Phosphine-Catalyzed Dual Umpolung Domino Michael Reaction

ters. b: This work. The umpolung Michael-type reaction of ynone derivatives, wherein a nitrogen nucleophile is installed at the α-position of a Micha...
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Phosphine-Catalyzed Dual Umpolung Domino Michael Reaction: Facile Synthesis of Hydroindole- and Hydrobenzofuran-2-Carboxylates Kenta Kishi, Shinobu Takizawa, and Hiroaki Sasai ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01011 • Publication Date (Web): 02 May 2018 Downloaded from http://pubs.acs.org on May 2, 2018

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Phosphine-Catalyzed Dual Umpolung Domino Michael Reaction: Facile Synthesis of Hydroindole- and Hydrobenzofuran-2Carboxylates Kenta Kishi, Shinobu Takizawa,* and Hiroaki Sasai* The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan ABSTRACT: A highly atom-economical, chemoselective, and stereoselective Lewis base (LB)-catalyzed dual umpolung domino Michael reaction between cyclohexadienones and alkynyl esters has been developed. PPh3, as a LB catalyst, afforded either the hydroindole-2-carboxylates or hydrobenzofuran-2-carboxylates 3 as a single diastereomer in high yields (up to 89%). An obtained product could be easily transformed to a (S*,S*,R*)-octahydroindole-2-carboxylic acid ((S*,S*,R*)-Oic) analogue. KEYWORDS: domino process, umpolung, hydroindole, hydrobenzofuran, phosphine catalyst Over the past few decades, organocatalyzed domino reactions have been recognized as practical environmentally friendly methods for organic synthesis owing to their lowtoxicity and simplicity.1 Nucleophilic phosphines as Lewis base (LB) catalysts have been extensively investigated because they can react with α,β-unsaturated carbonyl compounds to produce α-anionic intermediates I (Scheme 1a) that can further react with various electrophiles for C–C bond formation.2

ran-2-carboxylates 3 (Scheme 1b). Natural products and bioactive compounds often contain hydroindoles and hydrobenzofurans, bearing a carbonyl group at the 2-position (Scheme 2).4 Most hydroindole syntheses depend on the use of tyrosine or indoline-2-carboxylic acid as a building block,4c,4e,5 which limits the possibly for divergent syntheses. Moreover, creating an α-oxidized carbonyl functionality requires an umpolung reaction or an α-amination/alkoxylation of carbonyl compounds using explosive peroxides or toxic nitrogen electrophiles.6 Despite the importance of hydroindoles and hydrobenzofurans bearing a carbonyl group at the 2-position, their syntheses have been challenging.

Scheme 2. Examples of natural products and bioactive compounds containing carbonyl group at 2-position.

Scheme 1. a: Umpolung Michael reaction of α,β-unsaturated esters. b: This work

The umpolung Michael-type reaction of ynone derivatives, wherein a nitrogen nucleophile is installed at the α-position of a Michael acceptor, is an effective reaction for accessing natural and unnatural amino acid derivatives.3 As a pioneering work, in 1997, Trost presented phosphine-catalyzed αumpolung Michael reaction of alkynyl ester with sulfonyl amine or phthalimide affording α-amino carbonyl compounds3a through the key-intermediates II and III (Scheme 1a). 3b-h We envisioned that intermediate III could be trapped with an electrophile before the elimination of the LB to achieve a dual umpolung domino reaction: The LB-catalyzed dual umpolung domino Michael reaction of readily accessible cyclohexadienone 1 and alkynyl ester 2 could lead to highly functionalized hydroindole-2-carboxylates or hydrobenzofu-

To explore the possibility of the proposed dual umpolung domino reaction towards synthesis of hydroindoles and hydrobenzofurans bearing a carbonyl group at the 2-position, we first employed known cyclohexadienone 1a7,8 and commercially available alkynyl ester 2a as prototypical substrates (Table 1). The use of PPh2Me or PPh3 afforded the desired umpolung product 3a in 23% or 25% yield, respectively (Entries 1 and 2). An electron-rich PBu3 formed the normal sequential adduct 4a, possessing a carbonyl group at 3-position in 4% yield, together with many unidentified side products (entry 3).9 This result indicated that the electron-withdrawing ability of phosphonium in intermediate II (Scheme 1) played a key role in producing the umpolung reaction product. More electrondeficient phosphines, such as P(OMe)3 and P(C6F5)3, failed to produce the desired product because the nucleophilic addition of the phosphine catalyst to 2a could not occur (Entry 4). Amine-type LB catalysts, such as NEt310 and DABCO11, did not show any improvements in yields (Entries 5 and 6) proba-

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bly because of a preferential Brønsted base reaction with 1a. Finally, the dual umpolung domino Michael adduct 3a was selectively obtained in 86% isolated yield with PPh3 when the reaction was performed with 1.5 equivalents of 2a in 1,4dioxane at 100°C (Entry 8). For the details of the optimization procedure, see the ESI.

liminary result, the desired product 3j was obtained in 84%

Table 1. Screening of Lewis base catalysta

Entry

Lewis base catalyst

Yield of 3a [%]b

Yield of 4a [%]b

1

PPh2Me

23

Trace

2

PPh3

25

0

3

PBu3

0

4

4

P(OMe)3 or P(C6F5)3

0

0 20

5

NEt3

0

6

DABCO

0

0

7c

PPh2Me

25

Trace

8c

PPh3

86

0

a

Reaction conditions: 1a (0.10 mmol), 2a (0.20 mmol) and catalyst (20 mol %), in dry toluene-MeCN (4:1, 0.50 mL). bDetermined by 1 H NMR using 1,3,5-trimethoxybenzene as an internal standard. c In 1,4-dioxane at 100 °C with 1.5 equiv of 2a. dIsolated yield.

With the optimized condition in hand, our interest shifted to discovering the scope of the newly developed dual umpolung domino Michael reaction (Scheme 3). Aromatic substituents (1b: R1 = Ph; 1c: R1 = p-tolyl) were compatible, although the yields of 3b and 3c decreased. The Ms group could be replaced with the bulkier Ts group (3d–3f: X = NTs), while still maintaining moderate to good yields. The more electron-rich pmethoxybenzenesulfonyl group was also tolerated (3g). Methyl and benzyl esters (2b: R6 = Me; 2c: R6 = Bn) yielded products 3h and 3i, respectively. To our delight, cyclohexadienone 1j, which bears a hydroxy group,8 underwent the designed umpolung reaction to afford the corresponding hydrobenzofuran2-carboxylate (3j, X = O) in high yield. The o-tolyl group (1m, R1 = o-tolyl) was tolerated, and 3m was obtained after extending the reaction time. Both electron-withdrawing and electrondonating groups at the meta and para positions (1n–1r) were tolerated (3n: R1 = 3,5-Me2-C6H3; 3o: p-tolyl; 3p: 2-naphthyl; 3q: 3,4,5-F3C6H2; 3r: p-Br-C6H4). In all cases, a single diastereomer was obtained. Although monomethylated products (3u, R2 = Me and 3v, R4 = Me) were regioselectively obtained with moderate yields, no reaction occurred to yield 3s and 3t when substrates 1s and 1t with α,α’- dimethyl or β,β’-dimethyl substituents on the cyclohexadienone olefins (1s: R2 = R3 = Me; 1t: R4 = R5 = Me) were employed. The relative configuration and structure of the obtained product were unambiguously determined via X-ray crystallography 3a to be the S*,S*configuration for both chiral centers (Figure 1). This dual umpolung domino Michael reaction might proceed enantioselectively if an optically pure phosphine was employed. As a pre-

Scheme 3. Scope of the dual umpolung domino Michael reaction. Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), PPh3 (20 mol %), in 1,4-dioxane (0.50 mL); 3a–3e, 3g–3h, 3s–3t: At 100 °C for 48 h; 3f, 3i: At 100 °C for 5 min; 3j–3l, 3n–3r: At 60 °C for 3 h;

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ACS Catalysis 3m: At 60 °C for 24 h; 3u: At 100 °C for 36 h; 3v: At 60 °C for 13 h. aNo reaction of 1s occurred.

ee when the reaction of 1j with 2a was conducted using (R)PHANEPHOS (20 mol %) in DCM at −20°C (Scheme 4, see also the ESI).

Figure 1. X-ray structure of 3a

could work as a proton donor. The reaction of 1a and 2a in the presence of D2O (5.0 equiv) yielded the partially deuterated product D-3a (D content β: 85%, δ: 75%) (Eq. 2), thus indicating that anionic species were formed at the β- and δ-positions during the reaction sequence. Based on these experimental results, a plausible reaction mechanism is shown in Scheme 5. Initially, Michael addition of PPh3 with alkynyl ester 2a occurs to generate phosphonium intermediate A. Intermediate A acts as a Brønsted base to abstract an acidic proton from 1a. Then, deprotonated 1a (intermediate B) undergoes umpolung Michael addition at the α-position, induced by the electronwithdrawing ability of the phosphonium in intermediate C. A second ring-closing Michael reaction of intermediate D followed by the intermolecular proton-transfer through 1a and Int. B in the intermediate E yields product 3a with PPh3 catalyst regeneration. The second Michael reaction, from intermediates D to E, is believed to be irreversible since deuterium was not incorporated at the δ’-position during the deuterium experiment (Eq. 2).

Scheme 4. Enantioselective umpolung Michael reaction of 1j and 2a with (R)-PHANEPHOS.

Scheme 6. Synthetic transformations of 3d

Scheme 5. Plausible reaction mechanism

Next, a series of reactions was performed to confirm the mechanism of our dual umpolung domino Michael reaction. When Me-capped substrate 1w was treated under optimal conditions, 1w was recovered quantitatively (Eq. 1). This result indicated the importance of in situ nucleophile generation for initiating the α-addition to the alkynyl ester, and substrate 1

To demonstrate the utility of the obtained products, hydroindole-2-carboxylate 3d was subjected to further synthetic transformations (Scheme 6). Luche-reduction of 3d proceeded smoothly to produce 5 in quantitative yield with good diastereoselectivity. The hydrogenation of 3d with an Ir complex produced saturated 6 in 77% yield as a single diastereomer. The carbonyl group in ketone 6 could be reduced via 1,2reduction, elimination,12 followed by hydrogenation. Reductive detosylation of 7 was successful using magnesium in methanol. Finally, detosylated 8 was converted to a (S*,S*,R*)-Oic analogue 9 (Scheme 2a)4b,4e via hydrolysis, Boc-protection, and amidation in three steps. In summary, we developed a novel route for pharmaceutically important hydroindole-2-carboxylates and hydrobenzofuran-2-carboxylates via a newly developed phosphine-catalyzed dual umpolung domino Michael reaction. The utility of obtained products was demonstrated, and the epimer of a bioac-

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tive compound was synthesized. Further investigations of the enantioselective version of this reaction and applications to the synthesis of other bioactive compounds are currently underway.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, detailed screening of reaction conditions, and spectral data for all the new compounds (PDF) Crystallographic data (CIF)

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

ORCID Shinobu Takizawa: 0000-0002-9668-1888 Hiroaki Sasai: 0000-0002-7221-488X

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by JSPS KAKENHI Grant Numbers JP16K08163 (C), JP16H01152 (Middle Molecular Strategy) and JP17H05373 (Coordination Asymmetry), the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), and JST Advance Catalytic Transformation Program for Carbon Utilization (ACTC, Grant Number JPMJCR12YK), Japan. K. K. Thanks the Grantin-Aid for JSPS Research Fellow. We acknowledge the technical staff of the Comprehensive Analysis Center of ISIR, Osaka University (Japan).

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iodophenoxyacetic acid and Oxone as a co-oxidant. Tetrahedron 2010, 66, 5833–5840. (a) Inanaga, J.; Baba, Y.; Hanamoto, T. Organic synthesis with trialkylphosphine catalysts. Conjugate addition of alcohols to α,β-unsaturated alkynic acid esters. Chem. Lett. 1993, 22, 241– 244. (b) Kuroda, H.; Tomita, I.; Endo, T. Facile synthetic method for the preparation of dithioacetals by the double conjugate addition of acetylenes bearing electron-withdrawing groups with thiols. Synth. Commun. 1996, 26, 1539–1543. (c) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W. Phosphine-catalyzed annulation of thioamides and 2-alkynoates:  A new synthesis of thiazolines. J. Org. Chem. 2002, 67, 4595–4598. (d) Pedduri, Y.; Williamson, J. S. One-pot synthesis of highly substituted tetrahydrofurans from activated propargyl alcohols using Bu3P. Tetrahedron Lett. 2008, 49, 6009–6012. (a) Tejedor, D.; Cruz, D. G.; Expósito, A. S.; Tellado, J. J. M.; Armas, P.; Tellado, F. G. Multicomponent domino processes based on the organocatalytic generation of conjugated acetylides: Efficient synthetic manifolds for diversity-oriented molecular construction. Chem. Eur. J. 2005, 11, 3502–3510. (b) Tejedor, D.; Expósito, A. S.; Tellado, F. G. Chemodifferentiating MCRs based on α-ketoesters and terminal alkynoates. A homoaldol-based ABB’ system. Chem. Commun. 2006, 2667–2669. (c) Tejedor, D.; Expósito, A. S.; Tellado, F. G. A Substrate-based folding process incorporating chemodifferentiating ABB’ three-component reactions of terminal alkynoates and 1,2-dicarbonyl compounds: A skeletal-diversityoriented synthetic manifold. Chem. Eur. J. 2007, 13, 1201–1209. In the presence of DABCO, alkynyl ester undergoes dimerization quickly as a side reaction. For details, see: Ramachandran, P. V.; Rudd, M. T.; Reddy, M. V. R. Stereoselective synthesis of hex-2-(E)-en-4-yn-1,6-dioates and E,Z-muconic acid diesters via organo-catalyzed self-coupling of propiolates. Tetrahedron Lett. 2005, 46, 2547–2549. Mani, N. S.; Mapes, C. M.; Wu, J.; Deng, X.; Jones, T. K. Stereoselective synthesis of Z-α-aryl-α,β-unsaturated esters. J. Org. Chem. 2006, 71, 5039–5042.

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