Sterically controlled cyclization of 3′,4′,5,7-tetramethyldihydroquercetin amidophosphites. New synthesis of phostones

Article abstract of DOI:10.1016/S0040-4039(03)01485-0

A new sterically controlled reaction of α-hydroxyketones with phosphorus acid triamides resulting in new four-membered phostones is reported.

Full text of DOI:10.1016/S0040-4039(03)01485-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6327–6329
Sterically controlled cyclization of
3%,4%,5,7-tetramethyldihydroquercetin amidophosphites. New
synthesis of phostones
E. E. Nifantyev,a,* M. P. Koroteev,a G. Z. Kaziev,a I. S. Zakharova,a K. A. Lyssenko,b
L. N. Kuleshovab and M. Yu. Antipinb
aDepartment of Chemistry, Moscow Pedagogical State University, per. Nesvizhskii 3, Moscow 119021, Russia
bA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 119991, Russia
Received 30 January 2003; revised 28 May 2003; accepted 13 June 2003
Abstract—A new sterically controlled reaction of a-hydroxyketones with phosphorus acid triamides resulting in new four-mem-
bered phostones is reported.
© 2003 Published by Elsevier Ltd.
Chemical modifications of flavanoids with trivalent
phosphorus reagents have not been studied previously.
It was recently shown in our laboratory that dihy-
droquercetin, one of the most interesting natural com-
pounds of this class, could undergo regioselective
phosphorylation of some of its phenolic hydroxyls dur-
ing reaction with phosphorus acid amides.1 The aim of
the present work was to study the modification of this
flavanoid involving its a-hydroxyketone fragment under
the action of phosphamide reagents. To isolate this
fragment from the general dihydroquercetin system, we
performed the complete methylation of its phenolic
hydroxyl groups and thus obtained the corresponding
dihydroquercetin 3%,4%,5,7-tetramethyl ether 1.2
Product 1 was subjected to phosphorylation by reagents
containing one or two amide groups. For identification
purposes the phosphites obtained were converted into
thionophosphates.3,4
Hexaethylphosphorus triamide was used as the phos-
phorylating reagent. The phosphorylation was moni-
tored by 31P NMR spectroscopy. After refluxing
the reaction mixture in benzene for 30 min, almost
complete formation of diamidophosphite
2
was
observed, which was stabilised by transformation
into the corresponding thionophosphate 3, which
was isolated as a pure isomer in 80% yield (Scheme
1).
Scheme 1.
Keywords: phosphorylation; phosphorus acid amides; flavanoid; phostones; intramolecular rearrangement; X-ray crystal analysis.
* Corresponding author. E-mail: chemdept@mtu-net.ru
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01485-0

6328
E. E. Nifantye6 et al. / Tetrahedron Letters 44 (2003) 6327–6329
Scheme 2.
When primary amidophosphite 2a was heated for a
further 30 min, it underwent an intramolecular rear-
rangement into phostone 4a, which was isolated as a
pure isomer in 70% yield (Scheme 2).
It should be noted that the interaction between linear
a-hydroxyketones and phosphorus triamides has
already been reported in the literature.7 It was found
that the reaction follows another pathway to form
five-membered 1,3,2-dioxaphospholene systems. Differ-
ences in the directions of these formally related reac-
tions are probably determined by the spatial features of
the flavanoid structure.
The reaction is general; a similar result was obtained
when hexamethylphosphorus triamide and phosphorus
tripiperidide were used and the corresponding phos-
tones 4b and 4c were obtained.
The phosphones obtained seem to be very interesting
compounds. They are highly electrophilic and react
readily with nucleophiles (Scheme 3).
1
The structure of the phostones was supported by H,
13C, and 31P NMR spectroscopy and by X-ray diffrac-
tion (for 4c, see Fig. 1).
Thus we have shown that this new field of organic
synthesis, which combines the chemistry of flavanoids
and the chemistry of phosphorus acid amides, offers
great promise.
The rearrangement mechanism has not yet been deter-
mined. However, taking the published data5,6 into
account, we can suppose that it involves the formation
of a complex of the phosphamide fragment with the
amine chlorohydrate, a common impurity in phos-
phamides. The electrophilic phosphorus atom then
attacks the carbonyl oxygen atom and an amino group
is transferred from the phosphorus atom to a carbon
atom of the pyran ring with the formation of the
phostone ring.
Representative procedure for compounds 4a–c
A suspension of compound 1 (1 g, 0.028 mol) in
benzene (20 ml) was treated with 0.0028 mol of phos-
phorus triamide under vigorous stirring. The reaction
mixture was refluxed for 1 h. The solvent was evapo-
rated in vacuo; the residue was applied to a column
with silica gel and eluted with solvents: A: benzene–
dioxane 1:1, B: benzene–dioxane 3:1, C: benzene–dioxane
4:1. The solvent was removed and the products were
dried in vacuo.
,
Figure 1. The structure of 4c. Selected bond lengths (A):
P(1)ꢀO(1) 1.465(2), P(1)ꢀO(2) 1.612(2), P(1)ꢀN(1) 1.613(2),
P(1)ꢀC(1) 1.835(3); bond angles (°): O(1)ꢀP(1)ꢀO(2)
115.9(1), O(1)ꢀP(1)ꢀN(1) 112.8(1), O(2)ꢀP(1)ꢀN(1) 106.6(1),
O(1)ꢀP(1)ꢀC(1)
114.8(1),
N(1)ꢀP(1)ꢀC(1) 120.5(1).
O(2)ꢀP(1)ꢀC(1)
82.3(1),
Scheme 3.

E. E. Nifantye6 et al. / Tetrahedron Letters 44 (2003) 6327–6329
6329
X-Ray structural analysis of compound 4c
6.61 (d, 3JHH=8.25 Hz, 1H, H5%); 7.10 (s, 1H, H2%); 7.15
3
(d, JHH=8.80 Hz, 1H, H6%). 13C NMR (50 MHz): l
15.43 (s, 2C, C–N(CH2-CH3)2, 2CH3); 15.52 (s, 2C,
X-Ray structural analysis of compound 4c: at 100 K
3
(
P–N(CH2-CH3)2, 2CH3); 41.19 (d, JCP=3.87 Hz, 2C,
crystals of C29H39N2O7P (4c) are triclinic, space group P1,
2
C–N(CH2-CH3)2, 2CH2); 46.24 (d, JCP=10.23 Hz, 2C,
,
a=12.245(7), b=12.950(7), c=13.142(7) A, h=61.20(1),
3
P–N(CH2-CH3)2, 2CH2); 55.04 (s, 1C, OMe); 55.49 (s, 1C,
OMe); 55.62 (s, 1C, OMe); 55.77 (s, 1C, OMe); 78.93 (d,
1JCP=113.12 Hz, 1C, C4), 80.23 (d, 2JCP=20.91 Hz, 1C,
C3); 84.85 (d, 3JCP=3.07 Hz, 1C, C2); 95.65 (s, 1C, C8);
,
i=70.13(1), k=66.20(1)°, V=1643(2) A , Z=2, M=
636.70, Dcalcd=1.287 g cm−3, v(MoKa)=1.35 cm−1,
F(000)=680. Intensities of 8781 reflections were mea-
sured with a Smart 1000 CCD diffractometer at 100 K
2
95.75 (s, 1C, C6); 106.62 (d, JCP=2.81 Hz, 1C, C10);
,
(u(MoKa)=0.71072 A, v-scans with 0.3° step in v and
110.78 (s, 1C, C5%); 112.29 (s, 1C, C2%); 119.17 (s, 1C, C6%);
131.27 (s, 1C, C1%); 150.22 (s, 1C, C3%); 150.28 (s, 1C, C4%);
160.26 (d, 3JCP=5.02 Hz, 1C, C9); 160.39 (d, 3JCP=10.92
Hz, 1C, C5); 161.31 (s, 1C, C7). Anal. calcd for
C27H39N2O7P: C, 60.67; H, 7.30; N, 5.24; P, 5.81. Found:
C, 60.30; H, 7.42; N, 5.15; P, 5.71.
15 s per frame exposure, 2q<56°), and 5759 independent
reflections (Rint=0.0348) were used in further refinement.
The structure was solved by direct methods and refined
by the full-matrix least-squares technique against F2 in
the anisotropic–isotropic approximation. Hydrogen
atoms were located from the Fourier synthesis and refined
in the isotropic approximation. The refinement converged
to wR2=0.1208 and GOF=0.906 for all independent
reflections (R1=0.0543 was calculated against F for 3504
observed reflections with I>2|(I)). All calculations were
performed using SHELXTL PLUS 5.0 on an IBM PC
AT. Crystallographic data (excluding structure factors)
for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary no. CCDC-186169. Copies of
the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: (internat.) +44-1223/336-033; e-mail: deposit@
ccdc.cam.ac.uk).
3%,4%,5,7-Tetramethyldihydroquercetin 4-piperidylcyclo-
1
phosphonate 4c. Yellow powder. H NMR (200 MHz):
l 1.57 (m, 6H, CꢀN(CH2)5, 2bCH2 and gCH2); 1.64 (m,
3
6H, P–N(CH2)5, 2bCH2 and gCH2); 2.71 (t, JHH=6.05
3
Hz, 4H, C–N(CH2)5, 2aCH2); 3.36 (t, JPH=10.01 Hz,
3JHH=6.04 Hz, 4H, P–N(CH2)5, 2aCH2); 3.39 (s, 3H,
OMe); 3.41 (s, 3H, OMe); 3.43 (s, 3H, OMe); 3.44 (s, 3H,
OMe);4.65(dd, 3JPH=16.50Hz, 3JHH=9.34Hz, 1H, H3);
5.08 (d, 3JHH=9.34 Hz, 1H, H2); 6.37 (d, 4JHH=2.2 Hz,
1H, H6); 6.42 (d, 4JHH=2.2 Hz, 1H, H8); 6.69 (d,
3JHH=8.25 Hz, 1H, H5%); 7.10 (s, 1H, H2%); 7.20 (d,
3JHH=8.25 Hz, 1H, H6%). 13C NMR (50 MHz): l 24.87
(s, 1C, C–N(CH2)5, gCH2); 25.06 (s, 1C, P–N(CH2)5,
gCH2); 27.16 (s, 2C, C–N(CH2)5, 2bCH2); 27.32 (s, 2C,
3%,4%,5,7-Tetramethyldihydroquercetin 4-N,N-dimethylcy-
clophosphonate 4b. Yellow powder. 1H NMR (200 MHz):
l 2.20 (s, 6H, C–N(CH3)2, 2CH3); 2.74 (d, 3JPH=9.01 Hz,
6H, P–N(CH3)2, 2CH3); 3.34 (s, 3H, OMe); 3.35 (s, 3H,
OMe); 3.36 (s, 3H, OMe); 3.40 (s, 3H, OMe); 4.63 (dd,
3JPH=17.50 Hz, 3JHH=9.35 Hz, 1H, H3); 5.08 (d,
3JHH=9.35 Hz, 1H, H2); 6.31 (d, 4JHH=2.20 Hz, 1H, H6);
6.37 (d, 4JHH=2.2 Hz, 1H, H8); 6.65 (d, 3JHH=8.80 Hz,
1H, H5%); 7.08 (s, 1H, H2%); 7.18 (d, 3JHH=8.80 Hz, 1H,
H6%). 13C NMR (50 MHz): l 36.51 (d, 3JCP=4.71 Hz, 2C,
3
P–N(CH2)5, 2bCH2); 46.11 (d, JCP=3.87 Hz, 2C, C–
N(CH2)5, 2aCH2); 51.37 (d, 2JCP=10.21 Hz, 2C, P–
N(CH2)5, 2aCH2);54.98(s, 1C, OMe);55.54(s, 1C, OMe);
55.61 (s, 1C, OMe); 56.17 (s, 1C, OMe); 77.09 (d,
1JCP=107.91 Hz, 1C, C4); 80.22 (d, 2JCP=20.94 Hz, 1C,
3
C3); 84.91 (d, JHH=4.12 Hz, 1C,C2); 95.71 (s, 1C,C8);
2
95.94 (s, 1C, C6); 104.25 (d, JCP=2.53 Hz, 1C, C10);
110.85 (s, 1C, C5%); 112.39 (s, 1C, C2%); 118.82 (s, 1C, C6%);
131.38 (s, 1C, C1%); 150.25 (s, 1C, C3%); 150.35 (s, 1C, C4%);
160.49 (d, 3JCP=4.57 Hz, 1C, C9); 160.68 (d, 3JCP=11.72
Hz, 1C, C5); 161.3 (s, 1C, C7). Anal. calcd for
C29H39N2PO7: C, 62.36; H, 6.99; N, 5.02; P, 5.55. Found:
C, 62.18; H, 7.18; N, 4.78; P, 5.23.
2
C–N(CH3)2, 2CH3); 41.65 (d, JCP=9.81 Hz, 2C, P–
N(CH3)2, 2CH3); 54.96 (s, 1C, OMe); 55.55 (s, 1C, OMe);
55.61 (s, 1C, OMe); 55.93 (s, 1C, OMe); 77.71 (d,
1JCP=112.41 Hz, 1C, C4); 80.23 (d, 2JCP=20.91 Hz, 1C,
C3); 84.86 (d, 3JCP=3.51 Hz, 1C, C2); 95.58 (s, 1C, C8);
2
95.81 (s, 1C, C6); 103.14 (d, JCP=2.72 Hz, 1C, C10);
References
110.79 (s, 1C, C5%); 112.36 (s, 1C, C2%); 118.97 (s, 1C, C6%);
131.24 (s, 1C, C1%); 150.21 (s, 1C, C3%); 150.31 (s, 1C, C4%);
160.43 (d, 3JCP=4.71 Hz, 1C, C9); 160.81 (d, 3JCP=11.52
Hz, 1C, C5); 161.32 (s, 1C, C7). Anal. calcd for
C23H31N2O7P: C, 57.74; H, 6.48; N, 5.86; P, 6.49. Found:
C, 57.32; H, 6.57; N 5.97; P 6.59.
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3%,4%,5,7-Tetramethyldihydroquercetin 4-N,N-diethylcy-
clophosphonate 4a. Yellow powder. 1H NMR (200 MHz):
2
l 0.97 (t, JHH=7.03 Hz, 6H, C–N(CH2-CH3)2, 2CH3);
1.10 (t, 2JHH=7.14 Hz, 6H, P–N(CH2-CH3)2, 2CH3); 2.86
(m, 4H, C–N(CH2-CH3)2, 2CH2); 2.99 (m, 2H, P–N(CH2-
CH3)2, CH2); 3.33 (s, 3H, OMe); 3.35 (s, 3H, OMe); 3.38
(s, 3H, OMe); 3.41 (s, 3H, OMe); 3.80 (m, 2H, P–N(CH2-
3
3
CH3)2, CH2); 4.82 (dd, JPH=17.61 Hz, JHH=9.90 Hz,
1H, H3); 5.15 (d, 3JHH=9.90 Hz, 1H, H2); 6.29 (d,
4JHH=2.20 Hz, 1H, H6); 6.38 (d, 4JHH=2.20 Hz, 1H, H8);
7. Mukhametov, F. S. Zh. Obshch. Khim. 1991, 61, 10.