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Benzylarylation of N-Allyl Anilines: Synthesis of Benzylated Indolines Wenzhong Huang, Xiulan Li, Xuemei Song, Qing Luo, Yanping Li, Ying Dong, Deqiang Liang, and Baoling Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00237 • Publication Date (Web): 25 Apr 2019 Downloaded from http://pubs.acs.org on April 25, 2019

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The Journal of Organic Chemistry

Benzylarylation of N-Allyl Anilines: Synthesis of Benzylated Indolines Wenzhong Huang,† Xiulan Li,† Xuemei Song,† Qing Luo,† Yanping Li,† Ying Dong,‡ Deqiang Liang,†,§, and Baoling Wang†,§ †Department

of Chemistry, Kunming University, Kunming 650214, China. of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan 250014, China §Yunnan Engineering Technology Research Center for Plastic Films, Kunming 650214, China ‡College

Supporting Information

R1 N PG

R2

MnCl2.4H2O (10 mol%) DTBP (2 equiv) R1

Ar H H

N PG first benzylation across unactivated alkenes with toluene benzylated indolines provided 35 examples exo selective

R2

methyl arenes, 140 °C

ABSTRACT: An unprecedented benzylic C−H functionalization of methyl arenes across unactivated alkenes is presented. In the presence of MnCl24H2O and di-tert-butyl peroxide (DTBP), N-allyl anilines underwent benzylation/cyclization cascade to give benzylated indolines, which are a previously unmet synthetic goal. This protocol features simple operation, broad substrate scope, and great exo selectivity.

INTRODUCTION In the past decade, dehydrogenative C–H functionalization has emerged as a powerful tool for C–C bond construction, and is of fundamental interest in organic chemistry because of remarkable atom- and stepeconomy.1 The inexpensive and abundant hydrocarbon feedstocks are considered ideal C–H sources.2 For example, benzylic C−H functionalization of toluene has been extensively investigated, and its C−C coupling partners include aromatic,3,4 heteroaromatic,5,6 aldehydic,7 activated alkylic,8,9 and activated alkenylic C–H bonds,10,11 as well as C−halogen,12 C−B,13 C−NO2,14 C−CO2H15 and C−COMe bonds,16 and CuIIIbpy(CF3)3.17 Radical addition of benzylic C−H bonds across CO,18 activated alkynes19 or activated alkenes 20,21 has also been developed. In sharp contrast, benzylative coupling or addition of methyl arenes with unactivated alkenes has never been achieved (Scheme 1a). This could be rationalized by polarity mismatching.22 Benzylic radicals5a,d,e,8b,10a,20c,e,g and unactivated alkenes23 are both considered nucleophilic,22 and they tend to react with electron-deficient species.3,5,7,8,10,12-20 The coupling of methyl arene radicals with an electron-rich partner is a formidable challenge. In 2016, Greaney and co-workers reported an in situ bromination protocol to effect the remarkable crossdehydrogenative-coupling reaction of polarity-mismatched alkoxybenzenes with methyl arenes, wherein 2 equiv of CuBr2 were used and still poor yields were observed in

most cases.4 Assisted by a directing group and metal complexation, methyl arene derivatives were also reported to undergo cross-coupling with indoles,6 ferrocenes,24 and unactivated alkylic C–H bonds.25 In 2018, an exciting benzylation of enolates was reported by Yazaki and Ohshima, and the reaction proceeds through dual iron catalyst activation and is 2‑acylimidazole-dependent.8a Since examples of nucleophile benzylation using methyl arenes are rare,11,26 new chemistry needs to be developed. Scheme 1. Background a) Coupling of Unactivated Alkenes with Methyl Arenes Bn H polarity R Bn R mismatching not reported b) This Work: Benzylarylation of Unactivated Alkenes R

1

N PG

MnCl2.4H2O (10 mol%) DTBP (2 equiv) R1

R2

Ar H H

N PG first benzylation across unactivated alkenes with toluene benzylated indolines provided 35 examples exo selective

R2


c) Synthesis of Benzylated Oxoindoles from N-Arylacrylamides Bn

Bn H N

O

ACS Paragon Plus Environment

[O]

O N

? [H]

N

Bn H H

functional group intolerance

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Interestingly, several electron-rich activated alkenes,27 as well as 2-biphenyl isocyanides,28 have been reported to undergo cascade benzylic radical addition/cyclization sequence, like electron-deficient activated alkenes do,29,30 affording valuable carbo- and heterocyclic products. It is speculated that it might be the cyclization process which permits such polarity-mismatched couplings. Specifically, rapid intramolecular trapping of the transient radicals generated by addition, and related stabilization effect of cyclized intermediates as well as final products, might serve as the thermodynamic reaction driving force. Nevertheless, unactivated alkenes were not involved in such benzylation/cyclization processes either, probably attributed to two major problems: unfavourable polar effect and insufficiently stabilized radicals which might be difficult to trap in situ. In the past decades, activated olefin difunctionalization has proven to be a powerful tool to access molecule complexity,20,21,27,29,30 whereas the difunctionalization across unactivated ones remains more rudimentary.23,31 In continuation of our interest in radical chemistry,32 we wondered whether a challenging benzylation/cyclization sequence of unactivated alkenes could be enabled by the simple combination of an active aryl group and a transition metal salt. The active aryl group might function as both an inbuilt radical trap and an intermediate stabilizer, whereas the metal salt would facilitate final aromaticity restoration process. We examined protected N-allyl anilines as substrates,31,33 and to our delight, this synthetic plan was successful executed, delivering benzylated indolines with broad substrate scope and great exo/endo selectivity (Scheme 1b). To the best of our knowledge, this is the first benzylation reaction across unactivated alkenes with methyl arenes. The indoline is a privileged structural motif found in a broad range of alkaloids and pharmaceuticals.34 Their diverse biological properties and clinical applications in turn demand highly structure-diversified indoline derivatives as drug candidates. In indole chemistry, however, it is significantly more challenging to construct an indoline framework than to elaborate other indolic counterparts such as oxoindole.35 Oxoindoles could be prepared either by the derivatization of their parent indolic variants,36 or through the chemistry of Narylacrylamides (Scheme 1c),29,37 whereas access to indolines is mainly restricted to indole dearomatization reactions.38 Indoline syntheses from acyclic materials are rather limited, and transformation of oxoindoles to indolines suffers from severe functional group intolerance due to the strongly reducing conditions required.39 Our protocol provides a straightforward entry to benzylated indolines.

RESULTS AND DISCUSSION The initial investigations were performed with N-(2methylallyl)-N-phenylacetamide 1a1 as the model substrate (Table 1). To our delight, upon exposure of 1a1 to 2 equiv of di-tert-butyl peroxide (DTBP) in toluene at 140 C, the expected benzylation/cyclization reaction was

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Table 1. Optimization of Reaction Conditionsa catalyst, oxidant N Ac 1a1

N Ac 2a1

toluene, 140 °C, 6 h

Bn H H

N Ac 3

Bz H H

entry

catalyst

oxidant

yield of 2a1 (%)

1

none

DTBP

33 (11)b (36)c

2

TBAI

DTBP

55d (24)c

3

CuBr

DTBP

49 (8)b (21)c

4

Cu(OAc)2

DTBP

32 (10)c

5

Cu2O

DTBP

44 (30)c

6

AgNO3

DTBP

55 (8)b (23)c

7

FeCl36H2O

DTBP

56 (trace)b (13)c

8

FeCl24H2O

DTBP

59 (8)b (24)c

9

CoCl26H2O

DTBP

32 (26)c

10

NiCl26H2O

DTBP

58 (9)b (14)c

11

MnCl24H2O

DTBP

70 (56)e (7)b (8)c

12

Mn(OAc)32H2O

DTBP

61 (8)b (12)c

13

MnO2

DTBP

56 (14)b (15)c

14

KMnO4

DTBP

66 (20)c

15

MnCl24H2O

TBHPf

38 (16)b

16

MnCl24H2O

DCP

15

17

MnCl24H2O

BPO

26 (7)b (16)c

18

MnCl24H2O

TBPB

trace

19

MnCl24H2O

K2S2O8

trace (15)c

20g

MnCl24H2O

DTBP

58 (17)b (7)c

21h

MnCl24H2O

DTBP

46-62

aReaction conditions: 1a1 (0.25 mmol), catalyst (0.025 mmol), oxidant (0.5 mmol), toluene (5.0 mL), 140 C, 6 h. bYield of 3. cRecovery of 1a1. dThe same yield was achieved when the reaction was run using 20 mol% TBAI for 12 h. eThe reaction was performed using 5.3 mmol of 1a1. f5.0−6.0 mol/L in decane. gThe reaction was run in 2 mL toluene under otherwise identical conditions. hThe reaction was performed under otherwise identical conditions using 5 mol% MnCl24H2O or 1.5 equiv of DTBP, or at 120 C.

effected, furnishing benzylated indoline 2a1 albeit in a poor yield, along with benzoylated indoline 3 isolated in 11% yield, which might be related to the oxidation of toluene or the initial product 2a1 (entry 1). To improve the reaction efficiency, catalysts which might stabilize transient radicals and/or facilitate single electron transfer (SET) process were screened.40 The use of tetrabutylammonium iodide (TBAI, entry 2) or various metal salts, including CuBr (entry 3), Cu2O (entry 5), AgNO3 (entry 6), FeCl36H2O (entry 7), FeCl24H2O (entry 8), and NiCl26H2O(entry 10), led to better yields of indoline 2a1, while beneficial effect was not observed with Cu(OAc)2 (entry 4) or CoCl26H2O (entry 9). Almost identical results were obtained using 20 mol% TBAI after a prolonged reaction time (note d, entry 2). Manganese salts proved to be superior catalysts (entries 11-14), and use of

2 ACS Paragon Plus Environment

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Table 2. Synthesis of Benzylated Indolines a R

1

N PG 1

H

R1

N H PG 2


R2 H H

R1 N Ac

2a1, R1 = H, R2 = Bn, 70% 2a2, R1 = Me, R2 = Bn, 68% 2a3, R1 = Br, R2 = Bn, 54% 2a4, R1 = Cl, R2 = Bn, 60% 2a5, R1 = Ph, R2 = Bn, 46% 2a6, R1 = OMe, R2 = Bn, 52% 2a7, R1 = CF3, R2 = Bn, 41% 4, R1 = CN, R2 = Me, 12%

Bn H 2c H 72%

Bn H H

N COEt

Bn H H

N COR2

N Ac 2b, 53%

Bn H H

Cl

N SO2Et

2e, 46%

N

2d1, R2 = nC7H15, 54% 2d2, R2 = nC9H19, 55% 2d3, R2 = nC11H23, 66% 2d4, R2 = nC17H35, 57% 2d5, R2 = t-Bu, 60%

Bn H H

Cl

N Boc

Bn H H

N COR2 2g, R2 = nC7H15, 41% Cl

2f, 27%

Ar

Ar

Bn H H

R1

Ar

MnCl2.4H2O (10 mol%) DTBP (2 equiv)

H H

N COEt

N CO(CH2)6CH3

2h1, Ar = 2-MePh, 62% R1 = Me, 0% R1 = Cl, 0% (2c, 22%) 2h2, Ar = 3-MePh, 51% 2h3, Ar = 4-MePh, 45% 2

2

N CO(CH2)6CH3

F N COEt 2k, 76%

2j, 60% Ph

H N H COEt 2i1, Ar = 2-ClPh, 81% 2i2, Ar = 3-ClPh, 66% 2i3, Ar = 4-ClPh, 64% 2i4, Ar = 4-FPh, 50% F F F F

Ph

Bn Cl

N COEt

N COEt trace amounts of unidentified products

N Ac

conditions: 1 (0.25 mmol), MnCl24H2O (0.025 mmol), DTBP (0.5 mmol), solvent (5.0 mL), 140 C, 6 h.

aReaction

MnCl24H2O gave the highest yield of 70% (entry 11). Comparison of a series of oxidants was also conducted. Whereas poor yields of indoline 2a1 were afforded using tert-butyl hydroperoxide (TBHP, entry 15), dicumyl peroxide (DCP, entry 16), or benzoyl peroxide (BPO, entry 17), tert-butyl peroxybenzoate (TBPB, entry 18) and K2S2O8 (entry 19) proved ineffective for this transformation. When the reaction was performed in 2 mL toluene under otherwise identical conditions, the yield of indoline 2a1 was compromised (entry 20). Both reducing the loading of the catalyst or DCP, and lowering the reaction temperature, led to diminished yields (entry 21). It is worthy of notice that this synthesis could be carried out on a gram scale with only a slight loss of activity (note e, entry 11), rendering it highly practical. In all these reactions, benzoylated product 3 was produced in very

poor yields, thus we focused our studies on the synthesis of benzylated indolines 2. The optimized conditions were then tested on a broad collection of allylated anilines (Table 2). 5-Substituted indolines 2a2-6 were prepared in 46-68% yields from N(2-methylallyl) acetanilides bearing a methyl, bromo, chloro, phenyl, or methoxy group at the para position of the N-aryl group. Substrates with an electron-deficient Naryl group are less reactive, and 5-trifluoromethyl indoline 2a7 was produced in a poor yield. In the case of cyanosubstituted N-allylated acetanilide, the methyl radical derived from DTBP underwent methylarylation to afford 3-ethyl indoline 4 in 12% yield as the only product. Notably, this method tolerates allylated N-(pyridin-4yl)acetamide, and the corresponding 2,3-dihydro pyrrolo[3,2-c]pyridine product 2b was furnished in 53% yield. While propionyl-protected indoline 2c was also delivered in a good yield, slightly diminished yields were obtained when pivaloyl or long-chain N-protecting groups (PGs), such as octanoyl, decanoyl, dodecanoyl, and stearoyl, were used (2d1-5), probably due to steric conflict. The allylated aniline with a tert-butyloxy-carbonyl PG reacted with toluene to afford indoline 2e in a moderate yield, whereas N-ethylsulfonyl indoline 2f was produced in only a poor yield. The anilide derived from 3,5-dichloroaniline was compatible with this transformation as well, giving the expected benzylated indoline 2g albeit in a modest yield. Ortho-substituted anilides proved to be challenging substrates due to steric hindrance, and the corresponding indoline products were not produced. Instead, severe substrate decomposition was observe. Interestingly, in the case of the ortho-chlorinated anilide, intramolecular aromatic substitution occurred, furnishing arylunsubstituted indoline 2c in 22% yield. As for C−H coupling partners, methyl arenes with an electrondonating or -withdrawing group at the para, meta, or ortho position all worked well in this reaction to furnish the corresponding benzylated indolines 2h-i. Reactions run in ortho-substituted methyl arenes gave the highest yields, whereas methyl arenes with a para-substituent were the most unfavourable C−H sources, the origin of which is unclear at this time. Benzylarylations using mesitylene or 2,3,4,5,6-pentafluorotoluene as the solvent also proceeded smoothly, affording indolines 2j,k in moderate to high yields. To our disappointment, reactions performed in ethylbenzene or cumene, as well as the benzylarylation of a 1,2-disubstituted alkene, hardly occurred, probably due to steric hindrance. Unfortunately, no reaction occurred with aroylprotected allylated anilines even at an elevated temperature (Scheme 2a), which might be attributed to polarity mismatching during cyclizative radical trapping process as a result of -conjugation effect. These results further suggest that an inbuilt radical scavenger with matched electronic property which enables the rapid intramolecular radical trapping is the key for the title reaction. Allylated N-methylbenzamide, however, could undergo a similar benzylarylation reaction to afford 3,4-



dihydroisoquinolin-1-ones 3a,b, albeit in lower yields (Scheme 2b). Scheme 2. Synthesis dihydroisoquinolin-1-ones a)

O

Benzylated


R

N Tol

of

3,4-

nr

toluene, 160 °C, 6 h

R = H or Cl b)

O

O


N

N Ar

methyl arenes, 140 °C, 6 h

5a, Ar = Ph, 50% 5b, Ar = 2-MePh, 38%

Table 3. Benzylarylation of Non-Methyl-Branched Allyl Anilides a Bn 1

R standard N PG

H

R1

conditions

H

R1

N PG 6, 5-exo-trig

H H

Bn R1 N PG formal 6-endo-trig not detected H

Bn H H

N Ac 6a, R1 = H, 50% 1 6b, R = Me, 57% 6c, R1 = Cl, 62%

Bn H H

N COR2 6d, R2 = Et, 60% 6e, R2 = nC7H15, 46%

R2

N Ac Ph

N Ac complex

MnCl2 4H2O (10 mol%) DTBP (2 equiv) toluene, 140 °C

Bn H H

Cl

MeO2C N Ac 7, 55%

Bn H H

R1

a) 1a1

R2

N Ac

b) BHT

conditions: substrate (0.25 mmol), MnCl24H2O (0.025 mmol), DTBP (0.5 mmol), toluene (5.0 mL), 140 C, 6 h.

aReaction

In light of Baldwin's rules,41 exo- and endo-mode cyclizations are both favoured here, thus our initial studies focused on the benzylarylation of 2-methylallyl anilides in order to avoid the latter mode ring closure. Inspired by the exo selectivity achieved in all of the above reactions, we wondered whether the non-methyl-branched allyl anilides would be suitable substrates (Table 3). We were pleased to find that subjecting such unactivated alkenes having an electron-neutral, -rich, or -deficient N-aryl group to our

5, 71%

Cl toluene/toluene-d8 (1:1, v/v)

2a4 2a4-d7 otherwise standard conditions 46% 0%

N Ac

Cl toluene-d8 otherwise standard conditions

2a4-d7, 0%

D 1a1-d5

D

D standard conditions

N Ac

D

39%, KIE = 1

PhCH3 t-BuOH

1a1

PhCH2

2 t-BuO t-BuO Mn2+ Ac N

H Bn B

2a1 + 2a1-d4

D

f)

Bn H H

N Ac 8, R2 = Br, 67%

5, 28% Bn

t-Bu

standard conditions

c)

1a1 +

O

2a1, 0%

standard conditions

DTBP

Bn

t-Bu

TEMPO (3 equiv) or BHT (2 equiv)

e)

Table 4. Benzylarylation of Anilides with an Activated Allyl Moiety a .

Scheme 3. Mechanistic Investigations

N Ac

conditions: substrate (0.25 mmol), MnCl24H2O (0.025 mmol), DTBP (0.5 mmol), toluene (5.0 mL), 140 C, 6 h.

R

optimized conditions afforded benzylated indolines 4a-e in 46-62% yields. Still, formal 6-endo-trig product was not observed. Anilides having an activated N-allyl moiety were also tested (Table 4). While the reaction of 2-phenylallyl acetanilide led to complex mixtures, from which we failed to isolate any pure product, the ester group-activated substrate33 reacted to furnish methyl indoline-3carboxylate 7 in 55% yield. Interestingly, when 2bromoallyl acetanilide was used, aromatized indole product 8 was delivered in 67% yield, which might arise from the HBr elimination of the initial indoline product.

d)

aReaction

1

Page 4 of 15

Ac

N Bn

t-BuO A

Mn+ Ac N

H Bn

2a1 t-BuOH

C

Radical trapping experiments were performed to confirm the radical nature of this cyclizative benzylation (Scheme 3a). As might be expected, the model reaction under optimized conditions was completely suppressed by doping with either 3 equiv of 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) or 2 equiv of 2,6di-tert-butyl-4-methylphenol (BHT). Furthermore, benzylBHT adduct 5 was isolated in 28% yield in the BHT experiment, and subjecting BHT to our optimized conditions afforded the same adduct as the only product in 71% yield (Scheme 3b). These suggested that methyl arene radicals might be involved in this transformation. An intermolecular competing kinetic isotope effect (KIE) experiment was carried out using a toluene/toluene-d8


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mixture (1:1, v/v, Scheme 3c). Interestingly, deuterated indoline 2a4-d7 was not observed, and a control experiment confirmed that the title benzylation did not proceed in perdeuterated toluene (Scheme 3d), suggesting that the cleavage of the benzylic C–H bond might be a rateinfluencing step. A mixture of the substrates 1a1 and 1a1d5 (1:1) was subjected to the standard conditions, and a neglectable KIE was observed (Scheme 3e), indicating that the C–H bond cleavage of anilines is not involved in the rate-limiting step. On the basis of the above results and previous reports,2730 a tentative mechanistic pathway was proposed (Scheme 3f). At the beginning, tert-butoxyl radical was generated by thermal decomposition of DTBP. Hydrogen atom transfer from a benzylic C–H bond to this radical affords a methyl arene radical, addition of which across the tethered double bond leads to radical intermediate A possessing a newly formed C–C bond. Rapid intramolecular radical trapping by the N-aryl group ensues, furnishing ring closure intermediate B. Subsequent single-electron transfer from B to Mn2 affords cationic intermediate C as well as Mn. Finally, deprotonation of C gives the benzylated indoline 2a1. Mn is oxidized to Mn2 by tert-butoxyl radical to finish the catalytic cycle.

CONCLUSIONS To conclude, a benzylarylation reaction of N-allyl anilines has been developed. This is the first benzylic C−H functionalization of methyl arenes across unactivated alkenes, which provides a direct and straightforward access to benzylated indolines. This protocol features broad substrate scope and simple operation, and exoselectivity was always achieved even using non-methylbranched allyl anilines.

EXPERIMENTAL SECTION General. Chemicals were all purchased from commercial sources and used without treatment. Reactions were monitored by Thin Layer Chromatography (TLC) using silica gel F254 plates. Products were purified by column chromatography over 300-400 mesh silica gel. 1H NMR, 19F NMR, 13C NMR and DEPT NMR spectra were recorded at 25 C on a Bruker AscendTM 400 spectrometer using TMS as internal standard. The term "stack" is used to describe a region where resonances arising from nonequivalent nuclei are coincident, and multiplet, m, to describe a region where resonances arising from a single nucleus (or equivalent nuclei) are coincident but coupling constants cannot be readily assigned. High-resolution mass spectra (HRMS) were obtained using a Bruker microTOF II Focus spectrometer (ESI). Synthesis of Benzylated Indolines and 3,4dihydroisoquinolin-1-ones. To a screw-capped vial with a magnetic stirring bar were added N-allylated amines 1 (0.25 mmol), MnCl24H2O (5 mg, 0.025 mmol), DTBP (73 mg, 0.50 mmol) and methylarene solvent (5.0 mL) under argon. The mixture was stirred at 140 C (oil bath temperature) for 6 h, then it was quenched with saturated aqueous Na2S2O3 (1.0 mL) and water (10.0 mL), and

extracted with CH2Cl2 (10.0 mL) three times. The residue obtained after evaporation of the organic solvent was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as the eluent to give benzylated indolines 2. 2a1, 1-(3-methyl-3-phenethylindolin-1-yl)ethan-1-one, 1:5 mixture of rotamers due to the slow rotation of the N– (CO) bond,42 isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 70% yield (49 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.42 (s, 3H), 1.90-2.03 (m, 2H), 2.17 (s, 3H), 2.39-2.46 (m, 1H), 2.52-2.60 (m, 1H), 3.71 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 7.06-7.27 (m, 8H), 8.22 (d, J  8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.7, 142.3, 141.8, 138.6, 128.5, 128.3, 128.0, 126.0, 123.9, 122.3, 117.0, 61.2, 43.7, 43.4, 31.1, 27.3, 24.3; HRMS (ESI-TOF) Calcd for C19H22NO ([MH]) 280.1696. Found 280.1695. 2a1-d4, 1-(3-methyl-3-phenethylindolin-1-yl-4,5,6,7d4)ethan-1-one, 1:5 mixture of rotamers, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 40% yield (28 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.42 (s, 3H), 1.87-2.05 (m, 2H), 2.17 (s, 3H), 2.39-2.44 (m, 1H), 2.52-2.60 (m, 1H), 3.71 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 7.10 (d, J  7.0 Hz, 2H), 7.17 (dd, J  7.3, 7.3 Hz, 1H), 7.26 (dd, J  8.1, 6.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   168.6, 142.2, 141.8, 138.5, 128.5, 128.2, 126.0, 61.2, 43.7, 43.4, 31.1, 27.2, 24.2; HRMS (ESI-TOF) Calcd for C19H18D4NO ([MH]) 284.1947. Found 284.1944. 2a2, 1-(3,5-dimethyl-3-phenethylindolin-1-yl)ethan-1one, 1:4 mixture of rotamers, isolated by flash column chromatography (petroleum ether/ethyl acetate  24:1) in 68% yield (50 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.40 (s, 3H), 1.88-2.01 (m, 2H), 2.15 (s, 3H), 2.33 (s, 3H), 2.39-2.48 (m, 1H), 2.52-2.60 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.87 (d, J  10.3 Hz, 1H), 6.93 (s, 1H), 7.02 (d, J  8.5 Hz, 1H), 7.10 (d, J  7.2 Hz, 2H), 7.16 (dd, J  7.2, 7.2 Hz, 1H), 7.25 (dd, J  7.5, 7.3 Hz, 2H), 8.09 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl )   168.3, 141.8, 140.0, 3 138.7, 133.4, 128.5, 128.4, 128.2, 126.0, 122.9, 116.7, 61.4, 43.6, 43.3, 31.1, 27.2, 24.1, 21.2; HRMS (ESI-TOF) Calcd for C20H24NO ([MH]) 294.1852. Found 294.1864. 2a3, 1-(5-bromo-3-methyl-3-phenethylindolin-1yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  24:1) in 54% yield (48 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.41 (s, 3H), 1.88-2.02 (m, 2H), 2.15 (s, 3H), 2.40-2.48 (m, 1H), 2.52-2.60 (m, 1H), 3.70 (d,  10.3 Hz, 1H), 3.88 (d, J  10.3 Hz, 1H), 7.11 (d, J  7.1 Hz, 2H), 7.18 (dd, J  7.2, 7.2 Hz, 1H), 7.22-7.29 (m, 3H), 7.33 (dd, J  2.0, 8.6 Hz, 1H), 8.10 (d, J  8.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.7, 141.4, 141.3, 141.0, 130.9, 128.5, 128.2, 126.1, 125.6, 118.4, 116.2, 61.2, 43.8, 43.2, 31.0, 27.2, 24.1; HRMS (ESI-TOF) Calcd for C19H21BrNO ([MH]) 358.0801. Found 358.0799. 2a4, 1-(5-chloro-3-methyl-3-phenethylindolin-1yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  24:1) in 60% yield (47



mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.41 (s, 3H), 1.89-2.02 (m, 2H), 2.15 (s, 3H), 2.40-2.48 (m, 1H), 2.52-2.60 (m, 1H), 3.71 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 7.08 (d, J  2.0 Hz, 1H), 7.11 (d, J  7.0 Hz, 2H), 7.16-7.20 (m, 2H), 7.25-7.28 (m, 2H), 8.15 (d, J  8.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.7, 141.4, 140.9, 140.6, 128.7, 128.5, 128.2, 128.0, 126.1, 122.7, 118.0, 61.3, 43.8, 43.2, 31.0, 27.2, 24.1; HRMS (ESI-TOF) Calcd for C19H21ClNO ([MH]) 314.1306. Found 314.1298. 2a5, 1-(3-methyl-3-phenethyl-5-phenylindolin-1yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  30:1) in 46% yield (41 mg), white solid: mp 137-138 C. 1H NMR (400 MHz, CDCl3)   1.48 (s, 3H), 1.95-2.08 (m, 2H), 2.19 (s, 3H), 2.45-2.53 (m, 1H), 2.57-2.65 (m, 1H), 3.76 (d, J  10.3 Hz, 1H), 3.94 (d, J  10.3 Hz, 1H), 7.12 (d, J  7.0 Hz, 2H), 7.17 (dd, J  7.3, 7.2 Hz, 1H), 7.24-7.28 (m, 2H), 7.30-7.35 (m, 2H), 7.43 (dd, J  7.8, 7.4 Hz, 2H), 7.48 (dd, J  1.8, 8.4 Hz, 1H), 7.58 (d, J  7.4 Hz, 2H), 8.27 (d, J  8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.6, 141.71, 141.66, 141.0, 139.3, 137.1, 128.8, 128.5, 128.3, 127.00, 126.96, 126.9, 126.0, 121.0, 117.1, 61.5, 43.8, 43.4, 31.1, 27.3, 24.2; HRMS (ESI-TOF) Calcd for C25H26NO ([MH]) 356.2009. Found 356.2012. 2a6, 1-(5-methoxy-3-methyl-3-phenethylindolin-1yl)ethan-1-one, 1:5 mixture of rotamers, isolated by flash column chromatography (petroleum ether/ethyl acetate  15:1) in 52% yield (40 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.41 (s, 3H), 1.85-2.01 (m, 2H), 2.15 (s, 3H), 2.40-2.47 (m, 1H), 2.53-2.61 (m, 1H), 3.70 (d, J  10.3 Hz, 1H), 3.80 (s, 3H), 3.88 (d, J  10.3 Hz, 1H), 6.69 (d, J  2.5 Hz, 1H), 6.76 (dd, J  2.6, 8.7 Hz, 1H), 7.11 (d, J  7.1 Hz, 2H), 7.17 (dd, J  7.3, 7.3 Hz, 1H), 7.26 (dd, J  7.8, 7.0 Hz, 2H), 8.14 (d, J  8.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   167.9, 156.5, 141.7, 140.3, 136.1, 128.5, 128.2, 126.0, 117.6, 112.1, 108.9, 61.4, 55.7, 43.8, 43.3, 31.1, 27.2, 24.0; HRMS (ESI-TOF) Calcd for C20H24NO2 ([MH]) 310.1802. Found 310.1806. 2a7, 1-(3-methyl-3-phenethyl-5(trifluoromethyl)indolin-1-yl)ethan-1-one, 1:5 mixture of rotamers, isolated by flash column chromatography (petroleum ether/ethyl acetate  12:1) in 41% yield (36 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.45 (s, 3H), 1.92-2.08 (m, 2H), 2.18 (s, 3H), 2.40-2.48 (m, 1H), 2.53-2.61 (m, 1H), 3.75 (d, J  10.3 Hz, 1H), 3.94 (d, J  10.3 Hz, 1H), 7.10 (d, J  7.1 Hz, 2H), 7.18 (dd, J  7.3, 7.3 Hz, 1H), 7.27 (dd, J  7.5, 7.2 Hz, 2H), 7.35 (s, 1H), 7.50 (dd, J  0.8, 8.5 Hz, 1H), 8.30 (d, J  8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   169.2, 145.0, 141.2, 139.4, 128.6, 128.2, 126.6 (q, 1J(C–F)  274.3 Hz), 126.2, 125.75 (q, 3J(C–F)  3.3 Hz), 119.42 (q, 3J(C–F)  3.1 Hz), 116.7, 61.3, 43.7, 43.2, 31.0, 27.2, 24.3; 19F NMR (376 MHz, CDCl3)   –61.52 (s, 3F); HRMS (ESI-TOF) Calcd for C20H21F3NO ([MH]) 348.1570. Found 348.1567. 2b, 1-(3-methyl-3-phenethyl-2,3-dihydro-1Hpyrrolo[3,2-c]pyridin-1-yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  1:1) in 53% yield (37 mg), yellow oil. 1H NMR (400 MHz,

Page 6 of 15

CDCl3)   1.39 (s, 3H), 1.87-1.99 (m, 2H), 2.09 (s, 3H), 2.35-2.53 (m, 2H), 3.64 (d, J  10.2 Hz, 1H), 3.81 (d, J  10.2 Hz, 1H), 7.02 (d, J  7.1 Hz, 2H), 7.09 (dd, J  7.2, 7.2 Hz, 1H), 7.18 (dd, J  7.5, 7.2 Hz, 2H), 7.94 (d, J  4.9 Hz, 1H), 8.28 (s, 1H), 8.34 (d, J  5.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.7, 148.9, 147.8, 143.3, 140.1, 132.9, 127.5, 127.2, 125.1, 110.3, 60.3, 42.2, 42.1, 30.0, 26.3, 23.2; HRMS (ESI-TOF) Calcd for C18H21N2O ([MH]) 281.1648. Found 281.1659. 2c, 1-(3-methyl-3-phenethylindolin-1-yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  75:1) in 72% yield (53 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.22 (t, J  7.4 Hz, 3H), 1.42 (s, 3H), 1.89-2.00 (m, 2H), 2.33-2.46 (m, 3H), 2.51-2.59 (m, 1H), 3.69 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 7.05-7.11 (m, 3H), 7.13-7.18 (m, 2H), 7.21-7.27 (m, 3H), 8.25 (d, J  8.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   172.0, 142.5, 141.8, 138.5, 128.5, 128.2, 128.0, 126.0, 123.7, 122.3, 116.9, 60.3, 43.7, 43.5, 31.1, 29.2, 27.2, 8.7; HRMS (ESI-TOF) Calcd for C20H24NO ([MH]) 294.1852. Found 294.1864. 2d1, 1-(3,5-dimethyl-3-phenethylindolin-1-yl)octan-1one, isolated by flash column chromatography (petroleum ether/ethyl acetate  90:1) in 54% yield (51 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  6.8 Hz, 3H), 1.26-1.36 (m, 8H), 1.40 (s, 3H), 1.68-1.75 (m, 2H), 1.872.00 (m, 2H), 2.29-2.48 (m, 6H), 2.52-2.60 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.88 (d, J  10.3 Hz, 1H), 6.92 (s, 1H), 7.02 (d, J  8.5 Hz, 1H), 7.10 (d, J  7.1 Hz, 2H), 7.16 (dd, J  7.4, 7.2 Hz, 1H), 7.25 (dd, J  7.0, 7.7 Hz, 2H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 141.9, 140.2, 138.7, 133.3, 128.5, 128.4, 128.3, 125.9, 122.9, 116.7, 60.6, 43.6, 43.4, 36.0, 31.8, 31.1, 29.4, 29.2, 27.2, 24.7, 22.7, 21.2, 14.1; HRMS (ESI-TOF) Calcd for C26H36NO ([MH]) 378.2791. Found 378.2791. 2d2, 1-(3,5-dimethyl-3-phenethylindolin-1-yl)decan-1one, isolated by flash column chromatography (petroleum ether/ethyl acetate  90:1) in 55% yield (56 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  7.0 Hz, 3H), 1.27-1.36 (m, 12H), 1.40 (s, 3H), 1.68-1.75 (m, 2H), 1.872.00 (m, 2H), 2.26-2.48 (m, 6H), 2.52-2.60 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 6.92 (s, 1H), 7.03 (d, J  8.4 Hz, 1H), 7.11 (d, J  7.0 Hz, 2H), 7.16 (dd, J  7.3, 7.3 Hz, 1H), 7.25 (dd, J  7.6, 7.1 Hz, 2H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.2, 141.9, 140.2, 138.7, 133.3, 128.5, 128.4, 128.2, 125.9, 122.9, 116.7, 60.6, 43.6, 43.4, 36.0, 31.9, 31.1, 29.52, 29.46, 29.3, 27.1, 24.7, 22.7, 21.2, 14.1; HRMS (ESI-TOF) Calcd for C28H40NO ([MH]) 406.3104. Found 406.3108. 2d3, 1-(3,5-dimethyl-3-phenethylindolin-1-yl)dodecan1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  90:1) in 66% yield (72 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  7.0 Hz, 3H), 1.26-1.38 (m, 16H), 1.40 (s, 3H), 1.68-1.75 (m, 2H), 1.87-2.00 (m, 2H), 2.27-2.46 (m, 6H), 2.52-2.60 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 6.92 (s, 1H), 7.03 (d, J  8.4 Hz, 1H), 7.11 (d, J  7.0 Hz, 2H), 7.16


Page 7 of 15 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


(dd, J  7.3, 7.3 Hz, 1H), 7.25 (dd, J  7.6, 7.2 Hz, 2H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.2, 141.9, 140.2, 138.7, 133.3, 128.5, 128.4, 128.2, 125.9, 122.9, 116.7, 60.6, 43.6, 43.4, 36.0, 31.9, 31.1, 29.7, 29.64, 29.56, 29.53, 29.46, 29.4, 27.1, 24.7, 22.7, 21.2, 14.1; HRMS (ESITOF) Calcd for C30H44NO ([MH]) 434.3417. Found 434.3419. 2d4, 1-(3,5-dimethyl-3-phenethylindolin-1yl)octadecan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  95:1) in 57% yield (74 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  7.0 Hz, 3H), 1.25-1.36 (m, 28H), 1.40 (s, 3H), 1.68-1.75 (m, 2H), 1.87-2.00 (m, 2H), 2.29-2.49 (m, 6H), 2.52-2.60 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 6.92 (s, 1H), 7.03 (d, J  8.4 Hz, 1H), 7.11 (d, J  7.0 Hz, 2H), 7.16 (dd, J  7.3, 7.3 Hz, 1H), 7.25 (dd, J  7.6, 7.1 Hz, 2H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 141.9, 140.2, 138.7, 133.3, 128.5, 128.4, 128.2, 125.9, 122.9, 116.7, 60.6, 43.6, 43.4, 36.0, 31.9, 31.1, 29.71, 29.67, 29.6, 29.52, 29.46, 29.4, 27.1, 24.7, 22.7, 21.2, 14.1; HRMS (ESI-TOF) Calcd for C36H56NO ([MH]) 518.4356. Found 518.4352. 2d5, 1-(3,5-dimethyl-3-phenethylindolin-1-yl)-2,2dimethylpropan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 60% yield (50 mg), white solid: mp 59-60 C. 1H NMR (400 MHz, CDCl3)   1.36 (s, 9H), 1.38 (s, 3H), 1.84-1.99 (m, 2H), 2.33 (s, 3H), 2.44-2.51 (m, 1H), 2.59-2.66 (m, 1H), 3.85 (d, J  10.2 Hz, 1H), 4.11 (d, J  10.2 Hz, 1H), 6.93 (s, 1H), 7.02 (d, J  7.8 Hz, 1H), 7.11 (d, J  7.2 Hz, 2H), 7.16 (dd, J  7.4, 7.2 Hz, 1H), 7.25 (dd, J  7.7, 7.0 Hz, 2H), 8.10 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   176.1, 141.9, 141.6, 138.5, 133.4, 128.5, 128.3, 128.2, 126.0, 122.6, 118.2, 61.9, 44.2, 42.5, 40.1, 31.2, 27.7, 25.4, 21.1; HRMS (ESI-TOF) Calcd for C23H30NO ([MH]) 336.2322. Found 336.2322. 2e, tert-butyl 3,5-dimethyl-3-phenethylindoline-1carboxylate, 1:1 mixture of rotamers due to the slow rotation of the N–(CO) bond, isolated by flash column chromatography (petroleum ether/ethyl acetate  300:1) in 46% yield (40 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.36 (s, 3H), 1.57 (s, 9H), 1.83-1.96 (m, 2H), 2.31 (s, 3H), 2.35-2.43 (m, 1H), 2.56-2.63 (m, 1H), 3.64 (brs, 1H), 3.86 (brs, 0.5H), 3.94 (brs, 0.5H), 6.90 (s, 1H), 6.99 (d, J  7.7 Hz, 1H), 7.12 (d, J  7.2 Hz, 2H), 7.15 (dd, J  7.3, 7.3 Hz, 1H), 7.25 (dd, J  7.6, 7.2 Hz, 2H), 7.33 (brs, unexchangeable, 0.5H), 7.73 (brs, unexchangeable, 0.5H); 13C{1H} NMR (100 MHz, CDCl )   152.5 (br), 142.2, 140.03 138.4 (brm), 131.8, 128.4, 128.3, 125.8, 123.3 (br), 123.1 (br), 114.4, 81.4 (br), 80.4 (br), 60.1 (br), 59.8 (br), 43.6, 42.9 (br), 42.2 (br), 31.0, 28.5, 27.2, 21.0; HRMS (ESI-TOF) Calcd for C23H30NO2 ([MH]) 352.2271. Found 352.2273. 2f, 5-chloro-1-(ethylsulfonyl)-3-methyl-3phenethylindoline, isolated by flash column chromatography (petroleum ether/ethyl acetate  30:1) in 27% yield (25 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.41 (s, 3H), 1.42 (t, J  7.4 Hz, 3H), 1.86-2.01 (m, 2H), 2.40-2.47 (m, 1H), 2.62-2.70 (m, 1H), 3.12 (q, J  7.4 Hz,

2H), 3.73 (d, J  10.1 Hz, 1H), 3.98 (d, J  10.1 Hz, 1H), 7.09 (d, J  2.1 Hz, 1H), 7.12 (d, J  7.0 Hz, 2H), 7.15-7.20 (m, 2H), 7.25-7.27 (m, 2H), 7.30 (d, J  8.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   141.3, 140.4, 140.1, 128.54, 128.45, 128.20, 128.18, 126.1, 123.6, 114.1, 62.0, 44.2, 43.9, 42.8, 31.0, 26.5, 7.8; HRMS (ESI-TOF) Calcd for C19H23ClNO2S ([MH]) 364.1133. Found 364.1131. 2g, 1-(4,6-dichloro-3-methyl-3-phenethylindolin-1yl)octan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  100:1) in 41% yield (44 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.89 (t, J  7.0 Hz, 3H), 1.30-1.37 (m, 8H), 1.52 (s, 3H), 1.67-1.74 (m, 2H), 1.89-1.99 (m, 1H), 2.24-2.51 (m, 5H), 3.70 (d, J  10.3 Hz, 1H), 3.93 (d, J  10.3 Hz, 1H), 7.01 (d, J  1.8 Hz, 1H), 7.11 (d, J  7.0 Hz, 2H), 7.17 (dd, J  7.3, 7.3 Hz, 1H), 7.26 (dd, J  7.3, 7.3 Hz, 2H), 8.31 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.8, 145.3, 141.4, 134.4, 132.0, 130.4, 128.5, 128.3, 126.1, 124.7, 116.0, 60.8, 45.3, 40.3, 36.1, 31.7, 31.5, 29.3, 29.2, 26.4, 24.4, 22.7, 14.1; HRMS (ESI-TOF) Calcd for C25H32Cl2NO ([MH]) 432.1855. Found 432.1871. 2h1, 1-(3,5-dimethyl-3-(2-methylphenethyl)indolin-1yl)octan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  50:1) in 62% yield (61 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  7.0 Hz, 3H), 1.30-1.40 (m, 8H), 1.41 (s, 3H), 1.68-1.78 (m, 2H), 1.80-1.91 (m, 2H), 2.20 (s, 3H), 2.27-2.42 (m, 6H), 2.52-2.59 (m, 1H), 3.73 (d, J  10.3 Hz, 1H), 3.95 (d, J  10.3 Hz, 1H), 6.94 (s, 1H), 6.99-7.12 (m, 5H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 140.2, 140.0, 138.7, 135.6, 133.3, 130.3, 128.7, 128.5, 126.1, 122.9, 116.8, 60.6, 43.6, 42.2, 36.0, 31.8, 29.4, 29.2, 28.4, 26.9, 24.7, 22.7, 21.2, 19.1, 14.1; HRMS (ESI-TOF) Calcd for C27H38NO ([MH]) 392.2948. Found 392.2949. 2h2, 1-(3,5-dimethyl-3-(3-methylphenethyl)indolin-1yl)octan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 51% yield (50 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  6.8 Hz, 3H), 1.30-1.39 (m, 11H), 1.68-1.75 (m, 2H), 1.861.99 (m, 2H), 2.30-2.43 (m, 9H), 2.49-2.56 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 6.90-7.03 (m, 5H), 7.14 (dd, J  7.8, 7.8 Hz, 1H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 141.8, 140.2, 138.7, 138.0, 133.3, 129.1, 128.4, 128.3, 126.7, 125.2, 122.9, 116.7, 60.6, 43.6, 43.4, 36.0, 31.8, 31.0, 29.4, 29.2, 27.1, 24.7, 22.7, 21.4, 21.2, 14.1; HRMS (ESI-TOF) Calcd for C27H38NO ([MH]) 392.2948. Found 392.2946. 2h3, 1-(3,5-dimethyl-3-(4-methylphenethyl)indolin-1yl)octan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 45% yield (44 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  6.8 Hz, 3H), 1.30-1.39 (m, 11H), 1.68-1.75 (m, 2H), 1.861.94 (m, 2H), 2.30-2.42 (m, 9H), 2.48-2.56 (m, 1H), 3.67 (d, J  10.3 Hz, 1H), 3.88 (d, J  10.3 Hz, 1H), 6.92 (s, 1H), 6.987.07 (m, 5H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 140.2, 138.77, 138.75, 135.4, 133.3, 129.1, 128.4, 128.1, 122.9, 116.7, 60.6, 43.6, 43.5, 36.0,



31.8, 30.6, 29.4, 29.2, 27.2, 24.7, 22.7, 21.2, 21.0, 14.1; HRMS (ESI-TOF) Calcd for C27H38NO ([MH]) 392.2948. Found 392.2940. 2i1, 1-(3-(2-chlorophenethyl)-3,5-dimethylindolin-1yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 81% yield (69 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.24 (t, J  7.4 Hz, 3H), 1.41 (s, 3H), 1.82-1.95 (m, 2H), 2.33 (s, 3H), 2.41-2.53 (m, 3H), 2.65-2.73 (m, 1H), 3.72 (d, J  10.4 Hz, 1H), 4.01 (d, J  10.3 Hz, 1H), 6.95 (s, 1H), 7.03 (d, J  8.4 Hz, 1H), 7.08-7.17 (m, 3H), 7.31 (dd, J  2.0, 7.0 Hz, 1H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.7, 140.2, 139.4, 138.5, 133.7, 133.3, 130.3, 129.5, 128.5, 127.5, 126.9, 122.9, 116.7, 60.2, 43.7, 41.7, 29.22, 29.16, 27.0, 21.2, 8.8; HRMS (ESI-TOF) Calcd for C21H25ClNO ([MH]) 342.1619. Found 342.1622. 2i2, 1-(3-(3-chlorophenethyl)-3,5-dimethylindolin-1yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 66% yield (56 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.23 (t, J  7.4 Hz, 3H), 1.40 (s, 3H), 1.85-1.98 (m, 2H), 2.33 (s, 3H), 2.35-2.42 (m, 3H), 2.49-2.56 (m, 1H), 3.70 (d, J  10.4 Hz, 1H), 3.88 (d, J  10.4 Hz, 1H), 6.91 (s, 1H), 6.96 (d, J  6.9 Hz, 1H), 7.04 (d, J  8.4 Hz, 1H), 7.09 (s, 1H), 7.13-7.19 (m, 2H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.6, 143.9, 140.2, 138.2, 134.2, 133.3, 129.7, 128.6, 128.3, 126.5, 126.1, 122.9, 116.7, 60.4, 43.6, 43.2, 30.8, 29.1, 27.2, 21.2, 8.8; HRMS (ESI-TOF) Calcd for C21H25ClNO ([MH]) 342.1619. Found 342.1634. 2i3, 1-(3-(4-chlorophenethyl)-3,5-dimethylindolin-1yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 64% yield (55 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.22 (t, J  7.4 Hz, 3H), 1.40 (s, 3H), 1.83-1.97 (m, 2H), 2.33 (s, 3H), 2.35-2.43 (m, 3H), 2.45-2.56 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.86 (d, J  10.3 Hz, 1H), 6.91 (s, 1H), 7.01-7.04 (m, 3H), 7.21 (d, J  8.3 Hz, 2H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.6, 140.3, 138.3, 133.3, 131.7, 129.6, 128.6, 128.5, 122.9, 116.7, 60.4, 43.6, 43.4, 30.5, 29.1, 27.2, 21.2, 8.7; HRMS (ESI-TOF) Calcd for C21H25ClNO ([MH]) 342.1619. Found 342.1618. 2i4, 1-(3-(4-fluorophenethyl)-3,5-dimethylindolin-1yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 50% yield (41 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.22 (t, J  7.4 Hz, 3H), 1.40 (s, 3H), 1.84-1.97 (m, 2H), 2.33-2.41 (m, 6H), 2.48-2.56 (m, 1H), 3.68 (d, J  10.3 Hz, 1H), 3.87 (d, J  10.3 Hz, 1H), 6.91-6.95 (m, 3H), 7.02-7.06 (m, 3H), 8.12 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.6, 162.3 (d, 1J(C–F)  242.2 Hz), 140.2, 138.4, 137.4 (d, 4J(C–F)  3.0 Hz), 133.3, 129.6 (d, 3J(C–F)  7.7 Hz), 128.5, 122.9, 116.7, 115.1 (d, 2J(C–F)  21.0 Hz), 60.4, 43.6, 30.3, 29.1, 27.2, 21.2, 8.8; 19F NMR (376 MHz, CDCl3)   –117.54 (m, 1F); HRMS (ESI-TOF) Calcd for C21H25FNO ([MH]) 326.1915. Found 326.1919. 2j, 1-(3-(3,5-dimethylphenethyl)-3,5-dimethylindolin-1yl)octan-1-one, isolated by flash column chromatography

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(petroleum ether/ethyl acetate  30:1) in 60% yield (61 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   0.88 (t, J  6.8 Hz, 3H), 1.26-1.39 (m, 11H), 1.68-1.76 (m, 2H), 1.851.97 (m, 2H), 2.17-2.42 (m, 12H), 2.45-2.52 (m, 1H), 3.67 (d, J  10.3 Hz, 1H), 3.89 (d, J  10.3 Hz, 1H), 6.72 (s, 2H), 6.80 (s, 1H), 6.92 (s, 1H), 7.02 (d, J  8.4 Hz, 1H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 141.8, 140.2, 138.8, 137.9, 133.2, 128.4, 127.6, 126.1, 122.9, 116.7, 60.6, 43.6, 43.5, 36.0, 31.8, 30.9, 29.4, 29.2, 27.1, 24.7, 22.7, 21.24, 21.17, 14.1; HRMS (ESI-TOF) Calcd for C28H40NO ([MH]) 406.3104. Found 406.3108. 2k, 1-(3,5-dimethyl-3-(2(perfluorophenyl)ethyl)indolin-1-yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 76% yield (76 mg), colorless crystal: mp 94-95 C. 1H NMR (400 MHz, CDCl3)   1.25 (t, J  7.4 Hz, 3H), 1.41 (s, 3H), 1.80-1.92 (m, 2H), 2.33 (s, 3H), 2.40-2.52 (m, 3H), 2.59-2.69 (m, 1H), 3.76 (d, J  10.4 Hz, 1H), 3.98 (d, J  10.5 Hz, 1H), 6.92 (s, 1H), 7.04 (d, J  8.3 Hz, 1H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.6, 140.2, 137.4, 133.5, 128.8, 122.7, 116.7, 59.9, 43.6, 40.7, 29.2, 27.2, 21.1, 18.0, 8.8; 19F NMR (376 MHz, CDCl3)   –144.93 (m, 2F), –157.53 (m, 1F), –162.59 (m, 2F); HRMS (ESI-TOF) Calcd for C21H21F5NO ([MH]) 398.1538. Found 398.1540. 3, 2-(1-acetyl-3-methylindolin-3-yl)-1-phenylethan-1one, isolated by flash column chromatography (petroleum ether/ethyl acetate  15:1) in 17% yield (12 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.50 (s, 3H), 2.23 (s, 3H), 3.24 (d, J  17.3 Hz, 1H), 3.53 (d, J  17.3 Hz, 1H), 4.06 (d, J  11.0 Hz, 1H), 4.20 (d, J  11.0 Hz, 1H), 7.06 (dd, J  6.8, 6.8 Hz, 1H), 7.18-7.25 (m, 2H), 7.46 (dd, J  7.5, 7.5 Hz, 2H), 7.57 (dd, J  7.4, 7.4 Hz, 1H), 7.91 (d, J  7.3 Hz, 2H), 8.21 (d, J  8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   198.3, 168.9, 141.6, 139.2, 137.2, 133.4, 128.7, 128.3, 128.0, 123.8, 122.1, 117.2, 61.3, 48.1, 42.2, 26.4, 24.3; HRMS (ESI-TOF) Calcd for C19H20NO2 ([MH]) 294.1489. Found 294.1490. 4, 1-acetyl-3-ethyl-3-methylindoline-5-carbonitrile, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 12% yield (7 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.83 (t, J  7.5 Hz, 3H), 1.36 (s, 3H), 1.68 (q, J  7.5 Hz, 2H), 2.26 (s, 3H), 3.74 (d, J  10.3 Hz, 1H), 3.92 (d, J  10.3 Hz, 1H), 7.34 (s, 1H), 7.52 (dd, J  1.7, 8.4 Hz, 1H), 8.27 (d, J  8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   169.4, 145.9, 140.1, 132.9, 126.3, 119.4, 117.1, 106.6, 61.0, 43.9, 34.0, 26.6, 24.3, 8.8; HRMS (ESI-TOF) Calcd for C14H17N2O ([MH]) 229.1335. Found 229.1346 5a, 2,4-dimethyl-4-phenethyl-3,4-dihydroisoquinolin1(2H)-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 50% yield (35 mg), yellow oil. 1H NMR (400 MHz, CDCl3)   1.41 (s, 3H), 1.86-2.02 (m, 2H), 2.37-2.44 (m, 1H), 2.55-2.62 (m, 1H), 3.14 (s, 3H), 3.30 (d, J  12.5 Hz, 1H), 3.51 (d, J  12.6 Hz, 1H), 7.08 (d, J  7.3 Hz, 2H), 7.16 (dd, J  7.4, 7.4 Hz, 1H), 7.23 (dd, J  7.5, 7.5 Hz, 2H), 7.29 (d, J  7.8 Hz, 1H), 7.35 (dd, J  7.5, 7.6 Hz, 1H), 7.48 (dd, J  7.5, 7.5 Hz, 1H), 8.13


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(d, J  7.7 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   164.5, 145.1, 141.8, 131.7, 128.7, 128.5, 128.3, 128.2, 126.9, 126.0, 124.3, 58.6, 41.6, 37.3, 35.3, 31.0, 23.2; HRMS (ESI-TOF) Calcd for C19H22NO ([MH]) 280.1696. Found 280.1692. 5b, 2,4-dimethyl-4-(2-methylphenethyl)-3,4dihydroisoquinolin-1(2H)-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 38% yield (28 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.44 (s, 3H), 1.77-1.92 (m, 2H), 2.13 (s, 3H), 2.34-2.42 (m, 1H), 2.53-2.61 (m, 1H), 3.16 (s, 3H), 3.31 (d, J  12.5 Hz, 1H), 3.55 (d, J  12.5 Hz, 1H), 7.00-7.19 (m, 4H), 7.31 (d, J  7.7 Hz, 1H), 7.36 (dd, J  6.8, 7.5 Hz, 1H), 7.48 (ddd, J  1.2, 7.6, 7.4 Hz, 1H), 8.14 (d, J  6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   164.5, 145.1, 139.9, 135.6, 131.7, 130.3, 128.8, 128.7, 128.3, 126.9, 126.2, 126.1, 124.3, 58.7, 40.5, 37.3, 35.4, 28.2, 22.9, 19.0; HRMS (ESI-TOF) Calcd for C20H24NO ([MH]) 294.1852. Found 294.1851. 6a, 1-(3-phenethylindolin-1-yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 50% yield (33 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.86-1.95 (m, 1H), 2.13-2.18 (m, 1H), 2.20 (s, 3H), 2.72 (t, J  7.4 Hz, 2H), 3.40-3.47 (m, 1H), 3.68 (dd, J  6.0, 10.3 Hz, 1H), 4.14 (dd, J  9.9, 9.9 Hz, 1H), 7.03 (dd, J  7.4, 7.4 Hz, 1H), 7.17-7.23 (m, 5H), 7.31 (dd, J  7.1, 7.6 Hz, 2H), 8.20 (d, J  8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.7, 142.7, 141.3, 134.7, 128.6, 128.4, 128.0, 126.2, 123.8, 123.7, 117.0, 55.0, 39.7, 37.0, 33.2, 24.3; HRMS (ESI-TOF) Calcd for C18H20NO ([MH]) 266.1539. Found 266.1538. 6b, 1-(5-methyl-3-phenethylindolin-1-yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  40:1) in 57% yield (40 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.84-1.93 (m, 1H), 2.12-2.20 (m, 4H), 2.31 (s, 3H), 2.69-2.74 (m, 2H), 3.363.43 (m, 1H), 3.66 (dd, J  6.0, 10.4 Hz, 1H), 4.12 (dd, J  9.9, 9.9 Hz, 1H), 6.98-7.02 (m, 2H), 7.19-7.23 (m, 3H), 7.29-7.32 (m, 2H), 8.07 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.3, 141.4, 140.4, 134.9, 133.3, 128.6, 128.39, 128.35, 126.2, 124.4, 116.7, 55.1, 39.7, 37.0, 33.3, 24.1, 21.1; HRMS (ESI-TOF) Calcd for C19H22NO ([MH]) 280.1696. Found 280.1699. 6c, 1-(5-chloro-3-phenethylindolin-1-yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  30:1) in 62% yield (46 mg), white solid: mp 88-89 C. 1H NMR (400 MHz, CDCl3)   1.85-1.95 (m, 1H), 2.10-2.23 (m, 4H), 2.69-2.74 (m, 2H), 3.37-3.44 (m, 1H), 3.69 (dd, J  6.1, 10.4 Hz, 1H), 4.14 (dd, J  9.9, 9.9 Hz, 1H), 7.13-7.24 (m, 5H), 7.29-7.33 (m, 2H), 8.13 (d, J  8.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   168.6, 141.4, 140.9, 136.7, 128.6, 128.5, 128.3, 127.9, 126.3, 124.0, 118.0, 55.1, 39.5, 36.8, 33.1, 24.1; HRMS (ESI-TOF) Calcd for C18H19ClNO ([MH]) 300.1150. Found 300.1161. 6d, 1-(5-methyl-3-phenethylindolin-1-yl)propan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  40:1) in 60% yield (44 mg), white solid: mp 83-84 C. 1H NMR (400 MHz, CDCl3)   1.22 (t, J  7.4 Hz, 3H), 1.83-1.92 (m, 1H), 2.11-2.20 (m, 1H), 2.31 (s,

3H), 2.40 (q, J  7.4 Hz, 2H), 2.69-2.73 (m, 2H), 3.35-3.42 (m, 1H), 3.66 (dd, J  5.9, 10.3 Hz, 1H), 4.11 (dd, J  9.9, 9.9 Hz, 1H), 6.98-7.02 (m, 2H), 7.19-7.22 (m, 3H), 7.28-7.32 (m, 2H), 8.11 (d, J  8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.6, 141.4, 140.7, 134.7, 133.1, 128.5, 128.40, 128.35, 126.1, 124.4, 116.6, 54.1, 39.7, 37.0, 33.3, 29.1, 21.1, 8.8; HRMS (ESI-TOF) Calcd for C20H24NO ([MH]) 294.1852. Found 294.1850. 6e, 1-(5-methyl-3-phenethylindolin-1-yl)octan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  55:1) in 46% yield (42 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   0.89 (t, J  6.8 Hz, 3H), 1.29-1.40 (m, 8H), 1.68-1.75 (m, 2H), 1.83-1.92 (m, 1H), 2.11-2.19 (m, 1H), 2.30 (s, 3H), 2.36 (t, J  7.6 Hz, 2H), 2.71 (t, J  6.9 Hz, 2H), 3.34-3.41 (m, 1H), 3.66 (dd, J  6.0, 10.3 Hz, 1H), 4.11 (dd, J  9.8, 9.9 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H), 7.28-7.32 (m, 2H), 8.10 (d, J  8.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)   171.1, 141.4, 140.6, 134.8, 133.1, 128.5, 128.38, 128.36, 126.1, 124.4, 116.7, 54.3, 39.7, 37.0, 36.0, 33.3, 31.8, 29.4, 29.2, 24.7, 22.7, 21.1, 14.1; HRMS (ESI-TOF) Calcd for C25H34fNO ([MH]) 364.2635. Found 364.2628. 7, methyl 1-acetyl-5-chloro-3-phenethylindoline-3carboxylate, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 53% yield (49 mg), white solid: mp 154-155 C. 1H NMR (400 MHz, CDCl3)   2.11-2.18 (m, 1H), 2.21 (s, 3H), 2.45-2.58 (m, 3H), 3.76 (s, 3H), 3.84 (d, J  10.8 Hz, 1H), 4.71 (d, J  10.8 Hz, 1H), 7.13-7.15 (m, 2H), 7.18-7.25 (m, 2H), 7.29 (dd, J  7.6, 7.6 Hz, 2H), 7.38 (d, J  2.1 Hz, 1H), 8.15 (d, J  8.7 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl )   172.5, 168.5, 140.9, 3 140.2, 133.7, 129.3, 128.8, 128.6, 128.3, 126.5, 124.6, 118.0, 56.3, 54.9, 53.1, 40.5, 31.3, 24.1; HRMS (ESI-TOF) Calcd for C20H21ClNO3 ([MH]) 358.1204. Found 358.1207. 8, 1-(3-phenethyl-1H-indol-1-yl)ethan-1-one, isolated by flash column chromatography (petroleum ether/ethyl acetate  24:1) in 67% yield (44 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   2.54 (s, 3H), 3.01 (s, 4H), 7.07 (brs, 1H, unexchangeable), 7.20-7.24 (m, 3H), 7.26-7.37 (m, 4H), 7.52 (d, J  7.8 Hz, 1H), 8.43 (brd, J  6.5 Hz, 1H, unexchangeable); 13C{1H} NMR (100 MHz, CDCl3)   168.4, 141.6, 136.0, 130.6, 128.5, 126.2, 125.3, 123.4, 122.4, 122.0, 118.9, 116.7, 35.5, 27.0, 24.0; HRMS (ESI-TOF) Calcd for C18H18NO ([MH]) 264.1383. Found 264.1382. 9, 4-benzyl-2,6-di-tert-butyl-4-methylcyclohexa-2,5dien-1-one, isolated by flash column chromatography (pure petroleum ether) in 71% yield (55 mg), yellow solid: mp 83-84 C. 1H NMR (400 MHz, CDCl3)   1.14 (s, 18H), 1.27 (s, 3H), 2.82 (s, 2H), 6.47 (s, 2H), 6.94-6.97 (m, 2H), 7.12-7.20 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3)   186.1, 146.1, 145.9, 136.7, 130.1, 127.5, 126.6, 48.1, 40.9, 34.6, 29.3, 26.2; HRMS (ESI-TOF) Calcd for C22H31O ([MH]) 311.2369. Found 311.2371. Synthesis of Allyl Amines 1. Substrates 1 were prepared from anilides and allyl bromides according to the literature procedure, and spectral data of known compounds match those described.32a-c Spectral data of



new compounds or known compounds prepared by the new method are shown below. 1a1-d5, N-(2-methylallyl)-N-(phenyl-d5)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  15:1) in 92% yield (2681 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.76 (s, 3H), 1.90 (s, 3H), 4.29 (s, 2H), 4.70 (s, 1H), 4.81 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)   170.3, 143.0, 140.7, 129.0 (t, J(C– D)  24.1 Hz), 127.3 (t, J(C–D)  24.5 Hz), 127.2 (t, J(C–D)  23.7 Hz), 113.1, 55.0, 22.7, 20.3; HRMS (ESI-TOF) Calcd for C12H11D5NO ([MH]) 195.1540. Found 195.1542. 1a6, N-(4-methoxyphenyl)-N-(2-methylallyl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 88% yield (2895 mg), white solid: mp 60-61 C. 1H NMR (400 MHz, CDCl3)   1.75 (s, 3H), 1.88 (s, 3H), 3.82 (s, 3H), 4.24 (s, 2H), 4.69 (s, 1H), 4.81 (s, 1H), 6.89 (ddd, J  3.4, 2.2, 8.9 Hz, 2H), 7.07 (ddd, J  3.4, 2.2, 8.9 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   170.8, 158.8, 140.9, 136.0, 128.9, 114.6, 113.2, 55.4, 55.1, 22.7, 20.3; HRMS (ESI-TOF) Calcd for C13H18NO2 ([MH]) 220.1332. Found 220.1333. 1a7, N-(2-methylallyl)-N-(4(trifluoromethyl)phenyl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 90% yield (3473 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.67 (s, 3H), 1.86 (s, 3H), 4.22 (s, 2H), 4.63 (s, 1H), 4.76 (s, 1H), 7.25 (d, J  8.2 Hz, 2H), 7.58 (d, J  8.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   169.8, 146.2, 140.3, 129.5, 128.1, 126.6, 123.7 (q, 1J(C–F)  270.5 Hz), 113.4, 54.8, 22.7, 20.1; 19F NMR (376 MHz, CDCl3)   – 62.64 (s, 3F); HRMS (ESI-TOF) Calcd for C13H15F3NO ([MH]) 258.1100. Found 258.1106. N-(4-Cyanophenyl)-N-(2-methylallyl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  20:1) in 76% yield (2443 mg), white solid: mp 122-123 C. 1H NMR (400 MHz, CDCl3)   1.75 (s, 3H), 2.01 (s, 3H), 4.29 (s, 2H), 4.73 (s, 1H), 4.88 (s, 1H), 7.33 (d, J  8.2 Hz, 2H), 7.69 (d, J  8.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   169.8, 147.1, 140.2, 133.4, 128.1, 118.1, 113.4, 55.2, 22.8, 20.2; HRMS (ESI-TOF) Calcd for C13H15N2O ([MH]) 215.1179. Found 215.1171. 1b, N-(2-methylallyl)-N-(pyridin-4-yl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  1:1) in 44% yield (1256 mg), brown oil. 1H NMR (400 MHz, CDCl3)   1.75 (s, 3H), 2.09 (s, 3H), 4.29 (s, 2H), 4.77 (s, 1H), 4.90 (s, 1H), 7.18 (d, J  5.5 Hz, 2H), 8.62 (d, J  4.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   169.9, 151.0, 150.5, 140.1, 121.2, 112.9, 54.8, 22.9, 20.2; HRMS (ESI-TOF) Calcd for C11H15N2O ([MH]) 191.1179. Found 191.1180. 1d5, N-(2-methylallyl)-N-(p-tolyl)pivalamide, prepared from 4-methyl-N-(2-methylallyl)aniline and pivaloyl chloride and isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 77% yield (2834 mg), yellow oil. 1H NMR (400 MHz, CDCl3)   1.04 (s, 9H), 1.74 (s, 3H), 2.36 (s, 3H), 4.18 (s, 2H), 4.67 (s, 1H), 4.80 (s, 1H), 7.06 (ddd, J  1.6, 1.6, 8.2 Hz, 2H), 7.14 (d, J  8.0 Hz,

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2H); 13C{1H} NMR (100 MHz, CDCl3)   177.7, 141.2, 137.7, 129.5, 129.2, 112.3, 58.6, 41.1, 29.6, 21.1, 20.4; HRMS (ESITOF) Calcd for C16H24NO ([MH]) 246.1852. Found 246.1856. 1e, tert-butyl (2-methylallyl)(p-tolyl)carbamate, isolated by flash column chromatography (petroleum ether/ethyl acetate  300:1) in 81% yield (3176 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.44 (s, 9H), 1.74 (d, J  0.5 Hz, 3H), 2.31 (s, 3H), 4.14 (s, 2H), 4.79-4.81 (m, 1H), 4.83-4.84 (m, 1H), 7.10 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3)   154.8, 141.8, 140.3, 135.2, 129.1, 125.9, 111.3, 80.2, 55.9, 28.3, 21.0, 20.1; HRMS (ESI-TOF) Calcd for C16H24NO2 ([MH]) 262.1802. Found 262.1809. 1f, N-(4-chlorophenyl)-N-(2methylallyl)ethanesulfonamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  24:1) in 87% yield (3573 mg), yellow oil. 1H NMR (400 MHz, CDCl3)   1.38 (t, J  7.4 Hz, 3H), 1.74 (s, 3H), 3.04 (q, J  7.4 Hz, 2H), 4.27 (s, 2H), 4.78 (s, 1H), 4.81 (s, 1H), 7.27-7.35 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3)   139.8, 137.6, 133.4, 129.42, 129.38, 115.4, 57.2, 45.3, 19.8, 8.0; HRMS (ESI-TOF) Calcd for C12H17ClNO2S ([MH]) 274.0663. Found 274.0663. 1g, N-(3,5-dichlorophenyl)-N-(2-methylallyl)octanamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  80:1) in 91% yield (4672 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   0.86 (t, J  7.0 Hz, 3H), 1.23-1.27 (m, 8H), 1.60 (s, 2H), 1.74 (s, 3H), 2.13 (s, 2H), 4.22 (s, 2H), 4.71 (s, 1H), 4.88 (s, 1H), 7.08 (s, 2H), 7.33 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)   172.6, 144.8, 140.3, 135.4, 128.0, 126.7, 113.5, 55.2, 34.4, 31.6, 29.2, 29.0, 25.4, 22.6, 20.3, 14.1; HRMS (ESI-TOF) Calcd for C18H26Cl2NO ([MH]) 342.1386. Found 342.1385. N-(But-2-en-1-yl)-N-(4-chlorophenyl)acetamide, 4:17 mixture of Z/E isomers, isolated by flash column chromatography (petroleum ether/ethyl acetate  12:1) in 82% yield (2752 mg), colorless oil. 1H NMR (400 MHz, CDCl3)   1.46 (d, J  6.7 Hz, 3H minor), 1.60-1.68 (m, 3H major), 1.84 (s, 3H major and 3H minor), 4.16-4.23 (m, 2H major), 4.33 (d, J  7.0 Hz, 2H minor), 5.42-5.63 (stack, 2H major and 2H minor), 7.08-7.13 (stack, 2H major and 2H minor), 7.37 (d, J  8.5 Hz, 2H major and 2H minor); 13C{1H} NMR (100 MHz, CDCl3)   169.8 (minor), 169.7 (major), 141.54 (major), 141.50 (minor), 133.7 (minor), 133.6 (major), 129.8 (minor), 129.7 (major), 129.6 (major), 129.5 (minor), 128.2 (minor), 125.5 (major), 124.8 (minor), 51.2 (major), 45.4 (minor), 22.7 (major), 22.6 (minor), 17.7 (major), 12.7 (minor); HRMS (ESI-TOF) Calcd for C12H15ClNO ([MH]) 224.0837. Found 224.0831. 3-Chloro-N-(2-methylallyl)-N-(p-tolyl)benzamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 86% yield (3867 mg), pale yellow solid: mp 43-44 C. 1H NMR (400 MHz, CDCl3)   1.81 (s, 3H), 2.27 (s, 3H), 4.46 (s, 2H), 4.87 (s, 1H), 4.90 (s, 1H), 6.90 (d, J  8.1 Hz, 2H), 7.01 (d, J  8.1 Hz, 2H), 7.057.13 (m, 2H), 7.21 (ddd, J  1.6, 1.6, 7.6 Hz, 1H), 7.37 (s, 1H); 13C{1H} NMR (100 MHz, CDCl )   168.9, 140.8, 140.6, 3


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138.0, 136.7, 133.9, 129.7, 129.6, 129.0, 128.9, 126.9, 126.7, 112.8, 55.8, 21.0, 20.5; HRMS (ESI-TOF) Calcd for C18H19ClNO ([MH]) 300.1150. Found 300.1154. N-Methyl-N-(2-methylallyl)benzamide, 2:3 mixture of rotamers, isolated by flash column chromatography (petroleum ether/ethyl acetate  40:1) in 88% yield (2498 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.60 (s, 3H major), 1.78 (s, 3H minor), 2.88 (s, 3H minor), 3.04 (s, 3H major), 3.77 (s, 2H major), 4.13 (s, 2H minor), 4.89 (s, 1H minor), 4.92 (s, 1H major), 4.97 (s, 1H minor), 4.98 (s, 1H major), 7.36-7.44 (stack, 5H major and 5H minor); 13C{1H} NMR (100 MHz, CDCl )   172.3 (major), 171.4 3 (minor), 140.5 (major), 140.2 (minor), 136.4 (minor), 136.2 (major), 129.6 (major), 129.5 (minor), 128.3 (major and minor), 126.8 (minor), 126.6 (major), 112.5 (minor), 112.2 (major), 57.3 (major), 52.8 (minor), 36.8 (minor), 33.2 (major), 19.90 (minor), 19.86 (major); HRMS (ESITOF) Calcd for C12H16NO ([MH]) 190.1226. Found 190.1225. N-Allyl-N-(p-tolyl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  40:1) in 93% yield (2640 mg), yellow oil. 1H NMR (400 MHz, CDCl3)   1.85 (s, 3H), 2.37 (s, 3H), 4.27 (d, J  6.3 Hz, 2H), 5.045.11 (m, 2H), 5.80-5.90 (m, 1H), 7.03 (d, J  8.2 Hz, 2H), 7.19 (d, J  8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   170.3, 140.4, 137.8, 133.3, 130.2, 127.8, 117.7, 52.0, 22.6, 21.1; HRMS (ESI-TOF) Calcd for C12H16NO ([MH]) 190.1226. Found 190.1223. N-Allyl-N-(4-chlorophenyl)acetamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 90% yield (2831 mg), yellow solid: mp 45-46 C. 1H NMR (400 MHz, CDCl )   1.86 (s, 3H), 4.27 (ddd, J  3 1.2, 1.2, 6.2 Hz, 2H), 5.04-5.13 (m, 2H), 5.79-5.89 (m, 1H), 7.10 (d, J  8.5 Hz, 2H), 7.38 (d, J  8.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   169.9, 141.5, 133.8, 132.9, 129.8, 129.5, 118.2, 52.0, 22.7; HRMS (ESI-TOF) Calcd for C11H13ClNO ([MH]) 210.0680. Found 210.0682. N-Allyl-N-(p-tolyl)propionamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 89% yield (2714 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.04 (t, J  7.5 Hz, 3H), 2.06 (q, J  7.4 Hz, 2H), 2.37 (s, 3H), 4.27 (d, J  6.3 Hz, 2H), 5.03-5.10 (m, 2H), 5.81-5.91 (m, 1H), 7.03 (d, J  8.2 Hz, 2H), 7.19 (d, J  8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   173.7, 140.0, 137.7, 133.4, 130.1, 128.0, 117.6, 52.2, 27.7, 21.1, 9.6; HRMS (ESI-TOF) Calcd for C13H18NO ([MH]) 204.1383. Found 204.1377. N-Allyl-N-(p-tolyl)octanamide, isolated by flash column chromatography (petroleum ether/ethyl acetate  60:1) in 85% yield (3486 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   0.84 (t, J  6.8 Hz, 3H), 1.18-1.26 (m, 8H), 1.521.59 (m, 2H), 2.04 (t, J  7.7 Hz, 2H), 2.37 (s, 3H), 4.26 (ddd, J  1.1, 1.1, 6.3 Hz, 2H), 5.03-5.10 (m, 2H), 5.80-5.90 (m, 1H), 7.01 (d, J  8.1 Hz, 2H), 7.19 (d, J  8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   173.0, 140.1, 137.7, 133.5, 130.1, 128.1, 117.6, 52.2, 34.3, 31.6, 29.2, 29.0, 25.5, 22.6,

21.1, 14.1; HRMS (ESI-TOF) Calcd for C18H28NO ([MH]) 274.2165. Found 274.2168. N-Phenyl-N-(2-phenylallyl)acetamide,43 isolated by flash column chromatography (petroleum ether/ethyl acetate  32:1) in 77% yield (2903 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.79 (s, 3H), 4.87 (s, 2H), 5.00 (s, 1H), 5.33 (s, 1H), 6.90-6.92 (s, 2H), 7.25-7.35 (s, 6H), 7.40-7.42 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3)   170.3, 143.8, 142.2, 138.5, 129.3, 128.4, 128.2, 127.9, 127.8, 126.4, 115.9, 51.9, 22.8; HRMS (ESI-TOF) Calcd for C17H18NO ([MH]) 252.1383. Found 252.1392. Methyl 2-((N-(4chlorophenyl)acetamido)methyl)acrylate, prepared from methyl 2-(((4-chlorophenyl)amino)methyl)acrylate and acetyl chloride and isolated by flash column chromatography (petroleum ether/ethyl acetate  16:1) in 90% yield (3614 mg), white solid: mp 63-64 C. 1H NMR (400 MHz, CDCl3)   1.91 (s, 3H), 3.70 (s, 3H), 4.57 (s, 2H), 5.74 (d, J  1.0 Hz, 1H), 6.32 (s, 1H), 7.10 (d, J  8.5 Hz, 2H), 7.37 (d, J  8.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)   170.3, 166.3, 141.6, 135.4, 133.9, 129.9, 129.2, 127.3, 52.0, 50.0, 22.7; HRMS (ESI-TOF) Calcd for C13H15ClNO3 ([MH]) 268.0735. Found 268.0741. N-(2-Bromoallyl)-N-phenylacetamide,44 isolated by flash column chromatography (petroleum ether/ethyl acetate  16:1) in 42% yield (1601 mg), pale yellow oil. 1H NMR (400 MHz, CDCl3)   1.91 (s, 3H), 4.60 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 7.24-7.27 (m, 2H), 7.34-7.44 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3)   170.5, 142.2, 129.7, 128.6, 128.2, 128.0, 119.5, 56.3, 22.7; HRMS (ESI-TOF) Calcd for C11H13BrNO ([MH]) 254.0175. Found 254.0177.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H, 19F, 13C and DEPT NMR Spectra (PDF)

AUTHOR INFORMATION Corresponding Author [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21702083), the Yunnan Ten Thousand Talent Program for Young Top-Notch Talents, and the Program for Innovative Research Team (in Science and Technology) in Universities of Yunnan Province.

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