Synthesis of 2-phenoxy-2,75-spiro[1,3,2-benzodioxaphosphole-2,2'- 1,3,2-oxazophospholan]-5'-ones

Article abstract of DOI:10.1055/s-1998-2086

Phosphorus(V) chloride was sequentially displaced by catechol, N,O- bis(trimethylsilyl)amino acids and phenol (Method A) or catechol, phenol and N,O-bis(trimethylsilyl)amino acids (Method B) leading to a high yield synthesis of 2-phenoxy-2,7⁵ spiro[1,3,2-benzodioxaphosphole-2,2'-1,3,2- oxazophospholan]-5'ones under mild conditions. The products were characterized by ¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C COSY and field desorption mass spectrometry.

Full text of DOI:10.1055/s-1998-2086

June 1998
SYNTHESIS
855
5
¢
Synthesis of 2-Phenoxy-2,7 -spiro[1,3,2-benzodioxaphosphole-2,2 -1,3,2-oxazophos-
¢
pholan]-5 -ones
Hua Fua Guang-Zhong Tu,b Zhao-Long Li,a Yu-Fen Zhaoa*
a Bioorganic Phosphorus Chemistry Laboratory, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
Fax +86(10)62781695; E-mail: tp-dch@mail.tsinghua.edu.cn
b Biomembrane & Biomembrane Engineering National Laboratory, Department of Biological Science & Biotechnology, Tsinghua University,
Beijing 100084, P. R. China
Received 4 September 1997
Abstract: Phosphorus(V) chloride was sequentially displaced by
catechol, N,O-bis(trimethylsilyl)amino acids and phenol (Method
A) or catechol, phenol and N,O-bis(trimethylsilyl)amino acids
(Method B) leading to a high yield synthesis of 2-phenoxy-2,75-
spiro[1,3,2-benzodioxaphosphole-2,2¢-1,3,2-oxazophospholan]-5¢-
ones under mild conditions. The products were characterized by
1
1
1H, 13C, H-1H COSY, H-13C COSY and field desorption mass
spectrometry.
Key words: pentacoordinate 1,3,2-oxazophospholane, sequential
displacement, mild conditions
The chemistry of monocyclic and spirocyclic oxyphos-
phoranes is one of the most active research fields in organ-
ophosphorus chemistry.1–3 These phosphorus compounds
are closely related to the biologically important phosphate
esters and have attracted attention as models for the possi-
ble intermediates in phosphodiesterase-catalyzed hydroly-
sis of cAMP.4–7 Since the 1960s, a pentacovalent cyclic
acyloxyphosphorane containing high-energy anhydride
bond POC=O8 has been implicated as an intermediate inthe
hydrolysis of phosphoenolpyrurate.9–11
We have synthesized earlier a series of N-phosphoryl ami-
no acids12–16 and found that they could stimulate many in-
teresting bioorganic reactions under mild conditions.17, 18
For example, phosphoryl amino acids could autocatalyze
to give peptides, esters, phosphoryl ester-exchanged and
phosphoryl group migration products, and their reactivity
was dependent on the amino acid side chains. An intramo-
lecular pentacoordinate phosphoric-carboxylic mixed an-
hydride intermediate was considered as an important
transient species.17, 18 In 1995, an interesting experiment
based on silicon chemistry was applied to trap the penta-
coordinate phosphorus.19 Since Lipmann has proposed
that the biosynthesis of proteins proceeds through a mixed
phosphoric-carboxylic anhydride intermediate,20 it might
be significant to synthesize these stable pentacoordinate
phosphorus compounds. The present paper discloses a
new synthetic method and the isolation of the pentacoor-
dinate phosphoranes.
3,4,6,6¢
R
a
b
c
d
e
H
Me
Me2CH
Me2CH2(Me)CH
PhCH2
Scheme
Both the reaction routes proceed fast under quite mild
conditions with formation of fewer side products. For ex-
ample, the reactions can be carried out at room tempera-
ture and are over once the starting materials were
completelymixed. 2,2,2-Trichloro-1,3,2-benzodioxaphos-
phole (2) was prepared by reacting catechol with phos-
phorus(V) chloride according to the reported procedure.22
According to Method A, a solution of N,O-bis(trimethyl-
silyl)amino acid 3a–e in benzene or dichloro-methane
was added dropwise to a benzene or dichloromethane so-
lution of 2 in equimolecular amounts under nitrogen at-
mosphere at 25°C. The 2-chloro-2,75-spiro[1,3,2-benzo-
Amino acids are zwitterions and are not soluble in aprotic
organic solvents. However, their trimethylsilyl derivatives,
N,O-bis(trimethylsilyl)amino acids, are well soluble in or-
ganic solvents such as dichloromethane and benzene. N,O-
bis(trimethylsilyl)amino acids 3 were prepared by refluxing
the corresponding amino acids with hexa-methyl-
disilazane21 andconvertedto2-phenoxy-2,75-spiro-[1,3,2-
benzodioxaphosphole-2,2¢-1,3,2-oxazophospholan]-5¢-
¢
ones 6,6 by two different routes as shown in the Scheme.
¢
dioxaphosphole-2,2¢-1,3,2-oxazophospholan]-5¢-ones 4,4

856
Papers
SYNTHESIS
were formed within a few minutes. The reaction was mon-
itored by 31P NMR spectroscopy. For example, compound
2 shows a signal in the 31P NMR spectrum at d = –26.23
and was quickly transferred into a diastereoisomeric mix-
¢
ture of 4,4 , which exhibit two peaks between d = –29 and
–31 due to the chiral carbon of amino acids, except gly-
cine, together with a small amount of a side product at
¢
about d = 18.72. The intermediates 4,4 need not be isolat-
ed, and were reacted directly with an equimolar amount of
¢
phenol to afford quantitatively 5,5 . Because 2 possess a
five-membered ring, the reaction was favored to form a
spirophosphorane. Preparation and isolation of each phos-
phorane by Method A are listed in Table 1.
The only change in Method B is that 2 was quantitatively
transferred into 5 in the second step. Compound 5 was
characterized by its 31P NMR spectrum (d = –34.13).
Treatment of 5 with N,O-bis(trimethylsily])amino acids 3
In conclusion, the methods reported here for the prepara-
tion of pentacoordinated phosphoranes have the advan-
tages of high yield, rapid reaction rate and mild reaction
conditions.
¢
a–e afforded the products 6,6 (Table 1).
Since the P–O bond of the anhydride P-OC=O moiety in
the pentacoordinate phosphorane is longer than expect-
ed,23 it implies that this is the apical bond. Compounds
¢
6,6 were characterized by elemental analyses, field des-
All glassware was dried in an oven for at least 3 h at 120°C before use.
All the reactions were conducted under a N2 atmosphere. a-Amino
acids, catechol, phenol, PCl5 and hexamethyldisilazane were pur-
chased from local manufacturers. Et2O and benzene were dried over
Na and freshly distilled before use. CH2Cl2 was dried over CaCl2 for
1
orption mass spectrometry and H, 13C NMR (Table 2).
1H, 13C NMR chemical shifts of the diastereoisomers 6,6
¢
were assigned according to 1H-1H COSY and 1H-13C CO-
SY. Their 1H-31P COSY indicated that the 1H NMR chem-
1
1
1
1 d and distilled.1H, 13C, H-1H COSY, H-13C COSY and H-31P
ical shifts in high field region generally correspond to 31
NMR chemical shifts in the high field region.
P
COSY NMR spectra were recorded on a Bruker AM-500 at 500 MHz
spectrometer in CDCl3 solvent with shifts referenced to CDCl3 (dH
=
7.24, dC = 77). 31P NMR spectra were recorded on a Bruker AM-200p
at 200 MHz using 85% H3PO4 (dP = 0) as an external standard. Ele-
mental analyses were carried out on a Carlo Erba 1106 CHN analyzer.
Field desorption mass spectra were recorded on a Finnigan MAT 90
double-focusing mass spectrometer.
In order to readily interpret the 1H, 13C NMR spectroscop-
ical data, the carbon atoms in compounds 6,6 were num-
bered and the amino acid residues were marked with
signals a, b, g and d as shown below.
¢
Table 1. Preparation of Compounds 6,6¢a–e by Methods A and B
Prod- R
uct
Reaction mp (°C)
Solvent (Solvent,
5:1)
Yield (%)
31P NMR
(CDCl3/H3PO4) m/z
d
FD-MS
Method Method
A
B
6,6¢a
H
CH2Cl2 145–147
71
63
67
69
64
78
76
74
74
83
–42.02
305 (M+), 248 (M+ –X), 172 (MH+–X–Ph), 94 (YH+)
(C6H6/CH2Cl2)
CH2Cl2 152–153
(C6H6/CH2Cl2)
148–l50
6,6¢b Me
–44.91, –45.51 319 (M+), 248 (M+–X), 172 (MH+ –X–Ph), 94 (YH+)
–44.64, –44.83 347 (M+), 248 (M+–X), 172 (MH+–X–Ph), 94 (YH+)
–45.27, –45.44 361 (M+), 248 (M+–X), 172 (MH+ –X–Ph), 94 (YH+)
–45.20, –45.31 395 (M+), 248 (M+–X), 172 (MH+ –X–Ph), 94 (YH+)
6,6¢c Me2CH
C6H6
(Et2O/C6H6)
105–l13
(Et2O/C6H6)
6,6¢d MeCH2(Me)CH C6H6
6,6¢e PhCH2
CH2Cl2 166.5–167
(C6H6/CH2Cl2)
a Satisfactory microanalyses obtained: C ± 0.09, H ± 0.07, N ± 0.14.
b The solvents given refer to Method A. Benzene was used as the solvent for all reactions in Method. B
c The products 6,6¢a, b and e prepared by Method B were recrystallized from benzene.
d 31P NMR data for 4,4¢. 4,4¢a: d = –27.89; 4,4¢b: d = –31.05, –31.55; 4,4¢c: d = –29.39, –29.92; 4,4¢d: d = –29.75, –30.23; 4,4¢e: d = –29.79,
–30.26. 31P NMR data for 5a–e: d = –34.13.
e X = Amino acid residue, Y = PhO.

June 1998
SYNTHESIS
857
2-Phenoxy-2,75-spiro[1,3,2-benzodioxaphosphole-2,2¢-1,3,2-ox-
azophospholan]-5¢-ones 6,6¢; General Procedure:
(10 mL) was added dropwise to the mixture. After a reaction time of
10 min, the solvent and ClSiMe3 were removed by rotary evaporation,
Method A: To a stirred solution of 2 (1.23g, 5mmol) in anhyd CH2Cl2 and the product was crystallized (Table 2).The colorless precipitate
or benzene (15 mL) at r.t. under N2 atmosphere was added dropwise was filtered, washed three times with anhyd Et2O and dried in vacuo
a solution of N,O-bis(trimethylsilyl)amino acid 3 (5 mmol) in CH2Cl2 over P2O5 at 39°C.
or benzene (10 mL). After 10 min, 0.5 mL of the reaction mixture was
drawn and analyzed by 31P NMR spectroscopy to check whether the This work was supported by the National Natural Science Founda-
chemical shift at d = –26.23 belonging to 2 was completely shifted to tion of China, the National Science and Technology Committee of
d = –29 and –31 characteristic of the products. Then a solution of phe- China, Chinese National Ministry of Education and Tsinghua Uni-
nol (0.47 g, 5 mmol) in CH2Cl2 or benzene (10 mL) was added drop- versity.
wise to the resulting solution. After a reaction time of 10 min, the
solvent and ClSiMe3 were removed by rotary evaporation, and the
product was purified by crystallization (Table 1). The colorless crys-
tals were washed three times with anhyd Et2O and dried in vacuo over
P2O5 at 39°C.
Method B: To a stirred solution of 2 (1.23 g, 5 mmol) in anhyd ben-
zene (15 mL) at r.t. under N2 atmosphere was added dropwise a solu-
tion of phenol (0.47 g 5 mmol) in benzene (10 mL). After 10 min,
0.5 mL of the mixture was drawn and analyzed by 31 P NMR spectros-
copy to check whether the chemical shift at d = –26.23 belonging to 2
was completely shifted to d = –34, 13 characterstic of the product. A
solution of N,O-bis(trimethylsilyl)amino acid 3 (5 mmol) in benzene
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