Indium mediated allylation of glyoxylate oxime ethers, esters and cyanoformates

Article abstract of DOI:10.1039/b402764g

An indium mediated procedure has been developed for the allylation of activated O-functionalised oximes and nitriles as exemplified by a variety of glyoxylate derivatives. This method gives the corresponding free (or protected) amine in a one pot-process. The method is regiospecific and is carried out under remarkably mild conditions so that even oxime esters can be subjected to the typical reaction conditions.

Full text of DOI:10.1039/b402764g

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Indium mediated allylation of glyoxylate oxime ethers,
esters and cyanoformates
Dougal J. Ritson,*a Russell J. Cox*a and John Bergeb
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS.
E-mail: r.j.cox@bris.ac.uk; dougal.j.ritson@bris.ac.uk; Fax: ϩ44 (0) 117 929 8611
b GlaxoSmithKline, New Frontiers Science Park (North), 3rd Avenue, Harlow, Essex,
UK CM19 5AW
Received 24th February 2004, Accepted 28th April 2004
First published as an Advance Article on the web 9th June 2004
An indium mediated procedure has been developed for the allylation of activated O-functionalised oximes and
nitriles as exemplified by a variety of glyoxylate derivatives. This method gives the corresponding free (or protected)
amine in a one pot-process. The method is regiospecific and is carried out under remarkably mild conditions so
that even oxime esters can be subjected to the typical reaction conditions.
achieve even moderate yields of N-alkyl O-alkyl hydroxyl-
Introduction
amines from oxime ethers demands the use of unstabilised
organometallics (typically RLi or RMgX) often in the presence
of a Lewis acid.7 Given the harsh conditions required for the
addition of nucleophiles to oxime ethers, it is of little surprise
As part of a project to examine the synthesis of N-O containing
heterocycles, such as 1, by ring closing metathesis (RCM), we
required a synthetic route to dienes of the type 2. We considered
that these compounds could be accessed by allylation of the
corresponding oxime esters such as 3 which in turn could be
made from glyoxylates 5 ( Scheme 1).
that 1,2-additions to oxime esters (R᎐N–O–C(O)RЈ) are
᎐
prevented by competing addition at the ester carbon.
Despite the general difficulties experienced in adding nucleo-
philes to imines and oximes, it has been shown that electron-
withdrawn species such as the α-imino esters 6 are more reactive
to organometallics. However, few organometallics are com-
patible with α-imino esters as demonstrated by the fact that
benzylzinc is the only reagent which adds regiospecifically to
the desired position of 6 (Scheme 2).8 This emphasises the fine
balance between the reagents used and the reacting centre
through which the reaction proceeds.
Scheme 1 Proposed route to cyclic hydroxylamines.
Scheme 2 Addition of organometallic reagents to α-carboxy imines.
The key stage of this synthesis would be the nucleophilic
addition of an allyl unit to the substituted oxime 3. The
addition of nucleophiles to imines and imine derivatives is a
well known reaction but the low electrophilicity of imines as
compared to aldehydes and ketones has necessitated the use of
highly reactive reagents, often in conjunction with an activating
agent.1 Reports of ketimines undergoing 1,2-addition are rare,
highlighting the low reactivity of this species.2 Examples of
aldimines reacting as electrophiles with organometallics are
more prevalent. However, these reactions usually require a
Lewis acid or activating agent to prevent the strongly basic
nucleophiles deprotonating the α-position and forming
azaenolates.3
Recently, Hanessian has reported allylations of glyoxylic acid
and glyoxylate oxime ethers, such as 9, using an allylzinc
reagent under aqueous conditions (Scheme 3).9 These workers
reported yields up to 98% under mild conditions. We thus
considered this method to be ideal for our required allylation
of glyoxylate oxime esters.
Scheme 3 Hanessian’s allylation of oxime ethers. Reagents and
conditions: (i) Zn, CH2᎐᎐CHCH2Br, NH4Cl (aq), 98%.
Nucleophilic additions to oximes and oxime ethers (R᎐N–
᎐
ORЈ) have proven even more troublesome due to the increased
acidity of the α-protons, giving rise to side products such as
aziridines.4 Furthermore, the lower electrophilicity of the iminyl
bond of oximes, in comparison to imines, requires more forcing
conditions to allow nucleophilic addition to occur. For example
allyl boronates can add to aldimines but aldoximes require
prolonged reaction times and elevated temperatures.5,6 To
Results
Glyoxylate derived oximes
Methyl glyoxylate 11 was reacted with hydroxylamine hydro-
chloride under basic aqueous conditions to afford the corre-
sponding glyoxylate oxime 12 (Scheme 4). Carbodiimide
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
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an initial experiment, indium powder was reacted with allyl
bromide in DMF and addition of the oxime ester 13 provided
the desired product 16 in 56% yield after aqueous workup. The
less electrophilic oxime ether 14 was treated under the same
conditions which, gratifyingly, gave 15 in > 80% yield. In an
attempt to optimise the reaction we increased the concentration
of the reacting species. Analysis of the reaction mixture
indicated rapid consumption (typically conversion was com-
plete in 15 min) of the starting material 14 and its conversion to
product 15 (24%), the dimeric diketopiperazide 20 (19%) and
polymeric material (Scheme 6).
Scheme 4 Synthesis and reactions of oxime ether and ester. Reagents
and conditions: (i) HONH3Cl, NaHCO3 (aq), RT, 52%; (ii) CH2᎐᎐
CHCH2CO2H, EDCi, HOBt, THF, RT, 44%; (iii) BnONH3Cl, pyr,
MeOH, RT, 80%; (iv) Zn, CH2᎐᎐CHCH2Br, THF–NH4Cl (aq).
coupling with but-3-enoic acid, in the presence of hydroxy-
benzotriazole (HOBt), or treatment with but-3-enoic
anhydride, then led to the required oxime ester 13. The benzyl
oxime ether 14 was formed by reaction of methyl glyoxylate
with O-benzylhydroxylamine hydrochloride in methanol and
pyridine. We first attempted allylation of 14 using the aqueous
conditions developed by Hanessian. Thus treatment of 14 with
allyl bromide and Zn in aqueous NH4Cl gave the expected
secondary amine 15 in 92% yield. However, under the same
conditions the oxime ester 13 gave only a 38% yield of 16
(Scheme 4).
We next attempted an allylation of 13 using allyltrimethyl-
silane in the presence of BF3ؒOEt2. This reagent adds quickly
to p-nitrobenzyl glyoxylate 17 to give the corresponding
α-hydroxyester 18 (Scheme 5). However this reaction with
the oxime ester 13 failed.10 Grignard addition to 13 was also
unsuccessful (with and without BF3ؒOEt2). The major products
of this reaction were the oxime 12 and the bisallyl ketone 19,
resulting from Grignard addition to the but-3-enoyl ester.
The balance of the reaction was starting material 13
(Scheme 5). Predictably, the free oxime 12 did not react with
either Grignard reagents or allyltrimethylsilane. These results
dictated that an alternative means for the allylation of 13 had to
be employed.
Scheme 6 Indium mediated allylation of oxime ether. Reagents and
conditions: (i) In, CH2᎐᎐CHCH2Br, THF–DMF.
In order to prevent the dimerisation we added acetic
anhydride to the reaction mixture. Under these conditions two
allylation products were recovered – the expected N-acetyl
product 21 (42%) and the free amine 15 (40%) resulting from
protonation of the amine intermediate by AcOH. The same
reaction conditions were also successful with the glyoxylate
oxime ester 13, providing 22 in 57% and 16 in 21% overall yield
(Scheme 6).
Addition of Et3N to the reactions with acetic anhydride and
the allylating reagent forced full reaction with the anhydride
and gave 84% yield of the N-acetyl oxime ether 21. However,
although the oxime ester 13 reacted well under these conditions,
we observed formation of the isomeric olefin 23.
In order to examine the scope of this new allylation reaction
we synthesised a range of oxime ethers and esters as potential
substrates. We thus synthesised the benzoyl oxime ester 24 from
12 and benzoic anhydride. Fumaryl chloride 25 was converted
to the corresponding tert-butyl ester 26, and ozonolysis yielded
tert-butyl glyoxylate 29. In parallel, tartaric acid 27 was con-
verted to its p-nitrobenzyl (PNB) ester 28, and H6IO5 oxidation
gave the PNB glyoxylate hydrate 32 which was dehydrated
under Dean–Stark conditions to give the aldehyde 33 which was
used immediately (Scheme 7).
The glyoxylates 29 and 33 were then condensed with
O-benzylhydroxylamine to give the oxime ethers 30 and 34, or
condensed with hydroxylamine and the products coupled with
benzoic anhydride in the presence of pyridine to form the oxime
esters 31 and 35 (Scheme 7). The PNB ester 35 proved to be
unstable under basic conditions (pyr or dimethylaminopyridine,
DMAP), eliminating to form the corresponding nitrile 36.
However, 35 was made by coupling benzoic acid to the oxime
using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCi)
and HOBt and it was isolated in good yield.
Scheme 5 Reactions with allylsilane and Grignard reagents. Reagents
and conditions: (i) TMSCH2CH᎐CH2, BF3ؒOEt2, CH2Cl2, 78%;
᎐
(ii) BrMgCH2CH᎐CH2, Et2O.
᎐
Since the advent of indium mediated allyl additions to
carbonyl compounds, as reported by Butsugan,11 these
reactions have become the method of choice for formation of
homoallylic alcohols.12 Although indium mediated allylations
of imines are known (aldimines;13 aryl/tosyl hydrazones and
aldonitrones14 all react) these reactions appear to demand an
aromatic moiety adjacent to the imino group and there are no
known examples of additions to oximes, oxime esters or oxime
ethers.
We reasoned that the electron-withdrawn oxime glyoxylates
such as 13 and 14 might react with allylindium reagents. In
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Table 1 Results of allylation reactions. Bn = Benzyl, Bz = Benzoyl
Oxime
R
RЈ
Product
Yield (%)a
14
24
30
31
34
35
Me
Bn
Bz
Bn
Bz
Bn
Bz
21
37
38
39
40
41
84
81
80
72
86
47
Me
tBu
tBu
PNB
PNB
a Reaction conditions not optimised.
the oxime ester 24 gave the bis-acetamide 44 as a byproduct, via
elimination of 37. The PNB ester 41, derived from 35, proved
particularly unstable in this respect.
Other oximes
Methyl pyruvate 45 was also reacted with hydroxylamines to
produce the corresponding oxime benzyl ether 46 and benzoyl
ester 47. Methyl acetoacetate 48 reacted with hydroxylamine to
afford a mixture of the isoxazolone 49 and the corresponding
oxime which was coupled to benzoic anhydride to give 51.
Reaction of methyl acetoacetate with O-benzylhydroxylamine
gave the corresponding oxime ether 50. These substrates
were then reacted under the standard allylating conditions
(Scheme 9).
The only ketoxime which reacted was the oxime ester 47. The
product was obtained as a mixture of the expected N-acetyl
amide 53 (53%) and the corresponding free amine (38%) 54. All
Scheme 7 Substituted glyoxylate oxime ethers and esters. Reagents and
t
conditions: (i) (PhCO)2O, pyr, CH2Cl2, DMAP, RT, 62%; (ii) BuOH,
BuLi, Et2O, 0 ЊC, 39%; (iii) O3, CH2Cl2, Ϫ78 ЊC, (CH3)2S, 50%;
(iv) Et3N, O2N(C6H4)CH2Br, DMF, 79%; (v) THF, H6IO5, RT, 63%;
(vi) PhCH3, ∆; (vii) BnONH3Cl, pyr, MeOH, RT, 69%; (viii) HONH3Cl,
pyr, MeOH, 74%, then (PhCO)2O, pyr, DMAP, CH2Cl2, 59%;
(ix) BnONH3Cl, pyr, MeOH, RT, 86%; (x) HONH3Cl, pyr, MeOH,
81%, then C6H5CO2H, EDCi, HOBt, MeCN, 65%.
The standard allylation reaction consisted of premixing the
oxime ether or ester with an excess of freshly distilled Ac2O in
anhydrous THF. This was followed by the addition of the
allylating reagent consisting of 1.2 eq. indium and 1.8 eq. allyl
bromide in dimethylformamide (DMF). After 2 h, to ensure
acetylation was complete, an excess of Et3N (10 eq.) was added
followed by aqueous workup. For the oxime esters one
equivalent of Et3N was added to limit elimination (vide infra).
All the allylation reactions proceeded with good to excellent
yields (Table 1). The yields of the oxime ester reactions are
rather lower than those of the corresponding oxime ether
reactions. The likely cause of this is the ability of the oxime
esters to undergo elimination and tautomerisation to give
enamines (Scheme 8). For example, under reaction conditions,
Scheme 9 Ketoxime ethers and esters. Reagents and conditions:
(i) BnONH3Cl, pyr, MeOH, RT, 87%; (ii) HONH3Cl, pyr, MeOH, 83%,
then (PhCO)2O, pyr, DMAP, CH2Cl2, 97%; (iii) In, CH2᎐᎐CHCH2Br,
Ac2O, Et3N, THF–DMF, 53%; (iv) HONH3Cl, pyr, MeOH, 51%;
(v) HONH3Cl, pyr, MeOH, 37% then (PhCO)2O, pyr, DMAP, CH2Cl2,
78%; (vi) BnONH3Cl, pyr, MeOH, RT, 77%.
Scheme 8 Base catalysed elimination of oxime esters.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
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Table 2 Addition of crotyl units
diastereoselectivity was observed, most likely a product of the
higher reactivity of the oxime esters overcoming a steric barrier
in the transition state. Although crotyl bromide reacted well, we
found that prenyl bromide was unreactive under our conditions.
Cyanoformates
When Et3N was premixed with O-benzoyl methyl glyoxylate
oxime ester 24 the reaction turned black and an exotherm was
detected. The allylating suspension was decanted into the black
solution whereupon another exotherm was observed. The
solitary product was the bis-allylated amide 65. This compound
must have arisen via double addition to a nitrile formed by
elimination of benzoate from 24. To corroborate this finding
commercial methyl cyanoformate 66 was subjected to a typical
allylation procedure and this resulted in the same product
(Scheme 11).
Oxime
R
Product
Yield (%)a
d.e.
14
24
Bn
Bz
63
64
77
75
11.8 : 1
1.3 : 1
a Reaction conditions not optimised.
starting material was consumed. This demonstrated that the
iminyl carbons of the oxime esters were, as expected, more
electrophilic than those of the analogous oxime ethers. The
ketoxime ether 46 and the two acetoacetate derivatives 50 and
51 were not allylated. The isoxazolone 49 reacted with Ac2O to
give the known N-acetyl derivative 55.
We also examined a range of unsaturated and aromatic
aldehydes with the oxime ester derivatives as they had proven
more reactive. trans-2-Methylcinnamaldehyde 56 was con-
densed with hydroxylamine hydrochloride (Scheme 10) after
which the oxime was reacted with benzoic anhydride to give the
conjugated aldoxime 57, while phenylacetaldehyde 58 gave
the corresponding oxime ester 59 (the acidic nature of the
α-protons of phenylacetaldehyde, the corresponding oxime
and oxime ester resulted in low yielding reactions). Benzalde-
hyde 60 was used to make the corresponding oxime ether and
esters 61 and 62 in good yields. None of these compounds were
allylated under the standard conditions, or in the presence of
CF3CO2H (vide infra).
Scheme 11 Bis-allyl addition to methyl cyanoformate. Reagents and
conditions: (i) Et3N, DMF; (ii) In, allyl bromide, Ac2O, DMF; (iii) In,
allyl bromide, Ac2O, Et3N, DMF, 68%.
The only reported synthesis of amide 65 was by Hammer and
Undheim in 4 steps with an overall yield of 46%.15 Our method
gives the same unnatural amino acid (which can be subjected to
ring-closing metathesis conditions to produce conformationally
restricted amino acids) in 68% yield in a single step. Other
nitriles, such as acetonitrile and benzonitrile did not react under
these conditions, however.
Acidic conditions
To allow synthesis of the unprotected amine the allylating reac-
tion was carried out in the presence of one equivalent of
CF3CO2H and the absence of Ac2O and Et3N. The oxime ether
14 and oxime esters 24 and 13 reacted smoothly with the allyl-
ating reagent to give the corresponding allylated products in
excellent yields (Scheme 12). In contrast to the basic conditions
described previously, the butenoyl oxime ester 16 did not
undergo olefin isomerisation and neither oxime ester underwent
elimination reactions. The O-benzoyl hydroxylamine 67 proved
unstable, however, and degraded over time. The free oxime 12
and methyl cyanoformate 66 both underwent allyl additions,
giving 68 and 69 respectively, in the acidic medium. This
reinforces how weakly basic, and tolerant of functionality, the
allylindium species is.
Discussion
Scheme 10 Aldoxime esters and ethers. Reagents and conditions: (i)
HONH3Cl, pyr, MeOH, RT, 91% then (PhCO)2O, pyr, DMAP, CH2Cl2,
50%; (ii) HONH3Cl, pyr, MeOH, RT, 42% then C6H5CO2H, EDCi,
HOBt, CH2Cl2, 19%; (iii) BnONH3Cl, pyr, MeOH, RT, 89%; (iv)
HONH3Cl, pyr, MeOH, RT, 33% then (PhCO)2O, DMAP, CH2Cl2,
76%.
The difficulty associated with the reaction of oximes with
organometallic species has been highlighted recently. For
example, Moody et al. have shown that while vinyllithium,
generated from tetravinyltin, will add to oxime ethers, a variety
of other species, including phenyllithium, vinyl Grignard, furyl-
lithium, trimethylsilyl acetylide and cyanide (from Et2AlCN)
will not.16 We have shown here that other species such as
allylsilane also do not add to oxime ethers. In the case of oxime
ethers derived from glyoxylate, and of oxime esters, the nucleo-
phile generally attacks the ester carbonyl rather than the oxime.
In contrast to these results, allylindium reagents add
smoothly, and in high yield to both oxime ethers and oxime
The reaction of substituted allyl bromide species was then
investigated (Table 2). The use of crotyl bromide as the allyl-
ating agent did not impede the reaction with either oxime ethers
or esters. Exclusive γ-addition was observed, and in the case of
the oxime ethers some diastereoselectivity (11.8 : 1) was
observed. In the case of the oxime esters much lower (1.3 : 1)
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MHz (1H) and 68, 76 and 101 MHz (13C) respectively. Chemical
shifts are quoted in ppm relative to TMS. IR spectra were
obtained using a Perkin-Elmer FT-IR spectrometer. Mass
spectra were obtained in the indicated mode using a VG
analytical autospec instrument. Flash chromatography was
performed using the method of Still et al.17 or using an auto-
mated Biotage system. TLC analysis was performed using
Merck glass backed 0.2 mm silica plates developed using the
indicated solvent and visualised with UV and/or potassium
permanganate.
Procedure A. General procedure for preparation of O-benzyl
oxime ethers not containing a methyl ester
O-Benzylhydroxylamine hydrochloride (1.3 eq.) was added to
the glyoxylate (1 eq.) in EtOH followed by pyridine (1.1 eq.).
The reaction was heated to reflux for 40 min then allowed to
cool and the solvent removed in vacuo. The residue was then
dissolved in CH2Cl2 and washed with H2O and the aqueous
layer was further extracted with CH2Cl2. The combined
organics were dried (Na2SO4) and the solvent was evaporated.
Purification of the product was carried out by chromatography
eluting with petrol–EtOAc.
Procedure B. General procedure for allylation of oxime ethers
In powder (100 mesh, 276 mg, 2.4 mmol) was weighed into a
Wheaton vial. DMF (0.7 mL) was added followed by allyl
bromide (310 µL, 435 mg, 3.6 mmol). A triangular stirrer bar
was then dropped in and the mixture stirred vigorously. Within
a few minutes an exotherm could be felt and the mixture turned
into a very fine suspension that was dark green/black in colour.
After 40 min the allylating mixture was pipetted into a solution
of oxime derivative (2.0 mmol) and freshly distilled Ac2O
(4 mL) in anhydrous THF (14 mL) under a N2 atmosphere. The
Wheaton vial was washed out with dry THF (1 mL). After 2 h
Et3N (1 mL) was added and the reaction was left to stir
overnight. The reaction was quenched with NH4Cl (aq) (30 mL)
and extracted with Et2O (3 × 40 mL) which was dried (MgSO4),
filtered and concentrated. The residue was purified by flash
chromatography using petrol–EtOAc.
Scheme 12 Allylations carried out in an acidic environment. Reagents
and conditions: (i) In, allyl bromide, TFA, THF–DMF.
esters. To some extent this mirrors the results of Hanessian who
has shown that allylzinc species will also add to oxime ethers.
However, the allylindium reagents described here will add
smoothly to oxime esters, whereas allylzinc reagents add in
lower yield. Furthermore, the allylindium reactions can be
carried out under diverse conditions: in the presence of base
and an acid chloride the resulting oxyamines are acylated; in the
presence of acid, the oxyamines are protonated and protected
from further reaction. The reaction works with allyl bromide
and crotyl bromide equally well, but prenyl bromide does not
add, perhaps due to adverse steric interactions. The reaction
appears to rely on the presence of an ester α to the oxime. All
the glyoxylate derived oximes reacted in good yield. In the case
of the ketoxime derived from pyruvate, only the more reactive
oxime ester reacted: it appeared that the allylindium reagent
would not add to the benzyl oxime ether. Furthermore, oximes
α to aromatic groups, olefins and methylene groups were
unreactive.
In the presence of excess base, the oxime esters were prone to
elimination to form the corresponding cyanoformates. These
then underwent double allylation to form bis-allylglycine
derivatives, again in good yields. Once again, only nitriles α to
an ester reacted.
Overall the indium mediated allylation of glyoxylate derived
oxime ethers and esters provides a rapid and convenient route
to protected oxyaminoesters which we are investigating as sub-
strates for ring closing metathesis. The facile double addition
to cyanoformates provides rapid access to bis-allylglycine
derivatives which are difficult to make by other routes.
Procedure C. General procedure for allylation of oxime esters
In powder (100 mesh, 276 mg, 2.4 mmol) was weighed into a
Wheaton vial. DMF (0.7 mL) was added followed by allyl
bromide (310 µL, 435 mg, 3.6 mmol). A triangular stirrer bar
was then dropped in and the mixture stirred vigorously. Within
a few minutes an exotherm could be felt and the mixture turned
into a very fine suspension that was dark green/black in colour.
After 40 min the allylating mixture was pipetted into a
solution of oxime derivative (2.0 mmol) and freshly distilled
Ac2O (4 mL) in anhydrous THF (14 mL) under a N2 atmos-
phere. The Wheaton vial was washed out with dry THF (1 mL).
After 2 h Et3N (0.2 mL) was added and TLC monitoring began
(if any of the less polar amine intermediate remained Et3N was
added in no more than 0.1 mL portions with a minimum of 1 h
between additions). When complete, the reaction was quenched
with NH4Cl (aq) (30 mL) and extracted with Et2O (3 × 40 mL)
which was dried (MgSO4), filtered and concentrated. The
residue was purified by flash chromatography using petrol–
EtOAc.
Experimental
Procedure D. General procedure for allylation of oxime ethers,
esters and cyanoformates under acidic conditions
General
Commercially available reagents and solvents of ACS grade
were used throughout without prior purification unless
otherwise stated. Petrol refers to petroleum ethers 40/60.
All anhydrous solvents were purchased from Fluka and were
transferred under dried N2.
The oxime/nitrile derivative (2 mmol) was stirred in THF
(14 mL) with TFA (2 mmol). In parallel, indium powder
(100 mesh, 2.4 mmol for oxime/4.4 mmol for nitrile) was
weighed into a Wheaton vial. DMF (0.7 mL for oxime/1.5 mL
for nitrile) was added followed by allyl bromide (3.4 mmol for
oxime/6.6 mmol for nitrile). A triangular stirrer bar was then
NMR spectra were obtained using JEOL ∆-250, ∆-270,
λ-300 and ∆-400 spectrometers operating at 270, 300 and 400
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dropped in and the mixture stirred vigorously. Within a few
minutes an exotherm could be felt and the mixture turned into a
very fine suspension that was dark green/black in colour. After
40 min the allylating mixture was pipetted into the oxime/nitrile
solution and was washed out with DMF (0.4 mL). The reaction
was left to stir overnight then quenched with NaHCO3 (30 mL)
and Et2O (40 mL) was added. The organics were collected and
the aqueous layer extracted with Et2O (3 × 40 mL). All organics
were combined, dried (MgSO4), filtered and concentrated.
and the solvent was evaporated. The crude oil was purified by
passing the oil through a plug of silica using 9 : 1 petrol–EtOAc
as the solvent (7 : 3 petrol–EtOAc, RF 0.50) to give the title
compound 14 as a pale yellow oil (3.155 g, 16.3 mmol, 80%).
δH (400 MHz; CDCl3) 7.56 (1H, s, NCH), 7.38 (5H, m, 5 ×
ArH), 5.30, (2H, s, PhCH2), 3.86 (3H, s, OMe); δC (68 MHz;
CDCl3) 162.4 (CO), 141.0 (CN), 136.0 (ArCCH2), 128.6 (4 ×
ArC), 78.2 (PhCH2), 52.5 (OMe); m/z (CI) 194 [(MH)ϩ, (32%)],
ϩ
91 [PhCH2 , (100)].
Methyl glyoxylate oxime 1218
Methyl 2-[benzyloxy-amino]-pent-4-enoate 15
NaHCO3 (1.924 g, 22.3 mmol) was dissolved in H2O (15 mL)
and hydroxylamine hydrochloride (1.73 g, 24.9 mmol) was
slowly added with stirring. Stirring continued until effer-
vescence had subsided, then methyl glyoxylate 1119 (2.00 g, 22.7
mmol) was added. The reaction was stirred for a further 7 h
before being extracted with CH2Cl2 (3 × 25 mL). The aqueous
layer was returned to the flask and stirring continued overnight.
The solution was extracted again with CH2Cl2 (3 × 25 mL) and
the organic layers were combined and dried (Na2SO4) and
solvent removed in vacuo to give methyl glyoxylate oxime 12 as
a colourless solid (1.21 g, 11.8 mmol, 52%). (7 : 3 Petrol–
EtOAc, RF 0.25); mp 56–58 ЊC (lit.18 48–51 ЊC); νmax (solid)/
cmϪ1 3203 (OH), 1722 (CO); δH (270 MHz; CDCl3) 9.09 (1H, s,
OH), 7.58 (1H, s, CH), 3.87 (3H, s, OMe); δC (101 MHz;
CDCl3) 162.2 (CO), 142.1 (CN), 52.6 (OMe).
Using 14 (378 mg, 1.96 mmol) and general procedure B yielded
a colourless oil (434 mg, 1.8 mmol, 92%). νmax (neat)/cmϪ1
3261.8 (NH), 3032 (CH), 2953 (CH), 1739 (CO); δH (400 MHz;
CDCl3) 7.33 (5 H, s, 5 × ArH), 5.95 (1 H, brs, NH), 5.70 (1 H,
m, CH᎐), 5.10 (2 H, m, ᎐CH ), 4.71 (2 H, s, PhCH ), 3.74 (3 H,
᎐
᎐
2
2
s, OMe), 3.68 (1 H, t, J 6.8, COCH), 2.34 (2 H, m, COCHCH2);
δ (101 MHz; CDCl ) 174.6 (CO), 138.9 (ArCC), 134.3 (᎐CH),
᎐
C
3
129.6 (2 × ArCH), 129.4 (2 × ArCH), 128.9 (ArCH), 119.1
(᎐CH ), 77.4 (PhCH ), 64.4 (COCH), 53.0 (OMe), 35.0
᎐
2
2
(CHCH2CH); m/z (CI) 236 [(MH)ϩ, (64%)]; HRMS (CI) calc.
(MH)ϩ 236.1287 found 236.1284.
Methyl 2-[but-3-enoyloxy-amino]-pent-4-enoate 16
In powder (100 mesh, 257 mg, 2.2 mmol) was weighed into a
Wheaton vial. THF (1.0 mL) was added, followed by allyl
bromide (300 µL, 419 mg, 3.5 mmol). A triangular stirrer bar
was then dropped in and the mixture stirred vigorously. Within
a few minutes an exotherm could be felt and the mixture turned
into a very fine suspension that was dark green/black in colour.
After 1.5 h O-but-3-enoyl methyl glyoxylate oxime ester 13 (189
mg, 1.1 mmol) was added. The reaction was stirred overnight
before being quenched with NH4Cl (aq) (25 mL) and extracted
with Et2O (3 × 40 mL) which was dried (MgSO4), filtered and
concentrated. Purity was achieved through flash chromato-
graphy eluting with 9 : 1 petrol–EtOAc (7 : 3 petrol–EtOAc, RF
0.55) to give methyl 2-[but-3-enoyloxy-amino]-pent-4-enoate
(133 mg, 0.6 mmol, 56%) as a colourless oil. νmax (neat)/cmϪ1
3230 (NH), 3083 (CH), 2984 (CH), 1740 (CO); δH (400 MHz;
O-But-3-enoyl methyl glyoxylate oxime ester 13
Vinylacetic acid (1.21 mL, 1.18 g, 11.8 mmol) and EDCi (2.70 g,
14.1 mmol) were premixed in THF–Et2O (1 : 1, 45 mL) with
HOBt (cat.) for 20 min. Methyl glyoxylate oxime 12 (1.21 g,
11.7 mmol) was then added to the suspension and the reaction
left to stir for 4 h. The reaction was diluted with EtOAc (25
mL), washed with H2O (2 × 30 mL) and NaHCO3 (aq. 40 mL),
dried (MgSO4), filtered and concentrated. The yellow oil was
purified by column chromatography using 88 : 12 petrol–EtOAc
(7 : 3 petrol–EtOAc, RF 0.36) as the running solvent which
provided O-but-3-enoyl methyl glyoxylate oxime ester 13 as a
colourless oil (890 mg, 5.2 mmol, 44%). νmax (neat)/cmϪ1 3086
(CH), 2959 (CH), 1779 (CO), 1733 (CO); δH (400 MHz; CDCl3)
CDCl ) 7.68 (1 H, d, J 9.2, NH), 5.72–5.89 (2 H, m, 2 × CH᎐),
᎐
3
7.78 (1H, s, NCH), 5.95 (1H, ddt, J 17.2, 10.3, 7, CH᎐), 5.26
5.15 (4 H, m, 2 × ᎐CH ), 3.85 (1 H, m, COCH), 3.75 (3 H, s,
᎐
᎐
2
(2H, m, ᎐CH ), 3.92 (3H, s, OMe), 3.29 (2H, dt, J 7.0, 1.5,
OMe), 3.08 (2 H, m, COCH2), 2.49 (2 H, m, COCHCH2);
᎐
2
COCH2); δC (101 MHz; CDCl3) 167.8 (CO), 161.4 (CO), 147.4
δC (101 MHz; CDCl ) 172.1 (CO), 170.3 (CO), 132.2 (CH᎐),
᎐
3
(CN), 128.6 (CH᎐), 119.9 (᎐CH ), 53.1 (OMe), 37.3 (CH ); m/z
129.2 (CH᎐), 119.3 (᎐CH ), 119.0 (᎐CH ), 62.7 (COCH), 52.2
᎐ ᎐ ᎐
2 2
᎐
᎐
2
2
(FAB) 343 [(M2H)ϩ, (27)], 194 [(MNa)ϩ, (34)], 172 [(MH)ϩ,
(99%)]; (Found C, 48.99; H, 5.10; N, 8.37. C7H9NO4 requires C,
49.12; H, 5.30; N, 8.18%).
(OMe), 37.3 (COCH2), 33.8 (COCHCH2); m/z (FAB) 214
[(MH)ϩ, (100%)], 236 [(MNa)ϩ, (50)], 427 (M2H)ϩ, (6)].
16 was also synthesised using 13 (342 mg, 2.0 mmol) and
Procedure D to afford 16 (362 mg, 1.72 mmol, 84%) after
chromatography eluting with 9 : 1 petrol–EtOAc.
13 was also synthesised by pretreatment of vinylacetic acid
(2.1 mL, 2.06 g, 20.1 mmol) with EDCi (1.97 g, 10 mmol) in
CH2Cl2 (18 mL) for 60 min at RT to form the anhydride in situ.
The reaction ws diluted with CH2Cl2 (10 mL) and washed
with water (20 mL) and satd. aqueous NaHCO3 (15 mL).
The organics were collected, dried (MgSO4) and concentrated
in vacuo and the crude anhydride was added to a solution of
12 (524 mg, 5.1 mmol) in CH2Cl2 (18 mL) and pyridine (565 µL,
554 mg, 7.0 mmol). The reaction was stirred overnight and
worked-up and purified as before to afford 13 (559 mg, 3.3
mmol, 64%).
p-Nitrobenzyl 2-hydroxypent-4-enoate 18
p-Nitrobenzyl glyoxylate (2.04 g, 9.8 mmol) was dissolved in
anhydrous CH2Cl2 (15 mL) and the reaction vessel was cooled
to 0 ЊC. Boron trifluoride diethyl etherate (1.80 mL, 2.03 g, 14.3
mmol) was then added and allyltrimethylsilane (2.32 mL, 1.67
g, 14.6 mmol) was added to the solution 30 min later. After 1 h
the reaction was warmed to RT and left to stir overnight. The
reaction was washed with water (3 × 20 mL), dried (MgSO4),
filtered and concentrated. The orange oil was purified by flash
chromatography, eluting with 3 : 2 petrol–EtOAc (1 : 1 petrol–
EtOAc, RF 0.34), to give p-nitrobenzyl 2-hydroxypent-4-enoate
as an orange oil (1.91 g, 7.6 mmol, 78%). νmax (film)/cmϪ1 3492
(OH), 3090 (CH), 2950 (CH), 1738 (CO), 1518 (NO2), 1350
(NO2); δH (270 MHz; CDCl3) 8.24 (2 H, d, J 8.9, 2 × ArH), 7.57
O-Benzyl methyl glyoxylate oxime ether 1420
To a solution of O-benzylhydroxylamine hydrochloride (4.90 g,
30.6 mmol) and pyridine (1.99 mL, 1.942 g, 24.5 mmol)
in MeOH (22 mL) was added methyl glyoxylate 11 (1.80 g, 20.5
mmol) and the reaction refluxed for 3.5 h. The reaction was
cooled and the MeOH removed in vacuo. The residue was then
dissolved in CH2Cl2 (45 mL) and H2O (30 mL) and the organic
layer collected. The aqueous layer was extracted with CH2Cl2
(2 × 45 mL), the organics were combined and dried (Na2SO4)
(2 H, d, J 8.9, 2 × ArH), 5.79 (1 H, m, CH᎐), 5.3 (2 H, d, J 1.7,
᎐
PhCH ), 5.13 (2 H, m, ᎐CH ), 4.37 (1 H, td, J 6.3, 4.6, COCH),
᎐
2
2
2.72 (1 H, d, J 6.3, OH), 2.55 (2H, m, CHCH2CH); δC (101
MHz; CDCl3) 174.0 (CO), 147.6 (ArCN), 142.2 (ArCC), 132.0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1926

View Article Online
(CH᎐), 128.7 (2 × ArCH), 123.9 (2 × ArCH), 119.2 (᎐CH ),
Di-tert-butyl fumarate 2621
᎐
᎐
2
70.0 (COCH), 65.8 (PhCH2), 38.7 (CH2); m/z (CI) 252 [(MH)ϩ,
(24%)], 206 [(MϪHO2CCH(OH)CH2CHCH2)ϩ, (100)]; HRMS
(CI) calc [(MH)ϩ] 252.0872 found 252.0874.
tert-Butyl alcohol (10.0 mL, 105 mmol) was added under dry
N2 to a dry flask and the vessel was cooled to 0 ЊC. nBuLi (2.5 M,
24 mL, 60 mmol) was added over 10 min and the suspension
stirred for 40 min at 0 ЊC. A solution of fumaryl chloride 25
(6.12 mL, 60 mmol) in anhydrous Et2O (20 mL) was added
through a dropping funnel over 40 min, the temperature of the
reaction was maintained at room temperature. After 4 h the
reaction was quenched with water (20 mL) and the organics
were collected then washed with NaHCO3 (aq., 2 × 25 mL),
brine (2 × 20 mL) and dried (MgSO4). The brown solution was
filtered, concentrated and recrystallised from hexane to afford
pale brown needles. These were dissolved in 95 : 5, petrol–
EtOAc and passed through a plug of silica to yield 26 as a
colourless solid. The recrystallisation mother liquors were
purified by chromatography 96 : 4, petrol–EtOAc (9 : 1 petrol–
EtOAc, RF 0.55) to give the title compound as a colourless solid
which was combined with the rest of the material (5.40 g, 23.7
mmol, 39%). mp softened at 67 ЊC, melted at 68–70 ЊC (lit.21 71–
72 ЊC); νmax (solid)/cmϪ1 3006 (CH), 2939 (CH), 1704 (CO);
δH (400 MHz; CDCl3) 6.67 (2H, s, 2 × CH), 1.50 (18H, s, 6 ×
CH3); δC (101 MHz; CDCl3) 164.5 (2 × CO), 134.6 (2 × CH),
81.7 (2 × C(CH3)3), 28.0 (6 × CH3); m/z (FAB) 251 [(MNa)ϩ,
(7)], 229 [(MH)ϩ, (22%)], 173 [(MH2ϪC(CH)3)ϩ, (100)].
Methyl 2-[acetyl-benzyloxy-amino]-pent-4-enoate 21
Using 14 (391 mg, 2.02 mmol), Procedure B and 9 : 1 Petrol–
EtOAc as the solvent during chromatography (7 : 3 petrol–
EtOAc, RF 0.29) gave methyl 2-[acetyl-benzyloxy-amino]-pent-
4-enoate 21 as a pale yellow oil (465 mg, 1.7 mmol, 84%). νmax
(neat)/cmϪ1 3067 (CH), 2982 (CH), 1742 (CO), 1677 (CO);
δH (270 MHz; CDCl3) 7.38 (5H, s, 5 × ArH), 5.81 (1H, ddt,
J 6.9, 10.2, 16.8, CH᎐), 5.15 (2H, m, ᎐CH ), 4.99 (1H, m,
᎐
᎐
2
COCH), 4.98 (1H, d, J 10.6, PhCHH ), 4.90 (1H, d, J 10.2,
PhCHH), 3.75 (3H, s, OMe), 2.78 (2H, m, CH2), 2.15 (3H, s,
Me); δC (101 MHz; CDCl3) 174.4 (CO), 170.4 (CO), 134.7
(ArCC), 133.9 (CH᎐), 129.0 (2 × ArCH), 128.9 (ArCH), 128.7
᎐
(2 × ArCH), 118.2 (᎐CH ), 78.3 (PhCH ), 60.7 (COCH), 52.4
᎐
2
2
(OMe), 32.7 (CH2), 20.7 (Me); m/z (CI) 278 [(MH)ϩ, (59%)],
ϩ
236 [(MH2ϪAc)ϩ, (87%)], 91 [PhCH2 , (100)]; HRMS (CI)
calc. (MH)ϩ 278.1392 found 278.1396.
Methyl 2-[acetyl-but-3Ј-enoyloxy-amino]-pent-4-enoate 22
In powder (100 mesh, 252 mg, 2.2 mmol) was weighed into a
Wheaton vial. DMF (0.8 mL) was added, followed by allyl
bromide (290 µL, 411 mg, 3.4 mmol). A triangular stirrer bar
was then dropped in and the mixture stirred vigorously. Within
a few minutes an exotherm could be felt and the mixture turned
into a very fine suspension that was dark green/black in colour.
After 40 min a solution of O-but-3-enoyl methyl glyoxylate
oxime ester 13 (344 mg, 2.0 mmol) and freshly distilled Ac2O
(570 µL) in DMF (1.5 mL) were added to the allylating mixture.
After 2.5 h the reaction was quenched with NH4Cl (aq) (25 mL)
and extracted with Et2O (3 × 40 mL) which was dried (MgSO4),
filtered and concentrated. The residue was purified by flash
chromatography eluting with petrol–EtOAc 4 : 1 (7 : 3 petrol–
EtOAc, RF 0.34) to yield methyl 2-[acetyl-but-3Ј-enoyloxy-
amino]-pent-4-enoate 22 as a colourless oil (291 mg, 1.1 mmol,
57%). νmax (neat)/cmϪ1 3082 (CH), 2956 (CH), 1791 (CO), 1744
(CO), 1688 (CO); δH (270 MHz; CDCl3) 5.91 (1H, ddt, J 16.8,
Di-p-nitrobenzyl tartrate 2822
Tartaric acid 27 (3.15 g, 21 mmol) was dissolved in DMF
(40 mL) then cooled to 0 ЊC. Triethylamine (7.0 mL) was added
over 5 min. After 30 min of stirring, 4-nitrobenzyl bromide
(10.00 g, 46.3 mmol) in DMF (30 mL) was added dropwise at
0 ЊC. The solution was allowed to warm to RT and was then
stirred overnight. The reaction was decanted into ice/water (ca.
300 mL) and stirred for 30 min before the white precipitate was
filtered off under vacuum, washed with H2O (4 × 30 mL) and
air-dried. The colourless solid was then slurried in EtOH (270
mL) and after 16 h the suspension was filtered, air-dried then
dried under reduced pressure to yield the title compound as a
colourless solid (6.96 g, 16.6 mmol, 79%). mp softened at
162 ЊC, melted at 164–165 ЊC (lit.22 163–164 ЊC); νmax (solid)/
cmϪ1 3472 (OH), 3089 (CH), 2939 (CH), 1712 (CO); δH (270
MHz; DMSO) 8.20 (2 H, d, J 8.6, 4 × ArH), 7.66 (2 H, d, J 8.6,
4 × ArH), 5.82 (2 H, m, 2 × CH), 5.32 (4 H, s, 2 × CH2), 4.65
(2 H, m, 2 × OH); δC (68 MHz; DMSO) 171.9 (2 × CO), 147.9
(2 × ArCN), 144.0 (2 × ArCC), 129.4 (4 × ArCH), 124.5
(4 × ArCH), 73.6 (2 × CH), 65.8 (2 × CH2); (Found C, 51.43; H,
3.54; N, 6.49. C18H16N2O10 requires C, 51.43; H, 3.84; N,
6.66%).
9.9, 7.0, CH᎐), 5.78 (1H, m, CH᎐), 5.07–5.33 (5H, m, 2 × ᎐CH
᎐
᎐
᎐
2
and COCHCH2), 3.74 (3H, s, OMe), 3.23 (2H, d, J 7.0,
COCH2), 2.57 (2H, m, CH2), 2.05 (3H, s, COMe); δC (101 MHz;
CDCl ) 172.9 (CO), 169.3 (CO), 169.0 (CO), 133.0 (CH᎐),
᎐
3
128.1 (CH᎐), 120.3 (᎐CH ), 118.4 (᎐CH ), 59.3 (COCH), 52.5
᎐
᎐
᎐
2
2
(OMe), 36.6 (COCH2), 32.7 (CH2), 20.5 (Me); m/z (CI) 256
[(MH)ϩ, (16%)], 214 [(MH2ϪAc)ϩ, (100)]; HRMS (CI) calc.
(MH)ϩ 256.1185 found 256.1185.
tert-Butyl glyoxylate 2922
O-Benzoyl methyl glyoxylate oxime ester 24
Di-tert-butyl fumarate 26 (1.50 g, 6.6 mmol) was dissolved in
CH2Cl2 (25 mL) and cooled to Ϫ78 ЊC. O3 was bubbled through
until an excess was observed then the reaction was stirred for
another 30 min. Excess ozone was removed by passing O2
through the solution. Dimethyl sulfide (0.50 mL, 6.8 mmol) was
added and the reaction was warmed to RT. After 2 h the
solution was washed with brine (1 × 35 mL), dried (Na2SO4)
and the solvent evaporated. The crude product was applied to a
silica column and the product eluted with 3 : 2 petrol–EtOAc
to afford tert-butyl glyoxylate 29 as a colourless oil and
as a mixture of the aldehyde and hydrate (948 mg, 6.5 mmol,
50%). νmax (neat)/cmϪ1 3452 (OH), 2981 (CH), 1733 (CO);
δH (270 MHz; CDCl3) 9.3 (0.5 H, s, CH), 5.13 (0.5 H, m, CH),
1.57 (9 H, m, 3 × CH3); m/z (CI) 131 [(MH)ϩ, (3%)], 75
[(MH2ϪC(CH)3)ϩ, (7)], 57 [(tBu)ϩ, (100)].
Pyridine (2.15 g, 2.20 mL, 27.2 mmol) and benzoic anhydride
(6.69 g, 29.6 mmol) were added to a solution of the oxime 12
(2.37 g, 26.9 mmol) in CH2Cl2 (75 mL). 4-Dimethylamino-
pyridine (10 mol%) was then added and the reaction left to stir
until complete by TLC. CH2Cl2 (30 mL) was added and the
solution washed with H2O (2 × 50 mL) then 0.5 M HCl (50
mL). The organics were collected, dried (Na2SO4) and purified
twice by flash chromatography (7 : 3 petrol–EtOAc, RF 0.33) to
yield O-benzoyl methyl glyoxylate oxime ester 24 as a colourless
solid (3.45 g, 16.7 mmol, 62%). mp 73–75 ЊC; νmax (solid)/cmϪ1
3062 (CH), 2955 (CH), 1729 (CO); δH (400 MHz; CDCl3) 8.11
(2H, m, 2 × ArH), 7.97 (1 H, s, NCH), 7.65 (1H, m, ArH), 7.51
(2H, t, J 7.7, 2 × ArH), 3.95 (3H, s, OMe); δC (101 MHz;
CDCl3) 162.7 (CO), 161.5 (CO), 147.9 (NCH), 134.1 (ArCH),
130.1 (2 × ArCH), 128.8 (2 × ArCH), 127.5 (ArCC), 53.1
(OMe); m/z (FAB) 230 [(MNa)ϩ, (25)], 207 [(M)ϩ, (27%)];
(Found C, 58.35; H, 4.33; N, 6.86. C10H9NO4 requires C, 57.97;
H, 4.38; N, 6.76%).
O-Benzyl tert-butyl glyoxylate oxime ether 3023
Using 29 (600 mg, 4.6 mmol), procedure A and 9 : 1 petrol–
EtOAc (9 : 1 petrol–EtOAc, RF 0.45) as the running solvent
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1927

View Article Online
during chromatography gave O-benzyl tert-butyl glyoxylate
oxime ether 30 as a pale yellow oil (748 mg, 3.2 mmol, 69%).
δH (270 MHz; CDCl3) 7.46 (1 H, s, CH), 7.37 (5 H, s, 5 × ArH),
5.27 (2 H, s, CH2), 1.53 (9 H, s, 3 × CH3); δC (101 MHz; CDCl3)
161.1 (CO), 142.5 (CN), 136.1 (ArCC), 128.6 (5 × ArCH),
82.7 (C(CH3)3), 77.9 (CH2), 28.1 (3 × CH3); m/z (CI) 180
[(MH2ϪC(CH3)3)ϩ, (30%)], 57 [(tBu)ϩ, (100)].
ation. Using aldehyde 33 (1.21 g, 5.81 mmol), procedure A and
82 : 18 petrol–EtOAc as the solvent during flash chromato-
graphy (4 : 1 petrol–EtOAc, RF 0.30) gave O-benzyl p-nitro-
benzyl glyoxylate oxime ether 34 as a pale yellow solid (1.57 g,
5.0 mmol, 86%). νmax (solid)/cmϪ1 3081 (CH), 2953 (CH), 1720
(CO), 1514 (NO2), 1348 (NO2); δH (300 MHz; CDCl3) 8.23 (2H,
d, J 9, 2 × ArH), 7.60 (1H, s, NCH), 7.55 (2H, d, J 9, 2 × ArH),
7.37 (5H, s, 5 × ArH), 5.37 (2H, s, PhCH2), 5.31 (2H, s, PhCH2);
δC (76 MHz; CDCl3) 161.5 (CO), 147.9 (ArCNO2), 142.3
(ArCC), 140.3 (HCN), 135.7 (ArCC), 128.6 (5 × ArCH ϩ
2 × ArCH), 123.8 (2 × ArCH), 78.4 (PhCH2), 65.5 (PhCH2);
O-Benzoyl tert-butyl glyoxylate oxime ester 31
To a solution of 29 (948 mg, 7.3 mmol) in MeOH (12 mL) was
added hydroxylamine hydrochloride (585 mg, 8.5 mmol) then
pyridine (580 µL, 565 mg, 7.1 mmol). The reaction was stirred
(with heating, if neccessary) after which the MeOH was
removed in vacuo and the residue dissolved in CH2Cl2 (30 mL)
and water (30 mL). The layers were separated and the aqueous
layer extracted with CH2Cl2 (2 × 30 mL). All the organics were
combined, dried (Na2SO4), filtered then concentrated and
the resultant material purified by flash chromatography (9 : 1
petrol–EtOAc) to yield the oxime as a colourless oil (787 mg,
5.4 mmol, 74%). νmax (neat)/cmϪ1 3317 (OH), 2937 (CH), 1714
(CO); δH (270 MHz; CDCl3) 8.69 (1 H, s, OH), 7.47 (1 H, s,
CH), 1.54 (9 H, s, (CH3)3); δC (68 MHz; CDCl3) 161.2 (CO),
143.1 (CN), 83.1 (C(CH3)3), 28.0 (3 × CH3).
Pyridine (430 µL, 421 mg, 5.3 mmol) and benzoic anhydride
(1.22 g, 5.4 mmol) were added to a solution of the oxime (787
mg, 5.4 mmol) in CH2Cl2 (15 mL). 4-Dimethylaminopyridine
(10 mol%) was then added and the reaction left to stir until
complete by TLC. CH2Cl2 was added and the solution washed
with H2O (2 × 25 mL) then 0.5 M HCl (30 mL). The organics
were collected and dried (Na2SO4). The product was purified by
flash chromatography using 9 : 1 petrol–EtOAc as the running
solvent (9 : 1 petrol–EtOAc, RF 0.22) and the colourless solid
was then recrystallised from EtOAc–petrol to give O-benzoyl
tert-butyl glyoxylate oxime ester 31 as colourless needles (798
mg, 3.2 mmol, 59%). mp 107 ЊC; νmax (solid)/cmϪ1 3026 (CH),
2987 (CH), 1743 (CO), 1716 (CO); δH (400 MHz; CDCl3) 8.08
(2 H, m, 2 × ArH), 7.87 (1 H, s, CH), 7.63 (1 H, m, 1 × ArH),
7.49 (2 H, t, J 7.8, 2 × ArH), 1.58 (9 H, s, 3 × CH3); δC (101
MHz; CDCl3) 163.0 (CO), 159.9 (CO), 149.8 (CN), 133.9
(ArCH), 130.0 (2 × ArCH), 128.7 (2 × ArCH), 127.8 (ArCC),
84.4 (C(CH3)3), 28.0 (3 × CH3); m/z (FAB) 521 [(M2Na)ϩ,
(26%)], 499 [(MH2)ϩ, (8)], 272 [(MNa)ϩ, (14)], 250 [(MH)ϩ,
(20)], 194 [(MH2ϪC(CH3)3)ϩ, (76)]; HRMS (CI) calc.
(MH2ϪC(CH3)3)ϩ 194.0453 found 194.0452.
ϩ
m/z (CI) 315 [(MH)ϩ, (34%)], 91 [PhCH2 , (100)]; HRMS (CI)
calc. (MH)ϩ 315.0981 found 315.0973.
O-Benzoyl p-nitrobenzyl glyoxylate oxime ester 35
p-Nitrobenzyl glyoxylate hydrate 32 (2.54 g, 11.2 mmol) was
dehydrated under Dean–Stark conditions before oxime form-
ation. To a solution of the carbonyl compound 33 in MeOH (25
mL) was added hydroxylamine hydrochloride (1.01 g, 14.5
mmol) then pyridine (1.0 mL, 978 mg, 12.4 mmol). The reac-
tion was heated to reflux for 40 min after which the MeOH was
removed in vacuo and the residue dissolved in EtOAc (30 mL)
and water (30 mL). The layers were separated and the aqueous
layer extracted with EtOAc (2 × 30 mL). All the organics were
combined, dried (MgSO4), filtered then concentrated. The
residue was recrystallised from EtOAc–Petrol to afford
p-nitrobenzyl glyoxylate oxime as pale yellow plates (2.03 g, 9.1
mmol, 81%). mp softened at 150 ЊC melted at 156–157 ЊC; νmax
(solid)/cmϪ1 3272 (OH), 3020 (CH), 1713 (CO); δH (400 MHz;
DMSO) 8.25 (2 H, d, J 8.8, 2 × ArH), 7.67 (3 H, m, 2 × ArCH
ϩ CH), 5.39 (2 H, s, CH2); δC (101 MHz; CDCl3) 162.5 (CO),
147.8 (ArCN), 144.0 (ArCC), 141.2 (CN), 129.2 (2 × ArCH),
124.1 (2 × ArCH), 65.4 (CH2); m/z (CI) 225 [(MH)ϩ, (82%)],
ϩ
136 [O2N(C6H4)CH2 , (100)]; HRMS (CI) calc. (MH)ϩ
225.0511 found 225.0516; (Found C, 48.30; H, 3.45; N, 12.16.
C9H8N2O5 requires C, 48.22; H, 3.60; N, 12.50%).
p-Nitrobenzyl glyoxylate oxime (244 mg, 1.0 mmol) was
dissolved in MeCN (10 mL) to which benzoic acid (145 mg,
1.2 mmol), EDCi (246 mg, 1.3 mmol) and HOBt (catalytic
amount) were added. After 1.5 h the reaction was diluted with
EtOAc (30 mL) and the organics were washed with H2O (2 × 20
mL), dried (MgSO4) and concentrated. The crude product was
recrystallised from EtOAc–petrol to give O-benzoyl p-nitro-
benzyl glyoxylate oxime ester 35 as pale yellow plates (236 mg,
0.7 mmol, 65%). mp 121–124 ЊC; νmax (solid)/cmϪ1 3077 (CH),
1748 (CO), 1718 (CO); δH (400 MHz; CDCl3) 8.26 (2 H, d, J 8.8,
2 × ArH), 8.10 (2 H, m, 2 × ArH), 8.01 (1 H, s, CHN), 7.66
(1 H, m, ArH), 7.62 (2 H, d, J 8.8, 2 × ArH), 7.51 (2 H, t, J 7.8,
2 × ArH), 5.47 (2 H, s, CH2); δC (101 MHz; CDCl3) 162.6 (CO),
160.7 (CO), 148.2 (ArCN), 147.6 (CN), 141.7 (ArCC), 134.2
(ArCH), 130.1 (2 × ArCH), 128.9 (2 × ArCH), 128.8 (2 ×
ArCH), 126.7 (ArCC), 124.0 (2 × ArCH), 66.4 (CH2); m/z (CI)
329 [(MH)ϩ, (4%)], 207 [(MϪHO2CC6H5)ϩ, (25)]; HRMS (CI)
calc. (MϪHO2CC6H5)ϩ 207.0406 found 207.0404; (Found C,
58.44; H, 3.32; N, 8.35. C16H12N2O6 requires C, 58.54; H, 3.68;
N, 8.53%).
p-Nitrobenzyl glyoxylate hydrate 3222
Di-p-nitrobenzyl tartrate 28 (6.94 g, 16.5 mmol) was suspended
in THF (70 mL) and stirred for 5 min. Periodic acid (4.52 g,
19.8 mmol) was added over 10 min and after 1.5 h the reaction
was filtered. The solid inorganics were washed with THF
(2 × 10 mL), the organics were combined and then water
(150 mL) was poured into the flask which was subsequently left
for 3 days at 4 ЊC. The precipitated crystals were filtered off
under vacuum, washed with H2O (2 × 50 mL) and hexane
(2 × 50 mL) then dried to afford p-nitrobenzyl glyoxylate
hydrate 32 as very pale yellow plates (4.70 g, 20.7 mmol, 63%).
mp softened at 96 ЊC, melted at 103–105 ЊC (lit.22 100–102 ЊC);
δH (270 MHz; DMSO) 8.23 (2 H, d, J 8.9, 2 × ArH), 7.63 (2 H,
d, J 8.9, 2 × ArH), 6.81 (2 H, d, J 7.6, 2 × OH), 5.28 (2 H, s,
CH2), 5.12 (1 H, t, J 7.6, CH); δC (101 MHz; DMSO) 170.7
(CO), 147.7 (ArCN), 144.3 (ArCH), 129.0 (2 × ArCH), 124.0
p-Nitrobenzyl cyanoformate 36 was also obtained as a yellow
solid. νmax (solid)/cmϪ1 3113 (CH), 3081 (CH), 1741 (CO), 2252
(CN); δH (400 MHz; CDCl3) 8.28 (2 H, d, J 8.8, 2 × ArH), 7.58
(2 H, d, J 8.8, 2 × ArH), 5.42 (2 H, s, CH2); δC (101 MHz;
CDCl3) 180.1 (CO), 143.9 (ArCN), 139.4 (ArCC), 129.3 (2 ×
ArCH), 124.2 (2 × ArCH), 108.9 (CN), 68.6 (CH2); m/z (CI)
207 [(MH)ϩ, (74%)], 136 [(MϪHO2CCN)ϩ, (100)].
(2
× ArCH), 87.5 (CH), 64.8 (CH2); m/z (CI) 210
[(MHϪH2O)ϩ, (100%)], 136 [(MϪHO2CCH(OH)2)ϩ, (95)];
(Found C, 47.56; H, 3.86; N, 6.05. C9H9NO6 requires C, 47.58;
H, 3.99; N, 6.17%).
Methyl 2-[acetyl-benzoyloxy-amino]-pent-4-enoate 37
Using oxime ester 24 (407 mg, 1.98 mmol), procedure C and
85 : 15 petrol–EtOAc (4 : 1 petrol–EtOAc, RF 0.15) as the
chromatography solvent gave methyl 2-[acetyl-benzoyloxy-
amino]-pent-4-enoate 37 as a yellow oil (473 mg, 1.6 mmol,
O-Benzyl p-nitrobenzyl glyoxylate oxime ether 34
p-Nitrobenzyl glyoxylate hydrate 32 (2.54 g, 11.2 mmol) was
dehydrated under Dean–Stark conditions before oxime form-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1928

View Article Online
81%). νmax (neat)/cmϪ1 3075 (CH), 2954 (CH), 1769 (CO), 1747
(CO), 1693 (CO); δH (400 MHz; CDCl3) 8.07 (2 H, m, 2 × ArH),
7.67 (1 H, m, ArH), 7.52 (2 H, t, J 7.8, 2 × ArH), 5.84 (1 H, m,
CHCH2CH), 2.15 (3 H, s, Me); δC (76 MHz; CDCl3) 169.4
(CO), 147.8 (CO), 142.6 (ArCN), 134.3 (ArCC), 133.5 (CH᎐),
᎐
129.1 (ArCH ϩ ArCC), 129.0 (2 × ArCH), 128.7 (2 × ArCH),
CH᎐), 5.32 (1 H, brs, COCH), 5.15 (1 H, m, ᎐CHH ), 5.08 (1 H,
128.3 (2 × ArCH), 123.8 (2 × ArCH), 118.5 (᎐CH ), 78.5
᎐
᎐
᎐
2
d, J 10.2, ᎐CHH), 3.77 (3 H, s, OMe), 2.67 (2 H, m,
(ArCH2), 65.6 (ArCH2), 60.8 (COCH), 32.7 (COCHCH2), 20.8
(Me); m/z (CI) 399 [(MH)ϩ, (66%)], 357 [(MH2ϪAc)ϩ, (69)], 293
[(MH2ϪOBn)ϩ, (12)], 249 [(MHϪAcϪOBn)ϩ, (14)]; HRMS
(CI) calc. (MH)ϩ 399.1556 found 399.1557. Found C, 63.32; H,
5.34; N, 7.09. C21H22N2O6 requires C, 63.31; H, 5.57; N, 7.03%).
᎐
COCHCH2), 2.13 (3 H, s, Me); δC (101 MHz; CDCl3) 174.1
(CO), 169.8 (CO), 164.8 (CO), 135.0 (ArCH), 133.5
(CH2CHCH2), 130.5 (2 × ArCH), 129.4 (2 × ArCH), 126.9
(ArCC), 118.9 (CH2CHCH2), 60.0 (COCH), 52.8 (OMe), 33.2
(CH2CHCH2), 21.1 (Me); m/z (ESMS) 332 [(M.MeCN)ϩ,
(85%)], 314 [(MNa)ϩ, (10)], 250 [(MH2ϪAc)ϩ, (100)]; HRMS
calc. (MNa)ϩ 314.0999 found 314.0997.
Using oxime ester 24 (407 mg, 1.98 mmol), procedure B and
4 : 1 petrol–EtOAc for the running solvent in chromatography
provided methyl 2-[diacetylamino]-penta-2,4-dienoate 44 as a
yellow oil (140 mg, 0.7 mmol, 33%). δH (400 MHz; CDCl3) 7.43
(1 H, d, J 11.2, CCHCH), 6.35 (1 H, ddd, J 16.8, 11.2, 10.2,
CHCHCH2), 5.82 (1 H, d, J 16.8, CHCHH ), 5.68 (1 H, d,
J 10.2, CHCHH), 3.82 (3 H, s, OMe), 2.34 (6 H, s, 2 × COMe);
m/z (CI) 250 [(MK)ϩ, (21%)], 212 [(MH)ϩ, (31)], 170
[(MH2ϪAc)ϩ, (87)], 128 [(MH3Ϫ2 × Ac)ϩ, (78)].
p-Nitrobenzyl 2-[acetyl-benzoyloxy-amino]-pent-4-enoate 41
Using oxime ester 35 (663 mg, 2.02 mmol), procedure C and
4 : 1 petrol–EtOAc (7 : 3 petrol–EtOAc, RF 0.29) during
chromatography gave p-nitrobenzyl 2-[acetyl-benzoyloxy-
amino]-pent-4-enoate 41 as a very viscous yellow oil (390 mg,
0.95 mmol, 47%). δH (400 MHz; CDCl3) 8.21 (2 H, d, J 8.8, 2 ×
ArH), 7.99 (2 H, d, J 7.7, 2 × ArH), 7.68 (1 H, t, J 7.7, ArH),
7.51 (4 H, m, 4 × ArH), 5.84 (1 H, m, CH᎐), 5.09–5.46 (5 H, m,
᎐
PhCH ϩ COCH ϩ ᎐CH ), 2.71 (2 H, m, CH ), 2.12 (3 H, s,
᎐
2
2
2
Me); δC (101 MHz; CDCl3) 168.6 (CO), 164.2 (CO), 147.8
(ArCN), 142.5 (ArCC), 134.6 (ArCH), 132.7 (CH᎐), 130.0
᎐
(2 × ArCH), 129.0 (2 × ArCH), 128.7 (2 × ArCH), 126.6
tert-Butyl 2-[acetyl-benzyloxy-amino]-pent-4-enoate 38
(ArCC), 123.8 (2 × ArCH), 123.8 (᎐CH ), 65.8 (PhCH ), 59.8
᎐
2
2
(COCH), 32.9 (COCHCH2), 20.6 (Me); m/z (CI) 413 [(MH)ϩ,
(32%)], 371 [(MH2ϪAc)ϩ, (68)], 291 [(MϪHO2CC6H5)ϩ, (60)];
HRMS calc. (MH)ϩ 413.1349 found 413.1337.
Using oxime ether 30 (465 mg, 1.98 mmol), procedure B and
9 : 1 petrol–EtOAc (9 : 1 petrol–EtOAc, RF 0.19) as the
chromatography solvent gave tert-butyl 2-[acetyl-benzyloxy-
amino]-pent-4-enoate 38 as a yellow oil (511 mg, 1.6 mmol,
81%). νmax (neat)/cmϪ1 2979 (CH), 1733 (CO), 1679 (CO); δH
O-Benzyl methyl pyruvate oxime ether 4624
(400 MHz; CDCl ) 7.38 (5 H, s, 5 × ArH), 5.8 (1 H, m, CH᎐),
᎐
3
5.15 (1 H, dtd, J 17.2, 2.9, 1.5, ᎐CHH ), 5.10 (1 H, m, ᎐CHH),
5.00 (1 H, d, J 10.6, PhCHH ), 4.91 (1 H, d, J 10.6, PhCHH),
2.75 (2 H, m, COCHCH2), 1.46 (9 H, s, 3 × CH3); δC (101 MHz;
To a solution of O-benzylhydroxylamine hydrochloride (4.90 g,
30.6 mmol) and pyridine (1.99 mL, 1.942 g, 24.5 mmol) in
MeOH (22 mL) was added methyl pyruvate 45 (1.02 g, 10.0
mmol) and the reaction stirred for 3.5 h at RT. The MeOH was
removed in vacuo and the residue was then dissolved in CH2Cl2
(45 mL) and H2O (30 mL) and the organic layer collected. The
aqueous layer was extracted with CH2Cl2 (2 × 45 mL), the
organics were combined and dried (Na2SO4) and the solvent
was evaporated. The crude oil was purified by flash chromato-
graphy using petrol–EtOAc 9 : 1 (9 : 1 petrol–EtOAc, RF 0.28)
as the running solvent to give O-benzyl methyl pyruvate oxime
ether 46 as a colourless solid (1.80 g, 8.7 mmol, 87%). mp
41–45 ЊC; νmax (solid)/cmϪ1 3063 (CH), 2951 (CH), 1721 (CO);
δH (270 MHz; CDCl3) 7.37 (5 H, s, 5 × ArH), 5.31 (2 H, s,
PhCH2), 3.86 (3 H, s, OMe), 2.09 (3 H, s, Me); δC (101 MHz;
CDCl3) 164.3 (CO), 149.3 (CN), 136.8 (ArCC), 128.5 (2 ×
ArCH), 128.3 (3 × ArCH), 77.6 (PhCH2), 52.7 (OMe), 11.7
(Me); m/z (CI) 208 [(MH)ϩ, (16%)].
᎐
᎐
CDCl ) 174.7 (CO), 168.8 (CO), 134.9 (ArCC), 134.3 (CH᎐),
᎐
3
128.8 (5 × ArCH), 117.8 (᎐CH ), 82.1 (C(CH ) ), 78.2 (PhCH ),
᎐
2
3
3
2
61.8 (COCH), 32.8 (COCHCH2), 28.0 (3 × CH3), 20.8 (Me);
m/z 320 [(MH)ϩ, (1%)], 264 [(MH2ϪC(CH3)3)ϩ, (32)],
222 [(MH3ϪC(CH3)3ϪAc)ϩ, (27)]; HRMS (CI) calc.
(MH2ϪC(CH3)3)ϩ 264.1236 found 264.1226.
tert-Butyl 2-[acetyl-benzoyloxy-amino]-pent-4-enoate 39
Using oxime ester 31 (484 mg, 1.94 mmol), procedure C and 9 :
1 petrol–EtOAc (7 : 3 petrol–EtOAc, RF 0.51) as the chromato-
graphy solvent afforded tert-butyl 2-[acetyl-benzoyloxy-amino]-
pent-4-enoate 39 as a yellow oil (478 mg, 1.4 mmol, 72%).
νmax (neat)/cmϪ1 2980 (CH), 1768 (CO), 1734 (CO), 1694 (CO);
δH (400 MHz; CDCl3) 8.05 (2 H, dd, J 8.3, 1.5, 2 × ArH), 7.64
(1 H, t, J 7.3, ArH), 7.50 (2 H, m, 2 × ArH), 5.85 (1 H, m,
CH᎐), 5.2 (1 H, brs, COCH), 5.13 (1 H, dd, J 17.1, 1.5, ᎐CHH ),
᎐
᎐
O-Benzoyl methyl pyruvate oxime ester 47
5.06 (1 H, d, J 10.3, ᎐CHH), 2.52–2.73 (2 H, m, COCHCH ),
᎐
2
2.12 (3 H, s, Me), 1.46 (9 H, s, 3 × CH3); δC (101 MHz; CDCl3)
173.8 (CO), 167.9 (CO), 164.4 (CO), 134.3 (ArCH), 133.5
To a solution of methyl pyruvate 45 (1.03 g, 10.0 mmol) in
MeOH (18 mL) was added hydroxylamine hydrochloride (905
mg, 13.0 mmol) then pyridine (890 µL, 870 mg, 11.0 mmol).
The reaction was stirred for 4 h after which the MeOH was
removed in vacuo and the residue dissolved in CH2Cl2 (30 mL)
and water (30 mL). The layers were separated and the aqueous
layer extracted twice with CH2Cl2 (30 mL). All the organics
were combined, dried (Na2SO4), filtered then concentrated and
the resultant material purified by flash chromatography; 7 : 3
petrol–EtOAc was used as the running solvent (7 : 3 petrol–
EtOAc, RF 0.22) which gave methyl pyruvate oxime as a colour-
less solid (967 mg, 8.3 mmol, 83%). mp 75–76 ЊC; νmax (solid)/
cmϪ1 3228 (OH), 2964 (CH), 1722 (CO); δH (270 MHz; CDCl3)
8.50 (1 H, s, OH), 3.89 (3 H, s, OMe), 2.12 (3 H, s, Me); δC (101
MHz; CDCl3) 164.2 (CO), 149.4 (CN), 52.7 (OMe), 10.5 (Me);
m/z (CI) 118 [(MH)ϩ, (100%)]; HRMS (CI) calc. (MH)ϩ
118.0504 found 118.0504; (Found C, 41.34; H, 6.28; N, 12.09.
C4H7NO3 requires C, 41.03; H, 6.03; N, 11.96%).
(CH᎐), 130.0 (2 × ArCH), 128.9 (2 × ArCH), 118.1 (᎐CH ),
᎐
᎐
2
82.5 (C(CH3)3), 61.0 (COCH), 33.0 (COCHCH2), 28.0 (3 ×
CH3), 20.8 (Me); m/z (CI) 236 [(MH3ϪAcϪC(CH3)3)ϩ, (66%)],
156 [(MHϪC(CH3)3ϪHO2CC6H5)ϩ, (12)]; HRMS (CI) calc.
[(MH3ϪAcϪC(CH3)3)ϩ] 236.0923 found 236.0922.
p-Nitrobenzyl 2-[acetyl-benzyloxy-amino]-pent-4-enoate 40
Using oxime ether 34 (624 mg, 1.99 mmol), procedure B and
84 : 16 petrol–EtOAc as the eluting solvent during flash
chromatography (7 : 3 petrol–EtOAc, RF 0.25) gave p-nitro-
benzyl 2-[acetyl-benzyloxy-amino]-pent-4-enoate 40 as a yellow
oil (679 mg, 1.71 mmol, 86%). νmax (neat)/cmϪ1 3080 (CH), 2945
(CH), 1745 (CO), 1674 (CO), 1520 (NO2), 1341 (NO2); δH (300
MHz; CDCl3) 8.14 (2 H, d, J 8.8, 2 × ArH), 7.47 (2 H, d, J 8.8,
2 × ArH), 7.35 (5 H, m, 5 × ArH), 5.82 (1 H, m, CH᎐), 5.33
᎐
(1 H, d, J 13.4, PhCHH), 5.2 (1 H, d, J 13.6, PhCHH ), 5.16 (2
H, m, ᎐CH ), 5.05 (1 H, dd, J 6.0, 9.2, COCH), 4.94 (1 H, d,
J 10.5, PhCHH), 4.90 (1 H, d, J 10.2, PhCHH ), 2.82 (2 H, m,
Pyridine (610 µL, 599 mg, 7.6 mmol) and benzoic anhydride
(2.05 g, 9.1 mmol) were added to a solution of the oxime (900
᎐
2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1929

View Article Online
mg, 7.7 mmol) in CH2Cl2 (20 mL). 4-Dimethylaminopyridine
(10 mol%) was then added and the reaction left to stir until
complete by TLC. CH2Cl2 (10 mL) was added and the solution
washed with H2O (2 × 20 mL) then 0.5 M HCl (20 mL). The
organics were collected, dried (Na2SO4) and purified by flash
chromatography. The running solvent used for chromatography
was 4 : 1 petrol–EtOAc (7 : 3 petrol–EtOAc, RF 0.31) which
gave O-benzoyl methyl pyruvate oxime ester 47 as a colourless
solid (1.613 g, 7.3 mmol, 97%). mp 104–106 ЊC; νmax (solid)/
cmϪ1 3060 (CH), 2960 (CH), 1760 (CO), 1724 (CO); δH (400
MHz; CDCl3) 8.10 (2 H, m, 2 × ArH), 7.64 (1 H, m, ArH), 7.51
(2 H, t, J 7.8, 2 × ArH), 3.94 (3 H, s, OMe), 2.38 (3 H, s, Me);
δC (101 MHz; CDCl3) 163.7 (CO), 162.8 (CO), 156.7 (CN),
133.9 (ArCH), 129.9 (2 × ArCH), 128.8 (2 × ArCH), 128.2
(ArCC), 53.3 (OMe), 13.2 (Me); m/z (CI) 222 [(MH)ϩ, (10%)],
123 [(MH2ϪMeO2CC(CH3)N)ϩ, (94)]; HRMS (CI) calc.
(MH)ϩ 222.0766 found 222.0769; (Found C, 59.77; H, 4.92; N,
6.33. C11H11NO4 requires C, 59.73; H, 5.01; N, 6.33%).
Pyridine (380 µL, 368 mg, 4.6 mmol) and benzoic anhydride
(1.26 g, 5.6 mmol) were added to a solution of the oxime (609
mg, 4.6 mmol) in CH2Cl2 (12 mL). 4-Dimethylaminopyridine
(10 mol%) was then added and the reaction left to stir until
complete by TLC. CH2Cl2 (20 mL) was added and the solution
washed with H2O (2 × 20 mL) then 0.5 M HCl (20 mL). The
organics were collected, dried (Na2SO4) and purified by a
Horizon Biotage eluting from 9 : 1 to 4 : 1 petrol–EtOAc (7 : 3
petrol–EtOAc, RF 0.31) to give methyl acetoacetate O-benzoyl
oxime ester 51 as a yellow oil and a 1 : 3.8 mixture of geometric
isomers a and b (846 mg, 3.6 mmol, 78%). νmax (neat)/cmϪ1 3004
(CH), 2955 (CH), 1741 (CO); δH (270 MHz; CDCl3) 8.10 (2 H,
m, 2 × ArH, isomers a and b), 7.58 (1 H, m, ArH, isomers a and
b), 7.47 (2 H, m, 2 × ArH, isomers a and b), 3.76 (3 H, s, OMe,
isomer b), 3.74 (3 H, s, OMe, isomer a), 3.57 (2 H, s, CH2,
isomer a), 3.52 (2 H, s, CH2, isomer b), 2.26 (3 H, s, Me, isomer
a), 2.25 (3 H, s, Me, isomer b); δC (101 MHz; CDCl3) 169.1 (CO,
isomer b), 167.8 (CO, isomer a), 163.6 (CO, isomer b), 163.1
(CO, isomer a), 133.5 (ArCH, isomers a and b), 129.7 (2 ×
ArCH, isomers a and b) 128.9 (ArCC, isomers a and b), 128.6
(2 × ArCH, isomers a and b), 52.4 (OMe, isomers a and b), 41.0
(CH2, isomer b), 36.9 (CH2, isomer a), 21.3 (Me, isomer a), 16.3
(Me, isomer b); m/z (ESMS) 258 [(MNa)ϩ, (100%)]; HRMS
calc. (MNa)ϩ 258.0736 found 258.0736.
O-Benzyl methyl acetoacetate oxime ether 50
Using methyl acetoacetate 48 (870 mg, 7.5 mmol) and
procedure A yielded a crude product which was purified using a
Horizon Biotage automated column eluting with 9 : 1 petrol–
EtOAc (7 : 3 petrol–EtOAc RF 0.59) to give methyl acetoacetate
O-benzyl oxime ether 50, as a mixture of geometric isomers
1 : 1.8 a and b, as a colourless oil (1.28 g, 5.8 mmol, 77%). νmax
(neat)/cmϪ1 3031 (CH), 2953 (CH), 1741 (CO); δH (270 MHz;
CDCl3) 7.34 (5 H, m, 5 × ArH, isomers a and b), 5.11 (2 H, s,
PhCH2, isomer b), 5.08 (2 H, s, PhCH2, isomer a), 3.71 (3 H, s,
OMe, isomer b), 3.66 (3 H, s, OMe, isomer a), 3.38 (2 H, s, CH2,
isomer a), 3.23 (2 H, s, CH2, isomer b), 1.97 (3 H, s, Me, isomer
a), 1.96 (3 H, s, Me, isomer b); δC (101 MHz; CDCl3) 170.1 (CO,
isomer b), 169.2 (CO, isomer a), 151.9 (CN, isomer b), 150.7
(CN, isomer a), 137.9 (ArCC, isomers a and b), 128.3 (2 ×
ArCH, isomers a and b), 128.0 (2 × ArCH, isomers a and b),
127.8 (ArCH, isomers a and b), 75.6 (PhCH2, isomers a and
b), 52.1 (OMe, isomers a and b), 41.2 (CH2, isomer b), 35.3
(CH2, isomer a), 20.6 (Me, isomer a), 14.8 (Me, isomer b); m/z
(ESMS) 222 [(MH)ϩ, (25%)], 190 [(MϪMeOH)ϩ, (20)], 162
[(MϪMeCO2H)ϩ, (100)]; HRMS calc. (MNa)ϩ 244.0944 found
244.0944.
Methyl 2-[acetyl-benzoyloxy-amino]-2-methyl-pent-4-enoate 53
Using oxime ester 47 (459 mg, 2.08 mmol), procedure C and
flash chromatography eluting with 85 : 15 petrol–EtOAc (4 : 1
petrol–EtOAc, RF 0.21) gave methyl 2-methyl-2-[acetyl-benzo-
yloxy-amino]-pent-4-enoate 53 as a yellow oil (325 mg, 1.1
mmol, 53%). νmax (neat)/cmϪ1 3010 (CH), 2952 (CH), 1766
(CO), 1743 (CO), 1679 (CO); δH (400 MHz; CDCl3) 8.12 (2 H,
d, J 8.3, 2 × ArH), 7.70 (1 H, m, ArH), 7.54 (2 H, m, 2 × ArH),
5.76–5.96 (1 H, m, CH᎐), 5.13 (2 H, m, ᎐CH ), 3.77 (3 H, s,
᎐
᎐
2
OMe), 2.71–2.99 (1 H, m, C(Me)CHH ), 2.67 (1 H, m,
C(Me)CHH), 2.07 and 2.03 (3 H, s, COMe, 2 conformers);
δC (101 MHz; CDCl3) 172.2 and 171.8 (CO), 171.5 (CO), 165.0
and 164.8 (CO), 134.7 (ArCH), 132.2 and 132.5 (CH), 130.1
(2 × ArCH), 129.1 (2 × ArCH), 126.6 and 126.4 (ArCC), 119.4
and 119.0 (CH2CHCH2), 68.7 and 68.3 (C(Me)), 52.6 (OMe),
41.2 and 40.2 (C(Me)CH2), 21.7 and 21.4 (COMe), 21.4
and 20.1 (Me); m/z (CI) 264 [(MH2ϪAc)ϩ, (50%)], 142
[(MHϪAcϪHO2CC6H5)ϩ, (17)]; HRMS (CI) calc. (MH2ϪAc)ϩ
264.1236 found 264.1238.
After elution with 85 : 15 petrol–EtOAc methyl 2-methyl-2-
[benzoyloxy-amino]-pent-4-enoate 54 was recovered as a yellow
oil (198 mg, 0.8 mmol, 38%). δH (400 MHz; CDCl3) 8.03 (1 H, s,
NH), 7.95 (2 H, dd, J 1.0, 8.3, 2 × ArH), 7.56 (1 H, m, ArH),
7.44 (2 H, m, 2 × ArH), 5.82 (1 H, m, CHCH2), 5.17 (2 H, m,
CHCH2), 3.71 (3 H, s, OMe), 2.57 (2 H, m, C(Me)CH2), 1.46
(3 H, s, C(Me)).
O-Benzoyl methyl acetoacetate oxime ester 51 and 3-methyl-
isoxazolin-5-one 4925
To a solution of methyl acetoacetate 48 (1.16 g, 10.0 mmol) in
MeOH (18 mL) was added hydroxylamine hydrochloride (694
mg, 10.0 mmol) then pyridine (810 µL, 791 mg, 10.0 mmol).
The reaction was stirred for 10 min after which the MeOH was
removed in vacuo and the residue dissolved in CH2Cl2 (30 mL)
and water (30 mL). The layers were separated and the aqueous
layer extracted twice with CH2Cl2 (2 × 30 mL). All the organics
were combined, dried (Na2SO4), filtered then concentrated. The
residue was purified using 7 : 3 petrol–EtOAc as the running
solvent for chromatography by a Horizon Biotage (7 : 3 petrol–
EtOAc RF 0.25) which afforded methyl acetoacetate oxime as a
colourless oil in a mixture of geometric isomers a and b (494
mg, 3.8 mmol, 37%). νmax (neat)/cmϪ1 3342 (OH), 2956 (CH),
1741 (CO); δH (270 MHz; CDCl3) 7.73 (1 H, s, OH), 3.73 (3 H, s,
OMe), 3.24 (2 H, s, CH2), 1.97 (3 H, s, Me); δC (101 MHz;
CDCl3) 170.0 (CO, isomer a), 169.4 (CO, isomer b), 152.6 (CN,
isomer a), 151.3 (CN, isomer b), 52.2 (OMe, isomers a and b),
41.1 (CH2, isomer a), 34.5 (CH2, isomer b), 20.5 (Me, isomer b),
14.0 (Me, isomer a).
2-Acetyl-3-methylisoxazol-5-one 5527
Attempted allylation of 49 (398 mg, 2.0 mmol) using procedure
B yielded crude material which was purified by flash chromato-
graphy, eluting with 7 : 3 petrol–EtOAc to give 2-acetyl-3-meth-
ylisoxazol-5-one as a yellow oil (313 mg, 1.3 mmol, 63%).
δH (270 MHz; CDCl3) 5.30 (1 H, q, J 1.0, CH), 2.59 (3 H, d,
J 1.0, CMe), 2.44 (3 H, s, COMe); δC (68 MHz; CDCl3) 166.1
(CO), 165.0 (CO), 158.7 (CH3CCH), 95.0 (COCH), 22.6 (Me),
15.4 (Me); m/z (CI) 142 [(MH)ϩ, (25%)], 98 [(MϪAc)ϩ, (90)].
O-Benzoyl 2-methyl-trans-cinnamaldehyde oxime ester 57
3-Methylisoxazolin-5-one 4926 was purified by a Horizon
Biotage instrument eluting using a gradient from 9 : 1 to 4 : 1
petrol–EtOAc to give 3-methyl-2-isoxazolin-5-one 49 as a red/
brown oil (506 mg, 5.1 mmol, 51%). δH (250 MHz; CDCl3) 3.40
(2 H, s, CH2), 2.16 (3 H, s, Me).
2-Methyl-trans-cinnamaldehyde 56 (1.46 g, 10.0 mol) was dis-
solved in EtOH (18 mL) to which hydroxylamine hydrochloride
(1.04 g, 15 mmol) and pyridine (970 µL, 949 mg, 12.0 mmol)
were added. The reaction was stirred at RT for 2 h and the
solvent was evaporated then the residue was dissolved in
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1930

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CH2Cl2 (30 mL) and H2O (25 mL). The organic layer was
collected and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL) before the organics were combined and washed
with 1 M HCl (40 mL) and dried (Na2SO4). The inorganics were
filtered off and the solvent removed in vacuo then the crude
material was purified on a Horizon Biotage automated column.
9 : 1 Petrol–EtOAc was used as the running solvent (7 : 3 petrol–
EtOAc, RF 0.47) which gave 2-methyl-trans-cinnamaldehyde
oxime as a colourless solid (1.47 g, 9.1 mmol, 91%). mp 129–
131 ЊC; νmax (solid)/cmϪ1 3216 (OH), 2986 (CH); δH (400 MHz;
CDCl3) 8.08 (1 H, s, OH), 7.91 (1 H, s, NCH), 7.30 (5 H, m,
5 × ArH), 6.69 (1 H, m, ArCH), 2.10 (3 H, d, J 1.1, Me); δC (101
MHz; CDCl3) 155.2 (CN), 136.7 (CHC(Me)), 136.3 (CMe),
131.8 (ArCC), 129.3 (2 × ArCH), 128.3 (2 × ArCH), 127.6
(ArCH), 13.1 (Me).
7 × ArH), 3.79 (2 H, d, J 6.8, CH2); δC (101 MHz; CDCl3) 164.1
(CO), 158.2 (CN), 134.6 (ArCC), 133.4 (ArCH), 129.7
(2 × ArCH), 129.0 (2 × ArCH ϩ 2 × ArCH), 128.5 (2 × ArCH
ϩ ArCC), 127.3 (ArCH), 35.9 (CH2).
O-Benzyl benzaldehyde oxime ether 6129
Using benzaldehyde 60 (1.27 g, 12.0 mmol), procedure A and
96 : 4 petrol–EtOAc as the solvent for flash chromatography
yielded O-benzyl benzaldehyde oxime ether 61 as a colourless
oil (2.26 g, 10.7 mmol, 89%). δC (101 MHz; CDCl3) 149.1 (CH),
137.8 (ArCC), 132.5 (ArCC), 130.0 (ArCH), 128.8 (2 × ArCH),
128.6 (2 × ArCH), 128.5 (2 × ArCH), 128.1 (ArCH), 127.3
(2 × ArCH), 76.6 (CH2); m/z (CI) 212 [(MH)ϩ, (50%)], 104
[(MϪC6H5CH2OH)ϩ, (56)] (Found C, 79.88; H, 6.66; N, 6.77.
C14H13NO requires C, 79.59; H, 6.20; N, 6.63%).
2-Methyl-trans-cinnamaldehyde oxime (1.46 g, 9.1 mmol)
was suspended in CH2Cl2 (25 mL) and pyridine (730 µL,
714 mg, 9.0 mmol) and benzoic anhydride (2.47 g, 10.9 mmol)
were added. 4-Dimethylaminopyridine (10 mol%) was added
and the reaction left to stir for 18 h before it was diluted
(CH2Cl2, 10 mL). The reaction was washed with H2O (2 × 20
mL) and NaHCO3 (aq., 25 mL) and then dried (Na2SO4). The
solvent was removed and the resultant material purified with a
Quad 3 Biotage automated column using a 9 : 1 mixture of
petrol–EtOAc as the elutant (7 : 3 petrol–EtOAc, RF 0.55)
which afforded O-benzoyl 2-methyl-trans-cinnamaldehyde oxime
ester 57. The solid was recrystallised from Et2O–petrol to yield
the desired compound as colourless plates (1.21 g, 4.6 mmol,
50%). mp 88–90 ЊC; δH (400 MHz; CDCl3) 8.30 (1 H, d, J 0.7,
NCH), 8.13 (2 H, dd, J 1.5, 8.4, 2 × ArH), 7.30–7.63 (7 H, m,
7 × ArH), 6.89 (1 H, q, J 0.7, ArCH), 2.30 (3 H, d, J 1.5, Me);
δC (101 MHz; CDCl3) 164.1 (CO), 161.7 (CN), 141.1
(CHC(Me)), 135.9 (ArCC), 133.4 (ArCH), 131.4 (ArCC), 129.8
(2 × ArCH), 129.6 (2 × ArCH), 129.0 (CHC(Me)), 128.6
(2 × ArCH), 128.5 (2 × ArCH), 128.4 (ArCH), 13.3 (Me).
O-Benzoyl benzaldehyde oxime ester 6230
To a solution of benzaldehyde 60 (1.60 g, 15.1 mmol) in MeOH
(25 mL) was added hydroxylamine hydrochloride (1.36 g, 19.6
mmol) then pyridine (1.33 mL, 1.31 g, 16.5 mmol). The reaction
was stirred for 23 h after which the MeOH was removed
in vacuo and the resulting residue dissolved in CH2Cl2 (40 mL)
and water (30 mL). The layers were separated and the aqueous
layer extracted with CH2Cl2 (2 × 40 mL). All the organics were
combined, dried (Na2SO4), filtered then concentrated and the
resultant material purified by flash chromatography eluting
with 9 : 1 petrol–EtOAc (4 : 1 petrol–EtOAc, RF 0.34) to give
benzaldehyde oxime31 as a pale yellow oil (605 mg, 5 mmol,
33%). νmax (neat)/cmϪ1 3278 (OH), 3063 (CH), 2983 (CH);
δC (68 MHz; CDCl3) 150.6 (CN), 132.0 (ArCC), 130.2 (ArCH),
128.9 (2 × ArCH), 127.2 (2 × ArCH); m/z 122 [(MH)ϩ, (92%)],
104 [(MϪH2O)ϩ, (100)].
Benzoic anhydride (1.05 g, 4.6 mmol) was added to a solution
of benzaldehyde oxime (514 mg, 4.2 mmol) in CH2Cl2 (12 mL).
4-Dimethylaminopyridine (10 mol%) was then added and the
reaction left to stir until complete by TLC. CH2Cl2 (20 mL) was
added and the solution washed with H2O (2 × 25 mL) then
NaHCO3 (aq., 25 mL). The organics were collected, dried
(Na2SO4) and purified by flash chromatography. Product eluted
through a column of pre-slurried silica using 95 : 5 petrol–
EtOAc as the solvent (7 : 3 petrol–EtOAc, RF 0.49) to afford the
title compound 62 as a colourless solid (714 mg, 3.2 mmol,
76%). mp 99–101 ЊC; δH (400 MHz; CDCl3) 8.57 (1 H, s, CH),
8.13 (2 H, dd, J 1.5, 8.3, 2 × ArH), 7.81 (2 H, m, 2 × ArH), 7.62
(1 H, m, ArH), 7.48 (5 H, m, 5 × ArH); δC (68 MHz; CDCl3)
164.0 (CO), 156.9 (CN), 133.5 (ArCH), 131.8 (ArCH), 130.2
(ArCC), 129.8 (2 × ArCH), 128.9 (2 × ArCH), 128.7 (ArCC),
128.6 (2 × ArCH), 128.6 (2 × ArCH); (Found C, 74.96; H, 5.22;
N, 6.23. C14H11NO2 requires C, 74.65; H, 4.92; N, 6.22%).
O-Benzoyl phenylacetaldehyde oxime ester 59
Phenylacetaldehyde (1.81 g, 15.0 mmol) was dissolved in
MeOH (30 mL) and hydroxylamine hydrochloride (1.25 g, 18.0
mmol) and pyridine (1.19 mL, 1.16 g, 14.7 mmol) were added.
After 2.5 h the MeOH was removed in vacuo and the material
was suspended in CH2Cl2 (40 mL) and washed with H2O (2 × 30
mL) and 1 M HCl (30 mL). The organics were dried (Na2SO4)
then concentrated and purified with a Horizon Biotage auto-
mated column eluting through a gradient from 100% petrol to
4 : 1 petrol–EtOAc which gave phenylacetaldehyde oxime28 as
a colourless solid and a 1.9 : 1 mixture of geometric isomers a
and b (859 mg, 6.4 mmol, 42%). νmax (solid)/cmϪ1 3203.3 (OH),
3085 (CH), 2854 (CH); δH (250 MHz; CDCl3) 9.05 (1 H, br s,
OH, isomer a), 8.49 (1 H, br s, OH, isomer b), 7.54 (1 H, t, J 6.3,
ArH, isomer b), 7.27 (4 H, m, 4 × ArH, isomers a and b), 6.90
(1 H, t, J 5.3, ArH, isomer a), 3.74 (2 H, d, J 5.3, CH2, isomer
a), 3.54 (2 H, d, J 6.3, CH2, isomer b); δC (101 MHz; CDCl3)
150.9 (CN, isomer a), 150.7 (CN, isomer b), 136.9 (ArCC,
isomer a), 136.6 (ArCC, isomer b), 128.8 (2 × ArCH ϩ ArCH,
isomers a and b), 126.9 (2 × ArCH, isomer b), 126.7 (2 × ArCH,
isomer a), 35.9 (CH2, isomer b), 31.7 (CH2, isomer a).
To a solution of phenyacetaldehyde oxime (859 mg, 6.4
mmol) in CH2Cl2 (25 mL) was added benzoic acid (781 mg,
6.4 mmol), EDCi (1.35 g, 7.0 mmol) and HOBt hydrate
(10 mol%). The reaction was stirred overnight. The reaction
was then washed with H2O (2 × 20 mL) and NaHCO3 (aq.,
30 mL), dried (Na2SO4) and concentrated. The crude material
was purified on a Horizon Biotage eluting through a gradient
from 100% petrol to 9 : 1 petrol–EtOAc which gave O-benzoyl
phenylacetaldehyde oxime ester as a yellow oil (289 mg, 1.2
mmol, 19%). νmax (neat)/cmϪ1 3026 (CH), 1734 (CO); δH (400
MHz; CDCl3) 8.05 (2 H, dd, J 1.6, 7.2, 2 × ArH), 7.98 (1 H, t,
J 6.8, NCH), 7.57 (1 H, t, J 7.6, ArH), 7.26–7.47 (7 H, m,
Methyl 2-[acetyl-benzyloxy-amino]-3-methyl-pent-4-enoate 63
Using oxime ether 14 (376 mg, 1.95 mmol), crotyl bromide in
place of allyl bromide and procedure B yielded a product which
was purified by flash chromatography using 9 : 1 petrol–EtOAc
(4 : 1 petrol–EtOAc, RF 0.24) as the solvent to give methyl
2-[acetyl-benzyloxy-amino]-3-methyl-pent-4-enoate 63 as a very
pale yellow oil and a 11.8 : 1 mixture of diastereomers a and b
(446 mg, 1.5 mmol, 77%). νmax (neat)/cmϪ1 3006 (CH), 2953
(CH), 1743 (CO), 1675 (CO); δH (400 MHz; CDCl3) 7.40 (5 H,
m, 5 × ArH, dias. a ϩ b), 5.72–5.91 (1 H, m, CHCHCH2, dias. a
ϩ b), 4.86–5.22 (5 H, m, COCH ϩ CHCH2 ϩ PhCH2, dias. a ϩ
b), 3.73 (3 H, s, OMe, dias. a ϩ b), 3.08 (1 H, m, CH(Me), dias. a
ϩ b), 2.20 (3 H, s, COMe, dias. a), 2.14 (3 H, s, COMe, dias. b),
1.23 (3 H, d, J 6.8, CH(Me), dias. b), 1.05 (3 H, d, J 6.8,
CH(Me), dias. a); δC (101 MHz; CDCl3) Diastereomer a: 174.3
(CO), 170.4 (CO), 139.4 (CH(Me)CHCH2), 134.6 (ArCC),
129.2 (2 × ArCH), 128.9 (ArCH), 128.7 (2 × ArCH), 116.2
(CH(Me)CHCH2), 78.1 (PhCH2), 64.1 (COCH), 52.0 (OMe),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1931

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37.6 (CH(Me), 20.5 (COMe), 17.2 CH(Me); m/z (CI) 292
[(MH)ϩ, (14%)], 250 [(MH2ϪAc)ϩ, (57)]; HRMS (CI) calc.
(MH)ϩ 292.1549 found 292.1538.
Methyl 2-hydroxyaminopent-4-enoate 68
Using oxime 12 (206 mg, 2.0 mmol), procedure D and purifi-
cation by flash chromatography eluting with a 3 : 2 mixture of
petrol–EtOAc gave methyl 2-hydroxyaminopent-4-enoate 68
as a colourless solid (115 mg, 0.8 mmol, 40%). mp 43–46 ЊC;
νmax (solid)/cmϪ1 3261 (OH), 3138 (NH), 3077 (CH), 2955 (CH),
1741 (CO); δH (400 MHz; CDCl3) 5.75 (1 H, ddt, J 17.1, 10.3,
7.3, CH2CHCH2), 5.35 (1 H, s, br, NH), 5.12 (2 H, m,
CH2CHCH2), 3.78 (3 H, s, OMe), 3.72 (1 H, m, COCH), 2.30–
2.50 (2 H, m, CH2CHCH2); δC (68.0 MHz; CDCl3) 173.4 (CO),
132.9 (CH2CHCH2), 118.6 (CH2CHCH2), 64.5 (COCH), 52.1
(OMe), 33.7 (CH2CHCH2); m/z (CI) 146 [(MH)ϩ, (18%)], 128
[(MϪH2O)ϩ, (23)], [(MϪMeCO2H)ϩ, (100)]; HRMS (CI) calc.
(MH)ϩ 146.0817 found 146.0823.
Methyl 2-[acetyl-benzoyloxy-amino]-3-methyl-pent-4-enoate 64
Using oxime ester 24 (414 mg, 2.0 mmol), procedure C and
crotyl bromide in place of allyl bromide gave a residue which
was purified on a silica column eluting with 85 : 15 petrol–
EtOAc (4 : 1 petrol–EtOAc, RF 0.24) to give 2-[acetyl-benzo-
yloxy-amino]-3-methyl-pent-4-enoate 64 as a yellow solid and a
1 : 1.3 mixture of diasteromers a and b. The solid was passed
through a column once again to give a colourless solid (455 mg,
1.5 mmol, 75%). mp 59–61 ЊC; νmax (solid)/cmϪ1 2965 (CH),
1766 (CO), 1740 (CO), 1675 (CO); δH (270 MHz; CDCl3) 8.08
(2 H, m, 2 × ArH, dias. a ϩ b), 7.65 (1 H, m, ArH, dias. a ϩ b),
7.51 (2 H, m, 2 × ArH, dias. a ϩ b), 5.74 (1 H, m,
CH(Me)CHCH2, dias. a ϩ b), 5.01–5.30 (3 H, m, COCH ϩ
CH2, dias. a ϩ b), 3.73 (3 H, s, OMe, dias. a), 3.68 (3 H, s, OMe,
dias. b), 2.87–3.15 (1 H, m, CH(Me), dias. a ϩ b), 2.12 (3 H, s,
COMe, dias. b), 2.06 (3 H, s, COMe, dias. a), 1.18 (3 H, d, J 6.9,
CH(Me), dias. b), 1.10 (3 H, d, J 6.9, CH(Me), dias. a); δC (101
MHz; CDCl3) 172.9 (CO, dias. a ϩ b), 168.9 (CO, dias. a), 168.7
(CO, dias. b), 164.4 (CO, dias. a ϩ b), 139.0 (CHCH2, dias. a),
138.5 (CHCH2, dias. b), 134.4 (ArCH, dias. a ϩ b), 130.1 (2 ×
ArCH, dias. a ϩ b), 128.9 (2 × ArCH, dias. a ϩ b), 126.9
(ArCC, 2 × ArCH, dias. a ϩ b), 116.7 (CHCH2, dias. b), 116.5
(CHCH2, dias. a), 62.9 (COCH, dias. a ϩ b), 52.3 (OMe, dias.
a), 52.1 (OMe, dias. b), 37.8 (CH(Me), dias. a), 37.6 (CH(Me),
dias. b), 20.4 (COMe), 17.0 (Me, dias. b), 16.7 (Me, dias. a); m/z
(CI) 306 [(MH)ϩ, (40%)], 264 [(MH2ϪAc)ϩ, (77)], 184
[(MϪHO2CPh)ϩ, (45)]; HRMS (CI) calc. (MH)ϩ 306.1341
found 306.1338.
Methyl 2-allyl-2-aminopent-4-enoate 6915
Using methyl cyanoformate (177 mg, 2.08 mmol), procedure D
and purification by preparative chromatography eluting with 3 :
2 petrol–EtOAc gave the title compound 69 as a yellow oil (82
mg, 0.5 mmol, 24%). νmax (neat)/cmϪ1 3382 (NH), 33.17 (NH),
3078 (CH), 2952.0 (CH), 1730.6 (CO); δH (400 MHz; CDCl3)
5.69 (2 H, m, 2 × CH2CHCH2), 5.13 (4 H, m, 2 × CH2CHCH2),
3.72 (3 H, s, OMe), 2.55 (2 H, m, 2 × COCCHH ), 2.28 (2 H, dd,
J 13.5, 8.1, 2 × COCCHH); δC (101 MHz; CDCl3) 176.7 (CO),
132.6 (CH2CHCH2), 119.4 (CH2CHCH2), 60.7 (COC), 52.1
(OMe), 44.1 (CCH2).
Acknowledgements
DR thanks GlaxoSmithKline for the provision of a CASE
award and BBSRC for funding.
Methyl 2-acetamido-2-allylpent-4-enoate 6515
References
In powder (100 mesh, 505 mg, 4.4 mmol) was weighed into a
Wheaton vial. DMF (1.7 mL) was added followed by allyl
bromide (570 µL, 799 mg, 6.6 mmol). A triangular stirrer bar
was then dropped in and the mixture stirred vigorously. Within
a few minutes an exotherm could be felt and the mixture turned
into a very fine suspension that was dark green/black in colour.
After 40 min the allylating mixture was pipetted into a solution
of the nitrile 66 (2.0 mmol) and freshly distilled Ac2O (4 mL) in
anhydrous THF (14 mL) under a N2 atmosphere. The Wheaton
vial was washed out with dry THF (1 mL). After 2 h Et3N
(1 mL) was added and the reaction was left to stir overnight.
The reaction was quenched with NH4Cl (aq) (30 mL) and
extracted with Et2O (3 × 40 mL) which was dried (MgSO4),
filtered and concentrated. The residue was purified by flash
chromatography using petrol–EtOAc 7 : 3 as the elutant (7 : 3
petrol–EtOAc, RF 0.18) which provided a yellow solid. The
chromatography was repeated to yield the title compound 65 as
a colourless solid (288 mg, 1.4 mmol, 68%). mp 58–59 ЊC (lit.
60 ЊC);15 δH (300 MHz; CDCl3) 6.27 (1 H, s, NH), 5.56 (2 H,
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ddt, J 17.6, 9.5, 7.3, 2 × CH᎐), 5.08 (4 H, m, 2 × ᎐CH ), 3.76 (3
᎐
᎐
2
H, s, OMe), 3.19 (2 H, ddt, J 13.8, 7.3, 1.1, 2 × CCHH), 2.52 (2
H, dd, J 7.3, 13.9, 2 × CCHH ), 1.99 (3 H, s, Me); δC (76 MHz;
CDCl ) 173.5 (CO), 169.2 (CO), 132.3 (2 × CH᎐), 119.0
᎐
3
(2 × ᎐CH ), 64.4 (C), 52.7 (OMe), 39.0 (2 × CCH ), 24.0 (Me);
᎐
2
2
m/z (CI) 212 [(MH)ϩ, (57%)], 168 [(MH2ϪAc)ϩ, (26)], 152
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Methyl 2-[benzoyloxy-amino]-pent-4-enoate 67
Using oxime ester 24 (409 mg, 1.98 mmol), procedure D and an
aqueous NaHCO3 work-up gave the unstable methyl 2-[benzo-
yloxy-amino]-pent-4-enoate 67 as a yellow solid (455 mg, 1.8
mmol, 91%). δH (400 MHz; CDCl3) 7.98 (2 H, m, 2 × ArH),
7.56 (1 H, m, ArH), 7.44 (2 H, m, 2 × ArH), 5.82 (1 H, m, CH᎐),
᎐
5.19 (2 H, ᎐CH ), 4.01 (1 H, m, COCH), 3.75 (3 H, s, OMe),
᎐
2
2.56 (2 H, m, CHCH2CH).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1932

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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 2 1 – 1 9 3 3
1933