The Journal of Organic Chemistry
Note
vacuum oven (<45 Torr) at rt for 18 h. The dry product 2 was
obtained as a white solid (41.5 g, 90.1% yield, 99.1 LC purity, 94.5 wt
%, residual metal content: Pt, 15 ppm; S, 5 ppm, 4.4% mother liquor
that the relative rate of product formation increases in the order
2-Cl > 2-Br > 2-I. Consistent with data from Table 2 (entries
1−3), 2-iodo-5-nitropyridine reacts the slowest, and significant
amounts of the intermediate hydroxylamine and hydro-
deiodination side products were observed. Thus, a combination
of lower reactivity and product stability contributes to much
higher levels of hydrodehalogenation in the case of the 2-I
substrate.16
1
loss): H NMR (400 MHz, chloroform-d) δ ppm 2.38 (s, 3 H), 7.41
(s, 1 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.20 (s, 1 H); 13C NMR (101
MHz, chloroform-d) δ ppm 113.9 (s, 1 C), 116.1 (s, 1 C), 121.5 (s, 1
C), 126.4 (s, 1 C), 127.2 (s, 1 C), 131.7 (s, 1 C), 139.0 (s, 1 C), 140.2
(s, 1 C), 152.2 (s, 1 C). HRMS m/z calcd for C10H10ClN2 193.0527
(M + H), found 193.0537.
Chloro-nitropyridines with alternative substitution patterns
and substituents were also reduced with high selectivity (entries
4−6, Table 2). In the case of nitropyridines possessing multiple
halide substituents, including iodides, high selectivities were
observed with conversion to the corresponding dihaloamino
pyridines in excellent yield (entries 7−11, Table 2). The high
chemoselectivity of the platinum sulfided catalyst is believed to
be due to the poisoning effect of the sulfur, which occupies the
most active sites on the platinum surface, thereby enhancing
the selectivity of the process.17
In conclusion, a convenient and selective process for the
catalytic hydrogenation of nitro groups in the presence of
heteroaryl halides has been demonstrated, making use of a
readily available sulfided platinum catalyst. The method is
efficient, employs low catalyst loading (<0.10 mol %) and mild
reaction temperatures (<40 °C) and pressures (3−4 bar H2),
and can eliminate the need for screening additives in order to
obtain high selectivity in many cases. In addition, the method is
operationally convenient and minimizes waste, which repre-
sents a greener alternative to other reducing conditions.
5-Amino-2-chloro Pyridine (Entry 1, Table 2). Product 1,
Table 2 was prepared from commercially available 2-chloro-5-nitro
pyridine (161 mg, 1.25 mmol) as described in General Procedures for
Nitro Reduction. The reaction reached full conversion after 8 h. A
brown solid (121.5 mg, 95% yield, 96.6 LC purity containing 2.8
LCAP hydrodechlorination product) was obtained: 1H NMR (400
MHz, DMSO-d6) δ ppm 5.48 (s, 1 H), 6.98 (s, 1 H), 7.09 (s, 1 H),
7.70 (s, 2 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 123.7 (s, 1 C),
123.8 (s, 1 C), 135.1 (s, 1 C), 136.0 (s, 1 C), 144.5 (s, 1 C). HRMS
m/z calcd for C5H6ClN2 129.0214 (M + H), found 129.0214.
5-Amino-2-bromo Pyridine (Entry 2, Table 2). Product 2,
Table 2 was prepared from commercially available 2-bromo-5-nitro
pyridine (201.1 mg, 0.99 mmol) as described in General Procedures
for Nitro Reduction. The reaction reached full conversion after 18 h. A
brown solid (159.2 mg, 92% yield, 96.0 LC purity containing 1.9%
hydrodebromination product) was obtained: 1H NMR (400 MHz,
DMSO-d6) δ ppm 3.37 (s, 2 H), 7.99 (s, 1 H), 8.52 (s, 1 H), 9.22 (s, 1
H); 13C NMR (101 MHz, DMSO-d6) δ ppm 123.9 (s, 1 C), 125.2 (s,
1 C), 132.4 (s, 1 C), 133.3 (s, 1 C), 141.2 (s, 1 C). HRMS m/z calcd
for C5H6BrN2 172.9709 (M + H), found 172.9706.
3-Amino-2-chloro Pyridine (Entry 4, Table 2). Product 4,
Table 2 was prepared from commercially available 2-chloro-3-nitro
pyridine (162.3 mg, 1.02 mmol) as described in General Procedures
for Nitro Reduction. The reaction reached full conversion after 36 h. A
dark colored solid (120.9 mg, 92% yield, 95.4 LC purity containing
2.4% hydrodechlorination product) was obtained: 1H NMR (400
MHz, DMSO-d6) δ ppm 5.54 (s, 2 H), 7.11 (s, 1 H), 7.58 (s, 1 H);
13C NMR (101 MHz, DMSO-d6) δ ppm 121.8 (s, 1 C), 123.7 (s, 1 C),
135.0 (s, 1 C), 136.0 (s, 1 C), 141.5 (s, 1 C). HRMS m/z calcd for
C5H6ClN2 129.0214 (M + H), found 129.0211.
5-Amino-2-chloro-3-methyl Pyridine (Entry 5, Table 2).
Product 5, Table 2 was prepared from commercially available 2-chloro-
3-methyl-5-nitro pyridine (173.0 mg, 1.00 mmol) as described in
General Procedures for Nitro Reduction. The reaction reached full
conversion after 8 h. A brown solid (121.5 mg, 93.8% yield, 98.9 LC
purity) was obtained: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s,
3 H), 5.21 (s, 2 H), 6.73 (d, J = 2.35 Hz, 1 H), 7.37 (d, J = 2.74 Hz, 1
H); 13C NMR (101 MHz, DMSO-d6) δ ppm 124.1 (s, 1 C), 131.2 (s,
1 C), 132.8 (s, 1 C), 136.5 (s, 1 C), 144.7 (s, 1 C). HRMS m/z calcd
for C6H8ClN2 143.0370 (M + H), found 143.0370.
5-Amino-6-chloro-3-methoxy Pyridine (Entry 6, Table 2).
Product 6, Table 2 was prepared from commercially available 2-chloro-
6-methoxy-3-nitro pyridine (202.1 mg, 1.07 mmol) as described in
General Procedures for Nitro Reduction. The reaction reached full
conversion after 12 h. A red-brown oil (157.81 mg, 93% yield, 95.1 LC
purity containing 4.9% hydrodechlorination product) was obtained:
1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H), 4.97 (s, 2 H),
6.64 (s, 1 H), 7.22 (s, 1 H); 13C NMR (101 MHz, DMSO-d6) δ ppm
53.3 (s, 1 C), 109.9 (s, 1 C), 127.9 (s, 1 C), 129.6 (s, 1 C), 135.5 (s, 1
C), 154.2 (s, 1 C). HRMS m/z calcd for C6H8OClN2 159.0320 (M +
H), found 159.0315.
EXPERIMENTAL SECTION
■
General Experimental Procedures. 1H NMR and 13C NMR
were obtained at 400 and 100 MHz respectively, with CDCl3 (for
compound 2) and DMSO-d6 (for entries 1, 2, 4−11, Table 2) as
solvents. In the 1HNMR spectra of entries 1, 5, 6, 10, and 11, Table 2,
signals between 3.15 and 3.33 ppm originate from water in DMSO-d6
solvents and in entry 4, signals 3.32 and 1.36 ppm originate from
residual THF from the reaction. High resolution mass spectrometry
(HRMS) was conducted using positive mode electrospray ionization
(ESI) and produced spectra with less than 5 ppm mass accuracy. LC
chromatograms were obtained using an Agilent 3.0 × 150 mm Eclipse
XDB-Phenyl column.
General Procedures for Nitro Reduction. A mixture of nitro
starting material (substrates 1−11, Table 2) and 3% Pt(S)/C
(B109032-3, 62.80% wet, 0.09 mol %) in THF (4 mL/mmol
substrate) was purged with three nitrogen cycles followed by three
hydrogen cycles before pressurizing to 3 bar hydrogen pressure and
then heated at 37 °C. Upon reaction completion, the mixture was
cooled to rt, and the hydrogen was replaced with argon gas (via three
evacuation−backfill cycles). The mixture was vacuum filtered using a
fine glass frit to remove the catalyst, the filtrate was concentrated, and
the resulting solid was further dried in a vacuum oven (<45 Torr) for
18 h to afford the product.
5-Amino-1-chloro-6-methyl isoquinoline (2). 1-Chloro-6-
methyl-5-nitroisoquinoline (50.5 g, 0.22 mol), 3% Pt(S)/C (3.5 g,
0.09 mol % Pt, type: JM B109032-3, 62.80% water), and THF (250
mL) were charged to a 450 mL Parr reactor. The mixture was purged
with three evacuation−backfill cycles with nitrogen followed by three
cycles of hydrogen before pressurizing to 3 bar hydrogen pressure at rt.
The progress of the reaction was monitored by LC/MS analysis. Upon
completion (after 18 h), the catalyst was filtered, rinsing with THF
(150 mL). The filtrate was concentrated to 160 mL via distillation
under reduced pressure at 50 °C. The reaction mixture was then
cooled to rt and seeded (with 0.5 g 2). The mixture was aged for 1 h,
followed by addition of heptane (750 mL) over 2 h. The product was
collected via filtration, and the cake was washed with a mixture of
heptane (55 mL) and THF (10 mL). The product was dried in a
5-Amino-2,6-dichloro Pyridine (Entry 7, Table 2). Product 2,
Table 2 was prepared from commercially available 2-bromo-5-nitro
pyridine (197.6 mg, 1.02 mmol) as described in General Procedures
for Nitro Reduction. The reaction reached full conversion after 16 h. A
light brown solid (166.27 mg, 92% yield, 98.8 LC purity) was
1
obtained: H NMR (400 MHz, DMSO-d6) δ ppm 5.84 (s, 2 H), 7.26
(s, 2 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 123.9 (s, 1 C),
125.2 (s, 1 C), 132.4 (s, 1 C), 133.3 (s, 1 C), 141.2 (s, 1 C). HRMS
m/z calcd for C5H5Cl2N2 162.9824 (M + H), found 162.9823.
9843
dx.doi.org/10.1021/jo2015664|J. Org. Chem. 2011, 76, 9841−9844