Mechanism of the reaction of lawesson's reagent with N-alkylhydroxamic acids

Article abstract of DOI:10.1002/ejoc.200400727

The mechanism of the reaction under discussion has been established by investigating the products of the reaction between 2,4-bis(4-methoxyphenyl)-1,3, 2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent, LR) and N-alkylhydroxamic acids HAs 1. The p

Full text of DOI:10.1002/ejoc.200400727

FULL PAPER
Mechanism of the Reaction of Lawesson’s Reagent with N-Alkylhydroxamic
Acids
Witold Przychodzen´*[a]
Keywords: Reaction mechanisms / Reactive intermediates / Chemoselectivity / Reduction
The mechanism of the reaction under discussion has been
established by investigating the products of the reaction be-
tween 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphet-
ane 2,4-disulfide (Lawesson’s reagent, LR) and N-alkylhy-
thionation processes does not undergo oligomerisation to cy-
clic trimer 5 and linear oligomers, which is typical for amides
reacting with LR. Since there is unreacted HA 1 in the reac-
tion mixture, AnsPOS takes part in a controlled transforma-
droxamic acids HAs 1. The primary intermediate is an ad- tion to form a dimer, the corresponding pyrothiophosphonate
duct, O-dithiophosphonylated hydroxamic acid 19, which de- 3, together with the intermediate O-thiophosphonylated hy-
composes to yield metathiophosphonate (AnsPOS), a sulfur
atom, and an amide. At the same time, owing to the co-exis-
tence of 19 and metadithiophosphonate (AnsPSS) in equilib-
rium, the carbonyl group is thionated. It has also been estab-
lished that monomeric AnsPOS formed in both reduction and
droxamic acid 2. A hydrolysed product of AnsPOS, namely
(4-methoxyphenyl)thiophosphonic acid 4, participates in the
last reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
It has often been reported that 2,4-bis(4-methoxyphen-
yl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson’s
reagent, LR) is a very effective thionating reagent of car-
bonyl compounds.[1] The key issue here is the chemoselec-
tivity of the LR reaction when there is a nucleophilic centre
other than a carbonyl group in the molecule. Direct thion-
ation of hydroxamic acids (HAs) could potentially be very
useful in the synthesis of the thioanalogues of natural hy-
droxamates and N-hydroxythiopeptides.[2] It is evident that
this reaction could be of synthetic importance as it gives
reasonable yields of thiohydroxamic acids (THAs).[3] As we
have demonstrated before,[4] the action of LR in THF
causes N-alkylbenzohydroxamic acids 1 to transform into
three products: THAs, amides (A) and thioamides (TA).
The reaction can be thought of as involving four stages of
which two are competitive and two are subsequent. Thus,
initially thionation (T1) gives THA and reduction (R1) af-
fords A. Subsequent reduction (R2) and thionation (T2) ul-
timately yield TA (Scheme 1).
We have proved that both the stoichiometry and the sol-
vent used, as well as the temperature, have an effect on the
distribution of the reaction products and the yield of THA.
In our experiments the maximum yield of THA was 55–
60%.
Scheme 1.
The reactions of LR with selected representatives of
compounds with a N–O bond, excluding HAs, have been
investigated previously. Based on the presence of sulfur in
the post-reaction mixture, Lawesson and co-workers as-
[a] Faculty of Chemistry, Gdan´sk University of Technology,
Narutowicza 11/12, 80–952 Gdan´sk, Poland
Fax: +48-058-347-2922
E-mail: witold@chem.pg.gda.pl
2002
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DOI: 10.1002/ejoc.200400727
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Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
FULL PAPER
sumed that nitrones and the N-oxides of pyridines react
with LR to give labile N-sulfides as intermediates. These
N-sulfides yield the corresponding deoxygenated products
upon loss of the sulfur atom.[5] Meanwhile, the reaction of
LR with oximes, namely with benzaldoxime and diphenyl
ketoxime, yielded thiobenzaldehyde and a mixture of thio-
Results and Discussion
Identification of the Phosphorus Products of LR
Transformation
At a glance, the reaction does not resemble the generally
benzanilide and benzanilide, respectively.[6] In their work, accepted Wittig-like mechanism which assumes attack of
Lawesson and co-workers did not present any convincing metadithiophosphonate (AnsPSS) upon the carbonyl oxy-
evidence for the structures of the intermediates formed in gen atom via 1,3,2-oxathiaphosphetane 2-sulfide. This
these reactions, nor did he make any attempt to identify the would be the case when LR reacts with amides and other
products of the transformations. It appeared that the reac- carbonyl compounds. The reaction of LR with HA 1 occurs
tion of LR with nitrones does not always give deoxygen- immediately at room temperature and its rate is limited by
ation or Beckmann rearrangement products. Bertrand and the rate of dissolution of LR. The 31P NMR spectra of the
co-workers established that in the case of a sterically reaction mixtures containing HA 1 and LR in THF differ
crowded N-(tert-butyl)-C-phenyl nitrone LR acts as a di- substantially from those of reaction mixtures containing
polarophile to give the appropriate cycloadduct.[7]
amide A and LR (Figure 1).
A full investigation of the reactions of LR with hy-
A characteristic feature of these spectra is the presence
droxamic acids will significantly broaden the knowledge of of only three singlet signals from the three products of the
the reaction mechanism and will also contribute to a ratio- LR transformation. This distinguishes this reaction from a
nal selection of reaction conditions for HA thionation. Our typical reaction of A with LR, which produces a series of
former analysis of HA conversion products was not suf- oligomeric phosphorus products and exhibits a more com-
ficient for us to suggest a mechanism for this reaction. Thus plex 31P NMR spectrum with peak clusters centred at δP =
I have assumed that a thorough analysis of the transforma- 3 and 72 ppm. As is generally known, the oligomers of type
tion and fate of LR, and particularly of the metathiophos- [AnsP(S)(μ-O)n] and [AnsP(O)(μ-O)n] are formed by meta-
phonate species in the reaction with HAs 1 (mainly based thiophosphonate (AnsPOS) polymerisation.[8]
on 31P NMR spectroscopy), and identification of the stable
It should be stated here that the spectra obtained from
reaction products, supplemented with the results obtained the reaction mixture containing HA 1 and LR in THF dif-
in the previous report, will enable the mechanism of this fer considerably from the spectra obtained in benzene and
interesting reaction to be understood and explained.
nitrobenzene (reflux, 5 min). The latter exhibited character-
Figure 1. 31P NMR spectra of the reaction mixtures (THF, room temp., 1 h) formed from LR and A) N-isopropylbenzamide, B) 1a (Ar
= Ph), C) 1b (Ar = 4-MeOC6H4), and D) 1c (Ar = 4-NO2C6H4).
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W. Przychodzen´
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istic doublets of the dimeric products of the LR transforma- this way adduct 2a was transformed in situ to a mixture of
tion which contain a bridging sulfur or oxygen atom with O- and S-methyl esters 8a and 9a, respectively (δP = 98.1
a typical coupling constant (3JPP = 49 Hz).
and 54.1 ppm). Authentic samples of adducts 8a and 9a
The three phosphorus-containing products formed in the were obtained by an independent method from S-methyl
reaction of LR with HA 1 in THF have been identified, (4-methoxyphenyl)phosphonochloridothioate and O-
respectively, as O-thiophosphonylated HA 2, pyrothiophos- methyl (4-methoxyphenyl)phosphonochloridothioate (10),
phonate 3, and (4-methoxyphenyl)phosphonothioic acid (4) respectively. The 31P NMR chemical shifts of adducts 2 dif-
(Scheme 2). As it is impossible to isolate these compounds fer according to the structure of the initial hydroxamic acid.
from the reaction mixture owing to their high polarity, it They are 88.8 ppm for 2a (Y = H), 88.0 ppm for 2b (Y =
was decided to isolate their stable derivatives, authentic OCH3), 89.7 ppm for 2c (Y = NO2), and 87.7 ppm for 2d
samples of which were also synthesised by an independent (Y = NMe2), while the chemical shifts of the other two
route.
signals present in the spectra of the reaction mixtures are
the same, regardless of the initial HA 1 used. This is ad-
ditional proof of the structure of adducts 2.
An authentic sample of pyrothiophosphonate 3 was ob-
tained by two methods (Scheme 3). The first method did
not lead to 3 in its pure form. Starting with O-methyl thio-
phosphonic acid 6 (δP = 84.1 ppm), the corresponding chlo-
ride 10 was prepared following the method of He et al.[12]
The reaction of chloride 10 with the tetramethylammonium
salt of acid 6 gave a symmetric anhydride 11 (δP = 80.05
and 80.18 ppm). Note that treatment of O-methyl thiophos-
phonic acid 6 with condensing agents (DCC or Cl3CCN)
gave only the mixed anhydride 12 (δP = 13.0 and 80.9 ppm,
diastereomers). This is consistent with Mikołajczyk and
Kiełbasin´ski’s observation. They proved that dialkyl thio-
phosphoric acids attack the electrophilic DCC through the
sulfur atom to produce mixed pyrophosphates and thio-
urea.[13] Next, anhydride 11 was demethylated with NaI in
methyl ethyl ketone (MEK) to give the disodium salt of
Scheme 2.
Note also that the reaction of HA 1 with LR does not pyrothiophosphonate 13 which has poor solubility in meth-
yield the LR transformation product most often isolated anol. Salt 13 was treated with hydrogen chloride in meth-
in the thionation reactions of other carbonyl compounds, anol to give a mixture of pyrothiophosphonate 3, thiophos-
namely the trimer of (4-methoxyphenyl)thiophosphane ox- phonic acid 4 and its O-methyl ester 6 (δP = 70.4, 73.2 and
ide 5. From the data of McKenna[9] and Zubrikov[10] and 84.3 ppm) in a ratio of 4:1:1 (as determined from their 31P
their co-workers one could presume that the signal ob- NMR spectra). An attempt to obtain 3 directly from acid
served at δ = 71.4 ppm corresponds to trimer 5. However, 4 in the presence of DCC led to a mixture of three isomeric
the 31P NMR spectrum of trimer 5 synthesised by an alter- pyrothiophosphonates which did not include the desired
native method exhibits the A2B spin system [δP = 72.3 (d, product 3 [31P NMR: δ = 2.7 (s, 100%), 3.6, 64.2 (2×d, J
2 P, J = 49 Hz), 74.4 (t, 1 P, J = 49 Hz) ppm], in accordance = 34 Hz, 40%), 14.5 (s, 46%) ppm]. Quite unexpectedly, the
with other literature data.[11] Moreover, the presence of tri- reaction of acid 4 with a stoichiometric amount of TMOF
mer 5 in the reaction mixture has finally been excluded after (RT, 4 days) proved a more effective method for obtaining
investigating the results of reactions with derivatising rea- pyrothiophosphonate 3. Analysis of the 31P NMR spectrum
gents. Thus, it has been established that trimer 5 does not of the crude product indicated that it was slightly (ca. 10%)
react with trimethyl orthoformate (TMOF) at room tem- contaminated with by-products 6 and methyl phosphonate
perature, while the addition of trimethyl orthoformate to (Scheme 4).
the reaction mixture leads to the disappearance of the sig- The addition of pyrothiophosphonate 3 obtained in such
nal at δ = 71.4 ppm and quantitative formation of O-methyl a way has confirmed its presence in reaction mixtures of
phosphonothioate 6 (vide supra).
HA 1 and LR.
The suggested structure of the adduct of HA 1a and
Note that during the derivatisation of the reaction mix-
AnsPOS − 2a (δP = 88.8 ppm) − was confirmed by treating tures by the derivatising agents mentioned above I observed
the post-reaction mixture with tert-butyldimethylsilyl chlo- signals from the corresponding derivatives of pyrothiophos-
ride (TBDMSCl) in the presence of triethylamine. The de- phonate 3, that is, O,O-bis-TBDMS ester 14 (δP = 64.3 and
rivative of adduct 2a was isolated in a yield of 4% and iden- 65.0 ppm) and S,S-dimethyl ester 15 (δP = 53.2 and
tified as the O-TBDMS ester 7a (δP = 83.9 ppm). Further 53.9 ppm) (Scheme 5).
evidence of the presence of adduct 2a is provided by the 31
P
The 31P chemical shift of pyrothiophosphonate 3 can be
NMR spectra of reaction mixtures treated with diazometh- calculated by subtracting the effect of the methyl group de-
ane and methyl iodide in the presence of triethylamine. In termined for the O-methyl esters of (4-methoxyphenyl)thio-
2004
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Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
FULL PAPER
Scheme 3.
Scheme 5.
Scheme 4.
phosphonic acid (6 and 6Ј) (Δδ = +8.1 ppm) from the chem- by subtracting from the chemical shift of derivative 14 the
ical shift of the methyl diester of pyrothiophosphonate 11 increment due to the TBDMS group determined from the
(δ = 80 ppm). By estimation, δPcalcd. = 71.9 ppm, which is chemical shifts of the corresponding O-TBDMS esters of
similar to the value of the observed shift (δP = 71.4 ppm). (4-methoxyphenyl)thiophosphonic acid (16 and 17) (Δδ =
A better agreement (δPcalcd. = 71.1 ppm) can be obtained –6.4 ppm).
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The addition of an authentic sample of (4-meth- O-Dithiophosphonylated Hydroxamic Acid as an
oxyphenyl)thiophosphonic acid (4) unequivocally con- Intermediate and Its Transformations
firmed its presence in the reaction mixture. Additionally,
The results of these experiments indicate unequivocally
after silylation, its O-TBDMS derivatives were detected in
that the initial reaction step involves the electrophilic attack
the reaction mixture: monoester 16 (δP = 70.1 ppm) and
of metadithiophosphonate (AnsPSS) on the oxygen atom
diester 17 (δP = 63.7 ppm). Methylation with methyl iodide
of the hydroxy group in HA 1. This leads to the formation
in the presence of NEt3 led to the formation of the S-methyl
of O-dithiophosphonylated adducts 19. Metathiophos-
ester 18 (δP = 39.3 ppm).
phonate adducts with neutral donors (tertiary amines,
The results of the silylation experiments conducted on
HMPA) are known, thermodynamically stable com-
the reaction mixtures provide evidence beyond doubt that
pounds.[16] For this reason one can expect that AnsPSS will
2, 3 and 4 are produced from the LR transformation. Si-
preferentially attack the oxygen atom of the N-hydroxy
lylation is an unambiguous reaction and leads solely to the
group in 1 as it is more nucleophilic (α effect). During the
stable O-TBDMS derivatives of the three phosphorus prod-
first few minutes of reaction, adduct 19a (δP = 109.7 ppm;
ucts detected. Methylation (CH3I/NEt3, diazomethane), on
δP = 112.5 ppm for 19c) is present in the reaction mixture
the other hand, gives a very complex mixture of O- and S-
together with the unreacted LR (δP = 16.0 ppm) (Figure 2).
methyl products. Furthermore, under the reaction condi-
As the reaction progresses, the signals of 19a and LR
tions the products are susceptible to thiono–thiolo isomeris-
disappear, and the peaks of the above mentioned AnsPOS
ation.[14] A different and greatly simplified result is obtained
transformation products 2a, 3 and 4 begin to appear. In all
by treating the reaction mixture with an excess of TMOF.
probability, the first step in the reaction is a reversible pro-
It is surprising that the sole reaction product obtained from
cess. The results of experiments involving the addition of
mixtures of 2, 3 and 4 is the monoester 6. Although O-alkyl
TMOF provide supporting evidence for this statement.
thiophosphonic acids react with TMOF to produce only
TMOF totally inhibits the reaction of HA 1 with LR and
their corresponding S-methyl esters,[15] the presence of the
produces a quantitative amount of the O,S-dimethyl ester
S-methyl ester in the reaction mixture has not been con-
of (4-methoxyphenyl)dithiophosphonic acid (20) (see
firmed. As mentioned above, the control experiment involv-
Scheme 3). Attempts to capture adduct 19a by diazometh-
ing the reaction of acid 4 and a stoichiometric amount of
ane, vinyl acetate or methyl acrylate failed probably due to
TMOF demonstrated that this reaction produces only pyro-
the low reactivity of these reagents rather than the rate of
thiophosphonate 3. The different reactivity of TMOF
decomposition of adduct 19a. The 31P chemical shift of ad-
towards thiophosphonic acid 4 can only be explained
duct 19a is in accord with the proposed structure. The
through the formation of O-dimethoxymethyl thiophos-
structure has also been confirmed by a comparative analysis
phonate as an intermediate in the reaction. Like other
of the differences between the chemical shifts observed for
active derivatives of thiophosphonic acid, O-dimeth-
the O-alkyl (4-methoxyphenyl)dithiophosphonic acids, their
oxymethyl thiophosphonate is capable of generating electro-
salts and S-methyl esters,[17] and by referencing them to the
philic AnsPOS. Consequently, AnsPOS reacts with free acid
triethylammonium salt 21a (δP = 121.4 ppm) and S-methyl
4, which is in excess relative to the methanol, to give pyro-
ester 22a (δP = 113.4 ppm) (vide supra).
thiophosphonate 3. As mentioned before, 2 and 3 are also
It seems rather unlikely under the reaction conditions
sources of AnsPOS; they react in turn with TMOF or with
that adduct 19a could take part in the intramolecular thion-
methanol present in the reaction mixture to give product 6
ation of HA 1 to THA. Although the thionating nature of
(Scheme 4).
Figure 2. 31P NMR spectrum of the crude reaction mixture obtained 2 min after LR was added to 1a at room temperature.
2006
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Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
FULL PAPER
dithiophosphoric acids towards amides has been reported
in the literature,[18] this reaction requires drastic conditions
(125 °C). It is more likely that, due to the reversibility of
adduct 19a formation, AnsPSS reacts simultaneously with
HA 1 by a mechanism typical of the thionation of carbonyl
compounds (Scheme 6). Adduct 19a should be recognised
as a precursor of the amide which is a product of HA 1
reduction. The mechanism for the further transformation
of adduct 19a into amide and AnsPOS derivatives remains
partially unsolved. The presence of sulfur in the reaction
mixture indicates the existence of 3-(4-methoxyphenyl)oxa-
thiaphosphirane 3-sulfide 23 or 3-(4-methoxyphenyl)dithia-
phosphirane 3-oxide 23Ј as further intermediates, which are
direct precursors of AnsPOS. Although undetected as yet,
it has been suggested that compounds of this type are LR
transformation products formed in the deoxygenation of S-
oxides.[19] The 31P NMR spectra obtained for unsubstituted
hydroxamic acid 1a, which by reacting with LR produces a
mixture of thionation and deoxygenation products, and for
the hydroxamic acid undergoing reduction only (1d, Y = 4-
NMe2) are identical. This may prove that both processes,
that is, thionation and deoxygenation, occur by the same
mechanism and produce the same intermediates. However,
one can see that AnsPOS can be produced via both 1,3,2-
oxathiaphosphetane 2-sulfide 19Ј (thionation) and O-
dithiophosphonylated HA 19 (reduction). As the reaction
rates of both processes are comparable, at this stage it is
impossible to state whether there are one or two common
intermediates. Confirmation of the reversibility of the pro-
cess proves that the reactive electrophilic AnsPSS attacks
both the oxygen atoms of HA 1 (Scheme 6). The N–O bond
in HAs 1 with electron-donating substituents (1b, 1d) is rel-
atively weak, which leads to faster decomposition of 19-
type adducts to amides A. Also the results of earlier experi-
ments,[4] in which the amount of amide formed increased
with temperature, indicate the nature of 19 and its role in
the deoxygenation of HA 1.
Scheme 6.
nal vinyl reagents, nucleophilic or electrophilic in character
(vinyl acetate, methyl acrylate), were added.
Note that successive reduction of THA (R2) takes place
to a small extent. In a control experiment with N-isopropyl-
thiobenzohydroxamic acid under the same conditions
(THF, room temperature), TA was formed in only 11%
1
yield (as based on the H NMR spectrum). Thus, it can be
stated that TA is formed as a result of amide A thionation
(T2).
The results of additional experiments have not provided
convincing evidence as to whether the reduction reaction
(R1) is radical or nitrenic in character. The 31P NMR spec-
tra (relative intensities of product signals) of HA 1a and
LR mixtures for reactions performed in the dark and under
UV light are identical. A series of experiments on hy-
droxamic acids with tethered internal functional groups,
which would allow such intermediates as amidyl radicals or
Scheme 7.
It turned out that the reaction of HA 1a with LR in the
acyl nitrenes (4-pentenohydroxamic acid 1e, N-allyl- presence of triethylamine yields the triethylammonium salt
benzohydroxamic acid 1f) to be trapped, and also in the of adduct 21a (δP = 121.4 ppm), which is a relatively stable
presence of Ph2Se2,[20] have ruled out the formation of the compound. Apart from the signal from this salt, the 31P
corresponding cyclic products (Scheme 7). Similarly, the NMR spectrum of the reaction mixture included only a low
products of radical or nitrene addition to double bonds intensity signal from the LR–triethylamine adduct (δP
=
have not been observed in reaction mixtures to which exter- 96.0 ppm). However, the 15N NMR spectrum shows a trace
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W. Przychodzen´
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peak due to salt 1a (δN = –177.5 ppm) in addition to the S–H proton is indispensable for HA 1 reduction and that
peak of the adduct 21a salt (δN = –186.5 ppm).[21] Analysis concentration of negative charge on the oxygen atom of the
of the 31P and 15N NMR spectra of the reaction mixture HA 1 salt prevents thionation despite the reversibility of
rules out the N–O–P (21a) Ǟ N–S–P (21aЈ) isomerisation the reaction.
reaction, which could result in a system with a weak N–S
The reactions of the triethylammonium salts 21b (δP =
bond. Besides, attempts to capture the product of possible 120.8 ppm) and 21c (δP = 123.8 ppm) follow a similar
21aЈ isomerisation by TBDMSCl led to only O-silylated course. Under the same reaction conditions the correspond-
HA 1a (vide supra) (Scheme 8).
ing S-methyl esters 22b (δP = 110.1 ppm) and 22c (δP =
The addition of water to salt 21a causes the signal of 115.8 ppm) were formed. While derivative 22c, similarly to
adduct 19a (δP = 109.7 ppm) to appear, while the addition 22a, is stable and has been isolated in 77% yield, derivative
of a stoichiometric amount of methanesulfonic acid or tri- 22b decomposed during isolation on a silica gel column.
fluoroacetic acid leads, again via adduct 19a, to THA, A This result is in line with the domination of amide A over
and TA in the same amounts as was observed in the case THA, as was observed in the reaction of 1b with LR
of a mixture of 1a with LR. This is distinct evidence for the (Table 1), as it is evident that an electron-donating substitu-
formation of adduct 19a as an intermediate in this reaction. ent in the acyl group of HA 1 weakens the N–O bond sig-
Acidifying the salt of adduct 21a causes partial regeneration nificantly.
of LR (δP = 16 ppm), which confirms that the first stage of
the reaction between HA 1 and LR, namely the formation
of adduct 19, is reversible. The experiment results in the
salt of adduct 21a and derivatizing agents prove that salt
formation is reversible as well. The addition of TBDMSCl
gives (after isolation) O-silylated HA 1a in 40% yield, while
the reaction with methyl iodide yields the S-methyl ester of
adduct 22a (δP = 113.4 ppm) almost quantitatively with
10% unreacted HA 1a (Scheme 8).
Note that in the case of adduct 19 formation, the equilib-
rium is shifted to the left, while the equilibrium for the for-
mation of the salt of adduct 21 lies to the right. The stable
Table 1. Effect of aryl substituents (Y) on product distribution for
reaction of Y–C6H4CON(iPr)OH 1 with LR.
1
Y
Yield [%][a]
THA
1
2
A
TA
a
b
c
H
18
13
13
8
14
11
16
14
38
14
50
0
3
41
4
17
11
17
30
4-MeO
4-NO2
4-NMe2
d
48
[a] The yields were determined on the basis of the signal intensities
1
of the methyl and methine protons in the H NMR spectra of the
salt 21 does not transform further. This confirms that the reaction mixtures.
Scheme 8.
2008
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Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
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The Further Fate of Reactive Metathiophosphonate
AnsPOS
by both the generation of 3 from the salt 13 in methanol,
in which significant amounts of ester 6 are formed, and the
fact that after treating the reaction mixture with TMOF,
only ester 6 is formed (no traces of the corresponding
methyl derivatives of the pyrothiophosphonate, 11 and 15,
were observed). Owing to the differences in the acidity of
HA 1 and 4, the equilibrium constant for the decomposi-
tion of 3 to AnsPOS should be significantly higher than
that for the corresponding reaction of adduct 2.
The reaction of LR with HA 1a was followed for two
weeks. The relative intensities of the 31P NMR signals of
the phosphorus compounds 2a, 3 and 4 formed in this reac-
tion are shown in Figure 3. As can be seen, after one hour
the concentration of the adduct 2a reaches a maximum
(61%) and then, over 14 days, it decreases exponentially to
zero. The concentration of the pyrothiophosphonate 3
reaches a maximum of 37% after 48 hours and then de-
creases slowly to about 30%. The intensity of the signals of
the thiophosphonic acid 4 increases logarithmically, reach-
ing 65% after 14 days. After a week, signals arising from
(4-methoxy)phenylphosphonic acid and its anhydride (δ =
19.5 and 9.8 ppm) also appear. Despite the obvious differ-
ences in the stabilities of adduct 2a and pyrothiophosphon-
ate 3, the higher rate of decrease in the concentration of 2a
over time is due to the increase in the concentration of the
acid 4. Acid 4 is a product of AnsPOS hydrolysis. AnsPOS
generated from 2a and 3 reacts preferentially with acid 4,
whose concentration increases gradually.
Later in the reaction, the electrophilic AnsPOS, gener-
ated by thionation and reduction, reacts with the unreacted
HA 1a and with traces of moisture to give, respectively, ad-
duct 2a and acid 4. The control experiment involving the
addition of a stoichiometric amount of THA ruled out the
possibility of the corresponding AnsPOS–THA adduct be-
ing formed. It is probably due to the fact that THA is signif-
icantly less nucleophilic than HA 1 that adducts of the type
mentioned above are not formed in the reaction of HAs 1
with LR.[22] The successive reaction of HA 1 with AnsPOS
resulting in adduct 2 is also a reversible process. The high
reactivity and chemoselectivity (preferential O-methylation)
of TMOF towards the reaction mixture containing adduct 2
can only be explained by the presence of AnsPOS. Control
experiments with the O-methyl esters of (4-methoxyphenyl)
thiophosphonic (6) and (4-methoxyphenyl)dithiophos-
phonic acids indicate that at room temperature TMOF
preferentially alkylates the sulfur atom with yields of 9 and
100%, respectively, while the reaction with the reaction
mixture gives only the O-methyl ester 6.
The reactive AnsPOS also reacts with acid 4 present in
the reaction mixture to give pyrothiophosphonate 3. It can
be concluded that the pyrothiophosphonate 3 is not formed
in the reaction of adduct 2 with acid 4 as it has been estab-
lished that a derivative more reactive than the adduct, acid
chloride 10, does not react with acid 4 under these condi-
tions. In all probability, the pyrothiophosphonate 3 is also
in equilibrium with AnsPOS (Scheme 9). This is confirmed
Figure 3. The time course for the formation of the phosphorus
products in the reaction of 1a with LR (transformations of the
AnsPSO species): ᭡, adduct 2a; ◊, pyrothiophosphonate 3; ᭿, thio-
phosphonic acid 4.
The stabilities of adducts 2 vary depending on the struc-
ture of the parent HA 1. Hence, adduct 2b with a methoxy
substituent in the ring is the most stable (the most intense
peak in the 31P NMR spectrum), while adduct 2c (NO2 sub-
stituent) generates significant amounts of pyrothiophos-
phonate 3 in the initial phase of reaction (see Figure 1).
This can be explained by the fact that HA 1b is a more
powerful nucleophile and thus its formation equilibrium
constant is higher. The observed decrease in the intensities
1
of the signals of adducts 2 allowed their H NMR spectra
to be unequivocally assigned, and, consequently, their yields
to be determined. Regardless of the nature of the aromatic
ring substituent, the reaction with LR gives about 15% of
adducts 2. This may seem peculiar if one considers the ob-
served differences in the nucleophilic properties of these ac-
Scheme 9.
Eur. J. Org. Chem. 2005, 2002–2014
www.eurjoc.org
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2009

W. Przychodzen´
FULL PAPER
ids. However, it does indicate that both the dominating tion of HAs 1 with AnsPSS 19 are unstable and transform
original processes, that is the reduction (R1) of 1b and the into reduction products, that is, into the corresponding
thionation (T1) of 1c, are irreversible and likely to be faster amides, by breaking the N–O bond. The experiments in
than the subsequent reaction of AnsPOS with HA 1. More- which the reactive intermediates were captured have not
over, the 1H NMR spectra of the reaction mixtures re- confirmed the participation of radicals or nitrenes in the
corded at various times show that no N–O bonds are reaction. On the other hand, the salts of hydroxamic acids
broken in adducts 2 (unlike adducts 19) in order to form form stable salts of adducts 21 with LR, which do not isom-
amides (the yield of the amide does not increase), indepen- erise to compounds with a N–S bond but upon acidification
dently of the hydroxamic acid group, which is even more transform to THA and A via adduct 19.
important.
The formation of adducts 2 has a significant benefit.
Since the post-reaction mixture does not contain the basic
Experimental Section
product of LR transformation − the nonpolar trimer 5 −
the process of transforming AnsPOS to pyrothiophosphon-
ate 3 and ultimately to acid 4 makes the reaction of HA 1
with LR synthetically useful as there is no need for tedious
chromatographic purification of thiocarbonyl products.
General Remarks: All NMR spectra were recorded with a Varian
Unity 500 Plus spectrometer operating at 500 MHz (1H),
202.4 MHz (31P), 125.7 MHz (13C) and 50.7 MHz (15N) and were
measured in CDCl3 solutions unless stated otherwise in standard
NMR tubes (5 mm o.d.). 31P NMR spectra were obtained by using
broad-band 1H decoupling and chemical shifts are reported relative
to 85% H3PO4 as external standard. 15N long-range gHMQC spec-
tra were acquired as described previously.[21] 15N chemical shifts
are referenced to external CH3NO2. IR spectra were obtained with
a Bruker IFS66 spectrometer in KBr pellets. MS spectra were mea-
sured with an AMD 604 mass spectrometer (AMD Intectra
GmbH, Germany). Radial chromatography (RC) was performed
Conclusions
Analysis of the 31P NMR spectra (relevant spectroscopic
data are given in Table 2) and identification of the LR
transformation products has allowed the mechanism for the
reaction of N-alkylhydroxamic acids HAs 1 with LR to be
established. The reaction proceeds via the formation of the with a Chromatotron Model 4924T (Harrison Research) on 2 mm
glass plates. THF was distilled from potassium/benzophenone ke-
tyl. Commercial Lawesson’s reagent (Lancaster) was recrystallised
from chlorobenzene prior to use. Acyl chlorides, tribenzylphos-
phane oxide, TMOF and methyl iodide were commercial com-
pounds (Aldrich). N-Isopropyl hydroxylamine hydrogen oxalate
was obtained from 2-methylnitroethane by reduction using zinc
intermediate O-dithiophosphonylated hydroxamic acid 19.
The hydroxamic acid acts as a carrier for the reactive meta-
dithiophosphonate (AnsPS2) in the thionation of the car-
bonyl group. It also plays a role in the controlled transfor-
mation of metathiophosphonate (AnsPOS) to pyrothiopho-
sphonate 3 via the intermediate O-thiophosphonylated ad-
duct 2. This process distinguishes the reaction of LR with
HAs 1 from the reactions of other carbonyl compounds
with LR, in which a mixture of oligomers and trimer 5 are
powder. N-Allyl hydroxylamine was prepared by
a known
method.[23] N-Isopropyl-N-hydroxythiobenzamide[4] was isolated
from the reaction mixture of 1a with LR. All reactions with LR
were performed under argon in flame-dried flasks equipped with a
formed from AnsPOS. The adducts formed from the reac- stirring bar and a rubber septum.
Table 2. 31P NMR chemical shifts of the (4-methoxyphenyl)phosphonic acid derivatives under investigation.
X
Y
δP [ppm]
AnsP(S)SXOY
79.2
92.1
–
99.8
–
–
–
AnsP(O)SXOY
AnsP(S)OXOY
AnsP(O)OXOY
19.5
23.6
–
28.5
–
–
–
H
H
Me
Me
H
Me
HN(c-hex)2
Me
TBDMS
TBDMS
Me
–
4: 76.5
6: 84.1
70.8
6Ј: 92.7
16: 70.1
17: 63.7
78.4
39.3
–
49.1
–
H
TBDMS
TBDMS
–
–
H
H
H
HA 1a
19a: 109.7
2a: 88.8
2b: 88.0
2c: 89.7
8a: 98.1
–
7a: 83.9
3: 71.4
–
–
–
–
–
–
–
–
9.8
HA 1b
–
–
HA 1c
19c: 112.5
Me
Me
TBDMS
H
H
Me
HA 1a
22a: 113.4
9a: 54.1
HA 1c
22c: 115.8
–
–
–
–
–
HA
–
–
–
–
AnsP(S)OH
AnsP(O)OH
AnsP(S)OMe
15: 80.05, 80.18
12: 13.0 (2d),
80.9 (2d)
Me
Me
TBDMS
AnsP(O)SMe
AnsP(O)OMe
AnsP(S)OTBDMS
–
–
–
–
15: 53.2, 53.9
–
–
–
–
–
–
13.3, 13.4
–
–
14: 64.3, 65.0
5: 72.3 (d), 74.4(t)
-OAnsP(S)OP(S)AnsO-
2010
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2002–2014

Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
FULL PAPER
Typical Procedure for the Preparation of Hydroxamic Acids 1a–d: A
stirred suspension of N-isopropylhydroxylamine hydrogen oxalate
(1.98 g, 12 mmol) in CH2Cl2 (50 mL) containing triethylamine
(3.04 mL, 20 mmol) was cooled in an ice bath and the appropriate
acyl chloride (10 mmol) in CH2Cl2 (10 mL) was added dropwise
over 1 h. After an additional 2 h at room temperature the mixture
was washed with water (2×15 mL), 1 m HCl (10 mL), water and
brine, and dried with MgSO4. The solvent was evaporated and the
crude hydroxamic acid was crystallised or purified by radial
chromatography (RC).
was concentrated in vacuo to give a clear colourless oil. Crystalli-
1
sations from various solvent systems were unsuccessful. H NMR:
4
3
δ = 3.83 (s, 3 H, OCH3), 6.90 (dd, JHP = 3.4, JHH = 8.8 Hz, 2
3
3
H), 7.83 (dd, JHP = 13.7, JHH = 8.8 Hz, 2 H), 8.55 (s, 2 H,
OH) ppm. 31P NMR (CDCl3): δ = 73.2; (THF): 76.5 ppm.
The crude acid 4 was redissolved in THF (5 mL), TMOF (0.48 mL,
4.4 mmol) was added and the mixture was stirred for 16 h. 31P
NMR analysis showed that it contained two products: namely O,S-
dimethyl (4-methoxyphenyl)phosphonothioate (δP = 49.3 ppm) and
O,O-dimethyl (4-methoxyphenyl)phosphonothioate (6Ј) (δP
=
N-Hydroxy-N-isopropylbenzamide (1a): Yield 76%; m.p. 101 °C.[4]
92.7 ppm) in a 9:1 ratio. After chromatography through silica gel
(chloroform), pure O,S-dimethyl (4-methoxyphenyl)phospho-
N-Hydroxy-N-isopropyl-4-methoxybenzamide (1b): Yield 70%; m.p.
1
nothioate (0.3 g, 65%) was obtained as a colourless oil. H NMR:
121–122 °C (ethyl acetate).[21]
3
δ = 2.12 (d, JHP 13.7, 3 H, SCH3), 3.83 (s, 3 H, ArOCH3), 3.84
3
4
3
N-Hydroxy-N-isopropyl-4-nitrobenzamide (1c): Yield 60%; m.p.
(d, JHP = 12.2 Hz, 3 H, OCH3), 6.96 (dd, JHP = 3.4, JHH
=
107–110 °C (benzene/c-hexane).[21]
8.8 Hz, 2 H), 7.78 (dd, JHP = 13.2, JHH = 8.8 Hz, 2 H) ppm. 31P
3
3
NMR: δ = 49.3 ppm. MS (EI): m/z (%) = 232 (21) [M]+, 185 (100)
N-Hydroxy-N-isopropyl-4-dimethylaminobenzamide (1d): Yield
[M
–
SCH3]+, 170 (8) [AnsPO2]+. HRMS (EI): calcd. for
32%; m.p. 134–135 °C (benzene). IR (KBr): ν = 3223 (OH), 1616,
˜
C9H13O3SP: 232.03230; found 232.03244.
1584 (C=O) cm–1. 1H NMR: δ = 1.29 (d, J = 6.5 Hz, 6 H, CHCH3),
3.02 (s, 6 H, NCH3), 4.33 (sept, J = 6.5 Hz, 1 H, CHCH3), 6.69
(d, J = 9 Hz, 2 H, H-3/5), 7.46 (d, J = 9 Hz, 2 H, H-2/6) ppm. 13C
NMR: δ = 19.6 (CH3CH), 39.5 (NCH3), 53.5 (CH3CH), 111.1 (C-
3/5), 118.8 (C-1), 129.5 (C-2/6), 152.1 (C-4), 169.0 (C=O) ppm.
C12H18N2O2 (222.28): calcd. C 64.84, H 8.16, N 12.60; found C
64.62, H 8.44, N 12.47.
2,4,6-Tris(4-methoxyphenyl)-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-
Trisulfide (5): A mixture of tribenzylphosphane oxide (3.2 g,
10 mmol) and LR (2.02 g, 5 mmol) in toluene (30 mL) was refluxed
for 4 h. The resulting clear solution was cooled and solid tribenzyl-
phosphane sulfide was filtered off. The filtrate was concentrated in
vacuo and the residue was crystallised from benzene to yield pure
trimer 5 (3.16 g, 94%). M.p. 153–155 °C (lit.[9] m.p. 158–159 °C).
1H NMR: δ = 3.87 (s, 6 H, OCH3), 3.89 (s, 3 H, OCH3), 7.02 (dd,
J = 8.8, J = 3 Hz, 4 H), 7.06 (dd, J = 8.8, J = 4 Hz, 2 H), 8.11
(dd, J = 8.8, J = 15.8 Hz, 4 H), 8.27 (dd, J = 8.8, J = 16.6 Hz, 2
H) ppm. 31P NMR (CDCl3): δ = 72.33 (d, J = 49 Hz, 2 P), 74.43
(t, J = 49 Hz, 1 P) ppm.
N-Hydroxy-N-isopropyl-4-pentenamide (1e): Yield 47%; oil (RC,
chloroform). 1H NMR (Z/E isomer = 3:5): δ = 1.17, 1.31 (2×d, J
= 6.5 Hz, 6 H, CHCH3), 2.41, 2.55 (2×br. m, 4 H, CH2CH2), 4.19,
4.68 (2×m, 1 H, CHCH3), 5.04 (d, J = 10.2 Hz, 1 H, CH2=), 5.10
(d, J = 17.6 Hz, 1 H, CH2=), 5.82 (m, 1 H, CH=), 8.90 (br. s, OH,
1 H) ppm; δH (55 °C): 1.31 (d, J = 6.5 Hz, 6 H, CHCH3), 2.45 (m,
4 H, CH2CH2), 4.24 (m, 1 H, CHCH3), 5.04 (d, J = 10.2 Hz, 1 H,
CH2=), 5.10 (d, J = 17.6 Hz, 1 H, CH2=), 5.86 (m, 1 H, CH=),
8.22 (br. s, 1 H, OH) ppm. 13C NMR: δ = 19.34, 20.36 (CH3),
29.22, 29.57, 31.14, 32.59 (CH2, C-2 and C-3), 47.69, 51.08 (CH–
CH3), 115.47, 116.48 (C-5), 136.89, 137.97 (C-4), 166.20, 174.03
(C=O) ppm. HRMS (EI): calcd. for C8H15NO2: 157.11028; found
157.11096.
O-Methyl Hydrogen (4-Methoxyphenyl)phosphonothioate (6)
From O,O-Dimethyl (4-Methoxyphenyl)phosphonothioate 6Ј: (4-
Methoxyphenyl)phosphothioic dichloride (3.57 g, 14.8 mmol) (δP =
76.8 ppm) prepared from LR and SO2Cl2 according to the pro-
cedure of Lecher et al.[26] was added to a stirred solution of meth-
anol in excess (12 mL) and triethylamine (5.2 mL, 37.2 mmol) at
5 °C. After 16 h the mixture was concentrated in vacuo and diethyl
ether was added. The resulting suspension was washed three times
with water, and then with saturated NaHCO3 solution, water and
brine. After drying with MgSO4 and concentration the crude dies-
ter was purified by chromatography through silica gel (CH2Cl2/hex-
ane, 1:1) to yield O,O-dimethyl (4-methoxyphenyl)phosphonothio-
ate 6Ј (1.07 g, 31%). 1H NMR: δ = 3.70 (d, J = 13.7 Hz, 6 H,
POCH3), 3.83 (s, 3 H, ArOCH3), 6.94 (dd, J = 3.4, J = 8.8 Hz, 2
H), 7.82 (dd, J = 8.8, J = 13.7 Hz, 2 H) ppm. 31P NMR (CDCl3):
δ = 92.7 ppm.
N-Allyl-N-hydroxybenzamide (1f):[24] Compound 1f was obtained
following the standard procedure from N-allylhydroxylamine. Yield
1
77%, a colourless oil (RC, chloroform). H NMR: δ = 4.27 (dt, J
= 5.5, J = 2 Hz, 2 H, NCH2), 5.31 (dt, J = 10, J = 2 Hz, 1 H,
CH2=), 5.34 (dt, J = 17, J = 2 Hz, 1 H, CH2=), 5.95 (ddt, J = 10,
J = 5.5, J = 2 Hz, 1 H, CH=), 7.4–7.6 (m, 5 H), 8.70 (br. s, 1 H,
OH) ppm.
Reaction of Hydroxamic Acids 1a–1f with LR: LR (0.04 g,
0.1 mmol) was added to a stirred solution of the hydroxamic acid
1a–1f (0.2 mmol) in THF (2 mL) at room temperature. Aliquots of
the crude reaction mixture were analysed periodically by means of
31P NMR spectroscopy in THF or after derivatisation and concen-
tration in CDCl3 solutions.
The diester (0.93 g, 4 mmol) was refluxed with KOH (0.18 g,
3.2 mmol) in dry methanol (2 mL) for 2 h. Methanol was then re-
moved and the resulting oil was dissolved in water (10 mL). The
aqueous solution was washed with diethyl ether and acidified with
conc. HCl and then extracted with diethyl ether. Drying with
MgSO4 and concentration gave 6 (0.08 g, 8%) (δP = 84.3 ppm).
In the case of 1e and 1f the suspected products of intramolecular
radical cyclisation reactions, that is, 5-substituted 1-isopropylpyrro-
lidin-2-one (diagnostic δH-5 = 3.5–3.9 ppm[20]) and N-benzoylazeti-
dine (diagnostic δH-3 = 2.35 ppm[25]), were not detected even in the
presence of diphenyl diselenide (0.125 g, 0.4 mmol, –50 °C to room
temp.).
From LR: LR (0.4 g, 1 mmol) was treated with methanol (0.08 mL,
2 mmol) in dry THF (6 mL) and the resulting clear solution of
O-methyl (4-methoxyphenyl)phosphonothioate was refluxed with 1
equiv. of water (0.036 mL, 2 mmol). Evaporation in vacuo left al-
most pure 6 (δP = 84.3 ppm).
(4-Methoxyphenyl)phosphonothioic O,OЈ-Acid (4): (4-Meth-
oxyphenyl)phosphonothioic acid (4) was identified as its O,S-di-
methyl ester. LR (440 mg, 1 mmol) was treated with water (72 mg,
4 mmol) in THF (6 mL) and refluxed for 2 h. The resulting solution
From Trimer 5: Trimer 5 (0.056 g, 0.1 mmol) was refluxed in dry
methanol (3 mL) for 2 h until the starting material had disappeared
(TLC). The clear solution was concentrated in vacuo to yield pure
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2011

W. Przychodzen´
FULL PAPER
6 (0.06 g, 92%). H NMR: δ = 3.71 (d, J = 14 Hz, 3 H, POCH3),
3.84 (s, 3 H, ArOCH3), 6.78 (br. s, 1 H, OH), 6.94 (dd, J = 3.4, J
= 8.8 Hz, 2 H), 7.84 (dd, J = 8.8, J = 14.6, 2 H) ppm. 13C NMR:
δ = 50.65 (ArOCH3), 52.83 (d, J = 6 Hz, POCH3), 114.00 (d, J =
12.2 Hz, C-3), 124.92 (d, J = 159 Hz, C-1), 133.01 (d, J = 13.8 Hz,
1
3.08 (s, 3 H), 4.01 (sept, 1 H), 6.62 (dd, J = 8.8, J = 3.3 Hz, 2 H,
H-3Ј/5Ј), 6.94–7.08 (m, 3 H, H-3/4/5), 7.68 (dd, J = 7.5, J = 1.5 Hz,
2 H, H-2/6), 8.28 (dd, J = 12.7, J = 8.8 Hz, 2 H, H-2Ј/6Ј) ppm. 13
C
NMR: δ = 12.7 (d, J = 3 Hz), 19.5 and 20.5, 55.8 and 57.2 (CH
and OCH3), 114.5 (d, J = 16 Hz, C-3Ј/5Ј), 121.5 (d, J = 152 Hz, C-
C-2), 162.93 (d, J = 3.3 Hz, C-4) ppm. 31P NMR (CDCl3): δ = 1Ј), 129.1 and 129.2 (C-2/6 and C-3/5), 131.2 (C-4), 134.8 (d, J =
84.2 ppm. Dicyclohexylammonium salt: Yield 82%; m.p. 172–
174 °C. 31P NMR (CDCl3): δ = 70.8 ppm. MS (EI): m/z (%) = 218
(24) [M]+, 201 (2) [M – OH]+, 169 (13) [AnsPS + 1]+, 138 (100)
[AnsP]+. HRMS (EI): calcd. for C20H34NO3SP (399.51): C 60.12,
H 8.58, N 3.51, S 8.03; found C 60.14, H 8.62, N 3.50, S 8.10.
12.5 Hz, C-2Ј/6Ј), 134.6 (C-1), 164.0 (C-4Ј), 174.8 (C=O) ppm. 31P
NMR: δ = 54.1 ppm. MS (EI): m/z (%) = 332 (6) [M – SCH3]+,
290 (2) [M – SCH3 – iPr]+, 105 (100) [PhCO]+. HRMS (LSIMS):
calcd. for C18H22NO4PSNa: 402.08976; found 402.0899.
O-Methyl (4-Methoxyphenyl)phosphonochloridothioate (10): Pre-
pared from 6 (4.36 g, 20 mmol) and phosphoric trichloride by anal-
ogy to the reported procedure.[12] Yield 1.56 g (33%) as a colourless
oil (RC, CH2Cl2/hexane, 2:1). 1H NMR: δ = 3.87 (s, 3 H, ArOCH3),
3.96 (d, J = 16 Hz, 3 H, POCH3), 6.99 (dd, J = 4.4, J = 8.8 Hz, 2
H, H-3/5), 7.96 (dd, J = 8.8, J = 15.6 Hz, 2 H, H-2/6) ppm. 31P
NMR: δ = 92.5 ppm. MS (EI): m/z (%) = 236 (100) [M]+, 201 (47)
[M – Cl]+, 169 (13) [AnsPS + 1]+, 139 (45) [AnsP + 1]+. HRMS
(EI): calcd. for C8H10ClO2PS: 235.98277; found 235.98392.
N-Isopropyl-N-[(4-methoxyphenyl)(tert-butyldimethylsilyloxy)thio-
phosphonyloxy]benzamide (7a): LR (0.3 g, 0.74 mmol) was added to
a stirred solution of benzohydroxamic acid 1a (0.265 g, 1.48 mmol)
in THF (4 mL). After 16 h triethylamine (0.22 mL, 1.58 mmol) and
TBDMSCl (0.223 g, 1.48 mmol) were added at 0 °C. After an ad-
ditional 4 h the solvent was evaporated under reduced pressure. 31
P
NMR analysis showed that the residue consisted of 17, 14 and 7a
in nearly equal amounts. The mixture was purified by chromatog-
raphy through silica gel with CH2Cl2/hexane (1:2) as eluent to give
the following five fractions: THA, TA, 17 (δP = 63.7 ppm), a mix-
ture of 17 (δP = 63.7 ppm) and 14 (δP = 64.3 and 65.0 ppm) and
the desired product 7a contaminated with 17. Repeated chromatog-
raphy of the last fraction yielded 7a (0.03 g, 4%). 1H NMR
([D6]benzene): δ = 0.34 and 0.42 (2×s, 6 H, Me2Si), 0.90 (s, 9 H,
Me3C), 1.22 (2×d, J = 6.5 Hz, 6 H, CH3CH), 3.06 (s, 3 H, OCH3),
3.93 (sept, J = 6.5 Hz, 1 H, CHCH3), 6.94 (dd, J = 8.8, J = 3.4 Hz,
2 H, H-3Ј/5Ј), 6.95 (m, 3 H, H-3/4/5), 7.71 (dd, J = 7.5, J = 1.5 Hz,
2 H, H-2/6), 8.33 (dd, J = 14, J = 8.8 Hz, 2 H, H-2Ј/6Ј) ppm. 31P
NMR: δ = 83.9 ppm. MS (EI): m/z (%) = 421 (22) [M – tBu]+, 306
O-Methyl (4-Methoxyphenyl)phosphonothioic O,O-Anhydride (11):
A solution of tetramethylammonium O-methyl (4-methoxyphenyl)
phosphonothioate prepared in situ from the corresponding acid 6
(0.26 g, 1.18 mmol) in dichloromethane (2 mL) was added dropwise
to a solution of O-methyl (4-methoxyphenyl)phosphonochlorido-
thioate (10) in CH2Cl2 (3 mL). After 16 h a white solid of tetra-
methylammonium chloride was filtered off and the filtrate was con-
centrated in vacuo to yield the crude product (0.43 g, 87%). Radial
chromatography (CH2Cl2/hexane, 1:2 Ǟ 4:1) afforded pure pyrodi-
1
thiophosphonate 11 (0.13 g, 30%) as a colourless oil. H NMR: δ
= 3.77 and 3.84 (2×d, J = 14.7 Hz, 6 H, POCH3), 3.81 and 3.82
(2×s, 6 H, ArOCH3), 6.88 and 6.92 (2×dd, J = 3.4, J = 8.8 Hz, 4
H, H-3/5), 7.77 and 7.83 (2×dd, J = 8.8, J = 13.7 Hz, 4 H, H-2/
6) ppm. 31P NMR: δ = 80.05 and 80.18 (2×s) ppm. MS (EI): m/z
(65) [M
– OTBDMS –
iPr]+, 301 (38) [AnsPSOTBDMS]+.
C23H34NO4SPSi (479.65): calcd. C 57.59, H 7.14, N 2.92, S 6.69;
found C 57.57, H 7.15, N 2.95, S 6.68.
(%)
=
418 (100) [M]+, 201 (63) [AnsPSOCH3]+, 185 (45)
N-Isopropyl-N-[(methoxy)(4-methoxyphenyl)thiophosphonyloxy]ben-
zamide (8a): O-Methyl (4-methoxyphenyl)phosphonochloridothio-
ate (10) (vide supra) (0.24 g, 1 mmol) was added to a solution of 1a
(0.18 g, 1 mmol) and DBU (0.15 mL, 1 mmol) in dichloromethane
(5 mL) at 0 °C. After being stirred for 16 h the solvent was evapo-
[AnsPSOH]+, 169 (21) [AnsPS + 1]+, 139 (15) [AnsP + 1]+. HRMS
(EI): calcd. for C16H20O5P2S2: 418.02273; found 418.02205.
O-[(Methoxy)(4-methoxyphenyl)phosphinyl] OЈ-Methyl (4-Meth-
oxyphenyl)phosphonothioate (12): DCC (0.206 g, 1 mmol) was
added to a solution of 6 (0.41 g, 2 mmol) in CH2Cl2 (2 mL) at room
temperature. After 2 h DCTU was filtered off and the solution was
concentrated in vacuo. Radial chromatography of the residue in
CH2Cl2/acetone (1:1) gave 0.25 g of an inseparable mixture (low Rf
values) of 12 along with unreacted 6 (signal intensity ratio, 9:1).
31P NMR: δ = 13.0 (2×d, J = 33 Hz), 80.9 (2×d, J = 33 Hz) ppm.
rated in vacuo and the residue was purified by RC (CH2Cl2
Ǟ
acetone/CH2Cl2, 1:20) to yield pure 8a (0.28 g, 73%) as a colourless
1
oil. H NMR: δ = 1.04 and 1.12 (2×d, J = 6.5 Hz, 6 H, CH3CH),
3.86 (s, 3 H, OCH3), 3.94 (d, J = 14 Hz, 3 H, POCH3), 4.09 (sept,
J = 6.5 Hz, 1 H, CH3CH), 6.97 (dd, J = 3, J = 8.5 Hz, 2 H, H-3Ј/
5Ј), 7.42 (t, J = 7.5 Hz, 2 H, H-3/5), 7.44 (t, J = 7.5 Hz, 1 H, H-
4), 7.62 (d, J = 7.5 Hz, 2 H, H-2/6), 7.95 (dd, J = 8.8, J = 13.5 Hz,
2 H, H-2Ј/6Ј) ppm. 13C NMR: δ = 19.7 and 20.0, 54.4 and 54.5
(CH), 55.65 (ArOCH3), 56.2 (d, J = 8 Hz, POCH3), 113.8 (d, J =
16 Hz, C-3Ј/5Ј), 123.3 (d, J = 161 Hz, C-1Ј), 128.4 and 128.9 (C-2/
6 and C-3/5), 131.7 (C-4), 133.9 (d, J = 13 Hz, C-2Ј/6Ј), 134.6 (C-
1), 163.3 (C-4Ј), 173.3 (C=O) ppm. 31P NMR: δ = 98.1 ppm.
HRMS (EI): calcd. for C18H22NO4PS: 379.10069; found 379.1008.
(4-Methoxyphenyl)phosphonothioic O,O-Anhydride (3). Method a:
NaI (73 mg, 0.48 mmol) was added to a solution of O-methyl (4-
methoxyphenyl)phosphonothioic O,O-anhydride (11) (100 mg,
0.24 mmol) in methyl ethyl ketone (MEK) (2 mL). The resulting
mixture was refluxed for 1 h. After cooling to room temperature
the resulting precipitate was filtered, washed with MEK and dried
to yield the disodium salt 13 (0.07 g, 67%). This was then sus-
pended in methanol (3 mL) and a stoichiometric amount of SOCl2
(0.012 mL, 0.16 mmol) was added whilst stirring. Methanol was
removed to afford a mixture consisting of 3, 4 and 6 according to
31P NMR spectroscopy (δP = 70.4, 73.2 and 84.3 ppm; 4:1:1 inten-
sity ratio). Method b: TMOF (0.04 mL, 0.37 mmol) was added
through a syringe to a stirred solution of acid 4 (0.07 g, 0.33 mmol)
in THF (3 mL). After 4 days at room temperature the clear solution
N-Isopropyl-N-[(4-methoxyphenyl)(methylthio)phosphonyloxy]ben-
zamide (9a): Prepared from AnsP(O)(SCH3)Cl generated in situ
from O,O-dimethyl (4-methoxyphenyl)phosphonothioate and
phosphorus oxychloride by analogy to the procedure of Tang et
al.[27] Yield 32%; m.p. 111–112 °C [RC, chloroform/hexane, 1:1].
1H NMR: δ = 1.18 and 1.37 (2×d, J = 6.5 Hz, 3 H, CH3CH), 2.10
(d, J = 14.2 Hz, 3 H, SCH3), 3.83 (s, 3 H, OCH3), 4.18 (sept, J =
6.5 Hz, 1 H, CH3CH), 6.96 (dd, J = 3.4, J = 8.8 Hz, 2 H, H-3Ј/5Ј),
was concentrated in vacuo to leave a light oil which according to
7.40–7.56 (m, 3 H, H-3/4/5), 7.61 (dd, J = 7.5, J = 1.5 Hz, 2 H, H- 31P NMR analysis contained almost pure 3. H NMR: δ = 3.80 (s,
1
1
4
3
2/6), 7.97 (dd, J = 8.8, J = 12.7 Hz, 2 H, H-2Ј/6Ј) ppm. H NMR
6 H, OCH3), 6.89 (dd, JHP = 3.4, JHH = 8.8 Hz, 4 H), 7.84 (dd,
([D6]benzene): δ = 1.05 and 1.41 (d, 6 H), 2.05 (d, J = 14 Hz, 3 H), 3JHP = 13.7, JHH = 8.8 Hz, 4 H), 9.90 (s, 2 H, OH) ppm. 31P
3
2012
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2002–2014

Reaction of Lawesson’s Reagent with N-Alkylhydroxamic Acids
FULL PAPER
NMR: δ = 70.3 (100%), 24.4 (5%), 84.2 (6%) ppm. 31P NMR 4), 7.65 (dd, J = 7.5, J = 1.5 Hz, 2 H, H-2/6), 8.09 (dd, J = 8.8, J
(THF): δ = 71.4 (100%), 20.5 (10%), 84.6 (10%) ppm. HRMS = 13.7 Hz, 2 H, H-2Ј/6Ј) ppm. 13C NMR: δ = 15.7 (d, J = 4 Hz,
(LSIMS): calcd. for C14H16O5P2S2Na: 412.98120; found 412.9808.
PSCH3), 19.8 and 20.6 (CCH3), 55.7 (OCH3), 56.4 (CH), 114.1 (d,
J = 16 Hz, C-3Ј/5Ј), 125.6 (d, J = 120 Hz, C-1Ј), 128.6 and 128.9
(C-2/6 and C-3/5), 131.9 (C-4), 133.6 (d, J = 13 Hz, C-2Ј/6Ј), 134.6
(C-1), 163.4 (C-4Ј), 173.8 (C=O) ppm. 31P NMR: δ = 113.4 ppm.
S-Methyl (4-Methoxyphenyl)phosphonothioic O,O-Anhydride (15):
Methyl iodide (0.124 mL, 2 mmol) was added to a cooled solution
of crude 4 (0.46 g, 2 mmol) and triethylamine (0.278 mL, 2 mmol)
in THF (4 mL). After being stirred for 2 h the mixture was filtered
and concentrated in vacuo to leave a light oil. 31P NMR analysis
showed that it contained a 4:1 mixture of the S-methyl ester of 4
(δP = 39.3 ppm) and O-methyl (4-methoxyphenyl)phosphonate (δP
= 18.3 ppm). This mixture was dissolved in CH2Cl2 (2 mL) and
treated with DCCI (0.206 g, 1 mmol). After 2 h DCU was filtered
off and the solution was concentrated in vacuo. The residue was
analysed by 31P NMR spectroscopy which confirmed that it con-
tained an inseparable 3:1 mixture (low Rf values) of pyrophosphate
15 (δP = 53.2 and 53.9 ppm) and dimethyl bis(4-methoxyphenyl)-
diphosphonate (δP = 13.34 and 13.38 ppm).
IR: ν = 3047, 2966, 2931, 1691 (s, C=O), 1386 and 1367 (iPr), 1259
˜
(s, ArOCH3), 895 (s), 718 (s) cm–1. MS (EI): m/z (%) = 348 (41)
[M
– – SCH3 –
SCH3]+, 306 (5) [M C3H6]+, 217 (76)
[AnsPSSCH3]+, 187 (33) [AnsPSSCH3 – OCH3 + 1]+, 169 (17)
[AnsP=S – 1]+, 139 (45) [AnsP=S – OCH3]+, 105 (85) [PhCϵO]+,
77 (100) [Ph]+. C18H22NO3S2P (395.48): calcd. C 54.67, H 5.61, N
3.54, S 16.21; found C 54.83, H 5.64, N 3.50, S 15.89.
The second portion of triethylammonium salt 21a was treated with
TBDMSCl (0.29 g, 1.9 mmol). After 4 h the solvent was evaporated
in vacuo and the residue was purified by chromatography on silica
in benzene to afford the pure O-TBDMS ester of 1a (0.2 g, 40%).
1H NMR ([D6]benzene): δ = 0.31 (s, 6 H, Me2Si), 0.98 (d, J =
6.5 Hz, 6 H, CH3CH), 1.06 (s, 9 H, Me3C), 3.83 (sept, J = 6.5 Hz,
1 H, CH3CH), 7.00 (m, 3 H, H-3/4/6), 7.42 (d, J = 7.5 Hz, 3 H, H-
2/6) ppm. C16H27NO2Si (293.48): calcd. C 65.48, H 9.27, N 4.77;
found C 65.35, H 9.40, N 4.52.
O-tert-Butyldimethylsilyl Hydrogen (4-Methoxyphenyl)phospho-
nothioate (16): A solution of crude 4 (0.38 g, 1.86 mmol) and
TBDMS-OH (0.31 mL, 1.96 mmol) in benzene (20 mL) was re-
fluxed for 3 h using a Soxhlet apparatus containing 4-Å molecular
sieves. Concentration in vacuo gave a mixture of monoester 16 and
diester 17 (δP = 70.1 and 63.7 ppm; intensity ratio: 6:1)
N-Isopropyl-N-[(4-methoxyphenyl)(methylthio)thiophosphonyloxy]-
4-nitrobenzamide (22c): LR (0.022 g, 0.05 mmol) was added to a
stirred solution of N-hydroxy-N-isopropyl-4-nitrobenzamide 1c
(0.022 g, 0.1 mmol) and triethylamine (0.28 mL, 0.2 mmol) in THF
(2 mL). The resulting colourless solution of the triethylammonium
salt of 21c (δP = 123.8 ppm) was cooled in an ice bath and treated
with methyl iodide (0.01 mL, 0.15 mmol). After 4 h the solvent was
evaporated under reduced pressure and the residue purified by
chromatography through silica gel (chloroform/hexane, 1:1) to yield
O,O-Bis(tert-butyldimethylsilyl) (4-Methoxyphenyl)phosphonothio-
ate (17):[28] DBU (0.3 mL, 2 mmol) and then TBDMSCl (0.3 g,
2 mmol) were added with cooling to a stirred solution of crude 4
(0.2 g, 1 mmol) in THF (10 mL). After 2 h at room temperature the
mixture was concentrated in vacuo and dissolved in ethyl acetate.
Washing with a saturated NaHCO3 solution, water, brine, drying
with MgSO4 and concentration yielded the crude diester (0.31 g,
72%) as a colourless oil. Radial chromatography with CH2Cl2/hex-
1
22c (0.034 g, 77%). M.p. 102 °C. H NMR: δ = 1.20, 1.27 (2×d, J
1
ane as eluent afforded 17 (0.15 g, 35%). H NMR: δ = 0.17, 0.31
= 6.5 Hz, 6 H, CH3CH), 2.37 (d, J = 17 Hz, 3 H, PSCH3), 3.87 (s,
3 H, OCH3), 4.17 (sept, J = 6.5 Hz, 1 H, CH3CH), 6.96 (dd, J =
8.8, J = 3.4 Hz, 2 H, H-3Ј/5Ј), 7.74 (d, J = 8 Hz, 2 H, H-2/6), 7.94
(dd, J = 8.8, J = 13.7 Hz, 2 H, H-2Ј/6Ј), 8.21 (d, J = 8 Hz, 2 H,
H-3/5Ј) ppm. 31P NMR: δ = 115.8 ppm. MS (EI): m/z (%) = 393
(18) [M – SCH3]+, 351 (5) [M – SCH3 – C3H6]+, 217 (100)
[AnsPSSCH3]+, 187 (14) [AnsPSSCH3 – OCH3 + 1]+, 169 (14)
[AnsP=S – 1]+, 150 (47) [4-NO2C6H4CϵO]+ (47), 139 (29)
[AnsP=S – OCH3]+ (29). C18H21N2O5S2P (440.48): calcd. C 49.08,
H 4.81, N 6.36, S 14.56; found C 49.26, H 4.86, N 6.38, S 14.18.
(2×s, 12 H, Me2Si), 0.90 (s, 18 H, Me3C), 3.84 (s, 3 H, OCH3),
6.91 (dd, J = 3.3, J = 8.8 Hz, 2 H, H-3/5), 7.85 (dd, J = 14.5, J =
8.8 Hz, 2 H, H-2/6) ppm. 31P NMR: δ = 63.7 ppm.
O,S-Dimethyl (4-Methoxyphenyl)phosphonodithioate (20): LR
(0.040 g, 0.1 mmol) was suspended in TMOF (1 mL). After 4 h at
room temp. the resulting clear solution was concentrated in vacuo
1
to yield pure 20 (0.045 g, 90%) of as a colourless oil. H NMR: δ
= 2.15 (d, J = 14.9 Hz, 3 H, PSCH3), 3.81 (d, J = 15.4 Hz, 3 H,
POCH3), 3.85 (s, 3 H, OCH3), 6.97 (dd, J = 3.3, J = 8.8 Hz, 2 H,
H-3/5), 7.87 (dd, J = 13.7, J = 8.8 Hz, 2 H, H-2/6) ppm. 31P NMR:
δ = 98.9 ppm. MS (EI): m/z (%) = 248 (5) [M]+, 233 (8)
[M – CH3]+, 217 (100) [M – OCH3]+, 201 (15) [M – SCH3]+, 139
(36) [AnsPS – OCH3]+. HRMS (EI): calcd. for C9H13O2PS2:
248.00944; found 248.0092.
Acknowledgments
Financial support from the Polish State Committee for Scientific
Research (Grant No. T09A 06116) and Gdan´sk University of Tech-
nology is greatly appreciated.
N-Isopropyl-N-[(4-methoxyphenyl)(methylthio)thiophosphonyloxy]-
benzamide (22a) and N-tert-Butyldimethylsilyloxy-N-isopro-
pylbenzamide: LR (0.646 g, 1.6 mmol) was added in two equal por-
tions to a stirred solution of benzohydroxamic acid 1a (0.573 g,
3.8 mmol) and triethylamine (0.90 mL, 6.4 mmol) in THF (40 mL).
The resulting colourless solution of triethylammonium salt 21a [δP
= 121.4 ppm; δN = –186.5 ppm. FAB MS: m/z (%) = 384 (100), 303
(28, AnPSS-NEt3), 281 (92, 1a-NEt3] was divided into two equal
parts. One of them was treated with methyl iodide (0.12 mL,
1.9 mmol) at 0 °C. After 4 h the solvent was evaporated under re-
duced pressure and the residue purified by chromatography
through silica gel (chloroform) to yield 22a (0.62 g, 84%). M.p. 93–
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94 °C. H NMR: δ = 1.15, 1.18 (2×d, J = 6.5 Hz, 6 H, CH3CH),
2.43 (d, J = 17 Hz, 3 H, PSCH3), 3.86 (s, 3 H, OCH3), 4.13 (sept,
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Eur. J. Org. Chem. 2005, 2002–2014
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2013

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2014
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2002–2014