Reaction of phosgeniminium salts with enolates derived from Lewis acid complexes of 2′-hydroxypropiophenones and related β-diketones

Full text of DOI:10.1021/jo952213q

3218
J . Org. Chem. 1996, 61, 3218-3220
Sch em e 1
Rea ction of P h osgen im in iu m Sa lts w ith
En ola tes Der ived fr om Lew is Acid
Com p lexes of 2′-Hyd r oxyp r op iop h en on es
a n d Rela ted â-Dik eton es
J oel Morris,* George P. Luke, and Donn G. Wishka
Discovery Chemistry Research, Pharmacia & Upjohn, Inc.,
Kalamazoo, Michigan 49001
Received December 15, 1995
The 2-aminochromone ring system has proven to be a
rich pharmacophore for use in the design of compounds
with a diversity of biological effects that includes unique
antiplatelet derivatives,1 antiproliferative agents,2 and
phosphatidylinositol 3-kinase inhibitors.3 Our interest
in the utilization of this template4,5 as well as the related
2-aminopyrone system6 as part of our medicinal chem-
istry efforts led us to explore a variety of new methods
for their preparation.7 We recently reported a synthesis
of 2-aminochromones (eg 4) that involves the thermal
reaction of boron difluoride complexes of 2′-hydroxy-
acetophenones (or 2′-hydroxypropiophenones) with phos-
gene iminium chloride.4 Hydrolysis of the readily iso-
lated complex 3 with aqueous acetonitrile (or anhydrous
methanol) affords the desired 2-aminochromone 4. This
reaction is successfully performed either by preforming
the boron difluoride complex 2 or through the generation
of this complex in situ by the addition of boron trifluoride
etherate to an ethylene dichloride solution of the starting
2′-hydroxyacetophenone prior to the introduction of the
iminium chloride. As shown in Scheme 1, yields for the
overall conversion of 1a to 4a in both instances are
comparable (47 vs 56%). In contrast, attempts to utilize
this methodology for the conversion of benzoylacetone (6,
R′ ) H) to the 6-phenyl-2-aminopyrones 7a and 7b were
unsuccessful, providing only small amounts of the desired
products (Table 2).8
this sequence. Having previously explored the unravel-
ing of complex 3 to aminochromone 4,9 we chose to focus
on the events surrounding the formation and reaction of
the boron difluoride complex 2. Presumably, heating the
mixture of 2 with phosgene iminium chloride at 80 °C
allows for the generation of significant equilibrium
concentrations of the corresponding enol form of 2 that
is continuously siphoned off as the reaction proceeds. In
this note, we report that the prior enolization of related
Lewis acid complexes of 2 with Hunig’s base provides a
significant improvement to this synthesis that allows for
a smooth reaction with phosgene iminium chloride under
mild conditions (0 °C to rt), producing excellent overall
yields of the 2-aminochromone 4.10,11
We first examined the direct enolization and reaction
of the stable boron difluoride complex 2b. Treatment of
a methylene chloride solution of 2b with 1.2 equiv of
Hunig’s base at 0 °C followed by the addition of phosgene
iminium chloride (0 °C to rt) produced, after a methanol
quench, a 70% yield of 4b (41% overall yield from 1b)
(Table 1). For comparison purposes, this reaction was
also carried out by the in situ generation of 2b and its
subsequent enolization with 2.1 equiv of base, affording
a 33% yield of 4b. In an effort to improve the overall
efficiency of the process, we examined the use of two
alternate Lewis acids. Treatment of 1b with boron
trichloride, followed by enolization of the resultant boron
dichloride complex 5 with 2.1 equiv of Hunig’s base (0
°C), and reaction with phosgene iminium chloride af-
forded an excellent 80% overall isolated yield of 2-
Our desire to improve the overall efficiency of this
process and expand its applicability to related ring
systems (eg 7) prompted us to examine modifications to
(1) Morris, J .; Wishka, D. G.; Lin, A. H.; Humphrey, W. R.; Wiltse,
A. L.; Gammill, R. B.; J udge, T. M.; Bisaha, S. N.; Olds, N. L.; J acob,
C. S.; Bergh, C. L.; Cudahy, M. M.; Williams, D. J .; Nishizawa, E. E.;
Thomas, E. W.; Gorman, R. R.; Benjamin, C. W.; Shebuski, R. J . J .
Med. Chem. 1993, 36, 2026. Mazzei, M.; Balbi, A.; Roma, G.; Di Braccio,
M.; Leoncini, G.; Buzzi, E.; Maresca, M. Eur. J . Med. Chem. 1988, 23,
237. Mazzei, M.; Sottofattori, E; Di Braccio, M.; Balbi, A.; Leoncine,
G.; Buzzi, E.; Maresca, M. Eur. J . Med. Chem. 1990, 25, 617. Leoncini,
G.; Maresca, M.; Colao, C.; Buzzi, E.; Mazzei, M. Cell Biochem. Funct.
1991, 9, 79. Leoncini, G.; Maresca, M.; Colao, C.; Buzzi, E.; Mazzei,
M.; Balbi, A. Pharm. Res. 1991, 23, 139.
(2) Erickson, L. A.; Bonin, P. D.; Wishka, D. G.; Morris, J .; Dalga,
R. J .; Williams, D. J .; Wilson, G. J .; Hoover, J . L.; Simmons, C. A.;
Humphrey, S. J .; Shebuski, R. J . J . Pharm. Exp. Ther. 1994, 271, 415.
(3) Vlahos, C. J .; Matter, W. F.; Hui, K. Y.; Brown, R. F. J . Biol.
Chem. 1994, 269, 5241.
(4) Morris, J .; Wishka, D. G.; Fang, Y. J . Org. Chem. 1992, 57, 6502.
(5) Morris, J .; Wishka, D. G.; Humphrey, W. R.; Lin, A. H.; Wiltse,
A. L.; Benjamin, C. W.; Gorman, R. R.; Shebuski, R. J . Bioorg. Med.
Chem. Lett. 1994, 4, 2621. Morris, J .; Wishka, D. G.; Fang, Y. Synth.
Commun. 1994, 24, 849. Morris, J .; Wishka, D. G.; J ensen, R. M. J .
Org. Chem. 1993, 58, 7277.
(8) The preformed BF2 complex of 6 was reacted with either
phosgene iminium chloride or 4-(dichloromethylene)morpholinium
chloride under the conditions outlined in Table 2. In both examples,
the bulk of the unreacted BF2 compex of 6 was recovered along with
small amounts of 7a or 7b. Moreover, in the reaction producing 7b,
the 4-morpholine iminium salt appeared to decompose at the high
temperature required for reaction.
(9) Morris, J .; Fang, Y.; Wishka, D. G.; Han, F. Tetrahedron Lett.
1993, 34, 3817.
(10) For the reaction of enol borinates with Eschenmoser’s salt,
see: Hooz, J .; Bridson, J . N. J . Am. Chem. Soc. 1973, 95, 602.
(11) For the enolization and subsequent aldol reaction of related
titanium and boron complexes of â-hydroxy ketones, see: Luke, G. P.;
Morris, J . J . Org Chem. 1995, 60, 3013.
(6) Morris, J .; Wishka, D. G. Synthesis 1994, 43.
(7) Ermili, A.; Mazzei, M.; Roma, G.; Cacciatore, C. Farmaco Ed.
Sci. 1977, 32, 375. Ermili, A.; Balbi, A.; Di Braccio, M.; Roma, G.
Farmaco Ed. Sci. 1977, 32, 713. Ermili, A.; Roma, G.; Mazzei, M.; Balbi,
A.; Di Braccio, M.; Schianterelli, P.; Cadel, S. Farmaco Ed. Sci. 1974,
29, 225. Gammill, R. B.; Nash, S. A.; Mizsak, S. A. Tetrahedron Lett.
1983, 24, 3435. Bantick, J . R.; Suschitzky, J . L. J . Heterocycl. Chem.
1981, 18, 679.
S0022-3263(95)02213-4 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3219
Ta ble 1
Ta ble 2
iminium salt
reaction
%
yield
7
MLn
equiv of iPr2NEt
% yield 1b f 4b
equiv of
iPr2NEt
NR2
(a) NMe2
R′
MLn
conditions
BF3OEt2
BF3OEt2
BCl3
1.2a
2.1
2.1
2.1
41
33
80
84
H
BF3OEt2
0
70 °C, 24 h
Cl(CH2)2Cl
-78 °C f rt
CH2Cl2
-78 °C f rt
CH2Cl2
80 °C, 3 h
Cl(CH2)2Cl
-40 °C f rt
Cl(CH2)2Cl
-78 f 0 °C
CH2Cl2
trace
47
NMe2
H
H
H
H
BCl3
2.1
3.1
0
TiCl4
a
Enolization accomplished using preformed BF2 complex 2b.
NMe2
BCl3
84
(b) 4-morpholine
4-morpholine
(c) NMe2
BF3OEt2
BCl3
2
aminochromone 4b. Similar results (84% yield) were
obtained through the use of titanium tetrachloride as a
substitute Lewis acid in this process.
3.1
3.1
54
CH3 BCl3
91
Success was also achieved in the application of this
methodology for the preparation of the corresponding
6-phenyl-2-aminopyrones (Table 2). Enolization of the
boron dichloride complex generated from benzoylacetone
and boron trichloride at -78 °C with 2.1 equiv of Hunig’s
base, followed by treatment with phosgene iminium
chloride, afforded a 47% yield of 7a . Increasing the
amount of base to 3.1 equiv produced a significant
increase in the yield of this reaction to 84%. The
apparent need for an additional 1 equiv of Hunig’s base
in this conversion can be rationalized by consideration
of the relative acidities of the two complexes present
before and after reaction with the iminium salt. The
initial product intermediate complex 9 would be expected
to have a pKa on the order of a â-dicarbonyl system,
Sch em e 2
significantly lower than the pre-enolate complex 8.12
A
thesis of 2-aminochromones, 2-aminopyrones, and related
derivatives.
comparable yield (91%) was obtained in the reaction to
produce the corresponding 3-methyl derivative 7c. The
use of the less soluble 4-morpholine iminium salt4 with
6 (R′ ) H) in this process afforded a somewhat lower yield
(54%) of the desired 2-aminopyrone 7b.6
Exp er im en ta l Section
IR spectra were taken as a Nujol mull. 1H and 13C NMR
spectra were obtained in CDCl3 (unless otherwise indicated) at
300 MHz and 75 MHz, respectively. Column (flash) chroma-
tography was performed with Merck silica gel 60 (230-400
mesh).
R ep r esen t a t ive E xp er im en t a l: 2-(Dim et h yla m in o)-6-
p h en yl-4H-p yr a n -4-on e (7a ). A solution of benzoylacetone (6,
R′ ) H) (1.62 g, 10 mmol) in 30 mL of CH2Cl2 at 0 °C was treated
with 11 mL (11 mmol, 1 M in CH2Cl2) of BCl3. After stirring
for 1 h, the solution was cooled to -78 °C and treated with 5.4
mL (31 mmol) of iPr2EtN. After stirring 1 h, the mixture was
treated with phosgene iminium chloride (1.80 g, 12 mmol) and
stirred 15 min at -78 °C, 2 h at 0 °C, and 30 min at rt. The
mixture was cooled to 0 °C and diluted with 20 mL of MeOH
and stirred for 3 h at rt. The volatiles were removed in vacuo,
and the residue was partitioned between 50 mL of saturated
NaHCO3 and 4 × 25 mL of CH2Cl2. The combined organics were
concentrated in vacuo, and the material was chromatographed
over 150 g of silica gel, eluting with 4% MeOH/CH2Cl2 to afford
1.80 g (84%) of 7a : mp 157-158 °C; 1H NMR δ 3.09 (s, 6H),
5.35 (d, J ) 1.9 Hz, 1H), 6.53 (d, J ) 1.9 Hz, 1H), 7.47 (m, 3H),
7.69 (m, 2H); 13C NMR δ 37.5, 88.7, 109.0, 125.2, 128.9, 130.6,
131.4, 158.3, 163.4, 179.5. Anal. Calcd for C13H13NO2: C, 72.54;
H, 6.09; N, 6.51. Found: C, 72.29; H, 6.05; N, 6.47.
A useful extension of this methodology can be found
in the synthesis of two other classes of medicinally active
derivatives, the 4-hydroxycoumarins and 4-hydroxy-2-
pyrones.13 Hydrolysis of 3-methyl-2-aminochromone 4b
and 3-methyl-2-aminopyrone 7c with 10% aqueous hy-
drochloric acid/ethanol afforded 10 and 11, respectively,
in high yield (Scheme 2). In summary, reaction of
phosgeniminium salts with enolates derived from Lewis
acid complexes of 2′-hydroxypropiophenones and related
â-diketones provides an improved strategy for the syn-
2-(Dim et h yla m in o)-3-m et h yl-6-p h en yl-4H -p yr a n -4-on e
(7c): yield, 0.63 g (91%) from 0.54 g (3.05 mmol) of 6 (R’ ) CH3);
mp 115-118 °C; 1H NMR δ 2.02 (s, 3H), 3.06 (s, 6H); 6.66 (s,
1H), 7.47 (m, 3H), 7.72 (m, 2H); 13C NMR δ 10.6, 40.5, 103.9,
108.8, 125.2, 129.0, 130.6, 131.8, 158.3, 163.2, 181.1; IR 1643
cm-1. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.13; H, 6.62; N, 6.05.
(12) The related use of 3 equiv of Hunig’s base for the conversion of
1b to 4b had no effect on the overall yield of this reaction.
(13) For example, see: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh,
K. D.; Chong, K.-T.; Howe, W. J .; Yang, C.-P.; Strohbach, J . W.; Turner,
S. R.; McGrath, J . P.; Bohanon, M. J .; Lynn, J . C.; Mulichak, A. M.;
Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J .; Moon, J . B.; Ruwart, M.
J .; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J .; Schwende,
F. J .; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger,
K. A.; Kakuk, T. J .; Cole, S. L.; Zaya, R. M.; Piper, R. C.; J effrey, P. J .
Med. Chem. 1994, 37, 3200, and references cited therein.
2-(Dim eth ylam in o)-3-m eth yl-4H-1-ben zopyr an -4-on e (4b):
yield, 0.50 g (80%) from 0.46 g (3.07 mmol) of 1b; mp 98-100

3220 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
°C (lit.4 102-102.5 °C); 1H NMR δ 2.09 (s, 3H), 3.09 (s, 6H), 7.31
(t, J ) 8.3 Hz, 2H), 7.53 (d, J ) 7.8 Hz, 1H), 8.17 (d, J ) 7.9 Hz,
1H); 13C NMR δ 11.2, 40.3, 99.0, 116.4, 122.3, 124.2, 125.6, 131.8,
evaporated in vacuo. The resulting slurry was cooled to 0 °C
and filtered. The solids were washed with H2O and Et2O and
dried under high vacuum to afford 238 mg (92%) of 11: mp 270-
153.3, 163.1, 178.1; IR 1611,1551 cm-1. Anal. Calcd for C12H13
-
1
273 °C; H NMR δ 1.85 (s, 3H), 6.71 (s, 1H), 7.52 (m, 3H), 7.75
(m, 2H), 11.36 (s, 1H); 13C NMR δ 8.6, 97.8, 98.4, 125.0, 129.1,
NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.03; H, 6.46; N,
6.62.
4-Hyd r oxy-3-m eth yl-6-p h en yl-2H-p yr a n -2-on e (11). To a
solution of 292.6 mg (1.28 mmol) of 7c in 10 mL of ethanol at rt
was added 2 mL of 10% aqueous HCl. The mixture was heated
to reflux for 4 h, allowed to cool to rt, and the ethanol was
130.5, 131.1, 156.5, 164.2, 164.8; IR 2924, 2855, 1615, 1567 cm-1
.
Anal. Calcd for C12H10O3: C, 71.28; H, 4.98. Found: C, 71.20;
H, 5.07.
J O952213Q