A Novel Convenient Synthesis of Pyridinyl and Quinolinyl Triflates and Tosylates via One-Pot Diazotization of Aminopyridines and Aminoquinolines in Solution

Article abstract of DOI:10.1055/s-0035-1560392

The first effective and simple method for the direct one-pot transformation of 2-, 3-, and 4-aminopyridines, 2,6-diaminopyridines, and 2-aminoquinoline into the corresponding pyridinyl and quinolinyl trifluoromethanesulfonates and tosylates in solvents was developed. The procedure involves diazotization of the heterocyclic amines with sodium nitrite in mixed hexane-DMSO or hexane-DMF solutions in the presence of trifluoromethanesulfonic acid or p-toluenesulfonic acid.

Full text of DOI:10.1055/s-0035-1560392

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, 256–262
256
paper
Synthesis
A. Z. Kassanova et al.
Paper
A Novel Convenient Synthesis of Pyridinyl and Quinolinyl Triflates
and Tosylates via One-Pot Diazotization of Aminopyridines and
Aminoquinolines in Solution
Assiya Zh. Kassanova
R
R
Elena A. Krasnokutskaya*
2
Perizat S. Beisembai
NH2
OX
N
solvent
Victor D. Filimonov*
N
R = H, Me, Cl, Br, I, NO2, F
X = Ts, Tf
43–98%
14 examples
Department of Biotechnology and Organic Chemistry,
National Research Tomsk Polytechnic University,
634050 Tomsk, Russian Federation
eak@tpu.ru
filimonov@tpu.ru
3 3 2
CF SO H, NaNO
hexane–DMSO
N
NH2
N
OTf
83%
Received: 01.10.2015
Accepted after revision: 04.11.2015
Published online: 02.12.2015
Recently we have reported an alternative approach to
the synthesis of pyridinyl tosylates and pyridinyl triflates
through diazotization of available aminopyridines in the
presence of TsOH or TfOH by grinding reagents in water or
DMSO pastes, respectively, at room temperature (Scheme
DOI: 10.1055/s-0035-1560392; Art ID: ss-2015-z0565-op
4
5
Abstract The first effective and simple method for the direct one-pot
transformation of 2-, 3-, and 4-aminopyridines, 2,6-diaminopyridines,
and 2-aminoquinoline into the corresponding pyridinyl and quinolinyl
trifluoromethanesulfonates and tosylates in solvents was developed.
The procedure involves diazotization of the heterocyclic amines with
sodium nitrite in mixed hexane–DMSO or hexane–DMF solutions in the
presence of trifluoromethanesulfonic acid or p-toluenesulfonic acid.
1).
These reactions are unknown for aromatic amines,
which form stable arenediazonium tosylates at the diazoti-
6
zation step in the presence of p-toluenesulfonic acid. How-
ever, the reaction takes place due to the known instability
of intermediate pyridinediazonium salts (especially with 2-
and 4-pyridinediazonium cations) in comparison with
Key words diazotization, pyridine, quinoline, triflate, tosylate
7
arenediazonium salts.
The grinding methods4 are simple and are realized us-
ing cheap reagents. However, the grinding reactions in the
paste forms are difficult to implement on a large scale, and
,5
Pyridine and quinoline derivatives containing trifluoro-
methanesulfonates or 4-methylbenzenesulfonates2 as a
good leaving group are valuable blocks for the synthesis of
highly functionalized heterocycles with broader applica-
tions in medicinal and other fields of chemistry.
So far the only method for the synthesis of such com-
pounds was the acylation of hydroxypyridines and hy-
droxyquinoline by TsCl, TfCl, (Tf) O, or (Tf) NR. In gener-
al, these methods provide good yields, but the high cost of
reagents and the requirements for an inert atmosphere and
low temperature (down to –78 °C) in some cases make the
target products fairly expensive.
1
8
they cannot be used in flow or combinatorial chemistry.
Thus, it is important to develop a more versatile and scal-
able method for the synthesis of pyridinyl and quinolinyl
triflates and tosylates through aminopyridines and amino-
quinolines by the diazotization in the presence of TsOH and
TfOH in solution.
1–3
2
2
The selection of the optimal solvents for the diazotiza-
tion reaction in the presence of NaNO and TfOH was con-
2
ducted using 2-aminopyridine (1а). It was found that
+
XO–
[
NO ]/XOH
NH2
N2+
OX
–
N2
H2O or DMSO paste
N
N
XO–
N
N
X = Ts, Tf
Scheme 1 The one-pot transformation of aminopyridines in pyridinyl tosylates and triflates via the diazotization in the presence of p-toluenesulfonic
4,5
acid and trifluoromethanesulfonic acid
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Synthesis
A. Z. Kassanova et al.
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Table 1 Diazotization of Pyridine-2-amine (1a) by NaNO in the Pres-
ence of TfOH in Solvents at Room Temperature
during diazotization in EtOH, MeCN, CH Cl , benzene, and
2
2
2
a
toluene, the formation of target pyridinyl-2-trifluorometh-
anesulfonate (2a) is accompanied by the formation of by-
products 3a–e occurring as a result of substitution of the
amino group by solvent residues with incomplete conver-
sion of the starting amine 1а (Table 1).
NaNO2, TfOH
solvent, 20 °C
+
N
NH2
N
OTf
N
X
1a
3
2a
The best results were obtained using DMSO and DMF
(
Table 1, entries 6 and 7), but in the case of DMSO, the for-
Entry
Solvent
Composition of the reaction mass (GC/MS), %
1a
mation of 2-pyridinol (3f) was observed, perhaps, because
of the residual water present in the solvent. The full conver-
sion of starting amine 1а after 20–30 minutes with an ab-
sence of by-products was observed in DMF, but in this case
unexpected difficulties arose in the separation of 2-pyr-
idinyl triflate (2а) from residual amounts of the solvent.
Probably, DMF forms strong complexes with pyridine 2а as
significant amounts of DMF (up to 44%) can be found in the
NMR spectrum after multiple washings of the extract of 2a
in ethyl acetate or CH Cl with water or even after chro-
2
a
3
1
2
3
EtOH
5
90
N
OEt
NHAc
Ph
3
3
3
a (5)
MeCN
benzene
40
52
2.5
28
N
b (45)
2
2
matographic purification on silica gel.
For these reasons, inert hexane supplemented with 10%
DMSO was tested for better solubility of the reaction com-
ponents (Table 1, entry 8) and it was found that there were
no by-products upon complete conversion of amine 1а. This
solvent system was used for the further preparative synthe-
ses of pyridinyl triflates 2a–n (Table 2). The reactions were
conducted as follows. Trifluoromethanesulfonic acid was
added to a cooled (5 °C) mixture of hexane–DMSO (10:1
vol%), then the pre-ground mixture of the corresponding
aminopyridine 1a–n and sodium nitrite was added at sev-
eral stages to the reaction mass. After loading of the re-
agents, the reaction mass was stirred at 5 °C for 10 minutes
and then for 50 minutes at room temperature.
N
c (20)
4
5
toluene
55
28
N
Cl
3
3
d (17)b
CH
2
Cl
2
89
90
0
0
N
e (8)
6
7
DMSO
N
f (10)
OH
It is important to note that formation of pyridinyl tri-
3
0
0
flates 2a–n under the NaNO /TfOH treatment in hexane–
DMSO system takes place within 1 hour, that is, it is signifi-
cantly faster than in DMSO paste (2.5–38 h). Yields of the
2
DMF
100
100
0
0
8
hexane–DMSO
5
a
Mole ratio of 1a/NaNO
Mixture of o-, m-, and p-isomers.
2
/TfOH = 1:2.5:3; reaction time: 1 h.
target pyridinyl triflates 2a–n during diazotization in solu-
b
tion are also higher than in DMSO paste.5 The proposed
synthetic method has a general character, allowing the
preparation of 2-, 3-, and 4-pyridinyl trifluoromethanesul-
fonates as well as the almost unknown 2,6-pyridinyl ditri-
NaNO2, TfOH
hexane–DMSO, 20 °C
N
NH2
N
OTf
4a
5, 83%
NaNO2, TfOH
KI
NH2
N2 OTf
I
N
hexane–DMSO, 20 °C
N
H2O
N
4
4
b, 3-NH2
c, 6-NH2
6, 3-I,79%
7, 6-I, 79%
Scheme 2 Diazotization of aminoquinolines 4a–c in the presence of trifluoromethanesulfonic acid
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Synthesis
A. Z. Kassanova et al.
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5
flates 2k–n. At the same time, pyridine-3,4-diamine and 3-
nitropyridine-4-amine are inert under the described condi-
tions and are isolated unchanged from the reaction mix-
ture.
Table 2 (continued)
Substrate
Yield (%)b
Product
I
I
I
I
5
4
5
6
Table 2 Synthesis of Pyridinyl Trifluoromethanesulfonates 2a–na
H N
N
N
N
NH2
TfO
2l
N
N
N
OTf
2
1
l
Substrate
Product
Yield (%)b
Br
Br
Br
Br
3
H2N
1m
NH2
TfO
2m
OTf
F
9
6
2
N
NH2
N
OTf
1
a
2а
F
F
F
Br
Br
0c
H2N
NH2
TfO
2n
OTf
9
1
n
N
NH2
NH2
N
OTf
OTf
a
1
b
2b
2
The diazotization of aminopyridines 1a–n by NaNO was conducted in the
presence of TfOH in hexane–DMSO mixture. Mole ratio of 1a–j/NaNO
TfOH = 1:2.5:3, for 1k–n mole ratio = 1:5:6.
2
/
Cl
Cl
b
Isolated yields.
8
6
0
c
Inseparable mixture with 3,5-difluoropyridin-2-yl trifluoromethanesulfon-
ate in a ratio of 95:5.
N
N
1
1
c
2c
Br
Br
It is important to note also that the reaction of 3,5-diflu-
oropyridine-2,6-diamine (1n) is accompanied by a partial
hydro-dediazoniation and an inseparable mixture of the
target product 2n together with about 5% of 3,5-difluoropy-
ridin-2-yl trifluoromethanesulfonate was formed (GC/MS
data).
The found conditions were used in attempts to the first
direct conversion of 2-, 3- and 6-aminoquinolines 4a–c into
the corresponding triflate derivatives via diazotization in
the presence of TfOH. However, it was found that only 2-
aminoquinoline (4a) was converted into quinolin-2-yl tri-
fluoromethanesulfonate (5) in good yield similar to amino-
pyridines 1. At the same time, 3- and 6-aminoquinolines
6
N
N
NH2
NH2
N
OTf
OTf
d
2d
75
N
1
1
e
f
2e
78
98
90
N
NH2
N
OTf
2f
NH2
OTf
4
b,c form only relatively stable diazonium salts, which even
when heated were not converted into the 3- and 6-quino-
linyl triflates, but quickly gave 3- and 6-iodoquinolines 6
and 7 in 79% yield under the treatment of aqueous KI at
room temperature (Scheme 2).
We have also used this approach for obtaining 2-, 3-,
and 4-pyridinyl-4-methylbenzenesulfonates 8a–c and pyri-
dine-2,6-diyl bis(4-methylbenzenesulfonate) (8d) via the
solution diazotization of 2-, 3-, and 4-aminopyridines 1a,g,i
or pyridine-2,6-diamine (1k) in the presence of TsOH
N
N
N
1
1
g
h
2g
2h
NH2
Cl
OTf
Cl
N
NH2
N
OTf
73
(
Scheme 3) as well. However, in this case it is preferred to
use DMF instead of DMSO for better dissolution of TsOH.
This solution reaction takes place slightly faster than the di-
N
1
i
2i
Br
Br
Br
Br
4
azotization in the presence of TsOH in the aqueous paste.
The possibility of scaling up the developed method was
confirmed by the experiment in which 2-pyridinyl triflate
7
5
1
N
NH2
N
OTf
1
j
2j
(
2a) and 2-pyridinyl tosylate (8а) were obtained with an in-
creased load of pyridin-2-amine up to 10 mmol without a
reduction in target product yields.
6
H2N
1
N
NH2
TfO
2k
N
OTf
k
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Synthesis
A. Z. Kassanova et al.
Paper
Pyridin-2-yl Trifluoromethanesulfonate (2a)5
NaNO2, TsOH
OTs
Yield: 436 mg (96%, 1.92 mmol); colorless oil.
1a,g,i
hexane–DMF, 20 °C, 1 h
1
N
Н NMR (300 MHz, CDCl ): δ = 7.2 (d, J = 8.1 Hz, 1 Н), 7.4 (m, 1 Н), 7.9
3
8
8
8
a, 2-TsO, 53%
b, 3-TsO, 50%
c, 4-TsO, 70%
(m, 1 Н), 8.4 (d, J = 5.7 Hz, 1 H).
13
С NMR (75 MHz, CDCl ): δ = 115.3, 118.6 (q, J = 300 Hz), 124.3,
3
141.1, 148.8, 155.9.
NaNO2, TsOH
+
MS (EI): m/z (%) = 227 (38, [M] ), 199 (2), 163 (4), 135 (100), 116 (9),
1k
96 (13), 69 (60), 39 (45).
hexane–DMF, 20 °C, 1 h
TsO
N
OTs
8d, 68%
-Bromopyridin-2-yl Trifluoromethanesulfonate (2b)5
5
Scheme 3 Synthesis of pyridinyl tosylates 8a–d via the diazotization in
hexane–DMF solution in the presence of p-toluenesulfonic acid
Yield: 563 mg (92%, 1.84 mmol); light yellow oil.
1
H NMR (300 MHz, CDCl ): δ = 7.1 (d, J = 8.7 Hz, 1 Н), 7.99 (dd, J = 8.6,
3
2.4 Hz, 1 Н), 8.5 (d, J = 2.1 Hz, 1 Н).
13
С NMR (75 MHz, CDCl ): δ = 116.8, 118.5 (q, J = 300 Hz), 120.5,
3
In summary, we have presented a simple and scalable
method for the synthesis of pyridinyl triflates and tosylates
as well as quinolin-2-yl triflate from the available aminopy-
ridines and 2-aminoquinoline via the diazotization by sodi-
um nitrite in the presence of TsOH or TfOH in hexane solu-
tion with the addition of DMF or DMSO. Under the same
conditions, 3- and 6-aminoquinolines form relatively stable
diazonium salts, which can be easily converted into 3- and
143.6, 149.7, 154.5.
MS (EI): m/z (%) = 307 (15, [81Br, M]
(29), 117 (46), 96 (10), 69 (100), 38 (46).
+
), 243 (4), 213 (62), 174 (4), 144
5-Chloropyridin-2-yl Trifluoromethanesulfonate (2c)
Yield: 449 mg (86%, 1.72 mmol); white solid; mp 67 °C (Lit.5 mp
6
7 °C).
1Н NMR (300 MHz, CDCl
.4 Hz, 1 Н), 8.3 (d, J = 2.1 Hz, 1 Н).
): δ = 7.1 (d, J = 8.7 Hz, 1 Н), 7.85 (dd, J = 8.7,
3
2
6
-iodoquinolines.
13
С NMR (75 MHz, CDCl ): δ = 116.3, 118.4 (q, J = 317 Hz), 132.3,
3
140.6, 147.2, 153.7.
MS (EI): m/z (%) = 261 (30, [35Cl, M] ), 233 (2), 197 (4), 169 (100), 134
(9), 100 (30), 69 (53), 38 (9).
+
All starting materials 1a–j were ACS grade and used without further
purification except pyridine-2,6-diamine (1k) (Sigma Aldrich), which
was purified by recrystallization from benzene. Compound 1l was
prepared by the iodination of 1k with NIS. HPLC analyses were con-
ducted with an Agilent 1200 instrument fitted with an Eclipse Plus
9
3-Bromopyridin-2-yl Trifluoromethanesulfonate (2d)
Yield: 367 mg (60%, 1.2 mmol); colorless oil.
C18 column (5 μm, 4.6 × 150 mm) and UV detector. GC/MS measure-
1H NMR (300 MHz, CDCl
.95 Hz, J3,1 = 1.5 Hz, 1 H), 8.31–8.33 (dd, J1,2 = 4.8 Hz, J1,3 = 1.5 Hz, 1
H).
): δ = 7.25–7.29 (m, 1 H), 8.06–8.09 (dd, J3,2 =
3
1
13
ments were obtained with an Agilent 7890/5975C instrument. H,
C
7
NMR, and IR spectra were recorded on a Bruker and PerkinElmer BXII
instruments. Melting points (uncorrected) were obtained with a
melting point system MP50, Mettler, Toledo. Elemental analyses were
performed with a Vario MACRO cube CHNS instrument (Elementar
Analysensysteme GmbH, Germany). All the known compounds, 2a–
c,e–i,k,l, 5, and 8a–d, were characterized by comparison of melting
points and NMR spectra with the literature data and authentic sam-
ples.
13C NMR (75 MHz, CDCl
144.3, 146.5, 152.9.
): δ = 112.1, 120.6 (q, J = 318.0 Hz), 125.3,
3
MS (EI): m/z (%) = 307 (66, [81Br, M] ), 241 (10), 213 (100), 193 (3), 162
64), 144 (60), 117 (26), 93 (21), 69 (91), 38 (29).
Anal. Calcd for C H BrF NO S: C, 23.55; H, 0.99; N, 4.58; S, 10.48.
+
(
6
3
3
3
Found: C, 23.55; H, 1.07; N, 5.08; S, 10.48.
Pyridinyl and Quinolinyl Trifluoromethanesulfonates 2a–n, 5;
General Procedure
4
-Methylpyridin-2-yl Trifluoromethanesulfonate (2e)5
Yield: 361 mg (75%, 1.5 mmol); light yellow oil.
To a solution of hexane (5 mL), DMSO (0.5 mL), and trifluoromethane-
sulfonic acid (0.54 mL, 6 mmol) at 5 °C were sequentially added the
1
Н NMR (300 MHz, CDCl ): δ = 2.4 (s, 3 Н), 6.9 (s, 1 Н), 7.2 (d, J = 4.8
3
Hz, 1 Н), 8.2 (d, J = 4.5 Hz, 1 H).
13С NMR (75 MHz, CDCl ): δ = 20.9, 115.5, 118.6 (q, J = 318 Hz), 125.3,
148.0, 153.4, 156.2.
respective aminopyridine 1a–j (2 mmol) and NaNO (0.35 g, 5 mmol)
2
under stirring and the mixture was stirred for 10 min. An immediate
3
emission of N bubbles was observed. In the case of diamino deriva-
2
tives 1k–n, double amounts of NaNO2 and TfOH were used. The re-
sulting mixture was then stirred for 50 min at r.t. until the starting
amine had been consumed as monitored by TLC. The reaction mix-
ture was poured into H O and extracted with CH Cl (2 × 25 mL). The
+
MS (EI): m/z (%) = 241 (45, [M] ), 213 (9), 177 (6), 148 (100), 128 (3),
1
08 (9), 96 (1), 92 (20), 80 (30), 69 (38), 65 (15), 53 (52), 39 (13).
2
2
2
6
-Methylpyridin-2-yl Trifluoromethanesulfonate (2f)5
combined organic extracts were dried (Na SO ), filtered, and the sol-
2
4
Yield: 376 mg (78%, 1.6 mmol); light yellow oil.
vent was removed under reduced pressure on a rotary evaporator.
The product was purified by silica gel flash chromatography (eluent:
CH Cl ).
1
Н NMR (300 MHz, CDCl ): δ = 2.5 (s, 3 Н), 6.9 (d, J = 7.8 Hz, 1 Н), 7.2
(d, J = 7.5 Hz, 1 Н), 7.7 (m, 1 Н).
3
2
2
13
С NMR (75 MHz, CDCl ): δ = 23.7, 111.7, 118.6 (q, J = 319 Hz), 123.7,
3
140.9, 155.1, 159.0.
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Synthesis
A. Z. Kassanova et al.
Paper
+
1
MS (EI): m/z (%) = 241 (65, [M] ), 213 (13), 177 (6), 158 (1), 148 (55),
Н NMR (300 MHz, CDCl ): δ = 8.8 (s).
3
1
42 (1), 128 (1), 108 (6), 91 (100), 80 (35), 69 (41), 65 (20), 53 (33), 39
13
С NMR (75 MHz, CDCl ): δ = 83.5, 118.5 (q, J = 319 Hz), 154.5, 162.2.
3
(68).
+
MS (EI): m/z (%) = 627 (52, [M] ), 494 (7), 466 (2), 430 (4), 402 (31),
3
74 (9), 345 (27), 325 (2), 303 (18), 275 (21), 254 (2), 234 (17), 206
Pyridin-3-yl Trifluoromethanesulfonate (2g)5
(45), 178 (27), 163 (16), 148 (11), 127 (32), 69 (100), 39 (5).
Yield: 445 mg (98%, 1.9 mmol); yellow oil.
1
Н NMR (300 MHz, CDCl ): δ = 7.8 (dd, J = 8.4, 4.8 Hz, 1 Н), 8.0 (dd, J =
.4, 1.2 Hz, 1 Н), 9.0 (m, 2 Н).
3,5-Dibromopyridine-2,6-diyl Bis(trifluoromethanesulfonate)
(2m)
3
8
13
С NMR (75 MHz, CDCl ): δ = 118.5 (q, J = 319 Hz), 124.6, 128.9,
Yield: 458 mg (43%, 0.86 mmol); white solid; mp 64–65 °С.
3
1
42.7, 146.6, 149.4.
1
H NMR (400 MHz, CDCl ): δ = 8.44 (s).
3
+
MS (EI): m/z (%) = 227 (100, [M] ), 163 (36), 135 (5), 116 (4), 94 (25),
13
C NMR (100.6 MHz, CDCl ): δ = 112.2, 118.5 (q, J = 321.1 Hz), 149.3,
3
78 (20), 69 (69), 39 (64).
1
50.4.
MS (EI): m/z (%) = 533 (24, [81Br, M] ), 455 (2), 405 (4), 368 (2), 324
(
(
+
2
-Chloropyridin-3-yl Trifluoromethanesulfonate (2h)5
14), 308 (41), 280 (22), 251 (31), 213 (17), 160 (18), 144 (12), 130
14), 116 (8), 69 (100), 51 (8), 37 92).
Yield: 472 mg (90%, 1.8 mmol); yellow oil.
1
Н NMR (300 MHz, CDCl ): δ = 7.4 (dd, J = 8.3, 4.5 Hz, 1 Н), 7.7 (d, J =
3
Anal. Calcd for C HBr F NO S : C, 15.77; H, 0.19; N, 2.63; S, 12.03.
7 2 6 6 2
Found: C, 16.03; H, 0.33; N, 2.63; S, 12.20.
8.1 Hz, 1 Н), 8.4 (d, J = 4.5 Hz, 1 Н).
13
С NMR (75 MHz, CDCl ): δ = 118.4 (q, J = 319 Hz), 123.8, 131.4,
3
142.7, 144.1, 148.7.
3,5-Difluoropyridine-2,6-diyl Bis(trifluoromethanesulfonate) (2n)
MS (EI): m/z (%) = 261 (50, [35Cl, M] ), 197 (23), 169 (4), 150 (2), 128
+
Yield: 411 mg (50%, 1 mmol); yellow oil.
(11), 100 (100), 69 (68), 39 (48).
1
H NMR (400 MHz, CDCl ): δ = 7.77–7.80 (m).
3
1
3
C NMR (100.6 MHz, CDCl ): δ = 118.6 (q, J = 321 Hz), 119.18–119.61
3
Pyridin-4-yl Trifluoromethanesulfonate (2i)5
(m), 135.68–135.89 (m), 149.4 (dd, J = 272.6, 5.2 Hz).
Yield: 331 mg (73%, 1.46 mmol); light yellow oil.
+
MS (EI): m/z (%) = 411 (7, [M] ), 379 (1), 342 (1), 326 (1), 300 (1), 283
(3), 262 (3), 236 (1), 214 (1), 198 (5), 198 (43), 167 (5), 154 (10, 141
1
Н NMR (300 MHz, CDCl ): δ = 7.2 (d, J = 5.7 Hz, 2 H), 8.7 (d, J = 5.7 Hz,
3
2
Н).
(2), 129 (24), 117 (7), 101 (17), 89 (9), 69 (100), 48 (2), 31 (2).
13
С NMR (75 MHz, CDCl ): δ = 116.1, 118.3 (q, J = 334 Hz), 152.3,
3
Compound 2n according to GC/MS data was contaminated with about
5
m/z (%) = 411 (7, [M] ), 379 (1), 342 (1), 326 (1), 300 (1), 283 (3), 262
155.9.
% of 3,5-difluoropyridin-2-yl trifluoromethanesulfonate [MS (EI):
+
+
MS (EI): m/z (%) = 227 (100, [M] ), 163 (18), 136 (5), 109(2), 94 (17),
77 (13), 69 (87), 39 (25).
(3), 236 (1), 214 (1), 198 (5), 198 (43), 167 (5), 154 (10, 141 (2), 129
(24), 117 (7), 101 (17), 89 (9), 69 (100), 48 (2), 31 (2)].
3
,5-Dibromopyridin-2-yl Trifluoromethanesulfonate (2j)
Quinolin-2-yl Trifluoromethanesulfonate (5)2h
5
Yield: 573 mg (75%, 1.4 mmol); yellow solid; mp 100–101 °C (Lit. mp
100 °C).
Yield: 460 mg (83%, 1.66 mmol); light yellow oil.
1
1H NMR (300 MHz, CDCl
Н NMR (300 MHz, CDCl ): δ = 8.2 (d, J = 2.1 Hz, 1 Н), 8.4 (d, J = 2.1 Hz,
3
): δ = 7.18 (d, J = 8.7 Hz, 1 H), 7.54–7.59 (m, 1
3
1
Н).
H), 7.71–7.76 (m, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H),
8.25 (d, J = 8.7 Hz, 1 H).
13
С NMR (75 MHz, CDCl ): δ = 111.7, 118.3 (q, J = 319 Hz), 120.1,
3
13C NMR (75 MHz, CDCl
): δ = 112.9, 120.8 (q, J = 318 Hz), 127.5,
145.9, 147.6, 151.7.
3
MS (EI): m/z (%) = 385 (35, [81Br, M] ), 321 (8), 293 (75), 252 (10), 224
+
128.5, 131.1, 141.9, 145.6, 153.5.
+
(67), 197 (25), 172 (12), 144 (10), 118 (35), 69 (100), 37 (25).
MS (EI): m/z (%) = 277 (26, [M] ), 249 (1), 213 (14), 185 (32), 166 (4),
1
5
44 (16), 128 (20), 116 (100), 101 (5), 89 (23), 75 (5), 69 (27), 64 (18),
1 (5), 39 (7).
Pyridine-2,6-diyl Bis(trifluoromethanesulfonate) (2k)
Yield: 457 mg (61%, 1.22 mmol); yellow solid; mp 32–33 °C.
Diazotization-Iodination of 3- and 6-Quinoline Amines 4b,c; Gen-
eral Procedure
1
H NMR (300 MHz, CDCl ): δ = 7.32 (d, J = 8.1 Hz, 2 H), 8.11–8.15 (m, 1
3
H).
To a solution of hexane (5 mL), DMSO (0.5 mL), and trifluoromethane-
sulfonic acid (0.54 mL, 6 mmol) at 5 °C were sequentially added the
13
C NMR (100.6 MHz, CDCl ): δ = 116.1, 118.7 (q, J = 319.0 Hz), 145.4,
3
153.4.
quinoline amine 4b or 4c (2 mmol) and NaNO (350 mg, 5 mmol) un-
2
+
MS (EI): m/z (%) = 375 (11, [M] ), 283 (2), 247 (2), 219 (10), 180 (7),
der stirring, and the mixture was stirred for 10 min. The resulting
mixture was then stirred for 50 min at r.t. until the starting amine
150 (82), 122 (8), 93 (54), 69 (100), 39 (12).
had been consumed as monitored by TLC. An emission of N bubbles
was not observed and the reaction solution gave the positive probe
Anal. Calcd for C H F NO S : C, 22.41; H, 0.81; N, 3.73; S, 17.09.
Found: C, 22.9; H, 0.79; N, 4.06; S, 17.90.
2
7
3
6
6 2
on diazonium salts with β-naphthol. Next, KI (2.4 mmol) in H O (0.5
2
mL) was added and the mixture was stirred 10 min at r.t. until evolu-
3
,5-Diiodopyridine-2,6-diyl Bis(trifluoromethanesulfonate) (2l)
Yield: 702 mg (56%, 1.12 mmol); white solid; mp 128 °C (Lit.5 mp
28 °C).
tion of N bubbles ceased. In the case of 4b, the solid 3-iodoquinoline
2
6
obtained was filtered, washed with H O, and dried. In the case of 3c,
2
1
the reaction mixture was poured into H O and the oily product 7 was
2
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2
61
Synthesis
A. Z. Kassanova et al.
Paper
extracted with EtOAc (2 × 25 mL). The combined organic extracts
were dried (Na SO ), filtered, and the solvent was removed under re-
duced pressure on a rotary evaporator. The product 7 was purified by
Pyridin-4-yl 4-Methylbenzenesulfonate (8c)
Yield: 349 mg (70%, 1.4 mmol); white solid; mp 152–153 °C (Lit. mp
4
2
4
150–154 °C).
silica gel flash chromatography (eluent: CH Cl ).
2
2
1
Н NMR (300 MHz, CDCl ): δ = 2.44 (s, 3 H), 7.0 (d, J = 4.9 Hz, 2 H), 7.3
3
(
1
d, J = 8.1 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H), 8.55 (d, J = 3 Hz, 2 H).
3
-Iodoquinoline (6)
3
C NMR (75 MHz, CDCl ): δ = 21.6, 116.9, 128.2, 129.9, 131.7, 145.9,
3
Yield: 403 mg (79%, 1.27 mmol); white solid; mp 58–59 °C (Lit.10 mp
1
51.6, 156.2.
56–58 °C).
+
MS (EI): m/z = 249 (44, [M] ), 185 (13), 169 (2), 155 (75), 149 (2), 139
1
Н NMR (300 MHz, CDCl ): δ = 7.53–7.58 (m, 1 H), 7.68–7.75 (m, 2 H),
3
(
(
2), 129 (2), 115 (2), 107 (2), 91 (100), 82 (2), 77 (3), 65 (25), 57 (2), 51
3), 39 (9).
8.06 (d, J = 8.4 Hz, 1 H), 8.53 (s, 1 H), 9.03 (s, 1 H).
+
MS (EI): m/z (%) = 255 (100, [M] ), 128 (80), 101 (36), 75 (21), 51 (9).
Pyridine-2,6-diyl Bis(4-methylbenzenesulfonate) (8d)
Yield: 567 mg (68%, 1.48 mmol); white solid; mp 80–81 °C (Lit.4 mp
80 °C).
6
-Iodoquinoline (7)
Yield: 403 mg (79%, 1.27 mmol); yellow solid; mp 91–92 °C (Lit.11 mp
9
1 °C).
1
Н NMR (300 MHz, CDCl ): δ = 2.45 (s, 6 H), 7.01 (d, J = 7.8 Hz, 2 H),
3
1
Н NMR (300 MHz, CDCl ): δ = 7.39 (dd, J = 7.8, 4.2 Hz, 1 H), 7.81 (d, J =
7.32 (d, J = 8.1 Hz, 4 H), 7.79–7.84 (m, 5 H).
3
8
.7 Hz, 1 H), 7.92 (d, J = 9 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 8.18 (s, 1
13
С NMR (75 MHz, CDCl ): δ = 21.7, 114.2, 128.7, 129.8, 133.1, 143.4,
3
H), 8.89 (d, J = 4.2 Hz, 1 H).
145.6, 154.8.
+
MS (EI): m/z (%) = 255 (100, [M] ), 128 (54), 101 (25), 75 (13), 51 (7).
+
MS (EI): m/z (%) = 355 (6, M – SO ), 327 (2), 291 (3), 274 (2), 263 (2),
2
2
7
00 (25), 184 (3), 165 (2), 155 (59), 139 (5), 129 (1), 107 (2), 91 (100),
7 (2), 65 (16), 39 (5).
Pyridinyl 4-Methylbenzenesulfonates 8a–d: General Procedure
To a solution of hexane (5 mL), DMF (0.5 mL), and p-toluenesulfonic
acid (1.14 g, 6 mmol) at 5 °C were sequentially added the respective
aminopyridine 1a,g,i (2 mmol) and NaNO2 (350 mg, 5 mmol) under
stirring and the mixture was stirred for 10 min. An immediate emis-
Acknowledgment
sion of N bubbles was observed. In the case of diamino derivative 1k,
The authors gratefully acknowledge the Russian Scientific Fund (Proj-
ect No. 15-13-10023) supported the synthesis of pyridine derivatives
2a–n. Part of this work was supported by the Russian Foundation for
Basic Research (Project No. 14-03-00743a). E.A.K. acknowledges the
Scientific Program ‘Nauka’ (No 2387), V.F. acknowledges the Scientific
Program ‘Nauka’ (No 4.1991.2014 K). The analytical experiments
were performed by the scientific equipment network center of TPU.
2
double amounts of NaNO and TsOH were used. The resulting mixture
2
was then stirred for 50 min at r.t. until the starting amines had been
consumed as monitored by TLC. The reaction mixture was poured
into H O and extracted with EtOAc (2 × 25 mL). The combined organic
2
extracts were dried (Na SO ), filtered, and the solvent was removed
2
4
on a rotary evaporator under reduced pressure. The products 8a–d
were purified by crystallization from hexane.
Pyridin-2-yl 4-Methylbenzenesulfonate (8a)4
Supporting Information
Yield: 264 mg (53%, 1.06 mmol); colorless oil.
Supporting information for this article is available online at
1
Н NMR (300 MHz, CDCl ): δ = 2.45 (s, 3 H), 7.1 (d, J = 8.1 Hz, 1 H),
http://dx.doi.org/10.1055/s-0035-1561272.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
3
7.19–7.23 (m, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.74–7.79 (m, 1 H), 7.89
(d, J = 7.8 Hz, 2 H), 8.26 (d, J = 4.8 Hz, 1 H).
13
References
С NMR (75 MHz, CDCl ): δ = 21.6, 115.8, 122.5, 128.4, 129.5, 133.4,
3
1
40.0, 145.1, 148.2, 156.7.
(
1) (a) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058.
b) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett.
001, 3, 3049. (c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
d) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005,
70, 9364. (e) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
3848. (f) Pschierer, J.; Plenio, H. Eur. J. Org. Chem. 2010, 2934.
g) Lin, W.; Chen, L.; Knochel, P. Tetrahedron 2007, 63, 2787.
h) Sergeev, M. E.; Morgia, F.; Lazari, M.; Wang, C.; van Dam, R.
+
MS (EI): m/z (%) = 249 (2, [M] ), 184 (78), 166 (2), 157 (31), 139 (3),
(
2
129 (3), 115 (3), 102 (1.5), 91 (100), 78 (9), 65 (25), 57 (2), 51 (3), 39
(13).
(
Pyridin-3-yl 4-Methylbenzenesulfonate (8b)
1
(
(
Yield: 250 mg (50%, 1.0 mmol); white solid; mp 79–80 °C (Lit.[4] mp
80 °C).
1
Н NMR (300 MHz, CDCl ): δ = 2.43 (s, 3 H), 7.25–7.32 (m, 3 H), 7.42–
3
M. J. Am. Chem. Soc. 2015, 137, 5686. (i) Lin, C.-P.; Florio, P.;
Campi, E. M.; Zhang, C.; Fredericks, D. P.; Saito, K.; Jackson, W.
R.; Hearn, M. T. W. Tetrahedron 2014, 70, 8520.
7.46 (m, 1 H), 7.68 (d, J = 7.8 Hz, 2 H), 8.1 (d, J = 1.8 Hz, 1 H), 8.47 (d, J =
4
.8 Hz, 1 H).
13
C NMR (75 MHz, CDCl ): δ = 21.7, 124.2, 128.4, 130.0, 130.2, 131.4,
3
(2) (a) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63,
0048. (b) Kim, H.; Lee, K.; Lee, P. H.; Kim, S. Chem. Commun.
143.9, 145.9, 146.3, 148.2.
1
+
MS (EI): m/z (%) = 249 (34, [M] ), 182 (2), 167 (2), 155 (78), 149 (2),
2010, 6341. (c) Nicolaou, K. C.; Kiappes, J. L.; Tian, W.; Gondi, V.
B.; Becker, J. Org. Lett. 2011, 13, 3924. (d) Seganish, W. M.;
DeShong, Ph. J. Org. Chem. 2004, 69, 1137. (e) Hammoud, H.;
Schmitt, M.; Bihel, F.; Antheaume, C.; Bourguignon, J.-J. J. Org.
Chem. 2012, 77, 417. (f) Du, G.; Moulin, E.; Jouault, N.; Buhler,
139 (2), 102 (2), 91 (100), 83 (2), 77 (3), 65 (25), 57 (2), 51 (3), 39 (17).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 256–262

2
62
Synthesis
A. Z. Kassanova et al.
Paper
E.; Guiseppone, N. Angew. Chem. Int. Ed. 2012, 51, 12504.
g) Maloney, K. M.; Nwakpuda, E.; Kuethe, J. T.; Yin, J. J. Org.
Chem. 2009, 74, 5111. (h) Bissember, A. C.; Banwell, M. G. J. Org.
Chem. 2009, 74, 4893.
(6) (a) Filimonov, V. D.; Trusova, M. E.; Postnikov, P. S.;
Krasnokutskaya, E. A.; Lee, Y. M.; Hwang, H. Y.; Kim, H.; Ki-
Whan, C. Org. Lett. 2008, 10, 3961. (b) Krasnokutskaya, E. A.;
Semenischeva, N. I.; Filimonov, V. D.; Knochel, P. Synthesis 2007,
81. (c) Kutonova, K. V.; Trusova, M. E.; Postnikov, P. S.;
Filimonov, V. D.; Parello, J. Synthesis 2013, 45, 2706.
(7) Butler, R. N. Chem. Rev. 1975, 75, 241.
(
(
3) Wentworth, A. D.; Wentworth, P.; Mansoor, U. F.; Janda, K. D.
Org. Lett. 2000, 2, 477.
4) Tretyakov, A. N.; Krasnokutskaya, E. A.; Gorlushko, D. A.;
Ogorodnikov, V. D.; Filimonov, V. D. Tetrahedron Lett. 2011, 52,
(
(8) Oger, N.; Le Grognec, E.; Felpin, F.-X. J. Org. Chem. 2014, 79,
8255.
85.
(
5) Krasnokutskaya, E. A.; Kassanova, A. Z.; Estaeva, M. T.;
(9) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571.
Filimonov, V. D. Tetrahedron Lett. 2014, 55, 3771.
(
(
10) Boganyi, B.; Kaman, J. Tetrahedron 2013, 69, 9512.
11) Ullmann, F. Justus Liebigs Ann. Chem. 1904, 332, 38.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 256–262