Regioselective reduction of 3-methoxymaleimides: An efficient method for the synthesis of methyl 5-hydroxytetramates

Article abstract of DOI:10.1021/jo0605750

3-Methoxymaleimide and various N-alkyl-3-methoxymaleimides, synthesized by base-promoted N-alkylation of 3-methoxymaleimide, were reduced using sodium borohydride with complete regioselectivity. The resultant methyl 5-hydroxytetramates are useful intermediates in the synthesis of a variety of tetramate derivatives.

Full text of DOI:10.1021/jo0605750

subsequent hydrolysis appeared to be a potentially convenient
route to 5-hydroxytetramic acids.
Regioselective Reduction of
3-Methoxymaleimides: An Efficient Method for
the Synthesis of Methyl 5-Hydroxytetramates
Fatiah Issa, Joshua Fischer, Peter Turner, and
Mark J. Coster*
School of Chemistry, The UniVersity of Sydney,
NSW 2006, Australia
m.coster@chem.usyd.edu.au
ReceiVed March 15, 2006
3-Methoxymaleimide and various N-alkyl-3-methoxymale-
imides, synthesized by base-promoted N-alkylation of 3-meth-
oxymaleimide, were reduced using sodium borohydride with
complete regioselectivity. The resultant methyl 5-hydrox-
ytetramates are useful intermediates in the synthesis of a
variety of tetramate derivatives.
3-Methoxymaleimide (5a) is readily available from maleimide
by a convenient two-step procedure.4 A variety of N-alkyl-3-
methoxymaleimides 5b-f were prepared by base-promoted
alkylation of 5a (Table 1). The potassium carbonate promoted
N-benzylation6 and N-methylation7,8 of maleimides with benzyl
bromide and iodomethane, respectively, in acetone solvent, have
previously been reported. Reaction of 5a with a variety of
alkylating agents under these conditions (method A) provided
the desired N-alkyl-3-methoxymaleimides 5b-f in good yields
(87-92%) when MeI, EtI, or PMBCl were employed (entries
1, 2, and 5). The use of MeCN as solvent markedly improved
the yield of 5e (99% vs 55% with acetone); however, this
procedure with either solvent did not prove satisfactory for the
allylation of 5a to give 5d (10% with acetone vs 2% with
MeCN). An alternative procedure, employing cesium fluoride
in DMF (method B), inspired by the facile CsF-promoted
N-alkylation of phthalimide with alkyl chlorides reported by
Clark and Miller,9 proved to be facile for most alkylations,
including the reaction of 5a with allyl chloride (84%). 3-Meth-
oxy-N-phenylmaleimide (5g) was prepared in three steps from
N-phenylmaleimide by the method of Argade10 as another
substrate for the regioselective reduction.
Tetramic acids (pyrrolidine-2,4-diones) 1 are a common
structural feature in a number of biologically active natural
products, including compounds with antibacterial, antifungal,
and cytotoxic properties.1 5-Hydroxytetramic acids (5-hydroxy-
pyrrolidine-2,4-diones) 2, which exhibit an N-acylhemiaminal
functionality, are less common, though still represented in the
HIV-integrase inhibitory and immunomodulatory/antibacterial
natural products integramycin (3)2 and delaminomycin A (4),3
respectively. A direct and convenient approach to the synthesis
of 5-hydroxytetramic acids would rely on the regioselective
reduction of a suitable maleimide derivative. Given the ready
availability of 3-methoxymaleimide (5a),4 and the known facility
with which O-alkyl tetramates can be hydrolyzed to tetramic
acids,5 the regioselective reduction of 3-methoxymaleimides and
Citraconimide (3-methylmaleimide) and N-alkyl derivatives
have previously been shown to undergo regioselective reduction
with sodium borohydride to give predominantly the products
of attack at the more hindered C2 position (88:12 f >99:<1),
whereas a reversal in regioselectivity was observed with NaBH4
in the presence of cerium(III) chloride heptahydrate (CeCl3‚
7H2O) or by using diisobutylaluminum hydride (DIBAL-H).11
(1) Royles, B. J. L. Chem. ReV. 1995, 95, 1981-2001.
(2) Singh, S. B.; Zink, D. L.; Heimbach, B.; Genilloud, O.; Teran, A.;
Silverman, K. C.; Lingham, R. B.; Felock, P.; Hazuda, D. J. Org. Lett.
2002, 4, 1123-1126.
(3) (a) Ishizuka, M.; Kawatsu, M.; Yamashita, T.; Ueno, M.; Takeuchi,
T. Int. J. Immunopharmacol. 1995, 17, 133-139. (b) Ueno, M.; Amemiya,
M.; Iijima, M.; Osono, M.; Masuda, T.; Kinoshita, N.; Ikeda, T.; Iinuma,
H.; Hamada, M.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1993, 46, 719-
727. (c) Ueno, M.; Someno, T.; Sawa, R.; Iinuma, H.; Naganawa, H.;
Ishizuka, M.; Takeuchi, T. J. Antibiot. 1993, 46, 979-984. (d) Ueno, M.;
Someno, T.; Sawa, R.; Iinuma, H.; Naganawa, H.; Ishizuka, M.; Takeuchi,
T. J. Antibiot. 1993, 46, 1020-1023. (e) Ueno, M.; Amemiya, M.;
Yamazaki, K.; Iijima, M.; Osono, M.; Someno, T.; Iinuma, H.; Hamada,
M.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1993, 46, 1156-1162. (f) Ueno,
M.; Yoshinaga, I.; Amemiya, M.; Someno, T.; Iinuma, H.; Ishizuaki, M.;
Takeuchi, T. J. Antibiot. 1993, 46, 1390-1396.
(6) Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org. Chem. 1987, 52,
1177-1185.
(7) Lakatosh, S. A.; Balzarini, J.; Andrei, G.; Snoeck, R.; De Clercq,
E.; Preobrazhenskaya, M. N. J. Antibiot. 2002, 55, 768-773.
(8) (a) Tominaga, Y.; Shigemitsu, Y.; Sasaki, K. J. Heterocycl. Chem.
2002, 39, 571-591. (b) Shigemitsu, Y.; Tominaga, Y. Heterocycles 2001,
55, 2257-2260.
(4) Booker-Milburn, K. I.; Baker, J. R.; Bruce, I. Org. Lett. 2004, 6,
1481-1484.
(5) Baenziger, M.; McGarrity, J. F.; Meul, T. J. Org. Chem. 1993, 58,
4010-4012.
(9) Clark, J. H.; Miller, J. M. J. Am. Chem. Soc. 1977, 99, 498-504.
(10) Sahoo, M. K.; Mhaske, S. B.; Argade, N. P. Synthesis 2003, 346-
349.
10.1021/jo0605750 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/10/2006
J. Org. Chem. 2006, 71, 4703-4705
4703

TABLE 1. Alkylation of Methoxymaleimide (5a)a
SCHEME 1. Synthesis of Methyl Tetramate Derivatives
yieldb (%)
entry
RX
product
method A
method B
1
2
3
4
5
MeI
EtI
allyl chloride
BnCl
5b
5c
5d
5e
5f
87
92
10
99c
91
90
61
84
94
68
PMBCl
a Method A: 5a, RX (2-2.9 equiv), K2CO3 (1.2 equiv), acetone, reflux,
17-90 h. Method B: 5a, RX (3 equiv), CsF (3 equiv), DMF, 30-38 °C,
24 h. b Isolated yields. c MeCN as solvent, 50 °C (55% yield with acetone).
TABLE 2. Regioselective Reduction of 5a-g
entry
substrate
R
time (min)
producta
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
H
Me
Et
allyl
Bn
PMB
Ph
30
45
90
6a (87%)
6b (87%)
6c (84%)
6d (85%)
6e (83%)
6f (76%)
6g (70%)
structure of 6e was confirmed by single-crystal X-ray diffraction,
the ORTEP depiction is provided in the Supporting Information.
The structures of 6c-d,f-g, and therefore the regioselectivity
of the reduction, were assigned by analogy with the aforemen-
tioned, closely related examples.14
30
100
180
60
5g
Attempts to hydrolyze methyl 5-hydroxytetramates 6a and
6e (aq HCl) have thus far been thwarted by difficulties with
purification and/or instability of the resultant 5-hydroxytetramic
acids. It is possible that 3-acyl derivatives, such as the natural
products integramycin (3) and delaminomycin (4), are inherently
more stable, and as such, future work will be directed toward
these types of systems. Nevertheless, methyl 5-hydroxytetra-
mates 6a-g afforded by the regioselective reduction reported
herein, are versatile building blocks for the synthesis of a range
of tetramate derivatives (Scheme 1). Treatment of 6a and 6e
with methanolic HCl afforded methyl 5-methoxytetramates 7
and 8, in 100% and 89% yields, respectively. Reduction of 6e
with Et3SiH and BF3‚OEt2 to afford 9 (96% yield), demonstrates
that access to methyl N-alkyltetramates can be achieved.
Acetylation of 6e (Ac2O, pyridine, DMAP) followed by
treatment of the resultant acetate with allyltrimethylsilane and
BF3‚OEt2 provided 5-allyltetramate 10 in good yield (80% over
two steps).
a Isolated yields.
We reasoned that delocalization of a lone pair on the methoxy
oxygen of 5a-g would significantly decrease the reactivity of
the C5 carbonyl group toward nucleophilic attack by hydride
reducing reagents and that, for this reason, the reduction of these
systems should be particularly regioselective.12 A survey of
common reducing agents showed DIBAL-H, in THF or CH2-
Cl2, to be surprisingly nonselective in its reaction with 5e,
providing ca. 1:1 mixtures of regioisomeric reduction products.
Reduction of 5e with LiAlH4 gave an 88:12 mixture of products
resulting from attack at C2 and C5, respectively, and appreciable
quantities of over-reduced compounds. The use of NaBH4-
CeCl3 improved the regioselectivity to 97:3 in favor of the C2-
reduced compound; however, the use of NaBH4 by itself, in
THF-H2O at 0 °C proved particularly effective and convenient,
providing 6e as the sole isolated regioisomer in 83% yield (Table
2, entry 5). In all cases studied (Table 2), these conditions
provided good yields (70-87%) of the methyl 5-hydroxytet-
ramates 6a-g, with no evidence for the formation of the
regioisomeric products, resulting from borohydride attack at C5
of 5a-g.
Experimental Section
Method A Representative Procedure. To a solution of 3-meth-
oxymaleimide (5a) (40.0 mg, 0.315 mmol) in MeCN (0.52 mL)
were added K2CO3 (52.2 mg, 0.378 mmol, 1.2 equiv) and then
The physical and spectroscopic data, e.g., 1H and 13C NMR,
for 6a and 6b match that reported previously,12,13 while the
(13) Farina, F.; Victoria Martin, M.; Carmen Paredes, M.; Carmen Ortega,
M.; Tito, A. Heterocycles 1984, 22, 1733-1739.
(14) The chemical shift of the olefinic methine carbon in the two possible
regioisomers is also diagnostic, δC 93.2 for 6e, in which this carbon is R-
to the carbonyl, cf. δC 106.8 for the other regioisomer, in which this carbon
is â- to the carbonyl. See the Supporting Information for spectroscopic data
for this regioisomeric product.
(11) Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.; Yoda,
H.; Takabe, K. J. Chem. Soc., Perkin Trans. 1 2002, 707-709.
(12) Stachel, H.-D.; Schachtner, J.; Seidel, J. Z. Naturforsch., B: Chem.
Sci. 1996, 51, 409-416.
4704 J. Org. Chem., Vol. 71, No. 12, 2006

BnCl (72 µL, 0.63 mmol, 2.0 equiv) dropwise. The mixture was
heated to 50 °C until TLC analysis indicated complete conversion
of the starting material (90 h). After being cooled to rt, the reaction
mixture was concentrated in vacuo and then partitioned between
half-saturated aq NH4Cl and EtOAc. The layers were separated,
and the aqueous phase was extracted with EtOAc (2×). The
combined organic layers were dried (MgSO4) and filtered, and then
the filtrate was concentrated in vacuo. Purification of the residue
by flash chromatography (hexane/EtOAc 60:40) gave 1-benzyl-3-
methoxy-1H-pyrrole-2,5-dione (5e) as a colorless solid (67.6 mg,
95.2 (CH), 84.9 (CH), 58.2 (CH3), 50.4 (CH3), 42.5 (CH2); MS
(ESI) m/z 234 [M + H]+; HRMS (ESI) calcd for C13H16NO3 [M
+ H]+ 234.1125, found 234.1131.
1-Benzyl-4-methoxy-1H-pyrrol-2(5H)-one (9). To a cooled (0
°C) suspension of 6e (40.5 mg, 0.185 mmol, 1.0 equiv) in CH2Cl2
(1.3 mL) was added triethylsilane (59 µL, 0.37 mmol, 2.0 equiv),
followed by BF3‚OEt2 (47.0 µL, 0.370 mmol, 2.0 equiv.). The
mixture was slowly warmed to rt and stirred for 24 h. The solution
was quenched with saturated aq K2CO3 solution, and then the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3×),
and the combined organic portions were dried (Na2SO4), filtered,
and concentrated. Purification by flash chromatography (EtOAc/
acetone 95:5) afforded 9 as a colorless solid (36.1 mg, 96%): mp
99%): mp 68-69 °C; IR (thin film) 3117, 3032, 1709, 1639 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.27 (m, 5H), 5.39 (s, 1H), 4.62 (s,
2H), 3.85 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 169.6 (C), 165.0
(C), 160.8 (C), 136.1 (C), 128.4 (CH), 128.0 (CH), 127.5 (CH),
96.2 (CH), 58.8 (CH3), 40.9 (CH2); MS (ESI) m/z 240 [M + Na]+,
218 [M + H]+; HRMS (EI) calcd for C12H11NO3 (M+) 217.0739,
found 217.0737.
1
44-45 °C; IR (thin film) 3028, 1674, 1624 cm-1; H NMR (300
MHz, CDCl3) δ 7.34-7.22 (m, 5H), 5.10 (s, 1H), 4.57 (s, 2H),
3.76 (s, 3H), 3.72 (s, 2H); 13C NMR (75.5 MHz, CDCl3) δ 173.3
(C), 172.0 (C), 137.4 (C), 128.6 (CH), 127.8 (CH), 127.4 (CH),
94.1 (CH), 58.0 (CH3), 49.8 (CH2), 45.3 (CH2); MS (ESI) m/z 226
[M + Na]+, 204 [M + H]+; HRMS (ESI) calcd for C12H13NO2Na
[M + Na]+ 226.0839, found 226.0836.
Method B Representative Procedure. To a mixture of 3-meth-
oxymaleimide (5a) (63.5 mg, 0.500 mmol) and anhydrous CsF (228
mg, 1.50 mmol, 3.0 equiv) was added DMF (1.67 mL), followed
by allyl chloride (122 µL, 1.50 mmol, 3.0 equiv). The mixture was
heated at 30-38 °C for 24 h. The suspension was diluted with
half-saturated aq NaHCO3 solution and EtOAc, and then the layers
were separated. The aqueous phase was extracted with EtOAc (5×),
and the combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo. Purification of the residue by flash
chromatography (hexane/EtOAc 60:40) provided 1-allyl-3-methoxy-
1H-pyrrole-2,5-dione (5d) as a colorless solid (70.0 mg, 84%): mp
5-Allyl-1-benzyl-4-methoxy-1H-pyrrol-2(5H)-one (10). To a
solution of 6e (76.3 mg, 0.348 mmol, 1.0 equiv) in pyridine (7.0
mL) at rt was added Ac2O (329 µL, 3.48 mmol, 10 equiv) followed
by DMAP (4.3 mg, 0.0348 mmol, 0.1 equiv). After being stirred
for 3 h, the reaction was quenched with water and extracted with
Et2O (5 ×). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. Purification by flash chromatography
(hexane/EtOAc 60:40) afforded 5-acetoxy-1-benzyl-4-methoxy-1H-
pyrrol-2(5H)-one as a colorless solid (77.5 mg, 85%): mp 102-
1
61-63 °C; IR (thin film) 3111, 1705, 1626 cm-1; H NMR (300
1
104 °C; IR (thin film) 3115, 1749, 1711, 1641 cm-1; H NMR
MHz, CDCl3) δ 5.80 (ddt, J ) 17.2, 15.7, 5.5 Hz, 1H), 5.43 (s,
1H), 5.21 (dq, J ) 7.8, 1.5 Hz, 1H), 5.14 (m, 1H), 4.11 (dt, J )
5.6, 1.5 Hz, 2H), 3.94 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
169.6 (C), 165.1 (C), 160.9 (C), 131.5 (CH), 117.5 (CH2), 96.2
(CH), 58.9 (CH3), 39.6 (CH2); MS (ESI) m/z 190 [M + Na]+, 168
[M + H]+; HRMS (ESI) calcd for C8H9NO3Na [M + Na]+
190.0475, found 190.0477.
(300 MHz, CDCl3) δ 7.30-7.23 (m, 5H), 6.42 (s, 1H), 5.13 (s,
1H), 4.59 (d, J ) 15.3 Hz, 1H), 4.41 (d, J ) 15.3 Hz, 1H), 3.80 (s,
3H), 1.88 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 171.2 (C), 170.5
(C), 170.2 (C), 137.2 (C), 128.4 (CH), 128.0 (CH), 127.3 (CH),
94.5 (CH), 79.2 (CH), 58.5 (CH3), 43.8 (CH2), 20.4 (CH3); MS
(ESI) m/z 284 [M + Na]+; HRMS (ESI) calcd for C14H15NO4Na
[M + Na]+ 284.0894, found 284.0897. To a cooled (0 °C) solution
of 5-acetoxy-1-benzyl-4-methoxy-1H-pyrrol-2(5H)-one (20.5 mg,
0.0785 mmol, 1.0 equiv), from the above procedure, in CH2Cl2
(0.8 mL), was added BF3‚OEt2 (39.8 µL, 0.314 mmol, 4.0 equiv).
After the mixture was stirred at 0 °C for 10 min, allyltrimethylsilane
(37.4 µL, 0.236 mmol, 3.0 equiv) was added dropwise via syringe.
The reaction was stirred at 0 °C for 7 h, warmed to rt, and stirred
for another 16 h. After the mixture was poured into water (1 mL),
the layers were separated and the aqueous phase was extracted with
CH2Cl2 (3 ×). The combined organic portions were washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by flash chromatography (hexane/acetone 60:40) afforded 10
as a colorless oil (17.9 mg, 94%): IR (thin film) 3076, 3028, 1680,
Representative Procedure for the Regioselective Reduction
using NaBH4. To a cooled (0 °C) solution of 5e (65.5 mg, 0.302
mmol) in 2:1 THF (0.3 mL) and H2O (0.15 mL) was added NaBH4
(12 mg, 0.31 mmol, 1.0 equiv). The resulting solution was stirred
at 0 °C for 100 min and then quenched by the dropwise addition
of acetone (1 mL). Silica gel (0.7 g) was added, and the volatile
components were removed in vacuo. Purification by flash chro-
matography (MeOH/CH2Cl2 5:95) afforded 1-benzyl-5-hydroxy-
4-methoxy-1H-pyrrol-2(5H)-one (6e) as a colorless solid (54.9 mg,
83%): mp 134-138 °C; IR (thin film) 3130, 3032, 1655, 1643
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 5.06 (br d, J
) ∼9 Hz, 1H), 5.00 (s, 1H), 4.94 (d, J ) 15.1 Hz, 1H), 4.17 (d, J
) 15.1 Hz, 1H), 3.80 (s, 3H), 3.68 (br d, J ) ∼9 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 173.9 (C), 170.4 (C), 137.2 (C), 128.7
(CH), 128.2 (CH), 127.5 (CH), 93.2 (CH), 80.0 (CH), 58.4 (CH3),
42.3 (CH2); MS (ESI) m/z 242 [M + Na]+, 220 [M + H]+, 202
[M - OH]+; HRMS (ESI) calcd for C12H13NO3Na [M + Na]+
242.0788, found 242.0784.
1
1626 cm-1; H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 5H),
5.51 (ddt, J ) 17.1, 10.2, 7.1 Hz, 1H), 5.17 (d, J ) 15.4 Hz, 1H),
5.10 (s, 1H), 5.07 (m, 1H), 5.06 (m, 1H), 3.98 (d, J ) 15.4 Hz,
1H), 3.87 (t, J ) 4.3 Hz, 1H), 3.76 (s, 3H), 2.57-2.38 (m, 2H);
13C NMR (75.5 MHz, CDCl3) δ 175.3 (C), 171.7 (C), 137.6 (C),
131.0 (CH), 128.6 (CH), 127.9 (CH), 127.4 (CH), 118.8 (CH2),
94.2 (CH), 58.5 (CH3), 58.0 (CH), 43.2 (CH2), 32.6 (CH2); MS
(ESI) m/z 266 [M + Na]+, 244 [M + H]+; HRMS (ESI) calcd for
C15H17NO2Na [M + Na]+ 266.1152, found 266.1152.
1-Benzyl-4,5-dimethoxy-1H-pyrrol-2(5H)-one (8). To a cooled
(0 °C) solution of 6e (100 mg, 0.456 mmol) in MeOH (4.6 mL)
was added TMSCl (174 µL, 1.37 mmol, 3.0 equiv). The reaction
was warmed to rt and allowed to stir for 21 h, and then the mixture
was concentrated in vacuo. The residue was dissolved in EtOAc,
and the organic phase was washed with half-saturated aq NaHCO3
solution and then brine. The organic phase was dried (Na2SO4),
filtered, and concentrated. Purification of the residue by flash
chromatography (EtOAc/acetone 95:5) afforded 8 as a colorless
Acknowledgment. We thank the Australian Research Coun-
cil for funding and CSIRO for a scholarship to J.F.
Supporting Information Available: Experimental procedures
and characterization data for new compounds not included in the
Experimental Section; ORTEP depiction and X-ray crystallographic
data (CIF) for 6e; 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
oil (94.8 mg, 89%): IR (thin film) 3107, 3028, 1703, 1634 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 5H), 5.14 (s, 1H),
5.04 (s, 1H), 4.96 (d, J ) 14.9 Hz, 1H), 4.02 (d, J ) 14.9 Hz, 1H),
3.80 (s, 3H), 3.11 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 171.4
(C), 170.0 (C), 137.1 (C), 128.5 (CH), 128.3 (CH), 127.4 (CH),
JO0605750
J. Org. Chem, Vol. 71, No. 12, 2006 4705