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Synlett 2024; 35(20): 2453-2458
DOI: 10.1055/a-2403-2383
letter
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Asymmetric Intermolecular Conjugate Addition of 3-Substituted 2-Benzofuranones to Maleimides via Noncovalent NHC Catalysis

Bhaskar Deb Mondal‡
,
Sadhan Gorai‡
,
Joyram Guin∗

We gratefully acknowledge the generous financial support from the Science and Engineering Research Board, India, (CRG/2020/000800) and thank CSIR and UGC for fellowships to B.D.M. and S.G.
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Abstract

An efficient N-heterocyclic carbene (NHC)-catalyzed asymmetric conjugate addition reaction to afford synthetically challenging benzofuranone derivatives having vicinal all-carbon quaternary and tertiary stereocenters is presented. The reaction operates solely through noncovalent interaction between a newly designed NHC and the substrates, providing access to a series of functionalized benzofuranones in good yields and with high ee values. The protocol applies to preparative-scale synthesis. A catalytic cycle involving a noncovalent substrate–NHC interaction is implicated in the process, based on a mechanistic control study.


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Key words

asymmetric catalysis - N-heterocyclic carbenes - noncovalent interaction - conjugate addition - benzofuranones - maleimides

Enantioenriched benzofuranones having vicinal all-carbon quaternary and tertiary stereocenters are privileged structural motifs.[1] They are pharmacophores and are often found in many biologically relevant compounds.[2] A straightforward synthesis of such heterocyclic cores involves the catalytic asymmetric conjugate addition of 3-substituted 2-benzofuranones to suitable carbon electrophiles (Figure [1a]). Accordingly, efforts have been made to develop asymmetric polar conjugate additions of 3-substituted 2-benzofuranones to suitable C-electrophiles by using chiral Lewis acid or transition-metal catalysis.[3] An asymmetric organocatalytic variant of this transformation has also been reported with activated acyclic conjugate electrophiles[4] such as nitrostyrenes, chalcones, or conjugated esters.[5] Despite these reports, the organocatalytic asymmetric addition of 2-benzofuranones to cyclic polar electrophiles is less explored. For instance, chiral-amine-catalyzed 1,4-conjugate additions of prochiral 2-benzofuranones to cyclic enones[6] or N-substituted maleimides[7] have been reported (Figure [1b]). However, the substrate scope of these reactions remains exceedingly narrow, particularly with respect to the functional-group tolerance. Hence, there is a need to develop a novel organocatalytic system that would widen the scope of the conjugate addition reaction with cyclic electrophiles.

Zoom Image
Figure 1 Catalytic asymmetric conjugate addition of 3-substituted 2 benzofuranones: earlier reports and this study using a chiral NHC

Herein, we present an N-heterocyclic carbene (NHC)-catalyzed asymmetric intermolecular addition of 3-substituted 2-benzofuranones to maleimides (Figure [1b]). The reaction operates purely through noncovalent NHC–substrate interactions, providing access to the target compounds with various functional groups in good yields and high enantiomeric excesses under mild reaction conditions.

The use of NHCs as organocatalysts for developing novel asymmetric synthesis is constantly growing.[8] NHCs can activate substrates through either covalent or noncovalent interactions. Most asymmetric transformations involving NHCs rely on a reversible covalent bond formation with a substrate that requires the installation of a complementary functional group on the substrate.[9] On the other hand, asymmetric NHC catalysis through noncovalent interaction with a substrate has no such requirement and is, therefore, applicable to a wide range of substrate classes.[10] Nonetheless, there have been only a few successful reports on asymmetric noncovalent NHC catalysis.[11] Our group is actively involved in designing and developing novel asymmetric transformations using noncovalent NHC catalysis.

Following on from our previous work,[12] we expected that 2-benzofuranones having a pK a value in the range 8–11[13] might be easily activated through deprotonation with an NHC having a relatively higher pK a of about 17–19,[14] thereby forming a chiral ion pair[15] consisting of an enolate ion and an azolium ion. The chiral enolate formed in situ was expected to react with maleimide to afford a substituted benzofuranone having vicinal all-carbon quaternary and tertiary stereocenters, with good stereocontrol.

In concurrence with the above discussion, we began our study by using 3-phenyl-1-benzofuran-2(3H)-one (2a) as a representative substrate and 1-phenyl-1H-pyrrole-2,5-dione (3a) as the electrophile (Table [1]). The reaction-optimization study was conducted by using readily available aminoindanol-derived NHCs with varying reaction temperatures, solvents, and bases [for details, see the Supporting Information (SI)]. Our initial study gave promising results with NHC 1c. The ee value of product 4 was improved to a 50% ee of the major diastereomer (2:1 dr) by carrying out the standard reaction with 10 mol% of 1d in the presence of LiHMDS (8 mol%) and 4 Å MS in toluene at 25 °C (Table [1], entry 4). In view of the positive effect of the bromo-substituted NHC 1d on the ee value of 4, we decided to increase the steric bulk at the benzene ring of the aminoindanol unit of 1d. Accordingly, a mesityl group was installed in the place of Br through a cross-coupling reaction to afford the precatalyst 1e.[16] Importantly, when the standard reaction was conducted using the newly developed sterically hindered NHC precatalyst, an improvement in the ee of 4 was realized. Reducing the reaction temperature to –20 °C gave a further enhancement in the ee of 4 (entry 6). No significant change in the ee of 4 was realized on varying the metal ion of the HMDS base. A gradual improvement in the ee value of the major diastereomer of 4 was observed on carrying out the reaction below –20 °C, and the highest ee of 96% was obtained at –78 °C (entry 10). Reducing the 1e loading to 5 mol% gave similar results (entry 11). In all these studies (entries 1–11), a significant difference in the ee values of the major and minor diastereomers of 4 was realized. Notably, by using 2 mol% of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a proton-shuttling additive,[17] the reaction afforded both the diastereomers in 88% ee, albeit with a 1:1 dr (entry 12). In the presence of 1 mol% of HFIP, the reaction efficiency remained essentially intact on further lowering of the 1e loading to 3 mol% (entry 13). In the absence of MS, 4 was obtained with a slightly lower ee value.[18]

Table 1 Reaction Optimizationa

Entry

Precatalyst (mol%)

Base (mol%)

Temp (°C)

Yieldb (%)

drc

eed (%)

 1

1a (10)

LiHMDS (8)

 25

80

2:1

10*,  6**

 2

1b (10)

LiHMDS (8)

 25

82

2:1

20*, 10**

 3

1c (10)

LiHMDS (8)

 25

84

2:1

40*, 25**

 4

1d (10)

LiHMDS (8)

 25

84

2:1

50*, 30**

 5

1e (10)

LiHMDS (8)

 25

86

2:1

60*, 40**

 6

1e (10)

LiHMDS (8)

–20

84

2:1

84*, 60**

 7

1e (10)

NaHMDS (8)

–20

78

2:1

80*, 55**

 8

1e (10)

KHMDS (8)

–20

80

2:1

78*, 52**

 9

1e (10)

LiHMDS (8)

–40

84

2:1

90*, 70**

10

1e (10)

LiHMDS (8)

–78

83

2:1

96*, 75**

11

1e (5)

LiHMDS (4)

–78

83

2:1

94*, 74**

12e

1e (5)

LiHMDS (4)

–78

82

1:1

88*, 88**

13f

1e (3)

LiHMDS (2)

–78

82

1:1

86*, 86**

14f,g

1e (3)

LiHMDS (2)

–78

86

1:1

70*, 70**

a Reaction conditions: 2a (0.05 mmol), 3a (0.05 mmol), base (2–8 mol%), 1a–e (3–10 mol%), 4 Å MS (15 mg), toluene (0.5 mL), 12 h.

b Isolated yield.

c Determined by 1H NMR analysis.

d Determined by HPLC analysis on a chiral stationary phase: * ee of major diastereomer; ** ee of minor diastereomer.

e With 2 mol% HFIP.

f With 1 mol% HFIP.

g Without MS.

After identifying the optimal reaction conditions for the process, the substrate scope of the reaction was evaluated with varying substituents on both reaction partners (Scheme [1]). At first, various 3-aryl 2-benzofuranones with varying substituents on the benzofuranone core and the aryl moiety were examined. Substrates with various alkyl and aryl substituents at the benzofuranone core were successfully converted into products 5–7 in good yields and high ee values. Substrates containing an electron-rich methoxy group at the 5- or 7-position of the benzofuranone core were tolerated (8 and 9). Various halide-containing substrates were transformed into the corresponding products 10–13 with equal efficiency. Notably, substrates having a range of synthetically useful functional groups (OTBS, OH, NH2, and CO2Me) were amenable to the catalytic process, furnishing products 14–17 with good yields and high ee values. Moreover, products 15–17 were obtained with good to excellent dr values. With 3-phenylnaphtho[1,2-b]furan-2(3H)-one, the reaction afforded the desired product 18 in 86% yield and 96% ee.

Zoom Image
Scheme 1 Substrate scope. Reaction conditions: 2a–r (0.2 mmol), 3a–g (0.2 mmol), LiHMDS (2 mol%), 1e (3 mol%), HFIP (1 mol%), 4 Å MS (30 mg), toluene (2.0 mL), –78 °C, 12 h. Isolated yields are reported. The enantiomeric excess was determined by HPLC analysis on a chiral stationary phase. The diastereomeric ratio was determined by 1H NMR analysis.; *ee of the major diastereomer; **ee of the minor diastereomer.

Substrate scope studies were then performed by varying the substituents on the aryl ring. A substrate bearing a 4-fluoro substituent on the aryl ring afforded product 19 in a good yield and with a high ee. Moreover, the reaction worked well with substrates having substituents on both the aryl moiety and the benzofuranone core (20 and 21). Variations in the N-aryl moiety of the maleimide were also tolerated. The reaction remained equally effective using a mesityl amine-derived maleimide, delivering product 22 with a good yield and high ee. Also, maleimides derived from bromo-, methoxy, and nitro-substituted anilines were amenable to the reaction, furnishing products 23–27 in yields ranging from 80 to 90% with good ee values.

The synthetic usefulness of the catalytic process was further demonstrated by carrying out a preparative-scale experiment. Accordingly, the reaction was conducted using 0.68 g of 2k and 0.34 g of 3a to afford the major diastereomer 14 in 0.67 g (65% yield) with 86% ee, along with 0.25 g (24%) of the minor diastereomer 14′, after column chromatographic separation (Scheme [2]). Upon a single re-crystallization from a dichloromethane–hexane solvent system, the ee value of 14 improved to 99%, with 52% yield. The (S,S)-absolute stereochemistry of product 14 was confirmed by single-crystal X-ray analysis[19] (see the SI).

Zoom Image
Scheme 2 Preparative-scale experiment

Several mechanistic control experiments were then performed (Scheme [3] and SI). The reaction did not afford the desired product when conducted in the absence of a base and HFIP under the otherwise optimal conditions. These results indicate that the NHC, which is formed in situ through deprotonation of the azolium species with the base, is critical for the reaction. Also, no product formation was realized by using a catalytic amount of the azolium species and HFIP in the absence of a base, further confirming the key role of the NHC in this transformation. The standard reaction was then carried out with varying amounts of HFIP. As presented in the optimization study, in the absence of HFIP, the reaction furnished product 4 in 2:1 dr with a higher ee for the major diastereomer. However, on using 1 mol% of HFIP, 4 was obtained in 1:1 dr with an identical ee value for both isomers. Increasing the loading of HFIP was found to be detrimental to the process. These observations suggest that the conjugate addition is probably NHC controlled, and the observed difference in ee between the diastereomers in the absence of HFIP might be due to inefficient quenching of the adduct anion, leading to a retro-addition reaction, thereby permitting a competing noncatalytic formation of the minor diastereomer. Also, this study hints that HFIP assists in efficient quenching of the adduct anion by acting as an effective proton-shuttling agent in this process.[11]

Zoom Image
Scheme 3 Control experiments

Based on the results of the control experiments and our earlier study,[12a] a possible catalytic cycle for the addition reaction is depicted in Figure [2]. It is suggested that the in situ-formed NHC activates the substituted benzofuranone through deprotonation, resulting in a chiral ion pair I consisting of enolate and azolium species. The enolate undergoes enantioselective addition to the maleimide 3. A subsequent quenching of the adduct anion through HFIP-assisted proton transfer through a ternary intermediate II yields the desired product along with regeneration of the NHC. The lowering of the product dr with HFIP might be attributable to epimerization of the tertiary stereocenter of the product in the presence of the acidic additive.

Zoom Image
Figure 2 Proposed catalytic cycle

In summary, we have developed an efficient catalytic asymmetric conjugated addition of 3-substituted 2-benzofuranones to maleimides in the presence of an NHC.[20] The process is based on the utilization of a noncovalent mode of asymmetric NHC catalysis, offering access to several functionalized benzofuranone moieties with vicinal all-carbon quaternary and tertiary stereocenters in good yields and high stereocontrol (ee and dr). The NHC-catalyzed process broadens the scope of the reaction. The reaction was shown to be scalable. This study further demonstrates the synthetic potential of asymmetric noncovalent NHC catalysis.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Pradip Bhunia, IACS for helping with the single-crystal X-ray analysis.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2403-2383.
  • Supporting Information
  • CIF File

Corresponding Author

Joyram Guin
School of Chemical Sciences
Indian Association for the Cultivation of Science, 2a & 2b Raja S. C. Mullick Road, Jadavpur, Kolkata 700032
India   

Publication History

Received: 22 July 2024

Accepted after revision: 26 August 2024

Accepted Manuscript online:
26 August 2024

Article published online:
27 September 2024

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Zoom Image
Figure 1 Catalytic asymmetric conjugate addition of 3-substituted 2 benzofuranones: earlier reports and this study using a chiral NHC
Zoom Image
Scheme 1 Substrate scope. Reaction conditions: 2a–r (0.2 mmol), 3a–g (0.2 mmol), LiHMDS (2 mol%), 1e (3 mol%), HFIP (1 mol%), 4 Å MS (30 mg), toluene (2.0 mL), –78 °C, 12 h. Isolated yields are reported. The enantiomeric excess was determined by HPLC analysis on a chiral stationary phase. The diastereomeric ratio was determined by 1H NMR analysis.; *ee of the major diastereomer; **ee of the minor diastereomer.
Zoom Image
Scheme 2 Preparative-scale experiment
Zoom Image
Scheme 3 Control experiments
Zoom Image
Figure 2 Proposed catalytic cycle