Oxidative α-Trichloromethylation of Tertiary Amines: An Entry to α-Amino Acid Esters

Article abstract of DOI:10.1021/acs.joc.8b03238

α-Trichloromethylation of tertiary amines with trimethyl(trichloromethyl)silane by oxidative coupling, using DDQ as an oxidant, has been realized. The reaction is instantaneous, is scalable, and tolerates a broad range of functional groups and heteroarenes. The trichloromethylated products can be easily converted into 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.

Full text of DOI:10.1021/acs.joc.8b03238

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Article
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
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Page 1 of 9
The Journal of Organic Chemistry
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Oxidative α-Trichloromethylation of Tertiary Amines: an Entry to α-
Amino Acid Esters
9
Changming Xu,*a,b Zhaobin Zhu,a Yongchang Wang,a Zhiguo Jing,a Bin Gao,a Li Zhao,a and Wen-Kui
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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
N
R
R
N
TMSCCl3
Ar
R
Ar
N
N
R
CO2Et
DDQ, rt, 1 min
R
CCl3
Ar
N
Instantaneous reaction rate

Ar
N
Regional selective specificity
High functional group tolerance
Gram-scale synthesis

.

Cl
Cl
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.
aldehydes,16 imines17 and (iso)quinolone Reissert salts18 were
INTRODUCTION
presented (Scheme 1, A). In 1945, the substrate scopes of
Trichloromethyl groups are present in natural products that
addition reactions were extended to Michael acceptors
exhibit excellent biological activity, such as dysamide,1
(Scheme 1, B).19 At the same time, a breakthrough was made
dysidenin,2 sintokamide,3 barbamide,4 muironolide,5 herbacic
by Kharasch et al., who reported addition reactions of carbon
acid6 and neodysidenin.7 More significantly, they can be easily
tetrachloride and chloroform to terminal olefins to form new
converted to diverse one-carbon functional groups, including
C-CCl3 bond and C-X (X=Cl or H) bond simultaneously
methyl, chloromethyl, dichloromethyl,8 trifluoromethyl9 and
(Scheme 1, C), named atom transfer radical addition reactions
carboxyl groups,10 as well as carboxylic esters and amides.11 It
(ATRA).20 Following this pioneering work, Stephenson,
should be noted that direct introduction carboxyl groups into
Ready and others enriched this chemistry significantly,
organic molecules remains a challenge, which depends very
making this methodology a highly atom-economical synthetic
heavily on inert carbon dioxide insertion reactions12 and
method.21 Later, the cross-coupling reactions of LiCCl3 with
poisonous cyanation reactions.13 Although fluorine and
alkyl iodides22 and cyclic ethers,23 as well as alkynyllithiums
chlorine are in the same group on the periodic table and the
with carbon tetrachloride,24 were reported (Scheme 1, D). In
trifluoromethylation reactions have been well-developed,14 due
1990, Sutherland also disclosed a trichloromethylation of
to fluorine-containing groups play an important role in
cyclopentadienyliron complexed dialkylarenes followed by
pharmaceuticals and agrochemicals, as well as in materials
demetallation to give trichloromethylarenes (Scheme 1, E).25
science, it seems that the trifluoromethyl can’t replace
Recently,
Zakarian
demonstrated
diastereoselective
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,
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
chloroform has been disclosed by Shibata (Scheme 1, G).28
Page 2 of 9
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
1
2
3
4
5
6
7
8
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).
9
trifluoromethylation
of
N-aryl
substituted
Scheme 1. Overview on Trichloromethylation Reactions
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
10
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60
(A) 1,2-Addition, pioneered by Fishburn and Watson in 1939
R''
CCl Cl C
COOK,
H
,
3
R''
3
X
XH
CCl3
Cl C CCl
COOH or TMS
-
-
3
3
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 CCl3-
from 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).
R
R'
R
R'
X = O, N
(B) Michael addition, pioneered by Bruson in 1945
CCl CCl
R'
H
3, TMS
Cl C
,
3
R'
Cl3C
Cl C
Li or
MgCl
3
3
EWG
EWG
R
EWG = CN, COOR'', COR'', NO2
R
(C) ATRA, pioneered by Kharasch in 1945
X
CCl3
X
(X = H, Cl, Br)
R
CCl3
R
R
(D) Cross coupling
Weinreb, 1990
CCl3
RI
O
Cl C
Li
3
OH
Imai, 1994
CCl3
n
n
n = 1, 2, 3
CCl4
R
R
R
Martins, 2004
R
Li
CCl3
Table 1. Optimization of Reaction Conditionsa
(E) Trichloromethylation of cyclopentadienyliron complexed arenes
CCl
1) H
3
Sutherland, 1990
Rn
Rn
Oxidant (1.1 equiv)
Fluoride
2) I2
N
N
TMSCCl3
2
F6PCpFe
CCl3
Solvent, 1 min
CCl3
3a
(F) -Trichloromethylation of carbonyls
Zakarian, 2010
Meggers, 2015
1a
O
O
Entry
1b
Oxidant
Fluoride
Solvent
MeCN
Temp.
60 oC
Yield
34%
CCl
Br
3
R'
R'
*
R
R
TBHP/
CuBr (5%)
KF (1.5 eq)
CCl3
(G) Trichloromethylation of MBH-fluorides
CCl
2b
3c
4c
TBHP
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
MeCN
MeCN
MeCN
60 oC
rt
38%
NR
Ar
H
Ar
Shibata, 2016
3
*
CO2R
CO2R
TBHP
CCl3
F
O2 (1 atm)/
CuBr (5%)
O2 (1 atm)/
CuBr (5%)
BPO
60 oC
25%
This work
(H)
: oxidative coupling
R''
R''
R''
N
5d
KF (1.5 eq)
MeCN
rt
52%
R
N
CCl
TMS
R
3
R'
R'
N
R
DDQ
R'
COOEt
-amino acid ester
and more...
CCl3

6b
7c
8c
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
MeCN
MeCN
MeCN
60 oC
14%
trace
trace
BPO
rt
RESULTS AND DISCUSSION
TEMPO
rt or
60 oC
60 oC
rt
As summarized in Table 1, we selected N-phenyl-
tetrahydroisoquinoline 1a as model substrate and
equivalentsof Ruppert-Prakash reagent
trimethyl(trichloromethyl)silane (TMSCCl3) as
230
3
9b
PhI(OAc)2
PhI(OAc)2
DDQ
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
68%
52%
100%
25%
40%
73%
81%
55%
68%
55%
63%
mess
10e
11
12f
13
14
15
16
17
18g
19
20
rt
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
PBQ
rt
DDQ
rt
DDQ
KF (1.0 eq)
KF (1.2 eq)
rt
DDQ
rt
DDQ
NaF (1.5 eq)
CsF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
MeCN
MeCN
MeCN
Et2O
rt
DDQ
rt
DDQ
rt
DDQ
rt
DDQ
MeOH
rt
o
desired product was delivered in 25% yield at 60 C and 52%
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The Journal of Organic Chemistry
21
22
23
DDQ
DDQ
DDQ
KF (1.5 eq)
KF (1.5 eq)
KF (1.5 eq)
CH2Cl2
THF
rt
rt
rt
31%
28%
28%
substrates worked equally well and delivered the desired
products in high yield albeit at a slower rate (see 3e). N-alkyl
substituted tetrah- ydroisoquinolines 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
1
2
3
4
5
6
7
8
toluene
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.
oxidative condition. The
X-ray crystal structure of 3f
demonstrated that the reaction exclusively took place at the 1-
position 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 4,5,6,7-
tetrahydrothieno[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
9
Encouraged by these results, we further conducted a gram-
scale 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).
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60
variety
of
N-substituted
4,5,6,7-tetrahydrothieno[3,2-
Scheme 2. Substrate Scopea
c]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
DDQ (1.1 equiv)
KF(1.5 equiv)
Ar
Ar
TMSCCl3
2
N
N
MeCN, rt, 1 min
R
R
specificity of this reaction. Much to our surprise,
a
1
CCl3
3
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,N-
dimethyl-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.
N
N
N
CCl3
CCl3
CCl3
OCH3
Cl
3a
3a
, 100%
3b
, 98%
3c
, 83%
3a
X-ray for
b
, 99%
N
N
N
CCl3
CCl3
CCl3
CF3
c
3d
, 80%
3e
, 84%
3f
3f
X-ray for
, 67%
Scheme 3. Transformations of 3a
N
N
N
N
CH3
O
CCl3
CCl3
CCl3
CCl3
3h
N
N
LiAlH4 (5 eq)
THF, 70 oC, 6 h
MeONa (10 eq)
MeOH, 60 oC, 10 h
Ph
N
Ph
3j
3i
, 73%
, 75%
3g
,76%
, 47%
Ph
Cl
4
Cl
, 74%
CCl3
Cl
Cl
, 61%
S
3a
S
S
S
5
N
N
N
N
OEt
CCl3
3k
, 75%
CCl3
CCl3
CCl3
3m
3l
, 80%
3n
, 60%
, 55%
N
N
H
H2O:EtOH = 1:5 (v/v)
reflux, 48 h
LiAlH4 (5 eq)
THF, 70 oC, 10 h
Ph
Ph
S
S
S
O
O
O
OEt
H
N
N
N
N
7
, 64%
6
, 77%
OEt
OBn
CCl3
3q
CCl3
, 67%
CCl3
3r
, 66%
CCl3
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
3o
, 63%
3p
, 61%
O2N
Me
N
N
N
O
N
1t
, NR
1u
, NR
1v
, mess
CCl3
N
N
N
3s
, 86%
Cbz
Boc
1w
1x
, NR
, NR
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. Reaction was performed on 1
gram scale for 5 min. Reaction was run for 30 min. NR: No
Reaction
b
c
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
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The Journal of Organic Chemistry
Page 4 of 9
easily carried out only with commercially available ethanol
and water.
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).
1
2
3
4
5
6
7
8
CONCLUSIONS
1
Yellow oil, 1.2 g, 47% yield. H NMR (500 MHz, CDCl3) δ
In summary, we have developed the first oxidative α-
trichloromethylation of tertiary amines, which can be
completed almost instantaneously at room temperature by
using DDQ as oxidant. The reaction is amenable to be scaled-
up 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.
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.
9
Ethyl
2-(3,4-dihydroisoquinolin-2(1H)-yl)acetate
(1k).
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
1
Yellow oil, 1.5 g, 47%. H 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.
EXPERIMENTAL SECTION
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), 4,5,6,7-
tetrahydrothieno[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
General information: Commercial reagents were used as
received, unless otherwise indicated. Nuclear magnetic
resonance (NMR) spectra were recorded using Bruker AV-500
1
spectrometer. H and 13C NMR spectra were measured on a
1
NMR instrument (500 MHz and for H 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 thin-
layer 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 1s-
1v 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.
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).
1
Yellow oil, 1.0 g, 32% yield. H 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.
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.
5-Benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(1m).
1
Yellow oil, 2.0 g, 59% yield. H 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, CDCl3) δ ppm 138.5, 134.1, 133.6,
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.
2-Butyl-1,2,3,4-tetrahydroisoquinoline (1h). Yellow oil, 1.7
1
g, 59% yield. H 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,
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The Journal of Organic Chemistry
NMR (125 MHz, CDCl3) δ ppm 150.1, 136.5, 131.9, 129.9,
5-Butyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(1n).
1
1
2
3
4
5
6
7
8
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.
Yellow oil, 2.1 g, 72% yield. H 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.
1-(Trichloromethyl)-2-(4-methoxyphenyl)-
1,2,3,4-
tetrahydroisoquinoline (3b). White solid, 104 mg, 98% yield,
1
mp 74-76 °C. H 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.
5-Allyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(1o).
9
1
Yellow oil, 1.1 g, 41% yield. H 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.
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
1-(Trichloromethyl)-2-(4-chlorophenyl)-
1,2,3,4-
tetrahydroisoquinoline (3c). White solid, 89 mg, 83% yield,
1
mp 65-67 °C. H NMR (500 MHz, CDCl3) δ ppm 7.64 (d,
5-(Prop-2-yn-1-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(1p). Yellow oil, 1.1 g, 41% yield. H NMR (500 MHz,
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
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), 2.91-
2.88 (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.
1-(Trichloromethyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-
tetrahydroisoquinoline (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.
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
1
(1r). Yellow solid, 2.4 g, 56% yield, mp 48-51°C. H NMR
1-(Trichloromethyl)-2-(naphthalen-1-yl)-
-1,2,3,4-
(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.
1
tetrahydroisoquinoline (3e). Yellow oil, 90 mg, 84% yield. H
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), 7.59-
7.52 (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, CDCl3) δ ppm 150.8, 138.7, 135.2,
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.
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-benzyl-1,2,3,4-
tetrahydroisoquinoline (3f). White solid, 68 mg, 67% yield,
1
mp 65-67 °C. H 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-phenyl--1,2,3,4-
tetrahydroisoquinoline (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), 3.67-
3.59 (m, 1H), 3.24-3.14 (m, 1H), 3.11-3.02 (m, 1H). 13C{1H}
1-(Trichloromethyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline (3g). White solid, 60 mg, 76% yield,
1
mp 49-52 °C. H 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
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(s, 1H), 3.42-3.32 (m, 2H), 2.85 (s, 3H), 2.68-2.61 (m, 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.
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
2
3
4
5
6
7
8
1-(Trichloromethyl)-2-butyl-1,2,3,4-tetrahydroisoquinoline
1
4-(Trichloromethyl)-5-butyl-4,5,6,7-tetrahydrothieno[3,2-
(3h). Yellow oil, 43 mg, 47% yield. H NMR (500 MHz,
1
c]pyridine (3n). Yellow oil, 56 mg, 60% yield. H NMR (500
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.
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.
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
4-(Trichloromethyl)-5-allyl-4,5,6,7-tetrahydrothieno[3,2-
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, CDCl3) δ ppm 139.3, 135.0, 131.9,
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
c]pyridine (3o). Yellow oil, 60 mg, 67% yield. H 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)-
4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (3p). Yellow oil, 53 mg, 61%
1-(Trichloromethyl)-2-(prop-2-yn-1-yl)-
1,2,3,4-
1
yield. H NMR (500 MHz, CDCl3) δ ppm 7.30 (d, J=5.2 Hz,
tetrahydroisoquinoline (3j). Yellow solid, 63 mg, 73% yield,
1
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.
mp 75-78 °C. H 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), 3.74-
3.66 (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 (ESI-
TOF) m/z: [M+H]+ calcd for C13H13Cl3N+ 288.0108, found
288.0108.
Ethyl
2-(4-(trichloromethyl)-6,7-dihydrothieno[3,2-
c]pyridin-5(4H)-yl)acetate (3q). Yellow oil, 64 mg, 63% yield.
1H NMR (500 MHz, CDCl3) δ ppm 7.27 (d, J=5.1 Hz, 1H),
7.09 (d, J=5.2 Hz, 1H), 4.73 (s, 1H), 4.13-4.02 (m, 3H), 3.70-
3.58 (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.
Ethyl 2-(1-(trichloromethyl)-3,4-dihydroisoquinolin-2(1H)-
1
yl)acetate (3k). Yellow oil, 75 mg, 75% yield. H 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
Benzyl
2-(4-(trichloromethyl)-6,7-dihydrothieno[3,2-
c]pyridin-5(4H)-yl)acetate (3r). Yellow oil, 80 mg, 66% yield.
1H NMR (500 MHz, CDCl3) δ ppm 7.39-7.17 (m, 6H), 7.07
(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), 3.03-
2.94 (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.
+
(ESI-TOF) m/z: [M+H]+ calcd for C14H17Cl3NO2 336.0319,
found 336.0320.
4-(Trichloromethyl)-5-phenyl--4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (3l). Yellow oil, 79 mg, 80%
1
yield. H 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.
N-Methyl-N-(1-(4-N',N'-dimethylamino)phenyl-2,2,2-
trichloroethyl)aniline (3s). White solid, 92 mg, 86% yield, mp
1
67-70 °C. H 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.
4-(Trichloromethyl)-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-
1
c]pyridine (3m). Yellow oil, 57 mg, 55% yield. H 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),
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Synthesis of compound 4: A solution of 3a (100 mg, 0.31
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.
1
2
3
4
5
6
7
8
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.
Ethyl
2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
1
carboxylate (7). Yellow oil, 55 mg, 64% yield. H 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, CDCl3) δ ppm 173.0, 149.2, 135.9,
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.
9
1-(Dichloromethylene)-2-phenyl-1,2,3,4-
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
tetrahydroisoquinoline (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.
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)
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.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xucm@mail.lzjtu.cn
1-(Dichloromethyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (5). Yellow oil, 55 mg, 61% yield. H
1
ORCID
NMR (500 MHz, CDCl3) δ ppm 7.48 (d, J=7.5 Hz, 1H), 7.34-
7.28 (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.
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.
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. H NMR (500 MHz, CDCl3) δ
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