Metal- and Hydride-Free Pentannulative Reductive Aldol Reaction

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Metal- and Hydride-Free Pentannulative Reductive Aldol Reaction Bishnupada Satpathi, Lona Dutta, and S. S. V. Ramasastry* Organic Synthesis and Catalysis Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Manauli PO, S. A. S. Nagar, Punjab 140306, India

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S Supporting Information *

ABSTRACT: Traditionally, the reductive aldol reaction is a metal-catalyzed and hydride-promoted coupling between enones and aldehydes. We present a phosphine-mediated diastereoselective intramolecular reductive aldol reaction of αsubstituted dienones and aldehydes, which is metal-free and hydride-free. The synthetic utility of the reductive aldol adducts is demonstrated by elaborating them in one step to indeno[1,2-b]furanones, indeno[1,2-b]pyrans, and dibenzo[a,h]azulen-8-ones.

R

In 1987, Revis and Hilty reported inspirational work on the rhodium-catalyzed intermolecular RAR of enones and aldehydes.5 Soon after, several pioneering metal-catalyzed RARs of enones and aldehydes were developed.2 To date, catalysts based on rhodium,6 cobalt,7 iridium,8 copper,9 ruthenium,10 palladium,11 and indium,12 in combination with boranes, silanes, or hydrogen gas as reductants are known for the RAR (Scheme 1a). Regarding the Michael acceptors, interestingly, no other substrate class other than enones (A) is known to date.13 Moreover, methods to access RA adducts (C) bearing quaternary carbons are less common.14 Other limitations of the existing RA strategies include the usage of stoichiometric quantities of reductants and obtention of 1,4reduction products. Herein, we wish to report a metal- and reductant-free organophosphine-mediated intramolecular RAR of α-substituted dienone-aldehydes (D) for the synthesis of cyclopenta-fused arenes and heteroarenes (E) incorporated with two contiguous stereocenters, one of them being an allcarbon quaternary center (Scheme 1b).15 We commenced this study with the hypothesis that the αsubstituted enone-aldehyde 1a could undergo a phosphaMichael addition followed by an aldol reaction to generate the zwitterionic species F (Scheme 2). Furthermore, in the presence of water, F could provide indanone 2a by eliminating the phosphine oxide as depicted in G. The formation of 3a was also envisaged when phosphine elimination (regeneration) occurs as shown in G. However, the reaction of 1a with tributylphosphine in the presence of water failed to provide any desired product.16 Since several of our attempts to obtain RA product from 1a were unsuccessful, we then applied the prototypical conditions to the α-substituted dienone-aldehyde 4a (Table 1, entry 1).17 To our delight, the desired product 5a was isolated, albeit in moderate yield.18 The structure of 5a was readily deduced

egioselective or site-specific enolization of nonsymmetric ketones in direct aldol reactions remains a formidable challenge. This problem in part can be addressed by employing preformed enolates, viz., the Mukaiyama aldol reaction.1 Another solution to the regioselective formation of enolates comes through the reductive aldol reaction (RAR), which involves a metal-catalyzed coupling of enones (A) to aldehydes (B) in the presence of a hydride source (Scheme 1a).2 Thus, the RAR presents “enones as latent enolates,” the concept which was first introduced by Stork through his seminal work on the regiospecific generation of enolates from eneones via dissolving metal reductions.3 This discovery paved the way for subsequent developments in the reductive alkylation of enones.4 Scheme 1. Background and Significance of the Present Work

Received: November 15, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b03658 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Unsuccessful RAR of the α-Substituted EnoneAldehyde 1a

observed. While optimizing the quantity of phosphine, a marked improvement in the yield of 5a was observed with 1.2 equiv of PBu3 (entry 6). Substoichiometric quantities of PBu3 displayed poor performance (entries 7−9), indicating that the reaction might be proceeding through the stoichiometric pathway hypothesized in Scheme 2. A screening of various solvents did not offer any other encouraging result (entries 10−13). Further, no other P-centered or N-centered Lewis bases generated even traces of the expected product (entries 14−17).20 To understand the scope and generality of the method, the optimized conditions were applied to substrates bearing different steric and electronic features. The results are summarized in Scheme 3. Under the optimized conditions, a Scheme 3. Substrate Scope: Cyclopentannulated Arenes and Heteroarenes via Intramolecular RARa,b,c

Table 1. Optimization of the Reaction Parametersa

entry

Lewis base (equiv)

water (equiv)

solvent

t (h)

yield (%)b

c

PBu3 (1) PBu3 (1) PBu3 (1) PBu3 (1) PBu3 (1) PBu3 (1.2) PBu3 (0.75) PBu3 (0.5) PPh3 (0.25) PBu3 (1.2) PBu3 (1.2) PBu3 (1.2) PBu3 (1.2) PCy3 (1.2) PPh3 (1.2) DABCO (1.2) β-ICD (1.2)

5 10 30 50 75 30 30 30 30 30 30 30 30 30 30 30 30

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO MeCN toluene 1,2-DCE DMF DMF DMF DMF

96 96 40 48 48 34 96 120 160 96 96 120 96 120 120 120 120

51 58 77 75 74 87 50 39 8 21 38 31 6 − − − −

1 2 3 4 5 6 7 8 9 10 11 12 13d 14 15 16e 17f a

Reaction conditions: See the Supporting Information for details. Chromatographic yields. c5a was obtained in 2:1 diastereomeric ratio (dr). d1,2-Dichloroethane. e1,4-Diazabicyclo[2.2.2]octane. fβIsocupreidine. b

a

Reaction conditions: See Supporting Information for details. Chromatographic yields. cDiastereomeric ratio (dr) is shown in the parentheses.

b

from its spectral data, and the relative stereochemistry was assigned from the X-ray diffraction analysis of 6d (vide supra; CCDC 1848427). To our knowledge, the transformation of 4a to 5a represents the first metal- and hydride-free RAR of dienones. Further encouraged by the fact that pentannulated aromatics are privileged scaffolds owing to their occurrence in numerous biologically active natural products, pharmaceuticals, and organic materials, we commenced to optimize the reaction parameters (Table 1).19 An optimization with tributylphosphine as the Lewis base revealed that 30 equiv of water were optimal for an efficient conversion of 4a to 5a (Table 1, entries 2−5), beyond which no further improvement in the yield or the reaction time was

range of dienone-aldehydes engaged in cycloreduction to form an array of cyclopenta-fused arenes and heteroarenes possessing up to two contiguous stereogenic centers, one of them being an all-carbon quaternary center, in good diastereoselectivities and in excellent yields (5b−5m). A narrow yield range (77−92%) across the substrates verified herein is an indicative of the robustness of the method. Dienones bearing both alkyl and aryl groups at R1 (viz., 5b, 5c, and 5i) were well-tolerated. Contrary to the expectation, the presence of electron-donating groups either on the dienone moiety or on the aromatic backbone showed only marginal influence on the efficiency of the reaction (5d, 5g−j). The RAR proceeded smoothly even with the substrates bearing B

DOI: 10.1021/acs.orglett.8b03658 Org. Lett. XXXX, XXX, XXX−XXX

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anionic species I (as shown in Scheme 2). A subsequent protonation of I and isomerization of the double bond in 5a′ delivers 5a. To a certain extent, I can also undergo direct protonation to afford 5a. Thus, the mechanistic rationale is in concurrence with the extent of deuteration observed at β- and δ-positions of 5a-D (see Scheme 4c). It is also in line with the hypothesis presented in Scheme 2. Because of the significance of indanone-fused γ-lactones, which are important substructures in bioactive compounds such as GR24, solanacol, and others,24 Borhan’s lactonization protocol25 was applied on the RA products 5 (Scheme 6).

heteroarene backbones (5l and 5m), thereby significantly enhancing the scope of the method. However, this method is not without limitations. A substituent at R2 was not tolerated (5n) and δ,δ-disubstituted dienones also remained unsuccessful substrates (5o), hinting that the phosphine addition most likely occurs from the δ-position. Next, we investigated the mechanism of the pentannulative RAR. First, we intended to gain evidence for an initial 1,4- or 1,6-addition of phosphine.21 Accordingly, E,Z-4a was prepared (Scheme 4a). Under the optimized conditions, an exclusive Scheme 4. Mechanistic Studies of the Pentannulative RAR

Scheme 6. Elaboration of 5 to γ-Butyrolactones 6

formation of E-5a was observed. Thus, it can be surmised that a 1,6-addition of phosphine indeed takes place and therefore the stereochemical integrity of the Z-configured double bond (in E,Z-4a) is lost, leading to the formation of the thermodynamically favorable E-configured double bond in 5a. The most important evidence about the role of water during the transformation of 4 to 5 came when the reaction of 4a was performed with 18O-labeled water (Scheme 4b). The HRMS spectrum of the crude reaction mixture showed a distinct peak at m/z 221.1916 (expected m/z 221.1920) for 18O-containing tributylphoshine oxide [P(18O)Bu3].22 This result suggests that water reacts with the phosphonium center at a certain stage, eventually converting it to phosphine oxide. On the other hand, the reaction of 4a in the presence of D2O generated 5a-D with almost 90% ‘D’-incorporation at the δ-position and nearly 80% ‘D’-incorporation at the β-position, indicating that β- and δ-carbons experience anionic character during the transformation (Scheme 4c). Based on the experimental observations, a plausible mechanism is proposed in Scheme 5.23 The reaction commences with a 1,6-addition of phosphine to 4a and a subsequent aldol reaction to generate the zwitterionic species H. The protonation of the alkoxide (in H) follows the elimination of the tributylphosphine oxide to provide the

Accordingly, 5a was oxidatively converted to the lactone 6a in good yield using a catalytic amount of OsO4 and oxone as the co-oxidant. Employing this protocol, few other analogues (6b− 6e) were prepared. The lactones (6) can be converted in one step to achieve the complete molecular framework present in GR24 and solanacol, which are potent stimulants for parasitic weed seed germination.24 On the other hand, when 5a was treated with BF3OEt2, the indanone-fused tetrahydropyran 7a (CCDC 1848426 assigned for 7a′)26 was isolated in 83% yield in an unexpected manner (Scheme 7).27 This method was realized to be general and provided efficient access to other significant analogues 7b−7f. It is worth noting that indeno[1,2-b]pyrans are important structural motifs prevalent in several medicinally relevant compounds.28 To our surprise, indanones 5h and 5i upon treatment with BF3OEt2 generated dibenzo[a,h]azulen-8-ones 8a and 8b, respectively (Scheme 8). It was reasoned that the presence of a methoxy group para (C-6) to the benzylic alcohol moiety in 5h and 5i promotes the formation of para-quinomethide L, through which the formation of 8a and 8b can be explained. A similar setup is not feasible in the case of 5g or 5j [which afforded 7e and 7f, respectively (see Scheme 7)], where the methoxy groups are situated meta to the benzylic alcohol moiety. Interestingly, the tetracyclic scaffold of 8 represents part of the structure of the immunosuppressive natural products dalesconols A and B.29 Despite several efforts to develop an enantioselective version of the RAR with 4a as the model substrate,30 we were only able to obtain 5a in 35% ee with the exo-Kwon catalyst 9,31 although in good yield (Scheme 9).

Scheme 5. Plausible Mechanism for the RAR

C

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highly functionalized pentannulated aromatics such as indeno[1,2-b]furanones, indeno[1,2-b]pyrans, and dibenzo[a,h]azulen-8-ones. Efforts to apply the methods described herein for the synthesis of bioactive natural products are in progress, and the results will be communicated soon.

Scheme 7. Elaboration of 5 to Indeno[1,2-b]pyrans 7

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03658. Experimental procedures and spectral data for all new compounds (1H NMR, 13C NMR) (PDF) Accession Codes

CCDC 1848426−1848427 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

Scheme 8. Elaboration of 5 to Dibenzo[a,h]azulen-8-ones 8

*E-mail: [email protected]. ORCID

S. S. V. Ramasastry: 0000-0001-5814-9092 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS IISER Mohali is acknowledged for funding, and for the NMR, mass, and departmental X-ray facilities. B.S. thanks UGC and L.D. thanks IISER Mohali for research fellowships.

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REFERENCES

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Scheme 9. Best Result Obtained During the Evaluation of Chiral Catalysts

In summary, an unprecedented metal- and reductant-free intramolecular reductive aldol reaction of various dienonealdehydes is established. Some of the remarkable features of this method are (i) α-substituted dienones are employed as substrates for the first time in a RAR, (ii) an unusual role of water as the terminal oxidant is discovered, further, (iii) it is highly regio-, chemo-, and diastereoselective, and (iv) the reaction proceeds under extremely mild conditions and is insensitive to dry and inert conditions. We have also detailed a series of serendipitous one-step elaborations of reductive aldol products. Intriguing mechanistic details governing these processes are thoroughly elucidated. All the new strategies described herein provide straightforward and efficient access to D

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(20) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560. (21) For our earlier work involving 1,6-addition of phosphines, see: Satpathi, B.; Wagulde, S. V.; Ramasastry, S. S. V. Chem. Commun. 2017, 53, 8042. (22) See the Supporting Information for a comparison of the HRMS spectra of POBu3 and P(18O)Bu3, obtained with water and 18Olabeled water, respectively. (23) For related works that provide mechanistic insights, see: (a) Pal, B.; Pradhan, P. K.; Jaisankar, P.; Giri, V. S. Synthesis 2003, 1549. (b) Moiseev, D. V.; James, B. R.; Hu, T. Inorg. Chem. 2006, 45, 10338. (c) Wei, Y.; Liu, X.-G.; Shi, M. Eur. J. Org. Chem. 2012, 2386 and references cited therein . (24) (a) Chen, V. X.; Boyer, F.-D.; Rameau, C.; Retailleau, P.; Vors, J.-P.; Beau, J.-M. Chem. - Eur. J. 2010, 16, 13941. (b) Lachia, M.; Wolf, H. C.; De Mesmaeker, A. Bioorg. Med. Chem. Lett. 2014, 24, 2123. (c) Vinoth, P.; Vivekanand, T.; Suryavanshi, P. A.; Menéndez, J. C.; Sasai, H.; Sridharan, V. Org. Biomol. Chem. 2015, 13, 5175. (d) Liang, R.; Chen, K.; Zhang, Q.; Zhang, J.; Jiang, H.; Zhu, S. Angew. Chem., Int. Ed. 2016, 55, 2587. (e) Bromhead, L. J.; Norman, A. R.; Snowden, K. C.; Janssen, B. J.; McErlean, C. S. P. Org. Biomol. Chem. 2018, 16, 5500. (25) Schomaker, J. M.; Travis, B. R.; Borhan, B. Org. Lett. 2003, 5, 3089. (26) The structure was confirmed unambiguously from the X-ray diffraction analysis of 7a′ (the tosyl hydrazine derivative of 7a). (27) For related chemistry, see: (a) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (b) Sultana, S.; Devi, N. R.; Saikia, A. K. Asian J. Org. Chem. 2015, 4, 1281. (28) Mills, F. D.; Hodge, J. E.; Tjarks, L. W. J. Org. Chem. 1981, 46, 3597. (29) Snyder, S. A.; Sherwood, T. C.; Ross, A. G. Angew. Chem., Int. Ed. 2010, 49, 5146. (30) See the Supporting Information for the results obtained during the evaluation of chiral catalysts. (31) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding, L.; Dudding, T.; Kwon, O. J. Am. Chem. Soc. 2014, 136, 11890.

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