Diethyl chlorophosphite: A versatile reagent

Article abstract of DOI:10.1021/jo0106851

Diethyl chlorophosphite (DECP) was previously described as a reducing agent for nitro compounds to the corresponding amines (Fischer, B.; Sheihet, L. J. Org. Chem. 1998, 63, 393). Here, the utility of this reagent was extended to chemical conversions of other oxygenated functional groups. In this paper we report on the scope of the reaction of DECP with N-oxides, epoxides, sulfones, sulfoxides, hydroxylamines, ketoximes, and aldoximes. The chemoselectivity of DECP is described, and conditions for a stepwise multiple conversion of functional groups on the same molecule with this reagent are provided.

Full text of DOI:10.1021/jo0106851

J . Org. Chem. 2002, 67, 711-719
711
Dieth yl Ch lor op h osp h ite: A Ver sa tile Rea gen t
Zhou J ie, Vebumani Rammoorty, and Bilha Fischer*
Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University,
Ramat-Gan 52900, Israel
bfischer@mail.biu.ac.il
Received J uly 9, 2001
Diethyl chlorophosphite (DECP) was previously described as a reducing agent for nitro compounds
to the corresponding amines (Fischer, B.; Sheihet, L. J . Org. Chem. 1998, 63, 393). Here, the utility
of this reagent was extended to chemical conversions of other oxygenated functional groups. In
this paper we report on the scope of the reaction of DECP with N-oxides, epoxides, sulfones,
sulfoxides, hydroxylamines, ketoximes, and aldoximes. The chemoselectivity of DECP is described,
and conditions for a stepwise multiple conversion of functional groups on the same molecule with
this reagent are provided.
Sch em e 1
In tr od u ction
Tervalent organophosphorus compounds (X3P) such as
trialkyl- or triarylphosphines and trialkyl phosphites are
useful reagents in synthetic chemistry in several deoxy-
genation and dehydration reactions.1 The major driving
force for these reactions is the formation of a PdO bond
and the release of 120-150 kcal/mol.
We previously reported on the utility of diethyl chlo-
rophosphite (DECP) as an agent for the reduction of nitro
compounds to the corresponding phosphoramides, which
are further cleaved in situ, yielding amine derivatives
(Scheme 1).2 In this paper, we extend the scope of this
reagent to the deoxygenation of other functional groups.
Specifically, we report on the reaction of DECP with
N-oxides, epoxides, sulfones, sulfoxides, hydroxylamines,
ketoximes, and aldoximes. In addition, we report on the
chemoselectivity of DECP, provide conditions for stepwise
multiple conversion of functional groups on the same
molecule with this reagent, and propose mechanistic
explanations.
regioselectivity (entry 3), rather than the corresponding
olefin obtained with other phosphorus deoxygenating
agents.4 Cyclohexene oxide, however, gave a mixture of
isomers of 2-chlorocyclohexyl ethyl hydrogen phospho-
1
nate in 88% yield (entry 4), as indicated by MS, H, 31P,
and 13C NMR, and DEPT spectra. These compounds
exhibited the typical 700 Hz one-bond P-H coupling in
1
31P and H NMR.
Deoxygenation of hydroxylamines was reported to
proceed at room temperature with medium yields upon
treatment with triphenylphosphine derivatives.5 DECP,
however, is extremely reactive with phenylhydroxy-
lamine, yielding a multitude of products even at -100
°C. The same high reactivity was observed also with (p-
nitrophenyl)hydroxylamine and (p-methoxyphenyl)hy-
droxylamine (entry 5). However, no reaction occurred
between DECP and methyl (phenylsulfonyl)acetate, allyl
phenyl sulfone, or benzamide (entries 6 and 7) even after
they were heated under reflux in acetonitrile for 24 h.
Likewise, no reaction occurred with 2-indanone oxime
and DECP, with or without triethylamine; the ketone
isolated from the reaction mixture is the result of
hydrolysis of the oxime during workup (entry 8). Al-
doximes, on the other hand, proved to be efficiently
converted by DECP to the corresponding nitrile, even in
the absence of Et3N (Table 2).
Resu lts
Var iou s Ch em ical Con ver sion s with Dieth yl Ch lo-
r op h osp h ite. The versatility and efficiency of (EtO)2PCl,
DECP, as a deoxygenating agent, was evaluated with
various functional groups (Table 1). Thus, pyridine
N-oxide was quantitatively reduced to pyridine with
DECP in chloroform at room temperature (Table 1, entry
1). The reduction of methyl phenyl sulfoxide to the
corresponding sulfide was readily accomplished by DECP
at room temperature within 30 min (entry 2), providing
a facile alternative to other phosphorus reagents previ-
ously proposed for the deoxygenation of sulfoxides.3
When an aliphatic acyclic epoxide is treated with the
reagent, alone or in combination with triethylamine, a
chlorohydrin is formed in 85% yield with complete
* To whom correspondence should be addressed. Fax: 972-3-
5351250. Phone: 972-3-5318303.
(3) (a) Olah, G. A.; Balaram Gupta, B. G.; Narang, S. C. J . Org.
Chem. 1978, 43, 4503 and references therein. (b) Suzuki, H.; Sato, N.;
Osuka, A. Chem. Lett. 1980, 143.
(4) (a) Wong H. N. C.; Fok, C. C. M.; Wong, T. Heterocycles 1987,
26, 1345. (b) Yamada, K.; Goto, S.; Nagase, H.; Kyotani, Y.; Hirata, Y.
J . Org. Chem. 1978, 43, 2076. (c) Paryzek, Z.; Wydra, R. Tetrahedron
Lett. 1984, 25, 2601.
(1) (a) Cadogan, J . I. G. Q. Rev. 1968, 22, 222. (b) Smith, D. J . H. In
Comprehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.;
Pergamon Press: Oxford, 1979; pp 1127-1188. (c) Corbridge, D. E. C.
Phosphorus. An Outline of its Chemistry, Biochemistry and Uses;
Studies in Inorganic Chemistry 20; Elsevier: Amsterdam, 1995; pp
319-320 and 352-354.
(5) Kurtzweil, M.; Loo, D.; Beak, P. J . Am. Chem. Soc. 1993, 115,
421.
(2) Fischer, B.; Sheihet, L. J . Org. Chem. 1998, 63, 393.
10.1021/jo0106851 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

712 J . Org. Chem., Vol. 67, No. 3, 2002
J ie et al.
Ta ble 1. Con ver sion s of Va r iou s Oxygen a ted F u n ction s
by DECP
Ta ble 2. Con ver sion of Ald oxim es to Nitr iles by DECP :
a
All reactions were performed in CHCl3 unless otherwise stated.
The reaction was performed in acetonitrile. c The reactant pre-
b
cipitated upon addition of DECP as the diethyl (4-carboxaldoxime
pyridinium)phosphite chloride salt.
Deh yd r a tion of Ald oxim es to Nitr iles by Dieth yl
Ch lor op h osp h ite. Dehydration of aldoximes to nitriles
is a well-known transformation for which many reagents
have been proposed.6 The long list of reagents used for
this transformation includes several phosphorus re-
agents: phosphonitrilic chloride,7 polymer-supported triph-
enylphosphine/carbon tetrachloride,8 tributylphosphine/
DEAD,9 dialkyl hydrogen phosphonate,10 and diphosphorus
tetraiodide.11 Many of these methods have shortcomings
such as low yields, hazardous reagents, harsh and long
reaction conditions, and, in some cases, lack of generality
for variously substituted aldoximes. Thus, the search for
new and milder synthetic methodologies continues. Here
we illustrate the usefulness of diethyl chlorophosphite
for achieving this conversion in excellent yields under
mild reaction conditions.
The dehydration reaction involves stirring the al-
doxime with 3 equiv of (EtO)2PCl in dry chloroform at
-40 °C or room temperature under argon. Some cases
required heating for completion of the reaction (Table 2).
After a short reaction time, usually between 10 and 90
min, an aqueous workup affords the nitrile in 76-95%
yield. The method is general and is applicable for
aromatic, heterocyclic, and aliphatic aldoximes. The
advantage of this methodology lies both in the mild-
ness of the procedure and in the selective conversion
of an aldoxime functionality in the presence of other
DECP-sensitive groups such as hydroxyl and nitro
(Scheme 2d).
Dehydration of aldoxime to nitrile is best effected in
aprotic polar solvents. For instance, the conversion of
3-methoxy-5-nitrosalicylaldehyde oxime (Table 2, entry
9) in toluene is complete after 12 h at 90 °C, whereas in
chloroform and acetonitrile, the conversion is complete
at room temperature within 3 and 1.5 h, respectively.
Conversion of benzaldoxime to benzonitrile in good
yield was effected by DECP after 30 min at room
temperature (entry 1). Electron-withdrawing groups such
as chloro or nitro at either para or ortho positions
accelerated the reaction (entries 2-4). A similar behavior
was observed for cinnamaldehyde oxime (entry 7). Thus,
(6) (a) Lehnert, W. Tetrahedron Lett. 1971, 6, 559. (b) Clive, D. L.
J . Chem. Soc., Chem. Commun. 1970, 1014. (c) Rogic, M.; van Peppen,
J . F.; Klein, K. P.; Demmin, T. R. J . Org. Chem. 1974, 39, 3424. (d)
Foley, H. G.; Dalton, D. R. J . Chem. Soc., Chem. Commun. 1973, 628.
(e) Keumi, T.; Yamamoto, T.; Saga, T.; Kitajima, H. Bull. Chem. Soc.
J pn. 1981, 54, 1579. (f) Olah, G. A.; Vankar, Y. D. Synthesis 1978,
702. (g) Olah, G. A.; Vankar, Y. D.; Garcia-Luna, A. Synthesis 1979,
227. (h) Katrizky, A. R.; Zhang, G. F.; Fan, W. G. Org. Prep. Proced.
Int. 1993, 25, 315. (i) Molina, P.; Alajarin, M.; Vilaplana, M. J .
Synthesis 1982, 106. (j) Arrieta, A.; Paloma, C. Synthesis 1983, 472.
(k) Kim, S.; Yi, K. Y. Tetrahedron Lett. 1986, 27, 1925. (l) Tamami, B.;
Kiasat, A. R. Synth. Commun. 2000, 30, 235. (m) Sosnovsky, G.; Krogh,
J . A. Synthesis 1978, 703. (n) Babad, H.; Zeiler, A. G. Chem. Rev. 1973,
73, 75.
(7) Rossini, G.; Baccolini, G.; Cacchi, S. J . Org. Chem. 1973, 38, 1060.
(8) Harrison, C. R.; Hodge, P.; Rogers, W. J . Synthesis 1977, 41.
(9) Urpi, F.; Vilarrasa J . Tetrahedron Lett. 1990, 31, 7497.
(10) Surgie, A. S. J . Org. Chem. 1969, 34, 2805.
(11) Suzuki, H.; Fuchita, T.; Iwasa, A.; Mishina, T. Synthesis 1978,
905.

Diethyl Chlorophosphite
J . Org. Chem., Vol. 67, No. 3, 2002 713
Sch em e 2
p- and o-nitrobenzonitrile were obtained from the corre-
sponding aldoximes in high yield after 10 min at -40 °C.
On the other hand, electron-donating groups such as
methoxy or hydroxy at ortho/para/meta positions retarded
the reaction (entries 5 and 6). For instance, conversion
of 2,3-dimethoxybenzaldoxime was achieved in excellent
yield only after 6 h at 60 °C. DECP-sensitive groups, such
as nitro and hydroxyl, were not affected at all under the
mild reaction conditions (entries 3, 4, 6, and 9). The
reaction conditions proved to be general also for aliphatic
and heterocyclic aldoximes (entries 8 and 10), although
reaction with valeraldehyde was slower than with ben-
zaldoxime.
with DECP in comparison to the oxime moiety, thus
forming the diethyl phosphitylpyridinium chloride salt.
When P(OMe)3 (3 equiv) was used in place of DECP,
no conversion of benzaldoxime to benzonitrile was ef-
fected even under reflux in chloroform for 12 h. With PCl3
(3 equiv) conversion of benzaldoxime to benzonitrile was
effected in 11% yield only after addition of Et3N and
heating under reflux in chloroform for 20 h. No conver-
sion to a nitrile was effected upon treatment of p-
nitrobenzaldoxime O-methyl ether with DECP.
Ch em oselectivity of DECP . Conditions effecting the
conversion of aldoximes to nitriles left DECP-sensitive
substituents, such as nitro and hydroxyl, unaffected
(Table 2, entries 3, 4, 6, and 9). We then performed
competition studies designed to explore the chemoselec-
tivity of DECP for aldoxime, nitro, and hydroxyl substit-
uents in the same molecule. We also attempted to fine-
When pyridine 4-carboxaldoxime was subjected to the
reaction conditions, a precipitate was formed instanta-
neously and no nitrile product was obtained (entry 11).
Apparently, the pyridine moiety reacts more favorably

714 J . Org. Chem., Vol. 67, No. 3, 2002
J ie et al.
tune the conditions for the conversion of only a certain
function in the presence of others (Scheme 2).
withdrawing group para to the hydroxyl group reduces
considerably its nucleophilicity and renders this function
incapable of reaction with electrophilic DECP/Et3N under
these conditions. On the other hand, the presence of a
hydroxy group para to the nitro group retards the
reduction of this function to the corresponding phospho-
roamidate (Scheme 1), as we found before.2
When vanillin, 1, was treated with 1.5 equiv of DECP
and Et3N, followed by an oxidative workup with iodine/
water, a smooth conversion of the hydroxyl group to the
phosphoric acid triester 2 occurred. Aldoxime, 3, prepared
from 2, was quantitatively converted to nitrile 4 with
DECP in CHCl3 without base (Scheme 2a).
Chemoselectivity was demonstrated in a reversed
sequence (Scheme 2b). When 4-hydroxy-3-methoxyben-
zaldoxime, 5, was treated with DECP at room tempera-
ture, the conversion to nitrile 6 was quantitative, with
the hydroxyl remaining intact. However, upon the addi-
tion of 1 more equiv of DECP and triethylamine at room
temperature, phosphitylation of the hydroxyl, followed
by oxidation with iodine/water, was effected in 79% yield
to afford the corresponding stable phosphoric acid triester
4 (Scheme 2b).
We then investigated the conversion by DECP of both
nitro and aldoxime groups on the same molecule (Scheme
2c). Indeed, we found that conversion of p-nitrobenzal-
doxime to the corresponding nitrile occurs in high yield
(Table 2, entry 4). A one-pot conversion of both functions
by first adding DECP to form the nitrile, followed by the
addition of DECP/Et3N to reduce the nitro function,
would therefore seem an attractive pathway. However,
this was not attempted, since in our earlier work we
found that reduction of p-nitrobenzonitrile resulted in
only a 20% yield after 4 days at room temperature.2
Alternatively, these transformations were achieved in
high yield in the reversed sequence of steps (Scheme 2c).
Thus, the addition of 3 equiv of DECP/Et3N to p-
nitrobenzaldehyde afforded the reduced product 8 in 80%
yield. After conversion of 8 to oxime 9 in high yield,
another 3 equiv of DECP was added at room temperature
to afford nitrile 10 in 91% yield after 3 h.
When 2-hydroxy-3-methoxy-5-nitrobenzaldoxime, 11,
was subjected to DECP, a complete conversion of the
aldoxime to the nitrile was obtained at room temperature,
with the nitro and hydroxyl groups unaffected (Table 2,
entry 9). We then attempted the transformation of all
three DECP-sensitive groups in a one-pot reaction. Thus,
aldoxime 11 was completely converted to the nitrile upon
the addition of DECP in toluene under reflux for 12 h
(Scheme 2d). The addition of 4 more equiv of DECP and
Et3N and heating in toluene under reflux for 12 h effected
the conversion of the hydroxyl to a phosphite. The latter
was isolated as the stable phosphoric acid triester 13
after oxidative workup in 25% overall yield. Under these
conditions, the nitro group did not react. Here, the order
of chemical conversions with DECP is aldoxime > hy-
droxy > nitro.
One-pot sequential conversions of aldoxime, hydroxy,
and nitro groups on the same molecule by DECP were
found to be sluggish. Therefore, we attempted to reverse
the sequence of DECP transformations starting from
2-hydroxy-3-methoxy-5-nitrobenzaldehyde, 14 (Scheme
2e). We planned to effect first both phosphitylation of the
hydroxyl group and reduction of the nitro group of
aldehyde 14 by 4 equiv of DECP/Et3N to obtain 15. After
formation of the corresponding aldoxime, we planned to
convert it by DECP treatment to nitrile 16. However,
upon the addition of 4 equiv of DECP/Et3N, even under
reflux in acetonitrile for 24 h, neither reduction of the
nitro group nor phosphitylation of the hydroxyl group
occurred. Apparently, the presence of a strong electron-
Discu ssion
In our earlier work with DECP as a reducing agent
for nitro compounds, we noticed that this reagent, which
is a hybrid of PCl3 and P(OEt)3, possesses a biphilic
character.2 Namely, DECP is capable of acting either as
an electrophile or as a nucleophile.
Benzamide and methyl (phenylsulfonyl)acetate or allyl
phenyl sulfone are poor nucleophiles and electrophiles,
and therefore, they do not undergo any reaction with
DECP (Table 1, entries 6 and 7). Pyridine N-oxide and
methyl phenyl sulfoxide, however, are sufficiently nu-
cleophilic to undergo a facile deoxygenation with DECP
as the electrophile (Table 1, entries 1 and 2). As an
analogy, kinetic studies on the deoxygenation reaction
of heterocyclic N-oxides by PCl3 suggest a nucleophilic
attack upon phosphorus by the N-oxide oxygen atom.12
Replacement of chlorine atoms in phosphorus trichloride
with an electron-releasing ethoxyl group decreases the
rate of deoxygenation.12 Investigations of intramolecular
transfers of oxygen from nitrogen and sulfur to phos-
phines support the conclusion that the addition of N-oxide
oxygen to phosphorus is the preferred mechanism.13 In
these cases, DECP acts as an electrophile being attacked
by the oxygen of either the N-oxide or sulfoxide to form
a phosphitylpyridinium or a phosphitylsulfonium chloride
intermediate, 18 or 22, respectively (Scheme 3). When
the reaction of pyridine N-oxide with 3 equiv of DECP
was performed without exclusion of water, pyridine was
isolated in 90% yield after 3 h. However, when the
reaction was repeated with severe exclusion of water for
12 h, the yield dropped below 50%. With only 1 equiv of
DECP and no exclusion of water, the yield slightly
decreased to 81%. H and 31P NMR and mass spectra of
1
the latter crude reaction mixture indicated the formation
of pyridinium hydrochloride and diethyl phosphate (typi-
cal acidic proton signal at 11.2 ppm), but no diethyl
hydrogen phosphonate. The same phosphorus product
was also obtained in the reaction of methyl phenyl
sulfoxide with DECP.
On the basis of these observations, a mechanism
involving a facile addition-elimination reaction of phos-
phitylpyridinium chloride intermediate 18 in the pres-
ence of water is proposed (Scheme 3a). The addition of
water to the phosphitylpyridinium intermediate occurs
by phosphorus octet expansion to form a pentavalent
phosphorane intermediate, 19.5 This unstable trigonal
bipyramidal species then collapses to diethyl phosphate
and pyridinium hydrochloride.
Alternatively, a mechanism involving the elimination
of diethyl metaphosphate, 20, from the phosphitylpyri-
dinium intermediate 18 followed by the addition of water
to metaphosphate intermediate 20 could be considered
(Scheme 3b). However, this mechanism is less likely,
since there are no negative charges on the putative
(12) Emerson, T. R.; Rees, C. W. J . Chem. Soc. 1964, 2319.
(13) Kurtzweil M. L.; Beak, P. J . Am. Chem. Soc. 1996, 118, 3426.

Diethyl Chlorophosphite
J . Org. Chem., Vol. 67, No. 3, 2002 715
Sch em e 3
metaphosphate oxygens to stabilize the developing posi-
tive charge on the phosphorus.14
to form a phosphorane, and this unstable intermediate
then decomposes.17 Phosphorane 28 (Scheme 4a) elimi-
nates a chlorohydrin, rather than EtOH. It is well
established that the leaving group in phosphorane is
displaced from the axial position, and that the most
electronegative ligand occupies preferentially axial sites.18
The negative inductive effect of the adjacent chloro group,
which stabilizes the incipient negative charge on the
oxygen, makes the chlorohydrin a better leaving group.
However, phosphorane 32, derived from cyclohexene
oxide (Scheme 4b), eliminates EtOH preferentially. This
is a rare case of formation of “asymmetric” hydrogen
phosphonate diester from a trivalent phosphorus precur-
sor.19 The preferential elimination of EtOH is probably
due to the different positions of the cyclohexyloxy and
ethoxy substituents in the bipyramidal phosphorane 32,
where the large cyclohexyl substituent prefers the less
hindered equatorial position. However, elimination occurs
from the axial position, where the ethoxy group is found.
A different mode of decomposition of phosphorane is
proposed for the charged phosphoranes 19 and 23 in
Scheme 3 and the neutral phosphoranes 28 and 32 in
DECP also plays the electrophile role with an epoxide
moiety, effecting the formation of a chlorohydrin product
rather than the expected olefin (Table 1, entry 3).4 The
observation that the addition of Et3N to the reaction
mixture (which brings about the formation of a highly
electrophilic phosphorus species)2 leads also to a chloro-
hydrin product supports DECP’s electrophilic role. Thus,
a reactive oxonium moiety, 25, is formed by the attack
of the epoxide oxygen on DECP (Scheme 4a). However,
the mechanism of charge release of the oxonium moiety
is different from that proposed for phosphitylpyridinium
and phosphitylsulfonium ions 18 and 22 in Scheme 3 and
occurs through the regiospecific attack of the chloride on
the less hindered electrophilic carbon of intermediate 25.
The resulting trialkyl phosphite 26 is extremely sensitive
to acid-catalyzed hydrolysis.15 In the acidic medium pro-
duced by workup and hydrolysis of excess DECP, the tri-
alkyl phosphite intermediate 26 is cleaved to form 1-
chloro-2-hydroxydecane, 29, and diethyl phosphite, which
exists predominately as the hydrogen phosphonate.
The rate of acid hydrolysis of a phosphite is ca. 1012
times as great as that of the corresponding phosphate.15
This is because a phosphite binds a proton with the
unshared electrons and thus forms an electrophilic
phosphorus16 highly sensitive to nucleophilic attack by
water. Thus, the protonated phosphite rapidly adds water
(16) Hudson, H. R. In The Chemistry of Organophosphorus Com-
pounds; Hartley, F. R., Ed.; In The Chemistry of Functional Groups;
Patai, S., Ed.; J ohn Wiley: New York, 1990; Vol. 1, pp 483-4.
(17) Westheimer, F. H. The role of Phosphorous in Chemistry and
Biochemistry: An Overview. In Phosphorous Chemistry Developments
in American Science; Walsh, E. N., Griffith, E. J ., Parry, R. W., Quin,
L. D., Eds.; ACS Symposium Series 486; American Chemical Society:
Washington, DC, 1992.
(14) Caldwell, S. R.; Raushel, F. M.; Weiss, P. M.; Cleland W. W.
Biochemistry 1991, 30, 7444.
(15) Westheimer, F. H.; Huang, S.; Covitz F. J . Am. Chem. Soc.
1988, 110, 181.
(18) Holmes, R. R. Pentacoordinated Phosphorus; ACS Monograph
176; American Chemical Society: Washington, DC, 1980.
(19) Stawinski, J . In Handbook of Organophosphorus Chemistry;
Engel, R., Ed.; Marcel Dekker: New York, 1992; p 383.

716 J . Org. Chem., Vol. 67, No. 3, 2002
J ie et al.
Sch em e 4
Scheme 4. Whereas in Scheme 3 the charged species
decomposes to diethyl phosphate and pyridine or sulfide
by loss of proton and charge neutralization, in Scheme
4, the neutral phosphorane decomposes to hydrogen
phosphonate and alcohol.
DECP effected efficiently the conversion of aldoximes
to nitriles. Some observations were made concerning the
role of DECP in the reaction: (a) the efficient conversion
of aldoximes to the corresponding nitriles occurs even in
the absence of base; (b) the reaction is accelerated by
electron-withdrawing groups on the benzaldoxime (Table
2); (c) P(OMe)3 does not effect the conversion to the
nitrile, even under reflux in chloroform for 12 h; (d) with
PCl3 conversion to the nitrile occurs in low yield, only
after addition of Et3N and heating under reflux in
chloroform for 20 h.
polarizability of the phosphorus atom that can be affected
by both positive and negative charges.21
There are several precedents of nucleophilic reactions
of tervalent phosphorus compounds (PCl3 and P(OMe)3)
at an imine carbon or an electrophilic aldoxime ether
carbon.22 Hence, both the aldoxime and DECP bear
electrophilic and nucleophilic sites, and are capable of
reacting either way.
A mechanism consistent with the above-mentioned
data involves the attack of aldoxime’s oxygen at the
electrophilic DECP phosphorus, rather than DECP at-
tacking at the electrophilic aldoxime’s carbon. In the
former mechanism intermediates 34 and 35 are likely
Elucidation of the reaction’s mechanism was attempted
by monitoring it using 31P NMR. Thus, the reaction of
2,3-dimethoxybenzaldoxime with 3 equiv of DECP in
CDCl3 at 40 °C was followed, and the spectra were
recorded in 10 min intervals. The signal of DECP at 166
ppm decreased gradually, while a typical signal for hydro-
1
gen phosphonate at 5 ppm with a J P-H of 700 Hz ap-
formed. Collapse of phosphorane 35 will provide the
nitrile product, HCl, and diethyl hydrogen phosphonate.
peared. No phosphorus intermediates were observed. The
formation and decomposition of the intermediates are
apparently too fast to be observed on the NMR time scale.
Oximes are expected to react as oxygen nucleophiles
due to the R-effect of the adjacent nitrogen’s lone pair.
Ketoximes, indeed, react with PCl3 in the presence of
Et3N, with the oxygen acting as the nucleophile, followed
by an Arbuzov-type rearrangement.20 On the other hand,
an “amphoteric” behavior is most pronounced for terva-
lent phosphorus compounds. These compounds can act
either as electrophiles or as nucleophiles, due to the high
(20) (a) Kruglyak, Y.; Leibovskaya, G.; Sretenskaya, I.; Sheluchenn-
ko, V.; Martynov, I. Zh. Obsh. Khim. 1968, 38, 943; J . Gen. Chem.
(USSR), Engl. Transl. 1968, 38, 908. (b) Brown, C.; Hudson, R.; Maron,
A.; Record, K. J . J . Chem. Soc., Chem. Commun. 1976, 663.
(21) Hudson, R. F. Structure and Mechanism in Organo-phosphorus
Chemistry; Organic Chemistry A Series of Monographs; Academic
Press: New York, 1965; Chapter 4.
(22) (a) Elhaddadi, M.; J acquier, R.; Petrus, F.; Petrus, C. Phospho-
rus, Sulfur Silicon Relat. Elem. 1989, 45, 161. (b) Tyka, R.; Hagele,
G.; Peters, J . Synth. Commun. 1988, 18, 425. (c) J ahn, U.; Andersch,
J .; Schroth, W. Synthesis 1997, 573.

Diethyl Chlorophosphite
J . Org. Chem., Vol. 67, No. 3, 2002 717
The latter is clearly observed in H and 31P NMR spectra
of the crude reaction mixture. Elimination of hydrogen
phosphonate is the driving force for this reaction.
The nucleophilic role of the aldoxime is supported by
the absence of any reaction of p-nitrobenzaldoxime O-
methyl ether with DECP. Furthermore, acceleration of
the reaction by electron-withdrawing groups on the
aromatic aldoxime (Table 2, entries 2-4) indicates the
nucleophilic nature of the aldoxime’s oxygen. Electron-
withdrawing groups increase the acidity of the al-
doxime.23 Furthermore, linear relationships often exist
between nucleophilic rates and the pKa of the nucleo-
philes.24 This mechanism also explains the lack of
reactivity of P(OMe)3, due to its low electrophilicity.
Deoxygenation of N-oxide and sulfoxide by electrophilic
DECP is probably water-assisted, involving charged
phosophoranes. These putative phosphoranes decompose
to the deoxygenated product, HCl, and diethyl phosphate.
With epoxides, neutral phosphoranes are likely formed
and decompose to a hydrogen phosphonate and an
alcohol. Nitrile formation from aldoxime and DECP is
accelerated by electron-withdrawing groups which, to-
gether with the lack of reactivity of P(OMe)3, support the
electrophilic role of DECP.
1
Exp er im en ta l Section
Gen er a l P r oced u r es. All reagents were of analytical
grade. Chloroform was distilled over CaH2, and stored over 4
Å molecular sieves under Ar. Diethyl chlorophosphite, ben-
zaldoxime, 2-nitrobenzaldoxime, and 4-nitrobenzaldoxime were
used as received from commercial sources. Other oximes were
prepared from the corresponding aldehydes and NH2OH‚HCl
in the presence of NaOH in boiling EtOH. The oximes were
dried under vacuum prior to use. N-arylhydroxylamines were
prepared from the corresponding nitro compounds according
to a literature procedure.25 All reactions were carried out in
flame-dried flasks under dry Ar, unless otherwise mentioned.
The reagents were handled under Ar with airtight syringes.
The reactions’ progress was monitored by TLC on precoated
Merck silica gel plates (60F-254). Flash column chromatogra-
phy was performed with Merck silica gel 60 (230-400 mesh).
1H and 13C NMR spectra were recorded on a Bruker DPX300
machine and 31P NMR spectra on a Bruker AC-200 machine
in CDCl3 with TMS as internal standard. J PC values are given
in parentheses in the 13C NMR spectral data. The products
were also characterized on an AutoSpec-E fision VG high-
Con clu sion s
DECP was shown to be an effective deoxygenating
agent for N-oxide and sulfoxide functions. For the deoxy-
genation of the sulfoxide function, the use of DECP is
an attractive alternative to known phosphorus reagents.
Unlike other phosphorus reagents, DECP does not
effect deoxygenation of an epoxide to the corresponding
olefin. However, DECP effects the efficient formation of
a chlorohydrin or a chloro hydrogen phosphonate product,
depending on the nature of the leaving group. This
reagent proved to be too reactive with arylhydroxy-
lamines, and was completely unreactive with benzamide
and sulfones.
An attractive application of DECP is the transforma-
tion of aldoximes to nitriles, which is effected under mild
conditions in high yields. This reaction is of a wide scope,
and applies to aliphatic, heterocyclic, and aromatic
aldoximes bearing various substituents (Cl, NO2, OH,
OMe), however with no basic nitrogen function.
Among the various reagents for aldoxime’s dehydra-
tion, DECP provides some significant advantages: DECP
is a commercially available compound; DECP is conve-
niently used, unlike hazardous dehydration agents, such
as selenium dioxide6m or phosgene;6n unlike the reaction
with ortho esters6c or P2I46 and chlorothionoformate,6b the
reaction does not require acid or base catalysis; DECP
effects a chemoselective conversion of an aldoxime to the
nitrile, under conditions that leave intact functions such
as hydroxyl, nitro, amide, and sulfone. This is in contrast
to reagents such as Bu3P/DEAD9 and 1,1′-carbonyl-
benztriazole,6h which, in addition to their reaction with
aldoxime, react with nitro and amide functions, respec-
tively.
Although DECP is completely chemoselective for al-
doximes in the presence of nitro and hydroxyl, conditions
for the stepwise transformation of those DECP-sensitive
groups were explored. Thus, 2-hydroxy-3-methoxy-5-
nitrobenzaldoxime, 11, was completely converted to the
nitrile upon addition of DECP in toluene under reflux.
The addition of 4 more equiv of DECP and Et3N and
heating in toluene under reflux effected the conversion
of the hydroxyl to a phosphite, which was isolated as the
phosphoric acid triester 13. Under these conditions, the
nitro group did not react. Here, the order of chemical
conversions with DECP is aldoxime > hydroxy > nitro.
1
resolution mass spectrometer. For known compounds the H/
13C NMR and mass spectra are consistent with the given
structure and literature data.
Rea ction w ith P yr id in e N-Oxid e. DECP (213 µL, 1.5
mmol, in 10 mL of CHCl3) was added dropwise to a solution
of pyridine N-oxide (48 mg, 0.5 mmol) in CHCl3 (5 mL). The
solution was stirred at room temperature for 3 h, and then
concentrated under reduced pressure while the bath was cooled
to 0 °C. The residue was extracted with 5% NaOH and purified
by column chromatography (MeOH/CHCl3, 1:9). Pyridine was
obtained in 89% yield (35 mg).
Rea ction w ith Meth yl P h en yl Su lfoxid e. A solution of
DECP (213 µL, 1.5 mmol, in CHCl3, 5 mL) was added dropwise
over 5 min at room temperature to a solution of methyl phenyl
sulfoxide (70 mg, 0.5 mmol) in CHCl3 (5 mL). The solution was
stirred for 30 min till the reactant was completely consumed.
The reaction mixture was separated by silica gel chromatog-
raphy (hexane), and methyl phenyl sulfide was obtained in
83% yield (51 mg).
Rea ction w ith 1,2-Ep oxyd eca n e. DECP (213 mL, 1.5
mmol) was added dropwise to a solution of 1,2-epoxydecane
(78 mg, 0.5 mmol) in CHCl3 (5 mL) at 0 °C under Ar, and the
solution was stirred for 12 h at room temperature. The solvent
was removed under reduced pressure, and the residue was
dissolved in CHCl3, washed with saturated NH4Cl solution (3
× 25 mL), and dried over MgSO4. 1-Chloro-2-hydroxydecane,
29, was obtained after chromatography on silica gel and
elution with hexane/CHCl3 (3:1) in 83% yield (80 mg).
Rea ction w ith Cycloh exen e Oxid e. DECP (426 µL, 3
mmol) was added to a solution of cyclohexene oxide (98 mg, 1
mmol) in dry CHCl3 at -40 °C. The solution was then stirred
at room temperature for 3 h. Workup with aqueous NH4Cl,
followed by silica gel chromatography (EtOAc), gave a mixture
of isomers of 2-chlorocyclohexyl ethyl hydrogen phosphonate,
33, as an oil (visible with I2, Rf 0.78 with EtOAc as the eluent)
in 88% yield (199 mg). 1H NMR (CDCl3): 8.19, 5.83 (d, J )
705 Hz, 1H, one isomer), 8.10, 5.75 (d, J ) 705 Hz, 1H, second
(23) Bordwell, F. G.; J i, G.-Z. J . Org. Chem. 1992, 57, 3019.
(24) (a) J okinen, S.; Luukkonen, E.; Ruostesuo, J .; Virtanen, J .;
Koskikallio, J . Acta Chem. Scand. 1971, 25, 3367. (b) Bordwell, F., G.;
Hughes, D., L. J . Am. Chem. Soc. 1984, 106, 3234.
(25) Yanada, K.; Yamaguchi, H.; Meguri, H.; Uschida, S. J . Chem.
Soc., Chem. Commun. 1986, 1655.

718 J . Org. Chem., Vol. 67, No. 3, 2002
J ie et al.
isomer), 4.40 (m, 1H), 4.20 (m, 2H), 3.95 (m, 1H), 2.25 (m, 2H),
treated with a solution of I2 (200 mg, 0.80 mmol, 1.2 equiv) in
water/THF (1:1, v/v, 15 mL), and stirred for another hour.
Excess I2 was removed by washing with 10% Na2S2O3 solution,
and the organic phase was dried over Na2SO4. Evaporation of
the solvent followed by chromatography (silica gel, EtOAc)
gave pure phosphoric acid triester 4 in 79% yield (151 mg).
1.71 (m, 6H), 1.35 (m, 3H) ppm.13C NMR: 79.8 (d, J PC ) 2.5
Hz), 79.6 (d, J PC ) 2.5 Hz), 62.5 (d, J PC ) 4 Hz), 62.4 (d, J PC
)
4 Hz), 62.0, 61.9, 35.2, 34.9, 33.7, 33.0, 24.9, 24.6, 23.7, 23.5,
16.7, 16.6 ppm. 31P NMR: +7.6 (d, J ) 700 Hz, P-H) ppm.
MS: m/z 244 (M + NH4+), 227 (MH+). HRMS (DCI, isobu-
tane): calcd for C8H17O3PCl 227.0604, found 227.0584.
P r ep a r a t ion of Nit r iles fr om Ald oxim es. A Typ ica l
P r oced u r e. DECP (430 µL, 3 mmol) in CHCl3 (15 mL) was
added to a solution of the benzaldoxime (121 mg, 1 mmol) in
CHCl3 (20 mL) at 0 °C. When the reaction was complete, the
solvent was removed in a rotary evaporator. The residue was
dissolved in ether, washed several times with saturated NH4-
Cl, and dried over Na2SO4. Pure benzonitrile was obtained in
83% yield (85 mg) after flash chromatography upon elution
with hexane/EtOAc (1:1). Spectroscopic data (1H and 13C NMR
and mass spectra) for the nitriles shown in Table 2 were
consistent with the given structure and literature data.
P h osp h or ic Acid Dieth yl Ester 4-F or m yl-2-m eth oxy-
p h en yl Ester (2). A solution of vanillin, 1 (152 mg, 1.0 mmol),
in dry ether (40 mL) was cooled to 0 °C. DECP (213 µL, 1.5
equiv) and Et3N (210 µL, 1.5 equiv) were added to the solution
dropwise. After the reaction mixture was stirred at room
temperature under Ar for 2 h, a solution of I2 (304 mg, 1.2
equiv) in water/diethyl ether (3:1, v/v, 80 mL) was added. The
mixture was stirred for another 40 min at room temperature.
Then, the water phase was removed, and the organic phase
was washed three times with 10% NaOH and once with water
and dried over Na2SO4. Pure product 2 was obtained after
(4-F or m ylp h en yl)p h osp h or a m id ic Acid Dieth yl Ester
(8). DECP (286 µL, 3 equiv) and Et3N (278 µL, 3 equiv) were
added to a solution of 4-nitrobenzaldehyde (100 mg, 0.66 mmol)
in dry CHCl3 (3 mL) under Ar at -10 °C. The solution was
warmed to 0 °C and stirred at this temperature for 3 h. The
solvent was removed under reduced pressure, and the residue
was purified by chromatography (silica gel, EtOAc) to give the
1
pure product 8 in 78% yield (131 mg). H NMR (CDCl3): 9.79
(s, 1H), 7.70 (d, J ) 8.5 Hz, 2H), 7.51 (d, J ) 9 Hz, 1H), 7.08
(d, J ) 8.5 Hz, 2H), 4.10 (m, 4H), 1.26 (dt, J ) 6.5, 1 Hz, 6H)
ppm. 13C NMR: 191.1, 176.9, 146.2, 131.6, 130.2, 117.1 (7.5
Hz), 97.5, 63.2 (4.5 Hz), 16.1 (7.0 Hz) ppm. 31P NMR: 1.9 ppm.
MS: m/z 275 (M + NH4+), 258 (MH+).
[4-((H yd r oxyim in o)m et h yl)p h en yl]p h osp h or a m id ic
Acid Dieth yl Ester (9). NaOH (15.0 mg, 4 equiv) and NH2-
OH‚HCl (26.0 mg, 4 equiv) were added to a solution of 8 (24
mg, 0.093 mmol) in absolute EtOH (8 mL). The solution was
heated under reflux for 4 h. The solvent was removed under
reduced pressure, and the residue was partitioned between
diethyl ether and water (10 mL of each). The organic phase
was washed three times with water and dried over Na2SO4,
and the solvent was removed under vacuum. Product 9 was
obtained as a white solid, mp 135 °C, in 91% yield (23 mg)
after being dried in a vacuum oven overnight (Rf 0.50 with
1
solvent evaporation in 71% yield (206 mg). H NMR (CDCl3):
9.87 (s, 1H), 7.44 (m, 3H), 4.24 (m, 4H), 3.88 (s, 3H), 1.32 (dt,
J ) 6.5, 1 Hz, 6H) ppm. 13C NMR: 190.9, 151.4, 145.9, 134.0,
124.9, 121.4, 110.9, 64.9, 56.1, 16.0 ppm. 31P NMR: -6.1 ppm.
MS: m/z 289 (MH+), 288 (M+), 154 ([(EtO)2P(O)OH]+).
P h osp h or ic Acid Diet h yl E st er 4-((H yd r oxyim in o)-
m eth yl)-2-m eth oxyp h en yl Ester (3). A mixture of NH2OH‚
HCl (154 mg, 4 equiv) and NaOH (89 mg, 4 equiv) in absolute
EtOH (7 mL) was warmed to 70 °C. A solution of 2 (160 mg,
0.55 mmol) in absolute EtOH (8 mL) was added. After the
resulting mixture was heated under reflux for 4 h, the solvent
was removed under vacuum. The residue was partitioned
between ether and water. The organic phase was washed three
times with water and dried over Na2SO4. After evaporation of
the solvent and drying of the compound in a vacuum oven
1
EtOAc as the eluent). H NMR (CDCl3): 8.00 (s, 1H), 7.36 (d,
J ) 8.4 Hz, 2H), 7.15 (br. s, 1H), 6.93 (d, J ) 8.4 Hz, 2H), 4.13
(m, 4H), 1.23 (t, J ) 6 Hz, 6H) ppm. 13C NMR: 149.4, 141.5,
128.1, 125.6, 117.4 (7.5 Hz), 63.10 (4.5 Hz), 16.05 (7.0 Hz) ppm.
31P NMR: 3.1 ppm. MS: m/z 272 (M+), 227 (M+ - OEt). HRMS
(DCI, isobutane): calcd for C11H17N2O4P 272.0926, found
272.0912.
4-(Cya n op h en yl)p h osp h or a m id ic Acid Dieth yl Ester
(10). Et3N (35.5 µL, 3 equiv) was added to a solution of 9 (23
mg, 0.084 mmol) in dry CHCl3 (3 mL) under Ar at -40 °C,
followed by the addition of DECP (36 µL, 3 equiv) and stirring
for 20 min at -40 °C. Then the solution was washed once with
water and three times with 10% NaOH, dried over Na2SO4,
and evaporated to dryness. Pure product 10 was obtained as
a white solid, mp 108 °C, in 91% yield (20 mg) (Rf 0.71 with
EtOAc as the eluent). The product was obtained in a compa-
rable yield when the reaction was repeated without the
1
overnight, product 3 was obtained in 81% yield (135 mg). H
NMR (CDCl3): 7.95 (s, 1H), 7.22 (dd, J ) 8, 1.9 Hz, 1H), 7.16
(br “t”, 1H), 6.92 (dd, J ) 8, 1.9 Hz, 1H), 4.18 (m, 4H), 3.78 (s,
3H), 1.28 (dt, J ) 6.5, 1 Hz, 6H) ppm.
1
addition of Et3N. H NMR (CDCl3): 7.50 (br d, J ) 9 Hz, 1H),
P h osp h or ic Acid 4-Cya n o-2-m eth oxyp h en yl Ester Di-
eth yl Ester (4) (Sch em e 2a ). A solution of 3 (101 mg, 0.33
mmol) in dry CHCl3 (18 mL) was cooled to 0 °C, DECP (142
µL, 3 equiv) was added dropwise, and then the reaction
mixture was stirred at room temperature under Ar for 2 h.
The mixture was evaporated to dryness in vacuo followed by
addition of ether and water (20 mL of each) to the residue.
After the mixture was stirred for another 30 min, the organic
phase was washed five times with 10% NaOH, dried over Na2-
SO4, and evaporated. Pure phosphoric acid triester 4 was
obtained as an oil (Rf 0.40 with hexane/EtOAc, 3:2) in 96%
yield (91 mg). 1H NMR (CDCl3): 7.35 (dd, J ) 8.5, 1.5 Hz,
1H), 7.20 (ddd, J ) 8.5, 1.6, 0.4 Hz, 1H), 7.14 (m, 1H), 4.24-
4.13 (dq, 4H), 3.83 (s, 3H), 1.36-1.21 (dt, J ) 6.5, 1 Hz, 6H)
ppm. 13C NMR: 151.1 (d, J PC ) 6.0 Hz), 143.7 (d, J PC ) 6.8
Hz), 125.5, 122.0 (d, J PC ) 3.0 Hz), 118.3, 115.8, 109.2, 65.0
(d, J PC ) 6.0 Hz), 56.3, 16.0 (d, J PC ) 6.0 Hz) ppm. 31P NMR:
-6.1 ppm. MS: m/z 303 (M + NH4+), 286 (MH+). HRMS (DCI,
isobutane): calcd for C12H16NO5P 285.0766, found 285.0749.
P h osp h or ic Acid 4-Cya n o-2-m eth oxyp h en yl Ester Di-
eth yl Ester (4) (Sch em e 2b). DECP (120 µL, 1.2 equiv, 0.80
mmol) in dry THF (5 mL) was added to a solution of 3-meth-
oxy-4-hydroxybenzonitrile, 6 (100 mg, 0.67 mmol, the prepara-
tion of 6 is described in the typical procedure and in Table 2),
in dry THF (10 mL) under Ar at 0 °C, followed by addition of
solution of Et3N (113 µL, 1.2 equiv, 0.80 mmol) in THF (5 mL).
The solution was stirred for 3 h at room temperature, then
7.47 (d, J ) 9 Hz, 2H), 7.04 (d, J ) 9 Hz, 2H), 4.13 (m, 4H),
1.27 (dt, J ) 6.5, 1 Hz, 6H) ppm. 13C NMR: 144.5, 133.5, 132.1,
131.6, 128.9, 119.2, 117.5 (J PC ) 7.5 Hz), 104.3, 63.2 (J PC
)
4.5 Hz), 16.1 (J PC ) 7.0 Hz) ppm. 31P NMR: 1.7 ppm. MS: m/z
272 (M + NH4+), 255 (MH+). HRMS (CI, isobutane): calcd for
C
11H15N2O3P 254.0820, found 254.0816.
2-Cya n o-6-m eth oxy-4-n itr op h en ol (12). DECP (362 µL,
6 equiv) was added to dry 11 (90 mg, 0.425 mmol) in dry CH3-
CN (20 mL) at 0 °C. Then, the reaction mixture was stirred
at room temperature for 3 h. TLC, eluted with EtOAc, showed
that starting material disappeared and a new yellow spot
appeared at Rf 0.43. The solution was evaporated to dryness
under high vacuum (most of the DECP and hydrogen phos-
phonate were removed), and the residue was purified on a
silica gel column eluted with EtOAc. The yellow solid obtained
was dried under high vacuum overnight to give pure product
12 in 95% yield (77 mg).1H NMR (acetone-d6): 8.06 (d, J )
1.5 Hz, 1H), 7.75 (d, J ) 1.5 Hz, 1H), 4.03 (s, 3H) ppm. 13C
NMR: 150.0, 122.3, 116.3, 108.1, 98.2, 56.2 ppm. MS: m/z 194
(M+). HRMS (DCI, isobutane): calcd for C8H6N2O4 194.0327,
found 194.0322.
P h osp h or ic Acid 2-Cya n o-6-m et h oxy-4-n it r op h en yl
Ester Dieth yl Ester (13). DECP (213 µL, 1.5 mmol) in dry
toluene (5 mL) was added to a solution of 11 (98 mg, 0.46
mmol) in toluene (35 mL) at 0 °C. The mixture was stirred at
90 °C under Ar. After 12 h starting material was completely

Diethyl Chlorophosphite
J . Org. Chem., Vol. 67, No. 3, 2002 719
consumed. An additional 4 equiv of DECP and Et3N in toluene
were added while the reaction mixture was cooled to 0 °C. The
contents were then stirred at 90 °C for 12 h. The solvent was
removed under vacuum, and the residue was treated with I2
(140 mg, 1.2 equiv in water/diethyl ether, 3:1, v/v, 80 mL).
After being dried over Na2SO4, the residue was separated on
silica gel (EtOAc) to give pure 13 as a yellow semisolid in 25%
yield (38 mg). 1H NMR (CDCl3): 8.13 (d, J ) 1.5 Hz, 1H), 8.02
(d, J ) 1.5 Hz, 1H), 4.40 (m, 4H), 4.04 (s, 3H), 1.25 (dt, J )
6.0, 1.5 Hz, 6H) ppm. 31P NMR: -7.3 ppm. MS: m/z 331 (MH+).
HRMS (DCI, isobutane): calcd for C12H16N2O7P 331.0695,
found 331.0703.
Ack n ow led gm en t . This work was supported in
part by the Marcus Center for Medicinal Chemistry.
We thank Prof. M. Sprecher for a stimulating discus-
sion.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H, 13C,
and 31P NMR spectra and high-resolution mass spectra of 4,
6, 9, 10, 12, 13, and 33. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0106851