Organophosphine-Catalyzed Intramolecular Hydroacylation of

Feb 23, 2018 - ... Sciences, Indian Institute of Science Education and Research (IISER), Mohali , Sector 81, S A S Nagar, Manauli PO, Punjab 140 306 ,...
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An Organophosphine-Catalyzed Intramolecular Hydroacylation of Activated Alkynes Atanu Mondal, Raju Hazra, Jagdeep Grover, Moluguri Raghu, and S. S. V. Ramasastry ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00397 • Publication Date (Web): 23 Feb 2018 Downloaded from http://pubs.acs.org on February 23, 2018

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An Organophosphine-Catalyzed Intramolecular Hydroacylation of Activated Alkynes Atanu Mondal, Raju Hazra, Jagdeep Grover, Moluguri Raghu 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, S A S Nagar, Manauli PO, Punjab 140 306, India Supporting Information ABSTRACT: We present the details of an organophosphinecatalyzed Morita-Baylis-Hillman-type reaction of activated alkynes. The outcome is an intramolecular hydroacylation of α,βynones leading to the formation of 1,3-cyclopenta-, cycloheptaand cyclooctadione-fused arenes and heteroarenes. In addition, during the course of the investigation, a phosphine-catalyzed intramolecular aldol reaction of keto-ynones via δ’[C(sp3)-H]functionalization was discovered, and a new annulation event comprising of a ω’[C(sp3)-H]-functionalization of α,β-ynones was also uncovered. The mechanisms governing these processes have been thoroughly elucidated. KEYWORDS: hydroacylation, organophosphine, ynones, MoritaBaylis-Hillman reaction, cyclopentanes, heterocycles, annulation

The Morita-Baylis-Hillman (MBH) reaction is a versatile C-C bond-forming reaction between an activated alkene and a carbon electrophile, commonly facilitated by a nucleophilic catalyst (Scheme 1a).1 This reaction attracted the attention of synthetic chemists owing to its adaptability, operational simplicity, and being atom-economic and organocatalytic. Our own efforts in this field provided new approaches for the synthesis of an array of cyclopenta[b]annulated arenes and heteroarenes.2 Scheme 1. Background and Significance of this Work.1-6 a) General representation of the Morita-Baylis-Hillman (MBH) reaction Y Z R1 R3N or R3P R1 R2 X = Electron-withdrawing group R2 X X Y = O, NPg; Z = OH, NHPg R3 R3 b) Halo aldol and chalcogeno-MBH reactions of activated alkynes Y Z H O H MLn/activator R1 O M = metal; L = halide L R1 c) Organophosphine-catalyzed hydroacylation of α,β-ynones: This work O O

H

R1

PR3 (cat.)

R1 O

O d) Known so far: Metal- or NHC-catalyzed hydroacylation of alkynes O O O H

R1

[M] or [NHC]

(or) R1

R1

Whereas activated alkenes are the usual substrates in the MBH reaction, we are inquisitive about the fate of activated alkynes under the typical MBH set up. This proposition is indeed pursued with activated alkynes during the development of halo aldol reactions3 and chalcogeno-MBH reactions,4 which are typically mediated by metal-based Lewis acids (Scheme 1b). In his seminal report on the chalcogeno-MBH reaction,4a Kataoka mentions that ‘the Baylis-Hillman reaction of active alkynes with aldehydes cannot proceed from the mechanistic viewpoint of the reaction’. Herein, we report an organocatalytic intramolecular MBH-type reaction of α,β-ynones that provides straightforward access to 1,3-cyclopenta-, cyclohepta- and cyclooctadione-fused arenes and heteroarenes without the need to employ any external agents other than a nucleophilic trigger (Lewis base) in catalytic amounts (Scheme 1c). The overall transformation also represents an organophosphine-catalyzed hydroacylation of α,β-ynones. So far, the hydroacylation of unactivated and activated alkynes is known to be facilitated by either transition metal complexes5 or Nheterocyclic carbenes (NHCs) (Scheme 1d).6 The envisioned reaction was studied on the model substrate 1a,7 wherein the α,β-ynone and aldehyde functionalities were tethered ortho to each other (Scheme 2). To our surprise, the reaction of 1a in the presence of 10 mol% of PCy3 at room temperature furnished an unexpected product 2a8 in 78% yield. Scheme 2. An Unexpected Outcome of the MBH-Type Reaction of the Ynone 1a. O

O PCy3 (10 mol%)

Ph Ph CH2Cl2, 6 h, rt CHO O 78% 1a 2a Represents an organocatalytic hydroacyative cyclopentannulation α,β-ynones

Some of the noteworthy features associated with the conversion of 1a to 2a are: i) the present method constitutes a metal-free (and organocatalytic) alternative for the intramolecular hydroacylation of ynones. In this context, it is worth noting that α,βynones are rarely employed as substrates in a hydroacylation process,9 which is indeed a limitation of the existing methods, ii) it also exemplifies an unusual entry for the construction of densely functionalized indanes. The persistent and widespread occurrence of several bioactive natural products possessing indane framework can make this an attractive strategy.10 Having realized the significance of the aforementioned observation, we commenced to optimize the reaction conditions (Table 1). During the evaluation of phosphines, a marked improvement in the yield of 2a was observed with PPh3 (entry 4). A subsequent solvent screening with PPh3 as the catalyst did not offer any fur-

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ther improvements (entries 5-10). The feasibility of performing the reaction under aqueous conditions was also verified. Interestingly, the reaction generated 2a in 88% yield even in the presence of water (entry 9).2c,11 Indeed, the best yield of the product (93%) was realized when brine solution was employed as the solvent (entry 10). Table 1. Optimization of the Reaction Parametersa O

O catalyst (10 mol%)

1a

entry 1 2 3 4 5 6 7 8 9 10 11 12

CHO

Ph

catalyst (10 mol%) PCy3 PMe2Ph PEtPh2 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 DABCO β-ICD

Ph

solvent, rt 2a

solvent CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN toluene CH3OtBu 2-Me-THF water-THF (1:1) brine CH2Cl2 CH2Cl2

t (h) 6 8 4 5 3 12 4 72 40 8 48 12

O

yield b (%) 78 48 72 92 76 82 70 79 88 93 -

a Reaction conditions: A mixture of 1a (0.1 mmol) and a catalyst (0.01 mmol) in a solvent (1 mL) was stirred at room temperature until 1a disappeared (by TLC). bChromatographic yields.

On the other hand, nitrogen-centred Lewis bases such as 1,4diazabicyclo[2.2.2]octane (DABCO) and β-isocupreidine (βICD), which are some of the most successful catalysts in the Baylis-Hillman chemistry, failed to generate even traces of the expected product (Table 1, entries 11-12).

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Thus, 10 mol% of the cheap and readily available PPh3 was identified as the catalyst for the conversion of 1a to 2a. To understand the scope and generality of this process, we applied the optimized conditions to substrates bearing different electronic features. The results are summarized in Table 2. A wide range of 2-alkylidine and 2-arylidine-1,3-indanediones possessing both electron donating as well as electron withdrawing groups could be conveniently assembled in 67-91% yield range (Table 2, 2b-l). The reaction in brine was realized to be marginally less yielding compared to the respective reaction in DCM (2c,d,i,j), which could be attributed to the miscibility issues. The ynones with alkyl groups also conveniently furnished the respective indanediones in good yields (2g,h). Apart from ynones, enynone-bearing substrates were also demonstrated to be efficient under the optimized conditions. For example, 2l and 2m were obtained in 72% and 67% yields, respectively. The generality of this method is furthered with the synthesis of functionalized 1,3-cyclopentadionefused benzothiophenes (2n) and benzofurans (2m,o,p) in good to excellent yields. With the advent of the successful hydroacylative pentannulation reaction, we intended to extend this concept to a new substrate design 3 (Table 3). It was anticipated that the phoshinepromoted reaction of the biaryl-ynone 3 could provide 4.12 Indeed, gratifyingly, 3a under the prototypical conditions described in Table 2 delivered the desired product 4a in 54% yield. This result represents the first assemblage of fused seven-membered carbocycles via an intramolecular hydroacylation of α,β-ynones.12 Through a brief optimization,13 the yield of 4a could be improved to 86% with PCy3 as the catalyst in toluene. Table 3. Substrate Scope: Dibenzo[a,c]cycloheptanedionesa,b,c R1

R2

R2

O

R3

O

PCy3 (10 mol%) OHC

O

toluene, 40 oC

R3 3

Table 2. Substrate Scope: Cyclopentannulated Arenes and Heteroarenesa,b,c

R1 4

54%d

4a, R = Ph, 48 h, 4a, R = Ph, 7 h, 86% 4b, R = (p-Ph)C6H4, 7 h, 75% 4c, R = 1-naphthyl, 8 h, 74% R 4d, R = m-tolyl, 8 h, 86%e 4e, R = [m,p-(OMe)2]C6H3, 8 h, 78% 4f, R = cyclopropyl, 7 h, 82%

O

O

4d

OMe F

MeO

O

O

O Ph

O

Ph

O

MeO

O

R

OMe

4g, 7 h, 83% (1:1)

R 4i, R = H, 8 h, 86% (5:1) 4j, R = OMe, 8 h 72%

4h, 7 h, 80% (5:1) O

O

O

Ph O

Ph

4k, 18 h, 74% (5:1)e

O 4l, 36 h, 68% (3:1)

Ph

O 4m, 36 h, 73% (2:1)

a

a Reaction conditions: A mixture of 1 (0.1 mmol) and PPh3 (0.01 mmol) in DCM (1 mL) was stirred at room temperature until 1 disappeared (by TLC). bChromatographic yields. c2i, 2j, 2m-p were obtained in 1:1 E/Z ratio. dOutcome in brine medium. eAt 40 oC.

Reaction conditions: A mixture of 3 (0.1 mmol) and PCy3 (0.01 mmol) in toluene (1 mL) was stirred at 40 oC until 3 disappeared (by TLC). bChromatographic yields. cE/Z ratio in the parenthesis is that of the purified sample; crude E/Z is 1:1. dWith PPh3 (10 mol%) in DCM at room temperature. e40 mol% PCy3 was employed. eX-ray crystal structure of 4d was obtained (CCDC 1584071), see the Supporting Information for details.

An evaluation of the substrate scope under the optimized conditions provided an array of 2-arylidene and 2-alkylidene dibenzo[a,c]cycloheptadiones possessing diverse electronic characters

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ACS Catalysis in 68-86% yield (Table 3, 4b-m). In general, consistent turnaround times and excellent yields were achieved, thereby highlighting the generality of the method. The presence of electrondonating groups either on the alkyne (4e) or on the aryl backbone (4h-j) displayed only a minor influence on the efficiency of the reaction. Further, enynones also generated the respective products in good yield. For example, 4k was obtained in 74% yield. On the other hand, longer reaction times during the formation of 4l and 4m could be attributed to the restricted rotation across the arylaryl bond. Next, we turned our attention to gain insights about the mechanism of the phosphine-catalyzed hydroacylation process (Scheme 3). Towards this, the substrate 1nD possessing deuterated aldehyde functionality (95%D) was subjected to the optimized conditions (Scheme 3a). Interestingly, the extent of ‘D’incorporation in the product 2nD went down to 30%, indicating that the transformation of 1nD to 2nD at a certain stage may be involving a competing intermolecular protonation pathway, in addition to an intramolecular proton transfer. The hypothesized proton exchange with the solvent environment was further evidenced when 1a was treated in the presence of deuterated solvents (Scheme 3b) where the ‘D’-incorporation in the product 2aD was identified to be 70% in THF-D2O mixture, and 76% in THFCD3OD; but not 100%. A deuterium scrambling experiment between 1a and 1nD was also conducted (Scheme 3c). Realization of the products 2aD and 2nD with 10% and 25% ‘D’-incorporation, respectively, suggests that the aldehydic proton is lost to the solvent environment during the transformation, and due to the intermolecularity of the proton transfer step, it re-enters the system (10%D in 2aD).

Having realized the crucial role of the aldehydic proton in facilitating the reaction, it was anticipated that its replacement with an alkyl group may provide further insights about the reaction mechanism. In addition, it was also envisioned that the alkyl shifts, analogous to hydride and proton shifts, may lead to the formation of unexpected products. Based on these considerations, when 5a was subjected under the reaction conditions described in Table 2, an unexpected product 6a was isolated in 43% yield (Table 4). Through an optimization of different parameters,13 the yield of 6a could be improved to 87%. Table 4. Substrate Scope: 3-Ethynyl-3-hydroxyindanonesa,b

Scheme 3. Mechanistic Studies O

O

Ph D

~95%

S

O

D

PPh3 (10 mol%) CH2Cl2, rt 9 h, 90%

~30% Ph (a)

S O 2nD (E/Z = 1:1)

1nD

O PPh3 (10 mol%)

D

in THF-D2O (1:1): 42 h, 81%, ~70%D in THF-CD3OD (1:1): 11 h, 80%, ~76%D

Ph

1a

1nD 1a + (~95%D)

PPh3 (10 mol%) CH2Cl2, rt, 9 h

(b) 2aD O

(c) 2aD 2nD + (44%, ~10%D) (42%, ~25%D)

Based on the experimental evidence, a plausible mechanism is proposed in Scheme 4. Initial phospha-Michael addition followed by an intramolecular aldol reaction, which are typical of the MBH reaction, provides the zwitterionic species 1a1. The α-proton to alkoxide in 1a1 is acidic enough to undergo an intermolecular proton transfer (presumably assisted by adventitious water) to form the vinylogous ylide 1a2. The ylide 1a3 (in resonance with 1a2) upon further proton transfer converts to the enol 1a4, which upon elimination of phosphine generates 2a. The mechanism of formation of 4 from 3 can also be explained in an analogous manner. The ylide 1a314 is believed to be responsible for the H/D abstraction from the solvent, which is in line with the experimental observations. Further, the lack of stereoselectivity in products could be due to the free rotation across the C2-C1’ bond in 1a3 or 1a4.15 Scheme 4. Plausible Mechanism

a Reaction conditions: A mixture of 5 (0.1 mmol) and PBu3 (0.02 mmol) in tert-butanol (1 mL) was stirred at room temperature until 5 disappeared (by TLC). bIsolated yields after column chromatography. cPPh3 (10 mol%) in DCM at rt.

Subsequent evaluation of a variety of substrates under the optimized conditions provided access to a series of 3-ethynyl-3hydroxyindanones (6b-f) in 68-88% yield range. Furthermore, the heteroarene-fused 3-ethynyl-3-hydroxycyclopentanones (6g,h) could also be readily synthesized by this method, which would otherwise require a sequence of multi-step synthetic reactions. As a significant extension of this methodology, the δ’-branched substrate 5i (when R1 = Me, R2 = Ph) formed 6i containing two contiguous stereogenic centres in 72% yield, while 5j (when R1 = R2 = Ph) generated straightaway the ynenone 7j in 80% yield, apparently via the in situ dehydration of the respective β-hydroxy ketones (6j). The mechanism of the formation of 6 from 5 is depicted in Table 4. Michael addition of the phosphine to 5 followed by the δ’-proton abstraction of the zwitterion 5’ generates the enolate

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ACS Catalysis 5’’. Intramolecular aldol reaction of 5’’ and an inter- or intramolecular vinylic proton abstraction by the alkoxide provides 6.16 A striking feature of this transformation is that it involves an unprecedented organocatalytic δ’[C(sp3)-H]-functionalization of α,β-ynones.17 To the extent of our knowledge, this study also demonstrates a phoshine-catalyzed intramolecular aldol reaction of keto-ynones.18 Further, in analogy to the concept described in Table 4, it was anticipated that the biaryl-ynone 8a would produce 9a (Table 5). However, the reaction of 8a under the optimized conditions furnished the dibenzo[a,c]cyclooctadione 10a in 67% yield. Since such a transformation is without precedence, few other analogs (10b-e) were synthesized in good yields (65-78%).19 Regarding the mechanism, it can be postulated that the zwitterionic species 8a1 abstracts the ω’-proton to afford the enolate 8a2. Rather than undergoing an aldol reaction, the enolate 8a2 cyclizes to generate the ylide 8a3. An eventual 1,2-proton shift followed by the elimination of phosphine yields 10a. The P-O interaction depicted in 8a1 or 8a2 is considered responsible for the formation of Eselective products. In addition to providing access to several bioactive natural products possessing dibenzo[a,c]cyclooctane core,20 this method also exemplifies an organocatalyzed ω’[C(sp3-H)]functionalization of ynones. Table 5. Substrate Scope: Dibenzo[a,c]cyclooctanedionesa,b Ph

OH

O O

tBuOH,

7 h, rt

8a PR3

PR3

O PR3

PR3 Ph

Ph

Ph 8a1

ω’

O

Ph

O 10a, 67% (observed product)

O

O

O

8a2

O

8a3

F O

O

O R

Ph

Ph

O 10b, R = 1-naphtyl, 7 h, 78%c 10c, R = m-tolyl, 7 h, 65%

O 10d, 5 h, 66%

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.xxxxx. Experimental details and characterization data for all new compounds (1H NMR, 13C NMR) (PDF) X-ray crystal structure of 4d (CIF) X-ray crystal structure of 10b (CIF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT IISER Mohali is acknowledged for funding, and for the NMR, mass, and departmental X-ray facilities. A.M., R.H., J.G., and M.R. thank IISER Mohali for research fellowships.

REFERENCES

8

O 9a (expected in analogy, but not formed)

for the synthesis of bioactive natural products are underway. The results will be communicated in due course.

O

Ph

7

PCy3 (20 mol%)

X

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O 10e, 5 h, 70%

ORTEP diagram of 10b a

Reaction conditions: A mixture of 8 (0.1 mmol) and PCy3 (0.02 mmol) in tert-butanol (1 mL) was stirred at room temperature until 8 disappeared (by TLC). bIsolated yields after column chromatography. cX-ray crystal structure of 10b was obtained (CCDC 1814310), see the Supporting Information for details.

In conclusion, we presented an unprecedented case of the MBH-type reaction of α,β-ynones, which provides access to a variety of cyclopenta- and cyclohepta-fused arenes and heteroarenes. Further, serendipitous organocatalytic approaches for the synthesis of 3-ethynyl-3-hydroxyindanones involving a δ’[C(sp3)-H]-functionalization, and dibenzo[a,c]cyclooctadiones via ω’[C(sp3)-H]-functionalization of α,β-ynones have also been described. Intriguing mechanistic details governing these processes were elucidated. Efforts to apply the methods described herein

(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. A Tertiary Phosphinecatalyzed Reaction of Acrylic Compounds with Aldehydes. Bull. Chem. Soc. Jpn. 1968, 41, 2815-2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972 [Chem. Abstr. 1972, 77, 34174q]. (c) Masson, G.; Housseman, C.; Zhu, J. The Enantioselective Morita– Baylis–Hillman Reactionand Its Aza Counterpart. Angew. Chem., Int. Ed. 2007, 46, 4614-4628. (d) Singh, V.; Batra, S. Advances in the Baylis–Hillman Reaction-assisted Synthesis of Cyclic Frameworks. Tetrahedron 2008, 64, 4511-4574. (e) Declerck, V.; Martinez, J.; Lamaty, F. Aza-Baylis−Hillman Reaction. Chem. Rev. 2009, 109, 1-48. (f) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Recent Contributions from the Baylis−Hillman Reaction to Organic Chemistry. Chem. Rev. 2010, 110, 5447-5674. (g) Wei, Y.; Shi, M. Multifunctional Chiral Phosphine Organocatalysts in Catalytic Asymmetric Morita−Baylis−Hillman and Related Reactions. Acc. Chem. Res. 2010, 43, 1005-1018. (h) Mansilla, J.; Saá, J. M. Enantioselective, Organocatalytic Morita-Baylis-Hillman and Aza-Morita-Baylis-Hillman Reactions: Stereochemical Issues. Molecules 2010, 15, 709-734. (i) Basavaiah, D.; Veeraraghavaiah, G. The Baylis–Hillman Reaction: A Novel Concept for Creativity in Chemistry. Chem. Soc. Rev. 2012, 41, 68-78. (j) Wei, Y.; Shi, M. Recent Advances in Organocatalytic Asymmetric Morita–Baylis–Hillman/aza-Morita– Baylis–Hillman Reactions. Chem. Rev. 2013, 113, 6659-6690. (k) Fan, Y. C.; Kwon, O. Advances in Nucleophilic Phosphine Catalysis of Alkenes, Allenes, Alkynes, and MBHADs. Chem. Commun. 2013, 49, 11588-11619. (l) Bharadwaj, K. C. Intramolecular Morita–Baylis– Hillman and Rauhut–Currier reactions. A Catalytic and Atom Economic Route for Carbocycles and Heterocycles. RSC Adv. 2015, 5, 7592375946. (2) (a) Satpathi, B.; Ramasastry, S. S. V. Morita–Baylis–Hillman Reaction of β,β-Disubstituted Enones: An Enantioselective Organocatalytic Approach for the Synthesis of Cyclopenta[b]annulated Arenes and Heteroarenes. Angew. Chem., Int. Ed. 2016, 55, 1777-1781. (b) Satpathi, B.; Ramasastry, S. S. V. Enantioselective Organocatalytic Intramolecular Morita–Baylis–Hillman Reaction of Some Unusual Substrates. Synlett 2016, 27, 2178-2182. (c) Raghu, M.; Grover, J.; Ramasastry, S. S. V. Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)−H] Functionalization of Ynones. Chem.-Eur. J. 2016, 22, 18316-18321. (d) Satpathi, B.; Wagulde, S. V.; Ramasastry, S. S. V. An Enantioselective Organocatalytic Intramolecular Morita–Baylis– Hillman (IMBH) Reaction of Dienones, and Elaboration of the IMBH Adducts to Fluorenones. Chem. Commun. 2017, 53, 8042-8045. (3) Few selected articles on this topic, see: (a) Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Asymmetric Halo Aldol

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ACS Catalysis Reaction (AHA). Org. Lett. 2003, 5, 329-331. (b) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Enantioselective Synthesis of β-Iodo Morita–Baylis–Hillman Esters by a Catalytic Asymmetric ThreeComponent Coupling Reaction. Angew. Chem., Int. Ed. 2009, 48, 43984401. (c) Hachiya, I.; Ito, S.; Kayaki, S.; Shimizu, M. Diastereoselective Iodoaldol Reaction of γ-Alkoxy-α,β-Alkynyl Ketone Derivatives Promoted by Titanium Tetraiodide. Asian J. Org. Chem. 2013, 2, 931-934. (4) For a seminal contribution, see: (a) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S.-I. A Convenient Synthesis of αHalomethylene Aldols or β-Halo-α-(hydroxyalkyl)acrylates Using the Chalcogeno-Baylis–Hillman Reaction. Angew. Chem., Int. Ed. 2000, 39, 2358-2360. Recent reviews on this topic, see: (b) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chalcogenides as Organocatalysts. Chem. Rev. 2007, 107, 5841-5883. (c) Cież, D.; Pałasz, A.; Trzewik, B. Titanium Enolate Chemistry at the Beginning of the 21st Century. Eur. J. Org. Chem. 2016, 1476-1493. (5) (a) Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Synthetic Studies on Prostanoids 1 Synthesis of Methyl 9-oxoprostanoate. Tetrahedron Lett. 1972, 13, 1287-1290. (b) Tanaka, K.; Fu, G. C. A Versatile New Method for the Synthesis of Cyclopentenones via an Unusual RhodiumCatalyzed Intramolecular Trans Hydroacylation of an Alkyne. J. Am. Chem. Soc. 2001, 123, 11492-11493. (c) Takeishi, K.; Sugishima, K.; Sasaki, K.; Tanaka, K. Rhodium-Catalyzed Intramolecular Hydroacylation of 5- and 6-Alkynals: Convenient Synthesis of αAlkylidenecycloalkanones and Cycloalkenones. Chem.-Eur. J. 2004, 10, 5681-5688. (d) Tanaka, K.; Sasaki, K.; Takeishi, K.; Hirano, M. Cationic P(OPh)3- or PPh3-Rhodium(I) Complex-Catalyzed Isomerizations of 5-Alkynals to δ-Alkynyl Ketones, Cyclopent-1-enyl Ketones, and Cyclohexenones. Eur. J. Org. Chem. 2007, 5675-5685. (e) Jun, C.-H.; Jo, E-A.; Park, J.-W. Eur. J. Org. Chem. 2007, 1869-1881. (f) Willis, M. C. Chem. Rev. 2010, 110, 725-748. (g) Gonzalez-Rodriguez, C.; Pawley, R. J.; Chaplin, A. B.; Thompson, A. L.; Weller, A. S.; Willis, M. C. Rhodium-Catalyzed Branched-Selective Alkyne Hydroacylation: A Ligand-Controlled Regioselectivity Switch. Angew. Chem., Int. Ed. 2011, 50, 5134-5138. (h) Yang, F.; Jin, T.; Yamamoto, Y. Synthesis of 2,3-Dihydro-1H-Inden-1-One Derivatives via Ni-Catalyzed Intramolecular Hydroacylation. Tetrahedron 2012, 68, 5223-5228. (i) Oonishi, Y. Development of Novel Cyclizations via Rhodacycle Intermediate and Its Application to Synthetic Organic Chemistry. Chem. Pharm. Bull. 2015, 63, 397-407. (j) Ghosh, A.; Johnson, K. F.; Vickerman, K. L.; Walker, J. A.; Stanley, L. M. Recent Advances in Transition MetalCatalysed Hydroacylation of Alkenes and Alkynes. Org. Chem. Front. 2016, 3, 639-644. (6) (a) Biju, A. T.; Wurz, N. E.; Glorius, F. N-Heterocyclic CarbeneCatalyzed Cascade Reaction Involving the Hydroacylation of Unactivated Alkynes. J. Am. Chem. Soc. 2010, 132, 5970-5971. (b) Vedachalam, S.; Wong, Q.-L.; Maji, B.; Zeng, J.; Ma, J.; Liu, X.–W. NHeterocyclic Carbene Catalyzed Intramolecular Hydroacylation of Activated Alkynes: Synthesis of Chromones. Adv. Synth. Catal. 2011, 353, 219-225. (c) Wang, Z.; Yu, Z.; Wang, Y.; Shi, D. N-Heterocyclic Carbene Catalyzed Intramolecular Hydroacylation of Alkynylphosphonates. Synthesis 2012, 44, 1559-1568. (d) Yetra, S. R.; Patra, A.; Biju, A. T. Recent Advances in the N-Heterocyclic Carbene (NHC)Organocatalyzed Stetter Reaction and Related Chemistry. Synthesis 2015, 47, 1357-1378. (7) (a) Asahina, K.; Matsuoka, S.; Nakayama, R.; Hamura, T. An Efficient Synthetic Route to 1,3-bis(arylethynyl)isobenzofuran Using Alkoxybenzocyclobutenone as a Reactive Platform. Org. Biomol. Chem. 2014, 12, 9773-9776. (b) Zhang, Y.; Guo, D.; Ye, S.; Liu, Z.; Zhu, G. Synthesis of Trifluoromethylated Naphthoquinones via CopperCatalyzed Cascade Trifluoromethylation/Cyclization of 2-(3Arylpropioloyl)benzaldehydes. Org. Lett. 2017, 19, 1302-1305. (8) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. C−H Bond Oxidation Initiated Pummerer- and Knoevenagel-Type Reactions of Benzyl Sulfide and 1,3-Dicarbonyl Compounds. Org. Lett. 2008, 10, 803-805. (9) (a) Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; McNally, S. J.; Currie, G. S. Rhodium-Catalyzed Intermolecular Chelation Controlled Alkene and Alkyne Hydroacylation:  Synthetic Scope of β-SSubstituted Aldehyde Substrates. J. Org. Chem. 2006, 71, 5291-5297. (b) Khong, S.; Kwon, O. Phosphine-Initiated General-Base-Catalyzed Quinolone Synthesis. Asian J. Org. Chem. 2014, 3, 453-457. (10) (a) Gabriele, B.; Mancuso, R.; Veltri, L. Recent Advances in the Synthesis of Indanes and Indenes. Chem.-Eur. J. 2016, 22, 5056-5094. (b) Manisha.; Dhiman, S.; Mathew, J.; Ramasastry, S. S. V. One-Pot

Relay Catalysis: Divergent Synthesis of Furo[3,4-b]indoles and Cyclopenta[b]indoles from 3-(2-Aminophenyl)-1,4-enynols. Org. Biomol. Chem. 2016, 14, 5563-5568 and references cited therein. (11) Water-promoted phosphine-catalyzed reactions are not uncommon. For some selected works, see: (a) Methot, J. L.; Roush, W. R. Synthetic Studies toward FR182877. Remarkable Solvent Effect in the Vinylogous Morita−Baylis−Hillman Cyclization. Org. Lett. 2003, 5, 42234226. (b) Stewart, I. C.; Bergman, R. G.; Toste, F. D. PhosphineCatalyzed Hydration and Hydroalkoxylation of Activated Olefins:  Use of a Strong Nucleophile to Generate a Strong Base. J. Am. Chem. Soc. 2003, 125, 8696-8697. (c) Gonzalez-Cruz, D.; Tejedor, D.; de Armas, P.; Garcia-Tellado, F. Dual Reactivity Pattern of Allenolates “On Water”: The Chemical Basis for Efficient Allenolate-Driven Organocatalytic Systems. Chem. -Eur. J. 2007, 13, 4823-4832. (d) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.-X. An Unexpected Role of a Trace Amount of Water in Catalyzing Proton Transfer in Phosphine-Catalyzed (3 + 2) Cycloaddition of Allenoates and Alkenes. J. Am. Chem. Soc. 2007, 129, 3470-3471. (e) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Phosphine Triggered [3+2] Allenoate–Acrylate Annulation: A Mechanistic Enlightenment. Tetrahedron Lett. 2007, 48, 3617-3620. (f) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. Chiral Phosphine-Catalyzed Enantioselective Construction of γButenolides Through Substitution of Morita−Baylis−Hillman Acetates with 2-Trimethylsilyloxy Furan. J. Am. Chem. Soc. 2008, 130, 72027203. (g) Fang, Y.-Q.; Jacobsen, E. N. Cooperative, Highly Enantioselective Phosphinothiourea Catalysis of Imine−Allene [3 + 2] Cycloadditions. J. Am. Chem. Soc. 2008, 130, 5660-5661. (12) In the context of metal-catalyzed hydroacylation reactions, Willis opines that the intramolecular reactions to generate rings other than five-membered systems are not trivial, see Ref-5f. (13) See the Supporting Information for the optimization studies. (14) Efforts to trap 1a2 by a Wittig reaction were unsuccessful. (15) This is unlike the typical intramolecular MBH reaction, which is Eselective due to the favorable P--O interaction, see Ref-2. (16) Alternatively, a catalytic amount of tert-butoxide generated in situ may also deprotonate the vinylic proton in 5’’’. (17) For our earlier work on a phosphine-catalyzed γ’[C(sp3)-H]functionalization of α,β-ynones, see Ref-2c. (18) For a phosphine-catalyzed Mukaiyama aldol reaction, see: (a) Matsukawa, S.; Fukazawa, K.; Kimura, J. Polymer-Supported PPh3 as a Reusable Organocatalyst for the Mukaiyama Aldol and Mannich Reaction. RSC Adv. 2014, 4, 27780-27786. For a phosphine catalyzed nitroaldol reaction, see: (b) Weeden, J. A.; Chisholm, J. D. PhosphineCatalyzed Nitroaldol Reactions. Tetrahedron Lett. 2006, 47, 9313-9316. For an aldol reaction triggered by a Rauhut-Currier reaction, see: (c) Thalji, R. K.; Roush, W. R. Remarkable Phosphine-Effect on the Intramolecular Aldol Reactions of Unsaturated 1,5-Diketones:  Highly Regioselective Synthesis of Cross-Conjugated Dienones. J. Am. Chem. Soc. 2005, 127, 16778-16779. (19) The construction of medium-sized carbocycles is a challenge in organic synthesis, see: (a) Winnik, M. A. Cyclization and the Conformation of Hydrocarbon Chains. Chem. Rev. 1981, 81, 491-524. (b) Mehta, G.; Singh, V. Progress in the Construction of Cyclooctanoid Systems:  New Approaches and Applications to Natural Product Syntheses. Chem. Rev. 1999, 99, 881-930. (20) (a) Tan, R.; Li, L.; Fang, Q. The Stereostructure of Wuweizisu B. Planta Medica 1986, 52, 49-51. (b) Liu, J.-S.; Li, L. Schisantherins P and Q, Two Lignans from Kadsura Coccinea. Phytochemistry 1995, 38, 1009-1011. (c) Monovich, L. G.; Le Huerou, Y.; Roenn, M.; Molander, G. A. Total Synthesis of (−)-Steganone Utilizing a Samarium(II) Iodide Promoted 8-Endo Ketyl−Olefin Cyclization. J. Am. Chem. Soc. 2000, 122, 52-57. (d) Beryozkina, T.; Appukkuttan, P.; Mont, N.; Van der Eycken, E. Microwave-Enhanced Synthesis of New (−)-Steganacin and (−)-Steganone Aza Analogues. Org. Lett. 2006, 8, 487-490. (e) Gong, W.; Babu, T. V. R. Conformation and Reactivity in Dibenzocyclooctadienes (DBCOD). A General Approach to the Total Synthesis of Fully Substituted DBCOD Lignans via Borostannylative Cyclization of α,ωDiynes. Chem. Sci. 2013, 4, 3979-3985. (f) Iwai, T.; Okochi, H.; Ito, H.; Sawamura, M. Construction of Eight-Membered Carbocycles through Gold Catalysis with Acetylene-Tethered Silyl Enol Ethers. Angew. Chem., Int. Ed. 2013, 52, 4239-4242.

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ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For Table of Contents Only * products of the MBH-type reaction of α,β-ynones * intramolecular hydroacylation of α,β-ynones O

1

PR3

R1 O

R2

R en wh

wh en

R1

=H

O

Ar/ Het-Ar

7

and

5

R2

Ar/ Het-Ar

5

* phosphine-catalyzed aldol reaction * organocatalytic δ’- and ω’[C(sp3)-H]-functionalizations O

R2 O

Ar

O

O

R2

HO =a lky l

O

Ar

R2

Ar

R3

8

and Ar

O

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