The synthesis of some chiral 2-aminoalkyloxazole-4-carboxylates from isoxazol-5(2H)-ones

Article abstract of DOI:10.1071/CH03052

Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate can be N-acylated by a number of natural and synthetic phthalimidylamino acids in the presence of carbodiimides. The N-acyiated products form the corresponding oxazoles smoothly when irradiated at 300 nm in acetone. Removal of the phthalimido protecting group then gives 2-aminoalkyloxazole-4-carboxylate esters in good overall yields, and without significant racemization at any step.

Full text of DOI:10.1071/CH03052

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 887–896
The Synthesis of Some Chiral 2-Aminoalkyloxazole-4-carboxylates
from Isoxazol-5(2H)-ones
Matthew Cox,A Rolf H. PragerA,B and Carina E. SvenssonA
A School of Chemistry, Physics and Earth Sciences, Flinders University, Adelaide 5001, Australia.
B Author to whom correspondence should be addressed (e-mail: rolf.prager@flinders.edu.au).
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate can be N-acylated by a number of natural and synthetic
phthalimidylamino acids in the presence of carbodiimides. The N-acylated products form the corresponding oxa-
zoles smoothly when irradiated at 300 nm in acetone. Removal of the phthalimido protecting group then gives
2-aminoalkyloxazole-4-carboxylate esters in good overall yields, and without significant racemization at any step.
Manuscript received: 20 February 2003.
Final version: 23 April 2003.
Introduction
the synthesis of the required oxazole amino acids have also
been reported.[8–14] These have generally been biomimetic,
whichincludescyclodehydrationofamidesorthioamidesand
subsequent dehydrogenation or prior oxidation.
Although peptides display a range of therapeutic properties,
their usefulness as drugs is limited by their conformational
flexibility and their instability towards peptidases.[1,2] Cyclic
peptides have far less conformational flexibility than their
acyclic analogues and their ease of cleavage can be reduced
by the presence of hydrophobic side chains, which create a
protective exocyclic surface. l-Proline and d-amino acids are
frequently seen in naturally occurring cyclic peptides as they
stabilize turns in the backbone. Many other means of intro-
ducing further constraints are also found in nature, such as
the presence of unusual amino acids and disulfide bonds.[1–3]
Because of the wide range of biological properties displayed
by cyclic peptides,[4–6] we have examined the synthesis of a
range of cyclic amides based on oxazole and thiazole amino
acids.[7] Such building blocks are now being revealed with
increasingfrequencyamongsecondarymetabolitesofmarine
origin but their peptide origin dictates that the natural prod-
ucts, such as bistratamide C (1),[8] are generally based on
the 2-aminoalkyloxa(thia)zole-4-carboxylic acid skeleton (2)
(see Diagram 1). Recent work in this area has concentrated on
the synthesis of natural products but a number of strategies for
We have reported a new synthesis of oxazoles[15] and
thiazoles,[16] and here we report the application of the former
to the synthesis of some esters of 2-aminoalkyloxazole-4-
carboxylic acid that are capable of being elaborated into the
biogenetically ‘natural’ cyclic amides. A preliminary account
of some of this work has been published.[7]
Discussion
The chosen synthetic pathway involved the thermal or
photochemical conversion of protected aminoalkylacyl
isoxazolones into the corresonding oxazoles (Scheme 1).[15]
While our previous work showed that pyrolysis of the
N-acylisoxazolones was generally higher yielding than
photolysis, pyrolysis was not a feasible option in the present
context as the protected acylisoxazolones were generally
insufficiently volatile to sublime into the pyrolysis furnace
and would be totally impractical if polyamides were required.
For Scheme 1 to be a viable procedure a number of difficulties
needed to be overcome. The first was to obtain a conve-
nientsourceof non-natural, opticallypure α-aminoacids. The
second was to achieve a mild and efficient N-acylation of the
2-unsubstituted isoxazol-5(2H)-ones under conditions that
wouldnotresultinracemizationoftheaminoacidstereogenic
centre. This non-trivial requirement would necessitate a high
N- to O-acylation ratio. Next, since a carbene intermediate
is generated in the photolysis/pyrolysis,[15] the amino group
would need to be protected in such a way as to be regener-
ated without racemization. Finally, since coupling to make
the proposed cyclic amides could involve either the amino
or the carboxyl group, both mono-protected functionalities
were required.
O
R
O
N
H2N
H
S
N
N
N
X
COOH
O
NH
HN
Rꢀ
N
O
X = O, Rꢀ = Me
X = S, Rꢀ = H
S
(1)
(2)
Diagram 1.
© CSIRO 2003
10.1071/CH03052
0004-9425/03/090887

888
M. Cox, R. H. Prager and C. E. Svensson
R1
N
R1
ProtN
R1
hν 300 nm
O
ProtN
ProtN
N
or FVP, 550°C
CO2H
CO2Et
O
O
CO2Et
O
Me
Me
Scheme 1.
CH3
O
CH3
N
CH3
O
OLi
Base, LiCl
ꢁ78°C
0°C
NH2
NH2
NHLi
N
N
OH
CH3
OLi CH3
OLi
RX
CH3
(3)
0°C
CH3
O
H
H O
2
HO2C
NH2
NH2
a, R = C6H5CH2
b, R = C10H21
c, R = C12H25
N
R
OH
R
CH3
(5a)−(5d)
Scheme 2.
d, R = 9-MeO−C9H18
(4a)−(4d)
Formation of Unnatural α-Amino Acids
Table 1. Synthesis of stereochemically pure α-amino acids
20
20
The most direct routes for the preparation of α-amino acids
involve alkylation of glycine derivatives.[17–23] We chose to
adopt the method of Myers,[24] which is based on the dia-
stereoselective alkylation of either (1S,2S)-pseudoephedrine
glycinamide (3) or its enantiomer. Myers[24] observed that
addition of electrophiles at −78◦C to the O,N-dianion of
pseudoephedrine glycinamide gave N-alkylated products,
whereas the addition of electrophiles at 0◦C gave products
of C-alkylation. Initial deprotonation with slightly less than
two equivalents of strong base at −78◦C gave the kineti-
cally favourable O,N-dianion, which upon warming to 0◦C
rearranged to the thermodynamically stable (Z)-enolate by
carbon-to-nitrogen proton transfer (Scheme 2).
The alkylation of (1S,2S)-pseudoephedrine glycinamide
(3) with benzyl bromide and n-butyl lithium as the
base gave (1S,2S)-pseudoephedrine-(R)-phenylalaninamide
in 62% yield. We found that alkylation with benzyl
chloride[25] was sluggish, that long-chain alkyl chlorides and
bromides were completely unreactive, while the correspond-
ing iodides reacted slowly.[25] Electrophiles containing ester
or amide functionalities gave none of the desired product. The
results of the alkylation reactions are summarized in Table 1,
and led to the synthesis of the amino acids (5a)–(5d). (1S,2S)-
Pseudoephedrine glycinamide (3) was used for all of the
alkylations except in the case of 9-iodo-1-methoxynonane,
where the enantiomer was used.
Yield
[%]
Yield Configuration [α]D
Lit. [α]D
[%]
(4a)
(4b)
(4c)
(4d)
62
60
54
58
(5a)
(5b)
(5c)
(5d)
70
73
73
73
R
R
R
S
+36.8◦
−20.8◦
−18.9◦
+15.9◦
+34.5◦
−20.5◦
–
–
O
O
H
N
R
CH2CO2Et
R
N
O
O
O
N
O
COOH
N
Me
O
CH2CO2Et
O
(9) R = H
(10) R = Me
Me
(8)
O
(6) R = H
(7) R = Me
(16) R = C10H21
(17) R = C12H25
(18) R = 9-MeO–C9H18
(19) R = BzS–CH2
(20) R = 4-BzO–C4H6CH2
Diagram 2.
Table 2. DCC-induced coupling of (8) with (6) and (7)
Acid Temperature N/O Ratio Product Isolated yield
[◦C]
[%]
(6)
(7)
(7)
25
0
25
100 : 0
92 : 8
79 : 21
(9)
(10)
(10)
88
80
68
N-Acylation of Isoxazolones
Phthalimido-protected acids (6) and (7) (see Diagram 2) were
used to establish the optimal acylation conditions. They gave
goodyieldsandhigh N/Oselectivitywhencoupledwithisox-
azolones using dicyclohexylcarbodiimide (DCC) or other
diimides in dichloromethane. With the glycine derivative (6),
O-acylated products were not detected and yields of the N-
acylated products were high both at ambient temperature
and at 0◦C. However, as shown in Table 2, for the alanine
derivative (7), the N- to O-acylation ratio was found to be

Synthesis of Chiral 2-Aminoalkyloxazole-4-carboxylates from Isoxazol-5(2H)-ones
889
O
R
BzO
O
R
MeO
Ph
HN
O
CO2H
NPhth
N
O
BzS
C
CO2H
NPhth
N
N
CH2
N
F3C
CH2
O
O
CO2Et
CO2Et
O
Me
Me
(11) R = H
(12) R = Me
(14)
(15)
(29)
(30)
(21) R = C10H21
(22) R = C12H25
(23) R = 9-MeO–C9H18
(24) R = BzS–CH2
(25) R = 4-BzO–C6H4CH2
Diagram 3.
O
O
O
N
O
N
O
N
O
O
hν
H O
O
2
O
(9)
HN
HO
N
CO2Et
HN
O
CO
CO2Et
H
:
Me
Me
Me
(13)
Scheme 3.
O
O
O
R
R
R
N
O
hν, acetone
−CO
H abstr.
O
N
N
O
minor pathway
N
CO2Et
O
O
O
O
Me
(16) R = C10H21
(17) R = C12H25
(26) R = C10H21
(27) R = C12H25
Scheme 4.
optimal at lower temperatures, as was the yield of N-acylated
product. In this case, higher temperatures probably led to
formation of considerable amounts of N-acylurea as a by-
product.[26] We have recently reported that in some cases
acylation of the isoxazolone can be achieved by use of the
acid chloride of the phthalimido acid.[27]
A second advantage arising from the presence of the
phthalimido group became apparent at this stage. Whereas
photochemical conversion of the N-acylisoxazolones to oxa-
zoles has generally been inefficient relative to the correspond-
ing thermal reaction, the phthalimido analogues underwent
facile conversion to give the corresponding oxazoles upon
photolysis in acetone at 300 nm. Clearly, the protecting group
was responsible for initial light absorption in this case to yield
oxazoles (11) and (12) in 66 and 61% yield, respectively (see
Diagram 3). Photolysis of the isoxazolone (9) in acetonitrile
gave lower yields of the desired oxazole and the product was
contaminated with compound (13) (Scheme 3). This indi-
cated that the carbene intermediates were much more labile
to traces of water present in acetonitrile.
The above acylation/photolysis procedure was used to
convert the amino acids (5b)–(5d), (S)-benzylphthalimido-
cysteine (14), and 4-benzyloxyphthalimidophenylalanine
(15) into the corresponding N-acylated isoxazolones (16)–
(20), and then onto the corresponding oxazoles (21)–(25).
While acetone continues to be the solvent of choice, photo-
lysis of (16)–(20) revealed that triplet states were involved in
the photolysis to some extent. Thus photolysis of (16) gave
(21) (67% yield) and 10% of N-undecylphthalimide (26),
the origin of which is summarized by Scheme 4. Similarly,
photolysis of (17) gave (27) in 9% yield.
In the photolysis of (20) such triplet by-products were
more prominent and only in ethyl acetate was a respectable
yield of (25) obtained. In acetone, radical fragmentation of
the product (25) was the problem, and compound (25) was
accompanied by phthalimide (43% yield) and the vinyloxa-
zole (28) (38% yield). A plausible relevant fragmentation[28]
is shown in Scheme 5. Finally, photolysis of (19) in acetone
gave N-vinylphthalimide (29) (13% yield) in addition to the
desired (24).

890
M. Cox, R. H. Prager and C. E. Svensson
O
Me
O
O
N
oxazole
N
NH
O
ꢂ
EtO2C
H
O
OBz
OBz
(25)
(28)
Scheme 5.
Me
OH
Me
OH
O
7.98 ppm
N
4.54 ppm
H2N
CO2Et
ꢂ
N
N
O
N
O
N
BF Et O or TiCl
2
3.
2
CO2Et
CO2Et
Me
O
(31)
(32)
(33)
Me
Me
Scheme 6.
Hydrazinolysis readily cleaved the phthalimido group
A second unsuccessful approach involved attempts to
obtain chiral reduction products of the phthalimides fol-
lowing a method used by Easton,[36,37] who obtained both
enantiomers of α-deuteriated alanine by the temporary intro-
duction of a stereogenic centre on the phthaloyl group of the
protected amino acid.
In a similar manner, we envisaged that the desired optically
pure 2-aminoalkyloxazole-4- and 5-carboxylic acids might
be available by the introduction of a chiral auxiliary onto
the phthaloyl protecting group. The proposed sequence is
outlined in Scheme 7. The racemic alcohol (34) would form
a diastereomeric mixture of (35) and (36) by reaction with an
optically pure alcohol. Separation of the diastereomers and
subsequent alkylation and oxidation would give the desired
(37) and (38).
without effecting the ethyl ester.[29] The optical integrity of
the stereogenic centre in the resulting chiral amino acids
and oxazoles was determined by conversion of the amines
totheir(R)-α-methoxy-α-(trifluoromethyl)phenylacetamides
(30).[30] The two diastereomeric amides could be clearly dif-
ferentiated by 1H, 13C, and 19F NMR spectroscopy. Racem-
ization could not be detected in (30) (R = Me) by NMR
spectroscopy, which indicated a diastereomeric excess (d.e.)
ofgreaterthan98%. Alltheothercompoundshadad.e. which
was greater than 92%.
In addition to the approach detailed above using Myers’
procedure, we have investigated adapting the approach of
Shioiri,[31] who utilized (–)-(1S,2S,5S)-2-hydroxy-3-pinan-
one as a chiral auxiliary for the diastereoselective alkyla-
tion of the Schiff base derived from (aminomethyl)thiazole.
The same approach has been used by Dondoni[32] with
chiral Schiff bases of 2-(1-aminomethyl)thiazoles, 2-
(aminomethyl)pyridine,[33] and 2-(aminomethyl)furan.[34]
More recently, Liebscher[35] has applied the conditions
describe by Shioiri to the asymmetric synthesis of 2-(amino-
alkyl)-4,5-diphenyloxazoles, starting from 2-(aminomethyl)-
4,5-diphenyl-1,3-oxazole using both enantiomers of
2-hydroxypinan-3-one as chiral auxiliaries. The Lewis acids
TiCl4[32] or BF[331] were required for formation of the Schiff
bases.
Unfortunately, none of the methods for Schiff base forma-
tion with (31), which was formed from (11), were compatible
with the required functionality. Products were obtained in
unacceptable yields (18–31%) with 2-hydroxypinanone or
camphor in the presence of BF3 or TiCl4, and no desired
products were obtained in their absence.
Longer reaction times gave a mixture of the desired imine
(32) (21% yield) and the dehydrated imine (33) (22% yield),
which were readily recognizable by NMR spectroscopy
(Scheme 6). We suspect that the low yields are due to side
reactions which involve amide formation between the ester
and amine functionalities. Due to the failure of the above
procedure and the success of previous synthetic strategies
devised for the synthesis of chiral aminoalkyloxazoles, this
approach was not investigated further.
The alcohol (34) was treated with hydrogen chloride
and (S)-2-methyl-1-butanol or menthol to give the desired
diastereomeric ether mixtures (35a)/(35b) and (36a)/(36b)
1
(93% yield). H NMR analysis indicated approximately a
55/45 to 65/35 ratio for both diastereomers. Separation of
the above diastereomeric mixtures was totally unsuccess-
ful by normal and reverse-phase thin-layer chromatography,
radial chromatography, column chromatography, or analyti-
cal reverse-phase HPLC.
Racemic N-phthaloylalanine ethyl ester was treated with
(+)-B-chlorodiisopinocampheylborane(DIP-chloride)[38,39]
in an attempt to form chiral reduction products but only
starting material was recovered.
Conclusion
We have shown that hydrochlorides of aminoalkyloxazole-
carboxylate esters can be conveniently prepared with sat-
isfactory retention of optical purity by the acylation of
isoxazol-5(2H)-ones, photochemical conversion of the prod-
ucts to oxazoles, and subsequent deprotection. We hope to
report the synthesis and properties of polyamides from these
new building blocks shortly.
Experimental
All solvents used where freshly distilled and dried according to the meth-
ods of Perrin and Amarego.[40] Melting points were determined on a

Synthesis of Chiral 2-Aminoalkyloxazole-4-carboxylates from Isoxazol-5(2H)-ones
891
O*R
N
O*R
CH
N
OH
CH
CH
(ꢂ)ꢁ*ROH
CO2Et
N
N
N
N
CO2Et
CO2Et
O
O
O
O
O
O
(34)
Me
Me
Me
H
H
CH2
CH2
CH3
CH3
(35a) Rꢃ
(36a) R ꢃ
CH2CH3
CH2CH3
(35b) R ꢃ
(36b) R ꢃ
O
1. LDA
2. R'X
3. H+
1. LDA
2. R'X
3. H
+
4. [O]
4. [O]
O
O
R'
R'
N
N
N
N
CO2Et
CO2Et
O
O
O
O
(38)
(37)
Me
Me
Scheme 7.
Reichert hot-stage microscope and are uncorrected. 1H (300 MHz), 13
C
54%) as an orange oil (Found: [M + H]+•, 391.3324. C24H42N2O2
requires [M + H]+•, 391.3324). νmax/cm−1 2933, 1636. δH (2.6 : 1 ratio
of rotamers; an asterisk denotes the minor rotamer) 8.05 (2 H, br s,
exchangeable), 7.65 (1 H, d, J 7.1), 7.43 (2 H, t, J 7.4), 7.31 (1 H, t, J
7.3), 5.05 (1 H, m), 4.82 (1 H, d, J 9.9), 4.65 (1 H, m), 4.29 (1 H, br s,
exchangeable), 2.99∗ (3 H, s), 2.74 (3 H, s), 1.80 (2 H, m), 1.23 (20 H, br
s), 1.17∗ (20 H, br s), 0.88 (3 H, t, J 7.0), 0.78 (3 H, d, J 6.9) (OH signal
was not observed). δC (2.6 : 1 ratio of rotamers; an asterisk denotes the
minor rotamer) 170.2, 140.3, 129.0, 128.3, 128.2, 73.9, 54.8, 51.9, 31.9,
30.4, 29.9∗, 29.7, 29.6, 29.6, 29.5, 29.4∗, 29.3, 29.3, 24.7∗, 22.7, 14.7,
14.1. m/z 391 (0.1%, [M + H]+•), 77 (19), 58 (100).
(75.5 MHz), and 19F (283.3 MHz) NMR measurements were recorded
on a Gemini Varian 300 spectrometer in deuterochloroform with tetra-
methylsilane or CFCl3 as internal standards, unless otherwise stated.
Infrared spectra were recorded as Nujol mulls or films on a Perkin Elmer
1600 FT-infrared spectrophotometer using fused sodium chloride cells.
Optical rotations were measured on a POLAAR 21 instrument (Optical
Activity Ltd) at 589.44 nm and 18◦C, unless otherwise noted, and are
considered to be reliable to 1◦. Mass spectra and high-resolution mass
spectra were recorded on a Kratos MS25RF spectrometer, except for
compounds (21), (23), and (25), which were analyzed by means of liquid
secondary ion mass spectrometry (LSIMS) in mononitrobenzalde-
hyde. Microanalyses were performed by the Australian Microanalytical
Service and Chemical & Micro Analytical Services Pty Ltd, Melbourne.
Photolyses were performed under nitrogen using a Hanovia mercury
medium-pressure arc source filtered through pyrex, which gave an
irradiation source considered to be nominally 300 nm or above.
9-Iodo-1-methoxynonane
Asolutioncontaining9-bromo-1-methoxynonane[41] (2.5 g, 10.5 mmol)
and sodium iodide (8.4 g, 56 mmol) in anhydrous acetone (60 mL)
was stirred in the absence of light under N2 at rt for 3 days. After
removal of the solvent and the inorganic material, the crude 9-iodo-1-
methoxynonane (2.82 g, 93%) was used without further purification. δH
3.34 (2 H, t, J 6.6), 3.31 (3 H, s), 3.17 (2 H, t, J 7.0), 1.80 (2 H, m), 1.54
(2 H, m), 1.37–1.28 (10 H, br s). δC 71.8, 58.3, 33.5, 31.8, 30.5, 29.5,
28.5, 28.3, 22.7.
(1S,2S)-Pseudoephedrine-(R)-2-aminododecanamide (4b)
A solution of anhydrous (1S,2S)-pseudoephedrine glycinamide[24]
(2.7 g, 12.2 mmol) in THF (10 mL) was added, dropwise, to a slurry con-
taining anhydrous lithium chloride (3.10 g, 73 mmol), n-butyllithium
(9.5 mL, 2.5 M, 23.7 mmol), and diisopropylamine (2.4 g, 23.7 mmol) in
THF (20 mL) maintained at −78◦C under N2. The mixture was allowed
to warm to 0◦C and was maintained at this temperature for a further
20 min. n-Iododecane (3.91 g, 14.6 mmol) was then added dropwise and
the reaction mixture was stirred at 0◦C for 48 h. A saturated sodium chlo-
ridesolution(20 mL)wasaddedandtheproductwasextractedwithether
(3 × 20 mL). The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated to give the crude product (5.53 g) as an orange oil.
Chromatography (50% ethyl acetate/light petroleum) gave (4b) (2.64 g,
60%) as an orange oil (Found: [M + H]+•, 363.3018. C22H38N2O2
requires [M + H]+•, 363.3011). νmax/cm−1 2945, 1630, 1456. δH 8.01
(2 H, br s, exchangeable), 7.67 (1 H, d, J 6.9), 7.43 (3 H, t, J 7.4), 7.31
(1 H, t, J 7.3), 5.07 (1 H, m), 4.82 (1 H, d, J 9.9), 4.44 (1 H, m), 4.29
(1 H, br s, exchangeable), 2.92 (3 H, s), 1.80 (2 H, m), 1.23 (16 H, br s),
0.87 (3 H, t, J 7.0), 0.78 (3 H, d, J 6.9). δC 170.9, 140.1, 128.9, 128.3,
128.1, 74.2, 55.3, 52.5, 31.9, 30.3, 29.5, 29.3, 24.9, 22.6, 14.7, 14.1.
m/z 363 (0.2%, [M + H]+•), 77 (19), 58 (100).
(1R,2R)-Pseudoephedrine-(S)-2-amino-11-
methoxyundecanamide (4d)
The above procedure gave (1R,2R)-pseudoephedrine-(S)-2-amino-11-
methoxyundecanamide (4d) (1.82 g, 58%) as an orange oil (Found:
[M + H]+•, 379.2955. C22H38N2O3 requires [M + H]+•, 379.2961).
νmax/cm−1 2930, 2857, 1634, 1456, 1118. δH 7.38–7.24 (5 H, m), 4.70
(1 H, m), 4.55 (1 H, m), 4.29 (3 H, br s, exchangeable), 3.95 (1 H, m),
3.32 (2 H, t, J 6.6), 3.29 (3 H, s), 2.91 (3 H, s), 1.51 (4 H, m), 1.23 (12 H,
br s), 0.91 (3 H, d, J 5.2). δC 174.0, 141.1, 128.3, 127.7, 126.8, 74.6,
72.7, 58.2, 51.2, 49.9, 33.2, 29.3, 29.2, 29.1, 25.8, 25.1, 14.3. m/z 379
(0.2%, [M + H]+•), 77 (23), 58 (100).
(R)-2-Aminododecanoic Acid (5b)
Compound (4b) (2.14 g, 5.9 mmol) was refluxed in water (15 mL) and
ethanol (10 mL) for 24 h. The mixture was allowed to cool and the pre-
cipitate was collected by filtration and washed with cold chloroform
(3 × 5 mL). The mother liquor and chloroform extracts were com-
bined and evaporated to give (1S,2S)-pseudoephedrine (0.95 g, 97%)
as an orange oil. The air-dried, white crystalline solid was identified
as (R)-2-aminododecanoic acid (5b) (0.93 g, 73%), mp 208–210◦C
(1S,2S)-Pseudoephedrine-(R)-2-aminotetradecanamide (4c)
Following the method described above but using iodododecane gave
(1S,2S)-pseudoephedrine-(R)-2-aminotetradecanamide (4c) (0.61 g,

892
M. Cox, R. H. Prager and C. E. Svensson
20
20
(lit.[42] 205◦C), [α]D −20.8◦ (c 1.02 in AcOH) [lit.[42] [α]D −20.5◦
(c 1.02 in AcOH)] (Found: [M + H]+•, 216.1964. C12H25NO2 requires
[M + H]+•, 216.1963).
Ethyl 2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]-
4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate (9)
DCC (5.11 g, 24.3 mmol) was added to a mixture of phthalimidyl-
glycine (6)[44] (3.41 g, 16.6 mmol) and the isoxazolone (8)[45] (3.08 g,
18.00 mmol) in dichloromethane (30 mL) at ambient temperature and
the reaction was stirred for 16 h. After filtration, the solvent was removed
under vacuum and the residue was analyzed by 1H NMR spectroscopy
in order to determine the N/O-acylation ratio. The crude product was
then redissolved in dichloromethane, the volume was reduced under
vacuum to about 3 mL, and the residue was diluted with ether, where-
upon the N-acylated product (9) precipitated and was collected as white
crystals (5.21 g, 88%), mp 148–151◦C (Found: C 57.4, H 4.0, N, 7.8%;
[M−CO2]+•, 314.0905. C17H14N2O7 requires C 57.0, H 3.9, N, 7.8%;
[M−CO2]+•, 314.0903). νmax/cm−1 1787, 1728, 1414, 1304, 1239. δH
7.87 (2 H, m), 7.74 (2 H, m), 4.84 (2 H, s), 4.36 (2 H, q, J 7.1), 1.98
(3 H, s), 1.30 (3 H, t, J 7.1). δC 167.0, 166.4, 160.9, 157.8, 144.6, 134.4,
131.8, 123.7, 109.8, 63.4, 39.4, 13.8, 7.0. m/z 314 (1.2%, [M−CO2]+•),
160 (19), 43 (100).
(R)-2-Aminotetradecanoic Acid (5c)
Following the above procedure using (4c) gave (R)-2-aminotetradeca-
20
noic acid (5c) (0.132 g, 73%), mp 219–221◦C, [α]D −18.9◦ (c 1.02
in AcOH). The racemate has been resolved[43] but physical constants
were not reported (Found: [M + H]+•, 244.2277. C14H29NO2 requires
[M + H]+•, 244.2277). νmax/cm−1 2920, 1700. δH (CDCl3/[D6]DMSO)
8.40 (2 H, br s, exchangeable), 3.78 (1 H, m), 1.84 (2 H, m), 1.40–
1.23 (20 H, br s), 0.88 (3 H, t, J 7.0), (OH signal not observed). δC
(CDCl3/[D6]DMSO) 171.0, 52.3, 31.5, 30.1, 29.2, 29.1, 28.9, 28.8,
24.5, 22.3, 13.9. m/z (ESI) 244.3 (100%, [M + H]+•), 198 (12), 155
(6), 111 (3). MS/MS of daughter ion 198–198 (100%), 139 (4), 125 (8),
111 (49), 97 (83), 83 (92), 69 (75).
(S)-2-Amino-11-methoxyundecanoic Acid (5d)
Ethyl 2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]-
Following the above procedure using (4d) gave a white crystalline
4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate (10)
solid, which was identified as (S)-2-amino-11-methoxyundecanoic acid
DCC (1.30 g, 6.17 mmol) was added to a mixture of phthalimidylala-
nine (7)[46] (597 mg, 2.72 mmol) and the isoxazolone (8) (512 mg,
2.99 mmol) in dichloromethane (20 mL) at 0◦C. The reaction was stirred
for 3 h at 0◦C, then for 2 days at ambient temperature. The reaction
mixture was worked up as above. The N-acylated product (10) crys-
tallized as white crystals from diethyl ether (807 mg, 80%), mp 126–
130◦C [(S)-isomer], 125–131◦C [(R)-isomer], 122–124◦C (racemate),
20
(0.82 g, 73%), mp 204–215◦C, [α]D +15.9◦ (c 1.02 in AcOH) (Found:
[M + H]+•, 232.1920. C12H25NO3 requires [M + H]+•, 232.1913).
νmax/cm−1 2928, 1704. δH (CDCl3/[D6]DMSO) 7.90 (2 H, br s), 3.83
(1 H, m), 3.35 (2 H, t, J 6.6), 3.24 (3 H, s), 1.55 (2 H, m), 1.39–1.25
(14 H, br s), (OH signal not observed). δH (CDCl3/[D6]DMSO) 171.0,
72.5, 59.1, 53.3, 32.2, 30.1, 29.2, 28.8, 24.5. m/z (ESI) 232.2 (100%,
[M + H]+•), 186 (19).
[α]D +63.0◦ (c 0.793 in CHCl3) [(S)-isomer], [α]D −64.3◦ (c 0.933
•
in CHCl3) [(R)-isomer] (Found: C 58.2, H 4.4, N 7.6%; [M−CO2]+
,
,
•
328.1061. C18H16N2O7 requires C 58.1, H 4.3, N 7.5%; [M−CO2]+
(R)-N-Phthalimido-2-aminododecanoic Acid
328.1059). νmax/cm−1 1785, 1734, 1714, 1301, 1268, 1234, 1058. δH
7.88 (2 H, m), 7.76 (2 H, m), 5.36 (1 H, q, J 7.2), 4.45 (2 H, q, J 7.1),
1.81 (3 H, d, J 7.2), 1.97 (3 H, s), 1.41 (3 H, t, J 7.1). δC 167.1, 166.6,
164.5, 158.2, 145.4, 134.5, 131.7, 123.8, 109.7, 63.4, 48.0, 14.8, 13.7,
6.9. m/z 328 (5%, [M−CO2]+•), 202 (12), 174 (100).
(R)-2-Aminododecanoic acid (5b) (0.8 g, 3.72 mmol) and sodium car-
bonate (1.064 g, 10.3 mmol) were dissolved in water (40 mL) and THF
(28 mL) by heating (5 min). N-Ethoxycarbonylphthalimide (8.36 g,
3.8 mmol) was added and the solution was stirred at rt for 1 h. The
reaction mixture was then evaporated and acidified to pH 3 with conc.
HCl. The precipitate was extracted with hexane (3 × 20 mL). The com-
bined organic extracts were dried (Na2SO4), filtered, and evaporated to
give the title compound (0.81 g, 63%) as a colourless oil, which was
used without further purification (Found: M+•, 345.1944. C20H27NO4
requires M+•, 345.1940). νmax/cm−1 2952, 2855, 1706, 1476. δH 7.86
(2 H, m), 7.76 (2 H, m), 4.90 (1 H, dd, J 5.0 and 10.8), 2.25 (2 H, m),
1.34–1.20 (16 H, m), 0.86 (3 H, t, J 7.1). δC 174.5, 167.7, 134.2, 131.74,
123.6, 52.0, 31.8, 29.6, 29.5, 29.3, 29.2, 28.8, 28.4, 26.3, 22.6, 14.1. m/z
(ESI) 345.2 (48%, M+•), 327 (27), 299 (100). MS/MS of daughter ion
299–299 (13%), 282 (8), 147 (100).
(R)-Ethyl 4-Methyl-2-[2-phthalimidododecanoyl]-5-oxo-
2,5- dihydroisoxazole-3-carboxylate (16)
DCC (0.103 g, 0.5 mmol) was added to a solution containing (R)-
N-phthalimido-2-aminododecanoic acid (0.116 g, 0.34 mmol) and the
isoxazolone (8) (0.63 g, 0.37 mmol) in anhydrous dichloromethane
(10 mL) and dimethylformamide (1 mL) at 0◦C. The reaction was main-
tained under N2 at 0◦C for 3 h before being allowed to warm up to
room temperature for 16 h. The reaction mixture was then stirred with
10% aqueous acetic acid (3 mL) for 15 min. The mixture was filtered
and the filtrate was evaporated. The residue was dissolved in hexane
(40 mL) and washed with water (3 × 20 mL). The organic phase was
evaporated to give the crude product (0.17 g), which was purified by
(R)-N-Phthalimido-2-aminotetradecanoic Acid
radial chromatography (5% ethyl acetate/light petroleum) to give the
Following the above procedure using (5c) (1.2 g, 4.94 mmol) gave the
•
title compound (0.144 g, 87%) as a colourless oil (Found: [M−CO2]+
,
title compound (1.01 g, 55%) as a colourless oil, which was used without
454.2461. C27H34N2O7 requires [M−CO2]+•, 454.2468). νmax/cm−1
2953, 2861, 1762, 1722, 1610, 1554. δH 7.88 (2 H, m), 7.77 (2 H, m),
5.26 (1 H, dd, J 4.7 and 10.7), 4.43 (2 H, q, J 7.1), 2.42 (1 H, m),
2.21 (1 H, m), 1.97 (3 H, s), 1.39 (3 H, t, J 7.0), 1.38–1.22 (16 H, m),
0.86 (3 H, t, J 7.0). δC 167.2, 166.5, 164.2, 158.1, 145.3, 134.3, 131.5,
123.7, 109.6, 63.4, 52.6, 31.8, 29.5, 29.4, 29.2, 28.8, 28.1, 26.1, 22.6,
14.1, 13.8, 7.0. m/z (ESI) 454.2 (25%, [M−CO2]+•), 414 (30), 379
(57), 179 (100), 101 (35), 79 (48).
•
further purification (Found: M+•, 373.2255. C22H31NO4 requires M+
,
373.2253). νmax/cm−1 2947, 2851, 1705, 1476. δH 7.88 (2 H, m), 7.78
(2 H, m), 4.94 (1 H, dd, J 4.9 and 10.8), 2.25 (2 H, m), 1.31–1.22 (20 H,
m), 0.87 (3 H, t, J 7.0). δC 174.3, 168.1, 134.2, 131.7, 123.6, 52.3, 31.6,
29.4, 29.3, 29.2, 29.1, 28.6, 26.2, 22.5, 14.0. m/z (ESI) 373.2 (100%,
M+•), 355 (34), 327 (90).
(S)-N-Phthalimido-2-amino-11-methoxyundecane
(R)-Ethyl 4-Methyl-2-[2-phthalimidotetradecanoyl]-5-oxo-
2,5-dihydroisoxazole-3-carboxylate (17)
Following the above procedure using (5d) (1.15 g, 5 mmol) gave the title
compound (1.25 g, 70%) as a colourless oil, which was used without
•
further purification (Found: M+•, 361.1880. C20H27NO5 requires M+
,
The above procedure gave the title compound (1.27 g, 90%) as a
colourless oil (Found: [M−CO2]+•, 482.2779. C29H38N2O7 requires
[M−CO2]+•, 482.2781). νmax/cm−1 2951, 2858, 1761, 1724, 1603,
1558. δH 7.85 (2 H, m), 7.74 (2 H, m), 5.25 (1 H, dd, J 4.7 and 10.7),
4.41 (2 H, q, J 7.1), 2.42 (1 H, m), 2.18 (1 H, m), 1.98 (3 H, s), 1.37
(3 H, t, J 7.1), 1.41–1.20 (20 H, m), 0.87 (3 H, t, J 7.0). δC 167.3, 166.6,
361.1889). νmax/cm−1 2953, 2848, 1702. δH 7.82 (2 H, m), 7.73 (2 H,
m), 4.78 (1 H, dd, J 5.0 and 10.9), 3.35 (2 H, t, J 6.6), 3.32 (3 H, s), 2.17
(2 H, m), 1.53 (2 H, m), 1.32–1.18 (12 H, m). δH 173.3, 167.7, 134.0,
131.8, 123.3, 72.8, 58.3, 52.3, 29.4, 29.3, 29.3, 29.2, 28.9, 28.8, 26.4,
25.9. m/z (ESI) 361.2 (100%, M+•), 343 (17), 315 (75).

Synthesis of Chiral 2-Aminoalkyloxazole-4-carboxylates from Isoxazol-5(2H)-ones
893
164.3, 158.2, 145.4, 134.3, 131.5, 123.7, 110.1, 63.2, 52.5, 31.7, 29.4,
29.3, 29.1, 29.0, 28.7, 28.0, 26.0, 22.5, 14.0, 13.7. m/z (ESI) 482 (20%,
[M – CO2]+•), 437 (34), 409 (62), 207 (100), 129 (45).
1419, 1319, 1211, 1116, 952. δH 7.88 (2 H, m), 7.74 (2 H, m), 7.03 (1 H,
d, J 6.0, NH exchangeable), 5.25 (1 H, d, J 6.3), 4.52 (1 H, d, J 16.5),
4.44 (1 H, d, J 16.5), 4.29 (1 H, dq, J 7.2 and 10.5), 4.25 (1 H, dq, J
7.2 and 10.5), 2.39 (3 H, s), 1.30 (3 H, t, J 6.9). δC 198.2, 167.8, 166.1,
165.7, 134.4, 132.1, 123.8, 63.2, 62.8, 40.2, 27.8, 13.8.
(S)-Ethyl 4-Methyl-2-[2-phthalimido-11-methoxyundecanoyl]-
5-oxo-2,5-dihydroisoxazole-3-carboxylate (18)
Ethyl 2-[1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-
5-methyl-1,3-oxazole-4-carboxylate (12)
The above procedure gave the title compound (0.29 g, 73%) as a
pale-yellow oil (Found: [M−CO2]+•, 470.2426. C27H34N2O8 requires
[M−CO2]+•, 470.2417). νmax/cm−1 2961, 2846, 1771, 1713, 1634,
1556, 1498. δH 7.85 (2 H, m), 7.76 (2 H, m), 5.23 (1 H, dd, J 4.7 and
10.7), 4.41 (2 H, q, J 7.1), 3.32 (2 H, t, J 6.7), 3.30 (3 H, s), 2.41 (1 H,
m), 2.18 (1 H, m), 1.95 (3 H, s), 1.51 (2 H, m), 1.37 (3 H, t, J 7.1),
1.36–1.22 (12 H, m). δC 167.1, 166.4, 164.1, 158.0, 145.2, 134.3, 131.4,
123.7, 109.6, 72.8, 63.3, 58.4, 52.6, 29.5, 29.3, 29.2, 29.1, 28.7, 28.1,
26.0, 25.9, 13.8, 6.9. m/z (ESI) 470 (23%, [M−CO2]+•), 425 (54), 397
(61), 300 (100), 272 (84).
The isoxazolone (10) (104 mg, 0.279 mmol) was irradiated in acetone
(100 mL) for 3 h under N2 at 300 nm. The solvent was then removed
under reduced pressure and the resulting oil crystallized upon stand-
ing. The crude product was recrystallized from ethanol (5 mL) to give
colourless needles (56 mg, 61%), mp 128–131◦C [(S)-isomer], 130–
132◦C [(R)-isomer), [α]D −61.4◦ [(S)-isomer, c 0.847 in CHCl3],
[α]D + 60.0◦ [(R)-isomer, c 0.833 in CHCl3) (Found: C 62.5, H 4.9,
N 8.7%; M+•, 328.1053. C17H16N2O5 requires C 62.2, H 4.9, N 8.5%;
M+•, 3328.1059). νmax/cm−1 1778, 1708, 1622, 1334, 1063. δH 7.87
(2 H, m), 7.75 (2 H, m), 5.55 (1 H, q, J 7.1), 4.37 (2 H, q, J 7.1), 2.57
(3 H, s), 1.91 (3 H, d, J 7.1), 1.37 (3 H, t, J 7.1). δC 167.2, 162.3, 159.5,
156.7, 134.3, 131.9, 128.1, 123.6, 60.9, 43.2, 12.0, 16.1, 14.2. m/z 328
(100%, M+•), 211 (59), 174 (76).
(S)-Ethyl 2-[3-Benzylthio-2-phthalimidopropanoyl]-4-methyl-
5-oxo-2,5-dihydroisoxazole-3-carboxylate (19)
Following the procedure above using (14)[47] gave the title com-
pound (2.58 g, 63%) as an orange oil (Found: [M + Na]+•, 517.1040.
C25H22N2SO7 requires[M + Na]+•, 517.1046). νmax/cm−1 1773, 1722,
1384, 1310, 1241. δH 7.86 (2 H, m), 7.77 (2 H, m), 7.35–7.22 (5 H, m),
5.36 (1 H, dd, J 5.6 and 9.9), 4.40 (2 H, q, J 7.1), 3.74 (2 H, s), 3.35
(1 H, dd, J 9.9 and 14.5), 3.22 (1 H, dd, J 5.6 and 14.5), 1.95 (3 H, s),
1.36 (3 H, t, J 7.1). δC 166.9, 166.1, 162.6, 157.9, 145.0, 135.2, 134.4,
131.4, 128.9, 128.6, 124.4, 123.8, 110.2, 63.4, 51.3, 35.8, 29.4, 13.8,
7.0. m/z (ESI) 517 (100%, [M + Na]+•), 491 (10), 192 (20), 174 (89),
105 (87), 76 (59).
Ethyl 2-(Aminomethyl)-5-methyl-1,3-oxazole-4-carboxylate
Hydrochloride (31.HCl)
A suspension of the phthalimide (11) (2.802 g, 8.915 mmol) and
hydrazine hydrate (551 mg, 11.0 mmol) in ethanol (60 mL) was stirred
for 3 h at 68◦C. After the solvent was removed, the residue was stirred
with 1.5 M aqueous HCl (16 mL) for 10 min at ambient temperature.
Dichloromethane (16 mL) was added, the mixture was filtered, and the
organic layer was discarded. The aqueous layer was extracted once more
with dichloromethane (16 mL) and then evaporated to dryness. The
residue was dissolved in dichloromethane, dried (Na2SO4), filtered,
and evaporated to give the title compound as an orange gum (1.70 g,
86%) (Found: M+•, 184.0849. C8H13N2O3 requires M+•, 184.0848).
νmax/cm−1 3400, 1701, 1654, 1624, 1100. δH 9.22 (3 H, br s), 4.61 (2 H,
br s), 4.30 (2 H, q, J 6.9), 2.54 (3 H, s), 1.33 (3 H, t, J 6.9). δC 162.3,
157.1, 155.9, 127.5, 61.1, 36.4, 13.9, 11.9. m/z 184 (1.6%, M+•), 84
(100).
(S)-Ethyl 2-[3-(4-Benzyloxyphenyl)-2-phthalimidopropanoyl]-
4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate (20)
Following the above procedure using (15),[48] 1-(3-(dimethylamino)-
propyl)-3-ethylcarbodiimide hydrochloride (8.47 g, 41.1 mmol), and the
isoxazolone (8) (5.16 g, 30.2 mmol) gave the title compound (10.26 g,
20
67%), mp 122◦C, [α]D −22◦ (c 1.0 in CHCl3) [(S)-isomer] (Found:
[M + H]+•, 555.1781. C31H27N2O8 requires [M + H]+•, 555.1768).
The racemate was also synthesized by the above procedure. νmax/cm−1
1780, 1719, 1611, 1512, 1467, 1453, 1383. δH 7.82–7.79 (2 H, m), 7.72–
7.69 (2 H, m), 7.37–7.34 (5 H, m), 7.13 (2 H, d, J 8.8), 6.81 (2 H, d, J
8.8), 5.50 (1 H, dd, J 5.6 and 10.3), 4.96 (2 H, s), 4.45 (2 H, q, J 7.1),
3.67–3.50 (2 H, m), 1.97 (3 H, s), 1.41 (3 H, t, J 7.1). δC 166.9, 166.3,
163.4, 158.0, 157.8, 145.2, 136.8, 134.2, 131.2, 130.1, 128.4, 127.8,
127.7, 127.3, 123.6, 114.9, 109.9, 69.8, 63.4, 53.9, 33.2, 13.8. m/z 555
(6%, [M + H]+•), 511 (2), 460 (2), 384 (50), 356 (100), 313 (9), 197
(14).
Photolysis of (R)-Ethyl 4-Methyl-2-[2-phthalimidododecanoyl]-
5-oxo-2,5-dihydroisoxazole-3-carboxylate (16)
The isoxazolone (16) (0.576 g, 1.16 mmol) was photolyzed through
pyrex at 300 nm in anhydrous acetone (600 mL) under N2 at rt for
3 h. The solvent was evaporated and water (30 mL) was added to the
residue. The product was then extracted from the mixture with hexane
(3 × 20 mL). The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated to give the crude product, which was purified by
radial chromatography (10% ethyl acetate/light petroleum) to give two
fractions.
Ethyl 2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-
5-methyl-1,3-oxazole-4-carboxylate (11)
Method 1. The isoxazolone (9) (1.411 g, 3.94 mmol) was irradiated in
acetone (1000 mL) for 3 h under N2 at 300 nm. The solvent was then
removed under reduced pressure and the solid residue was recrystallized
from ethanol to yield the title compound as a white powder (822 mg,
66%), mp 166–169◦C (lit.[15] 166–167◦C) (Found: M+•, 314.0905.
C16H14N2O5 requires M+•, 314.0903). νmax/cm−1 1775, 1726, 1705,
1621, 1427, 1336, 1203, 1116, 1096. δH 7.90 (2 H, m), 7.78 (2 H, m),
4.99 (2 H, s), 4.36 (2 H, q, J 7.2), 2.58 (3 H, s), 1.37 (3 H, t, J 7.2). δC
167.2, 162.1, 156.9, 156.2, 134.4, 131.9, 128.0, 123.7, 60.8, 34.4, 14.1,
11.9. m/z 314 (1%, M+•), 160 (19), 43 (100).
The first fraction contained N-undecylphthalimide (26)[49] (0.035 g,
•
10%), which was isolated as a white solid, mp 34◦C (Found: M+
,
301.2045. C19H27NO2 requires M+•, 301.2042). νmax/cm−1 2917,
2849, 1697, 1465, 1054. δH 7.81 (2 H, m), 7.73 (2 H, m), 3.65 (2 H,
t, J 7.0), 1.63 (2 H, m), 1.40–1.21 (16 H, m), 0.89 (3 H, t, J 7.0). δC
168.4, 133.7, 132.1, 123.0, 38.0, 31.8, 29.5, 29.4, 29.2, 29.1, 28.5, 26.8,
22.6, 14.0. m/z 301 (66%, M+•), 188 (6), 174 (12), 160 (100), 148 (24),
130 (18), 104 (15), 77 (18).
Thesecondfractioncontained(R)-ethyl5-methyl-2-(1-phthalimido)
undecyloxazole-4-carboxylate (21) (0.352 g, 67%), which was isolated
•
Method 2. The isoxazolone (9) (2.0 g) was irradiated through pyrex
in acetonitrile (1000 mL) for 3 h. After crystallization of product (11)
(35%), the compounds in the mother liquors were separated by radial
as a colourless oil (Found: M+•, 454.2469. C26H34N2O5 requires M+
,
454.2468). νmax/cm−1 2926, 2856, 1775, 1719, 1617, 1463, 1381. δH
7.86 (2 H, m), 7.77 (2 H, m), 5.41 (1 H, dd, J 6.7 and 8.9), 4.36 (2 H,
q, J 7.1), 2.57 (3 H, s), 2.44 (2 H, m), 1.37 (3 H, t, J 7.1), 1.38–1.21
(16 H, m), 0.86 (3 H, t, J 6.5). δC 167.4, 162.2, 159.2, 156.5, 134.2,
131.7, 127.9, 123.6, 60.9, 47.9, 31.8, 29.5, 14.3, 14.1, 12.1. m/z 454
(2%, M+•), 409 (10), 381 (43), 146 (100).
chromatography to yield (13) as a white solid, mp 177–181◦C, in addi-
•
tion to unreacted starting material (30%) (Found (ESI): [M + Na]+
,
355.2; [M + H]+•, 333.1. C16H16N2O6N requires [M + Na]+•, 355.3;
[M + H]+•, 333.3). νmax/cm−1 3317, 1779, 1718, 1662, 1559, 1541,

894
M. Cox, R. H. Prager and C. E. Svensson
Photolysis of (R)-Ethyl 4-Methyl-2-[2-phthalimidotetradecanoyl]-
Photolysis of (S)-Ethyl 2-[3-(4-benzyloxyphenyl)-
5-oxo-2,5-dihydroisoxazole-3-carboxylate (17)
2-phthalimidopropanoyl]-4-methyl-5-oxo-2,5-dihydroisoxazole-
3-carboxylate (20)
The isoxazolone (17) (1.2 g, 2.28 mmol) was photolyzed as described
above to give a product which was purified by radial chromatography
(10% ethyl acetate/light petroleum) to give two fractions.
Method 1. The isoxazolone (20) (0.087 g, 0.16 mmol) in acetone
was photolyzed as described above and the residue was purified by
radial chromatography (10% ethyl acetate/light petroleum) to give two
fractions.
The first fraction contained N-tridecylphthalimide (27)[49] (0.065 g,
•
9%), which was isolated as a white solid, mp 45◦C (Found: M+
,
329.2355. C21H31NO2 requires M+•, 329.2355). νmax/cm−1 2919,
2850, 1699, 1444, 1051. δH 7.80 (2 H, m), 7.72 (2 H, m), 3.65 (2 H,
t, J 6.9), 1.61 (2 H, m), 1.40–1.21 (20 H, m), 0.88 (3 H, t, J 7.0). δC
168.3, 134.0, 131.9, 123.0, 37.9, 31.7, 29.4, 29.1, 28.5, 28.4, 26.6, 22.5,
13.9. m/z 329 (66%, M+•), 216 (9), 202 (17), 188 (100), 146 (24), 131
(28), 114 (91), 77 (89).
The first fraction contained phthalimide (0.01 g, 43%), which was
isolated as a white solid. Structural confirmation was obtained by direct
comparison to an authentic sample, mp 230–234◦C.
The second fraction contained ethyl (E)-2-[2-(4-benzyloxyphenyl)
ethenyl]-5-methyloxazole-4-carboxylate (28)(0.022 g, 38%), whichwas
recrystallized from ethanol as yellow needles, mp 229–230◦C (Found:
M+•, 363.1477. C22H21NO4 requires M+•, 363.1471). νmax/cm−1
1711, 1602, 1509, 1453, 1382, 1338, 1248, 1095. δH 7.60 (2 H, d, J
8.8), 7.46–7.33 (5 H, m), 6.95 (2 H, d, J 8.8), 6.81 (1 H, d, J 12.8),
6.28 (1 H, d, J 12.8), 5.11 (2 H, s), 4.38 (2 H, q, J 7.1), 2.55 (3 H, s),
1.40 (3 H, t, J 7.1). δC 162.3, 159.1, 158.4, 155.3, 136.9, 136.6, 131.1,
128.5, 128.3, 128.2, 128.0, 127.4, 114.3, 112.1, 69.9, 60.8, 14.3, 12.0.
m/z 363 (14%, M+•), 318 (2), 264 (9), 237 (4), 197 (4), 147 (5), 104
(3), 91 (100).
Thesecondfractioncontainedethyl(R)-5-methyl-2-(1-phthalimido)-
tridecyloxazole-4-carboxylate (22) (0.725 g, 66%), which was isolated
•
as a colourless oil (Found: M+•, 482.2783. C28H38N2O5 requires M+
,
482.2781). νmax/cm−1 2934, 2851, 1773, 1718, 1615, 1464, 1385. δH
7.85 (2 H, m), 7.76 (2 H, m), 5.40 (1 H, dd, J 6.7 and 8.9), 4.38 (2 H,
q, J 7.1), 2.56 (3 H, s), 2.42 (2 H, m), 1.38 (3 H, t, J 7.1), 1.39–1.19
(20 H, m), 0.88 (3 H, t, J 6.6). δC 167.8, 162.4, 159.2, 156.2, 134.2,
131.7, 128.3, 123.7, 61.1, 48.1, 31.7, 29.6, 29.4, 29.3, 29.2, 29.0, 28.8,
26.0, 22.7, 14.4, 14.1, 12.2. m/z 482 (9%, M+•), 437 (35), 409 (67),
146 (100).
Method 2. The isoxazolone (0.5 g, 0.9 mmol) in ethyl acetate was pho-
tolyzed through pyrex at 300 nm in anhydrous ethyl acetate (1000 mL)
under N2 at rt for 6 h. The solvent was evaporated and the residue was
purified by radial chromatography (10% ethyl acetate/light petroleum)
to give four fractions.
Thefirstfractioncontained4-benzyloxybenzaldehyde(0.005 g, 3%),
which was isolated as a white powder whose identity was confirmed
by direct comparison with an authentic sample synthesized inde-
pendently, mp 71–73◦C (Found: M+•, 212.0837. C14H12O2 requires
M+•, 212.0837). δH 9.86 (1 H, s), 7.82 (2 H, d, J 8.8), 7.41–7.30 (5 H,
m), 7.06 (2 H, d, J 8.8), 5.11 (2 H, s). δC 190.1, 163.6, 135.9, 131.8,
130.0, 126.6, 128.2, 115.1, 69.9. m/z 212 (5%, M+•), 91 (100), 65
(13), 43 (18).
Photolysis of (S)-Ethyl 4-Methyl-2-[2-phthalimido-
11-methoxyundecanoyl]-5-oxo-2,5-dihydroisoxazole-
3-carboxylate (18)
The isoxazolone (18) (0.18 g, 0.35 mmol) was photolyzed as above and
the crude product was purified by radial chromatography (10% ethyl
acetate/light petroleum) to give (S)-ethyl 5-methyl-2-(10-methoxy-
1-phthalimidodecyl)oxazole-4-carboxylate (23) (0.091 g, 55%) as
•
a colourless oil (Found: M+•, 470.2418. C26H34N2O6 requires M+
,
470.2417). νmax/cm−1 2927, 2856, 1773, 1720, 1618, 1467, 1385, 1339,
1300. δH 7.83 (2 H, m), 7.75 (2 H, m), 5.38 (1 H, dd, J 6.7 and 8.8), 4.33
(2 H, q, J 7.1), 3.31 (2 H, t, J 6.6), 3.29 (3 H, s), 2.54 (3 H, s), 2.41 (2 H,
m), 1.50 (2 H, m), 1.34 (3 H, t, J 7.1), 1.34–1.18 (12 H, m). δC 167.3,
162.1, 159.1, 156.4, 134.1, 131.6, 127.8, 123.5, 72.8, 60.8, 58.4, 47.8,
29.5, 29.4, 29.3, 29.2, 29.1, 28.8, 25.9, 25.8, 14.2, 12.0. m/z 470 (1%,
M+•), 256 (15), 228 (6), 195 (27), 129 (14), 69 (76), 43 (100).
The second fraction contained phthalimide (0.008 g, 6%).
The third fraction contained ethyl (E)-2-[2-(4-benzyloxyphenyl)
ethenyl]-5-methyloxazole-4-carboxylate(28)(0.035 g, 11%), whichwas
isolated as a yellow solid that was identical with the sample above.
The fourth fraction contained ethyl (S)-2-[3-(4-benzyloxyphenyl)-
1-phthalimidopropyl]-5-methyl-1, 3-oxazole-4-carboxylate (25) (0.3 g,
65%), which was isolated as a yellow oil, [α]D −90◦ (c 1.0
20
•
in CHCl3) (Found: M+•, 510.1792. C30H26N2O6 requires M+
,
510.1791). Racemic (25) was also synthesized from racemic (20) using
the above procedure. νmax/cm−1 1776, 1718, 1613, 1512, 1467, 1453,
1384, 1339, 1241, 1178, 1097, 1014. δH 7.79–7.76 (2 H, m), 7.70–7.68
(2 H, m), 7.36–7.28 (5 H, m), 7.10 (2 H, d, J 8.8), 6.79 (2 H, d, J 8.8),
5.65 (1 H, dd, J 7.6 and 8.9), 4.95 (2 H, s), 4.37 (2 H, q, J 7.1), 3.74–
3.69 (2 H, m), 2.57 (3 H, s), 1.37 (3 H, t, J 7.1). δC 167.1, 162.1, 158.6,
157.7, 156.6, 136.8, 134.1, 131.4, 130.0, 128.4, 128.3, 127.9, 127.8,
127.3, 123.4, 114.9, 69.8, 60.9, 49.0, 34.6, 14.3, 12.1. m/z 510 (20%,
M+•), 465 (30), 437 (2), 404 (3), 363 (45), 313 (12), 197 (15), 91 (100).
Photolysis of (S)-Ethyl 2-[3-Benzylthio-2-phthalimidopropanoyl]-
4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate (19)
in Acetone
The isoxazolone (19) (0.547 g, 1.11 mmol) was photolyzed through
pyrex at 300 nm in anhydrous acetone (700 mL) as described above
and the residue was purified by radial chromatography (30% ethyl
acetate/light petroleum) to give two fractions.
The first fraction contained N-vinylphthalimide (29) (0.024 g, 13%•),
whichwasisolatedasawhitesolid, mp79◦C(lit.[50] 82◦C)(Found:M+
,
General Procedure for the Synthesis of the Mosher Amides
173.0477. C10H7NO2 requires M+•, 173.0477). νmax/cm−1 1726, 1382,
1302. δH 7.89–7.87 (2 H, m), 7.76–7.74 (2 H, m), 6.88 (1 H, dd, J 9.8
and 16.5), 6.08 (1 H, d, J 16.5), 5.04 (1 H, d, J 9.8). δC 166.4, 134.4,
131.6, 123.8, 123.6, 104.5. m/z 173 (100%, M+•), 146 (11), 129 (13),
104 (57), 91 (52), 76 (83), 50 (52), 43 (27).
(R)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid (2 eq.) was
refluxed in oxalyl chloride for 1.5 h and the excess oxalyl chloride
was then evaporated. A solution of the amino acid hydrochlorides
(5a)–(5d), aminoalkyloxazoles (12), (21)–(25) (24–37 mg), and 4-
dimethylaminopyridine (1 eq.) at 0◦C in dichloromethane (0.5 mL)
The second fraction contained ethyl (S)-5-methyl-2-(2-benzylthio-
1-phthalimidoethyl)-oxazole-4-carboxylate (24) (0.118 g, 24%), which
was isolated as a clear, pale-yellow oil (Found: [M + Na]+•, 473.1132.
C24H22N2SO5 requires[M + Na]+•, 473.1147). νmax/cm−1 2982, 1773,
1720, 1617, 1384, 1191, 1097. δH 7.89–7.85 (2 H, m), 7.77–7.73 (2 H,
m), 7.33–7.19 (5 H, m), 5.56 (1 H, dd, J 7.7 and 7.7), 4.34 (2 H, q, J
7.1), 3.75 (2 H, s), 3.49–3.44 (2 H, m), 2.55 (3 H, s), 1.35 (3 H, t, J
7.1). δC 167.4, 162.2, 158.0, 156.9, 137.4, 134.5, 131.9, 129.7, 129.1,
128.8, 127.4, 123.9, 61.2, 46.8, 36.0, 31.2, 14.5, 12.3. m/z (ESI) 473
(100%, [M + Na]+•), 450 (3), 405 (5), 377 (45), 251 (2), 192 (6), 163
(28), 83 (18).
was added to
a solution of the above acid chloride and 4-
dimethylaminopyridine (1 eq.) in dichloromethane (1 mL) at 0◦C. The
reaction was stirred at 0◦C (40 min–1.5 h) and then at rt until TLC
analysis showed that the formation of the Mosher amide was complete.
The mixture was evaporated and the oily residue was dissolved in diethyl
ether (20 mL), washed with aqueous 1 M hydrochloric acid (3 × 15 mL),
water (10 mL), dried, and evaporated.
For the amides of (5a)–(5d), the diastereomers were character-
ized by 1H and 19F NMR spectroscopy of the methoxy group, the
methyl group α to the amide moiety, and the trifluoromethyl group.

Synthesis of Chiral 2-Aminoalkyloxazole-4-carboxylates from Isoxazol-5(2H)-ones
895
The aminoalkyloxazole carboxylic acid diastereomers were character-
ized by 1H and 13C NMR spectroscopy of the methoxy group [ca. δ
3.42 and 54.85 for (S,S) and δ 3.55 and 53.04 for (S,R)] and the proton
α to the amide group [ca. δ 5.42 for (S,S) and δ 5.50 for (S,R)]. The
(S,R) : (S,S) ratio of the latter was 9 : 91.
6.02 (1 H, s), 5.12 (1 H, d, J 16.2), 4.55 (1 H, d, J 16.2), 4.37 (2 H, q,
J 7.1), 2.99 (1 H, dd, J 5.8 and 8.9), 2.93 (1 H, dd, J 6.2 and 8.8), 2.84
(1 H, dd, J 6.0 and 8.9), 2.78 (1 H, dd, J 6.5 and 8.8), 2.58 (3 H, s),
1.52 (2 H, m), 1.38 (3 H, t, J 7.1), 1.07 (1 H, m), 0.87 (3 H, d, J 6.6),
0.83 (3 H, t, J 5.8). δC 167.3, 161.9, 157.5, 156.8, 141.2, 132.4, 131.9,
129.8, 127.7, 123.7, 123.5, 86.1, 67.7, 60.8, 36.2, 34.8, 34.7, 25.9, 16.5,
16.3, 14.2, 11.9, 11.2, 11.0. m/z 386 (0.6%, M+•), 315 (65), 298 (76),
269 (29), 197 (43), 169 (45), 160 (60), 133 (100), 123 (40), 105 (33),
84 (92), 77 (29).
Reaction of Aminomethyl Oxazole (31) with Camphor and
Hydroxypinanone
Method 1. To a solution of anhydrous toluene (15 mL) containing
(1R)-camphor (0.074 g, 0.48 mmol), ethyl 2-(aminomethyl)-5-methyl-
1,3-oxazole-4-carboxylate (31) (0.89 g, 0.48 mmol), and triethylamine
(0.134 g, 1.33 mmol) maintained at 0◦C was added a solution of TiCl4
(0.184 M, 2.58 mL, 0.47 mmol) in anhydrous toluene. After 5 min, the
reaction mixture was heated to reflux for 18 h using a Dean–Stark
apparatus. The reaction mixture was cooled and then washed with
water (10 mL) and brine (10 mL). The organic layer was then dried
(Na2SO4), filtered, and evaporated to give the crude product as an orange
oil (0.105 g, 72%). Further purification by column chromatography on
alumina (50% ethyl acetate/light petroleum) gave the imine (0.035 g,
24%), which was obtained as a yellow oil (Found: M+•, 318.1943.
C18H26N2O3 requires M+•, 318.1943). νmax/cm−1 1696, 1654. δH 4.48
(2 H, s), 4.37 (2 H, q, J 7.1), 2.63 (3 H, s), 2.52–2.43 (1 H, m), 2.06–1.84
(3 H, m), 1.74–1.64 (1 H, m), 1.47–1.38 (1 H, m), 1.40 (3 H, t, J 7.1),
1.30–1.20 (1 H, m), 0.99 (3 H, s), 0.90 (3 H, s), 0.77 (3 H, s). δC 188.1,
163.2, 160.5, 158.3, 128.9, 61.1, 55.1, 48.2, 46.0, 43.1, 36.2, 32.4, 27.5,
19.9, 19.3, 14.8, 13.6, 11.6. m/z 318 (0.4%, M+•), 169 (100).
Ethyl 2-{1-Oxo-3-(R,S)-[(1R,2S,5R)menthyloxy]isoindol-2-yl}
methyl-5-methyloxazole-4-carboxylate (35b) and (36b)
The use of (1R,2S,5R)-menthol (0.267 g, 1.71 mmol) as above gave a
single fraction containing both diastereomers (ca. 65/35 ratio) of the
title compound (0.338 g, 64%).
Acknowledgments
M.C. acknowledges the award of a Flinders University
research scholarship and C.E.S is grateful for the award of an
OPRS scholarship from Flinders University. We are grateful
for financial support from the Australian Research Council.
References
[1] P. Wipf, Chem. Rev. 1995, 95, 2115.
[2] D. P. Fairlie, G. Abbenante, D. R. March, Curr. Med. Chem.
1995, 2, 654, and references therein.
Method 2. Reaction of (1R,2R,5R)-2-hydroxypinan-3-one (0.094 g,
0.54 mmol) with (31) (0.1 g, 0.54 mmol) as described above but using
BF3 instead of TiCl4 allowed the isolation of (32) as a pale-yellow oil
(0.053 g, 31%) (Found: [M−H2O]+•, 316.1784. C18H27N2O4 requires
[M−H2O]+•, 316.1787). νmax/cm−1 3423, 1654. δH 4.60 (2 H, s), 4.37
(2 H, q, J 7.1), 2.66 (3 H, s), 2.65 (3 H, s), 2.42–2.34 (1 H, m), 2.08 (2 H,
d, J 5.9), 1.60 (1 H, d, J 10.7), 1.53 (3 H, s), 1.39 (3 H, t, J 7.1), 1.34
(3 H, s), 0.85 (3 H, s). δH 179.9, 162.6, 159.8, 157.3, 127.9, 76.8, 61.0,
50.4, 47.5, 38.8, 38.2, 34.2, 28.2, 28.1, 27.3, 22.9, 14.4, 12.1. m/z 316
(1%, [M−H2O]+•), 169 (30), 99 (63), 86 (56), 43 (100).
[3] N. Fusetani, S. Matsunaga, Chem. Rev. 1993, 93, 1793.
[4] T. Shioiri, Y. Hamada, S. Kato, M. Shibata, Y. Kondo,
H. Nakagawa, K. Kohda, Biochem. Pharmacol. 1987, 36, 4181.
[5] (a) D. J. Faulkner, Nat. Prod. Rep. 1984, 551. (b) D. J. Faulkner,
Nat. Prod. Rep. 1986, 24.
[6] B. S. Davidson, Chem. Rev. 1993, 93, 1771.
[7] J. Khalafy, C. E. Svensson, R. H. Prager, C. M. Williams,
Tetrahedron Lett. 1998, 39, 5405.
[8] M. P. Foster, G. P. Concepción, G. B. Caraan, C. M. Ireland,
J. Org. Chem. 1992, 57, 6671.
[9] I. J. Turchi (Ed.), Oxazoles 1986 (Wiley-Interscience: New York,
NY).
[10] R. Connel, M. Tebbe, A. Gangloff, P. Helquist, B. Akermark,
Tetrahedron 1993, 49, 5445, and references therein.
[11] P. Wipf, P. Miller, J. Org. Chem. 1993, 58, 3604, and references
therein.
[12] D. L. Evans, D. K. Minster, U. Jordis, S. M. Hecht, A. L. Mazzu,
A. I. Meyers, J. Org. Chem. 1979, 44, 497.
[13] R. Shapiro, J. Org. Chem. 1993, 58, 5759.
[14] E. Aguilar, A. I. Meyers, Tetrahedron Lett. 1994, 35, 2473.
[15] R. H. Prager, J. A. Smith, B. Weber, C. M. Williams, J. Chem.
Soc., Perkin Trans. 1 1997, 2665.
[16] R. H. Prager, M. R. Taylor, C. M. Williams, J. Chem. Soc.,
Perkin Trans. 1 1997, 2673.
When TiCl4 was used considerable dehydration of (32) occurred, as
judged by 1H NMR spectroscopy.
Reduction of Ethyl 2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-
2-yl)methyl]-5-methyl-1,3-oxazole-4-carboxylate (11)
The oxazole (11) (0.469 g, 1.49 mmol) in methanol (40 mL) was
reacted with sodium borohydride (0.068 g, 1.79 mmol) at −10◦C
for 55 min. Addition of 2 M HCl (2–3 drops) at regular inter-
vals followed by extraction with dichloromethane and chromato-
graphy gave ethyl 2-(1-hydroxy-1,3-dihydro-2H-isoindol-2-yl)methyl-
5-methyloxazole-4-carboxylate (34) (0.441 g, 93%), which was isolated
•
as a colourless oil (Found: M+•, 316.1062. C16H16N2O5 requires M+
,
316.1059). νmax/cm−1 3340, 1709, 1634. δH 7.75–7.73 (m, 1 H), 7.58–
7.46 (3 H, m), 5.96 (1 H, s), 4.81 (1 H, d, J 16.8), 4.70 (1 H, d, J 16.8),
4.30 (2 H, q, J 7.1), 2.55 (3 H, s), 1.34 (3 H, t, J 7.10. δC 167.6, 162.3,
158.6, 157.1, 144.4, 132.9, 131.1, 130.0, 127.8, 123.8, 123.7, 82.1,
61.2, 36.3, 14.3, 12.1. m/z 316 (21%, M+•), 298 (63), 269 (27), 197
(42), 169 (45), 160 (61), 133 (100), 123 (41), 105 (33), 84 (93), 77 (29),
43 (18).
[17] R. M. Williams, Synthesis of Optically Active α-Amino Acids
Vol. 7, 1989 (Pergamon Press: Oxford).
[18] T. Oguri, N. Kawai, T. Shioiri, S. I. Yamada, Chem. Pharm.
Bull. 1978, 26, 803.
[19] R. Fitzi, D. Seebach, Tetrahedron 1988, 44, 5277.
[20] J. M. McIntosh, R. K. Leavitt, P. Mishra, K. C. Cassidy,
J. E. Drake, R. Chadha, J. Org. Chem. 1988, 53, 1947.
[21] R. M. Williams, M. N. Im, J. Am. Chem. Soc. 1991, 113, 9276.
[22] H. G. Bossler, D. Seebach, Helv. Chim. Acta 1994, 77, 1124.
[23] U. Schollkopf, U. Groth, C. Deng, Angew. Chem. Int. Ed. Engl.
1981, 20, 798.
[24] A. Myers, T. Yoon, J. L. Gleason, Tetrahedron Lett. 1995, 36,
4555.
[25] A. G. Myers, J. L. Gleason, T. Yoon, D. W. Kung, J. Am. Chem.
Soc. 1997, 119, 656.
Ethyl 2-{1-Oxo-3-(R,S)-[(S)-2-methylbut-1-yloxy]isoindol-
2-yl}methyl-5-methyloxazole-4-carboxylate (35a) and (36a)
A solution containing the oxazole (34) (0.74 g, 2.34 mmol) in
dichloroethane (20 mL) was acidified with HCl gas to pH 3. (S)-2-
Methyl-1-butanol (0.310 g, 3.51 mmol) was added and the reaction
mixture was refluxed for 1.5 h. The reaction mixture was allowed to
cool before being washed with water (2 × 10 mL). The organic layer
yielded a clear oil and purification by radial chromatography (10% ethyl
acetate/light petroleum) gave both diastereomers (ca. 55/45 ratio) of the
title compound (35a) and (36a) (0.751 g, 83%) as a clear, pale-yellow
oil (Found: M+•, 386.1843. C21H26N2O5 requires M+•, 386.1842).
νmax/cm−1 2965, 1705, 1656. δH 7.86 (1 H, m), 7.65–7.52 (3 H, m),
[26] J. P. Michael, G. Pattenden, Angew. Chem. Int. Ed. Engl. 1993,
32, 1, and references therein.

896
M. Cox, R. H. Prager and C. E. Svensson
[27] J. Khalafy, R. H. Prager, C. M. Williams, Aust. J. Chem. 1999,
52, 31.
[38] R. P. Veeraraghavan, G. Baoqing, H. C. Brown, Tetrahedron
Lett. 1994, 35, 2141.
[28] A. G. Griesbeck, H. Mauder, Angew. Chem. Int. Ed. Engl. 1992,
31, 73.
[39] D. A. Beardsley, G. B. Fisher, C. T. Goralski, L. W. Nicholson,
B. Singaram, Tetrahedron Lett. 1994, 35, 1511.
[40] D. D. Perrin, W. L. F. Armarego, D. R. Perrin, Purification of
Laboratory Chemicals 3rd edn 1988 (Permagon Press: Oxford).
[41] F. Schaub, H. P. Schelling, German Pat. DE 2319573, 1973;
Chem. Abstr. 1974, 81, 400 561.
[42] Y. Endo, S. Takehana, M. Ohno, P. E. Driedger, S. Stabel,
M. Y. Mizutani, N. Tomioka, A. Itai, K. Shudo, J. Med. Chem.
1998, 41, 1476.
[43] W. A. Gibbons, R. A. Hughes, M. Charalambous, M. Christ,
Liebigs Ann. Chem. 1990, 1175.
[44] L. C. Reese, Liebigs Ann. Chem. 1887, 242, 1.
[45] G. Adembri, P. Tedeschi, Boll. Sci. Fac. Chim. Ind. Bologna
1965, 23, 203.
[29] (a) J. C. Sheehan, W. A. Bolhofe, J. Am. Chem. Soc. 1950,
72, 2786. (b) F. E. King, J. W. Clark-Lewis, D. A. A. Kidd,
G. R. Smith, J. Chem. Soc. 1954, 1039. (c) J. C. Sheehan,
W. L. Richardson, J. Am. Chem. Soc. 1954, 76, 6329. (d)
F. E. King, J. W. Clark-Lewis, W. A. Swindin, J. Chem. Soc.
1959, 2259.
[30] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org Chem. 1969, 34,
2543.
[31] N. Irako, Y. Hamada, T. Shioiri, Tetrahedron 1995, 51, 12 731.
[32] A. Dondoni, F. L. Merchan, P. Merino, I. Rojo, T. Tejero,
Synthesis 1996, 641.
[33] A. Mi, X. Xun, L. Wu, Y. Jiang, Synth. Commun. 1991, 21,
2207.
[34] Y. Jiang, J. Deng, W. Hu, G. Liu, A. Mi, Synth. Commun. 1990,
20, 3077.
[46] E. Fischer, Ber. Dtsch. Chem. Ges. 1907, 40, 489.
[47] A. G. Griesbeck, J. Hirt, K. Peters, E.-M. Peters, H. G. van
Schnering, Chem. Eur. J. 1996, 2, 1388.
[35] M. Thieme, E. Vieira, J. Liebscher, Synthesis 2000, 14, 2051.
[36] C. J. Easton, C. A. Hutton, Synlett. 1998, 457.
[37] C. J. Easton, N. L. Fryer, A. J. Ivory, E. R. T. Tiekink, J. Chem.
Soc., Perkin Trans. 1 1998, 3725.
[48] M. F. Francis, N. Chen, L. Benoiton, Synthesis 1979, 709.
[49] P. Dufek, J. Chromatogr. 1983, 281, 49.
[50] D. H. Davies, D. C. Phillips, J. D. B. Smith, J. Polym. Sci.,
Polym. Chem. Ed. 1979, 17, 1153.