Asymmetric Sonogashira Coupling with a Chiral Palladium Imidazoindole Phosphine Complex

Abstract

The asymmetric Sonogashira coupling of 1-(2,6-di­bromophenyl)naphthalene or 4,16-dibromo[2,2]paracyclophane with various terminal alkynes was carried out with a palladium complex of a homochiral imidazoindole phosphine, a derivative of a (3R,9aS)-2-aryl-[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H-imidazo[1,5a]indol-1-one, to give the corresponding axially chiral monoalkynylated biaryl products with up to 72% enantiomeric ­excess.

The Sonogashira coupling reaction between an aryl or alkenyl halide or triflate and a terminal alkyne has become one of the most straightforward and powerful methods for constructing C(sp²)–C(sp) bonds, and it has been extensively used in syntheses of natural products, pharmaceuticals, and other organic materials.[2] During the last two decades, the asymmetrization of various transition-metal-catalyzed cross-coupling reactions has intrigued many research groups in organic synthetic chemistry. However, although much work has been devoted to the development of asymmetric Kumada coupling,[3] asymmetric Suzuki–Miyaura coupling,[4] [5] and other asymmetric cross-coupling reactions,[6] the development of an asymmetric Sonogashira coupling remains a major challenge. To the best of our knowledge, only one pioneering work on this reaction has been reported;[7] in this, the double Sonogashira coupling of diiodoparacyclophanes with terminal alkynes proceeded in the presence of a chiral palladium ferrocenyl phosphine complex to give the corresponding planarly chiral dialkynylparacyclophanes.

We have previously reported a chiral palladium β-(aminoalkyl)phosphine complex-catalyzed asymmetric Kumada coupling of achiral biaryl ditriflates with alkynyl Grignard reagents to give the corresponding axially chiral monoalkynylated biaryl compounds (Scheme [1, a]); however, attempts to perform the coupling reaction with terminal alkynes (the so-called asymmetric Sonogashira coupling) resulted in poor catalytic and stereoselective outcomes.[3d] However, we have recently developed (3R,9aS)-2-aryl-[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H-imidazo[1,5a]indol-1-one derivatives as a series of novel chiral imidazoindole phosphine ligands that provide high enantioselectivities in palladium-catalyzed asymmetric allylic substitution reactions (also known as Tsuji–Trost reactions),[8] in Suzuki–Miyaura coupling reactions,[5e] and in copper-catalyzed asymmetric O–H insertion reactions.[9] As a part of our efforts to broaden the utility of these chiral imidazoindole phosphine ligands, we examined their application in the asymmetric Sonogashira cross-coupling reaction. Here we report that a chiral palladium imidazoindole phosphine complex catalyzed the asymmetric Sonogashira coupling reaction between dibromoarenes and terminal alkynes to form enantiomerically enriched monoalkynylated biaryl products of axial chirality (Scheme [1, b]).

When we examined the Sonogashira coupling reaction of 1-(2,6-dibromophenyl)naphthalene (1) with ethynylbenzene (2a) in the presence of 5 mol% tris(dibenzylideneacetone)dipalladium [Pd₂(dba)₃], 12 mol% chiral imidazoindole phosphine L3, 10 mol% copper(I) iodide, and 2.5 equivalents of triethylamine in toluene at 110 °C, the axially chiral monoalkynylated product 3a was obtained in 48% yield and 18% ee (Table [1], entries 1–3).[10] Thorough screening of bases and solvents showed that triethylamine in acetonitrile was an effective base/solvent combination, giving 3a in 57% yield and 29% ee (entries 4–12). We also examined other palladium sources under similar conditions and achieved a slightly higher enantioselectivity (32% ee) with dichlorobis(π-allyl)dipalladium {[PdCl(π-allyl)]₂} (entries 13–15). No significant enhancement in enantioselectivity was observed when the molar ratio of L3 to palladium was increased to 2.4 (entry 16). Interestingly, when 3.0 equivalents of 2a were used, the enantiomeric excess of 3a increased to 63% at the expense of its chemical yield (entry 17). Thus, in entry 16, 3a was obtained in 61% yield and 35% ee, accompanied by trace amounts of the dialkynylated product 4, whereas, when 3 equivalents of ethynylbenzene (2a) were used (entry 17), a considerable amount of the dialkynylated product 4 was formed, reducing the yield of 3a to 52% but increasing the enantiomeric excess to 63%.[11]

Table 1 Optimization of the Reaction Conditions^a

Entry	Pd source/ligand	Solvent	Temp (°C)	Yield (%)b	ee (%)c
1	Pd2(dba)3/L1	toluene	110	26	3
2	Pd2(dba)3/L2	toluene	110	33	14
3	Pd2(dba)3/L3	toluene	110	48	18
4	Pd2(dba)3/L3	1,4-dioxane	100	44	21
5	Pd2(dba)3/L3	DMF	100	43	26
6	Pd2(dba)3/L3	DMSO	100	52	23
7	Pd2(dba)3/L3	NMP	100	43	25
8	Pd2(dba)3/L3	MeCN	80	57	29
9d	Pd2(dba)3/L3	MeCN	80	26	27
10e	Pd2(dba)3/L3	MeCN	80	35	29
11f	Pd2(dba)3/L3	MeCN	80	30	16
12g	Pd2(dba)3/L3	MeCN	80	40	29
13	Pd2(OAc)2/L3	MeCN	80	49	24
14	Pd2(TFA)2/L3	MeCN	80	53	27
15	[PdCl(π-allyl)]2/L3	MeCN	80	53	32
16h	[PdCl(π-allyl)]2/L3	MeCN	80	61	35
17i	[PdCl(π-allyl)]2/L3	MeCN	80	52	63
18i	[PdCl(π-allyl)]2/L3	ILj	80	34	72
19i	[PdCl(π-allyl)]2/L4	MeCN	80	12	42
20i	[PdCl(π-allyl)]2/L5	MeCN	80	25	12
21i	[PdCl(π-allyl)]2/L6	MeCN	80	<5	–k

^a Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd source (10 mol%), ligand (12 mol%), CuI (10 mol%), Et₃N (0.25 mmol), under N₂, 24 h.

^b Isolated yield.

^c Determined by chiral HPLC analysis with a Chiralpac AD-H column.

^d Pyrrolidine (0.25 mmol) was used as the base instead of Et₃N.

^e Morpholine (0.25 mmol) was used as the base instead of Et₃N.

^f TBAF (0.25 mmol) was used as the base instead of Et₃N.

^g K₂CO₃ (0.25 mmol) was used as the base instead of Et₃N.

^h 24 mol% L3 was used.

ⁱ Alkyne 2a (0.3 mmol) and Et₃N (0.35 mmol) were used.

^j IL = ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate).

^k Not determined.

As shown in Scheme [2], the results show that the second Sonogashira coupling of 3a occurred successively, accompanied by a kinetic resolution process. The minor enantiomer (+)-3a that formed in the first asymmetric Sonogashira coupling was consumed preferentially in the second Sonogashira coupling, increasing the enantiomeric purity of 3a as the amount of dialkynylated product 4 increased. Hayashi and co-workers have previously reported a similar kinetic resolution that led to an improvement in enantiomeric purity.[3d] An even higher enantiomeric excess (72%), coupled with an even lower yield of 3a (34%), was observed when an ionic liquid was used as the reaction medium instead of acetonitrile under otherwise identical conditions (Table [1], entry 18), showing that the minor enantiomer (+)-3a was consumed faster in the ionic liquid than in acetonitrile. We also examined the use of the classical chiral ligands (R)-3,5-Xyl-BINAP (L4), (R)-MOP (L5), and (R,R)-Me-Duphos (L6) in the asymmetric Sonogashira coupling under the optimized conditions, but these gave results that were inferior to those obtained with chiral imidazoindole phosphine L3 (Table [1], entries 19–21).

We then examined the scope of the reaction with various terminal alkynes under the optimized reaction conditions (Table [2]). Treatment of 1 with a series of terminal alkynes 2a–i gave the corresponding products 3a–i in moderate yields and moderate enantioselectivities. The reaction was not significantly influenced by the presence of substituents on the aromatic ring of the alkyne. Both electron-rich (entries 2 and 3) and electron-deficient (entries 4–8) aryl-substituted alkynes were effective in giving the desired products. Furthermore, the reaction also proceeded well with oct-1-yne, with an enantioselectivity comparable to those obtained with the various arylalkynes (entry 9).

Table 2 Substrate Scope with Terminal Alkynes^a

Entry	2	R	Product	Yield (%)b	ee (%)c
1	2a	Ph	3a	52	63
2	2b	4-MeC6H4	3b	47	39
3	2c	4-MeOC6H4	3c	42	36
4	2d	2-F3CC6H4	3d	47	31
5	2e	2-FC6H4	3e	50	53
6	2f	3-FC6H4	3f	45	43
7	2g	4-FC6H4	3g	46	50
8	2h	2,4-F2C6H3	3h	38	45
9	2i	(CH2)5Me	3i	38	42

^a Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), [PdCl(π-allyl)]₂ (5 mol%), L3 (12 mol%), CuI (10 mol%), Et₃N (0.35 mmol), MeCN (1.0 mL), under N₂, 80 °C, 24 h. See refs. [12] and [13].

^b Isolated yield.

^c Determined by chiral HPLC analysis with a Chiralpac AD-H or OD-H column.

In addition to generating axial chirality, this asymmetric Sonogashira coupling can also be used to generate planar chirality. Thus, the reaction of 4,16-dibromo paracyclophane (5) with ethynylbenzene (2a) under the optimized reaction conditions gave the monoalkynylated paracyclophane 6 with planar chirality in 56% yield and 44% ee (Scheme [3]).

In conclusion, we have developed an asymmetric Sonogashira coupling with a chiral palladium catalyst. The palladium complex of imidazoindole phosphine L3 catalyzed the asymmetric Sonogashira coupling of 1-(2,6-dibromophenyl)naphthalene or 4,16-dibromo[2,2]paracyclophane with various terminal alkynes to give the corresponding axially or planarly chiral monoalkynylated products, respectively, in up to 61% yield and up to 72% ee.

Acknowledgment

We acknowledge the partial financial support extended by MEXT (Science Research on Priority Areas, no. 460) and JST (CREST Projects).

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• 10 The starting material 1, dialkynylated product 4, and homocoupling product of 2a were also detected by GC/MS, but were inseparable by column chromatography
• 11 The amount of dialkynylated product 4 was assessed on the basis of the peak area determined by GC/MS analysis.
• 12 General Procedure: [PdCl(π-allyl)]₂ (0.005 mmol), chiral imidazoindole phosphine ligand L₃ (0.012 mmol), and toluene (0.5 mL, degassed) were charged into a Schlenk tube under N₂, and the mixture was stirred at room temperature for 15 min. After removal of the solvent, 1-(2,6-dibromophenyl)naphthalene (1; 0.1 mmol), CuI (0.01 mmol), acetonitrile (2 mL, degassed), alkyne (2; 0.3 mmol) and Et₃N (0.35 mmol) were charged into the Schlenk tube. The mixture was stirred at 80 °C under a nitrogen atmosphere for 24 h. After cooling to room temperature, the reaction mixture was passed through a short pad of silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography with silica gel to give the mono- and dialkynylated products 3 and 4. The enantiomeric excess of 3 was determined by HPLC analysis with a chiral stationary phase column (Chiralcel AD-H, Chiralpak OD-H).
• 13 Analytical Data of Selected Compounds1-[2-Bromo-6-(phenylethynyl)phenyl]naphthalene (3a): [α]²⁵ _D −78.6 (c 1.0, CHCl₃); 63% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 13.68 (major isomer), 14.93 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.95 (t, J = 7.5 Hz, 2 H), 7.73–7.72 (m, 1 H), 7.64–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.16–7.07 (m, 3 H), 6.70–6.69 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.4, 138.1, 133.5, 132.5, 131.4, 131.2, 130.7, 128.8, 128.3, 128.2, 128.0, 127.3, 126.2, 125.8, 125.5, 125.2, 124.7, 122.5, 93.9, 88.1; HRMS (EI-TOF): m/z calcd for C₂₄H₁₅Br: 382.0357; found: 382.0348.1-[2-Bromo-6-(p-tolylethynyl)phenyl]naphthalene (3b): [α]²⁵ _D −69.6 (c 0.9, CHCl₃); 39% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.84 (major isomer), 14.16 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.49–7.38 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 6.58 (d, J = 8.0 Hz, 2 H), 2.23 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ 143.3, 138.4, 138.1, 133.5, 132.4, 131.5, 131.3, 131.1, 130.5, 129.2, 128.9, 128.8, 128.2, 127.4, 126.4, 126.2, 125.8, 125.6, 125.2, 124.7, 119.5, 94.2, 87.5, 21.4; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇Br: 396.0514; found: 396.0506.1-{2-Bromo-6-[(4-methoxyphenyl)ethynyl]phenyl}-naphthalene (3c): [α]²⁵ _D = −62.4 (c 0.5, CHCl₃); 36% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.8 mL/min; wavelength = 254 nm; t_R = 13.05 (major isomer), 14.00 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.0 Hz, 2 H), 7.70–7.69 (m, 1 H), 7.61–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.62 (s, 4 H), 3.71 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.5, 143.1, 138.2, 133.4, 132.7, 132.2, 131.5, 130.4, 128.8, 128.2, 127.4, 126.5, 126.1, 125.8, 125.6, 125.2, 124.7, 114.7, 113.7, 94.1, 86.9, 55.2; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇BrO: 412.0463; found: 412.0477.1-(2-Bromo-6-{[2-(trifluoromethyl)phenyl]ethynyl}-phenyl)naphthalene (3d): [α]²⁵ _D = −47.7 (c 0.9, CHCl₃); 31% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.18 (major isomer), 14.48 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 8.5 Hz, 2 H), 7.69–7.67 (m, 1 H), 7.60 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.43–7.32 (m, 5 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.18–7.12 (m, 2 H), 6.47–6.45 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 137.7, 133.9, 133.5, 133.1, 131.4, 131.0, 130.7, 128.9, 128.3, 128.2, 127.8, 127.4, 126.2, 125.8, 125.6, 125.5, 125.4, 125.2, 124.9, 122.0, 120.8, 93.2, 89.3; HRMS (EI-TOF): m/z calcd for C₂₅H₁₄BrF₃: 450.0231; found: 450.0235.1-{2-Bromo-6-[(2-fluorophenyl)ethynyl]phenyl}-naphthalene (3e): [α]²⁵ _D −84.4 (c 0.5, CHCl₃); 3% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.21 (major isomer), 13.21 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 8.0 Hz, 2 H), 7.74 (dd, J ₁= 8.0 Hz, J ₂ = 1.5 Hz, 1 H), 7.68–7.67 (m, 1 H), 7.60 7.57 (m, 1 H), 7.50–7.40 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.13–7.11 (m, 1 H), 6.88–6.83 (m, 2 H), 6.53–6.50 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.1, 143.4, 137.8, 133.5, 133.3, 132.9, 131.4, 131.0, 129.9, 128.8, 128.3, 128.2, 127.3, 126.2, 125.8, 125.5, 124.8, 123.6, 115.3, 115.1, 92.8, 87.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0251.1-{2-Bromo-6-[(3-fluorophenyl)ethynyl]phenyl}-naphthalene (3f): [α]²⁵ _D −77.6 (c 0.5, CHCl₃); 43% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 15.07 (major isomer), 17.13 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (t, J = 8.0 Hz, 2 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.63–7.58 (m, 2 H), 7.51–7.39 (m, 4 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.06–7.02 (m, 1 H), 6.86–6.82 (m, 1 H), 6.47 (d, J = 7.5 Hz, 1 H), 6.35–6.32 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.0, 143.6, 137.9, 133.5, 132.9, 131.4, 130.7, 129.6, 128.9, 128.4, 127.3, 127.0, 126.2, 125.9, 125.7, 125.2, 124.8, 124.4, 118.0, 117.9, 115.6, 115.4, 92.5, 88.9; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(4-fluorophenyl)ethynyl]phenyl}-naphthalene (3g): [α]²⁵ _D −71.3 (c 0.9, CHCl₃); 50% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 10.84 (major isomer), 12.27 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 7.5 Hz, 2 H), 7.65 (dd, J ₁ = 8.0, J ₂ = 1.0 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.43–7.31 (m, 4 H), 7.21 (t, J = 8.0 Hz, 1 H), 6.72–6.68 (m, 2 H), 6.59–6.55 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 161.3, 143.4, 138.0, 133.4, 133.1, 133.0, 132.6, 131.4, 130.5, 128.8, 128.2, 127.3, 126.2, 126.0, 125.8, 125.5, 125.2, 124.7, 118.6, 115.4, 115.2, 92.8, 87.8; HRMS (EI-TOF): m/zcalcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(2,4-difluorophenyl)ethynyl]phenyl}-naphthalene (3h): [α]²⁵ _D −74.0 (c 0.7, CHCl₃); 45% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.22 (major isomer), 13.01 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.50–7.39 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 6.65–6.58 (m, 2 H), 6.47 (q, J = 7.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.5, 161.4, 143.4, 137.8, 134.2, 133.5, 132.9, 131.4, 130.8, 128.8, 128.3, 127.3, 126.2, 125.8, 125.6, 125.4, 125.2, 124.8, 111.3, 111.1, 107.6, 103.9, 92.6, 86.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₃BrF₂: 418.0169; found: 418.0157.1-[2-Bromo-6-(pent-1-ynyl)phenyl]naphthalene (3i): [α]²⁵ _D −10.2 (c 0.8, CHCl₃); 42% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.3 mL/min; wavelength = 254 nm; t_R = 14.70 (major isomer), 16.08 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.88 (d, J = 8.0 Hz, 2 H), 7.66–7.64 (m, 1 H), 7.55–7.45 (m, 3 H), 7.39–7.34 (m, 3 H), 7.22 (t, J = 8.0 Hz, 1 H), 1.92–1.89 (m, 2 H), 1.32–1.25 (m, 2 H), 1.14–1.06 (m, 2 H), 0.96–0.70 (m, 7 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 138.4, 133.4, 131.8, 131.5, 130.8, 128.6, 128.1, 128.0, 127.1, 126.9, 126.0, 125.6, 125.5, 125.2, 124.7, 95.3, 79.1, 31.2, 27.9, 27.8, 22.3, 19.0, 14.1; HRMS (EI-TOF): m/z calcd for C₂₄H₂₃Br: 390.0983; found: 390.0994

• References

• 1 Present address: China Three Gorges University (CTGU); haifeng-zhou@hotmail.com.

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• 10 The starting material 1, dialkynylated product 4, and homocoupling product of 2a were also detected by GC/MS, but were inseparable by column chromatography
• 11 The amount of dialkynylated product 4 was assessed on the basis of the peak area determined by GC/MS analysis.
• 12 General Procedure: [PdCl(π-allyl)]₂ (0.005 mmol), chiral imidazoindole phosphine ligand L₃ (0.012 mmol), and toluene (0.5 mL, degassed) were charged into a Schlenk tube under N₂, and the mixture was stirred at room temperature for 15 min. After removal of the solvent, 1-(2,6-dibromophenyl)naphthalene (1; 0.1 mmol), CuI (0.01 mmol), acetonitrile (2 mL, degassed), alkyne (2; 0.3 mmol) and Et₃N (0.35 mmol) were charged into the Schlenk tube. The mixture was stirred at 80 °C under a nitrogen atmosphere for 24 h. After cooling to room temperature, the reaction mixture was passed through a short pad of silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography with silica gel to give the mono- and dialkynylated products 3 and 4. The enantiomeric excess of 3 was determined by HPLC analysis with a chiral stationary phase column (Chiralcel AD-H, Chiralpak OD-H).
• 13 Analytical Data of Selected Compounds1-[2-Bromo-6-(phenylethynyl)phenyl]naphthalene (3a): [α]²⁵ _D −78.6 (c 1.0, CHCl₃); 63% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 13.68 (major isomer), 14.93 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.95 (t, J = 7.5 Hz, 2 H), 7.73–7.72 (m, 1 H), 7.64–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.16–7.07 (m, 3 H), 6.70–6.69 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.4, 138.1, 133.5, 132.5, 131.4, 131.2, 130.7, 128.8, 128.3, 128.2, 128.0, 127.3, 126.2, 125.8, 125.5, 125.2, 124.7, 122.5, 93.9, 88.1; HRMS (EI-TOF): m/z calcd for C₂₄H₁₅Br: 382.0357; found: 382.0348.1-[2-Bromo-6-(p-tolylethynyl)phenyl]naphthalene (3b): [α]²⁵ _D −69.6 (c 0.9, CHCl₃); 39% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.84 (major isomer), 14.16 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.49–7.38 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 6.58 (d, J = 8.0 Hz, 2 H), 2.23 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ 143.3, 138.4, 138.1, 133.5, 132.4, 131.5, 131.3, 131.1, 130.5, 129.2, 128.9, 128.8, 128.2, 127.4, 126.4, 126.2, 125.8, 125.6, 125.2, 124.7, 119.5, 94.2, 87.5, 21.4; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇Br: 396.0514; found: 396.0506.1-{2-Bromo-6-[(4-methoxyphenyl)ethynyl]phenyl}-naphthalene (3c): [α]²⁵ _D = −62.4 (c 0.5, CHCl₃); 36% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.8 mL/min; wavelength = 254 nm; t_R = 13.05 (major isomer), 14.00 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.0 Hz, 2 H), 7.70–7.69 (m, 1 H), 7.61–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.62 (s, 4 H), 3.71 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.5, 143.1, 138.2, 133.4, 132.7, 132.2, 131.5, 130.4, 128.8, 128.2, 127.4, 126.5, 126.1, 125.8, 125.6, 125.2, 124.7, 114.7, 113.7, 94.1, 86.9, 55.2; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇BrO: 412.0463; found: 412.0477.1-(2-Bromo-6-{[2-(trifluoromethyl)phenyl]ethynyl}-phenyl)naphthalene (3d): [α]²⁵ _D = −47.7 (c 0.9, CHCl₃); 31% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.18 (major isomer), 14.48 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 8.5 Hz, 2 H), 7.69–7.67 (m, 1 H), 7.60 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.43–7.32 (m, 5 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.18–7.12 (m, 2 H), 6.47–6.45 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 137.7, 133.9, 133.5, 133.1, 131.4, 131.0, 130.7, 128.9, 128.3, 128.2, 127.8, 127.4, 126.2, 125.8, 125.6, 125.5, 125.4, 125.2, 124.9, 122.0, 120.8, 93.2, 89.3; HRMS (EI-TOF): m/z calcd for C₂₅H₁₄BrF₃: 450.0231; found: 450.0235.1-{2-Bromo-6-[(2-fluorophenyl)ethynyl]phenyl}-naphthalene (3e): [α]²⁵ _D −84.4 (c 0.5, CHCl₃); 3% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.21 (major isomer), 13.21 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 8.0 Hz, 2 H), 7.74 (dd, J ₁= 8.0 Hz, J ₂ = 1.5 Hz, 1 H), 7.68–7.67 (m, 1 H), 7.60 7.57 (m, 1 H), 7.50–7.40 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.13–7.11 (m, 1 H), 6.88–6.83 (m, 2 H), 6.53–6.50 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.1, 143.4, 137.8, 133.5, 133.3, 132.9, 131.4, 131.0, 129.9, 128.8, 128.3, 128.2, 127.3, 126.2, 125.8, 125.5, 124.8, 123.6, 115.3, 115.1, 92.8, 87.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0251.1-{2-Bromo-6-[(3-fluorophenyl)ethynyl]phenyl}-naphthalene (3f): [α]²⁵ _D −77.6 (c 0.5, CHCl₃); 43% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 15.07 (major isomer), 17.13 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (t, J = 8.0 Hz, 2 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.63–7.58 (m, 2 H), 7.51–7.39 (m, 4 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.06–7.02 (m, 1 H), 6.86–6.82 (m, 1 H), 6.47 (d, J = 7.5 Hz, 1 H), 6.35–6.32 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.0, 143.6, 137.9, 133.5, 132.9, 131.4, 130.7, 129.6, 128.9, 128.4, 127.3, 127.0, 126.2, 125.9, 125.7, 125.2, 124.8, 124.4, 118.0, 117.9, 115.6, 115.4, 92.5, 88.9; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(4-fluorophenyl)ethynyl]phenyl}-naphthalene (3g): [α]²⁵ _D −71.3 (c 0.9, CHCl₃); 50% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 10.84 (major isomer), 12.27 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 7.5 Hz, 2 H), 7.65 (dd, J ₁ = 8.0, J ₂ = 1.0 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.43–7.31 (m, 4 H), 7.21 (t, J = 8.0 Hz, 1 H), 6.72–6.68 (m, 2 H), 6.59–6.55 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 161.3, 143.4, 138.0, 133.4, 133.1, 133.0, 132.6, 131.4, 130.5, 128.8, 128.2, 127.3, 126.2, 126.0, 125.8, 125.5, 125.2, 124.7, 118.6, 115.4, 115.2, 92.8, 87.8; HRMS (EI-TOF): m/zcalcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(2,4-difluorophenyl)ethynyl]phenyl}-naphthalene (3h): [α]²⁵ _D −74.0 (c 0.7, CHCl₃); 45% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.22 (major isomer), 13.01 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.50–7.39 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 6.65–6.58 (m, 2 H), 6.47 (q, J = 7.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.5, 161.4, 143.4, 137.8, 134.2, 133.5, 132.9, 131.4, 130.8, 128.8, 128.3, 127.3, 126.2, 125.8, 125.6, 125.4, 125.2, 124.8, 111.3, 111.1, 107.6, 103.9, 92.6, 86.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₃BrF₂: 418.0169; found: 418.0157.1-[2-Bromo-6-(pent-1-ynyl)phenyl]naphthalene (3i): [α]²⁵ _D −10.2 (c 0.8, CHCl₃); 42% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.3 mL/min; wavelength = 254 nm; t_R = 14.70 (major isomer), 16.08 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.88 (d, J = 8.0 Hz, 2 H), 7.66–7.64 (m, 1 H), 7.55–7.45 (m, 3 H), 7.39–7.34 (m, 3 H), 7.22 (t, J = 8.0 Hz, 1 H), 1.92–1.89 (m, 2 H), 1.32–1.25 (m, 2 H), 1.14–1.06 (m, 2 H), 0.96–0.70 (m, 7 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 138.4, 133.4, 131.8, 131.5, 130.8, 128.6, 128.1, 128.0, 127.1, 126.9, 126.0, 125.6, 125.5, 125.2, 124.7, 95.3, 79.1, 31.2, 27.9, 27.8, 22.3, 19.0, 14.1; HRMS (EI-TOF): m/z calcd for C₂₄H₂₃Br: 390.0983; found: 390.0994

• Supplementary Material