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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Mechanism Problems from Reactions Give Expected Products198
8.42 (s, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.52–4.48 (m, 4H), 4.36 (q, J = 7.1 Hz, 2H),
3.32–3.30 (m, 2H), 2.88–2.85 (m, 2H), 1.47–1.44 (m, 6H), 1.38 (t, J = 7.1 Hz, 3H);
13
CNMR (CDCl
3
, 150 MHz) δ 168.3, 165.1, 161.0, 160.6, 143.8, 130.6, 128.1, 128.0,
127.0, 125.6, 125.2, 113.2, 63.4, 62.4, 61.0, 35.0, 21.1, 14.8, 14.7, 14.5; IR (film) ν
max
3328, 2981, 1709, 1368, 1251, 1227, 1186, 1098, 1022, 768 cm
–1
; HRMS (ESI-TOF)
m/z 387.1522 (C
20
H
22
N
2
O
6
+ H
+
requires 387.1551).
The Mechanism
The first stage is a Diels-Alder cycloaddition, followed by the extrusion of nitrogen
gas. The final stage involves the elimination of pyrrolidine. Due to its strong
hydrogen-bond-donating and Lewis acidic properties, HFIP forms hydrogen bonds
with the 1,2,3-triazine, thereby activating it for the cycloaddition. In the final
step, the acidity of HFIP may protonate the pyrrolidine moiety, thus promoting its
elimination.
N
HN
N
N
N
CO
2
Et
EtO
2
C
1
2
+
HFIP, 60 °C
24 h
95%
HN
3
N
1. DDQ, benzene
2. NaIO
4
, RuO
2
3. LiOH
59% 3 steps
HN
4, Methoxatin
N
HO
2
C
O
O
HO
2
C
CO
2
Et
EtO
2
C
EtO
2
C
CO
2
Et
CO
2
H
N
N
N
CO
2
Et
EtO
2
C
1
N
HN
2
+
[4+2]
N
HN
R
N
N
N
R
R
N
2
HN
R
N
N
H
R
R
R
=
CO2Et
HN
3
N
H
NH
F
O
F
F
F
F
H
HFIP
O
CH(CF
3
)
2
CO
2
Et
EtO
2
C
EtO
2
C
CO
2
Et
4.6 Formation of Monocyclic Aromatic Heterocycles 199
Problem 70: Preparation of Multisubstituted Pyridine
Recently, Chen et al. reported selective synthesis of poly-substituted
fluorine-containing pyridines and dihydropyrimidines via cascade C─F bond
cleavage protocol [192, 193]. As shown in the following representative example,
benzylamine (2) reacted with 1,1,1-trifluoro-N,4-diphenylbut-3-yn-2-imine (1) in
the presence of Cs
2
CO
3
in refluxing THF to give the 2,4,5,6-tetrasubstituted pyri-
dines (3) in high yield. However, when the reaction was carried out at 80 °C without
a base, the uncyclized vinylogous amidine (4) was obtained. Upon addition of a base
(Cs₂CO₃ or t-BuOK), continued heating of the reaction mixture at 80 °C also yielded
pyridine (3). In contrast, lowering the temperature to 40 °C resulted exclusively in
the formation of dihydropyrimidine (5).
The above methodology had been applied to the synthesis of Rinskor by Johnson
[194]. Rinskor is a new 6-arylpicolinate herbicide that is used for postemergent con-
trol of grass, broadleaf, and sedge weeds in rice and other crops. In Johnson’s paper,
the core multisubstitued pyridine 8 was prepared from 6 and 7, which was further
transferred to Rinskor in four steps.
Please provide a mechanism for the formation of 3 and 5.
Ph NH
2
+
N
Ph
F
F
F
Ph
2 (3 eq.)
1
THF
Cs
2
CO
3
80 °C
N
F
Ph Ph
HN
Ph
3
98%
THF, 80 °C
PhF
3
C
N
Ph
HN Ph
4
THF, t-BuOK, 80 °C
N
F
Ph Ph
HN
Ph
3 (47%)
+
N
N
Ph
Ph
PhF
F
H
5 (53%)
THF, t-BuOK
–40 °C
5 (98%)
NH
2
F
MeO
Cl
+
N
OEt
OEt
F
F
F
Ph
Ph
Ph
6
7
Cs
2
CO
3
DMSO
80 °C, 2 h
73%
N
F
MeO
Cl
8
F
HN
OEt
OEt
Ph
Ph
Ph
N
F
MeO
Cl
Rinskor
F
OBn
O
Cl
4 steps
NH
2
4 Mechanism Problems from Reactions Give Expected Products200
Experimental Procedure (from Org. Biomol. Chem., 2011, 9, 5682)
Representative Procedure for Pyridine 3 Synthesis. Alkynylimine 1 (0.4 mmol)
was added to a solution of amines 2 (3 equiv.), Cs
2
CO
3
(2.5 equiv.) in THF (2.0 mL).
The solution was then stirred at 80 °C. After completion of reaction as indicated by
TLC, the reaction crude was filtered and the filtrate evaporated. The residue was
purified by flash chromatography on silica gel to provide the desired product 3.
3-Fluoro-N,2,6-triphenylpyridin-4-amine (3a). White solid, mp 127–129 °C;
1
HNMR (300 MHz, CDCl
3
) δ 8.02 (d, J = 7.1 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H),
7.56–7.14 (m, 12H), 6.34 (d, J = 3.3 Hz, 1H);
19
FNMR (282 MHz, CDCl
3
) δ152.37;
13
CNMR (100 MHz, CDCl
3
) δ 153.3 (d, J = 5.9 Hz), 146.9 (d, J = 253.1 Hz), 144.0 (d,
J = 8.1 Hz), 140.6 (d, J = 10.2 Hz), 139.5, 139.2, 136.0 (d, J = 5.1 Hz), 129.8, 129.0,
129.0 (d, J = 5.9 Hz), 128.7, 128.6, 128.4, 127.0, 124.7, 122.2, 104.3; LRMS (EI) m/z
(relative intensity) 340 (99) [M
+
], 39 (100); Anal. Calcd for C
23
H
17
FN
2
: C, 81.16; H,
5.03; N, 8.23. Found: C, 80.89; H, 5.14; N, 8.15. IR (KBr): 3409, 3060, 1610, 1595,
1579, 1514, 1498, 1466, 1409, 1242, 694 cm
1
.
Procedure for 4a Synthesis. 1a (0.4 mmol) and benzylamine (2 equiv.) were
added to 2.0 mL THF, the mixture was stirred at 80 °C for two hours. Then the sol-
vent was evaporated, and the residue was purified by flash chromatography on
silica, providing 4a as a yellow solid in quantitative yield. Mp 76–77 °C;
1
HNMR
(300 MHz, CDCl
3
) δ 11.28 (br, 1H), 7.46–6.79 (m, 15H), 5.24 (s, 1H), 4.40 (s, 2H);
19
FNMR (282 MHz, CDCl
3
) δ − 62.63;
13
C NMR (100 MHz, CDCl
3
) δ 163.0, 152.6
(q, J = 26.4 Hz), 149.1, 139.0, 135.9, 129.5, 128.7, 128.6, 128.4, 128.0, 127.3, 126.6,
123.1, 120.3, 119.0 (q, J = 290.5 Hz), 89.9 (q, J = 3.7 Hz), 48.4; HRMS-ESI (m/z):
C
23
H
20
F
3
N
2
[M + H]
+
calcd 381.15731; found 381.15759; IR (KBr): 3029, 2927, 1616,
1554, 1483, 1281, 1231, 1182, 1137, 1089, 695 cm
1
.
Representative Procedure for Dihydropyrimidine 5 Synthesis. 1 (0.4 mmol)
and amine (2 equiv.) were added to 2.0 mL THF, the mixture was stirred at 80 °C for
two hours, and then cooled to –40 °C (room temperature for 5q, 5w), and t-BuOK
(2.0 equiv.) was added slowly, and quenched with ice water after 5 min. The mixture
was partitioned between ethyl acetate and water, the organic layer was washed with
brine, dried over MgSO
4
, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel to provide 5.
6-(Difluoromethyl)-1,2,4-triphenyl-1,2-dihydropyrimidine (5a) Yellow solid,
mp 106–107 °C;
1
HNMR (300 MHz, CDCl
3
) δ 7.96–7.85 (m, 2H), 7.64 (d, J = 7.5 Hz,
2H), 7.50–7.11 (m, 11H), 6.64 (s, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.28 (t, J = 54.4 Hz,
1H);
19
FNMR (282 MHz, CDCl
3
) δ112.22 (dd, J
F–F
= 301.3 Hz, J
H-F
= 55.5 Hz,
1F), 121.41 (dd, J
F–F
= 301.2 Hz, J
H–F
= 53.5 Hz, 1F);
13
CNMR (100 MHz, CDCl
3
)
δ 160.1, 143.7, 142.9 (dd, J = 27.9 Hz, J = 22.0 Hz), 140.6, 137.2, 130.5, 129.6, 128.6,
128.3, 128.1, 127.2, 126.5, 126.4, 124.7, 110.2 (t, J = 242.1 Hz), 103.1 (t, J = 5.1 Hz),
79.8; HRMS-ESI (m/z): C
23
H
19
F
2
N
2
[M + H]
+
calcd 361.15108; found 361.14966;
IR (KBr): 3060, 3032, 2925, 1629, 1580, 1492, 1446, 1376, 1352, 1264, 1125, 1047, 765,
695 cm
1
.
The Mechanism
The first step involves the hydroamination of alkynylimine 1 with amine 2, form-
ing the intermediate vinylogous amidine 4. This is followed by deprotonation and
4.6 Formation of Monocyclic Aromatic Heterocycles 201
dehydrofluorination, generating a molecule (A) that contains both an anion and
an imine. When the reaction is carried out at a low temperature with a soluble
base (t-BuOK) (path a), the in situ generated amide (B) nucleophilic attacks the
imine immediately without isomerization to form dihydropyrimidine (E) through
a kinetically controlled pathway. After proton migration, the dihydropyrimidine
(5) is produced. However, at elevated temperatures (path b), carbon nucleophilic
addition becomes favorable, leading to the formation of a 1,2-dihydropyridine ring
(C) under thermodynamic control. Subsequent proton migration, β-F elimination
(to D) and final aromatization to a pyridine ring provide additional driving force
for the formation of 3. Meanwhile, the use of an insoluble base (Cs
2
CO
3
) effectively
suppresses the kinetic pathway.
Problem 71: Preparation of 4-Perfluoroalkylpyridines
The incorporation of polyfluoroalkyl groups into organic molecules can improve
metabolic stability, lipophilicity, and conformational properties, thereby endow-
ing these compounds with advantageous physicochemical characteristics that are
highly valuable in medicinal chemistry. For instance, compound 1 has been uti-
lized in the treatment of central nervous system disorders [195], while compound 2
has been employed as an antifungal agent [196]. Consequently, the development of
efficient and straightforward synthetic methods for polyfluoroalkyl pyridine deriva-
tives is of significant importance in both organic synthesis and medicinal chemistry.
Recently Wang and Weng’s group described the perfluorocarboxylic anhydrides
(3) and enamide (4) triggered cyclization to 2,6-diaryl-4-perfluoroalkylpyridines (5)
in one step [197].
Please provide a mechanism for the reaction.
1
3
N
Ph
F
F
F
Ph
2
Ph
Ph N
F
N
Ph
F
F
H N
F
Ph
F
F
Ph
Ph N
F
HN
Ph
Ph
Ph N
F
Ph
F
Ph
Ph N
H
F
N
Ph
F
H
Cs
2
CO
3
CsF
Base
Ph
Ph
Ph
4
A
B
H
Ph N
H
F
N
Ph
Ph
Base
HF
Ph N
Ph
Ph
F
B
F
Ph N
N
Ph
Ph
F F
H
H
+
Ph N
N
Ph
Ph
F F
H
5
Path a
Path b
C
D
E
N
–
N
–
B
–
B
–
N
–
NH
2
4 Mechanism Problems from Reactions Give Expected Products202
Experimental Procedure (from J. Org. Chem., 2019, 84, 14926)
General Procedure for the Synthesis of 4-Polyfluoroalkylpyridines. The
N-(1-phenylvinyl)acetamide derivatives (4) (1.0 mmol, 1.0 equiv), perfluorocarbox-
ylic anhydride (3, 1.50 mmol, 1.5 equiv), and 1,2-dichloroethane (DCE) (4.0 mL)
were added to a 5 mL reaction tube with a Teflon screw cap equipped with a stir bar.
The mixture was stirred at the required temperature (60120 °C) in an oil bath for
24 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with
saturated NaHCO
3
(30 mL) and saturated brine (30 mL). The organic phase was
dried over MgSO
4
. The solvent was removed by rotary evaporation and the resulting
4-polyfluoroalkylpyridine product was purified by column chromatography over a
silica gel.
2,6-Diphenyl-4-(trifluoromethyl)pyridine (5a). Obtained as a white solid in
65% yield (97 mg). Mp: 81.782.5 °C. R
f
(n-pentane/ethyl acetate = 40:1) = 0.40.
1
HNMR (400 MHz, CDCl
3
): δ 8.23 (d, J = 7.4 Hz, 4H), 7.93 (s, 2H), 7.657.46 (m,
6H).
19
FNMR (376 MHz, CDCl
3
): δ 64.6 (s, 3F).
13
C
{
1
H
}
NMR (101 MHz, CDCl
3
):
δ 158.2 (s), 140.0 (q, J = 33.4 Hz), 138.2 (s), 129.9 (s), 128.9 (s), 127.2 (s), 123.3 (q, J =
273.3 Hz), 114.0 (q, J = 3.5 Hz). IR (ATR): ν 3046, 2921, 2851, 1611, 1567, 1461, 1413,
1367, 1263, 1166, 1116, 1049, 873, 769, 687 cm
1
. GC-MS m/z: [M]
+
299.
The Mechanism
Initially, the nucleophilic attack on the carbonyl of TFAA by the double bond of the
enamide would form intermediate A, which smoothly undergoes β-H elimination
to furnish intermediate B. Subsequently, the second nucleophilic attack on the car-
bonyl of B, which is much more electrophilic than the carbonyl of the acetamide,
generates C, which is then poised to undergo a 6-endo cyclization, generating the
intermediate D. Finally, the elimination of AcNH
2
and H
2
O, and deacylation under
acidic condition (the TFA is released from the first stage) from D furnishes the
desired perfluoroalkylated product 3.
N
N
S
O
O
1
N
N
H
O
NH
2
2
CF
3
CF
3
CF
3
NH
2
Ph N
H
O
+
F
3
C
O CF
3
O O
DCE, 80 °C
24 h
65%
NPh Ph
CF
3
4
3
5
4.6 Formation of Monocyclic Aromatic Heterocycles 203
It could also be possible that the second enamide 4 attacks intermediate B
in a Michael addition manner. While, this pathway would lead to the isomer,
2,4-diphenyl-6-(trifluoromethyl)pyridine I, that was not reported in Wang’s paper
[ 197 ].
Problem 72: C-2 Amination of Pyridine
The 2-aminopyridine motif is a key structural feature found in numerous pharma-
ceuticals [ 198 ], including lemborexant, used to treat insomnia, and lasmiditan, a
medication for migraines. Recently, Fier and colleagues developed a regioselective
C2 amination of pyridines using tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)
carbamate ( 2) as an amino source [ 199 ]. For instance, pyridine was successfully
converted to tert-butyl pyridin-2-ylcarbamate ( 3) with a high yield of 93%. This
approach falls under the category of late-stage C─H functionalization, a strategy
increasingly applied to optimize pharmaceutical compounds [ 200 ]. As an example,
2- N-Boc amino roflumilast was synthesized from Roflumilast in 42% yield [ 201 ].
These innovative methodologies provide medicinal chemists with efficient and
resource-effective tools to access novel analogs of bioactive compounds, signifi-
cantly advancing drug discovery efforts.
Ph N
O
F
3
C
O CF
3
O O
H
Ph N
O
O
H
TFA
Ph NH
O
O
Ph
N
O
H
Ph NH
O
HO
N
Ac
Ph
N
Ph Ph
Ac
HN
Ac
HO
H
AcNH
2
NPh Ph
O
+
O
O
O
H
OAc
O
+
H
2
O
N
Ph Ph
A
B
C
D
TFA
H
H
4
3
5
TFA
+
HOAc
4
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
F
3
C
Ph NHAc
O
CF
3
Ph
N
Ac
H
4
Ph
HN
HO
Ph
Ac
N Ac
Ph
HN
O
Ph
Ac
HN Ac
B
E
F
Ph
HN
HO
Ph
Ac
N
Ac
G
H
Ph
O
+
Ph
N
H
AcNH
2
O
OAc
F
3
C
O
+
H
2
O
N
Ph Ph
TFA
TFA
+
HOAc
H
H
O
O
H
I
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
4 Mechanism Problems from Reactions Give Expected Products204
Please provide a mechanism for the formation of 3 from 1 and 2.
Experimental Procedure (from J. Am. Chem. Soc., 2020, 142, 8614, Supporting
Information)
General Procedure for the C-2 Functionalization of Pyridines. To a screw
cap vial with a magnetic stirbar was added pyridine substrate (1, 1.0 equiv),
N,O-bis(trimethylsilyl)acetamide (3.0 equiv), and anhydrous dioxane (4 mL per
mmol of 1; 0.25 M). To the resulting mixture was added solid 2 (1.5 equiv), then
the vial was sealed and heated at 80 °C for 3 h. The reaction mixture was cooled
to ambient temperature, diluted with glacial AcOH (4 mL per mmol of 1, equal
volume as dioxane), and Zn powder (5.0 equiv) was added at once (note: a mild exo-
therm was observed on 5 mmol scale). The resulting slurry was stirred vigorously
for 3 h at ambient temperature. The mixture was concentrated to dryness, and the
product was purified on silica gel. For cases where assay yields of the products were
determined, the entire reaction mixture was diluted in a volumetric flask with 3:1
MeCN: 0.1% aqueous H
3
PO
4
and the resulting solution was analyzed on an HPLC
instrument calibrated to the product using the method shown below.
tert-Butyl pyridin-2-ylcarbamate (3). The compound was prepared using the
standard procedure on 0.5 mmol scale. The assay yield was determined by HPLC
to be 93% based on calibration with an authentic standard. NMR data for in situ
characterization at the end of reaction in 1:1 1,4-dioxane-d
8
/ CD
3
COOD is provided
below.
1
HNMR (600 MHz, 1:1 1,4-dioxane-d
8
/ CD
3
COOD) δ 8.28 (ddd, J = 5.6, 1.9,
N
H
N
Lasmiditan
O F
F F
O
N
N
F
N
H
O
H
O
N
N
F
Lemborexant
N
+
N
N
Cl
O
H
N
Boc
NC
NC
1
2
1. BSA (3 eq.)
dioxane, 80 °C, 3 h
2. Zn-HOAc, rt, 3 h
93%
N
3
NHBoc
N
Roflumilast
1. 2 (1.5 eq.)
BSA (3 eq.)
dioxane, 80 °C, 3 h
2. Zn-HOAc, rt, 3 h
42%
Cl
Cl
NHO
OF
F
O
N
2-Boc-aminoroflumilast
Cl Cl
NHO
OF
F
O
NHBoc
4.6 Formation of Monocyclic Aromatic Heterocycles 205
and 0.8 Hz, 1H), 7.94 (ddd, J = 9.0, 7.4, and 1.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.19
(ddd, J = 7.0, 5.6, and 1.1 Hz, 1H), 1.45 (s, 9H).
13
CNMR (151 MHz, 1:1 1,4-dioxane-
d
8
/ CD
3
COOD) δ 154.6, 152.2, 145.3, 143.5, 120.2, 115.8, 84.3, 28.4.
The Mechanism
The pyrazine chloride 2 is attacked by pyridine to give the pyridinium chloride A .
Then cyclization occurs to provide the tricyclic intermediate B and HCl. N ,O-bis-
(trimethylsilyl)acetamide (BSA) promoted the desired reaction by scavenging HCl
through the generation of TMSCl. Ring opening of B yields the hydroxyl pyrazine
C which is protected by forming TMS ether D. Rearrangement of D via zwitterionic
intermediate E affords N-pyrazinyl N-Boc-2-aminopyridine F. Finally, reductive
cleavage of the pyrazinyl-N bond by zinc followed by acidic aqueous workup fur-
nishes the N-Boc-2-aminopyridine 3 .
Problem 73: C-2 Amination of Pyridine N-oxide Derivatives
Lumacaftor ( 3) is a cystic fibrosis transmembrane (CFTR) corrector utilized in the
treatment of cystic fibrosis. The combination therapy of lumacaftor and ivacaftor,
marketed under the brand name ORKAMBI
TM
, is specifically designed to treat
cystic fibrosis patients who are homozygous for the F508del mutation in the CFTR
conductance regulator gene. This mutation results in the production of a defective
protein that is responsible for the disease. Developed by Vertex Pharmaceuticals, the
lumacaftor/ivacaftor combination received FDA approval in 2015. The synthesis of
lumacaftor has been detailed in a series of patents and patent applications by Vertex
[ 202 ]. A key intermediate in the synthesis of lumacaftor is 2-aminopyridine ( 2).
N
N
N
Cl
O
H
N
Boc
NC
NC
1
2
N
N
O
N
Boc
NC
NC
H
Cl
–
HCl
N
N N
O
N
Boc
NC
NC
H
N
N
N
O
N
Boc
NC
NC
H
N
N
N
O
N
Boc
NC
NC
Me
3
Si
N
OSiMe
3
N
H
N
N
O
Boc
NC
NC
SiMe
3
Zn
N
N
O
NC
NC
N
N
Boc
N
N
OH
NC
NC
N
H
N
Boc
H
+
+ Me
3
SiOH + Zn(OAc)
2
Rearrangement
at 80 °C
N
N
Zn
O
NC
NC
N
N
Boc
N
N
–
O
NC
NC
N
N
Boc
3
H
2
O
HOAc
Zn
A
B
C
D
E
F
G
H
BSA
N
H
+
BSA
N
+
OSiMe
3
Me
3
SiCl
N
–
N
+
SiMe
3
OSiMe
3
SiMe
3
SiMe
3
SiMe
3
Zn
+
4 Mechanism Problems from Reactions Give Expected Products206
The C-2 amination of pyridine N-oxide (1) was accomplished using acetonitrile as
the amino source [202]. In a published study, 2-aminopyridine (2) was used as a
crucial building block for constructing analogs of lumacaftor by the research group
of S. G. Aller and M. Turlington [203]. Additionally, Hughes proposed a reaction
mechanism in a review article [204].
Would you be able to propose your own mechanism without referring to the
literature?
Experimental Procedure (from Chem. Eur. J., 2019, 25, 3662, Supporting
Information)
tert-Butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (2). 2-(3-(tert-Butoxycarbonyl)-
phenyl)-3-methylpyridine 1-oxide 1 (2.62 g, 9.2 mmol, 1 equiv) was dissolved in MeCN
(92 mL, 0.1 M). Pyridine (2.98 mL, 36.8 mmol, 4 equiv) was added, and the reac-
tion was then heated to 70 °C under nitrogen atmosphere. Ms
2
O (2.40 g, 13.8 mmol,
1.5 equiv) was dissolved in MeCN (23 mL) in a flame-dried pear flask, and was then
transferred to a flame-dried slow addition funnel and was added dropwise. After
addition, the reaction was stirred at 70 °C for 1.5 h. The reaction was then cooled to
room temperature and ethanolamine (5.55 mL, 92 mmol, 10 equiv) was added drop-
wise via slow addition funnel. After stirring at room temperature for 2 h, the reaction
was quenched with H
2
O (100 mL) and stirred for 30 min. The reaction mixture was
extracted with EtOAc (150 mL × 3), and the combined organic layers were dried with
dried with Na
2
SO
4
, filtered, and concentrated via rotary evaporation. Flash silica gel
column chromatography (100% hexanes to 50:50 hexanes/EtOAc) afforded the prod-
uct as a tan solid in 53% yield (1.43 g). R
f
= 0.62 (2:1 hexanes/EtOAc). IR (neat, cm
1
)
3438, 3177, 2971, 1698, 1628, 1487, 1295, 1139.
1
HNMR (400 MHz, CDCl
3
) δ 8.11
(t, 1H, J = 1.4 Hz), 8.00 (dt, 1H, J = 7.8, 1.4 Hz), 7.65 (dt, 1H, J = 8.2 and 1.4 Hz), 7.47
(t, 1H, J = 7.4 Hz), 7.34 (d, 1H, J = 8.4 Hz), 6.45 (d, 1H, J = 8.2 Hz), 4.47 (bs, 2H), 2.19
(s, 3H), 1.60 (s, 9H).
13
CNMR (100 MHz, CDCl
3
) δ 165.8, 156.4, 155.5, 141.1, 140.8,
133.0, 132.0, 130.0, 128.7, 128.1, 120.4, 107.9, 81.1, 28.3, 18.9. HRMS (TOF, ESI+, M)
for C
17
H
20
N
2
O
2
: calc. mass 284.1525, found 284.1529.
The Mechanism
First, the N-oxide 1 is activated by methanesulfonic anhydride to form intermediate
A. Subsequently, the nitrogen atom in acetonitrile attacks the α-carbon of A,
N
O
H
N
OH
O
O
O
F
F
N
+
CO
2
t-Bu
1
1. Ms
2
O, Py, CH
3
CN
70–75 °C
2. HOCH
2
CH
2
NH
2
53%
N
2
H
2
N
Steps
Lumacaftor (3)
CO
2
t-Bu
O
–
4.6 Formation of Monocyclic Aromatic Heterocycles 207
leading to the formation of intermediate B. Deprotonation and elimination of
methanesulfonate then restore the aromatic ring, generating intermediate C. The
addition of methanesulfonate to C produces imidate D. Upon the introduction of
ethanolamine, the methanesulfonate (MsO) group is displaced, resulting in the
formation of amidine E. Further cyclization of E followed by hydrolysis yields
2-aminopyridine 2 and acetamide F. Notably, when a bromo substituent is present
at the C-2 position of the pyridine N-oxide, C-4 amination is also observed [205].
When 2-bromo-3-methylpyridine-1-oxide (4) was employed as a substrate, C-4
amination was also observed [205].
Problem 74: Nucleophilic Cyanation of Pyridines
In 2017, P. S. Fier designed (Z)-N-((methylsulfonyl)oxy)acetimidoyl chloride (1)
assisted functionalization of pyridines [206]. As shown in the following reaction,
4-phenylpicolinonitrile (3) was prepared in 84%. This method was applied for the
synthesis of a mixed progesterone agonist/antagonist 5.
Could you please propose a mechanism for this reaction?
Experimental Procedure (from J. Am. Chem. Soc., 2017, 139, 9499, Supporting
Information)
General Procedure for the Conversion of Pyridines to 2-cyanopyridines. To
a screw cap vial was added pyridine (2, 1.0 equiv), 1 (1.1 equiv), sodium trifluo-
romethanesulfonate (NaOTf, 1.2 equiv), and MeCN (1.0 mL per mmol of 1). The
vial was sealed and heated at 80 °C with rapid stirring for 1–8 h. The reaction mix-
ture was cooled to room temperature and diluted with DMF (4 mL per mmol of 2),
N
+
CO
2
t-Bu
1
N
2
H
2
N
Ms
2
O
Ar
O
S
O
O
MsO
−
N
CH
3
CN
N
Ar
O
S
O
H
O
Py
N Ar
N Ar
N
OMs
OH
NH
2
N Ar
N
NH
HO
N Ar
N
O
NH
H
Hydrolysis
+
N
H
OH
O
A
B
C
D
E
F
PyH
+
MsO
−
O
−
N
+
N
+
MsO
−
N
+
MsO
−
CO
2
t-Bu
N
+
Br
4
1. TFAA, Py
CH
3
CN, 70 °C
N
Br
5 (49%)
H
2
N
2. HOCH
2
CH
2
NH
2
N Br
6 (6%)
NH
2
+
O
−