Succinimides represent a privileged scaffold in medicinal chemistry, and this structural
motif can be found in many natural products such as moiramide B, andrimid, hirsutellone
A, and haterumaimide A (Figure [1]).[1]
Figure 1 Examples of biologically active succinimide-containing natural products
Succinimide-substructure-containing compounds show great pharmacological potential
acting as enzyme inhibitors, analgesics, antimicrobial agents, anxiolytics, cytotoxic,
anticonvulsants, antitumor drugs, and anti-Parkinson’s agents.[2] On the other hand, chromones are an important moiety, forming the nucleus of a class
of heterocyclic natural products called flavanoids that occur naturally in fruits,
vegetables, nuts, seeds, flowers, and bark.[3] They are an integral part of the human diet and have been reported to exhibit a
wide range of biological effects.[4] They display not only spasmolytic, diuretic, clotting, antibacterial, antiviral,
antitumoral, anti-inflammatory, and anti-anaphylactic activity, but can also be used
as antioxidants, pigments, photoactive materials, and biodegradable agrochemicals.[5]
Meldrum’s acid and its 5-arylidene or 5-alkylidene derivatives (which are readily
accessible from the reactions of Meldrum’s acid and aldehydes or ketones) have acquired
considerable interest as highly reactive electron-deficient heterodienes in isocyanide-based
multicomponent reactions. In our earlier publications,[6] we have described four relatively facile routes to amidodiesters and triamides by
taking advantage of Meldrum’s acid derivatives. These compounds were obtained by treatment
of Meldrum’s acids with aldehydes (5-alkylidene or 5-arylmethylidene Meldrum’s acids)
and isocyanides in the presence of such nucleophiles as alcohols,[6a]
[b]
[c] phenols,[6c] and primary amines[6d] in dichloromethane. Based on these efficient and useful multicomponent reactions,
more efforts were made to investigate the reactions of Meldrum’s acid derivatives
and isocyanides with other nucleophiles such as water,[7] diols,[8] arylhydroxylamines,[9] aryl hydrazines,[10] 2-hydroxy benzaldehydes,[11] sugar hydroxyaldehydes,[12] and urea,[13] which produced 4-oxobutanoic acids, 2-arylisoxazolidine-3,5-diones, 1,4-dioxepane-5,7-diones,
1-arylpyrazolidine-3,5-diones, 3,4-dihydrocoumarins, 5-oxo-perhydrofuro-[3,2-b]pyrans, and barbituric acid derivatives, respectively.
Recently, we reported the pseudo-five-component tandem reaction of 3-formylchromones,
Meldrum’s acid, and isocyanides with primary aryl amines, which offers an efficient
route to construct chromone-containing tripeptides under mild conditions with high
efficiency.[14] However, when the substrate combination was switched from primary aryl amines to
alcohols, to our surprise, none of the expected products 5 were obtained. We now disclose a new multicomponent cascade reaction of 3-formylchromones
1 with Meldrum’s acid (2), isocyanides 3, and alcohols 4 diastereoselectively providing polyfunctionalized succinimide derivatives 6 (Scheme [1]).
Scheme 1Synthesis of chromone-bound succinimides 6
In an initial experiment, a solution of equimolar amounts 6-methyl-3-formylchromone,
Meldrum’s acid, benzyl isocyanide, and 2-adamantol in dry dichloromethane was stirred
at room temperature for 24 hours to afford 2-adamantyl 1-benzyl-4-(6-methyl-4-oxo-4H-chromen-3-yl)-2,5-dioxopyrrolidine-3-carboxylate (6i) in 85% yield (Table [1], entry 9). To evaluate the use of this interesting approach, a variety of 3-formylchromones,
alkyl isocyanides, and various alcohols was examined. Notably, the reaction was straightforward
and proceeded cleanly at room temperature in dry dichloromethane to produce the corresponding
products 6a–k in moderate to good yields, and no undesirable side reactions were observed. The
structures of the new products 6a–k were established by their satisfactory elemental analyses and spectroscopic (1H, 13C NMR, and IR) studies.[15]
The elucidation of the structure of 6 using 1H NMR and 13C NMR spectroscopic data is discussed with 6i as an example. The 1H NMR spectrum of 6i consisted of multiplet signals for the adamantyl rings (δH = 1.49–2.06 ppm) and the OCH resonance (δH = 5.00–5.04 ppm), a sharp singlet for the methyl (δH = 2.45 ppm) hydrogens, and two AB systems for the two methine (δH = 4.02 and 4.08 ppm, 3
J
HH = 6.1 Hz) protons of the succinimide moiety and methylene protons (δH = 4.75 and 4.86 ppm, 2
J
HH = 14.4 Hz). The aromatic protons gave rise to multiplets and a doublet in the aromatic
region of the spectrum (δH = 7.26–7.94 and δH = 7.95 ppm, 3
J
HH = 5.9 Hz). The vinylic methine occurred as a sharp singlet (δH = 7.96 ppm).
The 1H-decoupled 13C NMR spectrum of 6i showed 30 distinct resonances in agreement with the suggested structure.
Encouraged by the results obtained with the above reaction conditions, and in order
to show the generality and scope of this new protocol, we turned our attention to
various 3-formylchromones, isocyanides, and alcohols. Four 3-formylchromones, six
alkyl or aryl isocyanides, and eleven alcohols were examined. Two 3-formylchromone
derivatives (3-formylchromone and 3-formyl-6-methyl-chromone) afforded chromone-bound
succinimides in moderate to good yields. Furthermore, it was observed that the nature
of the substituents at C-6 and C-8 of the chromone ring affects the reaction significantly.
Under similar reaction conditions, starting with Meldrum’s acid, cyclohexyl isocyanide,
ethanol, and chlorinated 3-formylchromones, such as 6-chloro-3-formylchromone or 6,8-dichloro-3-formylchromone,
the corresponding known products[16] (1Z)-7-chloro-1-[(6-chloro-4-oxo-4H-chromen-3-yl)methylene]-3-(cyclohexylimino)-1,3-dihydro-9H-furo[3,4-b]-chromen-9-one (7a) and (1Z)-5,7-dichloro-3-(cyclohexylimino)-1-[(6,8-dichloro-4-oxo-4H-chromen-3-yl)methylene]-1,3-dihydro-9H-furo[3,4-b]chromen-9-one (7b) were isolated, respectively, without the participation of Meldrum’s acid and ethanol,
which did not enter into these reactions.
In addition, found that the reactions proceeded very efficiently with alkyl isocyanides
(cyclohexyl isocyanide, benzyl isocyanide, 1,1,3,3-tetramethylbutyl isocyanide, and
2-morpholinoethyl isocyanide), but failed to furnish the expected chromone-bound succinimide
derivatives with aryl isocyanides (2,6-dimethylphenyl isocyanide and 2-naphthyl isocyanide).
A variety of structurally diverse alcohols underwent the one-pot reaction smoothly
without need for a catalyst to afford the corresponding succinimide derivatives in
good yields. As shown in Table [1], primary alcohols (ethanol, 1-propanol, 1-butanol, and 1-pentanol) benzylic alcohols
(benzyl- and 4-chlorobenzyl alcohol), heterocyclic alcohol (2-furylmethanol), hindered
and unhindered secondary and tertiary alcohols (2-adamantol, cyclohexanol, and tert-amyl alcohol) were used in this protocol with good results.
In the case of the sterically unhindered methanol, the amido diester fragments were
formed instead of the expected formation of succinimide moieties (Table [1], entries 12 and 13).
Table 1 Structure of Compounds 6a–k and 5a–b
|
Entry
|
3-Formylchromone
|
Alcohol
|
Isocyanide
|
Product
|
Yield (%)a
|
|
1
|
|
|
|
6a
|
69
|
|
2
|
|
|
|
6b
|
65
|
|
3
|
|
|
|
6c
|
67
|
|
4
|
|
|
|
6d
|
60
|
|
5
|
|
|
|
6e
|
60
|
|
6
|
|
|
|
6f
|
70
|
|
7
|
|
|
|
6g
|
55
|
|
8
|
|
|
|
6h
|
62
|
|
9
|
|
|
|
6i
|
85
|
|
10
|
|
|
|
6j
|
55
|
|
11
|
|
|
|
6k
|
50
|
|
12
|
|
|
|
5s
|
70
|
|
13
|
|
|
|
5b
|
65
|
a Yield of pure isolated product.
A plausible mechanism for the formation of the fully functionalized succinimides 6 is proposed in Scheme [2]. The reaction may be rationalized by initial formation of the conjugated electron-deficient
heterodiene by Knoevenagel condensation of the 3-formylchromone 1 and Meldrum’s acid (2), followed by a [4+1]-cycloaddition reaction with isocyanide 3 to afford an iminolactone intermediate 9. Conjugate addition of the alcohol on the enone moiety of 9, followed by cleavage of the five-membered iminolactone ring gives 10 and hence the α-oxoketene 11 by well precedented[17] electrocyclic ring opening of O-alkylated Meldrum’s acids. The α-oxoketene 11 can then undergo intramolecular reaction between the amide and ketene moieties to
give stable carbanion intermediate 12. The resulting enolate 12 undergoes stereoselective reprotonation to yield the thermodynamically favorable
isomer of the product 6. Among the alcohols studied, only methanol, as the least sterically hindered alcohol,
can compete with the adjacent amide nitrogen atom in attacking the ketene moiety to
produce the dimethyl malonate derivative 5.
Scheme 2 Possible mechanisms for the formation of products 5 and 6
It is important to note that compound 6 has two stereogenic centers, and therefore, two pairs of diastereoisomers are expected.
The 1H NMR and 13C NMR spectra of the crude reaction mixture obtained from products were consistent
with the presence of only one diastereomer. All measured coupling constants for the
protons H3 and H4 in compounds 6a–k are in the range of 6.0–6.8 Hz which suggests a trans arrangement for these two hydrogen atoms. The relative configuration was determined
by X-ray crystal-structure analysis in the case of 6i (Figure [2]).
Figure 2X-ray crystal structure of (3R,4S)-6i
In summary, we have developed a four-component tandem reaction for the formation of
biologically interesting chromone-bound succinimides. The merit of this diastereoselective
cascade reaction is highlighted by its mild reaction conditions, easy workup, acceptable
yields, high bond efficiency of producing five new bonds (two C–C and three C–heteroatom),
and two stereocenters in a single operation.
