The Journal of Organic Chemistry
Article
(0.3 mL) and crystallized via. slow vapor diffusion method with
pentane. These crystals of 12 were of X-ray quality and allowed for the
determination of the structure of this compound.
6.87 (dd, 1H, J = 3.2, 0.80 Hz); 13C NMR (100 MHz, CDCl3) δ 157.5,
155.9, 150.4, 149.0, 148.9, 148.4, 137.0, 136.9, 129.2, 127.7, 127.1,
123.1, 122.9, 121.1, 121.0, 110.81, 103.3; HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C17H13N4 273.1140, found 273.1131.
Optimized One Pot Reactions of Symmetrical-β-Diketones
with 3-Nitropyrrole under Reductive Tin Conditions: Synthesis
of Compounds 7−11. 5,7-Bis(trifluoromethyl)-1H-pyrrolo[3,2-b]-
pyridine (7, Table 4: Entry 1). A gray suspension of 1 (0.0350 g, 0.312
mmol), 4f (66.2 μL, 0.468 mmol, 1.5 equiv) and tin (0.185 g, 1.56
mmol, 5 equiv) in a 5:3 DCM/glacial AcOH (4.0 mL) mixture was
heated to reflux for 21 h. The pale orange reaction mixture was cooled
to room temperature and concentrated by rotary evaporation (50 °C,
vacuum pump) in the presence of SiO2 (0.500 g). The dry solids were
flash column chromatographed (SiO2; DCM). The product fractions
were concentrated by rotary evaporation (45 °C). The white solids
were recrystallized from a boiling 15:1 hexane/DCM mixture (5 mL)
which was slowly cooled to room temperature and then to 0 °C for 1
h. The precipitate was isolated by vacuum filtration, washed with
hexane (5 mL) and dried in vacuo over P2O5 to afford 7 as clear
crystalline needles (0.0633 g, 80%): Rf = 0.38 (SiO2; DCM); mp
144.5−145.8 °C, 1H NMR (400 MHz, CDCl3) δ 9.00 (br-s, 1H), 7.74
(m, 2H), 7.00 (dd, 1H, J = 3.6, 1.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 148.5, 142.0 (q, JCF = 35 Hz), 132.1, 124.5, 123.2 (q, JCF = 271 Hz),
5,7-Dimethyl-1H-pyrrolo[3,2-b]pyridine (10, Table 4: Entry 4). A
gray suspension of 1 (0.0350 g, 0.312 mmol), 4i (161 μL, 1.56 mmol,
5 equiv) and tin (0.185 g, 1.56 mmol, 5 equiv) in glacial AcOH (4.0
mL) was heated to reflux for 30 h. The homogeneous red/orange
mixture was cooled to room temperature and a solid precipitated.
Distilled water (1.5 mL) was added to the heavy suspension and after
stirring for 1 h at room temp, a cloudy solution resulted. This solution
was slowly added to a stirred mixture of DCM (25 mL) and a
saturated NaHCO3 (75 mL) solution. Following the addition, the
mixture was stirred for 30 min, emulsified and was vacuum filtered. A
brown solid was removed which contained no product by TLC (SiO2,
EtOAc). The DCM layer was then removed from the filtrate and the
aqueous layer was extracted with DCM (2 × 25 mL). The combined
DCM layers were dried (Na2SO4) and concentrated by rotary
evaporation (45 °C) in the presence of SiO2 (0.500 g). The dry
brown/orange solids were flash column chromatographed (SiO2;
EtOAc → EtOAc (1% MeOH) gradient). The product fractions were
combined and concentrated by rotary evaporation (50 °C). The
resulting yellow/orange oil was recrystallized from a boiling 7:1
hexane/DCM mixture (5 mL) which upon turbidity was cooled to
room temp and then to 0 °C for 1 h. The precipitate was isolated by
vacuum filtration, washed with hexane (5 mL) and dried in vacuo over
P2O5 to afford 10 as a pale yellow crystalline solid (0.0186 g, 41%): Rf
121.9 (q, JCF = 272 Hz), 121.0 (q, JCF = 35 Hz), 109.8 (m, 2C, JCF
=
3.0 Hz), 105.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H5F6N2
255.0357, found 255.0350.
5,7-Diphenyl-1H-pyrrolo[3,2-b]pyridine (8, Table 4: Entry 2). A
gray suspension of 1 (0.0250 g, 0.223 mmol), 4g (0.0500 g, 0.223
mmol, 1 equiv) and tin (0.133 g, 1.12 mmol, 5 equiv) in a 3:2 DCM/
glacial AcOH (2.5 mL) mixture was heated to reflux for 44 h. The dark
brown heterogeneous reaction mixture was cooled to room temper-
ature, concentrated by rotary evaporation (60 °C, vacuum pump) in
the presence of SiO2 (0.500 g) and further dried in vacuo over P2O5.
The dry solids were flash column chromatographed (SiO2; 1:1 DCM/
EtOAc). The product fractions were concentrated by rotary
evaporation (40 °C). The resulting yellow oil was recrystallized
from a boiling 5:1 hexane/DCM (10 mL) mixture which was cooled
to room temperature and then to 0 °C for 30 min. The precipitate was
isolated by vacuum filtration, washed with hexane (5 mL) and dried in
vacuo over P2O5 to afford 8 as a white crystalline solid (0.0271 g,
1
= 0.17 (SiO2, EtOAc); mp 178.5−179.1 °C; H NMR (400 MHz,
CDCl3) δ 8.99 (br-s, 1H), 7.37 (t, 1H, J = 2.8 Hz), 6.83 (s, 1H), 6.64
(dd, 1H, J = 2.8, J = 1.2 Hz), 2.62 (s, 3H), 2.47 (d, 3H, J = 0.8 Hz);
13C NMR (100 MHz, CDCl3) δ 151.8, 145.4, 129.5, 127.3, 127.0,
118.1, 103.1, 24.2, 16.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C9H11N2 147.0922, found 147.0933.
5,6,7-Trimethyl-1H-pyrrolo[3,2-b]pyridine (11, Table 4: Entry 5).
A gray suspension of 1 (0.0350 g, 0.312 mmol), 4j (109 μL, 0.936
mmol, 3 equiv) and tin (0.185 g, 1.56 mmol, 5 equiv) in glacial AcOH
(4.0 mL) was heated to reflux for 40 h. The dark black homogeneous
reaction mixture was cooled to room temperature and distilled water
(1.5 mL) was added. After 15 min of stirring, the solution was added
slowly to a stirred mixture of DCM (50 mL) and a saturated NaHCO3
(75 mL) solution. This mixture was stirred for 30 min, the DCM layer
was removed and the aqueous layer was extracted with DCM (3 × 35
mL). The combined DCM layers were dried (Na2SO4) and
concentrated by rotary evaporation (45 °C) in the presence of SiO2
(0.500 g). The dry yellow/orange solids were flash column
chromatographed (SiO2; EtOAc → EtOAc (5% MeOH) → EtOAc
(10% MeOH) gradient). The product fractions were concentrated by
rotary evaporation (50 °C). The resulting pale yellow solids were
recrystallized from a boiling 5:1 hexane/DCM mixture (4 mL) which
was slowly cooled to room temperature and then to 0 °C for 30 min.
The precipitate was isolated by vacuum filtration, washed with hexane
(5 mL) and dried in vacuo to afford 11 as a pale yellow crystalline
solid (0.0265 g, 53%): Rf = 0.11 (SiO2; EtOAc); mp 202.8−204.6 °C;
1H NMR (400 MHz, CDCl3) δ 8.98 (br-s, 1H), 7.30 (t, 1H, J = 2.8
Hz), 6.60 (d, 1H, J = 3.2 Hz), 2.62 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 150.8, 142.7, 128.3, 127.3, 126.3,
123.2, 102.9, 23.8, 14.9, 13.6; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C10H13N2 161.1079, found 161.1084.
1
45%): Rf = 0.39 (SiO2; 1:1 DCM/EtOAc); mp 186.6−187.0 °C, H
NMR (400 MHz, CDCl3) δ 8.66 (br-s, 1H), 8.07−8.04 (m, 2H),
7.70−7.68 (m, 2H), 7.61 (s, 1H), 7.56−7.52 (m, 2H), 7.49−7.44 (m,
4H), 7.40−7.36 (m, 1H), 6.85 (dd, 1H, J = 3.2, 1.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 152.6, 147.1, 140.9, 137.0, 133.1, 129.4 (2C),
128.8, 128.6 (2C), 128.5, 128.0 (3C), 127.3 (2C), 125.9, 114.4, 104.4;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15N2 271.1235,
found 271.1208.
5,7-Di(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridine (9, Table 4: Entry
3). A gray/brown suspension of 1 (0.0350 g, 0.312 mmol), 4h (0.0706
g, 0.312 mmol, 1 equiv) and tin (0.185 g, 1.56 mmol, 5 equiv) in a 5:3
DCM/glacial AcOH (4.0 mL) mixture was heated to reflux for 24 h.
The dark gray/brown reaction mixture was cooled to room
temperature and concentrated by rotary evaporation (55 °C, vacuum
pump). The residue was triturated with a saturated NaHCO3 solution
(15 mL) at room temperature for 1 h. The resulting gray/brown
precipitate was isolated by vacuum filtration, washed with distilled
water (2 × 15 mL), dried in vacuo over P2O5, suspended in EtOAc (40
mL) and concentrated by rotary evaporation (50 °C) in the presence
of SiO2 (0.500 g). The dry solids were flash column chromatographed
(SiO2; EtOAc). The product fractions were concentrated by rotary
evaporation (50 °C). The pale yellow oil was recrystallized from a
boiling 3:1 hexane/DCM mixture (5 mL) which upon turbidity was
cooled to room temperature and then to 0 °C for 30 min. The
precipitate was isolated by vacuum filtration, washed with hexane (5
mL) and dried in vacuo over P2O5 to afford 9 as a pale yellow
crystalline solid (0.0478 g, 56%): Rf = 0.25 (SiO2; EtOAc); mp 172.6−
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data (excluding structure factors) for structure
5a (CCDC 1421293), 6a (CCDC 1421221) and 12
(CCDC1421500) in this paper have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0) 1223-
1
173.7 °C; H NMR (400 MHz, CDCl3) δ 11.06 (br-s, 1H), 8.86 (s,
1H), 8.78 (dq, 1H, J = 4.0, 0.8 Hz), 8.71 (dq, 1H, J = 4.0, 0.80 Hz),
8.59 (dt, 1H, J = 6.8, 1.2 Hz), 8.36 (dt, 1H, J = 7.2, 0.80 Hz), 7.88−
7.82 (m, 2H), 7.62 (dd, 1H, J = 3.2, 0.40 Hz), 7.35−7.28 (m, 2H),
K
J. Org. Chem. XXXX, XXX, XXX−XXX