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Selective Cleavage of Inert Aryl C-N Bonds in N-Aryl Amides Zhiguo Zhang, Dan Zheng, Yameng Wan, Guisheng Zhang, Jingjing Bi, Qingfeng Liu, Tongxin Liu, and Lei Shi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02880 • Publication Date (Web): 05 Jan 2018 Downloaded from http://pubs.acs.org on January 5, 2018

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The Journal of Organic Chemistry

Selective Cleavage of Inert Aryl C−N Bonds in N-Aryl Amides

Zhiguo Zhang,*a,b Dan Zheng,a Yameng Wan,a Guisheng Zhang,*a Jingjing Bi,a Qingfeng Liu,a Tongxin Liu,a and Lei Shia a

Henan Key laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center

of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,

Henan

453007,

China.

Fax:

(+86)-373-332-5250;

E-mail:

[email protected]

or

[email protected] b

Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal Univer-

sity, Jilin, Changchun, 130024, China.

Abstract: A highly selective, IBX-promoted reaction has been developed for the oxidative cleavage of inert C(aryl)−N bonds on secondary amides whilst leaving the C(carbonyl)−N bond unchanged. This metal-free reaction proceeds under mild conditions (HFIP/H2O, 25 °C), providing facile access to various useful primary amides, some of which would be otherwise unattainable using conventional aminolysis and hydrolysis approaches. Keywords: IBX; C(aryl)-N bond cleavage; Oxidation; Metal-free; Amides INTRODUCTION The cleavage of C(aryl)−N bonds could become an important process for the selective fragmentation of N-aryl amides into smaller molecules, which could be used as building blocks in synthetic organic chemistry1 and further transformed into high-value chemicals.2 Furthermore, the development of a process of this type could add considerable value to organic synthesis, because it could be used to expand the utility of aryl substituents as removable protecting group. However, the cleavage of the inert C(aryl)−N bonds of N-aryl amides has been largely unexplored to date for two main reasons:3 (i) ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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C(carbonyl)–N bonds are generally broken prior to C(aryl)−N bonds in N-aryl amide when they are attacked by a suitable nucleophile (such as amide hydrolysis)4 because of the low bond dissociation energy of the former (95 kcal/mol) compared with the latter (104 kcal/mol) (Scheme 1);5 (ii) it can be difficult to stop reactions of this type at the C(aryl)−N bond cleavage stage without further derivatization.6 A review of the literature revealed that there is an urgent need for the development of a new method for the cleavage of the inert C(aryl)−N bonds of N-aryl amides using a highly selective and simplified catalyst system.

Scheme 1. Dissociation energies of C-N bonds of amides. Existing C(aryl)−N bond cleavage reactions are limited to a specific set of reagents, including aromatic hydrazines7 and N,N’-dimethyl substituted aromatic compounds.8 Compounds belonging to these two classes can be readily reacted with an electrophilic partner such as an aryl halide, aryl triflate or arylboronic acid in the presence of a suitable metal catalyst to afford the corresponding cross-coupling products (Eq. 1).9 Besides, the numbered cases of cleavage of the C(aryl)−N bond of some certain tertiary N-aryl amides with the help of a nickel(0) catalyst6 and ceric ammonium nitrate (CAN)10 are reported. Thus it can be seen that development of new methods to cleave the inert C(aryl)−N bonds using more types of N-aryl amides whilst leaving the C(carbonyl)−N bond unchanged are highly desirable. Herein, we report the development of a highly selective, 2-iodoxybenzoic acid (IBX)-mediated reaction for the oxidative cleavage of inert C(aryl)−N bonds in electronically neutral secondary aromatic amides in a mixed solvent system of hexafluoroisopropanol (HFIP) and water at 25 °C (Eq. 2). This novel metal-free method allows for the regioselective cleavage of inert C(aryl)−N bonds, thereby allowing the aryl groups to be used as removable protecting groups. This method could therefore be used to achieve the synthesis of a wide range of primary amides, and represents a valuable addition to the limited number of methods currently available for the cleavage of C(aryl)−N bonds.11

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IBX is a commercially available hypervalent iodine(V) reagent12 that has been widely used in organic synthesis to achieve a variety of different transformations, including the oxidization of alcohols to aldehydes13 and the oxidative cleavage of the C–C bonds of glycols to give two aldehydes or ketones.14 A review of the literature revealed that there are currently no methods available for the selective oxidative cleavage of the inert C(aryl)−N bonds in N-aryl amides using a hypervalent iodine reagent. We recently established two new reliable, efficient and green methods for the synthesis of 1H-indazoles and spirocyclopropane quinolinediones under mild conditions. Notably, both of these methods required the presence of a hypervalent iodine reagent and proceeded via an intramolecular oxidative C–N bond forming reaction.15 Encouraged by these results, we became interested in expanding the scope of organoiodine reagents in organic synthesis. RESULTS AND DISCUSSION We initiated our study using IBX with amide 1l as a model substrate. After several screening experiments, we found that the cleavage reaction occurred regiospecifically at the C(aryl)−N bond of the amide substrate when it was treated with 2.2 equiv. of IBX in a 2:1 (v/v) mixture of HFIP and H2O at 25 °C for 29 h. Furthermore, this reaction gave the desired primary amide in 83% yield (Table 1, entry 5). Given that IBX is insoluble in water, most of the amide substrate 1l was recovered when the reaction was performed in water (Table 1, entry 1). Interestingly, the reaction also failed to any of the desired product when it was conducted in HFIP (Table 1, entry 2). These preliminary results indicated that water plays an important role in the transformation. Further investigation revealed that the relative proportion of HFIP to H2O had a pronounced influence on the outcome of the reaction. (Table 1, entries 3 and 4). Increasing or decreasing the amount of IBX led to a decrease in the yield of 2l (Table 1, entries 6 and 7). ACS Paragon Plus Environment


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Accordingly, the optimum amount of IBX was determined to be 2.2 equiv. in terms of the yield of 2l. Several other hypervalent iodine reagents were also screened against this reaction, including [bis(trifluoroacetoxy)iodo]benzene (PIFA), phenyliodonium diacetate (PIDA), 1,1,1-triacetoxy-1,1-dihydro1,2-benziodoxol-3(1H)-one (DMP) and PhIO, but were all found to be much less efficient than IBX (Table 1, entries 8−11). The reaction was also screened against a variety of different mixed solvents at a ratio of 2:1, including TFE/H2O, 2,2,3,3-tetrafluoro-1-propanol (TFP)/H2O, 2,2,3,3,4,4,5,5-octafluoro-1pentanol (OFP)/H2O, trifluoroacetic acid ethyl ester (TFAET)/H2O, DMSO/H2O, DMF/H2O and DMF/H2O. However, all of these systems were found to be much less efficient than HFIP/H2O (Table 1, entries 12−17). It is noteworthy that this reaction was found to be amenable to gram-scale synthesis, as exemplified by the reaction of 1l (10.2 g, 40 mmol), which afforded 2l in 78% yield (5.18 g, 31 mmol). Table 1. Survey of the Reaction Conditionsa

Entry

Oxidant (equiv)

Solvent

Time

2l/%

Recovered of 1l/%

1

IBX (2.2)

H2O

3d

0

90

2

IBX (2.2)

HFIP

3d

0

92

3

IBX (2.2)

HFIP/H2O = 1:1

29 h

58

28

4

IBX (2.2)

HFIP/H2O = 3:1

29 h

69

21

5

IBX (2.2)

HFIP/H2O = 2:1

29 h

83

0

6

IBX (1.2)

HFIP/H2O = 2:1

3d

46

40

7

IBX (3.2)

HFIP/H2O = 2:1

3d

56

28

8

PIFA (2.2)

HFIP/H2O = 2:1

29 h

50

31

9

PIDA (2.2)

HFIP/H2O = 2:1

29 h

59

32

10

DMP (2.2)

HFIP/H2O = 2:1

29 h

45

40


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a


11

PhIO (2.2)

HFIP/H2O = 2:1

29 h

22

0

12

IBX (2.2)

TFE/H2O = 2:1

2.5 d

78

0

13

IBX (2.2)

TFP/H2O = 2:1

29 h

trace

75

14

IBX (2.2)

OFP/H2O = 2:1

3d

10

67

15

IBX (2.2)

TFAET/H2O = 2:1

3d

0

80

16

IBX (2.2)

DMSO/H2O = 2:1

3d

0

78

17

IBX (2.2)

DMF/H2O = 2:1

3d

0

72

Unless otherwise indicated, all of these reactions were conducted with 1l (0.2 mmol) in 2 mL of sol-

vent at 25 °C. With the optimized conditions in hand (Table 1, entry 5), we proceeded to investigate the scope of this intramolecular C(aryl)−N bond cleavage reaction (Table 2). We initially investigated the scope of the R2 group using a variety of different secondary amides (1a–f) bearing an electron-donating group (EDG) (e.g., -Me and -OMe) at their para-, ortho- or meta-position. We also investigated the unsubstituted system 1g for comparison. Pleasingly, all of these substrates afforded the desired products in 68– 78% yields. It is noteworthy that compound 1a was recovered in 19% yield and that this material could not be converted to 2a even after a prolonged reaction time of 5 days. Compound 1g also behaved in a similar manner. However, substrate 1h bearing a weak electron-withdrawing group (EWG) (-Cl) at its para-position and 1i (aliphatic amide) failed to afford the desired products, with the majority of these starting materials being recovered unchanged. This limitation suggested that IBX exhibited its activity via the formation of an interaction with the phenyl ring of the substrate (with the exception of phenyl rings bearing EWG). Based on these results, the p-methylphenyl group was selected as the best leaving group to investigate the scope of the R1 group. The results revealed that substituted phenyl groups bearing an EDG (e.g., 1j: -OMe, 1k: -NH2) or EWG (e.g., 1l−n: -NO2) at their ortho-, meta- or paraposition were tolerated, affording the desired amides in moderate to good yields (67–88%). Several other secondary amides (1o–u) also reacted smoothly under the optimized conditions to afford the corre-



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sponding amides in 44–85% yields. It is noteworthy that no excessive oxidation products were generated for the cinnamic acid amide (1q),16 thiobenzamide (1s),17 2-phenyl-N-(p-tolyl)acetamide (1t)18 and dodecanamide (1u) substrates.19 These results therefore highlight the selectivity of this new method. Further investigation revealed that this reaction was not amenable to the tertiary amide 1v or annular amide 1w, with most of these starting materials being recovered. The results therefore demonstrated that an IBX-oxidizable N−H moiety was important to the success of this reaction and that IBX could interact more effectively with acyclic amides. Table 2. Extension of the Reaction Scopea

1a: 2 d, 77%b

1b: 2 d, 75%

1c: 2 d, 70%

1d: 28 h, 78%

1f: 34 h, 68%

1g: 2 d, 72%c

1h: 5 d, NRd

1i: 5 d, NRe

1k: 4.5 h, 79%

1l: 29 h, 83%

1m: 22 h, 79%

1n: 16 h, 88%

1p: 48 h, 44%f

1q: 8 h, 83%

1r: 3 d, 76%

1s: 2 d, 74%

1u: 32 h, 72%g

1v: 5 d, NRh

1w: 5 d, NRi


1e: 32 h, 72%

1j: 28 h, 67%

1o: 6 h, 79%

1t: 48 h, 85%

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Unless otherwise indicated, all of these reactions were conducted with 1 (0.2 mmol) and IBX (2.2

equiv.) in 2 mL of the mixed solvent system (VHFIP/VH2O = 2 : 1) at 25 °C. b Compound 1a was recovered in 19% yield. c Compound 1g was recovered in 9% yield. d Compound 1h was recovered in 88% yield. e Compound 1i was recovered in 83% yield. f Compound 1p was recovered in 38% yield.

g

Compound 1u was recovered in 16% yield. h Compound 1v was recovered in 82% yield. i Compound 1w was recovered in 73% yield. A control experiment was performed with N-(naphthalen-1-yl)benzamide (1x) under the optimized conditions, resulting in the formation of benzamide in 72% yield, along with the corresponding 1,4naphthoquinone by-product, which was isolated in 60% yield (Eq. 3).20 A separate experiment starting from 1-naphthalenol also resulted in the formation of 1,4-naphthoquinone in 63% yield (Eq. 4). This result revealed that the aryl group on the nitrogen atom of compound 1 was being released in the form of the corresponding phenol. This result therefore explains why this reaction requires 2.2 equivalents of IBX. To further investigate the source of the oxygen atom incorporated in the 1,4-naphthoquinone, we conducted an experiment using

18

O-labeled H2O (Eq. 5). Mass spectrometry (MS) analysis of the two

products generated during this transformation suggested that

18

O was incorporated in 1,4-

naphthoquinone, indicating that H2O was acting as a nucleophilic oxygen donor and attacking the aryl group of the amides. It is noteworthy that 2-iodobenzoic acid was detected by TLC and HRMS in all of these reactions.



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Table 3. Radical Trapping Experimentsa Radical donors

None

TEMPO

PBN

DPE

Galvinoxyl

Yield of 2l/%

83

78

70

80

76

a

All of these reactions were conducted with 1l (0.2 mmol), IBX (2.2 equiv.) and radical trapping agents

(1 equiv.) in 2 mL of the mixed solvent system (VHFIP/VH2O = 2 : 1) at 25 °C. Yields were that of isolated products. Kits’s work21 showed that 1,4-naphthoquinone could be generated from 1-naphthalenol or naphthalene free radicals. With this in mind, we investigated the effects of adding four different radical scavengers (100 mol%) to the reaction of 1l under the optimized conditions to determine whether it proceeded via a radical intermediate (Table 3). The results revealed that the reaction proceed smoothly in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), N-benzylidene-tert-butylamine N-oxide (PBN), 1,1-diphenylethylene (DPE) and galvinoxyl radical scavengers, which suggested that this reaction did not involve a radical species. Based on the results of the current study, as well as previously published results from the literature,2122

we proposed a plausible mechanism for this reaction (Scheme 2). The initial interaction of IBX with 1

would result in formation of the annular π–complex species A,21-22 which would be attacked by the hydroxy derived from H2O, resulting in the regioselective cleavage of the C(aryl)−N bond in intermediate A to provide primary amide 2, 2-iodobenzoic acid and phenol, and the resulting phenol generated in site was then oxidized rapidly to the quinones by the excessive IBX (Scheme 2).23 The poor reactivity of substrates 1h, 1i and 1w could be attributed to their inability to form the π−complex A. The fact of C(aryl)−N bond of compound 1v being not cleaved indicated that secondary amides conducive to the formation of intermediate A.


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Scheme 2. Proposed Mechanism. Table 4. Application of the C(aryl)−N bond cleavage reactiona

2a’: 3 h, 86%

2f’: 24 h, 73%

2b’: 15 h, 88%

2g’: 36 h, 82%

2c’: 29 h, 71%

2d’: 2 d, 68%

2e’: 15 h, 68%

2h’: 37 h, 77%

2i’: 48 h, 80%

2j’: 45 h, 65%

2k’: 5 h, 42%[b] 2l’: 48 h, 79% a

Unless otherwise indicated, all of these reactions were conducted with 1 (0.2 mmol), IBX (2.2

equiv.) in 2 mL of the mixed solvent system (VHFIP/VH2O = 2 : 1) at 25 °C, and with the 4-Me-C6H4group serving as the leaving group. b Starting material 1k’ was recovered in 19% yield. Pleasingly, our newly developed method provided facile access to several primary amide derivatives that were otherwise difficult or impossible to prepare using conventional methods (Table 4).24 For example, this new strategy provided access to a variety of useful cyclopropyl-containing β-keto amides 1a–e’ in moderate to good yields (65–88%) from the corresponding doubly activated cyclopropanes25 without affecting the highly reactive cyclopropyl26 or oxime ether moieties.27 However, the reaction of the benzyl alcohol analogue 3a’ still afforded the β-keto amide 2a’ (Eq. 6).18a

Notably, we successfully extended this reaction to a wide variety of α-mono- and α,α-disubstituted βketoamides (1f’–j’), which afforded the desired amides in satisfactory yields (65–82%).28 Pleasingly, this method also allowed for the successful construction of 3-oxo-3-phenylpropanamide (2k’), however,



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2k’ decomposed when the reaction time was extended to more than 5 h. α-Oxo ketene dithioacetal 1l’ also reacted smoothly to give the corresponding product 2l’ in 79% yield without oxidizing the dithioacetal moiety.29 This result contrasted with that of our previous report, where IBX oxidized thiols to the corresponding disulfides.30 To further demonstrate the synthetic potential of this chemistry, we investigated the conversion of the L-lysine derivative (S)-1m’ under the standard reaction conditions. The results revealed that the 4-methylphenyl group of (S)-1m’ was readily removed and gave the desired product (S)-2m’ in 81% yield based on the 69% conversion rate of (S)-1m’ after 48 h, without change the enantiopurity (Eq. 7).31 This case highlighted key benefit of this C−N bond cleavage strategy in terms of its regioselectivity for C(aryl)−N bonds over other C−N bond types.

CONCLUSION In summary, we have developed a highly selective, IBX-promoted reaction for the oxidative cleavage of the inert C(aryl)−N bond of electronically neutral and structurally simple N-aryl amides. In contrast to previously reported nickel catalysts,6 the use of IBX offers operational convenience, as well as being unique in terms of its effectiveness for the cleavage of C(aryl)−N bonds of secondary amides whilst leaving the C(carbonyl)−N bond untouched. Notably, this study represents the first reported example of the use of an aryl group as a removable protecting group in the absence of metal catalyst under mild conditions. Although some of the aryl groups evaluated in the currently study reacted inefficiently, this method could be used to remove a variety of different aryl groups from the N atom of amides. Overall, we have developed a new strategy for the cleavage of the C(aryl)−N bonds of secondary amides to give the corresponding primary amides. Notably, this route provided access to 2-oxoamides and α-substituted benzoylacetamides, which are otherwise unattainable using conventional aminolysis and hydrolysis methods. EXPERIMENTAL SECTION ACS Paragon Plus Environment

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General Remarks. All reactions were carried out under air atmosphere, unless otherwise indicated. Other all reagents were purchased from commercial sources and used without further treatment, unless otherwise indicated. Petroleum ether (PE) used refers to the 60-90 oC boiling point fraction of petroleum. 1H NMR and 13C{1H} NMR spectra were recorded on Bruker Avance/600 (1H: 600 MHz, 13C{1H}: 150 MHz at 25 ºC) or Bruker Avance/400 (1H: 400 MHz, 13C{1H}: 100 MHz at 25 ºC) and TMS as internal standard. Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz). All high-resolution mass spectra (HRMS) were measured on a mass spectrometer by using electrospray ionization (ESI-oa-TOF), and the purity of all samples used for HRMS (>95%) were conﬁrmed by 1H NMR and

13

C{1H} NMR spectroscopic analysis. Melting points were measured on a

melting point apparatus equipped with a thermometer and were uncorrected. All reactions were monitored by TLC with GF254 silica gel coated plates. Flash chromatography was carried out on SiO2 (silica gel 200-300 mesh). Typical Experimental Procedure For 2 (2l as an example). To a round-bottom flask (25 mL) was added 4-nitro-N-(p-tolyl)benzamide 1l (51.2 mg, 0.2 mmol), and IBX (123 mg, 0.44 mmol), then the mixture was well stirred for 29 h in 2 mL mixed-solvent (VHFIP/VH2O = 2 : 1) at 25 oC (the whole process was closely monitored by TLC). Afterward the resulting solution was filtered through a plug of celite and the residue was washed with ethyl acetate (EA) (4 mL × 3). Then the organic solvent was concentrated in vacuo. The residue was purified by flash column chromatography with EA and PE as eluent to give primary amide 2l as white solid (27.6 mg, 83%).

Benzamide (2a). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (19 mg, 77%); mp: 127-128 oC; 1H NMR (600 MHz, DMSO) δ 7.98 (s, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 6.9 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.38 (s, 1H).

13

C NMR (150 MHz, CDCl3) δ

169.6, 133.4, 132.0, 128.6, 127.4. HRMS (ESI), m/z calcd. for C7H7NNaO ([M+Na]+) 144.0420, found: 144.0425. ACS Paragon Plus Environment


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4-Methoxybenzamide (2j).32 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (20 mg, 67%); mp: 166-167 oC; 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.97 (s, 1H), 5.75 (s, 1H), 3.86 (s, 3H).13C NMR (150 MHz, CDCl3) δ 168.9, 162.6, 129.3, 125.6, 113.8, 55.5. HRMS (ESI), m/z calcd. for C8H9NNaO2 ([M+Na]+) 174.0525, found: 174.0525. 2-Aminobenzamide (2k).32 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (21 mg, 79%); mp: 111-114 oC; 1H NMR (600 MHz, DMSO) δ 7.72 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 (s, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.55 (s, 2H), 6.48 (t, J = 7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.6, 149.4, 133.0, 128.0, 117.4, 116.4, 114.0. HRMS (ESI), m/z calcd. for C7H8N2NaO ([M+Na]+) 159.0529, found: 159.0529. 4-Nitrobenzamide (2l).32 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (27 mg, 83%); mp: 198-202 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.30 (t, J = 9.0 Hz, 3H), 8.10 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H).13C NMR (150 MHz, DMSO-d6) δ 166.7, 149.5, 140.5, 129.4, 123.9. HRMS (ESI), m/z calcd. for C7H7N2O3 ([M+H]+) 167.0451, found: 167.0452. 3-Nitrobenzamide (2m).32 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (26 mg, 79%); mp: 140-144 oC; 1H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 6.23 (s, 1H), 5.89 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 166.6, 134.9, 133.5, 130.0, 126.6, 122.3. HRMS (ESI), m/z calcd. for C7H6N2NaO3 ([M+Na]+) 189.0271, found: 189.0270. 2-Nitrobenzamide (2n).33 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (29 mg, 88%); mp: 175-179 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.78-7.75 (m, 1H), 7.69 (s, 1H), 7.68-7.65 (m, 1H), 7.63 (d, J = 7.8, 1H). 13C NMR (150 MHz, DMSO-d6) δ 167.6, 147.7, 133.8, 133.1, 131.1, 129.3, 124.4. HRMS (ESI), m/z calcd. for C7H6N2NaO3 ([M+Na]+) 189.0271, found: 189.0270. Furan-2-carboxamide (2o).34 The product was isolated by flash chromatography (eluent: EA:PE = ACS Paragon Plus Environment

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1:2) as a light yellow solid (17 mg, 79%); mp: 138-142 oC; 1H NMR (600 MHz, CDCl3) δ 7.46 (s, 1H), 7.18-7.14 (m, 1H), 6.51 (d, J = 3.6 Hz, 1H), 6.29 (s, 1H), 6.11 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 160.2, 147.4, 144.4, 115.2, 112.3. HRMS (ESI), m/z calcd. for C5H5NNaO2 ([M+Na]+) 134.0212, found: 134.0206. Quinoline-2-carboxamide (2p).32 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (15 mg, 44%); mp: 146-148 oC; 1H NMR (600 MHz, CDCl3) δ 8.35 – 8.27 (m, 2H), 8.12 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 6.35 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 166.9, 149.4, 146.7, 137.5, 130.2, 129.9, 129.4, 128.1, 127.8, 118.8. HRMS (ESI), m/z calcd. for C10H9N2O ([M+H]+) 173.0709, found: 173.0717. Cinnamamide (2q).34 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (24 mg, 83%); mp: 146-150 oC; 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 15.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.37 (d, J = 3.6 Hz, 3H), 6.47 (d, J = 15.6 Hz, 1H), 5.84 (s, 1H), 5.71 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 167.9, 142.5, 134.5, 130.0, 128.8, 127.9, 119.5. HRMS (ESI), m/z calcd. for C9H9NO ([M+H]+) 148.0757, found: 148.0775. 2-Oxo-2-phenylacetamide (2r).35 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (23 mg, 76%); mp: 90-93 oC; 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H).

13

C NMR (150 MHz, CDCl3) δ 163.1, 134.3,

129.8, 128.9, 125.7. Benzothioamide (2s). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a yellow solid (20 mg, 74%); mp: 114-117 oC; 1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.24 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 202.9, 139.2, 132.0, 128.5, 126.9. 2-Phenylacetamide (2t).35 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (23 mg, 85%); mp: 157-159 oC; 1H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 6.0 Hz, 2H), 7.27 (d, J = 6.6 Hz, 3H), 5.89 (s, 1H), 5.43 (s, 1H), 3.58 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 173.65, ACS Paragon Plus Environment


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134.89, 129.40, 129.06, 127.44, 43.35. HRMS (ESI), m/z calcd. for C8H9NNaO ([M+Na]+) 158.0576, found: 158.0581. Dodecanamide (2u).36 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (29 mg, 72%); mp: 100-103 oC; 1H NMR (600 MHz, CDCl3) δ 5.70 (s, 1H), 5.46 (s, 1H), 2.26-2.15 (m, 2H), 1.62 (d, J = 7.2 Hz, 2H), 1.35-1.21 (m, 16H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 175.88, 35.99, 31.91, 29.61, 29.48, 29.34 (d, J = 1.7 Hz), 29.3, 25.6, 22.7, 14.1. HRMS (ESI), m/z calcd. for C12H25NNaO ([M+Na]+) 222.1828, found: 222.1826. 1-Benzoylcyclopropane-1-carboxamide (2a’).26 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (32 mg, 86%); mp: 127-128 oC; 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 5.85 (s, 1H), 5.58 (s, 1H), 1.66 (dd, J1 = 4.8 Hz, J2 = 2.8 Hz, 2H), 1.43 (dd, J1 = 5.0 Hz, J2 = 2.6 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 197.9, 171.8, 136.1, 133.3, 128.8, 128.7, 34.6, 15.8. HRMS (ESI), m/z calcd. for C11H11NNaO2 ([M+Na]+) 212.0682, found: 212.0691. 1-(4-Methoxybenzoyl)cyclopropane-1-carboxamide (2b’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (39 mg, 88%); mp: 143-145 oC; 1H NMR (600 MHz, DMSO-d6) δ 7.90-7.84 (m, 2H), 7.20 (s, 1H), 7.05 (s, 1H), 7.05-7.01 (m, 2H), 3.83 (s, 3H), 1.36 (dd, J1 = 7.2 Hz, J2 = 4.2 Hz, 2H), 1.21 (dd, J2 = 7.2 Hz, J2 = 4.2 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 194.5, 172.3, 163.4, 131.2, 129.8, 114.2, 56.0, 35.0, 14.0. HRMS (ESI), m/z calcd. for C12H13NNaO3 ([M+Na]+) 242.0788, found: 242.0788. 1-Acetylcyclopropane-1-carboxamide (2c’).37 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (18 mg, 71%); mp: 85-87 oC; 1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 5.82 (s, 1H), 1.97 (s, 3H), 1.86 (dd, J1 = 7.2 Hz, J2 = 3.6 Hz, 2H), 1.53 (dd, J1 = 6.6 Hz, J2 = 4.2 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 207.0, 171.3, 34.3, 24.9, 19.51 19.50. HRMS (ESI), m/z calcd. for C6H9NNaO2 ([M+Na]+) 150.0525, found: 150.0529.


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1-Cyanocyclopropane-1-carboxamide (2d’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (15 mg, 68%); mp: 105-108 oC; 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 5.94 (s, 1H), 1.70 (dd, J1 = 8.0 Hz, J2 = 4.4 Hz, 2H), 1.55 (dd, J1 = 8.0 Hz, J2 = 4.4 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 167.4, 120.1, 18.1, 13.1. HRMS (ESI), m/z calcd. for C5H6N2O ([M+H]+) 111.0553, found: 111.0561. (Z)-1-((Acetoxyimino)(phenyl)methyl)cyclopropane-1-carboxamide(2e’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (50 mg, 68%); mp: 172-175 oC; 1H NMR (600 MHz, CDCl3) δ 7.52 (s, 1H), 7.44 (s, 3H), 7.37 (d, J = 5.4 Hz, 2H), 5.51 (s, 1H), 2.02 (s, 3H), 1.69 (s, 2H), 1.14 (s, 2H).

13

C NMR (150 MHz, CDCl3) δ 172.18, 168.18, 167.79, 131.16, 130.20, 128.46,

127.91, 29.13, 19.37, 16.54. HRMS (ESI), m/z calcd. for C13H14N2NaO3 ([M+Na]+) 269.0897, found: 269.0895. 1-benzoylcyclopentane-1-carboxamide (2f’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (32 mg, 73%); mp: 132-135 oC; 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 5.67 (s, 1H), 5.50 (s, 1H), 2.402.30 (m, 4H), 1.74-1.67 (m, 2H), 1.62-1.54 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 199.5, 174.6, 135.2, 133.0, 129.3, 128.4, 65.8, 34.8, 26.0. HRMS (ESI), m/z calcd. for C13H15NNaO2 ([M+Na]+) 240.0995, found: 240.1003. 2-Benzoyl-2-ethylbutanamide (2g’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (36 mg, 82%); mp: 125-130 oC; 1H NMR (400 MHz, CDCl3) δ 77.957.88 (m, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 5.57 (s, 1H), 5.49 (s, 1H), 2.15-2.00 (m, 4H), 0.76 (t, J = 7.6 Hz, 6H).

13

C NMR (100 MHz, DMSO-d6) δ 198.7, 174.2, 136.1, 132.5, 128.4,

128.1, 61.5, 23.9, 7.7. HRMS (ESI), m/z calcd. for C13H17NNaO2 ([M+Na]+) 242.1151, found: 242.1158. 2-Benzoylbutanamide (2h’).38 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (29 mg, 77%); mp: 146-149 oC; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.60 (s, 1H), 5.50 (s, 1H), 4.29 (t, J = 7.2 Hz, 1H),



Page 16 of 22

2.14 – 1.94 (m, 2H), 1.00 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 195.8, 170.7, 136.4, 133.2, 128.6, 128.1, 56.0, 21.9, 11.9. HRMS (ESI), m/z calcd. for C11H14NO2 ([M+H]+) 192.1019, found: 192.1024. 2,2-Difluoro-3-oxo-3-phenylpropanamide (2i’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (30 mg, 80%); mp: 93-96 oC; 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 7.8 Hz, 2H), 7.66 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 6.55 (s, 1H), 6.47 (s, 1H).

13

C

NMR (150 MHz, CDCl3) δ 187.0 (t, J = 27.0 Hz), 163.6 (t, J = 27.9 Hz), 135.1, 131.5, 130.4 (t, J = 2.8 Hz), 128.9, 110.7 (t, J = 264.0 Hz). HRMS (ESI), m/z calcd. for C9H7F2NNaO2 ([M+Na]+) 222.0337, found: 222.0341. 2-Fluoro-3-oxo-3-phenylpropanamide (2j’). The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (24 mg, 65%); mp: 124-127 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.05-8.02 (m, 2H), 8.01 (s, 1H), 7.79 (s, 1H), 7.72-7.69 (m, 1H), 7.57 (t, J = 7.8 Hz, 2H), 6.40 (d, J = 48.0 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 192.2 (d, J = 18.0 Hz), 166.7 (d, J = 20.7 Hz), 134.7, 134.5, 129.8, 129.1, 90.7 (d, J = 192.3 Hz). HRMS (ESI), m/z calcd. for C9H8FNNaO2 ([M+Na]+) 204.0431, found: 204.0437. 3-Oxo-3-phenylpropanamide (2k’).39 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (14 mg, 42%); mp: 103-106 oC; 1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.12 (s, 1H), 5.80 (s, 1H), 3.98 (s, 2H). 13

C NMR (150 MHz, CDCl3) δ 195.6, 168.1, 136.1, 134.1, 128.9, 128.5, 45.0. HRMS (ESI), m/z calcd.

for C9H10NO2 ([M+H]+) 164.0706, found: 164.0714. 2-(1,3-Dithiolan-2-ylidene)-3-oxobutanamide(2l’).40 The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (32 mg, 79%); mp: 217-220 oC; 1H NMR (600 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.49 (s, 1H), 3.37 (d, J = 3.6 Hz, 2H), 3.35 (d, J = 3.6 Hz, 2H), 2.17 (s, 3H). 13

C NMR (150 MHz, DMSO-d6) δ 190.7, 169.6, 165.9, 124.9, 38.6, 36.4, 28.0. HRMS (ESI), m/z calcd.

for C7H9NNaO2S2 ([M+Na]+) 225.9967, found: 225.9971.


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(9H-Fluoren-9-yl)methyl tert-butyl (6-oxo-6-(p-tolylamino)hexane-1,5-diyl)(S)-dicarbamate [(S)1m’]. The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (1.25 g, 90%); mp: 136-139 oC; 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.61-7.54 (m, 2H), 7.38 (t, J = 8.4 Hz, 4H), 7.29 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.63 (s, 1H), 4.64 (s, 1H), 4.41 (s, 2H), 4.28 (s, 1H), 4.20 (t, J = 6.8 Hz, 1H), 3.13-3.06 (m, 2H), 2.30 (s, 3H), 1.97 (s, 1H), 1.70 (s, 1H), 1.50 (s, 2H), 1.43 (s, 9H), 1.31-1.22 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 169.9, 156.3, 143.7, 141.3, 135.0, 134.1, 129.5, 127.8, 127.1, 125.1, 120.1, 120.0, 79.4, 67.2, 55.5, 47.1, 39.6, 31.8, 29.5, 28.4, 22.5, 20.9. HRMS (ESI), m/z calcd. for C33H40N3O5 ([M+H]+) 558.2968, found: 558.2970. Chiral HPLC purity: 100% ee (254 nm) [tR (major) = 11.37 min]. (9H-Fluoren-9-yl) methyl tert-butyl (6-amino-6-oxohexane-1,5-diyl)(S)-dicarbamate [(S)-2m’]. The product was isolated by flash chromatography (eluent: EA:PE = 7:10) as a white solid (42 mg, 45%); mp: 118-120 oC; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 6.22 (s, 1H), 5.68 (d, J = 6.8 Hz, 2H), 4.66 (s, 1H), 4.424.40 (m, 2H), 4.19 (t, J = 6.4 Hz, 2H), 4.15-4.09 (m, 1H), 3.09 (s, 2H), 1.86-1.81 (m, 2H), 1.72-1.68 (m, 1H), 1.42 (s, 9H), 1.26 (t, J = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 174.28, 156.30, 143.75 (d, J = 3.4 Hz), 141.3, 127.8, 127.1, 125.1, 120.0, 67.0, 60.4, 54.4, 47.2, 39.8, 31.7, 29.6, 28.4, 22.4, 14.2. HRMS (ESI), m/z calcd. for C26H34N3O5 ([M+H]+) 468.2498, found: 468.2495. Chiral HPLC purity: 99.43% ee (254 nm) [tR (major) = 16.47 min, tR (minor) = 12.87 min]. (9H-Fluoren-9-yl)methyl tert-butyl (6-oxo-6-(p-tolylamino)hexane-1,5-diyl)(R)-dicarbamate [(R)1m’]. The product was isolated by flash chromatography (eluent: EA:PE = 1:2) as a white solid (1.28 g, 92%); mp: 162-164 oC; 1H NMR (600 MHz, CDCl3) δ 8.21 (s, 1H), 7.75 (d, J = 6.6 Hz, 2H), 7.58 (s, 2H), 7.39 (s, 4H), 7.28 (s, 2H), 7.10 (d, J = 7.8 Hz, 2H), 5.61 (s, 1H), 4.64 (s, 1H), 4.42 (s, 2H), 4.28 (s, 1H), 4.21 (t, J = 6.6 Hz, 1H), 3.16 (s, 1H), 3.10 (s, 1H), 2.31 (s, 3H), 1.98 (s, 1H), 1.67 (s, 2H), 1.53 (s, 2H), 1.43 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 169.9 156.6, 156.3, 143.7, 141.3, 135.0, 134.1, 129.4, 127.7, 127.1, 125.0, 120.1, 120.0, 79.3, 67.2, 55.4, 47.1, 39.6, 31.7, 29.5, 28.4, 22.4, 20.9. HRMS (ESI),



Page 18 of 22

m/z calcd. for C33H39N3NaO5 ([M+Na]+) 580.2782, found: 580.2782. Chiral HPLC purity: 100% ee (254 nm) [tR (major) = 9.97 min]. (9H-Fluoren-9-yl)methyl tert-butyl (6-amino-6-oxohexane-1,5-diyl)(R)-dicarbamate [(R)-2m’]. The product was isolated by flash chromatography (eluent: EA:PE = 7:10) as a white solid (61 mg, 65%); mp: 105-108 oC; 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 6.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 6.18 (s, 1H), 5.59 (s, 2H), 4.64 (s, 1H), 4.49-4.35 (m, 2H), 4.19 (m, 2H), 3.11 (s, 2H), 1.87 (s, 1H), 1.72 (s, 3H), 1.50 (s, 2H), 1.42 (s, 9H), 1.39 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 174.5, 156.5, 156.3, 143.8, 141.3, 127.8, 127.1, 125.1, 120.0, 79.3, 67.0, 54.4, 47.2, 39.8, 31.7, 29.6, 28.4, 22.4. HRMS (ESI), m/z calcd. for C26H33N3NaO5 ([M+Na]+) 490.2303, found: 490.2312. Chiral HPLC purity: 99.75% ee (254 nm) [tR (major) = 12.83 min, tR (minor) = 16.48 min]. 1-(Hydroxy(phenyl)methyl)-N-(p-tolyl)cyclopropane-1-carboxamide (3a’). The product was isolated by flash chromatography (eluent: EA:PE = 3:10) as a white solid (0.74 g, 88%); mp: 133-137 oC; 1H NMR (600 MHz, CDCl3) δ 8.94 (s, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.29-7.25 (m, 3H), 7.04 (d, J = 7.8 Hz, 2H), 4.58 (s, 1H), 3.19 (s, 1H), 2.26 (s, 3H), 1.61-1.18 (m, 1H), 1.23-1.16 (m, 1H), 0.90-0.83 (m, 1H), 0.83-0.76 (m, 1H). 13C NMR (150 MHz, CDCl3) δ 170.4, 140.3, 135.5, 133.5, 129.3, 128.5, 127.9, 126.1, 120.0, 29.9, 20.8, 14.0, 11.4. HRMS (ESI), m/z calcd. for C18H19NNaO2 ([M+Na]+) 304.1308, found: 304.1308. ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.*******. Radical trapping experiments; Copies of HPLC spectra for racemic and enantiomerically enriched compounds 1m and 2m; 1H and 13C NMR spectra for all compounds (PDF) AUTHOR INFORMATION Corresponding Authors


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*E-mail: [email protected]. Fax: (+86)-373-332-5250. *E-mail: [email protected]. ORCID Zhiguo Zhang: 0000-0001-6920-0471 ACKNOWLEDGMENT We thank the NSFC (21272057, 21372065, 21772032, 21702051 and U1604285), Natural Science Foundation of Henan (162300410180), Henan Provincial Natural Science Foundation (162300410180), Young Backbone Teachers Fund of Henan (2014GGJS-049), Science & Technology Innovation Talents in Universities of Henan (17HASTIT002), and Outstanding Young Talent Cultivation Project Funding of Henan Normal University (14YR002), and Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028742). REFERENCES (1) (a) Berrino, R.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Org. Chem. 2012, 77, 2537; (b) García, J. M.; García, F. C.; Serna, F.; de la Peña, J. L. Prog. Polym. Sci. 2010, 35, 623; (c) Xie, L.-Y.; Duan, Y.; Lu, L.-H.; Li, Y.-J.; Peng, S.; Wu, C.; Liu, K.-J.; Wang, Z.; He, W.-M. ACS Sustainable Chem. Eng. 2017, 5, 10407. (2) (a) Xie, P.; Wang, Z.-Q.; Deng, G.-B.; Song, R.-J.; Xia, J.-D.; Hu, M. Li, J.-H. Adv. Synth. Catal. 2013, 355, 2257; (b) Hu, M.; Fan, J.-H.; Liu, Y.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Angew. Chem. Int. Ed. 2015, 54, 9577; (c) Yang, X.-H.; Song, R.-J.; Xie, Y.-X.; Li, J.-H. Chemcatchem 2016, 8, 2429. (3) Wang, Q.; Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45, 1257. (4) Robins, L. I.; Fogle, E. J.; Marlier, J. F. Biochim. Biophys. Acta 2015, 1854, 1756. (5) (a) R. T. Sanderson, Polar Covalence, 1983. (b) R. T. Sanderson, Chemical Bonds and Bond Energy, 1976. (6) Tobisu, M.; Nakamura, K.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 5587.



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