Letter pubs.acs.org/OrgLett
Decorated Cyclopentadienes from Acetylene and Ketones in Just Two Steps Elena Yu. Schmidt, Ivan A. Bidusenko, Igor’ A. Ushakov, Alexander V. Vashchenko, and Boris A. Trofimov* A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia S Supporting Information *
ABSTRACT: The products of the one-pot assembly of acetylene and ketones in the KOH/DMSO system, 7-methylene-6,8-dioxabicyclo[3.2.1]octanes, undergo an acid-catalyzed (CF3COOH, room temperature) rearrangement to rarely substituted cyclopentadienes in good-to-excellent yields. The mechanism of the rearrangement has been supported by the isolation and corresponding transformations of two intermediates.
C
Scheme 1. One-Pot Assembly of Vinyl Ethers 1 from Acetylene and Ketones in the KOH/DMSO System and Their AcidCatalyzed Rearrangements
yclopentadienes are useful not only as reactive diene components in the Diels−Alder reaction1 but also as important ligands2 for transition metal complexes of broad utility in catalysis.3 The selective introduction of aryl substituents into the cyclopentadienyl framework is often needed for a well-defined geometric environment in metal complexes with Cp-ligands.4 Unlike the alkyl groups, the aryl moieties are much less flexible and their geometry is therefore much better defined.4 However, the nature and position of the substituents in the cyclopentadienyl scaffold are known to dramatically affect the reactivity of transition metals containing Cp-ligands.5 Nevertheless, the preparation of highly substituted cyclopentadienes is not easy because of the absence of general methods6 and also the facile migration of the endocyclic double bonds.7 Functionalized cyclopentadienes still remain less studied, particularly acylated ones though several reports on these compounds are known.8 Thus, development of simple, selective methods for the preparation of highly substituted (especially aryl substituted) cyclopentadienes is challenging. This is in line with the fact that presently the search for new methods to prepare useful compounds from available simple starting materials, providing synthetic efficiency and pot−atom−step economy (PASE paradigm),9 is becoming an imperative goal of organic chemistry.10 Recently, we disclosed the one-pot transition-metal-free diastereoselective assembly of densely substituted bicyclic vinyl ethers 1, 7-methylene-6,8-dioxabicyclo[3.2.1]octanes, from two molecules of acetylene and two molecules of ketones in the KOH/DMSO superbase system (Scheme 1A).11 Readily available starting materials (ketones and acetylene gas), an inexpensive promoter and solvent, and mild reaction conditions make the synthesis practically feasible for the preparation of hitherto inaccessible bicyclic vinyl ethers, close congeners of insect pheromones12 and mammals hormones13 as well as reactive building blocks for organic synthesis.14 The highly reactive double bond present in vinyl ethers/acetals 1 promises particular synthetic benefit in terms of rearrangements and addition reactions. For example, we have found that ethers 1 © 2017 American Chemical Society
in the presence of acids (10 mol %) rearrange instantly and completely to diastereomerically pure substituted 2-acetyl-3,4dihydropyrans 2 (Scheme 1B).15 During a further in-depth study on the reactivity of vinyl ethers/ acetals 1 in acidic media, we have found that they undergo deeper rearrangement to afford acylated cyclopentadienes (Scheme 1C). To develop a general and selective synthesis of substituted acylcyclopentadienes, we have evaluated the effects of the reaction conditions (nature and concentration of acid, solvent, temperature and time) on the efficiency and selectivity of the rearrangement, first, on the example of vinyl ether 1a (Table 1). The reaction completion was monitored by 1H NMR and TLC. The rearrangement effectively proceeds (Table 1) under the action of HCl, the total yield of isomeric cyclopentadienes 3a and 4a being 89% (3a:4a ratio ∼1:1, entry 2). In the presence of TFA (entry 11), the rearrangement occurs with the prevalence of isomer 3a, although the 3a + 4a total yield is lower (70%). In experiments with H2SO4 and AcOH (entries 9, 10), the main Received: April 25, 2017 Published: May 26, 2017 3127
DOI: 10.1021/acs.orglett.7b01254 Org. Lett. 2017, 19, 3127−3130
Letter
Organic Letters
component) and the target cyclopentadiene 3a in low content (15%). At a higher temperature (entries 6, 7), the selectivity for cyclopentadiene 3a formation deteriorated, although the high overall yield of both isomers remained. The substrate scope of this reaction was successfully extended to the rearrangement of other vinyl ethers 1 with different substituents (Table 3). The rearrangement tolerates diverse acetals 1 with aromatic, condensed aromatic, and heteroaromatic substituents in the bicyclic core, as well as representatives having Me, Ph, MeO, and Hal substituents in the aryl ring, thus evidencing the generality of the reaction (Table 3). In most cases, cyclopentadienes 3 were obtained in 57−90% yield. Under these conditions, the conversion of 1 was close to 100%. Sometimes, the reaction mixture contained intermediate dihydropyran 2 or isomeric cyclopentadiene 4 (up to 10%) which were easily separated by SiO2 column chromatography. Note that in the case of ethers 1j,k, cyclopentadienes 4j,k were formed exclusively. The synthesis developed proved to be easily scaled up. For instance, 3a has been prepared in 76% yield from 2 g of 1a. The structures of compounds 3 and 4 were determined from single-crystal X-ray analyses of their representatives, 3f and 4k (Figure 1), and NMR spectra (Figure 2).
Table 1. Rearrangement of Ether 1a: Effects of Acid Nature and Reaction Conditions on Product Yield and Ratioa
entry 1 2 3 4 5 6 7 8 9 10 11
acid d
HCl HCld HCld HCld HCld HCld HCld HCld H2SO4 AcOH TFAh
acid/1ab e
5:1 5:1e 3:1e 38:1e 38:1e 38:1e 4:1e 43:1e 5:1g 5:1g 5:1g
solvent
t (h)
3a (%)c
4a (%)c
CHCl3 CHCl3 CHCl3f AcOEt AcOEt AcOEt C6H6 Et2O CHCl3 CHCl3 CHCl3
24 48 48 24 48 72 48 72 72 72 72
33 45 13 7 22 39 9 5 5 0 58
31 44 15 7 19 41 9 4 5 0 12
a
Reaction conditions: 1a (0.68 mmol, 0.2 g), solvent (6 mL), rt. Molar ratio. cIsolated yield (column chromatography, SiO2/ benzene). dGaseous HCl was used. eCalculated according to solubility of HClgas in a solvent. f3 mL of CHCl3. g3.4 mmol of acid. h CF3COOH. b
product is dihydropyran of type 2 (Scheme 2). It should be noted that TFA provides better selectivity for this rearrangement. Scheme 2. Tentative Mechanism Figure 1. X-ray structures of 3f (from Et2O; CCDC 1488234) and 4k (from Et2O; CCDC 1488235).
Figure 2. Main NOESY and HMBC correlations for 3f and 4k.
Next, we have screened the TFA:1a molar ratio and reaction conditions to optimize the yield and selectivity of the rearrangement of vinyl ether 1a (Table 2). It was delightful to observe that, under optimal conditions (TFA:1a molar ratio = 10:1, rt, 24 h), cyclopentadiene 3a was formed selectively in 81% yield, conversion of the starting vinyl ether 1a being 100% (entry 2). At a lower temperature (entry 4), the crude product consisted of dihydropyran 2a (as major
The rearrangement is likely triggered by the protonation of acetal 1 to generate cation A (Scheme 2), which is transformed with cleavage of the C−O bond to the cation B, in which the second C−O bond is cleaved to give carbocation C. Then migration of the carbocationic center to the position adjacent to the benzoyl group takes place via consecutive hydride ion transfers or the proton elimination/addition processes resulting in carbocation D. In more detail, the first hydride ion transfer from the α-position of C leads to the next carbocation, which in turn via similar hydride ion transfer from the neighboring α-position gives another carbocation further undergoing the same transformation to deliver D which releases a proton to form the 1,6-diketone E. Protonation of acetyl group of diketone E reversibly gives the carbocation species, which intramolecularly attacks the double bond thus closing the ring to form the cyclopentane cation F. The latter eliminates a proton and a molecule of water to produce the cyclopentadiene. The mechanism in Scheme 2 was proven by isolation of the dihydropyran 2a (the obvious product of proton elimination from cation B) from the reaction of ether 1a with TFA (rt, 1 h). Further treatment of 2a with TFA under the above conditions led to the expected 3a in 70% yield (Scheme 3).
Table 2. Rearrangement of Ether 1a: Effects of TFA:1a Molar Ratio and Reaction Conditions on Product Yield and Ratioa entry
TFA:1ab
temp (°C)
t (h)
3a (%)c
4a (%)c
1 2 3 4 5 6 7
5:1 10:1 20:1 10:1 10:1 10:1 10:1
20 20 20 0 20 40 60
67 24 11 24 5 5 5
51 81 76 15 49 67 77
9 7 4 0 traces 12 21
a
Reaction conditions: 1a (0.68 mmol, 0.2 g), CHCl3 (6 mL). bMolar ratio. cIsolated yield (column chromatography, SiO2, benzene). 3128
DOI: 10.1021/acs.orglett.7b01254 Org. Lett. 2017, 19, 3127−3130
Letter
Organic Letters Table 3. Rearrangement of Ethers 1 to Cyclopentadienesa
a
Reaction conditions: 1 (0.68 mmol), TFA (6.80 mmol, 0.775 g), CHCl3 (6 mL), rt. bIsolated yield. cThe crude contains corresponding dihydropyran 2. dPrepared from 1,3,5-triphenylpentane-1,5-dione and acetylene.16
Scheme 3. Rearrangement of Intermediate Dihydropyran 2a to Cyclopentadiene 3a
Figure 3. X-ray structure of 5g (from Et2O; CCDC 1488236).
crystal X-ray analysis (Figure 3). Further treatment of cyclopentane 5g with TFA (rt, 24 h) gave the expected 3g (78% yield, Scheme 4). In the experiments with TFA, intermediates of the type 5g but with the CF3COO moiety (instead of Cl) were discernible during the 1H NMR monitoring of the reaction (see Supporting Information (SI)). The signal intensity of the intermediates decreased in the course of the rearrangement. Another argument for the mechanism is the deuterium scrambling over the whole cyclopentadiene molecule when the rearrangement of 1a was carried out with CF3COOD in CDCl3. The cyclopentadiene 3a thus obtained contained deuterium atoms in all the positions of the cyclopentadiene ring and partially in the 2-Me group. Notably, in the 2-Me group exactly one deuterium atom was inserted, thus corresponding with the initial
Scheme 4. Formation of Intermediate 5g and Its Transformation to Cyclopentadiene 3g
Other evidence in favor of the proposed scheme is the trapping of the intermediate cation F in its stable covalent derivative 5g formed by its quenching with a chlorine counteranion (28% yield, Scheme 4). The structure of 5g has been established by single3129
DOI: 10.1021/acs.orglett.7b01254 Org. Lett. 2017, 19, 3127−3130
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Organic Letters Notes
proton (deuteron) transfer to the methylene group of the ether 1a as shown in Scheme 2. Such a distribution of deuterium is in keeping with the multiposition H-transfer, as postulated above. As a whole, the process with deuterium is ∼2 times slower than that with a proton, confirming the proton transfers to the double bonds as rate-determining steps. The substituent effect is also in agreement with the mechanism. Since the key step of the disassembling/assembling cascade sequence is postulated to be carbocation C formation (Scheme 2), donor substituents should facilitate the process. In fact, when the 4-Me and 4-Ph groups, having a π-donor effect toward the cationic center, were introduced into the benzene ring, acceleration of the process occurred (Table 3). The reaction was also fast in the case of the 2-thienyl substituent, which is capable of strongly stabilizing the adjacent cationic center (due to the positive charge transfer up to the sulfur atom). By way of contrast, 4-F, 4-Cl, 4-Br, and 3-OMe substituents in the benzene ring slowed down the reaction. As stated above, the synthesis of cyclopentadienes is ∼90% selective: mainly the isomers 3 are obtained. The minor isomers 4 lack continuity through conjugation. The latter are easily separable by SiO2 column chromatography and can be isolated as exemplified by the 3a and 4a pair. The isomer ratio is likely a thermodynamic result. This follows from equilibrium experiments. Thus, when pure minor isomer 4a was kept in TFA (rt, 24 h) a mixture of 3a:4a = 10:1 was obtained. Likewise, if pure isomer 3a was treated under the same conditions, the same isomer mixture (10:1) resulted. Evidently, the major isomers 3 are stabilized by a stronger conjugation compared to the alternative ones. This is supported by our quantum-chemical calculations [B3LYP/6-311G++(d,p)] confirming that isomer 3a is 1.5 kcal/ mol more stable than isomer 4a (relative population is 9:1 with a preference of 3a; see SI). Yet, two deviations from this rationale were observed (4j,k), for molecules lacking continuous conjugation. Quantum-chemical calculations of the equilibrium 3j⇌4j have shown that the predominant isomer is 3j (ΔE = 0.96 kcal/mol; isomer ratio, 84:16). Thus, the initially isolated isomer 4j should be kinetic in origin. This has been proved by keeping the isomer 4j in TFA for 10 h whereupon a mixture of 3j:4j = 80:20 was obtained that is consistent with the calculations. In summary, a highly efficient, selective acid-catalyzed rearrangement of 7-methylene-6,8-dioxabicyclo[3.2.1]octanes was developed. Significantly these substrates are readily accessible from acetylene and ketones. The methodology provides an unprecedented two-step transition from two simple molecules to uniquely decorated cyclopentadienes and opens new horizons toward the construction of complex molecular architectures.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant of Russian Scientific Foundation (Project No. 14-13-00588). (1) Encyclopedia of Polymer Science and Technology; John Wiley & Sons, Inc., 2007; pp 313−314. (2) For selected examples, see: (a) Schumann, H.; Stenz, S.; Grigsdies, F.; Muehle, S. H. Z. Naturforsch. B: J. Chem. Sci. 2002, 57, 1017. (b) Xu, S.; Yuan, F.; Zhuang, Y.; Wang, B.; Li, Y.; Zhou, X. Inorg. Chem. Commun. 2002, 5, 102. (c) Kanthak, M.; Aniol, A.; Nestola, M.; Merz, K.; Oppel, I. M.; Dyker, G. Organometallics 2011, 30, 215. (3) For selected examples, see: (a) Resconi, L.; Cavallo, L.; Fait, A.; Piemontesi, F. Chem. Rev. 2000, 100, 1253. (b) Hlatky, G. G. Chem. Rev. 2000, 100, 1347. (c) Fink, G.; Steinmetz, B.; Zechlin, J.; Przybyla, C.; Tesche, B. Chem. Rev. 2000, 100, 1377. (d) Angermund, K.; Fink, G.; Jensen, V. R.; Kleinschmidt, R. Chem. Rev. 2000, 100, 1457. (e) Alt, H. G.; Koeppl, A. Chem. Rev. 2000, 100, 1205. (f) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778. (4) Enders, M.; Baker, R. W. Curr. Org. Chem. 2006, 10, 937. (5) (a) Macomber, D. W.; Hart, W. P.; Rausch, M. D. Adv. Organomet. Chem. 1982, 21, 1. (b) Gassman, P. G.; Macomber, D. W.; Hershberger, J. W. Organometallics 1983, 2, 1470. (6) (a) Quindt, V.; Saurenz, D.; Schmitt, O.; Schaer, M.; Dezember, T.; Wolmershaeuser, G.; Sitzmann, H. J. Organomet. Chem. 1999, 579, 376. (b) Rausch, B. J.; Gleiter, R.; Rominger, F. J. Organomet. Chem. 2002, 658, 242. (c) Lv, Y.; Yan, X.; Yan, L.; Wang, Z.; Chen, J.; Deng, H.; Shao, M.; Zhang, H.; Cao, W. Tetrahedron 2013, 69, 4205. (7) (a) Venier, C. G.; Casserly, E. W. J. Am. Chem. Soc. 1990, 112, 2808. (b) Duan, Z.; Sun, W.-H.; Liu, Y.; Takahashi, T. Tetrahedron Lett. 2000, 41, 7471. (c) Fang, H.; Zhao, C.; Li, G.; Xi, Z. Tetrahedron 2003, 59, 3779. (d) Zhou, S.; Yan, B.; Liu, Y. J. Org. Chem. 2005, 70, 4006. (e) Datta, S.; Odedra, A.; Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 11606. (8) (a) Toda, T.; Tokida, A.; Mukai, T. Chem. Lett. 1982, 11, 763. (b) Yoshida, H.; Tamai, T.; Ogata, T.; Matsumoto, K. Bull. Chem. Soc. Jpn. 1988, 61, 2891. (c) Lund, H. J. Electroanal. Chem. 2005, 584, 174. (d) Cordes, D. B.; Hua, G.; Slawin, A. M. Z.; Woollins, J. D. Acta Crystallogr., Sect. E: Struct. Rep. Online 2011, 67, o1718. (e) Wang, L.; Zhang, J.; Lang, M.; Wang, J. Org. Chem. Front. 2016, 3, 603. (9) (a) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9, 438. (b) Xiang, H.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. RSC Adv. 2013, 3, 5807. (10) (a) Trost, B. M. Science 1991, 254, 1471. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (11) (a) Trofimov, B. A.; Schmidt, E.; Yu; Ushakov, I. A.; Mikhaleva, A. I.; Zorina, N. V.; Protsuk, N. I.; Senotrusova, E. Yu.; Skital’tseva, E. V.; Kazheva, O. N.; Alexandrov, G. G.; Dyachenko, O. A. Eur. J. Org. Chem. 2009, 2009, 5142. (b) Schmidt, E. Yu.; Bidusenko, I. A.; Cherimichkina, N. A.; Ushakov, I. A.; Trofimov, B. A. Tetrahedron 2016, 72, 4510. (12) (a) Francke, W.; Schroeder, W. Curr. Org. Chem. 1999, 3, 407. (b) Yus, M.; Ramon, D. J.; Prieto, O. Eur. J. Org. Chem. 2003, 2003, 2745. (c) Mori, K. In Pheromone and Other Semiochemicals I; Schulz, S., Ed.; Topics in Current Chemistry, Vol. 239; Springer: Heidelberg, 2004. (13) Greenwood, D. R.; Comeskey, D.; Hunt, M. B.; Rasmussen, L. E. L. Nature 2005, 438, 1097. (14) (a) Trotuş, I.-T.; Zimmermann, T.; Schueth, F. Chem. Rev. 2014, 114, 1761. (b) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (c) Goodwin, J. A.; Aponick, A. Chem. Commun. 2015, 51, 8730. (15) Schmidt, E. Yu.; Trofimov, B. A.; Zorina, N. V.; Mikhaleva, A. I.; Ushakov, I. A.; Skital’tseva, E. V.; Kazheva, O. N.; Alexandrov, G. G.; Dyachenko, O. A. Eur. J. Org. Chem. 2010, 2010, 6727. (16) Schmidt, E. Yu.; Bidusenko, I. A.; Protsuk, N. I.; Ushakov, I. A.; Trofimov, B. A. Eur. J. Org. Chem. 2013, 2013, 2453.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01254. Experimental procedure, compound characterizations, NMR spectra, crystallographic data, and computational details (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail: boris_trofi
[email protected]. ORCID
Boris A. Trofimov: 0000-0002-0430-3215 3130
DOI: 10.1021/acs.orglett.7b01254 Org. Lett. 2017, 19, 3127−3130
