D. S. Panmand et al. / Tetrahedron Letters 55 (2014) 5898–5901
5899
us to initiate a research program aimed at the development of sta-
ble but reactive surrogates of the classical and highly hydrolyzable
dialkyl/diaryl chlorophosphates.
We now report a convenient synthesis of novel benzotriazole-
based surrogates of dialkyl/diaryl halophosphates which enables
the efficient phosphonylation of N-, O-, and S-nucleophiles. The
1H-benzo[d][1,2,3]triazol-1-yl-1-phosphonates were obtained by
convenient and high-yielding procedures from cheap and readily
available reagents.
Hünig’s base (1.1 equiv) at room temperature for 15 min to give
2b in 97% yield as an air and moisture stable solid. Similar to 2a,
benzotriazole substitution from the spectral data was exclusively
at 1N.
The global electronic properties of compounds 2a,b and their
chloro-analogs 1a,b were computed using a reported proce-
dure19a–h in order to assess their global electrophilicity. Computa-
tions showed slightly higher global electrophilicities (x) for the
benzotriazole substituted phosphonates (1.23 eV, 1.77 eV,
1.75 eV, and 1.86 eV, respectively, for 1a, 2a, 1b, and 2b). These
results also emphasized that the dibenzo[d,f][1,3,2]dioxaphos-phe-
pine 6-oxide series (1b, 2b) are intrinsically slightly more reactive
on the electrophilicity scale than the diethoxy series (1a, 2a).
We then undertook phosphonylations using 2a and 2b, with a
series of N-, O-, and S-nucleophiles (Schemes 2 and 3). Compound
2a reacted smoothly with primary and secondary amines and alco-
hols (Table 1) to give the corresponding adducts 3a–d and 3h in
high yields (63–83%) under mild conditions in the presence of pyr-
idine (2.0 equiv). Surprisingly, aliphatic thiols required n-BuLi to
proceed, leading to the corresponding adducts in 76% yield; no
reaction was observed using the conditions optimized for the ali-
phatic amine series. Aromatic compounds also needed some adap-
tation of the protocol: reaction of aniline with 2a required NiCl2 to
proceed in good yield (3e, 68%), while the addition of aromatic
alcohols 3f,g reached 77–81% yields in the presence of anhydrous
sodium carbonate under microwave irradiation. None of the
above-described conditions were found suitable for the reaction
of thiols 3j,k with 2a which required conditions similar to those
Results and discussion
Two different strategies were developed for the transformation
of diethyl phosphite into its 1H-benzo[d][1,2,3]triazol-1-yl-
1-phosphonate derivative 2a (Scheme 1): (i) a one-pot two-step
procedure, in which diethyl phosphite was first converted into its
diethyl chlorophosphate intermediate 1a by treatment with
freshly prepared tert-butyl hypochlorite and subsequently trans-
formed into derivative 2a by quenching with a solution of 1H-ben-
zotriazole/Et3N under microwave conditions (92% total yield); (ii)
an alternative one-pot one step reaction using a 1/1 dry potassium
carbonate/1-chloro-1H-benzo[d][1,2,3]triazole mixture, affording
compound 2a (75%) from diethyl phosphite. Compound 2a was
obtained in high purity in each case. According to the spectral data
for 2a, substitution of the benzotriazole unit occurred exclusively
at 1N, a feature shared with most (acyl)benzotriazoles. Compound
2a was stable for up to one week at room temperature and for sev-
eral months at ꢀ40 °C. Combined with a superior resistance to
hydrolysis, 2a has significant advantages in terms of stability over
its chloro-analog for use in phosphonylation reactions. In contrast
to almost all of the (acyl)benzotriazoles that were studied over the
last decade in our lab and isolated as crystalline solids, 2a was
obtained as a liquid. Not only are solids easier to handle than liq-
uids, but crystalline solids are naturally more resistant to decom-
position in moist air than liquids. We therefore sought crystalline
analogs of 2a by considering various substitutions at R1 (results
not shown). Among the compounds generated, 2b was isolated
O
P
O
N
O
P
O
N
Base, Nucleophile
O
N
O
Nu
See Table 1
for conditions
2a
3a-k
Scheme 2. Reaction of 2a with N-, O-, and S-nucleophiles.
as
a crystalline solid (mp 154.5–155.5 °C) and was further
investigated.
O
O
O
Biphenol chlorophosphate 1b was synthesized according to
previously reported procedures using commercially available
2,20-biphenol and phosphoryl trichloride18 and was then further
reacted with 1H-benzotriazole (1.0 equiv) in the presence of
O
P
P
N
Base, Nucleophile
O
O
N
N
Nu
See Table 2
for conditions
3l-r
2b
Scheme 3. Reaction of 2b with N-, O-, and S-nucleophiles.
O
O
P
H
O
Table 1
Preparation of Compounds 3a–k
One-pot
Two-step
O
P
O
BtCl, K2CO3
MeCN, rt, 2 h
One-pot
One-step
3
Nucleophile, Nu
Yield (%) of 3
Mp (°C) of 3
1. t-BuOCl
CH2Cl2, rt, 2 h
O
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cyclohexylamine
Morpholine
Piperidine
Benzyl amine
Aniline
63a
70b
83b
81b
68c
77d
81d
74b
76e
75e
70e
74.5–75.0
Oil
Oil
Oil
94.5–95.5
Oil
Oil
Oil
Oil
R1
O
R1
2. BtH
O
P
O
N
N
O
P
Cl
O
N
Base,
conditions
O
R1
R1
Phenol
b-Naphthol
1a-b (quant.)
OH
OH
POCl3
2a (92%), R1 = Et
2b (97%, R1
(
L)-Menthol
DCM, rt, X h
=
Cyclohexane thiol
Benzyl thiol
p-Methylthiophenol
O
O
3j
3k
Oil
Oil
a
b
c
Pyridine, MW, 40 °C, 20 min.
Pyridine, MW, 80 °C, 30 min.
NiCl2, neat, rt.
Na2CO3 anh., MW, 80 °C, 30 min.
nBuLi, ꢀ78 °C to rt, 30 min.
Scheme 1. Conversion of diethyl phosphite into 2a using (i) the one-pot, two-step
(left) or (ii) the one-pot one-step approach (right). 6-(1H-Benzo[d][1,2,3]triazol-1-
yl)dibenzo[d,f][1,3,2]dioxaphos-phepine 6-oxide (2b) was obtained from its chloro
analog 1b. See Supplementary material for details.
d
e