Lawesson's reagent for direct thionation of hydroxamic acids: Substituent effects on LR reactivity

Article abstract of DOI:10.1002/hc.20259

To explore the generality and scope of direct thionation of hydroxamic acids (HAs), the reaction of various structurally diverse HAs with Lawesson's reagent was investigated. The yield of thiohydroxamic acid (THAs) is poor when HAs possess bulky acyl and/or N-substituents, acidic α-hydrogen atoms, or an N-phenyl ring. THAs yields were correlated with Brown sigma parameter. The relative rates of two subsequent processes k_T2 and k_R2 were also measured. Correlation was also found for methine proton chemical shifts of N-isopropyl benzothiohydroxamic acids.

Full text of DOI:10.1002/hc.20259

Heteroatom Chemistry
Volume 17, Number 7, 2006
Lawesson’s Reagent for Direct Thionation
of Hydroxamic Acids: Substituent Effects
on LR Reactivity
Witold Przychodzen´
Faculty of Chemistry, Gdan´sk University of Technology, Narutowicza 11/12, 80-952 Gdan´sk, Poland
Received 17 October 2005; revised 29 January 2006
(thiopivaloyl-, phenylthioacetyl-, and arothioyl-
ABSTRACT: To explore the generality and scope of
containing electron-donating groups), S-thioacyl-
direct thionation of hydroxamic acids (HAs), the reac-
dithiophosphates produce THAs in moderate to very
tion of various structurally diverse HAs with Lawes-
good yields.
son’s reagent was investigated. The yield of thiohydro-
On the other hand, direct thionation of HAs
xamic acid (THAs) is poor when HAs possess bulky
is of great interest since this route provides a
acyl and/or N-substituents, acidic ꢀ-hydrogen atoms,
synthetic pathway to thioanalogues of natural hy-
or an N-phenyl ring. THAs yields were correlated with
droxamate siderophores. Also the synthesis of N-
Brown sigma parameter. The relative rates of two subs-
hydroxythiopeptides has recently begun to attract
equent processes kT and kR were also measured.
2
2
considerable attention [3]. Unfortunately, thiona-
tion with P4S10 produces complex mixtures contain-
ing only small quantities of the desired THAs [4,5].
Rzepa and coworkers [6] proposed an approach
that involved a three-step procedure with protec-
tion and deprotection of the N OH moiety dur-
ing the synthesis of THAs using Lawesson’s reagent
(LR), but yields of the corresponding THAs 2 were
low (10–50%), probably because of lability of O-
acetylthiohydroxamic acids.
Previously [7], we managed to optimize cer-
tain parameters for obtaining THAs 2B directly
from their parent benzohydroxamic acids 1B us-
ing LR. We showed that the reaction of benzohy-
droxamic acids with LR should be performed in
THF at room temperature, using 0.5 equivalent of
LR. This procedure allows for obtaining the de-
sired N-alkyl benzothiohydroxamic acids in mod-
erate yields (40–60%). In addition, we found that
this reaction generates also the corresponding ben-
zamides 3B and thiobenzamides 4B as by-products.
Furthermore, we proved the coexistence of four inde-
pendent processes: two parallel—the benzohydrox-
amic acid thionation (T1) and deoxygenation (R1)
Correlation was also found for methine proton
chemical shifts of N-isopropyl benzothiohydroxamic
2006 Wiley Periodicals, Inc. Heteroatom Chem
17:676–684, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20259
ꢀ
C
acids.
INTRODUCTION
N-Substituted thiohydroxamic acids (THAs) 2 can be
obtained using two different methods [1]: (i) thioacy-
lation of the respective hydroxylamines or (ii) thion-
ation of hydroxamic acids (HAs) 1. The scope of
the first approach is often limited by availability of
a stable thioacylating agent. Recently, a highly effi-
cient class of S-thioacyldithiophosphates has been
successfully introduced [2]. With few exceptions
Correspondence to: Witold Przychodzen´; e-mail: witold@chem.
pg.gda.pl.
Contract grant sponsor: Polish State Committee for Scientific
Research.
Contract grant number: T09A 06116.
Contract grant sponsor: Gdan´ sk University of Technology.
2006 Wiley Periodicals, Inc.
c
ꢀ
676

Lawesson’s Reagent for Direct Thionation of Hydroxamic Acids 677
pathways—and two subsequent steps involving re-
duction of benzothiohydroxamic acid 2B (R2) and
thionation of benzamide 3B (T2). Also the mecha-
nism of LR action on HAs 1 was proposed [8]. Ac-
cording to the suggested mechanism, anisyldithio-
phosphorane (AnsPSS) generated from LR attacks
the hydroxyl group of HA 1 yielding an elusive
adduct, the O-dithiophosphonylated HA 1-PSSH. Its
stability depends on the N O bond energy. Break-
down of 1-PSSH gives amides 3. As formation of
adduct 1-PSSH is a reversible process, a further
reaction on the carbonyl oxygen atom of AnsPSS
occurs, which leads to THA 2 and anisylth-
iophosphorane (AnsPOS). Next AnsPOS, gener-
ated by thionation and deoxygenation of HA 1,
is transformed into O-thiophosphonylohydroxamic
acid 5 and finally into pyrothiophosphonate 6
in the presence of anisylthiophosphonic acid 7
(Scheme 1).
Significant acidity of THAs 2 facilitates their
isolation and purification from reaction mixtures.
Because anisylthiophosphonic acid 7 is the main
phosphorus-containing product formed from LR in
the course of thionation of HAs 1, basic aqueous
workup affords a mixture of THA 2 and anisylth-
iophosphonic acid 7 salts. After acidification, this
mixture can be easily separated on short silica gel
columns owing to marked difference of polarities of
both components.
Until now, reported studies regarding the elec-
tronic effect of substituents on the thionation rate of
carbonyl compounds have been limited to carboxylic
esters only. Bradshaw showed that esters with
electron-withdrawing groups treated with LR do
not give the corresponding thionoesters in isolable
yields while conjugated electron-donating groups in-
creased the rate of their thionation [9]. He also found
that tert-butyl benzoate failed to react with LR due
chiefly to steric hindrance. Amides are better nu-
cleophiles and therefore react with LR much faster
than esters, but the effect of substituents on the
thionation rate of amides has never been studied
[10]. In the previous report [8], it was found that
EWG-substituted HAs give better yields of the corre-
sponding THAs 2. It can be assumed that this effect
results from both lower nucleophilicity and stronger
N O bond of EWG-substituted HAs as compared
with EDG-substituted ones. This is quite opposite
to the above-mentioned tendency observed by
Bradshaw for carboxylates. In addition, it was ob-
served that the reaction of HAs 1 with LR is even
faster than that of amides.
RESULTS AND DISCUSSION
To determine the scope, limitations, and substituent
effects of direct thionation of HAs with LR, more
than 30 selected N-substituted HAs 1 were subjected
to LR action in THF at room temperature.
Examples include aliphatic and aromatic HAs,
1A and 1B, respectively, with steric extremes of acyl
(Rꢁ = Me, t-Bu, mesityl) and N-substitution (Rꢁꢁ = Me,
t-Bu); N-aryl HAs 1Ad–f (Rꢁꢁ = aryl); cinnamohy-
droxamic acid 1An and N-isopropyl benzohydrox-
amic acids 1Bf–s including substituents with vary-
ing electronic effect in their aromatic rings (Table 1).
The reaction was monitored by TLC using the Fe3+
test. Upon treatment with methanolic solution of fer-
ric chloride, HAs and THAs give magenta and black
stain, respectively. Quantitative analyses were per-
1
formed using H NMR by means of following the
appearance of the methyl, methylene, or methine
proton signals of THA 2 and other products of HA
transformations. The yield of THA 2 formed was
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

678 Przychodzen´
TABLE 1 Results of Direct Thionation of Hydroxamic Acids RꢁCON(OH)Rꢁꢁ 1 Using LR
THA 2 Diagnostic Protons
Other Products (%)a
Entry HA
R ꢁ
R ꢁꢁ
THA 2 (%)a
(δ ppm)
1
5
3
4
1
2
3
4
5
6
7
8
1Aa
1Ab
1Ac
1Ad
1Ae
1Af
1Ag
1Ah
1Ai
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
n-Pr
Bn
i Pr
t-Bu
Ph
46
30
15
<5
nd
nd
35
44
nd
nd
nd
nd
nd
<5
25
29
nd
2.62; 5.09
2.57; 4.55
1.63; 2.76
2.50; 11.3
10 15
1 + 5 + 3 38
0
31
38
29
28
44
10
20
10
35
23
–
b
21
13
24
22
20
11
12
nd
100
10
20
50
11
56
4
b
b
b
4-NO2C6H4
4-MeOC4H4
Me
–
–
2.67; 3.60
2.74; 4.58
–
16
13
12
nd
–
i Pr
t-Bu
Me
i Pr
Me
Me
i Pr
Me
Bn
t-Bu
Ph
Me
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
i Pr
13
41
41
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
1Aj
1Ak
1Al
t-Bu
t-Bu
Bn
–
–
–
–
4.50
3.57
5.02
–
–
–
nd
nd
54
b
1Am
1An
1Ba
1Bb
1Bc
1Bd
1Be
1Bf
1Bg
1Bh
1Bi
1Bj
1Bk
1Bl
1Bm
1Bn
1Bo
1Bp
1Bq
1Br
1Bs
1Bt
EtO2CCH2
PhCH CH
Ph
1 + 5 43
6
45
26
24
5
36
–
17
14
15
17
7
Ph
Ph
Ph
24
3
–
92
54
58
48
41
41
b
b
nd
nd
nd
14
2,4,6-(CH3)3C6H2
4-Me2NC6H4
4-BnOC6H4
4-MeOC6H4
4-t-BuC6H4
4-MeC6H4
Ph
4-FC6H4
4-ClC6H4
4-CNC6H4
4-NO2C6H4
3-MeOC6H4
3-MeC6H4
3-NO2C6H4
3,5-(NO2)2C6H3
2-Thienyl
2-Pyridyl
10
8
25
14
5
–
30
21
11
33
26
14
19
16
17
17
22
25
22
12
49
45
4.53
4.52
4.51
4.48
4.44
4.42
4.40
4.29
4.30
4.45
4.44
4.33
4.30
4.88
–
13
13
16 (10c)
24 (15c)
25
11
1 + 5 + 3 43
15
11
14
15
10
14
16
17
14
15
14
11
–
18
38
32
11
20
19
18
13
6
10
10
10
8
7
10
11
3
38 (37c)
53
58 (38c)
34 (28c)
28
4
5
5
3
56
70
11
nd
–
i Pr
Me
30
–
1Bu
10
aYields determined by 1H NMR; nd—not detected, confirmed by negative Fe3+ test.
bNot estimated due to overlapping signals.
cIsolated yield; characterized in [11].
calculated from the area integration of clearly iden-
tifiable resonances of the respective N-alkyl protons
in 1H NMR spectra of reaction mixtures.
in only 5% yield. In the case of benzohydroxamic
acids, a secondary alkyl group (iPr) constitutes the
optimum. N-Methyl 1Ba and N-benzyl 1Bb HAs give
lower yields of THAs (ca. 30%), whereas N-t-Bu HA
1Bc produces exclusively the corresponding benza-
mide 3Bc (92%). This is due to the irreversible for-
mation of the adduct of 1Bc and AnsPSS; there-
fore, only deoxygenation was observed in this case.
This fact was confirmed by 31P NMR spectroscopy. In
the 31P NMR spectrum of the reaction mixture pro-
duced by 1Bc and LR, the signal of the correspond-
ing adduct 1Bc-PSSH (δP = 112 ppm) was the most
intensive one during the first stage of the reaction.
From the data in Table 1 one can also see that
some HAs can be inactive toward LR. In the case of
N-isopropyl pivalohydroxamic acid 1Ak, the steric
Analysis of the results presented in Table 1 re-
veals that enlargement of N-alkyl substituent in ace-
tohydroxamic acids (1Aa–c) and butyrohydroxamic
acids (1Ag–i) lowers THA 2 yield. It is also interest-
ing to note that N-Me HAs usually afforded THAs
in lower yields. Among pivalohydroxamic acids only
N-methyl HA 1Aj reacts with LR, but it affords
solely a mixture of pivaloamide and pivalothioamide.
Phenylaceto-(1Al), malono-(1Am), 2-pyrido-(1Bu),
N-t-Bu-(1Ai, 1Bc), N-phenylhydroxamic acids (1Ae,
1Af, 1Bd) and 4-dimethylaminobenzohydroxamic
acid 1Bf did not produce the corresponding THAs
at all. Cinnamohydroxamic acid 1An gives THA 2An
Heteroatom Chemistry DOI 10.1002/hc

Lawesson’s Reagent for Direct Thionation of Hydroxamic Acids 679
hindrance around the carbonyl as well as around
the N OH group is responsible for total inertness.
N-Methyl 2,4,6-trimethylbenzohydroxamic acid 1Be
gives only the corresponding amide (58%) and no
THA or thioamide, which indicates that thionation
is impossible in that case because of steric crowding
near the carbonyl group.
The increase in yield of amides produced by
deoxygenation may also be associated with steric
crowding around the N-hydroxyl group. Particularly
steric compression dominates in the case of N-t-Bu
HAs, where the degree of pyramidization of the ni-
trogen atom due to the fact that its lone electron pair
is not coplanar with the carbonyl moiety is high.
Therefore, in N-t-Bu HAs the N O bond becomes
weaker and the carbonyl oxygen less nucle-
ophilic, which results in shifting the equilibrium
of adduct formation to the right (see above).
2-Pyridinohydroxamic acid 1Bu is deoxygenated ex-
clusively, probably because of existence of a compet-
itive nucleophilic center at the nitrogen atom of the
pyridine residue.
As it was demonstrated, the direct thionation
method could be useful for N-alkyl aceto- and benzo-
hydroxamic acids lacking electron-donating groups
in the aromatic ring. Some HAs were shown to fail
to undergo thionation due to either steric hindrance
(N-t-Bu-, mesitylhydroxamic acids), significant acid-
ity of ꢀ-hydrogens (phenylaceto- and malonohy-
droxamic acids), presence of an additional nucle-
ophilic center (1Bu), or ease of reduction of both
HA and THA (N-aryl, EDG-substituted benzohydrox-
amic acids). Therefore, in the case of these HAs direct
thionation is completely unfeasible under chosen re-
action conditions.
As mentioned before and confirmed in this re-
port, N-isopropyl benzohydroxamic acids bearing
EWG substituents produce the corresponding THAs
with higher yields, which seems quite unexpected in
light of previous reports [9]. In the case of electron-
rich HAs, the results are very poor (0% for 1Bf,
15% for 1Bg and 1Bh) because of the compet-
ing deoxygenation reaction. To evaluate the im-
pact of electronic effects on thionation, a series
of ring-substituted N-isopropyl benzohydroxamic
acids 1Bf–s was chosen. Correlation of the THA
yields (relative to the unsubstituted THA 2Bk)
with Hammett constants (ꢁ and ꢁ+) of substituents
was investigated. Clearly, the yields correlate bet-
ter with Brown ꢁ+ substituent constant (r = 0.95,
ρ = 0.33) (Fig. 1) than with ꢁ. Even though linear-
ity is not excellent in general, the Hammett plot
does provide useful insights into the reaction mech-
anism. First, the relatively small magnitude of the
reaction constants, ꢂ, indicates that this reaction is
FIGURE 1 Hammett plot of the Y-substituted THA 2Bg–s
relative yield against σ+ values (r = 0.95, ρ = 0.33).
only slightly sensitive to change in the electronic na-
ture of substituents in the phenyl ring. Second, the
observed dramatic fall of yields of EDG-substituted
THAs reflects the more nucleophilic/less acidic na-
ture of EDG-substituted HAs.
It is obvious that THA yields depend on rate dif-
ferences between two pairs of competitive processes,
but as mentioned before, higher electron densities on
N-hydroxyl group of both HA and THA determine the
extent of their deoxygenation (R1 and R2).
Very interesting substituent effects were ob-
1
served in H NMR spectra of N-isopropyl deriva-
tives under investigation. Good correlation (negative
slope) was found for methine proton NMR chem-
ical shifts of para-substituted HAs 1Be–r, and the
effect of substituents was compared to those ob-
tained for the corresponding THAs 2Be–r, amides
3B, and thioamides 4B. Surprisingly, the respec-
tive shifts for 4-substituted N-isopropyl benzamides
3B and thiobenzamides 4B are almost insensitive
to substituent effects (Fig. 2). On the contrary, we
previously showed that 15N chemical shifts of THAs
2B and HAs 1B are also linearly correlated with
FIGURE 2 Hammett plot of the methine proton chemical shift
ꢀ
values for HAs 1Bg–s ( , r = 0.9652, slope = −0.141 ppm)
and for the respective: A (+), THAs 2Bg–s (ꢁ, r = 0.9883,
slope = −0.231 ppm), and TA ( ) against σ values.
ꢂ
Heteroatom Chemistry DOI 10.1002/hc

680 Przychodzen´
TABLE 2 Effect of Substituents on 4-Y Substituted Benzoth-
iohydroxamic Acids 2B and Benzamides 3B Reactivity (k Rel-
ative Rates)
the Brown constant, but the substituent effects are
two times smaller than those for the corresponding
thioamides and amides [11]. It is well known that in
solution HAs and THAs exist as mixtures of Z and
E isomers. It was confirmed that in the cases of the
investigated HAs and THAs one isomer usually dom-
inates. At room temperature, 1H NMR spectra of HAs
1B and THAs 2B consist of averaged signals of both
isomers [11], whereas in spectra of aliphatic HAs,
e.g., 1Ag–I, two resonances are often seen. The po-
sition of averaged signals obtained at room temper-
ature for aromatic derivatives 1B and 2B depends
mainly on the both isomers population. Because the
isomers ratio reflects the difference in acidity of vari-
ous substituted compounds under investigation and
THAs are stronger acids than HAs, the observable in-
fluence of substituents on methine proton chemical
shift is greater in the case of THAs 2B.
Y
kR
kT
kT /kR
2
2
2
2
OMe
H
NO2
1.80a
1
0.22
1.21
1
0.70
0.57
1.52
1.92
aFor 2Bh + 2Bk → 4Bh + 4Bk kR
) = [4Bh]/[4Bk].
(OCH
2
3
Despite these observations, it seemed interest-
ing how the rates of both above-mentioned subse-
quent processes can influence THA yield depending
on substituent. Hence, relative rates of kT and kR
2
2
for pairs of different substituted benzamides 3B and
benzothiohydroxamic acids 2B were measured. In
addition, kT /kR ratios for pairs of benzamides 3B
2
2
and THAs 2B with the same substituents were de-
termined as well. Appropriate competition experi-
ments showed that the reaction rates increased with
electron-donating abilities of the substituent. Con-
sequently, it was found that 4-methoxy-substituted
THA 2Bh is deoxygenated eight times faster than
4-nitro-substituted one 2Bo. Its reduction is two
times faster than thionation of the correspond-
ing benzamide 3Bh. THA with 4-nitro substituent
2Bo is reduced two times slower than the corre-
sponding benzamide 3Bo is thionated. In the case
of benzamides, 4-methoxybenzamide 3Bh is thion-
ated 1.73 times faster than 4-nitrobenzamide 3Bo
(Table 2).
Although the initial intent was to determine the
relative rates of all the above-mentioned processes
(Scheme 1), we were able to determine only the rela-
tive rates of the two subsequent reactions (kR and
2
kT ). Attempts to study the kinetics of HAs reduc-
2
tion and HAs thionation (kR and kT ) were unsuc-
1
1
cessful. One must consider that the results obtained
in this way can only approximate the observed reac-
tivity of LR toward HAs. The n-Bu3P/Ph2S2 system,
very similar to LR as far as reactivity is concerned,
used by Barton and coworkers for reduction of N-
methylbenzohydroxamic acid 1Ba [12], was found
to be totally inert toward N-isopropylhydroxamic
acid 1Bk. On the other hand, TiCl3, which efficien-
tly splits N O bonds in N-methyl phenylacetohy-
droxamic acids [13], was probably too reactive
and produced a nearly equimolar mixture of the
corresponding 4-methoxybenzamide 3Bh and 4-
nitrobenzamide 3Bo. One could speculate that LR
action may be similar to that of TiCl3 in reduction of
HAs. However, everything indicates that the mode of
action of TiCl3 is quite different from that of LR. On
the other hand, so far no other efficient chemoselec-
tive reagent for thionation of HAs is known besides
LR. Therefore, we decided to involve N-methoxy
derivatives 8Bh and 8Bo to study the kinetics of
thionation (T1). Surprisingly, in this case it was found
that LR did not significantly differentiate substrates
with EDG and EWG substituents. In this way, it was
confirmed again that the hydroxyl group in HAs plays
a crucial role in their reaction with LR.
CONCLUSION
Strictly speaking, the more electron-donating the
substituent and the greater the steric hindrance, the
lower the THA yield. The observed trend in thion-
ation of HAs is opposite to that reported previously
for esters [9] and found in the present work in the
case of amides. In the case of EDG-substituted HAs
deoxygenation to the corresponding amide 3 pre-
dominates. EWG-substituted HAs are prone to thi-
onation due to relatively strong N O bond and
lower nucleophilicity. Thus, similarly to thioacy-
lation with S-thioacyldithiophosphates, also the
proposed method of direct thionation using LR is in-
efficient for obtaining EDG THAs and those with hin-
dered thioacyl residues. Still, some products could
be easily isolated, albeit in low yields (e.g., 2Bh).
This method does not work for N-phenylhydroxamic
acids or for those with a bulky N-substituent (t-Bu).
Correlation with the Brown substituent constant
was found for the yield of 4-substituted N-isoprop-
ylbenzohydroxamic acids (positive slope) and for
Fortunately, HAs are much more reactive toward
LR than THAs and amides. Therefore, addition of LR
in a stoichiometric amount yields the THA almost in-
tact for further reduction and both subsequent un-
desired processes (T2 and R2) have only a minuscule
impact on its yield.
Heteroatom Chemistry DOI 10.1002/hc

Lawesson’s Reagent for Direct Thionation of Hydroxamic Acids 681
chemical shifts of their methine protons (negative
slope), while H chemical shifts for the respective
amides and thioamides were observed to be insen-
sitive to substituent effects. Attempts were made to
measure the relative rates of the two subsequent pro-
N-Alkyl hydroxamic acids 1Aa–1Bu typical pro-
cedure. A stirred suspension of N-alkyl- or N-
arylhydroxylamine salt (12 mmol) in CH2Cl2 (50 mL)
containing triethylamine (3.04 mL, 20 mmol) was
cooled in an ice bath and treated with the appro-
priate acyl chloride (10 mmol) in CH2Cl2 (10 mL)
added dropwise over 1 h. After an additional 2 h at
room temperature, the mixture was washed with wa-
ter (2 × 15 mL), 1 M HCl (10 mL), water, and brine,
and dried with MgSO4. The solvent was evaporated,
and the crude HA was crystallized or purified by ra-
dial chromatography.
1
cesses, THA deoxygenation (kR ) and amide thiona-
2
tion (kT2). Kinetic studies showed that deoxygenation
of EDG-substituted THA is also faster than thiona-
tion of the corresponding benzamide but both un-
desired processes (T2 and R2) have only a minuscule
impact on THA yield.
EXPERIMENTAL
General Remarks
N-Methylbutyrohydroxamic acid 1Ag. Yield
55%,
a
colorless oil; δH (Z/E isomer = 1:1.6):
0.96 (3H, m, CH CH2), 1.63 and 1.67 (2H, 2 × m,
3
NMR spectra were recorded in CDCl3 on Varian 200
and 500 MHz spectrometers with TMS as internal
standard. Coupling constants are reported in Hertz.
IR spectra were obtained using a Bruker IFS66 spec-
trometer in KBr. MS spectra were measured with an
AMD 604 mass spectrometer (AMD Intectra GmbH,
Germany).
CH CH3), 2.31 and 2.46 (2H, 2 × t, CH CH2CH3),
2
2
3.24 and 3.37 (3H, 2 × s, N-CH ), 7.56 (1H, br s, OH);
3
δC 13.8 and 14.1 (CH3CH2), 18.4 and 18.9 (CH3CH2),
33.5 and 34.4 (CH2CO), 36.3 (NCH3), 167.9 and
175.1 (C O); HRMS: calcd for C5H11NO2 117.07898;
found 117.07932.
THF was distilled from potassium/benzophen-
one ketyl. Commercial LR (Lancaster) was recrysta-
llized from chlorobenzene prior to use. Almost all
aroyl chlorides were commercial compounds (Lan-
caster) with the exceptions of 4-benzyloxybenzoyl
chloride that was prepared from the corresponding
acid and oxalyl dichloride. N-Isopropyl hydroxylam-
ine hydrogen oxalate was prepared from 2-methyl-
nitroethane by reduction using zinc powder. N-
Methyl-, N-tert-butyl- and N-benzylhydroxylamine
hydrochlorides were obtained from Aldrich. Hydrox-
amic acids 1Aa [14], 1Ab [15], 1Ac [16], 1Ad [17],
1Ae–1Af [18], 1Aj–1Ak [19], 1Al [20], 1Am [21], 1An
[22], 1Ba [23], 1Bb–1Bc [24], 1Bd [25], 1Be [26],
1Bf [8], 1Bh [8], 1Bk [7], 1Bo [8], and 1Bu [27]
are known compounds and were synthesized accord-
ing to general procedure described below. Thiohy-
droxamic acids 2Bh, 2Bi, 2Bm, 2Bo, and 2Bp were
prepared and characterized previously [11]. Benza-
mides 3Bh, 3Bo [28] and thioamides 4Bh [29], 4Bo
[30] are already known compounds. Benzamides
were made by benzoylation of isopropylamine (in
excess) and thioamides by thionation of the corre-
sponding amides with LR in THF at room tempera-
ture.
N-Isopropylbutyrohydroxamic acid 1Ah. Yield
84%, a colorless oil; δH (Z/E isomer = 2.6: 1): 0.88
(3H, t, CH CH2), 1.07 and 1.24 (6H, 2 × d, CH CH),
3
3
1.56 (2H, m, CH CH3), 2.22 and 2.38 (2H, 2 × t,
2
CH CH2CH3), 4.12 and 4.60 (1H, 2 × spt, N-CH), 8.80
2
(1H, br s, OH); δC 13.7 and 14.0 (CH3CH2), 18.3 and
18.5 (CH3CH2), 19.0 and 20.0 (CH3CH), 34.8 and 36.2
(CH2CO), 46.4 and 47.2 (NCHCH3), 174.4 and 177.7
(C O); HRMS: calcd for C7H15NO2 145.11028; found
145.11065.
N-tert-Butylbutyrohydroxamic acid 1Ai. Yield
48%, a colorless oil, δH (Z/E isomer = 1:1.1): 0.78 and
0.83 (3H, 2 × t, CH CH2), 1.00 and 1.27 (9H, 2 × s,
3
CH C), 1.45 and 1.55 (2H, m, CH CH3), 2.21 and 2.28
3
2
(2H, 2 × t, CH CH2CH3), 8.90 (1H, br s, OH); δC 13.7
2
and 13.9 (CH3CH2), 18.1 and 18.5 (CH3CH2), 26.4
and 27.6 (CCH3), 34.5 and 36.9 (CH2CO), 55.7 and
60.8 (NCCH3), 173.5 and 175.9 (C O); HRMS: calcd
for C8H17NO2 159.12593; found 159.12544.
N-Isopropyl-4-benzyloxybenzohydroxamic acid
1Bg. Yield 73%, m.p. 123–125◦C (benzene–
cyclohexane); νmax/cm−1 3113 (OH), 1607 and 1586
All reactions with LR were performed under ar-
gon in flame-dried flasks equipped with a stirring bar
and a rubber septum.
THAs were detected on developed chro-
matograms by spraying with 1% methanolic FeCl3
solution. THAs gave black spots as compared to
HAs, which showed a violet coloration.
(C O); δH 1.31 (6H, d, CHCH ), 4.27 (1H, spt,
3
CHCH3), 5.11 (2H, s, OCH Ph), 7.01 (2H, d, J = 9,
2
H-3/5), 7.42 (5H, m, OCH2Ph), 7.48 (2H, d, J = 9,
H-2/6), 8.40 (1H, br s, OH); δC 19.6 (CH3CH), 52.7
(CH3CH), 70.0 (OCH2Ph), 114.7 (C-3/5), 125.1 (C-1),
129.4 (C-2/6), 160.7 (C-4), 127.4, 128.2, and 128.6
(OCH2Ph), 167.1 (C O). Found: C, 71.82; H, 6.80;
Heteroatom Chemistry DOI 10.1002/hc

682 Przychodzen´
N, 4.64%. C17H19NO3 requires: C, 71.56; H, 6.71; N,
4.91%.
N-Isopropyl-3-methoxybenzohydroxamic
acid
1Bp. Yield 96%, m.p. 104–105◦C (benzene–
hexane); νmax/cm−1 3116 (OH), 1604 and 1574 (C O);
δH 1.31 (6H, d, CHCH ), 3.84 (3H, s, OCH ), 4.23
N-Isopropyl-4-tert-butylbenzohydroxamic
acid
3
3
1Bi. Yield 69%, m.p. 103–105◦C (ethanol–water);
νmax/cm−1 3159 (OH), 1609 and 1593 (C O); δH 1.31
(1H, spt, CHCH3), 7.02 (1H, dt, J = 8 and 1.5, H-4),
7.04 (1H, t, J = 1.5, H-2), 7.06 (1H, dt, J = 8 and 1.5,
H-6), 7.35 (1H, t, J = 8, H-5), 8.40 (1H, br s, OH); δC
19.7 (CH3CH), 52.5 (CH3CH), 55.4 (ArOCH3), 112.8
(C-2), 116.7 (C-4), 119.6 (C-6), 129.7 (C-5), 134.0
(C-1), 159.6 (C-3), 166.2 (C O); HRMS: calcd for
C11H15NO3 209.10519; found 209.10424.
(6H, d, CHCH ), 1.34 (9H, s, ArBut), 4.26 (1H, spt,
3
CHCH3), 7.45 (4H, s, ArH), 8.60 (1H, br s, OH); δC
19.7 (CH3CH), 31.1 (ArCCH3), 34.8 (ArCCH3), 52.4
(CH3CH), 125.5 (C-3/5), 127.3 (C-2/6), 129.9 (C-1),
154.0 (C-4), 166.9 (C O). Found: C, 71.06; H, 9.17;
N, 5.87%. C14H21NO2 requires: C, 71.46; H, 8.99; N,
5.95%.
N-Isopropyl-3-methylbenzohydroxamic acid 1Bq.
Yield 76%, m.p. 61–62◦C (benzene–hexane); νmax
/
N-Isopropyl-4-methylbenzohydroxamic acid 1Bj.
Yield 88%, m.p. 115◦C (benzene–hexane); νmax/cm−1
3187 (OH), 1612 and 1591 (C O); δH 1.28 (6H, d,
CHCH ), 2.39 (3H, s, ArCH ), 4.23 (1H, spt, CHCH3),
cm−1 3140 (OH), 1613 and 1577 (C O); δH 1.29
(6H, d, CHCH ), 2.38 (3H, s, ArCH ), 4.20 (1H, spt,
3
3
CHCH3), 7.23–7.33 (4H, m, Ar H), 8.45 (1H, br s,
OH); δC 20.3 (CH3CH), 22.0 (ArCH3), 53.0 (CH3CH),
125.0 (C-6), 128.7 (C-2), 129.0 (C-5), 132.1 (C-4),
133.4 (C-1), 139.2 (C-3), 167.3 (C O); HRMS: calcd
for C11H15NO2 193.11028; found 193.11116.
3
3
7.23 (2H, d, J = 9, H-3/5), 7.39 (2H, d, J = 9, H-2/6),
8.55 (1H, br s, OH); δC 19.6 (CH3CH), 21.4 (ArCH3),
52.5 (CH3CH), 127.5 (C-2/6), 129.2 (C-3/5), 130.0 (C-
1), 141.0 (C-4), 167.0 (C O). Found: C, 68.61; H, 7.96;
N, 7.10%. C11H15NO2 requires: C, 68.37; H, 7.82; N,
7.25%.
N-Isopropyl-3-nitrobenzohydroxamic acid 1Br.
Yield 80%, m.p. 96◦C (benzene–hexane); νmax/cm−1
3171 (OH), 1602 and 1579 (C O), 1536 and 1346
N-Isopropyl-4-fluorobenzohydroxamic acid 1Bl.
Yield 82%, m.p. 97◦C (benzene–hexane); νmax/cm−1
3200 (OH), 1604 and 1584 (C O); δH 1.27 (6H, d,
(NO2); δH 1.34 (6H, d, CHCH ), 4.22 (1H, spt,
3
CHCH3), 7.65 (1H, t, J = 8, H-5), 7.86 (1H, dt, J = 8
and 1.5, H-6), 8.26 (1H, br s, OH), 8.34 (1H, dt,
J = 8 and 1.5, H-4), 8.38 (1H, t, J = 1.5, H-2); δC
20.3 (CH3CH), 52.8 (CH3CH), 123.4 (C-2), 126.0
(C-4), 130.5 (C-5), 134.1 (C-6), 135.3 (C-1), 148.3
(C-3), 166.0 (C O); HRMS: calcd for C10H12N2O4
224.07971; found 224.07984.
CHCH ), 4.22 (1H, spt, CHCH3), 7.07 (2H, dd, J = 8.8
3
and 8.9, H-3/5), 7.48 (2H, dd, J = 8.8 and 5.3, H-2/6),
8.62 (1H, br s, OH); δC 19.5 (CH3CH), 52.5 (CH3CH),
115.6 (d, J = 22, C-3/5), 129.8 (d, J = 9, C-2/6), 129.2
(C-1), 163.9 (d, J = 251, C-4), 166.2 (C O). Found:
C, 61.25; H, 6.25; N, 6.94%. C10H12NO2F requires: C,
60.90; H, 6.13; N, 7.10%.
N-Isopropyl-3,5-dinitrobenzohydroxamic
acid
N-Isopropyl-4-chlorobenzohydroxamic acid 1Bm.
1Bs. Yield 45%, m.p. 157–159◦C (ethyl acetate);
Yield 73%, m.p. 123–124◦C (benzene–hexane); νmax
/
νmax/cm−1 3119 (OH), 1614 (C O), 1543 and 1343
cm−1 3152 (OH), 1608 and 1592 (C O); δH 1.31 (6H,
(NO2); δH 1.40 (6H, d, CHCH ), 4.35 (1H, spt,
3
d, CHCH ), 4.19 (1H, spt, CHCH3), 7.35–7.50 (4H,
3
CHCH3), 8.75 (2H, d, J = 2, H-2/6), 9.16 (1H, t,
J = 2, H-4); δC (CDCl3–MeOD 2:1) 18.3 (CH3CH),
48.9 (CH3CH), 119.9 (C-4), 128.8 (C-2/6), 138.6
(C-1), 148.3 (C-3/5), 165.0 (C O); HRMS: calcd for
C10H11N3O6 269.06479; found 269.06394.
m, ArH), 8.50 (1H, br s, OH); δC 19.5 (CH3CH),
52.1 (CH3CH), 128.7 and 128.9 (CAr-H), 131.4 (C-1),
136.7 (C-4), 165.8 (C O). Found: C, 56.23; H, 5.63;
N, 6.31%. C10H12NO2Cl requires: C, 56.21; H, 5.66; N,
6.56%.
N-Isopropyl-4-cyanobenzohydroxamic acid 1Bn.
Yield 61%, m.p. 124–126◦C (benzene–hexane);
νmax/cm−1 3207 (OH), 2233 (CN), 1613 and 1600
N-Isopropyl-2-thienohydroxamic acid 1Bt. Yield
90%, m.p. 103–105◦C (chloroform–hexane); δH 1.31
(6H, d, CHCH ), 4.73 (1H, spt, CHCH3), 7.08 (1H, dd,
3
(C O); δH 1.32 (6H, d, CHCH ), 4.12 (1H, spt,
J = 3.5 and 5, H-4), 7.52 (1H, dd, J = 5 and 1, H-5),
7.68 (1H, dd, J = 3.5 and 1, H-3), 7.69 (1H, br s, OH);
δC 19.3 (CH3CH), 50.9 (CH3CH), 126.9 (C-4), 130.9
(C-5), 132.1 (C-3), 144.0 (C-2), 169.5 (C O). Found:
C, 51.98; H, 5.84; N, 7.31%. C8H11NO2S requires: C,
51.87; H, 5.99; N, 7.56%.
3
CHCH3), 7.62 (2H, d, J = 9, H-2/6), 7.78 (2H, d, J = 9,
H-3/5); δC 19.4 (CH3CH), 52.2 (CH3CH), 113.6 (C-4),
117.3 (CN), 128.2 (C-2/6), 132.3 (C-3/5), 137.6 (C-1),
164.6 (C O). Found: C, 64.81; H, 5.91; N, 13.40%.
C11H12N2O2 requires: C, 64.69; H, 5.92; N, 13.40%.
Heteroatom Chemistry DOI 10.1002/hc

Lawesson’s Reagent for Direct Thionation of Hydroxamic Acids 683
N-Isopropyl-4-methoxybenzamide
3Bh. Yield
and the resulting oil was evaporated three times with
CDCl3 before NMR analysis.
76%, m.p. 119–120◦C [28] 120◦C); δH 1.25 (6H, d,
CHCH ), 3.83 (3H, s, OCH ), 4.27 (1H, spt, CHCH3),
3
3
6.00 (1H, br s, NH), 6.89 (2H, d, J = 9, H-3/5),
7.73 (2H, d, J = 9, H-2/6); δC 22.2 (CH3CH), 41.1
(CH3CH), 54.7 (OCH3), 112.9 (C-3/5), 126.5 (C-1),
127.9 (C-2/6), 161.2 (C-4), 165.5 (C O).
Kinetic Studies. Equimolar amounts of two dif-
ferent substituted THAs 2B or benzamides 3B or a
mixture of THA 2B and benzamide 3B with the same
substituent (0.2 mmol) in 2 mL of THF were treated
with 0.05 mmol of LR at 25◦C, and the reaction mix-
tures were quenched with several drops of water af-
N-Isopropyl-4-nitrobenzamide 3Bo. Yield 63%,
m.p. 157–158◦C [28] 157–158◦C); δH 1.30 (6H, d,
1
CHCH ), 4.31 (1H, spt, CHCH3), 6.00 (1H, br s, NH),
ter 5 min. Relative rates were determined from H
3
7.92 (2H, d, J = 9, H-2/6), 8.28 (2H, d, J = 9, H-3/5);
δC 23.2 (CH3CH), 43.0 (CH3CH), 124.6 (C-3/5), 128.6
(C-2/6), 141.1 (C-1), 149.9 (C-4), 165.2 (C O).
NMR spectra of reaction mixtures (after removal of
solvents) on the basis of the thioamides 4B yield ra-
tio and/or unreacted starting materials yield ratios,
respectively.
General Procedure for Synthesis of HAs
O-Methyl Esters 8Bh and 8Bo
Reaction of Benzohydroxamic Acid O-Methyl Es-
ters 8Bh and 8Bo with LR. Equimolar amounts of
O-methyl esters 8Bh and 8Bo (0.2 mmol) in 2 mL
of THF were treated with 0.05 mmol of LR at 25◦C,
and the reaction mixtures were quenched with sev-
eral drops of water after 5 mins. After removal of
volatiles, 1H NMR spectrum analysis showed that the
residue consisted nearly equal amounts of the unre-
acted starting materials 8Bh and 8Bo.
A suspension of N-isopropyl 4-substituted benzohy-
droxamic acid 1Bh or 1Bo (1 mmol), potassium car-
bonate (0.276 g, 2 mmol), tetrabutylammonium bro-
mide (0.005 g), and methyl iodide (0.19 mL, 3 mmol)
was stirred at room temperature. After 16 h, 10 mL of
water was added and the mixture was extracted three
times with methylene dichloride. The combined or-
ganic layers were washed successively with water,
saturated NaHCO3 solution, and brine. After drying
with MgSO4 the solvent was removed to yield of chro-
matographically pure methyl ester 8B as colorless
oil.
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3
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3
NOCH3), 4.59 (1H, spt, CHCH3), 7.78 (2H, d, J = 8.8,
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