Michael-Michael Addition Reactions Promoted by Secondary Amine

Nov 15, 2017 - Michael-Michael Addition Reactions Promoted by Secondary Amine-Thiourea: Stereocontrolled Construction of Barbiturate-Fused ...
2 downloads 0 Views 1MB Size
Download PDF
Note pubs.acs.org/joc

Cite This: J. Org. Chem. 2017, 82, 13594−13601

Michael−Michael Addition Reactions Promoted by Secondary Amine-Thiourea: Stereocontrolled Construction of Barbiturate-Fused Tetrahydropyrano Scaffolds and Pyranocoumarins Jing Zhang,† Guohui Yin,‡ Yuchao Du,† Ziqi Yang,† Yang Li,*,† and Ligong Chen*,† †

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, PR China

‡

S Supporting Information *

ABSTRACT: Bifunctional secondary amine-thiourea organocatalysts were successfully applied in the stereocontrolled synthesis of barbiturate-fused tetrahydropyrano scaffolds. Compared with typically used tertiary amine-thiourea organocatalysts, the developed catalysts exhibited excellent catalytic performance in the domino Michael−Michael reaction between N, N′-dimethylbarbituric acid and Morita−Baylis− Hillman acetates of nitroalkenes to yield pharmaceutically important heterocycles in good yields with excellent enantioselectivities. Moreover, this catalytic protocol can also be applied to synthesize biologically active pyranocoumarin compounds.

T

asymmetric construction of barbiturate-fused tetrahydropyrano scaffold remains a challenge.6 In this context, we were interested in developing an enantioselective method to construct optically pure barbiturate-fused tetrahydropyrano compounds through a Michael−Michael addition reaction. Organocatalytic annulation reactions have proved to be efficient tools for the construction of privileged and diversified structural molecules.7 As an important class of organocatalysts, bifunctional amine-thiourea can be classified into primary, secondary and tertiary amines, which have been widely employed to promote carbon−carbon and carbon-heteroatom bond formation.8 Among these bifunctional catalysts, primary and tertiary amine-thioureas have been well investigated, and in contrast, the secondary amine-thiourea in asymmetric synthesis have been rarely studied. In most cases, the secondary aminethiourea combines with a carbonyl compound via a covalent bond to form an enamine intermediate, which controls the stereochemistry in the asymmetric process.9 In contrast, only limited examples of secondary amine-thioureas have been reported in asymmetric transformations, which function mainly through noncovalent interactions of the substrates and catalysts via hydrogen bonds.10 To expand the applications of this novel activation model in asymmetric transformations promoted by secondary amine-thioureas, to understand the nature of this interaction and to enantioselectively construct biologically active barbiturate derivatives. Herein, we report a diphenylethanediamine-based secondary amine-thiourea catalyst to

he Barbituric acid scaffold is a very important building block in the pharmaceutical industry, and many drugs derived from it have been widely applied in disease treatments, such as sedative, anesthetic, anxiolytic, anticonvulsant, analeptic, anticancer, and anti-AIDS treatments.1 The tetrahydropyrano scaffold as a privileged structural motif has attracted intensive attention.2 Thus, as a combination of these two versatile frameworks, barbiturate-fused tetrahydropyrano derivatives are of considerable importance for pharmaceutical and medicinal activities, such as antimicrobial,3 antiproliferative, 4 and antituberculosis activities (Figure 1).5 Recently, several works have reported the synthesis of racemic barbiturate-fused tetrahydropyrano scaffolds utilizing cyclization and cascade reactions.5 However, these processes involved multistep reactions, tedious operation procedures and/or toxic reagents, which limit their potential applications. To the best of our knowledge, an efficient method for the

Figure 1. Representative bioactive barbiturate-fused tetrahydropyrano derivatives. © 2017 American Chemical Society

Received: July 29, 2017 Published: November 15, 2017 13594

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

a

entry

catalyst

solvent

yield (%)b

drc

ee (%)d

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18e 19f 20f,g 21f,h

Ia Ib Ic Id Ie If Ig II III IV V VI II II II II II II II II II

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM Toluene THF CH3Cl DCE CCl4 DCM DCM DCM DCM

88 95 95 84 93 73 83 81 71 85 88 85 80 90 95 90 80 60 88 90 75

>19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1

57 58 63 67 −53 7 −9 86 82 83 80 75 71 69 79 79 80 86 91 88 86

Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), catalyst (0.01 mmol), and solvent (2.0 mL). bIsolated yield. cDetermined by 1H NMR. Determined by HPLC. eThe reaction was performed at 0 °C. f1.0 mL of solvent was used. gWith 20 mol % catalyst. hWith 5 mol % catalyst.

d

promote the stereocontrolled construction of barbiturate-fused tetrahydropyrano scaffolds. We began our studies with commercially available N,N′dimethylbarbiturate 1a and the Morita−Baylis−Hillman (MBH) acetate of nitroalkene 2a.11 The bifunctional tertiary amine-thiourea, named Takeymoto’s catalyst, was used (20 mol %) to evaluate the feasibility of this reaction in dichloromethane at room temperature. The domino reaction proceeded smoothly to afford the desired product 3a in 88% yield with moderate enantioselectivity (57% ee) and excellent diastereoselectivity (dr >19:1) (Table 1, entry 1). Several tertiary amine-thioureas were screened, but only moderate enantiose-

lectivities were observed despite the excellent yields and diastereoselectivities (Table 1, entries 2−7). Then, a series of secondary amine-thiourea catalysts (II−VI) were synthesized and applied in this reaction. Encouragingly, the above reaction proceeded smoothly to afford compound 3a in 81% yield with good stereoselectivity (dr >19:1, 86% ee) using catalyst II in DCM at room temperature (Table 1, entry 8). These promising results can be attributed to the unique structure of the secondary amino-thiourea (with an additional NH group), which can provide an additional hydrogen-bonding group to form a more stable transition state in the catalytic process,10a,d leading to high enantioselectivity. The other secondary amino-thioureas were also examined, and their 13595

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry

of our knowledge, only few approaches have been reported on the synthesis of this important framework.14 As shown in Table 3, the desired products16 in high yields (80−92%) with

catalytic performances were inferior to that of catalyst II (Table 1, entries 9−12). Next, we investigated the influence of solvents, including THF, toluene, CH3Cl, DCE, CCl4, and DCM, of which DCM was found to be the best reaction medium (Table 1, entries 13−17). Furthermore, decreasing the temperature to 0 °C was inefficient for improving the enantioselectivity (Table 1, entry 18). Lowering the amount of solvent to 1.0 mL led to an improved yield and enantioselectivity (Table 1, entry 19). Interestingly, the catalyst loading affected the conversion but had no obvious influence on the stereoselectivity (Table 1, entries 20, 21). With the optimized conditions in hand, the scope of the reaction was examined, and the results are summarized in Table 2. All the substrates decorated with electron-donating or

Table 3. Scope of the Asymmetric Synthesis of Pyranocoumarinsa

entry

Ar

time (h)

product

yieldb

drc

eed

1 2 3 4 5 6 7 8 9 10 11 12 13

Ph 2a 4-FC6H4 2b 4-ClC6H4 2c 4-BrC6H4 2d 4-MeC6H4 2e 4-MeOC6H4 2f 3-BrC6H4 2g 3-MeOC6H4 2h 2-MeOC6H4 2i 2-ClC6H4 2j 2,4-Cl2C6H3 2k 1-naphthyl 2l 2-thienyl 2m

8 8 8 12 24 36 12 24 24 12 8 12 12

5a 5b 5c 5d 5ess 5f 5g 5h 5i 5j 5k 5l 5m

87 85 92 83 82 85 86 85 83 80 95 86 55

>19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1

91 80 86 81 92 92 91 92 93 93 90 91 87

Table 2. Scope of the Asymmetric Synthesis of BarbiturateFused Tetrahydropyrano Scaffoldsa

entry

Ar

time (h)

product

yieldb

drc

eed

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

Ph 2a 4-ClC6H4 2c 4-BrC6H4 2d 4-MeC6H4 2e 4-MeOC6H4 2f 3-BrC6H4 2g 3-MeOC6H4 2h 2-ClC6H4 2j 2,4-Cl2C6H3 2k 1-naphthyl 2l 2-thienyl 2m cyclohexyl 2n

12 12 24 24 36 24 36 24 12 12 36 72

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l

95 95 83 89 89 95 85 76 99 95 51 NRe

>19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >10:1 >19:1

91 91 93 96 97 92 89 84 99 94 89

a

Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), catalyst (0.01 mmol), and solvent (1.0 mL). bIsolated yield. cDetermined by 1H NMR. dDetermined by HPLC.

excellent enantioselectivities and diastereoselectivities (80−93% ee, dr >19:1) were achieved regardless of the modification of the MBH acetates of nitroalkenes 2 (Table 3, entries 1−10). High yields (up to 80%) with excellent stereoselectivities (91− 93% ee, dr >19:1) can also be maintained with the meta- and ortho-substituted 2 (Table 3, entries 7−10). The 2,4-dichlorosubstituted substrate smoothly underwent this transformation, affording the desired product in high yield (86%) with excellent enantioselectivity (90% ee) and diastereoselectivity (dr >19:1). The naphthyl- and heteroaromatic-substituted MBH acetates were also successfully applied in this reaction, accessing the corresponding products in good to high yields with excellent stereoselectivities (Table 3, entries 12, 13). The absolute configurations of compounds 3i (5R,6R) and 5j (3R,4R) were determined by X-ray analysis (Figure 2).17

a

Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), catalyst (0.01 mmol), and solvent (1.0 mL). bIsolated yield. cDetermined by 1H NMR. dDetermined by HPLC. eNo reaction.

electron-withdrawing groups on the aromatic ring of 2 underwent the domino reaction smoothly to yield the barbiturate-based tetrahydropyrano scaffolds in high yields with excellent diastereo- and enantioselectivities (dr >19:1, 91− 97% ee) (Table 2, entries 1−5). Meanwhile, the characteristics and locations of the substituents on the aromatic ring presented no obvious effects on the reaction stereoselectivity (dr >19:1, 89−96% ee) (Table 2, entries 6−8). Interestingly, when a more srerically hindered 1-naphthyl group was introduced into the MBH acetates, remarkable enantioselectivity and good yield were still obtained (Table 2, entry 10). In this regard, the heteroaryl MBH acetate of nitroalkene 2m was also a suitable substrate for this transformation, providing the corresponding product in moderate yield (51%) with good enantioselectivity (89% ee) (Table 2, entry 11). However, a cyclohexyl substituted aliphatic substrate was incompatible with this synthetic protocol probably attributed to its poor reactivity for the first Michael addition step (Table 2, entry 12). Finally, this synthetic protocol was successfully applied in the stereocontrolled construction of the pyranocoumarins.12 Pyranocoumarin compounds have potential applications in chemical biology and drug discovery, serving as promising candidates for serious disease treatment.13 However, to the best

Figure 2. X-ray crystal structures of compounds 3i and 5j. 13596

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry Scheme 1. Control Experiments and Proposed Mechanism

afford intermediate C, which allows for the formation of the desired product 5 via a subsequent intramolecular 6-endo-trig annulation reaction. The excellent diastereoselectivity can be explained by two different transition states of intermediate C (TS1 and TS2), in which the more stable TS1 can lead to the trans-isomer of the product. In summary, we disclosed a bifunctional secondary aminethiourea catalyst, which facilitated the Michael−Michael addition reaction between N,N′-dimethylbarbituric acid and MBH acetates of nitroalkenes. Barbiturate-fused tetrahydropyrano scaffolds were constructed in high yields with excellent stereoselectivities. Meanwhile, this synthetic protocol can also be applied to construct pharmaceutically important pyranocoumarin compounds. Further investigations of the secondary amine-thiourea catalyst used in other asymmetric transformations are ongoing in our laboratory.

We also carried out control experiments to illustrate the function of the NH group of secondary amino-thiourea catalyst (Scheme 1a) in our asymmetric transformations. The tertary amino-thiourea promote the reaction between 4 and 2a smoothly affording the desired product 5a in 95% yield with 61% ee, However, in the presence of primary amino-thiourea catalyst, this reaction became sluggish and the corresponding product was formed in 35% yield with only 6% ee. These results indicated that the NH group plays a crucial role in promoting this cascade reaction, in terms of both enantioselectivity and reactivity. Based on the above results and previous references,10a,d,11d,15f we proposed a plausible mechanism to account for the stereochemical outcome of the domino reaction. As depicted in Scheme 1b, intermediate A can be formed through a hydrogen-bonding interaction between the secondary amino-thiourea catalyst and substrate 4. Meanwhile, intermediate B can be realized in the same way, which can control the reaction enantioselectivity. The following intermolecular Michael addition and the removal of the catalyst can 13597

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry

■

5.03 (dt, J = 12.8, 2.06 Hz, 1H), 7.16 (q, J = 8.07 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ = 21.0, 28.1, 28.8, 37.4, 64.2, 82.2, 85.2, 127.5, 130.1, 136.5, 138.0, 150.7, 155.4, 161.7. IR (KBr): 2950, 1702, 1658, 1552, 1496, 1361, 1120, 985, 759 cm−1. HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C16H17N3O5Na 354.1060; Found 354.1064. HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 16.9 min, tminor = 9.9 min, ee = 96%. (5S,6R)-5-(4-Methoxyphenyl)-1,3-dimethyl-6-nitro-6,7-dihydro1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3e). White solid, mp 207−208.4 °C, 28.4 mg, 82% yield, [α]D25 = +153 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.30 (s, 3H), 3.42 (s, 3H), 3.79 (s, 3H), 4.34 (d, J = 12.1 Hz, 1H), 4.69 (s, 1H), 4.90 (s, 1H), 5.03 (d, J = 12.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H). 7.17 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 37.0, 55.4, 64.1, 82.2, 85.3, 114.8, 128.7, 131.3, 150.7, 155.4, 159.4, 161.7. IR (KBr): 2948, 1700, 1639, 1544, 1488, 1361, 1249, 1197, 988, 759 cm−1. HRMS (ESITOF) m/z: [M+Na]+ Calcd for C16H17N3O6Na 370.1010; found 370.1010. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 9.5 min, tminor = 8.7 min, ee = 97%. (5S,6R)-5-(3-Bromophenyl)-1,3-dimethyl-6-nitro-6,7-dihydro-1Hpyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3f). White solid, mp 105.4−106.1 °C, 37.5 mg, 95% yield, [α]D25 = +130 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.30 (s, 3H), 3.43 (s, 3H), 4.31 (dd, J = 12.9, 2.12 Hz, 1H), 4.70 (q, J = 1.8 Hz, 1H), 4.94 (s, 1H), 5.07 (dt, J = 12.8, 2.12 Hz, 1H), 7.23−7.29 (m, 2H). 7.39 (s, 1H) 7.45 (dt, J = 7.32, 1.54 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 37.4, 64.1, 81.7, 84.4, 123.6, 126.5, 130.6, 130.9, 131.4, 141.8, 150.6, 155.7, 161.7. IR (KBr): 2954, 1702, 1631, 1546, 1490, 1197, 983, 846, 748 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H14BrN3O5Na 418.0009; found 418.0009. HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 14.6 min, tminor = 10.3 min, ee = 92%. (5S,6R)-5-(3-Methoxyphenyl)-1,3-dimethyl-6-nitro-6,7-dihydro1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3g). White solid, mp 213.3-214.0 °C, 29.5 mg, 85% yield, [α]D25 = +157.6 (c = 1.0 DCM). 1 H NMR (400 MHz, CDCl3): δ = 3.30 (s, 3H), 3.43 (s, 3H), 3.82 (s, 3H), 4.37 (dd, J = 12.8, 2.16 Hz, 1H), 4.74 (q, J = 1.8 Hz, 1H), 4.94 (s, 1H), 5.05 (dt, J = 12.8, 2.06 Hz, 1H), 6.79 (s, 1H), 6.83−6.87 (m, 2H). 7.31 (t, J = 7.94 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 37.6, 55.4, 64.2, 81.9, 84.9, 112.8, 114.2, 119.8, 130.5, 130.9, 131.4, 141.1, 150.7, 155.4, 160.3, 161.7. IR (KBr): 2923, 1698, 1646, 1548, 1484, 1255, 1184, 971, 757 cm−1. HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C16H17N3O6Na 370.1010; Found 370.1012. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 9.7 min, tminor = 9.2 min, ee = 89%. (5R,6R)-5-(2-Chlorophenyl)-1,3-dimethyl-6-nitro-6,7-dihydro-1Hpyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3h). White solid, mp 94.0−95.0 °C, 30.2 mg, 86% yield, [α]D25 = +108 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.31 (s, 3H), 3.42 (s, 3H), 4.25 (dd, J = 12.8, 1.92 Hz, 1H), 4.83 (q, J = 1.6 Hz, 1H), 5.07 (dt, J = 12.8, 2.08 Hz, 1H), 5.31 (s, 1H), 7.06 (dd, J = 6.84, 2.4 Hz, 1H), 7.24−7.26 (m, 1H), 7.27−7.31 (m, 1H), 7.46 (dd, J = 7.08, 2.08 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 35.2, 64.6, 79.6, 84.5, 127.5, 129.0, 129.6, 130.6, 133.8, 136.2, 150.7, 156.1, 161.4. IR (KBr): 2975, 1714, 1637, 1546, 1490, 1191, 981, 752 cm−1. HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C15H14ClN3O5Na 374.0514; Found 374.0518. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.9 min, tminor = 11.1 min, ee = 96%. (5R,6R)-5-(2,4-Dichlorophenyl)-1,3-dimethyl-6-nitro-6,7-dihydro1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3i). White solid, mp 221.2−221.4 °C, 36.6 mg, 95% yield, [α]D25 = +87.7 (c = 1.0 DCM). 1 H NMR (400 MHz, CDCl3): δ = 3.31 (s, 3H), 3.41 (s, 3H), 4.22 (dd, J = 12.8, 2.04, Hz, 1H), 4.83 (q, J = 1.8 Hz, 1H), 5.10 (dt, J = 12.8, 2.14, Hz, 1H), 5.25 (s, 1H), 7.01 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 8.3, 2.08, Hz, 1H), 7.50 (d, J = 2.08 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 28.1, 29.1, 35.2, 64.9, 79.7, 83.8, 128.1, 129.6, 132.0, 133.6, 134.4, 136.6, 150.7, 156.9, 161.5. IR (KBr): 2950, 1706, 1637, 1552, 1488, 1189, 981, 755 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H13Cl2N3O5Na 408.0124; Found 408.0129. HPLC

EXPERIMENTAL SECTION

General Information. Unless otherwise indicated, all reactions were conducted under nitrogen atmosphere in an oven-dried glassware with magnetic stirring bar. Column chromatograph was performed with silica gel (200−300 mesh) and analytical TLC on silica gel 60F254. 1H NMR (400 MHz), 13C NMR (100 MHz, CDCl3) spectra were recorded on a Bruker Advance III spectrometer in CDCl3, with tetramethylsilane as an internal standard and reported in ppm (δ). Melting points were measured on a WRS-1B melting point apparatus and were uncorrected. High-resolution mass spectra (HRMS) were recorded on TOF-MS. HPLC analysis was performed on chiral column (Daicel chiralpak AS-H, IA and ID). The X-ray diffraction data were measured on a Bruker SMART APEX II CCD area detector system. Anhydrous THF and toluene were distilled from sodium and benzophenone. DCM, CH3CN, DCE were distilled from calcium hydride. Petroleum ether (PE), where used, has a boiling range of 60− 90 °C. General Procedure A: For the Synthesis of BarbiturateFused Tetrahydropyranos (3). To a mixture of 0.1 mmol 1,3dimethylbarbituric acid (1) and 0.12 mmol nitroalkenes (2) in anhydrous DCM (1.0 mL) was added 0.01 mmol catalyst. The reaction mixture was then stirred at r.t. until full consume of the starting 1,3-dimethylbarbituric acid as indicated by TLC. After removal of the solvent under reduced pressure, the crude material was subjected to column chromatography (silica gel, PE/EtOAc, 3:1 or DCM/EtOAc, 50:1) to afford the desired product. (5S,6R)-1,3-Dimethyl-6-nitro-5-phenyl-6,7-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3a). White solid, mp 105.7− 106.0 °C, 30.1 mg, 95% yield, [α]D25 = +117 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.31 (s, 3H), 3.43 (s, 3H), 4.35 (dd, J = 12.7, 2.2 Hz, 1H), 4.73 (q, J = 1.46 Hz, 1H), 4.97 (s, 1H), 5.05 (dt, J = 12.8, 2.12 Hz, 1H), 7.26 (s, 1H), 7.27 (s, 1H), 7.31 (d, J = 4.92 Hz, 1H), 7.38 (t, J = 4.96 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.8, 37.7, 64.2, 82.1, 84.9, 127.6, 128.2, 129.4, 139.4, 150.7, 155.5, 161.7. IR (KBr): 2960, 1704, 1648, 1552, 1492, 1375, 1199, 987, 759 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H15N3O5Na 340.0904, Found 340.0906. HPLC (Chiralpak AS-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 34 min, tminor = 28 min, ee = 91%. (5S,6R)-5-(4-Chlorophenyl)-1,3-dimethyl-6-nitro-6,7-dihydro-1Hpyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3b). White solid, mp 111−112.0 °C, 33.3 mg, 95% yield, [α]D25 = +137 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.30 (s, 3H), 3.42 (s, 3H), 4.31 (dd, J = 12.7, 2.2 Hz, 1H), 4.69 (q, J = 1.46 Hz, 1H), 4.93 (s, 1H), 5.06 (dt, J = 12.8, 2.14 Hz, 1H), 7.21 (dt, J = 8.48, 2.24 Hz, 2H), 7.35 (dt, J = 8.48, 2.24 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 64.1, 81.8, 84.7, 129.0, 129.6, 134.2, 129.6, 137.9, 150.6, 155.6, 161.6. IR (KBr): 2979, 1708, 1639, 1550, 1490, 1201, 989, 771 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H14ClN3O5Na 374.0514; Found 374.0514. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 10.2 min, tminor = 8.8 min, ee = 91%. (5S,6R)-5-(4-Bromophenyl)-1,3-dimethyl-6-nitro-6,7-dihydro-1Hpyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3c). White solid, mp 195−196 °C, 32.8 mg, 83% yield, [α]D25 = +143.7 (c = 1.0 DCM). 1 H NMR (400 MHz, CDCl3): δ = 3.30 (s, 3H), 3.42 (s, 3H), 4,30 (dd, J = 12.8, 2.12 Hz, 1H), 4.69 (q, J = 1.88 Hz, 1H), 4.91 (s, 1H), 5.06 (dt, J = 12.8, 2.1 Hz, 1H), 7.15 (d, J = 8.36 Hz, 2H), 7.51 (d, J = 8.36 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 37.3, 64.1, 81.7, 84.6, 122.3, 129.3, 132.5, 138.5, 150.6, 155.6, 161.5. IR (KBr): 2952, 1702, 1635, 1544, 1488, 1363, 1197, 983, 746 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H14BrN3O5Na 418.0009; Found 418.0008. HPLC (Chiralpak AS-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 30.5 min, tminor = 36.4 min, ee = 93%. (5S,6R)-1,3-Dimethyl-6-nitro-5-(p-tolyl)-6,7-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3d). White solid, mp 189−189.9 °C, 30.1 mg, 89% yield, [α]D25 = +101.4 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 3H), 3.30 (s, 3H), 3.42 (s, 3H), 4,34 (dd, J = 12.7, 2.16 Hz, 1H), 4.69 (q, J = 1.82 Hz, 1H), 4.92 (s, 1H), 13598

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry (Chiralpak IA, DCM/MeOH = 99/1, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.0 min, tminor = 9.0 min, ee = 99%. (5S,6R)-1,3-Dimethyl-5-(naphthalen-1-yl)-6-nitro-6,7-dihydro1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3j). White solid, mp >230 °C, 34.9 mg, 95% yield, [α]D25 = +164 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.32 (s, 3H), 3.47 (s, 3H), 4.30 (d, J = 12.8 Hz, 1H), 4.87 (s, 1H), 5.04 (d, J = 12.6 Hz, 1H), 5.78 (s, 1H), 7.18 (d, J = 6.92 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.42 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.16 Hz, 1H), 8.35 (d, J = 8.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.9, 34.7, 64.1, 80.1, 84.5, 121.9, 125.3, 125.5, 126.5, 127.7, 129.2, 129.5, 130.3, 134.4, 134.7, 150.7, 155.9, 161.6. IR (KBr): 2952, 1708, 1637, 1548, 1484, 1186, 981, 752 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H17N3O5Na 390.1060; Found 390.1061. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.9 min, tminor = 9.4 min, ee = 94%. (5S,6R)-1,3-Dimethyl-6-nitro-5-(thiophen-2-yl)-6,7-dihydro-1Hpyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (3k). White solid, mp 162−163 °C, 16.5 mg, 51% yield, [α]D25 = +144 (c = 1.0 DCM). 1 H NMR (400 MHz, CDCl3): δ = 3.32 (s, 3H), 3.40 (s, 3H), 4.55 (dd, J = 12.8, 2.16 Hz, 1H), 4.83 (q, J = 1.95 Hz, 1H), 5.12 (dt, J = 12.8, 2.04 Hz, 1H), 5.19 (s, 1H) 6.97−7.07(m, 2H) 7.24 (dd, J = 4.92, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 28.1, 28.8, 32.9, 64.6, 81.6, 86.2, 125.6, 126.2, 127.8, 143.4, 150.6, 155.1, 161.6. IR (KBr): 2944, 1704, 1637, 1552, 1488, 1191, 983, 744 cm−1. HRMS (ESITOF) m/z: [M+Na]+ Calcd for C13H13N3O5SNa 346.0468; Found 346.0472. HPLC (Chiralpak IA, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 9.2 min, tminor = 8.7 min, ee = 89%. General Procedure B: For the Synthesis of Pyranocoumarins (5). To a mixture of 0.1 mmol 4-hydroxycoumarin (4) and 0.12 mmol nitroalkenes (2) in anhydrous DCM (1.0 mL) was added 0.01 mmol catalyst. The reaction mixture was then stirred at r.t. until full consume of the starting 4-hydroxycoumarin as indicated by TLC. After removal of the solvent under reduced pressure, the crude material was subjected to column chromatography (silica gel, DCM/EtOAc, 50:1) to give the desired product. (3R,4S)-3-Nitro-4-phenyl-3,4-dihydropyrano[3,2-c]chromen5(2H)-one (5a). White solid, mp 58.5−59 °C, 28.1 mg, 87% yield, [α]D25 = +128 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.41 (dd, J = 12.9, 2.24 Hz, 1H), 4.85 (q, J = 1.9 Hz, 1H), 5.02 (s, 1H), 5.10 (dt, J = 12.9, 2.18, Hz, 1H), 7.28−7.40 (m, 7H), 7.57−7.62 (m, 1H), 7.84 (dd, J = 7.88, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 38.3, 62.8, 82.3, 99.2, 114.4, 116.9, 122.9, 124.3, 127.9, 128.3, 129.5, 132.6, 138.9, 152.8, 159.7, 161.2. IR (KBr): 1706, 1631, 1550, 1112, 1047, 977, 755 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H13NO5Na 346.0686; Found 346.0691. HPLC (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 18.6 min, tminor = 11.5 min, ee = 91%. (3R,4S)-4-(4-Fluorophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5b). White solid, mp 60.5−61.2 °C, 29 mg, 85% yield, [α]D25 = +118.4 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.40 (dd, J = 13.0, 2.3 Hz, 1H), 4.85 (q, J = 2.0 Hz, 1H), 5.00 (s, 1H), 5.13 (dt, J = 13.0, 2.2 Hz, 1H), 7.08 (t, J = 8.5 Hz, 2H), 7.25− 7.28 (m, 2H), 7.33−7.38 (m, 2H), 7.58−7.62 (m, 1H), 7.84 (dd, J = 7.88, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 37.6, 62.7, 82.2, 99.1, 114.3, 116.4, 116.5, 116.9, 122.9, 124.3, 129.5 (d, J = 8.2 Hz), 132.7, 134.7, 152.7, 159.8, 161.1, 163.7. IR (KBr): 1710, 1631, 1550, 1116, 1052, 983, 831 755 cm−1. HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C18H12FNO5Na 364.0591; Found 364.0581. HPLC (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 19.4 min, tminor = 10.7 min, ee = 81%. (3R,4S)-4-(4-Chlorophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5c). White solid, mp 50.2−51 °C, 32.8 mg, 92% yield, [α]D25 = +145 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.38 (dd, J = 12.9, 2.2 Hz, 1H), 4.81 (q, J = 1.9 Hz, 1H), 4.99 (s, 1H), 5.13 (dt, J = 13.0, 2.2 Hz, 1H), 7.22 (s, 1H), 7.25 (s, 1H), 7.33− 7.38 (m, 4H), 7.59−7.63 (m, 1H), 7.83 (dd, J = 7.88, 1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 37.8, 62.8, 82.0, 98.8, 114.3, 116.9, 122.9, 124.4, 129.3, 129.7, 132.8, 134.4, 137.4, 152.8, 159.9, 161.0. IR (KBr): 1704, 1629, 1552, 1112, 1049, 981, 755 cm−1. HRMS (ESI-

TOF) m/z: [M+Na]+ Calcd for C18H12ClNO5Na 380.0296; Found 380.0296. HPLC (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 19.6 min, tminor = 10.8 min, ee = 86%. (3R,4S)-4-(4-Bromophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5d). White solid, mp 98−99 °C, 33.5 mg, 83% yield, [α]D25 = +182 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.37 (dd, J = 13, 2.2 Hz, 1H), 4.80 (q, J = 1.92 Hz, 1H), 4.98 (s, 1H), 5.13 (dt, J = 13, 2.24 Hz, 1H), 7.17 (s, 1H), 7.19 (s, 1H), 7.33− 7.38 (m, 2H), 7.50 (t, J = 2.2 Hz, 1H), 7.53 (t, J = 2.2 Hz, 1H), 7.83 (dd, J = 7.88, 1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 37.8, 62.8, 82.0, 98.8, 114.3, 116.9, 122.9, 124.4, 129.3, 129.7, 132.8, 134.4, 137.4, 152.8, 159.9, 161.0. IR (KBr): 1704, 1631, 1552, 1110, 1051, 981, 761 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H12BrNO5Na 425.9772; Found 425.9773. HPLC (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 20.2 min, tminor = 10.9 min, ee = 82%. (3R,4S)-3-Nitro-4-(p-tolyl)-3,4-dihydropyrano[3,2-c]chromen5(2H)-one(5e). White solid, mp 88.7−89 °C, 27.6 mg, 82% yield, [α]D25 = +178 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3H), 4.40 (dd, J = 12.8, 2.2 Hz, 1H), 4.82 (q, J = 1.96, 1H), 4.97 (s, 1H), 5.10 (dt, J = 12.9, 2.16 Hz, 1H), 7.14−7.19 (m, 4H), 7.32−7.37 (m, 2H), 7.57−7.61 (m, 1H), 7.83 (dd, J = 7.88, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 21.1, 37.9, 62.8, 82.4, 99.4, 114.5, 116.9, 122.8, 124.2, 127.8, 130.1, 132.5, 135.9, 138.1, 152.8, 159.6, 161.2. IR (KBr): 1712, 1631, 1548, 1114, 1045, 979, 754 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H15NO5Na 360.0842; Found 360.0849. HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 14.2 min, tminor = 9.5 min, ee = 92%. (3R,4S)-4-(4-Methoxyphenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5f). White solid, mp 79−80 °C, 30 mg, 85% yield, [α]D25 = +71 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.79 (s, 3H), 4.41 (dd, J = 12.9, 2.2 Hz, 1H), 4.81 (q, J = 1.97, 1H), 4.95 (s, 1H), 5.10 (dt, J = 12.9, 2.2 Hz, 1H), 6.88 (t, J = 3.0 Hz, 1H), 6.91 (t, J = 3.0 Hz, 1H), 7.18 (t, J = 2.9 Hz, 1H), 7.20 (t, J = 2.9 Hz, 1H), 7.32−7.37 (m, 1H), 7.57−7.61 (m, 1H), 7.83 (dd, J = 7.88, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 37.6, 55.4, 62.8, 82.4, 99.5, 114.5, 114.8, 116.8, 122.8, 124.2, 129.0, 130.8, 152.7, 159.5, 159.6, 161.2. IR (KBr): 1716, 1631, 1552, 1257, 1116, 1052, 987, 755 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H15NO6Na 376.0792; Found 376.0795. HPLC (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 21.2 min, tminor = 11.5 min, ee = 92%. (3R,4S)-4-(3-Bromophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5g). White solid, mp 93.7−95 °C, 34.6 mg, 87% yield, [α]D25 = +183 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.38 (dd, J = 13, 2.2 Hz, 1H), 4.83 (q, J = 1.97, 1H), 4.99 (s, 1H), 5.14 (dt, J = 13, 2.1 Hz, 1H), 7.23−7.29 (m, 2H), 7.34−7.39 (m, 2H), 7.41 (s, 1H), 7.46 (dt, J = 7.2, 1.6 Hz, 1H), 7.60−7.64 (m, 1H), 7.84 (dd, J = 7.84, 1.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 37.9, 62.8, 81.9, 98.6, 114.3, 116.9, 122.9, 123.6, 124.4, 126.7, 130.9, 131.0, 131.6, 132.8, 141.2, 152.8, 160.0, 161.0. IR (KBr): 1700, 1627, 1546, 1259, 1110, 1047(−O-C = C), 977, 858, 754 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H12BrNO5Na 425.9772; Found 425.9773. HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm): tmajor = 16.0 min, tminor = 11.2 min, ee = 90%. (3R,4S)-4-(3-Methoxyphenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5h). White solid, mp 84.4−85.2 °C, 30 mg, 85% yield, [α]D25 = +133 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.79 (s, 3H), 4.42 (dd, J = 12.9, 2.24 Hz, 1H), 4.85 (q, J = 1.89, 1H), 4.98 (s, 1H), 5.11 (dt, J = 13, 2.16 Hz, 1H), 6.80 (t, J = 1.92 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 6.84 (d, J = 2.36 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.57−7.61 (m, 1H), 7.83 (dd, J = 7.88, 1.44 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 38.2, 55.4, 62.9, 82.2, 99.1, 113.0, 114.3, 114.4, 116.9, 120.1, 122.9, 124.3, 130.5, 132.6, 140.6, 152.8, 159.7, 160.3, 161.2. IR (KBr): 1708, 1629, 1550, 1261, 1116, 1052, 991, 759 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H15NO6Na 376.0792; Found 376.0795. HPLC 13599

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry (Chiralpak ID, DCM/hexane = 80/20, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 16.1 min, tminor = 11.9 min, ee = 92%. (3R,4S)-4-(2-Methoxyphenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5i). White solid, mp 198.2−199 °C, 29.3 mg, 83% yield, [α]D25 = +113 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 3.94 (s, 3H), 4.30 (dd, J = 12.7, 1.8 Hz, 1H), 4.97 (q, J = 1.64, 1H), 5.06 (dt, J = 12.8, 2.04 Hz, 1H), 5.29 (s, 1H), 6.88−6.97 (m, 3H), 7.29−7.38 (m, 3H), 7.57−7.61 (m, 1H), 7.81 (dd, J = 7.88, 1.16 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 32.9, 55.6, 63.7, 79.9, 99.3, 110.8, 114.6, 116.9, 120.9, 122.8, 124.2, 126.4, 128.6, 129.5, 132.4, 152.8, 156.5, 160.2, 161.2. IR (KBr): 1720, 1635, 1550, 1247, 1128, 1056, 987, 759 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H15NO6Na 376.0792; Found 376.0796. HPLC (Chiralpak ID, DCM, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 9.3 min, tminor = 7.4 min, ee = 93%. (3R,4R)-4-(2-Chlorophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5j). White solid, mp >230 °C, 27.4 mg, 80% yield, [α]D25 = +172 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.30 (dd, J = 12.9, 2.0 Hz, 1H), 4.96 (q, J = 1.64, 1H), 5.14 (dt, J = 12.9, 2.12 Hz, 1H), 5.37 (s, 1H), 7.06 (dd, J = 7.6, 1.4 Hz, 1H), 7.23 (td, J = 7.48, 1.12 Hz, 1H), 7.30 (td, J = 7.68, 1.56 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.84, 1.16 Hz, 1H), 7.59−7.63 (m, 1H), 7.83 (dd, J = 7.88, 1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 35.8, 63.2, 79.8, 98.7, 114.3, 116.9, 122.8, 124.3, 127.6, 129.3, 129.7, 130.7, 132.7, 133.9, 135.9, 152.8, 160.4, 160.9. IR (KBr): 1710, 1637, 1556, 1191, 1049, 989, 761 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H12ClNO5Na 380.0296; Found 380.0299. HPLC (Chiralpak ID, DCM, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.7 min, tminor = 9.7 min, ee = 94%. (3R,4R)-4-(2,4-Dichlorophenyl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5k). White solid, mp 189−190 °C, 37 mg, 95% yield, [α]D25 = +156 (c = 0.9 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.27 (dd, J = 13, 1.76 Hz, 1H), 4.91 (q, J = 1.88, 1H), 5.16 (dt, J = 13, 2.2 Hz, 1H), 5.31 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.4, 2.12 Hz, 1H), 7.33−7.39 (m, 2H), 7.52 (d, J = 2.12 Hz, 1H), 7.60−7.64 (m, 1H), 7.83 (dd, J = 7.88, 1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 35.5, 63.1, 79.5, 98.4, 114.2, 116.9, 122.9, 124.4, 127.9, 130.1, 130.5, 132.9, 134.5, 134.6, 135.2, 152.8, 160.6, 160.8. IR (KBr): 1700, 1627, 1550, 1114, 1049 981, 750 cm−1. HRMS (ESITOF) m/z: [M+Na]+ Calcd for C18H11Cl2NO5Na 413.9906; Found 413.9915. HPLC (Chiralpak ID, DCM, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.9 min, tminor = 9.0 min, ee = 90%. (3R,4S)-4-(Naphthalen-1-yl)-3-nitro-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5l). White solid, mp 217−219 °C, 32.1 mg, 86% yield, [α]D25 = +96.6 (c = 0.6 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.37 (d, J = 13 Hz, 1H), 5.01 (s 1H), 5.16 (d, J = 13 Hz, 1H), 5.87 (s, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.38−7.43 (m, 3H), 7.63 (q, J = 8.6 Hz, 2H), 7.73 (t, J = 7.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 35.2, 62.8, 80.4, 98.9, 99.9, 114.5, 116.9, 121.9, 122.9, 124.3, 125.3, 125.9, 126.5, 127.8, 129.3, 129.6, 130.3, 132.6, 134.4, 152.8, 160.2, 161.0. IR (KBr): 1695, 1627, 1546, 1118, 1051, 981, 773 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H15NO5Na 396.0842; Found 396.0847. HPLC (Chiralpak ID, DCM, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 7.8 min, tminor = 8.9 min, ee = 92%. (3R,4S)-3-Nitro-4-(thiophen-2-yl)-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5m). White solid, mp 49−50 °C, 18.1 mg, 55% yield, [α]D25 = +138.4 (c = 1.0 DCM). 1H NMR (400 MHz, CDCl3): δ = 4.60 (dd, J = 12.7, 2.24 Hz, 1H), 4.98 (q, J = 2.0, 1H), 5.18 (dt, J = 12.9, 2.12 Hz, 1H), 5.23 (s, 1H), 6.9−7.0 (m, 2H), 7.28 (dd, J = 4.8 1.56 Hz, 1H), 7.31−7.37 (m, 2H), 7.59 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.85 (dd, J = 7.9, 1.52 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 33.4, 63.3, 81.8, 100, 114.4, 116.9, 122.9, 124.2, 125.9, 126.7, 127.6, 132.7, 142.2, 152.7, 159.1, 161.0. IR (KBr): 1704, 1641, 1550, 981, 840, 727 cm−1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H11NO5SNa: 352.0250; Found 352.0253. HPLC (Chiralpak ID, DCM, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 15.7 min, tminor = 11.1 min, ee = 87%.

Control Experiments Information. Under nitrogen atmosphere, 0.01 mmol catalyst was added to a mixture of (16.2 mg 0.1 mmol) 4hydroxycoumarin (4) and (26.5 mg 0.12 mmol) nitroalkenes (2a) in anhydrous DCM (1.0 mL). Then the reaction mixture was stirred at r.t. until full consume of the starting 4-hydroxycoumarin as indicated by TLC. After removal of the solvent under reduced pressure, the crude material was subjected to column chromatography (silica gel, DCM/EtOAc, 50:1) to afford the desired product.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01902. 1 H and 13CNMR spectra and HPLC analysis (PDF) X-ray crystallographic data for compound 3i (CIF) X-ray crystallographic data for compound 5j (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Ligong Chen: 0000-0002-3442-5694 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (NSFC) (grant number 21476163).

■

REFERENCES

(1) (a) Johns, M. W. Drugs 1975, 9, 448−478. (b) Gulliya, K. S. Anti-Cancer Uses for Barbituric Acid Analogs. U.S. PatentUS5674870A, Oct 7, 1997. (c) Guerin, D. J.; Mazeas, D.; Musale, M. S.; Naguib, F. N. M.; Al Safarjalani, O. N.; el Kouni, M. H.; Panzica, R. P. Bioorg. Med. Chem. Lett. 1999, 9, 1477−1480. (d) Singh, P.; Kaur, M.; Verma, P. Bioorg. Med. Chem. Lett. 2009, 19, 3054−3058. (e) Dhorajiya, B. D.; Ibrahim, A. S.; Badria, F. A.; Dholakiya, B. Z. Med. Chem. Res. 2014, 23, 839−847. (f) Penthala, N. R.; Ketkar, A.; Sekhar, K. R.; Freeman, M. L.; Eoff, R. L.; Balusu, R.; Crooks, P. A. Bioorg. Med. Chem. 2015, 23, 7226−7233. (2) (a) Zeng, M.; You, S.-L. Synlett 2010, 2010, 1289−1301. (b) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 2, 187−220. (c) Dong, S. H.; Nikolić, D.; Simmler, C.; Qiu, F.; van Breemen, R. B.; Soejarto, D. D.; Pauli, G. F.; Chen, S.-N. J. Nat. Prod. 2012, 75, 2168− 2177. (3) Singh, H.; Sindhu, J.; Khurana, J. M.; Sharma, C.; Aneja, K. R. Eur. J. Med. Chem. 2014, 77, 145−154. (4) Venkatesham, A.; Rao, R. S.; Nagaiah, K.; Yadav, J. S.; RoopaJones, G.; Basha, S. J.; Sridhar, B.; Addlagatta, A. MedChemComm 2012, 3, 652−658. (5) (a) Kalaria, P. N.; Satasia, S. P.; Raval, D. K. New J. Chem. 2014, 38, 1512−1521. (b) Subba Reddy, B. V.; Divya, B.; Swain, M.; Rao, T. P; Yadav, J. S.; VishnuVardhan, M. V. P. S. Bioorg. Med. Chem. Lett. 2012, 22, 1995−1999. (c) Pałasz, A.; Kalinowska-Tłuścik, J.; Jabłoński, M. Tetrahedron 2013, 69, 8216−8227. (6) For selected examples of asymmetric synthesis of barbituratefused skeletons see: (a) Ruble, J. C.; Hurd, A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn, M. R.; Toogood, P. L.; Bundy, G. L.; Graber, D. R.; Kamilar, G. M. J. Am. Chem. Soc. 2009, 131, 3991−3997. (b) Liu, H.; Liu, Y.; Yuan, C.; Wang, G.-P.; Zhu, S.-F.; Wu, Y.; Wang, B.; Sun, Z.; Xiao, Y.; Zhou, Q.-L.; Guo, H. Org. Lett. 2016, 18, 1302− 1305. (c) Zhao, H.-W.; Tian, T.; Pang, H.-L.; Li, B.; Chen, X.-Q.; Yang, Z.; Meng, W.; Song, X.-Q.; Zhao, Y.-D.; Liu, Y.-Y. Adv. Synth. 13600

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601

Note

The Journal of Organic Chemistry Catal. 2016, 358, 2619−230. (d) Liu, Y.; Yang, W.; Wu, Y.; Mao, B.; Gao, X.; Liu, H.; Sun, Z.; Xiao, Y.; Guo, H. Adv. Synth. Catal. 2016, 358, 2867−2872. (7) For selected examples see: (a) Wang, P.; Zhao, J. Z.; Li, H. F.; Liang, X. M.; Zhang, Y. L.; Da, C. S. Tetrahedron Lett. 2017, 58, 129− 133. (b) Wang, F. Q.; Yang, H.; He, B.; Jia, Y. K.; Meng, S. Y.; Zhang, C.; Liu, H. M.; Liu, F. W. Tetrahedron 2016, 72, 5769−5775. (c) Kim, C.-E.; Park, Y.; Park, S.; Lee, P. H. Adv. Synth. Catal. 2015, 357, 210− 220. (d) Ascic, E.; Ohm, R. G.; Petersen, R.; Hansen, M. R.; Hansen, C. L.; Madsen, D.; Tanner, D.; Nielsen, T. E. Chem. - Eur. J. 2014, 20, 3297−3300. (e) Enders, D.; Grossmann, A.; Gieraths, B.; Düzdemir, M.; Merkens, C. Org. Lett. 2012, 14, 4254−4257. (8) For selected reviews on chiral thiourea catalysis: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (b) Fang, X.; Wang, C. J. Chem. Commun. 2015, 51, 1185−1197. (c) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369−1378 For selected examples see. (d) Yang, G.; Du, J. W.; Chen, Y. C. J. Org. Chem. 2016, 81, 10056−10061. (e) Qiu, S.; Lee, R.; Zhu, B.; Coote, M. L.; Zhao, X.; Jiang, Z. J. Org. Chem. 2016, 81, 8061−8069. (f) Yang, C.; Zhang, E. G.; Li, X.; Cheng, J. P. Angew. Chem., Int. Ed. 2016, 55, 6506−6510. (g) Duan, J.; Cheng, Y.; Cheng, J.; Li, R.; Li, P. Chem. - Eur. J. 2017, 23, 519−523. (h) Liu, T.; Zhou, M.; Yuan, T.; Fu, B.; Wang, X.; Peng, F.; Shao, Z. Adv. Synth. Catal. 2017, 359, 89−95. (9) (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170−7171. (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366−6370. (c) Zhang, H.; Chuan, Y.; Li, Z.; Peng, Y. Adv. Synth. Catal. 2009, 351, 2288−2294. (d) Shen, Z. X.; Zhang, Y. Q.; Jiao, C. J.; Li, B.; Ding, J.; Zhang, Y. W. Chirality 2007, 19, 307−312. (e) Cao, C.-Li.; Sun, X.-L.; Zhou, J.-L.; Tang, Y. J. Org. Chem. 2007, 72, 4073−4076. (f) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901−2904. (10) (a) Han, B.; Liu, Q. P.; Li, R.; Tian, X.; Xiong, X. F.; Deng, J. G.; Chen, Y. C. Chem. - Eur. J. 2008, 14, 8094−8097. (b) Li, D. R.; He, A.; Falck, J. R. Org. Lett. 2010, 12, 1756−1759. (c) Meninno, S.; Croce, G.; Lattanzi, A. Org. Lett. 2013, 15, 3436−3439. (d) Bellavista, T.; Meninno, S.; Lattanzi, A.; Sala, G. D. Adv. Synth. Catal. 2015, 357, 3365−3373. (11) For reviews of MBH carbonates and acetates see Rios, R. Catal. Sci. Technol. 2012, 2, 267−278 For selected examples of MBH acetates of nitroalkenes see. (a) Cao, C. L.; Zhou, Y. Y.; Zhou, J.; Sun, X. L.; Tang, Y.; Li, Y. X.; Li, G. Y.; Sun, J. Chem. - Eur. J. 2009, 15, 11384− 11389. (b) Nair, D. K.; Menna-Barreto, R. F. S.; da Silva Júnior, E. N.; Mobin, S. M.; Namboothiri, I.i N. N Chem. Commun. 2014, 50, 6973− 6976. (c) Gopi, E.; Namboothiri, I. N. N J. Org. Chem. 2014, 79, 7468−7476. (d) Zheng, Y.; Cui, L.; Wang, Y.; Zhou, Z. J. Org. Chem. 2016, 81, 4340−4346. (e) Xiao, W.; Yin, X.; Zhou, Z.; Du, W.; Chen, Y. C. Org. Lett. 2016, 18, 116−119. (f) Shu, T.; Ni, Q.; Song, X.; Zhao, K.; Wu, T.; Puttreddy, R.; Rissanen, K.; Enders, D. Chem. Commun. 2016, 52, 2609−2611. (g) Liu, J. Y.; Zhao, J.; Zhang, J. L.; Xu, P. F. Org. Lett. 2017, 19, 1846−1849. (12) (a) Murray, R. D. H.; Medez, J.; Brown, S. A. The Natural Coumarins; Wiley: New York, 1982. (b) Ishikawa, T. Heterocycles 2000, 53, 453−474. (c) Melliou, E.; Magiatis, P.; Mitaku, S.; Skaltsounis, A.L.; Chinou, E.; Chinou, I. J. Nat. Prod. 2005, 68, 78−82. (d) Emmadi, N. R.; Atmakur, K.; Chityal, G. K.; Pombala, S.; Nanubolu, J. B. Bioorg. Med. Chem. Lett. 2012, 22, 7261−7264. (13) (a) Xu, Z.-Q.; Pupek, K.; Suling, W. J.; Enache, L.; Flavin, M. T. Bioorg. Med. Chem. 2006, 14, 4610−4626. (b) Zhou, X.; Wang, X. B.; Wang, T.; Kong, L.-Y. Bioorg. Med. Chem. 2008, 16, 8011−8021. (14) (a) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal. 2008, 350, 2127−2131. (b) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem. - Eur. J. 2010, 16, 13068−13071. (c) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Org. Lett. 2011, 13, 4382−4385. (15) Sagar, R.; Park, J.; Koh, M.; Park, S. B. J. Org. Chem. 2009, 74, 2171−2174. (e) Singh, S.; Srivastava, A.; Mobin, S. M.; Samanta, S. RSC Adv. 2015, 5, 5010−5014. (f) Gurubrahamam, R.; Gao, B.-F.; Chen, Y.; Chan, Y.-T.; Tsai, M.-K.; Chen, K. Org. Lett. 2016, 18, 3098−3101. (g) Ren, C.; Wei, F.; Xuan, Q.; Wang, D.; Liu, L. Adv. Synth. Catal. 2016, 358, 132−137.

(16) Note: the purified compound 5 is found to be racemized very easily at room temperature. (17) CCDC 1558022 and 1558021 contains the supplementary crystallographic data for compounds 3i and 5j. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

13601

DOI: 10.1021/acs.joc.7b01902 J. Org. Chem. 2017, 82, 13594−13601