Protonation of acyl anion equivalents generated from acylphosphonates: nonhydride access to the aldehyde oxidation state from the carboxylic acid oxidation state

Article abstract of DOI:10.1016/j.tet.2006.10.036

Acylphosphonates, which are easily available from carboxylic acids, are potent acyl anion precursors and undergo cyanide ion promoted phosphonate-phosphate rearrangement to provide the corresponding acyl anion equivalents as reactive intermediates. The protonation of these acyl anion equivalents furnished cyanohydrin O-phosphates in good yields. For the high yield formation of cyanohydrin O-phosphates from arylphosphonates THF should be used and from alkylphosphonates DME was used.

Full text of DOI:10.1016/j.tet.2006.10.036

Tetrahedron 63 (2007) 160–165
Protonation of acyl anion equivalents generated from
acylphosphonates: nonhydride access to the aldehyde oxidation
state from the carboxylic acid oxidation state
¨
Ayhan S. Demir, Omer Reis, Ilker Esiringu, Barbaros Reis and Sehriban Baris
*
€
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 7 July 2006; revised 27 September 2006; accepted 12 October 2006
Available online 2 November 2006
Abstract—Acylphosphonates, which are easily available from carboxylic acids, are potent acyl anion precursors and undergo cyanide ion
promoted phosphonate–phosphate rearrangement to provide the corresponding acyl anion equivalents as reactive intermediates. The proton-
ation of these acyl anion equivalents furnished cyanohydrin O-phosphates in good yields. For the high yield formation of cyanohydrin O-phos-
phates from arylphosphonates THF should be used and from alkylphosphonates DME was used.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of cyanohydrin O-phosphates. The synthesis of racemic
cyanohydrin O-phosphates from ketones and aldehydes
starting from lithium cyanide and diethyl chlorophosphate,
lithium cyanide, and diethyl cyanophosphonate,6 diethyl
cyanophosphonate in combination with lithium diisopropyl-
amine,7 cyanophosphonate and triethylamine at room
temperature in the absence of a solvent and nonracemic cy-
anohydrin O-phosphates from aldehydes, employing diethyl
cyanophosphonate and the chiral 3,30-bis-(diethylamino-
methyl)-1,10-binaphthol–AlCl (BINOLAM–AlCl) complex
as a bifunctional catalyst.3 Recently, Aoyama et al.8 de-
scribed a method for the cyano-phosphorylation of aldehydes
with diethyl cyanophosphonate in the presence of N-hetero-
cyclic carbenes, and Shibasaki et al.9 described the catalytic
asymmetric cyano-phosphorylation of aldehydes using a
YLi3 tris (binaphthoxide) complex.
Acyl anion equivalents provide a powerful alternative to
traditional carbon–carbon bond construction methods, and
adds new dimensions of flexibility to the design of synthetic
targets.1a–h These useful entities have been traditionally ob-
tained by functional group manipulation and stoichiometric
strong base deprotonation of the corresponding carbonyl
compounds. Recently, impressive progress has been made
in the catalytic generation of acyl anion equivalents, espe-
cially in the benzoin and Stetter reactions. As far as the
cross-benzoin and intramolecular Stetter reactions are con-
cerned, the use of acylsilanes as acyl anion precursors based
on the nucleophile-promoted Brook rearrangement are the
most practical and selective methods available.1i–n
Cyanohydrins are very important synthetic intermediates2
and are clear examples of unstable molecules that require a
suitable hydroxy-protecting group. This desirable protection
can be performed in a two-step sequence, starting from the
aldehyde or ketone, through the corresponding cyanohydrin,
followed by O-protection—although a one-pot procedure,
starting from aldehydes or ketones, has become syntheti-
cally more advantageous. Cyanophosphates are interesting
building blocks for the synthesis of b-amino alcohols and
The complexity and difficult availability of the reagents for
the above-mentioned methods prompted us to develop sim-
ple, generally applicable methods for the synthesis of these
important compounds.
2. Results and discussion
g-cyano-allylic alcohols3 and several intermediates.4
A
Recently, we have shown that acylphosphonates are potent
acyl anion precursors and undergo nucleophile-promoted
phosphonate–phosphate rearrangement to provide the corre-
sponding acyl anion equivalents as reactive intermediates.
Acylphosphonates 1 as the acyl anion precursors and
aldehydes 2 as electrophiles in the presence of a cyanide cat-
alyst provides cross-benzoin products. Aromatic–aromatic
number of different strategies are known5 for the synthesis
Keywords: Acylphosphonates; Cyanohydrin O-phosphates; Acyl anion;
Rearrangements; Carboxylic acids.
* Corresponding author. Tel.: +90 312 2103242; fax: +90 312 2103200;
e-mail: asdemir@metu.edu.tr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.036

A. S. Demir et al. / Tetrahedron 63 (2007) 160–165
161
cross-benzoin synthesis, aroylphosphonates with aliphatic al-
dehydes, aliphaticacylphosphonates, andaromaticaldehydes
furnished the acyloin products in good yields (Scheme 1).10
expected 4b in pure form, however, yields were just 51
and 66%, respectively. We examined the protonation of 3b
under various conditions. A high yield formation of the prod-
uct was achieved when mixing an ethereal solution of 1b
with KCN and then adding water to the mixture. This fur-
nished the product in 90% yield after the work-up procedure
(Scheme 2).
O
OPO(OEt)2
O
NC
R1
R1
R1
P(OEt)2
O
P(OEt)2
CN
O
O
1
When the reaction was carried out in ether, quenched, and
extracted with 1 N HCl, the crude products showed the
presence of both 4b and 4-F-benzoic acid 5. The generation
of 5 most likely results from the hydrolysis of 1b but it was
not obvious if 5 was formed directly by the action of water,
or if cyanide ion promotion has a role. In order to shed light
onto the hydrolysis, to DMF and ether solutions of 1a was
added water (pH¼7 and 10, without KCN). TLC moni-
toring of these mixtures for several hours showed that 1a
is stable in the absence of cyanide anion and only traces
of the corresponding acids were observable. When 1a was
stirred in MeOH, only traces of methyl benzoate were
observed. However, the same mixture in the presence of
KCN instantaneously provided methyl benzoate. These
are strong indications of a cyanide ion catalyzed hydrolysis
pathway.
CN
R2
H
2
O
CN
CN
O
O
R1
(EtO)2OPO
R1
R2
R2
R2
R1
OPO(OEt)2
OPO(OEt)2
Scheme 1.
Protonation of acyl anion equivalents generated from acyl-
phosphonates has twofold potential. First, the protonation
of these intermediates not only provides a practical nonhy-
dride reduction of carboxylic acids but also provides prod-
ucts that can be used as synthons for a variety of targets.
Second, they gave us the opportunity to identify the side
products of their reactions with aldehydes to be a proton ab-
straction from the environment or from reactants.10a,11 This
was the case in the reaction when utilizing aliphatic acyl-
phosphonates.
In DMF, crude product recovery was higher but contami-
nated with a side product. Upon closer examination of the
side product, a comparison with the literature values re-
vealed the side product as 6. This product probably arises
from the reaction of 7 with 1b. Addition of 7 to 1b promotes
a phosphonate–phosphate rearrangement via 8 forming 9,
which subsequently abstracts the proton to provide 6
(Scheme 3). Phosphonate–phosphate rearrangement pro-
moted by 7 is, however, already well known.13
As depicted in Scheme 2, the protonation of 3 would lead to
4, which is equivalent to an aldehyde under the appropriate
hydrolysis conditions. Therefore, this protonation strategy
has the advantage of the direct reduction of carboxylic acids
to aldehydes under aqueous conditions. The same transfor-
mation is known for the corresponding acylsilanes.12 How-
ever, this is not a feasible approach because the synthesis
of acylsilanes is laborious and generally obtained from alde-
hydes from which cyanohydrins are already available.
Next, we investigated the scope of this reaction for the syn-
thesis of typical cyanophosphates. Reaction with various
aryl- and alkylphosphonates furnished the expected prod-
ucts. Surprisingly the first example (1b) furnished the high-
est yield (90%). This result prompted us to carry out solvent
screening and we found that THF was a choice of the solvent
for arylphosphonates (Table 1, entries 1–6) and the products
were obtained in good to excellent yields (79–95%). For
alkylphosphonates, DME furnished the best results and the
products were obtained in 71–79% yields (entries 7–10).
The phosphonate–phosphate rearrangement and protonation
reaction of 1b was also carried out in Et2O–D2O and the cor-
responding deuterated product 4o was obtained in 78%
yield. This also indicated that water is the source of the
proton and this method could be used for the synthesis of
deuterated benzaldehyde derivatives.
Acylphosphonates are easily available from carboxylic acids
and the protonation of their cyanide promoted rearrange-
ment intermediates would lead to a common intermediate
for the synthesis of a-amino aldehydes, a-hydroxy-b-amino
acids, and diols.
Acylphosphonates were synthesized according to the litera-
ture procedures starting from the triethylphosphite and acyl-
chloride (82–89% yields).10 The phosphonates 1k–n were
obtained from thionyl chloride and the protected amino
acid by refluxing in benzene.
We examined the protonation of 3b under two-phase condi-
tions. Briefly, an organic solution (1 M DMF, toluene, or
ether) of 1b was mixed with an aqueous solution of KCN.
All reactions were complete in a few minutes by TLC mon-
itoring. Subsequent examination by NMR spectroscopy
showed that reactions in toluene and ether provided the
a-Amino aldehydes and a-hydroxy-b-amino acids are highly
important compounds. The former is a valuable synthon for
the synthesis of interesting targets. The latter can be found in
OPO(OEt)2
H2O
O
OPO(OEt)2
CN
OEt
OEt
1.1 equiv.KCN
Et2O:H2O
1:1
CN
P
O
F
F
F
1b
3b
4b
Scheme 2.

162
A. S. Demir et al. / Tetrahedron 63 (2007) 160–165
O
OPO(OEt)2
OPO(OEt)2
CN
OEt
OEt
1.1 equiv.KCN
P
O
P
OEt
+
OEt
DMF:H2O
1:1
O
F
F
F
1b
6
4b
OEt
OEt
O
P
H2O
O
COOH
7
F
PO(OEt)2
OEt
OPO(OEt)2
OEt
O
5
P
P
OEt
OEt
O
O
F
F
8
9
Scheme 3.
Table 1. Cyanophosphate synthesized
Table 1. (continued)
Entry
Acylphosphonate 1
Product 4a
Yield (%)
(solvent)
Entry
Acylphosphonate 1
Product 4a
Yield (%)
(solvent)
OPO(OEt)2
CN
O
O
OPO(OEt)2
CN
OEt
OEt
OEt
OEt
88 (Et2O),
91 (THF)
P
55 (Et2O),
71 (DME)b
P
O
1
9
O
3a,5b,8,9
11
a
a
i
i
O
OPO(OEt)2
CN
OEt
O
OPO(OEt)2
CN
OEt
OEt
90 (Et2O),
92 (THF)
P
O
2
3
OEt
P
O
54 (Et2O),
73 (DME)
10
11
12
F
F
b
b
3b,8,9
j
j
O
OPO(OEt)2
CN
OEt
OEt
OMe
OMe
O
P
P
81 (Et2O),
83 (THF)
OEt
OEt
O
CN
MeO
MeO
62 (Et2O)c
3a,5b,8
O
OPO(OEt)2
c
c
k
k
OMe
O
MeO
OPO(OEt)2
CN
OEt
OEt
OPO(OEt)2
CN
O
65 (Et2O),
80 (THF)
P
O
4
5
OEt
OEt
P
N
Cbz
N
Cbz
72 (Et2O)
5e
O
d
d
l
l
OPO(OEt)
O
2
OEt
OEt
Ph
66 (Et2O),
79 (THF)
CN
Ph
O
P
O
O
O
P
OEt
OEt
CN
N
N
e
e
13
14
66 (Et2O)
OPO(OEt)2
O
O
O
O
OPO(OEt)2
CN
OEt
OEt
m
m
P
O
64 (Et2O),
95 (THF)
6
7
8
O
O
O
P
Ph
Ph
OEt
OEt
Cl
Cl
CN
N
N
f
f
71 (Et2O)
O
OPO(OEt)2
O
O
O
OPO(OEt)2
CN
OEt
OEt
n
n
77 (Et2O),
79 (DME)
P
O
OPO(OEt)2
CN
O
OEt
OEt
g5b,8
g
P
O
15
78 (Et2O)
D
F
F
O
OPO(OEt)2
CN
OEt
OEt
b
O
64 (Et2O),
77 (DME)
P
O
a
All the products are colorless oil and the data of the known compounds are
in agreement with the literature values.
9
h
b
c
The reaction is carried out at 0 ꢀC.
Cat. amount of Zn(OTf)2 (5 mol %) is used.
h
(continued)

A. S. Demir et al. / Tetrahedron 63 (2007) 160–165
163
the structure of many biologically active compounds. The
4. Experimental
anticancer drug Taxol’s side chain, N-benzoyl-phenyliso-
serine, bestatin, and amprenavir is just three of the many
important compounds in this class. Acylphosphonates are
easily available from carboxylic acids, in which the proton-
ation of their cyanide promoted rearrangement intermediates
would lead to a common intermediate for the synthesis of
a-amino aldehydes and a-hydroxy-b-amino acids.
4.1. General
All reactions sensitive to air or moisture were conducted in
flame-dried glassware under an atmosphere of dry Argon.
THF and Et2O were distilled from purple sodium benzo-
phenone. KCN was dried at 100 ꢀC under vacuum. DMF
was distilled under reduced pressure and stored under nitro-
gen. Thin-layer chromatography (TLC) was performed on
glass-supported Merck silica gel 60 F254 plates. Spots were
visualized by UV light and by heat staining with 2% molyb-
dophosphoric acid in ethanol. Flash column chromatography
was performed on Merck silica gel 60 (63–200 mm). 1H and
13C NMR spectra were obtained on Bruker Avance 300 MHz
and DPX 400 spectrometers. All resonances are referenced
to residual solvent signals. Elemental analyses: Leco
CHNS 932 Analysator. IR spectra were obtained on Bruker
IFS 66/s. Acylphosphonates are synthesized according to the
literature procedures.10
Therefore, we carried out a preliminary experiment to test
the feasibility of this approach. When proloylphosphonate
1l was subjected to KCN in aqueous ether, product 4l
was obtained in a few minutes with complete consumption
of 1l. The reaction also afforded pure 4l in 72% yield
(Scheme 4).
O
P
CN
1.1 equiv.KCN
Et2O:H2O
OEt
OEt
N
N
OPO(OEt)2
O
BnO
1:1
BnO
O
O
4.2. General procedure for protonation of acyl anion
equivalents
1l
4l
72%, dr ~1:1.5
Scheme 4.
KCN (0.55 mmol) was added to the solution of 0.5 mmol
acylphosphonate in 2 mL diethyl ether (or appropriate sol-
vent). After 5 min stirring 1 mL water was added to the mix-
ture. After completion of the reaction (<15 min) (if solvent
DME or THF reaction time is 1–2 h), the mixture was diluted
with 5 mL ether and 5 mL water. Organic phase was sepa-
rated and dried with MgSO4 and evaporated under reduced
pressure. The products are purified by using flash column
chromatography (EtOAC–hexane).
The reaction of phenylalanine derived phosphonate 1m and
phenylglycine derived phosphonate 1n furnished the cyano-
phosphate 4m and 4n in 66–71% yields with 1:1.2 and 1:1.3
diastereomeric ratios, respectively. The same reaction with
the phosphonate of methylmandelic acid 1k afforded the
cyanophosphate derivative 4k in 62% yield with a 1:1.3 dia-
stereomeric ratio. These products are also valuable synthon
for the synthesis of interesting targets.
4.2.1. (S)-Diethyl 2-methoxy-1-oxo-2-phenylethylphos-
phonate 1k. Viscous yellow oil. Yield 2.37 g (83%), IR
In general, the arylcyanophosphates are obtained in a higher
yield than the alkylcyanophosphates and alkylcyanophos-
phates with a-CH furnished even lower yields.
1
(CHCl3): n¼1692, 1259, 1024 cmꢁ1. H NMR (400 MHz,
CDCl3): d 1.30 (t, J¼7.1 Hz, 3H), 1.37 (t, J¼7.1 Hz, 3H),
3.35 (s, 3H), 4.06–4.26 (m, 4H), 4.74 (s, 1H), 7.19–7.26
(m, 5H). 13C NMR (100 MHz, CDCl3): d 16.28, 57.5,
58.2, 62.1, 62.4, 82.0, 96.1, 127.2, 128.1, 128.2, 129.5,
204.5 (low intensity d, J¼170 Hz). 31P NMR (161 MHz,
CDCl3): d 8.91. C13H19O5P (286.26): Calcd C 54.54, H
6.69; found C 54.36, H 6.41.
3. Conclusions
We have shown that acylphosphonates that are easily avail-
able from carboxylic acids are potent acyl anion precursors
and undergo cyanide ion promoted phosphonate–phosphate
rearrangement to provide the corresponding acyl anion
equivalents as reactive intermediates. The protonation of
these acyl anion equivalents furnished cyanohydrin O-phos-
phates in good yields. The cyanophosphates are very
interesting building blocks for the synthesis of various inter-
esting compounds such as a-amino aldehydes, a-hydroxy-b-
amino acids, and diols. Compared to the laborious synthesis
of acylsilanes, the acylphosphonates are readily available in
multigram scale from the corresponding carboxylic acids
that offer an access to acyl anions. Thus, the generation of
acyl anion equivalents from the phosphonate–phosphate re-
arrangement adds a new strategy to the toolbox of synthetic
chemists. Moreover, the proven metal coordination ability of
the phosphonate moiety makes acylphosphonates a particu-
larly interesting platform for the diastereoselective and
enantioselective variants of the presented reactions, which
is the subject of current research.
4.2.2. Diethyl ((S)-1-((benzyloxy)carbonyl)pyrrolidin-2-
yl)oxomethylphosphonate 1l. Yellow oil. Yield 3.00 g
(81%). IR (CHCl3): n¼1692, 1417, 1355, 1259, 1079,
1
1024 cmꢁ1. H NMR (400 MHz, DMSO, 90 ꢀC): d 1.23
(m, 6H), 1.67–1.85 (m, 1H), 1.88–1.96 (m, 1H), 1.99–2.04
(m, 1H), 2.15–2.28 (m, 1H), 3.34–3.52 (m, 2H), 4.00–4.13
(m, 4H), 4.80–4.83 (m, 1H), 5.02–5.10 (m, 2H), 7.28–7.37
13
(m, 5H). C NMR (100 MHz, DMSO, 90 ꢀC): d 15.8,
15.9, 23.2, 28.4, 46.7, 63.3 (d, J¼7.2 Hz), 63.5 (d,
J¼7.3 Hz), 65.7 (d, J¼6.5 Hz), 66.3, 127.4, 127.6, 128.2,
128.4, 136.7, 209.1 (d, J¼159 Hz). 31P NMR (161 MHz,
CDCl3): d 12.03. C17H24NO6P (369.35): Calcd C 55.28,
H 6.55, N 3.79; found C 55.33, H 6.41, N 3.51.
4.2.3. (S)-Diethyl 1-oxo-2-(1,3-dioxoisoindolin-2-yl)-3-
phenylpropylphosphonate 1m. Yellow oil. Yield 3.56 g
(86%). IR (CHCl3): n¼1690, 1425, 1355, 1266, 1085,
1
1021 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.22–1.32 (m,

164
A. S. Demir et al. / Tetrahedron 63 (2007) 160–165
5H), 3.38 (dd, J¼3.4, 10.8 Hz, 1H), 3.67 (dd, J¼4.7, 9.6 Hz,
1H), 4.08–4.17 (m, 4H), 5.30–5.38 (m, 1H), 7.04–7.19 (m,
5H), 7.61–7.70 (m, 2H), 7.73–7.81 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 15.7 (d, J¼6.3 Hz), 15.8 (d,
J¼6.1 Hz), 32.2, 52.6, 63.6 (d, J¼7.5 Hz), 63.8 (d,
J¼7.2 Hz), 122.9, 126.3, 128.0, 128.4, 131.3, 133.4, 135.6,
166.5, 203.8 (d, J¼169 Hz). 31P NMR (161 MHz, CDCl3):
d 8.91. C21H22NO6P (415.38): Calcd C 60.72, H 5.34, N
3.37; found C 60.56, H 5.21, N 3.18.
d ꢁ2.10. C12H15ClNO4P (303.68): Calcd C 47.46, H 4.98,
N 4.61; found C 47.21, H 4.62, N 4.35.
4.2.8. (2S)-1-Cyano-2-methoxy-2-phenylethyl diethyl
phosphate 4k. Yellow oil. Yield 97 mg (62%). IR
1
(CHCl3): n¼2362, 1220, 1027 cmꢁ1. H NMR (400 MHz,
CDCl3): d 1.22–1.38 (m, 6H), 3.34 and 3.38 (2s, 3H),
3.77–4.19 (m, 4H), 4.47 (m, 1H), 4.96 and 5.12 (dd, J¼2.8,
6.2 Hz and dd, J¼2.8, 6.2 Hz, 1H), 7.25–7.40 (m, 5H). 13C
NMR (100 MHz, CDCl3): d 15.9 (d, J¼6.9 Hz), 16.0 (d,
J¼6.8 Hz), 18.9, 64.6 (d, J¼6.2 Hz), 64.7 (d, J¼4.9 Hz),
64.8 (d, J¼6.0 Hz), 116.1 (d, J¼5.6 Hz), 126.8, 128.3,
130.6, 130.7, 131.4, 136.6. 31P NMR (161 MHz, CDCl3):
d ꢁ2.86, ꢁ2.58. C14H20NO5P (313.29): Calcd C 53.67, H
6.43, N 4.47; found C 53.81, H 6.51, N 4.21.
4.2.4. (S)-Diethyl 1-oxo-2-(1,3-dioxoisoindolin-2-yl)-2-
phenylethylphosphonate 1n. Yellow oil. Yield 2.84 g
1
(71%). IR (CHCl3): n¼1728, 1382, 1218, 1014 cmꢁ1. H
NMR (400 MHz, CDCl3): d 1.19 (m, 6H), 4.08 (m, 4H),
7.24–7.30 (m, 3H), 7.43 (m, 1H), 7.56 (d, J¼7.6 Hz, 2H),
7.64–7.66 (m, 1H), 7.70–7.72 (m, 1H), 7.76–7.81 (m, 1H),
7.83–7.85 (m, 1H). 13C NMR (100 MHz, CDCl3): d 15.7,
15.8, 63.7, 63.8, 96.2, 123.5, 127.4, 128.3, 128.4, 130.5,
132.4, 134.1, 167.5, 204.1 (d, J¼169 Hz). 31P NMR
(161 MHz, CDCl3): d 12.20 ppm. C20H20NO6P (401.35):
Calcd C 59.85, H 5.02, N 3.49; found C 59.61, H 5.28, N
3.21.
4.2.9. ((S)-1-((Benzyloxy)carbonyl)pyrrolidin-2yl)(cya-
no)methyl diethyl phosphate 4l. Yellow oil. Yield 143 mg
(72%). IR (CHCl3): n¼2360, 1700, 1559, 1541, 1507,
1418, 1280, 1026 cmꢁ1 1H NMR (400 MHz, DMSO,
.
60 ꢀC): d 1.21–1.32 (m, 6H), 1.84–2.09 (m, 4H), 3.23–3.64
(m, 2H), 4.05–4.11 (m, 4H), 4.20–4.30 (m, 1H), 5.05–5.16
(m, 2H), 5.42–5.58 (m, 1H), 7.32–7.39 (m, 5H). 13C NMR
(100 MHz, DMSO, 60 ꢀC): d 17.5, 32.3, 49.0, 62.9, 66.1,
66.2, 66.3, 66.3, 66.4, 68.3, 68.5, 117.9, 129.4, 129.7,
130.2, 130.2, 138.3, 138.4. 31P NMR (161 MHz, DMSO,
60 ꢀC): d ꢁ2.54, ꢁ2.32, ꢁ1.44. C18H25N2O6P (396.37):
Calcd C 54.54, H 6.36, N 7.07; found C 54.32, H 6.67, N 6.83.
4.2.5. Cyano(4-fluorophenyl)methyl diethyl phosphate
4b. Yellow oil. Yield 132 mg (92%). IR (CHCl3): n¼2360,
1
1699, 1653, 1559, 1541, 1508, 1268, 1024 cmꢁ1. H NMR
(400 MHz, CDCl3): d 1.23 (J¼7.1 Hz, 3H), 1.38 (t, J¼
7.1 Hz, 3H), 3.94–4.01 (m, 2H), 4.15–4.25 (m, 2H), 6.04
(d, J¼8.9 Hz, 1H), 7.11–7.17 (m, 2H), 7.53–7.58 (m, 2H).
13C NMR (100 MHz, CDCl3): d 15.8 (d, J¼6.5 Hz), 15.9
(d, J¼6.6 Hz), 64.6 (d, J¼6.1 Hz), 64.9 (d, J¼6.1 Hz), 65.7
(d, J¼4.4 Hz), 116.0 (d, J¼6.2 Hz), 116.4 (d, J¼22 Hz),
128.6 (m), 129.7 (d, J¼8.8 Hz), 163.8 (d, J¼251.6 Hz). 31P
NMR (161 MHz, CDCl3) d ꢁ2.17. C12H15FNO4P (287.22):
Calcd C 50.18, H 5.26, N 4.88; found C 50.42, H 5.33,
N 5.23. Deuterated derivative 4o: 1H NMR (400 MHz,
CDCl3): d 1.23 (t, J¼6.7 Hz, 3H), 1.38 (t, J¼6.7 Hz, 3H),
3.94–4.01 (m, 2H), 4.15–4.25 (m, 2H), 7.11–7.17 (m, 2H),
7.53–7.58 (m, 2H).
4.2.10. (2S)-1-Cyano-2-(1,3-dioxoisoindolin-2-yl)-3-phe-
nylpropyl diethyl phosphate 4m. Yellow oil. Yield
145 mg (66%). IR (CHCl3): n¼2370, 1720, 1651, 1560,
1
1545, 1510, 1452, 1260, 1033 cmꢁ1. H NMR (400 MHz,
CDCl3): d 1.20–1.30 and 1.32–1.42 (m, 6H), 3.34–3.59
(m, 2H), 3.85–3.93 (m, 1H), 4.14–4.01 (m, 1H), 4.18–4.31
(m, 2H), 4.86–4.95 (m, 1H), 5.67–5.76 (m, 1H), 7.10–7.18
(m, 5H), 7.68–7.71 (m, 2H), 7.74–7.77 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 16.0, 16.1, 34.0, 54.1 (d, J¼8.8 Hz),
65.0, 65.1, 65.2, 115.0, 123.7, 127.2, 128.7, 128.8, 131.1,
134.4, 135.5. 31P NMR (161 MHz, CDCl3): d ꢁ2.86,
ꢁ2.78. C22H23N2O6P (442.4): Calcd C 59.73, H 5.24, N
6.33; found C 59.54, H 5.43, N 6.21.
4.2.6. Cyano(2-methylphenyl)methyl diethyl phosphate
4e. Yellow oil. Yield 112 mg (79%). IR (CHCl3): n¼2360,
1653, 1559, 1271, 1030 cmꢁ1
.
1H NMR (300 MHz,
4.2.11. (2S)-1-Cyano-2-(1,3-dioxoisoindolin-2-yl)-2-phe-
nylethyl diethyl phosphate 4n. Yellow oil. Yield 151 mg
(71%). IR (CHCl3): n¼2360, 1717, 1653, 1559, 1541,
CDCl3): d 1.23 (t, J¼7.1 Hz, 3H), 1.38 (t, J¼7.1 Hz, 3H),
2.50 (s, 3H), 3.98–4.10 (m, 2H), 4.12–4.31 (m, 2H), 6.16
(d, J¼8.7 Hz, 1H), 7.24–7.39 (m, 3H), 7.56 (d, J¼7.9 Hz,
1H). 13C NMR (75.5 MHz, CDCl3): d 15.9 (d, J¼6.9 Hz),
16.0 (d, J¼6.8 Hz), 18.9, 64.6 (d, J¼6.2 Hz), 64.7 (d,
J¼4.9 Hz), 64.8 (d, J¼6.0 Hz), 116.1 (d, J¼5.6 Hz),
126.8, 128.3, 130.6, 130.7, 131.4, 136.6. 31P NMR
(121.5 MHz, CDCl3): d ꢁ2.10. C13H18NO4P (283.26):
Calcd C 55.12, H 6.41, N 4.94; found C 55.41, H 6.33, N 4.73.
1507, 1457, 1260, 1026 cmꢁ1
.
1H NMR (400 MHz,
CDCl3): d 1.00 (t, J¼7.1 Hz, 3H), 1.25 (t, J¼7.1 Hz, 3H),
3.44–3.54 (m, 1H), 3.56–3.65 (m, 1H), 3.87–3.97 (m, 1H),
4.01–4.06 (m, 1H), 5.52 (d, J¼10.7 Hz, 1H), 6.34 (dd,
J¼1.8, 8.8 Hz, 1H), 7.23–7.32 (m, 3H), 7.56 (d, J¼7.1 Hz,
2H), 7.65–7.68 (m, 2H), 7.78–7.81 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 15.7 (d, J¼7.2 Hz), 16.0 (d,
J¼7.2 Hz), 56.7 (d, J¼9.3 Hz), 64.0 (d, J¼4.9 Hz), 64.2
(d, J¼5.9 Hz), 64.6 (d, J¼5.6 Hz), 96.2, 115.2, 123.9,
129.0, 129.1, 129.2, 131.6, 134.2, 134.3, 167.0. 31P NMR
(161 MHz, CDCl3) d ꢁ3.20. C21H21N2O6P (428.38): Calcd
C 58.88, H 4.94, N 6.54; found C 58.66, H 4.81, N 6.33.
4.2.7. Cyano(3-chlorophenyl)methyl diethyl phosphate
4f. Yellow oil. Yield 144 mg (95%). IR (CHCl3): n¼2360,
1559, 1474, 1271, 1028 cmꢁ1
.
1H NMR (300 MHz,
CDCl3): d 1.24 (t, J¼7.1 Hz, 3H), 1.31 (t, J¼7.1 Hz, 3H),
3.95–4.12 (m, 2H), 4.18–4.30 (m, 2H), 6.02 (d, J¼8.9 Hz,
1H), 7.36–7.47 (m, 3H), 7.56 (d, J¼1.8 Hz, 1H). 13C NMR
(75.5 MHz, CDCl3): d 15.9 (d, J¼6.9 Hz), 16.0 (d,
J¼6.9 Hz), 64.6 (d, J¼6.1 Hz), 64.7 (d, J¼4.9 Hz), 64.8
(d, J¼6.0 Hz), 116.1 (d, J¼5.6 Hz), 126.8, 128.3, 130.6,
130.7, 131.4, 136.6. 31P NMR (121.5 MHz, CDCl3):
Acknowledgements
Financial support was funded by the Middle East Technical
University (BAP-2005), the Scientific and Technical

A. S. Demir et al. / Tetrahedron 63 (2007) 160–165
165
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