General strategy for the synthesis of natural and unnatural dialkylmaleic anhydrides

Article abstract of DOI:10.1021/jo801284r

(Chemical Equation Presented) Starting from alkylidenesuccinimides, a wide range of dialkylmaleic anhydrides have been synthesized via the generation of a carbanion on a succinimide unit and its condensation with various alkyl halides as the key reaction.

Full text of DOI:10.1021/jo801284r

the carbonyl and was further confirmed by comparing with
similar known compounds.5t Recently, we have proved that the
alkylidenesuccinimides are thermodynamically more stable than
the corresponding alkylmaleimides and hence a direct proto-
tropic shift with an exocyclic to endocyclic double bond
migration is impossible.7 We reasoned and planned to take
advantage of this observation by studying the feasibility of
generation of an allylic carbanion on the alkylidenesuccinimide
nucleus and further explore its condensation reactions with a
variety of alkyl halides to develop a new general approach to
dialkyl maleimides and maleic anhydrides.
General Strategy for the Synthesis of Natural and
Unnatural Dialkylmaleic Anhydrides
Kishan P. Haval and Narshinha P. Argade*
DiVision of Organic Chemistry, National Chemical
Laboratory, Pune 411 008, India
np.argade@ncl.res.in
ReceiVed June 16, 2008
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3a-r.
Starting from alkylidenesuccinimides, a wide range of
dialkylmaleic anhydrides have been synthesized via the
generation of a carbanion on a succinimide unit and its
condensation with various alkyl halides as the key reaction.
The cyclic anhydride is one of the important functionalities
in chemistry and has been used to design a variety of bioactive
natural products, structurally interesting heterocyclic systems,
and polymers with tailored material characteristics.1 To date,
several dialkylmaleic anhydrides have also been isolated as
potent bioactive natural products2,3 and many product specific
syntheses with some limitations are known in the literature.4,5
Now, we herein report a general strategy for the synthesis of a
wide range of natural and unnatural dialkylmaleic anhydrides.
It is well established that maleimides couple with triph-
enylphosphine to generate an in situ Wittig reagent, which on
reaction with a variety of aldehydes provide the corresponding
thermodynamically more stable (E)-alkylidenesuccinimides in
decent yields.6 The exclusive formation of (E)-isomers in
products 2a-c was established on the basis of the lower field
1H NMR resonance for the vinylic proton in close proximity to
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(f) Baag, M.; Argade, N. P. Synthesis 2006, 1005. (g) Easwar, S.; Argade, N. P.
Synthesis 2006, 831. (h) Kar, A.; Gogoi, S.; Argade, N. P. Tetrahedron 2005,
61, 5297. (i) Buyck, L. D.; Danieli, C.; Ghelfi, F.; Pagnoni, U. M.; Parsons,
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Synthesis 2002, 2729. (q) Mangaleswaran, S.; Argade, N. P. J. Org. Chem. 2001,
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6936 J. Org. Chem. 2008, 73, 6936–6938
10.1021/jo801284r CCC: $40.75 2008 American Chemical Society
Published on Web 07/30/2008

TABLE 1. Synthesis of Natural and Unnatural Dialkylmaleic Anhydridesa
entry
RCHO
product 2 (% yield)
R′X
product 6 (% yield)
product 7 (% yield)
product 8 (% yield)
1
2
3
4
5
6
7
8
9
CH3(CH2)4CHO
CH3(CH2)4CHO
CH3(CH2)4CHO
CH3(CH2)4CHO
CH3(CH2)12CHO
PhCHO
PhCHO
PhCHO
PhCHO
2a (91)
2a (91)
2a (91)
2a (91)
2b (89)
2c (93)
2c (93)
2c (93)
2c (93)
EtO2CCH2Br
EtO2CCH2CH2Br
CH3(CH2)4CH2Br
PhCH2Br
CH3I
PhCH2Br
(CH3)2CHI
CH3I
(CH3)2CdCHCH2Br
6a (70)
6b (-)b
6c (72)
6d (80)
6e (65)
6f (87)
6g (92)
6h (68)
6i (85)
7a (92)
7b (70)c
7c (98)
7d (93)
7e (90)
7f (94)
7g (98)
7h (92)
8a (88)d
8b (85)d
8c (90)f
8d (97)f
8e (91)d
8f (97)e
8g (94)e
8h (89)f
a Reagents and conditions: (i) Ph3P (1.00 equiv), RCHO (1.50 equiv), THF, reflux, 10 h (89-93%); (ii) (a) NaH (1.00 equiv), THF, 0 °C, 0.5 h, (b)
R′X (1.00 equiv), 0 °C to rt, 3 h (65-92%); (iii) Et3N + THF (1:1), reflux, 48 h (90-98%); (iv) (a) THF + MeOH (1:2), KOH, H2O, reflux, 2 h, (b)
H+/HCl (85-97%). b Not isolated as both the starting material 2a and the product 6b were having the same Rf value. c Yield over two steps. d Natural
products. e Natural product precursors. f Unnatural analogues.
SCHEME 1a
In alkylidenesuccinimides 2a-c the methylene protons are
acidic because of the adjacent imide carbonyl group and their
allylic nature. As per our hypothesis, the alkylidenesuccinimides
2a-c on treatment with an equivalent amount of sodium hydride
in THF at 0 °C turned into a deep red solution, indicating the
formation of the carbanion. The reactions of the above carban-
a Reagents and conditions: (i) Et3N + THF (1:1), reflux, 2 h (98%).
ionic solutions with simple alkyl halides, activated alkyl halides,
allylic alkyl halides, and benzyl halides at 0 °C exclusively
furnished the corresponding desired ring monoalkylated products
6a-i in 65-92% yields (Table 1). Herein also the (E)-geometry
of the exocyclic carbon-carbon double bond in products 6a-i
was confirmed on the basis of 1H NMR data. These observations
clearly revealed that the alkylidenesuccinimidoyl carbanionic
species 3a-c can be in resonance with intermediates 4a-c and
alkylmaleimidoyl carbanionic species 5a-c. We feel that the
resonance hybrid prefers to react with alkyl halides via the
relatively more contributing carbanionic species 3a-c rather
than the carbanionic species 5a-c to form the products 6a-i.
With the introduction of suitable alkyl substituents on 2a-c to
form 6a-i, the trisubstituted exocyclic to tetrasubstituted
endocyclic carbon-carbon double bond isomerization became
feasible on treatment of 6a-h with triethylamine to obtain 7a-h
in 70-98% yields. Interestingly, the alkylsuccinimide 6i on
treatment with triethylamine underwent two successive proto-
tropic shifts to exclusively yield the thermodynamically more
stable alkylidenesuccinimide 10 via the unisolable dialkyl
maleimide intermediate 9 (Scheme 1). In the conversion of 6i
to 10, the loss of conjugation with the phenyl ring and
subsequent gain of conjugation with the acyclic carbon-carbon
double bond indicates that the order of thermodynamic stability
is 10 > 9 > 6i and it is noteworthy. The dialkylsubstituted
maleimides 7a, 7b, and 7e on base catalyzed hydrolysis followed
by acidification respectively furnished the natural products
2-carboxymethyl-3-hexylmaleic anhydride (8a) (Aspergillus FH-
X-213),3q 2-(ꢀ-carboxyethyl)-3-hexylmaleic anhydride (8b)
(Pseudomonas cepacica A-1419),3g and the potent ras fernesyl-
protein transferase inhibitor chaetomellic acid A (8e) (Cha-
etomella acutiseta)3j in 85-91% yields. The maleimides 7f and
7g on hydrolysis respectively furnished the dibenzylmaleic
anhydride 8f in 97% yield and isopropylbenzylmaleic anhydride
8g in 94% yield. The formal syntheses of naturally occurring
maculalactones A-C (Kyrtuthrix maculans)3d from dibenzyl-
maleic anhydride 8f and nostoclide I (Peltigera canina)3i from
isopropylbenzylmaleic anhydride 8g are known in the
literature.5h The analytical and spectral data obtained for natural
products 8a, 8b, and 8e and natural product precursors 8f and
8g were in complete agreement with the reported data.5l-n,h
Finally, the maleimides 7c, 7d, and 7h on hydrolysis furnished
the expected corresponding unnatural dialkylmaleic anhydrides
8c, 8d, and 8h in 89-97% yields.
In summary, we have demonstrated a new robust approach
to potentially useful natural and unnatural dialkylmaleic anhy-
drides via the generation of a carbanion on the alkylidenesuc-
cinimide core. We feel that the present general approach to
dialkylmaleimides/anhydrides will be useful to design several
structurally interesting and biologically important natural and
unnatural carbocycles and heterocycles.
J. Org. Chem. Vol. 73, No. 17, 2008 6937

triethylamine (10 mL) and the reaction mixture was refluxed for
48 h and then concentrated in vacuo. The residue was dissolved in
ethyl acetate and the organic layer was washed with water and brine
and dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica gel column chromatographic purification of the
residue with petroleum ether and ethyl acetate furnished 7a-h in
70-98% yields.
Experimental Section
General Procedure for the Synthesis of 2a-c. A solution of
N-p-tolylmaleimide (1, 10.00 mmol) and triphenylphosphine (10.00
mmol) in THF (100 mL) was stirred at room temperature for 30
min. To the reaction mixture was added the corresponding aliphatic/
aromatic aldehyde (15.00 mmol) and the reaction mixture was
refluxed for 10 h. The THF was distilled off in vacuo at 50 °C and
the residue was purified by silica gel column chromatography, using
a mixture of petroleum ether and ethyl acetate to obtain 2a-c in
89-93% yields.
Ethyl 2-(4-Hexyl-2,5-dioxo-1-p-tolyl-2,5-dihydro-1H-pyrrol-3-
1
yl)acetate (7a). Thick oil (262 mg, 92%): H NMR (CDCl3, 200
MHz) δ 0.90 (t, J ) 8 Hz, 3H), 1.29 (t, J ) 6 Hz, 3H), 1.20-1.45
(m, 6H), 1.61 (quintet, J ) 8 Hz, 2H), 2.38 (s, 3H), 2.50 (t, J ) 8
Hz, 2H), 3.52, (s, 2H), 4.21 (q, J ) 8 Hz, 2H), 7.15-7.30 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 13.9, 14.0, 21.0, 22.4, 24.2,
28.0, 29.0, 29.2, 31.3, 61.5, 125.6, 129.0, 129.5, 133.0, 137.4, 144.1,
(E)-3-Hexylidene-1-p-tolylpyrrolidene-2,5-dione (2a).7b White
solid (2.47 g, 91%): mp 112-113 °C; 1H NMR (CDCl3, 200 MHz)
δ 0.90 (t, J ) 6 Hz, 3H), 1.22-1.45 (m, 4H), 1.53 (quintet, J ) 6
Hz, 2H), 2.23 (q, J ) 6 Hz, 2H), 2.37 (s, 3H), 3.37 (d, J ) 2 Hz,
2H), 6.93 (tt, J ) 8 and 2 Hz, 1H), 7.18 (d, J ) 8 Hz, 2H), 7.27
(d, J ) 8 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 13.7, 20.9, 22.2,
27.5, 29.6, 31.2, 31.8, 125.1, 126.0, 129.2, 129.4, 138.1, 139.6,
168.7, 173.0; MS (m/e) 271, 242, 228, 214, 200, 189, 172, 133,
107, 95, 81, 67, 53; IR (nujol) νmax 1771, 1749, 1712, 1691, 1676
cm-1. Anal. Calcd for C17H21NO2: C, 75.24; H, 7.80; N, 5.16.
Found: C, 75.11; H, 7.92; N, 5.07.
168.5, 169.9, 170.2; IR (neat) νmax 1772, 1740, 1713, 1616 cm-1
.
Anal. Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C,
70.63; H, 7.72; N, 4.01.
Tabulated analytical and spectral data of compounds 7b-h have
been given in the Supporting Information.
General Procedure for the Synthesis of 8a-h. To a stirred
solution of 7a-h (0.50 mmol) in a THF-methanol mixture (1:2,
6 mL) was added 20% aqueous KOH solution (4 mL) and the
reaction mixture was refluxed for 2 h with stirring. The reaction
mixture was concentrated and the residue was acidified with 2 N
HCl then extracted with diethyl ether (3 × 20 mL) and the organic
layer was washed with water and brine and dried over Na2SO4.
Concentration of the organic layer in vacuo followed by silica gel
column chromatographic purification of the residue with petroleum
ether and ethyl acetate furnished 8a-h in 85-97% yields.
2-(4-Hexyl-2,5-dioxo-2,5-dihydrofuran-3-yl)acetic Acid (2-Car-
boxymethyl-3-hexylmaleic anhydride, 8a).5n Thick oil (104 mg,
Tabulated analytical and spectral data of compounds 2b and 2c
have been given in the Supporting Information.
General Procedure for the Synthesis of 6a-i. A solution of
2a-c (1.60 mmol) in THF (20 mL) was added to the slurry of
sodium hydride (1.60 mmol) in THF (10 mL) at 0 °C and the
reaction mixture was stirred for 30 min. Then, the corresponding
alkyl halide (1.60 mmol) was added to the reaction mixture at 0
°C and the solution was stirred for 3 h. The reaction mixture was
acidified by 2 N HCl and then it was concentrated in vacuo. The
residue was dissolved in ethyl acetate and the organic layer was
washed with water and brine and dried over Na2SO4. Concentration
of the organic layer in vacuo followed by silica gel column
chromatographic purification of residue with petroleum ether and
ethyl acetate furnished 6a-i in 65-92% yields.
1
88%): H NMR (CDCl3, 200 MHz) δ 0.89 (t, J ) 8 Hz, 3H),
1.15-1.45 (m, 6H), 1.60 (quintet, J ) 8 Hz, 2H), 2.50 (t, J ) 8
Hz, 2H), 3.57 (s, 2H), 8.60 (br s, 1H); 13C NMR (CDCl3, 50 MHz)
δ 13.9, 22.4, 24.9, 27.5, 29.1, 31.3, 135.5, 148.1, 165.1, 173.0; IR
(Neat) νmax 1820, 1771, 1718, 1216, 925, 670 cm-1. Anal. Calcd
for C12H16O5: C, 59.99; H, 6.71. Found: C, 60.12; H, 6.65.
Tabulated analytical and spectral data of compounds 8b-h have
been given in the Supporting Information.
(E)-Ethyl 2-(4-Hexylidene-2,5-dioxo-1-p-tolylpyrrolidin-3-yl)ac-
etate (6a). Thick oil (399 mg, 70%): 1H NMR (CDCl3, 200 MHz)
δ 0.92 (t, J ) 8 Hz, 3H), 1.21 (t, J ) 8 Hz, 3H), 1.27-1.43 (m,
4H), 1.53 (quintet, J ) 6 Hz, 2H), 2.29 (q, J ) 6 Hz, 2H), 2.39 (s,
3H), 3.01 (dd, J ) 17 and 6 Hz, 1H), 3.26 (dd, J ) 17 and 4 Hz,
1H), 3.57-3.68 (m, 1H), 4.12 (q, J ) 8 Hz, 2H), 6.94 (dt, J ) 7
and 2 Hz, 1H), 7.20-7.33 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ
13.9, 14.1, 21.2, 22.4, 28.2, 29.3, 31.5, 34.5, 38.8, 61.2, 126.3,
128.1, 129.5, 129.7, 138.5, 140.6, 169.2, 170.0, 176.1; IR (neat)
(E)-3-Benzyl-4-(3-methylbut-2-enylidene)-1-p-tolylpyrrolidine-
2,5-dione (10). This compound was obtained from 6i by using the
procedure used for the synthesis of 7a-h in 2 h as a thick oil (270
1
mg, 98%): H NMR (CDCl3, 200 MHz) δ 1.99 (s, 3H), 2.01 (s,
3H), 2.35 (s, 3H), 3.22-3.44 (m, 2H), 3.84 (t, J ) 4 Hz, 1H), 6.05
(td, J ) 12 and 2 Hz, 1H), 6.81 (d, J ) 10 Hz, 2H), 7.05-7.32 (m,
7H), 7.56 (dd, J ) 14 and 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
δ 19.1, 21.2, 27.2, 36.5, 44.5, 120.4, 124.4, 126.3, 127.2, 128.3,
129.2, 129.6, 129.8, 131.6, 135.4, 138.4, 150.2, 169.8, 176.0; IR
(Neat) νmax 1765, 1705, 1634 cm-1. Anal. Calcd for C23H23NO2:
C, 79.97; H, 6.71; N, 4.06. Found: C, 80.06; H, 6.83; N, 4.02.
ν
max 1771, 1732, 1713, 1672 cm-1. Anal. Calcd for C21H27NO4: C,
70.56; H, 7.61; N, 3.92. Found: C, 70.44; H, 7.80; N, 3.99.
Tabulated analytical and spectral data of compounds 6c-h have
been given in the Supporting Information.
(E)-3-Benzylidene-4-(3-methylbut-2-enyl)-1-p-tolylpyrrolidine-
2,5-dione (6i). Thick oil (468 mg, 85%): H NMR (CDCl3, 200
1
Acknowledgment. K.P.H. thanks CSIR, New Delhi, for the
award of a research fellowship.
MHz) δ 1.40 (s, 3H), 1.61 (s, 3H), 2.40 (s, 3H), 2.60-2.92 (m,
2H), 4.06 (dt, J ) 6 and 2 Hz, 1H), 4.92-5.06 (m, 1H), 7.18 (d,
J ) 8 Hz, 2H), 7.30 (d, J ) 8 Hz, 2H), 7.40-7.61 (m, 5H), 7.75
(d, J ) 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 17.8, 21.2, 25.9,
27.1, 43.4, 117.1, 126.2, 127.9, 129.0, 129.4, 129.8, 130.0, 130.1,
133.7, 135.4, 136.9, 138.6, 170.2, 176.7; IR (neat) νmax 1769, 1711,
1651 cm-1. Anal. Calcd for C23H23NO2: C, 79.97; H, 6.71; N, 4.06.
Found: C, 80.08; H, 6.90; N, 4.15.
Supporting Information Available: 1H and 13C NMR
spectra of 2a, 2c, 6a, 6c, 6d, 6f, 6i, 7a-d, 7f-h, 8a-d, 8f, 8h,
and 10 and tabulated analytical and spectral data of compounds
2b, 2c, 6c-h, 7b-h, and 8b-h. This material is available free
of charge via the Internet at http://pubs.acs.org.
General Procedure for the Synthesis of 7a-h. To a stirred
solution of 6a-h (0.80 mmol) in THF (10 mL) was added
JO801284R
6938 J. Org. Chem. Vol. 73, No. 17, 2008