Organic Process Research & Development
Article
dynamics and gives 6-F1, which is more stable than 4-F1 by 3.8
kcal/mol.
the crude product as a brown oil (74.9 g). The resulting brown
oil was charged to a 250 mL round-bottom flask fitted with a
nine-tray distillation head. The content was distilled under
vacuum to give 38.1 g of a colorless oil [24.5% (AUC) 4,5,6-
F3] at ∼4 mmHg/and ∼50 °C and 22 g of a colorless oil
[84.1% (AUC) 4,5,6-F3] at ∼2 mmHg/∼60 °C. The 22 g
sample [84.1% (AUC)] was dissolved in heptanes/MTBE (22
mL, 4:1) with heating and seeded with a pure sample of the
desired product, 4,5,6-F3 (50 mg) at 20 °C. The resulting
mixture was stirred at 20 °C for 2 h, cooled to 5 °C over 2 h,
and then further stirred at 5 °C for 3 h. The resulting
suspension was filtered, and the filter cake was rinsed with
heptanes (2 × 40 mL). The solid was dried to afford the
desired product 4,5,6-F3 as a white crystalline solid (15.8 g,
19.8% yield). Mp (DSC): 43−46 °C. 13C{1H} NMR (101
MHz, CDCl3): δ 154.58 (ddd, J = 270.1, 10.5, 6.7 Hz), 151.38
(ddd, JC−F = 246.9, 12.4, 5.3 Hz), 138.03 (ddd, JC−F = 279.1,
31.4, 13.2 Hz), 124.7 (ddd, JF−C = 16, 6, 2 Hz, C3), 124.4
(ddd, JF−C = 16, 7, 2 Hz, C2), 112.23 (d, JC−F = 3.3 Hz).
19F{1H} NMR (376 MHz, CDCl3): δ −78.02 (t, JF−F = 23.2
The reverse halex reaction and the halopyridine scrambling
reaction provide strategies for recycle of 3,4,5,6-F4 to obtain
useful intermediates. Of the products formed in Schemes 4 and
5, only those that contain fluorine atoms at the 3-position (e.g.,
3,6-F2) cannot be converted to the desired trifluorinated
regioisomer 4,5,6-F3 by subsequent halex reaction with
fluoride. As a demonstration of this strategy, the product
mixture from the catalytic halopyridine scrambling reaction of
3,4,5,6-F4 and F0 (Scheme 5) was reacted with CsF in DMSO
at 70 °C. After 2.5 h, GC showed the formation of a mixture
containing 3,4,5,6-F4 (61%), 4,5,6-F3 (31%), 3,5,6-F3 (3.4%),
and 4,6-F2 (4.8%), which is similar to the product composition
formed by the halex reaction of F0 with CsF in DMSO.
CONCLUSIONS
■
This detailed experimental and computational study has shown
that the regioselectivity of the halex reaction of tetrachlor-
opicolinonitrile is kinetically controlled. This halex reaction is
the key first step in a new synthesis of 6-aryl-5-fluoropicolinate
herbicides. The first two fluoride substitution reactions
produced a single regioisomer, 4,6-F2. The competition
between fluoride substitution at the 3- and 5-positions of
4,6-F2 favored the 5-position, producing the desired trifluoro
isomer, 4,5,6-F3. The undesired trifluoro isomer, 3,4,6-F3,
further reacted with additional fluoride with a lower barrier
than did the 4,5,6-F3 isomer to produce 3,4,5,6-F4. Although
these reactions both favor the formation of the desired 4,5,6-
F3, the similarity of the rates of the third and fourth fluoride
substitution reactions limits the overall yield of 4,5,6-F3 from
the halex reaction of tetrachloropicolinonitrile. The over-
fluorinated byproduct, 3,4,5,6-F4, could be recycled to useful
3-chloro intermediates by the reverse halex reaction with LiCl
in DMSO (kinetic control) or by a catalytic halopyridine
scrambling reaction (thermodynamic control).
Hz), −114.16 (dd, JF−F = 22.7, 18.5 Hz), −149.28 (dd, JF−F
=
23.7, 18.4 Hz). Anal. Calcd for C6ClF3N2: C, 37.43; N, 14.55.
Found: C, 36.91; N, 14.25. Single crystals were grown from 4:1
heptanes/MTBE.
4-Amino-3-chloro-5,6-difluoropicolinonitrile (2). A
solution of 4,5,6-F3 (200 g, 1.03 mol) in EtOAc (3 L) was
cooled to 10 °C. NH4OH solution (14%, 1296 g, 5.1 mol) was
added at a rate that kept the temperature between 18 and 23
°C. After the addition was complete, the organic layer was
separated and washed with aqueous NaCl solution (50 wt %,
500 mL) and then saturated NaCl solution (250 mL). The
organic layer was concentrated under vacuum to approximately
500 mL. Heptane (1 L) was added, and the product was
collected by filtration. The product was washed with pentane
and dried under vacuum to give 2 as a white crystalline solid
(173.8 g, 88% yield). Mp: 190−191.5 °C. 1H NMR (400 MHz,
DMSO-d6): δ 7.56 (s). 13C{1H} NMR (101 MHz, DMSO-d6):
δ 150.03 (dd, JC−F = 232.4, 12.5 Hz), 144.29 (dd, JC−F = 11.4,
6.9 Hz), 133.72 (dd, JC−F = 257.9, 30.8 Hz), 122.14 (dd, JC−F
= 19.6, 4.9 Hz), 119.31 (s), 114.25 (s). 19F{1H} NMR (376
MHz, DMSO-d6): δ −91.24 (d, JF−F = 24.2 Hz), −154.97 (d,
JF−F = 24.2 Hz). Anal. Calcd for C6H2ClF2N3: C, 38.02; H,
1.06; N, 22.17. Found: C, 37.91; H, 1.00; N, 22.02.
Methyl 4-Amino-6-bromo-3-chloro-5-fluoropicoli-
nate (4). Note: The reaction mixture is heated above the
boiling point of the HBr/acetic acid solution. As a safety
precaution, the pressure vessel should be placed in a fume
hood behind a blast shield, and the reactor should be fitted
with a Hastelloy C rupture disk that is compatible with the
corrosive reaction mixture. To a Hastelloy C Parr vessel were
added 2 (70 g, 0.37 mol) and 33 wt % HBr in acetic acid (700
mL). The vessel was sealed and heated at 120 °C for 2 h. After
cooling to room temperature, the vessel was opened, and the
supernatant was transferred into a rotary evaporator and
concentrated under vacuum. The concentrated residue of 4-
amino-6-bromo-3-chloro-5-fluoropicolinamide (3) was diluted
with methanol (600 mL). To this mixture was slowly added
concentrated H2SO4 (40 g), and the reactor was sealed and
heated at 110 °C for 6 h. The cooled reaction mixture was
slowly poured into saturated aqueous Na2CO3 (2 L) and Et2O
(l L). The Et2O extract was dried over anhydrous MgSO4,
filtered, and concentrated to give a tan solid. This solid was
purified by filtration through a 400 g pad of silica gel with 5%
EXPERIMENTAL SECTION
■
3-Chloro-4,5,6-trifluoropicolinonitrile (4,5,6-F3). To a
1000 mL three-neck round-bottom flask equipped with a
magnetic stirrer, a condenser, a heating mantle, and a N2 inlet
were charged CsF (220 g, 1447 mmol) and DMSO (500 mL).
On the basis of Karl Fischer analysis, the water content of the
mixture was determined to be 728 ppm. The mixture was
heated at ∼60 °C and distilled under vacuum at 50−60 °C
over 1 h to remove ∼200 mL of DMSO. The vacuum was
broken with N2 at 60 °C, and the mixture was cooled to 17 °C
over 5 min. On the basis of Karl Fischer analysis, the water
content of the mixture was determined to be 76 ppm. 3,4,5,6-
Tetrachloropicolinonitrile (F0) (100 g, 413 mmol) was
charged under N2 over 5 min at 17−20 °C. The resulting
yellow suspension was stirred at 20 °C for 10 min and heated
to 50 °C over 20 min (the reaction temperature increased to
60 °C from 50 °C because of an exotherm). The reaction
mixture was stirred at 50−60 °C for 1.5 h, at which point GC
analysis showed that a 39.8% total yield (area under the curve,
AUC) of the combined trifluoro products was formed, along
with 54.0% (AUC) 3,4,5,6-F4 and 6.3% (AUC) 4,6-F2. The
reaction mixture was cooled to 20 °C over 10 min and then
added to H2O (2 L) at 10−20 °C over 10 min. The mixture
was extracted with MTBE (3 × 500 mL), and the combined
organics were concentrated under vacuum at <20 °C to give
G
Org. Process Res. Dev. XXXX, XXX, XXX−XXX