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Asymmetric Cyclization/Nucleophilic Tandem Reaction of o‑Alkynylacetophenone with (Diazomethyl)phosphonate for the Synthesis of Functional Isochromenes Liu Cai,†,§ Yuan Chen,†,§ Hao Cao,† Qi Wei,† Yi Yang,† Qin Ouyang,*,‡ and Yungui Peng*,† †

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Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China ‡ College of Pharmacy, Third Military Medical University, Chongqing 400038, China S Supporting Information *

ABSTRACT: An efficient asymmetric reaction between (diazomethyl)phosphonate with o-alkynylacetophenone has been established by employing different stereocontrol strategy. A variety of isochromenes bearing tetrasubstituted stereocenters and (diazomethyl)phosphonate at the 1-position were prepared in yield up to 99% with enantioselectivity up to 94% enantiomeric excess (ee) for the first time. These functional isochromenes could be transformed to important structural motifs in biologically active compounds. Moreover, density functional theory calculations were conducted to gain insight into the process and the stereoselectivity.

I

position of isobenzopyrylium ions have been demonstrated as an efficient method for the construction of 1-substituted 1Hisochromenes derivatives.3−6 Such heterocycles are considered privileged scaffolds, since they are present in a wide variety of biologically active natural products and drug molecules.7 The asymmetric version of this reaction has mainly focused on the asymmetric formation of chiral 1-alkoxy-isochromenes4 and asymmetric hydrogenation5 (Scheme 1a). To the best of our knowledge, the asymmetric addition reactions of C-nucleophiles to isobenzopyrylium ions at the 1position to form carbon−carbon bonds remains largely unexplored.6 Such a methodology could provide a route to structurally diverse chiral 1-substituted 1H-isochromene derivatives. To date, only one example has been reported to afford tertiary stereocenter at the 1-position, and it was only moderately successful.6g Thus, developing an efficient methodology to realize the tandem asymmetric cyclization and subsequent C-nucleophile addition to form a carbon−carbon bond, especially to furnish isochromenes bearing tetrasubstituted stereocenters at the 1-position, is a formidable but potentially rewarding challenge. Since the transition-metal catalyst is still attached to the isobenzopyrylium ion at the 4position after it activated the alkyne bond to conduct the intramolecular cyclization with ortho-carbonyl, we surmised that it could be exploited to create a chiral environment. The central metal coordinated with a chiral ligand possessing a sufficiently long arm, which could pass on chiral environment proximity to the 1-position; thus, asymmetric nucleophile addition could be achieved at this position (Scheme 1b).

sobenzopyrylium ions, as key intermediates mainly formed in situ via intramolecular electrophilic cyclization of oalkynylaryl carbonyl compounds, have been extensively utilized in various cascade reactions,1−6 such as [4 + 2] cycloadditions2 and nucleophile additions at the 1-position.3−6 Despite the great progress that has been made, asymmetric variants of these transformations remain largely unexploited. This may be because the planar 10 π-electron aromatic structure of the isobenzopyrylium ion lacks an obvious coordination site for a chiral catalyst and cannot easily create a chiral environment around the reactive position. To overcome these difficulties, asymmetric counteranion-directed catalysis (ACDC)2c,d,5a−c or two metal catalysts acting cooperatively5d have been employed as asymmetric control strategies, but have had limited success in promoting cascade reactions (Scheme 1a). Following the electrophilic cyclization of o-alkynylaryl carbonyl compounds, nucleophile addition reactions at the 1Scheme 1. Asymmetric Nucleophile Tandem Reaction at the 1-Position of Isobenzopyrylium Ions

Received: August 14, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b02864 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters We have an ongoing interested in the chemistry of (diazomethyl)phosphonates,8 which have been employed as carbene precursors,8b−f 1,3-dipoles,8g−j and C-terminal nucleophiles.8k−o As C-nucleophiles, we wondered if they could undergo an asymmetric addition to the in-situ-generated isobenzopyrylium ion of o-alkynylacetophenone and actualize the asymmetric cyclization/nucleophile tandem reaction. A series of chiral isochromenes derivatives bearing tetrasubstituted carbon with functionalized (diazomethyl)phosphonates at the 1-position were easily prepared, which could be further transformed to phosphorus-containing isochromene derivatives with promising potential biological activities. Here, we report an efficient asymmetric cyclization/nucleophilic carbon− carbon bond-forming tandem reaction of o-alkynylacetophenone with (diazomethyl)phosphonate. The study began with a search for a catalytic system that would promote the model reaction between o-(alkynyl) aryl ketone (1a) with (diazomethyl)phosphonate (2a). In our previous work, we have demonstrated that chiral silver SPINOL phosphate could facilitate asymmetric [3 + 2] cycloaddition reactions of α,β-unsaturated compounds with α-(diazomethyl)phosphonates. 8j The reaction involves (diazomethyl)phosphonates and a catalytic central Ag(I), which has been extensively employed in the activation of triple bonds.1a,b Chiral BOXes have been successfully employed in many asymmetric reactions; the length of the BOX arms could be altered by using a different chiral starting material.9 These results and features inspired us to explore the chiral complex Ag(I)/BOX as the catalyst in the present model reaction. Especially, AgOTf/BOX, since it has been found to be able to promote the decomposition of α-diazo compounds into carbenes, which can take part in X-H10a,b and C−H10c bond insertion reaction at room temperature (rt). We envisioned that the decomposition of the (diazomethyl)phosphonate by extrusion of nitrogen could be suppressed if the reaction was conducted at lower temperature. After a preliminary experiment, we were delighted to find that the complex of AgOTf/BOX L1 could promote the reaction and proceeded smoothly to afford the desired product 3a in 80% yield with moderate enantioselectivity (64% ee) at 0 °C. The ring-enlarged byproduct 4a was formed in 4% yield (Table 1, entry 1). In the absence of BOX, AgOTf only led to a trace amount of 3a; this result demonstrated that BOX played a substantial role for both reactivity and enantioselectivity (see Table 1, entry 2). To improve the catalytic performance, a series of BOXes were synthesized and screened in the model reaction. When substituents were introduced onto the bridging carbon of BOX (L2−L4), no better results were observed (Table 1, entries 3−5). Pleasingly, when a cyclic ring was introduced to the bridging carbon of BOX (L5−L8), the enantioselectivity increased greatly, and all these variants gave similar ee values (85%−87%) (Table 1, entries 6−9). Next, we considered the yield and the ratio of 3a:4a. We selected the BOX with a five-membered ring on the bridging carbon (L6) for further structural modification via varying the substituent at the 4,4′-position. We found that the steric hindrance of the substituent has a great effect on the catalytic performance. Furthermore, the larger the substituent group, the better the enantioselectivity (see Table 1, entries 7 and 10−13). The best result was achieved when the substituent at the 4,4′-positions was adamantyl (L12); the product was obtained in excellent yield (92%) and enantioselectivity (93% ee) (see Table 1, entry 13). Next, a range of solvents such as DCM, PhMe,

Table 1. Screened Chiral Bis(oxazoline) and Optimization of Reaction Conditions

entrya

L

X

sol

yield of 3ab (%)

ee of 3ac

yield of 4ab (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23d 24e 25f 26g

L1 − L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L13 L12 L12 L12 L12 L12 L12 L12 L12 L12 L12 L12 L12

OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− OTf− BF4− SbF6− OAc− PF6− OTf− OTf− OTf− OTf−

PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhMe THF DCM acetone PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl

80 trace 69 78 trace 84 85 90 78 92 87 85 92 85 50 15 88 27 38 82 trace 94 84 82 98 47

64 − 48 63 − 86 87 86 85 77 89 55 93 87 89 90 93 88 85 93 − 92 93 93 94 89

4 − 6 10 − 10 3 6 13 4 3 4 3 4 − − 7 − − 12 − 3 3 − − −

a

The reaction was performed with 1a (0.2 mmol), 2a (0.2 mmol), 4 Å MS (100 mg), AgOTf (0.1 equiv), L (0.12 equiv) and solvent (1.0 mL) at 0 °C. bIsolated yield. cDetermined by HPLC analysis. d Reaction was performed at −10 °C. eAgOTf was lowing to 0.05 equiv and L to 0.06 equiv. f1a/2a (0.2 mmol) = 1.2:1. g4 Å MS was not added.

THF, and acetone were screened, no improvement was observed, compared with that of the PhCl. Other reaction parameters were also optimized, including the reaction temperature, catalyst loading, the ratio of 1a to 2a, the addition of molecular sieves (see Table 1, entries 23−26) and the reaction concentration (for more details, see the Supporting Information). The optimal reaction conditions were established as L12 (6 mol %)/AgOTf (5 mol %), 1a:2a = 1.2:1 at 0 °C in PhCl (0.2 M) with 4 Å MS. With the optimal reaction conditions in hand, we further explored the substrate scope, and the results are shown in Table 2. Generally, substrates with electron-donating substituents on the aryl moiety at the alkyne terminus led to excellent yields (83%−99%) and enantioselectivities (92%− 94% ee) (see Table 2, entries 1−7). Electron-withdrawing B

DOI: 10.1021/acs.orglett.9b02864 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

is located at para position, thereby attenuating its nucleophilicity. We also changed the substituent at the carbonyl from methyl to ethyl, which gave a modest yield (47%) and good ee (93%) (see Table 2, entry 23). When o-alkynyl benzaldehyde was treated with 2a in this catalytic system, no reaction was observed. Good results were obtained when ethyl (diazomethyl)phosphonate (2b) was employed as the nucleophile and resulted in 79% yield and 90% ee (see Table 2, entry 24). To demonstrate the potential utility of the present approach, in the case of 1a, a millimolar scale reaction was successfully performed and gave the desired product 3a (92% yield) with 93% ee (see values given in parentheses in entry 1 of Table 2). Inspired by the results achieved by employing (diazomethyl)phosphonate as the nucleophile, we attempted to enlarge the reaction scope of the nucleophile to diazoacetate (Scheme 2). Pleasingly, this reaction proceeded smoothly and afforded the corresponding desired product in good yield (70%) with excellent enantioselectivity (93% ee).

Table 2. Substrate Scope of the Tandem Reaction

entrya d

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24e

R1, R2, R3

yield of 3 (%)b

ee of 3 (%)c

Ph, H, Me 3-MeC6H4, H, Me 4-MeC6H4, H, Me 4-EtC6H4, H, Me 3-MeOC6H4, H, Me 4-MeOC6H4, H, Me 3,5-Me2C6H3, H, Me 3-ClC6H4, H, Me 4-ClC6H4, H, Me 3-FC6H4, H, Me 4-FC6H4, H, Me 3-BrC6H4, H, Me 4-BrC6H4, H, Me 4-EtO2CC6H4, H, Me 4-CF3C6H4, H, Me 2-thienyl, H, Me Ph, 4-Me, Me Ph, 5-Me, Me Ph, 5-MeO, Me Ph, 4-F, Me Ph, 4-Cl, Me Ph, 5-Cl, Me Ph, H, Et Ph, H, Me

3a, 98 (92) 3b, 97 3c, 98 3d, 83 3e, 96 3f, 94 3g, 99 3h, 94 3i, 94 3j, 48 3k, 95 3l, 62 3m, 65 3n, 33 3o, 48 3p, 98 3q, 91 3r, 97 3s, 97 3t, 97 3u, 92 3v, 21 3w, 47 3x, 79

94 (93) 94 92 93 94 92 94 95 89 90 90 89 90 89 89 84 94 92 91 93 85 84 93 90

Scheme 2. Employing Diazoacetate as a Nucleophile

Since phosphine-containing heterocyclic compounds are often present in natural compounds,11 we further derive the available product 3a by treating it with P(Bu)3 and obtained the corresponding hydrazone 5, then hydrogenated it into 7. Hydrazone 7 was transformed to the diazo compound 8. Compound 8 was then hydrogenated over Pd/C to give the final phosphine-containing isochromatic compound 9. The total yield was as high as 70% over the four-step process. We tried our best to realize this transformation in a one-step of hydrogenation, but it was not successful. We also transformed the bicyclic hydrazone 5 into tricyclic compound 6 with an oxygen bridge by the catalysis of Bi(OTf)3 via a hydroamination of the CC in 75% yield and retained the enantioselectivity (Scheme 3). The absolute configuration of 3s was unambiguously determined by X-ray crystallographic analysis (CCDC 1897869). Thus, the absolute configuration of other products 3 was deduced from this. To gain insight into the mechanism and the origin of enantioselectivity, control experiments were performed to demonstrate that the coordinated central metal Ag(I) attachment to the 4-position of the isochromenylium ion is vital to achieving efficient stereocontrol (see the Supporting Information). Deuterium labeling experiments suggested that the proton at the C4 position of the product could either be derived from residual water present in the reaction system or the (diazomethyl)phosphonate (see the Supporting Information). To further understand the mechanism, density functional theory (DFT) computational calculations were performed. The geometries of the intermediates and transition states (TSs) were optimized, in conjunction with the B3LYP function, using a combined basis set where LANL2DZ was used for the Ag atom and 6-31G(d) for the rest.12 The reaction

a

The reaction was performed with 1a (0.24 mmol), 2 (0.2 mmol) in the presence of L12 (6 mol %)/AgOTf (5 mol %) in PhCl (1.0 mL) with 4 Å MS (100 mg) at 0 °C. In all case, only a trace amount of 4 was observed. bIsolated yield. cDetermined by chiral HPLC. dThe results in parentheses were obtained when the reaction was run on a mmol scale. e2b was used.

substituents caused the reactivity to decrease in some cases and give only moderate yields, albeit with good enantioselectivities (Table 2, entries 9−15). This observed lower reactivity is presumably because the electron-withdrawing effect of those substituents reduced the stability of the in-situ-formed isobenzopyrylium ion. The substitution pattern has a great influence on the reactivity. Substrates with a heterocyclic ring at the terminal alkyne were accommodated in this reaction and gave the desired product in 98% yield with 84% ee (see Table 2, entry 16). No reaction was observed when a terminal alkyne (R1 = H), aliphatic (R1 = C5H11), or TMS-substituted alkyne was employed as a substrate. This possibly ascribes to the slightly lower stability of those in-situ-formed isobenzopyrylium ions. The influence of substituents on the aromatic moiety adjacent to the ketone was also investigated. In most cases, both of the substrates with electron-donating or electron-withdrawing groups afforded excellent yields (91%− 97%) and enantioselectivities (85%−94% ee) (see Table 2, entries 17−21). However, when the electron-withdrawing group Cl was located at the 5-position, only 21% yield was obtained with 84% ee (Table 2, entry 22). This result may be attributed to the electron-withdrawing substituent (Cl) at the meta position of the carbonyl group, reducing the electron density of the carbonyl oxygen to a greater degree than when it C

DOI: 10.1021/acs.orglett.9b02864 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Derivatization of the Products

Figure 2. Optimized structures and Gibbs free energies of L12-INT2, R-TS2, and S-TS2. The bond distances of the optimized structures are given in angstroms.

the Ag−N coordination. In brief, the steric hindrance from the isochromenylium appears to be the main reason for the stereoselectivity, and these calculations are consistent with the experimental results. The reaction procedure was also monitored by HRMS (ESI) in real-time, and the molecular weight of intermediate complex [L12-INT3-OTf − ]:C 5 0 H 6 3 AgN 4 O 6 P, calculated as 953.353071, was observed to be 953.354585. In conclusion, we have realized a highly efficiency asymmetric cyclization/C-nucleophile carbon−carbon bondformation tandem reaction sequence between o-alkynylacetophenone with (diazomethyl)phosphonate for the first time. Through the catalytic bis(oxazoline)/AgOTf system, a variety of functional phosphine-containing isochromenes and derivatives bearing tetrasubstituted stereocenters at the 1-position were made available. Moreover, the reaction mechanism was investigated by a deuterium labeling experiment and DFT calculation.

process was rationalized, and the favorable reaction pathway is shown in Figure 1. First, Ag-catalyzed 6-endo-dig oxo-

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02864. Experimental procedures and detailed characterization data of all new compounds (PDF)

Figure 1. Calculated intermediates and transition states of the favorable reaction pathway.

Accession Codes

cyclization of β-alkynyl ketone 1a generated a carbonyl ylide INT2. The addition of 2a then occurred, and deprotonation promoted by OTf anion afforded the key Ag-bound intermediate INT3. The formed HOTf reacted with the Ag coordination center to produce the final product 3a. Because the proton of HOTf could be exchanged with water, the production of 30% deuterium-labeled 3a in the presence of 1 equiv of D2O can be explained. Since the stereoselectivity of the final product was decided by the C−C bond formation step via TS2, the chiral ligand L12-bound complex L12-INT2 and 2a were calculated. As illustrated in Figure 2, the steric hindrance of the Si face is much higher than that of Re face, because the adamantyl of L12-INT2 is located at the Si face above the isochromenylium ring. Therefore, S-TS2, the TS resulting from attack at the Re face was the favorable TS to produce S-3a. The energy of STS2 was 1.5 kcal/mol lower than that of R-TS2. Moreover, as shown in R-TS2, the distances between the Ag and N was 3.39 Å, while the corresponding distance in S-TS2 was 2.88 Å, which is much longer than that of a normal Ag−N bond (2.46 Å in L12-INT2). This suggested that the steric hindrance between the isochromenylium and attacking 2a would affect

CCDC 1897869 contains 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 Authors

*E-mail address: [email protected] (Q. Ouyang). *E-mail addresses: [email protected], [email protected]. cn (Y. Peng). ORCID

Qin Ouyang: 0000-0002-1161-5102 Yungui Peng: 0000-0002-5815-1261 Author Contributions §

L.C. and Y.C. contributed equally.

Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.9b02864 Org. Lett. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS This work was sponsored by the National Science Foundation of China (No. 21472151), Natural Science Foundation of Chongqing (No. cstc2019jcyj-msxmX0414) and Fundamental Research Funds for the Central Universities (No. XDJK2019AA003).

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DOI: 10.1021/acs.orglett.9b02864 Org. Lett. XXXX, XXX, XXX−XXX