A new and general synthesis of substituted 2-azafluorenones

Article abstract of DOI:10.1055/s-2002-35630

A short high yield synthesis of polysubstituted 2-azafluorenones from 1,2,4-triazines using the metalation and intramolecular Diels-Alder reaction is described.

Full text of DOI:10.1055/s-2002-35630

2532
PAPER
A New and General Synthesis of Substituted 2-Azafluorenones
New
Synthesis
h
of 2-Azafluo
o
renones mas Hundsdorf, Evgeniy V. Blyumin, Hans Neunhoeffer*
Darmstadt University of Technology, Institute of Organic Chemistry, Petersenstraße 22, 64287 Darmstadt, Germany
Fax +49(6151)166016; E-mail: di88@hrzpub.tu-darmstadt.de
Received 3 July 2002; revised 30 August 2002
Abstract: A short high yield synthesis of polysubstituted 2-aza-
fluorenones from 1,2,4-triazines using the metalation and intra-
molecular Diels–Alder reaction is described.
Key words: 1,2,4-triazines, 2-azafluorenones, metalations, Sono-
gashira reaction, Diels–Alder reaction
Fluorenones and their derivatives are known to be good
antiviral1 and antibacterial2 agents, aldose reductase
inhibitors3 and anticancer agents (such as TAS-103).4
Therefore azafluorenone derivatives may also have inter-
esting biological properties. This led to an increasing in-
terest in the chemistry of azafluorenones over the last 20
years. Recently,5 we developed a flexible and quite a gen-
eral approach to 1-azafluorenones using metalation, So-
nogashira coupling and intramolecular inverse Diels–
Alder reactions of 1,2,4-triazines. Here we report a high
yield synthesis of 2-azafluorenones using the same strate-
gy.
A survey of the methods known for the preparation of 2-
azafluorenones indicated only a few routes: preparation
from 4-arylpyridine derivatives,6 via photochemical
Pschorr cyclization of 3-(2-aminoaryl)pyridine ketones,7
Scheme 1 Substituents for compounds 1a,b; 2a–c; 3a–d; 4a–d; 5a–
d; 6; 7a–k, see Table 1
from indenacetamides8 and cyclization of 2-arylphenyl-
carbenes.9 Most of these methods provided only a limited
choice of exocyclic functional groups.
TLC under mild reaction conditions (r.t. to 50 °C). Only
by heating the reaction mixture at 70–80 °C formation of
reaction products could be observed by TLC and the 2-
azafluorenones 7c–k were the only isolable reaction pro-
ducts. It is known that Sonogashira coupling of alkynes
with electron-donating substituents requires harder reac-
tion conditions.13 On the other hand the -deficient nature
of the 1,2,4-triazine and the electron-rich alkyne moiety in
6 facilitates the inverse intramolecular Diels–Alder reac-
tion. Therefore, both Sonogashira coupling and Diels–Al-
der reaction proceed at similar reaction conditions.
The general approach of our work is outlined in
Scheme 1, Table 1. The starting 5-methoxy-1,2,4-triaz-
ines 1a,b were obtained by methylation of the correspond-
ing 1,2,4-triazin-5-ones.10 Standard lithiation11 of 1a,b
with LiTMP at –100 °C, followed (after 1 h of accumula-
tion) by addition of the corresponding 2-bromobenzalde-
hydes 2a–c, afforded the alcohols 3a–d (47–76%).
Oxidation of 3a–d to 4a–d using MnO2 in THF proceeded
in yields greater than 80%. Treatment of the 2-bromoaryl
ketones 4a–d with alkynes 5a–d under Sonogashira
coupling12 conditions [PdCl2(Ph3P)2/CuI catalysis] led to
6 which under the reaction conditions underwent an in-
tramolecular Diels–Alder reaction affording the 1-meth-
oxy-2-azafluorenones 7a, 7c–k in good yields (57–84%).
In view of these results, we decided to use the one-pot
method for the synthesis of target compounds 7. Thus,
the 6-(2-bromobenzoyl)-5-methoxy-1,2,4-triazines 4a–d
were treated with 5b–d in dimethylformamide in the pres-
ence of a Pd/Cu catalyst and tripropylamine. After 1–1.5
hours of heating at 100–120 °C, the expected 2-azafluor-
enones 7c–k were isolated in good to high yields (57–
84%).
It is necessary to note that only in the reaction of 4a with
5a the corresponding 2-benzoylacetylene 6a could be iso-
lated. In the reactions of the alkynes 5b–d with the 2-bro-
moaryl ketones 4a–d no changes could be observed by
Desilylation of 7a with concentrated HCl resulted in the
2-azafluorenone 7b in quantitative yield (Scheme 2), in
contrast to the previously described 4-trimethylsilyl-1-
azafluorenones,5 which are less active toward similar
Synthesis 2002, No. 17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2532,2536,ftx,en;T07602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
New Synthesis of 2-Azafluorenones
2533
Table 1 Substituents for Compounds 1–7
Com-
pound
R1
R2
R3
R4
1a
1b
2a
2b
2c
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
7a
7b
7c
7d
7e
7f
Ph
–
–
–
–
–
4-MeOC6H4
–
–
H
H
–
–
OMe
OMe
–
–
OCH2O
OCH2O
–
Ph
H
H
–
Ph
OMe
OMe
–
Ph
–
Scheme 2
4-MeOC6H4
OMe
H
OMe
H
–
Therefore this new and efficient synthetic route to 2-
azafluorenones may complement and (or) supersede the
previous reported procedures.6–9
Ph
–
Ph
OMe
OMe
–
Ph
OCH2O
–
Metalation experiments were carried out under Ar in THF, which
was freshly distilled from sodium benzophenone ketyl under Ar pri-
or to use. Solvents used in all other experiments (oxidation, Sono-
gashira coupling, Diels–Alder reaction, desilylation) were dried
over molecular sieves. IR spectra were obtained on a Nicolet impact
4-MeOC6H4
OMe
–
OMe
–
–
SiMe3
CH2OH
CH2NMe2
(CH2)3Me
SiMe3
SiMe3
H
–
–
400 spectrometer. H and 13C NMR spectra were recorded on a
1
–
–
Bruker AC-300 or ARX-300 spectrometer using TMS as an internal
standard. MS were determined on a Varian 212 instrument at 70 eV.
Elemental analyses were obtained on a Perkin-Elmer CHN 240 A or
240 B.
–
–
Ph
H
H
H
3-Substituted 6-(2-Bromo- -hydroxybenzyl)-5-methoxy-1,2,4-
triazines 3a–d; General Procedure
Ph
H
Ph
H
H
To cold (–60 °C) THF (40 mL) were added 2,2,6,6-tetramethylpi-
peridine (TMPH, 1.6 mL, 9.4 mmol) and 2.5 M solution of BuLi in
hexanes (3.2 mL, 8.0 mmol). The mixture was allowed to warm to
r.t., stirred for 30 min and cooled to –100 °C. The 1,2,4-triazine
1a,b (2.0 mmol) in THF (10 mL) was added in portions while keep-
ing the internal temperature < –95 °C. After 60 min (accumulation
time), the corresponding 2-bromobenzaldehyde 2a–c (8.0 mmol)
was added and the solution was stirred for 60 min (< –95 °C). The
mixture was treated with conc. HCl–MeOH–THF (1:1:4, 4.5 mL),
and was allowed to warm to r.t. Then, aq sat. NaHCO3 solution was
added until pH 8, the organic solvent was removed under vacuum
(40 °C), and the remaining solution was extracted with CH2Cl2 (3
30 mL). The organic layer was dried (MgSO4), the solvent was re-
moved under vacuum and the crude residue was purified by column
chromatography with cyclohexane–EtOAc (2:1) as the eluent.
Ph
H
H
CH2OH
CH2NMe2
(CH2)3Me
CH2NMe2
(CH2)3Me
CH2NMe2
(CH2)3Me
CH2NMe2
Ph
H
H
Ph
H
H
Ph
OMe
OMe
OMe
OMe
7g
7h
7i
Ph
Ph
OCH2O
OCH2O
Ph
7k
4-MeOC6H4
OMe
OMe
6-(2-Bromo- -hydroxybenzyl)-5-methoxy-3-phenyl-1,2,4-tri-
azine (3a)
From 1a (374 mg) and 2a (1.48 g); yield: 566 mg (76%); light yel-
low crystals; mp 171–172 °C.
1H NMR (300 MHz, CDCl3): = 8.44 (2 H, m, ArH), 7.48 (5 H, m,
ArH), 7.18 (1 H, m, ArH), 7.09 (1 H, m, ArH), 6.50 (1 H, s, CHOH),
4.76 (1 H, s, OH), 4.03 (3 H, s, OCH3).
13C NMR (75.4 MHz, CDCl3): = 163.1, 160.8, 149.6, 139.4,
134.4, 133.2, 131.9, 129.8, 129.3, 128.9, 128.4, 127.8, 124.1, 70.0,
54.2.
transformation and could be desilylated only with TBAF,
and not with HCl. The different behaviour of 1- and 2-
azafluorenone derivatives in these reactions can be ex-
plained in terms of more effective delocalization of charge
in the transition state 8 in the case of the 2-azafluorenone.
In summary, it has been shown that the 1,2,4-triazines are
suitable precursors for the formation of 2-azafluorenone
ring. Moreover, the method allows widely varying substi-
tuents in the pyridine and benzene moiety. Finally, 2-
azafluorenones 7 were prepared in excellent overall yields
of 27–61% from readily available starting materials.
Anal. Calcd for C17H14BrN3O2: C, 54.86; H, 3.79; N, 11.29. Found:
C, 55.08; H, 3.83; N, 11.25.
Synthesis 2002, No. 17, 2532–2536 ISSN 0039-7881 © Thieme Stuttgart · New York

2534
T. Hundsdorf et al.
PAPER
6-(2-Bromo-3,4-dimethoxy- -hydroxybenzyl)-5-methoxy-3-
phenyl-1,2,4-triazine (3b)
138.5, 133.0, 132.3, 131.7, 131.6, 129.9, 128.0, 127.9, 126.5, 119.7,
53.6.
From 1a (374 mg) and 2b (1.96 g); yield: 572 mg (66%); light yel-
low crystals; mp 154–155 °C.
Anal. Calcd for C17H12BrN3O2: C, 55.16; H, 3.27; N, 11.35. Found:
C, 55.00; H, 3.49; N, 11.49.
IR (KBr): 3533, 3065, 2947, 1591, 1510, 1453, 1400, 1367, 775,
709 cm–1.
6-(2-Bromo-3,4-dimethoxybenzoyl)-5-methoxy-3-phenyl-1,2,4-
triazine (4b)
1H NMR (300 MHz, DMSO-d6): = 8.42 (2 H, m, ArH), 7.59 (3 H,
m, ArH), 7.41 (1 H, s, ArH), 7.10 (1 H, s, ArH), 6.53 (1 H, d,
J = 6.05 Hz, CHOH), 6.24 (1 H, d, J = 6.05 Hz, CHOH), 4.19 (3 H,
s, OCH3), 3.82 (3 H, s, OCH3), 3.79 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 161.8, 161.1, 151.2, 148.7,
147.9, 134.3, 132.5, 131.7, 128.9, 127.7, 115.1, 112.3, 111.1, 68.3,
55.9, 55.6, 54.2.
From 3b (216 mg); yield: 196 mg (91%); light yellow crystals; mp
168–169 °C.
IR (KBr): 2947, 1690, 1604, 1519, 1446, 1387, 1367, 1216, 985,
775 cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.50 (2 H, m, C6H5), 7.62 (3
H, m, C6H5), 7.37 (1 H, s, ArH), 7.30 (1 H, s, ArH), 4.21 (3 H, s,
OCH3), 3.90 (3 H, s, OCH3), 3.81 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 189.5, 162.3, 160.9, 152.7,
148.0, 147.0, 133.8, 132.5, 129.7, 129.0, 128.4, 116.3, 114.1, 113.2,
56.3, 55.9, 54.6.
Anal. Calcd for C19H18BrN3O4: C, 52.79; H, 4.20; N, 9.72. Found:
C, 52.50; H, 4.32; N, 10.04.
6-(2-Bromo- -hydroxy-4,5-methylenedioxybenzyl)-5-methoxy-
3-phenyl-1,2,4-triazine (3c)
From 1a (374 mg) and 2c (1.832 g); yield: 516 mg (62%); light yel-
low crystals; mp 135–137 °C.
Anal. Calcd for C19H16BrN3O4: C, 53.04; H, 3.75; N, 9.77. Found:
C, 52.76; H, 3.75; N, 9.42.
IR (KBr): 3342, 3039, 2854, 1552, 1459, 1380, 1038, 900, 168, 703
cm–1.
6-(2-Bromo-3,4-methylenedioxybenzoyl)-5-methoxy-3-phenyl-
1,2,4-triazine (4c)
From 3c (208 mg); yield: 174 mg (84%); light yellow crystals; mp
138–140 °C.
IR (KBr): 2927, 1677, 1552, 1525, 1486, 1374, 1255, 985, cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.52 (2 H, m, ArH), 7.67 (3 H,
m, ArH), 7.39 (1 H, s, ArH), 7.36 (1 H, s, ArH), 6.10 (2 H, s, CH2),
4.20 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 189.4, 170.0, 162.4, 151.3,
147.3, 146.4, 133.7, 132.5, 131.4, 129.0, 128.4, 113.5, 113.4, 111.0,
103.0, 54.6.
1H NMR (300 MHz, DMSO-d6): = 8.42 (2 H, m, ArH), 7.60 (3 H,
m, ArH), 7.31 (1 H, s, ArH), 7.18 (1 H, s, ArH), 6.52 (1 H, d,
J = 6.05 Hz, CHOH), 6.23 (1 H, d, J = 6.05 Hz, CHOH), 6.10 (2 H,
d, J = 6.15 Hz, CH2), 4.20 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 161.2, 160.7, 151.1, 147.4,
147.0, 134.3, 134.2, 131.7, 128.9, 127.7, 111.8, 111.5, 109.1, 101.9,
68.2, 54.3.
Anal. Calcd for C18H14BrN3O4: C, 51.94; H, 3.39; N, 10.10. Found:
C, 52.08; H, 3.32; N, 10.24.
Anal. Calcd for C18H12BrN3O4: C, 52.19; H, 2.92; N, 10.14. Found:
C, 51.86; H, 2.89; N, 10.12.
6-(2-Bromo-3,4-dimethoxy- -hydroxybenzyl)-5-methoxy-3-(4-
methoxyphenyl)-1,2,4-triazine (3d)
From 1b (434 mg) and 2b (1.96 g); yield: 434 mg (47%); light yel-
low crystals; mp 168–170 °C.
IR (KBr): 3508, 3060, 2897, 1584, 1500, 1453, 1390, 709 cm–1.
6-(2-Bromo-3,4-dimethoxybenzoyl)-5-methoxy-3-(4-methoxy-
phenyl)-1,2,4-triazine (4d)
From 3d (231 mg); 191 mg (83%); light yellow crystals; mp 182–
183 °C.
1H NMR (300 MHz, DMSO-d6): = 8.35 (2 H, d, J = 8.2 Hz, ArH),
7.39 (1 H, s, ArH), 7.11 (2 H, d, J = 8.2 Hz, ArH), 7.08 (1 H, s,
ArH), 6.42 (1 H, d, J = 5.85 Hz, CHOH), 6.21 (1 H, d, J = 5.85 Hz,
CHOH), 4.16 (3 H, s, OCH3), 3.85 (3 H, s, OCH3), 3.80 (3 H, s,
OCH3), 3.77 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 162.1, 161.0, 160.5, 150.5,
148.7, 148.0, 132.7, 129.5, 126.6, 115.2, 114.3, 112.5, 111.1, 68.3,
55.9, 55.6, 55.3, 54.0.
IR (KBr): 3007, 2941, 2839, 1683, 1607, 1510, 1459, 1362, 1265,
1164, 1031, 853, cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.46 (2 H, d, J = 8.2 Hz, ArH),
7.33 (1 H, s, ArH), 7.27 (1 H, s, ArH), 7.17 (2 H, d, J = 8.2 Hz,
ArH), 4.18 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 3.88 (3 H, s,
OCH3), 3.79 (3 H, s, OCH3).
13C NMR (75.4 MHz, DMSO-d6): = 191.5, 164.6, 163.9, 162.5,
154.3, 149.8, 147.8, 132.1, 131.9, 127.8, 118.1, 116.3, 115.9, 114.7,
58.0, 57.7, 57.2, 56.1.
Anal. Calcd for C20H20BrN3O5: C, 51.96; H, 4.36; N, 9.09. Found:
C, 51.66; H, 4.34; N, 8.87.
Anal. Calcd for C20H18BrN3O5: C, 52.19; H, 3.94; N, 9.13. Found:
C, 52.30; H, 3.80; N, 9.24.
6-(2-Bromobenzoyl)-5-methoxy-1,2,4-triazines 4a–d; General
Procedure
To a solution of 3a–d (0.5 mmol) in THF (20 mL) was added MnO2
(0.87 g, 10.0 mmol), and this suspension was stirred at r.t. for 5 h.
The mixture was filtered, the solvent evaporated under vacuum, and
the crude residue was purified by column chromatography with cy-
clohexane–EtOAc (1:1) as the eluent.
5-Methoxy-6-[2-(trimethylsilylethynyl)benzoyl]-3-phenyl-
1,2,4-triazine (6a)
To a solution of 4a (0.35 mmol, 130 mg) in DMF (2.0 mL) and Et3N
(2.0 mL) was added CuI (3.0 mg, 16 mol) and PdCl2(Ph3P)2 (10
mg, 14 mol). The mixture was stirred at r.t. for 20 min. Then tri-
methylsilylacetylene (5a; 0.1 mL, 0.79 mmol) was added, and the
mixture stirred at r.t. for 3 h. H2O (10 mL) and Et2O (10 mL) were
added, and the mixture was extracted with CH2Cl2 (3 20 mL). The
organic layers were separated, dried (MgSO4) and purified by
column chromatography (cyclohexane–EtOAc, 1:1); yield: 123 mg
(91%); light yellow crystals; mp 113–114 °C.
6-(2-Bromobenzoyl)-5-methoxy-3-phenyl-1,2,4-triazine (4a)
From 3a (186 mg); yield: 178 mg (96%); light yellow crystals; mp
135–136 °C.
1H NMR (300 MHz, CDCl3): = 8.52 (2 H, m, ArH), 7.44 (7 H, m,
ArH), 4.22 (3 H, s, OCH3).
13C NMR (75.4 MHz, CDCl3): = 190.6, 162.4, 160.5, 144.7,
1H NMR (300 MHz, CDCl3): = 8.60 (2 H, d, J = 8.1, ArH), 7.89
Synthesis 2002, No. 17, 2532–2536 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Synthesis of 2-Azafluorenones
2535
(1 H, m, ArH), 7.55 (6 H, m, ArH), 4.23 (3 H, s, OCH3), –0.08 [9 H,
s, Si(CH3)3].
13C NMR (75.4 MHz, CDCl3): = 191.6, 163.0, 161.2, 147.3,
144.3, 139.4, 134.2, 134.1, 132.3, 132.2, 129.7, 128.9, 128.8, 123.4,
102.8, 102.2, 54.3, 0.1.
13C NMR (75.4 MHz, DMSO-d6): = 190.9, 164.3, 158.0, 156.8,
140.3, 138.5, 134.5, 133.8, 131.1, 129.3, 129.2, 128.1, 125.8, 123.1,
122.8, 111.4, 57.0, 53.5.
EIMS: m/z (%) = 317 (M+, 100), 302 (13), 257 (21), 227 (21), 115
(17), 28 (60).
Anal. Calcd for C22H21N3O2Si: C, 68.19; H, 5.46; N, 10.84. Found:
C, 68.31; H, 5.35; N, 11.02.
Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N, 4.41. Found: C,
75.69; H, 4.90; N, 4.31.
1-Methoxy-4-(trimethylsilyl)-3-phenyl-2-azafluorenone (7a)
The alkyne 6a (97 mg, 0.25 mmol) in triisopropylbenzene (TIPB, 5
mL) was heated to 120 °C for 1 h. The mixture was cooled, the sol-
vent removed under high vacuum (0.1 mbar) and the crude residue
was purified by column chromatography (cyclohexane–EtOAc,
1:1); yield: 79 mg (88%); yellow crystals; mp 247–248 °C.
1H NMR (300 MHz, CDCl3): = 7.67 (2 H, m, ArH), 7.55 (2 H, m,
ArH), 7.42 (5 H, m, ArH), 4.09 (3 H, s, OCH3), 0.05 [9 H, s,
Si(CH3)3].
1-Methoxy-4-[(dimethylamino)methyl]-3-phenyl-2-azafluor-
enone (7d)
From 4a (92 mg) and 5c (42 mg); yield: 65 mg (76%); yellow crys-
tals; mp 212–214 °C.
IR (KBr): 2961, 2863, 1719, 1564, 1466, 1396, 1354, 1319, 996,
772 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.85 (1 H, d, J = 7.58 Hz, H-
9), 7.69 (2 H, m, ArH), 7.54 (6 H, m, ArH), 3.99 (3 H, s, OCH3),
3.69 (2 H, s, CH2NMe2), 1.97 [6 H, s, CH2N(CH3)2].
13C NMR (75.4 MHz, DMSO-d6): = 190.1, 165.7, 157.8, 156.3,
140.8, 139.4, 134.3, 133.7, 130.8, 129.3, 128.5, 127.8, 126.8, 122.8,
122.0, 111.8, 55.1, 53.4, 44.4.
EIMS: m/z (%) = 344 (M+, 34), 329 (25), 300 (95), 285 (38), 264
(25), 239 (22), 227 (16), 166 (10), 148 (25), 126 (6), 84 (7), 58
(100).
13C NMR (75.4 MHz, CDCl3): = 191.5, 172.0, 165.1, 159.9,
143.9, 143.2, 135.2, 133.1, 130.6, 129.8, 129.6, 128.3, 125.8, 123.8,
121.8, 112.1, 53.9, 2.2.
EIMS: m/z (%) = 359 (M+, 38), 344 (100), 314 (20), 73 (18).
Anal. Calcd for C22H21NO2Si: C, 73.50; H, 5.89; N, 3.90. Found: C,
73.19; H, 5.94; N, 3.83.
Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C,
76.77; H, 5.81; N, 8.40.
1-Methoxy-3-phenyl-2-azafluorenone (7b)
To a solution of 7a (24 mg, 67 mol) in MeOH–CH2Cl2 (1:1, 20
mL) was added conc. HCl (0.5 mL). The solution was stirred at r.t.
for 24 h. Aq sat. NaHCO3 (10 mL) was then added and the mixture
was extracted with CH2Cl2 (3 20 mL). The combined organic lay-
ers were dried (MgSO4) and the solvent removed under vacuum.
The crude product was purified by column chromatography (cyclo-
hexane–EtOAc, 1:1); yield: 18 mg (98%); yellow crystals; mp
208 °C.
1H NMR (300 MHz, CDCl3): = 8.09 (2 H, m, ArH), 7.48 (8 H, m,
ArH), 4.17 (3 H, s, OCH3).
13C NMR (75.4 MHz, CDCl3): = 189.6, 163.5, 161.2, 157.2,
140.9, 138.1, 133.8, 131.2, 130.5, 128.9, 128.8, 127.5, 124.1, 121.2,
120.2, 105.8, 54.0.
4-Butyl-1-methoxy-3-phenyl-2-azafluorenone (7e)
From 4a (92 mg) and 5d (41 mg); yield: 68 mg (79%); yellow crys-
tals; mp 141–143 °C.
IR (KBr): 3046, 2953, 2868, 1710, 1597, 1571, 1469, 1394, 1005,
894, 749, 705 cm–1.
1H NMR (300 MHz, CDCl3): = 7.70 (1 H, dd, J = 7.5, 0.73 Hz, H-
9), 7.59 (1 H, d, J = 7.55 Hz, ArH), 7.43 (7 H, m, ArH), 4.03 (3 H,
s, OCH3), 2.83 (2 H, m, ArCH2), 1.49 (2 H, m, ArCH2CH2), 1.23 (2
H, m, ArCH2CH2CH2CH3), 0.76 (3 H, t, J = 7.3 Hz, CH2CH3).
13C NMR (75.4 MHz,CDCl3): = 186.2, 160.0, 152.8, 149.2,
136.4, 134.8, 129.6, 128.7, 125.1, 123.5, 123.2, 122.9, 120.4, 118.9,
118.8, 107.2, 48.8, 27.1, 23.1, 17.4, 8.4.
EIMS: m/z (%) = 287 (M+, 100), 257 (35), 228 (14), 149 (16).
EIMS: m/z (%) = 343 (M+, 97), 314 (11), 300 (100), 285 (37), 270
(5), 239 (10), 86 (14), 71 (5), 57 (18).
Anal. Calcd for C19H13NO2: C, 79.43; H, 4.56; N, 4.87. Found: C,
79.16; H, 4.53; N, 4.82.
Anal. Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C,
80.22; H, 6.18; N, 4.02.
1-Methoxy-2-azafluorenones 7c–k; General Procedure
To 4a–d (0.25 mmol) in DMF (2.0 mL) and tripropylamine (2.0
mL) was added CuI (2.0 mg, 11 mol) and PdCl2(Ph3P)2 (7.0 mg,
10 mol). The solution was stirred at r.t. for 20 min. Then the cor-
responding acetylene 5b–d (0.50 mmol) was added, and the mixture
was stirred under Ar at 100–120 °C for 1–1.5 h (TLC control). The
solvent was removed under vacuum and the crude product was pu-
rified by column chromatography with cyclohexane–EtOAc (2:1)
(for 7e, cyclohexane–EtOAc, 3:1) as the eluent.
1,6,7-Trimethoxy-4-[dimethylamino)methyl]-3-phenyl-2-
azafluorenone (7f)
From 4b (107 mg) and 5c (42 mg); yield: 65 mg (64%); light orange
crystals; mp 174–176 °C.
IR (KBr): 2947, 2868, 2782, 1716, 1578, 1499, 1466, 1387, 1288,
1216, 1025, 782, 716 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.48 (5 H, m, C6H5), 7.46 (1
H, s, ArH), 7.20 (1 H, s, ArH), 3.94 (3 H, s, OCH3), 3.93 (3 H, s,
OCH3), 3.88 (3 H, s, OCH3), 3.66 (2 H, s, CH2NMe2), 2.00 [6 H, s,
CH2N(CH3)2].
13C NMR (75.4 MHz, DMSO-d6): = 189.4, 165.4, 157.1, 156.3,
153.0, 150.5, 139.6, 135.0, 129.2, 128.4, 127.9, 126.8, 121.0, 111.8,
110.5, 105.9, 55.8, 55.2, 53.3, 44.4.
4-Hydroxymethyl-1-methoxy-3-phenyl-2-azafluorenone (7c)
From 4a (92 mg) and 5b (28 mg); yield: 66 mg (84%); yellow crys-
tals; mp 215–217 °C.
IR (KBr): 3531, 3091, 2961, 2912, 1694, 1607, 1566, 1383, 1321,
1235, 1081, 975, 756, 700 cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.07 (1 H, d, J = 7.8 Hz, H-9),
7.82 (2 H, m, ArH), 7.70 (2 H, m, ArH), 7.54 (4 H, m, ArH), 5.55
(1 H, t, J = 3.9 Hz, OH), 4.65 (2 H, d, J = 3.9 Hz, CH2OH), 4.02 (3
H, s, OCH3).
EIMS: m/z (%) = 404 (M+, 35), 389 (29), 360 (100), 330 (9), 302
(8), 202 (9), 58 (38).
Anal. Calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C,
71.03; H, 5.71; N, 6.58.
Synthesis 2002, No. 17, 2532–2536 ISSN 0039-7881 © Thieme Stuttgart · New York

2536
T. Hundsdorf et al.
PAPER
4-Butyl-1,6,7-trimethoxy-3-phenyl-2-azafluorenone (7g)
From 4b (107 mg) and 5d (41 mg); yield: 78 mg (78%); light orange
crystals; mp 178–179 °C.
13C NMR (75.4 MHz, DMSO-d6): = 189.5, 165.2, 159.5, 157.1,
156.2, 152.9, 150.5, 135.1, 131.8, 130.8, 126.9, 121.0, 113.3, 111.4,
110.6, 105.9, 55.8, 55.3, 55.1, 53.1, 44.3.
IR (KBr): 3006, 2954, 2881, 1710, 1578, 1499, 1400, 1295, 1229,
1018, 795, 716 cm–1.
EIMS: m/z (%) = 434 (M+, 38), 419 (21), 390 (100), 374 (9), 58
(66).
1H NMR (300 MHz, DMSO-d6): = 7.52 (5 H, m, C6H5), 7.23 (1
H, s, ArH), 7.21 (1 H, s, ArH), 3.93 (6 H, s, 2 OCH3), 3.89 (3 H, s,
OCH3), 2.81 (2 H, m, ArCH2), 1.44 (2 H, m, ArCH2CH2), 1.28 (2 H,
m, ArCH2CH2CH2CH3), 0.70 (3 H, t, J = 7.3 Hz, CH2CH3).
13C NMR (75.4 MHz, DMSO-d6): = 189.5, 164.9, 157.6, 153.8,
153.3, 150.5, 139.5, 134.8, 128.4, 128.2, 128.1, 127.4, 124.4, 111.9,
107.9, 106.5, 55.9, 55.8, 53.2, 31.8, 27.5, 22.1, 13.5.
Anal. Calcd for C25H26N2O5: C, 69.11; H, 6.03; N, 6.45. Found: C,
68.95; H, 5.96; N, 6.33.
Acknowledgement
We are grateful to Deutscher Akademischer Austauschdienst
(DAAD) for a fellowship to E.V.B. and to Deutsche Forschungsge-
meinschaft (DFG) for support to T. H.
EIMS: m/z (%) = 403 (M+, 100), 388 (7), 360 (40), 344 (10), 302
(7).
Anal. Calcd for C25H25NO4: C, 74.42; H, 6.25; N, 3.47. Found: C,
74.43; H, 6.22; N, 3.30.
References
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L.; Utsugi, T.; Yamada, Y.; Oscheroff, N. Biochemistry
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16, 1259. (b) Fuson, R. C.; Miller, J. J. J. Am. Chem. Soc.
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P. Khim. Geterotsikl. Soedin. 1972, 1664; Chem. Abstr.
1973, 78, 71879. (e) Prostakov, N. S.; Obynochnyi, A. A.;
Dorogov, V. V.; Zvolinskiy, V. P.; Zakharov, V. P.; Savina,
A. A. Khim. Geterotsikl. Soedin. 1977, 814; Chem. Abstr.
1977, 87, 201278. (f) Shiao, M. J.; Peng, C. J.; Wang, J. S.;
Ma, Y. T. J. Chin. Chem. Soc. (Taipei, Taiwan) 1992, 39,
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K. H.; Lin, P. Y. Heterocycles 1993, 36, 507.
4-[(Dimethylamino)methyl]-1-methoxy-6,7-methylenedioxy-3-
phenyl-2-azafluorenone (7h)
From 4c (103 mg) and 5c (42 mg); yield: 55 mg (57%); light orange
crystals; mp 174–176 °C.
IR (KBr): 2940, 2874, 2776, 1710, 1585, 1486, 1394, 1295, 1038,
1012, 801, 709 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.50 (5 H, m, C6H5), 7.29 (1
H, s, ArH), 7.15 (1 H, s, ArH), 6.21 (2 H, s, CH2), 3.94 (3 H, s,
OCH3), 3.60 (2 H, s, CH2NMe2), 1.95 [6 H, s, CH2N(CH3)2].
13C NMR (75.4 MHz, DMSO-d6): = 189.6, 165.7, 157.7, 156.5,
153.1, 149.2, 139.5, 137.1, 129.2, 128.8, 128.5, 127.9, 121.1, 112.1,
107.9, 103.5, 102.7, 55.0, 53.3, 44.3.
EIMS: m/z (%) = 388 (M+, 47), 373 (26), 344 (100), 329 (20), 309
(9), 58 (66).
Anal. Calcd for C23H20N2O4: C, 71.12; H, 5.19; N, 7.21. Found: C,
71.03; H, 5.31; N, 7.08.
4-Butyl-1-methoxy-6,7-methylenedioxy-3-phenyl-2-azafluo-
renone (7i)
From 4c (103 mg) and 5d (41 mg); yield: 76 mg (79%); light orange
crystals; mp 204–205 °C.
IR (KBr): 3085, 2954, 2927, 2868, 1716, 1578, 1486, 1387, 1288,
1038, 999, 709 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.50 (5 H, m, C6H5), 7.25 (1
H, s, ArH), 7.18 (1 H, s, ArH), 6.22 (2 H, s, OCH2O), 3.91 (3 H, s,
2 OCH3), 2.80 (2 H, m, ArCH2), 1.44 (2 H, m, ArCH2CH2), 1.22 (2
H, m, ArCH2CH2CH2CH3), 0.72 (3 H, t, J = 7.3 Hz, CH2CH3).
(h) Yagupolskiy, L. M.; Petko, K. I.; Retchitsy, A. N.;
Maletina, I. I. J. Fluorine Chem. 1994, 67, 5. (i)Sreekumar,
R.; Rugmini, P.; Padmakumar, R. Synth. Commun. 1998, 28,
2071.
(7) Kuba, E. P.; Liu, S.; Chockalingam, K.; Reddy, B. R. J. Org.
Chem. 1988, 53, 3513.
(8) (a) Renfrew, A. H.; Bostock, S. B. J. Chem. Soc., Perk.
Trans. 1 1977, 84. (b) Chorvat, R. J.; Desai, B. N. J.
Heterocycl. Chem. 1980, 17, 1313. (c) Junek, H.; Klade, M.;
Sterk, H. Monatsh. Chem. 1989, 120, 781.
(9) Mayor, C.; Wentrup, C. J. Am. Chem. Soc. 1975, 97, 7467.
(10) Daunis, J.; Jacquier, R.; Pigiere, C. Tetrahedron 1974, 30,
3171.
13C NMR (75.4 MHz, DMSO-d6): = 189.1, 165.3, 157.2, 154.0,
153.7, 149.7, 139.6, 136.6, 128.9, 128.5, 128.2, 128.0, 124.5, 111.8,
105.5, 104.1, 53.3, 31.7, 21.9, 21.6, 22.1, 13.3.
EIMS: m/z (%) = 387 (M+, 100), 358 (9), 344 (73), 329 (21).
Anal. Calcd for C24H21NO4: C, 74.40; H, 5.46; N, 3.62. Found: C,
74.23; H, 5.55; N, 3.31.
1,6,7-Trimethoxy-4-[(dimethylamino)methyl]-3-(4-methoxy-
phenyl)-2-azafluorenone (7k)
(11) Snieckus, V. Chem. Rev. 1990, 90, 879.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Sonogashira, K. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998, 203–229.
(c) Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999,
549. (d) Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis
1999, 306.
From 4d (115 mg) and 5c (42 mg); yield: 74 mg (68%); orange crys-
tals; mp 250 °C.
IR (KBr): 3073, 3022, 2976, 2951, 2844, 2778, 1703, 1576, 1495,
1454, 1388, 1291, 1250, 1174, 1026, 1016, 838, 777 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.45 (3 H, m, ArH), 7.17 (1 H,
s, ArH), 7.05 (2 H, d, J = 8.73 Hz, ArH), 3.94 (3 H, s, OCH3), 3.93
(3 H, s, OCH3), 3.87 (3 H, s, OCH3), 3.84 (3 H, s, OCH3) 3.70 (2 H,
s, CH2NMe2), 2.00 [6 H, s, CH2N(CH3)2].
(13) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P.
Synthesis 1984, 728.
Synthesis 2002, No. 17, 2532–2536 ISSN 0039-7881 © Thieme Stuttgart · New York