Base catalysed rearrangement of N-alkyl-O-acyl hydroxamic acids: Synthesis of 2-acyloxyamides

Article abstract of DOI:10.1039/a909903d

Activated N-alkyl-O-acyl hydroxamic acid derivatives 21a-t undergo thermal and base catalysed rearrangement to give 2-acyloxyamides 22a-t in good to excellent yields (50-100%). A range of inorganic and organic bases were screened for their efficiency in mediating the rearrangement 21 to 22, however, simple organic bases such as Et₃N were found to be the most efficient. Both aromatic and aliphatic derived O-acyl groups were tolerated in the reaction. The electronic nature of the O-acyl group was found to effect the rate of the rearrangement with electron withdrawing groups (211 and 21o) increasing the observed rate and electron donating groups (21m and 21n) decreasing the observed rate. Cross-over experiments with 21a and 21h indicated a mechanism involving the intermediacy of free acyloxy anions. The requirement of a readily enolisable proton adjacent to the carbonyl group of the amide was found to be neccessary for the rearrangement as 21r and 21t both failed to rearrange under the reaction conditions investigated.

Full text of DOI:10.1039/a909903d

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Base catalysed rearrangement of N-alkyl-O-acyl hydroxamic
acids: synthesis of 2-acyloxyamides
Andrew J. Clark,*a Yassair S. S. Al-Faiyz,a Michael J. Broadhurst,b Divya Patela and
Joanne L. Peacocka
1
a Chemistry Department, University of Warwick, Coventry, UK CV4 7AL
b Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, UK AL7 3AY
Received (in Cambridge, UK) 16th December 1999, Accepted 27th January 2000
Published on the Web 10th March 2000
Activated N-alkyl-O-acyl hydroxamic acid derivatives 21a–t undergo thermal and base catalysed rearrangement to
give 2-acyloxyamides 22a–t in good to excellent yields (50–100%). A range of inorganic and organic bases were
screened for their efficiency in mediating the rearrangement 21 to 22, however, simple organic bases such as Et3N
were found to be the most efficient. Both aromatic and aliphatic derived O-acyl groups were tolerated in the reaction.
The electronic nature of the O-acyl group was found to effect the rate of the rearrangement with electron with-
drawing groups (21l and 21o) increasing the observed rate and electron donating groups (21m and 21n) decreasing the
observed rate. Cross-over experiments with 21a and 21h indicated a mechanism involving the intermediacy of free
acyloxy anions. The requirement of a readily enolisable proton adjacent to the carbonyl group of the amide was
found to be neccessary for the rearrangement as 21r and 21t both failed to rearrange under the reaction conditions
investigated.
transformation is similar to the reported thermal 1,3 rearrange-
Introduction
ment of O-benzoyl-N-(4-tolylsulfonyl)-N-arylhydroxylamine 7
While hydroxamic acids and their derivatives were first studied
which takes place on heating to 120 ЊC.5 On the basis of 18O
over 100 years ago very few investigations into their chemistry
tracer and kinetic experiments as well as examining substituent
have been reported.1 This is suprising in light of the important
effects Oae and Sakurai5 concluded that the mechanism of
biological properties of hydroxamic acid derivatives.1 Even
rearrangement of 7 was an intramolecular process, however
the degree of polarisation in the transition state was dependant
upon the overall substitution pattern of the compounds
(Scheme 2). During the course of our work another related
fewer synthetic studies have been reported on the reactions of
O-acyl hydroxamic acids 1. N-Alkyl-O-benzoyl hydroxamic
acid derivatives 1 have recently been used as precursors to
amidyl radicals 2 by both Zard and co-workers2 and ourselves.3
Amidyl radicals 2 could be conveniently generated from
these precursors via homolytic cleavage of the N–O bond using
either Bu3SnH–AIBN2,3a–c or CuII(OTf)2–DBN.†3d In this way
it was possible to mediate a range of 4-exo cyclisations,3a 5-exo
cyclisations,2,3b,c and tandem cyclisations.2,3d During these
studies we noticed that some substrates produced varying
amounts of 2-benzoyloxy amides as by-products.3a,4 For
example, reaction of the hydroxamic acid derivative 3a with
Scheme 2 Reagents and conditions: heat 120 ЊC.
Bu3SnH–AIBN in refluxing toluene furnished not only the
expected cyclisation 4a and reduction 5a products but also
the 2-benzoyloxyamide 6a in 20% yield (Scheme 1).2a This
rearrangement was reported by Endo et al.6 who described the
KHMDS mediated anionic rearrangement of hydroxamic acid
derivative 9 which gave 10 in 67% yield. The mechanism of
the reaction was proposed to take place via a [3,3]-sigma-
tropic rearrangement of the di-enolate (Scheme 3). In light of
Scheme 3 Reagents and conditions: i, KHMDS, Ϫ78 ЊC, THF; ii,
CH2N2.
these previous reports we hypothesised that the rearrangement
observed in the reaction 3a→6a might be occurring via a
[3,3]-sigmatropic rearrangement of the enol form 11 of
the substrate 3a (Scheme 4) and we thus examined whether this
reaction could be optimised to produce an efficient synthesis
Scheme 1 Reagents and conditions: i, Bu3SnH, AlBN, toluene, 110 ЊC.
† DBN = 1,5-diazabicyclo[4.3.0]non-5-ene.
DOI: 10.1039/a909903d
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127
This journal is © The Royal Society of Chemistry 2000
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Scheme 4
Scheme 7 Reagents and conditions: i, 140 ЊC, sealed tube, toluene,
1–4 days or see Table 1.
of 2-benzoyloxyamide derivatives from N-alkyl-O-benzoyl
hydroxamic acid derivatives 1.
proceeding to give 6b, albeit rather slowly (10% conversion).
Increasing the temperature to 140 ЊC (using a sealed tube for
24 h) resulted in the completion of the reaction to give 6b
in 95% yield after chromatography. Utilising this approach it
was also possible to obtain good yields of the N-butyl (6a
85%) and N-benzyl (6c 80%) analogues after 3 days and 4 days
respectively. Having established that the thermal rearrangement
of substrates 3a–c was possible (presumably by reaction via
their enol form 11) we next investigated whether the addition
of a base would help facilitate the rearrangement at a more
convenient temperature. Hence, we screened the substrates 12
and 3a–b using a variety of bases and under a variety of con-
ditions of temperature and solvent (Table 1). Initial attempts at
mediating the rearrangement of 12 with triethylamine at 40 ЊC
in CH2Cl2 required extended reaction periods and furnished 16
in only 20% yield after 2 days (Scheme 8). However this could
Synthesis of N-alkyl-O-benzoyl hydroxamic acids
We initially prepared a range of activated N-alkyl-O-benzoyl-4-
phenylbut-3-enamide derivatives 3a–c as well as the related N-
methyl-O-benzoylphenylacetamide 12 in order to determine if
the rearrangement could be mediated thermally. The precursors
were prepared by one of two methods. The N-butyl precursor
3a was prepared by a one-pot strategy in which butylamine
was reacted with benzoyl peroxide in the presence of sodium
carbonate followed by the addition of styrylacetyl chloride 13
according to the procedure of Psiorz and Zinner7 (Scheme 5,
Scheme 8 Reagents and conditions: i, Et3N, see Table 1.
be improved by heating 12 with a catalytic amount of Et3N
at 110 ЊC in toluene (65%). Attempts to mediate the reaction
using inorganic bases such as LiHMDS, NaHMDS and
KHMDS in a range of solvents failed. This is in line with the
observation of Endo et al. who reported the failure of the
related N-methyl substituted substrate 17 to undergo rearrange-
ment with KHMDS at a range of temperatures (Scheme 9).6
Scheme 5 Reagents: i, Bz2O2, Et2O, Na2CO3; ii, 13, CH2Cl2.
see method 1). While this approach was quick (3 h at room
temperature) a significant amount of the amide 14 (30%)
was also formed and the crude product was difficult to purify.
As a consequence we prepared the other precursors 3b,c and
12 via a two step strategy from the corresponding hydroxyl-
amine hydrochloride salts. Hence, initial acylation with 13 or
phenylacetyl chloride in the presence of Et3N furnished N-
alkylhydroxamic acids 15b,c which were then O-benzoylated
in a subsequent acylation step (benzoyl chloride, Et3N at 0 ЊC)
(Scheme 6). This two step procedure produced the desired
Scheme 9 Reagents and conditions: i, 2 eq. KHMDS, Ϫ78 ЊC, THF;
ii, CH2N2.
They explained their results by postulating that the potassium
enolate could not adopt the correct conformation for reaction
via a cyclic transition state, primarily due to steric factors.
Having shown that the organic base Et3N was sufficient to
facilitate the rearrangement of 12 we next examined a range
of other organic bases. Hence, reaction of 3a with either
Et3N or the more hindered Hunig’s base (i-Pr2EtN) furnished
the desired rearranged compound 6a in 63 and 48% yield
respectively. In this case the use of the more hindered base
slowed down the rate of the reaction. However, the use of 1
equivalent of the strong hindered phosphazene base 18 caused
a rapid increase in the rate of the reaction (complete in 10
minutes at 0 ЊC) however the yield decreased considerably
due to the formation of a second rearranged product 19 in
16% yield. The formation of this second product could be
Scheme 6 Reagents: i, R1NHOHؒHCl, Et3N, CH2Cl2; ii, PhCOCl,
Et3N, CH2Cl2.
compounds in good overall yield (combined yield of both steps
produced 3b in 51%, 3c in 90%, and 12 in 69% yield).
Thermal and base rearrangement of hydroxamic acid derivatives
3a–c and 12
We next attempted the thermal rearrangement of 3a–c to
give 2-benzoyloxyamides 6a–c (Scheme 7). Initial reactions
consisted of heating the N-methyl precursor 3b at 110 ЊC
in refluxing toluene for 24 h. After removal of the solvent,
1
250 MHz H NMR analysis indicated that the reaction was
1118
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127

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Table 1 Screening of bases in rearrangement reactions of 3a–b and 12
Substrate
Basea
Solvent
Temp/ЊC
Time/h
Yield (%)
12
12
12
12
12
12
3a
3a
3a
3a
3b
3b
3b
3b
Et3N
CH2Cl2
Toluene
CH2Cl2
THF
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
40
110
40
40
40
40
40
40
0
48
12
72
72
24
24
4
12
0.2
24
24
4
20
65
0
0
0
Et3Nb
NaHMDS
NaHMDS
KHMDS
LiHMDS
Et3N
0
63
48
19c
22d
53
56
85
58
iPr2EtN
18
18b
0
Et3N
Et3N
20
40
110
110
Et3N
0.5
0.5
Et3Nb
a 1 eq. of base. b 0.1 eq. of base. c 16% of compound 19 was also detected. d No 19 was detected.
suppressed if only a catalytic amount of 18 was used as base
but the overall yield still remained low. The most convenient
method for facilitating the rearrangements in good yield was to
use either a stoichiometric amount of Et3N at 40 ЊC in CH2Cl2
or a catalytic amount (10 mol%) of Et3N in refluxing toluene
Table 2 Synthesis of hydroxamic acids 20a–h
(110 ЊC).
Substrate
R1
Yield (%)
Effect of N-acyl and O-acyl substituents
20a
20b
20c
20d
20e
20f
20g
20h
4-MeC6H4
4-MeOC6H4
4-ClC6H4
88
86
71
80
55
98
87
96
The rearrangement described furnishes secondary 2-benzoyl-
oxyamide derivatives 6a–c and 16 which after deprotection of
the benzoyl group would lead to secondary 2-hydroxyamides.
In particular since 2-hydroxyamides are useful intermediates
for the preparation of ethanolamines,8 oxoindoles9 and oxazol-
idinediones10 new methods for their synthesis are of great
interest. Few methods for the synthesis of 2-hydroxyamides
are currently available. Most methods include oxidation of
tertiary amide enolates with various reagents (MoO5-
peroxide,11 sulfonyloxaziridines,12 and dimethyldioxirane13),
and reaction of α-hydroxyesters with amines.10 While the
former approach is useful for the synthesis of tertiary amides
it is less applicable to primary and secondary amides while
the latter approach often leads to low reaction yields. There
have been very few methods for the synthesis of secondary
2-hydroxyamides directly, the most successful include a Lewis
acid catalysed coupling between isocyanides and aldehydes14
and the base promoted reaction of O-sulfonated hydroxamic
acid derivatives in the presence of water.15 Consequently
we next investigated the scope and limitation of our rearrange-
ment to furnish 2-hydroxyamide derivatives by examining the
reaction of a range of different substrates. In particular we
were interested in determining the effect of different O-acyl
substituents upon the rearrangement as these would ultimately
end up as “protecting groups” which would liberate 2-hydroxy-
amides after deprotection. Hence a range of compounds were
prepared by initial acylation of N-methylhydroxylamine hydro-
chloride to produce 20a–h (Table 2) followed by O-acylation
to give 21a–u (Table 3) using the same procedure as shown
2-Thienyl
CH᎐CH2
᎐
(CH2)3Me
1-Naphthyl
2-Naphthyloxy
in Scheme 6, method 2. Rearrangement was then carried out
using Et3N in either refluxing toluene or CH2Cl2 to give
the rearranged compounds 22a–u (Table 4). While benzoyl
esters have been used as protecting groups for the alcohol
functionality the acetate protecting group is one of the most
common ester protecting groups16 and we were thus gratified to
find that the replacement of the O-benzoyl group with O-acetyl
or O-pivaloyl was possible furnishing 2-acetoxyamide (22a
and 22i) and 2-pivaloyloxyamide (22b and 22j) derivatives
respectively. Deprotection of 22a using K2CO3 in MeOH17
was facile liberating the known 2-hydroxyacetamide18 23
in 52% yield (Scheme 10). Interestingly replacement of the
Scheme 10 Reagents: i, K2CO3, MeOH, H2O.
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127
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O-benzoyloxy group in 12 with the electron withdrawing O-4-
nitrobenzoyloxy group 21c markedly increased the rate of the
rearrangement. This electronic effect was found to be general
with electron withdrawing O-aryloxy substituents increasing
the rate of the rearrangement (e.g. 21l and 21o) and electron
releasing O-aryloxy subsituents significantly retarding the rate
of the reaction (e.g. 21n and 21m). Although we did not under-
take a detailed kinetic study of these electronic effects it was
clearly observable in the series of rearrangements of the 2-
thienyl substituted hydroxamic derivatives 21k–21o. These
results indicated that there must be a significant build up
of negative charge on the oxygen of the N–O bond in the
transition state for the reaction suggesting that the rearrange-
ment is not a truly concerted process but either an intra-
molecular rearrangment in which the N–O bond is partially
broken before formation of the C–O bond or an ionic inter-
molecular reaction proceeding via a free acyloxy anion. Further
evidence for the latter mechanism was obtained from a cross-
over experiment, hence when a 1:1 mixture of 21a and 21h
was reacted with a stoichiometric amount of Et3N at 110 ЊC
in toluene for 5 days a 1:1:1:1 mixture of the expected
rearranged 22a, 22h and cross-over products 22f, 22v were
obtained respectively (as determined by comparison with
authentic samples by GC) (Scheme 11). That this cross-over
was not occurring by some other process (such as base catalysed
transesterification of the products 22a and 22h after rearrange-
ment) was discounted by subjecting a 1:1 mixture of the
Table 3 Synthesis of O-acyl hydroxamic acid derivatives 21a–t
Substrate
R1
R2
Yield (%)
21a
21b
21c
21d
21e
21f
21g
21h
21i
Ph
Ph
Ph
Ph
Me
t-Bu
4-NO2C6H4
CCl3
Me
Me
Me
Et
Me
80
72
52
0a
89
80
74
90
75
29
82
88
82
88
94
66
70
77
77
82
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
CH᎐CHPh
CH᎐CHPh
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
᎐
᎐
21j
t-Bu
Ph
21k
21l
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Me
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
21m
21n
21o
21p
21q
21r
21s
21t
CH᎐CH2
(CH2)3Me
1-Naphthyl
2-Naphthyloxy
᎐
a 10% of the rearranged compound 22d was isolated.
Scheme 11 Reagents and conditions: i, Et3N, toluene, 110 ЊC, 144 h.
Table 4 Rearrangement of O-acyl hydroxamic acid derivatives 21a–t
Substrate
R1
R2
Methoda
Time/h
Yield (%)
21a
21b
21c
21d
21e
21f
21g
21h
21i
Ph
Ph
Ph
Ph
Me
t-Bu
4-NO2C6H4
CCl3
Me
Me
Me
Et
Me
A
A
A
—
B
B
B
B
A
C
D
E
E
E
E
E
D
F
A
A
24
24
12
—
144
120
21
120
24
2
24
2
72
24
4
75
65
100
b
—
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
CH᎐CHPh
CH᎐CHPh
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
94
74
100
82
99
82
100
100
0c
100
100
90
᎐
᎐
21j
t-Bu
Ph
21k
21l
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Me
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
21m
21n
21o
21p
21q
21r
21s
21t
1
CH᎐CH2
(CH2)3Me
1-Naphthyl
2-Naphthyloxy
24
72
12
48
50
0
86
0
᎐
a Method A = 0.2 eq. Et3N, toluene, 110 ЊC; Method B = 1.0 eq. Et3N, toluene, 63 ЊC; Method C = 1.0 eq. Et3N, CH2Cl2, rt; Method D = 0.6 eq.
Et3N, CH2Cl2, rt; Method E = 0.2 eq. Et3N, CH2Cl2, 40 ЊC; Method F = 1.0 eq., Et3N, toluene, sealed tube 140 ЊC. b See Table 3. c 95% when
conducted at 110 ЊC with 0.1 eq. Et3N.
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rearranged compounds 22a and 22h to the same reaction con-
ditions (Et3N for 5 days at 110 ЊC). Under these conditions no
scrambling of the acyl groups to furnish cross-over products
22f and 22v occurred (as determined by GC). Recently,
Hoffmann and co-workers described the base (Et3N) mediated
reactions of structurally related O-sulfonated hydroxamic
acid derivatives 24 in the presence of nucleophiles.19 With
strong nucleophiles, products 25 were formed while with weak
nucleophiles products analogous to those observed in our
chemistry (e.g. 26) were obtained (Scheme 12). They explained
substituents occurs during the course of the reaction indicates a
free acyloxy anion is likely to be involved for the derivatives 21a
and 21h. The failure of strong inorganic bases to mediate the
transformation, however, is puzzling and currently unexplained.
The requirement of a readily enolisable proton adjacent to
the carbonyl of the amide remains a limitation, however, a wide
array of potentially useful products can be prepared by this
methodology.
Scheme 12 Reagents: i, Et3N, weak nucleophile; ii, Et3N, strong
nucleophile.
the formation of products 25 and 26 by postulating an initial
deprotonation followed by α-lactam 27 formation and ring
opening to give 28 followed by trapping with weak nucleo-
philes (Scheme 13). With strong nucleophiles, trapping of
Experimental
Melting points were recorded on a Stuart Scientific SMP1
melting point apparatus and are uncorrected. Accurate mass
determinations were performed either on a Kratos MS80
at the University of Warwick or on a LC-MS SSS at Knoll
Pharmaceuticals. Microanalyses were recorded on a Leeman
Labs Inc. CE440 Elemental Analyser. Infra-red spectra were
recorded in a solution cell, as Nujol mulls or neat, as stated
in the text, on a Perkin-Elmer 1720X Fourier transform
1
spectrometer. H NMR spectra were recorded at either 250,
300, or 400 MHz on a Bruker ACF250, Bruker DPS300
or Bruker ACP400 instrument respectively. Chemical shifts
are quoted in parts per million (ppm) and referenced to the
appropriate solvent peak. Coupling constants (J) are given in
hertz (Hz). 13C NMR spectra were recorded at 62.9, 75, and
100.6 MHz. GC were run on a Shimadzu GC-14A using a BP10
column with a column temperature of 190 ЊC and injection
temperature of 225 ЊC. Chemicals used in the experimental
were obtained from either Lancaster or Sigma-Aldrich at the
highest grade available. All solvents were purchased from
Fisons Scientific Equipment at SLR grade and purified,
when needed by literature methods. Flash chromatography was
carried out on silica gel (Merck Kieselgel 60F254, 230–400
mesh). TLC was carried out using aluminium backed plates
precoated with silica (0.2 mm, 60F254).
Scheme 13 Reagents: i, strong nucleophile; ii, weak nucleophile.
the C-2 of the intermediate α-lactam 27 was implicated to
explain the formation of the products 25.20 They too observed
that the electronic nature of the O-sulfonyl substituent affected
the rate of reaction. Groups that were better able to stabilise
a negative charge (i.e. better leaving groups) led to increased
rates of product formation.18 They also reported the same
effect for substitution at the aryl group in 24.18 This effect was
also paralleled in our chemistry with the chloro-substituted
compound 21g reacting substantially faster than the methoxy-
substituted precursor 21e.
Having established that the most efficient O-acyloxy sub-
stituent in terms of rate of migration was the 4-nitroaryloxy
substituent we next varied the nature of the N-acyl group from
activating 21q and 21s (i.e. groups which facilitate enolisation)
to deactivating 21r and 21t. While it was possible to mediate the
migrations of both 21q and 21s it was not possible to facilitate
the rearrangement of the two unactivated precursors even
under harsh reaction conditions. This type of limitation was
also reported in the base mediated reactions of O-sulfonyl
hydroxamic acid derivatives.19 In these reactions the relative
difficulty of the substrate to undergo facile enolisation is the
most likely cause for this reactivity difference. However, the
failure of the diphenyl analogue 21u to undergo rearrangement
(7 days, Et3N, 110 ЊC) is not consistent with proton removal by
base being the rate determining step indicating that the actual
mechanism is likely to be substrate dependant. It is of note
that the related O-sulfonylated derivative 29 was also reported
not to undergo base mediated reaction as was the related methyl
substituted precursor 30.19b
Synthesis of N-hydroxy-N-alkylacetamides. General procedure
Method 1: To a solution of N-alkylhydroxylamine hydro-
chloride (15 mmol) in dichloromethane (100 cm3) at 0 ЊC was
added triethylamine (30 mmol). The mixture was stirred for 10
min and a solution of the appropriate acid chloride (15 mmol)
in dichloromethane (75 cm3) was added dropwise over 45–60
minutes. The mixture was warmed to room temperature and
stirred for 1 hour. The mixture was washed with dilute HCl (50
cm3) and brine (50 cm3) and dried over MgSO4. Evaporation of
the solvent gave the crude products which were purified by
chromatography (petroleum ether–ethyl acetate 1:2).
N-Hydroxy-N-methylphenylacetamide. Yield 91%; white
crystalline solid, mp 55–56 ЊC (from hexane); mixture of two
rotomers (Found: C, 65.45; H, 6.6. C9H11NO2 requires C, 65.4;
H, 6.8%); νmax(Nujol)/cmϪ1 3158, 3018, 1628, 1520, 1490, and
1216; δH(300 MHz; CDCl3) 3.12 (3H, s, NMe, major rotomer),
3.37 (3H, s, NMe, minor rotomer), 3.70 (2H, s, CH2, minor
rotomer), 3.60 (2H, s, CH2, major rotomer), 7.10–7.30 (5H, m,
Ph), and 9.26 (1H, br s, OH); δC(75.5 MHz; CDCl3) for both
rotomers 36.4 (q), 37.2 (q), 39.0 (t), 39.4 (t), 127.1 (d), 127.5 (d),
In conclusion we have reported the efficient base catalysed
rearrangement of O-acyl hydroxamic acid derivatives to 2-
acyloxyamides. While the mechanism for the transformation
still remains unclear, the observation that cross-over of acyloxy
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128.9 (d), 129.0 (d), 129.4 (d), 129.8 (d), 133.8 (s), 135.5 (s),
166.0 (s), and 172.8 (s); m/z EI 165.0793 (Mϩ, C9H11NO2
requires 165.0790), 165 (Mϩ, 6%), 148 (3), 119 (9), 91 (68), and
83 (100).
C, 48.9; H, 5.25; N, 8.05. C17H17NO2 requires C, 49.1; H, 5.3; N,
8.2%); νmax(Nujol)/cmϪ1 3130, 3015, 1626, and 1209; δH(250
MHz; CDCl3) 3.15 (2H, br s, CH2), 3.93 (3H, br s, NMe), 6.85–
6.92 (2H, m, Ar), and 7.16 (1H, br d, J 4.9), OH not observed;
δC(75.5 MHz; CDCl3) 33.5 (t), 36.5 (q), 125.3 (d), 127.2 (d),
127.3 (d), 136.5 (s), and 171.6 (s); m/z CI 171.0345 (Mϩ,
C7H9NO2S requires 171.0354), 171 (Mϩ, 43%), 156 (35), 124
(26), 111 (42), and 97 (100).
N-Hydroxy-N-methyl-4-phenylbut-3-enamide 15b. Yield 95%;
white crystalline solid, mp 64–65 ЊC (from hexane) (Found:
C, 68.8; H, 6.8; N, 7.5. C11H13NO2 requires C, 69.1; H, 6.85; N,
7.3%); νmax(Nujol)/cmϪ1 3125, 1612, 1520, and 1476; δH(300
MHz; CDCl3) 3.29 (3H, s, NMe), 3.40 (2H, d, J 8.0, CH2),
N-Hydroxy-N-methylbut-3-enamide 20e. Yield 55%; white
crystalline solid, mp 168–170 ЊC (from hexane); mixture of
two rotomers; νmax(Nujol)/cmϪ1 3500–2500, 2922, 1628, and
1473; δH(250 MHz; CDCl3) 3.05–3.23 (5H, br m, CH2, NMe),
6.22–6.50 (2H, m, CH᎐CH), and 7.20–7.40 (5H, m, Ar), OH
᎐
not observed; m/z CI 192.1029 (MHϩ, C11H14NO2 requires
192.1023), 192 (MHϩ, 43%), 176 (100), 162 (7), 117 (22), and
91 (9).
5.08–5.14 (2H, br m, CH᎐CH ), 5.78–5.89 (1H, br m,
᎐
2
CH᎐CH ), and 7.51 (1H, br s, OH); m/z EI 115.0640 (Mϩ,
᎐
2
C5H9NO2 requires 115.0633), 115 (Mϩ, 22%), 101 (60), 85 (91),
69 (90), and 58 (100).
N-Hydroxy-N-benzyl-4-phenylbut-3-enamide 15c. Yield 95%;
white crystalline solid, mp 106–108 ЊC (from hexane); mixture
of two rotomers (Found: C, 76.2; H, 6.4; N, 5.3. C17H17NO2
requires C, 76.4; H, 6.4; N, 5.2%); νmax(Nujol)/cmϪ1 3130, 2922,
1607, and 1492; δH(250 MHz; CDCl3) 3.27–3.49 (2H, br m,
CH2, both rotomers), 4.85 (2H, br s, CH2Ph both rotomers),
N-Hydroxy-N-methylhexanamide 20f. Yield 98%; yellow oil;
νmax(neat)/cmϪ1 3172, 2922, and 1622; δH(400 MHz; CDCl3)
0.73 (3H, br t, J 7.0, Me), 1.20–1.24 (4H, br m, 2 × CH2), 1.55
(2H, br m, CH2), 2.24 (2H, br m, COCH2), 3.10 (3H, s, NMe),
and 3.22 (1H, br s, OH); δC(100.6 MHz; CDCl3) 13.7 (q), 22.2
(t), 24.4 (t), 31.2 (t), 32.4 (t), 35.1 (q), and 174.9 (s); m/z CI
145.1104 (Mϩ, C7H15NO2 requires 145.1103), 146 (MHϩ, 5%),
130 (100), 128 (2), and 117 (3).
6.16–6.50 (2H, br m, CH᎐CH both rotomers), and 7.17–7.37
᎐
(10H, br m, Ar both rotomers), OH not observed; m/z CI
268.1338 (MHϩ, C17H18NO2 requires 268.1338), 267 (Mϩ, 12%),
251 (11), 144 (56), 117 (100), and 91 (91).
N-Hydroxy-N-methyl-2-(4-methylphenyl)acetamide
20a.
Yield 88%; white crystalline solid, mp 40–41 ЊC (from hexane);
mixture of two rotomers. (Found: C, 66.7; H, 7.3; N, 7.7.
C10H13NO2 requires C, 67.0; H, 7.3; N, 7.8%); νmax(Nujol)/cmϪ1
3150, 3012, 1624, 1514, and 1422; δH(300 MHz; CDCl3) 2.31
(3H, s, CMe, major and minor rotomer), 3.18 (3H, s, NMe,
major rotomer), 3.32 (3H, s, NMe, minor rotomer), 3.65 (2H,
s, CH2, minor rotomer), 3.71 (2H, s, CH2, major rotomer), 7.12
(4H, m, Ph), and 9.20 (1H, br s, OH); δC(75.5 MHz; CDCl3) for
both rotomers 21.4 (2 × q), 36.4 (q), 37.1 (q), 38.7 (t), 39.0 (t),
128.8 (2 × d), 129.5 (2 × d), 129.7 (2 × d), 130.0 (2 × d), 130.8
(s), 132.4 (s), 136.6 (s), 137.6 (s), 166.3 (s), and 173.1 (s); m/z
EI 179.0952 (Mϩ, C10H13NO2 requires 179.0946), 179 (Mϩ,
50%), 132 (34), 105 (100), 91 (5), and 77 (12).
N-Hydroxy-N-methyl-2-(1-naphthyl)acetamide 20g. Yield
87%; white crystalline solid, mp 115–120 ЊC (from hexane)
(Found: C, 72.45; H, 6.1; N, 6.6. C13H13NO2 requires C, 72.5;
H, 6.1; N, 6.5%); νmax(Nujol)/cmϪ1 3008, 2922, and 1600; δH(400
MHz; DMSO-d6) 3.60 (3H, s, NMe), 4.20 (2H, s, CH2), 7.40–
8.00 (7H, m, Ar), and 10.21 (1H, br s, OH); δC(100.6 MHz;
DMSO-d6) 36.0 (q), 36.2 (t), 124.4 (s), 125.6 (d), 125.7 (d), 126.0
(d), 127.1 (d), 128.1 (s), 128.5 (s), 132.3 (d), 132.7 (d), 133.4 (d),
and 171.0 (s); m/z EI 215.0897 (Mϩ, C13H13NO2 requires
215.0946), 216 (MHϩ, 12%), 199 (18), 141 (100), 115 (25), 105
(10), and 89 (5).
N-Hydroxy-N-methyl-2-(2-naphthyloxy)acetamide 20h. Yield
96%; white crystalline solid, mp 180–190 ЊC (from hexane);
νmax(CHCl3)/cmϪ1 3426, 2962, and 1657; δH(400 MHz; DMSO-
d6) 3.20 (3H, s, NMe), 5.00 (2H, s, CH2), 7.20–7.44 (7H, m, Ar),
10.21 (1H, br s, OH); δC(100.6 MHz; DMSO-d6) 35.8 (q), 64.8
(t), 107.0 (s), 118.3 (s), 123.5 (d), 123.7 (d), 126.0 (d), 126.5 (d),
127.3 (s), 129.0 (s), 135.0 (d), 156.0 (s), and 168.0 (s); m/z EI
231.0851 (Mϩ, C13H13NO3 requires 231.0895), 231 (Mϩ, 10%),
215 (90), 144 (100), 127 (80), 115 (73), and 86 (20).
N-Hydroxy-N-methyl-2-(4-methoxyphenyl)acetamide
20b.
Yield 86%; white crystalline solid, mp 71–72 ЊC (from hexane);
mixture of two rotomers (Found: C, 61.25; H, 6.7; N, 6.7.
C10H13NO3 requires C, 61.2; H, 6.7; N, 7.2%); νmax(Nujol)/cmϪ1
3150, 2921, 1614, 1512, and 1476; δH(300 MHz; CDCl3) 3.18
(3H, s, NMe, minor rotomer), 3.33 (3H, s, NMe, major
rotomer), 3.62 (2H, br s, CH2, major rotomer), 3.64 (2H, br s,
CH2, minor rotomer), 3.68 (3H, s, OMe, major and minor
rotomer), 6.86 (2H, m, major and minor Ar), 7.15 (2H, m,
major and minor Ar), and 8.40 (1H, br s, OH); δC(75.5 MHz;
CDCl3) for major rotomer 36.6 (q), 37.9 (t), 55.7 (q), 114.7
(2 × d), 130.1 (2 × d), 127.5 (s), 158.7 (s), and 173.0 (s); m/z EI
195.0901 (Mϩ, C10H13NO3 requires 195.0896), 195 (Mϩ, 50%),
180 (6), 149 (5), 121 (100), and 91 (14).
N-Hydroxy-N-methyl-2,2-diphenylacetamide 20i.19b Yield
26%; white crystalline solid, mp 87.8–88.9 ЊC (from hexane);
mixture of two rotomers; νmax(CHCl3)/cmϪ1 3416, 2927, 1704,
and 1605; δH(250 MHz; CDCl3) 3.22 (3H, s, NMe, minor
rotomer), 3.35 (3H, s, NMe, major rotomer), 5.11 (1H, br
s, CH, major rotomer), 5.62 (1H, br s, CH, minor rotomer),
7.28–7.35 (10H, m, 2 × Ar), 9.09 (1H, br s, OH); m/z CI
242.1171 (MHϩ, C15H16NO2 requires 242.1182), 241 (Mϩ, 15%),
212 (25), 167 (100), and 152 (46).
N-Hydroxy-N-methyl-2-(4-chlorophenyl)acetamide 20c. Yield
71%; white crystalline solid, mp 70–71 ЊC (from hexane);
mixture of two rotomers (Found: C, 54.3; H, 5.0; N, 6.7.
C9H10NO2Cl requires C, 54.1; H, 5.0; N, 7.0%); νmax(Nujol)/
cmϪ1 3150, 3019, 1628, 1521, and 1476; δH(300 MHz; CDCl3)
3.15 (3H, s, NMe, minor rotomer), 3.33 (3H, s, NMe, major
rotomer), 3.63 (2H, br s, CH2, major rotomer), 3.68 (2H, br s,
CH2, minor rotomer), 7.07–7.22 (4H, m, Ar), and 8.80 (1H, br
s, OH); δC(75.5 MHz; CDCl3) for major rotomer 36.3 (q), 38.6
(t), 128.9 (2 × d), 131.2 (2 × d), 133.0 (s), 133.8 (s), and 172.3
(s); m/z EI 199 (Mϩ, 3%), 183 (30), 126 (95), 91 (65), and 58
(100).
N-Benzoyloxy-N-methyl-4-phenylbut-3-enamide 3b. Yield
54%; clear oil; νmax(neat)/cmϪ1 1763, 1710, and 1248; δH(250
MHz; CDCl3) 3.30 (2H, d, J 6.0, CH2CO), 3.44 (3H, s, NMe),
6.29 (1H, dt, J 16.0 and 6.0, CH᎐CHPh), 6.40 (1H, d, J 16.0,
᎐
CH᎐CHPh), 7.15–7.34 (5H, m, Ar), 7.51 (2H, m, Ar), 7.68
᎐
(1H, m, Ar), and 8.09 (2H, m, Ar); δC(100.6 MHz; CDCl3)
35.7 (q), 36.9 (t), 121.5 (d), 126.2 (d), 126.6 (2 × d), 127.4 (d),
128.4 (2 × d), 128.9 (2 × d), 129.9 (2 × d), 133.3 (s), 134.5 (d),
136.7 (s), 164.2 (s), and 171.1 (s); m/z CI 296.1287 (MHϩ,
C18H18NO3 requires 296.1287), CI 296 (MHϩ, 21%), 176 (100),
and 105 (27).
N-Hydroxy-N-methyl-2-(2-thienyl)acetamide 20d. Yield 80%;
white crystalline solid, mp 80–81 ЊC (from hexane) (Found:
1122
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127

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N-Benzyl-N-benzoyloxy-4-phenylbut-3-enamide 3c. Yield
95%; clear oil; νmax(neat)/cmϪ1 1766, and 1682; δH(250 MHz;
CDCl3) 3.36 (2H, d, J 5.2, CH2CO), 5.08 (2H, s, NCH2), 6.30–
(2H, d, J 9.8, Ar); δC(100.6 MHz; CDCl3) 18.2 (q), 38.5 (t),
128.5 (2 × d), 130.4 (2 × d), 132.0 (s), 132.8 (s), and 167.8 (s),
signals for NMe and CO not observed; m/z EI 241.0504 (Mϩ,
C11H12NO3Cl requires 241.0506), 241 (Mϩ, 16%), 184 (25), 152
(70), 125 (100), and 89 (55).
6.46 (2H, m, CH᎐CH), 7.21–7.52 (10H, m, Ar), 7.40 (2H, m,
᎐
Ar), 7.65 (1H, m, Ar), and 8.02 (2H, m, Ar); δC(100.6 MHz;
CDCl3) 37.1 (t), 51.7 (t), 121.8 (d), 126.2 (d), 126.5 (2 × d),
127.4 (d), 127.9 (2 × d), 128.4 (2 × d), 128.6 (2 × d), 128.8
(2 × d), 129.7 (2 × d), 129.9 (d), 133.6 (s), 134.5 (d), 135.0 (s),
136.7 (s), 164.8 (s), and 171.33 (s); m/z CI 372.1602 (MHϩ,
C24H21NO3 requires 372.1601), CI 372 (MHϩ, 61%), 266 (14),
250 (71), 105 (100), and 91 (37).
N-Propanoyloxy-N-methyl-2-(4-methylphenyl)acetamide 21h.
Yield 90%; clear oil (Found: C, 65.7; H, 7.3; N, 5.9. C13H17NO3
requires C, 66.3; H, 7.3; N, 5.95%); νmax(neat)/cmϪ1 1787,
and 1677; δH(250 MHz; CDCl3) 1.19 (3H, t, J 7.5, CH2CH3),
2.24 (3H, s, Me), 2.36 (2H, q, J 7.5, CH2CH3), 3.21 (3H, s,
NMe), 3.50 (2H, s, CH2), and 7.03 (4H, m, Ar); δC(100.6 MHz;
CDCl3) 9.0 (q), 21.4 (q), 25.6 (t), 39.7 (t), 129.3 (2 × d), 129. 7
(2 × d), 131.1 (s), 136.9 (s), 163.9 (s), and 172.1 (s), the NMe
signal was too broad to be observed; m/z EI 235.1208 (Mϩ,
C13H17NO3 requires 235.1205), EI 235 (Mϩ, 11%), 163 (11),
132 (52), 105 (100), and 91 (20).
N-Acetoxy-N-methyl-2-phenylacetamide 21a. Yield 80%;
white crystalline solid, mp 40.1–41.2 ЊC (from hexane) (Found:
C, 63.5; H, 6.25; N, 6.4. C11H13NO3 requires C, 63.75; H, 6.3;
N, 6.8%); νmax(CHCl3)/cmϪ1 1792, 1674, and 1600; δH(300 MHz;
CDCl3) 1.95 (3H, s, Me), 3.17 (3H, s, NMe), 3.53 (2H, s, CH2),
and 7.10–7.22 (5H, m, Ar); δC(100.6 MHz; CDCl3) 18.7 (q),
35.9 (br q), 40.1 (t), 127.4 (2 × d), 129.0 (2 × d), 129.5 (d), 134.3
(s), 168.5 (s), and 171.9 (br s); m/z EI 207.0894 (Mϩ, C11H13NO3
requires 207.0895), 207 (Mϩ, 55%), 148 (77), 118 (80), and 91
(100).
N-Acetoxy-N-methyl-4-phenylbut-3-enamide 21i. Yield 75%;
clear oil; νmax(neat)/cmϪ1 1778, and 1673; δH(400 MHz; CDCl3)
2.12 (3H, s, Me), 3.16 (2H, d, J 6.6, CH2), 3.25 (3H, s, NMe),
6.22 (1H, dt, J 16.0 and 6.8, CH CH᎐CH), 6.40 (1H, d, J 16.0,
᎐
2
CH CH᎐CH), and 7.31 (5H, m, Ph); δ (100.6 MHz; CDCl )
᎐
2
C
3
N-Pivaloyloxy-N-methyl-2-phenylacetamide 21b. Yield 72%;
colourless oil; νmax(neat)/cmϪ1 1762, 1676 and 1599; δH(250
MHz; CDCl3) 1.28 (9H, s, t-Bu), 3.24 (3H, s, NMe), 3.56 (2H,
s, CH2), and 7.21–7.28 (5H, m, Ph); δC(100.6 MHz; CDCl3)
26.3 (q), 26.7 (q), 26.9 (q), 27.0 (s), 35.0 (q), 38.2 (t), 126.8 (d),
128.7 (2 × d), 128.7 (2 × d), 133.3 (s), 168.1 (s), and 170.7 (s);
m/z EI 249.1368 (Mϩ, C14H19NO3 requires 249.1365), CI 250
(MHϩ, 20%), 166 (5), 150 (15), 118 (18), 91 (100), and 85 (70).
18.4 (q), 35.4 (t), 36.8 (q), 121.7 (d), 122.7 (d), 126.3 (d), 127.6
(2 × d), 128.5 (2 × d), 133.5 (s), 168.3 (s), and 171.0 (s); m/z
EI 233.1010 (Mϩ, C13H15NO3 requires 233.1052), 233 (Mϩ,
11%), 191 (100), 144 (60), 117 (60), and 91 (40).
N-Pivaloyloxy-N-methyl-4-phenylbut-3-enamide 21j. Yield
29%; clear oil; νmax(neat)/cmϪ1 1789, 1698, and 1620; δH(400
MHz; CDCl3) 1.31 (9H, s, t-Bu), 3.16 (2H, d, J 5.5, CH2), 3.27
(3H, s, NMe), 6.20 (1H, dt, J 15.9 and 6.8, CH CH᎐CH), 6.50
᎐
2
N-(4-Nitrobenzoyloxy)-N-methyl-2-phenylacetamide
21c.
(1H, d, J 15.9, CH CH᎐CH), and 7.20–7.31 (5H, m, Ph);
Yield 51%; yellow solid, mp 135–138 ЊC; νmax(Nujol)/cmϪ1 1770,
1677, and 1600; δH(250 MHz; CDCl3) 3.34 (3H, s, NMe), 3.63
(2H, s, CH2), 7.10–7.20 (5H, m, Ar), and 8.09–8.22 (4H, m, Ar);
δC(100.6 MHz; CDCl3) 36.7 (q), 40.5 (t), 124.2 (d), 127.5
(2 × d), 128.8 (2 × d), 129.4 (2 × d), 131.5 (2 × d), 132.5 (s),
133.8 (s), 151.6 (s), 162.8 (s), and 171.7 (s); m/z EI 314.0908
(Mϩ, C16H14N2O5 requires 314.0903), CI 315 (MHϩ, 20%), 150
(100), 120 (30), 92 (70), and 66 (20).
᎐
2
δC(100.6 MHz; CDCl3) 26.4 (q), 27.0 (q), 27.0 (s), 27.1 (q),
35.3 (q), 36.7 (t), 121.7 (d), 121.6 (d), 126.3 (d), 127.6 (2 × d),
128.5 (2 × d), 136.9 (s), 171.2 (s), and 175.6 (s); m/z EI 275.1523
(Mϩ, C16H21NO3 requires 275.1522), CI 276 (MHϩ, 35%),
234 (20), 174 (100), 117 (60), and 91 (20).
N-Benzoyloxy-N-methyl-2-(2-thienyl)acetamide 21k. Yield
82%; yellow oil (Found: C, 61.4; H, 4.7; N, 5.0. C14H13NO3S
requires C, 61.1; H, 4.75; N, 5.1%); νmax(neat)/cmϪ1 1709, 1675,
and 1579; δH(400 MHz; CDCl3) 3.31 (3H, s, NMe), 3.76 (2H, s,
CH2), 6.78 (2H, m, thienyl), 7.07 (1H, dd, J 4.3 and 1.1,
thienyl), and 7.15–7.60 (5H, m, Ar); δC(100.6 MHz; CDCl3)
33.7 (t), 35.8 (br q), 125.0 (d), 126.5 (d), 126.7 (d), 128.9 (2 × d),
130.0 (2 × d), 135.8 (d), 134.9 (s), 163.3 (s), and 164.1 (s); m/z EI
275.0606 (Mϩ, C14H13NO3S requires 275.0616), EI 275 (Mϩ,
1%), 155 (4), 135 (25), 105 (100), and 97 (51).
N-Acetoxy-N-methyl-2-(4-methoxyphenyl)acetamide
21e.
Yield 80%; white crystalline solid, mp 46–47 ЊC (from hexane)
(Found: C, 60.65; H, 6.4; N, 5.6. C12H15NO4 requires C, 60.7;
H, 6.4; N, 5.9%); νmax(CHCl3)/cmϪ1 1793, 1670, and 1611;
δH(300 MHz; CDCl3) 2.12 (3H, s, Me), 3.26 (3H, s, NMe), 3.53
(2H, s, CH2), 3.75 (3H, s, OMe), 6.81 (2H, d, J 8.5, Ar), and
7.11 (2H, d, J 8.5, Ar); δC(100.6 MHz; CDCl3) 18.8 (q), 22.5 (q),
39.2 (t), 55.6 (q), 114.4 (2 × d), 126.2 (s), 130.5 (2 × d), 159.0 (s),
and 168.5 (s), signals for NMe and CO not observed; m/z CI
237.1009 (Mϩ, C12H15NO4 requires 237.1002), 238 (MHϩ,
100%), 210 (45), 148 (62), and 121 (76).
N-(4-Nitrobenzoyloxy)-N-methyl-2-(2-thienyl)acetamide 21l.
Yield 88%; white crystalline solid, mp 121–122 ЊC (from
hexane) (Found: C, 52.2; H, 3.8; N, 8.1. C14H12N2O5S requires
C, 52.5; H, 3.8; N, 8.7%); νmax(neat)/cmϪ1 1774, 1683, and 1602;
δH(300 MHz; CDCl3) 3.46 (3H, s, NMe), 3.89 (2H, s, CH2),
6.87 (1H, br s, thienyl), 6.92 (1H, dd, J 3.7 and 2.0, thienyl), 7.19
(1H, d, J 3.7, thienyl), 8.24 (2H, d, J 7.1, Ar), and 8.35 (2H,
d, J 7.1, Ar); δC(100.6 MHz; CDCl3) 30.9 (q), 34.2 (t), 124.0
(2 × d), 125.2 (d), 126.8 (d), 126.9 (d), 131.3 (2 × d), 132.0 (s),
134.4 (s), 151.3 (s), and 162.4 (s), other CO not found at room
temperature (found at 170.6 in d8-toluene, Ϫ70 ЊC with 5 s
relaxation delay); m/z EI 320.0470 (Mϩ, C14H12N2O5S requires
320.0467), EI 320 (Mϩ, 1%), 266 (10), 150 (80), 97 (95), and
83 (100).
N-Acetoxy-N-methyl-2-(4-methylphenyl)acetamide 21f. Yield
89%; white crystalline solid, mp 48–49 ЊC (Found: C, 65.0; H,
6.8; N, 6.2. C12H15NO3 requires C, 65.1; H, 6.85; N, 6.3%);
νmax(CHCl3)/cmϪ1 1794, 1669, and 1601; δH(300 MHz; CDCl3)
2.07 (3H, s, Me), 2.22 (3H, s, Me), 3.20 (3H, s, NMe), 3.50 (2H,
s, CH2), and 7.01 (4H, m, Ar); δC(100.6 MHz; CDCl3) 18.8 (q),
21.4 (q), 39.8 (t), 129.3 (2 × d), 129.7 (2 × d), 131.1 (s), 137.0 (s),
and 168.5 (s), signals for NMe and CO not observed; m/z
EI 221.1056 (Mϩ, C12H15NO3 requires 221.1053), 221 (Mϩ,
12%), 179 (17), 132 (60), 105 (100), and 91 (10).
N-Acetoxy-N-methyl-2-(4-chlorophenyl)acetamide 21g. Yield
74%; yellow oil (Found: C, 54.3; H, 5.0; N, 5.6. C11H12NO3Cl
requires C, 54.6; H, 5.0; N, 5.8%); νmax(neat)/cmϪ1 1792, 1675,
and 1598; δH(300 MHz; CDCl3) 2.15 (3H, s, Me), 3.26 (3H,
s, NMe), 3.55 (2H, s, CH2), 7.12 (2H, d, J 9.8, Ar), and 7.25
N-(4-Methoxybenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
21m. Yield 82%; yellow oil (Found: C, 58.5; H, 5.0; N, 4.3.
C15H15NO4S requires C, 59.0; H, 4.95; N, 4.6%); νmax(CHCl3)/
cmϪ1 1756, 1675, and 1605; δH(300 MHz; CDCl3) 3.31 (3H, s,
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127
1123

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NMe), 3.75 (2H, s, CH2), 3.78 (3H, s, OMe), 6.77–6.82 (2H, m,
thienyl), 6.88 (2H, m, Ar), 7.07 (1H, dd, J 5.3 and 1.3, thienyl),
and 7.94 (2H, m, Ar); δC(100.6 MHz; CDCl3) 34.1 (t), 36.1
(br q), 56.0 (q), 114.6 (2 × d), 118.9 (s), 125.4 (d), 127.1 (d),
127.2 (d), 132.7 (2 × d), 134.9 (s), 164.1 (s), 164.2 (s), and 165.1
(s); m/z CI 306.0798 (MHϩ, C15H16NO4S requires 306.0800), CI
306 (MHϩ, 100%), 170 (71), 156 (95), and 135 (82).
m/z EI 364.1008 (Mϩ, C20H16N2O5 requires 364.1059), EI 364
(MHϩ, 25%), 168 (23), 150 (80), 141 (100), and 115 (35).
N-(4-Nitrobenzoyloxy)-N-methyl-2-(2-naphthyloxy)acet-
amide 21t. Yield 82%; white crystalline solid, mp 158–160 ЊC
(from hexane) (Found: C, 62.95; H, 4.2; N, 7.2. C20H16N2O6
requires C, 63.1; H, 4.2; N, 7.4%); νmax(Nujol)/cmϪ1 1776, 1695,
and 1602; δH(400 MHz; CDCl3) 3.50 (3H, s, NMe), 4.80 (2H, s,
CH2), 7.02–7.42 (7H, m, Ar), and 8.21–8.32 (4H, m, Ar);
δC(100.6 MHz; CDCl3) 36.4 (q), 66.0 (t), 107.3 (s), 118.21 (s),
123.7 (d), 124.1 (2 × d), 126.5 (d), 126.8 (d), 127.5 (d), 129.2
(d), 129.6 (d), 131.5 (2 × d), 131.6 (s), 134.1 (d), 151.0 (s), 157.0
(s), 160.2 (s), and 162.5 (s); m/z EI 380.0961 (Mϩ, C20H16N2O6
requires 380.1008), CI 381 (MHϩ, 25%), 215 (55), 144 (65),
127 (100), 120 (85), and 99 (45).
N-(4-Methylbenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
21n. Yield 88%; yellow oil (Found: C, 62.25; H, 5.2; N, 4.1.
C15H15NO3S requires C, 62.2; H, 5.2; N, 4.8%); νmax(CHCl3)/
cmϪ1 1757, 1676, and 1608; δH(250 MHz; CDCl3) 2.69 (3H,
s, Me), 3.23 (3H, s, NMe), 3.67 (2H, s, CH2), 6.68 (1H, br s,
thienyl), 6.72 (1H, dd, J 4.2 and 3.0, thienyl), 6.98 (1H, dd, J 4.2
and 1.0, thienyl), 7.13 (2H, d, J 6.8, Ar), and 7.80 (2H, d, J 6.8,
Ar); δC(100.6 MHz; CDCl3) 22.2 (q), 34.1 (t), 36.1 (br q), 124.1
(s), 125.4 (d), 127.1 (d), 127.2 (d), 130.1 (2 × d), 130.5 (2 × d),
N-Acetoxy-N-methyl-2,2-diphenylacetamide
21u.
Yield
135.3 (s), 146.2 (s), and 164.5 (s), other C᎐O not found; m/z
᎐
56%; white crystalline solid, mp 79.5–80.4 ЊC (from hexane)
(Found: C, 72.1; H, 6.1; N, 4.9. C17H17NO3 requires C, 72.1; H,
6.05; N, 4.9%); νmax(neat)/cmϪ1 1787, and 1651; δH(250 MHz;
CDCl3) 2.04 (3H, s, Ac), 3.36 (3H, s, NMe), 5.14 (1H, s, CH),
and 7.25–7.37 (10H, m, 2 × Ar); δC(100.6 MHz; CDCl3) 18.0
(q), 54.2 (d), 127.1 (2 × d), 128.3 (4 × d), 128.7 (4 × d), 138.0
EI 289.0766 (Mϩ, C15H15NO3S requires 289.0772), EI 289 (Mϩ,
1%), 149 (4), 136 (6), 119 (100), and 91 (40).
N-(4-Chlorobenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
21o. Yield 94%; white crystalline solid, mp 76–77 ЊC (Found: C,
54.7; H, 4.2; N, 4.1. C14H12NO3SCl requires C, 54.3; H, 3.9; N,
4.5%); νmax(CHCl3)/cmϪ1 1767, 1676, and 1595; δH(250 MHz;
CDCl3) 3.43 (3H, s, NMe), 3.86 (2H, s, CH2), 6.68 (1H, br
s, thienyl), 6.72 (1H, dd, J 4.2 and 3.0, thienyl), 7.19 (1H, d,
J 3.0, thienyl), 7.50 (2H, m, Ar), and 8.01 (2H, m, Ar); m/z EI
309.0227 (Mϩ, C14H12NO3SCl35 requires 309.0226), CI 310
(MHϩ, 40%), 156 (85), 139 (20), 97 (10), and 35 (100).
(2 × s), and 167.5 (s), one C᎐O and the NMe too broad to be
᎐
observed; m/z EI 284.1289 (Mϩ, C17H17NO3 requires 284.1287),
CI 284 (MHϩ, 50%), 226 (38), 167 (15), and 35 (100).
N-Benzyloxy-N-butyl-4-phenylbut-3-enamide 3a. Method 2:
Dibenzoyl peroxide (2.43 g, 13.4 mmol) in dichloromethane
(15 cm3) was added dropwise to n-butylamine (0.69 cm3, 6.92
mmol) and sodium carbonate (3.13 g, 23 mmol) in dichloro-
methane (15 cm3). The reaction was stirred at room tem-
perature for 2 hours and then a solution of (E)-styrylacetyl
chloride (1.25 g 13.4 mmol) was added and the mixture stirred
for another 1 hour. Water was added and the product extracted
with dichloromethane (3 × 30 cm3). The combined extracts
were washed with water, dried over MgSO4 and the solvent
removed in vacuo. Purification by column chromatography
(5:1 gradient to 2:1 petroleum ether–ethyl acetate) furnished
the butenamide 3a in 54% yield; yellow oil; νmax(neat)/cmϪ1
1766, 1674, and 1600; δH(250 MHz; CDCl3) 0.92 (3H, t, J 7.3,
Me), 1.39 (2H, sextet, J 7.4, CH2Me), 1.65 (2H, quintet, J 7.4,
CH2), 3.27 (2H, d, J 5.2, CH2CO), 3.85 (2H, t, J 7.4, NCH2),
N-Acetoxy-N-methyl-2-(2-thienyl)acetamide 21p. Yield 66%;
yellow oil; νmax(neat)/cmϪ1 1794, 1673, and 1602; δH(300 MHz;
CDCl3) 2.15 (3H, s, Ac), 3.26 (3H, s, NMe), 3.77 (2H, s, CH2),
6.88 (2H, m, thienyl), and 7.16 (1H, dd, J 5.2 and 1.2, thienyl);
δC(100.6 MHz; CDCl3) 18.7 (q), 34.2 (t), 36.1 (br q), 125.3 (d),
127.1 (d), 127.2 (d), 135.2 (s), and 168.4 (s), other CO not found
at room temperature; m/z EI 213.0456 (Mϩ, C19H11NO3S
requires 213.0459), EI 213 (Mϩ, 12%), 167 (16), 149 (52), 135
(86), and 113 (100).
N-(4-Nitrobenzoyloxy)-N-methylbut-3-enamide 21q. Yield
70%; clear oil; νmax(neat)/cmϪ1 1773, and 1606; δH(400 MHz;
CDCl3) 3.17 (2H, d, J 6.4, CH2), 3.46 (3H, s, NMe), 5.16 (2H,
6.24–6.47 (2H, m, CH᎐CHPh), 7.12–7.22 (5H, m, Ar), 7.48
᎐
m, CH᎐CH ), 6.92 (1H, m, CH᎐CH ), and 8.21–8.36 (4H, m,
᎐
᎐
2
2
(2H, m, Ar), 7.64 (1H, m, Ar), and 8.09 (2H, m, Ar); m/z CI
338.1756 (MHϩ, C21H23NO3 requires 338.1756), CI 338 (MHϩ,
0.5%), 217 (12), 118 (100), 105 (99), and 57 (97).
Ar); m/z CI 265.0825 (Mϩ, C12H13N2O5 requires 265.0824),
EI 179 (20), 167 (40), 150 (100), 104 (90), and 76 (87).
N-(4-Nitrobenzoyloxy)-N-methylhexanamide
21r.
Yield
General procedure for thermal rearrangement
77%; white crystalline solid, mp 215–220 ЊC (from hexane);
νmax(neat)/cmϪ1 1771, 1677, and 1606; δH(400 MHz; CDCl3)
0.80 (3H, br t, J 4.0, Me), 1.20–1.31 (4H, br m, CH2CH2), 1.52–
1.70 (2H, br m, CH2), 2.23 (2H, br t, J 6.0, C(O)CH2), 3.40 (3H,
s, NMe), and 8.20–8.31 (4H, m, Ar); δC(100.6 MHz; CDCl3)
13.9 (q), 22.3 (t), 24.0 (t), 31.3 (t), 34.0 (t), 36.2 (q), 124.0
(2 × d), 131.2 (2 × d), 132.2 (s), 151.2 (s), 162.6 (s), and 171.2
(s); m/z CI 294.1219 (Mϩ, C14H18N2O5 requires 294.1216),
CI 295 (MHϩ, 50%), 244 (23), 150 (60), 150 (60), 130 (100), and
120 (68).
A solution of the hydroxamic acid derivative (3a–c, 0.15 mmol)
in toluene (2.5 cm3) was heated at 140 ЊC in a sealed tube for
1–3 days. The solvent was then removed in vacuo and the
residue purified by chromatography (2:1 petroleum ether–ethyl
acetate).
2-Benzoyloxy-N-butyl-4-phenylbut-3-enamide
6a.
Yield
85%; colourless oil; νmax(neat)/cmϪ1 1723, 1665, and 1600;
δH(250 MHz; CDCl3) 0.90 (3H, t, J 7.2, Me), 1.25–1.57 (4H,
m, CH2CH2Me), 3.31 (2H, dt, J 7.2 and 6.0, NCH2), 6.00 (1H,
dd, J 6.7 and 1.2, CH), 6.20 (1H, br s, NH), 6.41 (1H, dd, J 15.9
N-(4-Nitrobenzoyloxy)-N-methyl(1-naphthyl)acetamide 21s.
Yield 98%; white crystalline solid, mp 215–220 ЊC (from
hexane) (Found: C, 65.4; H, 4.55; N, 7.3. C20H16N2O5 requires
C, 65.9; H, 4.4; N, 7.7%); νmax(CHCl3)/cmϪ1 1772, 1677, and
1607; δH(400 MHz; CDCl3) 3.50 (3H, s, NMe), 4.20 (2H, s,
CH2), and 7.31–8.30 (11H, m, Ar); δC(100.6 MHz; CDCl3) 36.3
(q), 37.0 (t), 123.5 (d), 123.8 (2 × d), 125.4 (d), 125.9 (d), 126.5
(d), 127.4 (s), 128.1 (s), 128.8 (d), 129.9 (s), 130.3 (d), 131.1
(2 × d), 132.0 (s), 133.8 (d), 151.1 (s), 162.5 (s), and 175.5 (s);
and 6.7, CH᎐CHPh), 6.81 (1H, dd, J 15.9 and 1.2, CH᎐CHPh),
᎐
᎐
7.26–7.88 (8H, m, Ar), and 8.12 (2H, m, Ar); m/z EI 337.1672
(Mϩ, C21H23NO3 requires 337.1679), EI 337 (Mϩ, 3%), 238 (50),
115 (36), and 105 (100).
2-Benzoyloxy-N-methyl-4-phenylbut-3-enamide 6b. Yield
95%; colourless oil; νmax(neat)/cmϪ1 1722, 1668, and 1600;
δH(250 MHz; CDCl3) 2.89 (3H, d, J 5.0, NMe), 6.04 (1H, dd,
1124
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127

View Article Online
J 6.7 and 1.2, CH), 6.29 (1H, br s, NH), 6.42 (1H, dd, J 16.0
and 6.7, CH᎐CHPh), 6.82 (1H, dd, J 16.0 and 1.2, CH᎐CHPh),
7.26–7.88 (8H, m, Ar), and 8.12 (2H, m, Ar); m/z EI 295.1208
(Mϩ, C18H17NO3 requires 295.1209), EI 295 (Mϩ, 6%), 238 (19),
115 (53), and 105 (100).
cmϪ1 3450, 1734, 1690, and 1602 (Found: C, 60.6; H, 4.6;
N, 8.55. C11H13NO3 requires C, 61.1; H, 4.5; N, 8.9%); δH(250
MHz; CDCl3) 2.73 (3H, d, J 5.0, NMe), 6.19 (1H, s, CH), 6.76
(1H, br s, NH), and 7.30–8.20 (9H, m, Ar); m/z EI 314.0903
(Mϩ, C16H14N2O5 requires 314.0900), CI 315 (MHϩ, 10%),
257 (20), 150 (50), 120 (100), and 91 (30).
᎐
᎐
2-Benzoyloxy-N-benzyl-4-phenylbut-3-enamide 6c. Yield 80%;
colourless oil; νmax(neat)/cmϪ1 1711, 1655, and 1600; δH(250
MHz; CDCl3) 4.50 (1H, dd, J 14.9 and 5.8, CHHPh), 4.57
(1H, dd, J 14.9 and 5.8, CHHPh), 6.07 (1H, dd, J 6.7 and 1.3,
2-(1Ј,1Ј,1Ј-Trichloroacetoxy)-N-methyl-4-phenylbut-3-enam-
ide 22d. Yield 10%; clear oil; νmax(CHCl3)/cmϪ1 3022, 1745, and
1688; δH(400 MHz; CDCl3) 2.83 (3H, d, J 4.9, NMe), 5.73 (1H,
d, J 7.0, CH), 6.23 (1H, dd, J 16.0 and 7.0, CH᎐CHPh), 6.33
CH), 6.45 (2H, br m, NH and CH᎐CHPh), 6.84 (1H, dd, J 15.9
᎐
᎐
(1H, br s, NH), 6.70 (1H, d, J 16.0, CH᎐CHPh), and 7.20–7.42
and 1.3, CH᎐CHPh), 7.23–7.65 (13H, m, Ar), and 8.10 (2H,
᎐
᎐
m, Ar); m/z EI 371.1529 (Mϩ, C24H21NO3 requires 371.1522),
(5H, m, Ar); δC(100.6 MHz; CDCl3) 26.2 (q), 68.2 (d), 80.0 (s),
118.0 (d), 118.6 (d), 127.0 (d), 128.8 (2 × d), 129.1 (2 × d), 136.3
(s), 155.3 (s) and 171.2 (s); m/z CI No MHϩ observed 190
(Mϩ Ϫ COCCl3, 2%), 172 (15), 131 (100), 115 (30), 105 (55) and
91 (20).
EI 371 (Mϩ, 2%), 238 (34), 105 (100), 91 (64), and 77 (57).
General procedure for triethylamine catalysed rearrangement
Method A: A solution of the hydroxamic acid derivative (21a–t,
0.15 mmol) and triethylamine (0.015 mmol) in toluene (2.5 cm3)
was heated at 110 ЊC. The volatiles were then removed in vacuo
and the residue purified by chromatography (2:1 petroleum
ether–ethyl acetate).
Method B: A solution of the hydroxamic acid derivative
(21a–t, 0.15 mmol) and triethylamine (0.15 mmol) in toluene
(2.5 cm3) was heated at 63 ЊC. The volatiles were then removed
in vacuo and the residue purified by chromatography (2:1
petroleum ether–ethyl acetate).
Method C: A solution of the hydroxamic acid derivative
(21a–t, 0.15 mmol) and triethylamine (0.15 mmol) in dichloro-
methane (2.5 cm3) was heated at 40 ЊC. The volatiles were then
removed in vacuo and the residue purified by chromatography
(2:1 petroleum ether–ethyl acetate).
Method D: A solution of the hydroxamic acid derivative
(21a–t, 0.15 mmol) and triethylamine (0.09 mmol) in CH2Cl2
(2.5 cm3) at room temperature. The volatiles were then removed
in vacuo and the residue purified by chromatography (2:1
petroleum ether–ethyl acetate).
Method E: A solution of the hydroxamic acid derivative
(21a–t, 0.15 mmol) and triethylamine (0.03 mmol) in CH2Cl2
(2.5 cm3) was heated at 40 ЊC in a sealed tube. The volatiles
were then removed in vacuo and the residue purified by chroma-
tography (2:1 petroleum ether–ethyl acetate).
Method F: A solution of the hydroxamic acid derivative
(21a–t, 0.15 mmol) and triethylamine (0.15 mmol) in toluene
(2.5 cm3) was heated at 160 ЊC in a sealed tube. The volatiles
were then removed in vacuo and the residue purified by chrom-
atography (2:1 petroleum ether–ethyl acetate).
2-Acetoxy-N-methyl-2-(4-methoxyphenyl)acetamide
22e.
Yield 94%; colourless oil; νmax(neat)/cmϪ1 3314, 1740, 1664,
and 1612; δH(250 MHz; CDCl3) 2.12 (3H, s, Me), 2.78 (3H, d,
J 5.4, NMe), 3.75 (3H, s, OMe), 5.99 (1H, s, CH), 6.48 (1H,
br s, NH), 6.85 (2H, d, J 8.8, Ar), and 7.32 (2H, d, J 8.8,
Ar); δC(100.6 MHz; CDCl3) 21.4 (q), 26.5 (q), 55.6 (q), 75.6
(d), 114.5 (2 × d), 128.2 (s), 129.4 (2 × d), 160.4 (s), 169.6 (s),
and 169.7 (s); m/z EI 237.1001 (Mϩ, C12H15NO4 requires
237.1004), EI 237 (Mϩ, 16%), 179 (25), 149 (40), 137 (55), and
121 (100).
2-Acetoxy-N-methyl-2-(4-methylphenyl)acetamide 22f. Yield
94%; colourless oil; νmax(neat)/cmϪ1 3269, 1742, and 1656
(Found: C, 64.7; H, 6.9; N, 6.4. C12H15NO3 requires C, 65.1;
H, 6.85; N, 6.3%); δH(250 MHz; CDCl3) 2.31 (3H, s, Me), 2.77
(3H, d, J 5.4, NMe), 6.01 (1H, s, CH), 6.52 (1H, br s, NH), 7.14
(2H, d, J 9.5, Ar), and 7.30 (2H, d, J 9.5, Ar); δC(100.6 MHz;
CDCl3) 21.4 (q), 21 5 (q), 26.5 (q), 75.8 (d), 127.8 (2 × d), 129.8
(2 × d), 133.1 (s), 139.2 (s), 169.5 (s), and 171.5 (s); m/z EI
221.1047 (Mϩ, C12H15NO3 requires 221.1052), EI 221 (Mϩ,
10%), 163 (42), 121 (100), and 91 (40).
2-Acetoxy-N-methyl-2-(4-chlorophenyl)acetamide 22g. Yield
100%; clear oil; νmax(neat)/cmϪ1 3290, 1745, and 1665 (Found:
C, 54.7; H, 5.3; N, 6.1. C13H17NO3 requires C, 54.65; H,
5.0; N, 5.8%); δH(250 MHz; CDCl3) 2.18 (3H, s, Me), 2.84 (3H,
d, J 4.9, NMe), 6.04 (1H, s, CH), 6.18 (1H, br s, NH), 7.25–7.38
(2H, m, Ar); δC(100.6 MHz; CDCl3) 21.4 (q), 26.6 (q), 75.1 (d),
129.2 (2 × d), 129.3 (2 × d), 134.5 (s), 135.3 (s), 169.0 (s), and
169.5 (s); m/z EI 241.0503 (Mϩ, C11H12NO3 requires 241.0506),
CI 242 (MHϩ, 100%), 184 (95), and 102 (25).
2-Acetoxy-N-methyl-2-phenylacetamide 22a. Yield 75%;
colourless oil; νmax(neat)/cmϪ1 3360, 1789, and 1666 (Found:
C, 63.8; H, 6.5; N, 6.95. C11H13NO3 requires C, 63.75; H, 6.3;
N, 6.8%); δH(250 MHz; CDCl3) 2.18 (3H, s, Me), 2.83 (3H, d,
J 5.0, NMe), 6.07 (1H, s, CH), 6.24 (1H, br s, NH), and 7.26–
7.37 (5H, m, Ph); δC(100.6 MHz; CDCl3) 18.2 (q), 35.4 (q), 74.4
(d), 127.3 (2 × d), 128.8 (2 × d), 129.3 (d), 134.0 (s), 167.9 (s),
and 168.6 (s); m/z EI 207.0891 (Mϩ, C11H13NO3 requires
207.0895), CI 208 (MHϩ, 23%), 166 (5), 150 (30), 118 (42), and
91 (100).
2-Propanoyloxy-N-methyl-2-(4-methylphenyl)acetamide 22h.
Yield 82%; white crystalline solid, mp 79.3–80.6 ЊC;
νmax(Nujol)/cmϪ1 3267, 1744, and 1657; δH(250 MHz; CDCl3)
1.17 (3H, t, J 7.5, CH2CH3), 2.34 (3H, s, Me), 2.45 (2H,
m, CH2CH3), 2.85 (3H, d, J 4.9, NMe), 6.07 (1H, s, CH), 6.11
(1H, br s, NH), 7.17 (2H, d, J 8.0, Ar), and 7.30 (2H, d, J 8.0,
Ar); δC(100.6 MHz; CDCl3) 9.3 (q), 21.6 (q), 26.6 (q), 27.9 (t),
75.6 (d), 127.7 (2 × d), 129.8 (2 × d), 133.2 (s), 139.2 (s), 169.6
(s), and 173.1 (s); m/z CI 236.1294 (MHϩ, C13H18NO3 requires
236.1287), EI 235 (Mϩ, 10%), 178 (72), 121 (85), 91 (74), and
57 (100).
2-Pivaloyloxy-N-methyl-2-phenylacetamide 22b. Yield 65%;
colourless oil; νmax(neat)/cmϪ1 3300, 1776, and 1680; δH(250
MHz; CDCl3) 1.30 (9H, s, t-Bu), 2.84 (3H, d, J 4.9, NMe), 6.05
(1H, s, CH), and 7.33–7.41 (6H, m, Ph, NH); δC(100.6 MHz;
CDCl3) 26.1 (q), 26.3 (q), 27.3 (s), 31.5 (q), 39.8 (q), 75.6 (s),
125.4 (2 × d), 128.3 (2 × d), 129.1 (d), 137.7 (s), 169.6 (s), and
176.9 (s); m/z EI 249.1361 (Mϩ, C14H19NO3 requires 249.1365),
CI 250 (MHϩ, 100%), 148 (70), 116 (15), and 91 (40).
2-Acetoxy-N-methyl-4-phenylbut-3-enamide 22i. Yield 99%;
colourless oil; νmax(neat)/cmϪ1 3378, 1735, and 1654; δH(400
MHz; CDCl3) 2.20 (3H, d, J 4.9, NMe), 5.73 (1H, d, J 7.0, CH),
6.23 (1H, dd, J 16.0 and 7.0, CH᎐CHPh), 6.70 (1H, d, J 16.0,
᎐
CH᎐CHPh), 7.26–7.88 (6H, m, Ar and NH); δ (100.6 MHz;
᎐
C
CDCl3) 20.0 (q), 21.5 (q), 25.2 (q), 73.4 (d), 121.5 (d), 124.3 (d),
125.8 (d), 127.4 (2 × d), 127.8 (2 × d), 133.8 (s), 167.8 (s), and
168.3 (s); m/z EI 233.1009 (Mϩ, C13H15NO3 requires 233.1052),
2-(4-Nitrobenzoyloxy)-N-methyl-2-phenylacetamide
Yield 99%; white crystalline solid, mp 140–143 ЊC; νmax(CHCl3)/
22c.
J. Chem. Soc., Perkin Trans. 1, 2000, 1117–1127
1125

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CI 234 (MHϩ, 2%), 191 (2), 176 (100), 161 (22), 115 (55), and
77 (35).
br m, thienyl), 7.37 (1H, dd, J 5.1 and 1.0, thienyl), 7.44 (2H, m,
Ar), and 8.03 (2H, m, Ar); δC(100.6 MHz; CDCl3) 26.4 (q), 71.7
(d), 127.1 (d), 128.9 (2 × d), 131.3 (2 × d), 137.1 (s), 140.3 (s),
144.7 (s), 164.1 (s), and 167.9 (s); m/z EI 309.0225 (Mϩ,
C14H12NO3SCl35 requires 309.0226), EI 309 (MHϩ, <0.5%),
156 (16), 139 (44), and 83 (100).
2-Pivaloyloxy-N-methyl-4-phenylbut-3-enamide 22j. Yield
82%; colourless oil; νmax(neat)/cmϪ1 3356, 1778, and 1672;
δH(250 MHz; CDCl3) 1.30 (9H, s, t-Bu), 2.84 (3H, d, J 4.8,
NMe), 5.72 (1H, dd, J 6.7 and 1.0, CH), 6.10 (1H, br s, NH),
6.22 (1H, dd, J 16.0 and 6.7, CH᎐CHPh), 6.70 (1H, dd, J 16.0
2-Acetoxy-N-methyl-2-(2-thienyl)acetamide
22p.
Yield
᎐
and 1.0, CH᎐CHPh), 7.26–7.88 (6H, m, Ar and NH); δ (100.6
90%; white crystalline solid, mp 135–136 ЊC (from hexane);
νmax(CHCl3)/cmϪ1 3455, 1740, 1686, and 1601 (Found: C, 50.5;
H, 5.2; N, 6.3. C9H11NO3S requires C, 50.7; H, 5.2; N, 6.6%);
δH(250 MHz; CDCl3) 2.16 (3H, s, Ac), 2.86 (3H, d, J 4.9, NMe),
6.23 (1H, br s, NH), 6.33 (1H, s, CH), 6.97 (1H, dd, J 5.2
and 3.6, thienyl), 7.14 (1H, dd, J 3.6 and 0.9, thienyl), and 7.30
(1H, dd, J 5.2 and 0.9, thienyl); δC(100.6 MHz; CDCl3) 21.3 (q),
26.7 (q), 71.4 (s), 127.3 (2 × d), 128.2 (d), 137.8 (s), 168.4 (s),
and 169.5 (s); m/z EI 213.0472 (Mϩ, C9H11NO3S requires
213.0460), CI 14 (MHϩ, 25%), 171 (81), 154 (100), 135 (60),
and 114 (24).
᎐
C
MHz; CDCl3) 26.3 (q), 26.9 (q), 27.1 (q), 27.2 (s), 31.1 (q), 74.1
(d), 121.6 (d), 122.8 (d), 126.8 (d), 128.3 (2 × d), 128.6 (2 × d),
135.7 (s), 169.3 (s), and 174.0 (s); m/z EI 275.1523 (Mϩ,
C13H15NO3 requires 275.1522), CI 276 (MHϩ, 48%), 192 (10),
174 (100), 117 (30), and 85 (50).
2-Benzoyloxy-N-methyl-2-(2-thienyl)acetamide 22k. Yield
100%; white crystalline solid, mp 86–86 ЊC (from hexane);
νmax(CHCl3)/cmϪ1 3455, 1724, 1684, and 1602 (Found: C,
61.3; H, 4.75; N, 4.6. C14H13NO3S requires C, 61.1; H, 4.75;
N, 5.1%); δH(400 MHz; CDCl3) 2.81 (3H, d, J 5.2, NMe),
6.32 (1H, br s, NH), 6.55 (1H, s, CH), 6.92 (1H, dd, J 4.9 and
3.4, thienyl), 7.17 (1H, m, thienyl), 7.25 (1H, dd, J 4.9 and 1.0,
thienyl), 7.38 (2H, m, Ar), 7.52 (1H, m, Ar), and 8.02 (2H, dd,
J 7.9 and 1.0, Ar); m/z EI 275.0610 (Mϩ, C14H13NO3S requires
275.0616), EI 275 (Mϩ, 3%), 218 (10), 122 (49), 105 (100), and
83 (82).
2-(4-Nitrobenzoyloxy)-N-(methyl)but-3-enamide 22q. Yield
55%; colourless oil; νmax(neat)/cmϪ1 3450, 1734, 1686, and 1599;
δH(300 MHz; CDCl3) 2.86 (3H, d, J 4.9, NMe), 5.43 (1H, ddd,
J 10.3, 1.0 and 1.0, CHH᎐CH), 5.53 (1H, ddd, J 17.1, 1.0 and
᎐
1.0, CHH᎐CH), 5.82 (1H, ddd, J 6.4, 1.0, and 1.0), 6.09 (1H, m,
᎐
CHH᎐CH), and 8.28 (4H, m, Ar); δ (100.6 MHz; CDCl ) 26.7
᎐
C
3
(q), 76.1 (d), 120.6 (t), 124.1 (2 × d), 131.4 (2 × d), 131.5 (d),
135.0 (s), 151.2 (s), 163.6 (s), and 168.2 (s); m/z EI 265.0826
(Mϩ, C12H12N2O4 requires 265.0824), CI 266 (MHϩ, 20%),
181 (90), 138 (100), and 94 (15).
2-(4-Nitrobenzoyloxy)-N-methyl-2-(2-thienyl)acetamide 22l.
Yield 100%; white crystalline solid, mp 139–140 ЊC (from
hexane); νmax(neat)/cmϪ1 3450, 1734, 1690, and 1602 (Found:
C, 52.2; H, 4.0; N, 8.4. C14H12N2O5S requires C, 52.5; H, 3.8; N,
8.8%); δH(250 MHz; CDCl3) 2.78 (3H, d, J 4.9, NMe), 6.53 (1H,
s, CH), 6.82 (1H, br q, J 4.9, NH), 6.97 (1H, dd, J 5.2 and 3.6,
thienyl), 7.22 (1H, dd, J 3.6 and 1.0, thienyl), 7.33 (1H, dd, J 5.2
and 1.0, thienyl), and 8.19 (4H, s, Ar); δC(100.6 MHz; CDCl3)
26.7 (q), 72.6 (d), 123.9 (2 × d), 127.4 (d), 127.8 (d), 128.7 (d),
131.5 (2 × d), 134.8 (s), 136.9 (s), 151.1 (s), 163.8 (s), and 168.2
(s); m/z EI 320.0472 (Mϩ, C14H12N2O3S requires 320.0466),
EI 320 (Mϩ, 6%), 263 (60), 150 (100), 104 (56), and 96 (61).
2-(4-Nitrobenzoyloxy)-N-methyl-2-(1-naphthyl)acetamide
22s. Yield 100%; colourless oil; νmax(neat)/cmϪ1 3368, 1772,
1677, and 1607; δH(250 MHz; CDCl3) 2.80 (3H, d, J 4.6, NMe),
6.90 (1H, br s, NH), 7.00 (1H, s, CH), and 7.40–8.30 (11H, m,
Ar); m/z EI 364.1014 (Mϩ, C20H16N2O5 requires 364.1059),
CI 365 (MHϩ, 10%), 307 (45), 150 (100), 141 (20), 120 (25),
and 92 (10).
2-Hydroxy-N-methyl-2-phenylacetamide 23.19b To a solution
of 2-acyloxy-N-methyl-2-phenylacetamide 22a (0.27 g, 1.3
mmol) in MeOH–H2O (4 cm3, 1:1 v/v) was added potassium
carbonate (0.18 g, 1.3 mmol). The mixture was stirred at
room temperature for 30 minutes. The solvent was removed
in vacuo and the residue taken up in ethyl acetate and extracted
with water (2 × 5 cm3). Drying with MgSO4 and removal of
the solvent in vacuo furnished the alcohol 23 (110 mg, 52%
yield) as a clear oil.
2-(4-Methoxybenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
22m. Yield 100%; yellow oil; νmax(neat)/cmϪ1 3464, 1757, 1672,
and 1605 (Found: C, 58.7; H, 5.0; N, 4.1. C15H15NO5S requires
C, 59.0; H, 5.0; N, 4.6%); δH(300 MHz; CDCl3) 2.87 (3H, d,
J 4.9, NMe), 3.86 (3H, s, OMe), 6.45 (1H, br s, NH), 6.58 (1H,
s, CH), 6.86–7.01 (3H, m, thienyl ϩ 2 Ar), 7.22 (1H, d, J 3.4,
thienyl), 7.32 (1H, dd, J 5.2 and 1.1, thienyl), and 8.04 (2H, m,
Ar); δC(100.6 MHz; CDCl3) 26.4 (q), 71.4 (d), 113.9 (2 × d),
121.2 (s), 126.6 (d), 126.8 (d), 127.5 (d), 132.1 (2 × d), 137.7 (s),
164.0 (s), 164.6 (s), and 168.4 (s); m/z EI 305.0724 (Mϩ,
C15H15NO4S requires 305.0722), EI 305 (Mϩ, <0.5%), 152 (6),
135 (100), 107 (4), and 97 (30).
Cross-over experiment with 21a and 21h
A mixture of 21a (31.1 mg, 0.15 mmol) and 21h (35.2 mg,
0.15 mmol) triethylamine (30 mg, 0.30 mmol) in toluene
(5.0 cm3) was heated at 110 ЊC for 5 days. The volatiles were
then removed in vacuo and the residue analysed by GC–NMR
to show a 1:1:1:1 mixture of 22a:22h:22f:22v. 2-Acetoxy-
N-methyl-2-phenylacetamide 22a, 6.7 minutes; 2-acetoxy-
N-methyl-2-(4-methylphenyl)acetamide 22f, 9.3 minutes;
2-propanoyloxy-N-methyl-2-(4-methylphenyl)acetamide 22h,
11.6 minutes; 2-propanoyloxy-N-methyl-2-phenylacetamide
22v, 8.3 minutes.
2-(4-Methylbenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
22n. Yield 100%; white crystalline solid, mp 103–105 ЊC (from
hexane); νmax(CHCl3)/cmϪ1 3455, 1724, 1687, and 1611; δH(300
MHz; CDCl3) 2.42 (3H, s, Me), 2.89 (3H, d, J 4.9, NMe), 6.26
(1H, br s, NH), 6.61 (1H, s, CH), 7.01 (1H, dd, J 5.1 and 3.4,
thienyl), 7.23–7.35 (4H, m, 2 × thienyl, 2 × Ar), and 7.99 (2H,
m, Ar); δC(100.6 MHz; CDCl3) 21.7 (q), 26.4 (q), 71.5 (d), 126.1
(s), 126.7 (d), 126.8 (d), 127.6 (d), 129.3 (2 × d), 129.9 (2 × d),
137.5 (s), 144.7 (s), 164.9 (s), and 168.3 (s); m/z EI 289.0771
(Mϩ, C15H15NO3S requires 289.0773), EI 289 (Mϩ, 10%), 258
(5), 232 (15), 136 (16), 119 (76), 91 (36), and 83 (200).
2-Propanoyloxy-N-methyl-2-phenylacetamide 22v. From
cross-over experiment, GC = 8.3 minutes; colourless oil;
νmax(Nujol)/cmϪ1 3274, 1743, and 1657 (Found: C, 64.8; H, 6.8;
N, 6.2. C12H16NO3 requires C, 65.1; H, 6.8; N, 6.3%); δH(250
MHz; CDCl3) 1.14 (3H, t, J 7.5, CH2CH3), 2.40 (2H, m,
CH2CH3), 2.79 (3H, d, J 4.6, NMe), 6.03 (1H, s, CH), 6.32 (1H,
br s, NH), and 7.27–7.35 (5H, m, Ph); δC(100.6 MHz; CDCl3)
9.3 (q), 26.5 (q), 27.9 (t), 75.7 (d), 127.7 (2 × d), 129.1 (2 × d),
2-(4-Chlorobenzoyloxy)-N-methyl-2-(2-thienyl)acetamide
22o. Yield 100%; white crystalline solid, mp 55–58 ЊC (from
hexane); νmax(CHCl3)/cmϪ1 3455, 1726, 1692, and 1594; δH(250
MHz; CDCl3) 2.90 (3H, d, J 4.9, NMe), 6.15 (1H, br s, NH),
6.58 (1H, s, CH), 7.02 (1H, dd, J 5.2 and 3.6, thienyl), 7.23 (1H,
1126
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View Article Online
9 Parke Davis and Co., British Patent, 1968, 1, 125671.
10 S. L. Shapiro, I. M. Rose and L. Freedman, J. Am. Chem. Soc., 1959,
19, 6322.
129.7 (d), 136.2 (s), 169.4 (s), and 173.1 (s); m/z CI 222.1131
(MHϩ, C12H16NO3 requires 364.1130), CI 221 (MHϩ, 50%),
164 (86), 152 (65), and 35 (100).
11 (a) W. Hartwig and L. Boon, J. Org. Chem., 1987, 52, 4352;
(b) H. H. Wasserman and B. H. Lipschutz, Tetrahedron Lett., 1975,
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12 F. A. Davis and B.-C. Chen, Chem. Rev., 1992, 92, 919.
13 K. R. Guertin and T.-H. Chan, Tetrahedron Lett., 1991, 32, 715.
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15 R. V. Hoffmann, N. K. Nayyar and W. Chen, J. Org. Chem., 1992,
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Acknowledgements
We acknowledge the EPSRC for a quota award (J. L. P.), Roche
Discovery Welwyn/EPSRC for a CASE award (D. P.) and the
Saudi Government for studentship support (Y. S. S. A.).
16 T. W. Greene and P. G. M. Wuts, Protecting groups in Organic
Synthesis, Wiley-Interscience, 1991.
17 J. J. Plattner, R. D. Gless and H. Rapoport, J. Am. Chem. Soc., 1972,
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18 R. V. Hoffmann, N. K. Nayyar and B. W. Klinekole, J. Am. Chem.
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19 (a) R. V. Hoffmann, N. K. Nayyar and W. Chen, J. Org. Chem.,
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J. Am. Chem. Soc., 1993, 115, 5031; (c) R. V. Hoffmann, N. K.
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Paper a909903d
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