Fride´n-Saxin et al.
2.05-1.88 (m, 1H); 13C NMR δ 190.1, 156.3, 140.4, 138.2, 128.5,
128.4, 126.8, 126.1, 125.6, 122.2, 112.6, 77.4, 42.2, 36.1, 30.8;
HRMS (FT-ICR-MS) [M + H]+ calcd for C17H15BrClO2 366.9919,
found 366.9933.
reaction. Alternatively, an azide ion attacks the trans-isomer,
forming the cis-2-phenethyl-3-azido derivative, which then
eliminates HN3 to form 17.
Dibromination of 1 was then performed using Py ·Br3 in
dichloromethane. Running the reaction at room temperature gave
very slow conversion and a lot of monobrominated material,
but raising the temperature to 80 °C using microwave heating
gave a smooth conversion to the dibrominated intermediate. An
HBr elimination yielded the brominated chromone 18 in 77%
(over two steps) using CaCO3 in DMF.24 Other bases such as
DBU or TEA in dichloromethane or Cs2CO3 in DMF also gave
product 18 but were always accompanied with other impurities.
CaCO3 in DMF was then also used to prepare chromone 17 in
94% yield from the monobrominated compound 15.
Finally, 3-hydroxychromone was synthesized with isoamyl
nitrite and HCl in EtOH.25 The reaction was performed at
different temperatures (60, 70, 100, and 120 °C) using micro-
wave as well as conventional heating sources and by using
different solvents (EtOH, iPrOH, or THF). For most of the
experiments, the desired alcohol was obtained in significant
amounts although together with several byproducts which
complicated the purification. The best result was obtained at
60 °C in EtOH using conventional heating. To facilitate the
purification, the alcohol was acetylated using acetyl chloride
and triethylamine, which gave the 3-acetoxy chromone 19 in
49% yield over two steps.
8-Bromo-6-chloro-2-(2-(1-naphthyl)ethyl)chroman-4-one (2):
Purification by trituration with MeOH, followed by column
chromatography toluene/heptane (8:2) gave 2 as a light yellow solid
(4.1 g, 84%): mp 36-37 °C; 1H NMR δ 8.14 (d, J ) 8.1 Hz, 1H),
7.87 (d, J ) 7.7 Hz, 1H), 7.81 (d, J ) 2.6 Hz, 1H), 7.77 (d, J )
2.6 Hz, 1H), 7.75 (d, J ) 7.3 Hz, 1H), 7.57-7.47 (m, 2H),
7.45-7.37 (m, 2H), 4.61-4.47 (m, 1H), 3.61-3.47 (m, 1H),
3.39-3.26 (m, 1H), 2.83-2.67 (m, 2H), 2.47-2.32 (m, 1H),
2.22-2.07 (m, 1H); 13C NMR δ 190.2, 156.5, 138.4, 136.6, 133.9,
131.6, 128.9, 127.1, 127.0, 126.4, 126.1, 125.8, 125.61, 125.55,
123.6, 122.4, 112.7, 77.8, 42.3, 35.7, 28.1; HRMS (FT-ICR-MS)
[2M + Na]+ calcd for [C21H16BrClO2]2Na 850.9938, found
850.9906.
8-Bromo-6-chloro-2-(2-(1H-indol-3-yl)ethyl)chroman-4-one (3):
Purification by column chromatography EtOAc/heptane (20%) gave
1
3 as a yellow solid (0.28 g, 86%): mp 134-136 °C; H NMR δ
8.01 (s, 1H), 7.79 (d, J ) 2.6 Hz, 1H), 7.74 (d, J ) 2.6 Hz, 1H),
7.66 (d, J ) 8.1 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 1H), 7.24-7.19 (m,
1H), 7.17-7.11 (m, 1H), 7.06 (d, J ) 1.8 Hz, 1H), 4.58-4.43 (m,
1H), 3.18-3.02 (m, 2H), 2.79-2.63 (m, 2H), 2.40-2.27 (m, 1H),
2.15-2.01 (m, 1H); 13C NMR δ 190.5, 156.5, 138.3, 136.3, 127.2,
126.8, 125.7, 122.4, 122.1, 121.8, 119.3, 118.7, 114.5, 112.7, 111.2,
77.8, 42.3, 34.9, 20.4; HRMS (FT-ICR-MS) [2M + Na]+ calcd
for [C19H15BrClNO2]2Na 830.9823, found 830.9860.
2-(2-(1-Benzyl-1H-indol-3-yl)ethyl)-8-bromo-6-chlorochroman-
4-one (4): Purification by column chromatography EtOAc/hexane
1
Conclusion
(5f20%) gave 4 as a yellow solid (0.33 g, 84%): mp 150 °C; H
NMR δ 7.77 (d, J ) 2.6 Hz, 1H), 7.69 (d, J ) 2.6 Hz, 1H), 7.63
(d, J ) 8.1 Hz, 1H), 7.31-7.01 (m, 8H), 6.98 (s, 1H), 5.24 (s,
2H), 4.56-4.39 (m, 1H), 3.17-3.01 (m, 2H), 2.78-2.62 (m, 2H),
2.38-2.24 (m, 1H), 2.14-2.00 (m, 1H); 13C NMR δ 190.4, 156.6,
138.4, 137.5, 136.8, 128.7, 127.8, 127.6, 126.9, 126.7, 125.9, 125.8,
122.4, 121.9, 119.1, 118.9, 113.8, 112.7, 109.7, 77.9, 49.8, 42.4,
An efficient method to synthesize a diverse set of 2-alkyl-
substituted 4-chromanones from 2-hydroxyacetophenones and
aliphatic aldehydes has been developed. Incorporation of
heterofunctional groups in the chromone 3-position provides
opportunities for further substitution. Compounds 16, 17, 18,
and deacetylated 19 could be applicable in Pd-mediated
chemistry to introduce appropriate substituents in the 3-, 6-,
and 8-positions.7b,c The 3-amine and the 3-hydroxy analogues
(16 and deacetylated 19) could also be useful in acylation and
alkylation reactions. This work is ongoing in our laboratory.
35.1, 20.4; HRMS (FT-ICR-MS) [M
C26H21BrClNNaO2 516.0337, found 516.0317.
+
Na]+ calcd for
8-Bromo-6-chloro-2-(2-(1-tosyl-1H-indol-3-yl)ethyl)chroman-
4-one (5): Purification by column chromatography toluene/heptane
1
(50%) gave 5 as a yellow solid (2.28 g, 74%): mp 57-60 °C; H
NMR δ 8.01 (d, J ) 8.1 Hz, 1H), 7.81 (d, J ) 2.2 Hz, 1H), 7.76
(d, J ) 2.6 Hz, 1H), 7.68 (d, J ) 8.4 Hz, 2H), 7.52 (d, J ) 8.1 Hz,
1H), 7.42 (s, 1H), 7.36-7.30 (m, 1H), 7.29-7.21 (m, 1H),
7.19-7.13 (m, 1H), 7.09 (d, J ) 8.1 Hz, 1H), 4.39-4.29 (m, 1H),
3.09-2.94 (m, 2H), 2.79-2.62 (m, 2H), 2.36 (s, 1H), 2.30 (s, 3H),
2.11-1.99 (m, 1H); 13C NMR δ 190.0, 156.4, 144.8, 138.5, 135.5,
135.1, 130.6, 129.7, 129.0, 128.2, 127.1, 126.6, 125.8, 124.6, 123.3,
123.1, 122.4, 121.3, 119.2, 113.9, 112.7, 77.5, 42.3, 33.9, 21.5,
20.3; HRMS (FT-ICR-MS) [M + H]+ calcd for C26H22BrClNO4S
558.0136, found 558.0137.
Experimental Section
General Procedure for Preparation of Chromanones 1-9:
DIPA (1.1 mmol) and the appropriate aldehyde (1.1 mmol) were
added to a solution of 3-bromo-5-chloro-2-hydroxyacetophenone
(1 mmol) in EtOH (2.5 mL). The reaction mixture was heated in a
microwave cavity at 170 °C for 1 h (fixed hold time, normal
absorption) and then cooled to rt. The resulting solution was diluted
with CH2Cl2. For chromanones 1-4, the organic phase was washed
twice with aqueous NaOH (1%). For all chromanones, the organic
phase was washed twice with aqueous HCl (10%) and then with
water and brine. The organic phase was dried with MgSO4, filtered,
and concentrated. Purification by column chromatography gave
chromanones 1-9.
8-Bromo-6-chloro-2-pentylchroman-4-one (6): Purification by
column chromatography EtOAc/heptane (5%) gave 6 as a white
1
solid (0.26 g, 80%): mp 67-68 °C; H NMR δ 7.79 (d, J ) 2.6
Hz, 1H), 7.69 (d, J ) 2.6 Hz, 1H), 4.57-4.46 (m, 1H), 2.78-2.65
(m, 2H), 2.02-1.88 (m, 1H), 1.80-1.67 (m, 1H), 1.67-1.56 (m,
1H), 1.56-1.42 (m, 1H), 1.42-1.27 (m, 4H), 1.00-0.79 (m, 3H);
13C NMR δ 190.7, 156.7, 138.4, 126.8, 125.7, 122.3, 112.7, 79.0,
42.4, 34.6, 31.4, 24.6, 22.5, 14.0; HRMS (FT-ICR-MS) [M + H]+
calcd for C14H17BrClO2 331.0095, found 331.0099.
8-Bromo-6-chloro-2-phenethylchroman-4-one (1): Purification
by column chromatography EtOAc/heptane (2.5%) gave 1 as an
orange oil (0.31 g, 88%). The yellow oil was converted to a yellow
1
solid over time: mp 58-60 °C; H NMR δ 7.78 (d, J ) 2.6 Hz,
8-Bromo-6-chloro-2-isopropylchroman-4-one (7): Purification
1H), 7.71 (d, J ) 2.6 Hz, 1H), 7.34-7.07 (m, 5H), 4.50-4.35 (m,
1H), 3.03-2.80 (m, 2H), 2.74-2.58 (m, 2H), 2.35-2.20 (m, 1H),
by column chromatography EtOAc/heptane (10%) gave 7 as a white
1
solid (0.13 g, 43%): mp 58-60 °C; H NMR δ 7.78 (d, J ) 2.6
Hz, 1H), 7.69 (d, J ) 2.6 Hz, 1H), 4.27-4.15 (m, 1H), 2.76-2.68
(m, 2H), 2.16-2.02 (m, 1H), 1.14 (d, J ) 7.0 Hz, 3H), 1.07 (d, J
) 7.0 Hz, 3H); 13C NMR δ 191.0, 156.9, 138.3, 126.7, 125.7, 122.2,
112.8, 83.7, 39.8, 32.3, 18.0, 17.9; HRMS (FT-ICR-MS) [M +
H]+ calcd for C12H13BrClO2 304.9753, found 304.9766.
(24) Acena, J. L.; Arjona, O.; Plumet, J. J. Org. Chem. 1997, 62, 3360–
3364.
(25) Ferrali, M.; Bambagioni, S.; Ceccanti, A.; Donati, D.; Giorgi, G.; Fontani,
M.; Laschi, F.; Zanello, P.; Casolaro, M.; Pietrangelo, A. J. Med. Chem. 2002,
45, 5776–5785.
2758 J. Org. Chem. Vol. 74, No. 7, 2009