Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction

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Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions Shanshan Liu, Wen-Chao Gao, Yu-Hang Miao, and Min-Can Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02943 • Publication Date (Web): 01 Feb 2019 Downloaded from http://pubs.acs.org on February 6, 2019

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The Journal of Organic Chemistry

Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions

Shanshan Liu,† Wen-Chao Gao,‡,§ Yu-Hang Miao,§ and Min-Can Wang*,§

†

Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical

Engineering, Shaanxi University of Science and Technology, 6 Xuefu Road, Weiyang District, Xi’an, Shaanxi 710021, P. R. China ‡

College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, 1638 Wolong Road,

Nanyang, Henan 473061, P. R. China §

The College of Chemistry and Molecular Engineering, Zhengzhou University, No. 75 Daxue Road,

Zhengzhou, Henan 450052, P. R. China E-mail: [email protected]

Abstract:

N Ar

Boc

L* (5 mol%) Et2Zn (10 mol%) 4Å MS

HN

Boc

R Ar THF NO2 rt 12–24 h • up to 97% yield, 99% ee, 14:1 dr • Asymmetric aza-Henry reaction • AzePhenol dinuclear zinc catalytic system + R

NO2

Ph Ph

OH N

HO OH

Ph Ph

N

Me L*

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol% dinuclear zinc-azePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to

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97%)

with

excellent

enantioselectivities

(up

to

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99%

ee)

and

high

diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

Keywords: dinuclear zinc catalyst, aza-Henry reaction, nitroalkane, imine, asymmetric catalysis

Introduction The asymmetric aza-Henry reaction between imines and carbonyl compounds has emerged as one of the most important strategies for the preparation of nitrogen-containing molecules. The resulting chiral β-nitroamines can be easily converted into highly valuable compounds, such as α-amino acids1 and vicinal diamines.2 Tremendous efforts have been devoted to the development of efficient catalytic version of the reactions with metal catalysts3–13 or organocatalysts.14–20 Since Shibasaki reported the first asymmetric aza-Henry reaction using a heterobimetallic Yb-K-binaphthol complex as catalyst,3 co-operative bi- or multi-metallic catalysis have been developed for this transformation.3,6,7,10,11 Qian and co-workers have accomplished an aza-Henry reaction between nitromethane and N-tosyl imine, modest yield and enantioselectivity was obtained in the presence of 30 mol% dinuclear zinc catalyst.6 Afterwards, the dinuclear zinc-ProPhenol catalyst has also been used by Trost in catalytic asymmetric aza-Henry reactions.7 Despite the modest diasteroselectivity and yields, the remarkable results in terms of enantioselectivity was obtained based on 15 mol% catalyst loading. To date, however, the high degrees of stereocontrol, high reactivity and low catalyst loading in this strategy is not being satisfactorily solved.


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Apart from these issues, the reaction is normally carried out at low temperature10,11 because the N-protected imines are unstable,20 resulting in a considerable limitation to the generality of their applications. To the best of our knowledge, there is no asymmetric multinuclear metal catalyzed aza-Henry reaction performed under mild conditions with high level of selectivity and catalytic efficiency. It is highly desirable to develop an efficient asymmetric catalytic system and convenient protocol for this transformation. In recent years, our group has explored an dinuclear zinc-AzePhenol catalyst and it has showed efficiency in a number of catalytic enantioselective transformations including asymmetric domino Michael/hemiketalization reaction,21 Friedel–Crafts alkylation,22 methylation,23 alkynylation,23 co-polymerization,24 enantioselective phospha-Michael addition,25 as well as asymmetric 1,6-conjugate addition of para-quinone methides.26 We envisage that the dual Lewis acid/Lewis base functionality should facilitate both formation of the nitronate anion and activation of the imine, and it is possible that the azetidine ring skeleton provides the appropriate sterically hindered microenvironment to promote the stereoselectivity of the aza-Henry reaction. Herein, we report a successful realization of the highly diastereo- and enantioselective nitroalkanes additions to N-Boc imines catalyzed by dinuclear zinc-AzePhenol under ambient conditions.

Results and Discussion Table 1. Optimization of Reaction Conditionsa



N

+

MeNO2

Ph 1a

Ph Ph

L/Et2Zn 4Å MS solvent T

Boc

2a

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HN

Boc

OH

HO OH

N

Ph Ph

N

NO2

Ph 3aa

Me L

Ligand Entry

4Å 1a:2a

(mol%)

Temperature Solvent

Yield (%)b

Ee (%)c

(oC)

MS (mg)

1

10

1:2

25

THF

RT

41

99

2

10

1:2

25

DCM

RT

40

99

3

10

1:2

25

toluene

RT

31

99

4

10

1:2

25

CH3CN

RT

40

77

5

10

1:2

25

THF

0

40

99

6

10

1:2

25

THF

30

28

99

7

10

1:2

0

THF

RT

22

99

8

10

1:2

50

THF

RT

67

99

9

10

1:2

75

THF

RT

50

99

10

10

1:5

50

THF

RT

70

99

11

10

1:10

50

THF

RT

73

97

12

30

1:5

50

THF

RT

57

99

13

5

1:5

50

THF

RT

75

99

14

2.5

1:5

50

THF

RT

50

94

a. Unless otherwise noted, all reactions were processed under argon in corresponding solvent at indicated temperature. b. Isolated yield. c. The ee values were determined by


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HPLC analysis (refer to the supporting information for detail). The absolute configurations were assigned by comparison to literature values.

Initially, the reaction between N-Boc imine 1a and nitromethane (2a) was selected as the model reaction, in which only one stereogenic center was formed, and the representative results are summarized in Table 1. The Boc-protected imines were used as desirable substrates due to its sufficient reactivity resulting from the electron withdrawing carbonyl groups and its possibility of multi-point binding. A survey of the solvents showed that THF was the choice of solvent to provide the product in high enantiomeric excess (Table 1, entries 1–4). The reaction in acetonitrile led to a diminishment of the asymmetric induction compared to that in THF (Table 1, entries 4 vs 1). The observed yield reduction in toluene might attribute to the low solubility of CH3NO2 (Table 1, entry 3). In general, low reaction temperature was beneficial for this reaction because the N-Boc imine was unstable and the products of aza-Henry reaction were prone to retroaddition.27 To our delight, the reaction could be performed at room temperature under our catalytic system without detriment to yield and ee, which showed the convenience of this approach (Table 1, entry 1). Interestingly, the yield was not increased when the temperature was further decreased to 0 oC (Table 1, entry 5). Additional efforts were made to enhance the catalytic activities, it was found that the 4Å molecular sieves had an important influence on the reactivity. More desired product was generated with the addition of 4Å molecular sieves (Table 1, entries 1 vs 7). A remarkably improvement of the chemical yield was observed with an increase in the amount of 4Å molecular sieves, the product was obtained in 67% yield and 99% ee in the presence of 50 mg 4Å molecular sieves (Table 1, entry 8). Nitromethane was normally used in excess because of its volatility, however, the more excess nitromethane would bind to the catalyst and result in inhibiting the



coordination of the imine, thus the loading of nitromethane was carefully examined. However, the comparable reactivity and enantioselectivity were obtained with the variation of the substrate loading (Table 1, entries 8, 10 and 11). In the end, 5 equivalences of nitromethane were identified as the optimal loading to afford the product in 70% yield and 99% ee (Table 1, entry 10). With these insights into the reaction conditions, we further explored the ligand loading. To our delight, an enhancement in yield was observed with reducing of ligand loading from 30 mol% to 5 mol%. 75% yield and 99% ee was achieved in the presence of 5 mol% chiral ligand (Table 1, entries 12 vs 13). Much better results in terms of reactivity and enantioselectivity were observed compared to that in the same reaction reported by using 30 mol% similar Trost catalyst,7 which suggested the efficiency of our catalyst system. Therefore, the optimal conditions revealed by variations in the conditions for the reaction are indicated in entry 13 of table 1.

Scheme 1. Variation of the Aromatic Imines and Nitroalkanes for Asymmetric Aza-Henry Reaction Catalyzed by the Dinuclear Zinc-AzePhenola


Page 6 of 26

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N

Boc + R

NO2

L (5 mol%) Et2Zn (10 mol%) 4Å MS (50 mg)

2a–2c (5.0 equiv.)

HN

Boc

HN

3aa–3ma, 3ab–3ac HN

NO2

Me

HN Cl

HN

Boc NO2

NO2 Cl 3ga (from 1g) yield (%): 60 ee (%): 90 Boc HN NO2

Me

F 3ha (from 1h) yield (%): 54 ee (%): 95 Boc HN NO2 OMe

Me 3ja (from 1j)b yield (%): 87 ee (%): 99 HN

Boc NO2

X X=O 3ma (from 1m yield (%): 85 ee (%): 93 X=S 3na (from 1n) yield (%): 72 ee (%): 92

Cl 3fa (from 1f)b yield (%): 35 ee (%): 93 Boc HN NO2

3ea (from 1e) yield (%): 96 ee (%): 87

Boc

NO2

3ca (from 1c) yield (%): 97 ee (%): 94 Boc HN NO2

MeO 3da (from 1d) yield (%): 78 ee (%): 96

Boc

Me

Me 3ba (from 1b) yield (%): 88 ee (%): 89 Boc HN NO2

3aa (from 1a) yield (%): 75 ee (%): 99 Boc HN NO2

R NO2

Boc

NO2

Boc

Ar

THF rt 14 h

Ar 1a–1m

HN

OMe 3ka (from 1k) yield (%): 80 ee (%): 94 HN

3ia (from 1i) yield (%): 61 ee (%): 89 HN

Boc NO2

O O

Boc

3la (from 1l) yield (%): 71 ee (%): 93 HN

Boc

Me NO2 3ab (from 1a) yield (%): 94 ee (%): 94 dr: 14:1

Me NO2 3ac (from 1a)b yield (%): 90 ee (%): 84 dr: 13:1

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a. Unless otherwise noted, all reactions were processed under argon in THF at room temperature for 14 h, isolated yield reported. The ee and dr values were determined by HPLC analysis (seeing the supporting information for detail). The absolute configurations were assigned by comparison to literature values. In all cases, the product chromatograms were compared against a known racemic mixture. The absolute configuration of 3aa was assigned by comparison of optical rotation and chiral HPLC traces with the literature.7 The other products were tentatively assigned by analogy. b. Reactions conducted for 24 h.

A variety of substituted N-Boc imines and nitroalkanes were examined under the optimized

reaction

conditions

(Scheme

1).

Both

aromatic

and

heteroaryl-substituted N-Boc imines reacted with nitromethane to provide β-nitroamines with high enantioselectivity (87–99% ee) and variable degrees of reactivity (35–97% yield). Electronically diverse aromatic N-Boc imines displayed excellent enantiomeric excesses. In addition, the imines with substituents on the different positions of the aryl ring showed generally similar level of the enantioselectivity (3ba–3da, 3fa–3ha). However, 2,3-dimethoxyl substituted N-Boc imine gave an improvement in enantiomeric excess compare to the 4-methoxyl substituent on imine (3ja). We assume the better enantioselectivity was probably due to the synergistic binding of the imine group and the ortho methoxyl group to the zinc center, which would stabilize the transition state of the asymmetric induction, while the 4-methoxyl group had a competitive binding effect with imine group to the metal center. As noted, the electronic nature of the substituents on the aryls had an effect on the reactivity of the products. The electron rich methyl (1b → 3ba) and methoxy (1e → 3ea) substituents provided the desired products in good chemical yields, while a diminished yield was obtained when a more electron poor chloride (1h → 3ha) or fluoride (1i → 3ia) substituent was employed instead. Only 35% yield was observed when chloride group was installed on the ortho position, which might be due to the steric effect


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(1f → 3fa). We were pleased to find that the imines bearing furyl and thienyl substituents, respectively, delivered the desired products with high yields and enantiomeric excess probably due to their less steric hindrance (3ma–3na). On the other hand, the furyl or thienyl group on the ortho position had the same synergistic chelation effect with imine group. Unfortunately, the steric bulky 2-naphthyl-derived Boc-protected imine gave a trace amount of products mixture and the pure compound could not be isolated. In addition, when ketimine derived from acetophenone was used, only starting material was recovered after the reaction. Gratifyingly, the aza-Henry reaction of phenyl imines with nitroethane or nitropropane was highly enantioselective, most notably, the corresponding anti products were afforded with excellent diastereoselectivity (14:1 and 13:1 dr of each substrate). Moreover, the chemical yields for the high order nitroalkane were impressive, although they are less acidic than nitromethane and thus not easy to deprotonate to form nitronate anion.

Scheme 2. Proposed Catalytic Cycle of the Aza-Henry Reaction



Ph Ph

OH N

HO OH

Ph Ph

N

Ph Ph

Et2Zn

O

O Et Zn Zn O

N

Page 10 of 26

Ph Ph

N

ethane Me L

Me A R

NO2

ethane O

HN

Boc R

Ph

Ph Ph

O N

NO2

R O Ph Ph

N

R

N O O Zn Zn O

Ph Ph

N

Me B

tBuO Ph H

NO2 OO N O R Ph O Zn Zn Ph N

O

Ph

Ph Ph

N

N

OtBu O PhN O N O O O Zn Zn N

Me E

tBuO Ph H

Ph Ph

NO2 O N O O R Ph Zn Zn Ph N

O

Boc

O

R

Ph Ph

N

Me C

N

Me D

In the present reaction, diethylzinc in combination with chiral ligands with a ratio of


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2:1 were essential to good enantioselectivity. According to these experimental results and previous studies,7,22a,28 we suspected that complex A would be the active species, and a possible catalytic cycle that would explain the asymmetric induction of the products was proposed (Scheme 2). The initial step of this cycle involves deprotonation of nitromethane by catalyst A to give the zinc nitronate intermediate B. Subsequently, the coordination of an imine to the zinc atoms from the most sterically accessible site leads to the formation of complexes C followed by the attack of nitronate to give intermediate D, which accounts for the diastereoand enantioselectivity of the reaction. Then the association of nitromethane generates complex E. The catalytic cycle is regenerated by a proton transfer with the nitroalkane (2a) to release the product (Scheme 2).

Conclusion In conclusion, we have described a new and convenient protocol for the asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes at room temperature. The catalysis appears highly attractive considering the mild conditions and the operational simplicity. Our catalytic system is proved to be efficient as well to provide the corresponding products in good chemical yields, and notably, with high diastereo- and enantioselectivity. From a synthetic point of view, this methodology provides a direct and efficient route for the asymmetric synthesis of substituted 1,2-diamines precursors.

Experimental Section General Remarks. All reactions were performed in flame-dried glassware using conventional Schlenk techniques under a static pressure of argon. All starting materials, ligands, and racemic products were prepared according to known procedures. Liquids



Page 12 of 26

and solutions were transferred with (micro)syringes. Solvents were purified and dried following standard procedures. Ligand L was synthesized according to literature procedures respectively.22a Diethylzinc was prepared from EtI with Zn and then diluted with toluene to 1.0 mol/L. Nitroalkanes 2a–2c were purchased from J&K Chemical and used directly without further purification. N-Boc imines 1a–1j, 1l–1n are known compounds which were synthesized according to literature procedures.29 N-Boc imine 1k is a new compound. All the racemic β-nitroamines were obtained according to known procedure.30 Technical grade solvents for extraction and chromatography were distilled prior

to

use.

Analytical

thin-layer

chromatography

(TLC)

and

Flash

column

chromatography were performed on silica gel using the indicated solvents. Infrared (IR) spectra were recorded on a Nicolet IR 200 spectrophotometer in KBr pellets and are reported (br = broad, vw = very weak, w = weak, m = medium, s = strong) in wavenumbers (cm–1). 1H and

13C{1H}

NMR spectra were recorded in CDCl3 on Bruker

DPX 400 (400 MHz). Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to the residual solvent resonance as the internal standard (δ = 7.26 ppm for 1H and δ = 77.16 ppm for 13C{1H}). Data are reported as follows: chemical shift, multiplicity (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz) and integration. Optical rotations were recorded on a Perkin-Elmer 341 polarimeter. Mass spectra were recorded on VG-FAB mass spectrometer. The ee value determination was carried out using chiral HPLC on a Chiralcel AD, AS, IA, IC, IE, OD-H, or OJ Column (for all the columns: 4.6 mmφ × 250 mm, Daicel Chemical Ind., LTD, Japan) combined with a JASCO model PU-1580 intelligent HPLC pump and a JASCO model UV-1575 intelligent UV-vis detector (216nm).

Preparation and characterisation of imine starting material 1k: A 50 mL round-bottomed flask equipped with a magnetic stir bar was charged with


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2,3-dimethoxybenzyl aldehyde (3 mmol, 1 equiv), carbamate (3 mmol, 1 equiv), and THF (1 mL). To this solution of H2O (3 mL) and benzene sulfinic acid-sodium salt (3.0 mmol, 1 equiv) were added. After stirring, formic acid (90% in H2O) was then added (15 mmol, 5.0 equiv). The reaction was stirred at room temperature for 48 hours then diluted with CH2Cl2 and water. The organic layer was separated. Then K2CO3 (48 mL, 1.4 M solution in H2O) was added, the resulting biphasic mixture was vigorously stirred in CH2Cl2 (48 mL) at RT for 5 h. The organic layer was decanted and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was stirred as a suspension in 20% Et2O/hexanes for 1 hour. Filtration with 20% Et2O/hexanes provided analytically pure 1k (636 mg, 81%) as a yellow viscous liquid. Analytical data for compound 1k: 1H NMR (400 MHz, Chloroform-d) δ = 9.15 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.98 (s, 2H), 3.83 (d, J = 1.8 Hz, 3H), 3.77 (d, J = 2.2 Hz, 3H), 1.49 (s, 9H) ppm;

13C{1H}

NMR (100

MHz, CDCl3) δ = 165.4, 162.9, 152.6, 151.5, 127.5, 124.0, 119.0, 117.0, 81.9, 61.9, 55.7, 27.8 ppm; HR-MS (ESI-TOF): [M+Na]+ Calcd. for C14H19NO4Na 288.1206; Found 288.1209; [M+H]+ Calcd. for C14H20NO4 266.1387; Found 266.1385. General Procedure for the Catalytic Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes. In a flame-dried 10 mL Schlenk tube equipped with a magnetic stir bar, 4Å molecular sieves (50 mg) is added, followed by the addition of chiral ligand L (4 mg, 0.00625 mmol, 5.0 mol%) in dry THF (0.5 mL) under nitrogen. Then a solution of diethylzinc (12.5 μL, 1.0 mol/L in toluene, 0.0125 mmol, 10 mol%) is added by a micro syringe to the system and the resulting mixture is stirred at room temperature for 30 min. Afterwards, N-Boc imines (1a–1n, 0.125 mmol, 1.0 equiv), notroalkanes (2a– 2c, 0.625 mmol, 5.0 equiv) and dry THF (0.5 mL) were added successively. The solution was stirred at room temperature for 14–24 h. After complete consumption of the imine starting material, as monitored by TLC analysis, saturated phosphoric acid (1.0 mL) and dichloromethane (2.0 mL) were added and the mixture was stirred for additional 30 min.



Page 14 of 26

The system was extracted with diethyl ether (3 × 10 mL). The combined organic phases were washed with brine (5.0 mL) and dried over anhydrous MgSO4. After evaporation of the solvent under reduced pressure, purification of the residue by silica gel chromatography (petroleum ether/EtOAc = 4:1 v/v ) to afford the analytically pure title compounds. HN

Boc NO2

(R)-tert-Butyl (2-nitro-1-phenylethyl)carbamate7 (3aa): [α]D25= -13.7 (c 0.6, CH2Cl2). A white solid, 25.0 mg, 75% yield, 99% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 210 nm); Retention time: tR(S) = 15.26 min, tR(R) = 19.63 min; IR (KBr) ~ /cm–1 = 3375, 2924, 1690, 1628, 1551, 1515, 1383, 701; 1H NMR (400 MHz, Chloroform-d): δ = 7.52 – 7.21 (m, 5H), 5.37 (br s, 2H), 4.85 (br s, 1H), 4.70 (br s, 1H), 1.44 (s, 9H) ppm;

13C{1H}

NMR (100 MHz, Chloroform-d): δ =

153.7, 135.8, 128.2, 127.7, 125.3, 79.6, 77.8, 51.8, 27.2 ppm.

HN

Boc NO2

Me

(R)-tert-Butyl [2-nitro-1-(o-tolyl)ethyl]carbamate8 (3ba): A white solid, 30.8 mg, 88% yield, 89% ee; HPLC (Chiralcel AS column, hexane/i-PrOH = 90/10, flow rate: 0.8 mL/min, UV detection at 220 nm); Retention time: tR(S) = 35.15 min, tR(R) = 18.04 min; IR (KBr) ~ /cm–1 = 3365, 2982, 1690, 1537, 1456, 1423, 757; 1H NMR (400 MHz, Chloroform-d): δ = 7.29 – 7.16 (m, 4H), 5.65 (d, J = 6.3 Hz, 1H), 5.14 (d, J = 7.5 Hz, 1H), 4.76 (s, 1H), 4.68 (s, 1H), 2.45 (s, 3H), 1.42 (s, 9H) ppm;

13C{1H}

NMR (100 MHz,

Chloroform-d): δ = 155.9, 137.3, 136.5, 132.6, 129.9, 128.1, 126.2, 81.9, 79.3, 50.6, 29.5, 20.5 ppm.


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HN

Boc NO2

Me

(R)-tert-Butyl [2-nitro-1-(m-tolyl)ethyl]carbamate30b (3ca): A white solid, 34.0 mg, 97% yield, 94% ee; HPLC (Chiralcel AS column, hexane/i-PrOH = 90/10, flow rate: 0.8 mL/min, UV detection at 220 nm); Retention time: tR(S) = 12.38 min, tR(R) = 14.68 min; IR (KBr) ~ /cm–1 = 3372, 2979, 1689, 1608, 1544, 1520, 1457, 786, 712; 1H NMR (400 MHz, Chloroform-d): δ = 7.27 (dd, J = 7.5 Hz, J = 7.5 Hz, 1H), 7.15 – 7.09 (m, 3H), 5.35 – 5.30 (m, 2H), 4.83 (br s, 1H), 4.70 – 4.65 (m, 1H), 2.36 (s, 3H), 1.44 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 154.8, 139.0, 136.8, 129.5, 129.1, 127.1, 123.3, 80.6, 78.9, 52.9, 28.3, 21.5 ppm.

HN

Boc NO2

Me

(R)-tert-Butyl [2-nitro-1-(p-tolyl)ethyl]carbamate8 (3da): A white solid, 27.3 mg, 78% yield, 96% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, flow rate: 0.3 mL/min, UV detection at 220 nm); Retention time: tR(S) = 85.43 min, tR(R) = 92.37 min; IR (KBr) ~ /cm–1 = 3374, 3132, 1682, 1546, 1522, 1456, 1399, 820; 1H NMR (400 MHz, Chloroform-d): δ = 7.20 – 7.18 (m, 4H), 5.34 (d, J = 7.6 Hz, 1H), 5.26 (s, 1H), 4.84 (d, J = 7.6 Hz, 1H), 4.71 – 4.67 (m, 1H), 2.34 (s, 3H), 1.44 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 153.7, 137.6, 132.7, 128.8, 125.2, 79.5, 77.9, 51.6, 27.2, 20.1 ppm.

HN

Boc NO2

MeO



(R)-tert-Butyl [1-(4-methoxyphenyl)-2-nitroethyl]carbamate7 (3ea): A white solid, 35.6 mg, 96% yield, 87% ee; HPLC (Chiralcel IA column, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) = 21.17 min, tR(R) = 39.12 min; IR (KBr) ~ /cm–1 = 3387, 3133, 1685, 1547, 1523, 1465, 1400, 827; 1H NMR (400 MHz, Chloroform-d): δ = 7.23 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 5.30 (d, J = 9.2 Hz, 2H), 4.84 (br s, 1H), 4.75 – 4.58 (m, 1H), 3.80 (s, 3H), 1.44 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 158.8, 153.7, 127.9, 126.5, 113.5, 79.5, 77.9, 54.2, 51.7, 27.2 ppm. HN

Boc NO2

Cl

(R)-tert-Butyl [1-(2-chlorophenyl)-2-nitroethyl]carbamate29a (3fa): A white solid, 13.2 mg, 35% yield, 93% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 16.21 min, tR(R) = 18.85 min; IR (KBr) ~ /cm–1 = 3356, 2925, 1689, 1539, 1520, 1473, 1420, 756; 1H NMR (400 MHz, Chloroform-d): δ = 7.51 – 7.18 (m, 4H), 5.77 – 5.75 (m, 2H), 4.91 – 4.79 (m, 2H), 1.45 (s, 9H) ppm;

13C{1H}

NMR (100 MHz, Chloroform-d): δ = 155.9, 135.5, 133.9,

131.6, 131.2, 129.3, 128.8, 82.1, 78.7, 51.9, 29.5 ppm. HN Cl

Boc NO2

(R)-tert-Butyl [1-(3-chlorophenyl)-2-nitroethyl]carbamate29a (3ga): A white solid, 22.6 mg, 60% yield, 90% ee; HPLC (Chiralcel AS column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 13.42 min, tR(R) = 17.90 min; IR (KBr) ~ /cm–1 = 3374, 2980, 1690, 1608, 1544, 1523, 1457, 787, 713; 1H NMR (400 MHz, Chloroform-d): δ = 7.36 – 7.28 (m, 3H), 7.23 – 7.17 (m, 1H), 5.45 – 5.36 (m,


Page 16 of 26

Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 4.82 (br s, 1H), 4.71 – 4.68 (m, 1H), 1.44 (s, 9H) ppm;

13C{1H}

NMR (100 MHz,

Chloroform-d): δ = 156.0, 140.3, 136.4, 131.8, 130.2, 127.9, 125.8, 82.3, 79.9, 53.6, 29.5 ppm. HN

Boc NO2

Cl

(R)-tert-Butyl [1-(4-chlorophenyl)-2-nitroethyl]carbamate8 (3ha): A white solid, 20.3 mg, 54% yield, 95% ee; HPLC (Chiralcel AS column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 15.94 min, tR(R) = 22.75 min; IR (KBr) ~ /cm–1 = 3401, 3131, 1695, 1553, 1511, 1452, 1400, 831; 1H NMR (400 MHz, Chloroform-d): δ = 7.36 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 5.40 – 5.36 (m, 2H), 4.84 (brs, 1H), 4.71 – 4.68 (m, 1H), 1.44 (s, 9H) ppm;

13C{1H}

NMR (100 MHz,

Chloroform-d): δ = 153.6, 134.6, 133.4, 128.1, 126.7, 79.6, 77.8, 51.1, 27.2 ppm. HN

Boc NO2

F

(R)-tert-Butyl [1-(4-fluorophenyl)-2-nitroethyl]carbamate14 (3ia): A white solid, 21.7 mg, 61% yield, 89% ee; HPLC (Chiralcel AD column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 15.08 min, tR(R) = 20.94 min; IR (KBr) ~ /cm–1 = 3433, 3132, 1662, 1616, 1560, 1522, 1465, 1401, 829; 1H NMR (400 MHz, Chloroform-d): δ = 7.36 – 7.25 (m, 2H), 7.06 (dd, J = 7.6 Hz, J = 7.6 Hz, 2H), 5.38 – 5.36 (m, 2H), 4.84 (br s, 1H), 4.69 – 7.64 (m, 1H), 1.43 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 158.0, 135.8 (d, J = 281.6 Hz), 129.5 (d, J = 12.0 Hz), 129.5 (d, J = 21.0 Hz), 105.9, 82.2, 80.1, 53.5, 29.5 ppm.



HN

Boc NO2

Me Me

(R)-tert-Butyl [1-(3,4-dimethylphenyl]-2-nitroethyl)carbamate (3ja): [α]D20= -23.8 (c 0.48, CHCl3). A white solid, 32.0 mg, 87% yield, 99% ee; HPLC (Chiralcel IC column, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) = 9.10 min, tR(R) = 6.94 min;1H NMR (400 MHz, Chloroform-d) δ = 7.14 (d, J = 7.8 Hz, 1H), 7.11 – 7.00 (m, 2H), 5.41 – 5.18 (m, 2H), 4.83 (s, 1H), 4.74 – 4.59 (m, 1H), 2.26 (d, J = 5.8 Hz, 6H), 1.45 (s, 9H) ppm;

13C{1H}

NMR (100 MHz, Chloroform-d) δ = 192.4,

154.9, 144.5, 137.3, 130.4, 127.8, 123.7, 79.1, 52.5, 28.4, 20.4, 20.0, 19.6 ppm; HR-MS (ESI-TOF): [M+Na]+ Calcd. for C15H22N2O4Na 317.1472; Found 317.1469. HN

Boc NO2

OMe OMe

(R)-tert-Butyl [1-(2,3-dimethoxyphenyl)-2-nitroethyl]carbamate (3ka): [α]D20= -7.9 (c 0.57, CHCl3). A white solid, 32.6 mg, 80% yield, 94% ee; HPLC (Chiralcel IA column, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) = 16.95 min, tR(R) = 31.93 min; 1H NMR (400 MHz, Chloroform-d) δ = 7.03 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.83 (d, J = 7.7 Hz, 1H), 5.71 – 5.40 (m, 2H), 4.84 – 4.71 (m, 1H), 4.67 (d, J = 11.9 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d) δ = 155.2, 153.1, 146.9, 130.2, 124.8, 120.3, 113.4, 80.7, 79.0, 61.3, 56.2, 50.5, 28.7 ppm; HR-MS (ESI-TOF): [M+H]+ Calcd. for C15H23N2O6 327.1551; Found 327.1555.


Page 18 of 26

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


HN

Boc NO2

O O

(R)-tert-Butyl [1-(benzo[d][1,3]dioxol-5-yl)-2-nitroethyl]carbamate (3la): [α]D20= -78.7 (c 0.23, CHCl3). A white solid, 27.5 mg, 71% yield, 93% ee; HPLC (Chiralcel AS column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 28.28 min, tR(R) = 36.04 min; IR (KBr) ~ /cm–1 = 3403, 2976, 1697, 1612, 1554, 1495, 1448, 855, 815; 1H NMR (400 MHz, Chloroform-d): δ = 6.80 – 6.77 (m, 3H), 5.96 (s, 2H), 5.28 (br s, 2H), 4.80 (br s, 1H), 4.65 – 4.62 (m, 1H), 1.43 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 153.6, 147.3, 146.8, 129.7, 118.8, 107.7, 105.8, 100.4, 79.7, 77.9, 51.8, 27.2 ppm. HR-MS (ESI-TOF): [M+H]+ Calcd. for C14H19N2O6 311.1238; Found 311.1239.

HN

Boc NO2

O

(S)-tert-Butyl [1-(furan-2-yl)-2-nitroethyl]carbamate7 (3ma): A white solid, 27.2 mg, 85% yield, 93% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 9.78 min, tR(R) = 11.44 min; IR (KBr) ~ /cm–1 = 3364, 2925, 1689, 1620, 1553, 1522, 1425, 754, 603; 1H NMR (400 MHz, Chloroform-d): δ = 7.38 (s, 1H), 6.36 – 6.30 (m, Hz, 2H), 5.48 – 5.44 (m, 1H), 5.32 (br s, 1H), 4.89 – 4.85 (m, 1H), 4.76 – 4.71 (m, 1H), 1.46 (s, 9H) ppm; 13C{1H} NMR (100 MHz, Chloroform-d): δ = 153.7, 135.8, 128.2, 127.7, 125.3, 79.6, 77.9, 51.8, 27.2 ppm.

HN

Boc NO2

S



Page 20 of 26

(S)-tert-Butyl [2-nitro-1-(thiophen-2-yl)ethyl]carbamate7 (3na): A white solid, 24.5 mg, 72% yield, 92% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: tR(S) = 20.46 min, tR(R) = 24.74 min; IR (KBr) ~ /cm–1 = 3383, 2978, 1691, 1551, 1515, 1427, 1371, 714; 1H NMR (400 MHz, Chloroform-d): δ = 7.29 – 7.26 (m, 1H), 7.03 – 6.98 (m, 2H), 5.65 – 5.60 (m, 1H), 5.35 – 5.32 (m, 1H), 4.91 (br s, 1H), 4.90 – 4.74 (m, 1H), 1.45 (s, 9H) ppm;

13C{1H}

NMR (100

MHz, Chloroform-d): δ = 154.5, 140.0, 127.3, 125.7, 125.3, 80.9, 78.6, 48.9, 28.2 ppm. HN

Boc Me NO2

(1R,2S)-tert-Butyl (2-nitro-1-phenylpropyl)carbamate10 (3ab): A white solid, 94% yield, 32.9 mg, 94% ee, 14:1 dr (anti:syn); HPLC (Chiralcel IE column, hexane/i-PrOH = 80/20, flow rate: 1 mL/min, UV detection at 254 nm); Retention time: Anti diasteroisomer: tminor = 28.39 min, tmajor = 23.52 min, Syn diasteroisomer: tminor = 11.28 min, tmajor = 15.71 min; IR (KBr) ~ /cm–1 = 3382, 2981, 1685, 1547, 1524, 1457, 1367, 705; 1H NMR (400 MHz, Chloroform-d): δ = 7.40 – 7.30 (m, 3H), 7.29 – 7.21 (m, 2H), 5.68 – 5.63 (m, 1H), 5.22 – 5.12 (m, 1H), 4.95 (br s, 1H), 1.54 (d, J = 3.6 Hz, 3H), 1.44 (s, 9H) ppm;

13C{1H}

NMR (100 MHz, Chloroform-d): δ = 154.9, 136.3, 128.9, 128.6, 126.8, 85.8, 80.5, 57.4, 28.2, 15.2 ppm. HN

Boc Me NO2

(1R,2S)-tert-Butyl (2-nitro-1-phenylbutyl)carbamate10 (3ac): A white solid, 37.1 mg, 90% yield, 84% ee, 13:1 dr (anti:syn); HPLC (Chiralcel OJ column, hexane/i-PrOH = 97/3, flow rate: 1.0 mL/min, UV detection at 220 nm); Retention time: Anti diasteroisomer: tminor = 56.97 min, tmajor = 24.22 min, Syn diasteroisomer: tminor = 44.60 min, tmajor = 18.47


Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


min; IR (KBr) ~ /cm–1 = 3388, 2977, 1686, 1546, 1522, 1457, 1367, 702; 1H NMR (400 MHz, Chloroform-d): δ = 7.35 – 7.30 (m, 3H), 7.26 – 7.22 (m, 2H), 5.20 – 5.11 (m, 2H), 4.74 (br s, 1H), 2.10 – 2.02 (m, 1H), 1.93 – 1.85 (m, 1H), 1.44 (s, 9H), 0.98 (t, J = 7.0 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, Chloroform-d): δ = 154.9, 136.6, 128.9, 128.6, 126.8,

93.0, 80.5, 56.8, 28.2, 23.4, 10.4 ppm.

Acknowledgments We are grateful to the National Natural Sciences Foundation of China (NSFC: 21871237， 21272216).

Supporting Information Chiral HPLC chromatograms data and copies of NMR spectra for the asymmetric aza-Henry products 3aa─3ac, 3aa─3na. This material is available free of charge via the Internet at

http://pubs.acs.org.

Notes The authors declare no competing ﬁnancial interest.

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Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction

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