Isocyanide-Based Multicomponent Reactions: Rapid Synthesis of a 5,5-Fused Bicyclic Skeleton from α,β-Unsaturated Ketones and Allenoates

Shibo Xu; Shikuan Su; Huiting Zhang; Lumin Tian; Pengcheng Liang; Jiawen Chen; Yuan Zhang; Chunju Li; Xueshun Jia; Jian Li

doi:10.1055/s-0034-1378736

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Synthesis 2015; 47(16): 2414-2430
DOI: 10.1055/s-0034-1378736

special topic

Isocyanide-Based Multicomponent Reactions: Rapid Synthesis of a 5,5-Fused Bicyclic Skeleton from α,β-Unsaturated Ketones and Allenoates

Shibo Xu

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Shikuan Su

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Huiting Zhang

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Lumin Tian

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Pengcheng Liang

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Jiawen Chen

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Yuan Zhang

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Chunju Li

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

,

Xueshun Jia*

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

^bState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. of China

,

Jian Li*

^aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China Email: xsjia@mail.shu.edu.cn Email: lijian@shu.edu.cn

› Author Affiliations

Further Information

Publication History

Received: 17 April 2015

Accepted after revision: 05 June 2015

Publication Date:
24 July 2015 (online)

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Abstract

An efficient multicomponent reaction of isocyanides, allenoates, and α,β-unsaturated ketones is disclosed, thus providing rapid access for the synthesis of bicyclic skeletons. From a mechanistic standpoint, the present cycloaddition proceeds through cascade cycloaddition followed by hydration and intramolecular cyclization. Several controlled experiments are also conducted to gain further insight into the reaction mechanism; some valuable and interesting findings were observed during this process. To enrich the structural diversity, 3-(2-oxoethylene)indolinones (i.e. with an α,β-unsaturated ketone at position 3) were also found to be compatible in this reaction. In addition, this method is also characterized by its broad substrate scope, mild conditions, and high efficiency, which makes it valuable for further application.

#

Key words

isocyanide - multicomponent reaction - allenoate - bicyclic skeleton - α,β-unsaturated ketone

Isocyanides represent highly valuable C1 building blocks and they have attracted much attention from synthetic chemists due to their ready availability and versatile reactivity.[2] For instance, isocyanides are excellent substrates in the construction of many nitrogen-containing heterocycles.[3] More recently, the transition-metal-catalyzed insertion and some radical-based transformations involving isocyanide have also enjoyed considerable interest from the synthetic community.[4] [5] On the other hand, the exceptional divalent carbon atom of isocyanides[6] makes them particularly flexible partners in multicomponent reactions.[7] In general, isocyanide-based multicomponent reactions (IMCRs) are superior in many respects to traditional methods in terms of good atom- and step-economy together with convergence.[8] Furthermore, IMCRs also have the possibility to attain molecular complexity and diversity in a single step,[9] which is of great significance for the construction of small-molecule libraries. As a result, a series of novel and highly efficient IMCRs reactions have been well documented.[10] Regardless of the great achievements realized in this field, the development of new IMCRs to ensure sufficient molecular diversity and complexity remains desirable.

Recently, we have focused our attention on exploring the potential synthetic utility of a novel multicomponent cycloaddition strategy involving isocyanide and allenoate. The first example dates back to 2011 when we published pioneering work, thus offering a new method for the construction of spiro-oxindole derivatives.[11]

Until now, several efficient and rapid approaches for the synthesis of functionalized carbocycles and natural-product-like N-containing heterocycles have been reported.[12] The mechanistic analysis based on these outcomes demonstrates that these multicomponent reactions have two typical pathways (Scheme [1]). The beginning of both transformations involves the formation of a reactive zwitterion generated from the Michael addition of isocyanide and allenoate. The resonance-stabilized species can be easily trapped by the electron-deficient species to form five-membered carbocycles and heterocycles, thus providing a so-called [2+2+1] cycloaddition (path a).[12a] [b] Recently, we have also found that the capture of this zwitterionic intermediate can be utilized to construct structurally complex bicyclic skeletons. Mechanistically, the formation of the first five-membered carbocycle is still a [2+2+1] cycloaddition, but the presence of α-substituents in the allenoate can induce a special [1,5]-hydride shift, which is considered to be the key step for the whole conversion (path b).[12c,d] As a bonus to this isocyanide-based multicomponent reaction system, we found that a third reaction route existed, which could be used to construct structurally unusual bicyclic skeletons. Remarkably, the cascade cycloaddition starts from a formal [3+2] cycloaddition, which is different from the previously reported examples (path c). As a continuation of our ongoing research program, we herein report that the combination of isocyanide, allenoate, and α,β-unsaturated ketones in the presence of water provides rapid access to bicyclic pyrrolidine-2,5-diones derivatives.

Scheme 1 Representative multicomponent cycloadditions based on isocyanide and allenoate in the presence of electron-deficient species

The initial experiment was performed with tert-butyl isocyanide (1a), ethyl 2-benzylbuta-2,3-dienoate (2a), chalcone (3a), and water as a model reaction (Table [1]). Simply heating the mixture under reflux directly produced bicyclic cycloadduct 4a in 56% yield (entry 1). Various aliphatic and aromatic isocyanides participated in this cascade cycloaddition reaction under reflux conditions, thereby affording the corresponding fused skeletons 4 in satisfactory yields (see the Supporting Information for details). The experimental results revealed that the present reaction is not sensitive to steric hindrance in the alkyl isocyanide component. For instance, tert-butyl and 1,1,3,3-tetramethylbutyl groups were compatible with this transformation (entries 1 and 4). A good result was also obtained when admantan-1-yl isocyanide (1g) was used (entry 7).

Table 1 Multicomponent Cycloaddition Reaction of Isocyanide 1, Ethyl 2-Benzylbuta-2,3-dienoate (2a), and Chalcone (3a)^a

Entry	R	Product	Yield^b (%)
1	t-Bu	4a	56
2	Bu	4b	52
3	Cy	4c	42
4	CMe₂CH₂ t-Bu	4d	62
5	i-Pr	4e	37
6	Bn	4f	71
7		4g	55
8^c	2,6-Me₂C₆H₃	4h	23
9^c	2-Cl-6-MeC₆H₃	4i	41

^a Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), 3a (0.5 mmol), toluene–H₂O (6:1, 5 mL), reflux, 12 h.

^b Yields of product after silica gel chromatography.

^c The reaction time was prolonged to 24 h.

Reactions with other aromatic isocyanides were also tried subsequently. While 2-chloro-6-methylphenyl isocyanide (1i) reacted smoothly under these conditions, the use of 2,6-dimethylphenyl isocyanide (1h) only led to a low yield of 4h albeit with long reaction time (Table [1], entries 7 and 8). It is also worthy of note that temperature has an important influence on the reaction performance. For example, the reaction yield decreased dramatically (< 10%) when the reaction was conducted at lower temperature (80 °C). In contrast, better yields were obtained when the temperature was increased; finally, reflux conditions were selected as the best choice.

After a broad isocyanide scope had been established, we then turned our attention to the feasibility of substituted allenoates. As shown in Table [2, a] variety of allenoates 2 having electron-withdrawing (entries 1–6) and electron-donating groups (entries 7–9) on the phenyl ring of the benzyl group were employed to react with 1,1,3,3-tetramethylbutyl isocyanide (1d) and chalcone (3a) under the standard reaction conditions. To our delight, most substituents were well tolerated giving the corresponding products 5. For example, the reaction with ethyl 2-(3-chlorobenzyl)allenoate 2c furnished the cycloadduct 5c in 76% yield (entry 3). Ethyl 2-methylallenoate 2j was also compatible with the cycloaddition reaction giving 5j in 45% yield (entry 10). The structure of compound 5d was unambiguously confirmed by single crystal X-ray analysis (Figure [1]).[13] Notably, this protocol represents a practical and efficient multicomponent example for the construction of complex bicyclic skeletons. In particular, 2-alkylallenoates act as a 4C synthon to form two fused rings, which demonstrated good synthetic efficiency since allenoates are often used as a 2C or 3C building block in cycloaddition reactions.

Table 2 Multicomponent Cascade Cycloaddition of 1,1,3,3-Tetramethylbutyl Isocyanide (1d), Substituted Allenoate 2, and Chalcone (3a)^a

Entry	R¹	Product	Yield^b (%)
1	3-FC₆H₄CH₂	5a	61
2	4-ClC₆H₄CH₂	5b	46
3	3-ClC₆H₄CH₂	5c	76
4	4-BrC₆H₄CH₂	5d	52
5	4-O₂NC₆H₄CH₂	5e	36
6	3-O₂NC₆H₄CH₂	5f	50
7	4-MeC₆H₄CH₂	5g	57
8	3-MeC₆H₄CH₂	5h	61
9	4-MeOC₆H₄CH₂	5i	64
10	Me	5j	45
11	CH₂CO₂Me	5k	47
12	CH₂CO₂Et	5l	51

^a Reaction conditions: 1d (0.5 mmol), 2 (0.6 mmol), 3a (0.5 mmol), toluene–H₂O (6:1, 5 mL), reflux.

^b Yields of product after silica gel chromatography.

Figure 1 X-ray crystal structure of product 5d

A series of substituted α,β-unsaturated ketones 3 were next examined with 1,1,3,3-tetramethylbutyl isocyanide (1d) and ethyl 2-benzylbuta-2,3-dienoate (2a) to further explore the versatility of this multicomponent cycloaddition strategy (Table [3]). Pleasingly, all reactions worked well to afford cycloadducts 6 in satisfactory yields. The structure of compound 6l was unambiguously confirmed by single crystal X-ray analysis.[14]

Table 3 Multicomponent Reaction of 1,1,3,3-Tetramethylbutyl Isocyanide (1d), Ethyl 2-Benzylbuta-2,3-dienoate (2a), and α,β-Unsaturated Ketone 3 ^a

Entry	R²	R³	Product	Yield^b (%)
1	Ph	4-FC₆H₄	6a	53
2	Ph	4-ClC₆H₄	6b	61
3	Ph	3-ClC₆H₄	6c	58
4	Ph	4-BrC₆H₄	6d	56
5	Ph	4-MeC₆H₄	6e	65
6	Ph	4-MeOC₆H₄	6f	38
7	Ph	1-naphthyl	6g	40
8	4-ClC₆H₄	Ph	6h	48
9	4-BrC₆H₄	Ph	6i	51
10	4-MeC₆H₄	Ph	6j	50
11	4-MeOC₆H₄	Ph	6k	56
12	styryl	Ph	6l	49

^a Reaction conditions: 1d (0.5 mmol), 2a (0.6 mmol), 3 (0.5 mmol), toluene–H₂O (6:1, 5 mL), reflux, 12 h.

^b Yields of product after silica gel chromatography.

The mechanism of this cycloaddition reaction has not been unequivocally established, but the formation of the bicyclic skeleton may be rationalized as illustrated in Scheme [2]. The cyclization process is triggered by the nucleophilic attack of isocyanide 1 toward allenoate 2, thus affording resonance-stabilized zwitterionic species A↔B.[12] This very reactive intermediate is then trapped by the electron-deficient C=C bond to produce key intermediate C. After that, two possible pathways may exist. According to path a, the intramolecular Michael addition takes place firstly to form reactive ketenimine D.[15] Subsequently, nucleophilic attack by water on the central position of the ketenimine essentially leads to the formation of cyclized intermediate E. The elimination of ethanol and tautomerization then occur to produce the final cycloadduct 4 or 5. Another pathway b is also reasonable. In this case, the nitrene intermediate is firstly captured by water to give F.[16] Finally, intramolecular proton transfer followed by cyclization will take place to give the final product 4 or 5. For the present, neither of the routes can be ruled out.

An isotope-labeling experiment was subsequently conducted to gain further insight into the reaction mechanism. As shown in Scheme [3], the corresponding O¹⁸-labeled cycloadduct 4a′ was isolated when H₂O¹⁸ rather than H₂O was used as a component. However, a lower yield was observed, albeit with a prolonged reaction time (36 h). Meanwhile, the same reaction was also performed without the addition of water. In this case, no bicyclic product 4a was observed. These experimental findings revealed that the presence of water is necessary for ring formation.

Since the spiro-oxindole derivatives are privileged skeleton in natural products with well-known biological activity,[17] [18] we thus attempted to test the reactivity of methyleneindolinones 7 (derived from oxindole and acetophenone) in this cycloaddition (Table [4]).

Table 4 Multicomponent Reaction of 2,6-Dimethylphenyl Isocyanide (1h), α-Substituted Allenoate 2, and Methyleneindolinone 7 ^a

Entry	R¹	R⁴	R⁵	Product	Yield^b (%)
1	Me	H	Ph	8a	35
2	Me	H	4-ClC₆H₄	8b	42
3	Me	H	3-ClC₆H₄	8c	36
4	Me	H	4-BrC₆H₄	8d	52
5	Me	H	4-O₂NC₆H₄	8e	21
6	Me	H	4-MeC₆H₄	8f	45
7	H	H	4-MeOC₆H₄	8g	55
8	Me	H	4-PhC₆H₄	8h	38
9	Bn	H	Ph	8i	36
10	3-FC₆H₄CH₂	H	Ph	8j	50
11	3-ClC₆H₄CH₂	H	Ph	8k	39
12	CH₂CO₂Et	H	Ph	8l	58
13	Me	4-Br	Ph	8m	45
14	Me	5-Cl	Ph	8n	34

^a Reaction conditions: 1h (0.5 mmol), 2 (0.6 mmol), 7 (0.5 mmol), toluene–H₂O (6:1, 5 mL), reflux, 24 h.

^b Yields of product after silica gel chromatography.

^c The time was prolonged to 36 h.

As we can see, the structure of substrate 7 features the α,β-unsaturated ketone unit at position 3 of the oxindole. To further establish the scope and limitations of this method, 2,6-dimethylphenyl isocyanide (1h) and substituted allenoate 2 were selected as reaction partners. The experimental results showed that this reaction has a broad scope with regard to the variation of allenoate 2 and methyleneindolinone 7. The structure of compound 8a was unambiguously confirmed by single crystal X-ray analysis.[19]

Other isocyanides were also employed under the standard conditions. The corresponding products were obtained in satisfactory yields when 2-chloro-6-methylphenyl and 2,6-diisopropylphenyl isocyanides were used (Scheme [4]). The easy variation of isocyanide component makes the present reaction more flexible, which is important to the fast and efficient construction of the corresponding compound library.

As we can see from these experimental results, reactions with 3-(2-oxoethylene)indolinones 7 demonstrated different regioselectivity compared to α,β-unsaturated ketones 3 (Scheme [5]). According to our mechanistic proposal, Michael addition will take place followed by formation of a reactive zwitterionic species. When the α,β-unsaturated ketones 3 were used, the nucleophilic addition started from the exocyclic vinyl carbon.[20] In contrast, the nucleophilic site transferred to another side when methyleneindolinones 7 were used. As a result, the steric hindrance plays a key role in the reaction behavior.

Scheme 4 Construction of spirocyclic oxindole 8 with aromatic isocyanides

Figure 2 X-ray crystal structure of product 9a

To our surprise, we also observed several interesting experimental results. As shown in Scheme [6], upon treatment of 2,6-diisopropylphenyl isocyanide (1j) with allenoate 2j and methyleneindolinone 7a under the standard reaction conditions, monocyclic compound 9a was unexpectedly isolated as side product. In addition, an analogous structure was obtained as the major product when 2,6-dimethylphenyl isocyanide (1h) reacted with methyl-substituted allenoate 2j and methyleneindolinone 7o.

Notably, the structure of compound 9a was unambiguously confirmed by single crystal X-ray analysis (Figure [2]).[21] It should be pointed out that the structure of 9 is quite strange at first glance. It seemed that an unusual ester group migration is involved, which is different from that described in the mechanism (Scheme [2]).

Based on these experimental outcomes, a reasonable possibility is outlined to explain the formation of compound 9 (Scheme [7]). As we have discussed, the reaction begins with [3+2] cycloaddition.[22] Accordingly, the blending of substrate 1, 2j, and 7 gives rise to intermediate H, which contains a reactive ketenimine unit. Subsequently, the nucleophilic attack of water followed by intramolecular cyclization yields intermediate J. Then the elimination of the ethoxy anion will take place to afford K. In this case, the nucleophilic ethoxy anion can attack the protonated carbonyl group, thus affording a new intermediate L. The ring opening followed by proton transfer finally gives the unexpected product 9.

Scheme 5 Different regioselectivity observed during the Michael addition with substrates 7 and 3

According to our analysis, the formation of product 9 and 8 may come from the same intermediate. At the beginning, we had no evidence for our hypothesis until we found that compound 9 could be converted into compound 8 under appropriate conditions. Initially, compound 9a was preserved in a NMR tube with CDCl₃. To our surprise, we found that compound 9a was completely transformed into compound 8r after about two weeks (Scheme [8]). Undoubtedly, the weak acidic environment plays an important role in this conversion. This finding allows us to have better understanding of this multicomponent cycloaddition.

In conclusion, we have described a novel multicomponent reaction of isocyanide, substituted allenoate, and α,β-unsaturated ketone. This method also provides a rapid access for the synthesis of complex bicyclic skeletons. Mechanistically, the cascade sequence may proceed through multiple Michael addition, hydration, and intramolecular cyclization. Several valuable findings are observed following the controlled experiments, thus we have further insight into the reaction mechanism. The present reaction has a broad substrate scope, which is significant for the construction of the corresponding compound library. During our investigation, we also found that the allenoate acts as a 4C synthon for the construction of the rings, which represents high synthetic efficiency.[23] Further works may include the investigation on structure-activity relationship (SAR).

The NMR spectra were recorded on 500 MHz spectrometer (500 MHz for ¹H NMR and 125 MHz for ¹³C NMR) with CDCl₃ as the solvent and TMS as internal reference. IR spectra were recorded on a FT-IR spectrophotometer. HRMS were recorded on a FTMS instrument in ESI mode. Melting points were obtained on digital melting point apparatus without correction. Unless otherwise stated, all reagents were commercially purchased and used without further purification. Aromatic isocyanides 1 were prepared from the corresponding anilines according to the method disclosed by Ugi with a slight modification.[24] All substituted allenoates 2 were synthesized according to procedures reported previously.[25] All α,β-unsaturated ketones 3 and 3-(2-aryl-2-oxoethylene)oxindoles 7 were synthesized according to the literature.[26] [27] [28]

Scheme 6 Formation of an interesting product 9

Scheme 7 Proposed mechanism for the formation of compound 9

Scheme 8 Conversion between compound 9 and 8

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2-Substituted 4-Benzoyl-3a-benzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 4; General Procedure

To a solution of isocyanide 1 (0.5 mmol) and substituted allenoate 2a (0.6 mmol) in a mixed solvent toluene–H₂O (6:1, 5 mL), α,β-unsaturated ketones 3a (0.5 mmol) was added under a N₂ atmosphere. The mixture was stirred under reflux for several hours (TLC monitoring). When the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel 200–300, petroleum ether–EtOAc) to afford the product 4.

#

4-Benzoyl-3a-benzyl-2-tert-butyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4a)

Pale yellow oil; yield: 130.2 mg (56%).

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.27–7.10 (m, 10 H), 4.06 (d, J = 11.0 Hz, 1 H), 3.67–3.61 (m, 1 H), 3.42 (d, J = 13.0 Hz, 1 H), 3.04 (d, J = 8.0 Hz, 1 H), 2.86 (d, J = 13.5 Hz, 1 H), 2.58 (dd, J = 13.0, 6.0 Hz, 1 H), 2.20–2.13 (td, J = 13.0, 9.0 Hz, 1 H), 1.53 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.5, 179.4, 140.1, 139.1, 136.1, 133.1, 130.2, 128.7, 128.7, 128.6, 128.2, 127.4, 127.1, 127.1, 63.0, 59.8, 59.0, 48.7, 47.4, 42.3, 35.7, 28.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₁NNaO₃: 488.2202; found: 488.2195.

#

4-Benzoyl-3a-benzyl-2-butyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4b)

White solid; yield: 120.9 mg (52%); mp 158–159 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.85 (d, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.25–7.08 (m, 10 H), 4.11 (d, J = 11.5 Hz, 1 H), 3.66–3.59 (m, 1 H), 3.47–3.42 (m, 3 H), 3.21 (d, J = 8.5 Hz, 1 H), 2.93 (d, J = 13.5 Hz, 1 H), 2.62 (dd, J = 13.5, 6.0 Hz, 1 H), 2.27–2.20 (td, J = 13.5, 9.0 Hz, 1 H), 1.49–1.40 (m, 2 H), 1.21–1.08 (m, 2 H), 0.88 (t, J = 7.0 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.6, 178.4, 178.3, 139.8, 139.0, 135.7, 133.2, 130.1, 128.7, 128.7, 128.2, 127.5, 127.2, 127.1, 62.8, 60.7, 48.7, 47.6, 42.1, 39.1, 35.2, 29.6, 19.9, 13.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₁NNaO₃: 488.2202; found: 488.2198.

#

4-Benzoyl-3a-benzyl-2-cyclohexyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4c)

White solid; yield: 103.1 mg (42%); mp 207–208 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.25–7.08 (m, 10 H), 4.09 (dd, J = 11.0, 5.0 Hz, 1 H), 3.92–3.87 (m, 1 H), 3.64–3.58 (m, 1 H), 3.44 (d, J = 13.5 Hz, 1 H), 3.11 (d, J = 9.0 Hz, 1 H), 2.89 (d, J = 13.5 Hz, 1 H), 2.60 (dd, J = 13.0, 6.0 Hz, 1 H), 2.25–2.18 (m, 1 H), 2.09 (m, 2 H), 1.81 (t, J = 13.5 Hz, 2 H), 1.63 (d, J = 11.0 Hz, 1 H), 1.53 (t, J = 13.5 Hz, 2 H), 1.29–1.19 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.5, 178.6, 178.4, 139.9, 139.0, 135.9, 133.2, 130.1, 128.7, 128.7, 128.2, 127.5, 127.1, 127.1, 62.9, 60.0, 52.2, 48.4, 47.5, 42.2, 35.41, 28.7, 28.6, 25.9, 25.8, 25.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₃NNaO₃: 514.2358; found: 514.2359.

#

4-Benzoyl-3a-benzyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4d)

White solid; yield: 161.5 mg (62%); mp 151–153 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.82 (d, J = 8.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.28–7.21 (m, 5 H), 7.17–7.13 (m, 5 H), 4.07 (d, J = 11.5 Hz, 1 H), 3.67 (td, J = 13.0, 6.0 Hz, 1 H), 3.37 (d, J = 13.5 Hz, 1 H), 3.11 (d, J = 8.0 Hz, 1 H), 2.90 (d, J = 13.5 Hz, 1 H), 2.64 (dd, J = 13.0, 6.0 Hz, 1 H), 2.17 (td, J = 13.5, 8.5 Hz, 1 H), 2.01 (d, J = 15.0 Hz, 1 H), 1.70 (s, 3 H), 1.68 (d, J = 9.0 Hz, 1 H), 1.63 (s, 3 H), 0.81 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.9, 180.0, 179.6, 140.1, 139.2, 136.0, 133.1, 130.7, 128.7, 128.2, 127.4, 127.1, 63.3, 63.0, 60.0, 50.1, 48.7, 47.5, 42.1, 35.7, 31.5, 30.9, 29.8, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₉NNaO₃: 544.2828; found: 544.2823.

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4-Benzoyl-3a-benzyl-2-isopropyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4e)

White solid; yield: 83.4 mg (37%); mp 147–149 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.85 (d, J = 7.0 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.25–7.08 (m, 10 H), 4.32–4.26 (m, 1 H), 4.08 (d, J = 11.5 Hz, 1 H), 3.64–3.58 (m, 1 H), 3.44 (d, J = 13.0 Hz, 1 H), 3.11 (d, J = 8.5 Hz, 1 H), 2.89 (d, J = 13.5 Hz, 1 H), 2.60 (dd, J = 13.5, 6.0 Hz, 1 H), 2.21 (td, J = 13.0, 9.0 Hz, 1 H), 1.32 (d, J = 4.5 Hz, 3 H), 1.31 (d, J = 5.0 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.5, 178.5, 178.3, 139.9, 138.9, 135.9, 133.2, 130.1, 128.7, 128.68, 128.2, 127.5, 127.1, 127.1, 62.8, 60.1, 48.5, 47.6, 44.3, 42.2, 35.3, 19.3, 19.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₂₉NNaO₃: 474.2045; found: 474.2037.

#

4-Benzoyl-2,3a-dibenzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4f)

White solid; yield: 177.1 mg (71%); mp 172–174 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.87 (d, J = 7.0 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.26–7.14 (m, 11 H), 7.08 (t, J = 7.5 Hz, 2 H), 6.96 (d, J = 7.0 Hz, 2 H), 4.73 (d, J = 14.0 Hz, 1 H), 4.60 (d, J = 14.0 Hz, 1 H), 4.13 (d, J = 11.5 Hz, 1 H), 3.68–3.62 (m, 1 H), 3.46 (d, J = 13.5 Hz, 1 H), 3.21 (d, J = 8.5 Hz, 1 H), 2.92 (d, J = 13.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.25 (td, J = 13.0, 9.0 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.5, 178.2, 177.9, 139.7, 138.9, 135.5, 135.4, 133.3, 129.9, 128.7, 128.5, 128.3, 128.3, 127.6, 127.4, 127.2, 127.1, 63.0, 60.8, 48.7, 47.7, 42.9, 42.3, 35.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₂₉NNaO₃: 522.2045; found: 522.2036.

#

2-(Adamantan-1-yl)-4-benzoyl-3a-benzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4g)

Colorless oil; yield: 143.2 mg (55%).

¹H NMR (500 MHz, CDCl₃): δ = 7.84 (d, J = 7.0 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.29–7.10 (m, 10 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.68–3.62 (m, 1 H), 3.41 (d, J = 13.0 Hz, 1 H), 3.00 (d, J = 8.5 Hz, 1 H), 2.86 (d, J = 13.5 Hz, 1 H), 2.56 (dd, J = 13.0, 6.0 Hz, 1 H), 2.35 (d, J = 3.0 Hz, 6 H), 2.19–2.14 (m, 1 H), 2.11 (s, 3 H), 1.75 (d, J = 11.5 Hz, 3 H), 1.65 (d, J = 12.5 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.8, 179.7, 179.6, 140.1, 139.1, 136.1, 133.1, 130.2, 128.7, 128.7, 128.6, 128.2, 127.4, 127.1, 127.0, 63.1, 61.7, 59.6, 48.5, 47.3, 42.4, 39.2, 36.2, 35.8, 29.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₇H₃₈NO₃: 544.2852; found: 544.2841.

#

4-Benzoyl-3a-benzyl-2-(2,6-dimethylphenyl)-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4h)

White solid; yield: 59.0 mg (23%); mp 271–273 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (dd, J = 9.0, 1.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.28–7.14 (m, 12 H), 6.97 (dd, J = 6.0, 3.0 Hz, 1 H), 4.18 (d, J = 11.5 Hz, 1 H), 3.95–3.89 (m, 1 H), 3.62 (d, J = 9.0 Hz, 1 H), 3.43 (d, J = 13.5 Hz, 1 H), 3.05 (d, J = 13.5 Hz, 1 H), 2.81 (dd, J = 13.0, 6.0 Hz, 1 H), 2.50 (s, 3 H), 2.41 (td, J = 13.5, 9.0 Hz, 1 H), 1.27 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.4, 177.4, 176.8, 139.6, 139.3, 136.5, 135.6, 135.4, 133.2, 130.9, 130.4, 129.3, 128.9, 128.8, 128.7, 128.6, 128.3, 128.2, 127.7, 127.3, 127.2, 63.4, 61.2, 48.8, 47.5, 42.7, 35.5, 18.7, 16.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₁NNaO₃: 536.2202; found: 536.2194.

#

4-Benzoyl-3a-benzyl-2-(2-chloro-6-methylphenyl)-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4i)

White solid; yield: 109.3 mg (41%); mp 261–262 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.32–7.17 (m, 13 H), 4.20 (d, J = 11.5 Hz, 1 H), 3.88–3.82 (m, 1 H), 3.64 (d, J = 9.0 Hz, 1 H), 3.42 (d, J = 13.5 Hz, 1 H), 3.06 (d, J = 13.5 Hz, 1 H), 2.77 (dd, J = 13.0, 6.0 Hz, 1 H), 2.58 (s, 3 H), 2.29 (td, J = 13.5, 9.0 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.9, 176.9, 176.6, 139.5, 139.4, 139.2, 135.3, 133.3, 132.5, 131.0, 130.3, 129.5, 129.3, 128.8, 128.8, 128.7, 128.3, 127.6, 127.3, 127.1, 63.1, 61.1, 49.3, 48.1, 42.4, 35.3, 18.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₂₈ClNNaO₃: 556.1655; found: 556.1658.

#

3a-Substituted 4-Benzoyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 5; General Procedure

To a solution of 1,1,3,3-tetramethylbutyl isocyanide (1d, 0.5 mmol) and substituted allenoate 2 (0.6 mmol) in toluene–H₂O (6:1, 5 mL), α,β-unsaturated ketone 3a (0.5 mmol) was added under a N₂ atmosphere. The mixture was stirred under reflux for several hours (TLC monitoring). When the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel 200–300, petroleum ether–EtOAc) to afford the product 5.

#

4-Benzoyl-3a-(3-fluorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5a)

White solid; yield: 164.4 mg (61%); mp 140–141 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.25–7.15 (m, 6 H), 6.95–6.91 (m, 2 H), 6.84 (d, J = 9.5 Hz, 1 H), 4.03 (d, J = 11.5 Hz, 1 H), 3.70–3.64 (m, 1 H), 3.39 (d, J = 13.5 Hz, 1 H), 3.05 (d, J = 8.0 Hz, 1 H), 2.87 (d, J = 13.5 Hz, 1 H), 2.66 (dd, J = 13.0, 6.0 Hz, 1 H), 2.23 (td, J = 13.0, 8.0 Hz, 1 H), 2.04 (d, J = 15.0 Hz, 1 H), 1.68 (s, 3 H), 1.66–1.63 (m, 4 H), 0.79 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.8, 179.3, 162.8 (d, ¹ J _C-F = 246.3 Hz), 139.9, 139.0, 138.4 (³ J _C-F = 7.5 Hz), 133.2, 130.2 (d, ³ J _C-F = 8.8 Hz), 128.7, 128.7, 128.1, 127.1, 127.0, 126.4 (d, ⁴ J _C-F = 3.8 Hz), 117.7 (² J _C-F = 21.3 Hz), 114.4 (² J _C-F = 21.3 Hz), 63.5, 63.2, 59.9, 50.1, 48.5, 47.4, 41.8, 35.7, 31.4, 30.8, 29.8, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈FNNaO₃: 562.2733; found: 562.2729.

#

4-Benzoyl-3a-(4-chlorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5b)

White solid; yield: 127.7 mg (46%); mp 177–178 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 7.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.25–7.15 (m, 7 H), 7.06 (d, J = 8.5 Hz, 2 H), 4.02 (d, J = 11.5 Hz, 1 H), 3.69–3.63 (m, 1 H), 3.35 (d, J = 13.5 Hz, 1 H), 3.03 (d, J = 8.0 Hz, 1 H), 2.85 (d, J = 13.5 Hz, 1 H), 2.66 (dd, J = 13.0, 6.0 Hz, 1 H), 2.22 (td, J = 13.0, 8.0 Hz, 1 H), 2.02 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.64–1.60 (m, 4 H), 0.77 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.7, 179.3, 139.9, 139.0, 134.4, 133.4, 133.2, 132.1, 128.8, 128.7, 128.1, 127.2, 127.0, 63.5, 63.2, 59.9, 50.1, 48.5, 47.4, 41.4, 35.6, 31.4, 30.8, 29.8, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈ClNNaO₃: 578.2438; found: 578.2434.

#

4-Benzoyl-3a-(3-chlorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5c)

White solid; yield: 210.9 mg (76%); mp 125–127 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 8.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.25–7.12 (m, 8 H), 7.02 (d, J = 7.0 Hz, 1 H), 4.03 (d, J = 11.5 Hz, 1 H), 3.70–3.64 (m, 1 H), 3.37 (d, J = 13.0 Hz, 1 H), 3.04 (d, J = 8.0 Hz, 1 H), 2.84 (d, J = 13.0 Hz, 1 H), 2.67 (dd, J = 13.0, 6.0 Hz, 1 H), 2.23 (td, J = 13.0, 8.0 Hz, 1 H), 2.05 (d, J = 15.0 Hz, 1 H), 1.69 (s, 3 H), 1.65–1.62 (m, 4 H), 0.80 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.6, 179.8, 179.2, 139.9, 139.0, 138.0, 134.5, 133.2, 130.8, 129.9, 128.8, 128.8, 128.7, 128.1, 127.6, 127.2, 127.0, 63.5, 63.2, 59.9, 50.1, 48.4, 47.4, 41.7, 35.7, 31.5, 30.9, 29.9, 29.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈ClNNaO₃: 578.2438; found: 578.2439.

#

4-Benzoyl-3a-(4-bromobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5d)

White solid; yield: 155.7 mg (52%); mp 187–188 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.78 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.0 Hz, 1 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.25–7.14 (m, 5 H), 7.00 (d, J = 8.0 Hz, 2 H), 4.01 (d, J = 11.5 Hz, 1 H), 3.68–3.62 (m, 1 H), 3.33 (d, J = 13.5 Hz, 1 H), 3.03 (d, J = 8.0 Hz, 1 H), 2.83 (d, J = 13.5 Hz, 1 H), 2.66 (dd, J = 13.0, 6.0 Hz, 1 H), 2.22 (td, J = 13.0, 8.0 Hz, 1 H), 2.01 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.63–1.60 (m, 4 H), 0.76 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.7, 179.2, 139.9, 139.0, 134.9, 133.2, 132.4, 131.7, 128.7, 128.1, 127.2, 127.1, 121.5, 63.5, 63.2, 59.9, 50.1, 48.5, 47.4, 41.5, 35.6, 31.4, 30.8, 29.8, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈BrNNaO₃: 622.1933; found: 622.1928.

#

4-Benzoyl-3a-(4-nitrobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5e)

White solid; yield: 101.9 mg (36%); mp 173–174 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.09 (d, J = 9.0 Hz, 2 H), 7.78 (d, J = 7.0 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.31 (d, J = 9.0 Hz, 2 H), 7.26–7.16 (m, 5 H), 4.03 (d, J = 11.5 Hz, 1 H), 3.70–3.63 (m, 1 H), 3.49 (d, J = 13.0 Hz, 1 H), 3.01–2.97 (m, 2 H), 2.70 (dd, J = 13.0, 6.0 Hz, 1 H), 2.29 (td, J = 13.0, 8.0 Hz, 1 H), 2.04 (d, J = 15.0 Hz, 1 H), 1.65 (s, 3 H), 1.64 (s, 3 H), 1.60–1.54 (m, 1 H), 0.71 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.4, 179.3, 178.9, 147.2, 143.5, 139.5, 138.9, 133.3, 131.8, 128.8, 128.8, 128.1, 127.3, 127.0, 123.7, 63.8, 63.4, 59.8, 50.0, 48.3, 47.4, 41.7, 35.6, 31.4, 30.8, 29.9, 28.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈N₂NaO₅: 589.2678; found: 589.2670.

#

4-Benzoyl-3a-(3-nitrobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5f)

White solid; yield: 141.5 mg (50%); mp 141–142 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.08 (d, J = 8.5 Hz, 1 H), 8.02 (t, J = 1.8 Hz, 1 H), 7.79 (d, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.49–7.40 (m, 4 H), 7.25–7.15 (m, 5 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.70–3.63 (m, 1 H), 3.50 (d, J = 13.5 Hz, 1 H), 3.01–2.97 (m, 2 H), 2.69 (dd, J = 13.0, 6.0 Hz, 1 H), 2.30 (td, J = 13.0, 8.0 Hz, 1 H), 2.05 (d, J = 15.0 Hz, 1 H), 1.66 (s, 3 H), 1.65 (s, 3 H), 1.55 (d, J = 15.0 Hz, 1 H), 0.70 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.5, 179.4, 178.9, 148.3, 139.5, 138.9, 138.1, 137.0, 133.4, 129.6, 128.8, 128.8, 128.1, 127.3, 127.0, 125.6, 122.5, 63.7, 63.3, 59.8, 50.0, 48.2, 47.5, 41.5, 35.7, 31.4, 30.8, 30.0, 28.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈N₂NaO₅: 589.2678; found: 589.2675.

#

4-Benzoyl-3a-(4-methylbenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5g)

White solid; yield: 152.5 mg (57%); mp 197–198 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 7.0 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.24–7.21 (m, 2 H), 7.16–7.13 (m, 3 H), 7.06 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.68–3.62 (m, 1 H), 3.31 (d, J = 13.5 Hz, 1 H), 3.09 (d, J = 8.0 Hz, 1 H), 2.85 (d, J = 13.5 Hz, 1 H), 2.62 (dd, J = 13.0, 6.0 Hz, 1 H), 2.30 (s, 3 H), 2.16 (td, J = 13.0, 8.0 Hz, 1 H), 1.98 (d, J = 15.0 Hz, 1 H), 1.68 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.63 (s, 3 H), 0.80 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 200.0, 180.1, 179.6, 140.2, 139.2, 137.0, 133.1, 132.8, 130.5, 129.3, 128.7, 128.2, 127.1, 127.0, 63.2, 63.0, 60.0, 50.1, 48.8, 47.5, 41.6, 35.7, 31.4, 30.9, 29.7, 29.2, 21.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₄₁NNaO₃: 558.2984; found: 558.2979.

#

4-Benzoyl-3a-(3-methylbenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5h)

White solid; yield: 163.2 mg (61%); mp 109–110 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 8.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.24–7.15 (m, 6 H), 7.05 (d, J = 7.5 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 2 H), 4.06 (d, J = 11.5 Hz, 1 H), 3.69–3.63 (m, 1 H), 3.34 (d, J = 13.5 Hz, 1 H), 3.12 (d, J = 8.0 Hz, 1 H), 2.86 (d, J = 13.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.29 (s, 3 H), 2.17 (td, J = 13.0, 8.0 Hz, 1 H), 2.04 (d, J = 15.0 Hz, 1 H), 1.67 (d, J = 15.0 Hz, 1 H), 1.66 (s, 3 H), 1.63 (s, 3 H), 0.82 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.9, 180.1, 179.6, 140.2, 139.1, 138.2, 135.9, 133.1, 131.4, 128.7, 128.5, 128.1, 128.1, 127.7, 127.1, 63.3, 63.0, 60.0, 50.1, 48.7, 47.5, 42.0, 35.7, 31.5, 30.9, 29.8, 29.1, 21.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₄₁NNaO₃: 558.2984; found: 558.2979.

#

4-Benzoyl-3a-(3-methoxybenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5i)

White solid; yield: 176.3 mg (64%); mp 213–214 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 7.0 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.24–7.14 (m, 5 H), 7.05 (d, J = 9.0 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.76 (s, 3 H), 3.66 (m, 1 H), 3.31 (d, J = 13.5 Hz, 1 H), 3.09 (d, J = 8.0 Hz, 1 H), 2.83 (d, J = 13.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.18 (td, J = 13.0, 8.0 Hz, 1 H), 2.01 (d, J = 15.0 Hz, 1 H), 1.69 (s, 3 H), 1.68 (d, J = 15.0 Hz, 1 H), 1.64 (s, 3 H), 0.81 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 200.0, 180.1, 179.6, 158.9, 140.2, 139.2, 133.1, 131.7, 128.7, 128.1, 128.0, 127.1, 114.1, 63.2, 63.0, 60.1, 55.3, 50.1, 48.7, 47.5, 41.2, 35.6, 31.5, 30.9, 29.8, 29.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₄₁NNaO₄: 574.2933; found: 574.2928.

#

4-Benzoyl-3a-methyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5j)

Colorless oil; yield: 100.1 mg (45%).

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 7.0 Hz, 2 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.24–7.20 (m, 4 H), 7.16–7.13 (m, 1 H), 3.89 (d, J = 11.5 Hz, 1 H), 3.70–3.64 (m, 1 H), 2.78 (d, J = 8.5 Hz, 1 H), 2.65 (dd, J = 13.0, 6.0 Hz, 1 H), 2.31 (td, J = 13.0, 8.5 Hz, 1 H), 2.00 (d, J = 15.0 Hz, 1 H), 1.87 (d, J = 15.0 Hz, 1 H), 1.77 (s, 3 H), 1.71 (s, 3 H), 1.49 (s, 3 H), 0.97 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.4, 180.8, 179.9, 140.0, 138.7, 133.1, 128.6, 128.6, 128.2, 127.1, 127.0, 63.9, 62.8, 54.0, 53.0, 50.0, 47.4, 35.9, 31.8, 31.1, 29.9, 29.3, 23.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₆NO₃: 446.2695; found: 446.2689.

#

Methyl [4-Benzoyl-1,3-dioxo-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)octahydrocyclopenta[c]pyrrol-3a-yl]acetate (5k)

White solid; yield: 118.2 mg (47%); mp 114–115 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.78 (d, J = 7.5 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.23–7.13 (m, 5 H), 4.26 (d, J = 11.5 Hz, 1 H), 3.71 (s, 3 H), 3.69–3.63 (m, 1 H), 3.10 (d, J = 8.5 Hz, 1 H), 2.83 (d, J = 16.5 Hz, 1 H), 2.76 (d, J = 16.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.36 (td, J = 13.0, 8.5 Hz, 1 H), 2.03 (d, J = 15.0 Hz, 1 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.77 (s, 3 H), 1.73 (s, 3 H), 1.00 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.2, 179.7, 179.3, 171.0, 139.9, 138.8, 133.3, 128.7, 128.7, 128.1, 127.2, 127.1, 63.3, 60.6, 55.4, 52.1, 50.7, 50.2, 46.8, 39.3, 36.6, 31.6, 31.2, 29.7, 28.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₈NO₅: 504.2750; found: 504.2743.

#

Ethyl [4-Benzoyl-1,3-dioxo-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)octahydrocyclopenta[c]pyrrol-3a-yl]acetate (5l)

White solid; yield: 131.8 mg (51%); mp 107–109 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 7.5 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.23–7.21 (m, 4 H), 7.17–7.13 (m, 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 4.24–4.14 (m, 2 H), 3.69–3.63 (m, 1 H), 3.13 (d, J = 8.5 Hz, 1 H), 2.82 (d, J = 16.5 Hz, 1 H), 2.73 (d, J = 16.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.37 (td, J = 13.0, 8.5 Hz, 1 H), 2.03 (d, J = 15.0 Hz, 1 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.77 (s, 3 H), 1.73 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.00 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.2, 179.7, 179.3, 170.6, 140.0, 138.8, 133.2, 128.7, 128.7, 128.1, 127.2, 127.1, 63.3, 61.2, 60.4, 55.4, 50.7, 50.2, 46.8, 39.4, 36.6, 31.6, 31.2, 29.7, 29.0, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₉NNaO₅: 540.2726; found: 540.2729.

#

4-Aroyl-5-aryl-3a-benzyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 6; General Procedure

To a solution of 1,1,3,3-tetramethylbutyl isocyanide (1d, 0.5 mmol) and substituted allenoate 2a (0.6 mmol) in toluene–H₂O (6:1, 5 mL), α,β-unsaturated ketone 3 (0.5 mmol) was added under a N₂ atmosphere. The mixture was stirred under reflux for several hours (TLC monitoring). When the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel 200–300, petroleum ether–EtOAc) to afford the product 6.

#

3a-Benzyl-4-(4-fluorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6a)

White solid; yield: 142.8 mg (53%); mp 148–149 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.85–7.81 (m, 2 H), 7.29–7.21 (m, 5 H), 7.17–7.09 (m, 7 H), 4.00 (d, J = 11.0 Hz, 1 H), 3.68–3.62 (m, 1 H), 3.37 (d, J = 13.5 Hz, 1 H), 3.11 (d, J = 8.0 Hz, 1 H), 2.89 (d, J = 13.5 Hz, 1 H), 2.64 (dd, J = 13.0, 6.0 Hz, 1 H), 2.22–2.15 (m, 1 H), 2.01 (d, J = 15.0 Hz, 1 H), 1.69 (s, 3 H), 1.68 (d, J = 15.0 Hz, 1 H), 1.62 (s, 3 H), 0.80 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.3, 179.9, 179.5, 165.8 (d, ¹ J _C-F = 252.5 Hz), 140.0, 135.9, 135.5 (d, ⁴ J _C-F = 2.5 Hz), 130.7 (d, ³ J _C-F = 8.8 Hz), 130.7, 128.7, 127.5, 127.1 (d, ² J _C-F = 17.5 Hz), 115.8 (d, ² J _C-F = 22.5 Hz), 63.4, 63.1, 60.0, 50.1, 48.7, 47.6, 42.1, 35.6, 31.5, 30.9, 29.8, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈FNNaO₃: 562.2733; found: 562.2727.

#

3a-Benzyl-4-(4-chlorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6b)

Colorless oil; yield: 169.3 mg (61%).

¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 8.5 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.27–7.21 (m, 5 H), 7.17–7.11 (m, 5 H), 3.97 (d, J = 11.5 Hz, 1 H), 3.66–3.59 (m, 1 H), 3.34 (d, J = 13.5 Hz, 1 H), 3.10 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.62 (dd, J = 13.0, 6.0 Hz, 1 H), 2.17 (td, J = 13.0, 8.0 Hz, 1 H), 1.99 (d, J = 15.0 Hz, 1 H), 1.66–1.63 (m, 4 H), 1.60 (s, 3 H), 0.79 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.8, 179.9, 179.5, 139.9, 139.6, 137.4, 135.8, 130.7, 129.5, 129.0, 128.7, 127.5, 127.2, 127.0, 63.4, 63.1, 60.0, 50.1, 48.7, 47.6, 42.1, 35.6, 31.4, 30.9, 29.7, 29.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₅H₃₉ClNO₃: 556.2618; found: 556.2617.

#

3a-Benzyl-4-(3-chlorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6c)

White solid; yield: 160.9 mg (58%); mp 126–127 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.76 (t, J = 1.8 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.30–7.22 (m, 5 H), 7.18–7.12 (m, 5 H), 3.97 (d, J = 12.0 Hz, 1 H), 3.65–3.59 (m, 1 H), 3.36 (d, J = 13.5 Hz, 1 H), 3.12 (d, J = 8.0 Hz, 1 H), 2.91 (d, J = 13.5 Hz, 1 H), 2.62 (dd, J = 13.0, 6.0 Hz, 1 H), 2.18 (td, J = 13.5, 8.0 Hz, 1 H), 1.99 (d, J = 15.0 Hz, 1 H), 1.70–1.67 (m, 4 H), 1.61 (s, 3 H), 0.81 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.8, 179.9, 179.5, 140.6, 139.8, 135.8, 135.0, 133.0, 130.7, 130.0, 128.8, 128.3, 127.5, 127.2, 127.0, 126.2, 63.4, 63.1, 60.1, 50.1, 48.8, 47.6, 42.09, 35.7, 31.5, 30.9, 29.7, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈ClNNaO₃: 578.2438; found: 578.2437.

#

3a-Benzyl-4-(4-bromobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6d)

White solid; yield: 167.7 mg (56%); mp 161–162 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.65 (d, J = 9.0 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.28–7.21 (m, 5 H), 7.17–7.10 (m, 5 H), 3.95 (d, J = 11.5 Hz, 1 H), 3.65–3.58 (m, 1 H), 3.33 (d, J = 13.5 Hz, 1 H), 3.10 (d, J = 8.0 Hz, 1 H), 2.87 (d, J = 13.5 Hz, 1 H), 2.62 (dd, J = 13.0, 6.0 Hz, 1 H), 2.15 (td, J = 13.0, 8.5 Hz, 1 H), 1.98 (d, J = 15.0 Hz, 1 H), 1.66 (d, J = 15.0 Hz, 1 H), 1.65 (s, 3 H), 1.59 (s, 3 H), 0.79 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.0, 179.9, 179.5, 139.9, 137.8, 135.8, 132.0, 130.7, 129.6, 128.7, 128.4, 127.5, 127.2, 127.9, 63.4, 63.1, 60.1, 50.1, 48.7, 47.5, 42.1, 35.6, 31.5, 30.9, 29.7, 29.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₈BrNNaO₃: 622.1933; found: 622.1926.

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3a-Benzyl-4-(4-methylbenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6e)

White solid; yield: 173.9 mg (65%); mp 139–140 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 8.5 Hz, 2 H), 7.28–7.20 (m, 7 H), 7.15–7.13 (m, 5 H), 4.03 (d, J = 11.5 Hz, 1 H), 3.69–3.63 (m, 1 H), 3.39 (d, J = 13.5 Hz, 1 H), 3.09 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.39 (s, 3 H), 2.15 (td, J = 13.0, 8.0 Hz, 1 H), 2.00 (d, J = 15.0 Hz, 1 H), 1.67–1.64 (m, 4 H), 1.62 (s, 3 H), 0.78 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.2, 180.1, 179.5, 144.0, 140.2, 136.6, 136.1, 130.7, 129.4, 128.7, 128.6, 128.3, 127.4, 127.1, 127.0, 63.10, 63.0, 59.9, 50.1, 48.7, 47.4, 42.0, 35.6, 31.4, 30.9, 29.8, 29.1, 21.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₄₂NO₃: 536.3165; found: 536.3156.

#

3a-Benzyl-4-(4-methoxybenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6f)

White solid; yield: 104.7 mg (38%); mp 145–146 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (d, J = 9.0 Hz, 2 H), 7.28–7.19 (m, 5 H), 7.15–7.12 (m, 5 H), 6.92 (d, J = 9.0 Hz, 2 H), 4.00 (d, J = 11.5 Hz, 1 H), 3.84 (s, 3 H), 3.68–3.62 (m, 1 H), 3.42 (d, J = 13.5 Hz, 1 H), 3.08 (d, J = 8.0 Hz, 1 H), 2.89 (d, J = 13.5 Hz, 1 H), 2.63 (dd, J = 13.0, 6.0 Hz, 1 H), 2.16 (td, J = 13.0, 8.0 Hz, 1 H), 2.01 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.65–1.62 (m, 4 H), 0.77 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 197.8, 180.1, 179.5, 163.7, 140.3, 136.1, 132.0, 130.7, 130.5, 128.7, 128.6, 127.3, 127.0, 127.0, 113.9, 63.0, 59.8, 55.5, 50.1, 48.7, 47.5, 42.1, 35.6, 31.4, 30.9, 29.8, 29.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₄₁NNaO₄: 574.2933; found: 574.2929.

#

3a-Benzyl-4-(1-naphthoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6g)

White solid; yield: 114.2 mg (40%); mp 172–173 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.12 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.53–7.47 (m, 3 H), 7.41 (t, J = 7.5 Hz, 1 H), 7.29–7.16 (m, 8 H), 6.97 (d, J = 7.5 Hz, 2 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.70–3.64 (m, 1 H), 3.12 (d, J = 11.5 Hz, 2 H), 2.79 (d, J = 13.5 Hz, 1 H), 2.59 (dd, J = 13.0, 6.0 Hz, 1 H), 2.13–2.07 (m, 2 H), 1.83–1.79 (m, 4 H), 1.78 (s, 3 H), 0.90 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 203.3, 180.1, 180.1, 139.9, 138.1, 135.9, 133.9, 132.6, 130.6, 130.2, 128.8, 128.6, 128.2, 127.7, 127.5, 127.3, 127.3, 127.1, 126.5, 126.2, 124.2, 66.2, 63.2, 59.9, 50.2, 49.2, 47.8, 41.7, 35.2, 31.6, 31.1, 29.9, 29.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₉H₄₁NNaO₃: 594.2984; found: 594.2978.

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4-Benzoyl-3a-benzyl-5-(4-chlorophenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6h)

Colorless oil; yield: 133.2 mg (48%).

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.28–7.06 (m, 9 H), 3.99 (d, J = 11.5 Hz, 1 H), 3.65–3.59 (m, 1 H), 3.35 (d, J = 13.5 Hz, 1 H), 3.10 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.60 (dd, J = 13.0, 6.0 Hz, 1 H), 2.11 (td, J = 13.0, 8.0 Hz, 1 H), 1.98 (d, J = 15.0 Hz, 1 H), 1.69–1.66 (m, 4 H), 1.60 (s, 3 H), 0.80 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.8, 179.4, 139.0, 138.6, 135.9, 133.3, 132.8, 130.7, 128.8, 128.8, 128.7, 128.4, 128.1, 127.5, 63.2, 63.1, 59.9, 50.1, 48.7, 46.8, 42.0, 35.5, 31.5, 30.9, 29.7, 29.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₅H₃₉ClNO₃: 556.2618; found: 556.2614.

#

4-Benzoyl-3a-benzyl-5-(4-bromophenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6i)

Colorless oil; yield: 152.7 mg (51%).

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 7.0 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.28–7.23 (m, 3 H), 7.12 (dd, J = 7.5, 1.5 Hz, 2 H), 7.01 (d, J = 8.5 Hz, 2 H), 3.98 (d, J = 11.5 Hz, 1 H), 3.64–3.58 (m, 1 H), 3.35 (d, J = 13.5 Hz, 1 H), 3.10 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.59 (dd, J = 13.0, 6.0 Hz, 1 H), 2.10 (td, J = 13.0, 8.0 Hz, 1 H), 1.98 (d, J = 15.0 Hz, 1 H), 1.69–1.66 (m, 4 H), 1.60 (s, 3 H), 0.80 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 179.8, 179.4, 139.1, 139.0, 135.9, 133.3, 131.8, 130.7, 128.8, 128.8, 128.7, 128.1, 127.5, 120.9, 63.2, 63.1, 59.9, 50.1, 48.7, 46.8, 43.9, 42.0, 36.1, 35.5, 32.9, 31.5, 31.2, 30.9, 30.0, 29.7, 29.4, 29.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₅H₃₉BrNO₃: 600.2113; found: 600.2101.

#

4-Benzoyl-3a-benzyl-5-(p-tolyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6j)

White solid; yield: 133.8 mg (50%); mp 134–135 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.27–7.21 (m, 3 H), 7.12 (d, J = 6.0 Hz, 2 H), 7.03 (s, 4 H), 4.03 (d, J = 11.5 Hz, 1 H), 3.64–3.58 (m, 1 H), 3.35 (d, J = 13.5 Hz, 1 H), 3.08 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.59 (dd, J = 13.0, 6.0 Hz, 1 H), 2.25 (s, 3 H), 2.13 (td, J = 13.0, 8.0 Hz, 1 H), 1.99 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.66 (d, J = 15.0 Hz, 1 H), 1.61 (s, 3 H), 0.79 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 200.0, 180.1, 179.6, 139.2, 137.0, 136.6, 136.0, 133.0, 130.7, 129.3, 128.7, 128.2, 127.4, 126.9, 63.3, 63.0, 59.9, 50.1, 48.7, 47.1, 42.1, 35.8, 31.4, 30.9, 29.8, 29.1, 21.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₄₂NO₃: 536.3165; found: 536.3156.

#

4-Benzoyl-3a-benzyl-5-(4-methoxyphenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6k)

White solid; yield: 154.3 mg (56%); mp 92–93 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.28–7.21 (m, 3 H), 7.13 (d, J = 6.0 Hz, 2 H), 7.06 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.5 Hz, 2 H), 4.00 (d, J = 11.5 Hz, 1 H), 3.72 (s, 3 H), 3.63–3.57 (m, 1 H), 3.34 (d, J = 13.5 Hz, 1 H), 3.09 (d, J = 8.0 Hz, 1 H), 2.88 (d, J = 13.5 Hz, 1 H), 2.59 (dd, J = 13.0, 6.0 Hz, 1 H), 2.12 (td, J = 13.0, 8.0 Hz, 1 H), 2.00 (d, J = 15.0 Hz, 1 H), 1.67 (s, 3 H), 1.66 (d, J = 15.0 Hz, 1 H), 1.62 (s, 3 H), 0.79 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 200.1, 180.1, 179.6, 158.5, 139.2, 136.0, 133.1, 132.1, 130.7, 128.7, 128.1, 128.0, 127.4, 114.1, 63.5, 63.0, 59.9, 55.2, 50.1, 48.7, 46.8, 42.1, 35.7, 31.5, 30.9, 29.8, 29.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₄₂NO₄: 552.3114; found: 552.3109.

#

4-Benzoyl-3a-benzyl-5-[(E)-styryl]-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6l)

White solid; yield: 134.0 mg (49%); mp 147–148 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.97 (d, J = 7.0 Hz, 2 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.25–7.17 (m, 8 H), 7.10 (d, J = 6.0 Hz, 2 H), 6.41 (d, J = 16.0 Hz, 1 H), 6.01 (dd, J = 16.0, 7.5 Hz, 1 H), 3.81 (d, J = 11.5 Hz, 1 H), 3.42 (d, J = 13.5 Hz, 1 H), 3.32–3.27 (m, 1 H), 3.04 (d, J = 8.0 Hz, 1 H), 2.84 (d, J = 13.5 Hz, 1 H), 2.54 (dd, J = 13.0, 6.0 Hz, 1 H), 2.02–1.95 (m, 2 H), 1.65–1.62 (m, 4 H), 1.60 (s, 3 H), 0.77 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 199.6, 180.0, 179.4, 139.0, 136.8, 136.0, 133.3, 131.6, 130.7, 128.8, 128.7, 128.5, 128.3, 127.5, 127.3, 126.2, 63.0, 62.0, 60.1, 50.1, 48.4, 45.4, 42.2, 34.5, 31.4, 30.9, 29.7, 29.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₇H₄₂NO₃: 548.3165; found: 548.3165.

#

3a-Substituted 5-Aroyl-2-(2,6-dimethylphenyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-triones 8 or Ethyl 5-Benzoyl-2-[(2,6-diisopropylphenyl)carbamoyl]-1′,2-dimethyl-2′-oxospiro[cyclopentane-1,3′-indoline]-3-carboxylates 9; General Procedure

To a solution of isocyanide 1 (0.5 mmol) and substituted allenoate 2 (0.6 mmol) in toluene–H₂O (6:1, 5 mL), methyleneindolinone 7 (0.5 mmol) was added under a N₂ atmosphere. The mixture was stirred and heated under reflux for several hours (TLC monitoring). When the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel 200–300, petroleum ether–EtOAc) to afford the desired product 8 or 9.

#

5-Benzoyl-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8a)

White solid; yield: 86.1 mg (35%); mp 300–302 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 7.5 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.21–7.14 (m, 3 H), 7.06 (d, J = 7.0 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 4.51 (dd, J = 13.5, 6.5 Hz, 1 H), 3.41 (t, J = 9.5 Hz, 1 H), 3.25–3.17 (m, 4 H), 2.87–2.81 (m, 1 H), 2.42 (s, 3 H), 2.05 (s, 3 H), 1.61 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.1, 178.5, 178.4, 175.5, 145.5, 138.0, 135.9, 135.4, 133.7, 130.2, 129.5, 129.3, 129.2, 128.8, 128.4, 128.3, 126.9, 124.5, 121.7, 108.9, 60.0, 58.8, 56.3, 53.4, 30.5, 26.5, 25.4, 18.3, 18.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₈N₂O₄: 493.2127; found: 493.2129.

#

5-(4-Chlorobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8b)

White solid; yield: 110.5 mg (42%); mp 314–315 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.72 (d, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.29 (td, J = 7.5, 0.5 Hz, 1 H), 7.22–7.12 (m, 3 H), 7.06 (d, J = 7.0 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 4.45 (dd, J = 13.5, 6.5 Hz, 1 H), 3.39 (t, J = 9.5 Hz, 1 H), 3.26–3.15 (m, 4 H), 2.83–2.77 (m, 1 H), 2.42 (s, 3 H), 2.05 (s, 3 H), 1.60 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.0, 178.4, 178.2, 175.4, 145.5, 140.2, 137.9, 135.3, 134.2, 130.1, 129.8, 129.5, 129.4, 129.2, 129.1, 128.3, 126.7, 124.5, 121.7, 108.9, 59.8, 58.8, 56.2, 53.3, 30.4, 26.4, 25.4, 18.2, 18.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₈ClN₂O₄: 527.1738; found: 527.1731.

#

5-(3-Chlorobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8c)

White solid; yield: 94.7 mg (36%); mp 292–293 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.73 (s, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 2 H), 7.15 (d, J = 7.0 Hz, 1 H), 7.06 (d, J = 7.0 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 4.42 (dd, J = 13.5, 6.5 Hz, 1 H), 3.41 (t, J = 9.5 Hz, 1 H), 3.25–3.17 (m, 4 H), 2.85–2.80 (m, 1 H), 2.41 (s, 3 H), 2.05 (s, 3 H), 1.62 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.1, 178.4, 178.1, 175.4, 145.5, 137.9, 137.5, 135.3, 135.2, 133.6, 130.2, 129.5, 129.4, 129.3, 128.5, 128.3, 126.7, 126.5, 124.6, 121.8, 109.0, 59.9, 58.9, 56.3, 53.3, 30.3, 26.5, 25.4, 18.2, 18.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₇ClN₂NaO₄: 549.1557; found: 549.1551.

#

5-(4-Bromobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8d)

White solid; yield: 148.2 mg (52%); mp 296–297 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.64 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.21–7.14 (m, 3 H), 7.06 (d, J = 7.0 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 4.43 (dd, J = 13.5, 6.5 Hz, 1 H), 3.40 (t, J = 9.5 Hz, 1 H), 3.24–3.16 (m, 4 H), 2.83–2.77 (m, 1 H), 2.41 (s, 3 H), 2.05 (s, 3 H), 1.60 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.2, 178.4, 178.2, 175.4, 145.5, 137.9, 135.3, 134.6, 132.1, 130.1, 129.9, 129.5, 129.4, 129.3, 128.9, 128.3, 126.7, 124.5, 121.8, 109.0, 59.8, 58.8, 56.3, 53.4, 30.4, 26.4, 25.4, 18.2, 18.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₇BrN₂NaO₄: 593.1052; found: 593.1056.

#

2-(2,6-Dimethylphenyl)-1′,3a-dimethyl-5-(4-nitrobenzoyl)-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8e)

White solid; yield: 56.4 mg (21%); mp 293–294 °C.

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.28 (d, J = 8.5 Hz, 2 H), 8.10 (d, J = 9.0 Hz, 2 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H), 7.03–6.95 (m, 2 H), 5.21 (dd, J = 12.5, 7.0 Hz, 1 H), 3.71 (t, J = 9.5 Hz, 1 H), 3.07 (s, 3 H), 2.81–2.65 (m, 2 H), 2.25 (s, 3 H), 1.99 (s, 3 H), 1.58 (s, 3 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 197.0, 178.1, 177.5, 175.8, 150.1, 144.7, 140.3, 137.2, 135.5, 130.5, 129.7, 128.9, 128.8, 128.5, 128.0, 126.8, 125.4, 123.8, 121.5, 108.5, 58.9, 58.4, 55.9, 51.7, 29.0, 26.0, 23.8, 17.7, 17.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₇N₃NaO₆: 560.1798; found: 560.1794.

#

2-(2,6-Dimethylphenyl)-1′,3a-dimethyl-5-(4-methylbenzoyl)-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8f)

White solid; yield: 113.9 mg (45%); mp 254–255 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.70 (d, J = 8.0 Hz, 2 H), 7.29–7.14 (m, 6 H), 7.06 (d, J = 7.0 Hz, 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 4.49 (dd, J = 13.5, 6.5 Hz, 1 H), 3.40 (t, J = 9.5 Hz, 1 H), 3.23–3.16 (m, 4 H), 2.86–2.81 (m, 1 H), 2.42 (s, 3 H), 2.38 (s, 3 H), 2.05 (s, 3 H), 1.60 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.6, 178.5, 175.6, 145.5, 144.6, 138.0, 135.3, 133.4, 130.2, 129.5, 129.4, 129.3, 129.2, 128.6, 128.2, 126.9, 124.5, 121.6, 108.9, 59.9, 58.8, 56.2, 53.5, 30.6, 26.4, 25.4, 21.8, 18.3, 18.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₀N₂NaO₄: 529.2103; found: 529.2091.

#

2-(2,6-Dimethylphenyl)-5-(4-methoxybenzoyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8g)

White solid; yield: 143.6 mg (55%); mp 235–236 °C.

¹H NMR (500 MHz, DMSO-d ₆): δ = 7.94 (d, J = 9.0 Hz, 2 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H), 7.03–6.97 (m, 4 H), 5.07 (dd, J = 13.0, 7.0 Hz, 1 H), 3.83 (s, 3 H), 3.70 (t, J = 9.0 Hz, 1 H), 3.08 (s, 3 H), 2.81–2.74 (m, 1 H), 2.69–2.63 (m, 1 H), 2.27 (s, 3 H), 1.99 (s, 3 H), 1.58 (s, 3 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 195.2, 178.2, 178.0, 175.8, 163.5, 144.94 137.2, 135.5, 130.8, 130.6, 128.9, 128.5, 128.3, 127.9, 127.2, 125.1, 121.2, 114.0, 108.3, 58.4, 58.3, 55.6, 55.6, 51.9, 29.6, 26.0, 23.7, 17.7, 17.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₀N₂NaO₅: 545.2052; found: 545.2041.

#

5-(Biphenyl-4-ylcarbonyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8h)

White solid; yield: 107.9 mg (38%); mp 239–240 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.87 (d, J = 8.5 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.21–7.16 (m, 3 H), 7.07 (d, J = 7.0 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 4.55 (dd, J = 13.5, 6.5 Hz, 1 H), 3.43 (t, J = 9.5 Hz, 1 H), 3.29–3.21 (m, 4 H), 2.92–2.86 (m, 1 H), 2.44 (s, 3 H), 2.06 (s, 3 H), 1.63 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.6, 178.5, 178.4, 175.6, 146.4, 145.5, 139.7, 138.0, 135.4, 134.5, 130.2, 129.5, 129.3, 129.2, 129.1, 129.0, 128.5, 128.3, 127.4, 127.4, 126.9, 124.6, 121.7, 108.9, 60.0, 58.9, 56.3, 53.5, 30.6, 26.5, 25.4, 18.3, 18.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₃₂N₂NaO₄: 591.2260; found: 591.2259.

#

5-Benzoyl-3a-benzyl-2-(2,6-dimethylphenyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8i)

White solid; yield: 102.2 mg (36%); mp 293–294 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.28–7.26 (m, 4 H), 7.20–7.18 (m, 2 H), 7.10–7.01 (m, 3 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 7.0 Hz, 1 H), 4.73 (dd, J = 13.0, 8.0 Hz, 1 H), 3.88 (dd, J = 10.0, 7.0 Hz, 1 H), 3.46 (d, J = 13.0 Hz, 1 H), 3.30–3.21 (m, 4 H), 3.12 (d, J = 13.0 Hz, 1 H), 2.93–2.87 (m, 1 H), 2.31 (s, 3 H), 0.92 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.3, 177.5, 176.4, 174.6, 145.9, 137.6, 135.9, 135.6, 134.7, 133.7, 131.5, 130.4, 129.5, 129.3, 129.0, 128.9, 128.8, 128.5, 128.2, 127.9, 126.3, 125.0, 121.8, 109.2, 60.8, 60.1, 59.3, 46.9, 41.7, 29.1, 26.6, 18.9, 16.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₃₂N₂NaO₄: 591.2260; found: 591.2255.

#

5-Benzoyl-2-(2,6-dimethylphenyl)-3a-(3-fluorobenzyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8j)

White solid; yield: 146.5 mg (50%); mp 299–300 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.85 (d, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.27–7.23 (m, 2 H), 7.11–6.88 (m, 8 H), 4.72 (dd, J = 13.0, 8.5 Hz, 1 H), 3.82 (dd, J = 10.0, 7.0 Hz, 1 H), 3.45 (d, J = 13.0 Hz, 1 H), 3.30–3.22 (m, 4 H), 3.12 (d, J = 13.0 Hz, 1 H), 2.93–2.87 (m, 1 H), 2.32 (s, 3 H), 1.04 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 177.4, 176.2, 174.5, 164.1, 162.1, 145.9, 137.6, 137.3, 137.2, 135.9, 135.4, 133.8, 130.8, 130.7, 130.4, 129.6, 129.1, 129.0, 128.9, 128.5, 128.3, 127.2, 127.2, 126.1, 124.9, 121.8, 118.6, 118.4, 115.0, 114.8, 109.2, 60.7, 60.2, 59.2, 47.0, 41.4, 29.1, 26.6, 18.9, 16.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₃₁FN₂NaO₄: 609.2166; found: 609.2164.

#

5-Benzoyl-3a-(3-chlorobenzyl)-2-(2,6-dimethylphenyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8k)

White solid; yield: 117.4 mg (39%); mp 303–304 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.0 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.27–7.19 (m, 4 H), 7.12–6.96 (m, 5 H), 6.89 (d, J = 7.0 Hz, 1 H), 4.70 (dd, J = 13.0, 8.0 Hz, 1 H), 3.81 (dd, J = 9.5, 7.5 Hz, 1 H), 3.42 (d, J = 13.0 Hz, 1 H), 3.29–3.23 (m, 4 H), 3.10 (d, J = 13.0 Hz, 1 H), 2.94–2.88 (m, 1 H), 2.32 (s, 3 H), 1.04 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 177.4, 176.2, 174.6, 145.9, 137.6, 136.8, 135.9, 135.4, 135.1, 133.8, 131.5, 130.5, 130.3, 129.7, 129.6, 129.1, 129.0, 128.9, 128.5, 128.3, 128.2, 126.1, 124.9, 121.8, 109.2, 60.6, 60.2, 59.2, 47.0, 41.4, 29.2, 26.6, 18.9, 16.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₃₁ClN₂NaO₄: 625.1870; found: 625.1863.

#

Ethyl 2-(5-Benzoyl-2-(2,6-dimethylphenyl)-1′-methyl-1,2′,3-trioxo-2,3,3a,5,6,6a-hexahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indolin]-3a-yl)acetate (8l)

White solid; yield: 163.6 mg (58%); mp 248–249 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.84 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.14–7.11 (m, 2 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 4.94 (dd, J = 13.5, 7.5 Hz, 1 H), 4.32–4.12 (m, 3 H), 3.23–3.17 (m, 4 H), 3.02 (d, J = 17.5 Hz, 1 H), 2.99–2.93 (m, 1 H), 2.87 (d, J = 17.5 Hz, 1 H), 2.43 (s, 3 H), 2.08 (s, 3 H), 1.32 (t, J = 7.0 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.6, 178.3, 176.8, 176.0, 171.1, 145.8, 137.9, 135.9, 135.8, 133.6, 130.1, 129.6, 129.3, 129.2, 128.8, 128.5, 128.4, 126.5, 124.2, 121.9, 109.1, 61.6, 60.0, 59.9, 57.8, 49.5, 39.9, 30.8, 26.5, 18.5, 18.4, 14.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₃₂N₂NaO₆: 587.2158; found: 587.2159.

#

5-Benzoyl-4′-bromo-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8m)

White solid; yield: 128.3 mg (45%); mp 314–315 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 7.0 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.17–7.13 (m, 3 H), 7.07 (d, J = 7.5 Hz, 1 H), 6.83–6.79 (m, 1 H), 5.78 (dd, J = 13.5, 7.0 Hz, 1 H), 3.47 (dd, J = 10.0, 8.5 Hz, 1 H), 3.27–3.18 (m, 4 H), 2.98–2.92 (m, 1 H), 2.38 (s, 3 H), 2.06 (s, 3 H), 1.83 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 197.2, 178.9, 178.3, 175.4, 147.8, 137.7, 136.1, 135.5, 133.5, 130.7, 129.9, 129.5, 129.1, 128.8, 128.3, 127.5, 125.4, 119.9, 108.3, 61.2, 59.7, 56.2, 53.6, 31.4, 26.5, 24.0, 18.1, 18.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₇BrN₂NaO₄: 593.1052; found: 593.1048.

#

5-Benzoyl-5′-chloro-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8n)

White solid; yield: 89.4 mg (34%); mp 241–242 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.45 (td, J = 7.5, 1.3 Hz, 3 H), 7.32–7.14 (m, 6 H), 7.08 (d, J = 7.5 Hz, 1 H), 6.51 (d, J = 8.5 Hz, 1 H), 4.49 (t, J = 8.0 Hz, 1 H), 3.49 (dd, J = 10.0, 8.0 Hz, 1 H), 3.15–3.09 (m, 1 H), 2.93 (s, 3 H), 2.82–2.75 (m, 1 H), 2.35 (s, 3 H), 2.06 (s, 3 H), 1.63 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.8, 177.1, 176.1, 175.9, 142.1, 136.9, 136.6, 135.7, 133.3, 130.1, 129.6, 129.3, 129.2, 128.8, 128.5, 128.3, 128.0, 127.8, 127.3, 108.8, 60.8, 58.8, 55.3, 52.7, 31.6, 26.5, 23.5, 18.7, 18.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₇ClN₂NaO₄: 549.1557; found: 549.1559.

#

5-Benzoyl-2-(2-chloro-6-methylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8o)

White solid; yield: 115.2 mg (45%); mp 279–280 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.40–7.14 (m, 10 H), 6.98 (t, J = 8.0 Hz, 1 H), 6.53 (d, J = 8.0 Hz, 1 H), 4.39 (dd, J = 10.5, 6.5 Hz, 1 H), 3.47 (dd, J = 9.5, 3.0 Hz, 1 H), 3.10–3.04 (m, 1 H), 2.91–2.87 (m, 1 H), 2.77 (s, 3 H), 2.65 (s, 3 H), 1.29 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.9, 178.2, 176.6, 176.4, 143.8, 139.9, 137.1, 132.8, 132.6, 130.4, 129.7, 129.4, 129.2, 128.1, 128.1, 127.4, 127.2, 125.6, 122.2, 108.4, 62.7, 58.7, 56.1, 54.0, 30.5, 26.4, 22.9, 18.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₆ClN₂O₄: 513.1581; found: 513.1595.

#

2-(2-Chloro-6-methylphenyl)-5-(4-chlorobenzoyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8p)

White solid; yield: 128.3 mg (47%); mp 282–283 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.72 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.31–7.21 (m, 4 H), 7.18 (d, J = 7.5 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.46 (dd, J = 13.5, 7.0 Hz, 1 H), 3.45 (t, J = 9.5 Hz, 1 H), 3.22–3.10 (m, 4 H), 2.82–2.76 (m, 1 H), 2.45 (s, 3 H), 1.65 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.1, 178.3, 177.5, 175.1, 145.4, 140.7, 140.2, 134.2, 132.5, 130.4, 129.9, 129.8, 129.4, 129.2, 129.0, 127.3, 126.7, 124.5, 121.8, 109.0, 59.7, 58.9, 56.4, 53.3, 30.1, 26.4, 24.9, 18.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₂₄Cl₂N₂NaO₄: 569.1011; found: 569.1018.

#

5-(4-Chlorobenzoyl)-2-(2,6-diisopropylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8q)

White solid; yield: 177.5 mg (61%); mp 272–273 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 8.5 Hz, 2 H), 7.30–7.37 (m, 3 H), 7.30–7.27 (m, 2 H), 7.18–7.17 (m, 2 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 4.47 (dd, J = 13.5, 6.5 Hz, 1 H), 3.45–3.36 (m, 2 H), 3.30–3.23 (m, 4 H), 2.83–2.78 (m, 1 H), 2.59–2.51 (m, 1 H), 1.61 (s, 3 H), 1.24 (d, J = 3.5 Hz, 3 H), 1.23 (d, J = 3.0 Hz, 3 H), 1.16 (d, J = 7.0 Hz, 3 H), 1.08 (d, J = 7.0 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 195.0, 179.0, 178.2, 176.6, 148.6, 145.5, 145.4, 140.2, 134.1, 130.2, 129.9, 129.3, 129.2, 127.4, 126.7, 124.8, 124.4, 123.6, 121.6, 108.9, 59.6, 58.5, 56.1, 53.3, 30.1, 29.2, 27.9, 26.3, 25.6, 25.0, 24.1, 23.9, 23.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₅ClN₂NaO₄: 605.2183; found: 605.2189.

#

5-Benzoyl-2-(2,6-diisopropylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8r)

White solid; yield: 95.9 mg (35%); mp 285–286 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.44–7.37 (m, 3 H), 7. 28 (t, J = 8.5 Hz, 2 H), 7.17 (d, J = 7.5 Hz, 2 H), 6.97 (t, J = 7.5 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 4.54 (dd, J = 13.5, 7.0 Hz, 1 H), 3.46–3.38 (m, 2 H), 3.31–3.24 (m, 4 H), 2.88–2.82 (m, 1 H), 2.56 (dt, J = 13.5, 7.0 Hz, 1 H), 1.62 (s, 3 H), 1.25–1.23 (m, 6 H), 1.16 (d, J = 7.0 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.1, 179.1, 178.4, 176.7, 148.6, 145.5, 145.4, 135.8, 133.7, 130.1, 129.2, 128.8, 128.5, 127.5, 126.9, 124.8, 124.4, 123.6, 121.6, 108.9, 59.7, 58.5, 56.2, 53.3, 30.2, 29.2, 27.9, 26.3, 25.6, 25.0, 24.1, 23.9, 23.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₆N₂NaO₄: 571.2573; found: 571.2568.

#

Ethyl 5-Benzoyl-2-[(2,6-diisopropylphenyl)carbamoyl]-1′,2-dimethyl-2′-oxospiro[cyclopentane-1,3′-indoline]-3-carboxylate (9a)

White solid; yield: 41.6 mg (14%); mp 224–225 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.27 (m, 1 H), 7.23 (d, J = 7.0 Hz, 1 H), 7.15–7.11 (m, 5 H), 7.04–6.99 (m, 3 H), 6.79 (td, J = 7.5, 1.0 Hz, 1 H), 6.50 (s, 1 H), 6.33 (d, J = 7.5 Hz, 1 H), 4.33 (dd, J = 11.0, 7.5 Hz, 1 H), 4.28–4.15 (m, 2 H), 3.62 (m, 1 H), 3.28 (dd, J = 13.0, 6.5 Hz, 1 H), 2.84 (s, 3 H), 2.49–2.43 (m, 1 H), 1.92 (s, 3 H), 1.61 (s, 2 H), 1.32 (t, J = 7.5 Hz, 3 H), 0.92 (s, 6 H), 0.91 (s, 6 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.6, 178.2, 172.6, 170.5, 143.4, 138.0, 132.0, 130.9, 129.2, 129.1, 127.9, 127.8, 127.7, 126.8, 123.4, 123.1, 107.1, 62.1, 60.8, 60.4, 54.8, 54.8, 31.0, 27.6, 26.4, 24.4, 14.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₄₂N₂NaO₅: 617.2991; found: 617.2987.

#

Ethyl 5-Benzoyl-5′-bromo-2-[(2,6-dimethylphenyl)carbamoyl]-1′,2-dimethyl-2′-oxospiro[cyclopentane-1,3′-indoline]-3-carboxylate (9b)

White solid; yield: 129.4 mg (42%); mp 271–272 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.24 (t, J = 7.5 Hz, 1 H), 7.17–7.14 (m, 3 H), 7.11–7.08 (m, 3 H), 7.01–6.92 (m, 3 H), 6.72 (s, 1 H), 6.20 (d, J = 8.5 Hz, 1 H), 4.35 (dd, J = 11.5, 7.0 Hz, 1 H), 4.26–4.12 (m, 2 H), 3.78 (q, J = 12.5 Hz, 1 H), 3.37 (dd, J = 13.0, 7.0 Hz, 1 H), 2.97 (s, 3 H), 2.49–2.44 (m, 1 H), 1.76 (s, 3 H), 1.71 (s, 6 H), 1.31 (t, J = 7.0 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 197.9, 178.7, 172.3, 169.5, 142.7, 138.2, 134.8, 133.1, 132.0, 131.8, 131.7, 128.8, 128.2, 127.9, 127.5, 126.9, 116.2, 108.7, 62.5, 61.0, 59.7, 54.4, 54.0, 31.1, 26.6, 22.2, 18.1, 14.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₃BrN₂NaO₅: 639.1471; found: 639.1468.

#
#

Acknowledgement

The authors thank the National Natural Science Foundation of China (Nos: 21272148, 21272147, 21472121), and the State Key Laboratory of Applied Organic Chemistry, Lanzhou University for financial support. The authors also thank Dr. Hongmei Deng and Min Shao of Laboratory for Microstructures, Shanghai University for the NMR and single crystal X-ray analysis.

Supporting Information

Supporting Information

References
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References
1 S.X. and S.S. contributed equally to this work.

For recent examples, see:

2a Buyck T, Wang Q, Zhu J. J. Am. Chem. Soc. 2014; 136: 11524

Crossref Search in Google Scholar
2b Mampuys P, Zhu Y, Vlaar T, Ruijter E, Orru RV. A, Maes BU. W. Angew. Chem. Int. Ed. 2014; 53: 12849

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3a Liu J, Liu Z, Liao P, Bi X. Org. Lett. 2014; 16: 6204

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3b Nanjo T, Tsukano C, Takemoto Y. Org. Lett. 2012; 14: 4270

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Oxazole:

3d Janvier P, Bois-Choussy M, Bienaymé H, Zhu J. Angew. Chem. Int. Ed. 2003; 42: 811

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3e Larionov OV, de Meijere A. Angew. Chem. Int. Ed. 2005; 44: 5664

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3g Helal CJ, Lucas JC. Org. Lett. 2002; 4: 4133

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3k Vlaar T, Mampuys P, Helliwell M, Maes BU. W, Orru RV. A, Ruijter E. J. Org. Chem. 2013; 78: 6735

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Crossref Search in Google Scholar
4b Baelen GV, Kuijer S, Rýcěk L, Sergeyev S, Janssen E, de Kanter FJ. J, Maes BU. W, Ruijter E, Orru RV. A. Chem. Eur. J. 2011; 17: 15039

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Search in Google Scholar
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Search in Google Scholar
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Crossref Search in Google Scholar

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7a Multicomponent Reactions in Organic Synthesis . Zhu J, Wang Q, Wang M.-X. Wiley-VCH; Weinheim: 2014

Crossref Search in Google Scholar
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Isocyanide-Based Multicomponent Reactions: Rapid Synthesis of a 5,5-Fused Bicyclic Skeleton from α,β-Unsaturated Ketones and Allenoates

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Abstract

Key words

Table 1 Multicomponent Cycloaddition Reaction of Isocyanide 1, Ethyl 2-Benzylbuta-2,3-dienoate (2a), and Chalcone (3a)a

Table 2 Multicomponent Cascade Cycloaddition of 1,1,3,3-Tetra­meth­yl­butyl Isocyanide (1d), Substituted Allenoate 2, and Chalcone (3a)a

Table 3 Multicomponent Reaction of 1,1,3,3-Tetramethylbutyl Isocyanide (1d), Ethyl 2-Benzylbuta-2,3-dienoate (2a), and α,β-Unsaturated Ketone 3 a

Table 4 Multicomponent Reaction of 2,6-Dimethylphenyl Isocyanide (1h), α-Substituted Allenoate 2, and Methyleneindolinone 7 a

2-Substituted 4-Benzoyl-3a-benzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 4; General Procedure

4-Benzoyl-3a-benzyl-2-tert-butyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4a)

4-Benzoyl-3a-benzyl-2-butyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4b)

4-Benzoyl-3a-benzyl-2-cyclohexyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4c)

4-Benzoyl-3a-benzyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4d)

4-Benzoyl-3a-benzyl-2-isopropyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4e)

4-Benzoyl-2,3a-dibenzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4f)

2-(Adamantan-1-yl)-4-benzoyl-3a-benzyl-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4g)

4-Benzoyl-3a-benzyl-2-(2,6-dimethylphenyl)-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4h)

4-Benzoyl-3a-benzyl-2-(2-chloro-6-methylphenyl)-5-phenyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4i)

3a-Substituted 4-Benzoyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 5; General Procedure

4-Benzoyl-3a-(3-fluorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5a)

4-Benzoyl-3a-(4-chlorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5b)

4-Benzoyl-3a-(3-chlorobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5c)

4-Benzoyl-3a-(4-bromobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5d)

4-Benzoyl-3a-(4-nitrobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5e)

4-Benzoyl-3a-(3-nitrobenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5f)

4-Benzoyl-3a-(4-methylbenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5g)

4-Benzoyl-3a-(3-methylbenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5h)

4-Benzoyl-3a-(3-methoxybenzyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5i)

4-Benzoyl-3a-methyl-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (5j)

Methyl [4-Benzoyl-1,3-dioxo-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)octahydrocyclopenta[c]pyrrol-3a-yl]acetate (5k)

Ethyl [4-Benzoyl-1,3-dioxo-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)octahydrocyclopenta[c]pyrrol-3a-yl]acetate (5l)

4-Aroyl-5-aryl-3a-benzyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-diones 6; General Procedure

3a-Benzyl-4-(4-fluorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6a)

3a-Benzyl-4-(4-chlorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6b)

3a-Benzyl-4-(3-chlorobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6c)

3a-Benzyl-4-(4-bromobenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6d)

3a-Benzyl-4-(4-methylbenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6e)

3a-Benzyl-4-(4-methoxybenzoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6f)

3a-Benzyl-4-(1-naphthoyl)-5-phenyl-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6g)

4-Benzoyl-3a-benzyl-5-(4-chlorophenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6h)

4-Benzoyl-3a-benzyl-5-(4-bromophenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6i)

4-Benzoyl-3a-benzyl-5-(p-tolyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6j)

4-Benzoyl-3a-benzyl-5-(4-methoxyphenyl)-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6k)

4-Benzoyl-3a-benzyl-5-[(E)-styryl]-2-(2,4,4-trimethylpentan-2-yl)tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (6l)

5-Benzoyl-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8a)

5-(4-Chlorobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8b)

5-(3-Chlorobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8c)

5-(4-Bromobenzoyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8d)

2-(2,6-Dimethylphenyl)-1′,3a-dimethyl-5-(4-nitrobenzoyl)-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8e)

2-(2,6-Dimethylphenyl)-1′,3a-dimethyl-5-(4-methylbenzoyl)-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8f)

2-(2,6-Dimethylphenyl)-5-(4-methoxybenzoyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8g)

5-(Biphenyl-4-ylcarbonyl)-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8h)

5-Benzoyl-3a-benzyl-2-(2,6-dimethylphenyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8i)

5-Benzoyl-2-(2,6-dimethylphenyl)-3a-(3-fluorobenzyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8j)

5-Benzoyl-3a-(3-chlorobenzyl)-2-(2,6-dimethylphenyl)-1′-methyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8k)

Ethyl 2-(5-Benzoyl-2-(2,6-dimethylphenyl)-1′-methyl-1,2′,3-trioxo-2,3,3a,5,6,6a-hexahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indolin]-3a-yl)acetate (8l)

5-Benzoyl-4′-bromo-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8m)

5-Benzoyl-5′-chloro-2-(2,6-dimethylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8n)

5-Benzoyl-2-(2-chloro-6-methylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8o)

2-(2-Chloro-6-methylphenyl)-5-(4-chlorobenzoyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8p)

5-(4-Chlorobenzoyl)-2-(2,6-diisopropylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8q)

5-Benzoyl-2-(2,6-diisopropylphenyl)-1′,3a-dimethyl-3a,5,6,6a-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-4,3′-indoline]-1,2′,3(2H)-trione (8r)

Ethyl 5-Benzoyl-2-[(2,6-diisopropylphenyl)carbamoyl]-1′,2-dimethyl-2′-oxospiro[cyclopentane-1,3′-indoline]-3-carboxylate (9a)

Ethyl 5-Benzoyl-5′-bromo-2-[(2,6-dimethylphenyl)carbamoyl]-1′,2-dimethyl-2′-oxospiro[cyclopentane-1,3′-indoline]-3-carboxylate (9b)

Acknowledgement

Supporting Information

References

References

Table 1 Multicomponent Cycloaddition Reaction of Isocyanide 1, Ethyl 2-Benzylbuta-2,3-dienoate (2a), and Chalcone (3a)^a

Table 2 Multicomponent Cascade Cycloaddition of 1,1,3,3-Tetramethylbutyl Isocyanide (1d), Substituted Allenoate 2, and Chalcone (3a)^a

Table 3 Multicomponent Reaction of 1,1,3,3-Tetramethylbutyl Isocyanide (1d), Ethyl 2-Benzylbuta-2,3-dienoate (2a), and α,β-Unsaturated Ketone 3 ^a

Table 4 Multicomponent Reaction of 2,6-Dimethylphenyl Isocyanide (1h), α-Substituted Allenoate 2, and Methyleneindolinone 7 ^a