ones from cyclo-Alkenecarboxylic Acids and Acrylates via CH Activation

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A Route to Substituted Furan-2(5H)-ones from cycloAlkenecarboxylic Acids and Acrylates via C-H Activation You-Quan Zhu, Ting-Feng Han, Jing-Li He, Man Li, Jun-Xian Li, and Kun Zhu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01423 • Publication Date (Web): 20 Jul 2017 Downloaded from http://pubs.acs.org on July 20, 2017

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The Journal of Organic Chemistry

A Route to Substituted Furan-2(5H)-ones from cycloAlkenecarboxylic Acids and Acrylates via C-H Activation You-Quan Zhu,* Ting-Feng Han, Jing-Li He, Man Li, Jun-Xian Li and Kun Zhu State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China. ∗Corresponding author. Tel.: +86 13116096161; fax: +86 22 23503627; E-mail: [email protected].

ABSTRACT: Under rhodium (III) catalysis, four kinds of cyclo-alkenecarboxylic acids successfully reacted with acrylates via direct activation of β-alkenyl C-H bond. The present protocol provides the facile and highly efficient synthesis of substituted furan-2(5H)-ones from readily available starting materials with moderate to good yields. In addition, their possible reaction mechanisms were also discussed.

INTRODUCTION

The C-H activation catalyzed by transition metals has evolved as an effective method for the synthesis of natural and unnatural compounds.1- 2 In particular,

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carboxyl-assisted ortho-C-H cleavage followed by coupling with acrylates, acrylonitrile, methyl vinyl ketone and allenes is popular in the construction of substituted furan-2(5H)-ones.3 Among these carboxyl acids, aromatic carboxylic acids and acrylic acids have been heavily tested, but cyclo-alkenyl acids are not explored. Our continuing interest in C-H activation reactions 3a, 4 has prompted us to explore cyclo-alkenyl acids in C-H activation reaction.

Figure 1. The Chemical Structures for Some Compounds.

The furan-2(5H)-one substructure is found in a wide variety of natural and bioactive compounds, such as senkyunolid H, Z-ligustilide and senkyunolid P (Figure 1).5 Consequently, a number of synthetic strategies have been developed for their construction (Scheme 1).6 The most commonly used strategies for the synthesis of substituted furan-2(5H)-ones involve transition-metal-catalyzed carbonylative cyclization of β-halo vinyl alcohols 6a-6c or aldehydes 6d and intramolecular nucleophilic cyclization of β-hydroxymethyl acrylates.6e-6f However,

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Scheme 1. Transition-metal Catalyzed Approaches to Synthesize Substituted Furan2(5H)-ones.

the limited availability of various starting materials above, mostly due to the harsh

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reaction conditions in their preparation, calls for alternative protocols. Herein, we report the synthesis of substituted furan-2(5H)-ones from readily available 1cycloalkenylcarboxylic acids and acrylates through β-vinyl C–H functionalization for the first time. Furthermore, experimental results substantiated the tandem mechanism for forming the cyclic esters. RESULTS AND DISCUSSION From a synthetic standpoint, the direct use of water as solvent is an ideal way for organic reactions, since it could offer some advantages of easy availability and low cost. Hence, the model reaction of 1-cyclohexene-1-carboxylic acid (1a) and methyl acrylate (2a) proceed firstly in water (Table 1). Initially, the model reaction was investigated in the absence of transition-metal catalyst. As shown in Table 1, none of desired product was detected (entry 1). Then the reaction was conducted in the presence of 5 mol% Pd(OAc)2, RhCl3, [Ru(p-cymene)Cl2]2 and [RhCl2Cp*]2 respectively (Table 1, entries 2 - 5). To our delight, the target product (3a) was generated in 30% yield when the reaction was carried out by employing [RhCl2Cp*]2 as catalyst (entry 5). However, when the temperature was elevated to 140 oC, the yield was decreased to 21% (Table 1, entry 6). When the temperature was decreased to 120 o

C, the yield was improved significantly (45%) (Table 1, entry 7), which suggested

that the optimal temperature was about 120 oC. When the reaction time was prolonged to 36h and 48h (Table 1, entries 8 - 9), the yields were 58% and 32% respectively, indicating that the optimal time was about 36 hours. Moreover, when the oxidant was replaced by CuSO4, MnO2, t-BuOOH, O2 (1atm) and CuCl2 respectively, no desired product was detected (Table 1, entries 11 - 14), thereby suggesting that CH3CO2- was

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Table 1. Effect of Catalyst, Solvent, Temperature, Oxidant and Time a

Oxidant

Time(h)

Yield(%)[c]

H2O

Cu(OAc)2•H2O

24

0

100

H2O

Cu(OAc)2•H2O

24

Trace

C-2

100

H2O

Cu(OAc)2•H2O

24

0

4

C-3

100

H2O

Cu(OAc)2•H2O

24

14

5

C-4

100

H2O

Cu(OAc)2•H2O

24

30

6

C-4

145

H2O

Cu(OAc)2•H2O

24

21

7

C-4

120

H2O

Cu(OAc)2•H2O

24

45

8

C-4

120

H2O

Cu(OAc)2•H2O

36

58

9

C-4

120

H2O

Cu(OAc)2•H2O

48

32

10

C-4

120

H2O

CuSO4

36

48

11

C-4

120

H2O

MnO2

36

0

12

C-4

120

H2O

t-BuOOH

36

0

13

C-4

120

H2O

O2

36

0

14

C-4

120

H2O

CuCl2

36

0

15 d

C-4

120

H2O

Cu(OAc)2•H2O

36

27

16

C-4

120

Dioxane

Cu(OAc)2•H2O

36

91

17

C-4

120

methanol

Cu(OAc)2•H2O

36

0

18

C-4

120

DMF

Cu(OAc)2•H2O

36

27

19

C-4

120

DMSO

Cu(OAc)2•H2O

36

31

20

C-4

120

CH3CN

Cu(OAc)2•H2O

36

43

21

C-4

120

m-xylene

Cu(OAc)2•H2O

36

57

Entry

Catalyst[b]

Temp(oC)

1

-

100

2

C-1

3

a)

Solvent

1a (0.2 mmol), 2a (0.5 mmol), catalyst (5 mol%), HOAc (0.2 mmol), oxidant(0.6

mmol), solvent (0.5 mL); the reaction vessels were closed and the reaction atmosphere was air. b) C-1(Pd(OAc)2), C-2(RhCl3), C-3([Ru(p-cymene)Cl2]2), C4([RhCl2Cp*]2). c) Yields were determined by the 1H NMR integration method using

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mesitylene as the internal standard. d) C-4 (2.5 mol%). Table 2. Scope of compound 3 a)

a

Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (5 mol%), acetic acid

(0.2 mmol), Cu(OAc)2•H2O (0.6 mmol), dioxane (0.5 mL), 36 h; the reaction vessels were closed and the reaction atmosphere was air.Yield of purified product is reported.

crucial to this reaction and cupric acetate was the optimal oxidant. When the catalyst

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loading was 2.5%, the yield was only 27% (Table 1, entry 15). Finally, the reaction was carried out in other solvents such as dioxane, N,N-dimethylformamide (DMF), methanol, dimethyl sulfoxide (DMSO), acetonitrile and m-xylene (Table 1, entries 1621) and the best result (91% yield) was obtained when dioxane was used as solvent. Under the optimized conditions, the scope of the reaction of 1a - 1c with acrylates was firstly explored. As shown in Table 2, when R was methyl or ethyl , the yields of the desired products 3 were generally higher than the others(3a, 3b and 3f). However, when the X was oxygen, the yields of corresponding products were generally decreased (3a vs 3f, 3b vs 3g, 3c vs 3h, 3d vs 3i, 3e vs 3j), presumably because the strong electron-donating effect of oxygen atom might result in the increase of the carboxyl-assisted ortho-C-H cleavage energy. When the allyl group was introduced at the 5-position of 1a, the yields of 3 were slightly decreased (3k - 3m). This indicated that the steric effect of the substituent had some extent influence on this reaction. However, when methyl / ethyl acrylate was reacted with 1c under the same reaction conditions, affording compounds 4a and 4b respectively, which could be resulted from the substituent effect.

Considering that many compounds containing nitrogen atom exhibit various bioactivities and consist of an important kind of organic compounds, the substrate scope of the reaction with respect to the model reaction of 1d with acrylates were investigated. As listed in Table 3, the desired products 3n – 3q were synthesized smoothly and the yield of 3n was up to 75%, thereby suggesting that, at the presence of transitional metals and acetic acid, the protecting group (N-Boc) was very stable. 7 / 20



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More importantly, similar molecule or compounds incorporating this functionalized substructure can be synthesized through deprotection and other reactions. Table 3. Scope of compound 3 a) O

O O

OH Boc

+

N

H 1d

O

R

[Cp*RhCl2]2 / dioxane / 36 h Cu(OAc)2 H2O/ HOAc / 120 oC

Boc

O

N

O

2 3

a

O R

Reaction conditions: 1d (0.2 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (5 mol%), acetic

acid (0.2 mmol), Cu(OAc)2•H2O (0.6 mmol), dioxane (0.5 mL), 36 h; the reaction vessels were closed and the reaction atmosphere was air. Yield of purified product is reported. In addition, the participation of 1e in this protocol was performed to examine the influence of the size of the ring. As listed in Table 4, no desired product 5 was detected and the tandem reaction ceased after intermediate 6 was formed in 63% - 95% yields

(Table 4). Further computational studies at the (SMD)-B3LYP-D3(BJ)/6-311++G(2df, 2p)//(SMD)-M06-2X/6-31+G(d) level of theory using Gaussian 09 packages [7] showed that the cyclization of 6a was computed to be endergonic by 3.1 kcal mol-1, indicating that this process is a thermodynamically unfavorable process. This well rationalize the experimental observation that no cyclization product was obtained for subtract 6a.This also suggested that the cyclization step was the rate-limiting step in

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this transformation. Table 4. The Reaction Between 1e and 2 a)

Entry

a)

2

R

5

6

a

CH2=CHCO2CH3

CH3

0

87%

b

CH2=CHCO2C2H5

C2H5

0

75%

c

CH2=CHCO2C4H9-n

C4H9-n

0

63%

d

CH2=CHCO2CH2C6H5

CH2C6H5

0

95%

e

CH2=CHCO2C6H11-cyclo

cyclo-C6H11

0

94%

Reaction conditions: 1e (0.2 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (5 mol%), acetic

acid (0.2 mmol), Cu(OAc)2•H2O (0.6 mmol), dioxane (0.5 mL), 36 h; the reaction vessels were closed and the reaction atmosphere was air. Yield of purified product is reported. On the base of the experiment results above and the mechanism of this kind reaction, [3d, 8]

a possible reaction pathway was thus proposed as Scheme 2. Initially, the

interaction of the RhIII catalyst with the acids 1 would lead to the formation of the rhodacycle intermediate 7. Next, intermediate 7 was coordinated with the olefin substrate 2, followed by the migration/insertion and β-hydride elimination to produce intermediate 10. Finally, an intramolecular cyclization (Mickael addition) of 10 was proceeded to afford the desired product 3. However, since this process of the intramolecular cyclization of 6 is a thermodynamically unfavorable process under this reaction condition, the desired product 5 was not formed through Mickael addition.

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Scheme 2. Postulated reaction pathway.

Conclusion We have developed a convenient tandem Rh(III)-catalyzed C-H activation and annulation reactions for the synthesis of substituted furan-2(5H)-ones by directly reacting β-cycloalkenyl acids and various acrylates. The reactions provided target products in good yields. This easy approach affords an alternative strategy for the construction of diverse and useful substituted furan-2(5H)-ones. The related computational studies showed that the cyclization of 6a was a thermodynamically unfavorable process.

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Experimental Section Solvents and reagents were purchased from Sigma-Aldrich and were used without further purification unless otherwise specified. 1H and

13

C NMR spectra were

recorded on Bruker 400 MHz spectrometers; internal reference of δ = 7.28 or 77.0 CHCl3 as standard. HRMS was conducted using electro-spraying ionization (ESI), and was performed on a Thermo-Scientific Exactive Orbitrap. Sodium adducts [M + Na+] were used for empirical formula confirmation. General Synthetic Procedure for Compounds 3, 4 and 6 An reaction vessel was charged with [Cp*RhCl2]2 (6.18 mg, 5 mol%, 0.02 mmol), Cu(OAc)2•H2O (120 mg, 0.6 mmol), acids 1 (0.2 mmol), CH3CO2H (0.2 mmol), acrylates 2 (0.6 mmol), and dioxane (0.5 mL). The mixture was stirred at 120 oC (oil bath temperature) for 36 h. After this time, the resulting mixture was cooled down to room temperature, extracted with ethyl acetate (15 mL) for three times. The organic phase was dried with dry Na2SO4, filtered, and then concentrated under vacuum. The residue was purified by preparative TLC to afford the corresponding product (Vpetroleum ether : Vethyl acetate = 4:1).

Methyl 2-(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)acetate (3a)

White

solid, mp 56 - 57 oC; yield, 34.9mg, 83%; 1H NMR (400 MHz, CDCl3) δ 5.22 (m, 1H), 3.74(s, 3H), 2.78 - 2.58 (m, 2H), 2.35 - 2.15 (m, 4H), 1.85 - 1.65 (m, 4H). 13C NMR

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(101 MHz, CDCl3) δ 172.8, 169.8, 162.5, 127.4, 78.8, 52.2, 37.4, 23.1, 21.5, 21.4, 19.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H14O4Na 233.0784; Found 233.0788. Ethyl 2-(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)acetate (3b)

Liquid;

yield, 35.4mg, 79%; 1H NMR (400 MHz, CDCl3) δ 5.25 - 5.19 (m, 1H), 4.19 (q, J = 6.4Hz, 2H), 2.78 - 2.56 (m, 2H), 2.35 - 2.15 (m, 4H), 1.90 - 1.60 (m, 4H), 1.28(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.9, 169.3, 162.6, 127.3, 78.9, 61.3, 37.6, 23.1, 21.5, 21.4, 19.9, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H16O4Na 247.0941; Found 247.0937. Butyl 2-(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)acetate (3c) Liquid; yield, 34.2mg, 68%; 1H NMR (400 MHz, CDCl3) δ 5.18 (t, J = 7.2 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 2.75 - 2.53 (m, 2H), 2.30 - 2.10 (m, 4H), 1.83 - 1.53 (m, 6H), 1.43 1.28 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.8, 169.4, 162.5, 127.3, 78.8, 65.1, 37.6, 30.5, 23.1, 21.5, 21.4, 19.9, 19.1, 13.7. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C14H20O4Na 275.1254; Found 275.1255. Benzyl 2-(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)acetate (3d)

Liquid;

yield, 33.2mg, 58%; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 5H), 5.25 - 5.03 (m, 3H), 2.85 - 2.60 (m, 2H), 2.19 (s, 4H), 1.80 - 1.55 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 172.8, 169.1, 162.4, 135.3, 128.7, 128.5, 127.4, 78.7, 67.1, 37.6, 23.1, 21.5, 21.4, 19.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H18O4Na 309.1067; Found 309.1098. Cyclo-hexyl 2-(3-oxo-1,3,4,5,6,7-hexahydroisobenzo furan-1-yl)acetate (3e) Liquid; yield, 42.8mg, 77%; 1H NMR (400 MHz, CDCl3) δ 5.19 (t, J = 6.4Hz, 1H), 4.83 - 4.70 (m, 1H), 2.75 - 2.55 (m, 2H), 2.33 - 2.13

(m, 4H), 1.95 – 1.60 (m, 8H),

1.48 - 1.15 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 171.9, 167.6, 161.6, 126.2, 77.9,

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72.8, 36.9, 30.5, 24.2, 22.7, 22.1, 20.5, 20.4, 18.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H22O4Na 301.1410; Found 301.1410. Methyl 2-(7-oxo-3,4,5,7-tetrahydro-2H-furo[3,4-b] pyran-5-yl)acetate (3f) White solid, mp 62 - 63 oC; yield, 31.0mg, 73%; 1H NMR (400 MHz, CDCl3) δ 5.19 (t, J = 6.4Hz, 1H), 4.23 - 4.04 (m, 2H), 3.67 (s, 3H), 2.72 - 2.57 (m, 2H), 2.35 - 2.12 (m, 2H), 1.98 - 1.87 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.6, 166.6, 141.5, 132.6, 76.4, 67.7, 52.2, 38.0, 21.1, 19.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H12O5Na 235.0577; Found 235.0575. Ethyl 2-(7-oxo-3,4,5,7-tetrahydro-2H-furo[3,4-b] pyran-5-yl)acetate (3g)

White

solid, mp 66-67 oC; yield, 30.3mg, 67%; 1H NMR (400 MHz, CDCl3) δ 5.23(m, 1H), 4.30 - 4.05(m, 4H), 2.64 (d, J = 6.4Hz, 2H), 2.33 - 2.12(m, 2H), 2.00 - 1.87 (m, 2H), 1.21(t, J = 7.2Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.1, 166.4, 141.5, 132.5, 76.4, 67.7, 61.3, 38.3, 21.1, 19.5, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H14O5Na 249.0733; Found 249.0739. Butyl 2-(7-oxo-3,4,5,7-tetrahydro-2H-furo[3,4-b] pyran-5-yl)acetate (3h)

Liquid;

yield, 30.0mg, 59%; 1H NMR (400 MHz, CDCl3) δ 5.19 (t, J = 6.4Hz, 1H), 4.22 4.03 (m, 4H), 2.65, 2.63 (dd, J = 2Hz, 6Hz, 2H), 2.35 - 2.05 (m, 2H),

2.00 - 1.85 (m,

2H), 1.63 - 1.50 (m, 2H), 1.40 - 1.25 (m, 2H), 0.87(t, J = 7.2Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 166.4, 141.5, 132.6, 76.5, 67.7, 65.2, 38.2, 30.5, 21.1, 19.5, 19.1, 13.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18O5Na 277.1046; Found 277.1031. Benzyl 2-(7-oxo-3,4,5,7-tetrahydro-2H-furo[3,4-b] pyran-5-yl)acetate (3i) Liquid; yield, 28.8mg, 50%; 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 5H), 5.28 5.22(m, 1H), 5.16 (d, J = 2.0 Hz, 2H), 4.23 - 4.16 (m, 1H), 4.12 - 4.05 (m, 1H), 2.75 (d, J = 6.4 Hz, 2H), 2.35 - 2.15(m, 2H), 2.00 - 1.85 (m, 2H). 13C NMR (101 MHz,

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CDCl3) δ 168.9, 166.3, 141.5, 135.2, 132.4, 128.7, 128.5, 76.3, 67.7, 67.1, 38.2, 21.1, 19.4. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H16O5Na 311.0890; Found 311.0887. Cyclo-hexyl 2-(7-oxo-3,4,5,7-tetrahydro-2H-furo[3,4-b] pyran-5-yl)acetate (3j) Liquid; yield, 37.0mg, 66%; 1H NMR (400 MHz, CDCl3) δ5.30 - 5.15 (s, 1H), 4.85 4.70 (m, 1H), 4.25 - 4.05 (m, 2H), 2.69 (d, J = 6.4 Hz, 2H), 2.40 - 2.20 (m, 2H), 2.25 1.95 (m, 2H), 1.90 - 1.77 (m, 2H), 1.75 - 1.63 (m, 2H), 1.45 - 1.15 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 168.5, 166.4, 141.4, 132.7, 76.5, 73.7, 67.7, 38.5, 31.6, 25.2, 23.7, 21.1, 19.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H20O5Na 303.1203; Found 303.1198. Benzyl 2-((6S)-3-oxo-6-(prop-1-en-2-yl)-1,3,4,5,6,7-hexahydroisobenzofuran-1yl)acetate (3k) Liquid; yield, 35.9mg, 55%; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 5H), 5.30 – 5.05 (m, 3H), 4.82(s, 1H), 4.73 (s, 1H), 2.90 – 2.63 (m, 2H), 2.43 – 2.05 (m, 5H), 2.00 – 1.85 (m, 1H), 1.76 (s, 3H), 1.60 – 1.40 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.4, 169.0, 162.3, 162.2, 147.5, 147.3, 135.3, 128.7, 128.6, 127.2, 110.3, 110.2, 78.6, 78.3, 67.1, 40.5, 40.4, 37.5(1), 37.4(6), 28.4, 28.1, 26.7, 26.6, 20.7(4), 20.6(8), 20.2, 20.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H22O4Na 349.1410; Found 349.1415. Butyl 2-((6S)-3-oxo-6-(prop-1-en-2-yl)-1,3,4,5,6,7-hexahydroisobenzofuran-1yl)acetate (3l) Liquid; yield, 29.2mg, 50%; 1H NMR (400 MHz, CDCl3) δ 5.30 - 5.20 (m, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 4.16 (t, J = 6.8 Hz, 2H), 2.83 – 2.60 (m, 2H), 2.47 – 2.30 (m, 3H), 2.30 – 2.15 (m, 2H), 2.05 – 1.93 (m, 1H), 1.80 (s, 3H), 1.70 – 1.50 (m, 3H), 1.47 – 1.35 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.4, 169.3, 162.4, 162.2, 147.5, 147.3, 127.2, 110.3, 110.2, 78.7, 78.8, 65.2, 40.6, 40.5, 37.61,

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(37.56), 30.6, 29.7, 28.4, 28.2, 26.7(4), 26.6(6), 20.8, 20.7, 20.2, 20.0, 19.1, 13.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H24O4Na 315.1567; Found 315.1565. Cyclohexyl 2-((6S)-3-oxo-6-(prop-1-en-2-yl)-1,3,4,5,6,7-hexahydroisobenzofuran1-yl)acetate (3m) Liquid; yield, 33.1mg, 52%; 1H NMR (400 MHz, CDCl3) δ 5.25 - 5.17 (m, 1H), 4.85 – 4.75 (m, 2H), 4.73 (s, 1H), 2.80 – 2.57 (m, 2H), 2.45 – 2.27 (m, 3H), 2.27 – 2.21 (m, 2H), 2.00 – 1.90 (m, 1H), 1.90 - 1.80 (m, 2H), 1.76 (s, 3H), 1.74 – 1.63 (m, 1H), 1.60 – 1.43 (m, 2H), 1.43 – 1.20 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 172.6, 172.5, 168.6(2), 168.6(1), 162.6, 162.4, 147.5, 147.4, 127.0, 110.3, 110.2, 78.8, 78.6, 73.9, 40.5(2), 40.5(0), 37.9, 37.8, 31.5, 28.4, 28.2, 26.7, 26.6, 25.3, 23.7, 20.8, 20.7, 20.2, 20.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H26O4Na 341.1723; Found 341.1741. tert-butyl 3-(2-methoxy-2-oxoethyl)-1-oxo-3,4,6,7-tetrahydrofuro[3,4-c]pyridine5(1H)-carboxylate (3n) Liquid; yield, 46.7mg, 75%; 1H NMR (400 MHz, CDCl3) δ 5.29 (s, 1H), 4.25 - 4.00 (m, 2H), 3.80 - 3.50(m, 5H), 2.80 - 2.65(m, 2H), 2.40(s, 2H), 1.47(s, 9H). 13C NMR (101 MHz, CDCl3) δ 170.4, 169.4, 161.9, 154.6, 125.5, 80.9, 79.0, 52.2, 40.3, 39.0, 36.7, 28.5, 23.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H21NO6Na 334.1261; Found 334.1253. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-1-oxo-3,4,6,7-tetrahydrofuro[3,4-c]pyridine5(1H)-carboxylate (3o) Liquid; yield, 29.3mg, 45%; 1H NMR (400 MHz, CDCl3) δ 5.30 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 4.14 – 4.00 (m, 2H), 3.79 – 3.69 (m, 1H), 3.59 – 3.50 (m, 1H), 2.80 – 2.65 (m, 2H), 2.41 (s, 2H), 1.48 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.6, 169.0, 161.7, 154.4, 125.3, 80.5, 78.9, 61.4, 39.9, 39.0, 37.0, 28.5,

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23.7, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H23NO6Na 348.1418; Found 348.1403. tert-Butyl 3-(2-(cyclohexyloxy)-2-oxoethyl)-1-oxo-3,4,6,7-tetrahydrofuro[3,4c]pyridine-5(1H)-carboxylate (3p) Liquid; yield, 51.5mg, 68%; 1H NMR (400 MHz, CDCl3) δ 5.29 (s, 1H), 4.80 (s, 1H), 4.22 - 4.08 (m, 2H), 3.85 - 3.65 (m, 1H), 3.65 – 3.45 (m, 1H), 2.80 – 2.60 (m, 2H), 2.50 – 2.30 (m, 2H), 1.95 – 1.80 (m, 2H), 1.80 – 1.65 (m, 2H), 1.53 – 1.10 (m, 15H). 13

C NMR (101 MHz, CDCl3) δ 170.5, 169.7, 168.5, 161.7, 154.7, 129.7, 125.6 115.1,

80.7, 78.8, 77.3, 74.2, 39.5, 38.9, 37.5, 31.5, 31.4, 29.7, 29.3, 28.4, 25.2(1), 25.1(5), 23.7, 23.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H29NO6Na

402.1887;

Found 402.1903. tert-Butyl 3-(2-butoxy-2-oxoethyl)-1-oxo-3,4,6,7-tetrahydrofuro[3,4-c]pyridine5(1H)-carboxylate (3q) Liquid; yield, 46.6mg, 66%; 1H NMR (400 MHz, CDCl3) δ 5.26 (s, 1H), 4.25 – 3.95 (m, 4H), 3.75 – 3.63 (m, 1H), 3.60 - 3.43 (m, 1H), 2.85 - 2.60 (m, 2H), 2.42 - 2.30 (m, 2H), 1.65 – 1.53 (m, 2H), 1.44 (s, 9H), 1.38 – 1.28 (m, 2H), 0.90(t, J = 6.8 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 169.3, 168.0, 160.6, 153.6, 124.4, 79.7, 77.8, 64.8,

64.3, 38.8, 36.2, 29.5, 29.3, 28.7, 27.4, 22.7, 18.0(4), 17.9(8), 12.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H27NO6Na 376.1731; Found 376.1739.

(S, Z)-Methyl 2-(3-oxo-6-(prop-1-en-2-yl)-4,5,6,7-tetrahydroisobenzofuran1(3H)-ylidene)acetate (4a) Liquid; yield, 35.2mg, 71%; 1H NMR (400 MHz, CDCl3) δ 5.37 (s, 1H), 4.88 (s, 1H), 4.79 (s, 1H), 3.84 (s, 3H), 2.62 – 2.49 (m, 2H), 2.44 - 2.27 (m, 3H), 2.10 – 1.97 (m, 1H), 1.82 (s, 3H), 1.72 – 1.57 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 167.8, 164.1,

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156.3, 151.9, 146.8, 131.9, 110.7, 96.3, 52.1, 40.1, 26.4, 26.0, 20.7, 20.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H16O4Na 271.0941; Found 271.0947. (S, Z)-Ethyl 2-(3-oxo-6-(prop-1-en-2-yl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)ylidene)acetate (4b) Liquid; yield, 33.5mg, 64%; 1H NMR (400 MHz, CDCl3) δ 5.35 (s, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 2.58 – 2.48 (m, 2H), 2.43 – 2.25 (m, 3H), 2.08 – 1.98 (m, 1H), 1.80 (s, 3H), 1.70 – 1.55 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.8, 163.6, 156.2, 151.9, 146.8, 131.8, 110.7, 96.7, 61.0, 40.2, 26.5, 26.0, 20.8, 20.5, 14.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H18O4Na 285.1097; Found 285.1095. (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)cyclopent-1-enecarboxylic acid (6a) White solid, mp 154-155 oC; yield, 34.1mg, 87%; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 16 Hz, 1H), 5.98 (d, J = 16 Hz, 1H), 3.73 (s, 3H), 2.80 - 2.60 (m, 4H), 1.95 1.80 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.2, 150.9, 137.8, 124.3, 51.9, 34.7, 34.2, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H12O4Na 219.0628; Found 219.0632. (E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)cyclopent-1-enecarboxylic acid (6b) White solid, mp 109-110 oC; yield, 31.5mg, 75%; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 16 Hz, 1H), 6.02 (d, J = 16 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.85 - 2.65 (m, 4H), 2.00 - 1.85 (m, 2H), 1.30 (t, J = 7.2Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.1, 166.7, 151.0, 137.5, 136.0, 124.9, 60.8, 34.7, 34.2, 21.1, 14.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H14O4Na 233.0784; Found 233.0796. (E)-2-(3-butoxy-3-oxoprop-1-en-1-yl)cyclopent-1-enecarboxylic acid (6c) White solid, mp 83-84 oC; yield, 30.0mg, 63%;1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 16Hz, 1H), 6.05 (d, J = 16Hz, 1H), 4.20 (t, J = 6.8 Hz, 2H), 2.87 - 2.67 (m, 4H), 2.03

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- 1.87 (m, 2H), 1.75 - 1.60 (m, 2H), 1.50 - 1.35 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.1, 166.8, 151.1, 137.5, 136.0, 124.8, 64.7, 34.6, 34.2, 30.7, 21.2, 19.2, 13.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18O4Na 261.1097; Found 261.1104. (E)-2-(3-benzyloxy-3-oxoprop-1-en-1-yl)cyclopent-1-enecarboxylic acid (6d) White solid, mp 116-118 oC; yield, 51.7mg, 95%; 1H NMR (400 MHz, CDCl3) δ 8.45(d, J = 16.0 Hz, 1H), 7.47 - 7.27 (m, 5H), 6.10 (d, J = 16.0 Hz, 1H), 5.24 (s, 2H), 2.85 - 2.77 (t, J = 7.6 Hz, 2H), 2.76 - 2.68 (t, J = 7.6 Hz, 2H), 2.01 - 1.90 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.2, 166.5, 150.9, 138.2, 136.4, 135.9, 128.6, 128.3, 128.2, 124.4, 66.5, 34.7, 34.2, 21.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H16O4Na 295.0941; Found 295.0928. (E)-2-(3-(cyclohexyloxy)-3-oxoprop-1-en-1-yl)cyclopent -1-enecarboxylic acid (6e) White solid, mp 122-123 oC; yield, 49.6mg, 94%; 1H NMR (400 MHz, CDCl3) δ 11.29 (b, 1H), 8.36 (d, J = 16.0 Hz, 1H), 6.05 (d, J = 16.0 Hz, 1H), 4.88 (s, 1H), 2.81 (m, 2H), 2.74 (m, 2H), 2.03 - 1.85 (m,4H), 1.83 - 1.78 (m, 2H), 1.63 - 1.23 (m, 6H). 13

C NMR (101 MHz, CDCl3) δ 170.2, 166.2, 151.0, 137.3, 136.0, 125.3, 73.1, 34.6,

34.2, 31.6, 25.4, 23.7, 21.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H20O4Na 287.1254; Found 287.1262.

ASSOCIATED CONTENT

Supporting Information Figures giving 1H and

13

C NMR spectra for all compounds and the computational

information for compound 5a and 6a are prepared. This information is available free of charge via the Internet at http://pubs.acs.org/. AUTHOR INFORMATION 18 / 20


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Corresponding Author E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEGEMENTS

We are grateful for the support from the National Natural Science Foundation of China (No. 21372134) and thank Prof. Chao-Jun Li (McGill University) for providing the lab and facility for the starting of the research. REFERENCES [1]

For recent reviews, see: a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451,

417; b) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076; c) Chen, D. Y. K.; Youn, S. W.; Chem. Eur. J. 2012, 18, 9452; d) Davies, H. M. L.; Lian, Y. Acc. Chem. Res. 2012, 45, 923; e) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem. Int. Ed. 2012, 51, 7507; Angew. Chem. 2012, 124, 7625; f) Wencel-Delord, J.; Glorius, F.; Nat. Chem. 2013, 5, 369. [2] a) Bond, G. C. Metal-Catalysed Reactions of Hydrocarbons, Kluwer Academic/Plenum Publishers, New York, 2005; b) Dyker, G. Handbook of CH Transformations: Applications in Organic Synthesis, Wiley-VCH, Weinheim, 2005; c) Yu, J.-Q.; Ackermann, L.; Shi, Z. C-H Activation, Springer, Heidelberg, 2010. [3] For recent reviews, see: a) Zhu, Y.-Q.; Li, J.-X.; Han, T.-F.; He, J.-L.; Zhu, K. Eur. J. Org. Chem. 2017, 2017, 806 and references cited therein; b) Warratz, S.; Kornhaass, C.; Cajaraville, A.; Niepoetter, B.; Stalke, Ackermann, D. L. Angew. Chem. Int. Ed. 2015, 54, 5513.; c) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. 19 / 20



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Chem. 1998, 63, 5211; d) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407; e) Shi, X; Li, C.-J. Adv. Synth. Catal. 2012, 354, 2933. [4] Zhu, Y.-Q.; Liu, Y.; Wang, H. N.; Liu, W. B.; Li, C.-J. Org. Chem. Front. 2016, 3, 971. [5] a) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891. b) Lin, G.; Chan, S. S.-K.; Chung H.-S.; Li, S.-L. Stud. Nat. Prod. Chem. 2005, 32, 611. [6] a) Lee, H. K.; Cho, C. S. Appl. Organometal. Chem. 2012, 26, 406. b) Miura, M.; Okuro, K.; Hattori, A.; Nomura, M. J. Chem. Soc., Perkin Trans. 1, 1989, (1), 73; c) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972; Hugelshofer, C. L.; Magauer, T. Angew. Chem. Int. Ed.2014, 53, 11351. d) Cho, C. S.; Kim, J. U.; Choi, H.-J. J. Organomet. Chem. 2008, 693, 3677. e) Wright, J; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am. Chem. Soc. 1988, 110, 5806. f) Sueki, S.; Wang, Z.; Kuninobu, Y. Org. Lett. 2016, 18, 304. g) Brownbridge, P.; Chan, T.-H. Tetrahedron Lett. 1980, 21, 3431. [7] See supporting information for computational details. [8] Jiang, Q.; Zhu, C.; Zhao, H.; Su, W. Chem. Asian J. 2016, 11, 356.

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ones from cyclo-Alkenecarboxylic Acids and Acrylates via CH Activation

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