Enantioselective addition of ArTi(OⁱPr)₃ to aldehydes catalyzed by a titanium complex of an N-sulfonylated amino alcohol

Abstract

Asymmetric additions of ArTi(OⁱPr)₃ to aldehydes catalyzed by a titanium catalyst of N-sulfonylated amino alcohols were reported, and results showed that the chiral N-sulfonylated amino alcohol with two stereogenic centers could catalyze the asymmetric addition of ArTi(OⁱPr)₃ to aldehydes to afford desired secondary alcohols in good yields with good to excellent enantioselectivities of up to 95% ee.

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Introduction

The enantioselective addition of aryl organometallic reagents to aldehydes provides a straightforward synthetic method for optically active diarylmethanols,¹ which are key intermediates leading to bioactive compounds.² The use of an arylzinc nucelophile for the catalytic asymmetric arylation of aldehydes has received much attention in the past two decades. A variety of arylzinc organometallic reagents, such as ZnPh₂,³ mixtures of ZnPh₂/ZnR₂ (R = Me or Et),⁴ arylzinc reagents from transmetallation of arylboronic acid or arylboron with ZnEt₂,⁵ and arylzinc from in situ reactions of aryl nucleophile with dialkylzinc or zinc halides,⁶ have been extensively employed in the titanium-catalyzed asymmetric addition for the synthesis of diarylmethanols. Recent studies have demonstrated that AlAr_xEt_3−x (THF) (x = 3 or 1),^7,8 ArMgX⁹ and ArLi¹⁰ compounds are efficient aryl sources for titanium-catalyzed asymmetric aryl addition reactions of organic carbonyls, and excess amounts of Ti(OⁱPr)₄ are required to ensure the high stereocontrol of the addition products. Mechanistic study suggested that the roles of excess Ti(OⁱPr)₄ are not only the formation of the dititanium active species bearing a chiral ligand, but also the transmetalation of an organic nucelophile from the organozinc or organoaluminum compounds to form the organotitanium reagents as the actual addition reagents.¹¹ Therefore, direct asymmetric additions of organotitanium reagents to organic carbonyls were the most effective method without doubt. The first catalytic asymmetric addition of RTi(OⁱPr)₃ (R = alkyl or aryl) to aldehydes was reported by Seebach and coworkers using Ti-TADDOLate catalysts at a low temperature of −78 °C.¹² Recently, we have also reported aryltitanium,¹³ 3-furyltitanium,¹⁴ and alkyltitanium compounds¹⁵ as efficient nucleophiles for catalytic asymmetric addition reactions at a mild temperature of 0 °C to room temperature. To further explore aryltitanium compounds as efficient nucleophiles for catalytic reactions, we report herein the asymmetric addition of aryltitanium to aldehydes employing a series of chiral N-sulfonylated amino alcohols as catalysts.

Results and discussion

Chiral β-amino alcohols have widely used as chiral ligands for a variety of asymmetric syntheses.¹⁶ Here, the asymmetric addition of PhTi(OⁱPr)₃ to 2-methoxybenzaldehyde (2a) were first screened using 10 mol% of the chiral N-sulfonylated amino alcohols 1a–f with one or two stereogenic centers from L-phenylalanine (Fig. 1), and the results are summarized in Table 1. It was found that the ligands have a strong influence on the enantioselectivities in asymmetric phenylation reactions (entries 1–6), and only the chiral N-sulfonylated amino alcohols 1e with two stereogenic centers showed high enantioselectivity (entry 5). In our previous mechanistic study, we have demonstrated that the dititanium complex that simultaneously beared the chiral directing ligand and the phenyl nucleophile was an active species in the crucial and final step of the catalytic addition reaction of organic carbonyl compounds.^13b The chiral N-sulfonylated amino alcohols 1e with two stereogenic centers showed high enantioselectivity probably due to the above reason. The investigations for the choice of the solvent showed that THF is the best one (entries 5, 7–10). The enantioselectivities of product 4a is nearly invariable with reduction of the temperature of reaction (entry 13). In order to suppress the racemic background reactions that would lower the enantioselectivities, further study showed that substrate in 1 mL THF was added dropwise to the catalytic solution to afford 4a in excellent enantioselectivity of 95% ee (entry 14).

Fig. 1 Different chiral N-sulfonylated amino alcohols.

Table 1 Optimizations of asymmetric PhTi(OⁱPr)₃ additions to 2-methoxybenzaldehyde^a

Entry	Ligand	PhTi(O^iPr)3 (equiv.)	Solvent	Temp (°C)	Conv^b. (%)	ee^c (%)
a 2-MeOC6H4CHO (0.50 mmol), ligand (0.05 mmol), THF (4 mL), equiv. of PhTi(O^iPr)3 is relative to 2-MeOC6H4CHO.b Conversions based on ^1H NMR spectra.c The ee values were determined by HPLC, and the absolute configuration of 4a was determined by comparison with optical rotation of known compounds.d Reaction time: 10 min.e 2-MeOC6H4CHO (0.50 mmol) in 1 mL THF was added to the catalytic solution dropwise over 20 min; then reacted another 10 min.
1	1a	1.4	THF	r.t.	97	3 (R)
2	1b	1.4	THF	r.t.	97	rac
3	1c	1.4	THF	r.t.	92	4 (R)
4	1d	1.4	THF	r.t.	97	22 (R)
5	1e	1.4	THF	r.t.	100	88 (R)
6	1f	1.4	THF	r.t.	92	4 (R)
7	1e	1.4	Toluene	r.t.	100	75 (R)
8	1e	1.4	Hexane	r.t.	100	66 (R)
9	1e	1.4	CH2Cl2	r.t.	100	82 (R)
10	1e	1.4	Et2O	r.t.	100	75 (R)
11	1e	1.6	THF	r.t.	100	85 (R)
12	1e	1.2	THF	r.t.	93	88 (R)
13^d	1e	1.4	THF	0	100	89 (R)
14^e	1e	1.4	THF	0	100	95 (R)

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Next, we explored the scope of the asymmetric addition of PhTi(OⁱPr)₃ to aldehydes using the best performing ligand 1e, and the results are listed in Table 2. Regardless of the electronic nature or the steric effect of the substituent on the aryl groups, asymmetric phenyl additions to aromatic aldehydes afforded diarylmethanols in high yields. However, a steric effect of the substrates on the enantioselectivities of products was observed. The addition reactions of aromatic aldehydes with an ortho-substituent gave the corresponding products in the enantioselectivities of ≥90% ee except for 2-nitrobenzaldehyde (85% ee, entry 15) and 1-naphthylaldehyde (86% ee, entry 18). The addition reactions of aromatic aldehydes with a para-substituent showed a slight lower enantioselectivities than those with an ortho-substituents. However, the addition reaction of heteroaromatic 2-furaldehyde furnished product 4t in good yield with a enantioselectivity of 78% ee (entry 20), and the addition reaction of α,β-unsaturated (E)-cinnamaldehyde afforded 4u in a good enantioselectivity of 84% ee (entry 21). Different to our previous catalytic system,^7a the addition reaction of PhTi(OⁱPr)₃ to aliphatic aldehydes afforded the corresponding products in moderate enantioselectivities of 56 to 76% ee (entries 22–24). The additions of aryl nucleophiles of ArTi(OⁱPr)₃ (Ar = p-tolyl, 4-MeOC₆H₄, 4-ClC₆H₄, 4-F₃CC₆H₄, and 2-naphathyl) to aldehyde were also studied, affording aryl addition products in excellent enantioselectivities for electron-donating aryltitanium reagents (entries 25, 26 and 35) but in moderate enantioselectivities for electron-withdrawing aryltitanium reagents (entries 27, 28, and 34). For ortho-substituted aryltitanium reagents ArTi(OⁱPr)₃ (Ar = 1-naphathyl, o-tolyl, o-anisyl and o-chlorophenyl), the low enantioselectivities were obtained (entries 30–33). Especially, the racemic diarylmethanols 4d′ and 4a′ were obtained for the bulky aryltitanium reagent (entries 31 and 32). For ortho-substituted aryltitanium reagents, the low enantioselectivities were obtained, probably because the steric hindrance made aldehydes' coordination to titanium metal in Re-face and Si-face equality of opportunities.

Table 2 Asymmetric ArTi(OⁱPr)₃ addition to aldehydes catalyzed by the titanium catalyst of N-sulfonylated amino alcohol^a

Entry	Substrate	ArTi(O^iPr)3	Product	Yield^b (%)	ee^c (%)
a Substrate/1e/ArTi(O^iPr)3 = 0.50/0.05/0.70 mmol, substrates in 1 mL THF was added dropwise over 20 min; reaction time (30 min) including the addition time of the substrate to the catalytic solution.b Isolated yield.c The ee values were determined by HPLC.
1	2-MeOC6H4CHO	Ph	4a	93	95 (R)
2	3-MeOC6H4CHO	Ph	4b	92	86 (R)
3	4-MeOC6H4CHO	Ph	4c	95	92 (R)
4	2-MeC6H4CHO	Ph	4d	97	91 (R)
5	3-MeC6H4CHO	Ph	4e	93	90 (R)
6	4-MeC6H4CHO	Ph	4f	83	84 (R)
7	2-ClC6H4CHO	Ph	4g	91	90 (R)
8	3-ClC6H4CHO	Ph	4h	94	90 (R)
9	4-ClC6H4CHO	Ph	4i	96	80 (R)
10	2-BrC6H4CHO	Ph	4j	98	90 (R)
11	3-BrC6H4CHO	Ph	4k	90	86 (R)
12	4-BrC6H4CHO	Ph	4l	92	82 (R)
13	2-FC6H4CHO	Ph	4m	90	90 (R)
14	4-F3CC6H4CHO	Ph	4n	95	77 (R)
15	2-O2NC6H4CHO	Ph	4o	91	90 (R)
16	3-O2NC6H4CHO	Ph	4p	93	76 (R)
17	4-O2NC6H4CHO	Ph	4q	89	72 (R)
18	1-Naphthaldehyde	Ph	4r	93	86 (R)
19	2-Naphthaldehyde	Ph	4s	96	82 (R)
20	Furan-2-carbaldehyde	Ph	4t	90	78 (R)
21	Cinnamaldehyde	Ph	4u	91	84 (S)
22	Isobutyraldehyde	Ph	4v	85	76 (S)
23	Pivalaldehyde	Ph	4w	88	56 (S)
24	Cyclohexane-carbaldehyde	Ph	4x	96	73 (S)
25	C6H5CHO	4-OMeC6H4	4c′	86	90 (S)
26	C6H5CHO	4-MeC6H4	4f′	89	87 (S)
27	C6H5CHO	4-ClC6H4	4i′	91	62 (S)
28	C6H5CHO	4-CF3C6H4	4n′	59	53 (S)
29	C6H5CHO	2-Naphthyl	4s′	93	77 (S)
30	C6H5CHO	1-Naphthyl	4r′	51	12 (S)
31	C6H5CHO	2-MeC6H4	4d′	57	rac
32	C6H5CHO	2-MeOC6H4	4a′	64	3 (S)
33	C6H5CHO	2-ClC6H4	4g′	55	52 (S)
34	2-OMeC6H4CHO	4-ClC6H4	4y	89	72 (S)
35	2-OMeC6H4CHO	4-MeC6H4	4z	91	93 (S)

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Based on our previous mechanistic study, the phenyl group of arylaldehyde pointing toward the same side of the bridging oxygen donor of the chiral ligand, predominantly giving the intermediate A for a Re-face addition of the nucleophile to aldehydes (Fig. 2).^11e

Fig. 2 (a) The Re-face addition of the phenyl nucleophile to arylaldehyde; (b) the Si-face addition of Ph to arylaldehyde.

Conclusion

In summary, the asymmetric aryl additions of ArTi(OⁱPr)₃ to aldehydes employing a series of N-sulfonylated amino alcohols were examined. Results showed that the chiral N-sulfonylated amino alcohol with two stereogenic centers could catalyzed asymmetric addition of ArTi(OⁱPr)₃ to aldehydes to afford the desired optically active diarylmethanols in good yields with good to excellent enantioselectivities of up to 95% ee.

Experimental section

General methods

All syntheses and manipulations were carried out under a dry nitrogen atmosphere using standard Schlenk techniques or in a glovebox. Solvents were dried by refluxing for at least 24 h over P₂O₅ (dichloromethane) or sodium/benzophenone (THF, n-hexane or toluene) and were freshly distilled prior to use. ArTi(OⁱPr)₃ was prepared according to the literature procedure.¹⁷ The chiral N-sulfonylated amino alcohols 1a, 1e and 1f were prepared according to the literature procedure.^{18 1}H NMR spectra were obtained with a Varian Mercury-400 (400 MHz) spectrometer, and ¹³C NMR spectra were recorded with the Varian Mercury-400 (100.70 MHz). ¹H and ¹³C chemical shifts were measured relative to TMS as the internal reference.

Synthesis of chiral N-sulfonylated amino alcohol 1b–1d

A solution of p-tolylsulphonyl chloride (0.95 g, 5.00 mmol) in CH₂Cl₂ (20 mL) was added to a cold (0 °C) solution of the corresponding chiral amino alcohol (5.00 mmol) and Et₃N (2.1 mL, 15 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with CH₂Cl₂ (10 mL) and washed with 1 N HCl (2–5 mL), saturated aqueous NaHCO₃ (3–10 mL), and brine (3–10 mL). The organic layer was dried over anhydrous MgSO₄, concentrated under reduced pressure, and recrystallized from EA–hexane to afford the chiral N-sulfonylated amino alcohols 1b–d.

(S)-3-(p-Toluenesulfonylamino)-2-methyl-4-phenyl-2-butanol (1b). ¹H NMR (400 MHz, CDCl₃): δ 7.34–6.89 (m, 9H, Ph and Ph(SO₂NH)), 5.30 (s, 1H, NH), 3.46 (m, 1H, CHN), 2.95 (m, 2H, PhCH_AH_B, OH), 2.43 (m, 1H, PhCH_AH_B), 2.35 (s, 3H, CH₃), 1.29 (s, 3H, (CH₃)₂CH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.6, 137.7, 137.1, 129.4, 129.0, 128.3, 126.6, 126.1, 72.8, 64.7, 37.4, 27.7, 25.5, 21.4 ppm.

(S)-3-Phenyl-2-(p-toluenesulfonylamino)-1-propanol (1c). ¹H NMR (400 MHz, CDCl₃): δ 7.61–6.95 (m, 9H, Ph and Ph(SO₂NH)), 5.74 (d, J = 7.2 Hz, 1H, NH), 3.61 (m, 1H, CH_AH_BOH), 3.53–3.45 (m, 2H, CH_AH_BOH, CHN), 2.75 (m, 2H, PhCH_AH_B, OH), 2.63 (m, 1H, PhCH_AH_B), 2.35 (s, 3H, CH₃) ppm. ¹³C NMR (400 MHz, CDCl₃): δ 143.0, 137.0, 129.5, 129.0, 128.3, 126.8, 126.2, 63.7, 56.8, 37.4, 21.3 ppm.

(2R,3S)-3-(p-Toluenesulfonylamino)-4-phenyl-2-butanol (1d). ¹H NMR (400 MHz, CDCl₃): δ 7.44–6.88 (m, 9H, Ph and Ph(SO₂NH)), 5.39 (d, J = 7.6 Hz, 1H, NH), 3.97 (m, 1H, PhCHOH), 3.42 (m, 1H, CHN), 2.72 (m, 1H, PhCH_AH_B), 2.56 (m, 1H, PhCH_AH_B), 2.36 (s, 3H, CH₃), 1.23 (d, J = 6.4 Hz, 3H, CH₃CHOH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.9, 137.0, 136.5, 129.4, 128.9, 128.4, 126.8, 126.2, 68.9, 60.6, 35.4, 21.4, 18.2 ppm.

General procedure for the asymmetric aryl addition of aldehydes

Under a dry nitrogen atmosphere, 1e (0.019 g, 0.05 mmol) and ArTi(OⁱPr)₃ (0.70 mmol) were mixed in dry THF (4 mL) at 0 °C. After stirring for 30 min, and an aldehyde (0.50 mmol) in THF (1 mL) was added dropwise to the resulting solution over 20 min at 0 °C. The mixture was allowed to react for 10 min at this temperature, and then quenched with 2 M NaOH. The aqueous phase was extracted with ethyl acetate (3 × 10 mL), dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography to give the secondary alcohol. Enantiomeric excesses of products were determined by HPLC using suitable chiral columns from Daicel.

(2-Methoxyphenyl)phenylmethanol (4a)^5a. [α]²⁵_D = +47.84 (c 1.08, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.38–7.21 (m, 7H, Ar), 6.94–6.85 (m, 2H, Ar), 6.03 (s, 1H, CHO), 3.77 (s, 3H, OCH₃), 3.12 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 156.6, 143.2, 131.9, 128.6, 128.1, 127.7, 127.1, 126.5, 120.7, 110.6, 72.1, 55.3 ppm.

(3-Methoxyphenyl)phenylmethanol (4b)^4b. [α]²⁵_D = −15.23 (c 1.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.33–7.18 (m, 6H, Ar), 6.88–6.91 (m, 2H, Ar), 6.77–6.69 (m, 1H, Ar), 5.69 (s, 1H, CHO), 3.71 (s, 3H, OCH₃), 2.77 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 159.6, 145.4, 143.6, 129.4, 128.3, 127.4, 126.4, 118.8, 112.8, 112.0, 75.9, 55.0 ppm.

(4-Methoxyphenyl)phenylmethanol (4c)^5a. [α]²⁵_D = +0.93 (c 1.08, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.39–7.25 (m, 7H, Ar), 6.87–6.81 (m, 2H, Ar), 5.81 (d, J = 2.0 Hz, 1H, CHO), 3.79 (s, 3H, OCH₃), 2.19 (d, J = 3.2 Hz, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 158.9, 144.0, 136.1, 128.4, 127.8, 127.3, 126.3, 113.8, 75.7, 55.2 ppm.

(2-Tolyl)phenylmethanol (4d)^5h. [α]²⁵_D = −2.70 (c 1.11, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.47–7.45 (m, 1H, Ar), 7.32–7.10 (m, 8H, Ar), 5.88 (s, 1H, CHO), 2.55 (br, 1H, OH), 2.18 (s, 3H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.8, 141.4, 135.2, 130.4, 128.3, 127.4, 127.3, 127.0, 126.2, 126.0, 73.2, 19.3 ppm.

(3-Tolyl)phenylmethanol (4e)¹⁹. [α]²⁵_D = +2.63 (c 1.14, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.33–7.05 (m, 9H, Ar), 5.69 (s, 1H, CHO), 2.60 (br, 1H, OH), 2.29 (s, 3H, CH₃), ppm. ¹³C NMR (100 MHz, CDCl₃): δ 144.2, 144.1, 138.4, 128.73, 128.68, 128.6, 127.8, 127.5, 126.8, 124.0, 76.5, 21.8 ppm.

(4-Tolyl)phenylmethanol (4f)^5a. [α]²⁵_D = +16.35 (c 1.04, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.32–7.09 (m, 9H, Ar), 5.69 (s, 1H, CHO), 2.51 (s, 1H, OH), 2.29 (s, 3H, CH₃), ppm. ¹³C NMR (100 MHz, CDCl₃): δ 144.3, 141.3, 137.5, 129.5, 128.7, 127.7, 126.9, 126.8, 76.3, 21.4 ppm.

(2-Chlorophenyl)phenylmethanol (4g)^5f. [α]²⁵_D = +15.26 (c 1.07, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.58–7.56 (m, 1H, Ar), 7.36–7.17 (m, 8H, Ar), 6.17 (s, 1H, CHO), 2.60 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.2, 140.9, 132.4, 129.5, 128.7, 128.4, 128.0, 127.7, 127.0, 126.9, 72.6 ppm.

(3-Chlorophenyl)phenylmethanol (4h)¹⁸. [α]²⁵_D = −29.36 (c 1.09, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.35–7.20 (m, 9H), 5.68 (s, 1H, CHO), 2.63 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 145.7, 143.1, 134.3, 129.6, 128.6, 127.8, 127.5, 126.5, 124.5, 75.5 ppm.

(4-Chlorophenyl)phenylmethanol (4i)^5a. [α]²⁵_D = −12.50 (c 1.04, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.33–7.26 (m, 9H, Ar), 5.76 (s, 1H, CHO), 2.48 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.4, 142.1, 133.2, 129.3, 128.6, 127.8, 126.5, 116.6, 75.5 ppm.

(2-Bromophenyl)phenylmethanol (4j)^5a. [α]²⁵_D = +24.64 (c 2.34, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.50–7.48 (m, 2H, Ar), 7.31–7.20 (m, 7H, Ar), 7.08–7.05 (m, 1H, Ar), 6.04 (s, 1H, CHO), 3.02 (s, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.3, 142.0, 132.6, 128.9, 128.4, 128.3, 127.8, 127.6, 126.9, 122.6, 74.5 ppm.

(3-Bromophenyl)phenylmethanol (4k)^5g. [α]²⁵_D = −29.70 (c 1.01, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.49–7.48 (m, 1H, Ar), 7.35–7.10 (m, 8H, Ar), 5.63 (s, 1H, CHO), 2.85 (d, J = 5.6 Hz, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 145.9, 143.0, 130.4, 129.9, 129.4, 128.6, 127.8, 126.5, 125.0, 122.5, 75.4 ppm.

(4-Bromophenyl)phenylmethanol (4l)^5a. [α]²⁵_D = −15.45 (c 1.10, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.43–7.41 (m, 2H, Ar), 7.33–7.19 (m, 7H, Ar), 5.71 (s, 1H, CHO), 2.51 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.2, 142.6, 131.5, 128.6, 128.2, 127.8, 126.5, 121.3, 75.5 ppm.

(2-Fluorophenyl)phenylmethanol (4m)^5h. [α]²⁵_D = −9.82 (c 0.95, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.47–6.94 (m, 9H, Ar), 6.03 (s, 1H, CHO), 2.82 (s, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 161.0, 158.5, 142.6, 130.9, 130.8, 129.4, 129.0, 128.9, 128.4, 127.6, 127.5, 126.3, 124.2, 115.3, 115.2, 115.1, 69.8 ppm.

(4-Trifluoromethylphenyl)phenylmethanol (4n)^2c. [α]²⁵_D = −26.30 (c 1.09, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.55–7.54 (m, 2H, Ar), 7.44–7.42 (m, 2H, Ar), 7.33–7.21 (m, 9H, Ar), 5.75 (s, 1H, CHO), 2.74 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 147.4, 143.0, 129.4, 128.7, 128.0, 126.61, 126.59, 125.45, 125.39, 125.35, 125.31, 125.28, 122.8, 75.6 ppm.

(2-Nitrophenyl)phenylmethanol (4o)²⁰. [α]²⁵_D = +82.24 (c 1.07, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.90 (dd, J = 8.0 Hz and 1.2 Hz, 1H, Ar), 7.72 (dd, J = 8.0 Hz and 0.8 Hz, 1H, Ar), 7.63–7.59 (m, 1H, Ar), 7.45–7.40 (m, 1H, Ar), 7.36–7.11 (m, 5H, Ar), 6.39 (s, 1H, CHO), 2.85 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 148.2, 141.4, 138.4, 133.4, 129.3, 128.5, 128.4, 128.0, 126.9, 124.6, 71.4 ppm.

(3-Nitrophenyl)phenylmethanol (4p)²¹. [α]²⁵_D = −42.31 (c 1.04, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 8.25–8.24 (m, 1H, Ar), 8.08–8.05 (m, 1H, Ar), 7.68–7.66 (m, 1H, Ar), 7.48–7.43 (m, 1H, Ar), 7.36–7.24 (m, 5H, Ar), 5.86 (s, 1H, CHO), 2.85 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 148.2, 145.7, 142.7, 132.4, 129.3, 128.8, 128.2, 126.6, 122.3, 121.2, 75.2 ppm.

(4-Nitrophenyl)phenylmethanol (4q)^16b. [α]²⁵_D = −57.02 (c 1.14, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 8.13–8.10 (m, 2H, Ar), 7.52–7.50 (m, 2H, Ar), 7.35–7.28 (m, 5H, Ar), 5.85 (d, J = 2.0 Hz 1H, CHO), 2.88 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 150.8, 147.2, 142.8, 128.8, 128.2, 127.0, 126.6, 123.5, 75.3 ppm.

Naphthalen-1-yl-phenylmethanol (4r)^5a. [α]²⁵_D = +38.36 (c 1.06, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.98–7.95 (m, 1H, Ar), 7.83–7.76 (m, 2H, Ar), δ 7.57–7.55 (m, 1H, Ar), δ 7.45–7.19 (m, 8H, Ar), 6.43 (s, 1H, CHO), 2.55 (s, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.1, 138.7, 133.9, 130.6, 128.7, 128.43, 128.39, 127.6, 127.0, 126.1, 125.5, 125.3, 124.5, 123.9, 73.5 ppm.

Naphthalen-2-yl-phenylmethanol (4s)^4b. [α]²⁵_D = −9.90 (c 1.01, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.81–7.71 (m, 4H, Ar), 7.46–7.17 (m, 8H, Ar), 5.87 (s, 1H, CHO), 2.64 (br, 1H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.5, 141.0, 133.1, 132.8, 128.4, 128.2, 128.0, 127.6, 127.5, 126.6, 126.1, 125.9, 124.9, 124.7, 76.2 ppm.

Furan-2-yl-phenylmethanol (4t)^4b. [α]²⁵_D = +6.23 (c 1.07, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.41–7.29 (m, 6H), 6.28 (dd, J = 2.0, 1.6 Hz, 1H), 6.07 (d, J = 1.6, 0.8 Hz), 5.75 (s, 1H), 2.79 (s, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 155.9, 142.4, 140.7, 125.6, 128.3, 127.9, 126.5, 110.1, 107.3, 69.9 ppm.

(E)-1,3-Diphenyl-prop-2-en-1-ol (4u)^4b. [α]²⁵_D = −9.91 (c 0.37, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.48–7.16 (m, 10H), 6.60–6.56 (m, 1H), 6.33–6.27 (m, 1H), 5.26–5.24 (m, 1H), 2.91 (br, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.7, 136.4, 131.5, 130.3, 128.5, 128.4, 127.59, 127.55, 126.5, 126.4, 126.3, 74.8 ppm.

2-Methyl-1-phenyl-propan-1-ol (4v)^4b. [α]²⁵_D = −26.07 (c 1.01, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.34–7.26 (m, 5H, Ph), 4.37–4.35 (m, 5H, CHPh), 1.97–1.95 (m, 1H, CH(CH₃)₂), 1.83 (s, 1H, OH), 1.01–0.99 (m, 3H, CH₃), 0.80–0.78 (m, 3H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.6, 128.2, 127.4, 126.5, 80.0, 77.3, 77.0, 76.7, 35.2, 19.0, 18.2 ppm.

2,2-Dimethyl-1-phenyl-propan-1-ol (4w)^4b. [α]²⁵_D = −17.13 (c 1.07, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.32–7.29 (m, 5H, Ph), 4.40 (d, J = 2.8 Hz, 1H, CHO), 1.87 (d, J = 2.8 Hz, 1H, OH), 0.92 (s, 9H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 142.1, 127.6, 127.5, 127.2, 82.3, 35.6, 25.9 ppm.

Cyclohexyl-phenyl-methanol (4x)^3b. [α]²⁵_D = −20.92 (c 1.02, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.34–7.24 (m, 5H, Ph), 4.33 (d, J = 7.2 Hz, 1H, CHO), 1.96–0.89 (m, 11H, OH and Cy) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 143.6, 128.1, 127.3, 126.6, 79.3, 44.9, 29.2, 28.8, 26.4, 26.0, 25.9 ppm.

(4-Chlorophenyl)(2-methoxyphenyl)methanol (4y). [α]²⁵_D = +44.34 (c 1.06, CH₂Cl₂). ¹H NMR (400 MHz, CDCl3): δ 7.29–7.18 (m, 6H, Ar), 6.93–6.83 (m, 2H, Ar), 5.96 (s, 1H, CHO), 3.75 (s, 3H, OCH₃) ppm. ¹³C NMR (100 MHz, CDCl3): δ 156.4, 141.8, 132.6, 131.4, 128.8, 128.1, 127.8, 127.5, 120.8, 110.7, 71.4, 55.3 ppm.

(4-Methylphenyl)(2-methoxyphenyl)methanol (4z)²². [α]²⁵_D = +40.56 (c 1.20, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.25–7.19 (m, 4H, Ar), 7.10–7.08 (m, 2H, Ar), 6.93–6.82 (m, 2H, Ar), 5.99 (s, 1H, CHO), 3.75 (s, 3H, OCH₃), 3.08 (s, 1H, OH), 2.30 (s, 1H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 156.6, 140.3, 136.6, 132.0, 128.7, 128.5, 127.6, 126.4, 120.6, 110.6, 71.8, 55.3, 21.0 ppm.

Acknowledgements

Financial support under the grant number of NSC 99-2113-M-005-005-MY3 from the National Science Council of Taiwan, Republic of China is appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra14173c

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