J. Farrokh et al. / Tetrahedron Letters 56 (2015) 5245–5247
5247
Table 1
6,7,6 diaryl-fused heterocyclic ketones prepared in this study
12. I. General procedure for synthesis of compounds 3a–e; 3g and 6
A 250 mL round bottom flask equipped with a magnetic stir bar was charged
with 100 mL dimethyl sulfoxide and 10 mmol of 2-bromophenol (2a), 2-
bromo-2-chlorophenol (2b), 2-bromo-5-flourophenol (2c), 2-bromo-3-
pyridinol (2d), 2-bromobenzene thiol (2e), or 1-bromo-2-napthol (2g) and
1.33 mol equiv of K2CO3. An equimolar amount of 2-cyanobenzylbromide (1)
or 2-bromobenzyl bromide (4) was added to the solution. The reaction mixture
was stirred at ambient temperature under a CaCl2 drying tube overnight. The
solution was poured into 200 mL of water and was stirred for 2 h. The mixture
was then extracted with ethyl acetate (3 Â 100 mL) and the organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo to afford the crude
product, which was recrystallized with methanol.
R
Z
Y
X
O
8
II. Procedure for the synthesis of compound 2-(((2-bromophenyl)(methyl)-
amino)methyl)benzonitrile 3f
Compound
X
Y
Z
R
% yield
Normal
Inverse
A 250 mL round bottom flask equipped with a magnetic stir bar was charged
with 100 mL of methanol, 2-bromo-N-methylaniline (2f; 2.00 g; 10.75 mmol),
1.1 equiv of 2-(bromomethyl)benzonitrile (1; 2.31 g; 12.07 mmol), and
1.1 equiv of triethylamine (1.82 mL; 1.33 g; 13.10 mmol). The mixture was
allowed to stir overnight and was then concentrated in vacuo and 100 mL of
diethyl ether was added to the residue. The resulting precipitate was removed
using vacuum filtration and the filtrate was again concentrated in vacuo to
provide crude 2f (2.55 g; 78.8%) as an oil which was purified using flash
chromatography on silica gel eluting with hexanes/EtOAc to provide the pure
8a (from 3)
8a (from 6)
8b
8c
8d
8e
8f
CH
CH
CH
CH
N
CH
CH
CH
H
H
2-Cl
3-F
H
H
H
H
O
O
O
O
H
S
NCH3
O
H
H
H
H
H
H
H
H
56
54
48
42
18
8
73
74
63
71
48
38
78
92
63
58
product as
a
water–white oil, yield = 0.785 g (24.3%): 1H NMR (CDCl3,
8g (naphthyl)
300 MHz) d 2.56 (s, NCH3; 3H), 4.25 (s, ArCH2, 2H), 7.73–6.77 (m, ArH, 8H);
13C NMR (CDCl3, 75 MHz) d 41.2, 58.0, 111.8, 118.8, 120.4, 122.4, 125.0, 127.6,
128.3, 129.4, 132.6, 132.9, 134.0, 142.1, 151.1. IR: 2228 cmÀ1; Anal. Calcd for
C15H13BrN2: C, 59.82; H, 4.35; Br, 26.53; N, 9.30. Found: C, 59.49; H, 4.00; Br,
26.51; N, 9.16.
Conclusion
III. General Procedure for synthesis of 8a–g using normal addition
A dry three-neck-250 mL round bottom flask equipped with a temperature
probe, magnetic stirrer, and nitrogen inlet was charged with 100 mL of
anhydrous THF. The starting material (3a–g or 6; 5 mmol) was added to the
reaction flask and the resulting solution was cooled under N2 to À78 °C using a
dry/ice acetone bath. n-Butyllithium (1.2 equiv) was added via syringe at such
a rate so as to maintain the temperature at or below À70 °C. The reaction
mixture was kept at or below À70 °C for 1 h, and then allowed to slowly warm
to room temperature overnight. The reaction mixture was quenched using 5%
HCl and stirred for an hour. For the preparation of 8d, sufficient 10% NaOH
solution was added to turn the solution basic and mixed for an additional hour
to account for the protonation of the pyridine moiety. The reaction mixture
was then extracted using ethyl acetate. The organic extracts were concentrated
to dryness and the desired product was separated from the crude mixture
using flash chromatography on a silica gel column eluting with hexanes/EtOAc.
IV. General procedure for synthesis of compounds 8a–g using inverse addition
A dry three-neck-250 mL round bottom flask equipped with a temperature
probe, magnetic stirrer, and nitrogen inlet was charged with 100 mL of
anhydrous tetrahydrofuran. The reaction mixture was cooled to À78 °C using a
dry/ice acetone bath and 6 mmol (1.2 equiv) of n-butyllithium were added to
the reaction flask. To the chilled solution was added 5 mmol of one of the
compounds elected from 3a–g dissolved in 30 mL of anhydrous THF dropwise.
The reaction mixture was kept at or below À70 °C for 1 h, and then allowed to
slowly warm to room temperature overnight. The reaction mixture was
quenched using 5% HCl and stirred for an hour. For the preparation of 8d,
sufficient 10% NaOH solution was added to turn the solution basic and mixed
for an additional hour to account for the protonation of the pyridine ring. The
reaction mixture was then extracted using EtOAc. The organic extracts were
concentrated to dryness and the desired product was separated from the crude
A new Parham cyclization methodology has been developed for
the preparation of diaryl fused oxapin-4-ones, thiooxapin-4-ones,
and azapin-4-ones that may permit entry to derivatives bearing
electrophilic functional groups difficult to prepare under the nor-
mally employed Friedel–Crafts acylation conditions. One possible
limitation for this process is poor yields for systems that can form
stabilized
a-anions at the benzylic position thereby leading to
butylated by-products as observed for the thiooxapin-4-ones.
Acknowledgements
The authors wish to thank to The College of New Jersey and the
New Jersey Space Consortium for their generous support and fund-
ing of this project.
References and notes
1. Rogers, K.; Patzke, H. U.S. Patent 20,110,288,070, November 24, 2011.
2. Kavey, N. B.; Dube, S. E. U.S. Patent 20,100,227,916, April 12, 2010.
3. Rogowski, R.; Dube, S.; Jochelson, P. U.S. Patent 20,090,042,971, February 12,
2009.
4. Edgar, D. M.; Hangauer, D. G.; White, J. F.; Solomon, M. U.S. Patent 7,411,069,
August 12, 2008.
6. Yamamoto, K.; Tamura, T.; Nakamura, R.; Ueno, K.; Hosoe, S. WO 2,013,018,899
A1, February 7, 2013.
mixture using flash chromatography on
hexanes/EtOAc.
a silica gel column eluting with
13. Data for 11: 1H NMR (CDCl3, 300 MHz) d 0.67 (t, J = 6.3 Hz, CH3, 3H), 1.01–1.38
(m, CH2, 4H), 1.70–1.85 (m, CH2, 2H), 4.30 (t, J = 6.9 Hz, benzylic –CH), 6.99–
7.40 (m, ArH, 9H); 13C NMR (CDCl3, 75 MHz) d 13.9, 22.4, 29.6, 35.7, 51.1, 112.5,
117.8, 127.4, 125.0, 127.6, 127.8, 128.1, 128.9, 132.4, 133.0, 133.2, 133.5, 146.6.
IR: 2213 cmÀ1; Anal. Calcd for C18H19NS: C, 76.82; H, 6.81; N, 4.98; N, 11.39.
Found: C, 76.58; H, 6.88; N, 4.73; S, 11.78.