Tunable synthesis of functionalized cyclohexa-1,3-dienes and 2

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Tunable synthesis of functionalized cyclohexa-1,3-dienes and 2-aminobenzophenones/benzoate from the cascade reactions of allenic ketones/allenoate with amines and enones Tian Feng, Miaomiao Tian, Xinying Zhang, and Xuesen Fan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00473 • Publication Date (Web): 13 Apr 2018 Downloaded from http://pubs.acs.org on April 14, 2018

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The Journal of Organic Chemistry

Tunable synthesis of functionalized cyclohexa-1,3-dienes and 2-aminobenzophenones/ benzoate from the cascade reactions of allenic ketones/allenoate with amines and enones Tian Feng, Miaomiao Tian, Xinying Zhang*, and Xuesen Fan* School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China E-mail: [email protected]; [email protected]

Abstract: A TEMPO-dependent tunable synthesis of functionalized cyclohexa-1,3-dienes and 2-aminobenzophenones/benzoate from the one-pot cascade reactions of allenic ketones/allenoate with amines and enones is presented. Mechanistically, the construction of the entitled six-membered carbocycles involves the in situ generation of an enaminone intermediate via the conjugate addition of allenic ketone with amine followed by its catalyst- and base-free [3+3] annulation with enone along with the simultaneous introduction of the valuable amino and carbonyl groups.

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The functionalized cyclohexa-1,3-diene skeleton is widely found in naturally occurring or manmade compounds with biological and medicinal activities.1 Owing to its importance, several elegant methods for the construction of functionalized cyclohexa-1,3-diene scaffold have been developed, which mainly include: enyne cross metathesis of 1,5-cyclooctadiene with alkyne,2a tandem Michael/Wittig reaction of (4-oxobut-2-en-yl)triphenylphosphonium with acrolein,2b intramolecular [2+2+2] cycloaddition of enediynes,2c annulation of 1,3-bis(alkoxycarbonyl)buta-1,3-dienes with aldehydes,2d base-catalyzed domino reaction of tertiary propargyl vinyl ethers,2e Co(I)-catalyzed [2+2+2] cycloaddition of butynoate with terminal alkene.2f While these literature processes are generally reliable, new methods with higher atom-economy starting from simple substrates and realized under mild conditions without using expensive catalysts are still urgently needed. Meanwhile, allene derivatives are highly valuable in synthetic chemistry owing to their rich reactivity and ready availability.3-4 Among various allene derivatives, allenic ketones and allenoates are excellent electrophiles and vigorous acceptors of conjugate additions. Moreover, many of these conjugate addition reactions could initiate simultaneous intramolecular condensation and cyclization, thus providing efficient and step-economic approaches toward advanced cyclic skeletons from simple acyclic substrates. As a continuation of our interest in allene chemistry,3c,5 and inspired by the advantages of multicomponent sequential reactions,6 we have studied the one-pot three-component reaction of allenic ketone with amine and enone. During this study, we serendipitously found that through formation of an enaminone intermediate with amine,7,8 allenic ketone could act as a bisnucleophile to undergo an unprecedented catalyst- and base-free [3+3] annulation with enone to give functionalized cyclohexa-1,3-diene or 2-aminobenzophenone derivative with excellent chemo- and regio-selectivity (Scheme 1, (2)). Notably, this new reaction could be considered as a complementary result to what had been observed by Wan et al in their three-component reaction of enaminone with amine and α,-unsaturated aldehyde, which led to the


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formation of N-heterocycle (1,4-dihydropyridine) instead of carbocyclic compound (Scheme 1, (1)).9 Herein we report our detailed study in this aspect.

Scheme 1. Formation of heterocycle and carbocycle from enaminone Our study was initiated by treating 1-phenylbuta-2,3-dien-1-one (1a) with phenylmethanamine (2a) and 1-phenylprop-2-en-1-one (3a) in DCE at 120 oC for 12 h. From this reaction, 4a, a functionalized cyclohexa-1,3-diene, was obtained in 44% yield. Meanwhile, 5a, a substituted 2-aminobenzophenone, was formed in a yield of 15% (Table 1, entry 1). Notably, the formation of the 1,4-dihydropyridine derivative (I) as shown in Scheme 1 was not observed. Encouraged by this preliminary result, we then tried several solvents including THF, dioxane, chlorobenzene (PhCl), toluene and CH3CN with the aim to improve the efficiency and selectivity (entries 2-6). We were delighted to find that by using dioxane as the reaction medium, 4a and 5a could be obtained in yields of 62% and 21%, respectively (entry 3). Further studies showed that reaction temperatures higher or lower than 120 oC resulted in decreased efficiency (entries 7-8 vs 3). Finally, it was observed that when the reaction was carried out under nitrogen instead of air, the yield of 4a increased to 80%, and 5a was formed only in trace amount (entry 9), thus resulting in a highly efficient and selective synthesis of functionalized cyclohexa-1,3-diene. As a further aspect, 2-aminobenzophenone is a privileged scaffold and versatile building block widely employed in medicinal and synthetic chemistry.10 Notwithstanding of its importance, reliable and efficient synthetic methods for the preparation of 2-aminobenzophenone and its derivatives are only sporadically reported in literatures,10,11 and some of these literature methods ACS Paragon Plus Environment


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still suffer from expensive catalysts, perishable organometallic intermediates, harsh reaction conditions, low regioselectivity, or poor atom-economy. Under this background, we continued our study to search for suitable reaction conditions under which 5a, rather than 4a, could be formed as a dominating product from the reaction of 1a with 2a and 3a. For this purpose, several oxidants including O2, 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ), tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) were tried (entries 10-14). We were pleased to find that in the presence of 1 equiv of TEMPO, the yield of 5a improved remarkably (entry 14). Further study showed that the suitable loading of TEMPO is 1.2 equiv (entries 15-17). Interestingly, when the reaction was carried out under nitrogen instead of air, the yield of 5a increased to 73% (entry 18).12 The above results demonstrated that either 4 or 5 could be obtained selectively and efficiently from the same starting materials under similar reaction conditions just simply depending on the absence or presence of TEMPO. Table 1. Optimization study on the formation of 4a and 5aa

Entry

Oxidant (equiv)

Solvent

T/ºC

1

DCE

2

Yield (%)b 4a

5a

120

44

15

THF

120

21

5

3

dioxane

120

62

21

4

PhCl

120

51

13

5

toluene

120

41

11

6

CH3CN

120

39

7

7

dioxane

100

56

14

8

dioxane

140

59

19

9c

dioxane

120

80

trace

10

O2

dioxane

120

56

25

11

DDQ (1)

dioxane

120

28

8


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12

TBHP (1)

dioxane

120

45

15

13

DTBP (1)

dioxane

120

48

22

14

TEMPO (1)

dioxane

120

36

45

15

TEMPO (0.5)

dioxane

120

51

33

16

TEMPO (1.2)

dioxane

120

33

49

17

TEMPO (1.5)

dioxane

120

33

50

18c

TEMPO (1.2)

dioxane

120

11

73

a

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 3a (0.6 mmol), solvent (3 mL), air, 12 h. b Isolated yields. c Under nitrogen.

With the optimized reaction conditions in hands, the substrate scope for the synthesis of 4 was investigated. First, a series of 1-phenyl allenic ketones with various substituents attached on the phenyl ring were found to take part in this cascade reaction smoothly to afford 4a-4m in moderate to good yields (Table 2). A range of functional groups, from the electron-donating methyl or methoxy to the electron-deficient fluoro or trifluoromethyl, were well compatible with the reaction conditions, allowing for subsequent structural elaboration. Notably, the electronic nature of the 1-phenyl unit had an obvious effect on the yield of 4 as substrates attached with electron-donating groups (EDG) on the phenyl ring usually gave the corresponding products in higher efficiency than those with electron-withdrawing groups (EWG) (4k, 4l vs 4h, 4i, 4j, 4m). Notably, 1 with either an ortho-, meta- or para-substituted 1-phenyl unit underwent this cascade process smoothly. From 1-(naphthalene-1-yl) and 1-(thien-2-yl) allenic ketones, 4n and 4o were obtained successfully. Moreover, the reaction was compatible with 1-benzyl allenic ketone, though the yield of the corresponding product 4p was lower. In addition to 2a, propan-1-amine, 2-phenylethan-1-amine and 1-phenylethan-1-amine underwent this reaction smoothly to afford 4q-4t in moderate to good yields. Promisingly, p-toluidine as an aromatic amine was also a suitable substrate to afford 4u in moderate yield. Finally, 3a was replaced by 1-(thiophen-2-yl)prop-2-en-1-one to react with 1a and 2a. From this reaction, 4v was obtained in a yield of 31%. Notably, with 4-methylpent-1-en-3-one as the



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enone substrate 3, the reaction gave a complicated mixture, and the desired product 4w could not be obtained. Table 2. Substrate scope for the preparation of 4a,b

4a, 80%

4b, 56%

4c, 50%

4d, 64%

4e, 65%

4f, 62%

4g, 76%

4h, 59%

4i, 56%

4j, 51%

4k, 71%

4l, 86%

4m, 50%

4n, 53%

4o, 45%

4p, 32%

4q, 71%

4r, 58%

4s, 63%

4t, 65%

4u, 60%

4v, 31%

4w, not obtained

a

Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3 (0.6 mmol), dioxane (3 mL), N2, 120 oC, 12 h. b Isolated yields.

After establishing an efficient and general synthesis of 4, we continued to explore the substrate scope for the synthesis of 5 (Table 3). First, a number of 1-aryl allenic ketones 1 with different substituents attached on the 1-aryl unit were let to react with 2a and 3a, and the corresponding reactions proceeded smoothly to give 5a-5f in moderate to good yields. Similar to what had been observed in the synthesis of 4, the electronic nature of the 1-phenyl unit of 1 affected the yield of 5 in that substrate with EDG afforded the corresponding product in better yield than those with EWGs (5f vs 5d, 5e). As for the amine substrates 2, both aliphatic and aromatic amines including


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propan-1-amine, 2-phenylethan-1-amine, 1-phenylethan-1-amine, aniline and p-toluidine took part in this reaction to give 5g-5p in reasonably good yields. Moreover, different enones (3) were also tried, and they were compatible partners for this reaction to afford 5q and 5r. Table 3. Substrate scope for the preparation of 5a,b

a o

5a, 73%

5b, 42%

5c, 71%

5d, 58%

5e, 55%

5f, 79%

5g, 62%

5h, 43%

5i, 67%

5j, 53%

5k, 62%

5l, 73%

5m, 59%

5n, 58%

5o, 56%

5p, 50%

5q, 45%

5r, 33%

Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3 (0.6 mmol), TEMPO (0.6 mmol), dioxane (3 mL), N2, 120 C, 12 h. b Isolated yields.

Furthermore, the scope of the allene substrate was extended from allenic ketones (1) to allenoate 6. It turned out that 6 reacted with 2a and 3a smoothly to give the expected ethyl 5-(benzyl amino)-2,3-dihydro-[1,1'-biphenyl]-4-carboxylate (7) in 52% yield. Moreover, in the presence of TEMPO, the 2-aminobenzoate derivative 8 could be obtained in a yield of 45% (Scheme 2).

Scheme 2. Reactions of allenoate 6 with amine 2a and enone 3a In order to elucidate the reaction mechanism, the following control experiments were carried out. ACS Paragon Plus Environment


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First, 1a was treated with 2a in dioxane at rt for 0.5 h. From this reaction, 1-phenyl-3-(benzylamino) but-2-en-1-one (A) was obtained in 91% yield (Scheme 3, (1)). A was then treated with 3a at 120 o

C under nitrogen. As a result, 4a was formed in a yield of 89% (Scheme 3, (2)).

Scheme 3. Control experiments (I) Second, 4a was treated with TEMPO in dioxane under nitrogen at 120 oC for 12 h. From this reaction, 5a was obtained in an excellent yield of 92% (Scheme 4).

Scheme 4. Control experiments (II) Based on the above observations, a plausible mechanism accounting for the formation of 4a and 5a is proposed in Scheme 5. Initially, nucleophilic addition of 2a onto 1a affords enaminone A, which then undergoes a Michael addition onto 3a to afford intermediate B. Tautomerization of B gives B'. Next, B' undergoes an intramolecular condensation to afford 4a via the formation of intermediate C. In the presence of TEMPO, 4a is readily dehydrogenated to afford 5a.

Scheme 5. Proposed mechanism accounting for the formation of 4a and 5a As a further aspect, it has been reported that acridinone derivatives are endowed with significant biological and medicinal activities.13 To showcase the usability of the products obtained above and ACS Paragon Plus Environment

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to develop an alternative synthetic pathway toward acridinones, 5b was treated with KOH in DMSO, affording the desired acridinone derivative 9a in a yield of 82% (Scheme 6).14 Similarly, 9b was obtained from 5h in 88% yield. Meanwhile, it is worth to be noted that the structure of 9b was ambiguously confirmed by its single crystal X-ray diffraction analysis (Figure 1).15

Scheme 6. Synthesis of acridinone derivatives Finally, to study whether these newly developed methods are suitable for large scale synthetic missions, the preparations of 4a and 5a were carried out in an enlarged scale of 5 mmol. It turned out that under the optimum reaction conditions as described above, the corresponding reactions proceeded smoothly to afford 4a and 5a in yields of 61% and 53%, respectively (Scheme 7).

Scheme 7. Gram-scale synthesis of 4a and 5a In summary, a systematic study on the one-pot three-component reactions of allenic ketones/ allenoate with amines and enones has been carried out. From this study, highly selective and efficient syntheses of functionalized cyclohexa-1,3-dienes and 2-aminobenzophenones/benzoate from commercially available or readily obtainable acyclic substrates were developed. To the best of our knowledge, this is the first example in which the title compounds are prepared from the sequential reactions of acyclic substrates featuring with an unprecedented catalyst- and base-free [3+3] annulation. With notable features such as simple starting materials, mild reaction conditions without using any catalyst and base, high selectivity and excellent atom economy, the synthetic methods developed herein are expected to be used as valuable alternative protocols in related areas. ACS Paragon Plus Environment


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EXPERIMENTAL SECTION 1. General Methods All commercial reagents and solvents were used without further purification. Melting points were recorded with a micro melting point apparatus and uncorrected. The 1H NMR spectra were recorded at 400 MHz or 600 MHz, and the

13

C NMR spectra were recorded at 100 MHz or 150 MHz.

Chemical shifts were expressed in parts per million (δ), and were reported as s (singlet), d (doublet), t (triplet), m (multiplet), etc. The coupling constants J were given in Hz. High resolution mass spectra (HRMS) were obtained via ESI mode by using a MicrOTOF mass spectrometer. All the reactions were monitored by thin-layer chromatography (TLC) using silica gel plates (silica gel 60 F254 0.25 mm), and components were visualized by observation under UV light (254 and 365 nm). 2. A typical procedure for the synthesis of 4a and spectroscopic data of 4a-4v, 7 To a 15 mL reaction tube equipped with a stir bar were added 1-phenylbuta-2,3-dien-1-one (1a, 72.1 mg, 0.5 mmol), phenylmethanamine (2a, 65.6 μL, 0.6 mmol) and dioxane (3 mL) with stirring, then 1-phenylprop-2-en-1-one (3a, 79.4 mg, 0.6 mmol) was added to the mixture. After being flushed with N2, the tube was sealed, and the mixture was stirred at 120 °C for 12 h. Then, it was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to afford 4a in a yield of 80%. 4b-4v and 7 were obtained in an analogous manner. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(phenyl)methanone (4a) Eluent: petroleum ether/ethyl acetate (20:1). Yellow oil (146.3 mg, 80%). 1H NMR (400 MHz, CDCl3) δ: 2.56-2.63 (m, 4H), 4.66 (d, J = 5.6 Hz, 2H), 6.68 (s, 1H), 7.28-7.31 (m, 1H), 7.36-7.42 (m, 12H), 7.48-7.49 (m, 2H), 12.26 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 25.4, 28.2, 46.9,

97.8, 116.1, 126.0, 127.1, 127.5, 127.9, 128.7, 128.9, 129.1, 138.3, 139.6, 142.6, 152.0, 158.4,


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192.3. HRMS calcd for C26H24NO: 366.1852 [M+H]+, found: 366.1827. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(2-fluorophenyl)methanone (4b) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (107.0 mg, 56%). 1H NMR (400 MHz, CDCl3) δ: 2.47 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 4.66 (d, J = 6.0 Hz, 2H), 6.67 (s, 1H), 7.07 (t, J = 8.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.28-7.41 (m, 12H), 12.25 (br s, 1H).

13

C NMR

(150 MHz, CDCl3) δ: 23.9, 28.1, 46.9, 98.9, 115.6 (d, 2JC-F = 21.9 Hz), 115.9, 124.2 (d, 4JC-F = 2.1 Hz), 126.0, 127.1, 127.6, 128.7, 128.9, 129.2 (d, 3JC-F = 6.6 Hz), 130.0 (d, 3JC-F = 7.7 Hz), 130.7 (d, 2

JC-F = 18.6 Hz), 130.9, 138.0, 139.7, 152.9, 158.42 (d, 1JC-F = 245.0 Hz), 158.43, 186.9. HRMS

calcd for C26H23FNO: 384.1758 [M+H]+, found: 384.1750. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(2-bromophenyl)methanone (4c) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (110.7 mg, 50%). 1H NMR (400 MHz, CDCl3) δ: 2.29-2.39 (m, 2H), 2.57-2.62 (m, 2H), 4.68 (d, J = 6.0 Hz, 2H), 6.66 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.27-7.39 (m, 12H), 7.57 (d, J = 8.0 Hz, 1H), 12.10 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 23.8, 28.1, 46.9, 97.6, 115.9, 119.3, 126.0, 127.0, 127.4, 127.5, 127.8, 128.7, 128.9, 129.1, 129.2, 132.5, 138.1, 139.7, 143.8, 152.8, 158.7, 190.2. HRMS calcd for C26H22BrNNaO: 466.0777 [M+Na]+, found: 466.0788. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(3-fluorophenyl)methanone (4d) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (122.5 mg, 64%). 1H NMR (400 MHz, CDCl3) δ: 2.50 (s, 4H), 4.58 (d, J = 6.0 Hz, 2H), 6.61 (s, 1H), 6.95-6.99 (m, 1H), 7.10 (d, J = 9.2 Hz, 1H), 7.16-7.34 (m, 12H), 12.18 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 25.2, 28.1, 46.9, 97.4,

114.1 (d, 2JC-F = 21.9 Hz), 115.5 (d, 2JC-F = 20.7 Hz), 115.9, 122.7 (d, 4JC-F = 3.3 Hz), 126.0, 127.1, 127.6, 128.8, 129.0, 129.3, 129.6 (d, 3JC-F = 7.7 Hz), 138.1, 139.5, 144.8 (d, 3JC-F = 6.6 Hz), 152.5, 158.9, 162.5 (d, 1JC-F = 245.0 Hz), 190.2. HRMS calcd for C26H23FNO: 384.1758 [M+H]+, found:



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384.1738. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(3-chlorophenyl)methanone (4e) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (129.6 mg, 65%). 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 4H), 4.66 (d, J = 6.0 Hz, 2H), 6.68 (s, 1H), 7.29-7.42 (m, 13H), 7.46 (s, 1H), 12.26 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.2, 28.1, 46.9, 97.4, 115.8, 125.2, 126.0, 127.0, 127.3, 127.6, 128.7, 128.8, 128.95, 129.29, 129.33, 133.9, 138.1, 139.5, 144.3, 152.6, 159.0, 190.0. HRMS calcd for C26H23ClNO: 400.1463 [M+H]+, found: 400.1453. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(3-bromophenyl)methanone (4f) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (137.2 mg, 62%). 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 4H), 4.66 (d, J = 5.6 Hz, 2H), 6.68 (s, 1H), 7.23-7.31 (m, 2H), 7.36-7.40 (m, 10H), 7.49 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 12.25 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.2, 28.1, 46.9, 97.4, 115.8, 122.1, 125.6, 126.0, 127.0, 127.6, 128.8, 129.0, 129.3, 129.6, 130.1, 131.6, 138.0, 139.5, 144.6, 152.6, 158.9, 189.8. HRMS calcd for C26H23BrNO: 444.0958 [M+H]+, found: 444.0920. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(3-methoxyphenyl)methanone (4g) Eluent: petroleum ether/ethyl acetate (10:1). Orange oil (150.2 mg, 76%). 1H NMR (400 MHz, CDCl3) δ: 2.56-2.62 (m, 4H), 3.83 (s, 3H), 4.65 (d, J = 6.0 Hz, 2H), 6.68 (s, 1H), 6.91 (dd, J1= 8.4 Hz, J2 = 2.0 Hz, 1H), 7.03-7.06 (m, 2H), 7.27-7.31 (m, 2H), 7.35-7.42 (m, 9H), 12.23 (br s, 1H). 13

C NMR (150 MHz, CDCl3) δ: 25.4, 28.2, 46.9, 55.3, 97.7, 112.1, 114.8, 116.0, 119.3, 126.0,

127.1, 127.5, 128.7, 128.9, 129.1, 138.2, 139.6, 144.0, 152.1, 158.5, 159.3, 191.9. HRMS calcd for C27H26NO2: 396.1958 [M+H]+, found: 396.1938. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(4-fluorophenyl)methanone (4h) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (112.8 mg, 59%). 1H NMR (400 MHz,


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CDCl3) δ: 2.60 (s, 4H), 4.65 (d, J = 6.0 Hz, 2H), 6.69 (s, 1H), 7.06 (t, J = 8.4 Hz, 2H), 7.28-7.31 (m, 1H), 7.36-7.42 (m, 9H), 7.47-7.50 (m, 2H), 12.24 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.5, 28.1, 46.9, 97.6, 114.8 (d, 2JC-F = 20.9 Hz), 116.0, 126.0, 127.0, 127.6, 128.7, 128.9, 129.18 (d, 3JC-F = 6.5 Hz), 129.22, 138.2, 138.68 (d, 4JC-F = 3.3 Hz), 139.5, 152.1, 158.6, 163.0 (d, 1JC-F = 247.2 Hz), 190.8. HRMS calcd for C26H23FNO: 384.1758 [M+H]+, found: 384.1729. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(4-chlorophenyl)methanone (4i) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (111.6 mg, 56%). 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 4H), 4.65 (d, J = 5.6 Hz, 2H), 6.68 (s, 1H), 7.28-7.31 (m, 1H), 7.34-7.44 (m, 13H), 12.26 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.4, 28.1, 46.9, 97.6, 115.9, 126.0, 127.1, 127.6, 128.1, 128.6, 128.8, 128.9, 129.3, 134.6, 138.1, 139.5, 140.9, 152.4, 158.8, 190.5. HRMS calcd for C26H23ClNO: 400.1463 [M+H]+, found: 400.1440. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(4-bromophenyl)methanone (4j) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (112.8 mg, 51%). 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 4H), 4.65 (d, J = 6.0 Hz, 2H), 6.68 (s, 1H), 7.28-7.31 (m, 1H), 7.35-7.42 (m, 11H), 7.51 (d, J = 8.0 Hz, 2H), 12.26 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.3, 28.1, 46.9, 97.5, 115.9, 122.9, 126.0, 127.1, 127.6, 128.8, 128.86, 128.94, 129.3, 131.1, 138.1, 139.5, 141.4, 152.4, 158.8, 190.5. HRMS calcd for C26H22BrNNaO: 466.0777 [M+Na]+, found: 466.0782 (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(p-tolyl)methanone (4k) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (134.5 mg, 71%). 1H NMR (400 MHz, CDCl3) δ: 2.38 (s, 3H), 2.54-2.58 (m, 2H), 2.62-2.65 (m, 2H), 4.64 (d, J = 6.0 Hz, 2H), 6.68 (s, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.27-7.30 (m, 1H), 7.35-7.41 (m, 11H), 12.21 (br s, 1H).

13

C NMR (150

MHz, CDCl3) δ: 21.4, 25.6, 28.2, 46.9, 97.9, 116.1, 125.9, 127.1, 127.2, 127.5, 128.5, 128.7, 128.9, 129.1, 138.4, 138.7, 139.7, 139.8, 151.7, 158.2, 192.4. HRMS calcd for C27H26NO: 380.2009



Page 14 of 32

[M+H]+, found: 380.1996. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(4-methoxyphenyl)methanone (4l) Eluent: petroleum ether/ethyl acetate (10:1). Orange oil (169.9 mg, 86%). 1H NMR (400 MHz, CDCl3) δ: 2.48-2.51 (m, 2H), 2.58-2.62 (m, 2H), 3.76 (s, 3H), 4.56 (d, J = 6.0 Hz, 2H), 6.60 (s, 1H), 6.83 (d, J = 8.4 Hz, 2H), 7.19-7.22 (m, 1H), 7.27-7.30 (m, 7H), 7.33-7.35 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 12.11 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 24.8, 27.1, 45.8, 54.3, 96.9, 112.1, 115.2, 124.9, 126.0, 126.4, 127.7, 127.8, 127.96, 128.01, 134.1, 137.4, 138.6, 150.5, 157.1, 159.1, 190.7. HRMS calcd for C27H26NO2: 396.1958 [M+H]+, found: 396.1946. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(4-(trifluoromethyl)phenyl)methanone (4m) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (108.1 mg, 50%). 1H NMR (400 MHz, CDCl3) δ: 2.53-2.60 (m, 4H), 4.66 (d, J = 5.6 Hz, 2H), 6.70 (s, 1H), 7.29-7.31 (m, 1H), 7.36-7.40 (m, 9H), 7.57 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 12.31 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.1, 28.1, 47.0, 97.4, 115.8, 124.1 (q, 1JC-F = 263.6 Hz), 125.0 (q, 3JC-F = 3.3 Hz), 126.0, 127.1, 127.4, 127.6, 128.8, 129.0, 129.4, 130.5 (q, 2JC-F = 31.8 Hz), 138.0, 139.4, 146.0, 152.8, 159.2, 190.0. HRMS calcd for C27H23F3NO: 434.1726 [M+H]+, found: 434.1710. (5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(naphthalen-1-yl)methanone (4n) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (109.8 mg, 53%). 1H NMR (600 MHz, CDCl3) δ: 2.29 (s, 2H), 2.50 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 6.72 (s, 1H), 7.30-7.51 (m, 14H), 7.83 (d, J = 7.8 Hz, 1H), 7.85-7.88 (m, 1H), 8.01-8.03 (m, 1H), 12.40 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 24.4, 28.2, 46.9, 99.0, 115.9, 123.4, 125.3, 125.8, 125.9, 126.0, 126.2, 127.1, 127.6, 128.0, 128.2, 128.7, 128.9, 129.2, 130.0, 133.5, 138.3, 139.7, 140.9, 152.6, 158.2, 192.5. HRMS calcd for C30H26NO: 416.2009 [M+H]+, found: 416.1993.


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(5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(thiophen-2-yl)methanone (4o) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (83.4 mg, 45%). 1H NMR (400 MHz, CDCl3) δ: 2.66 (t, J = 8.0 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 4.62 (d, J = 6.0 Hz, 2H), 6.68 (s, 1H), 7.05 (t, J = 4.8 Hz, 1H), 7.27-7.29 (m, 1H), 7.34-7.37 (m, 7H), 7.41-7.43 (m, 4H), 12.31 (br s, 1H). 13

C NMR (150 MHz, CDCl3) δ: 25.4, 27.9, 47.0, 97.9, 116.0, 126.0, 126.9, 127.1, 127.5, 127.8,

128.7, 128.8, 128.9, 129.2, 138.2, 139.5, 147.3, 151.5, 158.7, 182.0. HRMS calcd for C24H22NOS: 372.1417 [M+H]+, found: 372.1413. 1-(5-(Benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)-2-phenylethanone (4p) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (60.5 mg, 32%). 1H NMR (400 MHz, CDCl3) δ: 2.60-2.67 (m, 4H), 3.83 (s, 2H), 4.54 (d, J = 6.4 Hz, 2H), 6.58 (s, 1H), 7.19-7.41 (m, 15H), 11.84 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 23.5, 27.7, 46.3, 46.7, 97.6, 116.0, 125.9,

126.2, 127.0, 127.4, 128.4, 128.7, 128.8, 129.0, 129.3, 137.2, 138.6, 139.7, 150.8, 156.8, 193.9. HRMS calcd for C27H26NO: 380.2009 [M+H]+, found 380.2012. (3-Methoxyphenyl)(5-(propylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)methanone (4q) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (123.2 mg, 71%). 1H NMR (400 MHz, CDCl3) δ: 1.06 (t, J = 7.6 Hz, 3H), 1.69-1.79 (m, 2H), 2.58 (s, 4H), 3.41 (q, J = 6.4 Hz, 2H), 3.83 (s, 3H), 6.71 (s, 1H), 6.89-6.91 (m, 1H), 7.03 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.37-7.43 (m, 3H), 7.52 (d, J = 7.2 Hz, 2H). 12.02 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 11.6, 23.5, 25.3, 28.3, 44.7, 55.3, 96.8, 112.1, 114.7, 115.9, 119.3, 125.9, 128.7, 128.9, 129.1, 139.9, 144.1, 152.1, 158.6, 159.3, 191.0. HRMS calcd for C23H26NO2: 348.1958 [M+H]+, found: 348.1948. (4-Bromophenyl)(5-(propylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)methanone (4r) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (114.4 mg, 58%). 1H NMR (400 MHz, CDCl3) δ: 1.06 (t, J = 7.2 Hz, 3H), 1.69-1.78 (m, 2H), 2.54-2.60 (m, 4H), 3.39-3.44 (m, 2H), 6.70 (s,



1H), 7.34 (d, J = 8.0 Hz, 2H), 7.38-7.43 (m, 3H), 7.50-7.53 (m, 4H), 12.05 (br s, 1H).

Page 16 of 32

13

C NMR

(150 MHz, CDCl3) δ: 11.6, 23.5, 25.3, 28.2, 44.8, 96.8, 115.7, 122.7, 125.9, 128.78, 128.84, 129.2, 131.1, 139.7, 141.5, 152.4, 158.9, 189.6. HRMS calcd for C22H23BrNO: 396.0958 [M+H]+, found: 396.0922. (5-(Phenethylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)(phenyl)methanone (4s) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (119.3 mg, 63%). 1H NMR (400 MHz, CDCl3) δ: 2.55 (s, 4H), 3.00 (t, J = 7.2 Hz, 2H), 3.68 (q, J = 6.8 Hz, 2H), 6.61 (s, 1H), 7.21-7.34 (m, 6H), 7.37-7.47 (m, 9H), 12.07 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 25.3, 28.2, 37.0, 44.8,

97.2, 115.8, 125.9, 126.7, 127.0, 127.9, 128.6, 128.7, 128.9, 129.1, 138.6, 139.7, 142.7, 151.9, 158.4, 191.8. HRMS calcd for C27H26NO: 380.2009 [M+H]+, found: 380.1998. Phenyl(5-((1-phenylethyl)amino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)methanone (4t) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (123.2 mg, 65%). 1H NMR (400 MHz, CDCl3) δ: 1.64 (d, J = 6.8 Hz, 3H), 2.46-2.60 (m, 4H), 4.86-4.93 (m, 1H), 6.56 (s, 1H), 7.27-7.41 (m, 13H), 7.51 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 2H), 12.34 (d, J = 6.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.1, 25.4, 28.0, 53.3, 97.7, 116.7, 125.8, 126.0, 127.1, 127.3, 127.9, 128.7, 128.8, 128.99, 129.04, 139.6, 142.6, 144.9, 151.5, 157.8, 192.1. HRMS calcd for C27H26NO: 380.2009 [M+H]+, found: 380.2007. Phenyl(5-(p-tolylamino)-2,3-dihydro-[1,1'-biphenyl]-4-yl)methanone (4u) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (109.5 mg, 60%). 1H NMR (600 MHz, CDCl3) δ: 2.36 (s, 3H), 2.63-2.65 (m, 4H), 6.73 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 7.32-7.37 (m, 3H), 7.39-7.43 (m, 3H), 7.44 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 13.37 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 21.0, 25.3, 27.5, 99.5, 117.5, 124.6, 125.9, 127.0, 128.0, 128.7, 129.0, 129.8, 135.1, 136.0, 139.4, 142.4, 149.9, 155.5, 193.2. HRMS calcd for C26H24NO:


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366.1852 [M+H]+, found: 366.1848. (2-(Benzylamino)-4-(thiophen-2-yl)cyclohexa-1,3-dien-1-yl)(phenyl)methanone (4v) Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (57.5 mg, 31%). 1H NMR (400 MHz, CDCl3) δ: 2.55-2.62 (m, 4H), 4.63 (d, J = 5.6 Hz, 2H), 6.71 (s, 1H), 7.04 (t, J = 4.4 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.26-7.29 (m, 1H), 7.32-7.40 (m, 8H), 7.46 (d, J = 6.4 Hz, 2H), 12.22 (br s, 1H). 13

C NMR (150 MHz, CDCl3) δ: 25.3, 28.2, 47.0, 97.9, 113.7, 126.3, 127.05, 127.15, 127.4, 127.5,

127.9, 128.2, 128.7, 128.9, 138.3, 142.6, 143.5, 144.8, 158.5, 191.8. HRMS calcd for C24H22NOS: 372.1417 [M+H]+, found: 372.1427. Ethyl 5-(benzylamino)-2,3-dihydro-[1,1'-biphenyl]-4-carboxylate (7) Eluent: petroleum ether/ethyl acetate (50:1). Yellow oil (86.5 mg, 52%). 1H NMR (400 MHz, CDCl3) δ: 1.30 (t, J = 7.2 Hz, 3H), 2.59 (s, 4H), 4.18 (q, J = 7.2 Hz, 2H), 4.52 (d, J = 6.0 Hz, 2H), 6.53 (s, 1H), 7.30-7.40 (m, 10H), 9.13 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.7, 21.6, 27.2, 46.8, 58.9, 87.6, 116.3, 125.8, 126.9, 127.2, 128.5, 128.6, 128.8, 139.5, 140.1, 148.7, 154.6, 170.5. HRMS calcd for C22H24NO2: 334.1802 [M+H]+, found: 334.1817. 3. A typical procedure for the synthesis of 5a and spectroscopic data of 5a-5r, 8 To a 15 mL reaction tube equipped with a stir bar were added 1-phenylbuta-2,3-dien-1-one (1a, 72.1 mg, 0.5 mmol), phenylmethanamine (2a, 65.6 μL, 0.6 mmol), and dioxane (3 mL) with stirring. Then, 1-phenylprop-2-en-1-one (3a, 79.4 mg, 0.6 mmol) and TEMPO (93.8 mg, 0.6 mmol) were added to the mixture. After being flushed with N2, the tube was sealed, and the mixture was stirred at 120 °C for 12 h. It was then cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (100:1) as the eluent to afford 5a in a yield of 73%. 5b-5r and 8 were obtained in an analogous manner.



Page 18 of 32

(3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(phenyl)methanone (5a) Eluent: petroleum ether/ethyl acetate (100:1). Orange oil (132.5 mg, 73%). 1H NMR (600 MHz, CDCl3) δ: 4.57 (d, J = 4.8 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.94 (s, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 3H), 7.40-7.44 (m, 4H), 7.47 (t, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 9.14 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 47.1, 110.4, 113.5, 116.5, 127.28, 127.31, 127.34, 128.1, 128.2, 128.8, 129.1, 130.8, 136.1, 138.5, 140.6, 140.7, 147.6, 151.9, 199.1. HRMS calcd for C26H21NNaO: 386.1515 [M+Na]+, found: 386.1504. (3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(2-bromophenyl)methanone (5b) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (92.6 mg, 42%). 1H NMR (400 MHz, CDCl3) δ: 4.56 (d, J = 5.2 Hz, 2H), 6.66 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 6.85 (d, J = 1.2 Hz, 1H), 7.20-7.35 (m, 10H), 7.37-7.43 (m, 4H), 7.58 (d, J = 8.0 Hz, 1H), 9.40 (t, J = 5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 47.0, 110.5, 114.0, 115.8, 119.4, 127.16, 127.23, 127.3, 127.4, 128.4, 128.5, 128.78, 128.81, 130.3, 133.0, 136.1, 138.3, 140.5, 142.1, 148.4, 152.2, 197.6. HRMS calcd for C26H20BrNNaO: 464.0620 [M+Na]+, found: 464.0624. (3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(3-methoxyphenyl)methanone (5c) Eluent: petroleum ether/ethyl acetate (50:1). Orange oil (139.5 mg, 71%). 1H NMR (400 MHz, CDCl3) δ: 3.85 (s, 3H), 4.57 (d, J = 5.2 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 7.06 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.18-7.22 (m, 2H), 7.26-7.30 (m, 1H), 7.35-7.44 (m, 8H), 7.52 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 9.12 (t, J = 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ: 47.1, 55.5, 110.4, 113.5, 113.7, 116.5, 117.0, 121.6, 127.28, 127.32, 127.4, 128.3, 128.8, 129.1, 136.1, 138.5, 140.7, 141.9, 147.6, 151.9, 159.4, 198.8. HRMS calcd for C27H23NNaO2: 416.1621 [M+Na]+, found: 416.1616. (3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(4-fluorophenyl)methanone (5d)


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Eluent: petroleum ether/ethyl acetate (100:1). Yellow solid (110.4 mg, 58%), mp: 94-95 °C. 1H NMR (400 MHz, CDCl3) δ: 4.57 (d, J = 5.6 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.35-7.39 (m, 3H), 7.40-7.44 (m, 4H), 7.51-7.56 (m, 3H), 7.67-7.70 (m, 2H), 9.01 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 47.1, 110.5, 113.6, 115.2 (d,

2

JC-F = 20.9 Hz), 116.4, 127.2, 127.3, 127.4, 128.3, 128.8, 131.5 (d, 3JC-F = 8.9 Hz), 135.7, 136.7 (d,

4

JC-F = 3.3 Hz), 138.4, 140.6, 147.7, 151.8, 164.4 (d, 1JC-F = 249.5 Hz), 197.6. HRMS calcd for

C26H21FNO: 382.1602 [M+H]+, found: 382.1602. (3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(4-chlorophenyl)methanone (5e) Eluent: petroleum ether/ethyl acetate (100:1). Yellow solid (109.1 mg, 55%), mp: 60-61 °C. 1H NMR (600 MHz, CDCl3) δ: 4.50 (d, J = 5.4 Hz, 2H), 6.72 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H),7.28-7.31(m, 3H), 7.34-7.39 (m, 6H), 7.45 (t, J = 7.8 Hz, 3H), 7.53 (d, J = 8.4 Hz, 2H), 9.01 (t, J = 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ: 47.1, 110.5, 113.6, 116.2, 127.2, 127.3, 127.4, 128.3, 128.4, 128.8, 130.5, 135.7, 137.1, 138.4, 138.9, 140.5, 147.8, 151.9, 197.6. HRMS calcd for C26H20ClNNaO: 420.1126 [M+Na]+, found: 420.1110. (3-(Benzylamino)-[1,1'-biphenyl]-4-yl)(4-methoxyphenyl)methanone (5f) Eluent: petroleum ether/ethyl acetate (50:1). Yellow solid (155.8 mg, 79%), mp: 90-91 °C. 1H NMR (400 MHz, CDCl3) δ: 3.88 (s, 3H), 4.55 (d, J = 5.2 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 3H), 7.40-7.43 (m, 4H), 7.52 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H) 7.69 (d, J = 8.8 Hz, 2H), 8.83 (t, J = 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ: 47.2, 55.5, 110.4, 113.40, 113.44, 117.1, 127.28, 127.30, 127.34, 128.1, 128.8, 131.6, 132.9, 135.6, 138.6, 140.8, 147.1, 151.5, 162.1, 197.9. HRMS calcd for C27H23NNaO2: 416.1621 [M+Na]+, found: 416.1619. Phenyl(3-(propylamino)-[1,1'-biphenyl]-4-yl)methanone (5g)



Page 20 of 32

Eluent: petroleum ether/ethyl acetate (100:1). Yellow solid (97.6 mg, 62%), mp: 89-90 °C. 1H NMR (400 MHz, CDCl3) δ: 0.97 (t, J = 7.6 Hz, 3H), 1.62-1.71 (m, 2H), 3.18 (q, J = 6.4 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 7.24-7.39 (m, 6H), 7.43 (d, J = 8.4 Hz, 1H), 7.50-7.52 (m, 4H), 8.68 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 11.9, 22.5, 44.7, 110.0, 113.0, 116.0, 127.4, 128.1, 128.3, 128.9, 129.0, 130.7, 136.2, 140.8, 140.9, 147.7, 152.4, 199.0. HRMS calcd for C22H21NNaO: 338.1515 [M+Na]+, found: 338.1510. (2-Bromophenyl)(3-(propylamino)-[1,1'-biphenyl]-4-yl)methanone (5h) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (84.5 mg, 43%). 1H NMR (400 MHz, CDCl3) δ: 1.01 (t, J = 7.2 Hz, 3H), 1.69-1.78 (m, 2H), 3.25 (q, J = 6.8 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.19-7.23 (m, 2H), 7.28-7.37 (m, 4H), 7.51-7.55 (m, 3H), 9.00 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 11.9, 22.4, 44.7, 110.0, 113.5, 115.4, 119.5, 127.2, 127.4, 128.4, 128.6, 128.9, 130.3, 133.0, 136.2, 140.8, 142.2, 148.5, 152.6, 197.4. HRMS calcd for C22H21BrNO: 394.0801[M+H]+, found: 394.0794. (3-Methoxyphenyl)(3-(propylamino)-[1,1'-biphenyl]-4-yl)methanone (5i) Eluent: petroleum ether/ethyl acetate (50:1). Yellow oil (115.5 mg, 67%). 1H NMR (400 MHz, CDCl3) δ: 1.09 (t, J = 7.2 Hz, 3H), 1.75-1.84 (m, 2H), 3.31 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 6.74 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 7.05 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.17-7.20 (m, 2H), 7.34-7.41 (m, 2H), 7.44-7.47 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 8.76 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 11.8, 22.4, 44.7, 55.4, 109.9, 112.9, 113.6, 115.9, 116.9, 121.5, 127.3, 128.2, 128.8, 129.1, 136.2, 140.9, 142.1, 147.7, 152.3, 159.4, 198.7. HRMS calcd for C23H23NNaO2: 368.1621 [M+Na]+, found: 368.1620. (4-Bromophenyl)(3-(propylamino)-[1,1'-biphenyl]-4-yl)methanone (5j) Eluent: petroleum ether/ethyl acetate (100:1). Yellow solid (104.1 mg, 53%), mp: 80-82 °C. 1H


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NMR (600 MHz, CDCl3) δ: 1.01 (t, J = 7.8 Hz, 3H), 1.69-1.75 (m, 2H), 3.23 (q, J = 7.2 Hz, 2H), 6.67 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 7.32-7.34 (m, 1H), 7.38-7.44 (m, 5H), 7.52-7.56 (m, 4H), 8.66 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 11.8, 22.4, 44.7, 110.1, 113.0, 115.6, 125.3, 127.3, 128.3, 128.8, 130.6, 131.4, 135.8, 139.5, 140.8, 148.0, 152.4, 197.6. HRMS calcd for C22H20BrNNaO: 416.0620 [M+Na]+, found: 416.0603. (3-(Propylamino)-[1,1'-biphenyl]-4-yl)(p-tolyl)methanone (5k) Eluent: petroleum ether/ethyl acetate (100:1). Orange oil (101.9 mg, 62%). 1H NMR (400 MHz, CDCl3) δ: 1.08 (t, J = 7.6 Hz, 3H), 1.74-1.83 (m, 2H), 2.43 (s, 3H), 3.29 (q, J = 6.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 7.26 (d, J = 6.8 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.54-7.58 (m, 3H), 7.62 (d, J = 7.6 Hz, 2H), 8.66 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 11.8, 21.5, 22.4, 44.7, 109.9, 112.8, 116.3, 127.3, 128.2, 128.7, 128.8, 129.3, 136.0, 137.9, 141.0, 141.2, 147.4, 152.2, 198.8. HRMS calcd for C23H24NO: 330.1852 [M+H]+, found: 330.1850. (4-Methoxyphenyl)(3-(propylamino)-[1,1'-biphenyl]-4-yl)methanone (5l) Eluent: petroleum ether/ethyl acetate (50:1). Yellow oil (125.8 mg, 73%). 1H NMR (400 MHz, CDCl3) δ: 1.00 (t, J = 7.2 Hz, 3H), 1.66-1.75 (m, 2H), 3.21 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 6.69 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 6.86-6.90 (m, 3H), 7.30-7.34 (m, 1H), 7.37-7.41 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.56-7.61 (m, 4H), 8.42 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 11.8, 22.4, 44.7, 55.5, 109.9, 112.8, 113.4, 116.6, 127.3, 128.1, 128.8, 131.5, 133.1, 135.7, 141.0, 147.2, 152.0, 162.0, 197.9. HRMS calcd for C23H24NO2: 346.1802 [M+H]+, found: 346.1799. (3-(Phenethylamino)-[1,1'-biphenyl]-4-yl)(phenyl)methanone (5m) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (111.2 mg, 59%). 1H NMR (400 MHz, CDCl3) δ: 2.99 (t, J = 7.6 Hz, 2H), 3.52 (t, J = 7.2 Hz, 2H), 6.68 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 7.15-7.17 (m, 1H), 7.23-7.26 (m, 4H), 7.31-7.33 (m, 1H), 7.35-7.40 (m,



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4H), 7.42-7.48 (m, 2H), 7.52-7.55 (m, 4H), 8.74 (br s, 1H). 13C NMR (150 MHz, CDCl3) δ: 34.7, 43.7, 108.9, 112.2, 115.2, 125.5, 126.3, 127.1, 127.2, 127.6, 127.8, 127.9, 129.6, 135.1, 138.1, 139.6, 139.7, 146.6, 150.9, 197.9. HRMS calcd for C27H23NNaO: 400.1672 [M+Na]+, found: 400.1669. Phenyl(3-((1-phenylethyl)amino)-[1,1'-biphenyl]-4-yl)methanone (5n) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (109.3 mg, 58%). 1H NMR (400 MHz, CDCl3) δ: 1.57 (d, J = 6.8 Hz, 3H), 4.61-4.68 (m, 1H), 6.63 (dd, J1 = 8.0 Hz, J2 = 1.6, 1H), 6.69 (d, J = 1.6 Hz, 1H), 7.14-7.18 (m, 1H), 7.23-7.28 (m, 7H), 7.33-7.40 (m, 4H), 7.42-7.48 (m, 2H), 7.57-7.59 (m, 2H), 9.10 (d, J = 5.6 Hz, 1H).

13

C NMR (150 MHz, CDCl3) δ: 25.0, 53.0, 111.6,

113.3, 116.4, 126.0, 127.1, 127.2, 128.1, 128.8, 128.9, 129.1, 130.9, 136.0, 140.6, 140.7, 144.8, 147.2, 151.1, 199.2. HRMS calcd for C27H23NNaO: 400.1672 [M+Na]+, found: 400.1667. Phenyl(3-(phenylamino)-[1,1'-biphenyl]-4-yl)methanone (5o) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (97.7 mg, 56%). 1H NMR (600 MHz, CDCl3) δ: 6.93 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.35-7.39 (m, 5H), 7.40-7.43 (m, 2H), 7.48-7.51 (m, 2H), 7.54-7.57 (m, 3H), 7.60-7.62 (m, 2H), 7.72-7.74 (m, 2H), 10.28 (br s, 1H).

13

C NMR (100 MHz, CDCl3) δ: 112.9, 115.7, 118.5, 122.3, 123.7, 127.3, 128.2,

128.3, 128.8, 129.4, 129.5, 131.3, 135.7, 140.0, 140.3, 140.6, 147.0, 148.5, 198.9. HRMS calcd for C25H19NNaO: 372.1359 [M+Na]+, found: 372.1360. Phenyl(3-(p-tolylamino)-[1,1'-biphenyl]-4-yl)methanone (5p) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (90.7 mg, 50%). 1H NMR (400 MHz, CDCl3) δ: 2.29 (s, 3H), 6.82 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.11-7.13 (m, 2H), 7.17-7.19 (m, 2H), 7.27-7.36 (m, 3H), 7.41-7.49 (m, 6H), 7.54 (d, J = 8.4 Hz, 1H), 7.64-7.66 (m, 2H), 10.20 (br s, 1H).

13

C NMR (150 MHz, CDCl3) δ: 20.9, 112.5, 115.2, 117.9, 123.0, 127.3, 128.2, 128.3, 128.8,


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129.3, 130.1, 131.2, 133.7, 135.7, 137.7, 140.2, 140.4, 147.0, 149.3, 198.9. HRMS calcd for C26H21NNaO: 386.1515 [M+Na]+, found: 386.1513. (3-(Benzylamino)-4'-fluoro-[1,1'-biphenyl]-4-yl)(phenyl)methanone (5q) Eluent: petroleum ether/ethyl acetate (100:1). Yellow solid (85.7 mg, 45%), mp: 72-73 °C. 1H NMR (400 MHz, CDCl3) δ: 4.50 (s, 2H), 6.66 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 7.01-7.05 (m, 2H), 7.20-7.23 (m, 1H), 7.28-7.31 (m, 2H), 7.35-7.42 (m, 6H), 7.44-7.51 (m, 2H), 7.56-7.58 (m, 2H), 9.09 (br s, 1H). 2

13

C NMR (150 MHz, CDCl3) δ: 47.1, 110.3, 113.3, 115.7 (d,

JC-F = 21.9 Hz), 116.5, 127.3, 127.4, 128.1, 128.8, 128.9 (d, 3JC-F = 8.7 Hz), 129.1, 130.9, 136.2,

136.7 (d, 4JC-F = 3.3 Hz), 138.5, 140.5, 146.5, 151.9, 163.0 (d, 1JC-F = 247.2 Hz), 199.1. HRMS calcd for C26H20FNNaO: 404.1421 [M+Na]+, found: 404.1419. (3-(Benzylamino)-4'-bromo-[1,1'-biphenyl]-4-yl)(phenyl)methanone (5r) Eluent: petroleum ether/ethyl acetate (100:1). Orange oil (72.7 mg, 33%). 1H NMR (400 MHz, CDCl3) δ: 4.50 (d, J = 5.6 Hz, 2H), 6.66 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 7.20-7.24 (m, 1H), 7.28-7.32 (m, 4H), 7.35-7.42 (m, 4H), 7.45-7.48 (m, 3H), 7.51 (d, J = 8.4 Hz, 1H), 7.57-7.59 (m, 2H), 9.07 (t, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 47.1, 110.2, 113.1, 116.8, 122.6, 127.3, 127.4, 128.1, 128.8, 129.1, 130.9, 131.9, 136.2, 138.4, 139.6, 140.4, 146.2, 151.9, 199.1. HRMS calcd for C26H20BrNNaO: 464.0620 [M+Na]+, found: 464.0655. Ethyl 3-(benzylamino)-[1,1'-biphenyl]-4-carboxylate (8) Eluent: petroleum ether/ethyl acetate (100:1). Yellow oil (74.5 mg, 45%). 1H NMR (400 MHz, CDCl3) δ: 1.39 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H), 4.51 (d, J = 5.6 Hz, 2H), 6.83 (d, J = 6.4 Hz, 1H), 6.84 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.33-7.42 (m, 7H), 7.50 (d, J = 7.6 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 8.25 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.4, 47.2, 60.3, 109.5, 110.1, 114.1, 127.25, 127.28, 128.0, 128.8, 132.1, 138.8, 140.9, 147.1, 151.1, 168.7. HRMS calcd for



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C22H22NO2: 332.1645 [M+H]+, found: 332.1655. 4. A typical procedure for the synthesis of 9a and spectroscopic data of 9a, 9b A mixture of 5b (221.2 mg, 0.5 mmol) and KOH (56.1 mg, 1 mmol) in dry DMSO (5 mL) was stirred at 120 °C for 16 h in a sealed tube. Then, ethyl acetate (5 mL) and water (5 mL) were added to the resulting mixture, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with Na2SO4, the solvent was removed under reduced pressure and the product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to give 9a in a yield of 82%. 9b was obtained in an analogous manner. 10-Benzyl-3-phenylacridin-9(10H)-one (9a) Eluent: petroleum ether/ethyl acetate (20:1). Light brown oil (148.0 mg, 82%). 1H NMR (600 MHz, CDCl3) δ: 5.64 (s, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.29-7.32 (m, 2H), 7.35-7.38 (m, 4H), 7.42 (t, J = 7.2 Hz, 2H), 7.45-7.53 (m, 4H), 7.61 (t, J = 7.8 Hz, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H).

13

C NMR (150 MHz, CDCl3) δ: 50.9, 113.5, 115.3, 121.2, 121.5, 121.8, 122.8, 125.8,

127.6, 127.8, 127.9, 128.37, 128.43, 129.0, 129.3, 134.1, 135.6, 140.4, 142.7, 142.9, 147.0, 178.1. HRMS calcd for C26H20NO: 362.1539 [M+H]+, found: 362.1528. 3-Phenyl-10-propylacridin-9(10H)-one (9b) Eluent: petroleum ether/ethyl acetate (20:1). Light brown solid (137.6 mg, 88%), mp : 171-172 oC. 1

H NMR (400 MHz, CDCl3) δ: 1.08 (t, J = 7.2 Hz, 3H), 1.87-1.97 (m, 2H), 4.25 (t, J = 8.4 Hz, 2H),

7.19 (t, J = 8.0 Hz, 1H), 7.36-7.45 (m, 5H), 7.52 (s, 1H), 7.58-7.64 (m, 3H), 8.50 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 11.3, 20.7, 47.7, 113.1, 114.6, 120.8, 121.3, 121.4, 122.7, 127.6, 128.0, 128.4, 128.6, 129.1, 133.8, 140.8, 142.0, 142.1, 146.8, 177.7. HRMS calcd for C22H20NO: 314.1539 [M+H]+, found: 314.1533.


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5. Control Experiment (I) 5.1. To a solution of 1-phenylbuta-2,3-dien-1-one (1a, 72.1 mg, 0.5 mmol) in dioxane (3 mL) was added phenylmethanamine (2a, 65.6 μL, 0.6 mmol) with stirring. The resulting mixture was stirred at room temperature for 0.5 h. Then, it was concentrated under reduced pressure. The residue was purified by column chromatography on silica gal with petroleum ether/ethyl acetate (20:1) as the eluent to give intermediate A in a yield of 91%. 3-(Benzylamino)-1-phenylbut-2-en-1-one (A)16 Eluent: petroleum ether/ethyl acetate (20:1). Orange oil (114.2 mg, 91%). 1H NMR (400 MHz, CDCl3) δ: 2.04 (s, 3H), 4.51 (d, J = 6.4 Hz, 2H), 5.74 (s, 1H), 7.26-7.36 (m, 5H), 7.38-7.41 (m, 3H), 7.86-7.88 (m, 2H), 11.75 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 19.5, 47.1, 92.7, 126.9, 127.0, 127.6, 128.2, 128.9, 130.6, 137.8, 140.3, 165.0, 188.1. MS: m/z 252 [M+H]+. 5.2. To a 15 mL reaction tube equipped with a stir bar were added A (125.6 mg, 0.5 mmol), 3a (79.4 mg, 0.6 mmol) and dioxane (3 mL) with stirring. After being flushed with N2, the tube was sealed, and the mixture was stirred at 120 °C for 12 h. It was then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to afford 4a in a yield of 89%. 6. Control Experiment (II) To a 15 mL reaction tube equipped with a stir bar was added 4a (182.7 mg, 0.5 mmol), TEMPO (93.8 mg, 0.6 mmol) and dioxane (3 mL) with stirring. After being flushed with N2, the tube was sealed, and the mixture was stirred at 120 °C for 12 h. It was then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (100:1) as the eluent to afford 5a in a yield of 92%. Acknowledgments. We are grateful to the National Natural Science Foundation of China (NSFC) ACS Paragon Plus Environment


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(Grant Nos. 21272058 and 21572047), Program for Innovative Research Team in Science and Technology in Universities of Henan Province (15IRTSTHN003), Program for Science and Technology Innovation Talents in Universities of Henan Province (15HASTIT005), and Plan for Scientific Innovation Talents of Henan Province (184200510012) for financial support. Supporting Information. Copies of NMR spectra of all products and X-ray crystallographic data for 9b. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) (a) Palmgren, A.; Larsson, A. L. E.; Bäckvall, J.-E. Palladium(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes. Application to the Synthesis of (±)-Epibatidine and Analogues. J. Org. Chem. 1999, 64, 836-842. (b) Yeh, M.-C. P.; Lin, M.-N.; Chou, Y.-S.; Lin, T.-C.; Tseng, L.-Y. Synthesis of the Phenanthrene and Cyclohepta[a]naphthalene Skeletons via Gold(I)-Catalyzed Intramolecular Cyclization of Unactivated Cyclic 5-(2-Arylethyl)-1,3dienes. J. Org. Chem. 2011, 76, 4027-4033. (c) Maji, B.; Yamamoto, H. Catalytic Enantioselective Nitroso Diels–Alder Reaction. J. Am. Chem. Soc. 2015, 137, 15957-15963. (d) Zheng, B.; Schmidt, M. A.; Eastgate, M. D. Synergistic Catalysis: Pd(II) Catalyzed Oxidation of 1,4-Dihydroquinones in the Pd(II) Catalyzed 1,4-Oxidation of Cyclic 1,3-Dienes J. Org. Chem. 2016, 81, 3112-3118. (e) Lang, B.; Zhu, H.; Wang, C.; Lu, P.; Wang, Y. Rhodium-Catalyzed Cycloadditions between 3-Diazoindolin-2-imines and 1,3-Dienes. Org. Lett. 2017, 19, 1630-1633. (f) Cao, M.-H.; Green, N. J.; Xu, S.-Z. Application of the Aza-Diels– Alder Reaction in the Synthesis of Natural Products. Org. Biomol. Chem. 2017, 15, 3105-3129. (2) (a) Kulkarni, A. A.; Diver, S. T. Ring Synthesis by Stereoselective, Methylene-Free Enyne Cross Metathesis. J. Am. Chem. Soc. 2004, 126, 8110-8111. (b) Gradén, H.; Hallberg, J.; Kann, N. Iron Carbonyl-Mediated Parallel Solution-Phase Synthesis of Cyclohexadienoic Acid ACS Paragon Plus Environment

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Tunable synthesis of functionalized cyclohexa-1,3-dienes and 2

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