Cu-Mediated Stereoselective [4+2] Annulation between N

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Cu-Mediated Stereoselective [4+2] Annulation Between N-Hydroxybenzimidoyl Cyanide and Norbornene Kui Liu, Zhen-Bang Chen, Fang-Ling Zhang, Chun Qian, Shou-Wei Tao, Qiong Ming Xu, and Yong-Ming Zhu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01081 • Publication Date (Web): 15 Jun 2018 Downloaded from http://pubs.acs.org on June 15, 2018

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The Journal of Organic Chemistry

Cu-Mediated Stereoselective [4+2] Annulation Between N-Hydroxybenzimidoyl Cyanide and Norbornene Kui Liu, Zhen-Bang Chen, Fang-Ling Zhang, Chun qian, Shou-Wei Tao Qiong-Ming, Xu and Yong-Ming Zhu* College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

ABSTRACT: A Cu-mediated stereoselective [4+2] annulation between N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been developed for the synthesis of 4H-1,2-oxazin-4-ones. The reaction proceeds through sequentially forming C-O/C-C bond. The advantage of this reaction includes high stereoselectivity, excellent yields, as well as simple and mild reaction conditions. A total of 26 examples are presented along with some control experiments. Introduction Cycloaddition, in which multiple bonds are formed in a single step, has become increasingly popular among synthetic chemists not only owing to

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the advantages of a high degree of regioselectivity and stereoselectivity, atom economy, but the rapid assembly of complex and diverse carbo- and heterocyclic systems.1-4 Particular members of the cycloaddition family are [2 + 2], [3 + 2] and [4 + 2] variants.5 Since the initial work of Diels and Alder, the utility of [4+2] cycloaddition in formation of six-membered rings has been widely explored. Besides, norbornene (NBE) and norbomadiene (NBD) are an important class of organic molecules which have been widely applied in cycloaddition, especially in the homo Diels-Alder (HDA) reaction.6 However, these classical approaches suffer from cost of the catalytic systems, various competing cycloaddition reactions, and lower yield. Therefore, it is of considerable interest to develop a low-cost metals catalytical cycloaddition reaction of NBE and NBD which selectively generate single cycloadducts in high yield. Oximes and their derivatives are valuable synthetic building blocks as they can be easily transformed into ketones,7 amides,8 and nitriles.9 Moreover, they can also serve as internal oxidants and have been used as substrates for transition-metal-catalyzed C−H activation.10 Nevertheless, the most achievements mainly focus on the utility of oximes as the precursors of 1, 3-dipolar for the synthesis of oxygen/nitrogen-containing compounds.11 Only a few examples of cycloaddition of oximes have been reported. For instance, in 2012, Cheng12 reported nickel-catalyzed cycloaddition of ortho-iodoketoximes and ortho-iodoketimines with


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alkynes for synthesis of isoquinolines and isoquinolinium salts (Scheme 1a). At the same year, Rodrí guez-Borges13 presented boron-mediated cycloadditions between methyl glyoxylate oxime and cyclopentadiene or cyclopentene for synthesis of isoxazolidine (Scheme 1b). In 2016, Deng and Jiang14 developed palladium-catalyzed cycloaddition of aryloxime with vinyl azides for the synthesis of isoquinolines (Scheme 1c). On the other hand, oxazin-4-ones are important heterocyclic scaffolds that occur in many natural products, pharmaceuticals and materials.15 Seminal work by the group of Li reported [4+2] annulation of arylalkynes with tert-butyl nitrite to assemble benzo[e][1,2]oxazin-4-ones (Scheme 1d).16 Given the N-hydroxybenzimidoyl cyanides have never been previously reported as substrates for NBE cycloaddition. Herein, we report a new Cu-mediated [4+2] annulation protocol to assemble [1, 2]oxazin-4-ones (Scheme 1e), where NBE serve as 2-carbon units for reaction with N-hydroxybenzimidoyl cyanides through the formation of C=O double bond, C-C single bond and C-O single bond. Scheme 1. Cycloaddition of Oximes



Results and discussion Initial studies began with employing N-hydroxybenzimidoyl cyanide (1a), and NBE (2) as the standard substrates in the presence of Pd(OAc) 2 (5% mmol), Cu(OTf)2 (1.5 equiv) and Cs2CO3 (2 equiv) in toluene for 24 h, and the desired product was obtained in 55% yield (Table 1, entry 1). It should be noted that this reaction is highly stereoselective, with the ACS Paragon Plus Environment

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product existing only as cis-conformers. The result was validated by NOESY analysis. In NOESY, there has correlation between the hydrogens H-C4a and H-C8a, and the coupling constants between hydrogens H-C4a and H-C8a is 5.3 Hz (see supporting information). The product is a racemate, which was supported by the test of optical rotations. More surprisingly, with stoichiometric copper, this reaction could still proceed very smoothly without palladium, leading to more green and economic synthetic chemistry (Table 1, entries 2 and 3). Screening of various bases revealed that NaOAc was optimal to give the target product in 62% yield (Table 1, entries 4-10). Compared with CuCl2·2H2O, other copper source such as Cu(OAc)2, Cu(TFA)2, and CuI resulted in diminished yields (Table 1, entries 11-14). Subsequently, other solvents were also tested to improve the yield further. However, none of them were superior to toluene (Table 1, entries 15-18). Gratifyingly, the yield was dramatically improved to 81% when DCE/ toluene (v:v=1:1) was used as a mixed solvent (Table 1, entry 19). Replacing the CuCl2·2H2O by AgOAc led to decrease in the yield (Table 1, entry 20). The reaction was entirely hampered after CuCl2·2H2O was switched to FeCl3 or ZnCl2 (Table 1, entries 21 and 22). The decrease in the amount of CuCl2·2H2O to 1 equiv was not beneficial to the formation of 2a (Table 1, entry 23). Further investigation found that using catalytic CuCl2·2H2O (20%) with K2S2O8 (2 equiv) or O2 as the oxidant were less effective (Table 1 entries



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24 and 25) Table 1. Optimization of Reaction Conditionsa

Entry

[Cu]

base

solvent

Yield(%)b

1

Cu(OTf)2

Cs2CO3

toluene

55c

2

-

Cs2CO3

toluene

n.d

3

Cu(OTf)2

Cs2CO3

toluene

57

4

Cu(OTf)2

K2CO3

toluene

26

5

Cu(OTf)2

NaOAc

toluene

62

6

Cu(OTf)2

KF

toluene

20

7

Cu(OTf)2

K3PO4

toluene

49

8

Cu(OTf)2

HCOONa

toluene

10

9

Cu(OTf)2

Et3N

toluene

trace

10

Cu(OTf)2

-

toluene

13

11

Cu(OAc)2

NaOAc

toluene

57

12

Cu(TFA)2

NaOAc

toluene

63

13

CuI

NaOAc

toluene

15

14

CuCl2·2H2O

NaOAc

toluene

70

15

CuCl2·2H2O

NaOAc

1.4-dioxane

41


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16

CuCl2·2H2O

NaOAc

THF

20

17

CuCl2·2H2O

NaOAc

DMF

10

18

CuCl2·2H2O

NaOAc

DCE

15

19

CuCl2·2H2O

NaOAc

DCE/ Tol

81

20

AgOAc

NaOAc

DCE/ Tol

45

21

FeCl3

NaOAc

DCE/ Tol

n.d

22

ZnCl2

NaOAc

DCE/ Tol

n.d

23

CuCl2·2H2O

NaOAc

DCE/ Tol

70

24

CuCl2·2H2O

NaOAc

DCE/ Tol

47d

25

CuCl2·2H2O

NaOAc

DCE/ Tol

39e

a

General conditions: the reactions were run on a 0.5 mmol scale in

solvent (2 mL), NBE (1 equiv.), [Cu] (1.5 equiv.), base (2 equiv.) under nitrogen in a sealed tube at 100oC for 24 h. bIsolated yields. c5% mol Pd(OAc)2 were added. dUsing 20% CuCl2·2H2O and 2 equiv. K2S2O8. e

Using 20% CuCl2·2H2O and purged with O2.

With the optimized conditions in hand, we examined the scope of this [4+2] annulation protocol with a wide range of oximes (Table 2). Various N-hydroxybenzimidoyl cyanides with electron-neutral (2q, 2j) or electron-donating (2d-2g, 2n) or electron–withdrawing groups (2b, 2c, 2h, 2i etc) reacted smoothly with NBE, and moderate to good yields were



achieved.

However,

due

to

the

effect

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of

steric

hindrance,

N-hydroxybenzimidoyl cyanides with substituted o-methyl (2l) and ohalogen (2k, 2m) afforded lower yields. It is noted that heterocyclic substrates were less compatible with this reaction. Product 2r was still obtained in 27% yield from an electron-rich cyclic substrate such as N-hydroxythiophene-3-carbimidoyl cyanide, while no product was detected using an electron-deficient heteroatomic ring as substrate, e.g. N-hydroxypicolinimidoyl cyanide (2t). Table

2.

[4+2]

cycloadditions

of

N-hydroxybenzimidoyl cyanide with NBE a, b.


various

substituted

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a

All reactions were performed under nitrogen on a 0.5 mmol scale in

DCE/Tol (v:v=1:1, 2 mL), NBE (1 equiv.), CuCl2·2H2O (1.5 equiv.), NaOAc (2 equiv.) in a sealed tube at 100oC for 24 h. bIsolated yields. Further experiments were conducted to examine the compatibility of this reaction with respect to other olefins. As shown in table 3, the



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norbomadiene (NBD), as active as NBE, could transform to corresponding products by reacting with electron-poor or electron-rich N-hydroxybenzimidoyls

cyanides,

but

the

N-hydroxybenzimidoyl

cyanides with electron-donating groups (3b, 3e) gived much better results than the substrates with electron-withdrawing groups (3c, 3d). However, when cyclopentene was employed, the corresponding cyclization product 3f was obtained with only 21% yield. Unfortunately, the annulation of cyclohexene (3aa) and its other synthetic equivalents (1-decene 3ab, (Z)-1,2-diphenylethene 3ac) failed, and the phenylacetylene (3ad) also showed a sluggish reaction. Table

3.

[4+2]

cycloadditions

of

various

N-hydroxybenzimidoyl cyanidea, b


olefins

with

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Unsuccessful examples

a

All reactions were performed under nitrogen on a 0.5 mmol scale in

DCE/Tol (v:v=1:1, 2 mL), norbomadiene (1 equiv.), CuCl2·2H2O (1.5 equiv.), NaOAc (2 equiv.) in a sealed tube at 100oC for 24 h. bIsolated yields. Finally, some control experiments were performed to gain some insight into the reaction mechanism. Firstly, under the optimal conditions, a trace amount of 2a was observed using the N-acetoxybenzimidoyl cyanide as the substrate, indicating that –OH is necessary in this transformation (route a in scheme 2). In the absence of the NBE, 4a was obtained, which showed that –CN could be hydrolyzed easily under this condition (route b in scheme 2). Additionally, considering the precedent literatures,17 we envisioned that whether the reaction proceed through the radical pathway. However,

when

a

radical-trapping

reagent

TEMPO

(2,2,6,6-tetramethyl-1-oxylpiperidine) was added, the reaction still went on under the optimal conditions, manifesting that the reaction did not proceed by the radical pathway (route c in scheme 2). Scheme 2. Control experiments



On the basis of the above results, a plausible mechanism for the [4+2] cycloaddition was proposed in scheme 3. Initially, the splitting of the O−H bond of –OH occured under the effect of base to generate intermediate A. Owing to the intermediate A has no choice to the two carbons of the C-C double bond of the NBE, so it could attacked NBE from two directions and given the intermediates B and C (path a and path b). Subsequent nucleophilic addition of the intermediates B and C gives the intermediates D and E. Finally, the intermediates D and E are hydrolyzed to form the product, which is a racemate. Scheme 3. Plausible Mechanism for the Synthesis of 2a


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Conclusions In summary， we have developed a novel Cu-mediated [4+2] annulation of

N-hydroxybenzimidoyl

with

NBE

for

the

synthesis

of

[1,2]oxazin-4-ones. This method allows to access the [1,2]oxazin-4-ones skeletons by the formation of C=O bond, C-C bond and C-O bond. This synthetic protocol is characterized by commercially available reagents, ACS Paragon Plus Environment


excellent yields, as well as simple and mild reaction conditions. Further studies toward detailed mechanism and applications of this methodology are currently underway. EXPERIMENTAL SECTION General Information. Reagents were purchased from commercial suppliers. All solvents were dried and freshly distilled. TLC was performed on silica HSGF254 plates. Melting points were determined with a digital melting-point apparatus. NMR spectra were run in a solution of deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as the internal standard and were reported in parts per million (ppm). 1H and

13

C NMR spectra were obtained at 400/101 MHz (1H/13C),

respectively. High-resolution mass spectra (HRMS) analyses were carried out on a chemical ionization (CI) apparatus using time-of-flight (TOF) mass spectrometry. Optical rotations were measured with automatic polarimeter. Preparation of Hydroximoyl Cyanides All hydroximoyl cyanides are known compounds that were synthesized from commercially available acetonitriles according to the procedure that follows: a solution of isopentyl nitrite (1.5 equiv, 15 mmol) in ethyl alcohol (3 mL) was added dropwise to a solution of acetonitriles (10 mmol) and sodium ethoxide (1.5 equiv, 15 mmol) in ethyl alcohol (5 mL) at 0 °C. Once the addition was completed, the mixture was allowed to


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warm to room temperature. After stirring for 8-10 h, the reaction mixture was diluted with water and extracted with EtOAc three times. The organic fractions were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using petroleum ether/EtOAc as the eluent to afford the desired products. General Procedure for Synthesis of the 4H-1,2-oxazin-4-ones 1 (0.5 mmol), Norbornylene (0.5 mmol), CuCl2·2H2O (1.5 equiv, 0.75mmol), NaOAc (2 equiv, 1 mmol) were added into a 15 mL sealed tube equipped with a magnetic stirring bar. The mixture was stirred in DCE/Tol (v:v=1:1, 2 mL) under Nitrogen at 100 °C for 24 h. After completion, the reaction mixture was diluted with EtOAc and then filtered. The residue was purified on a silica gel column using petroleum ether/EtOAc as the eluent to give the pure target products. (±)-(4a,5,8,8a)-3-phenyl-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenzo[ e][1,2]oxazin-4-one (2a): EtOAc/petroleum ether =1/20. white solid (97 mg, 80% yield). [α]D28 = 0.574 (c = 0.4g/100ml, CHCl3). Mp: 120-124 oC. 1

H NMR (400 MHz, CDCl3) δ 8.49 – 8.39 (m, 2H), 7.50 – 7.40 (m, 3H),

4.18 (t, J = 5.3 Hz, 1H), 2.97 (s, 1H), 2.74 – 2.64 (m, 2H), 1.85 – 1.74 (m, 1H), 1.72 – 1.61 (m, 1H), 1.37 (d, J = 4.1 Hz, 2H), 1.25 (d, J = 9.0 Hz, 2H).

13

C NMR (101 MHz, CDCl3) δ 199.2, 140.5, 130.8, 128.2, 127.5,

125.3, 77.6, 52.1, 40.1, 39.8, 31.6, 28.1, 25.4. HRMS (ESI-TOF) m/z: [M



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+ H]+ Calcd for C15H16NO2 242.1182; found 242.1182. (±)-(4a,5,8,8a)-3-(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth anobenzo[e][1,2]oxazin-4-one (2b) : EtOAc/petroleum ether =1/20. White solid (118 mg, 91% yield). Mp: 143-145 oC. 1H NMR (400 MHz, CDCl3) δ 8.59 – 8.53 (m, 2H), 7.16 – 7.09 (m, 2H), 4.20 (d, J = 5.9 Hz, 1H), 2.97 (d, J = 4.7 Hz, 1H), 2.70 (t, J = 5.8 Hz, 2H), 1.86 – 1.76 (m, 1H), 1.69 (dd, J = 9.6, 5.6 Hz, 1H), 1.43 – 1.33 (m, 2H), 1.23 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.3, 165.0, 162.5, 139.7, 130.0 (d, JCF = 8.4 Hz), 121.8 (d, JCF = 3.3 Hz), 115.6, 115.4, 77.7, 52.3, 40.2, 39.9, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15FNO2 260.1088; found 260.1084. (±)-(4a,5,8,8a)-3-(4-(trifluoromethyl)phenyl)-4a,5,6,7,8,8a-hexahydro-4 H-5,8-methanobenzo[e][1,2]oxazin-4-one (2c) : EtOAc/petroleum ether =1/20. White solid (136 mg, 88% yield). Mp: 196-198 oC. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 4.23 (d, J = 5.8 Hz, 1H), 2.97 (s, 1H), 2.73 (d, J = 4.6 Hz, 2H), 1.87 – 1.76 (m, 1H), 1.74 – 1.63 (m, 1H), 1.44 – 1.33 (m, 2H), 1.25 (s, 2H).

13

C NMR

(101 MHz, CDCl3) δ 198.9, 139.6, 132.6, 132.2, 131.9, 131.6, 128.7, 127.7, 125.2 (d, JCF = 3.9 Hz), 122.5, 78.2, 52.3, 40.2 (d, JCF = 15.7 Hz), 31.7, 28.1, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15F3NO2 310.1056; found 310.1048. (±)-(4a,5,8,8a)-3-(4-methoxyphenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-me


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thanobenzo[e][1,2]oxazin-4-one (2d) : EtOAc/petroleum ether =1/15. White solid (122 mg, 90% yield). Mp: 120-123 oC. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 4.17 (d, J = 5.9 Hz, 1H), 3.84 (s, 3H), 2.97 (d, J = 4.2 Hz, 1H), 2.67 (dd, J = 12.7, 4.3 Hz, 2H), 1.84 – 1.74 (m, 1H), 1.72 – 1.62 (m, 1H), 1.43 – 1.31 (m, 2H), 1.27 – 1.17 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 199.6, 161.3, 140.0, 129.3, 118.2, 113.6, 77.1, 55.3, 52.2, 40.1, 39.8, 31.6, 28.1, 25.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H18NO3 272.1287; found 272.1293. (±)-(4a,5,8,8a)-3-(p-tolyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenz o[e][1,2]oxazin-4-one (2e) : EtOAc/petroleum ether =1/20. White solid (110 mg, 86% yield). Mp: 140-143 oC. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.19 (d, J = 5.7 Hz, 1H), 2.98 (d, J = 3.6 Hz, 1H), 2.73 – 2.66 (m, 2H), 2.39 (s, 3H), 1.86 – 1.75 (m, 1H), 1.67 (ddd, J = 12.8, 10.2, 5.9 Hz, 1H), 1.44 – 1.32 (m, 2H), 1.29 – 1.20 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 141.4, 140.6, 129.0, 127.5, 122.6, 77.5, 52.3, 40.2, 39.9, 31.7, 28.2, 25.5, 21.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H18NO2 256.1338; found 256.1314. (±)-(4a,5,8,8a)-3-(benzo[d][1,3]dioxol-5-yl)-4a,5,6,7,8,8a-hexahydro-4H -5,8-methanobenzo[e][1,2]oxazin-4-one (2f) : EtOAc/petroleum ether =1/15. Light yellow solid (88 mg, 62% yield). Mp: 169-171 oC. 1H NMR



(400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.00 (s, 2H), 4.16 (d, J = 5.8 Hz, 1H), 2.96 (d, J = 3.6 Hz, 1H), 2.70 – 2.63 (m, 2H), 1.84 – 1.74 (m, 1H), 1.72 – 1.63 (m, 1H), 1.42 – 1.31 (m, 2H), 1.21 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 149.5, 147.4, 140.0, 123.1, 119.4, 108.3, 107.6, 101.5, 77.2, 52.2, 40.2, 39.9, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H16NO4 286.1080; found 286.1082. (±)-(4a,5,8,8a)-3-(4-(tert-butyl)phenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8methanobenzo[e][1,2]oxazin-4-one (2g) : EtOAc/petroleum ether =1/25. White solid (123 mg, 83% yield). Mp: 161-164 oC. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 11.4 Hz, 2H), 4.20 (d, J = 5.7 Hz, 1H), 2.98 (d, J = 3.5 Hz, 1H), 2.69 (d, J = 6.6 Hz, 2H), 1.86 – 1.75 (m, 1H), 1.68 (ddd, J = 16.3, 10.1, 5.9 Hz, 1H), 1.35 (d, J = 21.9 Hz, 11H), 1.23 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 154.4, 140.8, 127.5, 125.4, 122.6, 77.5, 52.33, 40.2, 39.9, 35.1, 31.7, 31.2, 28.2, 25.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H25NO2 298.1808; found 298.1811. (±)-(4a,5,8,8a)-3-(4-bromophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth anobenzo[e][1,2]oxazin-4-one (2h) : EtOAc/petroleum ether =1/20. Light yellow solid (144 mg, 90% yield). Mp: 164-166 oC. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.19 (d, J = 5.8 Hz, 1H), 2.98 (d, J = 3.8 Hz, 1H), 2.70 (d, J = 6.4 Hz, 2H), 1.86 –


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1.76 (m, 1H), 1.75 – 1.65 (m, 1H), 1.44 – 1.33 (m, 2H), 1.24 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.2, 139.8, 131.7, 128.9, 125.3, 124.4, 77.9, 52.3, 40.3, 40.0, 31.8, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15BrNO2 320.0287; found 320.0295. (±)-(4a,5,8,8a)-3-(4-chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth anobenzo[e][1,2]oxazin-4-one (2i). : EtOAc/petroleum ether =1/20. White solid (105 mg, 76% yield). Mp: 147-148 oC. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.20 (d, J = 5.8 Hz, 1H), 2.98 (d, J = 3.5 Hz, 1H), 2.70 (d, J = 6.4 Hz, 2H), 1.87 – 1.77 (m, 1H), 1.69 (ddd, J = 16.9, 10.3, 3.8 Hz, 1H), 1.44 – 1.33 (m, 2H), 1.24 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.3, 139.8, 136.8, 128.9, 128.7, 123.9, 77.9, 52.3, 40.3, 40.0, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15ClNO2 276.0792; found 276.0790. (±)-(4a,5,8,8a)-3-([1,1'-biphenyl]-4-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8methanobenzo[e][1,2]oxazin-4-one (2j) : EtOAc/petroleum ether =1/20. White solid (128 mg, 81% yield). Mp: 210-213 oC. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 7.9 Hz, 2H), 7.67 (dd, J = 28.0, 7.7 Hz, 4H), 7.49 – 7.33 (m, 3H), 4.23 (d, J = 5.6 Hz, 1H), 3.01 (s, 1H), 2.73 (d, J = 5.6 Hz, 2H), 1.86 – 1.63 (m, 2H), 1.39 (s, 2H), 1.26 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 143.4, 140.4, 140.4, 129.0, 128.0, 128.0, 127.3, 127.0, 124.4, 77.7, 52.4, 40.3, 40.0, 31.8, 28.2, 25.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20NO2 318.1495; found 318.1508.



(±)-(4a,5,8,8a)-3-(2,4-dichlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8methanobenzo[e][1,2]oxazin-4-one (2k) : EtOAc/petroleum ether =1/20. White solid (76 mg, 49% yield). Mp: 162-165 oC. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 1.3 Hz, 1H), 7.34 (dd, J = 8.3, 1.4 Hz, 1H), 7.27 (t, J = 6.4 Hz, 1H), 4.26 (d, J = 5.5 Hz, 1H), 2.97 (d, J = 3.6 Hz, 1H), 2.83 – 2.70 (m, 2H), 1.87 – 1.77 (m, 1H), 1.75 – 1.64 (m, 1H), 1.44 – 1.34 (m, 2H), 1.33 – 1.23 (m, 2H).

13

C NMR (101 MHz, CDCl3) δ 197.3, 143.0,

137.3, 135.3, 132.3, 130.3, 127.4, 123.1, 78.8, 53.0, 40.0, 39.8, 31.9, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H14Cl2NO2 310.0402; found 310.0403. (±)-(4a,5,8,8a)-3-(o-tolyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenz o[e][1,2]oxazin-4-one (2l) : EtOAc/petroleum ether =1/20. White solid (42 mg, 33% yield). Mp: 147-150 oC. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.19 (m, 4H), 4.24 (s, 1H), 2.98 (s, 1H), 2.75 (d, J = 14.6 Hz, 2H), 2.21 (s, 3H), 1.75 (dd, J = 36.3, 10.3 Hz, 2H), 1.43 – 1.28 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 198.5, 145.9, 138.5, 130.7, 130.5, 129.7, 125.7, 124.1, 78.1, 52.8, 39.9, 39.7, 31.8, 28.1, 25.5, 20.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H18NO2 256.1338; found 256.1340. (±)-(4a,5,8,8a)-3-(2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth anobenzo[e][1,2]oxazin-4-one (2m) : EtOAc/petroleum ether =1/20. White solid (63 mg, 49% yield). Mp: 123-124 oC. 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.42 (m, 2H), 7.25 (dd, J = 13.2, 5.7 Hz, 1H), 7.17 (t, J =


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9.1 Hz, 1H), 4.28 (d, J = 5.6 Hz, 1H), 2.99 (d, J = 3.6 Hz, 1H), 2.82 – 2.71 (m, 2H), 1.89 – 1.76 (m, 1H), 1.74 – 1.65 (m, 1H), 1.37 (dd, J = 24.4, 8.2 Hz, 3H), 1.33 – 1.23 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 197.6, 161.6, 159.1, 141.2, 132.5 (d, JCF = 8.5 Hz), 130.7 (d, JCF = 3.2 Hz), 124.3 (d, JCF = 3.4 Hz), 116.5, 116.3, 113.0 (d, JCF = 15.1 Hz), 78.6, 52.8, 40.1, 39.9, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15FNO2 260.1088; found 260.1091. (±)-(4a,5,8,8a)-3-(3,5-dimethylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8methanobenzo[e][1,2]oxazin-4-one (2n) : EtOAc/petroleum ether =1/20. White solid (121 mg, 90% yield). Mp: 152-154 oC. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 2H), 7.09 (s, 1H), 4.19 (d, J = 5.6 Hz, 1H), 2.98 (s, 1H), 2.73 – 2.65 (m, 2H), 2.36 (s, 6H), 1.79 (d, J = 8.7 Hz, 1H), 1.68 (t, J = 14.1 Hz, 1H), 1.44 – 1.33 (m, 2H), 1.28 – 1.20 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 141.1, 137.9, 132.7, 125.3, 125.1, 77.6, 52.2, 40.2, 39.9, 31.7, 28.2, 25.5, 21.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H20NO2 270.1495; found 270.1499. (±)-(4a,5,8,8a)-3-(3-chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth anobenzo[e][1,2]oxazin-4-one (2o) : EtOAc/petroleum ether =1/20. White solid (113 mg, 82% yield). Mp: 165-167 oC. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 7.45 – 7.35 (m, 2H), 4.21 (d, J = 5.8 Hz, 1H), 2.97 (d, J = 3.8 Hz, 1H), 2.71 (d, J = 5.7 Hz, 2H), 1.80 (dd, J = 10.9, 3.2 Hz, 1H), 1.69 (dd, J = 11.6, 7.8 Hz, 1H), 1.44 –



1.32 (m, 2H), 1.24 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 198.9, 139.5, 134.4, 130.9, 129.6, 127.2, 127.0, 125.5, 78.0, 52.3, 40.2, 40.0, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15ClNO2 276.0792; found 276.0788. (±)-(4a,5,8,8a)-3-(4-(trifluoromethoxy)phenyl)-4a,5,6,7,8,8a-hexahydro-4 H-5,8-methanobenzo[e][1,2]oxazin-4-one (2p) : EtOAc/petroleum ether =1/20. White solid (73 mg, 45% yield). Mp: 125-128 oC. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 4.23 (d, J = 5.8 Hz, 1H), 2.99 (d, J = 3.8 Hz, 1H), 2.72 (d, J = 4.8 Hz, 2H), 1.86 – 1.77 (m, 1H), 1.74 – 1.65 (m, 1H), 1.41 (t, J = 9.0 Hz, 2H), 1.26 (d, J = 9.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.1, 150.4, 139.5, 129.4, 124.0, 121.7, 120.4, 77.9 52.3, 40.2, 40.0, 31.7, 28.1, 25.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15F3NO3 326.1005; found 326.1006. (±)-(4a,5,8,8a)-3-(naphthalen-2-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-met hanobenzo[e][1,2]oxazin-4-one (2q) : EtOAc/petroleum ether =1/20. White solid (143 mg, 98% yield). Mp: 184-185 oC. 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.56 – 7.49 (m, 2H), 4.26 (d, J = 4.5 Hz, 1H), 3.04 (s, 1H), 2.76 (s, 2H), 1.83 (d, J = 10.8 Hz, 1H), 1.71 (s, 1H), 1.42 (s, 2H), 1.31 – 1.25 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 199.6, 140.7, 134.3, 132.8, 129.4, 128.5, 127.9, 127.8, 127.7,


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126.5, 123.8, 122.9, 77.8, 52.4, 40.3, 40.1, 31.8, 28.3, 25.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NO2 292.1338; found 292.1339. (±)-(4a,5,8,8a)-3-(thiophen-3-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-metha nobenzo[e][1,2]oxazin-4-one (2r) : EtOAc/petroleum ether =1/20. White solid (33mg, 27% yield). Mp: 143-145 oC. 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.40 – 7.36 (m, 1H), 4.21 (d, J = 5.7 Hz, 1H), 2.98 (d, J = 3.7 Hz, 1H), 2.70 (d, J = 5.8 Hz, 2H), 1.84 – 1.76 (m, 1H), 1.73 – 1.66 (m, 1H), 1.38 (d, J = 4.4 Hz, 2H), 1.22 (s, 2H).

13

C NMR (101 MHz, CDCl3) δ 198.8, 138.4, 129.1, 126.0, 125.9,

125.2, 77.3, 52.5, 40.1, 39.8, 31.8, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14NO2S 248.0746; found 248.0749. (±)-4-((4a,5,8,8a)-4-oxo-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenzo[ e][1,2]oxazin-3-yl)benzonitrile (2s) : EtOAc/petroleum ether =1/20. White solid (68mg, 51% yield). Mp: 113-115 oC. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 4.25 (d, J = 5.7 Hz, 1H), 2.99 (d, J = 3.3 Hz, 1H), 2.75 (d, J = 4.3 Hz, 2H), 1.82 (dd, J = 12.5, 2.7 Hz, 1H), 1.72 (dd, J = 11.2, 7.7 Hz, 1H), 1.41 (s, 2H), 1.26 (d, J = 5.6 Hz, 2H).

13

C NMR (101 MHz, CDCl3) δ 198.9, 139.1, 132.1,

129.6, 127.7, 118.5, 113.9, 78.4, 52.4, 40.3, 40.2, 31.8, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15N2O2 267.1134; found 267.1140.



(±)-(4a,5,8,8a)-3-phenyl-4a,5,8,8a-tetrahydro-4H-5,8-methanobenzo[e][ 1,2]oxazin-4-one (3a) : EtOAc/petroleum ether =1/25. White solid (75mg, 63% yield). Mp: 125-127 oC. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.9 Hz, 2H), 7.44 (s, 3H), 6.41 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 2.1 Hz, 1H), 4.30 (d, J = 4.6 Hz, 1H), 3.51 (s, 1H), 3.24 (s, 1H), 2.85 (d, J = 4.2 Hz, 1H), 1.77 – 1.65 (m, 1H), 1.47 (d, J = 10.1 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 197.9, 142.1, 140.4, 135.6, 130.9, 128.3, 127.7, 125.6, 77.5, 51.2, 45.3, 44.9, 42.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H14NO2 240.1025; found 240.1028. (±)-(4a,5,8,8a)-3-(4-methoxyphenyl)-4a,5,8,8a-tetrahydro-4H-5,8-metha nobenzo[e][1,2]oxazin-4-one (3b) : EtOAc/petroleum ether =1/25. White solid (103mg, 76% yield). Mp: 130-132 oC. 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 6.28 (s, 1H), 4.30 (d, J = 5.6 Hz, 1H), 3.85 (s, 3H), 3.52 (s, 1H), 3.24 (s, 1H), 2.85 (d, J = 5.4 Hz, 1H), 1.69 (d, J = 9.9 Hz, 1H), 1.46 (d, J = 10.1 Hz, 1H).

13

C NMR (101 MHz, CDCl3) δ 198.3, 161.4, 141.7, 140.4, 135.7,

129.6, 118.5, 113.8, 77.1, 55.5, 51.3, 45.3, 44.9, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H16NO3 270.1131; found 270.1122. (±)-(4a,5,8,8a)-3-(4-(trifluoromethyl)phenyl)-4a,5,8,8a-tetrahydro-4H-5, 8-methanobenzo[e][1,2]oxazin-4-one (3c) : EtOAc/petroleum ether =1/25. White solid (86mg, 56% yield). Mp: 130-132 oC. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 6.47 –


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6.42 (m, 1H), 6.32 – 6.27 (m, 1H), 4.36 (d, J = 5.7 Hz, 1H), 3.54 (s, 1H), 3.28 (s, 1H), 2.92 (d, J = 5.6 Hz, 1H), 1.73 (d, J = 10.2 Hz, 1H), 1.48 (d, J = 10.2 Hz, 1H).

13

C NMR (101 MHz, CDCl3) δ 197.5, 141.0, 140.6,

135.6, 132.2 (d, JCF = 32.7 Hz), 128.9, 127.9, 125.3 (q, JCF = 3.8 Hz), 122.5, 78.1, 51.4, 45.5, 45.9, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H13F3NO2 308.0899; found 308,0897. (±)-(4a,5,8,8a)-3-(3-chlorophenyl)-4a,5,8,8a-tetrahydro-4H-5,8-methano benzo[e][1,2]oxazin-4-one (3d) : EtOAc/petroleum ether =1/25. White solid (59mg, 43% yield). Mp: 129-131 oC. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 7.40 (dd, J = 13.6, 5.7 Hz, 2H), 6.44 (dd, J = 5.0, 2.7 Hz, 1H), 6.31 – 6.26 (m, 1H), 4.33 (d, J = 5.7 Hz, 1H), 3.53 (s, 1H), 3.26 (s, 1H), 2.89 (d, J = 5.5 Hz, 1H), 1.72 (d, J = 10.1 Hz, 1H), 1.46 (d, J = 10.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.5, 140.9, 140.5, 135.6, 134.5, 131.0, 129.7, 127.4, 127.3, 125.7, 77.9, 51.3, 45.5, 45.0, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H13ClNO2 274.0636; found 274.0626. (±)-(4a,5,8,8a)-3-(benzo[d][1,3]dioxol-5-yl)-4a,5,8,8a-tetrahydro-4H-5,8 -methanobenzo[e][1,2]oxazin-4-one (3e) : EtOAc/petroleum ether =1/25. White solid (115mg, 81% yield). Mp: 178-180 oC. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 27.5 Hz, 2H), 6.90 (s, 1H), 6.42 (s, 1H), 6.28 (s, 1H), 6.01 (s, 2H), 4.29 (s, 1H), 3.51 (s, 1H), 3.24 (s, 1H), 2.84 (s, 1H), 1.69 (s, 1H), 1.45 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 198.1, 149.6,



Page 26 of 33

147.5, 141.6, 140.4, 135.7, 123.3, 119.6, 108.4, 107.8, 101.6, 77.1, 51.2, 45.3, 44.9, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H14NO4 284.0924; found 284.0920. (±)-(4a,7a)-3-phenyl-5,6,7,7a-tetrahydrocyclopenta[e][1,2]oxazin-4(4aH )-one (3f) : EtOAc/petroleum ether =1/25. yellow oil (23mg, 21%). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 6.7, 3.3 Hz, 2H), 7.45 (dd, J = 5.2, 2.1 Hz, 3H), 4.72 (t, J = 7.0 Hz, 1H), 3.24 (dd, J = 9.1, 6.7 Hz, 1H), 2.53 (dd, J = 14.3, 6.3 Hz, 1H), 2.23 (dd, J = 12.7, 6.1 Hz, 1H), 1.83 (dtd, J = 35.0, 13.0, 6.6 Hz, 3H), 1.44 – 1.29 (m, 1H).

13

C NMR (101 MHz,

CDCl3) δ 200.6, 139.3, 130.8, 128.3, 127.5, 125.5, 77.0, 48.9, 30.9, 30.1, 22.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14NO2 216.1027; found 216.1027. ASSOCIATED Supporting Information Figures giving 2D NMR spectra and 1H,

13

C

NMR spectra. AUTHOR INFORMATION Corresponding Authors *(Yong-Ming

Zhu)

E-mail:

[email protected];

(+86)-512-67166591. Notes The authors declare no competing financial interest. References


fax:

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(1) (a) Remy, R.; Bochet, C. G. Arene−Alkene Cycloaddition. Chem. Rev. 2016, 116, 9816-9849. (b) Pan, G.-H.; Ouyang, X.-H.; Hu, M.; Xie, Y.-X.; Li, J.-H. Copper-Catalyzed Intermolecular Amino-Alkylation of Alkenes with α-Bromoalkyl Esters and Amines toward Pyrrolidin-2-ones. Adv. Synth. Catal. 2017, 359, 2564-2570. (c) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.-L.; Li, J.-H. Oxidative 1,2-carboamination of alkenes with alkyl nitriles and amines toward γ -amino alkyl nitriles. Nature Communications. 2017, 8, 14720-14726. (d) Yang, Y.; Song, R.-J.; Ouyang, X.-H.; Wang, C.-Y.; Li, J.-H.; Luo, S.-L. Iron-Catalyzed Intermolecular 1,2-Difunctionalization of Styrenes and Conjugated Alkenes with Silanes and Nucleophiles. Angew. Chem. Int. Ed. 2017, 56, 7916 –7919. (2) Ylijoki, K. E. O.; Stryker, J. M. [5 + 2] Cycloaddition Reactions in Organic and Natural Product Synthesis. Chem. Rev. 2013, 113, 2244−2266. (3) (a)Advances in Cycloaddition, Vols. 1–6, JAI, Greenwich, CT, 1988– 1999; (b) W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series, Pergamon, Elmsford, NY, 1990; (c) Cycloaddition Reactions in Organic Synthesis, (Eds.: S.Kobayashi, K. A. J⌀gensen), Wiley-VCH, Weinheim, 2002; (d) G. Masson, C. Lalli, M. Benohoud, G. Dagousset. Catalytic Enantioselective [4+2]-Cycloaddition: A Strategy to Access Aza-Hexacycles. Chem. Soc. Rev. 2013, 42,



902-923. (4) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C−C Bond Formation via Heteroatom-Directed C−H Bond Activation. Chem. Rev. 2010, 110, 624–655. (b) Satoh, T.; Miura, M. Oxidative Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212-11222. (c) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)-Catalyzed C–H Bond Activation and Functionalization. Chem. Rev. 2012, 112, 5879–5918. (d) Song, G.-Y.; Wang, F.; Li, X.-W. C–C, C–O and C–N Bond Formation via Rhodium(III)-Catalyzed Oxidative C–H Activation. Chem. Soc. Rev. 2012, 41, 3651-3678. (5) Remy, R.; Bochet, C. G. Arene−Alkene Cycloaddition. Chem. Rev. 2016, 116, 9816-9849. (6) For homo-Diels-Alder reaction of norbomadienes. Furukawa, J.; Kobuke, Y.; Sugimoto, T.; Fueno, T. The Role of Attractive Interactions in Endo-Exo Stereoselectivities of Diels-Alder Reactions. J. Am. Chem. Soc. 1972, 94, 3633-3635. (7) Selected papers on oxidation of oximes to produce ketones: (a) Zhou, X.-T.; Yuan, Q.-L.; Jia, H.-B. Highly Efficient Aerobic Oxidation of Oximes to Carbonyl Compounds Catalyzed by Metalloporphyrins in the Presence of Benzaldehyde. Tetrahedron Lett. 2010, 51, 613-617. (b) Kim, B. R.; Lee, H.-G.; Kim, E. J.; Lee, S.-G.; Yoon, Y.-J. Conversion of


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Oximes

to

Carbonyl

Compounds

with

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Cyclization/Cyanation of Alkenyl Oximes. J. Org. Chem., 2017, 82, 10742-10747.


Cu-Mediated Stereoselective [4+2] Annulation between N

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