Nucleophilic difluoromethylation of C=N bonds in heterocycles with difluoromethyl silane reagents

Article abstract of DOI:10.1016/j.tet.2012.04.039

An efficient and straightforward nucleophilic difluoromethylation of CN bonds in heterocycles under the activation of alkylating agents has been developed. Cyclic iminium salts derived from dihydroisoquinolines, quinolines, and pyridines were successfully

Full text of DOI:10.1016/j.tet.2012.04.039

Tetrahedron 68 (2012) 5137e5144
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Nucleophilic difluoromethylation of C]N bonds in heterocycles with
difluoromethyl silane reagents
,
Weizhou Huang a, Chuanfa Ni a, Yanchuan Zhao a, Wei Zhang a, Alexander D. Dilman b, Jinbo Hu a
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, PR China
b N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward nucleophilic difluoromethylation of C]N bonds in heterocycles under
the activation of alkylating agents has been developed. Cyclic iminium salts derived from dihy-
droisoquinolines, quinolines, and pyridines were successfully difluoromethylated with sulfur-based
Received 19 March 2012
Received in revised form 5 April 2012
Accepted 10 April 2012
fluoroalkyl silanes affording
a
series of new difluoromethylated nitrogen-containing heterocyclic
Available online 19 April 2012
compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Zhangjie Shi on the
occasion of his receipt of the Tetrahedron
Young Investigator Award
Keywords:
Fluoroalkylation
Nucleophilic reaction
Silane reagents
Heterocycles
Fluorine chemistry
1. Introduction
However, the azomethine carbon in a neutral heterocyclic com-
pound is usually not electrophilic enough toward a fluoroalkyl
nucleophile. The currently known nucleophilic fluoroalkyl addition
to unactivated C]N bonds is limited to strained 3- and 4-
memebered heterocycles6 and perfluorinated six-membered het-
erocycles.7 The formation of iminium salts by alkylation or pro-
tonation has been widely used in the activation of inert C]N bonds
in both acyclic and cyclic systems.3 In 2007, Makosza and co-
workers reported the perfluoromethylation of quinoline and
pyridine by formation of their benzylazinium salts.4a,b In 2011,
Organic compounds possessing both nitrogen and fluorine
atoms and especially fluoroalkylated amines have received re-
markable attention in bioorganic and medical chemistry research
due to profound change of the basicity of the amine functionality,
which will enhance the bioavailability of a target molecule.1 Rep-
resentative methods for the synthesis of fluoroalkylated amines
including multi-step transformation of fluorinated building blocks
and fluoroalkylation of C]N bonds.2 Currently, the fluoroalkylation
approach mainly focuses on nucleophilic addition of fluoroalkyl
anions to C]N bonds in acyclic systems.3,4 Considering the wide
application of fluorinated heterocycles in drug design, crop pro-
tection, and new materials research, the synthesis of fluoroalky-
lated heterocyclic compounds is of great interest.5 Among various
available synthetic methods, the addition of fluoroalkyl anions to
C]N bonds in heterocycles is the most attractive one because of
the easy availability of many nucleophilic fluoroalkylating agents.
€
Nenajdenko, Roschenthaler and co-workers reported the tri-
fluoromethylation of 5- and 6-memebered cyclic imines with
RuppertePrakash reagent under acidic conditions.4e To the best of
our knowledge, there has been no report on the nucleophilic
difluoromethylation of C]N bonds in heterocyclic systems.8 Con-
sidering the unique properties of difluoromethylene functionality
(CF2),9 we have been interested in the introduction of a difluor-
omethyl group into these heterocyclic systems. In this article, we
would like to disclose our success in selective difluoromethylation
of C]N bonds in heterocycles including dihydroisoquinolines,
quinolines, and pyridines, which affords a series of difluor-
omethylated tetrahydroisoquinolines, dihydroquinolines, and
dihydropyridines.
* Corresponding author. Tel.: þ86 21 54925174; fax: þ86 21 64166128; e-mail
address: jinbohu@sioc.ac.cn (J. Hu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.039

5138
W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
2. Results and discussion
Based on the above results, we further investigated the
difluoromethylation of the iminium salts of cyclic imines 1 with
TMSCF2SPh (4) as the fluoroalkylation reagent. TMSCF2SPh is also
a
2.1. Nucleophilic fluoroalkylation of dihydroisoquinolines
stable and effective difluoromethylation reagent.12a,13b The
Firstly, we prepared a series of six-membered cyclic imines
1aed using the Bischler-Napieralski cyclization10 and a five-
memebered cyclic imine 1e by transformation of lactam with
PhMgBr under the activation of TMSCl.11 Thereafter, we in-
vestigated the direct nucleophilic difluoromethylation reaction
with 1a as model compound. Among many nucleophilic difluor-
omethylation reagents, such as PhSO2CF2H, PhSO2CF2Br,
TMSCF2SO2Ph, TMSCF2SPh and TMSCF2H, the sulfur-based silane
reagents can be handled under very mild conditions and have
been used in the nucleophilic difluoromethylation of aldehydes,
ketones, N-(tert-butylsulfinyl)imines and alkyl halides.12 With
TMSCF2SO2Ph (2) as the difluoromethylation reagent, it was found
that no expected reaction took place between 1a and 2. According
to Dilman’s report, the activation of the imine is a good strategy to
enhance the latter’s electrophilicity.3 As an alternative to the
reported activation of cyclic imines with Brønsted acid,4e we chose
the formation of iminium salts by alkylation to activate those im-
ines. Due to the hydroscopic nature of the N-(p-methoxybenzyl)
iminium salts, in our case, we chose methylation strategy using
methyl triflate (MeOTf) as efficient methylating agent.4c As shown
in Table 1, after methylation of the cyclic imines 1 with MeOTf
(1.2 equiv) in CH2Cl2 and subsequent removal of the solvent, the
iminium salt was then treated with 2 (2.0 equiv) in DMF under the
initiation of KF (3.0 equiv). All the cyclic aldimines and cyclic
ketimines showed high reactivity toward 2, giving the desired N-
methyl cyclic amines 3 in modertate to good yields (64e94% yields)
after short reaction time (0.5 h). For comparison purpose, the re-
action of the methylated 1a with PhSO2CF2H under strong basic
conditions was tested,13a and it was found that the iminium salt of
1a (using LiHMDS as a base) decomposed under such conditions,
indicating that the fluoroalkyl silanes proved to be the privileged
reagents for this fluoroalkylation reaction.
PhSCF2-containing tetrahydroisoquinolines can not only be trans-
formed into difluoromethylated compounds, but also have the
potential to be incorporated into alkenes via radiacal fluo-
roalkylation.13b Under similar reaction conditions, the PhSCF2-
substituted cyclic amines 5 were obtained in moderate to good
yields (43e94%) (Table 2). However, in most cases, the yields were
lower than those for (phenylsulfonyl)difluoromethylation of the
iminium salts (as shown in Table 1).
Table 2
Nucleophilic difluoromethylation of dihydroisoquinolines with TMSCF2SPh (4)
Entry
1
Substrate
Product
Yield(%)a
57
2
43
94
3
4
71
58
Table 1
Nucleophilic difluoromethylation of dihydroisoquinolines with TMSCF2SO2Ph (2)
5
a
Isolated yield.
To further extend this fluoroalkylation of iminium salts with
other fluoroalkylating agents, we conducted the tri-
fluoromethylation reactions with RuppertePrakash reagent
(TMSCF3) (6).14 Under similar reaction conditions, the addition
products 7 were obtained in moderate to excellent yields (56e99%)
(see Table 3).
Entry
1
Substrate
Product
Yield(%)a
94
2
3
4
80
2.2. Nucleophilic difluoromethylation of quinolines and
pyridines
68b
Quinoline and pyridine derivatives are usually regarded as
unactivated cyclic imines. It is almost impossible to conduct direct
nucleophilic fluoroalkylation reaction toward the C]N bonds in
these heterocycles.4a The nucleophilic addition of trifluoromethyl
and perfluoroisopropyl anions to C]N bonds in pyridinium and
quinolinium salts was reported by Makosza and co-workers in
2007.4a,b The 2-fluoroalkyl 1,2-dihydroazines were oxidized into 2-
fluoroalkyl azines after deprotection and aromatization, and
therefore, a formal oxidative fluoroalkylation of azines was reali-
zed.4a,b To further explore the difluoromethylation of C]N bonds
in heterocycles, we performed the reaction between N-(p-
64b
90
5
a
Isolated yield.
b
Purified by recrystallization after column chromatography.

W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
5139
Table 3
Nucleophilic trifluoromethylation of dihydroisoquinolines with TMSCF3 (6)
Table 4
Nucleophilic difluoromethylation of quinolinium and pyridinium salts (8) with 2
Yield(%)a
90
Entry
1
Substrate
Initiator
NaOAc
Product
Yield(%)a
81
Entry
1
Substrate
Product
2
3
KF
77
99
2
3
4
89
86
40
NaOAc
4
NaOAc
NaOAc
56
77
5
5
6
60, 30
a
Isolated yield.
54, 42
methoxybenzyl)quinolinium salt 8a and 2 in the presence of an
initiator at ambient temperature. After a quick screening of the
reaction conditions, it was found that the readily available KF was
better than tetrabutylammonium triphenyldifluorosilicate (TBAT)
as an initiator, and K2CO3 can also be used as an initiator (but in-
ferior to KF). The use of 2.0 equiv of 2 was beneficial for the high
yield (90%) of 9a when DMF was used as a solvent. When the re-
action was conducted in CH2Cl2, only moderate yields were
achieved.
7
44, 32, 16
a
Isolated yield.
With the optimized reaction conditions established, the
difluoromethylation of C]N bonds in a series of heterocycles was
investigated (Table 4). It was found that the nucleophilic difluor-
oalkylation of the quinolinium salts 8ae8c proceeded smoothly
and gave the desired product in high yields (86e90%). As for the
regioselectivity, the PhSO2CF2 anion added exclusively at the 2-
position of the quinoline ring (entries 1e3). When we invetigated
the reactivity of various pyridinium salts, a significant substituent
effect was observed. Although the difluoromethylation of simple
pyridinium salt 8d could afford the addition product 9d in high
yield (90% yield according to 19F NMR), 9d was not stable enough to
be isolated by flash column chromatography (Scheme 1, Eq. 1).
When the more electron-rich p-methyl pyridinium salt 8e was
used, no desired product was formed (Scheme 1, Eq. 2). In the case
of the electron-deficient p-cyano pyridinium salt 8f, the expected
product 9f could be isolated in 72% yield. However, we found that
compound 9f readily decomposed in pure form (Scheme 1, Eq. 3).
Finally, we found that the pyridinium salts substituted with an
electron withdrawing group at the 3-position could give the stable
(phenylsulfonyl)difluoromethylated
1,2-dihydropyridines
in
Scheme 1. Substituent effect in difluoromethylation of pyridinium salts.
40e96% yields (Table 4, entries 4e7). The reaction is of good tol-
erance to amide, ketone, ester, and nitrile groups. The reaction of 3-
benzoylpyridinium salt 8h (entry 5) was particularly notable as no
product resulting from nucleophilic difluoromethylation of car-
bonyl group was observed. Although the regioselectivity varied
with the substituent, the less sterically demanding 6-position al-
ways showed higher reactivity. In the case of 8g, the PhSO2CF2
anion added exclusively at the 6-position (entry 4), while in the
cases of pyridinium salts 8h and 8i, the anion added at the 2/6-
positions of the pyridine rings (entries 5e6). For pyridinium salt
8j, the 1,4-addition product 9j00 was also formed in 16% yield (entry
7). In all cases, the regioisomers were readily separated by flash

5140
W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
Table 5
Oxidative aromatization of addition products 9
Entry
1
Substrate
Product
Yield(%)a
93
Scheme 2. Conjugational stabilization.
2
3
4
92
at ambient temperature, and 2.5 equiv of CAN was used as an ox-
idizing agent. The aromatization reaction proceeded in high yield to
give a variety of substituted azines 10 containing a (phenylsulfonyl)
difluoromethyl group at 2- or 6-position (Table 5). However, these
PhSO2CF2-substituted azines failed to be transformed into the
CF2H-containing azines by reductive desulfonation. When the re-
ductive desulfonation15 was conducted before oxidative aromati-
zation, 2-(difluoromethyl)quinoline was obtained in moderate
yield (Scheme 3).
89
81
5
6
86
95
Scheme 3. Preparation of 2-difluoromethyl quinoline. Conditions: (1) Mg/HOAc/
NaOAc, DMF, rt, 66%; (2) NaeHg, Na2HPO4, anhydrous MeOH, ꢀ20 ꢁC to 0 ꢁC, 93%; (3)
CAN, MeOH/H2O 4:1, rt, 68%.
3. Conclusion
In conclusion, we have developed an efficient and straightfor-
ward nucleophilic difluoromethylation of inert C]N bonds in
heterocyclic systemes under the activation of alkylation reagents.
Cyclic iminium salts derived from dihydroisoquinolines, quinolines,
and pryridines were successfully difluoromethylated with
TMSCF2SO2Ph and TMSCF2SPh. This research not only extends the
synthetic application of sulfur-based fluoroalkyl silanes, but also
provides a facile method for the preparation of a series of novel
difluoromethylated nitrogen-containing heterocyclic compounds.
7
83
a
Isolated yield.
column chromatography. The preference of 1,2-addition over 1.4-
addition in these reactions indicated that the PhSO2CF2 anion is
a hard nucleophile. However, by comparing with the regiose-
lectivity observed in the trifluoromethylation of iminium salt 8d
(entry 7, 44/32/16 vs 29/32/0),4b it suggests that PhSO2CF2 anion is
a somewhat softer nucleophile than CF3 anion.
4. Experimental section
4.1. General information
An explanation for the substituent effect on the addition re-
action of aziniums and stability of the corresponding dihydroazines
is as shown in Scheme 2. As for the simple pyridine iminium salts,
such as 8d, the addition of PhSO2CF2 anion leads to the dearoma-
tization of pyridine aromatic ring, which could be thermodynam-
ically disfavored. On the other hand, since PhSO2CF2 anion is a good
leaving group, the product A readily undergoes decomposition due
to its aromatization to pyridinium ring (Scheme 2, Eq. 1). When the
3-position is substituted by an EWG, the nitrogen lone pair could
delocalize to the EWG, which reduces the tendency of aromatiza-
tion; as a result, such addition product is more stable (Scheme 2, Eq.
2). Furthermore, in the case of the quinoline derivatives, although
the addition of PhSO2CF2 anion will lead to the dearomatization of
quinoline aromatic ring, in this process a benzene ring still remains,
which could stabilize the addition products (Scheme 2, Eq. 3).
The p-methoxybenzyl substituent can be readily removed by
oxidizing agents, such as DDQ or CAN.4b The oxidative deprotection
was performed in a mixed solvent system of MeOH/H2O (v/v¼4:1)
All reactions were carried out in oven-dried glassware under
a nitrogen atmosphere. DMF was distilled from CaH2. Other com-
mercially available chemicals were used without further purifica-
tion. Column chromatography was performed on silica gel
300e400 (0.038e0.048 mm). 1H, 13C, and 19F NMR spectra were
recorded in CDCl3, chemical shifts (d) are given in parts per million
(ppm) and spinespin coupling constants (J) are given in Hertz (Hz).
1H NMR chemical shifts were determined relative to internal
(CH3)4Si (TMS) at
solvent: CDCl3
7.26. 13C NMR chemical shifts were determined
relative to internal TMS at
0.0. 19F NMR chemical shifts were
determined relative to CFCl3 at 0.0. Mass spectra were obtained on
d 0.0 or to the signal of a residual protonated
d
d
d
a mass spectrometer in the ESI mode. High-resolution mass data
were recorded on a high-resolution mass spectrometer in the ESI
mode. Melting points are uncorrected.

W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
5141
4.2. Typical procedure for the reaction of cyclic imines 1 with
TMSCF2SO2Ph (2)
2H), 7.34 (d, J¼6.3 Hz,1H), 7.11e7.23 (m, 2H), 7.07 (d, J¼12.0 Hz,1H),
3.03e3.12 (m, 1H), 2.87e2.98 (m, 1H), 2.59e2.67 (m, 2H), 2.49 (s,
3H), 1.84 (s, 3H). 19F NMR:
d
ꢀ90.4 (d, J¼239.7 Hz, 1F), ꢀ93.2 (dd,
Under a nitrogen atmosphere, into a CH2Cl2 (8 mL) solution of
cyclic imine 1a (96 mg, 0.5 mmol) was added MeOTf (0.068 mL,
0.6 mmol) dropwise in 10 min. After the reaction mixture was
stirred for 1 h at ambient temperature, the solvent CH2Cl2 was
gently evaporated and dry DMF (3 mL) and KF (87 mg, 1.5 mmol)
were added. Then a DMF (2 mL) solution of TMSCF2SO2Ph (2)
(264 mg, 1.0 mmol) was added to the reaction system dropwise in
10 min. After stirring at ambient temperature for 30 min, the re-
action mixture was quenched with a saturated NaHCO3 aqueous
solution (20 mL) and extracted with ethyl acetate (3ꢂ15 mL). The
combined organic phase was washed with saturated NaHCO3 so-
lution (15 mL), and dried by anhydrous Na2SO4. After the removal of
the solvent under reduced pressure, the residue was purified by
flash column chromatography (petroleum ether/ethyl acetate, 3:1)
to give 3a as a pale yellow solid (187 mg, 94%).
J¼239.1 Hz, 8.2 Hz, 1F). 13C NMR:
d 136.6, 136.5, 134.5, 134.1, 130.2,
129.1, 128.5, 127.7, 127.5, 126.2, 124.4 (t, J¼302.9 Hz), 64.9
(dd, J¼20.5 Hz, 18.6 Hz), 47.9 (d, J¼6.0 Hz), 38.0, 24.2, 21.0. MS
(ESI, m/z): 352.1 ([MþH]þ). HRMS (ESI): calcd for C18H20
F2NO2Sþ([MþH]þ): 352.1177; Found: 352.1173.
4.2.5. 2-(Difluoro(phenylsulfonyl)methyl)-1-methyl-2-
phenylpyrrolidine (3e). Colorless oil. IR (film): 3063, 2885, 2857,
2810, 1498, 1448, 1342, 1174, 1151, 1107, 1060, 1014, 912, 883, 756,
724, 710, 687, 610, 579, 530 cmꢀ1 1H NMR:
d
7.91 (d, J¼7.5 Hz, 2H),
7.61 (t, J¼7.8 Hz, 1H), 7.51 (t, J¼7.5 Hz, 2H), 7.15e7.25 (m, 5H),
3.24e3.31 (m, 1H), 3.08e3.18 (m, 1H), 2.94e3.02 (m, 1H), 2.09e2.02
(m, 2H), 2.09 (s, 3H), 1.86e1.95 (m, 1H). 19F NMR:
J¼239.4 Hz, 1F), ꢀ96.9 (d, J¼241.1 Hz, 1F). 13C NMR:
d
ꢀ87.6 (d,
d
140.8 (d,
J¼3.3 Hz), 136.1, 134.2, 130.0, 128.7, 128.0, 127.1, 126.7 (dd, J¼4.1 Hz,
1.9 Hz), 125.8 (dd, J¼306.3 Hz, 299.9 Hz), 73.8 (dd, J¼21.4 Hz,
17.5 Hz), 55.9, 38.7, 36.1 (dd, J¼3.5 Hz, 1.5 Hz), 22.1. MS (ESI, m/z):
352.1 ([MþH]þ). HRMS (ESI): calcd for C18H20F2NO2Sþ([MþH]þ):
352.1177; Found: 352.1173.
4.2.1. 1-(Difluoro(phenylsulfonyl)methyl)-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (3a). Pale yellow solid. Mp:
150e152 ꢁC. IR (KBr): 3073, 3029, 2955, 2945, 2837, 1612, 1520,
1328, 1257, 1162, 1015, 763, 722, 685, 635, 579, 557 cmꢀ1 1H NMR:
d
8.00 (d, J¼7.8 Hz, 2H), 7.69 (t, J¼7.5 Hz, 1H), 7.56 (t, J¼7.5 Hz, 2H),
4.2.6. 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (5a). Pale yellow solid. Mp:
97e99 ꢁC. IR (KBr): 3063, 2997, 2955, 2924, 2835, 2805, 2778, 1610,
1521, 1255, 1232, 1104, 1002, 981, 873, 848, 811, 747, 692, 585,
6.72 (d, J¼3.6 Hz, 1H), 6.60 (s, 1H), 4.40 (dd, J¼24.3 Hz, 7.5 Hz, 1H),
3.85 (s, 3H), 3.82 (s, 3H), 2.78e3.02 (m, 2H), 2.54 (s, 3H), 2.34e2.54
(m, 2H). 19F NMR:
d
ꢀ95.1 (d, J¼238.6 Hz, 1F), ꢀ109.6 (dd,
J¼237.4 Hz, 24.3 Hz, 1F). 13C NMR:
d
149.0, 147.3, 135.8, 134.4, 130.2,
500 cmꢀ1 1H NMR:
d
7.58 (d, J¼7.5 Hz, 2H), 7.32e7.34 (m, 3H), 6.77
128.8, 128.6, 123.1 (dd, J¼298.9 Hz, 290.1 Hz), 118.1, 111.7 (dd,
J¼6.4 Hz, 2.2 Hz),111.5, 61.6 (dd, J¼23.2 Hz,18.9 Hz), 55.9, 55.7, 45.2,
42.2, 21.6. MS (ESI, m/z): 398.1 ([MþH]þ). Anal. Calcd for
C19H21F2NO4S: C, 57.42; H, 5.33; N, 3.52; Found: C, 57.38; H, 5.32; N,
3.35.
(s,1H), 6.63 (s,1H), 4.04 (dd, J¼14.7 Hz, 7.8 Hz,1H), 3.86 (s, 3H), 3.80
(s, 3H), 3.35e3.43 (m, 1H), 2.78e2.91 (m, 2H), 2.62e2.69 (m, 1H),
2.62 (s, 3H). 19F NMR:
d
ꢀ70.7 (dd, J¼202.5 Hz, 6.5 Hz, 1F), ꢀ73.8
(dd, J¼202.2 Hz, 14.1 Hz, 1F). 13C NMR:
d 148.4, 147.0, 136.0, 132.3
(dd, J¼287.4 Hz, 281.7 Hz), 129.1, 128.6, 128.4, 128.0 (d, J¼2.5 Hz),
120.4, 112.0, 111.0, 67.9 (t, J¼24.6 Hz), 55.7, 55.6, 47.3 (d, J¼3.1 Hz),
43.5, 23.7. MS (ESI, m/z): 366.1 ([MþH]þ). HRMS (ESI): calcd for
C19H22F2NO2Sþ([MþH]þ): 366.1334; Found: 366.1329.
4.2.2. 1-(Difluoro(phenylsulfonyl)methyl)-6,7-dimethoxy-1,2-
dimethyl-1,2,3,4-tetrahydroisoquinoline (3b). pale yellow solid. Mp:
153e155 ꢁC. IR (KBr): 3008, 2962, 2931, 2836,1611, 1515,1327,1256,
1162,1093, 981, 867, 760, 723, 686, 597, 568 cmꢀ1 1H NMR:
d
7.93 (d,
4.2.7. 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-1,2-dimethyl-
1,2,3,4-tetrahydroisoquinoline (5b). Pale yellow oil. IR (film): 2997,
2806, 1611, 1516, 1257, 1222, 1064, 1027, 965, 842, 750, 693,
J¼7.5 Hz, 2H), 7.63 (t, J¼7.5 Hz, 1H), 7.52 (t, J¼7.5 Hz, 2H), 6.78 (s,
1H), 6.55 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.00e3.08 (m, 1H),
2.80e2.88 (m, 1H), 2.46e2.60 (m, 2H), 2.46 (s, 3H), 1.81 (s, 3H). 19F
NMR:
NMR:
J¼2.0 Hz), 124.4 (dd, J¼302.4 Hz, 300.5 Hz), 111.1, 110.6, 64.7 (dd,
J¼20.5 Hz, 19.4 Hz), 55.9, 55.6, 48.0 (d, J¼5.4 Hz), 37.9, 23.5, 21.1. MS
(ESI, m/z): 412.1 ([MþH]þ). Anal. Calcd for C20H23F2NO4S: C, 58.38;
H, 5.63; N, 3.40; Found: C, 58.34; H, 5.58; N, 3.16.
506 cmꢀ1 1H NMR:
d
7.51 (d, J¼7.2 Hz, 2H), 7.26e7.34 (m, 3H), 6.88
d
ꢀ90.5 (d, J¼239.4 Hz, 1F), ꢀ92.9 (d, J¼240.3 Hz, 1F). 13C
(s, 1H), 6.60 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.32e3.36 (m, 1H),
d
148.4, 147.2, 136.6, 134.0, 130.2, 129.0, 128.5, 125.9 (d,
2.72e2.89 (m, 3H), 2.57 (s, 3H), 1.67 (s, 3H). 19F NMR:
d
ꢀ68.8 (d,
J¼203.9 Hz, 1F), ꢀ73.1 (d, J¼203.6 Hz, 1F). 13C NMR:
d 148.1, 146.9,
136.2, 134.9 (t, J¼289.9 Hz), 128.94, 128.93, 128.7, 128.5, 126.6, 111.6,
110.8, 65.9 (t, J¼22.2 Hz), 55.9, 55.6, 48.4 (d, J¼4.5 Hz), 38.7, 25.7,
19.7 (d, J¼3.6 Hz). MS (ESI, m/z): 380.1 ([MþH]þ). HRMS (ESI): calcd
for C20H24F2NO2Sþ([MþH]þ): 380.1490; Found: 380.1487.
4.2.3. 1-(Difluoro(phenylsulfonyl)methyl)-2-methyl-1-phenyl-
1,2,3,4-tetrahydroisoquinoline (3c). White solid. Mp: 177e179 ꢁC. IR
(KBr): 3051, 2952, 2813, 1497, 1447, 1348, 1097, 1041, 771, 756, 709,
4.2.8. 1-(Difluoro(phenylthio)methyl)-2-methyl-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (5c). Orange solid. Mp: 99e101 ꢁC. IR (KBr):
3055, 2941, 2916, 2812, 2710, 1581, 1497, 1475, 1441, 1294, 1132,
698, 685, 576, 538, 518 cmꢀ1 1H NMR:
d
7.87 (d, J¼8.1 Hz, 2H), 7.64
(t, J¼7.8 Hz, 1H), 7.51 (t, J¼7.5 Hz, 2H), 7.21e7.28 (m, 7H), 6.98e7.03
1036, 1014, 822, 762, 746, 699, 641, 503 cmꢀ1 1H NMR:
d 7.13e7.26
(m, 1H), 6.87e6.91 (m, 1H), 3.61e3.72 (m, 1H), 3.03e3.08 (m, 1H),
(m, 12H), 6.94e6.98 (m, 1H), 6.83e6.89 (m, 1H), 3.32e3.45 (m, 1H),
2.84 (dt, J¼15.6 Hz, 3.0 Hz, 1H), 2.03 (s, 3H). 19F NMR:
d
ꢀ86.8 (dd,
141.5,
2.93e3.02 (m, 2H), 2.79 (d, J¼16.2 Hz, 1H), 2.16 (s, 3H). 19F NMR:
J¼232.4 Hz, 3.4 Hz, 1F), ꢀ94.0 (d, J¼237.2 Hz, 1F). 13C NMR:
d
d
d
ꢀ69.5 (d, J¼195.4 Hz, 1F), ꢀ72.6 (d, J¼196.8 Hz, 1F). 13C NMR:
141.1, 137.2, 136.7, 134.5 (t, J¼285.9 Hz), 132.1, 132.0, 129.4, 129.2,
137.6, 136.3, 134.2 (d, J¼5.6 Hz), 134.0, 132.0 (d, J¼7.3 Hz), 130.3,
128.6, 128.4, 127.9, 127.7, 127.6, 127.1, 125.4, 124.3 (t, J¼307.2 Hz),
71.6 (dd, J¼20.4 Hz, 16.1 Hz), 49.3, 41.6 (d, J¼7.8 Hz), 29.8. MS (ESI,
m/z): 414.1 ([MþH]þ). Anal. Calcd for C23H21F2NO2S: C, 66.81; H,
5.12; N, 3.39; Found: C, 66.81; H, 5.17; N, 3.23.
128.5, 128.2,127.8,127.5,127.1,126.9, 125.5, 73.3, 49.5, 41.8, 30.4. MS
(ESI, m/z): 382.1 ([MþH]þ). HRMS (ESI): calcd for
C23H22F2NSþ([MþH]þ): 382.1436; Found: 382.1439.
4.2.9. 1-(Difluoro(phenylthio)methyl)-1,2-dimethyl-1,2,3,4-
tetrahydroisoquinoline (5d). Pale yellow oil. IR (film): 3062, 2959,
2912, 2857, 2806, 1475, 1441, 1376, 1262, 1064, 1027, 960, 824, 751,
4.2.4. 1-(Difluoro(phenylsulfonyl)methyl)-1,2-dimethyl-1,2,3,4-
tetrahydroisoquinoline (3d). White solid. Mp: 119e121 ꢁC. IR (KBr):
3057, 2925, 1597, 1510, 1392, 1260, 1237, 1126, 979, 771 cmꢀ1 1H
692, 664, 602, 506 cmꢀ1 1H NMR:
d
7.39 (d, J¼6.9 Hz, 2H), 7.31 (d,
NMR:
d
7.94 (d, J¼8.1 Hz, 2H), 7.65 (t, J¼7.2 Hz, 1H), 7.53 (t, J¼7.8 Hz,
J¼7.5 Hz, 1H), 7.15e7.25 (m, 3H), 7.10 (t, J¼7.2 Hz, 2H), 7.03 (d,

5142
W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
J¼7.2 Hz, 1H), 3.23e3.33 (m, 1H), 2.74e2.83 (m, 3H), 2.49 (s, 3H),
J¼7.8 Hz, 2H), 7.16e7.28 (m, 3H), 2.94e3.08 (m, 2H), 2.42e2.52 (m,
1H), 2.33 (s, 3H), 1.96e2.06 (m, 1H), 1.77e1.82 (m, 2H). 19F NMR:
1.60 (s, 3H). 19F NMR:
d
ꢀ69.3 (d, J¼205.0 Hz, 1F), ꢀ73.1 (d,
136.5, 136.2, 135.1, 134.8 (t, J¼290.0 Hz),
J¼202.5 Hz, 1F). 13C NMR:
d
d
ꢀ68.3 (s, 3F). 13C NMR:
140.3, 128.5 (q, J¼290.4 Hz), 128.2, 127.3,
d
129.0, 128.71, 128.69, 128.6, 128.5, 127.1, 125.8, 66.2 (t, J¼22.7 Hz),
48.3 (d, J¼4.8 Hz), 38.9, 26.4, 19.5. MS (ESI, m/z): 320.1 ([MþH]þ).
HRMS (ESI): calcd for C18H20F2NSþ([MþH]þ): 320.1279; Found:
320.1282.
126.9 (q, J¼2.3 Hz), 71.5 (q, J¼23.9 Hz), 55.3, 38.3, 35.6, 22.7. MS
(ESI, m/z): 230.1 ([MþH]þ). HRMS (ESI): calcd for
C12H15F3Nþ([MþH]þ): 230.1151; Found: 230.1153.
4.2.10. 1-(Difluoro(phenylthio)methyl)-2-methyl-1,2,3,4-tetrahydroi-
soquinoline (5f). Pale yellow solid. Mp: 87e89 ꢁC. IR (KBr): 3018,
2960, 2947, 2814, 1473, 1442, 1263, 1105, 1031, 992, 813, 801, 759,
4.3. Typical procedure for the reaction of quinolinium or
pyridinium salts 8 with TMSCF2SO2Ph (2)
744, 693, 658, 504 cmꢀ1 1H NMR:
d
7.48 (d, J¼6.6 Hz, 2H), 7.07e7.27
Under a nitrogen atmosphere, into a mixture of iminium salt 8a
(165 mg, 0.5 mmol), KF(87 mg, 1.5 mmol) was added dry DMF
(2 mL). After the addition of a DMF (2 mL) solution of TMSCF2SO2Ph
(264 mg, 1.0 mmol) dropwise in 10 min, the reaction mixture was
stirred for 1 h at ambient temperature. Then the reaction mixture
was quenched with saturated NaHCO3 aqueous solution (20 mL),
and extracted with ethyl acetate (3ꢂ15 mL). The combined organic
phase was washed with saturated NaHCO3 aqueous solution
(15 mL), and dried with anhydrous Na2SO4. After the removal of the
solvent under reduced pressure, the residue was purified by flash
column chromatography (petroleum ether/ethyl acetate, 20:1) to
give 9a as a white solid (199 mg, 90%).
(m, 7H), 4.04 (dd, J¼13.8 Hz, 7.5 Hz, 1H), 3.32e3.34 (m, 1H),
2.69e2.87 (m, 3H), 2.58 (s, 3H). 19F NMR:
d
ꢀ71.0 (dd, J¼203.6 Hz,
7.1 Hz, 1F), ꢀ74.4 (dd, J¼201.6 Hz, 13.3 Hz, 1F). 13C NMR:
d 136.5,
136.2, 132.2 (dd, J¼287.2 Hz, 282.5 Hz), 129.7, 129.2, 129.1, 128.7,
128.6, 128.0, 127.7, 125.9, 68.5 (t, J¼24.4 Hz), 47.9, 44.0, 25.0.
MS (ESI, m/z): 306.0 ([MþH]þ). HRMS (ESI): calcd for
C17H18F2NSþ([MþH]þ): 306.1123; Found: 306.1120.
4.2.11. 6,7-Dimethoxy-2-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahy-
droisoquinoline (7a). Colorless oil. IR (film): 3001, 2951, 2913, 2864,
2837, 2804, 1612, 1521, 1467, 1339, 1268, 1232, 1147, 1114, 1011, 850,
807, 780, 709, 653 cmꢀ1 1H NMR:
d
6.71 (s, 1H), 6.64 (s, 1H), 3.97 (q,
J¼7.5 Hz,1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.18e3.25 (m,1H), 2.72e2.78
4.3.1. 2-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,2-
dihydroquinoline (9a). White solid. Mp: 131e133 ꢁC. IR (KBr): 3026,
2956, 2839, 1597, 1514, 1492, 1335, 1251, 1137, 815, 749, 683,
(m, 2H), 2.64 (s, 3H), 2.56e2.64 (m, 1H). 19F NMR:
d
ꢀ73.6 (d,
J¼5.1 Hz, 3F). 13C NMR:
d
148.8, 147.2, 129.7, 126.1 (q, J¼282.5 Hz),
119.6, 112.1, 111.0, 64.3 (q, J¼27.1 Hz), 56.0, 55.8, 49.5, 45.0, 26.9.
MS (ESI, m/z): 276.0 ([MþH]þ). HRMS (ESI): calcd for
C13H17F3NOþ2 ([MþH]þ): 276.1206; Found: 276.1204.
619 cmꢀ1 1H NMR:
d
7.92 (d, J¼7.5 Hz, 2H), 7.72 (t, J¼7.5 Hz,1H), 7.57
(t, J¼7.5 Hz, 2H), 7.17 (d, J¼8.7 Hz, 2H), 7.00e7.08 (m, 2H), 6.83 (d,
J¼9.0 Hz, 2H), 6.76 (d, J¼9.6 Hz, 1H), 6.66e6.72 (m, 2H), 5.82 (dd,
J¼9.6 Hz, 6.9 Hz,1H), 5.05e5.16 (m,1H), 4.86 (d, J¼15.6 Hz,1H), 4.47
4.2.12. 6,7-Dimethoxy-1,2-dimethyl-1-(trifluoromethyl)-1,2,3,4-
tetrahydroisoquinoline (7b). White solid. Mp: 61e63 ꢁC. IR (KBr):
3002, 2954, 2802, 1613, 1521, 1466, 1261, 1141, 1109, 1002, 870, 805,
(d, J¼15.9 Hz, 1H), 3.78 (s, 3H). 19F NMR:
d
ꢀ108.2 (dd, J¼232.1 Hz,
7.9 Hz, 1F), ꢀ112.1 (dd, J¼231.3 Hz, 16.4 Hz, 1F). 13C NMR:
d 159.0,
143.1, 135.2, 133.1, 130.8, 130.4, 129.24, 129.17, 128.9, 128.6, 127.5,
122.6, 122.3 (t, J¼298.3 Hz), 118.4, 115.1(d, J¼3.3 Hz), 114.1, 113.8,
57.8 (dd, J¼20.9 Hz, 18.7 Hz), 55.2, 55.0 (d, J¼3.1 Hz). MS (ESI, m/z):
442.0 ([MþH]þ). Anal. Calcd for C24H21F2NO3S: C, 65.29; H, 4.79; N,
3.17; Found: C, 65.22; H, 5.08; N, 3.13.
774, 723 cmꢀ1 1H NMR:
d 6.89 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 3.85
(s, 3H), 3.18e3.23 (m, 1H), 2.68e2.88 (m, 3H), 2.62 (s, 3H), 1.64 (s,
3H). 19F NMR:
d
ꢀ71.7 (s, 3F). 13C NMR:
d 148.5,146.9, 129.4,127.9 (q,
J¼290.7 Hz), 125.5, 111.4, 111.0, 62.2 (q, J¼23.3 Hz), 56.1, 55.7, 48.4,
39.7, 28.0,19.9. MS (ESI, m/z): 290.1 ([MþH]þ). HRMS (ESI): calcd for
C14H19F3NOþ2 ([MþH]þ): 290.1362; Found: 290.1360.
4.3.2. 2-(Difluoro(phenylsulfonyl)methyl)-6-methoxy-1-(4-
methoxybenzyl)-1,2-dihydroquinoline (9b). Pale yellow solid. Mp:
117e119 ꢁC. IR (KBr): 2950, 2892, 2833, 1612, 1515, 1498, 1336, 1247,
4.2.13. 2-Methyl-1-phenyl-1-(trifluoromethyl)-1,2,3,4-tetrahydroiso-
quinoline (7c). Pale yellow oil. IR (film): 3064, 3029, 2962, 2865,
2809, 1496, 1452, 1260, 1148, 1035, 928, 793, 764, 741, 699,
1147, 1030, 800, 717, 596, 530 cmꢀ1 1H NMR:
d
7.85 (d, J¼7.8 Hz, 2H),
7.65 (t, J¼6.9 Hz, 1H), 7.50 (t, J¼7.2 Hz, 2H), 7.08 (d, J¼8.4 Hz, 2H),
6.74 (d, J¼8.1 Hz, 2H), 6.64 (d, J¼9.3 Hz,1H), 6.50e6.60 (m, 3H), 5.77
(dd, J¼9.0 Hz, 5.7 Hz,1H), 4.93e5.04 (m,1H), 4.70 (d, J¼15.9 Hz,1H),
661 cmꢀ1 1H NMR:
d 7.16e7.22 (m, 5H), 7.05e7.10 (m, 2H), 6.89 (t,
J¼6.9 Hz, 1H), 6.75 (d, J¼7.8 Hz, 1H), 2.94e3.10 (m, 2H), 2.84e2.92
(m, 2H), 2.12 (s, 3H). 19F NMR:
d
ꢀ66.6 (s, 3F). 13C NMR:
d
140.5,
4.35 (d, J¼15.9 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 3H). 19F NMR:
ꢀ106.6
d
136.9, 135.1, 131.3, 128.8, 128.1, 127.8, 127.5, 127.44 (q, J¼290.7 Hz),
127.43, 125.5, 70.6 (q, J¼23.7 Hz), 48.4, 41.2, 29.8. MS (ESI, m/z):
292.1 ([MþH]þ). HRMS (ESI): calcd for C17H17F3Nþ([MþH]þ):
292.1308; Found: 292.1307.
(dd, J¼230.7 Hz, 8.8 Hz, 1F), ꢀ111.6 (dd, J¼231.0 Hz, 18.1 Hz, 1F). 13C
NMR:
d 158.9, 152.3, 137.1, 135.1, 133.2, 130.6, 130.4, 129.2, 129.1,
128.6, 123.5, 122.3 (t, J¼295.5 Hz), 116.2 (d, J¼3.0 Hz), 115.2, 114.8,
114.0, 112.6, 59.7(dd, J¼21.6 Hz, 18.6 Hz), 55.7 (d, J¼3.0 Hz), 55.5,
55.1. MS (ESI, m/z): 472.0 ([MþH]þ). Anal. Calcd for C25H23F2NO4S:
C, 63.68; H, 4.92; N, 2.97; Found: C, 63.56; H, 4.94; N, 3.04.
4.2.14. 1,2-Dimethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydroisoquino-
line (7d). Pale yellow oil. IR (film): 3011, 2926, 2866, 1454, 1380,
1280,1246,1172,1145,1123,1089,1061, 898, 759, 739, 733, 715, 652,
4.3.3. 2-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-6-
methyl-1,2-dihydroquinoline (9c). White solid. Mp: 151e153 ꢁC. IR
(KBr): 1637, 1613, 1515, 1501, 1332, 1249, 1148, 1101, 809, 716,
612 cmꢀ1 1H NMR:
d
7.36 (d, J¼4.2 Hz, 1H), 7.11e7.14 (m, 2H),
7.02e7.04 (m, 1H), 3.12e3.15 (m, 1H), 2.72e2.88 (m, 3H), 2.55 (s,
3H), 1.58 (s, 3H). 19F NMR:
d
ꢀ71.8 (s, 3F). 13C NMR:
d
136.7, 133.9,
608 cmꢀ1 1H NMR:
d
7.92 (d, J¼8.1 Hz, 2H), 7.72 (t, J¼8.1 Hz, 1H),
120.1, 128.1 (q, J¼2.2 Hz), 127.9 (q, J¼290.8 Hz), 127.5, 125.8, 62.6 (q,
J¼23.3 Hz), 48.3, 39.7, 28.6, 19.7. MS (ESI, m/z): 230.1 ([MþH]þ).
HRMS (ESI): calcd for C12H15F3Nþ([MþH]þ): 230.1151; Found:
230.1153.
7.57 (t, J¼7.2 Hz, 2H), 7.16 (d, J¼7.5 Hz, 2H), 6.81e6.88 (m, 4H), 6.72
(d, J¼10.2 Hz, 1H), 6.58 (d, J¼8.1 Hz, 1H), 5.78e5.83 (m, 1H),
5.03e5.13 (m, 1H), 4.83 (d, J¼16.2 Hz, 1H), 4.44 (d, J¼15.3 Hz, 1H),
3.78 (s, 3H), 2.20 (s, 3H). 19F NMR:
d
ꢀ106.3 (dd, J¼230.4 Hz, 7.6 Hz,
1F), ꢀ111.7 (dd, J¼230.4 Hz, 17.2 Hz, 1F). 13C NMR:
d 158.9, 140.8,
4.2.15. 1-Methyl-2-phenyl-2-(trifluoromethyl)pyrrolidine
Colorless oil. IR (film): 3063, 2964, 2856, 2808, 1494, 1448, 1262,
1147, 1093, 906, 806, 759, 726, 700, 520 cmꢀ1 1H NMR:
7.44 (d,
(7e).
135.1, 133.1, 130.8, 130.4, 129.8, 129.1, 128.6, 128.0, 127.4, 122.5, 122.3
(t, J¼295.5 Hz), 115.1 (d, J¼3.7 Hz), 114.0, 113.8, 57.9 (dd, J¼20.8 Hz,
18.6 Hz), 55.2, 55.1, 20.3. MS (ESI, m/z): 456.0 ([MþH]þ). Anal. Calcd
d

W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
5143
for C25H23F2NO3S: C, 65.92; H, 5.09; N, 3.07; Found: C, 66.02; H,
5.05; N, 3.15.
J¼7.2 Hz, 2H), 6.86 (d, J¼6.9 Hz, 2H), 6.63 (d, J¼6.6 Hz, 1H), 5.93 (dd,
J¼19.5 Hz, 6.9 Hz, 1H), 5.22 (t, J¼7.2 Hz, 1H), 4.77 (d, J¼15.3 Hz, 1H),
4.58 (d, J¼15.9 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H). 19F NMR:
ꢀ108.7
d
4.3.4. 6-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,6-
dihydropyridine-3-carboxamide (9g). Pale yellow solid. Mp:
142e144 ꢁC. IR (KBr): 3419, 3177, 1655, 1558, 1381, 1252, 1146, 825,
(dd, J¼239.7 Hz, 5.1 Hz, 1F), ꢀ113.4 (dd, J¼237.7 Hz, 19.2 Hz, 1F). 13C
NMR:
d 166.2, 159.4, 142.3, 138.1, 135.3, 130.7, 130.6, 129.2, 128.8,
128.7, 121.4 (dd, J¼302.3 Hz, 293.3 Hz), 114.3, 100.0, 98.8, 59.2, 56.6
(dd, J¼26.8 Hz,18.6 Hz), 55.3 (d, J¼5.2 Hz), 51.5. MS (ESI, m/z): 450.0
([MþH]þ). HRMS (ESI): calcd for C22H22F2NO5Sþ([MþH]þ):
450.1181; Found: 450.118.
716, 584 cmꢀ1 1H NMR:
d
7.96 (d, J¼8.1 Hz, 2H), 7.78 (t, J¼7.5 Hz,
1H), 7.63 (t, J¼7.2 Hz, 2H), 7.47 (s, 1H), 7.18 (d, J¼8.7 Hz, 2H), 6.89 (d,
J¼9.0 Hz, 2H), 6.56 (d, J¼9.0 Hz,1H), 5.26 (s, 2H), 5.06e5.20 (m, 2H),
4.60 (d, J¼15.0 Hz,1H), 4.50 (d, J¼15.0 Hz,1H), 3.81 (s, 3H). 19F NMR:
d
ꢀ108.2 (dd, J¼232.1 Hz, 7.9 Hz, 1F), ꢀ112.1 (dd, J¼231.3 Hz,
4.3.9. 6-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,6-
dihydropyridine-3-carbonitrile (9j). Yellow solid. Mp: 95e97 ꢁC. IR
(KBr): 3044, 2838, 2206, 1635, 1567, 1516, 1334, 1152, 1101, 1032,
16.4 Hz,1F). 13C NMR:
d 168.0,159.6, 144.3, 135.5, 132.6, 130.5, 129.3,
129.0, 127.5, 126.2, 121.0 (t, J¼296.3 Hz), 114.4, 103.8, 103.5, 59.4 (d,
J¼2.9 Hz), 56.5 (dd, J¼22.3 Hz, 17.9 Hz), 55.2. MS (ESI, m/z): 435.1
([MþH]þ). Anal. Calcd for C21H20F2N2O4S: C, 58.06; H, 4.64; N, 6.45;
Found: C, 58.20; H, 4.95; N, 6.38.
817, 719, 681, 609, 591 cmꢀ1 1H NMR:
d
7.97 (d, J¼7.8 Hz, 2H), 7.80 (t,
J¼8.1 Hz, 1H), 7.65 (t, J¼6.3 Hz, 2H), 7.18 (d, J¼6.9 Hz, 2H), 7.02 (s,
1H), 6.92 (d, J¼6.9 Hz, 2H), 6.28 (d, J¼9.3 Hz, 1H), 5.09e5.22 (m,
2H), 4.56 (d, J¼14.7 Hz, 1H), 4.47 (d, J¼15.0 Hz, 1H), 3.83 (s, 3H). 19F
4.3.5. (6-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,6-
dihydropyridin-3-yl)(phenyl)methanone (9h). Yellow solid. Mp:
39e42 ꢁC. IR (KBr): 3063, 2837, 1612, 1561, 1513, 1327, 1251, 1149,
NMR:
d
ꢀ108.7 (dd, J¼232.1 Hz, 8.5 Hz, 1F), ꢀ111.9 (dd, J¼233.0 Hz,
13.6 Hz, 1F). 13C NMR:
d
159.9, 147.3, 135.7, 132.4, 130.6, 129.4, 129.3,
126.51, 126.45, 120.6 (t, J¼296.3 Hz), 119.6, 114.6, 104.9, 82.1, 59.6 (d,
J¼3.0 Hz), 56.4 (dd, J¼23.9 Hz, 19.4 Hz), 55.3. MS (ESI, m/z): 439.1
([MþNa]þ). HRMS (ESI): calcd for C21H19F2N2O3Sþ([MþH]þ):
417.1079; Found: 417.1085.
1106, 1029, 909, 816, 712 cmꢀ1 1H NMR:
d
8.00 (d, J¼8.4 Hz, 2H),
7.80 (t, J¼6.6 Hz, 1H), 7.65 (t, J¼6.6 Hz, 2H), 7.58 (d, J¼9.9 Hz, 2H),
7.37e7.50 (m, 3H), 7.26 (s, 1H), 7.14 (d, J¼7.5 Hz, 2H), 7.08 (d,
J¼8.7 Hz, 1H), 6.88 (d, J¼6.9 Hz, 2H), 5.12e5.25 (m, 2H), 4.70 (d,
J¼15.0 Hz, 1H), 4.46 (d, J¼15.3 Hz, 1H), 3.80 (s, 3H). 19F NMR:
4.3.10. 2-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-
d
ꢀ108.4 (dd, J¼234.7 Hz, 9.0 Hz, 1F), ꢀ110.4 (dd, J¼234.9 Hz,
1,2-dihydropyridine-3-carbonitrile
116e118 ꢁC. IR (KBr): 2951, 2839, 2194, 1612, 1512, 1352, 1247, 1152,
1102, 1008, 713, 611, 547 cmꢀ1 1H NMR:
(9j0). Yellow
solid.
Mp:
15.0 Hz, 1F). 13C NMR:
d 190.9, 159.8, 150.6, 139.4, 135.6, 132.6, 130.7,
130.6, 129.4, 129.0, 128.7, 128.1, 127.4, 126.8, 120.9 (t, J¼295.5 Hz),
114.5, 111.7, 104.6, 59.7, 57.1 (dd, J¼23.1 Hz, 19.4 Hz), 55.3. MS (ESI,
m/z): 518.0 ([MþNa]þ). HRMS (ESI): calcd for C27H24NO4
F2Sþ([MþH]þ): 496.1389; Found: 496.1391.
d
7.98 (d, J¼7.5 Hz, 2H), 7.78
(t, J¼7.8 Hz, 1H), 7.63 (t, J¼7.8 Hz, 2H), 7.19 (d, J¼8.7 Hz, 2H), 6.98 (d,
J¼4.8 Hz, 1H), 6.91 (d, J¼8.4 Hz, 2H), 6.70 (d, J¼6.9 Hz, 1H), 5.32 (dd,
J¼19.8 Hz, 6.9 Hz, 1H), 5.20 (t, J¼6.9 Hz, 1H), 4.76 (d, J¼15.0 Hz, 1H),
4.52 (d, J¼15.3 Hz, 1H), 3.82 (s, 3H). 19F NMR:
d
ꢀ107.3 (dd,
4.3.6. (2-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,2-
dihydropyridin-3-yl)(phenyl)methanone (9h’). Yellow solid. Mp
124e126 ꢁC. IR (KBr): 3079, 2936, 2835, 1622, 1499, 1344, 1245,
J¼243.1 Hz, 5.9 Hz, 1F), ꢀ114.8 (dd, J¼239.1 Hz, 19.5 Hz, 1F). 13C
NMR:
d
159.7, 142.6 (d, J¼4.5 Hz), 135.7, 132.4, 130.7, 129.4, 128.9,
127.8, 120.5 (dd, J¼303.7 Hz, 291.8 Hz), 118.9, 114.5, 98.7, 79.4, 59.1,
57.3 (dd, J¼27.6 Hz, 20.1 Hz), 55.3. MS (ESI, m/z): 439.1 ([MþNa]þ).
HRMS (ESI): calcd for C21H19F2N2O3Sþ([MþH]þ): 417.1079; Found:
417.1089.
1150, 1108, 928, 844, 723, 594 cmꢀ1 1H NMR:
d
7.98 (d, J¼7.5 Hz,
2H), 7.71 (t, J¼7.2 Hz,1H), 7.55e7.63 (m, 4H), 7.35e7.44 (m, 3H), 7.16
(d, J¼8.1 Hz, 2H), 7.04 (d, J¼6.6 Hz, 1H), 6.86 (d, J¼7.5 Hz, 2H), 6.68
(d, J¼6.6 Hz, 1H), 6.38 (dd, J¼18.3 Hz, 7.5 Hz, 1H), 5.20 (t, J¼6.3 Hz,
1H), 4.79 (d, J¼15.3 Hz, 1H), 4.64 (d, J¼15.0 Hz, 1H), 3.78 (s, 3H). 19F
4.3.11. 4-(Difluoro(phenylsulfonyl)methyl)-1-(4-methoxybenzyl)-1,4-
dihydropyridine-3-carbonitrile (9j00). White solid. Mp: 158e160 ꢁC.
IR (film): 2191, 1672, 1579, 1514, 1409, 1338, 1255, 1152, 1099, 1034,
NMR:
d
ꢀ108.2 (dd, J¼239.2 Hz, 7.3 Hz, 1F), ꢀ112.2 (dd, J¼239.5 Hz,
18.6 Hz, 1F). 13C NMR:
d
193.8, 159.4, 143.0, 140.9, 138.9, 135.2, 133.1,
130.8, 130.6, 129.1, 128.9, 128.6, 128.2, 128.0, 121.3 (dd, J¼300.7 Hz,
292.5 Hz), 114.3, 110.2, 98.7, 59.4, 56.5 (dd, J¼26.8 Hz, 20.1 Hz), 55.2.
MS (ESI, m/z): 496.1 ([MþH]þ). Anal. Calcd for C27H23F2NO4S: C,
65.44; H, 4.68; N, 2.83; Found: C, 65.21; H, 4.62; N, 2.89.
821, 714, 610, 542 cmꢀ1 1H NMR:
J¼7.5 Hz, 1H), 7.62 (t, J¼7.5 Hz, 2H), 7.11 (d, J¼8.7 Hz, 2H), 6.91 (s,
1H), 6.90 (d, J¼8.4 Hz, 2H), 6.19 (d, J¼7.8 Hz, 1H), 5.09 (dd, J¼7.5 Hz,
4.5 Hz, 1H), 4.37e4.47 (m, 1H), 4.37 (s, 2H), 3.81 (s, 3H). 19F NMR:
d
7.98 (d, J¼7.8 Hz, 2H), 7.76 (t,
d
ꢀ103.8 (d, J¼229.0 Hz, 1F), ꢀ112.6 (dd, J¼230.4 Hz, 24.0 Hz, 1F).
4.3.7. Methyl 6-(difluoro(phenylsulfonyl)methyl)-1-(4-metho-
xybenzyl)-1,6-dihydropyridine-3-carboxylate (9i). White solid. Mp:
130e132 ꢁC. IR (KBr): 1695, 1637, 1570, 1513, 1342, 1305, 1153, 1107,
13C NMR:
d
159.7, 145.8, 135.4, 132.9, 131.8, 130.5, 129.3, 128.7, 127.0,
120.8 (t, J¼295.5 Hz), 120.0, 114.5, 96.8 (d, J¼6.0 Hz), 71.8, 57.4, 55.3,
37.7 (t, J¼21.6 Hz). MS (ESI, m/z): 439.1 ([MþNa]þ). HRMS (ESI):
calcd for C21H18F2N2O3SNaþ([MþNa]þ): 439.0898; Found:
439.0900.
1091,1023, 832, 719, 596 cmꢀ1 1H NMR:
d
7.96 (d, J¼7.8 Hz, 2H), 7.78
(t, J¼7.8 Hz, 1H), 7.63 (t, J¼8.1 Hz, 2H), 7.52 (s, 1H), 7.18 (d, J¼8.1 Hz,
2H), 6.90 (d, J¼8.4 Hz, 2H), 6.78 (d, J¼9.0 Hz,1H), 5.03e5.19 (m, 2H),
4.63 (d, J¼15.3 Hz, 1H), 4.50 (d, J¼15.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s,
4.4. Typical procedure for the oxidative deprotection/
aromatization of addition product 9 to form 10
3H). 19F NMR:
d
ꢀ109.1 (dd, J¼230.9 Hz, 7.9 Hz, 1F), ꢀ112.2 (dd,
J¼233.2 Hz, 14.4 Hz, 1F). 13C NMR:
d 166.3, 159.7, 146.4, 135.5, 132.7,
130.6, 129.3, 129.0, 127.4, 127.2, 121.0 (t, J¼296.3 Hz), 114.5, 103.3,
101.6, 59.5 (d, J¼3.0 Hz), 56.8 (dd, J¼23.8 Hz,18.6 Hz), 55.3, 50.9. MS
(ESI, m/z): 450.0 ([MþH]þ). Anal. Calcd for C22H21F2NO5S: C, 58.79;
H, 4.71; N, 3.12; Found: C, 58.88; H, 4.76; N, 3.31.
Into a MeOH (8 mL) solution of the addition product 9a (221 mg,
0.5 mmol) was added a water (2 mL) solution of CAN (685 mg,
1.25 mmol) dropwise in 10 min. After stirring overnight at ambient
temperature, a saturated NaHCO3 aqueous solution (20 mL) was
added to quench the reaction and extracted with ethyl acetate
(3ꢂ15 mL). The combined organic phase was washed with satu-
rated NaHCO3 aquaous solution (15 mL), and dried with anhydrous
Na2SO4. After removal of the solvent under reduced pressure, the
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 4:1) to give 10a as a white solid (148 mg, 93%).
4.3.8. Methyl 2-(difluoro(phenylsulfonyl)methyl)-1-(4-methoxy-
benzyl)-1,2-dihydropyridine-3-carboxylate (9i0). Yellow oil. IR
(film): 3005, 2953, 2840, 1695, 1612, 1514, 1345, 1253, 1155, 1090,
1008, 819, 740, 686, 594 cmꢀ1 1H NMR:
(t, J¼7.5 Hz, 1H), 7.59 (t, J¼7.5 Hz, 2H), 7.40 (d, J¼7.2 Hz, 1H), 7.15 (d,
d
7.98 (d, J¼7.8 Hz, 2H), 7.74

5144
W. Huang et al. / Tetrahedron 68 (2012) 5137e5144
4.4.1. 2-(Difluoro(phenylsulfonyl)methyl)quinoline (10a). Colorless
solid. Mp: 141e143 ꢁC. IR (KBr): 1583, 1449, 1346, 1308, 1170, 1124,
m/z): 327.9 ([MþH]þ). Anal. Calcd for C14H11F2NO4S: C, 51.37; H,
3.39; N, 4.28; Found: C, 51.52; H, 3.64; N, 4.34.
1098, 977, 821, 757, 719, 587 cmꢀ1 1H NMR:
d
8.36 (d, J¼8.1 Hz, 1H),
8.18 (d, J¼8.4 Hz, 1H), 8.04 (d, J¼8.1 Hz, 2H), 7.86e7.93 (m, 2H),
7.76e7.83 (m, 2H), 7.60e7.70 (m, 3H). 19F NMR: -104.8 (s, 2F). 13
NMR:
4.4.7. 2-(Difluoro(phenylsulfonyl)methyl)nicotinonitrile
White solid. Mp: 180e182 ꢁC. IR (KBr): 3094, 2234, 1579, 1448,
1344, 1168, 1116, 819, 712, 599 cmꢀ1 1H NMR:
8.91 (d, J¼5.1 Hz,
(10j0).
d
C
d
147.4, 146.2 (t, J¼23.1 Hz), 137.4, 135.4, 132.8, 131.0, 130.6,
d
130.2, 129.2, 128.7, 127.6, 119.4 (t, J¼3.0 Hz), 119.2 (t, J¼286.6 Hz).
MS (ESI, m/z): 320.0 ([MþH]þ). Anal. Calcd for C16H11F2NO2S: C,
60.18; H, 3.47; N, 4.39; Found: C, 60.10; H, 3.51; N, 4.45.
1H), 8.15 (d, J¼8.4 Hz, 1H), 8.03 (d, J¼7.8 Hz, 2H), 7.77 (t, J¼7.5 Hz,
1H), 7.59e7.65 (m, 3H). 19F NMR:
d
ꢀ101.6 (s, 2F). 13C NMR:
d 152.2,
148.0 (t, J¼23.1 Hz), 142.6, 136.0, 131.9, 131.1, 129.6, 125.9, 118.3 (t,
J¼289.6 Hz), 114.1, 110.8. MS (ESI, m/z): 294.9 ([MþH]þ). Anal. Calcd
for C14H11F2NO4S: C, 53.06; H, 2.74; N, 9.52; Found: C, 53.09; H,
3.01; N, 9.72.
4.4.2. 2-(Difluoro(phenylsulfonyl)methyl)-6-methoxyquinoline
(10b). White solid. Mp: 143e145 ꢁC. IR (film): 1623, 1500, 1484,
1344, 1232, 1170, 1097, 843, 722, 604 cmꢀ1 1H NMR:
d 8.22 (d,
J¼8.4 Hz, 1H), 8.02e8.07 (m, 3H), 7.75e7.83 (m, 2H), 7.61 (t,
4.4.8. 2-(Difluoromethyl)quinoline (11).16 Pale yellow oil. 1H NMR:
J¼8.1 Hz, 2H), 7.43 (dd, J¼9.0 Hz, 3.0 Hz, 1H), 7.12 (s, 1H), 3.96 (s,
d
8.24 (d, J¼8.7 Hz, 1H), 8.08 (d, J¼8.4 Hz, 1H), 7.80 (d, J¼8.1 Hz, 1H),
3H). 19F NMR:
d
ꢀ104.6 (s, 2F). 13C NMR:
d
159.4, 143.7, 143.4 (t,
7.64e7.74 (m, 2H), 7.56 (t, J¼7.2 Hz, 1H), 6.72 (t, J¼55.5 Hz, 1H). 19F
J¼23.3 Hz), 135.8, 135.3, 132.9, 131.6, 130.9, 130.2, 129.2, 123.8, 119.8,
119.4 (t, J¼286.6 Hz), 104.6, 55.6. MS (ESI, m/z): 350.0 ([MþH]þ).
Anal. Calcd for C17H13F2NO3S: C, 58.45; H, 3.75; N, 4.01; Found: C,
58.51; H, 3.89; N, 4.02.
NMR:
100.00).
d
ꢀ114.6 (d, J¼55.6 Hz, 2F). MS (EI, m/z, %): 179.0 (Mþ,
Acknowledgements
4.4.3. 2-(Difluoro(phenylsulfonyl)methyl)-6-methylquinoline
(10c). White solid. Mp: 166e168 ꢁC. IR (KBr): 1449, 1348, 1172,
Support of our work by the National Natural Science Foundation
of China (20825209, 20832008) and the National Basic Research
Program of China (2012CB821600, 2012CB215500) is gratefully
acknowledged.
1127, 1098, 981, 840, 723, 683, 590, 534 cmꢀ1 1H NMR:
d 8.15 (d,
J¼8.7 Hz, 1H), 7.93e7.98 (m, 3H), 7.66e7.75 (m, 2H), 7.50e7.56 (m,
4H), 2.48 (s, 3H). 19F NMR:
d
ꢀ104.8 (s, 2F). 13C NMR:
d 146.1, 145.2
(t, J¼23.1 Hz), 139.0, 136.6, 135.4, 133.0, 132.9, 131.0, 129.8, 129.2,
128.9, 126.4, 119.5 (t, J¼3.0 Hz), 119.3 (t, J¼287.4 Hz), 21.7. MS (ESI,
m/z): 333.9 ([MþH]þ). Anal. Calcd for C17H13F2NO2S: C, 61.25; H,
3.93; N, 4.20; Found: C, 61.19; H, 4.14; N, 4.22.
References and notes
1. (a) Fluorine in Medicinal Chemistry and Chemical Biolog; Ojima, I., Ed.; Wiley:
ꢀ
ꢀ
Chichester, 2009; (b) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008; (c) Filler, R.; Saha, R. Future
Med. Chem. 2009, 1, 777.
4.4.4. 6-(Difluoro(phenylsulfonyl)methyl)nicotinamide (10g). White
solid. Mp: 228e230 ꢁC. IR (KBr): 3407, 3194, 1687, 1624, 1398, 1351,
1164, 1098, 1075, 715, 688, 594, 543 cmꢀ1 1H NMR (DMSO-d6):
2. (a) Liu, J.; Hu, J. Future Med. Chem. 2009, 1, 875; (b) Sorochinsky, A. E.; Solo-
shonok, V. A. J. Fluorine Chem. 2010, 131, 127; (c) Prakash, G. K. S.; Mogi, R.; Olah,
G. A. Org. Lett. 2006, 8, 3589.
3. Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem. 2011, 831.
d
9.14 (s, 1H), 8.49 (d, J¼7.8 Hz, 1H), 8.42 (s, 1H), 7.92e8.01 (m, 5H),
4. (a) Loska, R.; Makosza, M. J. Org. Chem. 2007, 72, 1354; (b) Loska, R.; Majcher,
M.; Makosza, M. J. Org. Chem. 2007, 72, 5574; (c) Levin, V. V.; Kozlov, M. A.;
Song, Y.-H.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Tetrahedron Lett. 2008, 49, 3108; (d) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Eur. J. Org. Chem. 2008, 5226; (e) Shev-
7.77e7.82 (m, 2H). 19F NMR (DMSO-d6):
(DMSO-d6):
d
ꢀ104.6 (s, 2F). 13C NMR
d
165.7, 149.2, 147.5 (t, J¼23.1 Hz), 137.3, 136.8, 133.0,
132.0, 130.9, 130.4, 123.8, 119.2 (t, J¼285.9 Hz). MS (ESI, m/z): 334.9
([MþNa]þ). HRMS (ESI): calcd for C13H11F2N2O3Sþ([MþH]þ):
313.0453; Found: 313.0463.
€
chenko, N. E.; Vlasov, K.; Nenajdenko, V. G.; Roschenthaler, G.-V. Tetrahedron
2011, 67, 69.
5. Fluorinated Hererocyclic Compounds: Synthesis, Chemistry, and Applications;
Petrov, V. A., Ed.; John Wiley: Hobken, 2009.
4.4.5. (6-(Difluoro(phenylsulfonyl)methyl)pyridin-3-yl)(phenyl)
methanone (10h). White solid. Mp: 134e136 ꢁC. IR (film): 1652,
1587, 1449, 1348, 1285, 1171, 1102, 923, 711, 599, 544 cmꢀ1 1H NMR:
6. Felix, C. P.; Khatimi, N.; Laurent, A. J. Tetrahedron Lett. 1994, 35, 3303.
7. (a) Banks, R. E.; Besheesh, M. K.; Lawrence, N. J.; Tovell, D. J. J. Fluorine Chem.
1999, 97, 79; (b) Petrov, V. A. Tetrahedron Lett. 2000, 41, 6959.
8. Very recently, nucleophilic difluromethylation of acyclic imines with fluo-
roalkyl silanes activated by a Brønsted acid was reported by Dilman and co-
workers. See Kosobokov, M. D.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P.
A.; Hu, J. J. Org. Chem. 2012, 77, 2080.
d
9.10 (s, 1H), 8.29 (d, J¼8.7 Hz, 1H), 8.07 (d, J¼8.1 Hz, 2H), 7.98 (d,
J¼7.8 Hz, 1H), 7.80e7.86 (m, 3H), 7.64e7.69 (m, 3H), 7.55 (t,
J¼6.9 Hz, 2H). 19F NMR:
d d 193.5, 150.5,
-104.9 (s, 2F). 13C NMR:
9. Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7467.
149.0 (t, J¼23.1 Hz), 138.1, 135.9, 135.7, 135.4, 133.7, 132.5, 131.0,
130.0, 129.4, 128.8, 123.5 (t, J¼3.8 Hz), 118.8 (t, J¼287.3 Hz). MS (ESI,
m/z): 374.0 ([MþH]þ). Anal. Calcd for C19H13F2NO3S: C, 61.12; H,
3.51; N, 3.75; Found: C, 61.18; H, 3.54; N, 3.87.
10. (a) Werner, F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 3911; (b) Venkov, A. P.;
Ivanov, I. I. Tetrahedron 1996, 52, 12299; (c) Gray, N. M.; Cheng, B. K.; Mick, S. J.;
lair, C. M.; Contreras, P. C. J. Med. Chem. 1989, 32, 1242; (d) Elliott, M. C.; Wil-
liams, E. Org. Biomol. Chem. 2003, 1, 3038.
11. Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A. A. J. Org. Chem.
1990, 55, 3682.
12. (a) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921; (b) Ni, C.; Hu, J. Synlett
2011, 770; (c) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342.
13. (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882; (b) Li, Y.; Hu, J. Angew.
Chem., Int. Ed. 2007, 46, 2489.
14. (a) Prakash, G. K. S.; Krishnamuti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393;
(b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123.
15. (a) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273; (b) Prakash, G. K. S.; Hu, J.;
Wang, Y.; Olah, G. A. Eur. J. Org. Chem. 2005, 2218.
4.4.6. Methyl 6-(difluoro(phenylsulfonyl)methyl)nicotinate (10i).
White solid. Mp: 145e146 ꢁC. IR (KBr): 1732, 1595, 1343, 1282, 1118,
1021, 734, 601, 543 cmꢀ1 1H NMR:
d
9.32 (s, 1H), 8.51 (d, J¼8.1 Hz,
1H), 8.03 (d, J¼7.2 Hz, 2H), 7.92 (d, J¼8.4 Hz, 1H), 7.81 (t, J¼7.5 Hz,
1H), 7.65 (t, J¼8.1 Hz, 2H), 4.01 (s, 3H). 19F NMR:
d C
-105.3 (s, 2F). 13
NMR:
d
164.6, 150.8, 149.8 (t, J¼23.1 Hz), 138.3, 135.7, 132.5, 131.0,
129.4, 128.4, 123.5 (t, J¼3.7 Hz), 118.8 (t, J¼287.3 Hz), 52.9. MS (ESI,
16. Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560.