Diphosphate Formation from Dioxaphosphorinanes
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4153
boiling point until a clear solution was obtained. The solution was
cooled to ∼60 °C and was acidified with concentrated hydrochloric
acid (50 mL). When cool, the colorless precipitate was collected and
washed with water (500 mL) and ether (200 mL) and was dried in
vacuo at 80 °C over P2O5 to give the acid (()-6 (41.0 g, 85%):
mp 204-205 °C (from EtOH) (lit.6 mp 224-224.5 °C); 31P NMR
(CDCl3 + CD3OD) -5.4 ppm; 1H NMR (250 MHz, CDCl3 + CD3OD)
7.5-7.35 (m, 5 H), 5.33 (s, 1 H, H4), 4.38 (d, 1 H, JHH ) 11 Hz,
ax-H6), 3.98 (dd, 1 H, JPH ) 24.5, JHH ) 11 Hz, eq-H6), 1.11 (s, 3 H),
0.86 (s, 3 H); MS (-ES) m/z 241.
pattern for this signal (not included in Figure 5) in the spectrum
of the reaction mixture was in accord with the 18O-labeling
pattern that would be expected (Scheme 5).
Finally, it is worth noting that in our experiments conducted
at room temperature we have not observed the species with
multiple phosphorus couplings that were seen by Hulst et al.4
in diphosphate-forming reactions conducted at higher temper-
atures using 5a generated in situ, and we cannot therefore offer
any additional evidence on their possible structures, but it seems
unlikely to us that they would be chloro phosphoranes.
Resolution of 6.6 The racemic acid (()-6 (14.2 g, 59 mmol) and
(+)-2-amino-1-phenyl-1,3-propanediol (10.0 g, 60 mmol) were dis-
solved in hot ethanol (38 mL) containing water (1.5 mL). The solution
was stirred and allowed to cool to room temperature. Stirring was
continued for a further 2 h before the crystalline salt (8.9 g) was
collected and washed with a little ether. The salt was stirred with water
(56 mL) containing concentrated hydrochloric acid (17 mL) for 3 h,
and the liberated acid was collected, washed with water, and dried in
vacuo at 80 °C over P2O5 giving (-)-2-hydroxy-2-oxo-5,5-dimethyl-
4-(R)-phenyl-1,3,2-dioxaphosphorinane (-)-6 (4.95 g, 35%): mp 210-
211 °C (from EtOH); [R]589 -60.8° (c 0.46, MeOH) (lit.6 [R]578 -60.0°);
Conclusions
A number of important conclusions emerge from this study.
First, it confirms that reactions of dialkyl phosphate anions with
dialkyl phosphorochloridates occur by a simple displacement
mechanism, with no evidence for dioxadiphosphetane interme-
diates. Second, the 31P NMR signals previously assigned by
others to a pentacoordinate chlorooxyanionic phosphorane such
as 9 have been unambiguously reassigned to the unsymmetrical
ax-eq diphosphate 7b. Third, and unexpectedly, the stereose-
lectivity seen in the reaction of (R)-2-chloro-2-oxo-5,5-dimethyl-
4-(R)-phenyl-1,3,2-dioxaphosphorinane (5a) and 2-hydroxy-2-
oxo-5,5-dimethyl-4-(R)-phenyl-1,3,2-dioxa-phosphorinane (6)
has been found to arise more from high selectivity within the
nucleophile 6 (axial O atom) than from high stereoselectivity
in displacement of the axial leaving group from 5, with the major
in-line displacement pathway (inversion) leading to the ax-eq
diphosphate 7b and the minor adjacent displacement pathway
(retention) leading to the ax-ax diphosphate 7a. Finally, the
majority of the symmetric ax-ax diphosphate 7a is formed from
ax-eq diphosphate 7b by an intermolecular exchange process
involving attack of the axial oxygen of 6, probably on the
equatorially substituted phosphorus atom of 7b. The essentially
complete conversion to 7a is a consequence of the thermody-
namic stability of the symmetrical diphosphate in which an
electronegative OP(O)(OR)2 group is axial with respect to each
of the rings.
1
31P NMR (CDCl3 + CD3OD) -5.4 ppm; H NMR as for (()-6.
Preparation of 2-Chloro-2-oxo-5,5-dimethyl-4-phenyl-1,3,2-di-
oxaphosphorinane (5a) Using Oxalyl Chloride. (a) A suspension of
the racemic acid (()-6 (1.0 g, 4.1 mmol) in CH2Cl2 (20 mL) was stirred,
and oxalyl chloride (1.2 g, 9.2 mmol) was added together with DMF
(catalyst, 40 µL). A clear solution was obtained in ∼1 h, and after 2 h,
the volatile material was evaporated and the residue was crystallized
from ether to give the racemic phosphorochloridate (()-5a: mp 121-
1
125 °C (lit.6 mp 127.5-129.5 °C); 31P NMR (CDCl3) -2.1 ppm; H
NMR (CDCl3, 250 MHz) 7.45-7.25 (m, 5 H), 5.30 (d, JPH ) 3 Hz,
1 H, H4), 4.37 (dd, JPH ) 3, JHH ) 11.5 Hz, 1 H, ax-H6), 4.09 (dd,
JPH ) 31, JHH ) 11.5 Hz, 1 H, eq-H6), 1.09 (s, 3 H), 0.86 (s, 3 H); MS
(EI) m/z 260, 262 (1) (M+), 205, 207 (100) (M+ - C4H7); MS (FAB)
m/z 521, 523, 525 (20) (2M + H+), 261, 263 (40) (M + H+), 145
(100). Structure confirmed by X-ray crystallography (Figure 1).
(b) The optically active acid (-)-6 was similarly treated with oxalyl
chloride to give (-)-(R)-2-chloro-2-oxo-5,5-dimethyl-4-(R)-phenyl-
1,3,2-dioxaphosphorinane (-)-5a: mp 164-165 °C (softens above
157 °C) (lit.6 mp 162-164.5 °C); [R]589 -94.4° (c 0.32, CH2Cl2)
1
(lit.6 [R]578 -82.4°); 31P NMR (CDCl3) -2.2 ppm; H NMR and MS
(EI) as for (()-5a.
Experimental Section
Preparation of 2-(R)-[18O]Hydroxy-2-oxo-5,5-dimethyl-4-(R)-
phenyl-1,3,2-dioxaphosphorinane (18O-Labeled Acid (-)-6). A solu-
tion of potassium tert-butoxide (98 mg, 0.88 mmol) in anhydrous tert-
butyl alcohol (6 mL) was stirred efficiently (heavy magnet), and 18O-
labeled water (22 mg, 1.10 mmol) was added, followed almost
immediately (1 min) by 5a (100 mg, 0.38 mmol). After 1 h, methanol
(5 mL) was added to dissolve precipated salts: 31P NMR (101 MHz)
Instrumentation. Melting points were determined on a Kofler hot-
stage apparatus and are uncorrected. Optical rotations were measured
at 589 nm using a 100-mm cell in a Perkin-Elmer 341 polarimeter. 1H
NMR (Me4Si internal standard) and 31P NMR spectra (negative
chemical shifts upfield from external 85% H3PO4) were recorded at
250, 300, or 400 MHz using Bruker ARX 250, DPX 300, or DRX 400
spectrometers. 31P NMR spectra are 1H decoupled unless otherwise
indicated and were recorded at 101, 122, or 162 MHz. Mass spectra
were obtained in EI (70 eV) or FAB (NBA matrix) mode using a Kratos
Concept spectrometer or in ES mode using a Micromass Quattro
spectrometer.
1
-1.76 (without H decoupling, d, JPH ) 23.5 Hz); a small peak 3 Hz
downfield indicated ∼10% unlabeled product. MS(-ES) m/z 243 and
241 (ratio 90:10). Volatile matter was evaporated, and the residue was
dissolved in water (4 mL). The aqueous solution was cooled in ice
and acidified with CF3CO2H (114 mg, 1.0 mmol) to precipitate 18O-
labeled 6 (84 mg, 91%).
Preparation of (()-2-Hydroxy-2-oxo-5,5-dimethyl-4-phenyl-1,3,2-
dioxaphosphorinane (6).6 A solution of 1-phenyl-2,2-dimethyl-1,3-
propanediol6 (10; 36.0 g, 0.20 mol) and Et3N (42.4 g, 0.42 mol) in
CH2Cl2 (100 mL) was stirred and cooled in ice, and distilled POCl3
(32.2 g, 0.21 mol) in CH2Cl2 (50 mL) was added during 0.5 h (31P
NMR: diastereoisomers, δP 2.2 and -2.2 ppm, ratio 3:2). Additional
CH2Cl2 (50 mL) was added to facilitate stirring, and the mixture was
heated under reflux for 3 h (31P NMR: δP 2.2 and -2.2 ppm, ratio
1:3). When cool, the mixture was filtered and the filtrate was washed
with water (2 × 75 mL). The washings were extracted with CH2Cl2
(50 mL), and the combined organic portions were dried (Na2SO4) and
concentrated to give the phosphorochloridate (()-5 (mixture of ax and
eq diastereoisomers) as a crystalline solid. The crude product 5 was
hydrolyzed by portion-wise addition over 0.5 h to a stirred solution of
NaOH (24 g, 0.60 mol) in water (240 mL) maintained at ∼95 °C
(CAUTION: exothermic reaction), followed by brief heating at the
A sample of the labeled acid (-)-6 was treated with diazomethane,
giving a mixture (∼1:1) of the epimeric methyl esters. eq-OMe: 31P
NMR (162 MHz; CDCl3) δP -1.813, -1.832 (P-18OMe), -1.855
1
(Pd18O) (ratio 10:9:81); H NMR (400 MHz, CDCl3) 7.4-7.25 (m),
5.43 (d, JPH ) 2 Hz, H4), 4.46 (d, JHH ) 11 Hz, ax-H6), 3.94 (dd,
JPH ) 24, JHH ) 11 Hz, eq-H6), 3.96 (d, JPH ) 11 Hz, OMe), 1.025 (s,
Me), 0.81 (s, Me); ax-OMe δP -5.595, -5.610 (P-18OMe), -5.636
(Pd18O) (ratio 10:81:9); δH 7.4-7.25 (m), 5.15 (s, H4), 4.21 (d, JHH
)
11 Hz, ax-H6), 3.94 (dd, JPH ) 25, JHH ) 11 Hz, eq-H6), 3.83 (d,
JPH ) 11, OMe), 1.05 (s, Me), 0.785 (s, Me). [Assignment of 1H NMR
signals to the two epimers was based on comparison with the spectra
of mixtures in which the ax-OMe epimer 11a was largely dominant
(g90%); these were obtained from the methanolysis of the phospho-
rochloridate 5a with MeOH/Et3N in CH2Cl2 or KOMe in tert-butyl
alcohol.]