Synthesis of tetrafunctionalized 2-azido-3-hydroxy-1,4-diones and their transformation into 5-substituted 3-acylisoxazoles

Article abstract of DOI:10.1002/1099-0690(200209)2002:17<3055::AID-EJOC3055>3.0.CO;2-8

An efficient synthesis of 2-azido-3-hydroxy-1,4-diones, based on the base-induced coupling of α-azido ketones and α-oxo aldehydes, has been developed. The coupling reaction took place with moderate to good diastereoselectivity. The relative configurations of the adducts have been determined by X-ray analysis. Treatment of tetrafunctionalized synthons 2-azido-3-hydroxy-1,4-diones with mesyl chloride in the presence of base afforded 5-substituted 3-acylisoxazoles, through 2-azido-2-alkene-1,4-dione intermediates. Analogous treatment of α-azido ketones with α-oxo esters resulted in the formation of the unstable 3-azido-2-hydroxy-4-oxobut-anoates. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:17<3055::AID-EJOC3055>3.0.CO;2-8

FULL PAPER
Synthesis of Tetrafunctionalized 2-Azido-3-hydroxy-1,4-diones and Their
Transformation into 5-Substituted 3-Acylisoxazoles[
‡]
´
[a]
[a]
Eva Juh a´ sz-T o´ th and Tam a´ s Patonay*
Dedicated to Professor Waldemar Adam on the occasion of his 65th birthday
Keywords: Aldol reaction / Azides / CϪC coupling / Diastereoselectivity / Nitrogen heterocycles
An efficient synthesis of 2-azido-3-hydroxy-1,4-diones,
based on the base-induced coupling of α-azido ketones and
α-oxo aldehydes, has been developed. The coupling reaction
took place with moderate to good diastereoselectivity. The
relative configurations of the adducts have been determined
by X-ray analysis. Treatment of tetrafunctionalized synthons
presence of base afforded 5-substituted 3-acylisoxazoles,
through 2-azido-2-alkene-1,4-dione intermediates. Analog-
ous treatment of α-azido ketones with α-oxo esters resulted
in the formation of the unstable 3-azido-2-hydroxy-4-oxobut-
anoates.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
2-azido-3-hydroxy-1,4-diones with mesyl chloride in the
Introduction
and 3-azidochromanones 10 with α-keto aldehydes and α-
keto esters as electrophiles under basic conditions. When 2-
azido-4Ј-substituted-acetophenones 1aϪd were treated with
α-Azido ketones with α-hydrogen atoms are highly base-
sensitive species and can undergo a smooth, base-promoted
[4]
various phenylglyoxal hydrates 2؊4 in the presence of 1,8-
loss of nitrogen to give imines.[ In our previous papers
1]
[2,3]
[3]
diazabicyclo[5.4.0]undec-7-ene (DBU), previously found
we have demonstrated that various aldehydes and ketones
can be used as electrophiles to trap the corresponding car-
banion intermediate generated from α-azido ketones, to
yield the valuable 1,2,3-trifunctionalized synthons 2-azido-
to be the most effective base, we obtained 2-azido-3-hy-
droxy-1,4-diketones 6aϪd, 7d, and 8d in good yields
(Scheme 1, Table 1).
The best yields could be achieved by use of 2Ϫ3 equiv.
3-hydroxy ketones. Both acyclic derivatives and α-azido-α-
of the α-oxo aldehydes and a catalytic amount (10Ϫ11
mol %) of DBU at below ambient temperature. The syn-
thetic value of this aldol-type reaction was also demon-
strated by modification of the structure of the α-oxo alde-
(1-hydroxyalkyl)benzocyclanones and -benzoheterocy-
clanones were found to be available by this new procedure.
We were able to generate another anionic species Ϫ imino
anion Ϫ by a subsequent loss of nitrogen, trapping of this
latter nucleophile resulting in the formation of 2,5-dihydro-
[
5]
hyde. Experiments with tert-butylglyoxal hydrate as elec-
trophile resulted in the desired product 9d (Table 1, Entry
5-hydroxyoxazoles.
7). The data summarized in Table 1 show that the electronic
In this contribution we wish to demonstrate that it is not
effects of R groups in position 4Ј have no influence on the
conversion and yield of the CϪC bond-forming reaction
only simple aldehydes or ketones, but also other, more com-
plex carbonyl compounds, that can be used as electrophiles.
This extension allowed us to synthesize the valuable tetra-
functionalized synthons 2-azido-3-hydroxy-1,4-diketones,
and to develop a new route to 3,5-disubstituted isoxazoles.
(Entries 1Ϫ4). Moreover, both aryl- and alkylglyoxals gave
moderate to good yields (Entries 4Ϫ7), indicating the gen-
erality of the coupling reaction. Adducts 6aϪd, 7d, 8d, and
9d were isolated as mixtures of syn and anti isomers in all
cases. Repeated crystallization of the diastereomeric mix-
ture of 6d afforded the major component in a diastereopure
form, and its syn relative configuration was unequivocally
determined by X-ray analysis (Figure 1).
Results and Discussion
In continuation of our previous work,[2,3] we studied the
reactions of 2-azido-1-(4-substituted phenyl)ethanones 1
This allowed us to assign the diastereomers in the whole
series on the basis of the characteristic differences in their
NMR spectra. It is noteworthy that suitable separation of
[
‡]
a]
[3]
α-Azido Ketones, 4. Part 3: Ref.
[
Department of Organic Chemistry, University of Debrecen,
P. O. Box 20, 4010 Debrecen, Hungary
Fax: (internat.) ϩ 36-52/453-836
signals could be observed only in [D ]acetone as solvent,
6
E-mail: tpatonay@tigris.klte.hu
and not in CDCl . The diagnostic tools were the chemical
3
Eur. J. Org. Chem. 2002, 3055Ϫ3064  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0917Ϫ3055 $ 20.00ϩ.50/0
3055

´
E. Juh a´ sz-T o´ th, T. Patonay
FULL PAPER
Table 1. Treatment of phenacyl azides 1 with α-oxo aldehydes 2Ϫ5
Entry
Product[a]
R
R1
t [h]
Conversion (%)[b]
Yield (%)[c]
syn/anti
1
2
3
4
5
6
7
6a
6b
6c
6d
7d
8d
9d
H
Cl
F
OMe
OMe
OMe
OMe
Ph
Ph
Ph
Ph
4-MeO-C
4-Cl-C
tBu
3
6
6
4
24.5
24
4
100
100
100
100
52
84
100
55
52
63
62
84
82
52
77:23
76:24
76:24
87:13
80:20
77:23
6
H
4
6
H
4
[
d]
89:11
[
a]
[b]
1
[c]
Reactions were performed at 0 °C. Determined by H NMR analysis of the reaction mixture. Isolated yields, normalized to 100%
[
d]
1
conversion. An approximate 8:1 diastereomeric ratio was determined from the integrals of the tBu signals in the H NMR spectrum.
No assignment of relative configuration of syn and anti diastereomers was feasible, due to the overlapping 2Ј-H and 3Ј-H signals of
the isomers.
Figure 1. Crystal structure of azido alcohol syn-6d
A moderate to good diastereoselectivity (52Ϫ74% de)
with a syn preference was observed in the formation of
products 6aϪd, 7d, and 8d, these de values being markedly
[
3]
higher than the selectivities found in the reactions be-
tween azido ketones 1 and simple aldehydes. On the other
hand, excellent regioselectivity between the formyl and oxo
carbonyl groups was observed in favor of the former, azides
6Ϫ9 being formed exclusively and no other aldol products
being detected in the reaction mixtures. This selectivity
could be explained in terms of the higher electrophilicity
and the smaller steric hindrance of the formyl group.
As another point of interest, we also studied the coupling
reactions of cyclic systems. Analogous reactions between 3-
azidochromanones 10a, 10b, and 10e and α-oxo aldehydes
2Ϫ5 in the presence of catalytic amounts of DBU afforded
the desired 3-azido-3-(1-hydroxy-2-oxoalkyl)-4-chrom-
Scheme 1. Reactions between α-azido ketones 1 and 10 and α-oxo anones 11a, 11b, 11e, 12e, 13e, and 14e in high (usually Ͼ
aldehydes 2Ϫ5
80%) yields (Scheme 1, Table 2). These yields were signific-
antly higher than those found on treatment of the acyclic
shifts of the 2-H and 3-H hydrogen atoms of the syn iso- substrates 1. This observation may be explained in terms of
mers, whose signals appeared at lower field (∆δ ϭ the lack of α-hydrogen moieties in the α-azido ketone unit,
0.03Ϫ0.06 ppm and ∆δ ϭ 0.12Ϫ0.15 ppm, respectively). and hence the absence of retroaldol cleavage.
Similarly, the signals of the C-2 carbon atoms of the syn Again, azido alcohols 11Ϫ14 were isolated as mixtures
1
3
isomers appeared in the C NMR spectra at significantly of syn and anti diastereomers. The relative configuration of
lower field (∆δ ϭ 1.8Ϫ2.7 ppm) than those of their counter- the diastereomers was assigned by X-ray structure deter-
parts in the anti diastereomers.
mination. Recrystallization of the diastereomeric anti/syn
3056
Eur. J. Org. Chem. 2002, 3055Ϫ3064

Tetrafunctionalized 2-Azido-3-hydroxy-1,4-diones
FULL PAPER
Table 2. Treatment of 3-azidochromanones 10 with α-oxo alde-
hydes 2Ϫ5
We also extended our experiments to another cyclic sub-
strate, 2-azidobenzosuberone (15), which was synthesized
from 2-bromobenzosuberone by our previously described
Entry Product[a]
R
H
R1
t [h] Yield (%)[b] syn/anti
[3]
PTC method.
When azide 15 was treated with
phenylglyoxal hydrate (2) under our standard conditions, 2-
azido-2-(1-hydroxy-2-oxo-2-phenylethyl)benzosuberone (16)
was obtained in 86% yield (Scheme 2). Notably, the
degree of conversion was only 54%, in spite of the long
reaction period (4 d). It is very likely that the higher flexibil-
ity of the seven-membered ring results in greater steric hind-
rance in the attack of the intermediate carbanion on the
carbonyl center and thus lowers the efficiency of the coup-
ling reaction. Product 16 was isolated as a diastereomeric
mixture (50% de), the ratio being determined from the in-
1
2
3
4
5
6
11a
11b
11e
12e
13e
14e
Ph
3
3
89
65
63:37
60:40
62:38
67:33
58:42
46:54
Cl Ph
Me Ph
Me 4-MeO-C
6
Me 4-Cl-C H
3.5 80
6
H
4
3
3
87
87
4
Me tBu
2.5 94
[
a]
Reactions were performed at 0 °C. [b] Isolated yields.
1
tegrals of the 1Ј-H hydrogen signals in the H NMR spec-
trum, but no assignment of the relative configuration of the
isomers was feasible.
Figure 2. Crystal structure of azido alcohol anti-11e
Scheme 2. Reaction between 2-azidobenzosuberone (15) and
phenylglyoxal (2)
mixture of compound 11e afforded the minor product in a
diastereopure form, and this proved on X-ray analysis to be
the anti-11e isomer (Figure 2).
To extend the range of electrophiles, we also investigated
With the stereochemistry of the syn/anti-11e pair estab- base-induced reactions between phenacyl azides 1 and α-
lished, we were able to assign the isomers in the whole oxo esters. When azides 1aϪd were treated with ethyl py-
series, on the basis of their characteristic spectral differ- ruvate (17) as a model electrophile in the presence of DBU,
[
3]
1
ences. In good accordance with our previous results, the with the reaction being monitored by TLC and H NMR
1
characteristic feature in the H NMR spectra of the anti spectroscopy, considerable amounts of the coupled prod-
diastereomers was the well-separated AX doublets repres- ucts were detected, but attempts to isolate these compounds
enting the 2-methylene group of the chromanone ring (δ ϭ by column chromatography failed. Since chromatography
4
.18Ϫ4.21 and 4.71Ϫ4.75 ppm, respectively), whereas the of the crude product afforded the starting material 1 in high
syn isomers showed tight AB system (∆δAB amounts, it is very likely that the instability of ethyl 4-aryl-
.17Ϫ0.23 ppm). Another diagnostic tool was the chemical 3-azido-2-hydroxy-2-methyl-4-oxobutanoates can be ex-
a
ϭ
0
shift of hydrogen atom 1Ј-H, this signal appearing at lower plained in terms of their increased capability for decom-
1
field (∆δ ϭ 0.04Ϫ0.1 ppm) in the H NMR spectrum of the position by retroaldol cleavage, due to the increased steric
anti isomer than in that of the syn diastereomer. Moreover, interactions around the quaternary C-2 atom. The only
carbon atom C-1Ј of the syn diastereomer appeared at lower stable product, ethyl 3-azido-2-hydroxy-4-(4-methoxy-
field (∆δ ϭ 1.5Ϫ1.7 ppm) than that of the anti isomer in phenyl)-2-methyl-4-oxobutanoate (18), was isolated in 69%
1
3
the C NMR. In contrast with the coupling reaction of yield, confirming the efficiency and the usefulness of the
acyclic azides 1, products 11Ϫ13 were formed with low di- coupling with α-oxo esters (Scheme 3). Further experiments
astereoselectivity (16Ϫ34% de) and a syn preference. This to overcome this drawback are in progress.
selectivity is quite similar to the values and preferences ob-
2-Azido-3-hydroxy-1,4-diones and 3-azido-2-hydroxy-4-
[
3]
served previously in the reactions between 3-azidochrom- oxobutanoates, available from reactions between α-azido
anones 10 and simple aldehydes. The reaction between az- ketones and various α-oxo aldehydes or α-oxo esters, are
ide 10e and tert-butylglyoxal hydrate (5) gave a different useful tetrafunctionalized synthons. Their different func-
stereochemical outcome, as a weak anti preference (8% de) tionalities allow selective manipulations even without the
was observed.
use of any protecting groups. Out of the many possible ap-
Eur. J. Org. Chem. 2002, 3055Ϫ3064
3057

´
E. Juh a´ sz-T o´ th, T. Patonay
FULL PAPER
Scheme 3. Synthesis of α-oxo ester 18 and its transformation into
vinyl azide 28
plications, we investigated their transformation into vinyl
azides in detail. Thanks to their high reactivity in pyrolysis,
photolysis, and cycloadditions, and also in attack either by
electrophiles or by nucleophiles, vinyl azides represent an
important and synthetically useful class of organic com-
Scheme 4. Formation of isoxazoles 19Ϫ22 from azido alcohols 6؊9
Table 3. Synthesis of 5-substituted 3-acylisoxazoles 19Ϫ22 from 2-
azido-3-hydroxy-1,4-diketones 6؊9
[
6]
pounds. Several methods for the preparation of these un-
R1
t [h] Yield (%)[a]
Entry Starting material Product R
[
6a,6b]
saturated azides have been published in the literature.
The most reliable and general procedure involves dehy-
drohalogenation or dehydration from suitably substituted
azides or related intermediates, and works well in the syn-
thesis of simple vinyl azides and of α- or β-azido-α,β-unsat-
urated ketones or esters.[ Since the hydroxy groups in ad-
ducts 6Ϫ9 and 18 can be converted into good leaving
groups by conversion into sulfonates, we decided to study
their reactions with mesyl chloride under basic conditions.
Treatment of syn/anti-1-aryl-2-azido-3-hydroxy-1,4-di-
ones 6aϪd with mesyl chloride (MsCl, 2 equiv.) in dry pyr-
idine resulted in the formation of the corresponding 3-
aroyl-5-phenylisoxazoles 19aϪd in low yield (22Ϫ42%). We
attempted to optimize the conditions by variation of bases
and solvents, use of DBU, 1,4-diazabicyclo[2.2.2]octane
1
2
3
4
5
6
7
6a
6b
6c
6d
7d
8d
9d
19a
19b
19c
19d
20d
21d
22d
H
Ph
1.5 39
Cl Ph
Ph
4
4
5
46
48
42
F
OMe Ph
OMe 4-MeO-C
OMe 4-Cl-C H
OMe tBu
6
H
4
3.5 63
48
3.5 23
7]
6
4
4
[a]
Isolated yields.
(
DABCO), or triethylamine (TEA) in dry dichloromethane, Scheme 5. Independent route to isoxazole 19a
and adjustment of stoichiometry. The best results were
achieved by use of a slight excess (1.1Ϫ1.25 equiv.) of mesyl
chloride and 2.4Ϫ2.5 equiv. of TEA in dry dichlorome-
thane. Treatment of syn/anti-6aϪd, 7d, 8d, and 9d and of
syn-6d under the optimized conditions afforded the appro-
priate isoxazoles 19aϪd, 20d, 21d, and 22d in moderate
yields (Scheme 4, Table 3). Attempts to isolate the interme-
diate mesylate 23 and azide 24 (vide infra) failed. This new
reaction offers a new route to the field of 3,5-disubstituted
isoxazoles.
The suggested pathway for the formation of isoxazoles
9Ϫ22 is shown in Scheme 6. The primary product mesylate
3 should smoothly give the elimination product 24, thanks
1
2
Products 19Ϫ22 were identified by their spectral charac-
teristics (lack of OH and N absorption bands in their IR
3
spectra and any aliphatic proton or carbon signals in their
1
13
H and C NMR spectra), microanalyses and chemical
corroboration. 3-Benzoyl-5-phenylisoxazole (19a) was syn-
thesized from meso-2,3-dibromo-1,4-diphenyl-1,4-butane-
[7f]
dione (26) according to Hassner et al. and the product
was completely identical with our sample obtained from
syn/anti-6a (Scheme 5).
Scheme 6. Postulated intermediates in the formation of isoxazoles
19؊22
3058
Eur. J. Org. Chem. 2002, 3055Ϫ3064

Tetrafunctionalized 2-Azido-3-hydroxy-1,4-diones
to the activation by the two carbonyl groups. It is well docu- acetate, 11:1, v/v) to give 6a as a yellow oil (303 mg, 55%) made
FULL PAPER
1
up of a 77:23 mixture of the syn and anti diastereomers (by
NMR). The oil crystallized on standing with hexane to give yellow
crystals. M.p. 82Ϫ84 °C. IR: ν˜ ϭ 3474 (OH), 2110 (N
), 1686, 1676
CϭO), 1598, 1450, 1262, 686 cm . H NMR anti-6a: ([D ]ace-
H
mented that (Z)-β-azido-α,β-unsaturated ketones are highly
unstable and give isoxazoles at room temperature, presum-
ably via the corresponding nitrenes, while (E) isomers are
more stable and yield oxazoles or nitriles under thermolytic
3
Ϫ1
1
(
6
tone): δ ϭ 5.20 (d, J ϭ 7.6 Hz, 1 H, 3-OH), 5.31 (d, J ϭ 6.8 Hz, 1
H, 2-H), 5.58 (dd, J ϭ 7.6, 6.8 Hz, 1 H, 3-H) ppm. syn-6a: δ ϭ
.14 (d, J ϭ 6.3 Hz, 1 H, 3-OH), 5.34 (d, J ϭ 4.6 Hz, 1 H, 2-H),
[
6][7e,8,9]
conditions.
Neither azides (E)-24 nor their second-
ary products could be isolated or detected in our reaction
mixtures. This observation may be explained in terms of a
5
5
.70 (dd, J ϭ 6.3, 4.6 Hz, 1 H, 3-H) ppm. Inseparable signals: δ ϭ
higher thermodynamic stability of isomer (Z)-24. The hy- 7.54Ϫ7.75 (m, 6 H, 3Ј,4Ј,5Ј,3ЈЈ,4ЈЈ,5ЈЈ-H), 7.98Ϫ8.11 (m, 4 H,
drogen atoms at both C-2 and C-3 should be highly acidic, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR spectroscopic data were taken from the
1
3
due to the adjacent carbonyl functions. This feature results spectrum of the diastereomeric mixture. C NMR: anti-6a: δ ϭ
6
3.5 (C-2), 74.7 (C-3) ppm. syn-6a: δ ϭ 65.6 (C-2), 74.4 (C-3) ppm.
Inseparable signals: 128.3, 128.8, 129.1, 129.2 (C-
Ј,3Ј,5Ј,6Ј,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 133.2, 134.7 (C-1Ј,1ЈЈ), 134.0, 134.2, 134.5
C-4Ј,4ЈЈ), 194.2 (C-1), 197.6 (C-4) ppm. NMR spectroscopic data
were taken from the spectrum of the diastereomeric mixture.
(295.3): C 65.08, H 4.44, N 14.23; found C 64.95, H
.13, N 13.92.
in easy epimerization at both centers and therefore allows
thermodynamic control to predominate. The formation of
the azide intermediate (Z)-24 was also suggested by
Hassner et al. Further support for the intermediacy of
vinyl azides (Z)-24 was provided by analogous treatment of
pyruvate adduct 18 with MsCl in dry pyridine, which re-
sulted in the formation of ethyl 3-azido-4-(4-methoxy-
δ
ϭ
2
(
[
7f]
16 13 3 3
C H N O
4
phenyl)-2-methyl-4-oxo-2-butenoate (28, Scheme 3), which 2-Azido-1-(4-chlorophenyl)-3-hydroxy-4-phenyl-1,4-butanedione
was inevitably stable due to the lack of the β-azido-α,β- (6b): solution of 2-azido-1-(4-chlorophenyl)ethanone (1b)
400 mg, 2.05 mmol) in dry THF (20 mL) was cooled to 0 °C. Then
A
(
unsaturated ketone unit.
[
10]
phenylglyoxal (2) (823 mg, 5.41 mmol) and DBU (34 µL, 34 mg,
.23 mmol) were added, and the mixture was allowed to stand at 0
C. When the reaction was complete (6 h) the reaction mixture was
In summary, base-induced reactions between α-azido ke-
tones and α-oxo aldehydes and α-oxo esters constitute an
efficient method for the preparation of the tetrafunc-
tionalized 2-azido-3-hydroxy-1,4-dione and 3-azido-2-hy-
droxy-4-oxoalkanoate synthons. The reactions between
acyclic α-azido ketones and α-oxo aldehydes take place with
0
°
concentrated in vacuo and the residue was purified by column chro-
matography (toluene/ethyl acetate, 9:1, v/v) to give pure 6b (350 mg,
5
anti diastereomers (by H NMR). The oil crystallized on standing
2%) as a yellow oil made up of a 76:24 mixture of the syn and
1
remarkable diastereoselectivity. Treatment of 2-azido-3-hy- with hexane to give yellow crystals. M.p. 86Ϫ90 °C. IR: ν˜ ϭ 3440
droxy-1,4-diones with mesyl chloride in the presence of an (OH), 2112 (N ), 1690, 1676 (CϭO), 1596, 1258, 1092, 1010, 686
excess of base affords 3-acyl-5-substituted isoxazoles, pro- cm . H NMR ([D ]acetone): anti-6b: δ ϭ 5.26 (d, J ϭ 7.5 Hz, 1
H, 3-OH), 5.32 (d, J ϭ 6.4 Hz, 1 H, 2-H), 5.57 (dd, J ϭ 7.5, 6.4 Hz,
H, 3-H) ppm. syn-6b: δ ϭ 5.21 (d, J ϭ 6.5 Hz, 1 H, 3-OH), 5.35
d, J ϭ 4.6 Hz, 1 H, 2-H), 5.71 (dd, J ϭ 6.5, 4.6 Hz, 1 H, 3-H)
3
Ϫ1
1
6
viding a novel and synthetically valuable method for the
preparation of this family of compounds.
1
(
ppm. Inseparable signals: δ ϭ 7.53Ϫ7.75 (m, 5 H, 3Ј,5Ј,3ЈЈ,4ЈЈ,5ЈЈ-
H), 7.98Ϫ8.12 (m, 4 H, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR spectroscopic
data were taken from the spectrum of the diastereomeric mixture.
Experimental Section
1
3
C NMR: anti-6b: δ ϭ 63.5 (C-2), 74.8 (C-3), 134.5 (C-4ЈЈ), 194.1
General: All chemicals were used as purchased unless otherwise
stated. THF was distilled from benzophenone ketyl, triethylamine
(
(
C-1), 198.2 (C-4) ppm. syn-6b: δ ϭ 65.9 (C-2), 74.3 (C-3), 134.6
C-4ЈЈ), 193.3 (C-1), 197.6 (C-4) ppm. Inseparable signals: δ ϭ
was distilled from LAH. Phenylglyoxal hydrates 2Ϫ4 were prepared
as described by RiouxϪLacoste and Viel.[4] tert-Butylglyoxal hy-
128.4, 128.9, 129.3, 129.4, 129.9, 130.2 (C-2Ј,3Ј,5Ј,6Ј,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ),
133.3, 133.5 (C-1Ј,1ЈЈ), 140.6 (C-4Ј) ppm. NMR spectroscopic data
were taken from the spectrum of the diastereomeric mixture.
drate (5) was prepared as described by Fuson et al.[5] α-Azido ke-
tones 1aϪd and 10a, 10b, and 10e were prepared by the procedure
[
3]
C
16
H12ClN
3 3
O (329.7): C 58.28, H 3.67, N 12.74; found C 58.31,
reported previously. Column chromatography was performed on
Kieselgel 60 or Kieselgel 40. Melting points: Boetius hot-stage, un-
corrected values. IR: PerkinϪElmer 16 PC-FT-IR; KBr pellets un-
less otherwise stated. NMR: Varian Gemini 200, Bruker WP 200
H 3.66, N 12.71.
2
-Azido-1-(4-fluorophenyl)-3-hydroxy-4-phenyl-1,4-butanedione
(
6c): A solution of 2-azido-1-(4-fluorophenyl)ethanone (1c) (1.00 g,
1
SY, Bruker AM 360 (200 or 360 MHz for H; 50 or 90 MHz for
5
.58 mmol) in dry THF (36 mL) was cooled to 0 °C and
13
C). Recorded in CDCl
3
solution unless otherwise stated. Chem-
[10]
phenylglyoxal (2) (1.50 g, 9.85 mmol)
and DBU (0.09 mL,
ical shifts are given in δ relative to an internal standard TMS (δ ϭ
93 mg, 0.61 mmol) were added. After standing for 6 h at 0 °C, the
1
0
7
) or to the residual CHCl
3
(δ ϭ 7.26 ppm for H NMR and δ ϭ
mixture was worked up as described for 6b, and column chromato-
graphy (toluene/ethyl acetate, 9:1, v/v) gave 6c (1.10 g, 63%) as a
yellow crystalline solid made up of a 76:24 mixture of the syn and
7.0 ppm for 13C NMR). Elemental analyses: CarloϪErba appar-
atus.
-Azido-3-hydroxy-1,4-diphenyl-1,4-butanedione (6a): Molecular
1
2
anti diastereomers (by H NMR). M.p. 112Ϫ113 °C. IR: ν˜ ϭ 3455
˚
Ϫ1 1
sieves (4 A, 1.00 g) were added to a solution of 1a (300 mg,
.86 mmol) in dry THF (20 mL) and the mixture was cooled to 0
C. Then phenylglyoxal (2) (826 mg, 5.43 mmol)[10] and DBU (30 5.32 (d, J ϭ 7.6 Hz, 1 H, 2-H), 5.58 (dd, J ϭ 8.1, 7.6 Hz, 1 H, 3-
3
(OH), 2111 (N ), 1689, 1674 (CϭO), 1598, 1259, 1222 cm . H
1
°
NMR ([D ]acetone): anti-6c: δ ϭ 5.26 (d, J ϭ 8.1 Hz, 1 H, 3-OH),
6
µL, 31 mg, 0.21 mmol) were added and the mixture was allowed to
stand at 0 °C. After completion of the reaction (3 h), the molecular
sieves were filtered off, the filtrate was concentrated in vacuo, and
the residue was purified by column chromatography (toluene/ethyl
H). syn-6c: δ ϭ 5.24 (d, J ϭ 6.6 Hz, 1 H, 3-OH), 5.35 (d, J ϭ
4.7 Hz, 1 H, 2-H), 5.72 (dd, J ϭ 6.6, 4.7 Hz, 1 H, 3-H) ppm. Insep-
arable signals: δ ϭ 7.31Ϫ7.45 (m, 2 H, 3Ј,5Ј-H), 7.56Ϫ7.73 (m, 3
H, 3ЈЈ,4ЈЈ,5ЈЈ-H), 8.03Ϫ8.23 (m, 4-H, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR
Eur. J. Org. Chem. 2002, 3055Ϫ3064
3059

´
E. Juh a´ sz-T o´ th, T. Patonay
FULL PAPER
spectroscopic data were taken from the spectrum of the diastereom-
Center, 12, Union Road, Cambridge CB2 1EZ, UK [Fax:
eric mixture. 13C NMR: anti-6c: δ ϭ 63.4 (C-2), 74.8 (C-3), 116.1 (internat.) ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
(
(
2
d, JC,F ϭ 22.0 Hz, C-3Ј,5Ј), 131.7 (d, JC,F ϭ 9.4 Hz, C-2Ј,6Ј), 134.4
C-4ЈЈ) ppm. syn-6c: δ ϭ 65.8 (C-2), 74.3 (C-3), 116.3 (d, JC,F
1.9 Hz, C-3Ј,5Ј), 131.3 (d, JC,F ϭ 9.5 Hz, C-2Ј,6Ј), 134.5 (C-4ЈЈ)
ppm. Inseparable signals: δ ϭ 128.4, 128.9, 129.3 (C-2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ),
33.3 (C-1Ј,1ЈЈ), 166.2 (d, JC,F ϭ 256 Hz, C-4Ј), 192.8 (C-1), 197.6
C-4) ppm. NMR spectroscopic data were taken from the spectrum
of the diastereomeric mixture. C16 (313.3): C 61.34, H
.86, N 13.41; found C 61.30, H 3.84, N 13.39.
2
-Azido-3-hydroxy-1,4-bis(4-methoxyphenyl)-1,4-butanedione (7d):
A solution of 2-azido-1-(4-methoxyphenyl)ethanone (1d) (200 mg,
.05 mmol) in dry THF (11 mL) was cooled to 0 °C, 4-methoxy-
ϭ
1
[10]
phenylglyoxal (3) (571 mg, 3.14 mmol) and DBU (17 µL, 18 mg,
.12 mmol) were added, and the mixture was allowed to stand at 0
C. After 24.5 h, the reaction mixture was concentrated in vacuo
1
(
0
°
3 3
H12FN O
and the residue was purified by column chromatography (toluene/
ethyl acetate, 4:1, v/v) to give pure 7d (163 mg, conversion: 52%,
yield: 84%, normalized to 100% conversion) as a yellow, crystalline
3
2
-Azido-3-hydroxy-1-(4-methoxyphenyl)-4-phenyl-1,4-butanedione
(
(
6d): A solution of 2-azido-1-(4-methoxyphenyl)ethanone (1d)
356 mg, 1.86 mmol) in dry THF (20 mL) was cooled to 0 °C, (by H NMR). M.p. 81Ϫ108 °C. IR: ν˜ ϭ 3446 (OH), 2102 (N
solid made up of a 80:20 mixture of the syn and anti diastereomers
1
3
),
]a-
.21 mmol) were added, and the mixture was allowed to stand at 0 cetone): anti-7d: δ ϭ 3.91, 3.92 (2 ϫ s, 6 H, 4Ј,4ЈЈ-OMe), 5.02 (d,
[10]
Ϫ1 1
phenylglyoxal (2) (749 mg, 4.92 mmol) and DBU (31 µL, 32 mg,
0
1690, 1668 (CϭO), 1600, 1570, 1260, 1174 cm . H NMR ([D
6
°
C. When the reaction was complete (4 h), the reaction mixture
J ϭ 8.1 Hz, 1 H, 3-OH), 5.16 (d, J ϭ 6.5 Hz, 1 H, 2-H), 5.50 (dd,
J ϭ 8.1, 6.5 Hz, 1 H, 3-H) ppm. syn-7d: δ ϭ 3.93, 3.94 (2 ϫ s, 6
H, 4Ј,4ЈЈ-OMe), 5.05 (d, J ϭ 6.7 Hz, 1 H, 3-OH), 5.22 (d, J ϭ
4.8 Hz, 1 H, 2-H), 5.62 (dd, J ϭ 6.7, 4.8 Hz, 1 H, 3-H) ppm. Insep-
was concentrated in vacuo and the residue was purified by column
chromatography (toluene/ethyl acetate, 6:1, v/v) to give pure 6d
(378 mg, 62%) as a yellow crystalline solid made up of a 87:13
1
mixture of the syn and anti diastereomers (by H NMR). M.p. arable signals: δ ϭ 7.03Ϫ7.14 (m, 4 H, 3Ј,5Ј,3ЈЈ,5ЈЈ-H), 7.96Ϫ8.10
1
00Ϫ103 °C. IR: ν˜ ϭ 3471 (OH), 2126 (N
3
), 1686 (CϭO), 1604,
(m, 4 H, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR spectroscopic data were taken
from the spectrum of the diastereomeric mixture. C NMR ([D ]a-
6
Ϫ1
13
1264, 1248, 1176 cm . Pure syn-6d diastereomer was obtained by
crystallization from diisopropyl ether/ethyl acetate (2:1, v/v) mix-
ture.
cetone): anti-7d: δ ϭ 64.1 (C-2), 75.1 (C-3). syn-7d: δ ϭ 66.5 (C-2),
75.7 (C-3) ppm. Inseparable signals: δ ϭ 56.8 (4Ј,4ЈЈ-OMe), 115.8
(
2
C-3Ј,5Ј,3ЈЈ,5ЈЈ), 128.8, 129.5 (C-1Ј,1ЈЈ), 132.5, 132.8, 133.0 (C-
Ј,6Ј,2ЈЈ,6ЈЈ), 165.9 (C-4Ј), 194.2 (C-1), 197.6 (C-4) ppm. NMR
spectroscopic data were taken from the spectrum of the diastereom-
eric mixture. C18 (355.4): C 60.84, H 4.82, N 11.82; found
C 60.89, H 4.81, N 11.84.
17 3 5
H N O
J ϭ 6.5 Hz, 1 H, 3-OH), 5.25 (d, J ϭ 4.7 Hz, 1 H, 2-H), 5.70 (dd,
J ϭ 6.5, 4.7 Hz, 1 H, 3-H), 7.14 (d, J ϭ 9.0 Hz, 2 H, 3Ј,5Ј-H),
2
-Azido-4-(4-chlorophenyl)-3-hydroxy-1-(4-methoxyphenyl)-1,4-
7
.56Ϫ7.76 (m, 3 H, 3ЈЈ,4ЈЈ,5ЈЈ-H), 8.05Ϫ8.12 (m, 4 H, 2Ј,6Ј,2ЈЈ,6ЈЈ-
13
butanedione (8d): A solution of 2-azido-1-(4-methoxyphenyl)e-
thanone (1d) (300 mg, 1.57 mmol) in dry THF (15 mL) was cooled
H) ppm. C NMR ([D
6
]acetone): δ ϭ 56.0 (4Ј-OMe), 65.5 (C-2),
5.2 (C-3), 115.1 (C-3Ј,5Ј), 128.5 (C-1Ј), 129.6, 129.7 (C-
ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 131.8 (C-2Ј,6Ј), 134.6 (C-4ЈЈ), 135.5 (C-1ЈЈ), 165.1
(325.3): C 62.76,
7
2
[
10]
to 0 °C, 4-chlorophenylglyoxal (4) (879 mg, 4.71 mmol)
and
DBU (26 µL, 26 mg, 0.17 mmol) were added, and the mixture was
allowed to stand at 0 °C. After 24 h, the reaction mixture was con-
centrated in vacuo and the residue was purified by column chroma-
tography (toluene/ethyl acetate, 9:1, v/v) to give 463 mg of 8d (con-
version: 84%, yield: 82%, normalized to 100% conversion) as a yel-
low oil made up of a 77:23 mixture of the syn and anti diastereo-
(C-4Ј), 193.4 (C-1), 198.7 (C-4) ppm. C17
H
15
N
3
O
4
H 4.65, N 12.92; found C 62.72, H 4.67, N 12.94.
1
Isomer anti-6d: H NMR ([D
6
]acetone): δ ϭ 3.91 (s, 3 H, 4Ј-OMe),
5
.21 (d, J ϭ 7.0 Hz, 1 H, 2-H), 5.55 (dd, J ϭ 7.9, 7.0 Hz, 1 H, 3-
H), 7.05 (d, J ϭ 8.8 Hz, 2 H, 3Ј,5Ј-H), 7.54Ϫ7.74 (m, 3 H,
ЈЈ,4ЈЈ,5ЈЈ-H), 7.98Ϫ8.11 (m, 4-H, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR spec-
1
3
mers (by H NMR). The diastereomeric mixture was treated with
troscopic data were taken from the spectrum of the diastereomeric
hexane to afford pale yellow crystals, m.p. 117Ϫ136 °C. The syn/
mixture. 13C NMR: δ ϭ 55.5 (4Ј-OMe), 62.8 (C-2), 74.7 (C-3),
1
anti ratio was 74:26 by H NMR. IR: ν˜ ϭ 3456 (OH), 2122 (N ),
3
1
14.0 (C-3Ј,5Ј), 127.2 (C-1Ј), 128.7, 128.8 (C-2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 131.3 1682 (CϭO), 1600, 1256, 1172, 1092, 958, 558 cmϪ1
1
.
H NMR
(
C-2Ј,6Ј), 133.4 (C-1ЈЈ), 134.2 (C-4ЈЈ), 164.2 (C-4Ј), 193.2 (C-1), ([D ]acetone): anti-8d: δ ϭ 3.90 (s, 3 H, 4Ј-OMe), 5.25 (d, J ϭ
6
1
98.4 (C-4) ppm. NMR spectroscopic data were taken from the
spectrum of the diastereomeric mixture. C17 (325.3): C
2.76, H 4.65, N 12.92; found C 62.70, H 4.63, N 12.95.
6.6 Hz, 1 H, 2-H), 5.52 (dd, J ϭ 8.1, 6.6 Hz, 1 H, 3-H), 7.05 (d,
J ϭ 9.2 Hz, 2 H, 3Ј,5Ј-H) ppm. syn-8d: δ ϭ 3.91 (s, 3 H, 4Ј-OMe),
5.29 (d, J ϭ 5.3 Hz, 1 H, 2-H), 5.36 (d, J ϭ 6.7 Hz, 1 H, 3-OH),
15 3 4
H N O
6
5
3
.68 (dd, J ϭ 6.7, 5.3 Hz, 1 H, 3-H), 7.11 (d, J ϭ 8.7 Hz, 2 H,
Ј,5Ј-H) ppm. Inseparable signals: δ ϭ 7.55Ϫ7.63 (m, 2 H, 3ЈЈ,5ЈЈ-
Crystal Data of syn-6d: Colorless prism crystals (0.55 ϫ 0.4 ϫ
0
.35 mm) of C17
H
15
N
3
˚
O
4
, M ϭ 325.32, monoclinic, a ϭ 8.135(1)
H), 7.99Ϫ8.13 (m, 4 H, 2Ј,6Ј,2ЈЈ,6ЈЈ-H) ppm. NMR spectroscopic
˚
˚
A, b ϭ 8.8659(10) A, c ϭ 23.114(3) A, β ϭ 108.44(1)°, V ϭ
1
data were taken from the spectrum of the diastereomeric mixture.
˚
3
Ϫ3
581.5(3) A , Z ϭ 4, space group: P2
1
/c, ρcalcd. ϭ 1.366 g cm
.
13
6
C NMR ([D ]acetone): anti-8d: δ ϭ 63.5 (C-2), 74.9 (C-3), 114.9
Data were collected at 293(1) K, EnrafϪNonius MACH3 diffracto-
(
C-3Ј,5Ј). syn-8d: 65.3 (C-2), 75.2 (C-3), 115.0 (C-3Ј,5Ј). Inseparable
˚
meter, Mo-K
α
radiation, λ ϭ 0.71073 A, ω-2θ motion, θmax
ϭ
signals: δ ϭ 56.0 (4Ј-OMe), 128.5 (C-1Ј), 129.8 (C-3ЈЈ,5ЈЈ), 131.4,
2
5.95°, 3077 measured, 2323 reflections were unique with I Ͼ 2σ(I),
1
1
31.5, 131.8, 132.1 (C-2Ј,6Ј,2ЈЈ,6ЈЈ), 134.3 (C-1ЈЈ), 140.2 (C-4ЈЈ),
65.1 (C-4Ј), 193.3 (C-1), 197.8 (C-4) ppm. NMR spectroscopic
[13]
decay: none. The structure was solved by use of SIR-92 software
and refined on F2 with the SHELX-97
[14]
program, publication
data were taken from the spectrum of the diastereomeric mixture.
14ClN (359.8): C 56.76, H 3.92, N 11.68; found C 56.70,
[15]
material was prepared with the WINGX-97 suite, R(F) ϭ 0.049
and wR(F ) ϭ 0.148 for 3077 reflections, 277 parameters. Residual
electron density: 0.151/Ϫ0.204 e/A . CCDC-182538 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic Data
C
17
H
3 4
O
2
H 3.93, N 11.65.
˚
3
2-Azido-3-hydroxy-1-(4-methoxyphenyl)-5,5-dimethyl-1,4-hexa-
nedione (9d): A solution of 2-azido-1-(4-methoxyphenyl)ethanone
(1d) (300 mg, 1.57 mmol) in dry THF (15 mL) was cooled to 0
3060
Eur. J. Org. Chem. 2002, 3055Ϫ3064

Tetrafunctionalized 2-Azido-3-hydroxy-1,4-diones
FULL PAPER
°
2
C, tert-butylglyoxal (5) (622 mg, 4.71 mmol)[10] and DBU (26 µL, 2ЈЈ,6ЈЈ-H) ppm. anti-11b: δ ϭ 4.19, 4.72 (AB q, J ϭ 11.8 Hz, 2 H,
6 mg, 0.17 mmol) were added, and the mixture was allowed to 2-H), 5.60 (s, 1 H, 1Ј-H) 7.00 (d, J ϭ 9.0 Hz, 1 H, 8-H), 7.74 (d, J ϭ
stand at 0 °C. After 4 h, the reaction mixture was concentrated
in vacuo and the residue was purified by column chromatography
7.5 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm. Inseparable signals: δ ϭ 7.39Ϫ7.51,
7.58Ϫ7.71 (2 ϫ m, 3H ϩ 2 H, 3ЈЈ,4ЈЈ,5ЈЈ,5,7-H) ppm. NMR spec-
(
5
hexane/ethyl acetate, 4:1, v/v) to give 9d as a yellow oil (247 mg, troscopic data were taken from the spectrum of the diastereomeric
1
3
2%) made up of an 89:11 mixture of the 9d and 9dЈ diastereomers
mixture. C NMR: syn-11b: δ ϭ 67.6 (C-3), 69.4 (C-2), 72.9 (C-
), 1698, 1682 1Ј), 119.4 (C-8), 128.2 (C-6), 134.4 (C-4ЈЈ), 134.9 (C-1ЈЈ), 136.6 (C-
]acetone): 9d: δ ϭ 7), 159.1 (C-8a), 187.3 (C-4), 197.8 (C-2Ј) ppm. anti-11b: δ ϭ 66.7
.27 (s, 9 H, tBu), 8.01 (d, J ϭ 9.1 Hz, 2 H, 2Ј,6Ј-H) ppm. 9dЈ: δ ϭ (C-3), 69.7 (C-2), 71.4 (C-1Ј), 119.8 (C-8), 128.1 (C-6), 134.6 (C-
1
(
(
by H NMR). IR (neat): ν˜ ϭ 3452 (OH), 2110 (N
3
Ϫ1
1
CϭO), 1600, 1264, 1172 cm . H NMR ([D
6
1
1
.24 (s, 9 H, tBu), 8.05 (d, J ϭ 8.7 Hz, 2 H, 2Ј,6Ј-H) ppm. Insepar-
4ЈЈ), 135.1 (C-1ЈЈ), 137.0 (C-7), 159.2 (C-8a), 186.5 (C-4), 198.8 (C-
2Ј) ppm. Inseparable signals: δ ϭ 120.5 (C-4a), 127.2, 127.3, 128.7,
able signals: δ ϭ 3.91 (s, 3 H, 4Ј-OMe), 5.05Ϫ5.11, 5.16Ϫ5.23 (2
ϫ m, 2 ϫ 1 H, 2,3-H), 7.07Ϫ7.15 (m, 2 H, 3Ј,5Ј-H) ppm. NMR 128.8 (C-2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ,5) ppm. NMR spectroscopic data were
spectroscopic data were taken from the spectrum of the diastereom- taken from the spectrum of the diastereomeric mixture.
eric mixture. 13C NMR ([D
]acetone): 9d: 26.7 (CMe ), 64.8 (C-2),
4.7 (C-3) ppm. 9dЈ: δ ϭ 26.0 (CMe ), 62.0 (C-2), 71.4 (C-3) ppm. H 3.39, N 11.73.
Inseparable signals: δ ϭ 43.9 (C-5), 55.8 (4Ј-OMe), 114.8 (C-3Ј,5Ј),
6
3
C
17
H12ClN
3
O
4
(357.8): C 57.07, H 3.38, N 11.75; found C 56.98,
7
3
3
-Azido-3-(1-hydroxy-2-oxo-2-phenylethyl)-6-methyl-4-chromanone
1
1
28.2 (C-1Ј), 131.3, 131.5, 131.6 (C-2Ј,6Ј), 164.8 (C-4Ј), 193.4 (C-
), 213.1 (C-4) ppm. NMR spectroscopic data were taken from
(
4
(
11e): A solution of 3-azido-6-methyl-4-chromanone (10e) (863 mg,
.25 mmol) in dry THF (50 mL) was cooled to 0 °C. Phenylglyoxal
the spectrum of the diastereomeric mixture. C15
C 59.01, H 6.27, N 13.76; found C 59.04, H 6.26, N 13.78.
19 3 4
H N O (305.3):
2) (1.14 g, 7.49 mmol)[ and DBU (0.07 mL, 71 mg, 0.47 mmol)
10]
were added to the solution and the mixture was allowed to stand
at 0 °C. When the reaction was complete (3.5 h), the reaction mix-
ture was concentrated in vacuo and the residue was purified by
column chromatography (toluene/ethyl acetate, 6:1, v/v) to give
pure 11e (1.15 g, 80%) as a yellow crystalline solid made up of a
6
3-Azido-3-(1-hydroxy-2-oxo-2-phenylethyl)-4-chromanone (11a): A
solution of 3-azido-4-chromanone (10a) (500 mg, 2.64 mmol) in
dry THF (20 mL) was cooled to 0 °C. Phenylglyoxal (2) (709 mg,
[
10]
4.66 mmol)
and DBU (43 µL, 44 mg, 0.29 mmol) were added,
1
2:38 mixture of the syn and anti diastereomers (by H NMR).
and the mixture was allowed to stand at 0 °C. When the reaction
was complete (3 h), the reaction mixture was concentrated in vacuo
and the residue was purified by column chromatography (toluene/
ethyl acetate, 9:1, v/v) to give 11a (763 mg, 89%) as a yellow oil
made up of a 63:37 mixture of the syn and anti diastereomers (by
M.p. 102.5Ϫ105.5 °C. IR: ν˜ ϭ 3434 (OH), 2126 (N
), 1696 (Cϭ
3
Ϫ1
O), 1666, 1618, 1492, 1288, 1256, 1216, 830 cm . Pure anti-11e
diastereomer was obtained by crystallization from hexane/ethyl
acetate (2:1, v/v) mixture.
1
H NMR). The diastereomeric mixture was treated with hexane to
Isomer anti-11e: Colorless block crystals, m.p. 161Ϫ163 °C. IR: ν˜ ϭ
afford pale yellow crystals, m.p. 88Ϫ89.5 °C. The syn/anti ratio was
Ϫ1
3
3
458 (OH), 2124 (N ), 1684 (CϭO), 1616, 1490, 1290, 1262 cm .
1
5
9:41 by H NMR. IR: ν˜ ϭ 3465 (OH), 2108 (N
), 1685 (CϭO),
3
1
H NMR: δ ϭ 2.32 (s, 3 H, 6-Me), 3.96 (br. s, 1 H, 1Ј-OH), 4.18,
Ϫ1
1
1607, 1477, 1264 cm . H NMR: syn-11a: δ ϭ 4.11, 4.29 (AB q,
4
.72 (AB q, J ϭ 11.7 Hz, 2 H, 2-H), 5.62 (br. s, 1 H, 1Ј-H) 6.94 (d,
J ϭ 8.4 Hz, 1 H, 8-H), 7.37Ϫ7.44 (m, 3 H, 3ЈЈ,5ЈЈ,7-H), 7.52 (s, 1
H, 5-H), 7.62 (m, 1 H, 4ЈЈ-H), 7.74 (d, J ϭ 7.1 Hz, 2 H, 2ЈЈ,6ЈЈ-H)
J ϭ 12.5 Hz, 2 H, 2-H), 5.56 (s, 1 H, 1Ј-H) ppm. anti-11a: δ ϭ
.21, 4.75 (AB q, J ϭ 11.7 Hz, 2 H, 2-H), 5.62 (s, 1 H, 1Ј-H) ppm.
Inseparable signals: δ ϭ 6.95Ϫ7.11 (m, 2 H, 6,8-H), 7.36Ϫ7.88 (m,
H, Ph, 5,7-H) ppm. NMR spectroscopic data were taken from
4
1
3
ppm. C NMR: δ ϭ 20.4 (6-Me), 67.2 (C-3), 69.6 (C-2), 71.4 (C-
7
1
1
1
4
Ј), 117.9 (C-8), 119.4 (C-4a), 127.7, 128.7 (C-5,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ),
13
the spectrum of the diastereomeric mixture. C NMR: syn-11a:
δ ϭ 67.7 (C-3), 69.3 (C-2), 72.8 (C-1Ј), 117.7 (C-8), 122.6 (C-6)
1
1
1
1
δ ϭ 119.6 (C-4a), 128.1, 128.2, 128.7, 128.8 (C-2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ,5)
ppm. NMR spectroscopic data were taken from the spectrum of
the diastereomeric mixture. C17
N 13.00; found C 63.22, H 4.04, N 12.98.
32.1 (C-6), 134.4 (C-4ЈЈ), 135.3 (C-1ЈЈ), 138.3 (C-7), 158.9 (C-8a),
87.6 (C-4), 199.0 (C-2Ј) ppm. C18H N O (337.3): C 64.09, H
15 3 4
.48, N 12.46, found C 64.01, H 4.47, N 12.48.
34.3 (C-4ЈЈ), 135.1 (C-1ЈЈ), 136.7 (C-7), 160.6 (C-8a), 188.2 (C-4),
98.1 (C-2Ј) ppm. anti-11a: δ ϭ 67.2 (C-3), 69.6 (C-2), 71.1 (C-1Ј),
18.0 (C-8), 122.4 (C-6), 134.4 (C-4ЈЈ), 135.2 (C-1ЈЈ), 137.1 (C-7),
60.8 (C-8a), 187.5 (C-4), 198.9 (C-2Ј) ppm. Inseparable signals:
1
Isomer syn-11e: H NMR: δ ϭ 2.24 (s, 3 H, 6-Me), 4.11, 4.30 (AB
q, J ϭ 12.3 Hz, 2 H, 2-H), 5.58 (s, 1 H, 1Ј-H) 6.87 (d, J ϭ 8.4 Hz,
1
H, 3ЈЈ,5ЈЈ-H, 7-H (anti)], 7.52 (br. s, 1 H, 5-H), 7.57 (m, 1 H, 4ЈЈ-
H), 7.86 (d, J ϭ 7.9 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm. NMR spectroscopic
data were taken from the spectrum of the diastereomeric mixture.
H, 8-H), 7.29 (dd, J ϭ 8.4, 2.0 Hz, 1 H, 7-H), 7.35Ϫ7.45 [m, 3
13 3 4
H N O (323.3): C 63.16, H 4.05,
1
3
C NMR: δ ϭ 20.3 (6-Me), 67.8 (C-3), 69.3 (C-2), 72.9 (C-1Ј),
17.5 (C-8), 119.3 (C-4a), 127.6, 128.7, 128.9 (C-5,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ),
32.2 (C-6), 134.2 (C-4ЈЈ), 135.2 (C-1ЈЈ), 137.9 (C-7), 158.7 (C-8a),
88.4 (C-4), 198.2 (C-2Ј) ppm. NMR spectroscopic data were taken
3
(
-Azido-6-chloro-3-(1-hydroxy-2-oxo-2-phenylethyl)-4-chromanone
11b): A solution of 3-azido-6-chloro-4-chromanone (10b) (400 mg,
.79 mmol) in dry THF (20 mL) was cooled to 0 °C. Phenylglyoxal
1
1
1
1
(
2) (720 mg, 4.73 mmol)[ and DBU (29 µL, 30 mg, 0.20 mmol)
10]
from the spectrum of the diastereomeric mixture. C18
15 3 4
H N O
were added, and the mixture was allowed to stand at 0 °C until
completion of the reaction (3 h). The reaction mixture was concen-
trated in vacuo and the residue was purified by column chromato-
graphy (toluene/ethyl acetate, 9:1, v/v) to give 11b (415 mg, 65%)
(
337.3): C 64.09, H 4.48, N 12.46; found C 65.16, H 4.49, N 12.45.
Crystal Data of anti-11e: Colorless block crystals (0.56 ϫ 0.4 ϫ
0.36 mm) of C18
as a yellow oil made up of a 60:40 mixture of the syn and anti b ϭ 8.6527(10) A, c ϭ 13.1405(10) A, α ϭ 76.07(1), β ϭ 74.55(1), γ ϭ
70.39(1)°, V ϭ 784.93(15) A , Z ϭ 2, space group: P1, ρcalcd.
1.427 g cm . Data were collected at 293(1) K, EnrafϪNonius
C. The syn/anti ratio was 59:41 by H NMR. IR: ν˜ ϭ 3462 (OH), MACH3 diffractometer, Mo-K
˚
H
15
N
3
O
4
, M ϭ 337.33, triclinic, a ϭ 7.7112(10) A,
˚
˚
diastereomers (by 1H NMR). The diastereomeric mixture was
treated with hexane to afford pale yellow crystals, m.p. 105Ϫ110
˚
3
¯
ϭ
Ϫ3
1
˚
°
α
radiation, λ ϭ 0.71073 A, ω-2θ mo-
), 1702 (CϭO), 1683, 1474, 1261 cmϪ1
.
1
H NMR: syn-
tion, θmax ϭ 25.27°, 2684 measured, 2108 reflections were unique
2
1
1
124 (N
3
1b: δ ϭ 4.10, 4.33 (AB q, J ϭ 12.7 Hz, 2 H, 2-H), 5.51 (s, 1 H, with I Ͼ 2σ(I), decay: none. The structure was solved by use of SIR-
Ј-H), 6.92 (d, J ϭ 9.1 Hz, 1 H, 8-H), 7.80 (d, J ϭ 7.5 Hz, 2 H, 92 software[ and refined on F with the SHELX-97 program,
13]
2
[14]
Eur. J. Org. Chem. 2002, 3055Ϫ3064
3061

´
E. Juh a´ sz-T o´ th, T. Patonay
FULL PAPER
publication material was prepared with the WINGX-97 suite,[
15]
69.5 (C-2), 71.3 (C-1Ј), 117.8 (C-8), 133.5 (C-1ЈЈ), 138.4 (C-7), 140.9
(C-4ЈЈ), 158.9 (C-8a), 187.5 (C-4) 197.7 (C-2Ј) ppm. Inseparable sig-
meters. Residual electron density: 0.212/Ϫ0.179 e/A . CCDC-184120 nals: δ ϭ 20.2 (6-Me), 119.2 (C-4a), 127.4, 128.9, 130.0, 130.2 (C-
2
R(F) ϭ 0.0397 and wR(F ) ϭ 0.1145 for 2684 reflections, 230 para-
˚
3
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic Data
5,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 132.3 (C-6) ppm. NMR spectroscopic data were
taken from the spectrum of the diastereomeric mixture.
C H14ClN O (371.8): C 58.15, H 3.80, N 11.30; found C 58.09, H
18 3 4
Centre, 12, Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.) 3.79, N 11.33.
ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
3
-Azido-3-(1-hydroxy-3,3-dimethyl-2-oxobutyl)-6-methyl-4-
chromanone (14e): A solution of 3-azido-6-methyl-4-chromanone
3
-Azido-3-[1-hydroxy-2-(4-methoxyphenyl)-2-oxoethyl]-6-methyl-4-
(
10e) (100 mg, 0.49 mmol) in dry THF (6 mL) was cooled to 0 °C.
[10]
chromanone (12e): A solution of 3-azido-6-methyl-4-chromanone
tert-Butylglyoxal (5) (130 mg, 0.98 mmol)
and DBU (8.0 µL,
(10e) (100 mg, 0.49 mmol) in dry THF (6 mL) was cooled to 0 °C. 4-
[10]
8.2 mg, 0.05 mmol) were added, and the mixture was allowed to
stand at 0 °C. When the reaction was complete (2.5 h), the reaction
mixture was concentrated in vacuo and the residue was purified by
column chromatography (toluene/ethyl acetate, 9:1, v/v) to give 14e
Methoxyphenylglyoxal (3) (179 mg, 0.98 mmol)
and DBU (8.0
µL, 8.2 mg, 0.05 mmol) were added to the solution and the mixture
was allowed to stand at 0 °C. When the reaction was complete (3 h),
the reaction mixture was concentrated in vacuo and the residue was
purified by column chromatography (toluene/ethyl acetate, 6:1, v/v)
to give 12e (157 mg, 87%) as a yellow oil made up of a 67:33 mixture
of the syn and anti diastereomers (by H NMR). The diastereomeric
mixture was treated with hexane to afford yellow crystals, m.p.
1
(
146 mg, 94%) as a yellow oil made up of a 46:54 mixture of the syn
1
and anti diastereomers (by H NMR). IR (neat): ν˜ ϭ 3472 (OH),
Ϫ1
1
1
2114 (N
4e: δ ϭ 1.21 (s, 9 H, tBu), 2.34 (s, 3 H, 6-Me), 3.65 (d, J ϭ 9.8 Hz, 1
H, 1Ј-OH), 4.34, 4.48 (AB q, J ϭ 12.0 Hz, 2 H, 2-H), 4.99 (d, J ϭ
.8 Hz, 1 H, 1Ј-H), 6.91 (d, J ϭ 8.5 Hz, 1 H, 8-H) ppm. anti-14e: δ ϭ
3
), 1682 (CϭO), 1620, 1494, 1296, 1222 cm . H NMR: syn-
1
1
15Ϫ118 °C. The syn/anti ratio was 65:35 by H NMR. IR: ν˜ ϭ 3462
9
3
(OH), 2122 (N ), 1680 (CϭO), 1654, 1600, 1514, 1492, 1266, 1178,
Ϫ1
1
1.26 (s, 9 H, tBu), 2.33 (s, 3 H, 6-Me), 3.02 (d, J ϭ 6.1 Hz, 1 H, 1Ј-
OH), 4.48, 4.77 (AB q, J ϭ 12.5 Hz, 2 H, 2-H), 5.16 (d, J ϭ 6.1 Hz, 1
H, 1Ј-H), 6.92 (d, J ϭ 8.4 Hz, 1 H, 8-H) ppm. Inseparable signals:
δ ϭ 7.35Ϫ7.37 (m, 1 H, 7-H), 7.75 (overlapping doublets, 1 H, 5-H)
ppm. NMR spectroscopic data were taken from the spectrum of the
1
024, 828 cm . H NMR: syn-12e: δ ϭ 2.28 (s, 3 H, 6-Me), 4.08, 4.28
(
AB q, J ϭ 12.5 Hz, 2 H, 2-H), 5.53 (s, 1 H, 1Ј-H), 7.31 (d, J ϭ 9.0 Hz,
H, 7-H), 7.57 (br. s, 1 H, 5-H), 7.88 (d, J ϭ 9.0 Hz, 2 H, 2ЈЈ,6ЈЈ-H)
ppm. anti-12e: δ ϭ 2.34 (s, 3 H, 6-Me), 4.18, 4.72 (AB q, J ϭ 11.8 Hz,
H, 2-H), 5.59 (s, 1 H, 1Ј-H), 7.39 (d, J ϭ 8.7 Hz, 1 H, 7-H), 7.59 (br.
1
2
1
3
diastereomeric mixture. C NMR: syn-14e: δ ϭ 22.8 (6-Me), 26.4
CMe ), 65.6 (C-3), 69.9 (C-2), 72.1 (C-1Ј), 119.4 (C-4a), 132.1 (C-6),
38.4 (C-7), 188.8 (C-4), 213.2 (C-2Ј) ppm. anti-14e: δ ϭ 20.4 (6-Me),
26.1 (CMe ), 67.6 (C-3), 69.7 (C-2), 74.8 (C-1Ј), 119.1 (C-4a), 131.9
C-6), 138.0 (C-7), 187.3 (C-4), 211.9 (C-2Ј) ppm. Inseparable sig-
s, 1 H, 5-H), 7.77 (d, J ϭ 8.6 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm. Inseparable
signals: δ ϭ 3.89 (s, 3-H, 4ЈЈ-OMe), 6.87Ϫ6.96 (m, 3 H, 3ЈЈ,5ЈЈ,8-H)
(
3
1
ppm. NMR spectroscopic data were taken from the spectrum of the
diastereomeric mixture. 13C NMR: syn-12e: δ ϭ 69.1 (C-2), 72.4 (C-
3
(
1
4
2
Ј), 117.4 (C-8), 131.4 (C-2ЈЈ,6ЈЈ), 137.7 (C-7), 158.6 (C-8a), 188.6 (C-
) ppm. anti-12e: δ ϭ 69.5 (C-2), 70.8 (C-1Ј), 117.8 (C-8), 131.2 (C-
ЈЈ,6ЈЈ), 138.2 (C-7), 159.0 (C-8a), 187.6 (C-4) ppm. Inseparable sig-
nals: δ ϭ 44.5 (C-3Ј), 117.8 (C-8), 127.4 (C-5), 159.1 (C-8a) ppm.
NMR spectroscopic data were taken from the spectrum of the dia-
stereomeric mixture. C16
19 3 4
H N O (317.3): C 60.56, H 6.03, N 13.24;
nals: δ ϭ 20.2 (6-Me), 55.5 (4ЈЈ-OMe), 67.7 (C-3), 113.9 (C-3ЈЈ,5ЈЈ),
found C 60.45, H 6.04, N 13.22.
1
1
19.2 (C-4a), 127.5 (C-5), 127.7 (C-1ЈЈ), 132.0 (C-6), 164.6 (C-4ЈЈ),
95.9 (C-2Ј) ppm. NMR spectroscopic data were taken from the
2
-Azidobenzosuberone (15): A mixture of 2-bromobenzosuberone
spectrum of the diastereomeric mixture. C19
6
H
17
N
3
O
5
(367.4): C
[11]
(
1.139 g, 4.76 mmol),
sodium azide (619 mg, 9.52 mmol), 18-
2.12, H 4.66, N 11.44; found C 61.97, H 4.68, N 11.40.
crown-6 (126 mg, 0.47 mmol), and acetone (50 mL) was stirred at
room temperature for 25 h. It was then poured into water and ex-
3
-Azido-3-[2-(4-chlorophenyl)-1-hydroxy-2-oxoethyl]-6-methyl-4-
tracted with dichloromethane (3 ϫ 50 mL). The dried (MgSO
tion was concentrated and subjected to column chromatography
hexane/ethyl acetate, 11:1, v/v) to give pure 15 (609 mg, 64%) as a
colorless oil that spontaneously crystallized on standing in a refriger-
ator. M.p. 24Ϫ26 °C. IR (neat): ν˜ ϭ 3064, 2940, 2866, 2098 (N
), 1692
4
) solu-
chromanone (13e): A solution of 3-azido-6-methyl-4-chromanone
10e) (100 mg, 0.49 mmol) in dry THF (6 mL) was cooled to 0 °C. (4-
(
(
[10]
Chlorophenyl)glyoxal (4) (184 mg, 0.98 mmol) and DBU (8.0 µL,
.2 mg, 0.05 mmol) were added, and the mixture was allowed to
8
3
stand at 0 °C. When the reaction was complete (3 h), the reaction
mixture was concentrated in vacuo and the residue was purified by
column chromatography (toluene/ethyl acetate, 6:1, v/v) to give 13e
Ϫ1 1
(
(
CϭO), 1596, 1276, 1258, 1216, 768 cm . H NMR: δ ϭ 1.79, 1.95
2 ϫ m, 2 ϫ 1 H, 4-H), 2.07Ϫ2.28 (m, 2 H, 3-H), 3.00 (m, 2 H, 5-H),
4
7
7
2
.28 (dd, J ϭ 10.6, 4.9 Hz, 1 H, 2-H), 7.23 (d, J ϭ 7.5 Hz, 1 H, 6-H),
(159 mg, 87%) as a yellow oil made up of a 58:42 mixture of the syn
.33 (dd, J ϭ 7.7, 7.4 Hz, 1 H, 8-H), 7.45 (dd, J ϭ 7.5, 7.4 Hz, 1 H,
1
and anti diastereomers (by H NMR). The diastereomeric mixture
was treated with diisopropyl ether to afford yellow crystals, m.p.
1
13
-H), 7.78 (d, J ϭ 7.7 Hz, 1 H, 9-H) ppm. C NMR: δ ϭ 23.6 (C-4),
9.0, 33.4 (C-3,5), 66.1 (C-2), 126.7 (C-8), 129.0, 130.0 (C-6,9), 132.4
1
46Ϫ153 °C. The syn/anti ratio was 51:49 by H NMR. IR: ν˜ ϭ 3450
(
C-7), 136.6 (C-9a), 141.7 (C-5a), 200.6 (C-1) ppm. C11
11 3
H N O
Ϫ1
1
(OH), 2122 (N
3
), 1684 (CϭO), 1616, 1492, 1290, 1094 cm . H
(
201.2): C 65.66, H 5.51, N 20.88; found C 65.89, H 5.44, N 21.02.
NMR: syn-13e: δ ϭ 2.27 (s, 3 H, 6-Me), 4.13, 4.34 (AB q, J ϭ
12.1 Hz, 2 H, 2-H), 5.45 (s, 1 H, 1Ј-H), 6.85 (d, J ϭ 8.5 Hz, 1 H, 8- 2-Azido-2-(1-hydroxy-2-oxo-2-phenylethyl)benzosuberone (16): A so-
H), 7.30 (d, J ϭ 8.5 Hz, 1 H, 7-H), 7.78 (d, J ϭ 8.0 Hz, 2 H, 2ЈЈ,6ЈЈ- lution of 2-azidobenzosuberone (15) (250 mg, 1.24 mmol) in dry
H) ppm. anti-13e: δ ϭ 2.33 (s, 3 H, 6-Me), 4.20, 4.71 (AB q, J ϭ THF (10 mL) was cooled to 0 °C. Phenylglyoxal (2) (333 mg,
2.19 mmol)[ and DBU (20.5 µL, 20.9 mg, 0.14 mmol) were added,
10]
11.8 Hz, 2 H, 2-H), 5.54 (s, 1 H, 1Ј-H), 6.94 (d, J ϭ 8.5 Hz, 1 H, 8-
H), 7.69 (d, J ϭ 7.9 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm. Inseparable signals: δ ϭ
and the mixture was allowed to stand at 0 °C for 24 h. Another batch
7
.37Ϫ7.41 [m, 3 H, 3ЈЈ,5ЈЈ-H, 7-H (anti)], 7.52 (br. s, 1 H, 5-H) ppm. of DBU (20.5 µL) was then added to the reaction mixture. After 4
NMR spectroscopic data were taken from the spectrum of the dia- d, the reaction mixture was concentrated in vacuo and subjected to
stereomeric mixture. 13C NMR: syn-13e: δ ϭ 67.8 (C-3), 69.2 (C-2), column chromatography (hexane/ethyl acetate, 3:1, v/v) to give 16
7
1
3.2 (C-1Ј), 117.5 (C-8), 133.3 (C-1ЈЈ), 137.9 (C-7), 140.6 (C-4ЈЈ), (193 mg, conversion: 54%, yield: 86%, normalized to 100% conver-
58.6 (C-8a), 188.1 (C-4) 196.9 (C-2Ј) ppm. anti-13e: δ ϭ 67.1 (C-3), sion) as a yellow oil made up of a 75:25 mixture of the 16 and 16Ј
3062
Eur. J. Org. Chem. 2002, 3055Ϫ3064

Tetrafunctionalized 2-Azido-3-hydroxy-1,4-diones
FULL PAPER
N, 5.62; found C 77.12, H 4.43 N, 5.61. (b) Sodium azide (172 mg,
1
diastereomers (by H NMR). IR (neat): ν˜ ϭ 3444 (OH), 2110 (N
),
3
Ϫ1
1
1
676 (CϭO), 1596, 1448, 1252 cm . H NMR: 16: δ ϭ 5.60 (s, 1 H, 2.65 mmol) was added at room temperature to a stirred solution of
[
12]
1
Ј-H), 6.92 (d, J ϭ 7.2 Hz, 1 H, 6-H), 7.82 (d, J ϭ 7.2 Hz, 1 H, 2ЈЈ,6"-
trans-1,2-dibenzoylethylene dibromide (26) (477 mg, 1.20 mmol)
in dry DMF (6 mL). The stirring was maintained for 5 h and the mix-
H) ppm. Inseparable signals: 1.58Ϫ1.98 (m, 4 H, 3,4-H), 2.74Ϫ3.01 ture was then poured into water and extracted with diethyl ether (2
m, 2 H, 5-H), 7.06Ϫ7.64 (m, 6 H, 7,8,9,3ЈЈ,4ЈЈ,5"-H) ppm. NMR ϫ 60 mL). The dried (Na SO ) solution was concentrated in vacuo
H) ppm. 16Ј: δ ϭ 5.59 (s, 1 H, 1Ј-H), 7.93 (d, J ϭ 7.2 Hz, 1 H, 2ЈЈ,6"-
(
2
4
spectroscopic data were taken from the spectrum of the diastereom-
and the crude product was crystallized from methanol to give isox-
eric mixture. 13C NMR: 16: δ ϭ 77.1 (C-1Ј). 16Ј: δ ϭ 78.4 (C-1Ј) ppm. azole 19a (90 mg, 30%). M.p. 82Ϫ84 °C (ref. 86Ϫ87 °C).
[7f]
Inseparable signals: 22.3 (C-4), 29.0, 32.2 (C-3,5), 73.8 (C-2), 126.5,
3
(
-(4-Chlorobenzoyl)-5-phenylisoxazole (19b): Mesyl chloride
0.04 mL, 0.51 mmol) and TEA (0.14 mL, 1.02 mmol) were added to
a cooled (Ϫ15 °C) solution of azido alcohol 6b (140 mg, 0.42 mmol,
syn/anti ϭ 76:24) in dry CH Cl (3 mL), and the mixture was stirred
1
1
28.1, 128.6, 128.7, 129.1, 131.7, 133.7 (C-6,7,8,9,2ЈЈ,3ЈЈ,4ЈЈ,5ЈЈ,6"),
35.6, 138.3, 138.6 (C-5a,9a,1"), 199.5 (C-2Ј), 204.1 (C-1) ppm.
C
19
H
17
N
3
O
3
(335.4): C 68.05, H 5.11, N 12.53; found C 67.90, H
2
2
5.33, N 12.36.
at room temperature for 4 h. The reaction mixture was poured into
Ethyl 3-Azido-2-hydroxy-4-(4-methoxyphenyl)-2-methyl-4-oxobut-
anoate (18): A solution of 2-azido-1-(4-methoxyphenyl)ethanone
(
water and extracted with dichloromethane (3 ϫ 20 mL), and the or-
ganic layer was dried (MgSO ), concentrated in vacuo, and purified
4
1d) (1.00 g, 5.25 mmol) in dry THF (50 mL) was cooled to 0 °C, by column chromatography (hexane/ethyl acetate, 3:1, v/v) to give
ethyl 1-oxopropionate (17, 1.73 mL, 1.83 g, 15.75 mmol) and DBU
pure 19b (55 mg, 46%). Pale yellow needles, m.p. 134Ϫ136 °C (hex-
ane). IR: ν˜ ϭ 1651 (CϭO), 1587, 1442 (isoxazole ring), 1252, 897,
(84 µL, 86 mg, 0.56 mmol) were added to the solution, and the mix-
Ϫ1
1
ture was allowed to stand at 0 °C. After 43 h, the reaction mixture
was concentrated in vacuo and the residue was purified by column
chromatography (toluene/ethyl acetate, 9:1, v/v) to give pure 18
851, 765 cm . H NMR: δ ϭ 7.04 (s, 1 H, 4-H), 7.40Ϫ7.54 (m, 5 H,
3Ј,5Ј,3ЈЈ,4ЈЈ,5ЈЈ-H), 7.83 (m, 2 H, 2ЈЈ,6ЈЈ-H), 8.33 (d, J ϭ 9.2 Hz, 2 H,
1
3
2Ј,6Ј-H) ppm. C NMR: δ ϭ 100.2 (C-4), 126.0 (C-2ЈЈ,6ЈЈ), 126.6 (C-
(
982 mg, conversion: 88%, yield: 69%, normalized to 100% conver- 1"), 128.9, 129.1 (C-3Ј,5Ј,3ЈЈ,5ЈЈ), 130.8 (C-4ЈЈ), 132.1 (C-2Ј,6Ј), 133.9
sion) as a colorless oil made up of a 67:33 mixture of the 18 and 18Ј
(C-1Ј), 140.7 (C-4Ј), 162.2 (C-3), 170.9 (C-5), 184.3 (CϭO) ppm.
10ClNO (283.7): C 67.74, H 3.55, N 4.94; found C 67.78, H
3.53, N 4.95.
diastereomers (by 1H NMR). Repeated column chromatography
C
16
H
2
(toluene/ethyl acetate, 9:1, v/v) afforded pure diastereomers.
3
-(4-Fluorobenzoyl)-5-phenylisoxazole (19c): Mesyl chloride
Diastereomer 18: Colorless oil. IR (neat): ν˜ ϭ 3500 (OH), 2100 (N
),
3
1
Ϫ1
(0.06 mL, 0.77 mmol) and TEA (0.21 mL, 1.51 mmol) were added to
a cooled (Ϫ15 °C) solution of azido alcohol 6c (200 mg, 0.64 mmol,
syn/anti ϭ 76:24) in dry CH Cl (5 mL), and the mixture was stirred
2 2
at room temperature for 4 h. The reaction mixture was poured into
water and extracted with dichloromethane (3 ϫ 20 mL), and the or-
4
ganic layer was dried (MgSO ), concentrated in vacuo, and purified
by column chromatography (hexane/ethyl acetate, 3:1, v/v) to give
pure 19c (83 mg, 48%). Pale yellow needles, m.p. 98Ϫ101 °C (hex-
ane). IR: ν˜ ϭ 1653 (CϭO), 1599, 1442 (isoxazole ring), 1253, 1230,
1
746, 1732, 1682, 1674, 1600, 1312, 1266, 1224, 1174, 1020 cm . H
NMR: δ ϭ 1.13 (t, J ϭ 7.2 Hz, 3 H, OCH CH ), 1.57 (s, 3 H, 2-Me),
.86 (s, 3 H, 4Ј-OMe), 4.09 (q, J ϭ 7.2 Hz, 2 H, OCH CH ), 4.55 (s,
H, 3-H), 6.95 (d, J ϭ 9.1 Hz, 2 H, 3Ј,5Ј-H), 7.97 (d, J ϭ 9.1 Hz, 2
2
3
3
1
2
3
1
3
H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ 13.6 (OCH
4Ј-OMe), 61.6 (OCH CH ), 64.5 (C-3), 77.0 (C-2), 113.8 (C-3Ј,5Ј),
27.2 (C-1Ј), 131.4 (C-2Ј,6Ј), 164.4 (C-4Ј), 173.8 (C-1) 194.3 (C-4)
ppm. C14 (307.3): C 54.72, H 5.58, N 13.67; found C 54.59,
H 5.52, N 13.75.
2 3
CH ), 23.0 (2-Me), 55.3
(
1
2
3
17 3 5
H N O
Ϫ1
1
9
01, 771 cm . H NMR: δ ϭ 7.05 (s, 1 H, 4-H), 7.21 (dd, Jortho
9.1, JH,F ϭ 9.0 Hz, 2 H, 3Ј,5Ј-H), 7.46Ϫ7.55 (m, 3 H, 3ЈЈ,4ЈЈ,5ЈЈ-H),
), 1723, 1672, 1600, 1264, 1180 cm . H NMR: δ ϭ1.35 (t, 7.81Ϫ7.88 (m, 2 H, 2ЈЈ,6ЈЈ-H), 8.43 (dd, J
ϭ 9.1, JH,F ϭ 5.5 Hz,
ϭ
Diastereomer 18Ј: White prisms, m.p. 87Ϫ90 °C. IR: ν˜ ϭ 3470 (OH),
Ϫ1
1
2
101 (N
J ϭ 7.2 Hz, 3 H, OCH
OMe), 4.33 (dq, J ϭ 7.2, 2.2 Hz, 2 H, OCH
.96 (dd, J ϭ 9.2, 2.1 Hz, 2 H, 3Ј,5Ј-H), 7.99 (dd, J ϭ 9.2, 2.1 Hz, 2 130.8 (C-4ЈЈ), 132.0 (C-1Ј), 133.5 (d, JC,F ϭ 9.6 Hz, C-2Ј,6Ј), 162.3
3
ortho
1
3
2
CH
3
), 1.48 (s, 3 H, 2-Me), 3.88 (s, 3 H, 4Ј- 2 H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ 100.2 (C-4), 115.8 (d, JC,F
CH ), 4.67 (s, 1 H, 3-H),
21.8 Hz, C-3Ј,5Ј), 126.0 (C-2ЈЈ,6ЈЈ), 126.6 (C-1"), 129.1 (C-3ЈЈ,5ЈЈ),
ϭ
2
3
6
13
H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ 13.9 (OCH
4Ј-OMe), 61.9 (OCH CH ), 66.2 (C-3), 76.2 (C-2), 114.1 (C-3Ј,5Ј), C H FNO (267.2): C 71.91, H 3.77, N 5.24; found C 71.96, H 3.75,
28.6 (C-1Ј), 131.6 (C-2Ј,6Ј), 164.5 (C-4Ј), 174.3 (C-1) 192.7 (C-4)
ppm. C14 (307.3): C 54.72, H 5.58, N 13.67; found C 54.51,
H 5.54, N 13.62.
2 3
CH ), 24.0 (2-Me), 55.5 (C-3), 166.4 (d, JC,F ϭ 255 Hz, C-4Ј), 170.8 (C-5), 183.9 (CϭO) ppm.
(
2
3
1
6
10
2
1
N 5.25.
17 3 5
H N O
3-(4-Methoxybenzoyl)-5-phenylisoxazole (19d): Mesyl chloride
(
0.06 mL, 0.77 mmol) and TEA (0.21 mL, 1.51 mmol) were added to
a cooled (Ϫ15 °C) solution of azido alcohol 6d (200 mg, 0.61 mmol,
syn/anti ϭ 87:13) in dry CH Cl (5 mL), and the mixture was stirred
at room temperature for 5 h. It was then poured into water and ex-
2
(5 mL) and the mixture was stirred at tracted with dichloromethane (3 ϫ 15 mL), and the organic layer was
3-Benzoyl-5-phenylisoxazole (19a): (a) Mesyl chloride (0.06 mL,
0.77 mmol) and TEA (0.23 mL, 1.63 mmol) were added to a cooled
2
2
(Ϫ15 °C) solution of azido alcohol 6a (200 mg, 0.68 mmol) (syn/
anti ϭ 77:23) in dry CH Cl
2
room temperature for 1.5 h. The reaction mixture was poured into
4
dried (MgSO ), concentrated in vacuo, and purified by column chro-
water and extracted with dichloromethane (3 ϫ 20 mL), and the or-
ganic layer was dried (Na SO ), concentrated in vacuo, and purified
2 4
by column chromatography (hexane/ethyl acetate, 3:1, v/v) to give O), 1602, 1443 (isoxazole ring), 1252, 1178, 897 cm . H NMR: δ ϭ
matography (hexane/ethyl acetate, 3:1, v/v) to give pure 19d (73 mg,
42%). White needles, m.p. 111Ϫ114 °C (hexane). IR: ν˜ ϭ 1646 (Cϭ
Ϫ1
1
pure 19a (66 mg, 39%). White needles, m.p. 81Ϫ83 °C (hexane)
3.88 (s, 3 H, 4Ј-OMe), 7.00 (d, J ϭ 8.8 Hz, 2 H, 3Ј,5Ј-H), 7.01 (s, 1 H,
4-H), 7.48 (m, 3 H, 3ЈЈ,4ЈЈ,5ЈЈ-H), 7.83 (dd, J ϭ 7.9, 2.5 Hz, 2 H,
2ЈЈ,6ЈЈ-H), 8.38 (d, J ϭ 8.8 Hz, 2 H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ
[
7f]
[9a]
(
ref. 86Ϫ87 °C, ref. 80Ϫ82 °C). IR: ν˜ ϭ 1656 (CϭO), 1449 (isox-
Ϫ1 1
13
azole ring), 1243, 894, 726, 682 cm . H NMR: δ ϭ 7.05 (s, 1 H, 4-
H), 7.46Ϫ7.57 (m, 5 H, 3Ј,5Ј,3ЈЈ,4ЈЈ,5"-H), 7.66 (m, 1 H, 4Ј-H), 7.85 55.5 (4Ј-OMe), 100.3 (C-4), 113.8 (C-3Ј,5Ј), 125.9 (C-2ЈЈ,6ЈЈ), 126.7
3
(
(
3
1
m, 2 H, 2ЈЈ,6"-H), 8.34 (m, 2 H, 2Ј,6Ј-H) ppm. 1 C NMR: δ ϭ 100.2 (C-1ЈЈ), 128.6 (C-1Ј), 129.0 (C-3ЈЈ,5ЈЈ), 130.5 (C-4ЈЈ), 133.1 (C-2Ј,6Ј),
C-4), 126.0 (C-2ЈЈ,6"), 126.7 (C-1ЈЈ), 128.6 (C-3Ј,5Ј), 129.1 (C- 162.6 (C-3), 164.4 (C-4Ј), 170.4 (C-5), 183.8 (CϭO) ppm. C17
ЈЈ,5"), 130.7 (C-2Ј,6Ј,4ЈЈ), 134.0 (C-4Ј), 135.7 (C-1Ј), 162.4 (C-3), (279.3): C 73.11, H 4.69, N 5.02; found C 73.09, H 4.65, N 5.08. When
H13NO
3
70.7 (C-5), 185.8 (CϭO) ppm. C16
H11NO
2
(249.2): C 77.10, H 4.45 the reaction was repeated starting from pure syn-6d (80 mg,
Eur. J. Org. Chem. 2002, 3055Ϫ3064
3063

´
E. Juh a´ sz-T o´ th, T. Patonay
FULL PAPER
0
1
.246 mmol), isoxazole 19d (26 mg, 38%) was obtained, m.p.
08Ϫ110 °C.
tracted with saturated NaHCO
(MgSO
3
solution (25 mL) and water, dried
), concentrated in vacuo, and purified by column chromato-
4
graphy (hexane/ethyl acetate, 3:1, v/v) to give pure 28 (66 mg, conver-
sion: 69%, yield: 50%, normalized to 100% conversion) as a yellow
3
-(4-Methoxybenzoyl)-5-(4-methoxyphenyl)isoxazole (20d): Mesyl
chloride (0.03 mL, 0.39 mmol) and TEA (0.11 mL, 0.79 mmol) were
added to a cooled (Ϫ15 °C) solution of azido alcohol 7d (117 mg,
0
was stirred at room temperature for 3.5 h. It was then poured into
water and extracted with dichloromethane (3 ϫ 15 mL), and the or-
4
ganic layer was dried (MgSO ), concentrated in vacuo, and purified
by column chromatography (hexane/ethyl acetate, 3:1, v/v) to give
pure 20d (65 mg, 63%). Pale yellow needles, m.p. 118Ϫ121 °C (hex-
ane). IR: ν˜ ϭ 1652 (CϭO), 1592, 1506, 1436 (isoxazole ring), 1252,
oil. IR (neat): ν˜ ϭ 2108 (N
1
), 1712, 1662 (CϭO), 1598, 1290, 1264,
244, 1172, 844 cm . H NMR: δ ϭ 0.98 (t, J ϭ 7.0 Hz, 3 H,
OCH CH ), 1.99 (s, 3 H, 2-Me), 3.89 (s, 3 H, 4Ј-OMe), 3.94 (q, J ϭ
.0 Hz, 2 H, OCH CH ), 6.98 (d, J ϭ 9.4 Hz, 2 H, 3Ј,5Ј-H), 7.92 (d,
J ϭ 9.4 Hz, 2 H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ 12.6 (2-Me), 13.5
3
Ϫ1 1
2 2
.33 mmol, syn/anti ϭ 72:28) in dry CH Cl (3 mL), and the mixture
2
3
7
2
3
13
(
(
(
OCH
C-3), 127.9 (C-1Ј), 131.3 (C-2Ј,6Ј), 144.6 (C-2), 164.4 (C-4Ј), 166.0
C-1), 188.6 (C-4) ppm. C14 (289.3): C 58.13, H 5.23, N
4.53; found C 57.91, H 5.20, N 14.49.
2 3 2 3
CH ), 55.5 (4Ј-OMe), 61.0 (OCH CH ), 114.3 (C-3Ј,5Ј) 116.5
15 3 4
H N O
1
Ϫ1
1
1174 cm . H NMR: δ ϭ 3.88, 3.91 (2 ϫ s, 2 ϫ 3 H, 4Ј,4ЈЈ-OMe),
6.90 (s, 1 H, 3-H), 7.01 (overlapping doublets, 4 H, 3Ј,5Ј,3ЈЈ,5ЈЈ-H),
7.79 (d, J ϭ 8.7 Hz, 2 H, 2ЈЈ,6"-H), 8.38 (d, J ϭ 9.2 Hz, 2 H, 2Ј,6Ј-H)
Acknowledgments
13
ppm. C NMR: δ ϭ 55.4, 55.5 (4Ј,4ЈЈ-OMe), 99.0 (C-4), 114.0, 114.6 This work was financially supported by the Hungarian Scientific Re-
´
nyei
(
(
C-3Ј,5Ј,3ЈЈ,5ЈЈ), 119.7 (C-1"), 127.8 (C-2ЈЈ,6ЈЈ), 129.0 (C-1Ј), 133.4 search Found (OTKA T22290). The authors thank Dr. Attila Be
C-2Ј,6Ј), 161.7, 162.9 (C-3,4"), 164.7 (C-4Ј), 170.8 (C-5), 184.5 (Cϭ
for the X-ray analyses.
(309.3): C 69.89, H 4.89, N 4.53; found C 69.91,
O) ppm. C18
H 4.69, N 4.55.
H15NO
4
[
[
[
1]
2]
3]
J. H. Boyer, F. Canter, Chem. Rev. 1954, 54, 1Ϫ57.
T. Patonay, R. V. Hoffman, J. Org. Chem. 1995, 60, 2368Ϫ2377.
T. Patonay, E. Juh a´ sz-T o´ th, A. B e´ nyei, Eur. J. Org. Chem. 2002,
´
5-(4-Chlorophenyl)-3-(4-methoxybenzoyl)isoxazole (21d): Mesyl
chloride (0.02 mL, 0.25 mmol) and TEA (0.07 mL, 0.49 mmol) were
added to a cooled (Ϫ15 °C) solution of azido alcohol 8d (74 mg,
285Ϫ295.
[
[
[
4]
5]
C. Rioux-Lacoste, C. Viel, Bull. Soc. Chim. Fr. 1974, 11,
2463Ϫ2477.
2 2
0.20 mmol, syn/anti ϭ 74:26) in dry CH Cl (2 mL) and the mixture
R.C. Fuson, H. Gray, J. J. Gouza, J. Chem. Soc. 1939, 61,
was stirred at room temperature for 4 h. It was then poured into
water and extracted with dichloromethane (3 ϫ 10 mL), and the or-
ganic layer was dried (MgSO ), concentrated in vacuo, and purified
4
by column chromatography (toluene/ethyl acetate, 6:1, v/v) to give
pure 21d (30 mg, 48%). Pale yellow needles, m.p. 185Ϫ188 °C (hex-
ane/ethyl acetate). IR: ν˜ ϭ 1646 (CϭO), 1602, 1438 (isoxazole ring),
1
937Ϫ1940.
6] [6a]
G. Smolinsky, C. A. Pride, ‘‘The Chemistry of Vinyl Azides’’
in The Chemistry of the Azido Group (Ed.: S. Patai), Wiley Inter-
[6b]
science, New York, 1971, p. 555Ϫ585.
A. Hassner, ‘‘Vinyl
Azides and Nitrenes’’ in Azides and Nitrenes; Reactivity and
Utility (Ed.: E. F. V. Scriven), Academic Press, Orlando, 1984,
Ϫ1
1
[6c]
[6d]
1252, 896 cm . H NMR: δ ϭ 3.90 (s, 3 H, 4Ј-OMe), 7.00 (d, J ϭ
8.9 Hz, 2 H, 3Ј,5Ј-H), 7.01 (s, 1 H, 4-H), 7.48 (d, J ϭ 8.8 Hz, 2 H,
3ЈЈ,5ЈЈ-H), 7.78 (d, J ϭ 8.8 Hz, 2 H, 2ЈЈ,6"-H), 8.37 (d, J ϭ 8.9 Hz, 2
p. 35Ϫ94.
, Angew. Chem. 1975, 87, 831Ϫ838.
7] [7a]
G. L’abb e´ , Chem. Rev. 1968, 68, 345Ϫ363.
G.
L’abbe
´
[
A. Hassner, L. A. Levy, J. Am. Chem. Soc. 1965, 87,
4203Ϫ4204. [ A. Hassner, F. Boerwinkle, J. Am. Chem. Soc.
7b]
13
H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ 55.5 (4Ј-OMe), 100.7 (C-4), 113.9
C-3Ј,5Ј), 125.2 (C-1"), 127.2 (C-2ЈЈ,6"), 128.5 (C-1Ј), 129.5 (C-
ЈЈ,5ЈЈ), 133.2 (C-2Ј,6Ј), 136.7 (C-4ЈЈ), 162.7 (C-3), 164.5 (C-4Ј), 169.3
C-5), 183.7 (CϭO) ppm. C17 12ClNO (313.7): 65.08, H 3.86, N
.46; found C 65.12, H 3.79 N 4.47.
[7c]
1
1
1
1
968, 90, 216Ϫ218.
A. Hassner, F. W. Fowler, J. Org. Chem.
(
3
(
4
968, 33, 2686Ϫ2691. [ G. L’abb e´ , A. Hassner, J. Org. Chem.
7d]
[7e]
971, 36, 258Ϫ260.
[7f]
G. L’abb e´ , A. Hassner, Angew. Chem.
H
3
971, 83, 103Ϫ109. A. Hassner, G. L’abb e´ , M. J. Miller, J. Am.
[7g]
Chem. Soc. 1971, 93, 981Ϫ985.
H. Hemetsberger, D. Knittel,
[
7h]
H. Weidmann, Monatsh. Chem. 1969, 100, 1599Ϫ1603.
D.
5-tert-Butyl-3-(4-methoxybenzoyl)isoxazole (22d): Mesyl chloride
Knittel, H. Hemetsberger, H. Weidmann, Monatsh. Chem. 1970,
[7i]
(
0.04 mL, 0.51 mmol) and TEA (0.14 mL, 1.02 mmol) were added to
a cooled (Ϫ15 °C) solution of azido alcohol 9d (130 mg, 0.43 mmol)
9d/9dЈ ϭ 89:11) in dry CH Cl (2.5 mL) and the mixture was stirred
101, 157Ϫ160. H. Hemetsberger, D. Knittel, Monatsh. Chem.
1972, 103, 194Ϫ204. [ Gy. Litkei, T. Mester, T. Patonay, R. Bog-
7j]
na
´
r, Liebigs Ann. Chem. 1979, 174Ϫ180. [ T. Patonay, R. Bog-
7k]
(
2
2
n a´ r, Tetrahedron 1984, 40, 2555Ϫ2562.
at room temperature for 3.5 h. It was then poured into water and ex-
tracted with dichloromethane (3 ϫ 15 mL), and the organic layer was
[
[
8]
W. Weyler, D. S. Pearce, H. W. Moore, J. Am. Chem. Soc. 1973,
9
5, 2603Ϫ2610.
dried (MgSO
matography (hexane/ethyl acetate, 6:1, v/v) to give pure 22d (26 mg,
3%) as a colorless oil. IR (neat): ν˜ ϭ 1652 (CϭO), 1600, 1574, 1448
4
), concentrated in vacuo, and purified by column chro-
9] [9a]
U. Türck, H. Behringer, Chem. Ber. 1965, 98, 3020Ϫ3024. [9b]
A. N. Nesmeyanov, M. I. Rybinskaya, T. G. Kelekhsaeva, Izv.
Akad. Nauk. SSSR Ser. Khim. 1969, 4, 866Ϫ870.
2
[9c]
A. N. Nes-
Ϫ1
1
(
(
isoxazole ring), 1252, 1178, 896 cm . H NMR: δ ϭ 1.40 (s, 9 H,
tBu), 3.89 (s, 3 H, 4Ј-OMe), 6.45 (s, 1 H, 4-H), 6.98 (d, J ϭ 8.8 Hz, 2
meyanov, M. I. Rybinskaya, Izv. Akad. Nauk. SSSR, Otd. Khim.
Nauk. 1962, 5, 816Ϫ820. [ A. N. Nesmeyanov, M. I. Rybin-
skaya, T. G. Kelekhsaeva, Zh. Org. Khim. 1967, 4, 921Ϫ929.
Glyoxal was used in its hydrate form.
9d]
13
H, 3Ј,5Ј-H), 8.34 (d, J ϭ 8.8 Hz, 2 H, 2Ј,6Ј-H) ppm. C NMR: δ ϭ
[
10]
28.8 (CMe
128.8 (C-1Ј), 133.2 (C-2Ј,6Ј), 161.9 (C-3), 162.9 (C-4Ј), 181.9 (C-5),
184.5 (CϭO) ppm. C15 (259.3): C 69.48, H 6.61, N 5.40;
3 3
), 32.8 (CMe ), 55.5 (4Ј-OMe), 99.4 (C-4), 113.8 (C-3Ј,5Ј),
[
[
[
11]
D. S. Tarbell, H. F. Wilson, E. Ott, J. Am. Chem. Soc. 1952, 74,
6
263Ϫ6266.
H17NO
3
12]
13]
J.-J. Zhang, G. B. Schuster, J. Am. Chem. Soc. 1989, 111,
found C 69.52, H 6.58, N 5.43.
7149Ϫ7155.
A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, J.
Appl. Crystallogr. 1993, 26, 343Ϫ350.
G. M. Sheldrick, SHELXL-97, Universität Göttingen, 1997.
L. J. Farrugia, WINGX-97 System, University of Glasgow,
U.K., 1996.
Ethyl
3-Azido-4-(4-methoxyphenyl)-2-methyl-4-oxo-2-butenoate
28): Mesyl chloride (0.1 mL, 1.32 mmol) was added to a cooled
Ϫ15 °C) solution of azido alcohol 18 (203 mg, 0.66 mmol, 18/18Ј ϭ
7:33) in dry pyridine (5 mL) and the mixture was stirred at room
(
(
6
[14]
[15]
temperature for 25 h. It was then poured into water and extracted
Received May 28, 2002
with dichloromethane (3 ϫ 30 mL), and the organic layer was ex-
[O02286]
3064
Eur. J. Org. Chem. 2002, 3055Ϫ3064