Reaction of 3-phenylisoxazole with alkyllithiums

Article abstract of DOI:10.1016/j.tet.2005.01.049

Alkyllithiums react with 3-phenylisoxazole giving C₅-H abstraction followed either mainly by ring fragmentation to benzonitrile and ethynolate ion (in the case of t-BuLi) or (less hindered alkyllithiums: n-BuLi, EtLi, MeLi) also by formation of

Full text of DOI:10.1016/j.tet.2005.01.049

Tetrahedron 61 (2005) 2623–2630
Reaction of 3-phenylisoxazole with alkyllithiums
*
Leonardo Di Nunno, Antonio Scilimati and Paola Vitale
`
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari, Via E.Orabona 4, 70125 Bari, Italy
Received 16 November 2004; revised 22 December 2004; accepted 14 January 2005
Abstract—Alkyllithiums react with 3-phenylisoxazole giving C5–H abstraction followed either mainly by ring fragmentation to benzonitrile
and ethynolate ion (in the case of t-BuLi) or (less hindered alkyllithiums: n-BuLi, EtLi, MeLi) also by formation of alkylated enaminones.
Appreciable amounts of 2-alkyl-4,6-diphenylpyrimidines have also been isolated for certain alkyllithiums (EtLi and MeLi). This is at
variance with the reported behaviour with hindered lithium amides (LTMP) for which only C5–H abstraction followed by ring fragmentation
was described. The mechanistic significance of the observed results is discussed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
formed anion with formation of benzonitrile and a ynolate
ion, as depicted in Scheme 1.
Reaction of 3,4-diphenylisoxazole with strong bases
(lithium dialkylamides or n-BuLi) is known to give the
C5–H abstraction followed by ring fragmentation of the
As for the fragmentation reaction, it was not clear whether
a pericyclic [(2pC4p) cycloreversion] or a stepwise
Scheme 1.
Scheme 2.
Keywords: 3-Phenylisoxazole ring-fragmentation; Alkyllithiums; Enaminones; Pyrimidines.
* Corresponding author. Tel.:C39 080 5442734; fax: C39 080 5442231; e-mail: dinunno@farmchim.uniba.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.049

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L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
mechanism (via lithium iminoketene intermediate 5) was
involved (Scheme 2).1
On the other hand, concerning the reaction with t-BuLi,
full investigation of the reaction products revealed the
formation also of the enaminone 11 as the minor product
(Scheme 4).
A similar reaction was carried out starting from 3-phenyl-
isoxazole (6), but using a very hindered lithium amide
(LTMP) (Scheme 3).1
We repeated the reaction with n-BuLi, observing an
increasing formation of enaminone (Scheme 6 and Table 1).
We have repeated the reaction of 3-phenylisoxazole using
t-butyllithium, observing apparently the same behaviour, as
it can be deduced by the formation of t-butyl phenyl ketone
(10) as the main (86% yield) isolated product after
quenching with aqueous NH4Cl (Scheme 4).
Quenching the reaction mixture with aqueous NH4Cl
allowed, in fact, isolation of comparable amounts of
valerophenone 12 (indicative of ring fragmentation) and
1-amino-1-phenyl-1-hepten-3-one 13, together with its
N-acetyl derivative 14, presumably formed by further
reaction with ketene from ynolate ion 8.
The above ketone 10, in fact, is just what one could have
expected as the ultimate product (under the used quenching
conditions) by C5–H abstraction and subsequent fragmenta-
tion, followed by further reaction of the formed benzonitrile
with t-BuLi and final hydrolysis of the lithium imine
intermediate (Scheme 5).
Formation of enaminones from isoxazoles using alkyl-
lithiums is unprecedented. In general, in fact, they are
obtained from isoxazoles by selective reductive cleavage of
O–N bond by a number of reducing agents (e.g. by catalytic
Scheme 3.
Scheme 4.
Scheme 5.
Scheme 6.

L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
2625
Table 1. Percentages of productsa formed in the reaction of 3-phenylisoxazole (6) and n-BuLi
Substrate: n-BuLi
Time (h)
Valerophenone (12)
(Z)-1-Amino-1-phenyl-1-hep-
ten-3-one (13)
N-[(Z)-3-oxo-1-phenylhept-1-
enyl]acetamide (14)
1:2
1:3
1:5
1
1
8
50
45
37
40
45
43
10
10
20
1
a % Determined by H NMR spectra recorded on reaction crudes.
hydrogenation).2–4 The latter is also a rather common
reaction so that the isoxazoles are just considered masked
forms of enaminones (as well as of the related beta-
dicarbonyl compounds).
However, a completely different mechanism of formation of
enaminones cannot in principle be excluded.
In this case, enaminone would be formed by direct
nucleophilic addition of RLi onto the position 5 of
isoxazole, as hypothesized in Scheme 8.
Novelty is also represented by the particular enaminones
that are formed by this way (Schemes 4 and 6). At variance
with the reductive methods, in fact, simultaneous formation
of a new C–C bond occurs, so that, by using different
alkyllithiums, variously elongated enaminones could be
directly obtained in this case.
Yet, formation of enaminone by this way under the used
conditions can be ruled out on the basis of the following
experiments.
Independent generation of 18 (RZMe) by treating
3-phenyl-5-methylisoxazoline5 19 with MeLi under con-
ditions strictly similar (K78 8C; MeLi/substrateZ3:1; 1 h)
to those used in reactions of 3-phenylisoxazole with
MeLi and subsequent quenching with aq. NH4Cl
indicated, in fact, no formation of enaminone, the starting
isoxazoline being recovered substantially unchanged
(Scheme 9, route a). At variance, by the same treatment
of 3-phenylisoxazole, ca. 40% of enaminone 17b and
related product N-acetylenaminone 22b are instead formed
(Table 2).
Formation of enaminones seems also to be very interesting
in relation to the mechanism of fragmentation of isoxazole
anions (both 2 and 7), suggesting a stepwise rather than a
pericyclic mechanism.
Enaminones 17 (Scheme 7), in fact, could just be the
ultimate products of further reaction of the lithium
iminoketene 15 (i.e. the postulated intermediate of the
stepwise mechanism of fragmentation) with a second
molecule of RLi, as reported in Scheme 7.
Scheme 7.
Scheme 8.

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L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
Scheme 9.
Table 2. Percentages of productsa formed in the reaction of 3-phenylisoxazole (6) and EtLi or MeLi
Substrate: EtLi
Time
(h)
Propiophenone
(21a)
(Z)-1-Amino-1-
phenyl-1-penten-
3-one (17a)
N-[(Z)-3-Oxo-1-
phenylpent-1-enyl]-
acetamide (22a)
2-Ethyl-4,6-diphenyl-
pyrimidine (23a)
1:3
1
40
40
5
7
Substrate: MeLi
Time
(h)
Acetophenone
(21b)
(Z)-1-Amino-1-
phenyl-1-buten-
3-one (17b)
N-[(Z)-3-Oxo-1-
phenylbut-1-enyl]-
acetamide (22b)
2-Methyl-4,6-diphenyl-
pyrimidine (23b)
150
1
1:3
1:3
1:3
73
61
50
8
28
30
—
—
10
19
11
10
8
a % Determined by 1H NMR spectra recorded on reaction crudes.
Thus, under our conditions, the main (or the only)
mechanism for formation of enaminone should be the one
depicted in Scheme 7, which also means, as said, a stepwise
mechanism of isoxazole ring fragmentation.
diphenylpyrimidines is proposed in Scheme 11, in which
1-azetin-4-one 24, originated from benzonitrile and, once
again, the iminoketene anion 15, is hypothesized as the key
reaction intermediate. Iminoketenes (and by obvious
extension also iminoketene anions 15) could be, in fact,
precursors of azetinones.7 Furthermore, the actual existence
of some 1-azetin-4-ones has previously also been
evidenced.8
It must be pointed out, however, that little amounts of
enaminone can actually be generated also from 18, but this
requires higher temperatures. By allowing, in fact, the
reaction mixture containing 18 (from 3-phenyl-5-methyl-
isoxazoline and MeLi) to warm to room temperature (two
more hours), 7% of enaminone 17b together with 90% of an
unsaturated oxime 20 (already described as the product
formed from 18 at higher temperatures)6 are isolated
(Scheme 9, route b).
Subsequent nucleophilic attack by RLi should then cause
the azetinone ring-opening (by C–C rather than C–N bond
breaking possibly because of the resonance stabilization of
the open intermediate formed by this way), and, finally, a
new ring-closing with aromatization to give the observed
pyrimidine 23a-b.
On the other hand, concerning the reactions of MeLi (and
EtLi) with 3-phenylisoxazole, an additional product
of reaction [2-ethyl-4,6-diphenylpyrimidine (23a) and
2-methyl-4,6-diphenylpyrimidine (23b) from EtLi
and MeLi, respectively] is also formed (Scheme 10 and
Table 2).
Accordingly, the fact that the relative amount of pyrimidine
decreases from MeLi to EtLi and that no pyrimidine is
observed for both n-BuLi and t-BuLi should reflect, as
expected, an increasing difficulty in the nucleophilic attack
of RLi onto azetinone intermediate 24 on going from less to
more hindered alkyllithiums. Further investigations are in
progress on this point.
A possible mechanism for formation of 2-alkyl-4,6-
Scheme 10.

L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
2627
Scheme 11.
In conclusion, the reaction of 3-phenylisoxazole (and likely
of other isoxazoles similarly ‘protected’ at the position 3)
with t-BuLi could be an alternative way (with respect to the
reported use of LTMP)1 for accomplishing, in a substan-
tially clean manner, the C5–H abstraction and subsequent
ring fragmentation. By this way benzonitrile (further
reacting with t-BuLi) and ethynolate ion (a potentially
starting material, in turn, in the synthesis of other interesting
products, e.g. b-lactams)9,10 are formed.
Varian Mercury 300 MHz spectrometer and chemical shifts
are reported in parts per million (d). Absolute values of the
coupling constant are reported. FT-IR spectra were recorded
on a Perkin–Elmer 681 spectrometer. GC analyses were
performed by using a HP1 column (methyl siloxane; 30 m!
0.32 mm!0.25 mm film thickness) on a HP 6890 model,
Series II. Thin-layer chromatography (TLC) was performed
on silica gel sheets with fluorescent indicator, the spots on
the TLC were observed under ultraviolet light or were
visualized with I2 vapour. Chromatography was conducted
by using silica gel with an average particle size of 60 mm, a
particle size distribution 40–63 mm and 230–400 ASTM.
GC–MS analyses were performed on a HP 5995C model
and microanalyses on an Elemental Analyzer 1106-Carlo
Erba-instrument.
However, with t-BuLi itself, and to a much greater extent
with other less hindered alkyllithiums (n-BuLi, EtLi, MeLi),
an interesting and unprecedented reaction is also observed.
In the latter case, no ring fragmentation but only O–N bond-
breaking takes place, with direct formation of elongated
enaminones (useful starting molecules, again, for the
construction of various other structures).11–13 Depending
on RLi, appreciable amounts of compounds (N-acetyl-
enaminones and pyrimidines) due to a further interaction of
the primary products of both reactions are also isolated.
2.2. Materials
3-Phenylisoxazole (6) has been synthesized from benzo-
nitrile oxide and the enolate ion of acetaldehyde.14
3-Phenyl-5-methyl-2-isoxazoline has been synthesized
from benzonitrile oxide and propene.5
Apart from some synthetic utility, direct formation of
alkylated enaminones 11 and 17 as well as of alkylated
pyrimidines 23a and 23b seems to be interesting especially
from a mechanistic point of view. In particular, it provides
useful indications concerning the not previously defined
mechanism of the base-induced ring-fragmentation of
3-arylisoxazoles (and by extension, of 3,4-diarylisoxa-
zoles), supporting a stepwise rather than a synchronous
mechanism of reaction.
Tetrahydrofuran (THF) from commercial source was
purified by distillation (twice) from sodium wire under
nitrogen. Standardized 2.5 M n-butyllithium in hexane,
0.5 M ethyllithium in cyclohexane/toluene, 1.6 M methyl-
lithium in diethyl ether and 1.7 M t-butyllithium in pentane
were purchased from Aldrich Chemical Co. Titration of
n-butyllithium and t-butyllithium was performed by using
N-pivaloyl-o-toluidine.15 All other chemicals and solvents
were commercial grade further purified by distillation or
crystallization prior to use. 2,2-Dimethyl-1-phenylpropan-
1-one (pivalophenone) (10), 1-phenylpentan-1-one (valero-
phenone) (12), 1-phenylpropanone (propiophenone) (21a)
and 1-phenylethanone (acetophenone) (21b) isolated as
products of the reaction mentioned above had analytical and
spectroscopic data identical to those ones commercially
available.
Wider investigations are in progress aimed to extend the
reaction to other alkyllithiums and isoxazoles, as well as to
possibly optimize the reaction conditions in order to more
selectively favour each of the reaction products.
2. Experimental
2.1. General methods
2.3. Reaction of 3-phenylisoxazole (6) with t-BuLi
Melting points taken on Electrothermal apparatus were
uncorrected. 1H NMR spectra were recorded in CDCl3 on a
0.90 M t-Butyllithium in hexane (1.4 mL, 1.26 mmol) was

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L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
added to a solution of the isoxazole (61 mg, 0.42 mmol) in
THF (2 mL) at K78 8C under nitrogen, using a nitrogen-
flushed, three necked flask equipped with a magnetic stirrer,
a nitrogen inlet and one dropping funnels. The brown
reaction mixture kept at K78 8C was stirred for 1 h and then
quenched by adding aq. NH4Cl. The two phases were
separated and the aqueous phase was extracted three times
with ethyl acetate. The organic extracts were combined,
dried over anhydrous Na2SO4 and then the solvent
evaporated under reduced pressure. Column chroma-
tography (silica gel, petroleum ether/ethyl acetateZ7:3) of
the residue afforded the products indicated in the Scheme 4:
10 (86% yield, 59 mg) and 11 (14% yield, 12 mg).
10–20% Yield. Yellow oil. FT-IR (neat): 3324, 3061, 3029,
2957, 2927, 2855, 1723, 1642, 1593, 1574, 1493, 1466,
1
1367, 1282, 1224, 1140, 1076, 1000, 762, 697 cmK1. H
NMR (CDCl3, d): 0.90–0.96 (3H, t, JZ7.3 Hz); 1.28–1.43
(2H, sextet, JZ7.3 Hz); 1.57–1.68 (2H, quintet, JZ7.3 Hz);
2.16 (3H, s, CH3CO); 2.46–2.53 (2H, t, JZ7.3 Hz); 5.60
(1H, s); 7.34–7.41 (5H, m, aromatic protons); 11.70–11.90
(1H, bs, NH: exchanges with D2O). 13C NMR (75 MHz,
CDCl3, d): 14.12, 22.61, 25.20, 27.03, 43.85, 108.35,
126.26, 127.52, 128.25, 128.95, 129.90, 136.02, 154.22,
169.16, 203.28. GC–MS (70 eV) m/z (rel. int.): 245 (MC,
1), 227 (1), 202 (4), 198 (6), 188 (14), 174 (2), 161 (14), 160
(100), 146 (58), 129 (2), 119 (6), 104 (10), 103 (10), 91 (6),
77 (5), 43 (9). Anal. Calcd for C15H19NO2: C, 73.47; H,
7.75; N, 5.71. Found: C, 73.48; H, 7.77; N, 5.70.
2.3.1. (Z)-1-Amino-4,4-dimethyl-1-phenylpent-1-en-3-
one (11).16 14% Yield (12 mg of yellow oil) 1H NMR
(CDCl3, d): 1.21 (9H, s); 4.90–5.30 (1H, bs, NH: exchanges
with D2O); 5.63 (1H, s); 7.41–7.49 (3H, m, aromatic
protons); 7.53–7.57 (2H, m, aromatic protons); 9.80–10.15
(1H, bs, NH: exchanges with D2O). GC–MS (70 eV) m/z
(rel. int.): 203 (MC, 9), 160 (4), 147 (17), 146 (100), 128 (2),
117 (7), 104 (11), 103 (19), 91 (13), 77 (6), 41 (4).
2.5. Reaction of 3-phenylisoxazole (6) with EtLi
0.5 M Ethyllithium in cyclohexane/toluene (16.56 mL,
8.28 mmol) was added to a solution of the 3-phenylisox-
azole (400 mg, 2.76 mmol) in THF (15 mL) at K788C
under nitrogen, using a nitrogen-flushed, three necked flask
equipped with a magnetic stirrer, a nitrogen inlet and a
dropping funnel. The brown reaction mixture kept at
K78 8C was stirred for 3 h. Then, quenched by adding aq.
NH4Cl. The two phases were separated and the aqueous
phase was extracted three times with ethyl acetate. The
organic extracts were combined, dried with anhydrous
Na2SO4 and then the solvent evaporated under reduced
pressure. Column chromatography (silica gel, petroleum
ether/ethyl ether Z8:2 to 5:5) of the residue afforded the
products indicated on Table 2.
2.4. Reaction of 3-phenylisoxazole (6) with n-BuLi:
general procedure
The amount of 3-phenylisoxazole, n-BuLi and solvent
indicated below refer to a ratio substrate/n-BuLi 1:1. See
Table 1 for other substrate/n-BuLi ratios.
A 2.21 M solution of n-butyllithium in hexane (0.187 mL,
0.414 mmol) was added to a solution of the isoxazole
(60 mg, 0.414 mmol) in THF (2 mL) at K78 8C under
nitrogen, using a nitrogen-flushed, three necked flask
equipped with a magnetic stirrer, a nitrogen inlet and two
dropping funnels. The brown reaction mixture kept at
K78 8C was stirred for the time indicated on Table 1 and
then quenched by adding aq. NH4Cl. The two phases were
separated and the aqueous phase was extracted three times
with ethyl acetate. The organic extracts combined were
dried over anhydrous Na2SO4 and then the solvent
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetateZ7:3) of
the residue afforded the products indicated in Table 1.
2.5.1. (Z)-1-Amino-1-phenyl-1-penten-3-one (17a).17 40%
Yield. Yellow oil. FT-IR (neat): 3358, 3176, 3062, 2969,
2928, 2851, 1720 (w), 1611, 1572, 1529, 1487, 1412, 1293,
1157, 1038, 759, 697 cmK1. 1H NMR (CDCl3, d): 1.12–1.17
(3H, t, JZ7.5 Hz); 2.37–2.46 (2H, q, JZ7.5 Hz); 5.10–5.40
(1H, bs, NH: exchanges with D2O); 5.44 (1H, s); 7.38–7.49
(3H, m, aromatic protons); 7.50–7.57 (2H, m, aromatic
protons); 9.70–10.15 (1H, bs, NH: exchanges with D2O).
13C NMR (75 MHz, CDCl3, d): 9.96, 35.96, 94.45, 126.55,
129.14, 130.74, 137.65, 161.19, 201.46. GC–MS (70 eV)
m/z (rel. int.): 175 (MC, 32), 147 (18), 146 (100), 117 (12),
104 (19), 103 (30), 91 (19), 77 (11), 65 (5), 51 (5). Anal.
Calcd for C11H13NO: C, 75.43; H, 7.43; N, 7.99. Found: C,
75.41; H, 7.45; N, 8.00.
2.4.1. (Z)-1-Amino-1-phenyl-1-hepten-3-one (13).
40–45% Yield. Yellow oil; FT-IR (neat): 3488, 3246,
2993, 2956, 2929, 2857, 1717 (w), 1620, 1594, 1573, 1487,
1
1465, 1379, 1325, 1302, 1154, 1108, 1000, 898 cmK1. H
2.5.2. N-[(Z)-3-Oxo-1-phenylpent-1-enyl]acetamide
(22a). 5% Yield. Yellow oil. The product was not isolated
due to the rather small quantity that was formed, and so not
fully characterized. Its formation was detected by GC–MS
analysis of the reaction crude. GC–MS (70 eV) m/z (rel.
int.): 217 (MC, 100), 190 (15), 189 (71), 161 (37), 133 (9),
105 (20), 103 (9), 80 (8), 77 (10), 66 (10), 59 (6), 43 (5).
NMR (CDCl3, d): 0.89–0.94 (3H, t, JZ7.3 Hz); 1.29–1.42
(2H, sextet, JZ7.3 Hz); 1.57–1.60 (2H, quintet, JZ7.3 Hz);
2.34–2.40 (2H, t, JZ7.3 Hz); 5.20–5.40 (1H, bs, NH:
exchanges with D2O); 5.43 (1H, s); 7.35–7.47 (3H, m,
aromatic protons); 7.52–7.56 (2H, m, aromatic protons);
9.75–10.15 (1H, bs, NH: exchanges with D2O). 13C NMR
(75 MHz, CDCl3, d): 14.22, 22.88, 28.34, 42.91, 94.91,
126.51, 129.12, 130.71, 137.60, 161.21, 200.96. GC–MS
(70 eV) m/z (rel. int.): 203 (MC, 10), 161 (42), 160 (31), 147
(11), 146 (100), 119 (23), 117 (8), 104 (15), 103 (21), 91
(14), 77 (7). Anal. Calcd for C13H17NO: C, 76.85; H, 8.37;
N, 6.90. Found: C, 76.83; H, 8.39; N, 6.89.
2.5.3. 2-Ethyl-4,6-diphenylpyrimidine (23a). 7% Yield
FT-IR (neat): 3062, 3030, 2924, 2853, 1574, 1533, 1496,
1463, 1365, 761, 691 cmK1. 1H NMR (CDCl3, d): 1.46–1.53
(3H, t, JZ7.6 Hz); 3.08–3.18 (2H, q, JZ7.6 Hz); 7.46–7.55
(6H, m, phenyl protons); 7.90 (1H, s, pyrimidine proton);
8.13–8.17 (4H, m, phenyl protons). GC–MS (70 eV) m/z
(rel. int.): 260 (MC, 95), 259 (100), 232 (16), 231 (9), 129
2.4.2. N-[(Z)-3-Oxo-1-phenylhept-1-enyl]acetamide (14).

L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
2629
(7), 128 (6), 104 (13), 102 (16), 77 (9), 76 (7). Anal. Calcd
for C17H14N2: C, 83.08; H, 6.15; N, 10.77. Found: C, 83.05;
H, 6.16; N, 10.75.
(10), 231 (3), 206 (11), 205 (69), 204 (70), 178 (7), 128 (6),
103 (10), 102 (58), 77 (11), 76 (14), 51 (7). Anal. Calcd for
C17H14N2: C, 82.93; H, 5.69; N, 11.38. Found: C, 82.91; H,
5.70; N, 11.37.
2.6. Reaction of 3-phenylisoxazole (6) with MeLi:
general procedure
The structure of 2-methyl-4,6-diphenylpyrimidine (23b)
was also been established by direct comparison with the
authentic sample supplied by SPECS and BioSPECS B.V.23
The amount of 3-phenylisoxazole, MeLi and solvent
indicated below refer to a ratio substrate/MeLi 1:3. See
Table 2 for other substrate/MeLi ratios).
2.7. Reaction of 3-phenyl-5-methyl-2-isoxazoline (19)5
with MeLi
1.6 M Methyllithium in diethyl ether (2.72 mL, 4.34 mmol)
was added to a solution of the 3-phenylisoxazole (210 mg,
1.45 mmol) in THF (7 mL) at K78 8C under nitrogen, using
a nitrogen-flushed, three necked flask equipped with a
magnetic stirrer, a nitrogen inlet and a dropping funnel. The
brown reaction mixture kept at K78 8C was stirred for the
time indicated on Table 2. Then, quenched by adding aq.
NH4Cl. The two phases were separated and the aqueous
phase was extracted three times with ethyl acetate. The
organic extracts were combined, dried over anhydrous
Na2SO4 and then the solvent evaporated under reduced
pressure. Column chromatography (silica gel, petroleum
ether/ethyl ether Z8:2 to 5:5) of the residue afforded the
products indicated in Table 2.
Route a. A 1.6 M solution of MeLi in diethyl ether (1.8 mL,
2.868 mmol) was added to a solution of the isoxazoline 19
(154 mg, 0.956 mmol) in THF (4 mL) at K788C under
nitrogen, using a nitrogen-flushed three necked flask
equipped with a magnetic stirrer and a nitrogen inlet. The
yellow reaction mixture kept at K78 8C was stirred for one
hour and then quenched by adding aq. NH4Cl. The two
phases were separated and the aqueous layer was extracted
three times with ethyl acetate. The organic extracts
combined were dried with anhydrous Na2SO4 and then the
solvent evaporated under reduced pressure. The crude
mixture afforded unreacted 3-phenyl-5-methyl-2-isoxazo-
line 19.
2.6.1. (Z)-1-Amino-1-phenyl-1-buten-3-one (17b).18 30%
yield. Yellow oil; FT-IR (neat): 3489, 3406 (w), 3060, 3030,
2929, 2855, 1718 (m-w), 1624, 1593, 1566, 1487, 1360,
Route b. A 1.6 M solution of MeLi in diethyl ether
(1.234 mL, 1.974 mmol) was added to a solution of the
isoxazoline 19 (106 mg, 0.658 mmol) in THF (3 mL) at
K78 8C under nitrogen, using a nitrogen-flushed three
necked flask equipped with a magnetic stirrer and a nitrogen
inlet. The yellow reaction mixture was stirred for 2 h at
K78 8C and then was allowed to reach room temperature in
two hours. After this time the reaction was quenched by
adding aq. NH4Cl. The two phases were separated and the
aqueous layer was extracted three times with ethyl acetate.
The organic extracts combined were dried with anhydrous
Na2SO4 and then the solvent evaporated under reduced
pressure. Column chromatography (silica gel, petroleum
ether/ethyl acetateZ8:2) of the residue afforded (E)-1-
phenylbut-2-en-1-one oxime 20 (90%) and (Z)-1-amino-1-
phenyl-1-buten-3-one 17b (7%).
1
1290, 1128, 974 cmK1. H NMR (CDCl3, d): 2.16 (3H, s);
5.05–5.30 (1H, bs, NH: exchanges with D2O); 5.45 (1H, s);
7.40–7.50 (3H, m, aromatic protons); 7.52–7.60 (2H, m,
aromatic protons); 9.80–10.10 (1H, bs, NH: exchanges with
D2O). 13C NMR (75 MHz, CDCl3, d): 30.05, 95.45, 126.46,
129.18, 130.80, 137.50, 161.11, 197.81. GC–MS (70 eV)
m/z (rel. int.): 161 (MC, 46), 160 (27), 147 (11), 146 (100),
117 (9), 104 (19), 103 (35), 91 (16), 77 (12), 65 (5), 43 (10).
Anal. Calcd for C10H11NO: C, 74.53; H, 6.83; N, 8.70.
Found: 74.54; H, 6.81; N, 8.69.
2.6.2.
N-[(Z)-3-Oxo-1-phenylbut-1-enyl]acetamide
(22b).19 3–10% Yield. Yellow oil. FT-IR (neat): 3421,
3030, 2928, 2856, 1713, 1631, 1591, 1570, 1492, 1458,
1366, 1337, 1289, 1176, 1101, 963 cmK1. 1H NMR (CDCl3,
d): 2.17 (3H, s); 2.25 (3H, s); 5.61 (1H, s); 7.32–7.44 (5H,
m, aromatic protons); 11.70–11.85 (1H, bs, NH: exchanges
with D2O). 13C NMR (75 MHz, CDCl3, d): 14.37, 22.91,
108.55, 127.51, 128.25, 129.31, 129.95, 131.23, 135.90,
154.44, 169.12, 200.23. GC–MS (70 eV) m/z (rel. int.): 203
(MC, 2), 185 (5), 161 (12), 160 (100), 146 (49), 117 (4), 104
(8), 103 (10), 91 (6), 77 (7), 51 (3), 43 (18). Anal. Calcd for
C12H13NO2: C, 70.93; H, 6.40; N, 6.90. Found: C, 70.95; H,
6.39; N, 6.89.
2.7.1. (E)-1-phenyl-2-buten-1-one oxime (20).24 90%
Yield. Mp 89–91 8C (lit23 88.5 8C), white crystals. FT-IR
(KBr): 3260, 3054, 3024, 2913, 2853, 1640, 1497, 1444,
1332, 1089, 957, 765, 699 cmK1.1H NMR (CDCl3, d): 1.89
(3H, d, J3Z6.9 Hz, J4Z1.6 Hz); 6.00–6.13 (1H, m); 6.93–
7.00 (1H, dq, J3Z15.95 Hz, J4Z1.6 Hz); 7.35–7.47 (5H, m,
aromatic protons); 9.00–10.00 (1H, bs, OH: exchanges with
D2O). 13C NMR (75 MHz, CDCl3, d): 19.2, 121.1, 126.8,
128.5, 128.9, 129.2, 135.3, 139.2, 157.8. GC–MS (70 eV)
m/z (rel. int.): 161 (MC, 22), 146 (100), 144 (41), 130 (13),
128 (17), 115 (21), 104 (27), 91 (13), 77 (46), 51 (17).
2.6.3. 2-Methyl-4,6-diphenylpyrimidine (23b).20–22 19%
Yield. Mp 90–92 8C (lit.22 91–92 8C, lit.20–21 96–97 8C),
white crystals. FT-IR (neat): 3035, 2928, 2855, 1586, 1576,
1533, 1496, 1449, 1370, 1075, 874 cmK1. 1H NMR (CDCl3,
d): 2.87 (3H, s); 7.40–7.55 (6H, m, phenyl protons); 7.89
(1H, s, pyrimidine proton); 8.10–8.20 (4H, m, phenyl
protons). 13C NMR (75 MHz, CDCl3, d): 26.73, 110.32,
127.49, 128.94, 129.16, 129.25, 130.85, 137.76, 165.13,
168.82. GC–MS (70 eV) m/z (rel. int.): 246 (MC, 100), 245
Acknowledgements
Work carried out under the framework of the National
Projects ‘Stereoselezione in Sintesi Organica. Metodologie
ed Applicazioni’ supported by the Ministero dell’Istruzione,
`
dell’Universita e della Ricerca Scientifica (MIUR,
Rome) and ‘Progetto Strategico BS2-‘PREVENZIONE,

2630
L. Di Nunno et al. / Tetrahedron 61 (2005) 2623–2630
14. Di Nunno, L.; Scilimati, A. Tetrahedron 1987, 43, 2181–2189.
15. Suffert, J. J. Org. Chem. 1989, 54, 509–510.
DIAGNOSTICA PRECOCE E CONTROLLO DELLA
MALATTIA NEOPLASTICA’ supported by the Ministero
della Salute (MinSan, Rome). Thanks are also due to the
University of Bari and Istituto di Chimica dei Composti
OrganoMetallici (ICCOM-CNR, Bari).
16. (Z)-1-Amino-4,4-dimethyl-1-phenylpent-1-en-3-one
(RN:
107970-92-3) is commercially available by MCL Moscow
Ltd. (www.mosmedchemlabs.com) and Ambinter: 46 quai
Louis Bleriot Paris, F-75016 France. See also: Sasnovskikh, V.
Ya.; Ovsyannikov, I. S. Zhurnal Organicheskoi Kihmii 1990,
26(10), 2086–2091; LAN 115: 158145, AN 1991: 558145.
Sasnovskikh, V. Ya.; Krostrikova, T. P. Zhurnal Organicheskoi
Kihmii 1986, 22(4), 883–884; LAN 106: 175883, AN 1987:
175883.
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