Asymmetric Alkynylation of Aldehydes Catalyzed by Bifunctional Zinc(salen) Complex

Chinese Journal of Chemistry, 2009, 27, 413—418 Full Paper

* E-mail: [email protected] Received August 14, 2008; revised and accepted September 25, 2008. Project supported by the Chinese Academy of Sciences, the National Natural Science Foundation of China and the Shanghai Institute of Materia

Medica.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric Alkynylation of Aldehydes Catalyzed by Bifunctional Zinc(salen) Complex

SHEN, Chuna,b(沈淳) CHEN, Leib(陈磊) TANG, Jiea(汤杰) XU, Minghua*,b(徐明华) aDepartment of Chemistry, East China Normal University, 3663 Zhongshan Road, Shanghai 200062, China

bShanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China

The asymmetric alkynylation of aldehydes catalyzed by bifunctional Zn(salen) catalyst was realized. With a Kozlowski salen ligand (7e) bearing secondary basic 1-piperidinylmethyl groups at C-3 and C-3', the enhanced catalytic reactivity and stereoselectivity in comparison with that of normal salen ligands in the alkynylzinc addition to aldehydes were observed.

Keywords asymmetric, alkynylation, bifunctional catalyst, salen

Introduction

The enantioselective addition of organic zinc reagent to prochiral carbonyl compounds is an effective method for the asymmetric carbon-carbon bond construction.1 Among them, the asymmetric addition of alkynylzinc to aldehydes is an important synthetic approach for propargyl alcohols that are versatile building blocks for a wide range of biologically active compounds and pharmaceuticals.1c,d During the past ten years, a variety of chiral ligands including N-methylephedrine,2 BINOL and its derivatives,3 many chiral amino alcohols and their derivatives4 have been developed and successfully employed in the catalytic enantioselective alkynylation.

Recently, the use of bifunctional catalysts in asym-metric reactions has been approved as an attractive strategy.5 The bifunctional catalyst derived from BINOL, developed by Shibasaki,6 is a representative example. These catalysts often have Lewis acid and Lewis base sites that can activate both the electrophile and the nucleophile in a reaction. Notably, the utility of bifunctional Zn(salen) catalysts has been demonstrated in several organozinc involved reactions.7 However, few of them were used in the enantioselective alkynylation.8 In 2003, Cozzi8a for the first time reported that a simple Zn(salen) complex could catalyze the addition of termi-nal alkynes to ketones with moderate to good enantioselectivity (up to 81% ee). The phenoxide oxygen atom in salen ligand was considered to activate the alkynyl-znic nucleophile as a Lewis base. Surprisingly, despite the double activation, the catalyst exhibited a relatively low reactivity (the reactions were generally carried out for 36—96 h). Furthermore, the catalyst was found not effective when more reactive benzaldehyde was exam-

ined as substrate. In this case, the Lewis acid is directly coordinated to the Lewis base moiety and the two groups may alter interdependently (Figure 1 A). We therefore envisioned if Kozlowski-type bifunctional salen catalysts containing a separate basic functional group such as piperidine would provide better reactivity and selectivity in the reaction (Figure 1 B). In this sys-tem, the zinc at the salen center could act as a Lewis acid to activate the aldehyde while the tethered base could activate the alkynylzinc nucleophile independ-

Figure 1 Bifunctional salen catalysis.

414 Chin. J. Chem., 2009, Vol. 27, No. 2 SHEN et al.


ently. To our knowledge, the use of this type of bifunc-tional salen catalysts for asymmetric alkynylation of aldehydes has not been extensively explored. Herein, we wish to report our studies on bifunctional Zn(salen)- catalyzed asymmetric alkynylation of aldehydes. When a Kozlowski salen ligand bearing two secondary basic 1-piperidinylmethyl groups at C-3 and C-3' was used, dual activation of the electrophile and nucleophile as proposed in B (Figure 1) was found.

Results and discussion

To understand how different zinc(salen) complexes catalyze the asymmetric alkynylzinc addition to alde-hydes, we considered to test a series of chiral salen ligands with different diamine linkers and C-3,3' substi-tutions. Using the approach of SmI2-mediated highly stereoselective homo-coupling of N-tert-butanesulfinyl- imines we developed,9 enantiomerically pure C2 sym-metrical vicinal diamines 5 and 6 were readily obtained (Scheme 1). Condensation of the corresponding sali-cyaldehydes with (S,S)-cyclohexanediamine and (S,S)- diarylethylenediamine (DPEN, 5 and 6), respectively, gave a set of chiral salen ligands 7a—7g (Figure 2). The diamine linkers were expected to adjust the stereo-chemical conformation of ligands while coordinating to zinc. In salens 7e—7g, two secondary basic piperidine or morpholine groups were assembled at C-3,3' posi-tions.

Scheme 1 Synthesis of C2-symmetrical vicinal diamines

With salen ligands 7a—7g in hand, we investigated their efficiency as chiral zinc catalyst in the addition of phenylacetylene to benzaldehyde. Although Jacobsen’s salen 7a could catalyze the reaction of acetophenone to give a moderate enantioselectivity (62% ee) after 96 h,8a only 39% ee was observed, as reported by Pu,8b in the alkynylation of benzaldehyde. In the initial study, we also examined the use of this ligand under the similar condition with ZnMe2 in toluene. In our hands, the reac-tion went to completion in 12 h in the presence of 20

Figure 2 C2-symmetrical chiral salen ligands.

mol% of 7a giving 43% ee (Table 1, Entry 1). When other salen ligands bearing (S,S)-diarylethylenediamine units (7b—7d) were employed, disappointingly, all di-minished enantioselectivities were observed (Entries 4—6). With two electron-donating methoxy groups on phenyl rings, a slightly better ee of 29% was found (En-try 6 vs. Entries 4—5). Interestingly, when 10 mol% of N-methylmorpholine (NMM) was used as a Lewis base additive in combination with 7a, the reaction afforded the addition product in low ee but with opposite stereo-selectivity (Entry 3). This result suggests that introduc-tion of a proper Lewis base may possibly tune the reac-tion stereoselectivity. We next evaluated bifunctional ligands 7e—7g in the reaction. To our delight, the reac-tions all proceeded smoothly with rapid rates and very

Asymmetric alkynylation Chin. J. Chem., 2009 Vol. 27 No. 2 415


high yields (96%—99%) in 3—4 h (Entries 7—11). Both piperidine and morpholine salen 7e and 7f showed an enhanced enantioselectivity of 54% (Entries 7 and 9). In addition, an opposite stereocontrol of the reaction was also observed. In contrast to the results obtained with salens 7a—7d lacking secondary Lewis bases, these observations indicated much higher catalyst ac-tivities as well as selectivities of bifunctional zinc(salen) (7e/7f), suggesting that the expected dual activation of the benzaldehyde electrophile and phenylethynylzinc nucleophile as depicted in B (Figure 1) might be in-volved. Notably, unlike in the case of 7a (Entries 1—2), a decrease of catalyst loading of bifunctional 7e/7f to 10 mol% did not influence the reaction enantioselectivity significantly (Entries 7—8 and 9—10).

Table 1 Asymmetric addition of phenylacetylene to benalde-hyde catalyzed by salen ligandsa

Entry Ligand Time/h Yield b/% eec,d/%

1 (S,S)-7a 12 82 43 (S)

2e (S,S)-7a 14 72 15 (S)

3e,f (S,S)-7a 10 84 6 (R)

4 (S,S)-7b 10 79 25 (R)

5 (S,S)-7c 10 84 25 (R)

6 (S,S)-7d 10 84 29 (R)

7 (S,S)-7e 3 99 54 (R)

8e (S,S)-7e 4 99 52 (R)

9 (S,S)-7f 3 94 54 (R)

10e (S,S)-7f 4 96 49 (R)

11 (S,S)-7g 3 99 47 (R) a The reaction was carried out with the molar ratio of benzalde-hyde/phenylacetylene/Me2Zn/ligand＝1∶3∶3∶0.2 at room temperature in toluene, unless otherwise noted. b Isolated yield. c Determined by HPLC on a Chiralcel OD-H column. d The ab-solute configuration of the major product was determined by comparison with the sign of the reported optical rotation value. e 10 mol% of the ligand was used. f 10 mol% of NMM was used as additive.

Further investigations into the optimization of the reaction conditions, such as reaction temperature, sol-vent and so on for the asymmetric alkynylation of ben-zaldehyde with salen 7e as catalyst are listed in Table 2. In toluene, when the reaction temperature was lowered from room temperature to －40 ℃, the ee values in-

creased obviously (Entries 1—6). A better enantioselec-tivity of 79% was obtained at －40 ℃ (Entry 6). However, a substantial loss of catalytic activity was also observed and a largely reduced yield was provided (55%, Entry 6). The solvent also seems to affect the reaction significantly. With CH2Cl2 at －10 ℃, a rela-tively good enantioselectivity (72%) as well as a high yield (96%) was afforded (Entry 7). When the reaction temperature was further decreased, a slightly increased enantioselectivity was observed (Entries 8—10). At －40 ℃, though the ee was improved to the best of 82%, the reaction proceeded very slowly and gave only 75% yield after 48 h (Entry 10). The low reactivities conducted in THF and tBuOMe are probably due to the coordination of the solvent to zinc atom (Entries 11 and 13). Furthermore, attempts to improve the reaction se-lectivity with the addition of Ti(OPr-i)4 and Et2AlCl were unsuccessful (Entries 14—15). We also examined the use of Et2Zn instead of Me2Zn, and surprisingly, a dramatic drop of ee was observed (Entry 4 vs. 16), in-dicating that the use of Me2Zn in this alkynylation is essential.

Table 2 Asymmetric addition of phenylacetylene to benzalde-hyde catalyzed by salen 7ea

Entry Solvent T/℃ Time/h Yieldb/% eec/%

1d toluene r.t. 4 99 52

2d toluene 0 4 99 61

3 toluene 0 4 94 59

4 toluene －10 5 96 65

5e toluene －10 5 99 60

6 toluene －40 24 55 79

7 CH2Cl2 －10 3 96 72

8 CH2Cl2 －20 18 82 77

9 CH2Cl2 －30 24 75 79

10 CH2Cl2 －40 48 75 82

11 THF －10 21 36 72

12 hexane －10 6 99 54

13 tBuOMe －10 9 38 62

14f toluene －10 4 98 63

15g toluene －10 7 60 －19

16h toluene －10 5 91 44 a The molar ratio: benzaldehyde/phenylacetylene/Me2Zn/ligand＝1∶2∶2∶0.1. b Isolated yield. c Determined by HPLC on a Dai-cel OD-H column. d 3.0 equiv. phenylacetylene and 3.0 equiv. Me2Zn were added. e 20 mol% of the ligand was used. f 10 mol% of Ti(OPr-i)4 was added. g 10 mol% of Et2AlCl was added. h Et2Zn was used instead of Me2Zn.

Utilizing the reaction conditions optimized in Entry 7 of Table 2, we evaluated the use of piperidine salen 7e in asymmetric alkynylation of phenylacetylene to a va-riety of aldehydes. The results are summarized in Table 3. In most cases, the reactions proceeded smoothly and completed in 6 h in CH2Cl2 at －10 ℃ to give the



corresponding propargylic alcohols in good yields with moderate enantioselectivities (53%—80%). A slightly decreased ee was observed when ortho-substituted benzaldehyde substrate was employed (Entries 9—10). With 2-naphthaldehyde, the best ee of 80% was ob-tained (Entry 11). For aliphatic substrate isobutyralde-hyde, the reaction provided an enantioselectivity of 59% (Entry 12).

Table 3 Asymmetric addition of phenylacetylene to aldehydes catalyzed by salen 7e

Entry R Time/h Yielda/% eeb/%

1 Ph 3 96 72

2 4-FC6H4 6 71 56

3 4-ClC6H4 6 70 67

4 4-BrC6H4 6 75 66

5 4-MeC6H4 6 79 73

6 4-MeOC6H4 6 76 69

7 3-MeC6H4 6 79 69

8 3-NO2C6H4 6 93 66

9 2-ClC6H4 6 62 53

10 2-MeC6H4 6 76 61

11 2-Naphthyl 6 85 80

12 i-Pr 6 80 59 a Isolated yield. b Determined by HPLC on a Daicel OD-H or AD-H column.

Conclusion

In summary, we have studied the bifunctional Zn(salen)-catalyzed asymmetric alkynylation of alde-hydes. With a Kozlowski salen ligand (7e) bearing two secondary basic 1-piperidinylmethyl groups at C-3 and C-3', dual activation of the electrophile and nucleophile was found as mechanistically proposed. Compared to the results of using simple Jacobsen’s salen 7a, a much improved catalytic activity as well as stereoselectivity was observed. These findings provide a new example of bifunctional catalysts in asymmetric reaction, which should be useful for further development of related catalyst.

Experimental

General data

All the reactions were carried out under nitrogen. The solvents were dried before use according to estab-lished procedures. Reactions were monitored by thin layer chromatography (TLC). Column chromatography purifications were carried out using silica gel. All alde-hydes were purified before use. Me2Zn and Et2Zn were purchased from Acros. NMR spectra were obtained us-

ing a Varian-300 MHz spectrometer. Chiral HPLC was carried out with a JACSO PU-2080 instrument using a Daicel OD-H column or AD-H column and hexane/ i-PrOH as eluant.

Vicinal diamines 5, 6,9 salen ligands 7a,10 7b11 and 7e,7a and 7f7a were synthesized according to the litera-ture procedures.

General procedure for the synthesis of salens 7a—7d

To a solution of vicinal diamine hydrochloride (1 mmol) in 10 mL of EtOH and 1 mL of H2O was added K2CO3 (2 mmol), and the mixture was stirred at room temperature for 1 h. Then the mixture was heated to reflux, and the solution of 3,5-di-tert-butyl-2-hydroxy- benzaldehyde (2 mmol) in 5 mL of EtOH was slowly added. The yellow slurry was stirred at reflux for 3 h, and then cooled to 0 . The solid was collected by va℃ c-uum filtration and washed with ethanol. The crude product was re-dissolved in CH2Cl2, washed with brine, and dried over Na2SO4. After removing the solvent, the salen product was obtained as a yellow solid.

(S,S)-7c: 95% yield. 20D[ ]α 11.2 (c 0.89, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 13.36 (s, 2H), 8.38 (s, 2H), 7.33 (d, J＝2.4 Hz, 2H), 7.20 (d, J＝8.4 Hz, 4H), 7.08 (d, J＝8.7 Hz, 4H), 6.98 (d, J＝2.4 Hz, 2H), 4.65 (s, 2H), 1.42 (s, 18H), 1.23 (s, 18H); 13C NMR (100 MHz, CDCl3) δ: 29.43, 31.39, 34.05, 35.07, 79.35, 117.69, 126.43, 127.51, 128.61, 129.28, 133.41, 136.53, 138.00, 140.29, 157.90, 167.72; ESI-MS m/z (%): 713 (M＋

＋1, 100).

(S,S)-7d: 90% yield. 20D[ ]α 11.8 (c 1.15, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 13.62 (s, 2H), 8.37 (s, 2H), 7.26 (d, J＝2.4 Hz, 2H), 7.08 (d, J＝8.7 Hz, 4H), 6.97 (d, J＝2.4 Hz, 2H), 6.74 (d, J＝8.7 Hz, 2H), 4.65 (s, 2H), 3.75 (s, 6H), 1.42 (s, 18H), 1.21 (s, 18H); 13C NMR (100 MHz, CDCl3) δ: 29.45, 31.42, 34.03, 34.98, 55.18, 79.46, 113.67, 117.91, 126.27, 127.01, 129.06, 132.13, 136.34, 139.94, 157.97,158.73, 166.85; ESI-MS m/z (%): 705 (M＋

＋1, 100).

Synthesis of salen ligand (S,S)-7g

5-tert-Butyl-2-hydroxy-3-(morpholinomethyl)benzaldehyde (2.0 equiv.) was dissolved in EtOH and diamine (1.0 equiv) was added. The mixture was stirred for 1 d at r.t., then concentrated. The salen product 7g was ob-tained as a yellow solid without further purification (97% yield). 20

D[ ]α 35.0 (c 1.50, CHCl3); 1H NMR (300

MHz, CDCl3) δ: 13.33 (s, 2H), 8.36 (s, 2H), 7.36 (d, J＝2.4 Hz, 2H), 7.05—7.07 (m, 6H,), 6.72—6.75 (m, 4H), 4.64 (s, 2H), 3.79—3.53 (m, 18H), 2.46 (br s, 8H), 1.18 (s, 18H); 13C NMR (100 MHz, CDCl3) δ: 31.38, 33.87, 53.67, 55.19, 56.52, 67.04, 79.65, 113.72, 117.89, 123.99, 127.16, 128.98, 130.92, 131.92, 140.75, 157.08, 158.78, 166.11; ESI-MS m/z (%): 791 (M＋

＋1, 55), 396 (100).

Typical procedure for the addition of phenylacetylene to aldehydes

To a solution of phenylacetylene (44 µL, 0.4 mmol)

Asymmetric alkynylation Chin. J. Chem., 2009 Vol. 27 No. 2 417


in dry CH2Cl2 (1 mL) in a nitrogen atmosphere at room temperature was added a solution of Me2Zn (0.33 mL, 0.4 mmol) in toluene (1.2 mol•L－1). The mixture was stirred for 1 h, then the ligand (13 mg, 10 mol%) was added, after a further 1 h, the mixture was cooled to －10 , then t℃ he aldehyde (0.2 mmol) was added. The reaction was monitored by TLC and quenched by satu-rated NH4Cl solution. The mixture was extracted with EtOAc, and the organic layer was washed by brine, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by column chromatog-raphy. The ee value was determined by HPLC on a Daicel OD-H or AD-H column.

(R)-1,3-Diphenylprop-2-yn-1ol: 96% yield, 72% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/ V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝

8.6 min, tminor＝11.3 min]; 1H NMR (300 MHz, CDCl3) δ: 2.49 (d, J＝5.7 Hz, 1H), 5.70 (d, J＝5.7 Hz, 1H), 7.31—7.65 (m, 10H).

(R)-1-(4-Fluorephenyl)-3-phenylprop-2-yn-1-ol: 71% yield, 56% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/V(i-propanol)＝90∶10, 0.7 mL/min, 254 nm, tmajor＝13.3 min, tminor＝33.4 min]; 1H NMR (300 MHz, CDCl3) δ: 2.54 (s, 1H), 5.68 (s, 1H), 7.06—7.62 (m, 9H).

(R)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol: 70% yield, 67% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝7.5 min, tminor＝15.5 min]; 1H NMR (300 MHz, CDCl3) δ: 2.35 (d, J＝5.7 Hz, 1H), 5.66 (d, J＝5.7 Hz, 1H), 7.33—7.57 (m, 9H).

(R)-1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol: 75% yield, 66% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝7.2 min, tminor＝14.5 min]; 1H NMR (300 MHz, CDCl3) δ: 2.30 (d, J＝6.0 Hz, 1H), 5.65 (d, J＝6.0 Hz, 1H), 7.26—7.55 (m, 9H).

(R)-1-(4-Tolyl)-3-phenylprop-2-yn-1-ol: 79% yield, 73% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/ V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝

7.3 min, tminor＝10.9 min]; 1H NMR (300 MHz, CDCl3) δ: 2.24 (d, J＝6.0 Hz, 1H), 2.38 (s, 3H), 5.65 (d, J＝6.0 Hz, 1H), 7.21—7.53 (m, 9H).

(R)-1-(4-Anisyl)-3-phenylprop-2-yn-1-ol: 76% yield, 69% ee [HPLC, Daicel Chiralpak AD-H, V(n-hexane)/V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝11.7 min, tminor＝10.9 min]; 1H NMR (300 MHz, CDCl3) δ: 2.25 (d, J＝5.7 Hz, 2H), 3.82 (s, 3H), 5.64 (d, J＝5.7 Hz, 1H), 6.92 (d, J＝8.7 Hz, 2H), 7.30—7.56 (m, 7H).

(R)-1-(3-Tolyl)-3-phenylprop-2-yn-1-ol: 79% yield, 69% ee [HPLC, Daicel Chiralpak AD-H, V(n-hexane)/ V(i-propanol)＝90∶10, 0.7 mL/min, 254 nm, tmajor＝

15.9 min, tminor＝14.9 min]; 1H NMR (300 MHz, CDCl3) δ: 2.40 (s, 4H), 5.67 (s, 1H), 7.19—7.51 (m, 9H).

(R)-1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-ol: 93% yield, 66% ee [HPLC, Daicel Chiralpak AD-H, V(n-hexane)/V(i-propanol)＝90∶10, 0.7 mL/min, 254

nm, tmajor＝21.3 min, tminor＝22.6 min]; 1H NMR (300 MHz, CDCl3) δ: 2.64 (s, 1H), 5.80 (s, 1H), 7.26—8.50 (m, 9H).

(R)-1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol: 62% yield, 53% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/V(i-propanol)＝90∶10, 0.5 mL/min, 254 nm, tmajor＝19.9 min, tminor＝21.7 min]; 1H NMR (300 MHz, CDCl3) δ: 2.60 (s, 1H), 6.05 (s, 1H), 7.26—7.86 (m, 9H).

(R)-1-(2-Tolyl)-3-phenylprop-2-yn-1-ol: 76% yield, 61% ee [HPLC, Daicel Chiralpakcel OD-H, V(n-hexane)/V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝7.3 min, tminor＝10.9 min]; 1H NMR (300 MHz, CDCl3) δ: 2.26 (d, J＝5.7 Hz, 1H), 2.51 (s, 3H), 5.84 (d, J＝5.7 Hz, 1H), 7.21—7.74 (m, 9H).

(R)-2-(Napth-1-yl)-3-phenylprop-2-yn-1-ol: 85% yield, 80% ee [HPLC, Daicel Chiralpak AD-H, V(n-hexane)/V(i-propanol)＝70∶30, 0.7 mL/min, 254 nm, tmajor＝15.2 min, tminor＝12.4 min]; 1H NMR (300 MHz, CDCl3) δ: 2.37 (d, J＝6.3 Hz, 1H), 5.86 (d, J＝6.0 Hz, 1H), 7.26—8.03 (m, 12H).

(R)-4-Methyl-1-phenylpent-1-yn-3-ol: 80% yield, 59% ee [HPLC, Daicel Chiralcel OD-H, V(n-hexane)/ V(i-propanol)＝95∶5, 0.7 mL/min, 254 nm, tmajor＝

11.3 min, tminor＝24.9 min]; 1H NMR (300 MHz, CDCl3) δ: 1.07 (t, J＝6.9 Hz, 6H), 1.95—2.01 (m, 1H), 4.39 (d, J＝5.4 Hz, 1H), 7.30—7.46 (m, 5H).

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Asymmetric Alkynylation of Aldehydes Catalyzed by Bifunctional Zinc(salen) Complex