Solution-and solid-phase synthesis of novel hydantoin and isoxazoline-containing heterocycles

Article abstract of DOI:10.1039/a803400a

Exploiting 1,3-dipolar cycloaddition and carbanilide cyclization transformations, novel isoxazolylmethylimidazolidinedione heterocycles have been prepared using both solution- and solid-phase methods.

Full text of DOI:10.1039/a803400a

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Solution- and solid-phase synthesis of novel hydantoin and
isoxazoline-containing heterocycles
Kyung-Ho Park,a Eric Abbate,a Samir Najdi,b† Marilyn M. Olmsteada and Mark J. Kurth*a‡
a Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
b Department of Chemistry, Al-Quds University, East Jerusalem, Israel
Exploiting 1,3-dipolar cycloaddition and carbanilide cycli-
zation transformations, novel isoxazolylmethylimidazolidi-
nedione heterocycles have been prepared using both solu-
tion- and solid-phase methods.
The condensation of glycine ethyl ester HCl salt with
benzophenone imine gave benzophenone Schiff base 17 (5
mmol scale, 95% yield) which was alkylated with allyl bromide
to give protected amino ester 2 (5 mmol scale, 90% yield)
(Scheme 1). Hydrolysis of the imine moiety in 2 with aq. HCl
and subsequent neutralization of the resulting ammonium salt
with aq. NaOH delivered 3 (5 mmol scale, 86%).
The hydantoin moiety has important medicinal1 as well as
agrochemical2,3 activities and a large number of hydantoins
have been synthesized for various biological applications.4
Moreover, the isoxazoline heterocycle has been used ex-
tensively to modulate various other biologically active motifs.5
As part of our efforts toward the preparation and biological
evaluation of novel hydantoin-containing heterocycles, we
disclose here a useful route for the synthesis of isoxazoline-
containing hydantoins6 as well as present a synthetic strategy
applicable to solid-phase combinatorial approaches.
The free amine of 3 was reacted with phenyl isocyanate in
CH2Cl2 at ambient temperature for 2 h to give urea 4 in 90%
yield (5 mmol scale) (Scheme 2). 1,3 Dipolar cycloaddition to
the alkene in 4 with a Mukaiyama-generated nitrile oxide8 gave
isoxazoline heterocycle 59 as a C4a and C4b mixture of
O(1)
N(2)
O(3)
N(1)
C(13)
C(11)
C(9)
C(10)
N(3)
C(3)
O
O
C(19)
C(18)
C(12)
C(1)
i
C(8)
C(14)
C(15)
C(4)
C(5)
EtO
EtO
C(2)
C(7)
O(2)
C(17)
NH2•HCl
N
ii
CPh2
1
C(16)
C(6)
O
O
iii, iv
Fig. 1 Crystallographic projection of 6a (R = Ph)
EtO
EtO
O
O
NH2
N
CPh2
i
ii, iii
3
2
3
EtO
EtO
Scheme 1 Reagents and conditions: i, HNNCPh2, CH2Cl2, room temp., ii,
allyl bromide, NaH, DMF, room temp.; iii, HCl (1 ); iv, NaOH (1
NHBoc
iv, v
NHBoc
M
M)
7
8
R′
N
O
O
vi, vii
O
O
O
O
O
N
4
NH2
NHBoc
EtO
O
EtO
O
i
ii
10
9
2
2
3
N
N
R′
R′
H
H
viii
N
N
N
O
Ph
H
O
Ph
H
O
O
5a C4 = α
b C4 = β
4
O
4
4
x
ix
O
O
2
iii
2
2
R
N
N
O
N
O
N
H
H
R′
H
H
O
N
N
N
R
H
R
O
O
12
6a C4 = α
b C4 = β
11
O
4
4
H
N
R′ = Ph, p-BrC6H4, p-MeC6H4
C4α
R = Ph, p-ClC6H4, p-FC6H4, Bu
2
Ph
N
R′ = Ph, Me
H
CH2Cl = Merrifield resin
O
6a C4 = α
b C4 = β
Scheme 3 Reagents and conditions: i, Boc2O, CH2Cl2, reflux; ii, NaOH (1
); iii, HCl (1 ); iv, KOH; v, 18-crown-6, Merrifield resin, DMF, 70 °C;
M
M
Scheme 2 Reagents and conditions: i, PhNNCNO, CH2Cl2, room temp.; ii,
RCH2NO2, PhNNCNO, Et3N, THF, 60 °C; iii, NaOEt, EtOH, room temp.
vi, TFA, CH2Cl2; vii, Et3N, CH2Cl2; viii, RNNCNO, CH2Cl2, room temp.;
ix, RACH2NO2, PhNNCNO, Et3N, THF, 60 °C; x, Et3N, THF, 60 °C
Chem. Commun., 1998
1679

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CH2Cl2 (20 ml) was added and, after 10 h at ambient temperature, the resin
was washed with DMF (20 ml), THF (20 ml) and CH2Cl2 (20 ml) and dried
to give resin 11 (R = Ph; nmax/cm21 1740, 1700, 1662). a-Nitrotoluene
(123 mg, 0.9 mmol), phenyl isocyanate (214 mg, 1.8 mmol) and Et3N (10
µl) were added to this resin in THF (20 ml). After incubating at 60 °C for
20 h, washing the resin with DMF (20 ml), THF (20 ml) and CH2Cl2 (20 ml)
gave resin 12 (R = RA = Ph; nmax/cm21 1738, 1699) which was finally
treated with Et3N (1 ml) in THF (20 ml) at 60 °C for 20 h. Resin was
removed from the liberated product to give 6a/6b (R = RA = Ph) in 35%
overall yield from Merrifield resin. These two isomers were easily separated
by flash chromatography (EtOAc–hexane 1:2) to give 6a (R = RA = Ph; 16
mg, 16% overall yield) and 6b (R = RA = Ph; 19 mg, 19% overall yield).
The optimized solid-phase overall yield of 6a + 6b is 35%, which translates
to ca. 84% yield per step from 8. With catalytic Et3N, we saw no evidence
for formation of 6 in 11?12.
diastereomers (4 mmol scale, 5a : 5b : 1 : 1 ratio, yield
60–70%). While separable by flash-column chromatography,
each diastereomer of 5 gave the same mixture of two
diastereomeric isoxazoloimidazolidinediones 6 upon treatment
with NaOEt (1.0 equiv.) in EtOH. Due to this propensity for C2
epimerization during the carbanilide cyclization (5a?6a + 6b
or 5b?6a + 6b; 4 mmol scale; 6a : 6b : 1 : 1; 80% yield), it was
in fact most expedient to effect this transformation on the 5a/5b
mixture. X-Ray crystallographic analysis§ of 6a (R = Ph) (Fig.
1) verified the relative stereochemistries of 5a/5b and 6a/6b.
Our solid-phase approach10 to isoxazolylmethylimidazolidi-
nedione 6 began with amino ester 3, which was Boc-protected
to give 7 (4 mmol scale, 95% yield) (Scheme 3). Saponification
delivered 8 (4 mmol scale, 90% yield) which was coupled with
Merrifield resin to give resin 9.11¶ TFA-mediated removal of
the Boc protecting group followed by a resin wash with Et3N–
CH2Cl2 delivered 10, the solid-phase analog of 3. Paralleling
the solution results, isocyanate treatment of 10 gave urea 11 and
subsequent 1,3-dipolar cycloaddition with a Mukaiyama-
generated nitrile oxide gave 12. A ca. 1: 1 mixture of
isoxazolylmethylimidazolidinedione diastereomers (6a/6b)
was obtained on cyclative release.
1 E. Ware, Chem. Rev., 1950, 46, 403; A. Spinks and W.S. Waring, Prog.
Med. Chem., 1963, 3, 313; J. Karolakwojciechowska, W. Kwiatkowski
and K. Kieckonono, Pharmazie, 1995, 50, 114; W. J. Brouillette, V. P.
Jestkov, M. L. Brown and M. S. Akhtar, J. Med. Chem., 1994, 37, 3289;
W. J. Brouillette, G. B. Brown, T. M. Deloreg and G. Liang, J. Pharm.
Sci., 1990, 79, 871.
2 C.J. Mappes, E.H. Pommer, C. Rentzea and B. Zeeh, U.S. Pat., 1980,
4,198,423.
3 H. Ohta, T. Jikihara, K. Wakabayashi and T. Fujita, Pestic. Biochem.
Physiol., 1980, 14, 153.
4 C. Avendano Lopez and G. Gonzalez Trigo, Adv. Heterocycl. Chem.,
1985, 38, 177.
We thank the National Science Foundation and Novartis
Crop Protection AG for financial support of this research.
Notes and References
5 M. A. Khalil, M. F. Maponya, D.-H. Ko, Z. You, E. T. Oriaku and H. J.
Lee, Med. Chem. Res., 1996, 6, 52; W. C. Groutas, R. Venkataraman,
L. S. Chong, J. E. Yooder, J. B. Epp, M. A. Stanga and E.-H. Kim,
Bioorg. Med. Chem., 1995, 3, 125; J. I. Levin, P. S. Chan, J. Coupet,
T. K. Bailey, G. Vice, L. Thibault, F. Lai, A. M. Venkatesan and A.
Cobuzzi, Bioorg. Med. Chem. Lett., 1994, 4, 1703.
6 K.-H. Park, M. M. Olmstead and M. J. Kurth, J. Org. Chem., 1998, 63,
113; J. Wityak, T. M. Sielecki, D. J. Pinto, G. Emmett, J. Y. Sze, J. Liu,
A. E. Tobin, S. Wang, B. Jiang, P. Ma, S. A. Mousa, R. R. Wexler and
R. E. Olson, J. Med. Chem., 1997, 40, 50.
7 M. J. OADonnell and R. L. Polt, J. Org. Chem., 1982, 47, 2663.
8 T. Mukaiyama and T. Hoshin, J. Am. Chem. Soc., 1960, 62, 5339.
9 D. P. Curran, Adv. Cycloaddition, 1988, 1, 129; K. B. G. Torssel,
Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, VCH,
Weinheim, 1988.
10 S. H. DeWitt, J. S. Kiely, C. J. Stankovic, M. C. Schroeder, D. R. Cody
and M. R. Pavia, Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 6909; B. A.
Dressman, L. A. Spangle and S. W. Kaldor, Tetrahedron Lett., 1996, 37,
937.
† Fulbright Fellow, 1996–1997, University of California, Davis, USA.
‡ E-mail: mjkurth@ucdavis.edu
§ Crystal data: for 6a (R = Ph): C19H17N3O3, colorless crystals, M =
335.36, orthorhombic, space group Pbca,
a = 9.0062(11), b =
11.1037(10), c = 32.472(3) Å, U = 3247.3(6) Å3, Z = 8, Dc = 1.372 Mg
m23, m = 0.776 mm21, R = 0.0392, wR = 0.0955, GOF = 1.092, T =
130(2) K, F(000) = 1408, 2189 independent reflections were collected on
a Syntex P21 diffractometer using graphite-monochromated Cu-Ka radia-
tion. CCDC 182/917.
¶ Typical procedure for solid-phase isoxazolylmethylimidazolidinedione
synthesis: Boc-protected glycine acid 8 (130 mg, 0.6 mmol) was neutralized
(room temp., 1 h) with KOH (1.0 equiv., 0.6 mmol) in EtOH–H2O (2:1) and,
after removing the solvent and drying in vacuo, the potassium salt was
dissolved in DMF (20 ml) and reacted with Merrifield resin (300 mg, 0.3
mmol; loading ca. 1 mmol Cl g21) and 18-crown-6 (158 mg, 0.6 mmol).
The resulting mixture was stirred at 70 °C for 40 h and then washed with
DMF (20 ml), THF (20 ml), THF–H2O (20 ml3 2), and THF (20 ml). Dried
resin 9 (nmax/cm21 1723) was treated with 50% TFA–CH2Cl2 (20 ml) at
ambient temperature for 1 h, after which time the resin was washed with
CH2Cl2 (20 ml), dioxane (20 ml) and CH2Cl2 (20 ml3 2). An Et3N wash
(10% in CH2Cl2, 20 ml) followed by CH2Cl2 washes (20 ml3 2) gave resin
10 (nmax/cm21 3383, 1735). Phenyl isocyanate (107 mg, 0.9 mmol) in
11 R. W. Roeske and P. D. Gesellchen, Tetrahedron Lett., 1976, 38,
3369.
Received in Corvallis, OR, USA, 5th May 1998; 8/03400A
1680
Chem. Commun., 1998