chen and Rodios’s groups [7] have synthesized phosphacoumarins by a con-
densation reaction of salicylaldehyde with triethylphosphonoacetate in low yields (not
more than 21%), and the major products were phosphonocoumarins. Mironov et al. [8]
have also reported the preparation of 4-aryl phosphacoumarin using benzene-1,2-diol
and substituted phenyl acetylene as the starting materials.
In our previous work [9], a convenient and efficient approach to 4-O-acylated, phos-
phorylated and sulfonylated phosphacoumarins has been developed through reactions
of phosphachroman-2,4-diones and 4-hydroxy phosphacoumarins with acetic anhydride,
diethoxylphosphoryl chloride, p-toluenesulfonyl chloride, and methylsulfonyl chloride.
In order to enrich the library of phosphacoumarins, we attempted reactions of phosphach-
roman-2,4-diones and 4-hydroxy phosphacoumarins with alkyl halides, and a mixture of
O-alkylation and C-alkylation products was obtained in different ratios. To the best of our
knowledge, the C-alkylation products, phosphachromones have not been reported so far.
2. Materials and methods
1H, 31P, and 13C NMR spectra were recorded on a JEOL JNM-ECA 300 spectrometer
using tetramethylsilane as the internal standard. High resolution mass spectra were record-
ed on a Bruker APEX-II Fourier transform ion cyclotron resonance (FT-ICR) MS instru-
ment equipped with 4.7 T super-conduction magnet and an analytical electrospray source.
2.1. General procedure for the preparation of 3 and 4
Anhydrous K2CO3 (1 mmol) was added to mixture of 1 and 2 (0.5 mmol) in 5 mL of
anhydrous acetonitrile, and the mixture was stirred for 20 min. Methyl iodide, benzyl
bromide or allyl bromide (0.6 mmol) in 2 mL of acetonitrile was then added dropwise

X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
107
within 10 min. The mixture was stirred at room temperature for another 1 h, 10 mL of
dichloromethane was added to the resulting solution, and filtered. The solid was washed
with dichloromethane (2· 5 mL), and the filtrate was combined. The solvent was removed
by rotary evaporation, and the residue was purified by column chromatography on silica
gel with petroleum ether/ethyl acetate (3:1–2:1) as eluent to give 3 and 4.
2.2. The numbers of the core structure
R3
O
4
O
4
R2
R3
R2
5
5
4a
8a
3
4a
8a
6
7
6
3
2
OR1
P
OR1
2
P
7
O
1
O
1
8
O
8
O
4
3
2.3. 2-Ethoxy-3-methyl-3-(4-methylphenyl)-phosphachroman-2,4-dione (3ag)
and 2-ethoxy-3-(4-methylphenyl)-4-methoxy-phosphacoumarin (4ag)
Yellowish solid; total yield: 84%; 31P NMR (121 MHz, CDCl3) d 14.46 (4ag), 25.35
3
(3ag) the ratio of 3ag to 4ag is 1.3:1; 1H NMR (300 MHz, CDCl3) d 1.11 (tt, JH–
H = 6.6 Hz, 3H, OCH2CH3), 1.98 (qs, 3-CH3 of 3ag), 2.36 (qs, of 3-PhCH3, 3H), 3.49
(ds, 4-CH3O of 4ag), 4.03 (m, 3H, OCH2CH3 of 3ag and 4ag), 7.15–8.11 (m, 8H, Ar-
3
H); 13C NMR (75 MHz, CDCl3) d 16.1 (d, JP–C = 4.5 Hz, POCH2CH3), 20.1 (m, 3-
1
PhCH3 and 3-CH3 of 3ag), 55.5 (d, JC–P = 121.5 Hz, C-3 of 3ag), 60.8 (m, OCH3 of
2
1
4ag) 64.4 (td, JP–C = 7.5 Hz, POCH2CH3), 106.1 (d, JC–P = 175.0 Hz, C-3 of 4ag),
2
118.0–137.9 (Ar-C), 149.8 (d, JP–C = 5.0 Hz, C-8a), 152.5 (C-8a of 3ag) 158.5 (C-4 of
4ag), 193.2 (C-4 of 3ag); HR-MS of [M+H]+ m/z Calcd: 331.1099. Found: 331.1095.
2.4. 3-Methoxy-2-methyl-3-phenyl-phosphachroman-2,4-dione (3bg)
and 2,4-dimethoxy-3-phenyl-phosphacoumarin (4bg)
Yellowish solid; total yield: 84%; 31P NMR (121 MHz, CDCl3) d 15.49 (4bg), 26.27
3
(3bg), the ratio of 3bg to 4bg is 4:1; 1H NMR (300 MHz, CDCl3) d 2.00 (d, JH–
P = 17.5 Hz, 2.4H, 3-CH3 of 3bg), 3.53–3.68 (m, 4-OCH3 and POCH3, 3.6H), 7.20–8.13
2
(m, Ar-H, 9H); 13C NMR (75 MHz, CDCl3) d 19.5 (dd, JP–C = 4.5 Hz, 3-CH3of 3bg),
1
54.4 (4-OCH3 of 4ag and POCH3), 57.0 (d, JP–C = 121.0 Hz, C-3 of 3bg), 119.9–136.7
(Ar-C), 152.5 (C-8a), 160.0 (C-4 of 4bg), 192.9 (C-4 of 3bg); HR-MS of [M+H]+ m/z
Calcd: 303.0786. Found: 303.0780.
2.5. 2-Ethoxy-3-methyl-3-(4-chlorophenyl)-phosphachroman-2,4-dione (3dg)
and 2-ethoxy-3-(4-chlorophenyl)-4-methoxy-phosphacoumarin (4dg)
Yellowish solid; total yield: 81%; 31P NMR (121 MHz, CDCl3) d 14.10 (4dg, trace),
1
3
24.39 (3dg); H NMR (300 MHz, CDCl3) d 1.13 (t, JH–P = 7.1 Hz, 3H, OCH2CH3),

108
X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
1.96 (d, 3H, 3-CH3), 4.06 (m, 2H, OCH2CH3), 7.20–8.14 (m, Ar-H, 8H); 13C NMR
2
2
(75 MHz, CDCl3) d 16.0 (d, JP–C = 5.1 Hz, POCH2CH3), 19.3 (d, JP–C = 5.0 Hz,
1
2
3-CH3), 55.2 (d, JP–C = 121.3 Hz, C-3), 64.4 (d, JP–C = 7.9 Hz, POCH2CH3), 119.8–
136.7 (Ar-C), 152.8 (d, 2JP–C = 4.3 Hz, C-8a), 192.5 (C-4); HR-MS of [M+H]+ m/z Calcd:
350.0475. Found: 350.0472.
2.6. 2-Ethoxy-3-methyl-3-(4-cyanophenyl)-phosphachroman-2,4-dione (3eg)
and 2-ethoxy-3-(4-cyanophenyl)-4-methoxy-phosphacoumarin (4eg)
Yellowish solid; total yield: 86%; 31P NMR (121 MHz, CDCl3) d 13.03 (4eg), 23.22
3
(3eg), the ratio of 3eg to 4eg is 12:1; 1H NMR (300 MHz, CDCl3) d 1.09 (t, JH–
H = 6.9 Hz, 3H, OCH2CH3), 1.97 (ds, 2.8H, 3-CH3 of 3eg), 3.53 (s, 0.2H, 4-CH3O of
4eg), 4.05 (m, 2H, OCH2CH3 of 3eg and 4eg), 7.23–8.11 (m, 8H, Ar-H); 13C NMR
3
2
(75 MHz, CDCl3) d 16.1 (d, JP–C = 5.0 Hz, POCH2CH3), 19.4 (d, JP–C = 5.0 Hz,
1
2
3-CH3 of 3eg), 56.0 (d, JP–C = 120.5 Hz, C-3 of 3eg), 64.7 (d, JP–C = 7.2 Hz,
POCH2CH3), 112.0 (CN), 118.5–138.8 (Ar-C), 152.8 (C-8a of 3eg), 192.1 (C-4 of 3eg);
HR-MS of [M+H]+ m/z Calcd: 342.0895. Found: 342.0896.
2.7. 3-Benzyl-2-ethoxy-3-(4-methylphenyl)-phosphachroman-2,4-dione (3ah)
1
Yellowish solid; mp 90–92 ꢁC; yield: 72%; 31P NMR (121 MHz, CDCl3) d 23.74; H
3
NMR (300 MHz, CDCl3) d 0.99 (t, JH–H = 6.8 Hz, 3H, OCH2CH3), 2.35 (s, 3H,
PhCH3), 3.67–3.94 (m, 4H, OCH2CH3, PhCH2), 6.99–8.00 (m, 13H, Ar-H); 13C
3
NMR (75 MHz, CDCl3) d 15.9 (d, JP–C = 5.4 Hz, POCH2CH3), 21.0 (PhCH3), 40.1
1
2
(PhCH2), 61.3 (d, JP–C = 120.1 Hz, C-3), 64.4 (d, JP–C = 7.9 Hz, OCH2CH3), 119.4–
136.1 (Ar-C), 152.5 (C-8a), 192.1 (C-4); HR-MS of [M+H]+ m/z Calcd: 407.1412.
Found: 407.1415.
2.8. 4-Benzoxy-2-ethoxy-3-(4-methxylphenyl)-phosphacoumarin (4ah)
Yellowish solid; mp 83–85 ꢁC; yield: 12%; 31P NMR (121 MHz, CDCl3) d 14.04, 14.18,
14.69; 1H NMR (300 MHz, CDCl3) d 1.04, 1.46, 1.26 (tt, 3JH–H = 7.2 Hz, 3H, OCH2CH3),
2.32, 2.39, 2.45 (ts, 3H, PhCH3), 4.01–4.07 (m, 2H, OCH2CH3), 4.51–4.57 (m, 2H,
3
PhCH2O), 7.28–7.78 (m, 13H, Ar-H); 13C NMR (75 MHz, CDCl3) d 15.9 (d, JP–C
=
2
5.8 Hz, POCH2CH3), 19.9, 20.5, 21.3 (ts, PhCH3), 63.8 (d, JP–C = 6.5 Hz, POCH2CH3),
1
75.1 (PhCH2O), 107.5 (d, JP–C = 112.8 Hz, C-3), 118.5–138.3 (Ar-C), 149.8
(d, 2JP–C = 5.1 Hz, C-8a), 157.8 (d, 2JP–C = 20.0 Hz, C-4); HR-MS of [M+H]+ m/z Calcd:
407.1412. Found: 407.1417.
2.9. 3-Benzyl-2-ethoxy-3-phenyl-phosphachroman-2,4-dione (3ch)
1
Yellowish solid; mp 105–108 ꢁC; yield: 51%; 31P NMR (121 MHz, CDCl3) d 23.57; H
3
NMR (300 MHz, CDCl3) d 0.96 (t, JH–H = 6.9 Hz, 3H, OCH2CH3), 3.87–3.95 (m, 4H,
OCH2CH3, PhCH2), 6.95–8.00 (m, 14H, Ar-H); 13C NMR (75 MHz, CDCl3) d 16.0
1
2
(OCH2CH3), 40.1 (3-PhCH2), 61.7 (d, JP–C = 119.0 Hz, C-3), 64.5 (d, JP–C = 7.5 Hz,
POCH2CH3), 118.0–136.3 (Ar-C), 152.6 (C-8a), 192.1 (C-4); HR-MS of [M+H]+ m/z
Calcd: 317.0943. Found: 317.0942.

X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
109
1
2.10. 4-Benzoxy-2-ethoxy-3-phenyl-phosphacoumarin (4ch)
Yellowish solid; mp 112–114 ꢁC; yield: 31%; 31P NMR (121 MHz, CDCl3) d 13.92; H
3
NMR (300 MHz, CDCl3) d 1.14 (t, JH–H = 7.2 Hz, 3H, OCH2CH3), 4.07 (m, 2H,
POCH2CH3), 4.62 (s, 2H, PhCH2O), 7.16–7.44 (m, 14H, Ar-H); 13C NMR (75 MHz,
3
2
CDCl3) d 16.2 (d, JP–C = 6.5 Hz, POCH2CH3), 63.9 (d, JP–C = 6.2 Hz, POCH2CH3),
2
75.4 (PhCH2O), 109.5 (C-3), 123.8–131.6 (Ar-C), 150.0 (d, JP–C = 5.0 Hz, C-8a), 158.9
(d, JP–C = 18.6 Hz, C-4); HR-MS of [M+H]+ m/z Calcd: 317.0943. Found: 317.0940.
2
2.11. 3-Benzyl-2-ethoxy-3-(4-chlorophenyl)-phosphachroman-2,4-dione (3dh)
and 4-benzoxy-2-ethoxy-3-(4-chlorophenyl)-phosphacoumarin (4dh)
Yellowish solid; total yield: 83%; 31P NMR (121 MHz, CDCl3) d 13.52 (4dh), 22.92
1
3
(3dh), the ratio of 3dh to 4dh is 13.2:1; H NMR (300 MHz, CDCl3) d 1.00 (t, JH–
3
H = 7.2 Hz, 3H, OCH2CH3), 3.80 (d, JP–H = 23.0 Hz, 1.9H, PhCH2of 3dh), 4.65 (s,
PhCH2O, 0.2H), 7.04–8.00 (m, Ar-H, 13H); 13C NMR (75 MHz, CDCl3) d 15.9 (d, JP–
2
1
C = 5.8 Hz, OCH2CH3), 39.9 (PhCH2 of 3dh), 61.1 (d, JP–C = 119.0 Hz, C-3 of 3dh),
64.5 (d, JP–C = 7.9 Hz, OCH2CH3), 119.1–136.4 (Ar-C), 152.2 (d, JP–C = 4.3 Hz,
C-8a), 191.5 (C-4 of 3dh); HR-MS of [M+H]+ m/z Calcd: 427.0866. Found: 427.0862.
2
2
2.12. 3-Allyl-2-ethoxy-3-(4-chlorophenyl)-phosphachroman-2,4-dione (3di)
and 4-alloxy-2-ethoxy-3-(4-chlorophenyl)-phosphacoumarin (4di)
Yellowish solid; total yield: 80%; 31P NMR (121 MHz, CDCl3) d 13.12 (4di), 23.13
1
3
(3di), the ratio of 3di to 4di is 2.1:1; H NMR (300 MHz, CDCl3) d 1.09 (m, JH–H
=
7.2 Hz, 3H, OCH2CH3 of 3di and 4di), 2.97, 3.58 (m, about 1.3H, 3-CH2CH@CH2 of
3di), 4.03 (m, about 2.6H, POCH2CH3 and 4-OCH2CH@CH2 of 4di), 5.00 (dm, 0.66H,
3-CH2CH@CH2 of 3di), 5.10 (dm, 0.33H, 4-OCH2CH@CH2 of 4di), 5.56 (m, 0.66H,
3-CH2CH@CH2 of 3di), 5.80 (m, 0.33H, 4-OCH2CH@CH2 of 4di), 7.21–8.10 (m, 8H,
2
Ar-H); 13C NMR (75 MHz, CDCl3) d 16.1 (dd, JP–C = 5.1 Hz, POCH2CH3), 35.9
1
2
(3-CH2CH@CH2 of 3di), 59.6 (d, JP–C = 120.5 Hz, C-3 of 3di), 64.6 (dd, JP–C
=
1
7.9 Hz, POCH2CH3), 74.2 (4-OCH2CH@CH2 of 4di), 109.8 (d, JP–C = 172.8 Hz, C-3 of
4di), 120.2–136.7 (Ar-C), 149.9 (d, JP–C = 5.7 Hz, C-8a of 4di), 152.6 (d, JP–C
5.0 Hz, C-8a of 3di), 159.1 (d, JP–C = 18.7 Hz, C-4 of 4di), 190.7 (C-4 of 3di); HR-MS
of [M+H]+ m/z Calcd: 377.0709. Found: 377.0701.
2
2
=
2
2.13. 3-Benzyl-2-ethoxy-3-(4-cyanophenyl)-phosphachroman-2,4-dione (3eh)
and 4-benzoxy-2-ethoxy-3-(4-cyanophenyl)-phosphacoumarin (4eh)
Yellowish solid; total yield: 82%; 31P NMR (121 MHz, CDCl3) d 12.73 (4eh), 21.87
1
3
(3eh), the ratio of 3eh to 4eh is 2.1:1; H NMR (300 MHz, CDCl3) d 1.11 (dt, JH–H
=
7.2 Hz, 3H, OCH2CH3), 3.85 (m, 3.4H, OCH2CH3 and PhCH2of 3eh), 4.62 (q, 0.6H,
2
PhCH2O), 6.92–7.74 (m, Ar-H, 13H); 13C NMR (75 MHz, CDCl3) d 16.0 (dd, JP–C
=
1
5.0 Hz, POCH2CH3), 39.9 (PhCH2 of 3eh), 61.4 (d, JP–C = 119.0 Hz, C-3 of 3eh), 64.7
(d, JP–C = 7.8 Hz, POCH2CH3), 111.9 (CN), 124.9–136.9 (Ar-C), 150.2 (C-8a of 4eh),
152.3 (d, JP–C = 5.0 Hz, C-8a pf 3eh), 160.2 (d, JP–C = 17.2 Hz, C-4 of 4eh), 191.1
(C-4 of 3eh); HR-MS of [M+H]+ m/z Calcd: 418.1208. Found: 418.1204.
2
2
2

110
X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
2.14. 3-(2-Bromophenyl-2-ethoxy-3-methyl-phosphachroman-2,4-dione (3fg)
and 3-(2-bromophenyl-2-ethoxy-4-methoxy-phosphacoumarin (4fg)
Yellowish solid; total yield: 90%; 31P NMR (121 MHz, CDCl3) d 12.95 (4fg), 22.76
3
(3fg), the ratio of 3fg to 4fg is 1:49; 1H NMR (300 MHz, CDCl3) d 1.09 (dt, JH–H
=
7.3Hz, 3H, OCH2CH3), 1.99 (ds, 0.3H, 3-CH3 of 3fg), 3.51 (s, 0.2.7H, 4-CH3O of 4fg),
3.95 (m, 2H, OCH2CH3 of 3fg and 4fg), 7.11–8.14 (m, 8H, Ar-H); 13C NMR (75 MHz,
3
3
CDCl3) d 16.1 (dd, JP–C = 5.6 Hz, POCH2CH3), 22.7 (3-CH3 of 3fg), 60.4 (d, JP–
2
C = 15.8 Hz, CH3O of 4fg), 64.0 (d, JP–C = 7.2 Hz, POCH2CH3), 105.0 (dd, C-3 of
4fg), 118.7–132.8 (Ar-C), 149.9 (C-8a of 4fg), 159.3 (C-4 of 4fg), 191.2 (C-4 of 3fg);
HR-MS of [M+H]+ m/z Calcd: 395.0048. Found: 395.0042.
2.15. 3-Benzyl-3-(2-bromophenyl)-2-ethoxy-phosphachroman-2,4- dione (3fh)
and 4-benzoxy-3-(2-bromophenyl-2-ethoxy-phosphacoumarin (4fh)
Yellowish solid; total yield: 85%; 31P NMR (121 MHz, CDCl3) d 12.85 (4fh), 22.31
1
3
(3fh), the ratio of 3fh to 4fh is 1:19; H NMR (300 MHz, CDCl3) d 1.2 (dt, JH–H
=
7.2 Hz, 3H, OCH2CH3), 3.42 (m, 0.1H, PhCH2 of 3fh), 4.06 (m, 2H, OCH2CH3), 4.70
(m, 1.9H, PhCH2O of 3fh), 7.14–7.77 (m, Ar-H, 13H); 13C NMR (75 MHz, CDCl3) d
2
2
16.2 (dd, JP–C = 5.7;Hz, POCH2CH3), 29.8 (PhCH2 of 3fh), 64.1 (d, JP–C = 7.2 Hz,
2
POCH2CH3), 106.6 (d, JP–C = 176.4 Hz, C-3 of 3fh), 123.9–133.4 (Ar-C), 150.1 (d,
2JP–C = 15.8 Hz, C-8a of 4fh), 158.9 (d, JP–C = 18.6 Hz, C-4 of 4fh); HR-MS of
2
[M+H]+ m/z Calcd: 471.0361. Found: 471.0369.
2.16. 3-Allyl-3-(2-bromophenyl)-2-ethoxy-phosphachroman-2,4-dione (3fi)
and 4-alloxy-3-(2-bromophenyl)-2-ethoxy-phosphacoumarin (4fi)
Yellowish solid; total yield: 90%; 31P NMR (121 MHz, CDCl3) d 12.35 (4fi), 22.89 (3fi),
the ratio of 3fi to 4fi is 1:49; 1H NMR (300 MHz, CDCl3) d 1.09 (dm, 3JH–H = 6.9 Hz, 3H,
OCH2CH3 of 3fi and 4fi), 3.66 (d, trace), 4.16 (m, 4H, POCH2CH3 and 4-OCH2CH@CH2
of 4fi), 5.17 (m, 2H, 4-OCH2CH@CH2 of 4fi), 5.77 (m, 1H, 4-OCH2CH@CH2 of 4fi), 7.18–
7.86 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3) d 16.2 (dd, 2JP–C = 6.4 Hz, POCH2CH3),
2
29.7 (3-CH2CH@CH2 of 3fi), 64.1 (dd, JP–C = 6.5 Hz, POCH2CH3), 73.5 (4-
1
OCH2CH@CH2 of 4fi), 106.6 (d, JP–C = 176.4 Hz, C-3 of 4fi), 118.5–133.3 (Ar-C),
2
2
149.9 (d, JP–C = 5.7 Hz, C-8a of 4fi), 158.6 (d, JP–C = 18.6 Hz, C-4 of 4fi); HR-MS of
[M+H]+ m/z Calcd: 421.0204. Found: 421.0206.
3. Results and discussion
As shown in Scheme 1, there is an equilibrium between phosphachroman-2,4-diones (1)
and phosphacoumarins (2), and the ratios of 1 to 2 in CDCl3 at room temperature depend
on their structures (see Table 1). The alkylation products phosphachromones (3) and
phosphacoumarins (4) were obtained in good yields (77–90%) through K2CO3-catalyzed
reaction of 1 and 2 with different alkyl halides in various ratios (see Table 2).
In the presence of base, compounds 1 and 2 produced the corresponding ambident
nucleophile, which can react with electrophiles, including acetic anhydride, p-toluenesulfo-
nyl chloride (Ts-Cl), methyl sulfonyl chloride (Ms-Cl), diethoxylphosphoryl chloride

X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
111
CO2CH3
R2
P
O
O
OR1
KOH
dry pyridine
O
R2
O
O
+
O
R3
P
R2
(AcO)2O
DEP-Cl
TsCl
P
O
OR1
OR1
BnBr
O
O
R3'
O
3
4
R2
major
1
MeI
O
Allyl bromide
MsCl
R3
P
OR1
R2
Alkylation
OH
R2
O
R3' = Ac, DEP, Ts, Ms
P
O
OR1
P
O
OR1
2
O
O
R3 = Me, PhCH2, H2C=CHCH2
minor
R1 = Me, Et
R2 = H, 4'-Me, 4'-Cl, 4'-CN, 2'-Br
Scheme 1. Reaction of phosphachroman-2,4-diones, 4-OH phosphacoumarins with acetic anhydride,
p-toluenesulfonyl chloride (Ts-Cl), methylsulfonyl chloride (Ms-Cl), diethoxylphosphoryl chloride (DEP-Cl)
and alkyl halides.
Table 1
Ratios of the intermediate products 1 and 2
Entry
1/2
R1
R2
Ratioa
1
2
3
4
5
6
a
1a/2a
1b/2b
1c/2c
1d/2d
1e/2e
1f/2f
CH2CH3
CH3
CH2CH
CH2CH3
CH2CH3
CH2CH
4-CH3
H
H
4-Cl
4-CN
2-Br
2.5:1.0
7.3:1.0
8.0:1.0
9.3:1.0
7.7:1.0
5.2:1.0
Ratio of 1 to 2 determined by 31P NMR in CDCl3.
Table 2
Yields and ratios of phosphachromones (3) and phosphacoumarins (4) from reaction of 1 and 2 with alkyl halides
Entry
3
4
R1
R2
R3
Yielda (%)
Ratiob
1
2
3
4
5
6
7
8
9
10
11
12
a
3ag
3bg
3dg
3eg
3ah
3ch
3dh
3di
4ag
4bg
4dg
4eg
4ah
4ch
4dh
4di
CH2CH3
CH3
4-CH3
H
4-Cl
4-CN
4-CH3
H
4-Cl
4-Cl
4-CN
2-Br
2-Br
2-Br
CH3
CH3
CH3
CH3
PhCH2
PhCH2
PhCH2
Allyl
PhCH2
CH3
84
84
81
86
79
82
83
80
82
90
85
90
1.3:1
4:1
c
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
11.5:1
1.3:1
1.6:1
13.2:1
2.1:1
2.1:1
1:49
3eh
3fg
3fh
3fi
4eh
4fg
4fh
4fi
PhCH2
Allyl
1:19
1:49
Total isolated yield.
The ratio of 3 to 4.
Trace amount of 4dg.
b
c

112
X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
R3
X
OH
O
O
O
O
R2
R2
B
- HB
R2
OR1
P
O
OR1
P
P
O
O
OR1
O
2
1
- X-
path b
R3
path a
R3
X
a
R2
O
O
OR3
R2
b
R2
P
P
O
O
O
P
OR1
O
OR1
O
OR1
O
3
4
Scheme 2. The proposed mechanism and the steric effect of the alkylation reaction.
(DEP-Cl) and alkyl halides. Addition of acetic anhydride, Ts-Cl, Ms-Cl, DEP-Cl in the
reaction system only yielded O-modified products, while reaction of alkyl halides with
the ambident nucleophile led to 3-alkylated (3) and O-substituted products (4).
We tried different reaction conditions including solvents (CH2Cl2, acetone, and aceto-
nitrile) and bases (K2CO3, TEA, and DMAP), and the experimental results showed that
the ratios of 3 to 4 were not remarkably affected by these factors. By introducing different
substituted group R2 to the benzene ring at the 3-position and changing the alkyl halides,
we found that the ratios of the both greatly depended on steric effect (Scheme 2). For
example, when Br is ortho-position substituted group on the benzene ring, 4 are prominent
products, and the ratios of the both are from 1:19 to 1:49 (entries 10–12 in Table 2). When
R3X is CH3I, 3 are major products because methyl is a smaller group, and the ratios are
from 1.3:1 to 13.2:1 (compare with entries 1, 2, 4 with 5–7 in Table 2). Interestingly, the
ratios usually are high when R3 is 4-Cl (entries 3, 9 in Table 2). In addition, the ratios were
also affected by the electronic effect. For example, the ratios became larger when electron-
donating group CH3 of R2 was replaced with electron-withdrawing group CN for same
R3. The electron-withdrawing group can improve the acidity of the 3-H of compound 1
and stabilize the negative ions at 3-position, which were favor to the nucleophilic reaction
at 3-position.
In addition, 3 and 4, such as 3ah and 4ah, 3fh and 4fh, could be isolated by silica gel
column chromatography. Unfortunately, other phosphachromones (3) and phos-
phacoumarins (4) could not be done because of their similar polarity.
4. Conclusion
We have developed a convenient and efficient method for the synthesis of phosphachr-
omones and phosphacoumarins via the alkylation of phosphachroman-2,4-diones and
phosphacoumarins. The ratios of phosphachromones and phosphacoumarins depend on
steric and electronic effects of the substituent groups. Some of phosphachromone and
phosphacoumarin derivatives could be isolated by silica gel column chromatography.
This can provide opportunity for the screening of molecules with biological and medicinal
activity.

X. Li et al. / Bioorganic Chemistry 34 (2006) 105–113
113
Acknowledgments
This work was supported by the Excellent Dissertation Foundation of the Chinese Min-
istry of Education (No. 200222), the Excellent Young Teacher Program of MOE, P.R.C.,
the National Natural Science Foundation of China (Grant No. 20472042) and the Key
Subject Foundation from Beijing Department of Education (XK100030514).
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