Cross-Dehydrogenative Coupling of Tetrahydroisoquinolines and 2-Fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide: A New Synthetic Approach to α-Monofluoromethyl Tertiary Amines

Article abstract of DOI:10.1002/ejoc.202100537

A cross dehydrogenative coupling reaction of tetrahydroisoquinolines with 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide had been developed. CuBr/TBHP was identified as the best catalyst and oxidant. A variety of coupling products were obtained with good t

Full text of DOI:10.1002/ejoc.202100537

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Cross-dehydrogenative coupling of tetrahydroisoquinolines and
2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide: a new synthetic
approach to α-monofluoromethyl tertiary amines
Authors: Bao-qin Huang, Yuan Chen, Xue-jing Zhang, and Ming Yan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100537
Link to VoR: https://doi.org/10.1002/ejoc.202100537
01/2020

10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
Cross-dehydrogenative coupling of tetrahydroisoquinolines and
2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide: a new synthetic
approach to α-monofluoromethyl tertiary amines
Bao-qin Huang,a Yuan Chen,b Xue-jing Zhang,a Ming Yana*
[a]
B-q. Huang, Dr. X-j. Zhang, Prof. Dr. M. Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
E-mail: yanming@mail.sysu.edu.cn
http://sps.sysu.edu.cn/teacher/140
[b]
Y. Chen
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University, Tianjin 300353, China.
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
cross dehydrogenative coupling reaction of
with 2-fluoro-1,3-benzodithiole-1,1,3,3-
(scheme 2, eq. a).[4] Recently, cross dehydrogenative couplings
(CDCs) have emerged as a powerful tool for the functionalization
of inactive C-H bonds.[5] Taking the advantages of high resistance
of FBSM and FBDT to the oxidation and their nucleophilic
reactivity, we envisioned that the CDC reaction of FBSM or FBDT
with tertiary amines can be achieved. The subsequent
desulfonylation provides α-monofluoromethyl amines, which are
attractive pharmacophores for medicinal chemistry.[6] In 2013, Hu
and co-workers reported the DIAD-mediated CDC reaction
between tertiary amines and FBSM. The monofluoromethylated
products were obtained after the reductive desulfonylation,
however the method is limited to methyl tertiary amines (scheme
2, eq. b).[7] In this paper, we would like to report an efficient CDC
reaction of tetrahydroisoquinolines and FBDT. The reductive
tetrahydroisoquinolines
tetraoxide had been developed. CuBr/TBHP was identified as the best
catalyst and oxidant. A variety of coupling products were obtained with
good to excellent yields under mild reaction conditions. 1-
Monofluoromethyl tetrahydroisoquinoline derivatives were prepared
via the subsequent desulfonylation with sodium amalgam. This
method provides a new synthetic approach to α-monofluoromethyl
tertiary amines.
Introduction
The monofluoromethyl group has been widely applied in the
pharmaceutical and agricultural industries.[1] It is generally used
as a bioisostere of methyl to improve the biological activity and
metabolic stability of the drugs. For examples, afloqualone,
sevoflurane and fluticasone propionate are representative
examples of drugs with monofluoromethyl group (scheme 1).
desulfonylation
tetrahydroisoquinolines in good yields (scheme 2, eq. c)..
provided
1-monofluoromethyl
a) Studies of Hu, Shibata and co-workers
SO2Ph
O
NBoc
F
F
(FBSM)
(FBDT)
R
H
R
SO2Ph
fluoromethyl
products
F
with
O
S
or
O
EWG
O
HO
O
O
O
O
S
N
O
R
F
R
CF3
F
F
N
H2N
S
F3C
O
F
O
O
Fluticasone propionate
Sevoflurane
b) Studies of Hu and co-workers (2013)
Afloqualone
SO2Ph
F
R'
N
R'
N
R'
N
SO2Ph
SO2Ph
Scheme 1. Representative drugs with monofluoromethyl group.
SO2Ph
[H]
R
R
R
F
DIAD
F
In the past two decades, great efforts had been made to develop
efficient monofluoromethylation reactions and reagents.[2,3]
Among the various monofluoromethylation reagents, 1-
fluorobis(phenylsulfonyl)methane (FBSM) and 2-fluoro-1,3-
benzodithiole-1,1,3,3-tetraoxide (FBDT) are two nucleophilic
monofluoromethylation reagents with excellent reactivity and
stability. Their addition reactions with epoxides, aldehydes,
ketones, imines, Michael acceptors and other electrophilic
reagents were successfully developed by Hu, Shibata and their
co-workers. The monofluoromethylated products were generally
obtained via the subsequent reductive desulfonylation process
c) This study
O
O
O
S
F
S
R'
R'
[H]
N
F
N
O
R
R
O
catalyst
[O]
R'
O
N
R
S
F
O
S
O
Scheme 2. Monofluoromethylation with fluorobis(sulfonyl)methanes.
1
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10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
metal catalyst. Product 2a was obtained in a moderate yield
(Table 1, entry 5).[13] Finally, CuBr/TBHP was found to be the best
combination. An excellent yield was obtained in acetonitrile (Table
1, entry 6).[14] Other copper sources such as CuCl and CuI
showed inferior catalytic activity (Table 1, entries 7-8). A control
experiment in the absence of CuBr was examined and only trace
of the product 2a was obtained (Table 1, entry 9). The result
confirmed the indispensability of copper catalyst. Several other
solvents (MeOH, DMF, THF, DCM, PhMe) were examined,
however inferior yields were obtained (Table 1, entries 10-14).
The decrease of the loading of cuprous bromide led to the lower
yields (Table 1, entries 15-16). The replacement of TBHP with
hydrogen peroxide resulted in a poor yield (Table 1, entry 17). The
use of excess amount of 1a (1.2 eq) provided a quantitative NMR
yield. Excellent isolated yield (96%) was obtained after the column
chromatography.
Initially, 2-phenyl-1,2,3,4-tetrahydroisoquinoline 1a was
selected as the substrate. Ferric chloride/DTBP were used as the
catalyst and the oxidant based on the report of Hayashi et al.[8]
The reaction of 1a with FBSM and FBDT was examined at room
temperature. No reaction was observed for FBSM, however, the
expected product 2a was obtained with a moderate yield for FBDT.
The bigger steric hindrance of FBSM may prevent the
transformation. The similar phenomena was also observed in the
reaction of FBSM and FBDT with aldehydes and imines by
Shibata et al.[9] The further optimization of the reaction conditions
was carried out and the results are summarized in Table 1.
Table 1. Optimization of reaction conditions.[a]
R1
Ar
N
O
CuBr (15 mol%)
TBHP (1.3 eq.)
O
O
Ar R2
O
N
O
S
F
R1 Ar
O
O
O
S
F
+
S
N
F
catalyst/oxidant
solvent
rt, 12 h
MeCN
O
O
S
S
S
Ar R2
F
+
N
O
O
S
S
O
O
O
O
2a-2s
1a-1s
1a
FBDT
2a
Br
O
Entry
1[c]
2[d]
3[e]
4[f]
Catalyst
FeCl3
RuCl3
Co(OAc)2
PtCl2
/
Oxidant
DTBP
O2
Solvent
DCE
Yield (%) [b]
N
F
N
F
N
N
F
Cl
O
O
O
F
O
O
O
O
60
O
S
S
S
S
O
S
O
O
O
S
O
O
S
S
O
O
MeOH
60
NHPI/O2
/
MeCN
DMF:H2O
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DMF
70
2a,96%[a]
2b
2c
,83%
,98%
2d
,77%
78
5[g]
6[h]
7
DDQ
68
N
N
F
N
F
N
F
O
O
S
O
O
F
O
O
O
O
O
CuBr
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
93
S
S
CN
S
Cl
O
O
O
S
O
O
S
S
S
O
O
O
O
O
34
8
CuCl
/
28
2e,85%
2f,92%
2g,90%
2h,93%
9
6
O
10
11
12
13
14
15[i]
16[j]
17
18[k]
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
80
N
F
N
N
N
F
O
O
O
O
F
F
O
O
O
81
O
S
S
S
S
S
O
O
S
O
O
O
O
S
O
S
O
O
THF
79
DCM
83
2l,96%
2i,89%
2j,52%
2k
,62%
PhMe
MeCN
MeCN
MeCN
MeCN
73
CN
87
N
F
N
N
F
N
F
O
S
O
S
O
O
F
81
O
N
O
O
O
O
S
S
O
O
O
S
O
S
S
S
24
O
O
O
TBHP
>99 (96[l])
2m,88%
2n,92%
2p[b]
,88%
2o,88%
[a] Reaction conditions: 1a (0.10 mmol), FBDT (0.10 mmol), catalyst (0.015
mmol,15 mmol%), oxidant (0.13 mmol) and solvent (1.0 mL) at rt. [b] Yield was
determined by 1H NMR using dimethyl terephthalate as the internal standard.
[c] FeCl3 (0.01 mmol, 10 mol%) and t-BuOOt-Bu (0.2 mmol, 2.0 eq) were used
at 80 °C. [d] RuCl3 (0.0025 mmol, 2.5 mol%) and O2 (1 atm) were used at rt. [e]
Co(OAc)2 (0.002 mmol, 2 mol%), NHPI (0.02 mmol, 20 mol% ) and O2 (1 atm)
were used at rt. [f] PtCl2 (0.01 mmol, 10 mol%) was used at 60 °C. [g] DDQ
(0.11 mmol, 1.1eq) was used at rt. [h] CuBr (0.015 mmol, 15 mol%) and TBHP
(0.13 mmol, 1.3 eq) were used at rt. [i] CuBr (0.01 mmol, 10 mol%) was used.
[j] CuBr (0.005 mmol, 5 mol%) was used. [k] 1a (0.12 mmol, 1.2 eq) was used.
[l] Isolated yield after column chromatography.
N
N
N
N
O
F
S
O
F
N
O
O
S
O
S
O
S
O
O
2r[c],92%
2q
,64%
Scheme 3. Cross-dehydrogenative coupling reaction of 1a–1r with FBDT.
Reaction conditions: 1a–1r (0.24 mmol), FBDT (0.2 mmol), CuBr (0.03 mmol),
TBHP (0.26 mmol) and MeCN (2.0 mL) at rt. [a] Isolated yield after column
chromatography. [b] 1p (0.3 mmol), FBDT (0.2 mmol), CuBr (0.04 mmol), TBHP
(0.39 mmol) and MeCN (2.0 mL) was used. [c] 1r (0.3 mmol), FBDT (0.15
mmol), CuBr (0.045 mmol), TBHP (0.39 mmol) and MeCN (2.0 mL) was used.
A number of privileged catalyst/oxidant systems were
screened according to the literatures. The combination of
RuCl3/O2 provided the similar yield (Table 1, entry 2).[10] The use
of Co(OAc)2/NHPI/O2 slightly improved the yield (Table 2, entry
3).[11] An acceptorless dehydrogenation coupling was achieved
with PtCl2 to give 2a with a 78% yield (Table 2, entry 4).[12] The
reaction was also promoted by DDQ in the absence of a transition
With the optimal conditions in hand, the reaction of a series
of tetrahydroisoquinoline derivatives 1a-1r was examined the
results are summarized in Scheme 3. The substitutions on the
tetrahydroisoquinoline were tolerated well. The reaction of 7-
2
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10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
Table 2. Reductive desulfonylation of product 2a. [a]
chloro-tetrahydroisoquinoline 1b, 5-bromo-tetrahydroisoquinoline
1c and 6-methoxy-tetrahydroisoquinoline 1d afforded the
products 2c-2d in good yields. Furthermore, the substitutions on
the N-phenyl group were explored. The para-substitutions with
electron-withdrawing group (methoxycarbonyl, acetyl, cyano,
chloro) and electron-donating group (methyl) were tolerated well.
The products were obtained with good yields. The 4-methoxy
derivative 1j gave a low yield, probably due to the partially
oxidation of 4-methoxy-aniline moiety. The reaction of 3-acetyl
derivative 1k provided the product in a moderate yield. However,
3-methyl derivatives 1l gave the products with a good yield.
Similarly, 2-cyano and 2-methyl derivatives 1m-1n also afforded
good yields. The results suggested that the reaction has good
tolerance of the different substituents.
N
F
O
[H]
O
N
S
O
S
O
F
3a
2a
Entry
Reagent
Solvent
T (°C )
Yield (%)
[b]
1
2
Mg (30 eq)
MeOH
MeOH
50
0
33
64
Na(Hg) (30 eq)
Na2HPO4 (30 eq)
N-naphthylmethyl and N-pyridinyl derivatives 1o-1p are also
applicable. The products 2o-2p were obtained with good yields.
N-pyrimidinyl derivative 1q gave a moderate yield. To our delight,
the indole analogue 1r underwent the reaction smoothly. The
product 2r was obtained with an excellent yield. The scaffold was
frequently applied in many biological active compounds and
drugs.[15]
3
4
Na (10 eq)
Naphthalene (5 eq)
DMF/H2O
THF
rt
rt
n.d.[c]
n.d.[c]
SmI2 (4 eq)
HMPA (18.5 eq)
5
6
Raney-Ni (30 eq)
EtOH
85
80
n.d.[c]
n.r.[d]
We also examined the reaction of other tertiary amines and
the results are summarized in Scheme 4. N-methyl-
tetrahydroisoquinoline is unreactive under the present conditions.
The reaction of N-benzyl-tetrahydroisoquinoline, N-allyl-
tetrahydroisoquinoline and N-phenyl piperidine afforded
complicated products. Small amount of expected products could
be identified via 1H NMR analysis, however no enough pure
products were obtained by column chromatography. The
structure of the tertiary amines seems to exert profound effect on
the transformation.
Bu3SnH (3.7 eq)
AIBN (1.1 eq)
Benzene
[a] Reaction conditions: 2a (0.20 mmol), reagents and solvent (1.0 mL) under
nitrogen atmosphere. [b] Isolated yield. [c] not determined. [d] no reaction.
Furthermore, the products 2h, 2i, 2j, 2o and 2r were
desulfonylated smoothly with Na(Hg). 1-Monofluoromethyl
products 3h, 3i, 3j, 3o and 3r were obtained with good yields
(Scheme 5).
N
O
S
N
N
F
O
O
CuBr (15 mol%)
TBHP (1.3 eq.)
6 wt% Na(Hg)
O
R
F
O
O
O
S
R
Na2HPO4, MeOH
+
F
S
O
N
F
rt, 12 h
S
R
S
O
R
S
O
O
O
3h
)
R= Cl
69% (
2h, 2i, 2j
R= Me 73% (3i)
R= OMe 89% (3j)
N
N
N
N
N
O
6 wt% Na(Hg)
F
O
N
S
Na2HPO4, MeOH
O
S
no reaction
O
complicated products
F
2o
73% (3o)
Scheme 4. Reaction of other tertiary amines with FBDT.
N
N
6 wt% Na(Hg)
N
F
N
O
Na2HPO4, MeOH
The desulfonylation reaction of the product 2a was examined
under a variety of reported conditions[16,17]. The results are listed
in Table 2. Mg/MeOH was found to give low yield of 3a. Sodium
amalgam afforded the product 3a with 64% yield. On the other
hand, Na/naphthalene, SmI2/HMPA, Raney-Ni/EtOH, and
SnBu3H/AIBN are inefficient for the transformation. The results
demonstrated that the desulfonylation reaction is highly sensitive
to the structure of the substrate.
O
O
F
O
S
S
48% (3r)
2r
Scheme 5. Desulfonylation of products.
A tentative mechanism is proposed in scheme 6 based on
the previous report.[14] The decomposition of TBHP in the
presence of copper (I) catalyst generates tert-butoxy radical and
copper (II) species. The abstraction of a hydrogen atom from
substrate 1a by tert-butoxy radical provides a radical intermediate
A. The single electron transfer (SET) from A to the copper (II)
species affords an iminium intermediate B and the copper (I)
catalyst. The subsequent addition of FBDT anion to B produces
the product 3a.
3
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10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
consumption of 2a as indicated by TLC detection, the mixture was
filtered through a pack of Celite and washed with MeOH. The
filtrate was concentrated under vacuum. Saturated brine (10 mL)
was added to the residue and the mixture was extracted with
EtOAc (5 mL  2). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column
chromatography (n-hexane). Product 3a was obtained as a yellow
liquid (31.0 mg, 64% yield); 1H NMR (400 MHz, CDCl3) δ 7.26 (t,
J = 7.9 Hz, 2H), 7.21–7.13 (m, 4H), 6.94 (d, J = 8.3 Hz, 2H), 6.78
(t, J = 7.2 Hz, 1H), 5.00–4.94 (m, 1H), 4.68 (ddd, J = 47.8, 9.4,
6.4 Hz, 1H), 4.52 (ddd, J = 47.3, 9.3, 6.1 Hz, 1H), 3.66–3.49 (m,
2H), 3.05–2.98 (m, 1H), 2.89–2.80 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 149.52, 135.99, 133.89 (d, JC-C-C-F= 4.1 Hz), 129.41,
N
F
O
S
N
O
O
O
TBHP
+
Cu(I)
1a
S
2a
t-BuO + OH
O
S
O
F
S
O
O
N
t-BuOH
N
Cu(II)
SET
A
B
Scheme 6. Possible mechanism.
128.61, 127.80, 127.47, 126.33, 118.22, 114.23, 84.95 (d, JC-F
=
178.4 Hz), 59.32 (d, JC-C-F= 20.8 Hz), 42.72, 27.82; 19F NMR (376
MHz, CDCl3) δ -217.48; HRMS (ESI) calculated for C16H17NF
(M+H)+: 242.1340, found: 242.1328.
Conclusion
In conclusion, we have developed an efficient CDC reaction
of tetrahydroisoquinolines with FBDT. CuBr/TBHP was identified
as the best combination. A variety of tetrahydroisoquinolines were
applied in the transformation with good to excellent yields. The
desulfonylation of the products was furnished with sodium
2-(7-Chloro-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-2-
fluoro-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2b)
The compound was obtained via analogous method described for
the preparation of 1b. It was obtained as a white solid (93.4 mg,
98%); m.p. 202.3–203.4°C; 1H NMR (400 MHz, DMSO) δ 8.48–
8.43 (m, 1H), 8.41–8.36 (m, 1H), 8.22–8.16 (m, 2H), 7.62 (d, J =
1.9 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 7.32–7.23 (m, 3H),
7.10 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.12 (d, J = 27.8
Hz, 1H), 3.99 (dd, J = 16.9, 6.6 Hz, 1H), 3.94–3.83 (m, 1H), 2.93–
2.83 (m, 1H), 2.79 (dd, J = 17.4, 4.4 Hz, 1H); 13C NMR (101 MHz,
DMSO) δ 149.07, 138.00, 137.55, 136.34, 135.69, 133.39, 132.19,
130.80, 129.74, 129.57, 129.14, 128.13, 124.96, 124.53, 121.62,
118.42, 108.32 (d, JC-F = 277.3 Hz), 56.02 (d, JC-C-F = 18.1 Hz),
44.30 (d, JC-N-C-C-F = 6.5 Hz), 23.24; 19F NMR (376 MHz, DMSO) δ
-149.44; HRMS (ESI) calculated for C22H18ClFNO4S2 (M+H)+:
478.0345, found: 478.0344.
amalgam.
The
corresponding
1-monofluoromethyl
tetrahydroisoquinolines could be obtained with good yields. The
finding provides a new synthetic approach to -monofluoromethyl
tertiary amines. The expand of the scope of the tertiary amines
and the development of an asymmetric version are currently
under investigation in our laboratory.
Experimental Section
Procedure for cross-dehydrogenative coupling (CDC)
reaction: To a 10 mL reaction tube, were added 1a (50.2 mg,
0.24 mmol), FBDT (47.2 mg, 0.20 mmol), CuBr (4.3 mg, 0.03
mmol), TBHP (40 μL, 6.5 M in n-hexane, 0.26 mmol) and MeCN
(2 mL). The mixture was stirred at room temperature for 12 h.
After the solvent was removed under reduced pressure, the
residue was purified by column chromatography (petroleum
ether/EtOAc) to afford 2a as a white solid (84.8 mg, 96% yield);
m.p. 201.2–202.2°C; 1H NMR (400 MHz, CDCl3) δ 8.04–7.98 (m,
2H), 7.91–7.84 (m, 2H), 7.69 (s, 1H), 7.34–7.26 (m, 3H), 7.24–
7.16 (m, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.93 (t, J = 7.1 Hz, 1H),
6.18 (d, J = 27.5 Hz, 1H), 4.08 (t, J = 12.9 Hz, 1H), 3.89 (dd, J =
14.7, 5.9 Hz, 1H), 3.08–2.97 (m, 1H), 2.73 (dd, J = 16.8, 3.1 Hz,
1H); 13C NMR (101 MHz, CDCl3): δ 149.63, 137.04, 137.00,
135.68, 135.20, 134.72, 129.87, 129.24, 129.05, 128.05, 127.23,
126.52, 123.72, 123.53, 121.76, 119.10, 109.07 (d, JC-F = 280.4
Hz), 56.77 (d, JC-C-F = 18.5 Hz), 45.40 (d, JC-N-C-C-F = 6.1 Hz), 24.05;
19F NMR (376 MHz, CDCl3) δ -149.33; HRMS (ESI) calculated for
C22H19FNO4S2 (M+H)+: 444.0734, found: 444.0721.
2-(5-Bromo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-2-
fluoro-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2c)
The compound was obtained via analogous method described for
the preparation of 1c. It was obtained as a white solid (86.6 mg,
83%); m.p. 202.1–203.4°C; 1H NMR (400 MHz, DMSO) δ 8.48–
8.38 (m, 2H), 8.23–8.16 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.63 (d,
J = 7.7 Hz, 1H), 7.34–7.25 (m, 3H), 7.11 (d, J = 8.1 Hz, 2H), 6.90
(t, J = 7.2 Hz, 1H), 6.15 (d, J = 27.9 Hz, 1H), 4.12 (d, J = 15.2 Hz,
1H), 3.95 (dt, J = 8.7, 5.9 Hz, 1H), 2.83–2.76 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 153.54, 142.73, 142.30, 141.23, 140.35,
138.48, 138.24, 134.77, 134.59, 133.14, 132.75, 130.90, 129.74,
129.30, 126.29, 122.68, 113.15 (d, JC-F = 277.6 Hz), 61.49 (d, JC-
C-F = 18.0 Hz), 48.53 (d, JC-N-C-C-F = 6.9 Hz), 30.01; 19F NMR (376
MHz, DMSO)
δ
-149.20; HRMS (ESI) calculated for
C22H18NO4FS2Br (M+H)+: 521.9839, found: 521.9823.
2-Fluoro-2-(6-methoxy-2-phenyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)-2H-benzo[d][1,3]dithiole 1,1,3,3-
tetraoxide (2d)
Procedure for the reductive desulfonylation: Na(Hg) (6 wt.%
Na in Hg, net sodium content 6.0 mmol) was added to a test tube
containing 2a (88.6 mg, 0.2 mmol), Na2HPO4 (851.8 mg, 6.0
mmol) and anhydrous MeOH (2.0 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was stirred at 0 °C for 2 h, then
was warmed to room temperature. After the complete
The compound was obtained via analogous method described for
the preparation of 1d. It was obtained as a white solid (72.7 mg,
77%); m.p. 204.2–205.6°C; 1H NMR (500 MHz, DMSO) δ 8.45–
8.35 (m, 2H), 8.21–8.14 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.26 (t,
J = 7.4 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 7.5 Hz, 2H),
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
1
6.82 (s, 1H), 6.06 (d, J = 27.7 Hz, 1H), 4.01–3.83 (m, 2H), 3.76 (s,
3H), 2.97–2.86 (m, 1H), 2.76 (d, J = 14.2 Hz, 1H); 13C NMR (126
MHz, DMSO) δ 159.94, 149.36, 138.81, 137.84, 137.41, 135.83,
133.66, 129.70, 129.42, 124.81, 124.42, 121.32, 118.85, 118.16,
114.79, 113.16, 108.53 (d, JC-F = 276.6 Hz), 56.10 (d, JC-C-F = 18.3
93%); m.p.213.2–214.4°C; H NMR (400 MHz, CDCl3) δ 8.06–
7.99 (m, 2H), 7.95–7.87 (m, 2H), 7.72–7.64 (m, 1H), 7.35–7.29
(m, 2H), 7.22–7.17 (m, 3H), 7.03–6.98 (m, 2H), 6.09 (d, JC-C-F
=
27.1 Hz, 1H), 4.13–4.03 (m, 1H), 3.82 (dd, J = 14.9, 5.2 Hz, 1H),
3.06–2.93 (m, 1H), 2.76 (dd, J = 17.0, 3.8 Hz, 1H); 13C NMR (126
Hz), 55.60, 44.16 (d, JC-N-C-C-F = 6.4 Hz), 24.12;19F NMR (471 MHz, MHz, CDCl3) δ 148.21, 136.82, 136.70, 135.70, 135.26, 134.65,
DMSO) δ -149.96; HRMS (ESI) calculated for C23H21NO5FS2
129.86, 129.18, 129.15, 128.02, 126.84, 126.74, 126.62, 123.71,
123.50, 120.35, 108.77 (d, JC-F = 280.1 Hz), 56.79 (d, JC-C-F = 18.5
Hz), 45.47 (d, JC-N-C-C-F = 6.0 Hz), 23.99; 19F NMR (376 MHz,
CDCl3) δ -149.69; HRMS (ESI) calculated for C22H18NO4FS2Cl
(M+H)+: 478.0344, found: 478.0323.
(M+H)+: 474.0841, found: 474.0840.
Methyl-4-(1-(2-fluoro-1,1,3,3-tetraoxido-2H-
benzo[d][1,3]dithiol-2-yl)-3,4-dihydroisoquinolin-2(1H)-
yl)benzoate (2e)
The compound was obtained via analogous method described for
the preparation of 1e. It was obtained as a white solid (84.6 mg,
85%); m.p. 208.6–209.8°C; 1H NMR (400 MHz, CDCl3) δ 8.06–
7.98 (m, 2H), 7.96–7.88 (m, 4H), 7.69–7.65 (m, 1H), 7.35–7.28
(m, 2H), 7.21–7.17 (m, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.36 (d, J =
26.4 Hz, 1H), 4.18–4.01 (m, 1H), 3.84 (s, 3H), 3.15–3.04 (m, 1H),
2.86 (dd, J = 16.8, 2.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
166.81, 152.52, 136.59, 136.40, 135.77, 135.39, 134.75, 131.17,
129.80, 129.33, 128.09, 127.00, 126.58, 123.82, 123.48, 121.97,
116.28, 108.29 (d, JC-F = 279.6 Hz), 56.25 (d, JC-C-F = 18.9 Hz),
51.77, 43.97 (d, JC-N-C-C-F = 5.8 Hz), 24.69; 19F NMR (376 MHz,
CDCl3) δ -148.66; HRMS (ESI) calculated for C24H21NO6FS2
(M+H)+: 502.0809, found: 502.0789.
2-Fluoro-2-(2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-2H-
benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2i)
The compound was obtained via analogous method described for
the preparation of 1i. It was obtained as a white solid (81.0 mg,
89%); m.p. 195.2–196.1°C; 1H NMR (400 MHz, CDCl3) δ 8.01 (dd,
J = 5.4, 2.2 Hz, 2H), 7.93–7.85 (m, 2H), 7.73–7.66 (m, 1H), 7.35–
7.28 (m, 2H), 7.22–7.15 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.97 (d,
J = 8.5 Hz, 2H), 6.10 (d, J = 27.7 Hz, 1H), 4.11–4.00 (m, 1H), 3.81
(dd, J = 14.3, 5.9 Hz, 1H), 3.06–2.94 (m, 1H), 2.70 (dd, J = 17.0,
3.9 Hz, 1H), 2.25 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 147.43,
137.08, 135.61, 135.11, 134.64, 131.35, 129.82, 129.74, 128.94,
128.01, 127.24, 126.46, 123.62, 123.48, 119.44, 109.18 (d, JC-F
=
280.5 Hz), 56.87 (d, JC-C-F = 18.3 Hz), 45.74 (d, JC-N-C-C-F = 6.1 Hz),
23.86, 20.55; 19F NMR (376 MHz, CDCl3) δ -149.60; HRMS (ESI)
calculated for C23H21NO4FS2 (M+H)+: 458.0891, found: 458.0911.
1-(4-(1-(2-Fluoro-1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-
yl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethan-1-one (2f)
The compound was obtained via analogous method described for
the preparation of 1f. It was obtained as a white solid (89.1 mg,
2-Fuoro-2-(2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)-2H-benzo[d][1,3]dithiole 1,1,3,3-
tetraoxide (2j)
1
92%); m.p.183.5–185.1°C; H NMR (400 MHz, CDCl3) δ 8.09–
7.99 (m, 2H), 7.97–7.86 (m, 4H), 7.70–7.63 (m, 1H), 7.36–7.28
(m, 2H), 7.23–7.18 (m, 1H), 7.17–7.11 (m, 2H), 6.39 (d, J = 26.2
Hz, 1H), 4.19–4.03 (m, 2H), 3.19–3.06 (m, 1H), 2.93–2.84 (m, 1H), 52%); m.p.175.0–177.4°C; 1H NMR (400 MHz, CDCl3) δ 8.02 (ddd,
2.51 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 196.56, 152.55, 136.54, J = 5.8, 4.2, 2.1 Hz, 2H), 7.93–7.86 (m, 2H), 7.72–7.67 (m, 1H),
The compound was obtained via analogous method described for
the preparation of 1j. It was obtained as a white solid (49.2 mg,
136.33, 135.80, 135.44, 134.78, 130.24, 129.79, 129.54, 129.39,
128.09, 127.00, 126.61, 123.86, 123.48, 116.03, 108.21 (d, JC-F
7.35–7.30 (m, 2H), 7.22–7.18 (m, 1H), 7.02–6.97 (m, 2H), 6.81–
6.76 (m, 2H), 5.98 (d, J = 27.9 Hz, 1H), 4.08–3.99 (m, 1H), 3.73
(s, 3H), 3.67 (dd, J = 14.9, 5.3 Hz, 1H), 3.01– 2.90(m, 1H), 2.69
(dd, J = 17.1, 4.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 155.26,
143.94, 137.21, 137.17, 135.61, 135.09, 134.63, 129.85, 128.93,
127.97, 127.26, 126.55, 123.61, 123.52, 121.95, 114.39, 109.35
(d, JC-F = 280.7 Hz), 57.35 (d, JC-C-F = 18.4 Hz), 55.45, 46.75 (d,
JC-N-C-C-F = 6.1 Hz), 23.67; 19F NMR (376 MHz, CDCl3) δ -150.18;
HRMS (ESI) calculated for C23H21NO5FS2 (M+H)+: 474.0840,
found: 474.0822
=
279.5 Hz), 56.16 (d, JC-C-F = 18.9 Hz), 43.83 (d, JC-N-C-C-F = 5.8 Hz),
26.25, 24.82; 19F NMR (376 MHz, CDCl3) δ -148.58; HRMS (ESI)
calculated for C24H21NO5FS2 (M+H)+: 486.0863, found: 486.0840.
4-(1-(2-Fluoro-1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-
yl)-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile (2g)
The compound was obtained via analogous method described for
the preparation of 1g. It was obtained as a white solid (84.0 mg,
1
90%); m.p.201.3–202.6°C; H NMR (400 MHz, CDCl3) δ 8.09–
7.99 (m, 2H), 7.98–7.91 (m, 2H), 7.65 (d, J = 6.9 Hz, 1H), 7.54 (d,
J = 8.7 Hz, 2H), 7.37–7.29 (m, 2H), 7.22 (d, J = 6.7 Hz, 1H), 7.14
(d, J = 8.7 Hz, 2H), 6.34 (d, J = 25.8 Hz, 1H), 4.19–4.08 (m, 1H),
4.01 (dd, J = 14.0, 5.1 Hz, 1H), 3.17–3.06 (m, 1H), 2.92 (d, J =
16.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 151.93, 136.41,
136.11, 135.86, 135.54, 134.79, 133.53, 129.80, 129.55, 128.07,
1-(3-(1-(2-Fluoro-1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-
yl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ethan-1-one (2k)
The compound was obtained via analogous method described for
the preparation of 1k. It was obtained as a white solid (60.1 mg,
62%); m.p. 184.3–185.2°C; 1H NMR (400 MHz, CDCl3) δ 8.07–
7.99 (m, 2H), 7.95–7.89 (m, 2H), 7.72–7.66 (m, 2H), 7.52–7.47
(m, 1H), 7.37–7.28 (m, 4H), 7.22–7.18 (m, 1H), 6.22 (d, J = 26.8
Hz, 1H), 4.18–4.08 (m, 1H), 3.97 (dd, J = 14.9, 5.2 Hz, 1H), 3.12–
3.00 (m, 1H), 2.81 (dd, J = 17.1, 3.4 Hz, 1H), 2.56 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 198.13, 149.71, 138.15, 136.82, 136.69,
135.76, 135.34, 134.74, 129.88, 129.50, 129.26, 128.09, 126.90,
126.81, 126.75, 123.93, 123.51, 119.49, 116.72, 107.98 (d, JC-F
=
279.9 Hz), 102.83, 56.16 (d, JC-C-F = 19.3 Hz), 43.73 (d, JC-N-C-C-F
= 5.3 Hz), 24.83; 19F NMR (376 MHz, CDCl3) δ -153.38; HRMS
(ESI) calculated for C23H18N2O4FS2 (M+H)+: 469.0707, found:
469.0687.
2-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-2-
fluoro-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2h)
The compound was obtained via analogous method described for
the preparation of 1h. It was obtained as a white solid (89.2 mg,
126.65, 123.80, 123.54, 123.24, 121.65, 117.56, 108.71 (d, JC-F =
280.0 Hz), 56.84 (d, J C-C-F= 18.7 Hz), 44.92 (d, JC-N-C-C-F = 5.9 Hz),
26.77, 24.22; 19F NMR (376 MHz, CDCl3) δ -149.19; HRMS (ESI)
calculated for C24H21NO5FS2 (M+H)+: 486.0840, found: 486.0858.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
1H), 4.16 (t, J = 13.3 Hz, 1H), 4.03 (dd, J = 14.4, 5.5 Hz, 1H),
3.09–2.98 (m, 1H), 2.76 (dd, J = 16.6, 2.8 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 147.32, 137.01, 136.97, 135.67, 135.19, 134.72,
134.11, 129.91, 129.50, 129.24, 129.11, 128.13, 127.46, 127.03,
126.65, 126.30, 124.18, 123.71, 123.55, 121.02, 114.28, 109.03
(d, JC-F = 280.5 Hz), 56.74 (d, JC-C-F = 18.5 Hz), 45.60 (d, JC-N-C-C-
F = 6.3 Hz), 24.17; 19F NMR (376 MHz, CDCl3) δ -149.34; HRMS
(ESI) calculated for C26H21NO4FS2 (M+H)+: 494.0891, found:
494.0870.
2-Fluoro-2-(2-(m-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-
2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2l)
The compound was obtained via analogous method described for
the preparation of 1l. It was obtained as a white solid (87.8 mg,
1
96%); m.p. 197.0–198.1°C; H NMR (400 MHz, CDCl3) δ 8.05–
7.99 (m, 2H), 7.93–7.86 (m, 2H), 7.69 (dd, J = 5.1, 3.9 Hz, 1H),
7.35–7.28 (m, 2H), 7.18 (dd, J = 5.1, 3.8 Hz, 1H), 7.12 (t, J = 7.8
Hz, 1H), 6.91–6.84 (m, 2H), 6.75 (d, J = 7.4 Hz, 1H), 6.17 (d, J =
27.5 Hz, 1H), 4.12–4.02 (m, 1H), 3.95–3.83 (m, 1H), 3.08–2.94
(m, 1H), 2.72 (dd, J = 17.0, 3.7 Hz, 1H), 2.29 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 149.62, 138.96, 137.06, 137.04, 135.62,
135.14, 134.72, 129.82, 128.97, 128.02, 127.24, 126.45, 123.68,
123.50, 122.65, 119.80, 116.06, 109.09 (d, JC-F = 280.2 Hz), 56.67
(d, JC-C-F = 18.4 Hz), 45.44 (d, JC-N-C-C-F = 6.2 Hz), 24.05, 21.74;
19F NMR (376 MHz, CDCl3) δ -149.20; HRMS (ESI) calculated for
C23H21NO4FS2 (M+H)+: 458.0891, found: 458.0899.
2-Fluoro-2-(2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-
yl)-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2p)
The compound was obtained via analogous method described for
the preparation of 1p. It was obtained as a white solid (78.4 mg,
88%); m.p. 153.3–155.2°C; 1H NMR (400 MHz, DMSO) δ 8.42 (dd,
J = 5.7, 3.0 Hz, 1H), 8.34 (dd, J = 5.7, 3.0 Hz, 1H), 8.19–8.13 (m,
3H), 7.74–7.64 (m, 2H), 7.58 (d, J = 6.9 Hz, 1H), 7.36–7.27 (m,
2H), 7.22 (dd, J = 11.9, 8.1 Hz, 2H), 6.79 (dd, J = 6.7, 5.2 Hz, 1H),
4.30 (d, J = 14.8 Hz, 1H), 3.98–3.86 (m, 1H), 2.90 (s, 2H); 13C
NMR (101 MHz, DMSO) δ 157.43, 147.81, 138.75, 137.79,
137.45, 137.04, 135.57, 133.83, 130.27, 129.32, 128.48, 128.24,
126.59, 124.79, 124.33, 115.51, 109.19, 108.52 (d, JC-F = 276.0
Hz), 50.54 (d, JC-C-F = 17.6 Hz), 41.75 (d, JC-N-C-C-F = 5.4 Hz), 25.12;
19F NMR (376 MHz, DMSO) δ -147.51; HRMS (ESI) calculated for
C21H18N2O4FS2 (M+H)+: 445.0687, found: 445.0675.
2-(1-(2-Fluoro-1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-
yl)-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile (2m)
The compound was obtained via analogous method described for
the preparation of 1m. It was obtained as a white solid (82.2 mg,
1
79%); m.p. 229.4–230.5°C; H NMR (400 MHz, CDCl3) δ 8.11–
8.06 (m, 1H), 8.03–7.99 (m, 1H), 7.96–7.88 (m, 2H), 7.82–7.75
(m, 1H), 7.66 (dd, J = 7.7, 1.4 Hz, 1H), 7.44–7.32 (m, 3H), 7.25–
7.20 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H),
5.98 (d, J = 26.9 Hz, 1H), 4.30–4.19 (m, 1H), 4.00 (dd, J = 13.1,
2.6 Hz, 1H), 2.83–2.75 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
153.73, 136.95, 136.85, 135.87, 135.19, 134.91, 134.47, 133.54,
129.90, 129.35, 127.70, 127.05, 126.77, 123.98, 123.78, 123.53,
121.86, 117.71, 108.36 (d, JC-F = 281.1 Hz), 108.10, 57.31 (d, JC-
C-F = 18.8 Hz), 47.85 (d, JC-N-C-C-F = 5.9 Hz), 24.33; 19F NMR (376
2-Fluoro-2-(2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-
1-yl)-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2q)
The compound was obtained via analogous method described for
the preparation of 1q. It was obtained as a white solid (56.5 mg,
64%); m.p. 184.4–185.0°C; 1H NMR (400 MHz, DMSO) δ 8.53 (d,
J = 4.7 Hz, 2H), 8.44 (dd, J = 6.1, 2.7 Hz, 1H), 8.36 (dd, J = 5.9,
2.9 Hz, 1H), 8.18 (dd, J = 5.7, 3.2 Hz, 2H), 7.66 (d, J = 29.8 Hz,
1H), 7.56 (d, J = 7.3 Hz, 1H), 7.39–7.24 (m, 3H), 6.86 (t, J = 4.7
Hz, 1H), 4.94 (d, J = 14.8 Hz, 1H), 3.85–3.73 (m, 1H), 3.01–2.86
(m, 2H); 13C NMR (126 MHz, DMSO) δ 161.15, 158.76, 137.90,
137.62, 137.02, 135.25, 133.82, 130.48, 129.58, 128.27, 127.69,
126.60, 124.86, 124.36, 112.95, 107.93 (d, JC-F = 276.4 Hz), 51.02
(d, JC-C-F = 18.0 Hz), 25.70; 19F NMR (376 MHz, DMSO) δ -147.55;
HRMS (ESI) calculated for C20H17N3O4FS2 (M+H)+: 446.0639,
found: 446.0623.
MHz, CDCl3)
δ
-150.48; HRMS (ESI) calculated for
C23H18N2O4FS2 (M+H)+: 469.0687, found: 469.0701.
2-Fluoro-2-(2-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-2H-
benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (2n)
The compound was obtained via analogous method described for
the preparation of 1n. It was obtained as a white solid (83.7 mg,
1
92%); m.p. 196.7–198.2°C; H NMR (400 MHz, CDCl3) δ 8.05–
7.97 (m, 2H), 7.91–7.84 (m, 2H), 7.81–7.75 (m, 1H), 7.41–7.33
(m, 2H), 7.21 (d, J = 7.1 Hz, 2H), 6.99 (td, J = 7.3, 0.8 Hz, 1H),
6.93 (td, J = 7.6, 1.2 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 5.88 (d, J
= 28.0 Hz, 1H), 4.01–3.89 (m, 1H), 3.46–3.36 (m, 1H), 2.83–2.72
(m, 1H), 2.69–2.62 (m, 1H), 2.53 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 149.25, 137.59, 137.05, 135.61, 135.07, 134.66, 133.30,
131.80, 129.75, 128.92, 127.99, 127.64, 126.70, 126.19, 124.56,
123.54, 123.47, 121.51, 109.23 (d, JC-F = 280.6 Hz), 58.28 (d, JC-
C-F = 18.3 Hz), 45.54 (d, JC-N-C-C-F = 6.0 Hz), 23.44, 18.29; 19F NMR
(376 MHz, CDCl3) δ -150.30; HRMS (ESI) calculated for
C23H21NO4FS2 (M+H)+: 458.0891, found: 458.0887.
2-Fluoro-2-(9-methyl-2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-1-yl)-2H-benzo[d][1,3]dithiole
1,1,3,3-
tetraoxide (2r)
The compound was obtained via analogous method described for
the preparation of 1r. It was obtained as a white solid (68.4 mg,
92%); m.p. 177.4–178.5°C; 1H NMR (400 MHz, CDCl3) δ 8.06–
7.97 (m, 2H), 7.90–7.82 (m, 2H), 7.53 (d, J = 7.7 Hz, 1H), 7.38 (d,
J = 8.1 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H),
7.12 (dd, J = 19.5, 7.6 Hz, 3H), 6.93 (t, J = 7.1 Hz, 1H), 6.12 (d, J
= 23.4 Hz, 1H), 4.14 (t, J = 12.7 Hz, 1H), 3.99 (dd, J = 15.2, 6.3
Hz, 1H), 3.90 (s, 3H), 3.06 (t, J = 16.6 Hz, 1H), 2.85 (dd, J = 16.0,
5.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 150.04, 138.97, 137.60,
135.75, 135.15, 134.55, 129.26, 126.82, 125.19, 123.88, 123.61,
123.07, 122.30, 119.62, 119.56, 118.70, 114.07, 110.15, 108.64
(d, JC-F = 279.7 Hz), 53.35 (d, JC-C-F = 18.7 Hz), 45.37 (d, JC-N-C-C-
F = 6.4 Hz), 32.13, 18.54; 19F NMR (376 MHz, DMSO) δ -147.55;
HRMS (APCI) calculated for C25H22FN2O4S2 (M+H)+: 497.1000,
found:497.1002.
2-Fluoro-2-(2-(naphthalen-2-yl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)-2H-benzo[d][1,3]dithiole 1,1,3,3-
tetraoxide (2o)
The compound was obtained via analogous method described for
the preparation of 1o.It was obtained as a white solid (87.1 mg,
1
88%); m.p. 220.6–221.7°C; H NMR (400 MHz, CDCl3) δ 8.04–
7.95 (m, 2H), 7.88–7.82 (m, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (d,
J = 7.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H),
7.41–7.26 (m, 5H), 7.19 (d, J = 5.1 Hz, 1H), 6.32 (d, J = 27.4 Hz,
6
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10.1002/ejoc.202100537
European Journal of Organic Chemistry
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2-(4-Chlorophenyl)-1-(fluoromethyl)-1,2,3,4-
tetrahydroisoquinoline (3h)
The compound was obtained via analogous method described for
the preparation of 2r. It was obtained as a yellow liquid (28.1 mg,
48%); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 1H), 7.32–
7.19 (m, 5H), 7.09 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H),
6.81 (t, J = 7.2 Hz, 1H), 5.12–5.04 (m, 1H), 4.90–4.75 (m, 1H),
4.75–4.60 (m, 1H)., 3.96 (dd, J = 14.1, 5.3 Hz, 1H), 3.71 (s, 3H),
3.66–3.57 (m, 1H), 3.05–2.94 (m, 1H), 2.71 (dd, J = 15.5, 3.7 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 150.32, 137.59, 131.34 (d, JC-
The compound was obtained via analogous method described for
the preparation of 2h. It was obtained as a yellow liquid (38.0 mg,
69%); 1H NMR (400 MHz, CDCl3) δ 7.27–7.15 (m, 6H), 6.89–6.82
(m, 2H), 4.92 (dt, J = 14.5, 6.1 Hz, 1H), 4.74–4.59 (m, 1H), 4.59–
4.44 (m, 1H), 3.65–3.57 (m, 1H), 3.54–3.46 (m, 1H), 3.06–2.96
(m, 1H), 2.90–2.81 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 148.14,
135.74, 133.35 (d, JC-C-C-F = 4.5 Hz), 129.13, 128.65, 127.70,
127.61, 126.43, 122.96, 115.38, 84.86 (d, JC-F = 178.7 Hz), 59.45
(d, JC-C-F = 20.7 Hz), 42.81, 27.64; 19F NMR (376 MHz, CDCl3) δ -
= 6.2 Hz), 129.31, 126.58, 121.93, 119.62, 119.29, 118.34,
C-C-F
116.97, 110.18, 109.10, 83.54 (d, JC-F = 178.1 Hz), 55.70 (d, JC-C-
F = 22.1 Hz), 42.43, 30.16 (d, JC-N-C-C-C-F = 2.9 Hz), 19.63;19F NMR
217.08; HRMS (ESI) calculated for C16H16ClNF (M+H)+: 276.0950, (376 MHz, CDCl3) δ -217.37; HRMS (ESI) calculated for C20H19NF
found: 276.0951.
(M+H)+: 295.1605, found: 295.1607.
1-(Fluoromethyl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline
(3i)
Acknowledgements
The compound was obtained via analogous method described for
the preparation of 2i.It was obtained as a yellow liquid (37.2 mg,
73%); 1H NMR (400 MHz, CDCl3) δ 7.25–7.13 (m, 4H), 7.07 (d, J
= 8.2 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 4.97–4.87 (m, 1H), 4.77–
4.60 (m, 1H), 4.52 (ddd, J = 47.4, 9.3, 6.0 Hz, 1H), 3.64–3.56 (m,
1H), 3.55–3.48 (m, 1H), 3.05–2.96 (m, 1H), 2.87–2.78 (m, 1H),
2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.47, 136.00, 133.91
(d, JC-C-C-F = 4.1 Hz), 129.87, 128.64, 127.76, 127.34, 126.23,
114.89, 85.04 (d, JC-F = 178.3 Hz), 59.53 (d, JC-C-F = 20.6 Hz),
43.01, 27.67, 20.35; 19F NMR (376 MHz, CDCl3) δ -217.46;
HRMS (ESI) calculated for C17H19NF (M+H)+: 256.1496, found:
256.1493.
We thank the National Natural Science Foundation of China
(21772240, 82061128001), and Guangdong Provincial Key
Laboratory of Chiral Molecules and Drug Discovery
(2019B030301005) for the financial support.
Keywords: cross-dehydrogenative coupling •
fluorobis(sulfonyl)methane • monofluoromethylation •
tetrahydroisoquinoline • tertiary amine
[1]
a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529-2591; b) Y. Zhou, J.
Wang, Z. Gu, S. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok, K. Izawa,
H. Liu, Chem. Rev. 2016, 116, 422-518; c) N. A. Meanwell, J. Med. Chem.
2018, 61, 5822-5880.
1-(Fluoromethyl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (3j)
[2]
a) J. Hu, W. Zhang, F. Wang, Chem. Commun. 2009, 7465-7478; b) B.
Lantano, M. R. Torviso, S. M. Bonesi, S. Barata-Vallejo, A. Postigo,
Coord. Chem. Rev. 2015, 285, 76-108; c) T. Chatterjee, N. Iqbal, Y. You,
E. J. Cho, Acc. Chem. Res. 2016, 49, 2284-2294; d) T. Koike, M. Akita,
Acc. Chem. Res. 2016, 49, 1937-1945; e) A. Lemos, C. Lemaire, A.
Luxen, Adv. Synth. Catal. 2019, 361, 1500-1537; f) M. Reichel, K.
Karaghiosoff, Angew. Chem. Int. Ed. 2020, 59, 12268-12281.
a) Y. Liu, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2017, 56, 9930-9934;
b) H. Yin, J. Sheng, K. F. Zhang, Z. Q. Zhang, K. J. Bian, X. S. Wang,
Chem. Commun. 2019, 55, 7635-7638; c) N. Noto, K. Takahashi, S.
Goryo, A. Takakado, K. Iwata, T. Koike, M. Akita, J. Org. Chem. 2020,
85, 13220-13227; d) R. Senatore, M. Malik, M. Spreitzer, W. Holzer, V.
Pace, Org. Lett. 2020, 22, 1345-1349.
The compound was obtained via analogous method described for
the preparation of 2j. It was obtained as a yellow liquid (47.0 mg,
87%); 1H NMR (400 MHz, CDCl3) δ 7.25–7.13 (m, 4H), 6.93 (d, J
= 8.9 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.88-4.78 (m, 1H), 4.76–
4.60 (m, 1H), 4.60–4.44 (m, 1H), 3.75 (s, 3H), 3.63–3.55 (m, 1H),
3.53–3.45 (m, 1H), 3.04–2.94 (m, 1H), 2.84-2.74 (m, 1H) ; 13C
NMR (101 MHz, CDCl3) δ 153.12, 144.21, 135.99, 133.75 (d, JC-
[3]
= 4.5 Hz), 128.79, 127.68, 127.25, 126.19, 117.50, 114.73,
C-C-F
85.20 (d, JC-F = 178.0 Hz), 60.15 (d, JC-C-F = 20.1 Hz), 55.70, 43.79,
27.38; 19F NMR (376 MHz, CDCl3) δ -217.48; HRMS (ESI)
calculated for C17H20FNO (M+H)+: 272.1445, found: 272.1443.
[4]
[5]
a) C. Ni, L. Zhang, J. Hu, J. Org. Chem. 2008, 73, 5699–5713; b) G. K.
Surya Prakash, S. Chacko, H. Vaghoo, N. Shao, L. Gurung, T. Mathew,
G. S. Olah, Org. Lett. 2009, 11, 1127–1130; c) G. K. S. Prakash , N.
Shao, Z. Zhang, C. Ni, F. Wang, R. Haiges, G. A. Olah, J. Fluorine Chem.
2012, 133, 27–32.
1-(Fluoromethyl)-2-(naphthalen-2-yl)-1,2,3,4-
tetrahydroisoquinoline (3o)
The compound was obtained via analogous method described for
the preparation of 2o. It was obtained as a yellow liquid (42.7 mg,
73%); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 9.1 Hz, 1H), 7.70
(d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.40–7.32 (m, 2H),
7.28–7.16 (m, 6H), 5.18–5.09 (m, 1H), 4.76 (ddd, J = 44.7, 8.0,
5.0 Hz, 1H), 4.61 (ddd, J = 15.0, 8.0, 4.2 Hz, 1H)., 3.78–3.69 (m,
2H), 3.14–3.05 (m, 1H), 2.96–2.85 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 147.26, 135.83, 134.80, 133.52 (d, JC-C-C-F = 4.4 Hz),
129.04, 128.71, 127.72, 127.45, 127.40, 126.43, 126.32, 126.30,
122.79, 117.64, 108.78, 84.98 (d, JC-F = 178.5 Hz), 59.35 (d, JC-C-
F = 20.5 Hz), 42.84, 27.66; 19F NMR (376 MHz, CDCl3) δ -217.33;
HRMS (ESI) calculated for C20H19NF (M+H)+: 292.1496, found:
292.1488.
a) C. Li, Acc. Chem. Res. 2009, 42, 335–344; b) C. J. Scheuermann,
Chem. Asian. J. 2010, 5, 436-451; c) C. S. Yeung, V. M. Dong, Chem.
Rev. 2011, 111, 1215-1292; d) C. Y. Huang, H. Kang, J. Li, C. J. Li, J.
Org. Chem. 2019, 84, 12705-12721; e) I. Bosque, R. Chinchilla, J. C.
Gonzalez-Gomez, D. Guijarro, F. Alonso, Org. Chem. Front. 2020, 7,
1717-1742.
[6]
A. Hillisch, K. M. Gericke, S. Allerheiligen, S. Roehrig, M. Schaefer, A.
Tersteegen, S. Schulz, P. Lienau, M. Gnoth, V. Puetter, R. C. Hillig, S.
Heitmeier, J. Med. Chem. 2020, 63, 12574-12594.
[7]
[8]
W. Huang, C. Ni, Y. Zhao, J. Hu, New J. Chem. 2013, 37, 1684-1687.
E. Shirakawa, T. Yoneda, K. Moriya, K. Ota, N. Uchiyama, R. Nishikawa,
T. Hayashi, Chem. Lett. 2011, 40, 1041-1043.
[9]
a) S. Mizuta, N. Shibata, Y. Goto, T. Furukawa, S. Nakamura, T. Toru, J.
Am. Chem. Soc. 2007, 129, 6394–6395; b) T. Furukawa, Y. Goto, J.
Kawazoe, E. Tokunaga, S. Nakamura, Y. Yang, H. Du, A. Kakehi, M.
Shiro, N. Shibata, Angew. Chem. Int. Ed. 2010, 49, 1642-1647; c) X.
1-(Fluoromethyl)-9-methyl-2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole (3r)
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100537
European Journal of Organic Chemistry
FULL PAPER
Shen, L. Zhang, Y. Zhao, L. Zhu, G. Li, J. Hu, Angew. Chem. Int. Ed.
2011, 50, 2588-2592.
[10] A. Yu, Z. Gu, D. Chen, W. He, P. Tan, J. Xiang, Catal. Commun. 2009,
11, 162-166.
[11]
M. R. Patil, N. P. Dedhia, A. R. Kapdi, A. V. Kumar, J. Org. Chem. 2018,
83, 4477-4490.
[12] X. Z. Shu, Y. F. Yang, X. F. Xia, K. G. Ji, X. Y. Liu, Y. M. Liang, Org.
Biomol. Chem. 2010, 8, 4077-4079.
[13] A. S. Tsang, A. S. K. Hashmi, P. Comba, M. Kerscher, B. Chan, M. H.
Todd, Chem. Eur. J. 2017, 23, 9313-9318.
[14] Z. Li, D. S. Bohle, C. Li, Proc. Natl. Acad. Sci. 2006, 103, 8928-8933.
[15] a) S. S. Klioze, F. J. Ehrgott Jr, J. C. Wilker, D. L. Woodward, J. Med.
Chem. 1979, 22, 1497–1504; b) P. Abreu, A. Pereira, Nat. Prod. Lett.
2006, 15, 43-48; c) K. Huber, L. Brault, O. Fedorov, C. Gasser, P.
Filippakopoulos, A. N. Bullock, D. Fabbro, J. Trappe, J. Schwaller, S.
Knapp, F. Bracher, J. Med. Chem. 2012, 55, 403−413.
[16] C. Najera, M. Yus, Tetrahedron 1999, 55, 10547-10658.
[17] a) A. Brown, L. Carpino, J. Org. Chem. 1985, 50, 1749-1750; b) Z. Li, M.
Nakashige, W. J. Chain, J. Am. Chem. Soc. 2011, 133, 6553–6556; c) J.
Gui, Q. Zhou, C. M. Pan, Y. Yabe, A. C. Burns, M. R. Collins, M. A.
Ornelas, Y. Ishihara, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 4853-
4856.
8
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European Journal of Organic Chemistry
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Entry for the Table of Contents
A cross-dehydrogenative coupling of
tetrahydroisoquinolines and 2-fluoro-
1,3-benzodithiole-1,1,3,3-tetraoxide
had been developed. The products
could be transformed to 1-
Bao-qin Huang, Yuan Chen, Xue-jing
Zhang, Ming Yan*
1-9
monofluoromethyl
Cross-dehydrogenative coupling of
tetrahydroisoquinolines and 2-fluoro-
tetrahydroisoquinolines via the
subsequent desulfonylation. This method
provides a new synthetic approach to α-
monofluoromethyl tertiary amines.
1,3-benzodithiole-1,1,3,3-tetraoxide:
a
new synthetic approach to α-
monofluoromethyl tertiary amines
9
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