DOI: 10.1002/chem.201500181

Communication

& Calcium Catalysis

Calcium-Catalyzed Formal [2 + 2 + 2] Cycloaddition Vera J. Meyer, Christoph Ascheberg, and Meike Niggemann*[a] demonstrate that a reactive intermediate C, synonymous to B, can be generated with our highly efficient calcium based catalyst system[5] and give access to highly substituted cyclopropanes also in the absence of the stabilizing gold substituent.[6] Therefore, in pursuit of our program aiming at the development of carbocation cascade reactions for the generation of molecular complexity with simple non-transition metal catalysts, we reasoned that, following the same reaction pathway as the parent gold catalyzed reaction, trapping the intermediate C with carbonyl compounds will provide access to highly substituted formal [2 + 2 + 2] cycloaddition products.

Abstract: A formal intermolecular [2 + 2 + 2] cycloaddition reaction of enynes to aldehydes is presented, which can be realized in the presence of a simple and benign calcium catalyst. The reaction proceeds with excellent chemo, regio- and diastereoselectivity and leads to a one-step assembly of highly interesting bicyclic building blocks containing up to three stereocenters from simple precursors via a new type of skeletal rearrangement of enynes. The observed diastereoselectivity is accounted for by two different mechanistic proposals. The first one engages mechanistic prospects arising from a gold catalyzed reaction in the absence of the stabilizing gold substituent. The second proposal involves an unprecedented cyclization– carbonyl allene ene reaction–hydroalkoxylation cascade.

The [2 + 2 + 2] cycloaddition reaction provides an efficient approach to six-membered carbo- and heterocycles of various substitution patterns.[1] Thereby, this intriguing reaction allows for the generation of complex molecular structures from simple starting materials in a single synthetic operation. Typically, the [2 + 2 + 2] cycloaddition of enynes is a domain of transition metal catalysis, proceeding via Rh-, Ru-, Co- or Nimetallacycles A. Despite its versatility for the formation of carbacycles and nitrogen-containing heterocycles, the process has met limitations with regard to the corresponding oxygen-containing heterocycles.[2] Here, product formation would have to occur via an energetically demanding C O bond forming reductive elimination after insertion of a carbonyl moiety into metallacycle A. Therefore, the transformation is plagued by competing b-hydride elimination, yielding open chain products.[3] A recently discovered, alternative mechanistic scenario, elegantly circumventing the regioselectivity issues is initiated by a gold-catalyzed rearrangement of 1,n-enynes (n = 5,6). The interception of a thus generated reactive intermediate B with the nucleophilic carbonyl oxygen of a carbonyl compound followed by Prins-type cyclization, yields the product of a formal [2 + 2 + 2] cycloaddition with excellent chemo and regioselectivity (Scheme 1).[4] In a previous publication, we have been able to

Scheme 1. Transition-metal-catalyzed and formal [2 + 2 + 2] cycloaddition.

Using 1 as a model compound and benzaldehyde as the carbonyl compound we started the investigation of the above stated hypothesis. We were pleased to find that generation of the reactive intermediate C in presence of five equivalents of the aldehyde under the reaction conditions of the cyclopropanation reaction (Table 1, entry 1) readily yields the desired [2 + 2 + 2]-cycloaddition product 3 as a single diastereomer after only 30 minutes reaction time. Further optimization studies revealed that both, Bu4NPF6 and Bu4NSbF6, are efficient additives for this reaction (Table 1, entry 1/3). In analogy to the cyclopropanation reaction even subtle changes in the dielectric properties of the solvent largely influenced the outcome of the reaction (Table 1, entry 4–6). The reaction was substantially slower in dichloromethane and completed only after 10 h reaction time. In nitromethane rapid decomposition of the enyne starting material was observed. Reducing the amount of aldeyde to two equivalents resulted in a diminished yield (Table 1, entry 6) and increasing it to 10 equivalents showed little impact on the reaction outcome (Table 2, entry 7). In analogy to our previous publications, comparison of the calcium catalyst’s efficiency

[a] Dr. V. J. Meyer, C. Ascheberg, Prof. M. Niggemann Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500181. Chem. Eur. J. 2015, 21, 1 – 5

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Communication Table 1. Optimization of the reaction conditions.

Table 2. Scope of the reaction.

Entry[a]

Catalyst

Aldehyde 2 [equiv]

Additive [mol %]

Solvent

Yield[b] [%]

1 2 3 4 5[c] 6 7 8[d] 9[d] 10[d]

Ca(NTf2)2 Ca(NTf2)2 Ca(NTf2)2 Ca(NTf2)2 Ca(NTf2)2 Ca(NTf2)2 Ca(NTf2)2 HNTf2 HBF4 Sc(OTf)3

5 5 5 5 5 2 10 5 5 5

Bu4NSbF6 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5) Bu4NBF4 (5)

DCE DCE DCE MeNO2 DCM DCE DCE DCE DCE DCE

75 68 76 – 72 69 77 60 – 15

Entry[a]

with Brønsted and other Lewis acids (Table 2, entries 8–10) clearly demonstrates its superior performance. Having established the optimal reaction conditions we investigated the reaction of different enynols 4 with aldehydes 5 (Table 2). Variation of the electronic properties of the carbonyl compound 5 shows that yields for cyclizations with aldehydes 5 bearing electron donating groups (entries 1/2, 11/12) are generally higher than with aldehydes bearing electron-withdrawing substituents (entries 3–5, 13). Aryl moieties such as a naphthyl- or a furanyl substituent are well tolerated. Due to the very short reaction times, the cyclization was found high yielding also with aliphatic aldehydes, which are prone to entangle in side reactions upon extended reaction times under Lewis acidic reaction conditions. The presence of one of the methyl groups adjacent to the alkyne moiety in 4 proved mandatory for a satisfactory yield. It presumably either facilitates the final deprotonation step to the terminal double bond in 6 or the carbonyl allene ene reaction step to 10 (cf. mechanism, see below). The reaction of enynols 4 with a monosubstitution at the alkene moiety yielded complex reaction mixtures. We reasoned that a disubstitution of the olefin piece of the enynol is necessary to stabilize the homoallenyl-/cyclopropyl intermediate C. The reaction with ketones as an alternative for the aldehydes proved unsuccessful. The high diastereoselectivity of our previously published cyclopropanation reaction, which proceeds through the same reactive key intermediate C, was found to originate in the biomimetic nature of its mechanism.[6] In this transformation bond rotations are precluded, due to concertedness, and full transposition of the olefin geometry in the cyclization precursor into the relative configuration of the product was observed. The analysis of the origin of the high diastereoselectivity of the herein presented formal [2 + 2 + 2] cycloaddition hence started with the reaction of mechanistic probes 7 with 2 different sub&

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Yield [%][b]

10 20 20 20

77 75 68 65

5

15

75

6

15

71

7

20

62

8

20

69

9

20

82

10 5 15 10

60 74 64 52

1 2 3 4

[a] 5 mol % additive and 5 mol % catalyst were added at room temperature to alcohol 1 (0.25 mmol) and aldehyde 2 in 1 mL of solvent and stirred for 30 min. [b] Isolated yield of 3. [c] 10 h reaction time. [d] 24 h reaction time.

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t [min]

10 11 12 13

Product X X X X

X X X X

= = = =

= = = =

OMe (6 a) OH (6 b) Cl (6 c) CF3 (6 d)

H (6 j) OMe (6 k) OH (6 l) Cl (6 m)

[a] Additive and 5 mol% Ca(NTf2)2 were added at room temperature to alcohol 4 (0.25 mmol) and aldehyde 5 in 1 mL of solvent and stirred for the indicated time. [b] Isolated yield of 6.

stituents at the alkene moiety in either an E- (7 a) or a Z-configuration (7 b). To our surprise both substrates reacted fully selectively to the same dihydropyrane 8, the relative configuration of which was proven unequivocally by a crystal structure analysis of the corresponding diacid (see Supporting Information). Analysis of the reaction mixture of the Z-configured cyclization precursor 7 b at various times prior to completion revealed none of the corresponding E-configured 7 a. In addition, no intermediates were detected in both reactions. Hence, the transformation proceeds directly from (E)-7 a/(Z)-7 b to the product 8 (Scheme 2). A first mechanistic proposal is lined out in analogy to both, our previously published cyclopropanation reaction and the parent gold-catalyzed formal [2 + 2 + 2] cycloaddition (see Scheme 3).[4d, g] Calcium-catalyzed dehydration yields a propargylic cation (not shown) which can also assume an allenyl cation rendition I. Nucleophilic attack of the olefin results 2

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Communication Alternatively, the intermediacy of a sp2 carbon center on the way to the quarternary stereocenter in 8 seems likely. This might be formed by deprotonation of key intermediate (E)-Ca to the allene ene 9, thereby initiating pathway b. For this deprotonation the empty p-orbital of the cationic carbon atom and the to be cleaved C,H s-bond must be aligned. Therefore Scheme 2. Reaction of mechanistic probe 7 yields 8 as a single diastereoa ~ 908 rotation of the said p-orbital is necessarily following mer. ring closure to Ca, as illustrated in Scheme 3. This rotation most likely moves the large phenyl group outwards and the smaller methyl group to the core of the molecule so that the in the formation of the key intermediate C, the cyclic homoalsame E-configured allene ene 9 is formed from both precursors lenyl cation Ca, which is in equilibrium with its cyclopropyl con(E)-7 a/(Z)-7 b by bond rotation in opposite directions (illustratgener Cb. From this key intermediate, that assumes the spatial ed for (E)-7 a). In principle, one of the main division points beorientation of conformer (E)-Ca when formed from the E-enyne tween the two presented mechanisms lays within this bond ro(E)-7 a, the reaction can ensue via two different pathways (for tation. When the activation barrier of the deprotonation toa more detailed discussion including a Scheme for Z-enyne (Z)wards allene 9 is low in energy, the molecule readily deproto7 a, see Supporting Information). In pathway a, nucleophilic nates as soon as the orientation of the empty p-orbital favors attack of the carbonyl oxygen atom at the homoallenyl carbohyperconjugation of the C,H s-bond. A comparative DFT-based cation in (E)-Ca, sets the stage for the subsequent Prins-type computational analysis of the transition state of the deprotocyclization, which proceeds via the six membered transition nation towards 9 and the conformational analysis of the bond state TSPrins in a chair configuration with all the substituents in rotation at a mPW1PW91/6-31 + G(d,p) level of theory reveals an equatorial orientation.[7] Cleavage of the indicated C,H bond that the activation barrier for the deprotonation is indeed very in II by deprotonation finally results in the formation of the small (0.7 kcal mol 1) and that the energy of the transition diene system in 8. For a reaction mechanism with a concerted state lays within the range of the highest energy conformers nature such as observed in the previously published cycloproof the bond rotation. Hence, deprotonation is likely but none panation reaction, the E/Z-configuration of the double bond in of the two mechanistic events is clearly preferred (for a graphi7 translates to the orientation of the substituents at the quarcal representation and more detailed discussion see Supportternary carbon stereocenter in 8. The observed stereochemical ing Information). The second mechanistic proposal then prooutcome of the reaction matches the case of (E)-7 a as illustratceeds with a carbonyl allene ene reaction yielding alcohol 10.[8] ed in Scheme 3, but the reverse orientation of the quarternary stereocenter in the case of (Z)-7 b would be expected. NeverThis alcohol assumes a helical conformer in which the alcohol theless, due to its benzylic nature, the carbocation in Ca is moiety hovers either above or below the double bond depending on its stereocenter, so that a protonation of the much more stable than any of the transition structures on the double bond by the alcohol hydrogen atom, the acidity of concerted reaction pathway towards the cyclopropane. This which is significantly enhanced by coordination of the Ca2 + high stability might render this structure a distinct minimum on the hence non-concerted reaction pathway and therefore Lewis acid, happens on the same side of the molecule (see allow bond rotation at this stage, so that the preferred all Figure 1). Subsequent ring closure then yields the observed equatorial chair transition state TSPrins can be assumed for the diastereomer via the all equatorial flattened chair-like transition subsequent Prins cyclization. state TSalkoxy. Some aspects of our experimental studies support each of the proposed mechanisms. Literature precedent from gold chemistry and the absence of detectable amounts of the intermediates 9 and 10 rather support the first mechanism. On the other hand the low activation barrier of the deprotonation towards 9 indicates for the second mechanism. As both of them account well for the observed stereochemistry no further efforts were undertaken to distinguish between the two. In addition, the question whether either of the mechanisms is of a concerted nature cannot be answered at Scheme 3. Mechanistic proposals rationalizing the stereochemical outcome of the reaction of (E)-7 a to 8. Chem. Eur. J. 2015, 21, 1 – 5

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Communication Keywords: allenes · calcium catalysis · cycloaddition · cycloisomerization · enynes

Acknowledgements We are grateful to Professor Gerhard Raabe for the analysis of the crystal structures.

Received: January 15, 2015 Published online on && &&, 0000

this point of our studies, but in light of the above discussed results a stepwise process seems more likely. Further investigations of the prospects arising from the chemistry of key intermediate C, both experimentally and mechanistically, are currently under way in our laboratories.

Experimental Section General procedure for the Ca2 + -catalyzed [2 + 2 + 2] cycloaddition: Aldehyde (5–10 equiv), nBu4NPF4 (5 mol %), Ca(NTf2)2 (5 mol %) and the enyne (0.25 mmol, 1.0 equiv) are solved in 1.5 mL DCE at room temperature and stirred until complete conversion of the starting material was observed (monitored by TLC). For the isolation of the product, 5 mL sat. NaHCO3 solution is added, the aqueous phase extracted with dichloromethane, the combined organic phases dried over Na2SO4 and concentrated in vacuo. The crude product is purified by column chromatography.

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[1] a) P. A. Inglesby, P. A. Evans, Chem. Soc. Rev. 2010, 39, 2791 – 2805; b) G. Dominguez, J. Perez-Castells, Chem. Soc. Rev. 2011, 40, 3430 – 3444; c) D.H. Zhang, Z. Zhang, M. Shi, Chem. Commun. 2012, 48, 10271 – 10279. [2] a) T. Tsuda, T. Kiyoi, T. Miyane, T. Saegusa, J. Am. Chem. Soc. 1988, 110, 8570 – 8572; b) D. F. Harvey, B. M. Johnson, C. S. Ung, K. P. C. Vollhardt, Synlett 1989, 15 – 18; c) B. M. Trost, R. E. Brown, F. D. Toste, J. Am. Chem. Soc. 2000, 122, 5877 – 5878; d) Y. Yamamoto, H. Takagishi, K. Itoh, J. Am. Chem. Soc. 2002, 124, 6844 – 6845; e) T. Takahashi, Y. Li, T. Ito, F. Xu, K. Nakajima, Y. Liu, J. Am. Chem. Soc. 2002, 124, 1144 – 1145; f) B. Bennacer, M. Fujiwara, S.-Y. Lee, I. Ojima, J. Am. Chem. Soc. 2005, 127, 17756 – 17767; g) T. N. Tekevac, J. Louie, Org. Lett. 2005, 7, 4037 – 4039; h) J. R. Kong, M. J. Krische, J. Am. Chem. Soc. 2006, 128, 16040 – 16041; i) M. Murakami, S. Ashida, T. Matsuda, J. Am. Chem. Soc. 2006, 128, 2166 – 2167; j) T. N. Tekavec, J. Louie, J. Org. Chem. 2008, 73, 2641 – 2648; k) M. Ishida, Y. Shibata, K. Noguchi, K. Tanaka, Chem. Eur. J. 2011, 17, 12578 – 12581; l) Y. Oonishi, T. Yokoe, A. Hosotani, Y. Sato, Angew. Chem. 2014, 126, 1153 – 1157; Angew. Chem. Int. Ed. 2014, 53, 1135 – 1139. [3] C. Krug, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 1674 – 1679. [4] a) E. Jimnez-NfflÇez, C. K. Claverie, C. Nieto-Oberhuber, A. M. Echavarren, Angew. Chem. 2006, 118, 5578 – 5581; Angew. Chem. Int. Ed. 2006, 45, 5452 – 5455; b) M. Schelwies, A. L. Dempwolff, F. Rominger, G. Helmchen, Angew. Chem. Int. Ed. 2007, 46, 5694 – 5697; Angew. Chem. 2007, 119, 5694 – 5697; Angew. Chem. Int. Ed. 2007, 46, 5598 – 5601; c) M. Schelwies, R. Moser, A. L. Dempwolff, F. Rominger, G. Helmchen, Chem. Eur. J. 2009, 15, 10888 – 10900; d) A. Escribano-Cuesta, V. Lpez-Carrillo, D. Janssen, A. M. Echavarren, Chem. Eur. J. 2009, 15, 5646 – 5650; e) D. B. Huple, R.-S. Liu, Chem. Commun. 2012, 48, 10975 – 10977; f) C.-H. Chen, Y.-C. Tsai, R.-S. Liu, Angew. Chem. 2013, 125, 4697 – 4701; Angew. Chem. Int. Ed. 2013, 52, 4599 – 4603; g) C. Obradors, A. M. Echavarren, Chem. Eur. J. 2013, 19, 3547 – 3551; h) T. Matsuda, Y. Sakurai, J. Org. Chem. 2014, 79, 2739 – 2745. [5] J.-M. Begouin, M. Niggemann, Chem. Eur. J. 2013, 19, 8030 – 8041. [6] T. Haven, G. Kubik, S. Haubenreisser, M. Niggemann, Angew. Chem. 2013, 125, 4108 – 4111; Angew. Chem. Int. Ed. 2013, 52, 4016 – 4019. [7] a) T. C. Gahman, L. E. Overman, Tetrahedron 2002, 58, 6473 – 6483; b) R. Jasti, C. D. Anderson, S. D. Rychnovsky, J. Am. Chem. Soc. 2005, 127, 9939 – 9945; c) L. E. Overman, Tetrahedron 2009, 65, 6432 – 6446; d) C. Olier, M. Kaafarani, S. Gastaldi, M. P. Bertrand, Tetrahedron 2010, 66, 413 – 445; e) T. Okada, A. Shimoda, T. Shinada, K. Sakaguchi, Y. Ohfune, Org. Lett. 2012, 14, 6130 – 6133; f) J. Cheng, X. Tang, S. Ma, ACS Catal. 2013, 3, 663 – 666. [8] I. Diaf, G. Lemiere, E. Dunach, Angew. Chem. 2014, 126, 4261 – 4264; Angew. Chem. Int. Ed. 2014, 53, 4177 – 4180.

Figure 1. Models for the proposed transition states of the intramolecular protonation of the olefin in alcohol 10 initiating the hydroalkoxylation step.

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carbocations

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Communication

COMMUNICATION & Calcium Catalysis V. J. Meyer, C. Ascheberg, M. Niggemann* && – && A simple catalyst for a complex task: A formal intermolecular [2 + 2 + 2] cycloaddition reaction of enynes to aldehydes was realized in the presence of a simple and benign calcium catalyst (see scheme). The reaction proceeds with excellent chemo-, regio- and dia-

Chem. Eur. J. 2015, 21, 1 – 5

stereoselectivity and leads to a one-step assembly of highly interesting bicyclic building blocks containing up to three stereocenters from simple precursors via a new type of skeletal rearrangement of enynes.

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These are not the final page numbers! ÞÞ

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Calcium-Catalyzed Formal [2 + 2 + 2] Cycloaddition

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