
==== Front
J Org Chem
J Org Chem
jo
joceah
The Journal of Organic Chemistry
0022-3263
1520-6904
American Chemical Society

39121450
10.1021/acs.joc.4c01286
Article
Preparation of Benzo[a]fluorenes via Pd-Catalyzed Annulation of 5-(2-Bromophenyl)pent-3-en-1-ynes
Hsu Cheng-Kai
Liu Yi-Hung
https://orcid.org/0000-0002-0544-006X
Liu Shiuh-Tzung *
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
* Email: stliu@ntu.edu.tw.
09 08 2024
06 09 2024
89 17 1234112348
23 05 2024
30 07 2024
23 07 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

A palladium-promoted cascade cyclization of 5-(2-bromophenyl)pent-3-en-1-ynes is developed for the synthesis of benzo[a]fluorene derivatives. The reaction proceeds with oxidative addition of C–Br, insertion, C–H activation, and reductive elimination in sequential steps.

National Science and Technology Council 10.13039/501100020950 NSTC112-2113-M-002-023 document-id-old-9jo4c01286
document-id-new-14jo4c01286
ccc-price
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pmcIntroduction

1,3-Enynes are important organic scaffolds and have been implemented in many synthetic applications.1−7 Among them, constructions of cyclic compounds from 1,3-enynes have attracted significant interest due to the important application of these obtained molecules.2 However, the methodologies leading to polycyclic compounds with the use of four carbon units of 1,3-enynes as part of ring frameworks are somewhat limited and selected examples are summarized in Scheme 1.3−8 [4 + 2] Cycloaddition to construct ring systems ought to be an efficient way. Thus, intramolecular cycloaddition of the 1,3-enyne moiety with an alkyne or with in situ generated benzyne provided fluoren-9-one I and dihydro-1H-benzo[de]isoquinoline II, respectively (Scheme 1A, B).3,4 Liang and co-workers discovered a unique preparation of 9-substituted fluorenes III via a sequential cyclization of 2-en-4-yn-1-yl acetate with a terminal alkyne in the presence of BiBr3.5 Transition metal-promoted cyclization of enynes leading to cyclic rings is another useful approach in synthesis. Toste and co-workers reported that Au(I)-catalyzed annulation of aryl-substituted enynes and propargyl esters gave the fluorene products IV (Scheme 1D).6 Pd-catalyzed [4 + 1] reaction of 1,3-enynes with pyrazolidine-3,5-dione leading spiro compounds V was disclosed by Shao’s group (Scheme 1E).7

Scheme 1

We are also interested in the reactivity of 1,3-enyne systems and have reported the preparation of pyrroles, furans, and tetrahydropentalenopyrroles from 1-en-4-yn-3-ol derivatives.9 In this work, we anticipated that an enyne VI with a pendant bromoaryl group for studying the intramolecular insertion might lead to the cyclization products via Pd-catalyzed cascade reactions (Scheme 2). Activation of C–Br in VI gives the Pd-aryl intermediate VII, which may undergo the migratory insertion with either ene or yne moiety of the molecule, giving indenyl species VIII (Scheme 2, path a) or naphthalenyl species IX (Scheme 2, path b), respectively. Subsequently, VIII undergoes β-elimination provides indene derivatives, whereas IX may proceed C–H activation with the adjacent phenyl ring and render the benzo[a]fluorenes.

Scheme 2 Our Approach in Preparation of Benzofluorenes

Results and Discussion

Substrates in this investigation were prepared by the electrophilic aromatic substitution of m-bromoanilines with 2-en-4-yn-1-ol under acidic conditions (eq 1). It is noticed that m-bromophenols did not undergo this kind of substitution. In addition, when the R2 group is an alkyl group, the substitution reaction gave a complicated mixture of products. To validate our idea, the investigation started with 1a as the model reaction to establish the optimized catalytic conditions (Table 1).1

Table 1 Reaction Optimizationa

entry	catalyst	base	solvent	yieldb	
1	Pd(PPh3)4	Bu3Nd	DMF	18%	
2	Pd(PPh3)4	Bu3N	DMF	71%	
3	Pd(PPh3)4	KOH	DMF	f	
4	Pd(PPh3)4	Cs2CO3	DMF	f	
5	Pd(OAc)2/PPh3c	Bu3N	DMF	23%	
6	Pd(OAc)2/dppp	Bu3N	DMF	54%	
7	Pd(OAc)2/DPEphos	Bu3N	DMF	83%	
8	PdCl2/DPEphos	Bu3N	DMF	30%	
9	Pd(OAc)2/DPEphos	Bu3N	DMSO	f	
10	Pd(OAc)2/DPEphos	Bu3N	xylene	14%	
11	Pd(OAc)2/DPEphos	Bu3N	DMA	f	
12e	Pd(OAc)2/DPEphos	Bu3N	DMF	86%	
a Reaction conditions: 1a (0.4 mmol), Pd complex (5 mol %), ligands (6 mol %) and base (1.2 mmol) in 8 mL DMF under N2 at 140 °C for 16 h. DPEphos = bis[(2-diphenylphosphino)phenyl] ether.

b Yields were determined by 1H NMR with 1,3,5-trimethoxybenzene as the internal standard.

c PPh3 (0.04 mmol, 10 mol %).

d 0.6 mmol Bu3N.

e 160 °C instead of 140 °C.

f Complicated mixture.

After several trials, we found that the Pd(PPh3)4-catalyzed reaction of 1a in the presence of tributylamine in DMF at 140 °C gave the fluorene product 2a in 18% (entry 1). By increasing the amount of tributylamine to 3 equiv, compound 2a was obtained in 71% (entry 2). Among various bases, tributylamine gave the best result (entry 2–4). Then, various palladium sources and ligand combination were screened (entries 5–8). To our delight, the use of Pd(OAc)2 and DPEphos as the catalytic system provided 2a in 83% yield (entry 7). Carrying out the reaction in other solvents provided inferior results (entries 9–11). Finally, the yield was improved up to 86% by running the reaction at 160 °C (entry 12). It is also noticed that no indene derivative was detected in this reaction, presumably due to the unfavorable ring strain of the transition state during the insertion.

With the above optimized conditions, exploration of the Pd-catalyzed reaction of various substituents in 1 was investigated and compounds 1 with a variety of aryl groups at positions 1 and 3 underwent the cyclization to render the corresponding fluorenes (Table 2). First, reactants 1a–1g with electron-withdrawing (−F, −NO2) or electron-donating (−OCH3, −Me) substituents on phenyl rings has no significant effect on the reaction, giving the corresponding products 1a–1g in good to excellent yields except 1c (entries 1a–1g). Presumably, the extra aryl bromide moiety causes the complication of the reaction. As expected, substrate 1h with the meta-methyl group gave a mixture of regio-isomers (entry 1h) and the structures are shown in Scheme 3. On the other hand, under the optimized catalyzed conditions, 1j–1o with R2 as various aryl groups yielded the corresponding product 2j–2o in excellent yields, respectively, even with a thienyl group (entry 1o). All products were characterized by NMR and mass spectroscopy. Crystallographic analysis of 2d was determined, and the proposed structure was confirmed (Figure 1). To further demonstrate the practicality and efficiency of the developed method, gram-scale reactions were performed. Under the optimal conditions, reaction of 1a (1.05 g, 2 mmol) rendered 2a in 85% isolating yield.

Table 2 Substrate Scopea

reactant	R1	R2	yield (%)	
1a	p-Cl	p-MeC6H4	2a (86%)	
1b	p-F	p-MeC6H4	2b (84%)	
1c	p-Br	p-MeC6H4	2c (0%)	
1d	p-NO2	p-MeC6H4	2d (55%)	
1e	H	p-MeC6H4	2e (79%)	
1f	p-MeO	p-MeC6H4	2f (76%)	
1g	p-Me	p-MeC6H4	2g (83%)	
1h	m-Me	p-MeC6H4	2h (42%) + 2h (30%)b	
1i	o-Me	p-MeC6H4	2i (48%)	
1j	p-Cl	p-ClC6H4	2j (89%)	
1k	p-Cl	p-(CF3)C6H4	2k (88%)	
1l	p-Cl	p-MeOC6H4	2l (78%)	
1m	p-Cl	m-MeC6H4	2m (88%)	
1n	p-Cl	o-MeC6H4	2n (90%)	
1o	p-Cl	2-thiophenyl	2o (80%)	
a Reaction conditions: 1 (0.4 mmol), Pd(OAc)2 (5 mol %), DPEphos (6 mol %), Bu3N (3.0 equiv) in 8 mL of DMF under N2 at 160 °C for 16 h; isolated yields.

b Structures given in Scheme 3.

Figure 1 ORTEP plot of 2d (30% probability ellipsoids).

Scheme 3 Structures of 2h and 2h′.

The substituent effect on alkynyl carbon was also studied. Four examples with a different substituent at the alkynyl-carbon (1p–1s with TMS, butyl, p-MeC6H4 and, 3,5-Cl2C6H3, respectively) were investigated, and the results are shown in Scheme 4. Compound 1p underwent the cyclization to give the benzo[a]fluorene product 2p, but the TMS group was removed during the reaction. When the alkynyl carbon is attaching to a butyl group, a naphthalene product 3 was obtained. Apparently, the β-elimination is superior to the C–H activation. As for substituted phenyl groups at the alkynyl carbon (R3 position), reaction of 1r and 1s proceeded smoothly giving the desired benzo[a]fluorene derivatives 2r and 2s in 81 and 73% yields, respectively, showing a slightly substituent effect.

Scheme 4 Substituent Effect on the Alkynyl Carbon

To gain further understanding about the substituent effect of the R2 group in 1, we prepared compound 4 by the treatment of (E)-1-(2-bromophenyl)-3-(4-chlorophenyl)-5-(trimethylsilyl)pent-1-en-4-yn-3-ol in methanol under acidic conditions. Under the Pd-catalyzed conditions described above, 4 was transformed into the desired benzofluorene 5 in 51% yield (eq 2), showing an extensive substrate scope in this methodology.2

As for the mechanistic pathway, we found that carrying out the reaction of 1a in the presence of trace of D2O provided the deuterium-labeled product 2a-D2, suggesting that intermediate X might be operating in the reaction. C–H activation could be occurred with the two positions of the two adjacent phenyl rings (Scheme 5). Step i gives a five-membered palladacycle XI, which is quite unlikely to undergo the reductive elimination. Step ii is a more favorable process and leads to the final product.

Scheme 5 Possible Mechanistic Pathway

In summary, we have successfully demonstrated an efficient preparation of benzo[a]fluorenes from 5-(2-bromophenyl)pent-3-en-1-ynes via Pd-catalyzed activation of C–Br, insertion, C–H activation, and reductive elimination. Further studies involving various aryl rings for further annulation are currently under investigation.

Experimental Section

General Information

1H and 13C NMR were recorded in a 400 MHZ spectrometer in CDCl3 referenced to TMS. All chemicals were commercially purchased and used without further purification. Flash chromatography was performed using silica gel 230–400 mesh. Melting points were determined on a Fargo MP-1D instrument. HRMS was recorded in a Bruker micrOTOF-Q II instrument. Cell parameters were determined by a Bruker AXS D8 VENTURE diffractometer. Pent-1-en-4-yn-3-ols were prepared according our previously reported method.9b All reactions were performed without any special precautions.

General Procedure for Preparation of (Z)-(5-(2-Bromoaryl)pent-3-en-1-ynes 1

To a solution of pent-1-en-4-yn-3-ols (4 mmol) and 3-bromo-N-methylaniline (0.85 mL, 6.8 mmol, 1.7 equiv) in DCM (40 mL) was added dropwise the boron trifluoride-diethyl etherate (0.6 mmol, 15 mol %) with stirring at ice bath temperature for 0.5 h. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aq. NaHCO3, and the mixture was extracted with DCM (30 mL × 2). The combined organic layer was washed with water (20 mL × 2) and brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica gel with hexane/ethyl acetate (19:1) as the eluent, unless noted.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-phenyl-1-(p-tolyl)-pent-2-en-4-yn-1-yl)-N-methylaniline (1a)

Yellow oil. (1.85 g, 88%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.71 (d, J = 8.6 Hz, 2H), 7.64–7.61 (m, 2H), 7.42–7.38 (m, 5H), 7.23–7.15 (m, 5H), 6.90 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 6.01 (d, J = 9.8 Hz, 1H), 3.74 (s, 1H, broad), 2.84 (s, 3H), 2.39 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.9, 140.3, 139.5, 136.4, 135.9, 133.6, 131.7, 130.5, 130.0, 129.2, 128.5, 128.4, 128.3, 127.9, 127.6, 125.6, 123.2, 123.0, 116.1, 112.2, 96.3, 86.3, 50.1, 30.5, 21.0 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2579BrClN: 526.0932; found 526.0945. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2581BrClN+: 528.0913; found 528.0937.

(Z)-3-Bromo-4-(3-(4-fluorophenyl)-5-phenyl-1-(p-tolyl)-pent-2-en-4-yn-1-yl)-N-methylaniline (1b)

Yellow oil. (1.34 g, 65%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.78–7.75 (m, 2H), 7.65–7.63 (m, 2H), 7.42–7.40 (m, 3H), 7.25 (d, J = 9.8 Hz, 2H), 7.21–7.18 (m, 3H), 7.13 (t, J = 8.7 Hz, 2H), 6.93 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 9.8 Hz, 1H), 6.62 (dd, J = 8.4, 2.4 Hz, 1H), 6.03 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.40 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 162.5 (d, J = 247.3 Hz), 148.7, 140.4, 139.0, 135.8, 134.1 (d, J = 3.6 Hz), 131.7, 130.8, 130.1, 129.2, 128.3, 128.2 (d, J = 40.1 Hz), 128.0, 127.9, 125.6, 123.2, 123.0, 116.2, 115.2 (d, J = 21.6 Hz), 112.4, 96.2, 86.6, 50.1, 30.6, 21.0 ppm; 19F NMR (400 MHz): δ −114.3 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679Br FN: 510.1227; found 510.1218. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681BrFN: 512.1211; found 512.1202.

(Z)-3-Bromo-4-(3-(4-bromophenyl)-5-phenyl-1-(p-tolyl)-pent-2-en-4-yn-1-yl)-N-methylaniline (1c)

Yellow oil. (1.58 g, 73%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.71–7.69 (m, 3H), 7.67 (m, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.45–7.43 (m, 3H), 7.30–7.20 (m, 5H), 6.95 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.62 (dd, J = 8.4, 2.5 Hz, 1H), 6.08 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.43 (s, 3H) ppm; 13C{1H}NMR (100 MHz): δ = 148.9, 140.4, 139.7, 137.0, 135.9 131.5, 130.5, 130.1, 129.3, 128.5, 128.4, 128.0, 125.7, 123.2, 123.1, 116.2, 112.4, 96.4, 86.3, 50.2, 30.6, 21.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679Br2N: 570.0427; found 570.0421. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679Br81BrN: 572.0408; found 572.0429. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681Br2N: 574.0395; found 574.0389.

(Z)-3-Bromo-N-methyl-4-(3-(4-nitrophenyl)-5-phenyl-1-(p-tolyl)pent-2-en-4-yn-1-yl)aniline (1d)

Yellow oil. (207 mg, 76%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 8.25 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.62–7.60 (m, 2H), 7.42–7.40 (m, 3H), 7.22–7.14 (m, 5H), 7.03 (d, J = 9.8 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.5, 2.5 Hz, 1H), 6.01 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.37 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.7, 147.1, 144.2, 142.7, 139.7, 136.1, 131.7, 130.2, 130.0, 129.3, 128.7, 128.4, 127.9, 126.9, 125.6, 123.7, 122.7, 122.6, 116.3, 112.4, 97.1, 85.4, 50.3, 30.6, 21.0 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679BrN2O2: 537.1172; found 537.1130. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681BrN2O2: 539.1157; found 539.1110.

(Z)-3-Bromo-4-(3,5-diphenyl-1-(p-tolyl)pent-2-en-4-yn-1-yl)-N-methylaniline (1e)

Yellow oil. (1.19 g, 68%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.78–7.82 (m, 2H), 7.68–7.66 (m, 2H), 7.48–7.39 (m, 6H), 7.28 (d, J = 7.8 Hz, 2H), 7.23–7.21 (m, 3H), 6.94 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.62 (dd, J = 8.5, 2.5 Hz, 1H), 6.08 (d, J = 9.8 Hz, 1H), 2.85 (s, 3H), 2.42 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.8, 140.6, 139.2, 138.0, 135.8, 131.7, 130.8, 130.1, 129.2, 128.4, 128.3, 128.0, 127.8, 126.3, 125.7, 124.1, 123.4, 116.1, 112.4, 96.0, 86.9, 50.1, 30.6, 21.0 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2779BrN: 492.1321; found 492.1329. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2781BrN: 494.1306; found 494.1316.

(Z)-3-Bromo-4-(3-(4-methoxyphenyl)-5-phenyl-1-(p-tolyl)pent-2-en-4-yn-1-yl)-N-methylaniline (1f)

Yellow oil. (673 mg, 40%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.80 (d, J = 8.8 Hz, 2H), 7.72–7.69 (m, 2H), 7.47–7.42 (m, 3H), 7.32 (d, J = 8.0 Hz, 2H), 7.26–7.23 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 9.8 Hz, 1H), 6.62 (dd, J = 8.4, 2.4 Hz, 1H), 6.10 (d, J = 9.8 Hz, 1H), 3.90 (s,3H), 2.84 (s, 3H), 2.44 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 159.5, 148.8, 140.8, 137.5, 135.7, 131.7, 130.9, 130.6, 130.1, 129.2, 128.3, 128.0, 127.5, 125.7, 123.5, 123.4, 116.1, 113.8, 112.3, 95.9, 87.1, 55.3, 50.1, 30.6, 21.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2979BrNO: 522.1427; found 522.1416. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2981BrNO: 524.1408; found 524.1409.

(Z)-3-Bromo-N-methyl-4-(5-phenyl-1,3-di-p-tolylpent-2-en-4-yn-1-yl)aniline (1g)

Yellow oil. (1.48g, 73%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.74 (d, J = 8.2 Hz, 2H), 7.69–7.67 (m, 2H), 7.44–7.42 (m, 3H), 7.30–7.28 (m, 4H), 7.24–7.21 (m, 3H), 6.94 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 9.8 Hz, 1H), 6.62 (dd, J = 8.4, 2.5 Hz, 1H), 6.08 (d, J = 9.8 Hz, 1H), 2.85 (s, 3H), 2.47 (s, 3H), 2.43 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.7, 140.7, 138.4, 137.7, 135.7, 135.2, 131.7, 131.0, 130.1, 129.1, 128.3, 128.3, 128.0, 126.2, 125.7, 123.9, 123.5, 116.1, 112.4, 95.9, 87.0, 50.0, 30.6, 21.2, 21.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2979BrN: 506.1483; found 506.1502. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2981BrN: 508.1462; found 508.1491.

(Z)-3-Bromo-N-methyl-4-(5-phenyl-3-(m-tolyl)-1-(p-tolyl)-pent-2-en-4-yn-1-yl)aniline (1h)

Yellow oil. (1.17g, 78%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.63–7.58 (m, 4H), 7.41–7.38 (m, 3H), 7.32 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.19–7.16 (m, 4H), 6.91 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 9.8 Hz, 1H), 6.60 (dd, J = 8.5, 2.5 Hz, 1H), 6.00 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.45 (s, 3H), 2.38 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.7, 140.6, 139.1, 137.9, 135.7, 131.7, 130.9, 130.1, 129.1, 128.6, 128.2, 128.2, 127.9, 126.9, 125.7, 124.1, 123.5, 123.5, 116.1, 112.3, 95.8, 86.9, 50.0, 30.6, 21.5, 21.0 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2979BrN: 506.1478; found 506.1464. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2981BrN: 508.1462; found 506.1447.

(E)-3-Bromo-N-methyl-4-(5-phenyl-3-(o-tolyl)-1-(p-tolyl)pent-2-en-4-yn-1-yl)aniline (1i)

Yellow oil. (1.39 g, 71%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.54–7.52 (m, 2H), 7.37–7.34 (m, 4H), 7.28–7.23 (m, 5H), 7.17 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.4, 2.5 Hz, 1H), 6.43 (d, J = 9.9 Hz, 1H), 5.99 (d, J = 9.9 Hz, 1H), 2.85 (s, 3H), 2.53 (s, 3H), 2.38 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.6, 143.0, 140.5, 139.4, 136.0, 135.7, 131.5, 131.0, 130.3, 130.0, 129.1, 129.1, 128.2, 128.1, 127.9, 127.6, 125.8, 125.7, 124.4, 123.5, 116.2, 112.4, 95.8, 87.4, 49.6, 30.6, 21.0, 20.3 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2979BrN: 506.1478; found 506.1482. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2981BrN: 508.1462; found 508.1467.

(Z)-4-(1,3-Bis(4-chlorophenyl)-5-phenylpent-2-en-4-yn-1-yl)-3-Bromo-N-methylaniline (1j)

Yellow oil. (1.07 g, 60%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.67 (d, J = 8.7 Hz, 2H), 7.57–7.55 (m, 2H), 7.38–7.36 (m, 5H), 7.30–7.28 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.77 (d, J = 9.7 Hz, 1H), 6.61 (dd, J = 8.4, 2.5 Hz, 1H), 5.94 (d, J = 9.7 Hz, 1H), 2.84 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 148.7, 141.8, 138.4, 136.1, 133.8, 132.1, 131.6, 130.1, 130.0, 129.3, 128.5, 128.3, 127.5, 125.6, 123.7, 122.9, 116.4, 112.5, 96.6, 86.0, 49.9, 30.7 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C30H2379BrCl2N: 546.0385; found 546.0385. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C30H2381BrCl2N: 548.0364; found 548.0373.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-phenyl-1-(4-(trifluoromethyl)phenyl)pent-2-en-4-yn-1-yl)-N-methylaniline (1k)

Yellow oil. (407 mg, 47%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.70 (d, J = 8.6 Hz, 2H), 7.62–7.57 (m, 4H), 7.43 (d, J = 8.4 Hz, 2H), 7.40–7.38 (m, 5H), 7.13 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 9.6 Hz, 1H), 6.61 (dd, J = 8.4, 2.5 Hz, 1H), 6.07 (d, J = 9.6 Hz, 1H), 2.85 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 149.0, 147.4, 137.9, 136.1, 133.9, 131.7, 130.0, 129.5, 128.6 (q, J = 32.4 Hz), 128.6, 128.5, 128.3, 128.3, 127.6, 125.6, 125.4, 125.3, 124.2 (q, J = 272.2 Hz), 124.1, 122.8, 116.2, 112.4, 96.9, 85.9, 77.3, 77.0, 76.7, 50.4, 30.5 ppm; 19F NMR (400 MHz): δ - 62.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2379BrClF3N: 580.0649; found 580.0665. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2381BrClF3N: 582.0630; found 582.0650.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-phenylpent-2-en-4-yn-1-yl)-N-methylaniline (1l)

Yellow oil. (1.52 g, 72%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.69 (d, J = 8.6 Hz, 2H), 7.63–7.60 (m, 2H), 7.40–7.37 (m, 5H), 7.23 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.5 Hz, 1H), 6.91–6.89 (m, 3H), 6.85 (d, J = 9.8 Hz, 1H), 6.59 (dd, J = 8.4, 2.5 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H), 3.82 (s, 3H), 2.83 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 158.1, 148.8, 139.6, 136.4, 135.4, 133.6, 131.7, 130.6, 130.0, 129.0, 128.5, 128.4, 128.3, 127.6, 125.6, 123.1, 122.9, 116.1, 113.9, 112.3, 96.3, 86.3, 55.2, 49.6, 30.5 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679BrClNO: 542.0881; found 542.0903. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681BrClNO: 544.0862; found 544.0891.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-phenyl-1-(m-tolyl)-pent-2-en-4-yn-1-yl)-N-methylaniline (1m)

Yellow oil. (1.45 g, 70%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.70 (d, J = 8.6 Hz, 2H), 7.62–7.60 (m, 2H), 7.41–7.37 (m, 5H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.12–7.07 (m, 3H), 6.91 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 6.60 (dd, J = 8.4, 2.5 Hz, 1H), 6.00 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.37 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ = 148.7, 143.2, 139.4, 138.0, 136.4, 133.6, 131.7, 130.6, 130.1, 128.7, 128.4, 128.4, 128.3, 127.6, 127.1, 125.6, 125.0, 123.1, 123.0, 116.2, 112.3, 96.3, 86.3, 50.4, 30.6, 21.5 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679BrClN: 526.0932; found 526.0930. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681BrClN: 528.0913; found 528.0920.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-phenyl-1-(o-tolyl)-pent-2-en-4-yn-1-yl)-N-methylaniline (1n)

Yellow oil. (929 mg, 72%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.77 (d, J = 8.6 Hz, 2H), 7.69–7.66 (m, 2H), 7.46–7.44 (m, 5H), 7.31–7.28 (m, 4H), 7.14 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 9.6 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 6.12 (d, J = 9.6 Hz, 1H), 2.83 (s, 3H), 2.56 (s, 3H) ppm; 13C NMR (100 MHz): δ 148.9, 141.9, 139.3, 137.0, 136.3, 133.7, 131.7, 130.6, 129.9, 128.6, 128.5, 127.6, 127.5, 126.6, 126.1, 125.8, 123.3, 123.2, 116.2, 112.0, 96.7, 86.4, 48.1, 30.6, 19.9 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2679BrClN: 526.0932; found 526.0910. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2681BrClN: 528.0913; found 528.0889.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-phenyl-1-(thiophen-2-yl)pent-2-en-4-yn-1-yl)-N-methylaniline (1o)

Yellow oil. (1.36 g, 67%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.70 (d, J = 8.6 Hz, 2H), 7.64–7.62 (m, 2H), 7.40–7.38 (m, 5H), 7.24–7.22 (m, 2H), 7.01–6.99 (m, 1H), 6.89–6.86 (m, 3H), 6.59 (dd, J = 8.5, 2.4 Hz, 1H), 6.20 (d, J = 9.5 Hz, 1H), 2.83 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 149.1, 147.7, 138.3, 136.2, 133.8, 131.7, 130.2, 129.8, 128.5, 128.5, 128.3, 127.7, 126.8, 125.1, 124.5, 124.1, 123.3, 123.0, 115.9, 112.4, 96.7, 85.9, 46.2, 30.5; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C28H2279BrClNS: 518.0307; found 518.0339. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C28H2281BrClNS: 520.0319; found 520.0291.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-1-(p-tolyl)-5-(trimethylsilyl)pent-2-en-4-yn-1-yl)-N-methylaniline (1p)

Yellow oil. (1.70 g, 54%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.63 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.20–7.18 (m, 4H), 7.14 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 6.58 (dd, J = 8.4, 2.5 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.38 (s, 3H), 0.34 (s, 9H); 13C{1H} NMR (100 MHz): δ 148.8, 140.5, 140.3, 136.1, 135.8, 133.5, 130.3, 130.0, 129.1, 128.4, 127.8, 127.5, 125.7, 123.0, 116.1, 112.1, 101.9, 101.5, 49.9, 30.5, 21.0, 0.0; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C28H3079BrClNSi: 522.1014; found 522.1019. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C28H3081BrClNSi: 524.0995; found 524.1006.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-1-(p-tolyl)non-2-en-4-yn-1-yl)-N-methylaniline (1q)

Yellow oil. (1.22 g, 60%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.61 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.14 (m, 4H), 7.10 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 6.71 (d, J = 9.7 Hz, 1H), 6.57 (dd, J = 8.4, 2.5 Hz, 1H), 5.83 (d, J = 9.7 Hz, 1H), 2.84 (s, 3H), 2.50 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.64 (quintet, J = 7.3 Hz, 2H), 1.50 (sextet, J = 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz): δ 148.6, 140.6, 138.1, 137.0, 135.6, 133.2, 130.9, 130.0, 129.0, 128.2, 127.8, 127.5, 125.6, 123.4, 116.1, 112.3, 97.8, 49.8, 30.8, 30.6, 22.0, 20.9, 19.4, 13.6; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C29H3079BrClN: 506.1245; found 506.1238. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C29H3081BrClN: 508.1225; found 508.1224.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-1,5-di-p-tolylpent-2-en-4-yn-1-yl)-N-methylaniline (1r)

Yellow oil. (491 mg, 67%). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.69 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.21–7.14 (m, 7H), 6.89 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 9.8 Hz, 1H), 6.58 (dd, J = 8.5, 2.5 Hz, 1H), 5.98 (d, J = 9.8 Hz, 1H), 3.73 (s, broad, 1H), 2.83 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H); 13C{1H}NMR (100 MHz): δ 148.8, 140.4, 139.1, 138.5, 136.5, 135.8, 133.5, 131.6, 130.6, 130.0, 129.1, 129.0, 128.4, 127.9, 127.6, 125.6, 123.1, 120.1, 116.1, 112.2, 96.5, 85.7, 50.0, 30.5, 21.5, 21.0; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2879BrClN: 540.1088; found 540.1112. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H2881BrClN: 542.1069; found 542.1106.

(Z)-3-Bromo-4-(3-(4-chlorophenyl)-5-(3,5-dichlorophenyl)-1-(p-tolyl)pent-2-en-4-yn-1-yl)-N-methylaniline (1s)

Yellow oil. (420 mg, 61%). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.68 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 1.9 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.39 (t, J = 1.9 Hz, 1H), 7.27–7.21 (m, 4H), 7.17 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 9.5 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.5, 2.5 Hz, 1H), 5.95 (d, J = 9.5 Hz, 1H), 3.77 (s, broad, 1H), 2.85 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz): δ 149.0, 141.4, 140.0, 136.1, 135.9, 134.9, 133.9, 130.3, 130.1, 129.8, 129.3, 128.7, 128.6, 127.9, 127.5, 125.9, 125.6, 122.6, 116.0, 112.3, 93.7, 88.7, 50.2, 30.5, 21.1; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2479BrCl3N: 594.0152; found 594.0146. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H2481BrCl3N: 596.0130; found 596.0159.

General Procedure for Preparation of Benzofluorenes 2

To a flask was loaded with a solution of 1 (0.4 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol, 5 mol %), DPEphos (0.02 mmol, 6 mol %), and tributylamine (1.2 mmol, 3.0 equiv) in DMF (8 mL) under a N2 atmosphere. The resulting mixture was heated in an oil bath at 160 °C for 16 h. The reaction mixture was neutralized with a diluted HCl solution and then extracted with diethyl ether (15 mL × 2). The combined organic layer was washed with water (10 mL × 5) and brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by chromatography using hexane/ethyl acetate (19:1) as eluent, unless noted.

9-Chloro-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2a)

Pale-yellow oil. (376 mg, 86%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.78 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.41–7.36 (m, 3H), 7.33–7.28 (m, 4H), 7.23–7.21 (m, 2H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 5.22 (s, 1H), 2.65 (s, 3H), 2.55 (s, 3H); 13C{1H} NMR (100 MHz): δ 151.0, 146.9, 141.3, 141.0, 140.1, 139.8, 138.5, 137.9, 136.8, 132.3, 132.2, 130.0, 128.9, 128.9, 128.2, 127.3, 126.8, 125.5, 125.2, 120.4, 116.9, 115.4, 101.1, 54.2, 30.2, 21.2; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25ClN: 446.1670; found 446.1672.

9-Fluoro-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2b)

Pale-yellow oil. (216 mg, 84%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.81 (d, J = 9.1 Hz, 1H), 7.76 (dd, J = 8.3, 4.9 Hz, 1H), 7.68 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.37–7.30 (m, 3H), 7.26–7.24 (m, 2H), 7.15–7.09 (m, 2H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.25 (s, 1H), 2.66 (s, 3H), 2.58 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 162.5 (d, J = 244.6 Hz), 151.5, 151.5, 146.9, 141.3, 139.6, 138.6, 138.1, 137.5, 136.8, 132.3, 130.0, 128.9, 128.9, 128.2, 126.8, 125.2, 120.3 (d, J = 8.6 Hz), 116.8, 115.4, 114.1 (d, J = 22.9 Hz), 112.4 (d, J = 23.2 Hz), 101.0, 54.3, 30.2, 21.3 ppm; 19F NMR (400 MHz): δ - 115.3 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25FN: 430.1966; found 430.1936.

N-Methyl-9-nitro-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2d)

Brown solid. (106 mg, 55%), eluent: hexane/ethyl acetate (19:1). m.p.: 108–109 °C. 1H NMR (400 MHz, CDCl3, 298 K): δ 8.28 (dd, J = 8.4, 1.7 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 9.1 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.34–7.27 (m, 3H), 7.20–7.18 (m, 2H), 6.82 (dd, J = 9.1, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 5.28 (s, 1H), 2.67 (s, 3H), 2.52 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 150.0, 148.0, 146.7, 146.4, 142.6, 141.9, 139.7, 137.9, 137.1, 136.7, 132.0, 129.8, 129.1, 129.0, 128.4, 128.1, 127.2, 126.5, 123.5, 120.2, 119.4, 117.9, 115.8, 102.3, 54.2, 30.5, 21.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25N2O2: 457.1911; found 457.1899.

N-Methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2e)

Pale-yellow oil. (181 mg, 79%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.87 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.74 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.45–7.40 (m, 4H), 7.34–7.27 (m, 6H), 6.76–6.72 (m, 2H), 5.34 (s, 1H), 2.68 (s, 3H), 2.57 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ = 149.4, 146.6, 141.9, 141.5, 141.0, 140.0, 139.0, 138.7, 136.7, 132.3, 130.0, 128.9, 128.7, 128.3, 128.3, 127.1, 126.7, 126.6, 125.5, 124.8, 119.6, 116.7, 115.8, 101.5, 54.3, 30.3, 21.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H26N: 412.2060; found 412.2082.

9-Methoxy-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2f)

Pale-yellow oil. (215 mg, 76%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.75 (d, J = 9.0 Hz, 1H), 7.72 (dd, J = 8.0, 0.5 Hz, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.34–7.30 (m, 2H), 7.27–7.24 (m, 3H), 6.97–6.94 (m, 2H), 6.70 (dd, J = 9.1, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 5.27 (s, 1H), 3.82 (s, 3H), 2.67 (s, 3H), 2.53 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 159.3, 151.3, 146.4, 142.0, 141.0, 139.1, 138.9, 138.7, 136.6, 134.5, 132.3, 130.0, 128.8, 128.7, 128.3, 128.2, 126.5, 125.0, 120.1, 116.3, 115.5, 112.7, 111.0, 101.3, 55.4, 54.3, 30.4, 21.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H28NO: 442.2165; found 442.2131.

9-Methyl-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2g)

Pale-yellow oil. (220 mg, 83%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.80 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 7.37–7.33 (m, 2H), 7.29–7.22 (m, 5H), 6.76–6.73 (m, 2H), 5.30 (s, 1H), 2.68 (s, 3H), 2.57 (s, 3H), 2.43 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 149.7, 146.2, 142.1, 140.9, 139.7, 139.1, 138.8, 138.7, 136.7, 136.6, 132.3, 130.0, 128.9, 128.7, 128.3, 128.3, 127.9, 126.5, 125.6, 125.5, 119.3, 116.6, 115.8, 101.9, 54.2, 30.5, 21.6, 21.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H28N: 426.2216; found 426.2195.

8-Methyl-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2h) + 10-methyl-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2h′)

Pale-yellow oil. (186 mg, 2h: 2h′ = 42%: 30%, not separable), eluent: hexane/ethyl acetate (19:1). Compound 2h. 1H NMR (400 MHz, CDCl3, 298 K): δ 7.88 (d, J = 9.8 Hz, 1H), 7.85–7.81 (m, 1H), 7.78 (s, 1H), 7.66–7.62 (m, 2H), 7.50–7.44 (m, 3H), 7.41–7.32 (m, 5H), 7.19 (d, J = 8.1 Hz, 1H), 6.76–6.73 (m, 2H), 5.34 (s, 1H), 2.69 (s, 3H), 2.64 (s, 3H), 2.59 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 146.8, 146.8, 142.3, 141.7, 141.0, 140.5, 139.1, 138.9, 136.8, 132.5, 130.1, 129.2, 129.0, 128.8, 128.3, 128.3, 127.7, 126.5, 125.5, 124.6, 120.3, 116.8, 115.8, 101.3, 54.0, 30.3, 21.7, 21.3 ppm. Compound 2h′. 1H NMR (400 MHz, CDCl3, 298 K): δ 7.85–7.81 (m, 3H), 7.66–7.62 (m, 2H), 7.50–7.44 (m, 2H), 7.41–7.32 (m, 6H), 7.16 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 9.1, 2.3 Hz, 1H), 5.37 (s, 1H), 2.78 (s, 3H), 2.63 (s, 3H), 2.27 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 147.7, 146.8, 142.1, 141.2, 141.0, 138.9, 138.6, 136.8, 134.8, 132.3, 130.1, 129.0, 128.6, 128.5, 128.3, 128.2, 127.7, 126.3, 125.6, 124.6, 117.3, 116.9, 115.8, 100.8, 54.2, 30.5, 21.3, 19.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25ClN: 446.1670; found 446.1638.

7-Methyl-N-methyl-11-phenyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2i)

Pale-yellow oil. (99.4 mg, 48%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.91 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.33–7.23 (m, 6H), 7.19–7.18 (m, 2H), 6.75 (dd, J = 9.0, 2.4 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 5.30 (s, 1H), 2.86 (s, 3H), 2.68 (s, 3H), 2.55 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 149.8, 146.4, 142.4, 140.6, 140.4, 140.2, 139.4, 139.0, 136.7, 132.4, 132.0, 130.1, 129.5, 128.9, 128.7, 128.3, 128.0, 126.4, 126.4, 124.9, 122.5, 118.9, 117.0, 101.5, 54.2, 30.4, 21.2, 21.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H28N: 426.2216; found 426.2230.

9-Chloro-5-(4-chlorophenyl)-N-methyl-11-phenyl-11H-benzo[a]fluoren-2-amine (2j)

Pale-yellow oil. (165 mg, 89%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.70–7.65 (m, 2H), 7.58 (s, 1H), 7.53–7.52 (m, 4H), 7.36 (dd, J = 8.1, 1.9 Hz, 1H), 7.32–7.27 (m, 4H), 7.20–7.18 (m, 2H), 6.73 (dd, J = 9.1, 2.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 5.20 (s, 1H), 2.65 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 150.9, 146.8, 140.8, 140.3, 139.9, 139.8, 137.9, 133.2, 132.5, 132.2, 131.4, 128.9, 128.4, 128.2, 127.8, 127.4, 126.9, 125.2, 125.2, 120.4, 117.2, 115.4, 101.3, 54.2, 30.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C30H22Cl2N: 466.1124; found 466.1103.

9-Chloro-N-methyl-11-phenyl-5-(4-(trifluoromethyl)phenyl)-11H-benzo[a]fluoren-2-amine (2k)

Yellow oil. (114 mg, 88%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.82 (d, J = 8.0 Hz, 2H), 7.71–7.69 (m, 3H), 7.62 (d, J = 9.1 Hz, 1H), 7.59 (s, 1H), 7.37 (dd, J = 8.1, 1.8 Hz, 1H), 7.34–7.27 (m, 4H), 7.21–7.19 (m, 2H), 6.75 (dd, J = 9.1, 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 5.23 (s, 1H), 2.66 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 150.9, 146.9, 145.1, 140.7, 140.6, 139.7, 137.9, 132.6, 132.2, 130.4, 129.4 (q, J = 32.8 Hz), 128.9, 128.2, 127.6, 127.4, 126.9, 125.3, 125.1, 124.9, 124.3, 120.4 (q, J = 272.6 Hz), 117.3, 115.4, 101.2, 54.2, 30.2 ppm; 19F NMR (400 MHz): δ - 62.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H22ClF3N: 500.1387; found 500.1364.

9-Chloro-5-(4-methoxyphenyl)-N-methyl-11-phenyl-11H-benzo[a]fluoren-2-amine (2l)

Yellow oil. (173 mg, 78%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.78 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.38–7.28 (m, 5H), 7.22–7.20 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.73 (dd, J = 9.1, 2.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 5.21 (s, 1H), 3.96 (s, 3H), 2.65 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 158.9, 151.0, 146.7, 141.0, 140.9, 140.1, 139.7, 137.9, 133.8, 132.3, 132.2, 131.1, 128.9, 128.2, 127.3, 126.8, 125.6, 125.2, 120.4, 116.9, 115.5, 113.7, 101.3, 55.3, 54.1, 30.3 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25ClNO: 462.1619; found 462.1632.

9-Chloro-N-methyl-11-phenyl-5-(m-tolyl)-11H-benzo[a]fluoren-2-amine (2m)

Pale-yellow oil. (136 mg, 88%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ = 7.80 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.50–7.45 (m, 3H), 7.39–7.37 (m, 2H), 7.35–7.28 (m, 4H), 7.24–7.22 (m, 2H), 6.75 (dd, J = 9.1, 2.4 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 5.21 (s, 1H), 2.66 (s, 3H), 2.56 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 151.0, 146.7, 141.5, 141.4, 141.0, 140.1, 139.9, 137.9, 137.8, 132.4, 132.2, 130.8, 128.9, 128.3, 128.2, 128.1, 127.9, 127.4, 127.2, 126.9, 125.5, 125.2, 120.4, 117.0, 115.5, 101.3, 54.2, 30.3, 21.5 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25ClN: 446.1670; found 446.1664.

9-Chloro-N-methyl-11-phenyl-5-(o-tolyl)-11H-benzo[a]fluoren-2-amine (2n)

Pale-yellow oil. (190 mg, 90%, two rotamers 1:1), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.74 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.48–7.45 (m, 4H), 7.42–7.35 (m, 5H), 7.33–7.32 (m, 1H), 7.29–7.27 (m, 2H), 6.72–6.69 (m, 1H), 6.68–6.66 (m, 1H), 5.35 (s, 1H), 2.67 (s, 3H), 2.23 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 151.0, 146.9, 141.0, 140.8, 140.2, 139.9, 138.0, 136.9, 132.4, 132.0, 130.4, 129.9, 128.9, 128.3, 127.6, 127.4, 126.9, 125.8, 125.6, 125.3, 120.5, 117.1, 115.2, 101.1, 54.3, 30.2, 20.2 ppm. The other isomer: 1H NMR (400 MHz, CDCl3, 298 K): δ 7.73 (dd, J = 7.6, 0.8 Hz, 1H), 7.64 (s, 1H), 7.48–7.45 (m, 4H), 7.42–7.35 (m, 5H), 7.33–7.32 (m, 1H), 7.29–7.27 (m, 2H), 6.72–6.69 (m, 1H), 6.68–6.66 (m, 1H), 5.29 (s, 1H), 2.67 (s, 3H), 2.24 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 151.0, 146.9, 141.1, 140.9, 140.2, 139.9, 137.9, 136.9, 132.4, 132.0, 130.4, 129.9, 128.9, 128.3, 127.6, 127.4, 126.9, 125.8, 125.6, 125.3, 120.5, 117.1, 115.2, 101.1, 54.2, 30.2, 20.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H25ClN: 446.1670; found 446.1659.

9-Chloro-N-methyl-11-phenyl-5-(thiophen-2-yl)-11H-benzo[a]fluoren-2-amine (2o)

Yellow oil. (177 mg, 80%), eluent: hexane/ethyl acetate (19:1). 1H NMR (400 MHz, CDCl3, 298 K): δ 8.10 (d, J = 9.1 Hz, 1H) 7.80 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.39–7.37 (m, 2H), 7.33–7.29 (m, 5H), 7.18 (d, J = 6.9 Hz, 1H), 6.76 (dd, J = 9.0, 1.4 Hz, 1H), 6.55 (d, J = 1.4 Hz, 1H), 5.09 (s, 1H), 2.62 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 150.9, 146.9, 142.6, 140.8, 140.7, 139.7, 137.8, 133.2, 132.5, 132.3, 128.9, 128.2, 127.8, 127.4, 127.3, 126.9, 125.5, 125.5, 125.2, 120.5, 117.4, 116.7, 101.1, 54.1, 30.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C28H21ClNS: 438.1078; found 438.1069.

9-Chloro-N-methyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2p)

White solid. (105 mg, 73%), eluent: hexane/ethyl acetate (19:1). m.p.: 225–226 °C. 1H NMR (400 MHz, CDCl3, 298 K): δ 7.76 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 (dd, J = 8.1, 1.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 6.90 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 9.1, 2.4 Hz, 1H), 4.13 (s, 2H), 4.00 (s, broad, 1H), 3.02 (s, 3H), 2.50 (s, 3H) ppm; 13C{1H} NMR (100 MHz): δ 147.3, 145.1, 141.5, 140.4, 138.5, 137.6, 136.7, 132.5, 131.7, 129.9, 128.8, 128.3, 126.9, 125.0, 124.9, 120.3, 117.1, 115.6, 100.0, 35.7, 30.6, 21.2 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C25H21ClN: 370.1357; found 370.1351.

9-Chloro-N-methyl-5,11-di-p-tolyl-11H-benzo[a]fluoren-2-amine (2r)

Yellow oil. (148 mg, 81%). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.81 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.39–7.36 (m, 2H), 7.17–7.11 (m, 4H), 6.74 (dd, J = 9.1, 2.3 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 5.20 (s, 1H), 3.79 (s, broad, 1H), 2.69 (s, 3H), 2.57 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz): δ 151.1, 146.8, 141.1, 140.0, 139.9, 138.5, 137.8, 137.8, 136.8, 136.3, 132.3, 132.2, 129.9, 129.5, 128.9, 128.2, 128.0, 127.2, 125.4, 125.2, 120.3, 116.8, 115.4, 101.2, 53.8, 30.2, 21.2, 21.0; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C32H27ClN: 460.1827; found 460.1844.

9-Chloro-11-(3,5-dichlorophenyl)-N-methyl-5-(p-tolyl)-11H-benzo[a]fluoren-2-amine (2s)

Yellow oil. (150 mg, 73%). 1H NMR (400 MHz, CDCl3, 298 K): δ 7.75 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.39–7.36 (m, 3H), 7.28–7.27 (m, 2H), 7.07 (d, J = 1.6 Hz, 2H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.51 (d, J = 2.2 Hz, 1H), 5.12 (s, 1H), 3.91 (s, broad, 1H), 2.75 (s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz): δ 149.4, 147.1, 144.8, 141.8, 140.1, 138.2, 138.2, 137.9, 137.0, 135.2, 132.5, 132.0, 129.9, 128.9, 128.5, 127.9, 127.2, 126.6, 125.5, 125.1, 120.6, 117.0, 115.3, 100.3, 53.1, 30.2, 21.2; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C31H23Cl3N: 514.0896; found 514.0906.

7-(4-Chlorophenyl)-N-methyl-8-(pent-1-en-1-yl)-5-(p-tolyl)naphthalen-2-amine (3)

Pale-yellow oil. (174 mg, 83%; E:Z = 3.4:1, not separable). Eluent: hexane/ethyl acetate (49:1). E-isomer: 1H NMR (400 MHz, CDCl3, 298 K): δ 7.79 (d, J = 9.0 Hz, 1H), 7.47–7.41 (m, 3H), 7.40–7.32 (m, 5H), 7.30–7.28 (m, 2H), 7.12 (s, 1H), 6.87 (dd, J = 9.1, 2.4 Hz, 1H), 6.57 (dt, J = 16.0, 1.4 Hz, 1H), 5.73 (dt, J = 16.1, 7.0 Hz, 1H), 2.98 (s, 3H), 2.47 (s, 3H), 2.19 (qd, J = 7.2, 1.3 Hz, 2H), 1.45 (sextet, J = 7.3, 2H), 0.95 (t, J = 7.3, 3H) ppm; 13C{1H} NMR (100 MHz): δ 147.1, 141.5, 139.0, 138.0, 136.7, 136.6, 134.3, 132.2, 131.7, 131.3, 131.3, 129.9, 128.9, 127.8, 127.4, 126.9, 125.3, 125.0, 117.3, 102.8, 35.6, 30.7, 22.4, 21.2, 13.7 ppm. Z-isomer:1H NMR (400 MHz, CDCl3, 298 K): δ 7.80 (d, J = 9.0 Hz, 1H), 7.47–7.41 (m, 3H), 7.40–7.32 (m, 5H), 7.30–7.28 (m, 2H), 7.12 (s, 1H), 6.87 (dd, J = 9.1, 2.3 Hz, 1H), 6.60 (dt, J = 11.2, 1.2 Hz, 1H), 5.73 (dt, J = 11.7, 7.1 Hz, 1H), 2.97 (s, 3H), 2.48 (s, 3H), 1.71–1.69 (m, 2H), 1.30 (m, 2H), 0.77 (t, J = 7.4, 3H) ppm; 13C{1H} NMR (100 MHz): δ 147.1, 141.4, 139.4, 138.0, 137.1, 136.7, 134.2, 133.6, 132.4, 131.7, 130.8, 130.2, 128.9, 128.0, 127.3, 126.6, 124.9, 124.7, 117.3, 103.0, 35.6, 31.3, 22.0, 21.2, 13.9 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C29H29ClN: 426.1983; found 426.1974.

9-Chloro-5-methoxy-11H-benzo[a]fluorene (5)

White solid. (96.1 mg, 51%); eluent: hexane/ethyl acetate (99:1). m.p.: 135–136 °C. 1H NMR (400 MHz, CDCl3, 298 K): δ 8.33 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.59–7.47 (m, 3H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (s, 1H), 4.09 (s, 3H), 3.95 (s, 2H) ppm; 13C{1H} NMR (100 MHz): δ 155.8, 145.4, 141.4, 137.7, 131.7, 131.5, 131.0, 127.0, 126.8, 125.2, 125.0, 124.8, 123.7, 123.2, 119.9, 96.5, 55.6, 34.9 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C18H14ClO: 281.0728; found 281.0710.

(Z)-(5-(2-Bromophenyl)-3-(4-chlorophenyl)-5-methoxypent-3-en-1-yn-1-yl)trimethylsilane (4)

To a stirring solution of (E)-1-(2-bromophenyl)-3-(4-chlorophenyl)-5-(trimethylsilyl)-pent-1-en-4-yn-3-ol (4 mmol) in MeOH (40 mL) was added sulfuric acid (0.6 mmol, 15 mol %). The reaction was kept at room temperature for 16 h. The solution was neutralized with a saturated aqueous solution of NaHCO3. The mixture was concentrated under reduced pressure, and then the residue was extracted with EtOAc (30 mL × 2). The combined extracts were washed with water (20 mL × 2) and brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 4 (868 mg, 100%) as pale-yellow oil. This compound was used for the next step without further purification. 1H NMR (400 MHz, CDCl3, 298 K): δ 7.66–7.61 (m, 4H), 7.41 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.20 (td, J = 7.6, 1.6 Hz, 1H), 6.41 (d, J = 9.0 Hz, 1H), 5.84 (d, J = 9.0 Hz, 1H), 3.53 (s, 3H), 0.38 (s, 9H) ppm; 13C{1H} NMR (100 MHz): δ 140.1, 135.7, 135.2, 134.2, 132.9, 129.1, 128.5, 128.4, 127.7, 127.6, 126.3, 123.4, 102.8, 101.1, 80.3, 56.6, −0.1 ppm; HRMS (ESI-TOF): m/z [M + H]+ calcd. for C21H2379BrClOSi: 433.0390; found 433.0399. HRMS (ESI-TOF): m/z [M + H]+ calcd. for C21H2381BrClOSi: 435.0370; found 435.0381.

Gram-Scale Test

To a flask were loaded 1a (2.0 mmol, 1.05 g), Pd(OAc)2 (22.5 mg, 0.10 mmol, 5 mol %), DPEphos (0.12 mmol, 6 mol %), and tributylamine (6.0 mmol, 3.0 equiv) in DMF (40 mL) under a N2 atmosphere. The mixture was heated in an oil bath at 160 °C for 16 h. The reaction mixture was neutralized with a diluted HCl solution and then extracted with diethyl ether (40 mL × 2). The combined organic layer was washed with water (30 mL × 5) and brine (30 mL), dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by chromatography using hexane/ethyl acetate (19:1) as eluent to give 2a (758 mg, 85%).

Crystallography

Crystal of 2d for X-ray determination was obtained by recrystallization from diethyl ether/hexane solutions. The structure was solved using the SHELXS-97 program10 and refined using the SHELXL-97 program11 by full-matrix least squares on F2 values.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01286.ORTEP plot (Figure S1) and crystal data of 2d (Table S1) and spectra of all compounds (PDF)

Supplementary Material

jo4c01286_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

We thank the National Science and Technology Council of Taiwan for financial support (NSTC112-2113-M-002-023). We also thank the Instrumentation Center (NTU), Ministry of Science and Technology Taiwan, for the assistance in X-ray crystallography. The mass spectrometry technical research services from NTU Consortia of Key Technologies for mass measurement are acknowledged.
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