Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with

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Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides Bu-Qing Cheng, Shi-Wen Zhao, Xuan-Di Song, Xue-Qiang Chu, Weidong Rao, Teck-Peng Loh, and Zhi-Liang Shen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00370 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 12, 2019

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The Journal of Organic Chemistry

Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides

Bu-Qing Cheng,† Shi-Wen Zhao,† Xuan-Di Song,† Xue-Qiang Chu,† Weidong Rao,‡ Teck-Peng Loh,*,†,§ and ZhiLiang Shen*,†

† Institute

of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China E-mail: [email protected]

‡ Jiangsu

Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China

§

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore E-mail: [email protected]

Abstract: Lead was found to efficiently mediate the allylation reactions of carbonyl compounds with

cyclic allylic halides in the presence of stoichiometric amounts of lithium chloride and a catalytic amount of GaCl3 (20 mol%), leading to the desired homoallylic alcohols in modest to high yields with excellent diastereocontrol (>99:1 syn/anti) and good functional group tolerance. In contrast, the use of either 2pyridinecarboxaldehyde as carbonyl substrate or (E)-cinnamyl bromide as allylating agent produced the corresponding product with reversed diastereoselectivity (>99:1 anti/syn).

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OH

Ar-CHO Br

Pb LiCl, GaCl3 (cat.) DMSO, rt

52-95% yields (>99:1 syn/anti)

Page 2 of 33

Ar syn OH

N

CHO

65% yield (>99:1 anti/syn)

N

anti

INTRODUCTION Homoallylic alcohols are a class of synthetically important organic molecules, which can be efficiently prepared by the allylation reaction of carbonyl compounds with allylic metallic compounds, where the latter could be in situ- or pre-prepared via the reaction of metal with allylic halides.1,2 In recent decades, although acyclic allylic halides have been extensively studied as allylating agents for the synthesis of various homoallylic alcohols,1 the use of cyclic allylic halides as substrates have not been widely explored. Typically, Knochel group has reported three examples of highly diastereoselective allylation reactions involving carbonyl compounds and pre-synthesized cyclic allylic zinc3 or aluminium4 reagents under moisture- and air-free conditions, producing the corresponding homoallylic alcohols as syndiastereomers exclusively (usually 99:1 dr). The group of Khan has also demonstrated that indium served as an effective mediator for promoting the allylation reactions of aldehydes with cyclic allylic halides, leading to the desired homoallylic alcohols with reasonable diastereoselectivity (mostly 90:10 dr).5 More recently, our group has disclosed that bismuth was also capable of efficiently promoting the allylation of carbonyl compounds with cyclic allylic halides in the presence of LiI, affording the expected homoallylic alcohols with >99:1 diastereoselectivity.6 In recent decades, although many main group metals have been extensively studied and used for effecting various organic reactions,7,8 the employment of lead as a cheap and readily available metal mediator in organic synthesis is sparsely explored. In this regard, though several cases of lead-mediated


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allylation reactions using acyclic allylic halide as starting materials have been reported,9 the study of analogous allylation reaction by employing cyclic allylic halide as substrate has not been reported thus far. Also, our initial assessment of the allylation reaction involving 4-chlorobenzaldehyde (1a) and 3bromocyclohexene (2a) by using lead as the sole reaction mediator showed that the reaction proceeded sluggishly to afford the corresponding product only in 7% yield (Table 1, entry 1). On the other hand, recent advancements achieved during the course of synthesizing organometallic reagents via direct metal insertion into organohalides7,8 have implied that the addition of additives (e.g., LiX3,10,11) and/or catalysts (e.g., InX3,1e,4,11,12 BiX3,11,13 and PbX211,14) might remarkably facilitate the insertion of metals (e.g., Mg, Zn, Al, and In) into organic halides. Thus, in continuation of our endeavors to develop metal-mediated organic transformations,15 herein we report an efficient lead-mediated highly diastereoselective allylation of carbonyl compounds with cyclic allylic halides in the presence of stoichiometric amounts of LiCl and a catalytic amount of GaCl3.16 The reactions proceeded smoothly at room temperature to afford the desired homoallylic alcohols with excellent diastereocontrol (>99:1 syn/anti) and good functional group compatibility.

RESULTS AND DISCUSSION

Table

1.

Optimization

of

Reaction

Conditionsa CHO

Br +

Cl

OH

Pb (3 equiv.) additive or catalyst DMSO, rt, 24 h Cl

1a

2a

>99:1 dr 3a

entry

additive or catalyst

yieldb (%)

1

--

7

2

BiCl3 (0.2 equiv.)

27

3

InCl3 (0.2 equiv.)

26

4

PbBr2 (0.2 equiv.)

19

5

LiI (2 equiv.)

26



6

LiCl (2 equiv.)

Page 4 of 33

34

7 LiCl (4 equiv.) 54 The reactions were performed at room temperature for 24 h by using aldehyde 1a (0.5 mmol), 3-bromocyclohexene (2a, 1.5 mmol), Pb (1.5 mmol), and additive (1-2 mmol) or catalyst (0.1 mmol) in DMSO (1 mL). b Yields were determined by NMR analysis of crude reaction mixture after work-up by using 1,4dimethoxybenzene as an internal standard. a

Initially, 4-chlorobenzaldehyde (1a) and 3-bromocyclohexene (2a) were selected as substrates to probe the allylation reaction by using lead as mediator (pre-activated by 1,2-dibromoethane and TMSCl) in the presence of different catalysts (0.2 equiv.) or additives (2 equiv.) in DMSO at room temperature for 24 h. As summarized in Table 1, it was found that the allylation reaction proceeded sluggishly in the presence of commonly used catalyst (e.g., BiCl3, InCl3, or PbBr2) or additive (e.g., LiI or LiCl), which were previously proven to be effective for promoting metal insertion into organohalides or metalmediated organic transformations, leading to the desired product 3a only in 19-34% yields (entries 2-6). Interestingly, the product yield could be improved to 54% when the model reaction was performed by using 4 equiv. of LiCl as reaction additive (entry 7). With this promising result in hand, we proceeded to optimize the reaction conditions by employing LiCl as reaction additive (4 equiv.) and various metallic salts (0.2 equiv.) as reaction catalysts, in the hope of further enhancing the reaction performance.

Table 2. Optimization of Reaction Conditionsa Pb (3 equiv.) LiCl (4 equiv.) Br catalyst (0.2 equiv.)

CHO +

OH

DMSO, rt, 24 h

Cl

Cl 1a

2a

entry

catalyst

1

CrCl3

yieldb (%) 24

2

PbCl2

3 4 5 6 7

>99:1 dr 3a

entry

catalyst

10

InCl3

yieldb (%) 81g

25

11

InBr3

76h

FeCl3

38

12

GaBr3

49

ZnCl2

21c

13

BiBr3

51

CeCl3

32c

14

CuBr2

43

AlCl3

24c

15

CoBr2

35

MnCl2

45c

16

CsBr

24


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8

BiCl3

72

17

73g

In(OTf)3

78d,e,f

9 GaCl3 18 Ni(acac)2 51 The reactions were performed at room temperature for 24 h by using aldehyde 1a (0.5 mmol), 3-bromocyclohexene (2a, 1.5 mmol), Pb (1.5 mmol), LiCl (2 mmol), and catalyst (0.1 mmol) in DMSO (1 mL). b Yields were determined by NMR analysis of crude reaction mixture after work-up by using 1,4-dimethoxybenzene as an internal standard. c 98:2 dr. d 74% isolated yield. e 63% isolated yield was obtained when the reaction was performed on a 2 mmol scale. f 18% NMR yield was observed when the reaction was carried out in the absence of LiCl. g 95:5 dr. h 93:7 dr. a

As shown in Table 2, different metallic salts (0.2 equiv.) catalyzed the allylation reaction with varying catalytic activity. Among the various metallic chlorides evaluated (entries 1-10), GaCl3 and InCl3 exhibited the best catalytic activities for the reaction, leading to the corresponding homoallylic alcohol 3a in 78% and 81% yields, respectively (entries 9-10). In view that >99:1 dr was obtained by using GaCl3 as catalyst and the use of InCl3 as catalyst led to slightly eroded diastereoselectivity (95:5 dr), thus GaCl3 was chosen as optimum catalyst for the ensuing allylation reaction. In contrast to metallic chloride, the utilization of metallic bromide as reaction catalyst resulted in decreased product yields (entries 11-16). In addition, the use of metallic salts containing other anions, including In(OTf)3 and Ni(acac)2, did not enhance the reaction performance further (entries 17-18). Furthermore, it should be mentioned that the combinatorial use of both LiCl and GaCl3 is necessary, because the sole use of GaCl3 led to markedly decreased product yield (18%; entry 9, footnote f).

Table 3. Optimization of Reaction Conditions by Using Different Metalsa CHO

Br +

OH

DMSO, rt, 24 h

Cl 1a

Metal (3 equiv.) LiCl (4 equiv.) GaCl3 (0.2 equiv.) Cl

2a

3a

entry

metal

yieldb (dr)

1

Fe

99:1 dr 3

2e

product (yield)b


( )n

Br

2f

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OH

NC

1

2a

3c (95%)

2

2b

3c (90%) OH

NC

3

2c

3n (74%) OH

CN

NC

4

2d

3o (90%) OH

NC

5

2e

3p (55%) OH

NC

6 2f 3q (63%) The reactions were performed at room temperature for 24 h by using aldehyde 1c (0.5 mmol), cyclic allylic halide (2a-f, 1.5 mmol), Pb (1.5 mmol), LiCl (2 mmol), and GaCl3 (0.1 mmol) in DMSO (1 mL). b Isolated yields. a

Both the mildness of the reaction conditions and the in situ formed allylic lead intermediate also entailed the selective allylation of formyl group in the co-existence of less reactive keto group. As shown in Scheme 1, the allylation employing substrate 1n reacted selectively at the formyl group to furnish the product 3r in 81% yield as a syn-diastereomer, leaving the keto group completely untouched.

Scheme 1. Selective Allylation of Formyl Group of Substrate 1n in the Presence of Acetyl Group

CHO

Br +

Pb (3 equiv.) LiCl (4 equiv.) GaCl3 (0.2 equiv.)

OH

DMSO, rt, 24 h

Ac

Ac 1n

2a

3r, 81% yield, >99:1 dr

When isatins 1o-p containing more reactive keto group were treated with substrate 2a under optimized



Page 10 of 33

reaction conditions, the reaction could take place at the keto group regioselectively, leading to the desired products 3s-t in good to excellent yields with excellent stereoselectivities (Scheme 2).

Scheme 2. Lead-Mediated Highly Diastereoselective Allylation Reaction Using Isatin (1op) as Substrates O RN

Br

O +


O OH

RN

DMSO, rt, 24 h

1o (R = H) 1p (R = Me)

>99:1 dr 3s (R = H): 91% yield 3t (R = Me): 83% yield

2a

In a same manner, the lead-mediated allylation reaction involving 2-pyridinecarboxaldehyde (1q) also proceeded smoothly to generate the corresponding homoallylic alcohol 3u in 65% yield (Scheme 3). In this case, the anti-diastereomer was obtained exclusively which might be due to the presence of a nitrogen atom adjacent to the formyl group, functioning as a chelating atom in the transition state of the reaction.6,17

Scheme

3.

Lead-Mediated

Highly

Diastereoselective

Allylation

Using

2-

Pyridinecarboxaldehyde (1q) as Substrate with Inversion of Stereochemistry

Br +

1q

OH

DMSO, rt, 24 h

CHO

N


2a

N 3u, 65%, >99:1 dr

Furthermore, (E)-cinnamyl bromide, as a representative example of acyclic allylic halide, was able to efficiently react with aryl aldehydes to give the expected products 3v-x in excellent yields, with the antidiastereomers being the product (Scheme 4).

Scheme 4. Lead-Mediated Highly Diastereoselective Allylation Using (E)-Cinnamyl Bromide (2g) as Substrate


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CHO + Ph

Br

R


OH

DMSO, rt, 24 h

Ph

R

1b (R = CO2Me) 1c (R = CN) 1e (R = Br)

> 99:1 dr 3v (R = CO2Me): 93% yield 3w (R = CN): 90% yield 3x (R = Br): 91% yield

2g

When 2-pyridinecarboxaldehyde (1q) was subjected to allylation reaction with (E)-cinnamyl bromide (2g) under optimized reaction conditions, the reaction worked equally well to afford the desired product 3y in 85% yield with >99:1 dr (Scheme 5). In the present case, the exclusive formation of a syndiastereomer was obtained, presumably as a result of the presence of a chelated nitrogen atom in the substrate 1r. The stereochemistry of the product 3y was unambiguously determined by comparison with reported data of the same compound prepared by other method.18

Scheme 5. Lead-Mediated Highly Diastereoselective Allylation Pyridinecarboxaldehyde (1r) and (E)-Cinnamyl Bromide (2g) as Substrates

N

CHO 1r

+ Ph

Br 2g


Using

2-

OH

DMSO, rt, 24 h

N

Ph

3y, 85% yield, >99:1 dr

In contrast to the allylation using (E)-cinnamyl bromide (2g) as substrate, the allylation using crotyl bromide (2h) bearing a sterically less congested methyl group proceeded as well to give the corresponding syn-3z as the major product, but with slightly reduced but acceptable diastereoselectivity (90:10 dr; Scheme 6).19

Scheme 6. Lead-Mediated Highly Diastereoselective Allylation Chlorobenzaldehyde (1a) and (E)-Crotyl Bromide (2h) as Substrates


Using

4-


CHO +

Br


OH

DMSO, rt, 24 h

Cl 1a

Page 12 of 33

Me Cl 3z, 85% yield, 90:10 dr

2h

With regard to the functions of LiCl and GaCl3,20 it is unclear thus far. Based on the relevant works of Knochel and co-workers11 in which LiCl and metallic salt (such as InCl3, PbCl2, BiCl3, and TiCl4) have been simultaneously employed to promote aluminium metal into aryl halides, we speculated that LiCl and GaCl3 used in the present protocol might work together to enhance the oxidative addition of metallic lead into allylic halides for generating the corresponding allylic lead compounds, which subsequently underwent allylation reaction with carbonyl compounds. As for the excellent diastereoselectivities obtained, Zimmerman-Traxler21 six-membered ring transition states A-D, with or without the coordination of nitrogen to lead atom, could be introduced to explain the exclusive formation of the syn- or anti-diastereomer, depending on the starting materials employed (Figure 1). H Ar H

O PbXn H ( )n A

Figure

1.

Zimmerman-Traxler

N H H

O PbXn

Ph

O H

H B

six-membered

R

PbXn

H Ph

C

ring

transition

N O PbXn

D

state

accounted

for

the

high

diastereoselectivity obtained.

CONCLUSIONS In conclusion, we have developed an efficient lead-mediated allylation reactions of carbonyl compounds with cyclic allylic halides. The reactions proceeded efficiently in the presence of LiCl and GaCl3 to afford the desired products in modest to high yields with excellent diastereoselectivity (>99:1 dr of syn-


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diastereomer). Lead was found to be the catalyst of choice among the various metals screened and the reactions could be easily manipulated without the necessity of precluding moisture and air. The mildness of the reaction also allowed the existence of various functional groups embedded in the starting materials and the selective allylation of formyl group while in the co-existence of keto group. In contrast to normal carbonyl substrate, the use of 2-pyridinecarboxaldehyde containing neighboring chelating nitrogen atom as reactant led to reversed diastereoselectivity of the product.

EXPERIMENTAL SECTION General information. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.

3-Chlorocyclohex-1-ene

(2b),22,23

3-chloro-5,5-dimethylcyclohex-1-ene

(2c),24

6-

bromocyclohex-1-ene-1-carbonitrile (2d),25 3-bromocyclohept-1-ene (2e),26 and 3-bromocyclooct-1-ene (2f),26 were synthesized according to reported methods. All reactions were carried out under air using undistilled solvent, without the need to exclude air and moisture. Analytical thin layer chromatography (TLC) was performed using silica gel plate (0.2 mm thickness). Subsequent to elution, plates were visualized using UV radiation (254 nm). Flash chromatography was performed using Merck silica gel (200-300 mesh) for column chromatography with freshly distilled solvents. Columns were typically packed as slurry and equilibrated with the appropriate solvent system prior to use. IR spectra were recorded on a FT-IR spectrophotometer using KBr optics. 1H and 13C NMR spectra were recorded in CDCl3 on Jeol 400 MHz spectrometers. Tetramethylsilane (TMS) served as internal standard for 1H and 13C

NMR analysis. High resolution mass spectra (HRMS) were recorded on a Waters Q–TOF Permier

Spectrometer (ESI or EI source).



Typical procedures for the preparation of homoallylic alcohols by the allylation of carbonyl compounds with allyl halides: To a 10 mL Schlenk flask was sequentially added lead powder (311 mg, 1.5 mmol) and DMSO (1 mL). Then lead was activated by the addition of 1,2-dibromoethane (18.8 mg, 20 mol%) and TMSCl (10.9 mg, 20 mol%). After stirring for 5 min, LiCl (85 mg, 2 mmol), GaCl3 (18 mg, 0.1 mmol), allyl halides (1.5 mmol), and aldehyde or ketone (0.5 mmol) was sequentially added to the reaction mixture. The suspension was vigorously stirred at room temperature for 24 h before quenching with sat. NH4Cl solution (30 mL) and extracting with ethyl acetate (20 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent to give the pure products (petroleum ether:EtOAc = 20:1 for 3g−3m, 3v-3x, and 3z; petroleum ether:EtOAc = 15:1 for 3a-3f, 3n-3r, and 3u; petroleum ether:EtOAc = 4:1 for 3y; petroleum ether:EtOAc = 2:1 for 3s-3t).

4-Chlorophenyl(cyclohex-2-en-1-yl)methanol (3a).6 82.5 mg, 74% yield (0.5 mmol scale); 279.6 mg, 63% yield (2 mmol scale); >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.33-7.26 (m, 4H), 5.93-5.75 (m, 1H), 5.38 (dd, J = 10.2, 2.5 Hz, 1H), 4.59 (d, J = 6.2 Hz, 1H), 2.46 (dd, J = 5.7, 2.9 Hz, 1H), 1.99-1.95 (m, 3H), 1.75 (td, J = 10.8, 4.8 Hz, 1H), 1.64 (dt, J = 10.1, 6.4 Hz, 1H), 1.52-1.46 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 141.2, 132.9, 130.9, 128.3, 127.8, 127.5, 76.6, 43.0, 25.2, 23.5, 21.0 ppm. IR (KBr):  = 3340, 2926, 1495, 1089, 1013, 815, 724 cm-1. HRMS (m/z): calcd for C13H16ClO [M+H]+ 223.0890, found: 223.0885.

Methyl 4-(cyclohex-2-en-1-yl(hydroxy)methyl)benzoate (3b).6 89.9 mg, 73% yield, >99:1 dr, white


Page 14 of 33

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solid; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.4 Hz, 2H), 7.45-7.38 (m, 2H), 5.95-5.77 (m, 1H), 5.46-5.37 (m, 1H), 4.69 (d, J = 5.9 Hz, 1H), 3.91 (s, 3H), 2.51 (dt, J = 5.6, 2.8 Hz, 1H), 2.04 (s, 1H), 2.01-1.94 (m, 2H), 1.80-1.70 (m, 1H), 1.63-1.56 (m, 1H), 1.54-1.45 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 148.1, 130.8, 129.3, 128.9, 127.5, 126.3, 76.6, 52.0, 42.9, 25.0, 23.4, 20.9 ppm. IR (KBr):  = 3508, 2936, 1707, 1436, 1290, 1119, 753 cm-1. HRMS (m/z): calcd for C15H19O3 [M+H]+ 247.1334, found: 247.1330.

4-(Cyclohex-2-en-1-yl(hydroxy)methyl)benzonitrile (3c).6 101.3 mg, 95% yield, >99:1 dr, white solid; 1H

NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 5.91 (dq, J = 10.1, 3.4

Hz, 1H), 5.42 (dd, J = 10.3, 2.6 Hz, 1H), 4.72 (d, J = 5.5 Hz, 1H), 2.53-2.48 (m, 1H), 2.05 (s, 1H), 1.99 (d, J = 2.8 Hz, 2H), 1.74 (d, J = 4.5 Hz, 1H), 1.55-1.44 (m, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 148.1, 131.9, 131.6, 127.1, 127.1, 118.9, 110.8, 76.2, 42.9, 25.0, 22.9, 20.9 ppm. IR (KBr):  = 3475, 2931, 2233, 1080, 563 cm-1. HRMS (m/z): calcd for C14H16NO [M+H]+ 214.1232, found: 214.1231.

Cyclohex-2-en-1-yl(4-(trifluoromethyl)phenyl)methanol (3d).27 79.5 mg, 62% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.88 (dq, J = 10.1, 3.4 Hz, 1H), 5.42 (dd, J = 10.1, 2.6 Hz, 1H), 4.70 (d, J = 6.1 Hz, 1H), 2.51 (ddt, J = 8.5, 5.6, 2.6 Hz, 1H), 2.00 (d, J = 2.7 Hz, 3H), 1.79-1.71 (m, 1H), 1.61-1.47 (m, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 146.7 (q, J = 1.4 Hz), 131.3, 129.5 (q, J = 32.4 Hz), 127.4, 126.7, 125.1 (q, J = 3.8 Hz), 124.2 (q, J = 270.5 Hz), 76.5, 43.0, 25.1, 23.2, 21.0 ppm. 19F NMR (376 MHz, CDCl3) : δ -62.26 (s, 3H) ppm. IR (KBr):  =3394, 2929, 1621, 1325, 1128, 848 cm-1. HRMS (m/z): calcd for C14H16F3O [M+H]+ 257.1153, found: 257.1153.



Page 16 of 33

(4-Bromophenyl)(cyclohex-2-en-1-yl)methanol (3e).6 112.2 mg, 84% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 5.93-5.78 (m, 1H), 5.445.34 (m, 1H), 4.57 (dd, J = 6.2, 2.2 Hz, 1H), 2.46 (dd, J = 5.4, 2.8 Hz, 1H), 2.04-1.95 (m, 2H), 1.89 (t, J = 2.2 Hz, 1H), 1.78-1.71 (m, 1H), 1.66-1.61 (m, 1H), 1.51-1.46 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 141.7, 131.2, 130.8, 128.1, 127.5, 121.0, 76.5, 42.9, 25.1, 23.5, 21.0 ppm. IR (KBr):  = 3319, 2932, 1483, 1009, 813, 672 cm-1. HRMS (m/z): calcd for C13H16BrO [M+H]+ 267.0385, found: 267.0378.

(2-Bromophenyl)(cyclohex-2-en-1-yl)methanol (3f).28 118.4 mg, 89% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.63-7.45 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 5.90 (dt, J = 10.1, 3.3 Hz, 1H), 5.63-5.45 (m, 1H), 5.06 (d, J = 4.8 Hz, 1H), 2.68 (dt, J = 5.7, 2.8 Hz, 1H), 2.14-1.93 (m, 3H), 1.87-1.71 (m, 1H), 1.60-1.41 (m, 3H) ppm.

13C{1H}

NMR (100 MHz, CDCl3): δ

141.4, 132.6, 131.1, 128.6, 128.5, 128.1, 127.2, 122.2, 75.3, 40.7, 25.1, 22.6, 21.3 ppm. IR (KBr):  = 3568, 3292, 2901, 1296, 1021, 739 cm-1. HRMS (m/z): calcd for C13H16BrO [M+H]+ 267.0385, found: 267.0385.

(3-Bromophenyl)(cyclohex-2-en-1-yl)methanol (3g).29 77.1 mg, 58% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.51 (t, J = 1.7 Hz, 1H), 7.40 (dt, J = 7.7, 1.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.21 (dd, J = 8.3, 7.0 Hz, 1H), 5.92-5.82 (m, 1H), 5.40 (ddd, J = 10.2, 2.6, 1.1 Hz, 1H), 4.59 (d, J = 6.1 Hz, 1H), 2.49-2.45 (m, 1H), 2.03-1.95 (m, 2H), 1.92 (d, J = 2.4 Hz, 1H), 1.82-1.70 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.48 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 131.1, 130.4, 129.7, 129.5,


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127.5, 125.1, 122.4, 76.5, 43.0, 25.2, 23.4, 21.0 ppm. IR (KBr):  = 3383, 2926, 1570, 1429, 1070, 783 cm-1. HRMS (m/z): calcd for C13H16BrO [M+H]+ 267.0385, found: 267.0385.

Cyclohex-2-en-1-yl(phenyl)methanol (3h).6 49.0 mg, 52% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.44-7.20 (m, 5H), 5.83-5.80 (m, 1H), 5.51-5.32 (m, 1H), 4.59 (d, J = 6.5 Hz, 1H), 2.662.42 (m, 1H), 2.13-1.94 (m, 2H), 1.88 (s, 1H), 1.78-1.68 (m, 2H), 1.62-1.43 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 142.9, 130.3, 128.1, 128.0, 127.3, 126.5, 77.3, 42.9, 25.2, 23.8, 21.1 ppm. IR (KBr):  = 3385, 3026, 1453, 1017, 763, 701 cm-1. HRMS (m/z): calcd for C13H17O [M+H]+ 189.1279, found: 189.1279.

Cyclohex-2-en-1-yl(p-tolyl)methanol (3i).6 63.7 mg, 63% yield, >99:1 dr, coloress oil; 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 5.81-5.76 (m, 1H), 5.36 (dd, J = 10.2, 2.5 Hz, 1H), 4.52 (d, J = 6.7 Hz, 1H), 2.47 (dtd, J = 8.8, 4.7, 2.2 Hz, 1H), 2.34 (s, 3H), 2.01-1.94 (m, 2H), 1.94-1.83 (m, 1H), 1.74 (dt, J = 11.1, 4.5 Hz, 2H), 1.59-1.46 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 139.9, 136.9, 130.0, 128.8, 128.0, 126.4, 77.3, 42.9, 25.2, 24.0, 21.1, 21.1 ppm. IR (KBr):  = 3346, 2924, 2866, 1514, 1015, 807, 721, 691 cm-1. HRMS (m/z): calcd for C14H19O [M+H]+ 203.1436, found: 203.1438.

Cyclohex-2-en-1-yl(4-methoxyphenyl)methanol (3j).6 61.2 mg, 56% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.83-5.74 (m, 1H), 5.41-5.32 (m, 1H), 4.51 (d, J = 6.9 Hz, 1H), 3.81 (s, 3H), 2.50-2.44 (m, 1H), 2.04-1.93 (m, 2H), 1.83 (s, 1H), 1.801.69 (m, 2H), 1.57-1.45 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 158.8, 135.1, 130.0, 127.9,



127.7, 113.5, 77.1, 55.2, 42.9, 25.2, 24.2, 21.0 ppm. IR (KBr):  = 3443, 3030, 2882, 1612, 1254, 1034, 814 cm-1. HRMS (m/z): calcd for C14H19O2 [M+H]+ 219.1385, found: 219.1386.

Cyclohex-2-en-1-yl(naphthalen-2-yl)methanol (3k).6 106.1 mg, 89% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.99 (dt, J = 5.3, 1.9 Hz, 1H), 7.83 (dt, J = 7.2, 2.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67-7.58 (m, 1H), 7.46-7.41 (m, 3H), 5.80 (ddd, J = 10.0, 4.7, 2.4 Hz, 1H), 5.44 (dt, J = 10.2, 2.3 Hz, 1H), 5.36 (dd, J = 5.7, 1.7 Hz, 1H), 2.74-2.70 (m, 1H), 2.25 (s, 1H), 1.96 (dt, J = 6.2, 3.2 Hz, 2H), 1.75-1.69 (m, 1H), 1.62-1.44 (m, 2H), 1.44-1.33 (m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 138.2, 133.6, 130.5, 130.4, 128.8, 128.5, 127.6, 125.7, 125.3, 125.2, 123.9, 123.1, 73.4, 41.8, 25.1, 23.4, 21.2 ppm. IR (KBr):  = 3409, 2926, 2859, 1090, 993, 778, 724 cm-1. HRMS (m/z): calcd for C17H19O [M+H]+ 239.1436, found: 239.1436.

Cyclohex-2-en-1-yl(furan-2-yl)methanol (3l).30 82.0 mg, 92% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.38 (dt, J = 1.9, 1.0 Hz, 1H), 6.34 (dd, J = 3.3, 1.8 Hz, 1H), 6.30-6.24 (m, 1H), 5.81 (ddt, J = 10.0, 3.8, 1.8 Hz, 1H), 5.38 (dt, J = 10.0, 1.9 Hz, 1H), 4.54 (ddd, J = 7.3, 4.6, 1.9 Hz, 1H), 2.66 (ddt, J = 8.3, 6.1, 2.8 Hz, 1H), 2.04-1.98 (m, 2H), 1.96 (d, J = 4.6 Hz, 1H), 1.88-1.72 (m, 2H), 1.601.51 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 141.8, 130.1, 127.2, 110.1, 106.8, 71.3, 40.7, 25.2, 24.4, 20.9 ppm. IR (KBr):  = 3377, 2928, 1149, 1010, 735 cm-1. HRMS (m/z): calcd for C11H15O2 [M+H]+ 179.1072, found: 179.1072.

(E)-1-(cyclohex-2-en-1-yl)-3-phenylprop-2-en-1-ol (3m).6 77.2 mg, 72% yield, >99:1 dr, colorless oil; 1H

NMR (400 MHz, CDCl3): δ 7.39 (dd, J = 8.4, 1.4 Hz, 2H), 7.34-7.29 (m, 2H), 7.26-7.21 (m, 1H),


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6.60 (dd, J = 16.0, 1.1 Hz, 1H), 6.25 (dd, J = 15.9, 7.0 Hz, 1H), 5.86 (dtd, J = 9.9, 3.6, 2.5 Hz, 1H), 5.685.63 (m, 1H), 4.20 (ddd, J = 7.0, 5.7, 1.2 Hz, 1H), 2.42-2.37 (m, 1H), 2.02-1.98 (m, 2H), 1.90-1.74 (m, 3H), 1.60-1.45 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 136.7, 131.4, 130.5, 130.2, 128.5, 127.6, 126.4, 76.1, 41.8, 25.2, 24.1, 21.3 ppm. IR (KBr):  = 3439, 2924, 2856, 1648, 1448, 966, 751, 693 cm-1. HRMS (m/z): calcd for C15H19O [M+H]+ 215.1436, found: 215.1437.

4-((5,5-Dimethylcyclohex-2-en-1-yl)(hydroxy)methyl)benzonitrile (3n).6 89.2 mg, 74% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.865.82 (m, 1H), 5.48 (d, J = 10.2 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 2.56-2.49 (m, 1H), 1.99 (d, J = 2.0 Hz, 1H), 1.88-1.84 (m, 1H), 1.75-1.69 (m, 1H), 1.25-1.19 (m, 1H), 1.09-1.05 (m, 1H), 0.92 (s, 3H), 0.82 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 147.9, 132.0, 130.6, 127.0, 125.9, 118.9, 111.0, 76.3, 41.8, 39.0, 35.6, 31.9, 29.3, 25.0 ppm. IR (KBr):  = 3516, 2950, 2855, 2226, 1609, 1361, 1056, 846, 684 cm-1. HRMS (m/z): calcd for C16H20NO [M+H]+ 242.1545; found: 242.1546.

4-((2-Cyanocyclohex-2-en-1-yl)(hydroxy)methyl)benzonitrile (3o). 107.2 mg, 90% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 6.85 (td, J = 4.1, 2.2 Hz, 1H), 5.31 (d, J = 2.9 Hz, 1H), 2.95 (s, 1H), 2.54 (ddd, J = 8.8, 5.9, 2.9 Hz, 1H), 2.252.12 (m, 2H), 1.88-1.72 (m, 1H), 1.66-1.56 (m, 1H), 1.49-1.36 (m, 1H), 1.29-1.21 (m, 1H) ppm.. 13C{1H} NMR (100 MHz, CDCl3): δ 149.3, 147.6, 132.0, 126.6, 118.7, 118.6, 114.3, 111.0, 72.4, 42.8, 25.8, 20.1, 19.7 ppm. IR (KBr):  = 3448, 2953, 2228, 1609, 1420, 1078, 909, 693 cm-1. HRMS (m/z): calcd for C15H15N2O [M+H]+ 239.1184; found: 239.1184.



4-(Cyclohept-2-en-1-yl(hydroxy)methyl)benzonitrile (3p).6 62.5 mg, 55% yield, >99:1 dr, colorless oil; 1H

NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 5.88-5.81 (m, 1H),

5.55-5.51 (m, 1H), 4.77 (dd, J = 6.0, 2.9 Hz, 1H), 2.63 (s, 1H), 2.26-2.03 (m, 3H), 1.99-1.91 (m, 1H), 1.74-1.64 (m, 2H), 1.53 (m, 1H), 1.40-1.26 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 148.5, 133.4, 132.5, 132.0, 127.3, 118.8, 111.0, 76.6, 47.0, 29.6, 28.5, 27.5, 26.6 ppm. IR (KBr):  = 3516, 3013, 2922, 2225, 1446, 1017, 837, 690 cm-1. HRMS (m/z): calcd for C15H18NO [M+H]+ 228.1388; found: 228.1387.

(Z)-4-(Cyclooct-2-en-1-yl(hydroxy)methyl)benzonitrile (3q). 76 mg, 63% yield, >99:1 dr, white solid; 1H

NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 5.67-5.60 (m, 1H),

5.25 (ddd, J = 10.5, 9.0, 1.4 Hz, 1H), 4.66 (dd, J = 6.9, 3.4 Hz, 1H), 2.87 (dt, J = 7.2, 3.6 Hz, 1H), 2.19 (d, J = 3.8 Hz, 1H), 2.15-2.07 (m, 1H), 2.05-1.99 (m, 1H), 1.87-1.79 (m, 1H), 1.66 (dd, J = 6.9, 3.8 Hz, 2H), 1.52 (ddd, J = 9.6, 4.5, 1.9 Hz, 1H), 1.43-1.18 (m, 4H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 148.8, 132.0, 131.1, 129.3, 127.4, 118.9, 111.1, 77.2, 43.4, 31.1, 29.2, 26.7, 26.6, 25.3 ppm. IR (KBr):  = 3480, 2923, 2226, 1702, 1456, 758 cm-1. HRMS (m/z): calcd for C16H20NO [M+H]+ 242.1545, found: 242.1545.

1-(4'-(Cyclohex-2-en-1-yl(hydroxy)methyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (3r).6 124.1 mg, 81% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 5.89-5.84 (m, 1H), 5.45 (dd, J = 10.2, 2.4 Hz, 1H), 4.67 (dd, J = 6.4, 2.5 Hz, 1H), 2.64 (s, 3H), 2.58-2.53 (m, 1H), 2.05-1.98 (m, 2H), 1.94 (d, J = 2.6 Hz, 1H), 1.84-1.68 (m, 2H), 1.59-1.50 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 197.8, 145.4,


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143.0, 138.8, 135.7, 130.8, 128.9, 127.8, 127.1, 127.1, 127.0, 76.9, 43.0, 26.7, 25.2, 23.6, 21.1 ppm. IR (KBr):  = 3531, 2923, 2866, 1672, 1600, 1358, 1270, 812, 674 cm-1. HRMS (m/z): calcd for C21H23O2 [M+H]+ 307.1698, found: 307.1697.

3-(Cyclohex-2-en-1-yl)-3-hydroxyindolin-2-one (3s).6 104.7 mg, 91% yield, >99:1 dr, white solid; 1H NMR (400 MHz, Methanol-d4): δ = 7.29-7.21 (m, 2H), 6.97 (td, J = 7.7, 1.0 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.10-6.06 (m, 1H), 5.92-5.87 (m, 1H), 2.80-2.74 (m, 1H), 1.96-1.88 (m, 1H), 1.81-1.72 (m, 1H), 1.63-1.52 (m, 2H), 1.49-1.39 (m, 1H), 0.79-0.69 (m, 1H) ppm. 13C{1H} NMR (100 MHz, Methanol-d4): δ = 181.9, 143.3, 131.2, 131.1, 130.4, 126.5, 126.4, 123.2, 110.8, 79.7, 44.1, 26.0, 24.6, 22.5 ppm. IR (KBr):  = 3342, 2944, 1705, 1472, 1049, 778, 621 cm-1. HRMS (m/z): calcd for C14H16NO2 [M+H]+ 230.1181, found: 230.1178.

3-(Cyclohex-2-en-1-yl)-3-hydroxy-1-methylindolin-2-one (3t).6 100.9 mg, 83% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 7.38-7.34 (m, 1H), 7.32 (dd, J = 7.8, 1.3 Hz, 1H), 7.06 (td, J = 7.5, 1.0 Hz, 1H), 6.83 (dt, J = 7.8, 0.8 Hz, 1H), 6.08 (dtt, J = 10.1, 2.5, 1.4 Hz, 1H), 5.99-5.89 (m, 1H), 3.20 (s, 3H), 2.80 (dtt, J = 9.1, 3.9, 2.1 Hz, 1H), 2.60 (s, 1H), 2.02-1.88 (m, 1H), 1.86-1.73 (m, 1H), 1.59-1.53 (m, 2H), 1.49-1.38 (m, 1H), 0.80-0.69 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.8, 143.9, 131.0, 129.6, 128.2, 125.1, 124.6, 122.8, 108.0, 78.4, 43.7, 26.1, 24.9, 23.4, 21.2 ppm. IR (KBr):  = 3330, 2927, 2836, 1698, 1087, 757, 664 cm-1. HRMS (m/z): calcd for C15H18NO2 [M+H]+ 244.1338, found: 244.1320.



Cyclohex-2-en-1-yl)(pyridin-2-yl)methanol (3u).6 61.5 mg, 65% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 8.56 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.68 (td, J = 7.7, 1.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.21 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 5.88-5.77 (m, 1H), 5.59-5.48 (m, 1H), 4.62 (d, J = 4.7 Hz, 1H), 4.12 (s, 1H), 2.77-2.47 (m, 1H), 2.03-1.90 (m, 2H), 1.77-1.66 (m, 2H), 1.60-1.44 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ = 160.8, 148.1, 136.3, 130.0, 126.5, 122.2, 121.1, 75.9, 42.9, 25.9, 25.1, 21.7 ppm. IR (KBr):  = 3156, 2858, 1596, 1111, 760 cm-1. HRMS (m/z): calcd for C12H16NO [M+H]+ 190.1232, found: 190.1232.

Methyl 4-(1-hydroxy-2-phenylbut-3-en-1-yl)benzoate (3v).6 131.3 mg, 93% yield, >99:1 dr, white solid; 1H

NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 2H), 7.23-7.14 (m, 5H), 7.08-6.98 (m, 2H), 6.23

(ddd, J = 17.0, 10.3, 9.0 Hz, 1H), 5.31-5.19 (m, 2H), 4.88 (dd, J = 7.7, 2.2 Hz, 1H), 3.87 (s, 3H), 3.51 (t, J = 8.4 Hz, 1H), 2.47 (d, J = 2.5 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 166.9, 147.0, 140.0, 137.3, 129.2, 129.1, 128.5, 128.2, 126.8, 126.6, 118.9, 76.8, 59.3, 52.0 ppm. IR (KBr):  = 3508, 2958, 2898, 1694, 1431, 1289, 1113, 924, 721 cm-1. HRMS (m/z): calcd for C18H19O3 [M+H]+ 283.1334, found: 283.1339.

4-(1-Hydroxy-2-phenylbut-3-en-1-yl)benzonitrile (3w).6 112.2 mg, 90% yield, >99:1 dr, white solid; 1H

NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.3 Hz, 2H), 7.26-7.16 (m, 5H), 7.08-6.95 (m, 2H), 6.22

(ddd, J = 17.0, 10.2, 9.1 Hz, 1H), 5.43-5.20 (m, 2H), 4.87 (d, J = 7.9 Hz, 1H), 3.45 (t, J = 8.5 Hz, 1H), 2.45 (s, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 147.1, 139.6, 136.9, 131.6, 128.6, 128.1, 127.3, 127.0, 119.3, 118.8, 111.0, 76.5, 59.4 ppm. IR (KBr):  = 3508, 3083, 2887, 2226, 1605, 1391, 1067, 920, 704 cm-1. HRMS (m/z): calcd for C17H16NO [M+H]+ 250.1232, found: 250.1232.


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1-(4-Bromophenyl)-2-phenylbut-3-en-1-ol (3x).6 138.0 mg, 91% yield, >99:1 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.5 Hz, 2H), 7.24-7.13 (m, 3H), 7.06-6.95 (m, 4H), 6.27-6.15 (m, 1H), 5.30-5.19 (m, 2H), 4.77 (dd, J = 7.9, 2.2 Hz, 1H), 3.46 (t, J = 8.4 Hz, 1H), 2.40 (dd, J = 2.3, 0.8 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 140.7, 140.1, 137.5, 130.9, 128.5, 128.3, 128.2, 126.8, 121.2, 118.8, 76.5, 59.3 ppm. IR (KBr):  = 3432, 3028, 2897, 1487, 1070, 1010, 819, 701 cm-1. HRMS (m/z): calcd for C16H16BrO [M+H]+ 303.0385, found: 303.0381.

2-Phenyl-1-(pyridin-2-yl)but-3-en-1-ol (3y).18 96.1 mg, 85% yield, >99:1 dr, white solid; 1H NMR (400 MHz, CDCl3): δ 8.48 (dt, J = 4.9, 1.3 Hz, 1H), 7.60 (td, J = 7.7, 1.8 Hz, 1H), 7.26-7.08 (m, 7H), 6.15-6.06 (m, 1H), 5.15-5.03 (m, 3H), 3.93 (brs, 1H), 3.82-3.73 (m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 148.1, 139.7, 137.7, 136.1, 128.8, 128.2, 126.7, 122.5, 121.7, 117.1, 76.1, 57.4 ppm. IR (KBr):  = 3278, 2963, 1596, 1452, 1261, 1054, 703 cm-1. HRMS (m/z): calcd for C15H16NO [M+H]+ 226.1232, found: 226.1229.

1-(4-Chlorophenyl)-2-methylbut-3-en-1-ol (3z).19 85.6 mg, 85% yield, 90:10 dr, colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.34-7.19 (m, 4H), 5.78-5.69 (m, 1H), 5.09-5.03 (m, 2H), 4.60 (dd, J = 5.3, 3.6 Hz, 1H), 2.54 (q, J = 6.6 Hz, 1H), 1.99 (d, J = 3.6 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 140.9, 139.8, 132.9, 128.2, 127.8, 116.0, 76.5, 44.6, 13.8 ppm. IR (KBr):  = 3408, 3030, 2973, 1640, 1495, 1013, 849 cm-1. HRMS (m/z): calcd for C11H14ClO [M+H]+ 197.0733, found: 197.0741.



ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publication website at DOI: xxxxxx 1H

and 13C NMR spectra of products (PDF)

AUTHOR INFORMATION Corresponding Author *Email: [email protected] *Email: [email protected] ORCID Teck-Peng Loh: 0000-0002-2936-337X Zhi-Liang Shen: 0000-0002-3365-9288 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We gratefully acknowledge the financial support from Nanjing Tech University (Start-up Grant No. 39837118, 39837101, and 39837146), the SICAM Fellowship from Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Forestry University, and Nanyang Technological University.

REFERENCES


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1 For selected reviews, see: (a) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P. Organoindium Reagents: the Preparation and Application in Organic Synthesis. Chem. Rev. 2013, 113, 271. (b) Roy, U. K.; Roy, S. Making and Breaking of Sn−C and In−C Bonds in situ: the Cases of Allyltins and Allylindiums. Chem. Rev. 2010, 110, 2472. (c) Yus, M.; GonzalezGomez, J. C.; Foubelo, F. Catalytic Enantioselective Allylation of Carbonyl Compounds and Imines. Chem. Rev. 2011, 111, 7774; (d) Denmark, S. E.; Fu, J. Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones. Chem. Rev. 2003, 103, 2763. (e) Loh, T.-P.; Chua, G.-L. Discovery of Indium Complexes as Water-Tolerant Lewis Acids. Chem. Commun. 2006, 2739. 2 For selected examples, see: (a) Araki, S.; Ito, H.; Butsugan, Y. Indium in Organic Synthesis: Indium-Mediated Allylation of Carbonyl Compounds. J. Org. Chem. 1988, 53, 1831; (b) Li, C. J.; Chan, T. H. Organometallic Reactions in Aqueous Media with Indium. Tetrahedron Lett. 1991, 32, 7017; (c) Paquette, L. A.; Mitzel, T. M. Addition of Allylindium Reagents to Aldehydes Substituted at Cα or Cβ with Heteroatomic Functional Groups. Analysis of the Modulation in Diastereoselectivity Attainable in Aqueous, Organic, and Mixed Solvent Systems. J. Am. Chem. Soc. 1996, 118, 1931. (d) Huang, J.-M.; Wang, X.-X.; Dong, Y. Electrochemical Allylation Reactions of Simple Imines in Aqueous Solution Mediated by Nanoscale Zinc Architectures. Angew. Chem. Int. Ed. 2011, 50, 924. (e) Hilt, G.; Smolko, K. I. Electrochemical Regeneration of Low-Valent Indium(I) Species as Catalysts for C−C Bond Formations. Angew. Chem., Int. Ed. 2001, 40, 3399. (f) Paquette, L. A.; Lobben, P. C. π-Facial Diastereoselection in the 1,2-Addition of Allylmetal Reagents to 2-Methoxycyclohexanone and Tetrahydrofuranspiro(2-cyclohexanone). J. Am. Chem. Soc. 1996, 118, 1917. (g) Loh, T.-P.; Tan, K.-T.; Chng, S.-S.;



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Cheng, H.-S. Development of a Highly α-Regioselective Metal-Mediated Allylation Reaction in Aqueous Media: New Mechanistic Proposal for the Origin of α-Homoallylic Alcohols. J. Am. Chem. Soc. 2003, 125, 2958. (h) Yasuda, M.; Hirata, K.; Nishino, M.; Yamamoto, A.; Baba, A. Diastereoselective Addition of γ-Substituted Allylic Nucleophiles to Ketones: Highly Stereoselective

Synthesis

of

Tertiary

Homoallylic

Alcohols

Using

an

Allylic

Tributylstannane/Stannous Chloride System. J. Am. Chem. Soc. 2002, 124, 13442. (i) Draskovits, M.; Stanetty, C.; Baxendale, I. R.; Mihovilovic, M. D. Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses—Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal. J. Org. Chem. 2018, 83, 2647. 3 Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing Adjacent Quaternary Centers Using Substituted Allylic Zinc Reagents. J. Am. Chem. Soc. 2007, 129, 5376. 4 (a) Peng, Z.; Blumke, T. D.; Mayer, P.; Knochel, P. Diastereoselective Synthesis of Homoallylic Alcohols with Adjacent Tertiary and Quaternary Centers by Using Functionalized Allylic Aluminum Reagents. Angew. Chem., Int. Ed. 2010, 49, 8516. (b) Shen, Z.-L.; Peng, Z.; Yang, C.-M.; Helberg, J.; Mayer, P.; Marek, I.; Knochel, P. Highly Diastereoselective Preparation of Aldol Products Using New Functionalized Allylic Aluminum Reagents. Org. Lett. 2014, 16, 956. 5 Khan, F. A.; Prabhudas, B. Indium-Mediated, Highly Efficient and Diastereoselective Addition of Cyclic Secondary Allylic Bromides to Carbonyl Compounds. Tetrahedron 2000, 56, 7595.


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6 Liu, X.-Y.; Cheng, B.-Q.; Guo, Y.-C.; Chu, X.-Q.; Li, Y.-X.; Loh, T.-P.; Shen, Z.-L. BismuthMediated Diastereoselective Allylation Reaction of Carbonyl Compounds with Cyclic Allylic Halides or Cinnamyl Halide. Adv. Synth. Catal. 2019, 361, 542. 7 Knochel, P. Handbook of Functionalized Organometallics; Wiley-VCH, Weinheim, Germany, 2005. 8 Crabtree, R. H.; Mingos, D. M. P. Comprehensive Organometallic Chemistry III; Elsevier, Oxford, U.K., 2007. 9 (a) Tanaka, H.; Yamashita, S.; Hamatani, T.; Ikemoto, Y.; Torii, S. Lead-Promoted Allylation of Carbonyl Compounds with Allyl Bromide. Chem. Lett. 1986, 1611. (b) Zhou, J.-Y.; Jia, Y.; Sun, G.-F.; Wu, S.-H. Barbier-Type Allylation of Aldehydes and Ketones with Metallic Lead in Aqueous Media. Synth. Commun. 1997, 27, 1899. (c) Tanaka, H.; Yamashita, S.; Hamatani, T.; Ikemoto, Y.; Torii, S. PbBr2/Al-Promoted Allylation of Carbonyl Compounds with Allyl Halides. Synth. Commun. 1987, 17, 789. 10 For selected typical lithium halide-mediated metal insertions into organic halides, see: (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Convenient Preparation of Polyfunctional Aryl Magnesium Reagents by a Direct Magnesium Insertion in the Presence of LiCl. Angew. Chem., Int. Ed. 2008, 47, 6802. (b) Shen, Z.-L.; Knochel, P. C60-Catalyzed Preparation of Aryl and Heteroaryl Magnesium and Zinc Reagents Using Mg/LiCl. ACS Catal. 2015, 5, 2324. (c) Lee, K.; Seomoon, D.; Lee, P. H. Highly Efficient Catalytic Synthesis of Substituted Allenes Using Indium. Angew. Chem., Int. Ed. 2002, 41, 3901. (d) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.; Yang, Y.-S.; Lai, Y.-C.; Cheong, H.-L.; Loh, T.-P. Direct Synthesis of Ester-Containing Indium Homoenolate and Its Application in Palladium-Catalyzed Cross-



Coupling with Aryl Halide. Chem. Commun. 2011, 47, 4778. (e) Chen, B.-Z.; Zhi, M.-L.; Wang, C.-X.; Chu, X.-Q.; Shen, Z.-L.; Loh, T.-P. Synthesis of Alkyl Indium Reagents by Using Unactivated Alkyl Chlorides and Their Applications in Palladium-Catalyzed Cross-Coupling Reactions with Aryl Halides. Org. Lett. 2018, 20, 1902. For selected examples of using lithium halide as reaction additive/catalyst in other organic transformations, see: (f) Wang, G. J.; Fu, Z. Q.; Huang, W. Access to Amide from Aldimine via Aerobic Oxidative Carbene Catalysis and LiCI as Cooperative Lewis Acid. Org. Lett. 2017, 19, 3362. (g) Gao, Y. R.; Ma, Y. F.; Xu, C.; Li, L.; Yang, T. J.; Sima, G. Q.; Fu, Z. Q.; Huang, W. Potassium 2-Oxo-3-enoates as Effective and Versatile Surrogates for α,β-Unsaturated Aldehydes in NHC-Catalyzed Asymmetric Reactions. Adv. Synth. Catal. 2018, 360, 479. (h) Chang, M.-Y.; Tsai, Y.-L. Stereocontrolled Synthesis of 3-Sulfonyl Chroman-4-ols. J. Org. Chem. 2018, 83, 6798. (i) Chang, M.-Y.; Chen, H.-Y.; Tsai, Y.-L. Intramolecular Benzannulation of 3-Sulfonyl-2-benzylchromen-4-ones: Synthesis of Sulfonyl Dibenzooxabicyclo[3.3.1]nonanes. J. Org. Chem. 2019, 84, 443. (j) Zhang, L.; Lu, H.; Xu, G.-Q.; Wang, Z.-Y.; Xu, P.-F. PPh3 Mediated Reductive Annulation Reaction between Isatins and Electron Deficient Dienes to Construct Spirooxindole Compounds. J. Org. Chem. 2017, 82, 5782. 11 Blümke, T. D.; Chen, Y.-H.; Peng, Z.; Knochel, P. Preparation of Functionalized Organoaluminiums by Direct Insertion of Aluminium to Unsaturated Halides. Nat. Chem. 2010, 2, 313. 12 (a) Blümke, T. D.; Klatt, T.; Koszinowski, K.; Knochel, P. InCl3-Catalyzed Synthesis of 1,2Dimetallic Compounds by Direct Insertion of Aluminum or Zinc Powder. Angew. Chem., Int. Ed. 2012, 51, 9926. (b) Takai, K.; Ikawa, Y. Indium-Catalyzed Reduction of Allyl Bromide with


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Gallium or Aluminum. Formation of Allylgallium and Allylaluminum Sesquibromides. Org. Lett. 2002, 4, 1727. (c) Chen, B.-Z.; Wang, C.-X.; Jing, Z.-H.; Chu, X.-Q.; Loh, T.-P.; Shen, Z.L. Metallic Salt-Catalyzed Direct Indium Insertion into Alkyl Iodides and Their Applications in Cross-Coupling Reactions. Org. Chem. Front. 2019, 6, 313. (d) Wu, C.; Wang, Z.; Hu, Z.; Zeng, F.; Zhang, X.-Y.; Cao, Z.; Tang, Z.; He, W.-M.; Xu, X.-H. Direct Synthesis of Alkenyl Iodides via IndiumCatalyzed Iodoalkylation of Alkynes with Alcohols and Aqueous HI. Org. Biomol. Chem. 2018, 16, 3177.

13 For selected reviews of using Bi(III) salt as reaction catalyst, see: (a) Ollevier, T. BismuthMediated Organic Reactions; Springer, Berlin, Heidelberg, 2012. (b) Ollevier, T. New Trends in Bismuth-Catalyzed Synthetic Transformations. Org. Biomol. Chem. 2013, 11, 2740. 14 Takai, K.; Kakiuchi, T.; Utimoto, K. A Dramatic Effect of a Catalytic Amount of Lead on the Simmons-Smith Reaction and Formation of Alkylzinc Compounds from Iodoalkanes. Reactivity of Zinc Metal: Activation and Deactivation. J. Org. Chem. 1994, 59, 2671. 15 For selected examples of metal-mediated or metallic salt-catalyzed organic reactions developed in our group, see: (a) Shen, Z.-L.; Loh, T.-P. Indium-Copper-Mediated Barbier-Grignard-Type Alkylation Reaction of Imines in Aqueous Media. Org. Lett. 2007, 9, 5413. (b) Shen, Z. L.; Cheong, H. L.; Loh, T. P. Indium-Silver- and Zinc-Silver-Mediated Barbier-Grignard-Type Alkylation Reactions of Imines by Using Unactivated Alkyl Halides in Aqueous Media. Chem.Eur. J. 2008, 14, 1875. (c) Wu, L.-H.; Zhao, K.; Shen, Z.-L.; Loh, T.-P. Copper-Catalyzed Trifluoromethylation of Styrene Derivatives with CF3SO2Na. Org. Chem. Front. 2017, 4, 1872. (d) Shen, Z.-L.; Goh, K. K. K.; Cheong, H.-L.; Wong, C. H. A.; Lai, Y.-C.; Yang, Y.-S.; Loh, T.-P. Synthesis of Water-Tolerant Indium Homoenolate in Aqueous Media and Its Application in the Synthesis of 1,4-Dicarbonyl Compounds via Palladium-Catalyzed Coupling with Acid



Chloride. J. Am. Chem. Soc. 2010, 132, 15852. (e) Zhi, M.-L.; Chen, B.-Z.; Deng W.; Chu X.Q.; Loh, T.-P.; Shen, Z.-L. Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions. J. Org. Chem. 2019, 84, 3017. (f) Yun, J.-J.; Liu, X.-Y.; Deng, W.; Chu, X.-Q.; Shen, Z.-L.; Loh, T.-P. Chromium(III)Catalyzed Addition of Water and Alcohol to α,β-Unsaturated Ketones for the Synthesis of β‑Hydroxyl and β‑Alkoxyl Ketones in Aqueous Media. J. Org. Chem. 2018, 83, 10898. (g) Yun, J.-J.; Zhi, M.-L.; Shi, W.-X.; Chu, X.-Q.; Shen, Z.-L.; Loh, T.-P. Indium(III)-Catalyzed Hydration and Hydroalkoxylation of α,β-Unsaturated Ketones in Aqueous Media. Adv. Synth. Catal. 2018, 360, 2632. (h) Chu, X.-Q.; Cheng, B.-Q.; Zhang, Y.-W.; Ge, D.; Shen, Z.-L.; Loh. T.-P. Copper-Catalyzed Three-Component Cyclization of Amidines, Styrenes, and Fluoroalkyl Halides for the Synthesis of Modular Fluoroalkylated Pyrimidines. Chem. Commun. 2018, 54, 2615. (i) Shen, L.; Zhao, K.; Doitomi, K.; Ganguly, R.; Li, Y.-X.; Shen, Z.-L.; Hirao, H.; Loh, T.-P. Lewis Acid-Catalyzed Selective [2+2]-Cycloaddition and Dearomatizing Cascade Reaction of Aryl Alkynes with Acrylates. J. Am. Chem. Soc. 2017, 139, 13570. 16 (a) Wang, C.-S.; Fan, T.; Zhang, H.-H.; Li, C.; Shen, Y.; Mei, G.-J.; Shi, F. Gallium BromidePromoted Dearomative Indole Insertion in 3-Indolylmethanols: Chemoselective and (Z/E)Selective Synthesis of 3,3′-Bisindole Derivatives. J. Org. Chem. 2016, 81, 11734. (b) Tu, P.-C.; Zhou, L.; Kirillov, A. M.; Fang, R.; Yang, L. Computational Study on GaCl3-Mediated Reactions of Donor–Acceptor Cyclopropanes with Aromatic Aldehydes: Mechanism and Role of GaCl3 and Aldehydes. Org. Chem. Front. 2018, 5, 1702. (c) Novikov, R. A.; Tarasova, A. V.; Denisov, D. A.; Borisov, D. D.; Korolev, V. A.; Timofeev, V. P.; Tomilov, Y. V. [4 + 2] Annulation of Donor–Acceptor Cyclopropanes with Acetylenes Using 1,2-Zwitterionic


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Reactivity. J. Org. Chem. 2017, 82, 2724. (d) Zotova, M. A.; Novikov, R. A.; Shulishov, E. V.; Tomilov, Y. V. GaCl3-Mediated “Inverted” Formal [3 + 2]-Cycloaddition of Donor–Acceptor Cyclopropanes to Allylic Systems. J. Org. Chem. 2018, 83, 8193. 17 Loh, T. P.; Li, X. R. A Highly Stereoselective Synthesis of β-Trifluoromethylated Homoallylic Alchols in Water. Angew. Chem., Int. Ed. 1997, 36, 980. 18 Hirashita,

T.;

Kamei,

T.;

Satake,

M.;

Horie,

T.;

Shimizu,

H.;

Araki,

S.

Control of Diastereoselectivity in the Crotylation and Cinnamylation of Aldehydes by the Sele ction of Ligands on Allylic Indium Reagents. Org. Biomol. Chem. 2003, 1, 3799. 19 (a) Weber, F.; Ballmann, M.; Kohlmeyer, C.; Hilt, G. Nickel-Catalyzed Double Bond Transposition of Alkenyl Boronates for in Situ syn-Selective Allylboration Reactions. Org. Lett. 2016, 18, 548. (b) Shimizu, H.; Igarashi, T.; Miura, T.; Murakami, M. Rhodium-Catalyzed Reaction of 1-Alkenylboronates with Aldehydes Leading to Allylation Products. Angew. Chem. Int. Ed. 2011, 50, 11465. 20 For selected reviews related to the use of gallium(III) salt in organic synthesis, see: (a) Prakash, G. K. S.; Mathew, T.; Olah, G. A. Gallium(III) Triflate: An Efficient and a Sustainable Lewis Acid Catalyst for Organic Synthetic Transformations. Acc. Chem. Res. 2012, 45, 565. (b) Yamaguchi, M.; Nishimura, Y. Trichlorogallium and Trialkylgalliums in Organic Synthesis. Chem. Commun. 2008, 35. 21 (a) Zimmerman, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov and Reformatsky Reactions. I. J. Am. Chem. Soc. 1957, 79, 1920; (b) Heathcock, C. H. Acyclic Stereocontrol through the Aldol Condensation. Science 1981, 214, 395.



22 You, H.; Rideau, E.; Sidera, M.; Fletcher, S. P. Non-Stabilized Nucleophiles in Cu-Catalysed Dynamic Kinetic Asymmetric Allylic Alkylation. Nature 2015, 517, 351. 23 Brooner, R. E. M.; Widenhoefer, R. A. Stereochemistry and Mechanism of the Brønsted Acid Catalyzed Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene. Chem. Eur. J. 2011, 17, 6170. 24 Rideau, E.; You, H.; Sidera, M.; Claridge, T. D. W.; Fletcher, S. P. Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials. J. Am. Chem. Soc. 2017, 139, 5614. 25 Langloisa, J.-B.; Alexakisa, A. Copper‐Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates: Application of Dynamic Kinetic Asymmetric Transformation. Adv. Synth. Catal. 2010, 352, 447. 26 Bond, C. W.; Cresswell, A. J.; Davies, S. J.; Fletcher, A. M.; Kurosawa, W. AmmoniumDirected Oxidation of Cyclic Allylic and Homoallylic Amines. J. Org. Chem. 2009, 74, 6735. 27 Wang, W.; Zhang, T.; Shi, M. Chiral Bis(NHC)−Palladium(II) Complex Catalyzed and Diethylzinc-Mediated Enantioselective Umpolung Allylation of Aldehydes. Organometallics 2009, 28, 2640. 28 Kurono, N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M. Regioselective Synthesis of Substituted 1-Indanols, 2,3-Dihydrobenzofurans and 2,3-Dihydroindoles by Electrochemical Radical Cyclization Using an Arene Mediator. Tetrahedron 2004, 60, 1791. 29 Zheng, Y.; Bao, W.; Zhang, Y. Carbon-Carbon Bond Formation Reaction Promoted by Cadmium in Aqueous Media. Synth. Commun. 2000, 30, 3517.


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30 Howell, G. P.; Minnaard, A. J.; Feringa, B. L. Asymmetric Allylation of Aryl aldehydes: Studies on the Scope and Mechanism of the Palladium Catalysed Diethylzinc Mediated Umpolung Using Phosphoramidite Ligands. Org. Biomol. Chem. 2006, 4, 1278.


Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with

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