Birch reduction of (-)-ephedrine. Formation of a new, versatile intermediate for organic synthesis

Article abstract of DOI:10.1021/jo049726u

The reduction of (-)-ephedrine by lithium in liquid ammonia resulted in the formation of S-1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine. In addition to the reduction of the aromatic ring, the hydroxy group was reduced as well. The resulting 1,4-cyclo

Full text of DOI:10.1021/jo049726u

SCHEME 1
Bir ch Red u ction of (-)-Ep h ed r in e.
F or m a tion of a New , Ver sa tile
In ter m ed ia te for Or ga n ic Syn th esis
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 16, 2004
Abstr a ct: The reduction of (-)-ephedrine by lithium in
liquid ammonia resulted in the formation of S-1-(1,4-
cyclohexadien-1-yl)-N-methyl-2-propanamine. In addition to
the reduction of the aromatic ring, the hydroxy group was
reduced as well. The resulting 1,4-cyclohexadienyl group is
a potentially versatile intermediate for further synthetic
transformations. The ozonolysis of this group was investi-
gated, producing derivatives of â-keto-δ-methylamino esters
and â-keto aldehydes which could be subsequently converted
to heterocycles. The restriction to rotation of the C-N bond
in N-benzoyl-1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propan-
amine is described.
SCHEME 2
In the late 1990s, we investigated the transformation
of aromatic amino acids such as phenylalanine and
phenylglycine to functionalized amino acids by the com-
bination of Birch reduction of the benzene ring followed
by ozonolysis. We reported the synthesis of various new
heterocyclic R-amino acids (Scheme 1) by using this
methodology.1-5 Recently, we have also found that ozo-
nolysis of 1,4-cyclohexadiene derivatives in the presence
of methanol and acid can lead to â-keto esters (Scheme
1).6
SCHEME 3
In the present work, (-)-ephedrine (1) was treated with
lithium in liquid ammonia at -70 °C. tert-Butyl alcohol
was used as a proton donor. Both the phenyl and the
hydroxyl were reduced in these conditions to yield 1-(1,4-
cyclohexadien-1-yl)-N-methyl-2-propanamine (2, Scheme
2). The ozonolysis of the resulting 1,4-cyclohexadienyl
group was investigated, showing the possibility of de-
rivatization. It was assumed that the chiral center in 2
and 3, which is two carbons away from the functionalized
group is not affected by this sequence of reactions.
In previous work, it was found1-4 that for the purpose
of treatment with ozone it was necessary to protect the
amino group. The N-benzoyl-N-methyl-1-(1,4-cyclohexa-
dien-1-yl)propanamine (4) was prepared and subjected
to acid-catalyzed ozonolysis in the presence of methanol6
resulting in methyl N-benzoyl-5-methylamino-3-oxohex-
anoate (3). Both the amide 4 and the ester 3 gave complex
proton NMR spectra. The spectra had broad peaks of two
conformers in each of these products. This phenomenon
indicated that at room temperature there is some restric-
tion to the rotation of the amidic C-N bond resulting in
a slow equilibrium compared to the NMR time scale. Two
conformers in about equal amounts were observed. By
cooling to a lower temperature the signals sharpened. By
heating to 430 K in DMSO-d6 coalescence to one con-
former occurred. This trend is known in substituted
amides and was suggested many years ago by Pauling
as part of the explanation of the secondary structure of
proteins. There is a large difference between the chemical
shift of the proton adjacent to the amide group in the
two conformers of about 1.0 ppm in 4 and 0.9 ppm in 3.
The large difference is probably due to the “through
space” deshielding effect of the carbonyl oxygen. The
rotational barrier could be estimated from the coalescence
temperature.7 The calculated free energy of activation
(1) Zvilichovsky, G.; Gurvich, V. J . Chem. Soc., Perkin Trans. 1 1995,
2509.
(2) Zvilichovsky, G.; Gurvich, V. Tetrahedron 1995, 51, 5479.
(3) Zvilichovsky, G.; Gurvich, V. J . Chem. Soc., Perkin Trans. 1 1997,
1069.
(4) . Zvilichovsky, G.; Gurvich, V. Tetrahedron 1997, 53, 4457.
(5) Zvilichovsky, G.; Gurvich, V. Recent Res. Dev. Org. Chem. 1999,
3, 87.
(6) Gbara-Haj-Yahia, I.; Zvilichovsky, G.; Seri, N. J . Org. Chem.
2004, 69, 4135.
10.1021/jo049726u CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/08/2004
5490
J . Org. Chem. 2004, 69, 5490-5493

SCHEME 4
SCHEME 5
(∆Gq’s) in DMSO-d6 were 16.0 ( 1 and 13.7 ( 1 kcal mol-1
for 3 and 4, respectively. One could observe about 10%
of the enolate form of 3 in the NMR spectrum as well.
The N-tosyl derivative of 2 was also prepared and
subjected to the same process, yielding the tosyl ester
(6, Scheme 3). As expected, there was no restricted bond
rotation in both 5 and 6 at room temperature.
to produce the isoxazole derivative (11) was accompanied
by the formation of the amino ester 12 as well.
The rather unstable isoxazolopyrimidine derivative (7)
was transformed by a nucleophilic ring opening8 with
N-cyclohexylvalinamide (14, Scheme 5) to 16. The latter
has a somewhat related structure to pyrimidoblamic acid
(15). Pyrimidoblamic acid (15) is an important constitu-
ent of bleomycins, which are anticancer drugs.9-11 The
amino amide derivative which is obtained has three
chiral centers, of which one was formed in this ring
opening process. Thus, two stereoisomers (16a and 16b)
were obtained in a 1:2 ratio. The two diasteromers could
be separated by column chromatography.
As described previously,1-4 it was impossible to isolate
keto aldehydes such as 9 (Scheme 4). Upon treatment
with ozone in methylene chloride at -78 °C, followed by
treatment with dimethyl sulfide as a reducing agent, a
major fragmentation occurred. In addition to formic acid,
one product of partial fragmentation, e.g., N-methyl-4-
oxo-N-tosyl-2-hexaneamine (10), was isolated. By react-
ing the ozonolysis reaction mixture directly with dinu-
cleophiles, fair yields of heterocyclic derivatives (7, 8, 11,
and 13) were obtained (Scheme 4). However, in all
experiments certain amounts of the chain contraction and
rearomatization products (10 and 8a , respectively) were
observed. The reaction with hydroxylamine in methanol
Exp er im en ta l Section
Bir ch Red u ction of (-)-Ep h ed r in e. (-) Ephedrine (6 g,
0.036 mol) was placed in a 1 L flask on a dry ice-acetone bath
with
a dry ice condenser. Liquid ammonia (300 mL) was
(8) (a) Zvilichovsky, G.; Gurvich. V.; Segev, S. J . Org. Chem. 1995,
60, 5250. (b) Zvilichovsky, G.; Gbara-Hag-Yahia, I. J . Org. Chem. 2004,
69, 4966-4973.
(9) Vloon, W. J .; Kruk, C.; Pandit, U. K.; Hofs, H. P.; McVie, J . G.
J . Med. Chem. 1987, 30, 20.
(10) 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.
(7) ∆Gq Values were calculated with the equation: ∆Gq ) 4.58Tc-
[9.972 + log(Tc/∆ν)] × 10-3 kcal mol-1 where Tc is the coalescence
temperature and ∆ν is the separation in Hz between the signals of
the two conformers. See: Paek, K.; Ihm, H.; Yun, S.; Lee, H. C.; No,
K. T. J . Org. Chem. 2001, 66, 5736.
(11) Stubbe, J . Kozarich, J . W. Chem. Rev. 1987, 87, 1107.
J . Org. Chem, Vol. 69, No. 16, 2004 5491

introduced, and then tert-butyl alcohol (100 mL) was added
slowly during 1 h. Small pieces of lithium ribbon (3 g, 0.4 mol)
were added during 6 h with stirring, retaining the blue color of
the solution. The reaction mixture was stirred and allowed to
warm to room temperature in the hood overnight, while most
of the ammonia evaporated. Solvents were removed by vacuum,
and the white residue was dissolved in water (150 mL). The
resulting 1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine (2)
was extracted by ethyl acetate (oil, 4 g, 73%). 1H NMR (300 NHz,
CDCl3) δ: 5.67 (br s, 2H), 5.46 (br s, 1H), 2.68-2.54 (m, 5H),
2.36 (s, 3H), 2.01 (part A of double AB system, J ) 13.3, 8.0 Hz,
1H), (part B of double AB system, J ) 13.3, 6.0 Hz, 1H), 1.03 (d,
J ) 6.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ: (132.1, 123.9,
123.9, 121.1, 51.8, 45.6, 33.9, 28.7, 26.5, 19.7).
For elemental analysis, a small portion was transformed into
the HCl salt: The oil (0.05 g) was dissolved in dichloromethane
(1 mL). Ethanolic HCl (4 N, 0.5 mL) and excess ether were
added. The salt precipitated and was collected by filtration (0.05
g, mp 185 °C). 1H NMR (CDCl3) δ: 5.69 (br s, 2H), 5.60 (br s,
1H), 3.21 (m, 1H), 2.72-2.55 (m, 4H + s. 3H), 2.30 (d, J ) 13.2
Hz, 1H), 2.26 (d, J ) 13.2 Hz, 1H), 1.39 (d, J ) 6.6 Hz, 3H).
Anal. Calcd for C10H18NCl: C, 64.00; H, 9.67; N, 7.46. Found:
C, 64.12; H, 9.59; N, 7.33
N-Ben zoyl-1-(1,4-cycloh exa d ien -1-yl)-N-m et h yl-2-p r o-
p a n a m in e (4). 1-(1,4-Cyclohexadien-1-yl)-N-methylpropan-
amine (2) (2 g, 13.2 mmol) was suspended in water (30 mL) and
cooled on an ice-water bath. Benzoyl chloride (2 g, 14 mmol)
and 2 N NaOH were added simultaneously during 2 h. The pH
was kept at values 8-9. The reaction mixture was stirred on
the ice-water bath for an additional 1 h and then stirred for 1
h at room temperature, keeping the pH between 8 and 9. The
mixture was extracted with ethyl acetate. The organic layer was
washed with dilute NaOH and then with 0.1 N HCl. The organic
layer was dried on sodium sulfate and the solvent evaporated
in a vacuum. The oily residue was purified on a silica gel column
and eluted with a petroleum ether-ethyl acetate gradient (oil,
1.8 g, 53%). At temperatures below 150 °C, a coalescence of two
conformers was observed in the NMR. 1H NMR (DMSO-d6, T )
430 K, 400 MHz) δ: 7.41-7.07 (m, 5H), 5.68 (br s, 2H), 5.44 (br
s, 1H), 4.42-4.33 (m, 1H), 2.80 (s, 3H), 2.72-2.45 (m, 4H), 2.33-
water bath for an additional 1 h and then stirred for 1 h at room
temperature, keeping the pH between 9 and 10. The mixture
was extracted with ethyl acetate. The organic layer was washed
with dilute NaOH and then with 0.1 N HCl. The organic layer
was dried on sodium sulfate and the solvent evaporated in a
vacuum. The oily residue was purified on a silica gel column,
eluted with petroleum ether-ethyl acetate gradient (oil, 4.5 g,
64%). 1H NMR (300 NHz, CDCl3) δ: 7.67 (d, J ) 8.1 Hz, 2H),
7.25 (d, J ) 8.1 Hz, 2H), 5.66 (br s, 2H), 5.38 (br s, 1H), 4.26-
4.13 (m, 1H), 2.66 (s, 3H), 2.65-2.55 (m, 4H), 2.38 (s, 3H), 2.04-
1.91 (m, 2H), 0.95 (d, J ) 6.9 Hz, 3H). 13C NMR (300 NHz,
CDCl3) δ: (142.8, 137.0, 131.3, 129.4, 127.0, 124.0, 123.7, 121.5,
50.3, 42.6, 29.4, 27.3, 26.7, 21.4, 17.0). Anal. Calcd for C17H23
-
NO2S: C, 66.85; H, 7.59; N, 4.59. Found: C, 66.84; H, 7.36; N,
4.57.
Meth yl 5-Meth ylam in o-3-oxo-N-tosylh exan oate (6). 1-(1,4-
Cyclohexadien-1-yl)-N-methyl-N-tosyl-2-propanamine (5, 1 g, 3.2
mmol) was dissolved in dichloromethane (20 mL). p-Toluene-
sulfonic acid (0.2 g, 1.1 mmol), 5 mL of methanol, and a drop of
a methanolic solution of Sudan III indicator were added. The
dilution of the indicator solution was adjusted so that the
reaction mixture had a very slight pink color. The solution was
cooled on an acetone-dry ice bath (-78 °C), and a mixture of
ozone and oxygen was passed carefully until the light pink color
faded. After the mixture was allowed to stand for 72 h at room
temperature, the solvent was evaporated to a small volume and
loaded on a silica gel column. Upon elution with petroleum
ether-ethyl acetate gradient the keto ester methyl 5-methyl-
amino-3-oxo-N-tosylhexanoate (6) was obtained, 0.42 g (oil, 40%).
The NMR revealed a 7:1 mixture of tautomers. 1H NMR of major
tautomer (CDCl3, 300 MHz) δ: 7.66 (d, J ) 8.1 Hz, 2H), 7.28 (d,
J ) 8.1 Hz, 2H), 4.51 (m, 1H), 3.70 (s, 3H), 3.52 (part A of AB
system, J ) 16.0 Hz, 1H), 3.40 (part B of AB system, J ) 16.0
Hz, 1H) 1H), 2.70 (s, 3H), 2.60 (br s, 5H), 2.44 (part A of partly
hidden double AB system, J ) 16.4, 6.1 Hz, 1H), 1.21 (d, J )
6.7 Hz, 3H), 2.68 (part B of partly hidden double AB system, J
) 16.4, 6.1 Hz, 1H), 2.40 (s, 3H), 0.92 (d, J ) 6.7 Hz, 3H). 13C
NMR (CDCl3) δ: (199.9, 167.3, 143.3, 129.6, 127.1, 90.6, 52.5,
49.0, 48.7, 47.8, 28.4, 21.3, 17.0). Anal. Calcd for C15H21NO5S:
C, 55.03; H, 6.47; N, 4.28; S, 9.79. Found: C, 55.17; H, 6.40; N,
4.46; S, 9.59
2.06 (m, 2H), 1.18 (d, J ) 6.0 Hz, 3H). Anal. Calcd for C17H21
-
NO: C, 79.96; H, 8.29; N, 5.49. Found: C, 79.73; H, 8.08; N,
5.49
Rea ction of 1-(1,4-Cycloh exa d ien -1-yl)-N-m eth yl-N-to-
syl-2-p r op a n a m in e (5) w ith Ozon e. Dichloromethane (20
mL), buffered with 0.1 of NaHCO3, was saturated with ozone at
-70 °C. 1-(1,4-Cyclohexadien-1-yl)-N-methyl-N-tosyl-2-propan-
amine (5, 1.0 g, 3.2 mmol) was added, and more ozone was
introduced until the blue color persisted. After the reaction
mixture was washed with nitrogen, dimethyl sulfide (10 mL)
was added and the solution left at room temperature overnight.
After filtration, the solvent was removed and the residue
suspended in ethyl acetate (1 mL), and the resulting products
were isolated by silica gel column chromatography. Two products
were identified. None was the expected aldehyde 9. One fraction
was a very minor amount of rearomatized product N-methyl-1-
Meth yl N-Ben zoyl-5-m eth yla m in o-3-oxoh exa n oa te (3).
N-Benzoyl-1-(1,4-cyclohexadien-1-yl)-N-methylpropanamine (4,
1 g, 4 mmol) was dissolved in dichloromethane (20 mL).
p-Toluenesulfonic acid (0.2 g, 1.1 mmol), 5 mL of methanol, and
a drop of a methanolic solution of Sudan III indicator were
added. The dilution of the indicator solution was adjusted so
that the reaction mixture had a very slight pink color. The
solution was cooled on an acetone-dry ice bath (-78 °C), and a
mixture of ozone and oxygen was passed carefully until the light
pink color faded. After the mixture was allowed to stand for 72
h at room temperature, the solvent was evaporated to a small
volume and loaded on a silica gel column. Upon elution with
petroleum ether-ethyl acetate gradient the keto ester methyl
N-benzoyl-5-methylamino-3-oxohexanoate (3) was obtained, 0.6
g (oil, 55%). At temperatures below 150 °C, a coalescence of two
conformers was observed in the NMR. 1H NMR (DMSO, 400
MHz, T ) 430 Κ) δ: 7.46-7.32 (m, 5H), 4.54 (m, 1H), 3.68 (s,
3H,), 3.25 (s, 2H), 2.79 (s, 3H), 2.83 (part A of partly hidden
double AB system, J ) 16.0, 6.9 Hz, 1H), 1.21 (d, J ) 6.7 Hz,
3H), 2.68 (part B of partly hidden doubleAB system, J ) 16.0,
6.9 Hz, 1H), 1.21 (d, J ) 6.7 Hz, 3H). 13C NMR (CDCl3, T ) 298
Κ) δ: (172.1, 171.5, 170.6, 129.3, 128.3, 126.7, 126.3, 51.8, 51,0,
1
phenyl-N-tosyl-2-propanamine 8a (0.05 g, oil). HNMR (CDCl3)
δ: 7.57 (d, J ) 8.1 Hz, 2H), 7.28-7.20 (m, 5H), 7.12 (d, J ) 8.1
Hz, 2H), 4.32-4.27 (m, 1H), 2.74 (s, 3H), 2.59 (m, 2H), 2.39 (s,
3H), 0.96 (d, J ) 6.72, 3H). Anal. Calcd for C17H21NO2S: C,
67.29; H, 6.98; N, 4.62. Found: C, 67.09; H, 7.10; N, 4.58.
The second identified product was the cleavage product
N-methyl-4-oxo-N-tosyl-2-pentanamine (10, oil, 0.33 g 40%). 1H
NMR (300 MHz, CDCl3) δ: 7.65 (d, J ) 8.0 Hz, 2H), 7.29 (d, J
) 8.0 Hz, 2H), 4.52-4.45 (m, 1H), 2.69 (s, 3H), 2.47 (d, J ) 7.0
Hz, 2H), 2.40 (s, 3H), 2.02 (s, 3H), 0.91 (d, J ) 6.6 Hz). 13C NMR
(CDCl3) δ: (205.8, 143.3, 136.5, 129.7, 127.1, 49.3, 48.8, 30.0,
28.4, 21.5, 17.3). Anal. Calcd for C13H19NO3S: C, 57.97; H, 7.11;
N, 5.20. Found: C, 57.74; H, 7.10; N, 5.24.
Rea ction of 1-(1,4-Cycloh exa d ien -1-yl)-N-m eth yl-N-to-
syl-2-p r op a n a m in e (5) w ith Ozon e F ollow ed by Tr ea tm en t
w ith Hyd r oxyla m in e. Dichloromethane (15 mL), buffered with
0.1 of NaHCO3, was saturated with ozone at -78°C. 1-(1,4-
Cyclohexadien-1-yl)-N-methyl-N-tosyl-2-propanamine (5, 0.7 g,
3.3 mmol) was added, and more ozone was introduced until the
blue color persisted. After the reaction mixture was washed with
46.8, 38.8, 38.3, 31.9, 26.3, 18.8, 17.5). Anal. Calcd for C15H19
-
NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.70; H, 7.15; N,
5.08
1-(1,4-Cycloh exa d ien -1-yl)-N-m et h yl-N-t osyl-2-p r op a n -
a m in e (5). 1-(1,4-Cyclohexadien-1-yl)-N-methyl-2-propanamine
(2) (3.5 g, 23 mmol) was suspended in water (50 mL) and cooled
on an ice-water bath. Tosyl chloride (4.5 g, 23.6 mmol) and 2 N
NaOH were added simultaneously during 2 h. The pH was kept
at values of 9-10. The reaction mixture was stirred on the ice-
5492 J . Org. Chem., Vol. 69, No. 16, 2004

nitrogen, dimethyl sulfide (10 mL) was added and the solution
left at room temperature overnight. After filtration, the solvent
was removed, the residue was dissolved again in methanol (20
mL), and hydroxylamine hydrochloride (0.32 g, 50 mmol) was
added. The solution was refluxed for 5 h, ice-water (50 mL) was
added, and the solution was neutralized to pH ) 7 by NaHCO3
and extracted with ethyl acetate. The organic layer was dried
on Na2SO4, evaporated, and subjected to column chromatogra-
phy. Upon elution with petroleum ether-ethyl acetate gradient,
in addition to the desired isoxazole derivative (11), two additional
products were identified (10 and 12). Ester 12, oil (0.1 g, 15%).
1H NMR (CDCl3) δ: 7.70 (d, J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1
Hz, 2H), 4.49 (m, 1H), 3.64 (s, 3H), 2.72 (s, 3H), 2.44 (s, 3H),
2.41-2.31 (m, 2H), 0.86 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3)
δ: (171.0, 145.1, 136.7, 129.7, 127.1, 51.8, 50.1, 38.7, 28.1, 21.5,
17.4). Anal. Calcd for C13H19NO3S: C, 54.72; H, 6.71; N, 4.91.
Found: C, 54.32; H, 6.99; N, 4.90. Main product, 1-(isoxazol-5-
yl)-N-methyl-N-tosyl-2-propanamine (11), oil (0.2 g, 31%). 1H
NMR (300 MHz, CDCl3) δ: 8.12 (d, J ) 1.7 Hz, 1H), 7.61 (d, J
) 8.3 Hz, 2H), 7.27 (d, J ) 8.3 Hz, 2H), 6.11 (d, J ) 1.7 Hz),
4.45-4.38 (m, 1H), 2.83 (dd, J 1 ) 7.4 Hz, J 2 ) 4.7 Hz, 2H), 2.69
(s, 3H), 2.39 (s, 3H), 0.96 (d, J ) 6.8 Hz). 13C NMR (CDCl3) δ:
(168.8, 150.3, 143.3, 136.4, 129.7, 127.0, 101.6, 51.5, 31.6, 27.7,
21.4, 17.0). Anal. Calcd for C14H18N2O3S: C, 57.12; H, 6.16; N,
9.52. Found: C, 57.13; H, 6.28; N, 9.28.
42.5, 33.3, 32.8, 31.5, 31.2, 28.0, 25.5, 24.71, 21.4, 19.7, 17.7,
17.3). [R]25 ) -53.8 (CHCl3, c ) 1). ESI-HRMS (MH+ m/z):
D
614.3105 (calcd for C33H45N5O3S + Na 614.3140). The second
isomer was 16b (0.016 g, 18% yield). 1H NMR (CDCl3) δ: 8.52
(d, J ) 5.1 Hz, 1H), 7.53 (d, J ) 8.1 Hz, 2H), 7.39-7.26 (m, 5H),
7.17 (d, J ) 8.1 Hz), 7.00 (d, J ) 5.1, 1H), 4.84 (s, 1H), 4.48 (m,
1H), 3.77 (m, 2H), 2.90-2.76 (m, 2H), 2.75 (s, 3H), 2.38 (s, 3H),
2.17 (m, 1H,), 1.82-0.85 (m, 19H). [R]25 ) +20.6 (CHCl3, c )
D
1). ESI-HRMS (MH+ m/z): 614.3105 (calcd for C33H45N5O3S +
Na 614.3140).
1-(2-Hyd r oxy-3-p h en ylp yr a zolo[1,5-a ]p yr im id in -5-yl)-N-
m eth yl-N-tosyl-2-pr opan am in e (8). Dichloromethane (20 mL),
buffered with 0.1 of NaHCO3, was saturated with ozone at -70
°C. 1-(1,4-Cyclohexadien-1-yl)-N-methyl-N-tosyl-2-propanamine
(5, 0.5 g, 1.6 mmol) was added, and more ozone was introduced
until the blue color persisted. After the reaction mixture was
washed with nitrogen, dimethyl sulfide (5 mL) was added and
the solution left at room temperature overnight. After filtration,
the solvent was removed and the residue dissolved again in 1 N
ethanolic HCl. 3-Amino-5-hydroxy-3-phenylpyrazole12 (0.57 g, 3,-
25 mmol) was added and the solution refluxed for 20 min. Ice-
water was added and the oil that separated extracted with ethyl
acetate. The organic layer was separated, dried on MgSO4, and
evaporated to dryness. The product was obtained by silica gel
column chromatography. The product 8 was eluted from the
column by petroleum ether-ethyl acetate gradient, mp 211 °C
N-Meth yl-1-(2-oxo-3-p h en ylisoxa zolo[2,3-a ]p yr im id in -5-
yl)-N-tosyl-2-p r op a n a m in e (7). Dichloromethane (20 mL),
buffered with 0.1 of NaHCO3, was saturated with ozone at -78
°C. 1-(1,4-Cyclohexadien-1-yl)-N-methyl-N-tosyl-2-propanamine
(5, 0.5 g, 1.6 mmol) was added, and more ozone was introduced
until the blue color persisted. After the reaction mixture was
washed with nitrogen, dimethyl sulfide (5 mL) was added and
the solution left at room temperature overnight. After filtration,
the solvent was removed and the residue dissolved again in 1 N
ethanolic HCl. 3-Amino-5-hydroxy-3-phenylisoxazole7 was added
and the solution refluxed for 20 min, under argon and protected
from light. Ice-water was added, the oil that separated was
extracted with ethyl acetate, the solvent was evaporated and
suspended in ethyl acetate (1 mL), and the product was isolated
by silica gel column chromatography. The product 7 was eluted
from the column by petroleum ether-ethyl acetate gradient, 0.3
1
(0.14 g, 20%). H NMR (DMSO-d6) δ: 8.30 (d, J ) 7.5 Hz, 2H),
8.28 (d, J ) 3.6 Hz, 1H), 7.40 (t, J ) 7.5 Hz, 2H), 7.30 (d, J )
8.1 Hz, 2H), 7.16 (partially hidden t, 1H) 7.12 (d, J ) 8.1 Hz,
2H), 6.78 (d, J ) 3.6 Hz, 1H), 4.76 (m, 1H), 3.14 (m, 2H), 2.81
(s, 3H), 2.16 (s, 3H), 1.08 (d, J ) 6.5 Hz, 3H). 13C NMR (CDCl3)
δ: (148.8, 146.1, 145.0, 143.3, 136.69, 133.2, 129.8, 128.5, 127.2,
126.5, 126.3, 125.0, 107.6, 91.7, 49.6, 35.0, 27.8, 21.3, 18.2). ESI-
HRMS (MH+ m/z): 459.1498 (calcd for C23H24N4O3S + Na
459.1468).
1-(P yr a zol-3-yl)-N-m eth yl-N-tosyl-2-p r op a n a m in e (13).
Dichloromethane (20 mL), buffered with 0.1 of NaHCO3, was
saturated with ozone at -70 °C. 1-(1,4-Cyclohexadien-1-yl)-N-
methyl-N-tosyl-2-propanamine (5, 0.7 g, 2.3 mmol) was added,
and more ozone was introduced until the blue color persisted.
After the reaction mixture was washed with nitrogen, dimethyl
sulfide (5 mL) was added and the solution left at room temper-
ature overnight. After filtration, the solvent was removed and
the residue dissolved again in THF. 3,5-Dihydroxy-3-phenylpyra-
zole13,14 (0.6 g, 3.4 mmol) was added and the solution left at room
temperature for 48 h. Morpholine (0.5 g, 56 mmol) was added
and left overnight at room temperature, while the red color of
the paraionic intermediate faded. The solvent evaporated to
dryness and the residue loaded on a silica gel column. The
product (13) was eluted from the column by petroleum ether-
ethyl acetate gradient. Oil (0.15 g, 22%). 1H NMR (CDCl3) δ:
7.55 (d, J ) 8.3 Hz, 2H), 7.44 (d, J ) 2.0 Hz, 1H), 7.19 (d, J )
1
g (orange-yellow semisolid). H NMR (300 NHz, CDCl3) δ: 8.20
(d, J ) 7.8 Hz, 2H), 7.94 (d, J ) 7.1 Hz, 1H), 7.52 (d, J ) 8.0 Hz,
2H), 7.41 (t, J ) 7.8 Hz, 2H), 7.21 (t, J ) 7.8 Hz, 1H), 7.10 (d, J
) 8.0 Hz, 2H) 6.41 (d, J ) 7.1 Hz, 1H), 4.58-4.51 (m, 1H), 2.85
(s, 3H), 2.81-2.65 (partially hidden double AB system, 2H), 2.35
(s, 3H), 1.10 [d, J ) 6.6 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ:
(169.1, 165.7, 152.6, 143.4, 136.8, 133.0, 130.1, 129.4, 128.2,
126.6, 125.5, 125.0, 105.2, 81.1, 52.7, 43.3, 27.8, 18.1, 15.4). ESI-
HRMS (MH+ m/z): 460.1287 (calcd for C23H23N3O4S + Na
460.1306).
Rin g-Op en in g P r ocess of S-N-Meth yl-3-(5-m eth yl-2-oxo-
3-p h en ylisoxa zolo[2,3-a ]p yr im id in -7-yl)-N-tosyl-2-p r op a n -
a m in e (7) by L-N-Cycloh exylva lin a m id e To P r od u ce 16.
S-N-Methyl-3-(5-methyl-2-oxo-3-phenylisoxazolo[2,3-a]pyrimidin-
7-yl)-N-tosyl-2-propanamine (7) (0.085 g, 0.19 mmol) was dis-
solved in dioxane (10 mL). L-N-Cyclohexylvalinamide (0.04 g,
0.2 mmol) was added, and the mixture was refluxed in the dark
and under argon for 18 h. The reaction was monitored by TLC
and NMR of aliquots. The solvent was removed by evaporation
in a vacuum. The ratio of isomers was determined by NMR (2:
1) and the residue loaded on silica gel column and eluted with
ethyl acetate-petroleum ether gradient (40-100%). The isomer
that came first out of the column was 16a , oil (0.03 g, 26% yield).
1H NMR (CDCl3) δ: 8.50 (d, J ) 5.1 Hz, 1H), 7.50 (d, J ) 8.1
Hz, 2H), 7.39-7.23 (m, 5H), 7.14 (d, J ) 8.1 Hz), 6.98 (d, J )
5.1 Hz, 1H), 4.85 (s, 1H), 4.49 (m, 1H), 3.81-3.71 (m, 1H), 2.91
(d, J ) 4.1 Hz, 1H), 2.89-2.77 (m, 2H), 2.75 (s, 3H), 2.37 (s,
3H), 2.17-2.11 (m, 1H), 1.85-1.01 (m, 10H), 0.96 (m, 9H) 13C
NMR (CDCl3) δ: (172.2, 170.2, 166.9, 157.1, 143.1, 142.2, 136.7,
129.6, 128.6, 127.4, 127.3, 126.9, 118.8, 67.29, 7.14, 52.6, 47.3,
8.04, 2H), 6.05 (d, J ) 2.0 Hz, 1H), 4.33 (m, 1H), 2.73 (dd, J 1
)
7.4 Hz, J 2 ) 2.8 Hz), 2.65 (s, 3H), 2.32 (s, 3H), 0.88(d, J ) 6.8
Hz). 13C NMR (CDCl3) δ: (145.2, 143.0, 136.4, 133.2, 129.5,
126.9, 104.3, 52.8, 32.3, 27.7, 21.3, 16.6). ESI-HRMS (MH+
m/z): 316.1092 (calcd for C14H19N3O2S + Na 316.1096).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal data, NMR figures of dynamic equilibrium between con-
formers in 3 and 4, copies of 1HNMR and 13CNMR of new
products, and high-resolution MS of 7, 8, 13, and 16a ,b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O049726U
(12) Bauer, L.; Nambury, C. N. V. J . Org. Chem. 1961, 26, 4917.
(13) Breuniger, H.; Moede, R. Pharm. Zentralh. 1969, 108, 615.
(14) Zvilichovsky, G.; David, M. J . Org. Chem. 1982, 47, 295.
J . Org. Chem, Vol. 69, No. 16, 2004 5493