Oxidative Î±-Trichloromethylation of Tertiary Amines: an Entry to Î±

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Oxidative #-Trichloromethylation of Tertiary Amines: an Entry to #-Amino Acid Esters Changming Xu, Zhaobin Zhu, Yongchang Wang, Zhiguo Jing, Bin Gao, Li Zhao, and Wen-Kui Dong J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03238 • Publication Date (Web): 23 Jan 2019 Downloaded from http://pubs.acs.org on January 27, 2019

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The Journal of Organic Chemistry

Oxidative α-Trichloromethylation of Tertiary Amines: an Entry to αAmino Acid Esters Changming Xu,*a,b Zhaobin Zhu,a Yongchang Wang,a Zhiguo Jing,a Bin Gao,a Li Zhao,a and Wen-Kui Donga aSchool

of Chemical and Biological Engineering, Lanzhou Jiaotong University, 88 Anning West Road, Lanzhou 730070, China. bKey Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Ar

Ar Ar

TMSCCl3 N

Ar

R DDQ, rt, 1 min

 Instantaneous reaction rate  Regional selective specificity  High functional group tolerance  Gram-scale synthesis

N

N

N

R CO2Et

R

CCl3

Ar Ar Cl

N

R

Cl

N

R

R

Cl

Cl

ABSTRACT: α-Trichloromethylation of tertiary amines with trimethyl(trichloromethyl)silane by oxidative coupling, using DDQ as oxidant, has been realized. The reaction is instantaneous, scalable and tolerates a broad range of functional groups and heteroarenes. The trichloromethylated products can be easily converted to β,β-dichloroamines, enamines, and α-amino acid esters under operationally simple conditions. This methodology provides an efficient alternative to the poisonous cyanation reactions for the synthesis of carboxylic acid and their derivatives.

INTRODUCTION Trichloromethyl groups are present in natural products that exhibit excellent biological activity, such as dysamide,1 dysidenin,2 sintokamide,3 barbamide,4 muironolide,5 herbacic acid6 and neodysidenin.7 More significantly, they can be easily converted to diverse one-carbon functional groups, including methyl, chloromethyl, dichloromethyl,8 trifluoromethyl9 and carboxyl groups,10 as well as carboxylic esters and amides.11 It should be noted that direct introduction carboxyl groups into organic molecules remains a challenge, which depends very heavily on inert carbon dioxide insertion reactions12 and poisonous cyanation reactions.13 Although fluorine and chlorine are in the same group on the periodic table and the trifluoromethylation reactions have been well-developed,14 due to fluorine-containing groups play an important role in pharmaceuticals and agrochemicals, as well as in materials science, it seems that the trifluoromethyl can’t replace trichloromethyl to achieve above transformations so far. Despite the useful and versatile chemical properties of trichloromethyl groups, the trichloromethylation reactions have received relatively little attention. Trichloromethylation reactions can date back to 1939, when the condensation of acetone with chloroform under strongly basic conditions was discovered by Fishburn and Watson.15 Subsequently, various 1,2-addition reactions of trichloromethyl anion to ketones,

aldehydes,16 imines17 and (iso)quinolone Reissert salts18 were presented (Scheme 1, A). In 1945, the substrate scopes of addition reactions were extended to Michael acceptors (Scheme 1, B).19 At the same time, a breakthrough was made by Kharasch et al., who reported addition reactions of carbon tetrachloride and chloroform to terminal olefins to form new C-CCl3 bond and C-X (X=Cl or H) bond simultaneously (Scheme 1, C), named atom transfer radical addition reactions (ATRA).20 Following this pioneering work, Stephenson, Ready and others enriched this chemistry significantly, making this methodology a highly atom-economical synthetic method.21 Later, the cross-coupling reactions of LiCCl3 with alkyl iodides22 and cyclic ethers,23 as well as alkynyllithiums with carbon tetrachloride,24 were reported (Scheme 1, D). In 1990, Sutherland also disclosed a trichloromethylation of cyclopentadienyliron complexed dialkylarenes followed by demetallation to give trichloromethylarenes (Scheme 1, E).25 Recently, Zakarian demonstrated diastereoselective trichloromethylation of N-acyl oxazolidinones by dual Ti-Ru catalysis, which was applied in the total synthesis of neodysidenin.26 Then Meggers developed the enantioselective trichloromethylation of 2-acyl imidazoles and 2-acylpyridines through visible-light-activated photoredox catalysis (Scheme 1, F).27 In addition, an enantioselective trichloromethylation of Morita-Baylis-Hillman (MBH)-type allylic fluorides with

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chloroform has been disclosed by Shibata (Scheme 1, G).28 Given the prevalence of nitrogen-containing compounds in pharmaceuticals and bioactive natural products, there is a compelling need to develop powerful synthetic methods for functionalization of amines. Herein, we describe a highly efficient procedure for the α-trichloromethylation of tertiary amines through an oxidative coupling reaction,29 whose products can be easily converted to α-amino acid esters via hydrolysis of the trichloromethyl groups in a water-ethanol mixed solvent under mild conditions (Scheme 1, H). Scheme 1. Overview on Trichloromethylation Reactions (A) 1,2-Addition, pioneered by Fishburn and Watson in 1939 R''

HCCl3, Cl3CCOOK, Cl3CCOOH or TMSCCl3

X

R''

XH CCl3

R'

R

X = O, N (B) Michael addition, pioneered by Bruson in 1945 HCCl3, TMSCCl3, R' Cl3CLi or Cl3CMgCl EWG EWG = CN, COOR'', COR'', NO2 R

R'

R

R' Cl3C

EWG R

(C) ATRA, pioneered by Kharasch in 1945 X

X CCl3 (X = H, Cl, Br)

R (D) Cross coupling

Weinreb, 1990

RI

OH

Imai, 1994 n n = 1, 2, 3

CCl3 n

R

CCl4

Li

R

CCl3

R

Cl3CLi

O R

CCl3

R

Martins, 2004

CCl3

R

(E) Trichloromethylation of cyclopentadienyliron complexed arenes 1) HCCl3

Rn

Sutherland, 1990

2) I2

CO2R

HCCl3

Shibata, 2016

1a

O *

R

R'

CCl3 Ar

*

CO2R

CCl3

F (H) This work: oxidative coupling

R

R'' N

R'

N

CCl3

(G) Trichloromethylation of MBH-fluorides Ar

yield at rt respectively (Entries 4-5), and various unknown byproducts were observed by TLC analysis. Subsequently, some other chemical oxidants were examined. Both BPO and TEMPO were confirmed to be ineffective for this transformation (Entries 6-8). Nevertheless, PhI(OAc)2 could enable this oxidative trichloromethylation, giving moderate yields at 60 oC or rt (Entries 9-10). To our delight, the reaction could complete within seconds, furnishing the desired product 3a in quantitative yield at rt by changing the oxidant to DDQ (Entry 11).31 It should be noted that a DDQ oxidative trifluoromethylation of N-aryl substituted tetrahydroisoquinoline with TMSCF3/KF was also reported,31a but the catalytic amount of Cu(I) was indispensable compared with this trichloromethylation reaction, which indicated the completely different reactivity between CF3- and CCl3-. Furthermore, the replacement of oxidant by p-benzoquinone (PBQ) led to the formation of targeted product in only 25% yield (Entry 12). A control reaction showed that omission of KF resulted in low yield (Entry 13). Either reducing the amount of KF or replacing it with NaF or CsF, the reaction proceeded smoothly to afford the desired product but in decreased yields (Entries 14-17). Above results indicate that the consistence of the formation rate of nucleophile CCl3from TMSCCl3/KF with the generation rate of the iminium ions is a key factor for the oxidative coupling reaction. Next, attempts to reduce the amount of TMSCCl3 proved deleterious to the yield of the reaction (Entry 18). Further screening of solvents showed that MeCN was the best choice for this transformation (Entries 19–23). Table 1. Optimization of Reaction Conditionsa

Rn

F6PCpFe (F) -Trichloromethylation of carbonyls Zakarian, 2010 O BrCCl3 Meggers, 2015 R' R

TMSCCl3 DDQ

R'' N

R

CCl3

R'

Page 2 of 9

R

R'' N

R' COOEt -amino acid ester and more...

RESULTS AND DISCUSSION As summarized in Table 1, we selected N-phenyltetrahydroisoquinoline 1a as model substrate and 3 equivalentsof Ruppert-Prakash reagent trimethyl(trichloromethyl)silane (TMSCCl3) 230 as trichloromethyl source to optimize the reaction conditions in the presence of 1.5 equivalents of KF. Initially, TBHP/CuBr (5 mol%) was employed as oxidant, which had been proved to be highly efficient in many oxidative coupling reactions,29 but the trichloromethylated product 3a was afforded only with 34% yield in acetonitrile at 60 oC (Entry 1). In the absence of CuBr, the reaction still proceeded in nearly the same yield (Entry 2). To our disappointment, when the reaction was carried out at room temperature, it was shut down completely (Entry 3). Switching the oxidant to O2 (1 atm)/CuBr (5 mol%), the desired product was delivered in 25% yield at 60 oC and 52%

Entry

Oxidant

TMSCCl3 2

Oxidant (1.1 equiv) Fluoride

Fluoride

1b

TBHP/ CuBr (5%)

KF (1.5 eq)

2b

TBHP

3c 4c

N

Solvent, 1 min

Solvent

CCl3 3a

Temp.

Yield

MeCN

60

oC

34%

KF (1.5 eq)

MeCN

60 oC

38%

TBHP

KF (1.5 eq)

MeCN

rt

NR

O2 (1 atm)/

KF (1.5 eq)

MeCN

60 oC

25%

KF (1.5 eq)

MeCN

rt

52%

CuBr (5%) 5d

O2 (1 atm)/ CuBr (5%)

6b

BPO

KF (1.5 eq)

MeCN

60 oC

14%

7c

BPO

KF (1.5 eq)

MeCN

rt

trace

8c

TEMPO

KF (1.5 eq)

MeCN

rt or

trace

60 oC 9b

PhI(OAc)2

KF (1.5 eq)

MeCN

60 oC

68%

10e

PhI(OAc)2

KF (1.5 eq)

MeCN

rt

52%

11

DDQ

KF (1.5 eq)

MeCN

rt

100%

12f

PBQ

KF (1.5 eq)

MeCN

rt

25%

13

DDQ

MeCN

rt

40%

14

DDQ

KF (1.0 eq)

MeCN

rt

73%

15

DDQ

KF (1.2 eq)

MeCN

rt

81%

16

DDQ

NaF (1.5 eq)

MeCN

rt

55%

17

DDQ

CsF (1.5 eq)

MeCN

rt

68%

18g

DDQ

KF (1.5 eq)

MeCN

rt

55%

19

DDQ

KF (1.5 eq)

Et2O

rt

63%

20

DDQ

KF (1.5 eq)

MeOH

rt

mess


-

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The Journal of Organic Chemistry 21

DDQ

KF (1.5 eq)

CH2Cl2

rt

31%

22

DDQ

KF (1.5 eq)

THF

rt

28%

23

DDQ

KF (1.5 eq)

toluene

rt

28%

aUnless

otherwise noted, all the reactions were run with 1a (0.3 mmol), 2 (0.9 mmol) and oxidant (0.33 mmol) in 3.0 mL solvent for 1 min. bReaction was run for 30 min. cReaction was run for 12 h. dReaction was run for 30 h. eReaction was run for 2 h. fReaction was run for 7 h. g2.0 equivalents (0.6 mmol) of 2 was used. NR: No Reaction. Encouraged by these results, we further conducted a gramscale experiment using model substrate under the optimized conditions. Gratifyingly, the reaction could also quickly complete within 5 min, furnishing the trichloromethylated product 3a in 99% yield, and its structure was confirmed by X-ray crystal structure determination (Figure S1). Scheme 2. Substrate Scopea

Ar

N

TMSCCl3 2

R

1

DDQ (1.1 equiv) KF(1.5 equiv)

N

CCl3

CCl3

N

N

N

CCl3

CCl3

CCl3

3e, 84%c

3f, 67%

3d, 80%

N

3g,76% O N CCl3 3k, 75% S N

S

CCl3

Me N

1t, NR

N 1w, NR

N

1u, NR

N

3s, 86%

OBn

CCl3 3r, 66%

O2N N

N

O N

OEt

CCl3 3q, 63%

CCl3 3p, 61%

N

S

O N

N

CCl3 3o, 67%

MeONa (10 eq)

N

MeOH, 60 oC, 10 h

Cl Cl 4, 74% CCl3 3n, 60%

CCl3 3m, 55%

S

Ph

3a

CCl3

Ph

1v, mess

N

Boc 1x, NR

O

Cbz 1y, NR

aUnless

otherwise noted, all the reactions were run with 1 (0.3 mmol), 2 (0.9 mmol), KF (0.45 mmol) and DDQ (0.33 mmol) in 3.0 mL solvent for 1 min. bReaction was performed on 1 gram scale for 5 min. cReaction was run for 30 min. NR: No Reaction Having established an optimal protocol for this reaction (Table 1, entry 11), we then examined the scope of the tetrahydroisoquinolines bearing N-aryl and N-alkyl substituent. As shown in Scheme 2, both electron-poor and electron-rich N-aryltetrahydroisoquinolines are suitable substrates and provide the trichloromethylated products in high yields (see 3b-3e). Notably, the reaction with sterically hindered

Ph

H2O:EtOH = 1:5 (v/v)

O OEt 7, 64%

reflux, 48 h

N

LiAlH4 (5 eq) THF, 70 oC, 6 h

N

N

CCl3 3l, 80%

N

S

S N

OEt

N CCl3 3j, 73%

3i, 75%

S

Cl

X-ray for 3f

CCl3

CCl3 3h, 47%

CCl3 3c, 83%

N

N

CH3

CCl3

R

N OCH3

3b, 98%

X-ray for 3a

CF3

N 3 CCl3

N

3a, 100% 3a, 99%b

Ar

MeCN, rt, 1 min

substrates worked equally well and delivered the desired products in high yield albeit at a slower rate (see 3e). N-alkyl substituted tetrahydroisoquinolines participated in the reaction to afford the corresponding products 3f-3k in moderate to good yields. It should be noted that benzyl, allyl, propargyl and ester substituents were well tolerated under this oxidative condition. The X-ray crystal structure of 3f demonstrated that the reaction exclusively took place at the 1position of tetrahydroisoquinoline ring but not the N-benzyl group (Figure S2), despite the fact that both of them were highly active sites. To extend the scope of this novel reaction, we further turned our attention to the use of 4,5,6,7tetrahydrothieno[3,2-c]pyridine, which was a core structure of many popular medicines, including (S)-clopidogrel,32 prasugrel33 and ticlopidine.34 To our gratification, this mild and operationally simple protocol rapidly transformed a wide variety of N-substituted 4,5,6,7-tetrahydrothieno[3,2c]pyridines into the corresponding trichloromethylated products in moderate yields (see 3l-3r). These successful examples have generally rendered heterocycles compatible with this protocol, and highlighted the regional selective specificity of this reaction. Much to our surprise, a trichloromethylation reaction of N,N-dimethylanilin also proceeded smoothly but afforded an abnormal product 3s, which formed by a three-molecule coupling reaction. However, no reaction occurred when either N,N-diethylanilin 1t or N,Ndimethyl-4-nitroanilin 1u was used. In contrast, the reaction of 4,N,N-trimethylanilin 1v was messy. We also studied the reactivities of N-Boc/Cbz tetrahydroisoquinolines (1w, 1x) and isochroman 1y, and found that they didn’t work under standard conditions. Scheme 3. Transformations of 3a

LiAlH4 (5 eq) THF, 70 oC, 10 h

Cl

Ph

Cl 5, 61%

N

Ph

H H 6, 77%

To demonstrate the synthetic versatility of the trichloromethylated products, several diversifications of 3a were performed (Scheme 3). First, it could be easily converted to 2,2-dichloroenamine 4 via dehydrochlorination under basic conditions. Next, treatment of 3a with LiAlH4 in THF at 70 oC for 6 h gave the dichloromethylated product 5 and enamine 6 with 61% and 33% yield respectively, and they could be easily separated by standard silica gel chromatography. Prolonging reaction time to 10 h resulted in the exclusive formation of enamine 6 in 77% yield. We speculated that the enamine 6 was derived from monochloromethylated product via dehydrochlorination. As expected, hydrolysis of the trichloromethyl group could be easily accomplished in a water-ethanol (1/5, v/v) mixed solvent under refluxing conditions, furnishing α-amino acid esters 7 with 64% yield. It means that the trichloromethylation reactions provide an effective alternative to the poisonous cyanation reactions for the synthesis of carboxylic acid and their derivatives. Most notably, Shimakoshi recently developed a system for the transformation of trichlorinated compounds into esters or amides, catalyzed by a vitamin B12-TiO2 hybrid under UV light irradiation in air.11 Compared with it, our methods can be



easily carried out only with commercially available ethanol and water.

CONCLUSIONS In summary, we have developed the first oxidative αtrichloromethylation of tertiary amines, which can be completed almost instantaneously at room temperature by using DDQ as oxidant. The reaction is amenable to be scaledup to a gram scale with no detriment to the yield and compatible with a variety of functional groups, including benzyl, allyl, propargyl and ester substituents, as well as heterocycles. The trichloromethylated products were transformed into β,β-dichloroamines, enamines, and α-amino acid esters under operationally simple conditions. We anticipate that the trichloromethylation reactions will offer a useful alternative to the poisonous cyanation reactions for the synthesis of carboxylic acid and their derivatives.

EXPERIMENTAL SECTION General information: Commercial reagents were used as received, unless otherwise indicated. Nuclear magnetic resonance (NMR) spectra were recorded using Bruker AV-500 spectrometer. 1H and 13C NMR spectra were measured on a NMR instrument (500 MHz and for 1H NMR, 125 MHz for 13C NMR). Tetramethylsilane (TMS) served as the internal standard for 1H NMR, and CDCl3 served as the internal standard for 13C NMR. HRMS were recorded by ESI on a TOF mass spectrometer. Reactions were monitored using thinlayer chromatography (TLC). Materials: Acetonitrile was dried over CaH2 and distilled just before use. N-aryl-1,2,3,4-tetrahydroisoquinolines 1a-1f and 1l (Scheme S2) were prepared according to the procedure of Li and Buchwald.29c,35 1h-1k (Scheme S1) and 1m-1r (Scheme S3) were prepared according to the procedure of Grigg.36 N-methyl-1,2,3,4-tetrahydroisoquinoline 1g was prepared according to the procedure of Lasne.37 Substrates 1s1v and 1y were commercially available. Substrates 1w, 1x,38 TMSCCl3 (2)30 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine39 were prepared according to literature precedent. Compounds 1a-1g, 1i, 1w, 1x, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine and TMSCCl3 (2) are known and the NMR data are identical to those previously reported. Compounds 1h, 1j-1r and 3a-3s are new and their synthetic procedures and characterization data are listed as below. A typical procedure for the synthesis of compound substrates 1h, 1j, 1k: 1,2,3,4-Tetrahydro-isoquinoline (15.0 mmol, 2.0 g), alkyl bromide (15.0 mmol) and anhydrous potassium carbonate (19.5 mmol, 2.7 g) were mixed in dry CH3CN (30 mL) and stirred at room temperature for 4 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (20:1) to give the target product. 2-Butyl-1,2,3,4-tetrahydroisoquinoline (1h). Yellow oil, 1.7 g, 59% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.17-7.06 (m, 3H), 7.05-7.00 (m, 1H), 3.64 (s, 2H), 2.94-2.90 (m, 2H), 2.76-2.72 (m, 2H), 2.53-2.49 (m, 2H), 1.64-1.57 (m, 2H), 1.46-1.35(m, 2H), 0.96 (t, J=7.3 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 135.0, 134.5, 128.7, 126.7, 126.1, 125.6,

Page 4 of 9

58.4, 56.4, 51.1, 29.5, 29.2, 20.9, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H20N+ 190.1595, found 190.1593. 2-(Prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline(1j). Yellow oil, 1.2 g, 47% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.16-7.09 (m, 3H), 7.07-7.03 (m, 1H), 3.78 (s, 2H), 3.52 (d, J=2.5 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.85 (t, J=5.9 Hz, 2H), 2.29 (t, J=2.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 134.6, 133.8, 128.7, 126.7, 126.2, 125.7, 78.8, 73.4, 54.4, 49.8, 46.7, 29.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H14N+ 172.1126, found 172.1125. Ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetate (1k). Yellow oil, 1.5 g, 47%. 1H NMR (500 MHz, CDCl3) δ ppm 7.10 (d, J=7.0 Hz, 3H), 7.00 (d, J=6.9 Hz, 1H), 4.27-4.19 (m, 2H), 3.80 (s, 2H), 3.41 (s, 2H), 2.97-2.88 (m, 4H), 1.29 (t, J=7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 170.5, 134.3, 133.9, 128.6, 126.5, 126.2, 125.7, 60.7, 59.2, 55.4, 50.7, 29.0, 14.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H18NO2+ 220.1336, found 220.1330. The procedure for the synthesis of substrate 1l: Copper (I) iodide (200 mg, 1 mmol) and potassium phosphate (4.25 g, 20 mmol) were put into a Schlenk tube. The tube was evacuated and back filled with nitrogen. 2-Propanol (10 mL), ethylene glycol (1.11 mL, 20 mmol), 4,5,6,7tetrahydrothieno[3,2-c]pyridine (2.1 g, 15 mmol) and iodobenzene (1.12 mL, 10 mmol) were added successively by micro-syringe at room temperature. The reaction mixture was heated at 50 °C and kept for 72 h and then allowed to cool to room temperature. Diethyl ether (20 mL) and water (20 mL) were then added to the reaction mixture. The aqueous layer was extracted by diethyl ether (2×20 mL). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (100:1) to give the desired product. 5-Phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1l). Yellow oil, 1.0 g, 32% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.24 (t, J=7.7 Hz, 2H), 7.06 (d, J=5.1 Hz, 1H), 6.95 (d, J=8.1 Hz, 2H), 6.81 (t, J=7.3 Hz, 1H), 6.78 (d, J=5.2 Hz, 1H), 4.25 (s, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.95-2.88 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 150.7, 133.7, 133.3, 129.2, 125.2, 122.7, 119.3, 116.0, 49.0, 47.4, 25.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H14NS+ 216.0847, found 216.0847. A typical procedure for the synthesis of compound substrates 1m-lr: 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (15 mmol, 2.1 g), alkyl bromide (15 mmol) and anhydrous potassium carbonate (19.5 mmol, 2.7 g) were mixed in dry CH3CN (30 mL) and stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (20:1) to give the target product. 5-Benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1m). Yellow oil, 2.0 g, 59% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.43-7.38 (m, 2H), 7.37-7.32 (m, 2H), 7.29-7.25 (m, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.69 (d, J=5.1 Hz, 1H), 3.71 (s, 2H), 3.59-3.55(m, 2H), 2.93-2.88 (m, 2H), 2.85-2.80 (m, 2H). 13C{1H} NMR (125 MHz, CDCl ) δ ppm 138.5, 134.1, 133.6, 3 129.2, 128.5, 127.3, 125.4, 122.8, 62.4, 53.3, 50.7, 25.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H16NS+ 230.1003, found 230.1007.


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The Journal of Organic Chemistry 5-Butyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1n). Yellow oil, 2.1 g, 72% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.06 (d, J=5.1 Hz, 1H), 6.72 (d, J=5.1 Hz, 1H), 3.55 (s, 2H), 2.93-2.86 (m, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.53 (t, J=8.0 Hz, 2H), 1.61-1.52 (m, 2H), 1.43-1.33 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 134.1, 133.5, 125.4, 122.7, 57.8, 53.3, 51.1, 29.7, 25.6, 20.9, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H18NS+ 196.1160, found 196.1158. 5-Allyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1o). Yellow oil, 1.1 g, 41% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.06 (d, J=5.2 Hz, 1H), 6.72 (d, J=5.2 Hz, 1H), 5.99-5.89 (m, 1H), 5.27-5.18 (m, 2H), 3.56 (s, 2H), 3.20 (d, J=6.6 Hz, 2H), 2.92-2.88 (m, 2H), 2.80 (t, J=5.8 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 135.5, 133.9, 133.5, 125.3, 122.8, 118.0, 61.0, 53.1, 50.6, 25.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H14NS+ 180.0847, found 180.0844. 5-(Prop-2-yn-1-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1p). Yellow oil, 1.1 g, 41% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.08 (d, J=5.1 Hz, 1H), 6.74 (d, J=5.1 Hz, 1H), 3.69 (s, 2H), 3.53 (d, J=2.4 Hz, 2H), 2.95-2.92 (m, 2H), 2.912.88 (m, 2H), 2.27 (t, J=2.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 133.7, 133.0, 125.3, 122.9, 78.9, 73.4, 51.6, 49.8, 46.5, 25.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H12NS+ 178.0691, found 178.0689. Ethyl 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (1q). Yellow oil, 2.1 g, 63% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.06 (d, J=5.1 Hz, 1H), 6.70 (d, J=4.5 Hz, 1H), 4.24-4.17 (m, 2H), 3.74 (s, 2H), 3.44 (s, 2H), 3.00-2.88 (m, 4H), 1.28 (t, J=6.7 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 170.6, 133.3, 133.1, 125.2, 122.8, 60.8, 58.5, 52.5, 50.6, 25.3, 14.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H16NO2S+ 226.0902, found 226.0907. Benzyl 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (1r). Yellow solid, 2.4 g, 56% yield, mp 48-51°C. 1H NMR (500 MHz, CDCl3) δ ppm 7.40-7.34 (m, 5H), 7.07 (d, J=5.1 Hz, 1H), 6.71 (d, J=5.1 Hz, 1H), 5.20 (s, 2H), 3.75 (s, 2H), 3.50 (s, 2H), 3.00-2.94 (m, 2H), 2.94-2.90 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 170.4, 135.7, 133.3, 133.1, 128.6, 128.4, 128.4, 125.2, 122.7, 66.4, 58.4, 52.4, 50.5, 25.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18NO2S+ 288.1058, found 288.1060. General procedure for trichloromethylation reactions: To tertiary amine (0.3 mmol), KF (0.45 mmol, 26 mg) and TMSCCl3 (0.9 mmol, 171 mg) in dry CH3CN (3 mL) was added DDQ (0.33 mmol, 75 mg). The reaction was stirred at room temperature, until completion as indicated by TLC. The solution was diluted with ethyl acetate (20 mL) and then washed with 2 N sodium bicarbonate solution (20 mL). The aqueous phase was extracted by ethyl acetate (2×20 mL). The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation.The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (100:1) to give the target product 3a-3s. 1-(Trichloromethyl)2-phenyl--1,2,3,4tetrahydroisoquinoline (3a). White solid, 98 mg, 100% yield,mp 75-77 °C. 1H NMR (500 MHz,CDCl3) δ ppm 7.65 (d, J=7.7 Hz, 1H), 7.38-7.14 (m, 5H), 7.03 (d, J=8.2 Hz, 2H), 6.84 (t, J=7.3 Hz, 1H), 5.64 (s, 1H), 4.12-4.04 (m, 1H), 3.673.59 (m, 1H), 3.24-3.14 (m, 1H), 3.11-3.02 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3) δ ppm 150.1, 136.5, 131.9, 129.9, 129.4, 129.0, 128.8, 125.9, 119.5, 116.0, 106.4, 74.3, 43.0, 27.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H15Cl3N+ 326.0265, found 326.0265. 1-(Trichloromethyl)-2-(4-methoxyphenyl)1,2,3,4tetrahydroisoquinoline (3b). White solid, 104 mg, 98% yield, mp 74-76 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.65 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.25-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.87-6.79 (m, 2H), 5.46 (s, 1H), 4.07-3.99 (m, 1H), 3.75 (s, 3H), 3.46-3.38(m, 1H), 3.28-3.16 (m, 1H), 3.02-2.92 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 154.0, 145.3, 137.1, 131.7, 130.4, 128.9, 128.8, 125.7, 120.0, 114.7, 106.7, 75.5, 55.7, 45.9, 27.9. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C17H17Cl3NO+ 356.0370, found 356.0361. 1-(Trichloromethyl)-2-(4-chlorophenyl)1,2,3,4tetrahydroisoquinoline (3c). White solid, 89 mg, 83% yield, mp 65-67 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.64 (d, J=7.7 Hz, 1H), 7.37-7.28 (m, 1H), 7.28-7.12 (m, 4H), 6.94 (d, J=8.6 Hz, 2H), 5.57 (s, 1H), 4.18-3.95 (m, 1H), 3.64-3.48(m, 1H), 3.26-3.14 (m, 1H), 3.11-3.00 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 148.7, 136.3, 131.5, 130.0, 129.2, 129.0, 128.95, 126.0, 124.3, 117.3, 106.1, 74.3, 43.3, 27.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14Cl4N+ 359.9875, found 359.9875. 1-(Trichloromethyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4tetrahydroisoquinoline (3d). Yellow oil, 94 mg, 80% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.66 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.38-7.32 (m, 1H), 7.30-7.19 (m, 2H), 7.06 (d, J=8.6 Hz, 2H), 5.72 (s, 1H), 4.16-4.06 (m, 1H), 3.75-3.67 (m, 1H), 3.30-3.22 (m, 1H), 3.16-3.08 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 151.9, 135.9, 131.4, 129.8, 129.2, 129.0, 126.7, 126.7, 126.62, 126.59, 126.2, 125.9, 123.7, 120.8, 120.5, 114.4, 105.7, 77.4, 73.7, 42.4, 27.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H14Cl3F3N+ 394.0138, found 394.0140. 1-(Trichloromethyl)-2-(naphthalen-1-yl)-1,2,3,4tetrahydroisoquinoline (3e). Yellow oil, 90 mg, 84% yield. 1H NMR (500 MHz, CDCl3) δ ppm 8.49 (s, 1H), 7.84 (d, J =8.1 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.597.52 (m, 1H), 7.52-7.47 (m, 1H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 5.54 (s, 1H), 4.00 (s, 1H), 3.45-3.35 (m, 1H), 3.13 (s, 1H), 2.78 (d, J=15.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl ) δ ppm 150.8, 138.7, 135.2, 3 131.5, 131.4, 130.5, 128.83, 128.79, 128.4, 126.2, 126.09, 126.06, 125.8, 125.2, 124.7, 120.5, 106.7, 77.7, 51.1, 28.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H17Cl3N+ 376.0421, found 376.0419. 1-(Trichloromethyl)-2-benzyl-1,2,3,4tetrahydroisoquinoline (3f). White solid, 68 mg, 67% yield, mp 65-67 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (d, J=7.7 Hz, 1H), 7.47 (d, J=7.5 Hz, 2H), 7.36-7.19 (m, 5H), 7.16 (d, J=7.5 Hz, 1H), 4.65 (s, 1H), 4.55 (d, J=13.8 Hz, 1H), 3.92 (d, J=13.8 Hz, 1H), 3.32-3.22 (m, 2H), 2.67-2.58 (m, 1H), 2.42-2.31 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.3, 139.1, 132.2, 130.7, 128.6, 128.5, 128.4, 128.2, 127.3, 125.4, 107.2, 78.7, 64.2, 48.5, 29.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H17Cl3N+ 340.0421, found 340.0421. 1-(Trichloromethyl)-2-methyl-1,2,3,4tetrahydroisoquinoline (3g). White solid, 60 mg, 76% yield, mp 49-52 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.49 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.26-7.15 (m, 2H), 4.37



(s, 1H), 3.42-3.32 (m, 2H), 2.85 (s, 3H), 2.68-2.61 (m, 1H), 2.53-2.45 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.3, 132.2, 130.3, 128.5, 128.0, 125.4, 107.1, 80.0, 52.9, 48.1, 30.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H13Cl3N+ 264.0108, found 264.0108. 1-(Trichloromethyl)-2-butyl-1,2,3,4-tetrahydroisoquinoline (3h). Yellow oil, 43 mg, 47% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.51 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 7.25-7.15 (m, 2H), 4.47 (s, 1H), 3.50-3.42 (m, 1H), 3.35-3.25 (m, 1H), 3.14-3.06 (m, 1H), 2.97-2.88 (m, 1H), 2.73-2.66 (m, 1H), 2.54-2.43 (m, 1H), 1.67-1.54 (m, 2H), 1.37-1.29 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.3, 131.9, 131.0, 128.5, 128.0, 125.4, 107.4, 79.2, 60.1, 48.1, 29.6, 29.4, 20.6, 14.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H19Cl3N+ 306.0578, found 306.0578. 1-(Trichloromethyl)-2-allyl-1,2,3,4-tetrahydroisoquinoline (3i). Yellow oil, 65 mg, 75% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.52 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.25-7.17 (m, 2H), 6.03-5.92 (m, 1H), 5.27-5.16 (m, 2H), 4.56 (s, 1H), 3.85-3.77 (m, 1H), 3.63-3.56 (m, 1H), 3.48-3.41 (m, 1H), 3.39-3.28 (m, 1H), 2.73-2.66 (m, 1H), 2.59-2.51 (m, 1H). 13C{1H} NMR (125 MHz, CDCl ) δ ppm 139.3, 135.0, 131.9, 3 130.8, 128.5, 128.1, 125.5, 118.0, 107.3, 78.0, 62.7, 48.5, 29.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H15Cl3N+ 290.0265, found 290.0264. 1-(Trichloromethyl)-2-(prop-2-yn-1-yl)1,2,3,4tetrahydroisoquinoline (3j). Yellow solid, 63 mg, 73% yield, mp 75-78 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.52 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 4.70 (s, 1H), 4.28-4.21 (m, 1H), 3.743.66 (m, 1H), 3.50-3.38 (m, 1H), 3.31-3.24 (m, 1H), 2.97-2.89 (m, 1H), 2.72-2.65 (m, 1H), 2.17-2.08 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.1, 132.0, 130.6, 128.6, 127.9, 125.6, 106.9, 79.5, 76.9, 73.1, 49.8, 48.0, 30.1. HRMS (ESITOF) m/z: [M+H]+ calcd for C13H13Cl3N+ 288.0108, found 288.0108. Ethyl 2-(1-(trichloromethyl)-3,4-dihydroisoquinolin-2(1H)yl)acetate (3k). Yellow oil, 75 mg, 75% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.49 (d, J=7.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 1H), 7.17 (d, J=7.4 Hz, 1H), 4.84 (s, 1H), 4.28 (d, J=17.9 Hz, 1H), 4.13-4.06 (m, 2H), 3.74 (d, J=17.9 Hz, 1H), 3.51-3.43 (m, 1H), 3.32-3.28 (m, 1H), 2.85-2.79(m, 1H), 2.69-2.63 (m, 1H), 1.14 (t, J=7.1 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 171.4, 138.2, 131.9, 131.2, 128.5, 128.0, 125.6, 107.3, 77.9, 60.7, 59.4, 49.6, 30.2, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H17Cl3NO2+ 336.0319, found 336.0320. 4-(Trichloromethyl)-5-phenyl--4,5,6,7tetrahydrothieno[3,2-c]pyridine (3l). Yellow oil, 79 mg, 80% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.47-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.17 (d, J=5.3 Hz, 1H), 7.09-7.04 (m, 2H), 6.93-6.88 (m, 1H), 5.45 (s, 1H), 4.31-4.20 (m, 1H), 4.01-3.93 (m, 1H), 3.19-3.05 (m, 1H), 2.87-2.77 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 150.2, 139.3, 129.5, 129.4, 127.6, 122.1, 120.2, 117.2, 104.9, 72.8, 42.3, 22.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H13Cl3NS+ 331.9829, found 331.9829. 4-(Trichloromethyl)-5-benzyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine (3m). Yellow oil, 57 mg, 55% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (d, J=7.4 Hz, 2H), 7.41-7.33 (m, 3H), 7.33-7.27 (m, 1H), 7.15 (d, J=5.3 Hz, 1H), 4.53 (s, 1H),

4.10 (d, J=13.5 Hz, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.65-3.58 (m, 1H), 2.99-2.91 (m, 1H), 2.88-2.82 (m, 1H), 2.79-2.72 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.5, 138.8, 129.0, 128.9, 128.5, 127.5, 121.5, 105.4, 74.6, 60.9, 44.0, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H15Cl3NS+ 345.9985, found 345.9983. 4-(Trichloromethyl)-5-butyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine (3n). Yellow oil, 56 mg, 60% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.35 (d, J=5.3 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 4.35 (s, 1H), 3.78-3.68 (m, 1H), 2.99-2.86 (m, 2H), 2.79-2.69 (m, 3H), 1.59-1.53 (m, 2H), 1.40-1.32 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.5, 128.91, 128.86, 121.3, 105.4, 74.4, 56.8, 45.1, 30.7, 21.5, 20.5, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H17Cl3NS+ 312.0142, found 312.0144. 4-(Trichloromethyl)-5-allyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine (3o). Yellow oil, 60 mg, 67% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J=5.1 Hz, 1H), 7.12 (d, J=5.3 Hz, 1H), 6.03-5.92 (m, 1H), 5.22-5.14 (m, 2H), 4.42 (s, 1H), 3.76-3.67 (m, 1H), 3.48-3.39 (m, 2H), 3.03-2.89 (m, 2H), 2.80-2.72 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.5, 135.9, 128.9, 128.8, 121.4, 118.2, 105.3, 73.2, 60.1, 45.3, 21.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H13Cl3NS+ 295.9829, found 295.9828. 4-(Trichloromethyl)-5-(prop-2-yn-1-yl)4,5,6,7tetrahydrothieno[3,2-c]pyridine (3p). Yellow oil, 53 mg, 61% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.30 (d, J=5.2 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 4.63 (s, 1H), 4.00 (dd, J=17.4, 2.4 Hz, 1H), 3.67-3.61 (m, 1H), 3.59-3.53 (m, 1H), 3.1-3.12 (m, 1H), 3.00-2.95 (m, 2H), 2.17 (t, J=2.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 139.8, 129.3, 128.9, 121.4, 105.5, 80.0, 73.1, 73.0, 47.9, 46.8, 23.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H11Cl3NS+ 293.9672, found 293.9672. Ethyl 2-(4-(trichloromethyl)-6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)acetate (3q). Yellow oil, 64 mg, 63% yield. 1H NMR (500 MHz, CDCl ) δ ppm 7.27 (d, J=5.1 Hz, 1H), 3 7.09 (d, J=5.2 Hz, 1H), 4.73 (s, 1H), 4.13-4.02 (m, 3H), 3.703.58 (m, 2H), 3.05-2.96 (m, 2H), 2.94-2.86 (m, 1H), 1.16 (t, J=7.1 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 171.4, 139.2, 130.0, 128.6, 121.3, 106.0, 74.1, 60.8, 59.1, 48.0, 23.6, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H15Cl3NO2S+ 341.9884, found 341.9881. Benzyl 2-(4-(trichloromethyl)-6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)acetate (3r). Yellow oil, 80 mg, 66% yield. 1H NMR (500 MHz, CDCl ) δ ppm 7.39-7.17 (m, 6H), 7.07 3 (d, J=5.3 Hz, 1H), 5.08 (s, 2H), 4.74 (s, 1H), 4.11 (d, J=17.4 Hz, 1H), 3.72 (d, J=17.4 Hz, 1H), 3.64-3.53 (m, 1H), 3.032.94 (m, 2H), 2.92-2.80(m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 171.3, 139.3, 135.5, 130.0, 128.7, 128.5, 128.4, 121.3, 106.1, 74.2, 66.6, 59.2, 48.0, 23.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H17Cl3NO2S+ 404.0040, found 404.0040. N-Methyl-N-(1-(4-N',N'-dimethylamino)phenyl-2,2,2trichloroethyl)aniline (3s). White solid, 92 mg, 86% yield, mp 67-70 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (d, J=8.6 Hz, 2H), 7.30 (t, J=7.7 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 6.85 (t, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 2H), 5.83 (s, 1H), 2.97 (s, 6H), 2.93 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 150.7, 150.1, 130.0, 129.3, 118.6, 114.2, 111.9, 103.3, 76.5, 40.4, 34.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H20Cl3N2+ 357.0687, found 357.0685.


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The Journal of Organic Chemistry Synthesis of compound 4: A solution of 3a (100 mg, 0.31 mmol), NaOCH3 (180 mg, 3.10 mmol) in CH3OH (5 mL) was stirred in a reaction tube under N2 (1 atm) at 60 °C for 10 h, then cooled to room temperature. The reaction mixture was quenched with H2O (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer were combined and dried (MgSO4), concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (40:1) to give the target product. 1-(Dichloromethylene)-2-phenyl-1,2,3,4tetrahydroisoquinoline (4). Yellow solid, 66 mg, 74% yield, mp 65-67 °C. 1H NMR (500 MHz, CDCl3) δ ppm 7.82 (s, 1H), 7.26-7.16 (m, 5H), 6.90 (d, J=7.8 Hz, 2H), 6.85-6.78 (m, 1H), 3.66 (t, J=6.5 Hz, 2H), 2.92 (t, J=6.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 146.3, 137.0, 135.9, 133.8, 129.2, 128.7, 127.2, 127.0, 126.0, 119.8, 116.4, 115.9, 48.2, 28.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14Cl2N+ 290.0498, found 290.0493. Synthesis of compound 5: A solution of 3a (100 mg, 0.31 mmol), LiAlH4 (88 mg, 1.55 mmol) in THF (3 mL) was stirred in a reaction tube at 70 °C for 6 h, then cooled to room temperature. The reaction mixture was quenched with H2O (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried (MgSO4), concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (100:1) to give the target product. 1-(Dichloromethyl)-2-phenyl-1,2,3,4tetrahydroisoquinoline (5). Yellow oil, 55 mg, 61% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.48 (d, J=7.5 Hz, 1H), 7.347.28 (m, 3H), 7.25-7.21 (m, 2H), 6.94 (d, J=8.1 Hz, 2H), 6.84 (t, J=7.3 Hz, 1H), 5.99 (d, J=4.2 Hz, 1H), 5.23 (d, J=4.3 Hz, 1H), 3.88-3.81 (m, 1H), 3.37-3.30 (m, 1H), 3.25-3.15 (m, 1H), 3.03-2.96 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 148.7, 136.4, 131.9, 129.6, 129.4, 128.5, 128.2, 126.2, 118.7, 113.7, 76.0, 67.0, 43.6, 28.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16Cl2N+ 292.0654, found 292.0663. Synthesis of compound 6: A solution of 3a (100 mg, 0.31 mmol), LiAlH4 (88 mg, 1.55 mmol) in THF (3 mL) was stirred in a reaction tube at 70 °C for 10 h, then cooled to room temperature. The reaction mixture was quenched with H2O (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried (MgSO4), concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (100:1) to give the target product. 1-Methylene-2-phenyl-1,2,3,4-tetrahydroisoquinoline (6). Yellow oil, 53 mg, 77% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.53-7.49 (m, 1H), 7.24-7.22 (m, 2H), 7.20-7.15 (m, 3H), 7.04-6.97(m, 1H), 6.71 (t, J=7.5 Hz, 1H), 6.61 (d, J=7.9 Hz, 2H), 5.66 (d, J=17.3 Hz, 1H), 5.32 (d, J=11.0 Hz, 1H), 3.35 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.0 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ ppm 148.0, 137.1, 136.7, 134.5, 130.1, 129.4, 128.1, 127.0, 126.2, 117.7, 116.3, 113.1, 44.7, 33.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16N+ 222.1277, found 222.1271. Synthesis of compound 7: A solution of 3a (100 mg, 0.31 mmol), 2 mL H2O and 10 mL EtOH was refluxed in a reaction tube for 48 h, then cooled to room temperature. The solvent was removed by rotary evaporation, then 10 mL H2O were

added and the mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried (MgSO4), concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with petroether/ethyl acetate (50:1) to give the target product. Ethyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-1carboxylate (7). Yellow oil, 55 mg, 64% yield. 1H NMR (500 MHz, CDCl3) δ ppm 7.46-7.41 (m, 1H), 7.30-7.25 (m, 2H), 7.24-7.19 (m, 3H), 6.88-6.83 (m, 2H), 6.82-6.78 (m, 1H), 5.30 (s, 1H), 4.17-4.06 (m, 2H), 3.91-3.83 (m, 1H), 3.64-3.55 (m, 1H), 3.22-3.13 (m, 1H), 3.05-2.96 (m, 1H), 1.20-1.16 (m, 3H). 13C{1H} NMR (125 MHz, CDCl ) δ ppm 173.0, 149.2, 135.9, 3 132.1, 129.4, 128.4, 127.9, 127.8, 126.5, 118.2, 113.6, 62.36, 61.35, 43.1, 29.0, 14.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H20NO2+ 282.1489, found 282.1488.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: X-ray date for 3a and 3f (CIF) The reaction schemes for synthesis of new substrates, copies of NMR spectra for all new compounds and X-ray date for 3a and 3f (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID Changming Xu: 0000-0001-9608-7013

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This paper is dedicated to the 60th anniversary of Lanzhou Jiaotong University. We acknowledge financial support by the National Natural Science Foundation of China (NSFC) (Grant No. 21662024), Natural Science Foundation of Gansu Province (Grant No. 1606RJZA028), Foundation of A Hundred Youth Talents Training Program of Lanzhou Jiaotong University and the Young Scholars Science Foundation of Lanzhou Jiaotong University (Grant No. 2016008). We thank Prof. Sanzhong Luo (Tsinghua University) for helpful advices and Dr. Xiao-Qiang Yao (Northwest Normal University) for X-ray crystallographic assistance.

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Oxidative Î±-Trichloromethylation of Tertiary Amines: an Entry to Î±

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