Synthesis of 1,4:3,6-dianhydro-d-mannitol 2,5-(hydrogenphosphate) and its usage in palladium-catalyzed hydroxycarbonylation of styrene

Article abstract of DOI:10.3987/COM-04-10222

Phosphorylation of 1,4:3,6-dianhydro-d-mannitol by phosphorus oxychloride in the presence of triethylamine followed by hydrolysis gave a cyclie hydrogen phosphate, which has the crystal structure of 6-hydroxy-6-oxo-2,5,7,10-tetraoxa-6-phospha-tricyclo[6.3.0.0^4,11]undecane. It was used as a chiral ligand in palladium-catalyzed hydroxycarbonylation of styrene. The regioselectivity was good, but the optical yield was limited.

Full text of DOI:10.3987/COM-04-10222

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2797 - 2803
Received, 6th September, 2004, Accepted, 21st October, 2004, Published online, 26th October, 2004
SYNTHESIS OF 1,4:3,6-DIANHYDRO-D-MANNITOL 2,5-(HYDROGEN
PHOSPHATE) AND ITS USAGE IN PALLADIUM-CATALYZED
HYDROXYCARBONYLATION OF STYRENE
Biao Jiang*, Zuo-Gang Huang, and Ke-Jun Cheng
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032, China. E-mail: Jiangb@mail.sioc.ac.cn
Abstract – Phosphorylation of 1,4:3,6-dianhydro-D-mannitol by phosphorus
oxychloride in the presence of triethylamine followed by hydrolysis gave a cyclic
hydrogen phosphate, which has the crystal structure of 6-hydroxy-6-oxo-2,5,7,10-
tetraoxa-6-phospha-tricyclo[6.3.0.04,11]undecane. It was used as a chiral ligand in
palladium-catalyzed hydroxycarbonylation of styrene. The regioselectivity was
good, but the optical yield was limited.
INTRODUCTION
1,4:3,6-dianhydro-D-mannitol (1), also known as isomannide, is a C-2 symmetric hexahydro[3,2-b]furan
3,6-diol with two cis hydroxyl groups located on the endo face of the cis fused bicyclic oxa
five-membered rings. This skeleton might be utilized as a chiral platform for asymmetric synthesis and
catalysis.1
O
*
P
HO
O
H
H
H
H
O
O
O
O
X
O
O
O
O
H
H
OH
O
P
*
1
2
3 X=O, NH
O
In 1999, Reetz et al. reported a highly enantioselective rhodium-catalyzed hydrogenation reaction using
biphosphite (2) as the chiral ligand.2 And we noticed with interest that two constrained tricyclic rings (3)
(X = O, NH) were described by Cope et al. decades ago.3 Thus, we envisioned a less constrained

1,4:3,6-dianhydro-D-mannitol 2,5-(hydrogen phosphate) (4) resembling the cyclic nature of
1,1’-binaphthlene-2,2’-diyl hydrogen phosphate (5), which is known as a resolving agent for many
organic bases.4
O
5
6
Ar
O
P
OH
10
H
O
O
O
4
O
O
O
P
P
11
O
8
7
3
9
OH
OH
1
O
O
2
H
Ar
6
5
4
In 1983, Alper et al. developed a palladium-catalyzed regiospecific hydroxycarbonylation of alkenes
under mild conditions.5 Later, they used 5 as a chiral ligand for the enantioselective synthesis of
2-arylpropionic acid and claimed a quite high optical yield of 91% based on optical rotation
measurement.6 Recently, renewed interest in asymmetric catalysis by chiral Brønsted acid (6) was
reported.7 Nifant'ev et al. extensively examined the phosphorylation of alcohols and phenols including
many carbohydrates by trivalent phosphorus chlorides and amides.8 The preparation and purification of
some phosphites and phosphoramides based on 1,4:3,6-dianhydro-D-mannitol were also described.
Herein, we report the synthesis of the free monophosphoric acid (4) through direct phosphorylation of 1
by phosphorus oxychloride and following hydrolysis. Its usage in Alper’s catalytic system was examined.
RESULTS AND DISCUSSION
Scheme 1
O
O
P
Cl
OH
O
P
O
O
HO
H
H
H
H
1 eq. P(O)Cl3,
2 eq. Et3N
O
O
O
O
O
2 M NaOH, 0 oC;
2 M HCl, 0 oC
O
CH2Cl2, rt, 6 h
O
OH
H
H
1
7
4
As illustrated in Scheme 1, phosphorylation of 1 with phosphorus oxychloride in the presence of
triethylamine followed by hydrolysis gave the cyclic hydrogen phosphate (4). However, the solubility of
1 in aprotic solvent such as benzene, THF and dichloromethane was not good. Addition of triethylamine
ruptured the hydrogen bonding, thus improving the solubility of the substrate. The reaction was
monitored by 31P NMR sampling. As can be expected, monophosphorylation, bisphosphorylation, and
intermolecular or intramolecular phosphorylation made the 31P NMR spectrum somewhat complicated.

o
After optimization including searching for the solvent, changing the reaction temperature from -78 C to
reflux, varying the reactants ratio and employing a slow addition procedure or reverse addition protocol,
the intramolecular bisphosphorylated 7 became the major intermediate as indicated by 31P NMR spectrum.
Phosphorus oxychloride was added slowly by syringe into the solution of 1 and two equivalents of
triethylamine in dichloromethane at room temperature. After filtration and evaporation, the residue was
o
hydrolyzed in 2 M aqueous sodium hydroxide at 0 C and then neutralized by 2 M hydrochloric acid.
Recrystallization from water provided the desired product (4). Its X-Ray structure is illustrated in Figure
1 with selected bond lengths and bond angles listed in Table 1.9
Figure 1 Molecular Structure of Compound (4)
Table 1 Selected bond lengths (×10-1 nm) and bond angles (o) for 4
P—O(5)
P—O(6)
P—O(3)
P—O(4)
1.4680(11) O(5)-P-O(6) 109.55(7)
1.5360(12) O(5)-P-O(3) 110.51(8)
1.5560(11) O(6)-P-O(3) 106.27(7)
1.5657(11) O(5)-P-O(4) 115.06(8)
O(3)—C(2) 1.4406(18) O(6)-P-O(4) 104.35(6)
O(4)—C(5)
O(6)—H(9)
1.447(2)
O(3)-P-O(4) 110.57(6)
112(2)
0.871(18) P-O(6)-H(9)
With this unique cyclic hydrogen phosphate in hand, we examined its usage as a chiral ligand in Alper’s
catalytic system5, 6 (Scheme 2). As it was stated, 10% mol palladium(II) chloride, 5% mol hydrogen
phosphate combined with 20% mol cupric chloride and oxygen constituted the catalyst and additive

system. The reaction was conducted in THF under acidic condition at room temperature with a mixed
carbon monoxide and oxygen atmosphere.
Scheme 2
∗
CO2H
PdCl2-CuCl2, 4
CO2H
+
CO / H2O, O2, THF, HCl
R
R
R
Table 2 Palladium-catalyzed asymmetric hydroxycarbonylation of styrenes
Entry
1d
2
Substrate
R = H
Additive
CuCl2
Yielda / %
Iso : linearb
89/11
91/9
Eec / %
40
9
11
2
48
3
CoCl2
NiCl2
SnCl2
LaCl3
CuCl2
21
97/3
4
34
91/9
11
2
5
40
97/3
6
7d
39
98/2
2
CH3
20
91/9
23
22
24
13
4
8
43
88/12
95/5
9e
10f
11
12
13
14
32
45
85/15
94/6
OCH3
Cl
50
28
71/29
77/23
91/9
-
C(CH3)3
CH2CH(CH3)2
40
7
56
4
1
(a) isolated yields; (b) based on H NMR spectrometry; (c) determined by chiral HPLC: KROMASIL
KR100-5CHI- TBB, hexane/i-propanol/HOAc = 100/1/0.05 or 0.1, 1.0 mL/min, retention time: 10-15
min or 20-30 min; (d) CO/O2 (1/1) was bubbled through the mixture; (e) 10% mol 4; (f) 5% mol PdCl2,
10% mol CuCl2.
The result is shown in Table 2. In general, the regioselectivity was good (up to 98/2), but both the yield
and enantioselectivity were poor. p-Methylstyrene gave better optical yield (S configuration by
comparing with reported optical rotation). Cupric chloride was a superior additive. The difference
between bubbling carbon monoxide and oxygen or a closed balloon atmosphere was small (Entries 1, 7).
The reaction became very sluggish with insufficient oxygen supply. Increasing the amount of chiral
ligand gave only similar results (Entry 9). Decreasing the amounts of catalyst and additive led to poorer
regioselectivity and enantioselectivity (Entry 10). The yield and regioselectivity were poor for substrate

with chlorine in the para position (Entry 12). Bulky substituent t-Bu also decreased the branch to linear
ratio (Entry 13). Ibuprofen was obtained in 56% yield, but the enantioselectivity was only 4% ee (Entry
14). For all substrates, several undesired side products were isolated and identified as acetophenone (8),
1,4-diphenylbutane-2,3-dione (9) and styrene oxide (10), which hampered improvement and limited the
scope in this reaction.
O
O
O
R
R
O
R
R
8
9
10
To conclude, some informative aspects of the phosphorylation of 1,4:3,6-dianhydro-D-mannitol by
phosphorus oxychloride were described. The crystal structure of a new cyclic hydrogen phosphate is
reported. And the preliminary results of its usage in palladium-catalyzed hydroxycarbonylation of styrene
are presented.
EXPERIMENTAL
Melting points were uncorrected. Specific rotation was recorded on a PERKIN-ELMER 341 polarimeter.
13
31
1H NMR, C NMR and P NMR spectra were obtained on a VARIAN MERCURY 300 spectrometer.
IR spectrum was recorded on a BIO-RAD FTS-185 spectrometer. EIMS and HRMS were obtained on an
AGILENT 5973N MSD and an IONSPEC 4.7 TESLA FTMS spectrometer.
1,4:3,6-Dianhydro-D-mannitol 2,5-(hydrogen phosphate) (4):
2.0 mL (20 mmol) of phosphorus oxychloride was added by syringe into a solution of 2.92 g (20 mmol) of
1 and 7.0 mL (50 mmol) of triethylamine in 50 mL of dichloromethane over 1 h at rt. The stirring was
continued for 5 h (31P NMR spectrum indicating a major peak δ -0.8 ppm). After filtration and
evaporation, the residue was taken up by aqueous NaOH (2 M, 50 mL) at 0 oC, and then neutralized with
2 M HCl. White solid was collected after concentrated at temperature below 20 oC. Recrystallization from
o
20
water and MeOH provided 1.0 g of the product (25%). mp: 283 C (decomp); [α]D +8.1o (c 0.5,
H2O); IR (KBr): ν 2565, 2297, 1725, 1251, 1218, 1127, 1057, 1015, 938, 765 cm-1; 1H NMR (300 MHz,
DMSO-d6): δ 4.84-4.83 (m, 2H), 4.62-4.60 (m, 1H), 4.52-4.50 (m, 1H), 4.40-4.36 (d, J = 11.7 Hz, 2H),
13
4.02-4.01 (d, J = 3.3 Hz, 1H), 3.98-3.97 (d, J = 3.3 Hz, 1H); C NMR (75 MHz, DMSO-d6): δ 79.9,
77.1-77.0 (d, J = 8.7 Hz), 74.2-74.1 (d, J = 2.9 Hz); 31P NMR (121 MHz, DMSO-d6): δ -3.4; EIMS: m/z
209 ([M+H]+, 2%); HRMS: calcd for C6H10O6P ([M+H]+) 209.0209, found 209.0206.
Typical procedure for the hydroxycarbonylation (also see refs. 5 and 6):

1.0 mL of HCl (37%) and 1.0 mL of water were added into a solution of 35 mg of PdCl2 in 10 mL of THF.
Carbon monoxide was bubbled through the mixture for 5 min before 0.4 mmol of CuCl2 and 0.1 or 0.2
mmol of 4 were added. Oxygen was bubbled for 10 min, and then p-methylstyrene (1.9 mmol) was
introduced. The reaction was kept under 1 atm of CO/O2 (1/1) at rt for 12 h with stirring. The mixture was
diluted with water (25 mL) and extracted with ether (3 × 30 mL). The combined organic layer was
washed with 2 M NaOH (3 × 30 mL). The aqueous phase was acidified to pH 2 by 2 M HCl and extracted
with ether (3 × 30 mL). The ether layer was dried over MgSO4, filtrated and evaporated in vacuo. The
residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 4/1 to 1/1)
and the product was obtained as a colorless oil.
ACKNOWLEDGEMENTS
We thank National Natural Science Foundation of China and Shanghai Municipal Committee of Science
and Technology for financial support.
REFERENCES AND NOTES
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ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.