Stereoselectivity and regioselectivity in nucleophilic ring opening in derivatives of 3-phenylisoxazolo[2,3-a]pyrimidine. Unpredicted dimerization and ring transformation. Syntheses of derivatives of pyrimidinylmethylamine, pyrimidinylmethylamino acid ami

Article abstract of DOI:10.1021/jo0497196

The nucleophilic ring opening of the isoxazolone ring in 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine derivatives by optically active amino acid amides and ephedrine led to pyrimidinylmethylamino acid amides. Using amides of different L-amino acids and (-)-ep

Full text of DOI:10.1021/jo0497196

Ster eoselectivity a n d Regioselectivity in Nu cleop h ilic Rin g
Op en in g in Der iva tives of 3-P h en ylisoxa zolo[2,3-a ]p yr im id in e.
Un p r ed icted Dim er iza tion a n d Rin g Tr a n sfor m a tion . Syn th eses of
Der iva tives of P yr im id in ylm eth yla m in e, P yr im id in ylm eth yla m in o
Acid Am id es, a n d r-Am in o-2-p yr im id in yla ceta m id es1
Gury Zvilichovsky* and Isra Gbara-Haj-Yahia
Department of Organic Chemistry, The Hebrew University of J erusalem, J erusalem 91904, Israel
gury@vms.huji.ac.il
Received February 17, 2004
The nucleophilic ring opening of the isoxazolone ring in 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine
derivatives by optically active amino acid amides and ephedrine led to pyrimidinylmethylamino
acid amides. Using amides of different L-amino acids and (-)-ephedrine resulted in different degrees
of stereoselectivity. The degree of streoselectivity depended mostly on the nucleophile used. When
applying hydroxy amines such as ephedrine, the attack via the secondary amino group was found
as the favored regioselectivity. Upon replacement of the oxo group in position 2 in the phenylisoxa-
zolo[2,3-a]pyrimidine system by an imino group, it was expected that the spontaneous decarbox-
ylation that follows the ring opening would not take place, thus achieving amino acid amide
derivatives of 2-pyrimidinylacetamide, which are closely related to pyrimidoblamic acid, an
important constituent of Bleomycins, used in cancer therapy. However, by heating 5,7-dimethyl-
2-imino-3-phenylisoxazolo[2,3-a]pyrimidine in solution, it underwent an unprecedented dimerization
process that involved both the phenyl and the imino group. After protecting the imino group by
acetylation, the ring opening by nucleophiles was possible, resulting in the formation of derivatives
of 2-pyrimidinylacetamide. 2-Acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine also
underwent a ring transformation, yielding an interesting indolone derivative. Selectivity in ring
opening and mechanisms of dimerization and ring transformation are discussed.
SCHEME 1
In tr od u ction
The heterocyclic system 2-oxo-3-phenylisoxazolo[2,3-
a]pyrimidine (1) was previously shown to undergo a
nucleophilic ring opening with water and alcohols, fol-
lowed by decarboxylation to produce pyrimidinyl phenyl
methanol derivatives2(Scheme 1). Therefore, the use of
amino acid derivatives as nucleophiles in this reaction
seemed a promising method for the preparation of
interesting pyrimidine derivatives. Derivatives of amino
acids play important roles in many biological systems.3-8
Pyrimidoblamic acid (2) is an important constituent of
Bleomycins, which are used in cancer therapy.9,10
(1) Portions of this investigation have been presented: Zvilichovsky,
G.; Gurvich, V.; Klausner, Y. S.; Gbara, I. The XVIth International
Congress of Heterocyclic Chemistry; Bozeman MT, August 10-15, 1997;
Abstract p POII-302. Zvilichovsky, G.; Gbara, I. The 63rd Meeting of
The Israel Chemical Society; Tel Aviv, Israel February 9-11, 1998;
Abstract p 184. Zvilichovsky, G.; Gbara, I. XVIIIth European Collo-
quium on Heterocyclic Chemistry; Roen, France, October 4-7, 1998; p
B-82.
In the present work various optically active amino acid
amides were heated with derivatives of 2-oxo-3-phenyl-
isoxazolo[2,3-a]pyrimidines (1), resulting in ring opening
by the amino group and subsequent decarboxylation to
produce new pyrimidine amino amides (Scheme 2). A
chiral center is produced in this process, and it was
observed that by using optically active amino amides,
there is a modest stereoinduction to produce different
(2) Zvilichovsky, G.; Gurvich. V. Segev, S. J . Org. Chem. 1995, 60,
5250.
(3) Bell, E. A.; Foster, R G. Nature 1962, 91, 194. Dewar, J . H.;
Shaw, G. J . J . Chem. Soc., Perkin Trans. I 1962, 583.
(4) Shinamo, S.; Kaya, T. J . Agr. Chem. Soc. J pn. 1957, 31, 759.
(5) Krogsgaard-Larsen, P.; Brehm, L.; J ohansen, J . S.; Vinzents, P.;
Lauridsen, J .; Curtis, D. R. J . Med. Chem. 1985, 28, 673.
(6) Madsen, U.; Wong, E. H. F. J . Med. Chem. 1992, 35, 107.
(7) Winkler. D. A.; Holan, G. J . Med. Chem. 1989, 32, 2084.
(8) Vloon, W. J .; Kruk, C.; Pandit, U. K.; Hofs, H. P.; McVie, J . G.
J . Med. Chem. 1987, 30, 20.
(9) Umezawa, Y.; Morishima, H.; Saito, S.; Takita, T.; Umezawa,
H.; Kobayashi, S.; Otsuka, M.; Narita, M.; Ohno, M. J . Am. Chem.
Soc. 1980, 102, 6631.
(10) Stubbe, J .; Kozarich, J . W.Chem. Rev. 1987, 87, 1107.
10.1021/jo0497196 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/26/2004
4966
J . Org. Chem. 2004, 69, 4966-4973

Derivatives of 3-Phenylisoxazolo[2,3-a]pyrimidine
TABLE 1. Exp er im en ta l Con d ition s a n d Resu lts of th e
Rin g Op en in g of 2-oxo-3-p h en ylisoxa zolo[2,3-a ]-
p yr im id in es by L-a m in o Acid Am id es
SCHEME 2
amino
amide of
time
(h)
de
overall
no.
R′
R1 R2
(%) yield (%)
3
4
5
6
7
8
9
Ala
cyclohexyl
H
H
H
H
H
24
36
36
48
72
24
36
36
24
48
36
50
48
32
24
30
15
15
12
9
15
33
33
67
82
60
60
43
50
60
55
66
77
55
76
75
64
65
80
62
50
45
50
61
55
40
69
Ala
Phe
Phe
Phe
Val
Val
cyclohexyl Me
cyclohexyl
cyclohexyl Me
cyclohexyl Me Ph
cyclohexyl Me
cyclohexyl Me Ph
cyclohexyl Me
cyclohexyl Me Ph
H
H
10 Pro
11 Pro
12 Val
13 Val
14 Val
15 Leu
16 Val
17 Val
H
H
H
H
H
Me
Me Ph
Me Ph
Me
H
H
benzyl
benzyl
benzyl
H
Me Ph
Me Ph
18 NR-Boc Lys benzyl
∼100
amounts of the expected diasteromers. Upon replacement
of the oxo group in position 2 in the phenylisoxazolo[2,3-
a]pyrimidine system by an imino group, it was expected
that the spontaneous decarboxylation would not take
place, thus achieving amino acid amide derivatives of
2-pyrimidinylacetamide, which are closely related to
pyrimidoblamic acid (2), which is a pyrimidinylacetamide
derivative as well. The same as in pyrimidoblamic acid
(2), the side chain is linked through the amino group on
the chiral R carbon at position 2 of the pyrimidine ring.
However, by heating 5,7-dimethyl-2-imino-3-phenylisox-
azolo[2,3-a]pyrimidine (27) in solution it underwent an
unprecedented dimerization process that involved both
the phenyl and the imino group. After protecting the
imino group by acetylation, the ring opening by nucleo-
philes was possible resulting in the formation of deriva-
tives of 2-pyrimidinylacetamide. 2-Acetylimino-5,7-di-
methyl-3-phenylisoxazolo[2,3-a]pyrimidine (32) also un-
derwent a ring transformation, yielding an interesting
indolone derivative (45c).
SCHEME 3
shown2,11 that the heterocyclic system (1) is sensitive to
light and oxygen and may react with water. Conditions
of the reaction and results are summarized in Table 1.
Regardless of the structure of the heterocyclic system
(1) and the alkyl group on the amidic nitrogen, L-alanine
and L-phenylalanine derivatives gave only 12-15% di-
asteromeric excess. All valine derivatives and L-leucine
showed a higher selectivity 33-60%. L-Proline and L-
lysine gave the highest selectivity (above 82%).
An example of a further approach to pyrimidoblamic
acid analogues was the introduction of chiral functional
groups at the pyrimidine ring (Scheme 3). The prepara-
tion of 19, which was reacted with N-cyclohexylamide of
L-valine to yield the amino acid ester derivative (20), has
been described earlier.12
Rin g Op en in g of 2-Oxo-3-p h en ylisoxa zolo[2,3-a ]-
p yr im id in es (1) w ith N-Meth yl-2-h yd r oxya m in es.
The isoxazolopyrimidine system (1b) was heated with
(-)-ephedrine (21) under the same conditions. Theoreti-
cally one could get four isomers: two stereoisomers as a
result of interaction through the N-methylamino group
(22, Scheme 4) and two stereoisomers arising from
interaction through the hydroxy group (23, Scheme 4).
In practice only two isomers of ring opening were
observed.
The fact that no traces of more isomers were observed
could lead to one of two conclusions that either the
stereoselectivity is quantitative in both OH and NHMe
interaction or a regiospecific course takes place and the
two products are strereoisomers. Although the NMR
spectra of the two isomers showed significant differences,
it was concluded that they are two stereoisomers (22a
Resu lts a n d Discu ssion
Rin g Op en in g of 2-Oxo-3-p h en ylisoxa zolo[2,3-a ]-
p yr im id in es (1) w ith Am in o Acid Am id es. The reac-
tion between optically active amino acid amides and
derivatives of 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidines
(1) were carried out by reflux in dioxane, resulting in ring
opening by the amino group and subsequent decarbox-
ylation to produce new pyrimidine amino amides (3-18,
Scheme 2). The diasteromeric excess was determined by
NMR of the reaction mixture, e.g., by estimation of the
ratio of the NMR signals of the two isomers. In most cases
it was possible to separate the two stereoisomers on a
silica gel column, using a petroleum ether-ethyl acetate
gradient. The driving force for this reaction is probably
due to both the aromatization of the pyrimidine ring and
the good carboxylate leaving group. The spontaneous
decarboxylation occurs because pyrimidinylacetic acid
undergoes facile decarboxylation, similarly to â-keto
acids. The steric induction is probably due to an interac-
tion between the chiral amide side chain and the pyrim-
idine ring. Pyrimidines are known to interact by both
hydrogen bonding and electronic interactions. The reac-
tion is performed in dry solvents and protected from air
and light. These conditions are necessary because it was
(11) Zvilichovsky, G.; Gurvich, V. J . Org. Chem. 1996, 61, 3212.
(12) Zvilichovsky, G.; Gurvich. V. J . Chem. Soc., Perkin Trans. 1
1997, 1069.
J . Org. Chem, Vol. 69, No. 15, 2004 4967

Zvilichovsky and Gbara-Haj-Yahia
SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
boiling dioxane for periods longer than 18 h, the imino
analogue (27) underwent a much faster transformation,
leaving the nucleophile unchanged. The solution turns
red, and two colored products were detected and sepa-
rated by chromatography: an orange-red product, which
was quite unstable, and another yellow-orange solid.
Considering the reactivity toward nucleophiles (Scheme
1) and the fact that the imino group may function as a
nucleophile, a dimerization was expected leading to the
dimer 28, which was not the case (Scheme 6).
Unexpectedly, upon submission to mass spectrometry
the dimer lacked two hydrogens. In addition, the NMR
spectrum of this yellow product showed only four hydro-
gens for each of the phenyl groups. These findings and
the fact that the ring transformation, described below,
involved an attack of the iminic nitrogen on the phenyl
ring and considering the reactivity of position 3 in 1 and
19 (Scheme 1) allowed us to suggest the structure and
mechanisms for the formation of the dimerization product
(30, Scheme 7).
The mechanisms are not necessarily concerted. The
ionic mechanism is based on the somewhat unexpected
behavior of the phenyl double bond as a vinylog of the
reactive site at position 3 toward nucleophiles (see
Scheme 1). A radical mechanism is possible as well. The
feasibility of a radical mechanism is based on the known
homolytic cleavage of O-acyl picoline N-oxide15 and the
evidence for a free radical cleavage shown16 for interme-
diate (31). The latter may be looked upon as an open
chain analogue of the structure of the oxo and imino
isoxazole moieties in the isoxazolopyrimidine systems, 1,
19, and 27. Referring to both the free radical and the
ionic mechanisms, it seems that a hydrogen acceptor is
necessary for the steps leading from 29 to 30. This might
and 22b) in a 3:4 ratio, which are the result of the attack
of the amino group. To verify this selectivity it was
advisable to react the hetereocyclic system (1b) with the
achiral 2-(N-methylamino)ethanol and see whether only
one product is obtained. The latter experiment resulted
in one product, presumably by the interaction through
the secondary amino group (24, Scheme 5). It is also
assumed that 22a has the S configuration. This assump-
tion is a result of building a hydrogen-bonded model,
showing the influence of the 3D structure on the chemical
shift of both the protons of the C-methyl group and the
proton at the new chiral center. For comparison the chiral
secondary amine (25)13 was used in the reaction with 1b
yielding two stereoisomers 26, without any stereoselec-
tivity (Scheme 5). However, the isomers could be sepa-
rated by column chromatography. The chemical shifts in
the NMR spectra of the two isomers were not as different
from each other as in those derived from ephedrine.
Dim er iza tion of 5,7-Dim eth yl-2-im in o-3-p h en yl-
isoxa zolo[2,3-a ]p yr im id in e. Although the ring opening
of the heterocyclic system (1 and 19) is followed by a
spontaneous decrboxylation, in the imino analogue (27),
which was described earlier,14 the decarboxylation should
not take place. The result of such a ring opening should
lead to pyrimidinylacetamide derivatives, structures
closely related to pyrimidoblamic (2) acid, which is a
pyrimidinylacetamide as well. We tried to heat the imino
derivative 5,7-dimethyl-2-imino-3-phenylisoxazolo[2,3-a]-
pyrimidine (27), with nucleophiles. Whereas the reaction
of 1 or 19 with nucleophiles takes place by heating in
(13) Zvilichovsky, G.; Gbara-Haj-Yahia, I. J . Org. Chem. 2004,
accepted for publication.
(14) Zvilichovsky, G.; David, M. J . Org. Chem. 1983, 48, 575.
(15) Traynelis, V. J .; Martello, R. F. J . Am. Chem. Soc. 1958, 80,
6590.
(16) Cohen, T.; Fager, J . H. J . Am. Chem. Soc. 1965, 87, 6590.
4968 J . Org. Chem., Vol. 69, No. 15, 2004

Derivatives of 3-Phenylisoxazolo[2,3-a]pyrimidine
SCHEME 8
SCHEME 10
SCHEME 9
rimidine (32) was heated with (R)-1-phenylethylamine
and also with (S)-1-phenylethylamine. In both cases two
stereoisomers were obtained in a ratio of 4:1 (Scheme 10).
The diasteromers could be separated by column chroma-
tography. An interesting phenomenon was the pro-
nounced difference in the chemical shifts of the methyl
group, near the amino group, in the two diasteromers.
Whereas in one isomer the chemical shift of this methyl
group was at δ 1.52, in the second isomer it was at δ
0.81. This observed difference could be explained by a
“through space” effect, probably due to a relatively rigid
structure as a result of hydrogen bonding, keeping this
methyl group in a different shielding environment. By
building models and looking at the spatial environment
of the methyl groups, the steric structures of all four
products (37-40) were proposed (Scheme 10).
To show the synthetic applicability to pyrimidine
derivatives related to pyrimidoblamic acid (2), 2-acetyl-
imino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine (32)
was heated with cyclohexylamides of L-alanine and
L-valine. The diastereomeric ratios in these reactions
were 2:1 and 3:1, respectively. As in the case described
above (products 37-40), the alkyl groups of both alanine
and valine segments showed considerable chemical shift
differences within the pairs of diastereomers. This ob-
servation permitted us to try to suggest the spatial
structures of these products (41-44).
be explained by the formation of the unidentified orange-
red product, which could have been involved in ac-
ceptance of hydrogens.
Nu cleop h ilic Rin g Op en in g of th e Isoxa zole Rin g
in 2-Acet ylim in o-5,7-d im et h yl-3-p h en ylisoxa zolo-
[2,3-a ]pyr im idin e. Syn th esis of Der ivatives of r-Am i-
n o-2-p yr im id in yla ceta m id e. To continue in our syn-
thetic studies on the nucleophilic opening of the isoxazole
ring by nucleophiles and avoid the dimerization reaction,
the imino group was acetylated. The driving forces for
the isoxazole ring opening in the carbonyl analogue (1)
are both the good carboxylate ion leaving group and the
aromatization of the pyrimidine ring, as shown in Scheme
1. Therefore we thought that an acetyl group should bring
about enhanced stabilization of the anion produced in a
nucleophilic attack, by extended resonance, as shown in
Scheme 8. Indeed it slowed the dimerization and enabled
the nucleophilic ring opening of the isoxazolone ring.
2-Acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]py-
rimidine (32) reacted with nucleophiles the same way as
the carbonyl derivative (1) and even faster. The absence
of the competing fast reaction also served as a clue for
the assumption that the free imino group has a role in
the competing dimerization process.
The reaction of 32 with water in wet dioxane resulted
in ring opening. The imide group that is formed in the
reaction can undergo hydrolysis in two pathways, leading
either to the known product (36, Scheme 9) by the
spontaneous decarcboxylation of the intermediate 35 or
directly to the pyrmidinylacetamide derivative (34). In
the conditions of the experiment, two products were
isolated, 33 and 34 (Scheme 9). The pyrimidinylaceta-
mide derivative (34) could be crystallized for X-ray
diffraction analysis.
The process of the ring opening brings about the
formation of a new chiral center, and it was of interest
to determine whether this reaction is stereospecific. Thus,
2-acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]py-
Rin g Tr a n sfor m a tion of 2-Acetylim in o-5,7-d i-
m eth yl-3-p h en ylisoxa zolo[2,3-a ]p yr im id in e. When
the nucleophile failed to open the isoxazole ring in
2-acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]py-
J . Org. Chem, Vol. 69, No. 15, 2004 4969

Zvilichovsky and Gbara-Haj-Yahia
2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine derivative (1)10 (1.0
mmol) were refluxed in 1,4-dioxane (25 mL) under dry nitrogen
or argon, protected from light. The progress of the reaction
was monitored by TLC and NMR of aliquots. The period of
heating is reported in Table 1. The solvent was evaporated in
a vacuum. The ratio of diasteroisomers was determined by 1H
NMR of the residue. The residue was subjected to silica gel
column chromatography, and the isomers eluted with ethyl
acetate-petroleum ether gradient. The isomer that came out
first from the column was labeled a and the second as b.
Overall yields and diasteromeric excess are given in Table 1.
Rotations, which are given below, are for products with purity
as shown by NMR. The overall yields include fractions that
consisted of a mixture of diasteromers. All products were
hygroscopic oils or semisolids. Elementary analyses were not
always reliable, so the high-resolution MS is reported in most
of the ring opening products.
SCHEME 11
Data for 3a : yield of isolated isomer 23%. 1H NMR
(CDCl3): δ 8.70 (d, J ) 5.0 Hz, 2H), 7.5-7.3(m, 5H), 7.20(t,
J ) 5.0 Hz, 1H), 5.0 (s, 1H), 3.8 (m, 1H), 3.2 (m, 1H), 1.9-0.9
(m, 10H), 1.36 (d, J ) 6.3 Hz, 3H). 13C NMR (CDCl3, 400
MHz): δ 173.8, 170.6, 157.3, 141.7, 130.9, 128.8, 127.6, 127.2,
rimidine (32), a new rearrangement product of 32 was
observed. It proved to be, by a single-crystal X-ray
diffraction, the ring transformation product (3E)-1-acetyl-
3-(4,6-dimethylpyrimidin-2(1H)-ylidene)-1,3-dihydro-2H-
indol-2-one (45c). The product 45c is one of the tauto-
meric forms of 4,6-dimethylpyrimidin-2-yl)indol-2-ol (45a-
c), and its stability deserves explanation as the aromaticity
of both the pyrimidine and the indole ring are lost. A
proposed mechanism for the transformation of 32 to 45
is outlined in Scheme 11. Both ionic and free radical
mechanisms may be considered.
119.4, 67.4, 57.5, 47.3, 33.0, 25.4, 24.7, 20.2. [R]25 ) +12.9°
D
(CHCl3, c ) 2). ESI-HRMS (MH+/z): 339.2164 (calcd for
C20H26N4O + H 339.2184). Data for 3b: yield of isolated isomer
18%. 1H NMR (CDCl3): δ 8.69 (d, J ) 5.0 Hz, 2H), 7.4-7.2
(m, 5H), 7.1 (d, J ) 5.0 Hz, 1H), 4.96 (s, 1H), 3.7 (m, 1H), 3.2
(m, 1H), 1.8-0.9 (m, 10H), 1.32 (d, J ) 6.3 Hz, 3H). 13C NMR
(CDCl3, 400 MHz): δ 173.7, 170.0, 157.3, 140.6, 128.8, 127.9,
127.5, 119.4, 66.8, 55.2, 47.5, 33.2, 33.1, 25.5, 24.80, 20.2.
[R]25D ) -90.1° (CHCl3, c ) 2). ESI-HRMS (MH+/z): 339.2186
(calcd for C20H26N4O + H 339.2184).
Data for 4a : yield of isolated isomer 30%. 1H NMR
(CDCl3): δ 8.52 (d, J ) 5.1 Hz, 1H), 7.43-7.20 (m, 5H), 7.00
(d, J ) 5.1 Hz, 1H), 4.96 (s, 1H) 3.8 (m, 1H), 3.2 (m, 1H), 2.46
Su m m a r y. The reactivity of position 3 in both the
2-oxo and 2-imino derivatives of 3-phenylisoxazolo[2,3-
a]pyrimidine toward nucleophiles was demonstrated. The
dimerization of the 2-imino derivative (27) and the ring
transformation in the acetylimino derivative (32) show
an extension of this reactivity to the phenyl ring at
position 3. The steric induction that occurs in the ring
opening of the isoxazole ring in these derivatives of
3-phenylisoxazolo[2,3-a]pyrimidine is probably due to an
interaction between the chiral nucleophile and the py-
rimidine ring. The nature of the interaction is most likely
by hydrogen bonding. Pyrimidines are known to interact
by both hydrogen bonding and electronic interactions.
This interaction could be with either the attacking nu-
cleophilic molecule or with surrounding molecules. The
fact that the diasteroselectivity also takes place in the
2-acetylimino derivative (32) eliminates the possibility
that it occurs at the decarboxylation step. The ratio
(s, 3H), 1.87-0.84 (m, 10H), 1.3 (d, J ) 6.9 Hz, 3H). [R]25
)
D
+14.1° (CHCl3, c ) 4). Anal. Calcd for C21H28N4O‚0.5HOH: C,
69.78; H, 8.09. Found: C, 69.53; H, 7.87. Data for 4b: yield of
1
isolated isomer 25%. H NMR (CDCl3): δ 8.54 (d, J ) 5.1 Hz,
1H), 7.48-7.22 (m, 5H), 7.02 (d, J ) 5.1 Hz, 1H), 4.93 (s, 1H)
3.7 (m, 1H), 3.1 (m, 1H), 2.48 (s, 3H), 0.9-1.9 (m, 10H), 1.36
(d, J ) 6.9 Hz, 3H). [R]25D ) -81.8° (CHCl3, c ) 2). Anal. Calcd
for C21H28N4O‚HOH: C, 68.08; H, 8.16. Found: C, 68.23; H,
7.88.
Data for 5a : yield of isolated isomer 20%. 1H NMR
(CDCl3): δ 8.40 (d, J ) 4.8 Hz, 2H), 7.3-7.04(m, 10H), 6.9 (t,
J ) 4.8, Hz, 1H) 4.82 (s, 1H), 3.9 (m, 1H), 3.2 (m, 1H), 3.21
(m, 2H), 1.7-1.0 (m, 10H). [R]25 ) +149°. Anal. Calcd for
D
C
26H30N4O‚HOH: C, 72.19; H, 7.46. Found: C, 72.17; H, 7.43.
1
Data for 5b: yield of isolated isomer 30%. H NMR (CDCl3):
δ 8.47 (d, J ) 4.9 Hz), 7.51-7.10 (m, 10H), 7.02 (t, J ) 4.9 Hz,
1H), 4.85 (s, 1H), 3.70 (m, 1H), 3.38 (m, 1H), 3.19 (dd, J 1
)
13.7 Hz, J 2 ) 3.8 Hz, 2H), 1.77-1.02 (m). [R]25 ) +10.2°
D
1
between the diasteroisomers was determined by the H
(CHCl3, c ) 2). Anal. Calcd for C26H30N4O‚HOH: C, 72.19; H,
NMR signals in the reaction mixtures. The diasteromeric
excess is in most of the cases modest but it was possible
to separate the isomers. Where possible, attempts to
determine the absolute configuration were done by
studying the 1H NMR spectra, because crystals for X-ray
diffraction were not available. It is worthy to note that
when two enantiomeric amines were used as nucleo-
philes, the major products (e.g., 37 and 39) had the same
configuration at the newly produced chiral center as the
reactants.
7.46. Found: C, 71.99; H, 7.68.
Data for 6a : yield of isolated isomer 29%. 1H NMR
(CDCl3): δ 8.45 (d, J ) 5.2 Hz, 1H), 7.45-7.11 (m, 10H), 6.95
(d, J ) 5.2 Hz, 1H), 4.85 (s, 1H), 3.83-3.72 (m, 1H), 2.75-
2.66 (m, 1H), 3.22-3.10 (m, 2H), 2.46 (s, 3H), 1.93-1.10 (m,
10H). [R]25 ) -47.4° (CHCl3, c ) 3). ESI-HRMS (MH+/z):
D
429.2662 (calcd for C27H32N4O + H 429.2654). Anal. Calcd for
C27H32N4O: C, 75.67; H, 7.53. Found: C, 75.61; H, 7.82. Data
for 6b: yield of isolated isomer 36%. 1H NMR (CDCl3): δ 8.29
(d, J ) 5.1 Hz, 1H), 7.34-7.17 (m, 10H), 6.89 (d, J ) 5.1 Hz,
1H), 4.76 (s, 1H), 3.78-3.72 (m, 1H), 3.29-3.27 (m, 1H), 3.18
(dd, J 1 ) 13.7 Hz, J 2 ) 3.8 Hz, 2H), 2.33 (s, 3H), 1.79-0.88
(m, 10H). 13C NMR (CDCl3): δ 172.4, 169.5, 167.1, 156.5, 141.8,
137.5, 129.4, 128.5, 128.4, 127.3, 127.15, 126.6, 118.6, 67.1,
Exp er im en ta l Section
63.2, 47.3, 39.9, 32.9, 32.8, 25.4, 24.6, 24.1. [R]25 ) +91.2°
Gen er a l P r oced u r e for Rea ction of 2-oxo-3-p h en yl-
isoxa zolo[2,3-a ]p yr im id in es (1) w ith Am id es of Am in o
Acid s. An amino acid amide (1.1 mmol) and a derivative of
D
(CHCl3, c ) 2). ESI-HRMS (MH+/z): 429.2620 (calcd for
C27H32N4O + H 429.2654).
4970 J . Org. Chem., Vol. 69, No. 15, 2004

Derivatives of 3-Phenylisoxazolo[2,3-a]pyrimidine
Data for 7a : yield of isolated isomer 41%. 1H NMR
(CDCl3): δ 8.02-7.98 (m, 2H), 7.54-6.95 (m, 14H), 4.87 (s,
1H), 3.84-3.80 (m, 1H), 3.27-3.2 (m, 2H), 2.75-2.66 (m, 1H),
2.4 (s, 3H), 1.6-1.0 (m, 10H). 13C NMR (CDCl3): δ 172.4, 169.2,
167.9, 163.3, 139.9, 137.7, 136.6, 130.8, 129.6, 128.8, 128.6,
128.3, 127.8, 127.4, 127.1, 126.8, 114.1, 66.3, 60.1, 47.6, 39.9,
33.2, 33.0, 25.5, 24.8, 24.4. [R]25D ) -22.1° (CHCl3, c ) 4). ESI-
HRMS (MH+/z): 505.2959 (calcd for C33H36N4O + H 505.2967).
(d, J ) 6.9 Hz, 3H), 0.99 (d, J ) 6.9 Hz, 3H). Anal. Calcd for
C16H20N4O‚0.5HOH: C, 65.51; H, 7.22. Found: C, 65.23; H,
7.05.
Data for 13a : yield of isolated isomer 25%. 1H NMR
(CDCl3): δ 8.43 (d, J ) 5.0 Hz, 1H), 7.33 (d, J ) 7.8 Hz, 2H),
7.24-7.08 (m, 3H), 6.92 (d, J ) 5.0 Hz, 1H), 5.82 (br s, 1H),
4.84 (s, 1H), 2.78 (d, J ) 3.9 Hz, 1H), 2.42 (s, 3H), 2.09-2.01
(m, 1H), 0.91 (d, J ) 6.9 Hz, 6H). [R]25 ) -10.8° (CHCl3, c )
D
1
Data for 7b: yield of isolated isomer 41%. H NMR (CDCl3):
3). Anal. Calcd for C17H22N4O‚HOH: C, 64.53; H, 7.65.
Found: C, 74.79; H, 7.70.
δ 7.82-7.80 (m, 2H), 7.5-7.0 (m, 14H), 4.79 (s, 1H), 3.7 (m,
1H), 3.1 (m, 1H), 2.65 (m, 2H), 2.42 (s, 3H), 1.7-0.9 (m, 10H).
[R]25D ) -86.7° (CHCl3, c ) 2). ESI-HRMS (MH+/z): 505.2913
(calcd for C33H36N4O + H 505.2967).
Data for 14a : yield of isolated isomer 20%. 1H NMR
(CDCl3): δ 8.1-8.07 (m, 2H), 7.73-7.14 (m, 8H), 7.41 (s, 1H),
5.88 (d, J ) 4.4 Hz, 1H), 5.00 (s, 1H), 2.94 (d, J ) 4.4 Hz, 1H),
Data for 8a : yield of isolated isomer 18%. 1H NMR
(CDCl3): δ 8.44 (d, J ) 5.1 Hz, 1H), 7.33-7.13(m, 5H), 6.92
(d, J ) 5.1 Hz, 1H) 4.74 (s, 1H), 3.8 (m, 1H), 2.8 (d, J ) 4.0
Hz, 1H), 2.35 (s, 3H), 2.1-0.8 (m, 11H), 0.91 (d, J ) 7.0 Hz,
3H), 0.87 (d, J ) 7.0 Hz, 3H). ESI-HRMS (MH+/z): 381.2651
(calcd for C21H28N4O + H 381.2654). Anal. Calcd for C23H32N4O‚
0.5HOH: C, 70.92; H, 8.54. Found: C, 71.07; H, 8.48. Data
for 8b: yield of isolated isomer 37%. 1H NMR (CDCl3): δ 8.52
(d, J ) 5.1 Hz, 1H), 7.40-7.21 (m, 5H), 7.00 (d, J ) 5.1 Hz,
1H) 4.81 (s, 1H), 3.83-3.71 (m, 1H), 2.87 (d, J ) 3.9 Hz, 1H),
2.50 (s, 3H), 2.1-0. 99 (m, 11H), 0.98 (d, J ) 7.0 Hz, 3H), 0.94
(d, J ) 7.0 Hz, 3H). 13C NMR (CDCl3): δ 172.3, 170.0, 167.2,
156.7, 142.1, 128.6, 127.3, 127.2, 118.9, 67.1, 67.1, 47.2, 33.3,
2.54 (s, 3H), 2.03 (m, 1H), 0.92 (d, J ) 6.9 Hz, 6H). [R]25
)
D
+7.39ï (CHCl3, c ) 2). Anal. Calcd for C23H25N4O‚HOH: C,
70.38; H, 7.19. Found: C, 71.00; H, 7.16.
Data for 15a : yield of purified mixture of two isomers 39%.
1H NMR (CDCl3): δ 8.11-7.24 (m, 15H), 7.42 (s, 1H), 4.90 (s,
1H), 4.35 (m, 2H), 3.2 (m, 1H), 2.55 (s, 3H), 1.8-1.4 (m, 3H),
0.94 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H). Anal. Calcd
for C31H34N4O: C, 77.79; H, 7.16; N, 11.71. Found: C, 77.42;
H, 7.41; N, 11.37. Data for 15b: as seen in the mixture. 1H
NMR (CDCl3): δ 8.11-7.24 (m, 15H), 7.42 (s, 1H), 5.0 (s, 1H),
4.35 (m, 2H), 3.2 (m, 1H), 2.52 (s, 3H), 1.8-1.4 (m, 3H), 0.69
(d, J ) 6.4 Hz, 3H), 0.65 (d, J ) 6.4 Hz, 3H).
Data for 16a : yield of isolated isomer 11%. 1H NMR
(CDCl3): δ 8.52 (d, J ) 5.1 Hz, 1H), 7.68 (t, J ) 5.7 Hz, 2H),
7.32-7.21 (m, 10H), 7.00 (d, J ) 5.1 Hz, 1H), 4.83 (s, 1H),
4.43 (A of double AB system, J ) 14.7, 5.7 Hz, 1H), 4.36 (B of
double AB system, J ) 14.7, 5.7 Hz, 1H), 2.97 (d, J ) 4.15 Hz,
1H), 2.50 (s, 3H), 2.18 (m, 1H), 1.00 (d, J ) 7.0 Hz, 3H), 0.96
(d, J ) 7.0 Hz, 3H). 13C NMR (CDCl3): δ 173.4, 169.9, 167.2,
156.7, 141.9, 138.5, 128.6, 128.5, 127.8, 127.5, 127.3, 127.2,
32.8, 31.4, 25.5, 24.7, 24.6, 24.1, 19.8, 17.4. [R]26 ) -75.4°
D
(CHCl3, c ) 1). ESI-HRMS (MH+/z): 381.2622 (calcd for
C
23H32N4O + H 381.2654).
Data for 9a : yield of isolated isomer 28%. 1H NMR
(CDCl3): δ 8.1 (m, 2H), 7.5-7.2 (m, 9H), 4.83 (s, 1H), 3.9 (m,
1H), 2.9 (m, 1H), 2.5 (s, 3H), 2.2-0.9 (m, 17H), [R]25D ) -208°
(CHCl3, c ) 2). Anal. Calcd for C29H36N4O‚0.5HOH: C, 74.80;
H, 8.01. Found: C, 74.82; H, 8.33. ESI-HRMS (MH+/z):
457.2955 (calcd for C29H36N4O + H 457.2967). Data for 9b:
yield of isolated isomer 16%. 1H NMR (CDCl3): δ 8.0 (m, 2H),
7.4-7.1 (m, 9H), 4.88 (s, 1H), 3.8 (m, 1H), 2.8 (m, 1H), 2.48 (s,
3H), 2.12-0.80 (m, 17H). [R]25D ) +10.3° (CHCl3, c ) 2). Anal.
Calcd for C29H36N4O‚0.5HOH: C, 74.80; H, 8.01. Found: C,
74.50; H, 7.94. ESI-HRMS (MH+/z): 457.2943 (calcd for
118.9, 67.4, 67.3, 42.9, 31.6, 24.1, 19.8, 17.8. [R]25 ) -50.91°
D
(CHCl3, c ) 2). Anal. Calcd for C30H32N4‚0.5HOH: C, 76.11;
H, 6.98; Found: C, 76.38; H, 7.23.
Data for 17a : yield of isolated isomer 39%. 1H NMR
(CDCl3): δ 8.09 (dd, J 1 ) 6.4 Hz, J 2 ) 2.8 Hz, 2H), 7.74 (t,
J ) 5.7 Hz, 1H), 7.52-7.21(m, 11H), 7.46 (s, 1H), 4.95 (s, 1H),
4.49 (A of double AB system, J ) 14.7, 5.7 Hz, 1H), 4.40 (B of
double AB system, J ) 14.7, 5.7 Hz, 1H), 3.08 (d, J ) 4.2 Hz,
1H), 2.59 (s, 3H), 2.39 (m, 1H), 1.00 (d, J ) 6.9 Hz, 3H), 0.99
(d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3): δ 173.5, 169.9, 167.7,
163.6, 142.0, 138.43, 136.6, 130.8, 128.8, 128.6, 128.5, 127.8,
127.3, 127.2, 127.1, 127.1, 114.3, 67.4, 67.3, 43.0, 31.6, 24.3,
19.8, 17.9. ESI-HRMS (MH+/z): 465.2645 (calcd for C30H32N4-
O + H 465.2654). Data for 17b: Only traces of isolated isomer.
Data for 18: overall yield, one isomer 69%. 1H NMR
(CDCl3): δ 8.06 (m, 2H), 7.61-7.16 (m, 13H), 7.34 (s, 1H), 6.82
(br s, 1H), 5.23 (t, J ) 5.7 Hz, 1H), 5.06 (s, 1H), 4.34-4.29 (m,
2H), 4.11-4.06 (m, 1H), 2.70-2.54 (m, 3H), 2.51 (s, 3H), 1.81-
1.52 (m, 5H), 1.38 (s, 9H). 13C NMR (CDCl3): δ 172.0, 169.8,
167.8, 163.7, 163.7, 141.0, 138.0, 136.8, 130.9, 128.8, 128.5,
128.4, 127.7, 127.4, 127.4, 127.2, 127.1, 114.3, 68.1, 68.0, 47.0,
C
29H36N4O + H 457.2967).
Data for 10a : yield of isolated isomer 43%. 1H NMR
(CDCl3): δ 8.47 (d, J ) 5.0 Hz, 1H), 7.5-7.2 (m, 5H), 6.95 (d,
J ) 5.0 Hz, 1H), 5.04 (s, 1H), 3.61-3.57 (m, 2H), 3.01 (m, 1H),
2.4 (m, 4H), 2.1-0.9 (m, 14H). [R]25 ) -207° (CHCl3, c ) 2).
D
ESI-HRMS (MH+/z): 379.2491 (calcd for C23H30N4O + H
379.2497). Data for 10b: yield of isolated isomer 12%. 1H NMR
(CDCl3): δ 8.59 (d, J ) 5.0 Hz, 1H), 7.44-7.24 (m, 5H), 7.04
(d, J ) 5.0 Hz, 1H) 5.09 (s, 1H), 3.8 (m, 1H), 3.8 (m, 1H), 3.0
(m, 2H), 2.4 (s, 3H), 2.2-0.9 (m, 14H). [R]25D ) -62.4° (CHCl3,
c ) 1).
Data for 11a : yield of isolated isomer 11%. 1H NMR
(CDCl3): δ 8.01-6.80 (m, 10H), 7.34 (s, 1H), 5.14 (s, 1H), 3.7
(dd, J 1 ) 8.8 Hz, J 2 ) 2.9 Hz, 1H), 3.53-3.40 (m, 1H), 3.1-
3.04 (m, 1H), 2.5 (s, 3H), 2.56-2.53 (m, 1H), 2.1-0.9 (m, 12H).
13C NMR (CDCl3): δ 174.0, 169.6, 167.4, 163.8, 139.9, 136.9,
130.5, 129.3, 128.7, 128.0, 127.5, 127.2, 114.4, 74.6, 64.2, 52.98,
47.3, 32.9, 32.2, 30.5, 25.3, 24.6, 24.5, 24.4, 24.3. ESI-HRMS
(MH+/z): 455.2782 (calcd for C29H34N4O + H 455.2810). Data
for 11b: yield of isolated isomer 39%. 1H NMR (CDCl3): δ
43.2, 32.3, 29.14, 28.2, 24.3, 23.1. [R]25 ) +8.11° (CHCl3, c )
D
4). ESI-HRMS (MH+/z): 594.3398 (calcd for C36H43N5O3 + H
594.3444).
Rea ction betw een Meth yl (S)-N-Ben zoyl-2-(5-m eth yl-
2-oxo-3-p h e n ylisoxa zolo[2,3-a ]p yr im id in -7-yl)a la n i-
n a te (19) a n d L-N-Cycloh exylva lin a m id e. Methyl (S)-N-
benzoyl-2-(5-methyl-2-oxo-3-phenylisoxazolo[2,3-a]pyrimidin-
7-yl)alaninate12 (19) (0.08 g, 0.19 mmol) was dissolved in
dioxane (10 mL). L-N-Cyclohexylvalinamide (0.042 g, 0.21
mmol) was added, and the mixture was refluxed in the
conditions described above for 18 h. The reaction was moni-
tored by TLC and NMR of aliquots. The solvent was removed
8.02-7.23 (m, 10H), 7.36 (s, 1H), 5.13 (s, 1H), 3.8 (dd, J 1
)
8.8 Hz, J 2 ) 3.0 Hz, 1H), 3.51-3.39 (m, 1H), 3.11-3.04 (m,
1H), 2.61-2.53 (m, 1H), 2.52 (s, 3H), 2.1-1.09 (m, 14H). 13C
NMR (CDCl3): δ 174.1, 169.7, 167.5, 163.9, 140.0, 137.1, 130.6,
129.4, 128.7, 128.1, 127.5, 127.3, 114.5, 74.7, 64.3, 53.1, 47.4,
33.0, 32.3, 30.5, 25.4, 24.6, 24.6, 24.5, 24.4. [R]25 ) -91.55
D
(CHCl3, c ) 4). ESI-HRMS (MH+/z): 455.2806 (calcd for
by evaporation in
a vacuum. The ratio of isomers was
C
29H34N4O + H 455.2810).
determined by NMR (3:2), and the residue was loaded on silica
gel column and eluted with ethyl acetate-petroleum ether
gradient (40-100%). First eluted isomer, 20a (0.2 g of isolated
Data for 12a : yield of isolated isomer 62%. 1H NMR
(CDCl3): δ 8.70 (d, J ) 4.9 Hz, 2H), 7.39 (d, J ) 7.1 Hz, 2H),
7.29 (t, J ) 7.1 Hz, 2H), 7.26-7.12 (m, 4H), 5.64 (br s, 1H),
4.97 (s, 1H), 2.89 (d, J ) 4.4 Hz, 1H), 2.21-2.09 (m, 1H), 1.00
1
isomer, 43% isolated yield). H NMR (CDCl3): δ 8.54 (d, J )
5.1 Hz, 1H), 7.63 (dd, J 1 ) 6.99 Hz, J 2 ) 1.41 Hz, 2H), 7.48-
J . Org. Chem, Vol. 69, No. 15, 2004 4971

Zvilichovsky and Gbara-Haj-Yahia
7.19 (m, 8H), 7.00 (d, J ) 5.1 Hz, 1H), 6.89 (d, J ) 8.1 Hz,
1H), 5.20 (dt, J 1 ) 8.1 Hz, J 2 ) 4.6 Hz, 1H), 4.85 (s, 1H), 3.70
(m, 1H), 3.68 (s, 3H), 3.57 (A of double AB system, J ) 16.6,
4.6 Hz, 1H), 3.57 (B of double AB system, J ) 16.6, 4.6 Hz,
1H), 2.79 (d, J ) 4.9 Hz, 1H), 1.8-0.9 (m, 11H, 10H), 0.92 (d,
J ) 6.0 Hz, 3H), 0.91 (d, J ) 6.0 Hz, 3H). 13C NMR (CDCl3):
δ 172.0, 171.7, 170.1, 166.7, 166.2, 157.2, 133.4, 131.7, 128.7,
128.5, 127.5, 127.2, 126.9, 119.4, 67.6, 67.42, 4.99, 33.2, 32.8,
31.5, 25.5, 24.7, 19.6, 17.7. [R]25D) +11.2° (CHCl3, c ) 1) ESI-
HRMS (MH+/z): 594.3022 (calcd for C33H40N5O4 + Na 594.3056).
7.23-7.15 (m, 3H), 6.86 (d, J ) 5.1 Hz, 1H), 5.57 (br s, 2H),
5.29 (br s, 1H), 4.89 (s, 1H), 2.82 (m, 1H), 2.58 (m, 2H), 2.43
(s, 3H), 2.33 (m, 4H), 2.08 (s, 3H), 0.96 (d, J ) 6.6 Hz, 3H).
Anal. Calcd for C22H27N3: C, 79.24; H, 8.16; N, 12.60. Found:
C, 79.39; H, 7.91; N, 12.51. Second isomer, 26b (0.084 g of
isolated isomer, hygroscopic oil, 18% yield). 1H NMR (CDCl3):
δ 8.53 (d, J ) 5.1 Hz, 1H), 7.61 (dd, J 1 ) 7.8 Hz, J 2 ) 1.2 Hz,
2H), 7.28-7.18 (m, 3H), 6.92 (d, J ) 5.1 Hz, 1H), 5.60 (br s,
2H), 5.31 (br s, 1H), 4.89 (s, 1H), 2.89-2.84 (m, 1H), 2.64-
2.59 (m, 2H), 2.47 (s, 3H), 2.37-2.32 (m, 4H), 2.10 (s, 3H), 0.87
(d, J ) 6.3 Hz, 3H). Anal. Calcd for C22H27N3‚0.5HOH: C,
77.15; H, 8.24; N, 12.27. Found: C, 77.38; H, 7.97; N, 12.49.
1
Second isomer, 20b (37% isolated yield). H NMR (CDCl3): δ
8.57 (d, J ) 5.1 Hz, 1H), 7.48 (dd, J 1 ) 8.3 Hz, J 2 ) 1.32 Hz,
2H), 7.48-7.22 (m, 9H), 7.01 (d, J ) 5.1 Hz, 1H), 5.15 (dt,
J 1 ) 7.5 Hz, J 2 ) 4.9 Hz, 1H), 4.76 (s, 1H), 3.70 (m, 1H), 3.66
(s, 3H), 3.50 (A of double AB system, J ) 16.2, 4.9 Hz, 1H),
3.40 (B of double AB system, J ) 16.2, 4.9 Hz, 1H), 2.81 (d,
J ) 4.2 Hz, 1H), 2.0-0.89 (m, 11H), 0.93 (d, J ) 7.0 Hz, 3H),
0.89 (d, J ) 7.0, Hz, 3H). 13C NMR (CDCl3): δ 172.1, 171.9,
169.7, 166.9, 166.4, 157.1, 140.5, 133.6, 131.8, 128.7, 128.6,
127.8, 127.7, 127.1, 119.3, 67.2, 65.2, 52.6, 50.4, 47.45, 37.9,
33.4, 33.2, 31.4, 25.5, 24.8, 19.5, 18.1. [R]25D ) +26.06° (CHCl3,
c ) 2) ESI-HRMS (MH+/z): 594.3029 (calcd for C33H40N5O4 +
Na 594.3056).
Rea ction betw een 5-Meth yl-2-oxo-3-p h en ylisoxa zolo-
[2,3-a ]p yr im id in es (1b) a n d (-)-Ep h ed r in e. (-)-Ephedrine
(0.16 g, 0.97 mmol was dissolved in dry dioxane (15 mL).
5-Methyl-2-oxo-3-phenylisoxazolo[2,3-a]pyrimidines (1b) (0.2
g, 0.87 mmol) was added, and the mixture was refluxed in the
conditions described above for 24 h. The solvent was removed
Dim er iza tion of 5,7-Dim eth yl-2-im in o-3-p h en ylisox-
a zolo[2,3-a ]p yr im id in e (27). F or m a tion of 30. 5,7-Dimeth-
yl-2-imino-3-phenylisoxazolo[2,3-a]pyrimidine (27)14 (0.22 g,
0.78 mmol) was dissolved in dry dioxane (10 mL). The solution
was refluxed for 2 h. After sitting overnight at room temper-
ature an orange solid precipitated. The solid proved to be by
TLC a mixture of two products. Separation by silica gel column
resulted in a red product (0.08 g, dec 260-265°), which came
first out of the column. 1H NMR of the red product (300 MHz,
DMSO-d6): δ 11.42 (br s, 1H, NH), 7.96 (d, J ) 7.5 Hz, 2H,
o-Ph), 7.35 (t, J ) 7.5 Hz, 2H, m-Ph), 7.12 (t, J ) 7.5 Hz, 1H,
p-Ph), 5.85 (s, 1H), 2.59 (s, 3H), 2.20 (s, 3H). Also eluted was
a yellow product (30, 0.09 g, mp 283°). 1H NMR (300 MHz,
DMSO-d6): δ 10.48 (s, 2H), 7.84 (m, 2H), 6.93-6.88 (m, 6H,
Ph), 6.54 (s, 2H, pyrimidine), 2.43 (s, 12H). 13C NMR (300 MHz,
DMSO-d6): δ 169.2, 154.7, 134.0, 124.9, 120.6, 119.7, 118.6,
108.4, 107.7, 86.4. ESI-HRMS (MH+/z): 477.2030 (calcd for
by evaporation in
a vacuum. The ratio of isomers was
C
28H24N6O2 + H 477.2038).
determined by NMR, and the residue was loaded on a silica
gel column and eluted with ethyl acetate-petroleum ether
gradient. The two isomers came too close to one another and
could not be separated. However, because of the different
amounts, the 1H NMR could be assigned for each of the two
isomers. Data for isomer 22a . 1H NMR (CDCl3): δ 8.57 (d,
J ) 5.1 Hz, 1H), 7.61 (d, J ) 7.1 Hz, 2H), 7.39-7.21 (m, 6H),
7.00 (d, J ) 5.1 Hz, 1H), 4.99 (s, 1H), 4.58 (d, J ) 3.7 Hz, 1H),
3.19 (m, 1H), 2.57 (s, 3H), 1.72 (s, 3H), 1.07 (d, J ) 7.0 Hz,
3H). Data for 22b. 1H NMR (CDCl3): δ 8.60 (d, J ) 5.1 Hz,
1H), 7.45 (d, J ) 7.4 Hz, 2H), 7.39-7.21 (m, 6H), 7.10 (d, J )
5.1 Hz, 1H), 5.41 (s, 1H), 4.93 (d, J ) 3.1, 1H), 3.20 (m, 1H),
2.57 (s, 3H), 2.30 (s, 3H) 0.88 (d, J ) 7.0 Hz, 3H). ESI-HRMS
(MH+/z): 370.1875 (calcd for C22H25N3O + Na 370.1895).
Rea ction betw een 5-Meth yl-2-oxo-3-p h en ylisoxa zolo-
[2,3-a ]p yr im id in es (1b ) a n d 2-(Met h yla m in o)et h a n ol.
2-(Methylamino)ethanol (0.08 g, 0.96 mmol) was dissolved in
dioxane (10 mL). 5-Methyl-2-oxo-3-phenylisoxazolo[2,3-a]py-
rimidines (1b) (0.2 g, 0.87 mmol) was added, and the mixture
was refluxed in conditions described above for 18 h. The
solvent was removed by evaporation in a vacuum. The residue
was purified on silica gel column, eluted with ethyl acetate-
petroleum ether gradient, yield 0.13 g of 24 (oil, 57%). 1H NMR
(CDCl3): δ 8.53 (d, J ) 5.1 Hz, 1H), 7.49 (dd, J 1 ) 8.3 Hz,
J 2 ) 1.4 Hz, 2H), 7.32-7.23 (m, 3H), 6.99 (d, J ) 5.1 Hz, 1H),
4.83 (s, 1H), 3.70-3.54 (m, 2H), 2.66-2.48 (m, 2H), 2.55 (s,
3H), 2.27 (s, 3H). 13C NMR (CDCl3): δ 170.1, 167.5, 156.9,
139.89, 129.0, 128.3, 127.6, 118.8, 59.1, 56.5, 40.2, 24.1. ESI-
HRMS (MH+/z): 280.1411 (calc for C15H19N3O + Na 280.1425).
2-Acetylim in o-5,7-d im eth yl-3-p h en ylisoxa zolo[2,3-a ]-
p yr im id in e (32). 5,7-Dimethyl-2-imino-3-phenylisoxazolo[2,3-
a]pyrimidine14 (27, 0.3 g, 1.25 mmol) was dissolved in acetic
anhydride (1 mL). After 10 min a yellow precipitate appeared.
The mixture was stirred for additional 1 h at room tempera-
ture, the precipitate collected and washed with ether, mp 138°
(0.31 g, 88%). 1H NMR (CDCl3): δ 8.31 (d, J ) 7.6 Hz, 2H),
7.39 (t, J ) 7.6 Hz, 2H), 7.21 (t, J ) 7.6 Hz, 1H), 6.34 (s, 1H),
2.59 (s, 3H), 2.51 (s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3): δ
178.9, 169.7, 161.9, 151.2, 145.7, 129.3, 128.0, 126.7, 126.1,
107.6, 88.6, 27.8, 25.2, 15.4. Anal. Calcd for C16H15N3O2: C,
68.31; H, 5.37; N, 14.94. Found: C, 68.33; H, 5.42; N, 14.57.
Rea ction of 2-Acetylim in o-5,7-d im eth yl-3-p h en ylisox-
a zolo[2,3-a ]p yr im id in e (32) w ith Wa ter . 2-Acetylimino-5,7-
dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine (32, 0.2 g, 0.7
mmol) was dissolved in dioxane (9 mL), water was added (0.5
mL), and the solution was refluxed for 3 h. The solvent was
evaporated, and the residue was loaded on a silica gel column.
The column was eluted with petroleum ether-ethyl acetate
gradient. Two products were isolated, the ring opening product
(33) and its hydrolysis product (34). Ring opening product
1
(33): mp 116° (0.1 g, 50%). H NMR (CDCl3): δ 7.88 (d, J )
8.1 Hz, 2H), 7.39-7.31 (m, 3H), 7.02 (s, 1H), 6.65 (br s, 1H),
2.54 (s, 6H), 2.46 (s, 3H). 13C NMR (CDCl3): δ 172.2, 169.7,
167.0, 164.6, 138.9, 128.0, 127.7, 126.7, 119.3, 79.7, 24.9, 23.7.
Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04.
Found: C, 63.98; H, 5.79; N, 13.96. Data for 34: mp 132° (0.05
1
g, 27%). H NMR (CDCl3): δ 7.77 (dd, J 1 ) 6.60 Hz, J 2 ) 1.75
Hz, 2H), 7.32-7.26 (m, 3H), 6.97 (s, 1H), 6.45 (br s, 1H), 2.51
(s, 6H). Structure determined by single-crystal X-ray diffrac-
tion. Crystallographic protocol and data are included in
Supporting Information.
Rea ction betw een 5-Meth yl-2-oxo-3-p h en ylisoxa zolo-
[2,3-a ]p yr im id in es (1b) a n d (S)-2-(Cycloh exa d ien -1-yl)-
N-m et h yl-2-p r op a n a m in e. (S)-2-(Cyclohexadien-1-yl)-N-
methyl-2-propanamine13 (0.21 g, 1.39 mmol) was dissolved in
dioxane (15 mL). 5-Methyl-2-oxo-3-phenylisoxazolo[2,3-a]py-
rimidines (1b) (0.28 g, 1.24 mmol) was added, and the mixture
was refluxed in the conditions described above for 18 h. The
solvent was removed by evaporation in a vacuum. The ratio
of isomers was determined by NMR, and the residue was
loaded on a silica gel column and eluted with ethyl acetate-
petroleum ether gradient (20-60%). First eluted isomer, 26a
Rea ction of 2-Acetylim in o-5,7-d im eth yl-3-p h en ylisox-
a zolo[2,3-a ]p yr im id in e (32) w ith Am in es a n d Am in o
Am id es. 2-acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]-
pyrimidine (32, 0.2 g, 0.7 mmol) was dissolved in dioxane (10
mL), the amine or amino amide (0.77 mmol) was added, and
the solution was refluxed for 2-4 h. The disappearance of 32
was monitored by TLC. The solvent was removed, and the
residue was loaded on a silica gel column and eluted with
petroleum ether-ethyl acetate gradient.
1
(0.2 g of isolated isomer, 43% yield). H NMR (CDCl3): δ 8.51
(d, J ) 5.1 Hz, 1H), 7.61 (dd, J 1 ) 7.5 Hz, J 2 ) 1.5 Hz, 2H),
4972 J . Org. Chem., Vol. 69, No. 15, 2004

Derivatives of 3-Phenylisoxazolo[2,3-a]pyrimidine
Data for 37: oil (45%). 1H NMR (CDCl3, 400 MHz): δ 10.06
(br d, J ) 6.7 Hz, 1H), 7.09-7.34 (m, 10H), 6.99 (s, 1H), 4.63-
4.60 (m, 1H), 2.31 (s, 6H), 2.29 (s, 3H), 0.81 (d, J ) 6.8 Hz,
3H). 13C NMR (CDCl3, 400 MHz): δ 171.6, 168.1, 167.7, 154.2,
143.3, 137.7, 129.1, 128.9, 128.8, 128.3, 127.9, 126.7, 119.5,
63.4, 50.9, 24.3, 24.1, 20.5. ESI-HRMS (MH+/z): 403.2131
(calcd for C24H26N4O2 + H 403.2133).
δ 171.2, 169.5, 167.5, 167.4, 155.4, 136.9, 128.4, 128.1, 127.8,
119.1, 62.8, 61.0, 48.1, 33.1, 33.0, 30.3, 25.4, 24.7, 23.9, 23.9,
18.8, 18.3. ESI-HRMS (MH+/z): 502.2787 (calcd for C27H37N5-
O3 + Na 502.2794).
(3E)-1-Acetyl-3-(4,6-d im eth ylp yr im id in -2(1H)-ylid en e)-
1,3-d ih yd r o-2H-in d ol-2-on e (45c). This product was ob-
tained upon heating of 2-acetylimino-5,7-dimethyl-3-phenyl-
Data for 38: oil (22%). 1H NMR (CDCl3, 400 MHz): δ 10.09
(br d, J ) 6.4 Hz, 1H), 7.26-7.05 (m, 10H), 6.97 (s, 1H), 4.60-
4.53 (m, 1H), 2.44 (s, 6H), 2.29 (s, 3H), 1.52 (d, J ) 6.9 Hz,
3H). 13C NMR (CDCl3, 400 MHz): δ 171.1, 167.7, 167.1, 154.1,
142.0, 136.5, 128.5, 128.4, 128.3, 127.7, 127.1, 126.4, 118.93,
62.8, 50.8, 23.8, 23.7, 21.7. ESI-HRMS (MH+/z): 403.2133
(calcd for C24H26N4O2 + H 403.2133).
isoxazolo[2,3-a]pyrimidine (32) with (-)-ephedrine as
a
nucleophile; 0.13 g of 32 (0.45 mmol) was heated in boiling
dioxane (10 mL) with (-)-ephedrine (0.08 g, 0.45 mmol) for
10 h. The solvent was evaporated. Upon silica gel column
chromatography (as above), ephedrine was recovered un-
changed. In one of the fractions, red crystal separated upon
1
concentration: mp 185° (0.05 g). H NMR (CDCl3): δ 8.31 (d,
Data for 39: hygroscopic oil (50%). 1H NMR (300 MHz,
CDCl3): δ 10.10 (br d, J ) 6.6 Hz, 1H), 7.35-7.09 (m, 10H),
6.99 (s, 1H), 4.62 (m, 1H), 2.32 (s, 6H), 2.30 (s, 3H), 0.81 (d,
J ) 6.6 Hz, 3H). Anal. Calcd for C24H26N4O2‚1.5 H2O: C, 67.11;
H, 6.81; N, 13.05. Found: C, 66.85; H, 6.91; N, 12.88.
J ) 7.5 Hz, 1H), 8.16 (d, J ) 7.50 Hz, 1H), 7.22 (t, J ) 7.5 Hz,
1H), 7.12 (t, J ) 7.5 Hz, 1H), 6.35 (s, 1H), 2.8 (s, 3H), 2.56 (s,
3H), 2.46 (s, 3H).
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of 45c. A
single crystal was coated with vaseline, attached to a glass
fiber, and transferred to a Bruker SMART APEX CCD X-ray
diffractometer system controlled by a pentium-based PC
running the SMART software package.1 The crystal was
mounted on the three-circle goniometer with ø fixed at +54.72°
and was rapidly cooled to -150 °C with a Bruker KRYOFLEX
nitrogen cryostat. The diffracted graphite-monochromated Mo
KR radiation (λ ) 0.71073 Å) was detected on a phosphor
screen held at a distance of 6.0 cm from the crystal operating
at -44 °C. A detector array of 512 × 512 pixels, with a pixel
size of approximately 120 µm, was employed for data collection.
The detector centroid and crystal-to-detector distance were
1
Data for 40: mp 188° (33%). H NMR (300 NHz, CDCl3): δ
10.10 (br d, J ) 6.3 Hz, 1H), 7.26-7.05 (m, 10H), 6.97 (s, 1H),
4.56 (m, 1H), 2.44 (s, 6H), 2.32 (s, 3H), 1.52 (d, J ) 6.9 Hz,
3H). Anal. Calcd for C24H26N4O2: C, 71.62; H, 6.51; N, 13.92.
Found: C, 71.53; H, 6.49; N, 13.76.
Data for 41 and 42: oil (72%). Major isomer in the
1
inseparable mixture H NMR (300 MHz, CDCl3): δ 10.52 (br
d, J ) 6.9 Hz, 1H), 7.24-7.16 (m, 5H), 6.98 (s, 1H), 5.50 (d,
J ) 7.5 Hz, 1H), 4.08 (q, J ) 7.0 Hz, 1H), 3.53-3.48 (m, 1H),
2.53 (s, 6H), 2.25 (s, 3H), 1.81-1.14 (m, 11H), 0.76 (d, J ) 7.0
Hz). Minor isomer in the inseparable mixture 1H NMR (300
MHz, CDCl3): δ 10.32 (br d, J ) 7.2 Hz, 1H), 7.04-6.9 (m,
5H), 6.95 (s, 1H), 6.17 (br d, J ) 8.1 Hz, 1H), 3.76 (q, J ) 7.0
Hz, 1H), 3.74-3.67 (m, 1H), 2.52 (s, 6H), 2.25 (s, 3H), 1.81-
1.14 (m, 11H), 1.32 (d, J ) 7.0 Hz, 3H). Anal. Calcd for
calibrated from
a least-squares analysis of the unit cell
parameters of a carefully centered YLID reference crystal.
Empirical formula C16H15N3O2. Further steps, crystal data, and
structure refinements are given in Supporting Information.
Bond lengths, angles, discrepancy indices, standard calibra-
tions, data formats, positional parameters, and structure
factors, and U values are also included in Supporting Informa-
tion.
C
25H33N5O3‚2H2O C, 61.58; H, 7.65; N, 14.34. Found: C, 61.31;
H, 7.36; N, 14.64.
Data for 43: hygroscopic solid (45%). [R]25 ) -116.04°
D
(CHCl3, c ) 2). 1H NMR (300 MHz, CDCl3): δ 10.31 (br d, J )
8.4 Hz, 1H), 7.26-7.17 (m, 5H), 6.95 (s, 1H), 5.73 (br d, J )
8.1 Hz, 1H), 3.70-3.65 (m, 2H), 2.58 (s, 6H), 2.28 (s, 3H), 1.78-
1.13 (m, 11H), 0.53 (d, J ) 6.9 Hz, 6H). 13C NMR (300 MHz,
CDCl3): δ 170.5, 168.4, 167.3, 167.2, 154.7, 136.0, 129.5, 128.1,
127.7, 119.0, 62.8, 60.5, 48.0, 33.0, 32.6, 32.2, 25.4, 24.7, 24.5,
23.8, 23.3, 19.0, 18.7. ESI-HRMS (MH+/z): 502.2777 (calcd for
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal data, general procedure for the preparation of amino acid
amides, copies of 1H NMR spectra of reaction mixtures of ring
opening products; 1H NMR, 13C NMR, and high-resolution MS
of most of the products; and protocols, data, and Ortep of
single-crystal X-ray diffraction of compounds 34 and 45c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
C
27H37N5O3 + Na 502.2794).
Data for 44: mp 138° (27%). [R]25 ) +20.76° (CHCl3, c )
D
1
2). H NMR (300 MHz, CDCl3): δ 10.62 (br d, 1H), 7.26-7.17
(m, 5H), 6.99 (s, 1H), 5.74 (br d, J ) 8.1 Hz), 3.62-3.56 (m,
2H), 2.55 (s, 6H), 2.29 (s, 3H), 1.74-1.25 (m, 11H), 1.01 (d,
J ) 6.8 Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H). 13C NMR (CDCl3):
J O0497196
J . Org. Chem, Vol. 69, No. 15, 2004 4973