DOI: 10.1002/chem.201304839
Communication
& Synthetic Methods
Bioinspired Intramolecular Diels–Alder Reaction: A Rapid Access to the Highly-Strained Cyclopropane-Fused Polycyclic Skeleton Shifa Zhu,* Zhengjiang Guo, Zhipeng Huang, and Huanfeng Jiang[a] Abstract: A bioinsipred gold-catalyzed tandem Diels– Alder/Diels–Alder reaction of an enynal and a 1,3-diene, forming the highly-strained benzotricyclo[3.2.1.02,7]octane skeleton, was reported. In contrast, a Diels–Alder/Friedel– Crafts tandem reaction occurred instead when silver salts were used as the catalyst. Although both reactions experienced the similar Diels–Alder reaction of a pyrylium intermediate with a 1,3-diene, they have different reaction mechanisms. The former proceeded with a stepwise Diels–Alder reaction, while the latter one with a concerted one.
Scheme 1. Naturally occurring compounds containing tricyclo[3,2,1.02,7]octane.
Architecturally complex natural or unnatural molecules continue to serve as a testing ground for state-of-the-art synthetic organic chemistry and as a powerful avenue for the invention of novel synthetic technologies and strategies.[1] One of the most challenging issues in synthesizing these complex molecules is how to efficiently and selectively construct the highly strained polycyclic skeleton.[2] Cyclopropane is the smallest allcarbon cyclic molecule with the highest ring-strain in cycloalkanes.[3] The cyclopropane-fused polycyclic structure represents an even higher-strained motif. Construction of such an unusual system still remains highly challenging despite extensive research in the area of metal-catalyzed cyclopropanation.[3, 4] Cyclopropane-fused tricyclo[3.2.1.02,7]octane consists of fused three-, five-, and six-membered rings. It is the core structure of many naturally occurring and biologically active substances, such as cycloseychellene,[5] ishwarane/ishwarone,[6] ent-trachyloban-3b-ol,[7] and salvileucalin B[8] (Scheme 1). For example, salvileucalin B, obtained from the plant Salvia leucantha, was found to exhibit cytotoxic activity against A549 (human lung adenocarcinoma) and HT-29 (human colon adenocarcinoma) cells.[8] Although many of these molecules were found to exhibit excellent biological activities, the construction of the cyclopropane-based polycyclic structures typically required a multi-step procedure or harsh reaction conditions.[4] Nature has endowed the chemical world with an elegant and magic power to as-
Scheme 2. Proposed biosynthesis of salvileucalin B.
semble these tough skeletons. For instance, salvileucalin B has been hypothesized to originate biosynthetically from salvileucalin A by a tandem enzymatic oxidation and intramolecular Diels–Alder reaction (Scheme 2).[8b, 9] Such a highly efficient molecular architecture strategy in nature has sparked strong interest from synthetic chemists. For example, Chen and co-workers reported an elegant modular synthetic strategy to construct the key tricyclo[3.2.1.02,7]octane fragment B of salvileucalin B from cyclohexadiene A through the intramolecular Diels–Alder reaction (Scheme 3).[8b] However, the reaction was limited by its harsh conditions: iterative microwave heating and high temperature (250 8C). Such harsh reaction conditions may be attributed to the high strain of the fully substituted cyclopropane and the abnormal electron-
[a] Prof. Dr. S. Zhu, Z. Guo, Z. Huang, Prof. Dr. H. Jiang School of Chemistry and Chemical Engineering South China University of Technology Guangzhou 510640 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304839. Chem. Eur. J. 2014, 20, 2425 – 2430
Scheme 3. Biomimetic synthesis of the core structure of salvileucalin B.
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Communication matching between the diene and dienophine (both are electron rich). o-Quinodimethane (o-QDM) is a transient short-lived and highly reactive species.[10] A cis-diene, o-QDM is much more reactive than the related classical diene (such as butadiene and cyclopentadiene) in Diels–Alder reactions. Inspired by the above biosynthetic proposal of salvileucalin B, also as part of our continuing efforts to develop o-QDM chemistry,[11] we envisioned that benzotricyclo[3.2.1.02, 7]octane D could be readily available from the vinyl-substituted cyclic-o-QDM C through an intramolecular Diels–Alder reaction (Scheme 4).
Table 1. Optimization of reaction conditions.[a]
Scheme 4. Proposed bioinspired synthesis of tricyclo[3.2.1.02,7]octane D from vinyl cyclic-o-QDM C.
Initial efforts were made to systematically investigate various catalytic reaction conditions for the reaction of enynal and 1,3diene. Heating equimolar amounts of enynal (1 a) and phenyl 1,3-butadiene (2 a) in 1,2-dichloroethane (DCE) with a catalytic amount of AgSbF6 did not furnish the desired product 3 a, however, an unexpected Friedel–Crafts product 4 a was obtained in 34 % instead (Table 1, entry 1). Gratifyingly, the desired product 3 a could be obtained in low yields when FeCl3, ZnCl2, and CuCl2·2 H2O were used as catalysts (entries 2–4). In these cases, 4 a was also observed as a side product. Further screening of the catalysts and additives revealed that AuIII can catalyze this reaction leading to 3 a as the sole product (entries 5–12). For example, 3 a could be obtained in 20 % yield when KAuCl4·2 H2O was used as the catalyst. N-heterocyclic carbene (NHC)-supported gold(I) complex ([AuCl(IMes)]) alone was inefficient for this transformation (entry 6). With the fact that AuIII was a better catalyst to promote this transformation, we then focused our attention to find other AuIII sources. Recently, Selectfluor was extensively used as a mild organic oxiChem. Eur. J. 2014, 20, 2425 – 2430
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Catalyst
Additive
Yield 3 a [%]
Yield 4 a [%]
1 2 3 4 5 6 7 8 9 10 11[b] 12[b,c] 13
AgSbF6 FeCl3 ZnCl2 CuCl2·2 H2O KAuCl4·2 H2O [AuCl(IMes)] [AuCl(IMes)] [AuCl(SIMes)] [AuCl(IPr)] [AuCl(SIPr)] [AuCl(SIMes)] [AuCl(SIMes)] –
– – – – – – Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor
n.d. 3 9 10 20 n.d. 41 51 32 43 78 96[d] n.d.
34 7 13 5 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
[a] Unless otherwise noted, the reactions were performed in DCE at 80 8C for 14 h using 5 mol % catalyst and 10 mol % additive under N2, 1 a/2 a = 1:1. [1 a] = 0.05 m. The yield was determined by 1H NMR spectroscopy with MeNO2 as the internal standard. IMes: 1,3-dimesitylimidazol-2-ylidene; SIMes: 1,3-dimesitylimidazolin-2-ylidene; IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; SIPr: 1,3-bis(2,6-diisopropylphenyl)imidazolin2-ylidene. [b] 1 a/2 a = 1:5. [c] 15 mol % Selectfluor. [d] Isolated yield.
Herein, we would like to report the realization of such a hypothesis to rapid access to the benzotricyclo[3.2.1.02,7]octane skeleton through the gold-catalyzed generation and trapping of the cyclic-o-QDM from the reaction of enynals and 1,3-butadienes. The reaction proceeded through the well-known pyryilium intermediate[12] (Scheme 5).
Scheme 5. Rapid synthesis of the highly strained polycyclic structure.
Entry
dant in generating NHC–AuIII + in situ through the reaction of NHC–AuI and Selectfluor.[11b, 13] Inspired by these facts, we tried to produce the NHC–AuIII + complex through the reaction of NHC–AuI and Selectfluor. Interestingly, a significant positive effect was observed when the combination of [AuCl(IMes)]/Selectfluor (1:2) was applied. The yield of 3 a was improved to 41 % (entry 7). Among four different [AuCl(NHC)] complexes being tested, [AuCl(SIMes)] functioned better than the other three (entries 7–10). The yield of 3 a was enhanced to 51 % for the combination of [AuCl(SIMes)]/Selectfluor. Increasing the amount of diene (2 a) or Selectfluor could improve the yields further (entries 11–12). For example, the yield of 3 a was 78 % when five equivalents of 2 a were applied (entry 11). The best result was obtained when the reaction was conducted in DCE at 80 8C for 14 h by using 5 mol % [AuCl(SIMes)] as the catalyst and 15 mol % Selectfluor as additive under N2, and the molar ratio of 1 a/2 a = 1:5 (entry 12). Under the optimized reaction conditions, the yield of 3 a climbed to 96 % (entry 12). The reaction did not occur without the gold catalyst (entry 13, see the Supporting Information for detailed condition screening). The structures of 3 a and 4 a were confirmed by their X-ray diffraction analysis (see the Supporting Information). It’s interesting to find that only one isomer of 3 a was found for all cases in Table 1, although the mixture of cis- and trans-diene 2 a was used as the starting material. With the optimized reaction conditions (Table 1, entry 12) in hand, the substrate scope was then examined. As summarized in Table 2, the catalytic process could be successfully applied to a variety of enynals/enynones 1 and dienes 2. For example,
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Communication Table 2. Substrate scopes of enynal/enynone with 1,3-diene.[a]
Table 2. (Continued)
[a] Unless specified, the reactions were carried out under N2 with a molar ratio of 1/2 = 1:5. [1] = 0.05 m. The yield refers to isolated yield.
in addition to phenyl 1,3-butadiene 2 a, various 1,3-butadiene derivatives could be effectively reacted with enynal 1 a as well (Table 2, 3 a–s). The reaction proceeded particularly smoothly for different aryl-substituted 1,3-butadiene derivatives, with the yields typically higher than 60 % (3 a–l). The reactions were not sensitive to the electron properties of aryl 1,3-butadienes. Both the electron-rich and -poor aryl 1,3-butadienes could give satisfactory yields (electron-rich dienes: 3 a–d; electron-poor dienes: 3 g–l). Notably, the reaction could proceed smoothly even for the extremely electron-deficient pentafluoro-phenylsubstituted 1,3-butadiene with the yield up to 85 % (3 l). Bulky 1,3-butadienes typically gave a little bit lower yields (3 e, 3 f). In addition to the aryl 1,3-butadienes, 1,3,5-hexatriene could be used as the substrate as well, giving the desired product 3 m in 52 % yield. Furyl 1,3-butadiene, a heteroaryl substrate, was also successfully converted into the desired product 3 n in 26 % yield. Furthermore, the reaction could smoothly occur even for the 1,3-butadiene with a free hydroxyl group, albeit in lower yield (3 o, 30 %). The alkyl-substituted 1,3-butadienes provided the corresponding products in moderate yields (3 p, 3 q). It is worth noting that an ester functional group was introduced in the cases of 3 r and 3 s when 4-methyl- or 4phenyl-substituted 1-carboalkoxy-1,3-butadienes were used as the substrates. The yields of 3 r and 3 s were 63 and 55 %, respectively. Compared with the 1,3-butadienes 2, the reaction was more sensitive to the properties of enynals 1 (3 t–ae). For example, the enynals substituted with electron-donating groups furnished the desired products in higher yields than those with electron-withdrawing groups (3 t–x). The reaction was depressed completely when a pyridine was introduced into the enynal (3 y). Presumably, the strong coordinating capability of the pyridine poisoned the catalyst. For enynals bearing the alkyl alkynes, the reactions proceed smoothly as well (3 z–ab), with the yields ranging from 72–85 %. Importantly, the enynal with a terminal alkyne could be applied as the substrate as well, furnishing the product 3 ac (30 %) with an aldehyde functional group. The reaction functioned particularly efficiently for the enynones, which gave the products 3 ad and 3 ae in 84 and 91 % yields, respectively. Once again, only a single isomer was found for all the cases in Table 2 when Chem. Eur. J. 2014, 20, 2425 – 2430
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Communication mixtures of cis- and trans-dienes 2 were applied as the starting materials. Based on the above results, a possible reaction mechanism was then proposed (Scheme 6). The coordination of the triple bond of enynal 1 to [Au] enhances the electrophilicity of the
teresting bridged compound 4, which was observed as a side product during the course of optimization of reaction conditions (Table 1). It could be obtained as the sole product when silver salt was used as the catalyst (Table 1, entry 1). As shown by its X-ray structure (see the Supporting Information), 4 contains a benzocycloheptene, in which the C=C double bond takes cis-configuration. Therefore, retrosynthetically, the product 4 may be generated only from cis-1,3-butadiene 2. The control reactions were carried out as well to clarify the silvercatalyzed reaction pathway. As shown in Scheme 8, 4 a could
Scheme 8. Control Reactions: 1/2 = 1:1; [1] = 0.05 m; isolated yield.
Scheme 6. Proposed gold-catalyzed reaction mechanism.
alkyne, and the subsequent nucleophilic attack of the carbonyl oxygen to the electron-deficient alkyne would form the intermediate pyrylium E. A stepwise Diels–Alder reaction between 1,3-diene 2 (cis + trans) and pyrylium E can then be then followed to furnish the intermediate G. In this course, an allyl cation F was formed initially. Then elimination of the catalyst [Au] led to the key intermediate C, vinyl-substituted cyclic-oQDM. Finally, an intramolecular Diels–Alder reaction then occurs to furnish the desired product 3. To clarify the reaction pathway, a set of control reactions were then carried out. As shown in Scheme 7, three different cis/trans ratios of 2 a were used as the starting materials. The
Scheme 7. Control reactions: 1/2 = 1:5; [1] = 0.05 m; isolated yield.
yields of 3 a remained almost unchanged regardless the cis/ trans ratios of 1,3-diene 2 a. These observations clearly supported the ionic stepwise Diels–Alder reaction mechanism. Having established the gold-catalyzed reaction of enynals and 1,3-butadienes as a reliable and efficient synthetic process to construct the benzotricyclo[3.2.1.02, 7]octane structure, we then turned our attention to another minor, but structurally inChem. Eur. J. 2014, 20, 2425 – 2430
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be obtained only in 34 % yield when 1,3-diene 2 a (cis/trans 50:50) was used. The yield almost doubled to 62 % when the cis/trans ratio was increased to > 90:10. All of trans-2 a (cis/ trans < 1:99) failed to give the desired product. Obviously, this indicated that only cis-1,3-diene 2 can result in the desired product 4. Based on the control reactions above, the scope and generality of this silver-catalyzed transformation was then investigated further (Table 3). With the cis-dominant 1,3-butadiene 2 a (cis/trans > 9:1) as the substrate, different enynals were then tested for this process. The aryl–enynals (1 a–b) produced the desired products 4 a and 4 b in 62 and 51 % yields, respectively. However, alkyl–enyal 1 c gave the desired bridged product 4 c only in 20 % yield. Actually, another unexpected product dihydronaphthalene 5 c was isolated as the dominant product in 49 % yield (entry 3). Similarly, enynal 1 d also gave the mixture of 4 d and 5 d, with the yields being 41 and 48 % respectively. The bridged compound 4 e was isolated as the sole product in 46 % when the enynal with a terminal alkyne 1 e was applied. Furthermore, the reaction proceeded smoothly as well when naphthalene-substituted cis-1,3-diene was used as the substrate, giving the desired product 4 f in 59 % yield. As for the silver-catalyzed transformation, a tentative mechanism was also depicted in Scheme 9 to account for its different product formation with the gold-catalyzed system. Initially, silver catalyzed the intramolecular reaction of enynal to form the pyrylium H. Different from the gold-catalyzed version, a concerted Diels–Alder reaction was proposed between 1,3diene 2 and pyrylium H to form the intermediate K. In this process, the diene’s configuration remained unchanged in this course. For example, cis-diene 2 would result in only cis-K intermediate. Finally, a Friedel–Crafts reaction or b-H elimination then occurred to furnish the products 4 and 5, respectively. In conclusion, we have developed an efficient method to rapidly construct the highly-strained benzotricyclo[3.2.1.02,7]octane skeleton through the gold-catalyzed reactions of enynals 1 and 1,3-butadienes 2. The reaction was proposed to
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Communication functional-group tolerance, this system holds considerable potential in the construction of complex molecules with a tricyclo[3.2.1.02,7]octane skeleton. Moreover, another structurally interesting bridged compound 4 could be formed instead when the catalyst was changed into silver salt. The control reactions revealed that only cis-isomers of 1,3-butadienes 2 could be converted into the desired product 4. The asymmetric version, a detailed reaction mechanism, and additional applications of these transformations are underway in our laboratory.
Table 3. Substrate scope of enynal with 1,3-diene.[a]
Entry
1
4
5
Experimental Section General experimental procedure 1 2
1 a (X = H) 1 b (X = Me)
62 % (4 a) 51 % (4 b)
trace (5 a) trace (5 b)
3 4 5
1 c (R = cyclopropyl) 1 d (R = tert-butyl) 1 e (R = H)
20 % (4 c) 41 % (4 d) 46 % (4 e)
49 % (5 c) 48 % (5 d) trace (5 e)
Enynals/enynones (0.1 mmol) and 1,3-dienes (0.5 mmol) were added to a solution of the corresponding catalyst combination of [AuCl(SIMes)] (2.7 mg, 0.005 mmol) and Selectfluor (5.31 mg, 0.015 mmol) in DCE (2 mL, 0.05 m). The reaction mixture was stirred under nitrogen atmosphere at 80 8C for 14 h. After the reaction was finished, the mixture was filtered by short silica, then the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to afford the desired product 3.
Acknowledgements
6
1a
< 59 % (4 f)
We are grateful to the NNSFC (21172077, 21372086), the Program for New Century Excellent Talents in University (NCET-10– 0403), The National Basic Research Program of China (973) (2011CB808600), the Changjiang Scholars and Innovation Team Project of the Ministry of Education, SRF for ROCS, State Education Ministry, Guangdong NSF (10351064101000000), and the Fundamental Research Funds for the Central Universities.
trace (5 f)
[a] Unless specified, the reactions were carried out under N2 with a molar ratio of 1/2 = 1:1. [1] = 0.05 m. The yield refers to isolated yield.
Keywords: catalysis · cyclopropanes · Diels–Alder reaction · gold · tandem reactions
Scheme 9. Proposed silver-catalyzed reaction mechanism.
proceed through the intramolecular Diels–Alder reaction of an in situ-generated vinyl-substituted cyclic-o-QDM. Owing to the mild reaction conditions, excellent substrate scope and high Chem. Eur. J. 2014, 20, 2425 – 2430
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Received: December 10, 2013 Published online on February 5, 2014
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Communication
& Synthetic Methods
Bioinspired Intramolecular Diels–Alder Reaction: A Rapid Access to the Highly-Strained Cyclopropane-Fused Polycyclic Skeleton Shifa Zhu,* Zhengjiang Guo, Zhipeng Huang, and Huanfeng Jiang[a] Abstract: A bioinsipred gold-catalyzed tandem Diels– Alder/Diels–Alder reaction of an enynal and a 1,3-diene, forming the highly-strained benzotricyclo[3.2.1.02,7]octane skeleton, was reported. In contrast, a Diels–Alder/Friedel– Crafts tandem reaction occurred instead when silver salts were used as the catalyst. Although both reactions experienced the similar Diels–Alder reaction of a pyrylium intermediate with a 1,3-diene, they have different reaction mechanisms. The former proceeded with a stepwise Diels–Alder reaction, while the latter one with a concerted one.
Scheme 1. Naturally occurring compounds containing tricyclo[3,2,1.02,7]octane.
Architecturally complex natural or unnatural molecules continue to serve as a testing ground for state-of-the-art synthetic organic chemistry and as a powerful avenue for the invention of novel synthetic technologies and strategies.[1] One of the most challenging issues in synthesizing these complex molecules is how to efficiently and selectively construct the highly strained polycyclic skeleton.[2] Cyclopropane is the smallest allcarbon cyclic molecule with the highest ring-strain in cycloalkanes.[3] The cyclopropane-fused polycyclic structure represents an even higher-strained motif. Construction of such an unusual system still remains highly challenging despite extensive research in the area of metal-catalyzed cyclopropanation.[3, 4] Cyclopropane-fused tricyclo[3.2.1.02,7]octane consists of fused three-, five-, and six-membered rings. It is the core structure of many naturally occurring and biologically active substances, such as cycloseychellene,[5] ishwarane/ishwarone,[6] ent-trachyloban-3b-ol,[7] and salvileucalin B[8] (Scheme 1). For example, salvileucalin B, obtained from the plant Salvia leucantha, was found to exhibit cytotoxic activity against A549 (human lung adenocarcinoma) and HT-29 (human colon adenocarcinoma) cells.[8] Although many of these molecules were found to exhibit excellent biological activities, the construction of the cyclopropane-based polycyclic structures typically required a multi-step procedure or harsh reaction conditions.[4] Nature has endowed the chemical world with an elegant and magic power to as-
Scheme 2. Proposed biosynthesis of salvileucalin B.
semble these tough skeletons. For instance, salvileucalin B has been hypothesized to originate biosynthetically from salvileucalin A by a tandem enzymatic oxidation and intramolecular Diels–Alder reaction (Scheme 2).[8b, 9] Such a highly efficient molecular architecture strategy in nature has sparked strong interest from synthetic chemists. For example, Chen and co-workers reported an elegant modular synthetic strategy to construct the key tricyclo[3.2.1.02,7]octane fragment B of salvileucalin B from cyclohexadiene A through the intramolecular Diels–Alder reaction (Scheme 3).[8b] However, the reaction was limited by its harsh conditions: iterative microwave heating and high temperature (250 8C). Such harsh reaction conditions may be attributed to the high strain of the fully substituted cyclopropane and the abnormal electron-
[a] Prof. Dr. S. Zhu, Z. Guo, Z. Huang, Prof. Dr. H. Jiang School of Chemistry and Chemical Engineering South China University of Technology Guangzhou 510640 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304839. Chem. Eur. J. 2014, 20, 2425 – 2430
Scheme 3. Biomimetic synthesis of the core structure of salvileucalin B.
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Communication matching between the diene and dienophine (both are electron rich). o-Quinodimethane (o-QDM) is a transient short-lived and highly reactive species.[10] A cis-diene, o-QDM is much more reactive than the related classical diene (such as butadiene and cyclopentadiene) in Diels–Alder reactions. Inspired by the above biosynthetic proposal of salvileucalin B, also as part of our continuing efforts to develop o-QDM chemistry,[11] we envisioned that benzotricyclo[3.2.1.02, 7]octane D could be readily available from the vinyl-substituted cyclic-o-QDM C through an intramolecular Diels–Alder reaction (Scheme 4).
Table 1. Optimization of reaction conditions.[a]
Scheme 4. Proposed bioinspired synthesis of tricyclo[3.2.1.02,7]octane D from vinyl cyclic-o-QDM C.
Initial efforts were made to systematically investigate various catalytic reaction conditions for the reaction of enynal and 1,3diene. Heating equimolar amounts of enynal (1 a) and phenyl 1,3-butadiene (2 a) in 1,2-dichloroethane (DCE) with a catalytic amount of AgSbF6 did not furnish the desired product 3 a, however, an unexpected Friedel–Crafts product 4 a was obtained in 34 % instead (Table 1, entry 1). Gratifyingly, the desired product 3 a could be obtained in low yields when FeCl3, ZnCl2, and CuCl2·2 H2O were used as catalysts (entries 2–4). In these cases, 4 a was also observed as a side product. Further screening of the catalysts and additives revealed that AuIII can catalyze this reaction leading to 3 a as the sole product (entries 5–12). For example, 3 a could be obtained in 20 % yield when KAuCl4·2 H2O was used as the catalyst. N-heterocyclic carbene (NHC)-supported gold(I) complex ([AuCl(IMes)]) alone was inefficient for this transformation (entry 6). With the fact that AuIII was a better catalyst to promote this transformation, we then focused our attention to find other AuIII sources. Recently, Selectfluor was extensively used as a mild organic oxiChem. Eur. J. 2014, 20, 2425 – 2430
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Catalyst
Additive
Yield 3 a [%]
Yield 4 a [%]
1 2 3 4 5 6 7 8 9 10 11[b] 12[b,c] 13
AgSbF6 FeCl3 ZnCl2 CuCl2·2 H2O KAuCl4·2 H2O [AuCl(IMes)] [AuCl(IMes)] [AuCl(SIMes)] [AuCl(IPr)] [AuCl(SIPr)] [AuCl(SIMes)] [AuCl(SIMes)] –
– – – – – – Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor
n.d. 3 9 10 20 n.d. 41 51 32 43 78 96[d] n.d.
34 7 13 5 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
[a] Unless otherwise noted, the reactions were performed in DCE at 80 8C for 14 h using 5 mol % catalyst and 10 mol % additive under N2, 1 a/2 a = 1:1. [1 a] = 0.05 m. The yield was determined by 1H NMR spectroscopy with MeNO2 as the internal standard. IMes: 1,3-dimesitylimidazol-2-ylidene; SIMes: 1,3-dimesitylimidazolin-2-ylidene; IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; SIPr: 1,3-bis(2,6-diisopropylphenyl)imidazolin2-ylidene. [b] 1 a/2 a = 1:5. [c] 15 mol % Selectfluor. [d] Isolated yield.
Herein, we would like to report the realization of such a hypothesis to rapid access to the benzotricyclo[3.2.1.02,7]octane skeleton through the gold-catalyzed generation and trapping of the cyclic-o-QDM from the reaction of enynals and 1,3-butadienes. The reaction proceeded through the well-known pyryilium intermediate[12] (Scheme 5).
Scheme 5. Rapid synthesis of the highly strained polycyclic structure.
Entry
dant in generating NHC–AuIII + in situ through the reaction of NHC–AuI and Selectfluor.[11b, 13] Inspired by these facts, we tried to produce the NHC–AuIII + complex through the reaction of NHC–AuI and Selectfluor. Interestingly, a significant positive effect was observed when the combination of [AuCl(IMes)]/Selectfluor (1:2) was applied. The yield of 3 a was improved to 41 % (entry 7). Among four different [AuCl(NHC)] complexes being tested, [AuCl(SIMes)] functioned better than the other three (entries 7–10). The yield of 3 a was enhanced to 51 % for the combination of [AuCl(SIMes)]/Selectfluor. Increasing the amount of diene (2 a) or Selectfluor could improve the yields further (entries 11–12). For example, the yield of 3 a was 78 % when five equivalents of 2 a were applied (entry 11). The best result was obtained when the reaction was conducted in DCE at 80 8C for 14 h by using 5 mol % [AuCl(SIMes)] as the catalyst and 15 mol % Selectfluor as additive under N2, and the molar ratio of 1 a/2 a = 1:5 (entry 12). Under the optimized reaction conditions, the yield of 3 a climbed to 96 % (entry 12). The reaction did not occur without the gold catalyst (entry 13, see the Supporting Information for detailed condition screening). The structures of 3 a and 4 a were confirmed by their X-ray diffraction analysis (see the Supporting Information). It’s interesting to find that only one isomer of 3 a was found for all cases in Table 1, although the mixture of cis- and trans-diene 2 a was used as the starting material. With the optimized reaction conditions (Table 1, entry 12) in hand, the substrate scope was then examined. As summarized in Table 2, the catalytic process could be successfully applied to a variety of enynals/enynones 1 and dienes 2. For example,
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Communication Table 2. Substrate scopes of enynal/enynone with 1,3-diene.[a]
Table 2. (Continued)
[a] Unless specified, the reactions were carried out under N2 with a molar ratio of 1/2 = 1:5. [1] = 0.05 m. The yield refers to isolated yield.
in addition to phenyl 1,3-butadiene 2 a, various 1,3-butadiene derivatives could be effectively reacted with enynal 1 a as well (Table 2, 3 a–s). The reaction proceeded particularly smoothly for different aryl-substituted 1,3-butadiene derivatives, with the yields typically higher than 60 % (3 a–l). The reactions were not sensitive to the electron properties of aryl 1,3-butadienes. Both the electron-rich and -poor aryl 1,3-butadienes could give satisfactory yields (electron-rich dienes: 3 a–d; electron-poor dienes: 3 g–l). Notably, the reaction could proceed smoothly even for the extremely electron-deficient pentafluoro-phenylsubstituted 1,3-butadiene with the yield up to 85 % (3 l). Bulky 1,3-butadienes typically gave a little bit lower yields (3 e, 3 f). In addition to the aryl 1,3-butadienes, 1,3,5-hexatriene could be used as the substrate as well, giving the desired product 3 m in 52 % yield. Furyl 1,3-butadiene, a heteroaryl substrate, was also successfully converted into the desired product 3 n in 26 % yield. Furthermore, the reaction could smoothly occur even for the 1,3-butadiene with a free hydroxyl group, albeit in lower yield (3 o, 30 %). The alkyl-substituted 1,3-butadienes provided the corresponding products in moderate yields (3 p, 3 q). It is worth noting that an ester functional group was introduced in the cases of 3 r and 3 s when 4-methyl- or 4phenyl-substituted 1-carboalkoxy-1,3-butadienes were used as the substrates. The yields of 3 r and 3 s were 63 and 55 %, respectively. Compared with the 1,3-butadienes 2, the reaction was more sensitive to the properties of enynals 1 (3 t–ae). For example, the enynals substituted with electron-donating groups furnished the desired products in higher yields than those with electron-withdrawing groups (3 t–x). The reaction was depressed completely when a pyridine was introduced into the enynal (3 y). Presumably, the strong coordinating capability of the pyridine poisoned the catalyst. For enynals bearing the alkyl alkynes, the reactions proceed smoothly as well (3 z–ab), with the yields ranging from 72–85 %. Importantly, the enynal with a terminal alkyne could be applied as the substrate as well, furnishing the product 3 ac (30 %) with an aldehyde functional group. The reaction functioned particularly efficiently for the enynones, which gave the products 3 ad and 3 ae in 84 and 91 % yields, respectively. Once again, only a single isomer was found for all the cases in Table 2 when Chem. Eur. J. 2014, 20, 2425 – 2430
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Communication mixtures of cis- and trans-dienes 2 were applied as the starting materials. Based on the above results, a possible reaction mechanism was then proposed (Scheme 6). The coordination of the triple bond of enynal 1 to [Au] enhances the electrophilicity of the
teresting bridged compound 4, which was observed as a side product during the course of optimization of reaction conditions (Table 1). It could be obtained as the sole product when silver salt was used as the catalyst (Table 1, entry 1). As shown by its X-ray structure (see the Supporting Information), 4 contains a benzocycloheptene, in which the C=C double bond takes cis-configuration. Therefore, retrosynthetically, the product 4 may be generated only from cis-1,3-butadiene 2. The control reactions were carried out as well to clarify the silvercatalyzed reaction pathway. As shown in Scheme 8, 4 a could
Scheme 8. Control Reactions: 1/2 = 1:1; [1] = 0.05 m; isolated yield.
Scheme 6. Proposed gold-catalyzed reaction mechanism.
alkyne, and the subsequent nucleophilic attack of the carbonyl oxygen to the electron-deficient alkyne would form the intermediate pyrylium E. A stepwise Diels–Alder reaction between 1,3-diene 2 (cis + trans) and pyrylium E can then be then followed to furnish the intermediate G. In this course, an allyl cation F was formed initially. Then elimination of the catalyst [Au] led to the key intermediate C, vinyl-substituted cyclic-oQDM. Finally, an intramolecular Diels–Alder reaction then occurs to furnish the desired product 3. To clarify the reaction pathway, a set of control reactions were then carried out. As shown in Scheme 7, three different cis/trans ratios of 2 a were used as the starting materials. The
Scheme 7. Control reactions: 1/2 = 1:5; [1] = 0.05 m; isolated yield.
yields of 3 a remained almost unchanged regardless the cis/ trans ratios of 1,3-diene 2 a. These observations clearly supported the ionic stepwise Diels–Alder reaction mechanism. Having established the gold-catalyzed reaction of enynals and 1,3-butadienes as a reliable and efficient synthetic process to construct the benzotricyclo[3.2.1.02, 7]octane structure, we then turned our attention to another minor, but structurally inChem. Eur. J. 2014, 20, 2425 – 2430
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be obtained only in 34 % yield when 1,3-diene 2 a (cis/trans 50:50) was used. The yield almost doubled to 62 % when the cis/trans ratio was increased to > 90:10. All of trans-2 a (cis/ trans < 1:99) failed to give the desired product. Obviously, this indicated that only cis-1,3-diene 2 can result in the desired product 4. Based on the control reactions above, the scope and generality of this silver-catalyzed transformation was then investigated further (Table 3). With the cis-dominant 1,3-butadiene 2 a (cis/trans > 9:1) as the substrate, different enynals were then tested for this process. The aryl–enynals (1 a–b) produced the desired products 4 a and 4 b in 62 and 51 % yields, respectively. However, alkyl–enyal 1 c gave the desired bridged product 4 c only in 20 % yield. Actually, another unexpected product dihydronaphthalene 5 c was isolated as the dominant product in 49 % yield (entry 3). Similarly, enynal 1 d also gave the mixture of 4 d and 5 d, with the yields being 41 and 48 % respectively. The bridged compound 4 e was isolated as the sole product in 46 % when the enynal with a terminal alkyne 1 e was applied. Furthermore, the reaction proceeded smoothly as well when naphthalene-substituted cis-1,3-diene was used as the substrate, giving the desired product 4 f in 59 % yield. As for the silver-catalyzed transformation, a tentative mechanism was also depicted in Scheme 9 to account for its different product formation with the gold-catalyzed system. Initially, silver catalyzed the intramolecular reaction of enynal to form the pyrylium H. Different from the gold-catalyzed version, a concerted Diels–Alder reaction was proposed between 1,3diene 2 and pyrylium H to form the intermediate K. In this process, the diene’s configuration remained unchanged in this course. For example, cis-diene 2 would result in only cis-K intermediate. Finally, a Friedel–Crafts reaction or b-H elimination then occurred to furnish the products 4 and 5, respectively. In conclusion, we have developed an efficient method to rapidly construct the highly-strained benzotricyclo[3.2.1.02,7]octane skeleton through the gold-catalyzed reactions of enynals 1 and 1,3-butadienes 2. The reaction was proposed to
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Communication functional-group tolerance, this system holds considerable potential in the construction of complex molecules with a tricyclo[3.2.1.02,7]octane skeleton. Moreover, another structurally interesting bridged compound 4 could be formed instead when the catalyst was changed into silver salt. The control reactions revealed that only cis-isomers of 1,3-butadienes 2 could be converted into the desired product 4. The asymmetric version, a detailed reaction mechanism, and additional applications of these transformations are underway in our laboratory.
Table 3. Substrate scope of enynal with 1,3-diene.[a]
Entry
1
4
5
Experimental Section General experimental procedure 1 2
1 a (X = H) 1 b (X = Me)
62 % (4 a) 51 % (4 b)
trace (5 a) trace (5 b)
3 4 5
1 c (R = cyclopropyl) 1 d (R = tert-butyl) 1 e (R = H)
20 % (4 c) 41 % (4 d) 46 % (4 e)
49 % (5 c) 48 % (5 d) trace (5 e)
Enynals/enynones (0.1 mmol) and 1,3-dienes (0.5 mmol) were added to a solution of the corresponding catalyst combination of [AuCl(SIMes)] (2.7 mg, 0.005 mmol) and Selectfluor (5.31 mg, 0.015 mmol) in DCE (2 mL, 0.05 m). The reaction mixture was stirred under nitrogen atmosphere at 80 8C for 14 h. After the reaction was finished, the mixture was filtered by short silica, then the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to afford the desired product 3.
Acknowledgements
6
1a
< 59 % (4 f)
We are grateful to the NNSFC (21172077, 21372086), the Program for New Century Excellent Talents in University (NCET-10– 0403), The National Basic Research Program of China (973) (2011CB808600), the Changjiang Scholars and Innovation Team Project of the Ministry of Education, SRF for ROCS, State Education Ministry, Guangdong NSF (10351064101000000), and the Fundamental Research Funds for the Central Universities.
trace (5 f)
[a] Unless specified, the reactions were carried out under N2 with a molar ratio of 1/2 = 1:1. [1] = 0.05 m. The yield refers to isolated yield.
Keywords: catalysis · cyclopropanes · Diels–Alder reaction · gold · tandem reactions
Scheme 9. Proposed silver-catalyzed reaction mechanism.
proceed through the intramolecular Diels–Alder reaction of an in situ-generated vinyl-substituted cyclic-o-QDM. Owing to the mild reaction conditions, excellent substrate scope and high Chem. Eur. J. 2014, 20, 2425 – 2430
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Received: December 10, 2013 Published online on February 5, 2014
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