Cu(I)-catalyzed intramolecular cyclizations of substituted 2-iodobenzophenones under thermal and microwave conditions

Article abstract of DOI:10.1016/j.tet.2013.05.077

Novel, easy-to-perform and practical intramolecular Cu(I)-catalyzed cyclizations of substituted 2-iodobenzophenones under thermal and microwave conditions are reported. The isolated cyclized products under microwave conditions are obtained with high yields and with short reaction times offering a valuable and reliable alternative to other protocols for the synthesis of fluorene analogues.

Full text of DOI:10.1016/j.tet.2013.05.077

Tetrahedron 69 (2013) 6488e6494
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cu(I)-catalyzed intramolecular cyclizations of substituted
2-iodobenzophenones under thermal and microwave conditions
*
Reda A. Haggam
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel, easy-to-perform and practical intramolecular Cu(I)-catalyzed cyclizations of substituted 2-
iodobenzophenones under thermal and microwave conditions are reported. The isolated cyclized
products under microwave conditions are obtained with high yields and with short reaction times of-
fering a valuable and reliable alternative to other protocols for the synthesis of fluorene analogues.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 22 October 2012
Received in revised form 3 May 2013
Accepted 20 May 2013
Available online 24 May 2013
Keywords:
Copper arylations
Microwaves
Domino reactions
Fluorenones
Cyclizations
1. Introduction
acids, two naturaldyes with a fluorene framework, have been isolated
from the red sweat of Hippopotamus amphibius by Hashimoto, Nakata
Fluoren-9-one and its derivatives are currently attracting
widespread interest owing to their utilization in several diverse
fields. For instance, due to their attractive luminescent properties,
fluorenone-based materials are employed as organic and polymer
light-emitting diodes, bulk heterojunction solar cells and photo-
chemical sensitizers.1 In addition, fluoren-9-ones have pharma-
ceutical applications2e4 and are key building blocks of many
natural products.5 The synthesis of substituted fluorenones is
therefore an important topic for synthetic chemists.
Moreover, there are biologically active fluoren-9-ones, such as
dendroflorin, denchrysan A and 1,4,5-trihydroxy-7-methoxyfluoren-
9-one, which have been isolated from plants. These fluorene ana-
logues are used as health-foods.6 The three compounds were evalu-
ated in vitro for their inhibitory effects against the growth of the
human lung adenocarcinoma A549 and the human stomach cancer
SGC-7901. Additionally, tilorone hydrochloride with a fluorene skel-
eton has been recognized to be an orally active interferon stimulating
agent.7 It is also used as an antiviral drug for the treatment of
a number of viral diseases, diarrhea, herpes and hepatitis.8 The telo-
merase enzyme is an essential factor in tumorigenesis.9 So, there is
a great interest in the inhibition of telomerase as a new anticancer
strategy.10 During the last decade hipposudoric and norhipposudoric
et al.2bed It has been demonstrated that hipposudoric acid exhibits
antibiotic activity while the two natural dyes may act as sunscreens.
To conclude, fluorenes and related compounds have a broad
spectrum biological activities. Various methods have been de-
veloped to synthesize these compounds. For example, one ap-
proach involves the intramolecular FriedeleCrafts acylation of
biaryls.11 Using an alternative directed metallation methodologies,
Snieckus and co-workers have prepared a range of substituted
fluoren-9-ones.12 Langer et al., have recently reported the synthesis
of fluoren-9-one using a [3þ3] cyclization/Suzuki cross-coupling/
FriedeleCrafts acylation route starting from a 1,3-bis-silyl enol
ether and a silyloxypentenone.13
Over the past years notable progress has been achieved in the
field of Cu(I)-catalyzed C-, N-, O- and S-arylations.14 Depending on
the substrate ratio and the reaction conditions, 4H-chromenes or
naphthalenes were synthesized via Cu(I)-catalyzed domino
reactions.15
2. Results and discussion
We report a new and simple intramolecular Cu(I)-catalyzed cycli-
zation of substituted 2-iodobenzophenones to methoxy-substituted
fluoren-9-ones under both thermal and microwave conditions. The
deprotection of the methoxy-substituents wasperformed using boron
tribromide16 to liberate the hydroxyfluoren-9-one derivative. For this
strategy, the substituted 2-aminobenzophenones 1aef were prepared
* Tel.: þ20 1000960389; fax: þ20 552308213; e-mail address: rhaggam@
yahoo.com.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.077

R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
6489
Table 2
by the reduction of the nitro group of the substituted 2-
nitrobenzophenones as starting materials. The reduction process
was achieved according to the procedure of Stephenson et al.17 The
substituted 2-iodobenzophenones 2aef were prepared with yields
ranging from 65 to 73% via the protocol of Coffen et al.18 (Scheme 1).
The influence of the reaction time on the cyclization of 2a into 5a with 3.0 equiv
K3PO4
Entry
CuI (mol %)
Time (h)
Yield (%)a 5a
1
2
3
4
5
6
7
8
6.0
6.0
8.0
10.0
12.0
14.0
15.0
16.0
24
35
40
42
48
48
48
48
15
37
49
55
78
85
89
89
2.3 equiv. n-amyl nitrite
R1
R2
O
R3
R6
R1
R2
O
I
R3
AcOH
R4
R5
2.3 equiv. KI
r.t, 3 h
R4
R5
65-73%
H2N
a
Isolated yields.
R6
1a-f
2a-f
Scheme 1. Preparation of the starting materials 2aef.
was performed with 6.0 mol % Cu(I) for 35 h, the yield of 5a was 37%
(Table 2, entry 2). We observed the yield of the product was 55% on
using 10.0 mol % Cu(I) for 42 h (Table 2, entry 4). On carrying out the
reaction using 12.0 mol % and 14.0 mol % Cu(I) for 48 h, 5a was
isolated in 78% and 85% yield, respectively (Table 2, entries 5, 6).
The best yield of 5a was 89% when the reaction was run for 48 h
using 15.0e16.0 mol % Cu(I), (Table 2, entries 7, 8).
Further experiments revealed that the influence of the amount
of the base on the formation of 5a was studied (Scheme 2, Table 3).
With 0.5 equiv K3PO4 it was possible to separate the product 5a
with yield 78% (Table 3, entry 1). It was found that the yield slightly
differs by increasing the amount of the base (Table 3, entries 1e4).
The highest yield (89%) of 5a was observed when 2a was treated
with 3.0 equiv K3PO4 and 15.0 mol % Cu(I) for 48 h.
Unfortunately, we could not prepare (2,5-dimethoxyphenyl)(20-
iodophenyl)methanone (2c) by the procedure of Coffen et al.18
Therefore, 2c was synthesized by FriedeleCrafts acylation of 1,4-
dimethoxybenzene (3) with 2-iodobenzoic acid (4) with 98%
yield according to the method described by Qabaja and Jones.19,20
With the substituted 2-iodobenzophenones 2aef in hand we
were ready to investigate their Cu(I)-catalyzed cyclizations. In or-
der to optimize the reaction, the Cu(I)-catalyzed cyclization of the
unsubstituted 2-iodobenzophenone (2a) was studied under dif-
ferent thermal reaction conditions (Scheme 2).
O
O
CuI(I)/K3PO4
DMF
155 °C
Table 3
I
2a
The influence of the amount of K3PO4 on the model reaction
5a
Entry
CuI (mol %)
K3PO4 (equiv)
Time (h)
Yield (%)a 5a
Scheme 2. Reaction of 2a with Cu(I) in DMF.
1
2
3
4
5
6
15.0
15.0
15.0
15.0
15.0
15.0
0.5
1.0
2.0
3.0
3.5
4.0
48
48
48
48
48
48
78
83
85
89
89
89
Initially, 2-iodobenzophenone (2a) and Cu(I) were reacted un-
der different reaction conditions (Scheme 2, Table 1). We started
with the cyclization of 2a, which was reacted using different
amounts of Cu(I). The formation of 5a was not observed if the re-
action time is 20 h using 4.0 mol % Cu(I). If additional Cu(I) was
employed, we observed a gradual increasing in the yield of the
product and the starting material was consumed only partially
(Table 1, entries 2e6). Thus mixtures of the substrate 2a and fluo-
ren-9-one (5a) were isolated after column chromatography. The
highest yield of 5a was observed when 2a was treated with
15.0e19.0 mol % Cu(I), 3.0 equiv K3PO4 and DMF as a solvent for
24 h at 155 ꢀC (Table 1, entries 7e9). The yield of 5a, however,
amounted to only 47%.
a
Isolated yields.
Optimization of the reaction of 2-iodobenzophenone (2a) with
Cu(I) resulted in a reliable and simple procedure for the synthesis of
the methoxy-substituted fluoren-9-ones with high yields and with
very easy workup. For evaluation the scope of the cyclization of
substituted 2-iodobenzophenones 2aef a series of methoxy-sub-
stituents at different positions of the aromatic ring was tested. The
cyclization was carried out with a number of mono-, di- tri- and
tetrasubstituted 2-iodobenzophenones using the optimized pro-
tocol (Scheme 3, Table 4). The highest yields (92% and 91%) of the
trisubstituted 5d and the tetrasubstituted 5e were isolated when
the reaction was running under thermal conditions for 48 h (Table
4, entries 4, 5). Yields of 5aef were in the range 77e92%.
Table 1
The influence of the amount of Cu(I) on the conversion of 2a into 5a with 3.0 equiv
K3PO4
Entry
CuI (mol %)
Time (h)
Yield 5a (%)a
1
2
3
4
5
6
7
8
9
10
4.0
6.0
8.0
10.0
12.0
14.0
15.0
16.0
18.0
19.0
20
24
24
24
24
24
24
24
24
24
d
15
22
31
36
41
47
47
47
46
R1
R2
O
R3
R6
R1
R2
O
R3
R6
15 mol% Cu(I)
3 equiv. K3PO4
DMF, 155 °C, 48 h
R4
R5
R4
R5
77-92%
a
Isolated yields.
I
After that, we studied the conversion of 2a into 5a under dif-
ferent reaction times (Scheme 2, Table 2). We have found that, no
reaction on using 6.0 mol % Cu(I) within the first 20 h. If the reaction
2a-f
5a-f
Scheme 3. Reaction of substituted 2-iodobenzophenones 2aef with Cu(I) in DMF.

6490
R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
Table 4
DMF
R1
R2
O
R3
R6
15 mol% Cu(I)
3 equiv. K3PO4
MW / 250 W, 160 °C
R1
O
R3
Cu(I)-catalyzed cyclizations of substituted 2-iodobenzophenones 2aef under ther-
mal conditions
R4
R5
R4
R5
Entry
2
R1
R2
R3
R4
R5
R6
5aef (%)a
71-90%
1
2
3
4
5
6
a
b
c
d
e
f
H
H
H
OMe
H
OMe
OMe
H
H
H
H
H
OMe
H
H
H
OMe
OMe
H
H
H
H
OMe
OMe
H
H
H
H
H
H
OMe
89
77
87
92
91
84
I
OMe
OMe
OMe
OMe
OMe
R2
R6
2a-f
5a-f
Scheme 5. Reaction of substituted 2-iodobenzophenones 2aef with Cu(I) in DMF
under microwave conditions.
a
Isolated yields.
Table 6
After the successful Cu(I)-catalyzed cyclizations of the
substituted 2-iodobenzophenones 2aef into the corresponding
methoxy-substituted fluoren-9-ones 5aef, the methoxy groups in
the cyclized products 5bef were transformed into free hydroxyl
groups. A standard method for the cleavage of methoxy groups is
according to the protocol of Bergeron and Bharti.16 After purifica-
tion the hydroxy-sustituted fluoren-9-ones 6bef were isolated
with yields ranging from 60 to 84% (Scheme 4, Table 5, entries 1e5).
Both compounds 6e and 6f were obtained with 80% and 83%,
respectively (Table 5, entries 4, 5), while 6d was obtained with 84%
yield (Table 5, entry 3).
Cu(I)-catalyzed cyclizations of substituted 2-iodobenzophenones 2aef to
substituted fluoren-9-ones 5aef under microwave conditions
Entry
2
R1
R2
R3
R4
R5
R6
Time 5aef Yield
(min)
5aef (%)a
1
2
3
4
5
6
7
8
a
a
b
b
c
c
c
d
d
e
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
20
30
25
30
20
30
35
35
40
55
60
a
a
b
b
c
c
c
d
d
e
e
f
88
83
79
84
71
87
80
82
85
89
90
75
72
OMe
OMe
OMe OMe
OMe OMe
OMe OMe
OMe
OMe
OMe OMe
OMe OMe
H
H
OMe OMe
OMe OMe
OMe OMe
OMe OMe
H
H
9
10
11
12
13
R1
O
R3
R1
O
R3
8 equiv. BBr3
CH2Cl2
R4
R5
R4
R5
OMe OMe OMe
OMe OMe OMe
H
H
OMe 55
OMe 60
- 78 °C, 24 h
60-84%
f
f
a
Isolated yields.
R2
R6
R2
R6
5b-f
6b-f
90% yields within reaction times 55 and 60 min. However, the
tetrasubstituted fluoren-9-one 5f could be obtained with 75% and
72% yields through the same reaction time. The yield decreasing of
compound 5f may due to the crowding effect of the methoxy-
substituents. The reaction time required to cyclize 2f into 5f could
be reduced from 48 h under thermal conditions to 55 min (Table 6,
entry 12). The best yield (90%) of 5e was separated when the re-
action was running for 60 min (Table 6, entry 11). All cyclizations
proceeded within 20e60 min with formation of methoxy-
substituted fluoren-9-ones 5aef in yields of 71e90%.
Scheme 4. Deprotection of the compounds 5bef using BBr3.16
Table 5
Synthesis of hydroxy-substituted fluoren-9-ones 6bef
Entry
5
R1
R2
R3
R4
R5
R6
6bef (%)a
1
2
3
4
5
b
c
d
e
f
OMe
OMe
OMe
OMe
OMe
H
OMe
H
OMe
OMe
H
H
H
H
H
H
OMe
OMe
H
H
H
OMe
OMe
H
H
H
H
H
60
68
84
83
80
Generally, the yields under MW conditions (Table 6) (71e90%)
are approximately in the same range in comparison with the con-
ventional thermal conditions (Table 4) (77e92%) but much shorter
reaction times.
OMe
OMe
a
Isolated yields.
In recent years microwave (MW) irradiation has become
a broadly used tool in organic synthesis. Under MW heating,
chemical reactions usually proceed faster, with shorter reaction
times, in higher yields and can give purer products with fewer side
products.21 As a result of the long reaction times (48 h) under
thermal conditions, the cyclizations of 2aef were repeated under
MW conditions (Scheme 5, Table 6). Microwave assisted reactions
were run at (250 W, 160 ꢀC). To start with, the unsubstituted 2-
iodobenzophenone (2a) was reacted with 15.0 mol % Cu(I) and
3.0 equiv K3PO4 for 20 and 30 min to afford the cyclized product 5a
with 88 and 83% yields (Table 6, entries 1, 2), respectively. It turned
out that indeed the reaction times of the intramolecular cyclization
of 2aef under MW conditions could be shortened. By analysis of
the data in (Table 6) we have found that the substituents affect on
the yields and the rate of the reactions. For example, the mono-
substituted fluoren-9-one 5a was prepared with 88% through re-
action rate of 20 min. On increasing the reaction time to 30 min, the
yield slightly decreased to 83% (Table 6, entries 1, 2). On the other
hand, the disubstituted fluoren-9-one 5b could be synthesized in
79% yield with a reaction time of 25 min. But by increasing the
reaction time to 30 min the yield increases (84%). Another example,
the tetrasubstituted fluoren-9-one 5e was obtained with 89% and
A proposal for the reaction mechanism of the intramolecular
copper-catalyzed cyclization of 2-iodoenzophenones 6 to substituted
fluorenones 9 is shown in Scheme 6.22 It is assumed that the reaction
startswithformation of coordinativeCu(0)species. The secondstep of
the sequence is the oxidative addition of the copper complex into the
CeI bond of 6 generating the intermediate 7, which undergoes
CuI
Cu(0)L
+
I
O
O
I
O
K PO
-HI
Cu
L
Cu
L
RO
RO
OR
OR
RO
OR
I
L
H
L
I
6
7
8
O
O
Cu(0)L
Cu
RO
RO
OR
OR
L
L
9
10
Scheme 6. Proposal for the reaction mechanism of substituted 2-iodobenzophenones
6 with K3PO4 and Cu(I) in DMF.

R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
6491
FreideleCrafts type addition to give a cationic intermediate 8. Sub-
sequently, elimination of HI results in the copper complex 9. Re-
ductive elimination of 9 gives fluorenones 10 with regeneration of the
Cu(0) catalyst.
with n-amyl nitrite (1.46 mL, 10.7 mmol) and potassium iodide
(1.78 g, 10.7 mmol). After column chromatography (SiO2; cyclo-
hexane/EtOAc¼32:1) the title compound 2a (1.32 g, 73%) was iso-
lated as a pale yellow liquid; Rf (cyclohexane/EtOAc¼20:1) 0.40;
nmax (ATR) 3065, 2933, 2821, 1652, 1624, 1597, 1473, 789, 773 cmꢂ1
;
dH (300 MHz, CDCl3) 7.93 (1H, d, 3J 7.8 Hz, 3-H), 7.81 (2H, d, 3J 7.8 Hz,
20-H and 60-H), 7.61 (1H, t, 3J 7.8 Hz, 40-H), 7.48 (1H, d, 3J 7.8 Hz, 30-H
and 50-H), 7.44 (1H, dd, 3J 7.8 Hz, 4J 1.6, 4-H), 7.30 (1H, dd, 3J 7.8 Hz, 4J
1.6, 6-H), 7.19 (1H, dt, 3J 7.8 Hz, 4J 1.6, 5-H); dC (300 MHz, CDCl3)
197.5 (C]O), 144.6 (C-10), 140.0 (C-3), 136.0 (C-1), 134.0 (C-5), 131.4
(C-4), 130.8 (C-30 or C-50), 128.9 (C-20 or C-60), 128.8 (C-6), 128.1 (C-
40), 92.5 (C-2).
3. Conclusion
In summary,
a valuable and simple intramolecular Cu(I)-
catalyzed cyclization of substituted 2-iodobenzophenones to
substituted fluoren-9-ones under thermal and microwave condi-
tions is reported. Achievement the reaction under MW conditions
showed considerably reduction reaction times as well as very good
yields.
4.2.2. (2-Iodophenyl)(20-methoxyphenyl)methanone (2b). According
to the general procedure (2-aminophenyl)(20-methoxyphenyl)
methanone (1b) (1.07 g, 4.73 mmol) was treated with n-amyl nitrite
(1.46 mL,10.7 mmol) and potassium iodide (1.26 g,10.7 mmol). After
column chromatography (SiO2; cyclohexane/EtOAc¼8:1), the title
compound 2b (1.10 g, 69%) was isolated as pale yellow crystals; mp
120e121 ꢀC; Rf (cyclohexane/EtOAc¼4:1) 0.45; nmax (ATR) 3058,
4. Experimental section
4.1. General methods
The structures of the compounds described in this paper have
been elucidated unambiguously by NMR-spectroscopic methods
including HH COSY, HSQC and HMBC experiments. All starting
materials were purchased from commercial suppliers (Sigma-
eAldrich Chemical Co. and Lancaster Organics) and used without
further purification unless otherwise indicated. All reactions were
carried out under an argon atmosphere in oven-dried glassware
with magnetic stirring. Temperatures are reported as inner tem-
peratures. Solvents used in extraction and purification were dis-
tilled prior to use. Thin-layer chromatography (TLC) was performed
on Alugram SIL G/UV 254 (Macherey and Nagel). Compounds were
2927, 2830, 1664, 1638, 1595, 1481, 1239 cmꢂ1
; lmax (MeCN) (log ε)
333 (3.08), 285 (2.88), 260 (3.43), 237 nm; dH (300 MHz, CDCl3) 7.90
(1H, d, 3J 7.9 Hz, 6-H), 7.64 (1H, dd, 3J 7.9 Hz, 4J 1.6 Hz, 3-H), 7.52 (1H,
dt, 3J 7.9 Hz, 4J 1.6 Hz, 4-H), 7.37 (1H, t, 3J 7.6 Hz, 50-H), 7.30 (1H, dd, 3J
7.6 Hz, 60-H), 7.11 (1H, dt, 3J 7.9 Hz, 4J 1.6 Hz, 5-H), 7.03 (1H, t, 3J
3
7.6 Hz, 40-H), 6.94 (1H, d, J 7.6 Hz, 30-H), 3.66 (3H, s, 20-OCH3); dC
(300 MHz, CDCl3) 196.8 (C]O), 159.7 (C-20), 146.1 (C-1), 140.1 (C-3),
134.7 (C-4), 132.3 (C-6), 131.2 (C-5), 129.2 (C-40), 127.0 (C-10), 120.9
(C-60), 118.3 (C-50), 112.3 (C-30), 92.3 (C-2), 56.1 (20-OCH3); m/z (EI,
70 eV) 338 (31, Mþ), 196 (Mþ-CH3I) (100), 32 (18%); HRMS (EI,
70 eV): Mþ, found 337.9830. C14H11IO2 requires 337.9838.
visualized with UV light (
ethanolic vanillin solution followed by heating. Products were
l¼254 nm) and/or by immersion in an
purified by flash chromatography on silica gel 60 M, 230e400 mesh
4.2.3. (2-Iodo-4,5-dimethoxyphenyl)(20methoxyphenyl)methanone
(2d). According to the general procedure (2-amino-4,5-dimeth
oxyphenyl)(20-methoxyphenyl)methanone (1d) (1.36 g, 4.73
mmol) was treated with n-amyl nitrite (1.46 mL, 10.7 mmol) and
potassium iodide (1.78 g, 10.7 mmol). After column chromatogra-
phy (SiO2; cyclohexane/EtOAc¼4:1), the title compound 2d (1.35 g,
72%) was isolated as pale yellow crystals; mp 81e82 ꢀC; Rf (cyclo-
hexane/EtOAc¼3:1) 0.35; nmax (ATR) 2967, 2830, 1645, 1584, 1488,
€
(Macherey & Nagel). Melting points were determined on a Buchi
melting point apparatus B-545 with open capillary tubes and are
uncorrected. IR spectra were measured on a PerkineElmer Spec-
trum One (FT-IR-spectrometer). UV/VIS spectra were recorded with
a Varian Cary 50. 1H (13C) NMR spectra were recorded at 300
(75) MHz on a Varian Inova Spectrometer using CDCl3 or DMSO as
a solvent. The 1H and 13C chemical shifts were referenced to re-
sidual solvent signals at dH/C 7.26/77.00 (CDCl3) and at dH/C 2.49/
39.50 (DMSO) relative to TMS as internal standards. HSQC-, HMBC-
and COSY-spectra were recorded on a Varian Inova at 300 MHz.
Coupling constants J [Hertz] were directly taken from the spectra
and are averaged. Low-resolution electron impact mass spectra
(MS) and exact mass electron impact mass spectra (HRMS) were
obtained at 70 eV on a Finnigan MAT 90 spectrometer. Elemental
1455, 1296 cmꢂ1
; lmax (MeCN) (log ε) 317 (3.53), 239 (4.03), 209
(4.24) nm; dH (300 MHz, CDCl3) 7.55e7.47 (2H, m, 50-H and 60-H),
7.30 (1H, s, 3-H), 7.02 (1H, t, 3J 7.5 Hz, 40-H), 6.95 (1H, d, 3J 7.5 Hz, 30-
H), 6.94 (1H, s, 6-H), 3.91 (3H, s, 4-OCH3), 3.80 (3H, s, 5-OCH3), 3.72
(3H, s, 20-OCH3); dC (300 MHz, CDCl3) 196.1 (C]O), 159.3 (C-20),
151.2 (C-4), 149.0 (C-5), 137.4 (C-1), 134.0 (C-50), 132.0 (C-60), 127.5
(C-10), 122.8 (C-3), 120.9 (C-40), 113.5 (C-6), 112.1 (C-30), 82.7 (C-2),
56.5 (4-OCH3), 56.3 (5-OCH3), 56.1 (20-OCH3); m/z (EI, 70 eV) 398
(100, Mþ), 290 (40), 271 (26), 256 (92), 240 (16),151 (24), 135 (80%);
HRMS (EI, 70 eV): Mþ, found 398.0012. C16H15IO4 requires
398.0026.
€
analyses were carried out at Gottingen University, Germany.
4.2. General procedure for synthesis of methanones 2aef
n-Amyl nitrite (1.46 mL, 10.7 mmol) was added dropwise to
a
solution of the (2-aminophenyl)(phenyl)methanones 1aef
4.2.4. (20,50-Dimethoxyphenyl)(2-iodo-4,5-dimethoxyphenyl)meth-
anone (2e). According to the general procedure (2-amino-4,5-
dimethoxyphenyl)(20,50-dimethoxyphenyl)methanone (1e) (1.50 g,
4.73 mmol) was treated with n-amyl nitrite (1.46 mL, 10.7 mmol)
and potassium iodide (1.78 g, 10.7 mmol). After column chroma-
tography (SiO2; cyclohexane/EtOAc¼3:1), the title compound 2e
(1.32 g, 65%) was isolated as pale yellow crystals; mp 107e108 ꢀC;
[found: C, 47.75; H, 3.84. C17H17IO5 requires C, 47.66; H, 4.00%]; Rf
(cyclohexane/EtOAc¼2:1) 0.45; nmax (ATR) 2960, 2820, 1661, 1585,
(4.73 mmol) in acetic acid (50 mL) and the resulting reaction
mixture was stirred for 1 h at 0 ꢀC. A solution of potassium iodide
(1.78 g, 10.7 mmol) in water (10 mL) was added and the reaction
mixture was stirred for 3 h at room temperature. The reaction
mixture was poured into ice-cold water (300 mL), neutralized with
10% NaOH solution (80 mL) and extracted with dichloromethane
(4ꢁ80 mL). The combined organic layers were washed with water
(2ꢁ50 mL) and brine (2ꢁ50 mL), dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified by column
chromatography (SiO2; cyclohexane/EtOAc).
1493, 1461, 1282 cmꢂ1
; lmax (MeCN) (log ε) 327 (3.15), 260 (3.34)
nm; dH (300 MHz, CDCl3) 7.30 (1H, s, 3-H), 7.12 (1H, d, 4J 3.1 Hz, 60-
H), 7.06 (1H, dd, 3J 8.9 Hz, 4J 3.1 Hz, 40-H), 6.94 (1H, s, 6-H), 6.88 (1H,
4.2.1. 2-Iodobenzophenone (2a).23 According to the general pro-
cedure 2-aminobenzophenone (1a) (1.50 g, 4.73 mmol) was treated
d, J 8.9 Hz, 30-H), 3.92 (3H, s, 5-OCH3), 3.81 (3H, s, 4-OCH3), 3.80
3
(3H, s, 50-OCH3), 3.64 (3H, s, 20-OCH3); dC (300 MHz, CDCl3) 195.8

6492
R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
(C]O), 153.9 (C-50), 153.6 (C-20), 151.2 (C-5), 149.0 (C-4), 137.4 (C-1),
128.0 (C-10), 122.8 (C-3), 120.3 (C-40), 115.8 (C-60), 113.9 (C-30), 113.5
(C-6), 82.5 (C-2), 56.9 (20-OCH3), 56.5 (5-OCH3), 56.3 (4-OCH3), 56.2
(50-OCH3); m/z (EI, 70 eV) 428 (100, Mþ), 291 (28), 286 (83), 271
(16), 255 (10), 165 (25), 151 (17%).
(3ꢁ50 mL). The combined organic layers were dried over anhy-
drous MgSO4 and concentrated in vacuo. The crude product ob-
tained was purified by flash column chromatography over silica gel.
4.3.1. Fluoren-9-one (5a).7 According to the general procedure 2-
iodobenzophenone (2a) (0.31 g, 1.00 mmol), CuI (0.03 g,
0.15 mmol) and K3PO4 (0.64 g, 3.00 mmol) were reacted in DMF
(6 mL) in a sealed vial in an argon atmosphere at 155 ꢀC for 48 h.
After column chromatography over silica gel (cyclohexane/
EtOAc¼3:1), the title compound 5a (0.16 g, 89%) was isolated as
yellow chips; mp 83e84 ꢀC; Rf (cyclohexane/EtOAc¼2:1) 0.42; nmax
4.2.5. (2,5-Dimethoxyphenyl)(20-iodo-30,60-dimethoxyphenyl)meth-
anone (2f). According to the general procedure (2-amino-3,6-
dimethoxyphenyl)(20,50-dimethoxyphenyl)methanone (1f) (1.50 g,
4.73 mmol) was treated with n-amyl nitrite (1.46 mL, 10.7 mmol)
and potassium iodide (1.78 g, 10.7 mmol). After column chroma-
tography (SiO2; cyclohexane/EtOAc¼3:1), the title compound 2f
(1.34 g, 66%) was isolated as pale yellow crystals; mp 195e196 ꢀC;
[found: C, 48.09; H, 3.90. C17H17IO5 requires C, 47.99; H, 4.00%]; Rf
(cyclohexane/EtOAc¼1:1) 0.60; nmax (ATR) 2918, 2800, 1649, 1496,
(ATR) 3053, 2944, 2837,1663,1591,1585 cmꢂ1
; dH (300 MHz, CDCl3)
7.62 (2H, d, 3J 7.3 Hz, 1-H, 8-H), 7.47 (2H, d, 3J 7.3 Hz, 4-H, 5-H), 7.45
(2H, dd, 3J 7.3 Hz, 4J 1.6 Hz, 3-H, 6-H), 7.23 (2H, dd, 3J 7.3 Hz, 4J 1.6 Hz,
2-H, 7-H); dC (300 MHz, CDCl3) 194.2 (C]O), 144.7 (C-4a, C-4b),
134.9 (C-3, C-6), 134.4 (C-8a, C-9a), 129.3 (C-1, C-8), 124.6 (C-4, C-5),
120.6 (C-2, C-7).
1471, 1416, 1283 cmꢂ1
; lmax (MeCN) (log ε) 354 (3.09), 260 (3.34),
226 (3.77) nm; dH (300 MHz, CDCl3) 7.44 (1H, d, 4J 3.2 Hz, 6-H), 7.09
(1H, dd, 3J 8.9 Hz, 4J 3.2 Hz, 4-H), 6.89 (1H, d, 3J 8.9 Hz, 3-H), 6.89
3
3
(1H, d, J 8.9 Hz, 50-H), 6.79 (1H, d, J 8.9 Hz, 40-H), 3.86 (3H, s, 60-
OCH3), 3.81 (3H, s, 2-OCH3), 3.68 (3H, s, 30-OCH3), 3.59 (3H, s, 5-
OCH3); dC (300 MHz, CDCl3) 194.2 (C]O), 155.1 (C-5), 153.8 (C-2),
152.7 (C-60), 151.1 (C-30), 139.7 (C-10), 126.2 (C-1), 122.1 (C-4), 115.6
(C-6), 114.8 (C-50), 112.2 (C-3), 110.9 (C-40), 84.7 (C-20), 57.4 (60-
OCH3), 57.1 (30-OCH3), 57.0 (5-OCH3), 56.1 (2-OCH3); m/z (EI, 70 eV)
428 (100, Mþ), 301 (MþꢂI) (13), 209 (35), 165 (45%); HRMS (EI,
70 eV): Mþ, found 428.0073. C17H17IO5 requires 428.0075.
4.3.2. 1-Methoxyfluoren-9-one (5b).24 According to the general
procedure (2-iodophenyl)(20-methoxyphenyl)methanone (2b)
(0.34 g, 1.00 mmol), CuI (0.03 g, 0.15 mmol) and K3PO4 (0.64 g,
3.00 mmol) were reacted in DMF (6 mL) in a sealed vial in an argon
atmosphere at 155 ꢀC for 48 h. After column chromatography over
silica gel (cyclohexane/CH2Cl2¼1:1), the title compound 5b (0.16 g,
77%) was isolated as pale yellow crystals; mp 133e134 ꢀC; Rf (cy-
clohexane/EtOAc¼8:1) 0.33; nmax (ATR) 2947, 1660, 1597, 1580,
1486, 1293 cmꢂ1
; lmax (MeCN) (log ε) 249 (3.89), 203 (4.15) nm; dH
4.2.6. (2,5-Dimethoxyphenyl)(20-iodophenyl)methanone (2c).14 1,4-
Dimethoxybenzene (3) (0.89 g, 6.41 mmol) was treated with tri-
fluoroacetic acid (10 mL, 13.7 mmol), trifluoroacetic anhydride
(5 mL, 5.95 mmol) and 2-iodobenzoic acid (4) (1.50 g, 6.41 mmol)
and the reaction was refluxed for 12 h. After cooling to room
temperature crushed ice (100 g) were added, followed by tert-
butylmethyl ether (100 mL). After phase separation the organic
layer was washed with saturated sodium hydrocarbonate solution
(25 mL). The combined organic layers were washed with water
(1ꢁ50 mL) and brine (2ꢁ50 mL), dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified by re-
crystallization from cyclohexane to obtain the title compound 2c
(2.32 g, 98%) as colourless crystals; mp 79e80 ꢀC; Rf (cyclohexane/
EtOAc¼3:1) 0.57; nmax (ATR) 2941, 2840, 1656, 1577, 1491, 1467,
(300 MHz, CDCl3) 7.85 (1H, d, 3J 7.8 Hz, 8-H), 7.58 (1H, dd, 3J 7.8 Hz,
4J 1.3 Hz, 3-H), 7.44e7.53 (2H, m, 5-H and 6-H), 7.40 (1H, dd, 3J
7.8 Hz, 4J 1.3 Hz, 7-H), 7.09 (1H, t, 3J 7.8 Hz, 4-H), 7.03 (1H, dd, 3J
8.5 Hz, 4J 1.3 Hz, 2-H), 3.76 (3H, s, 1-OCH3); dC (300 MHz, CDCl3)
196.7 (C]O), 157.6 (C-1), 138.1 (C-4a), 133.2 (C-4b), 132.1 (C-3),
130.1 (C-8), 130.1 (C-7), 129.8 (C-8a), 129.1 (C-9a), 128.5 (C-5), 120.8
(C-2), 111.7 (C-4), 55.9 (1-OCH3), m/z (EI, 70 eV) 212 (87, M2þ), 201
(MþꢂCH2]CH2) 195 (66), 194 (33), 136 (15), 135 (M2þ-C6H5) (100),
105 (73), 77 (90%).
4.3.3. 1,4-Dimethoxyfluoren-9-one (5c).19,20 According to the gen-
eral procedure (2,5-dimethoxyphenyl)(20-iodophenyl)methanone
(2c) (0.37 g, 1.00 mmol), CuI (0.03 g, 0.15 mmol) and K3PO4 (0.64 g,
3.00 mmol) were reacted in DMF (6 mL) in a sealed vial in an argon
atmosphere at 155 ꢀC for 48 h. After column chromatography over
silica gel (cyclohexane/EtOAc¼3:1), the title compound 5c (0.21 g,
87%) was isolated as orange crystals crystals; mp 170e171 ꢀC; Rf
(cyclohexane/EtOAc¼1:1) 0.26; nmax (ATR) 2930, 1698, 1584, 1499,
1287 cmꢂ1
; lmax (MeCN) (log ε) 348 (3.17), 229 (4.09), 207
(4.16) nm; dH (300 MHz, CDCl3) 7.89 (1H, d, 3J 7.6 Hz, 30-H), 7.37 (1H,
dt, 3J 7.6 Hz, 4J 1.8 Hz, 4-H), 7.29 (1H, dd, 3J 7.6 Hz, 4J 1.8 Hz, 3-H),
4
7.24 (1H, d, J 1.8 Hz, 6-H), 7.07e7.13 (2H, m, 40-H and 50-H), 6.87
(1H, d, 3J 7.6 Hz, 60-H), 3.81 (3H, s, 5-OCH3), 3.56 (3H, s, 2-OCH3); dC
(300 MHz, CDCl3) 196.5 (C]O),154.2 (C-2), 153.9 (C-5),146.3 (C-10),
140.0 (C-30), 131.2 (C-40), 129.0 (C-3), 128.0 (C-4), 127.3 (C-1), 121.3
(C-50), 115.6 (C-6), 114.2 (C-60), 92.1 (C-20), 56.8 (2-OCH3), 56.2 (5-
OCH3), m/z (EI, 70 eV) 368 (100, Mþ), 230 (41), 226 (12), 165 (42),
151 (11%).
1453, 1263 cmꢂ1
; lmax (MeCN) (log ε) 433 (2.95), 373 (2.96), 250
(4.15), 244 (4.03) nm; dH (300 MHz, CDCl3) 7.83 (1H, d, 3J 7.8 Hz, 5-
H), 7.62 (1H, d, 3J 7.8 Hz, 8-H), 7.42 (1H, dd, 3J 7.8 Hz, 4J 1.2 Hz, 6-H),
7.21 (1H, dd, 3J 7.8 Hz, 4J 1.2 Hz, 7-H), 7.02 (1H, d, 3J 9.0 Hz, 3-H), 6.78
(1H, d, 3J 9.0 Hz, 2-H), 3.96 (6H, s, 1-OCH3 and 4-OCH3); dC
(300 MHz, CDCl3) 192.4 (C]O), 152.8 (C-4), 149.9 (C-1), 142.8 (C-
4b), 136.8 (C-4a), 134.4 (C-8a), 134.2 (C-6), 132.6 (C-9a), 128.5 (C-7),
124.6 (C-5), 124.0 (C-8), 120.6 (C-3), 114.4 (C-2), 56.5 (4-OCH3), 56.3
(1-OCH3); m/z (EI, 70 eV) 240 (60, Mþ), 211 (MþꢂCHO) (85), 197
(37), 169 (30),139 (17%); HRMS (EI, 70 eV): Mþ, found 240.0803.
C15H12O3 requires 240.0783.
4.3. General procedure for the Cu(I)-catalyzed synthesis of
the methoxy-substituted fluoren-9-ones under thermal con-
ditions 5aef
A dry microwave glass vial (10 mL) with magnetic stirrer bar
was charged with (2-iodophenyl)(phenyl)methanones 2aef
(1.00 mmol), CuI (0.03 g, 0.15 mmol) and potassium phosphate
(0.64 g, 3.00 mmol) under air. The vial was sealed, evacuated and
backfilled with argon three times, then freshly distilled dry DMF
(6 mL) were added. The reaction mixture was stirred for 48 h at
155 ꢀC until complete consumption of the substrate (TLC control).
After cooling to room temperature the reaction mixture was par-
titioned between 80 mL dichloromethane and 20 mL saturated
brine. The aqueous phase was extracted with dichloromethane
4.3.4. 1,6,7-Trimethoxyfluoren-9-one (5d). According to the general
procedure (2-iodo-4,5-dimethoxyphenyl)(20-methoxyphenyl)met
hanone (2d) (0.40 g, 1.00 mmol), CuI (0.03 g, 0.15 mmol) and
K3PO4 (0.64 g, 3.00 mmol) were reacted in DMF (6 mL) in a sealed
vial in an argon atmosphere at 155 ꢀC for 48 h. After column
chromatography over silica gel (cyclohexane/EtOAc¼2:1), the title
compound 5d (0.25 g, 92%) was isolated as dark orange crystals;
mp 178e179 ꢀC; [found: C, 71.36; H, 5.44. C16H14O4 requires C,
71.09; H, 5.22%]; Rf (cyclohexane/EtOAc¼2:1) 0.49; nmax (ATR)

R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
6493
2825, 1694, 1589, 1499, 1406, 1264 cmꢂ1
;
lmax (MeCN) (log ε) 365
4.4.1. 1-Hydroxyfluoren-9-one (6b).24 According to the general
procedure 1-methoxyfluoren-9-one (5b) (0.14 g, 0.67 mmol) was
treated with boron tribromide 1 M in DCM (1.33 mL, 1.33 mmol).
After column chromatography over silica gel (cyclohexane/
DCM¼4:3), the title compound 6b (0.097 g, 60%) was isolated as
orange crystals; mp 110e111 ꢀC; Rf (cyclohexane/DCM¼1:1) 0.39;
(3.50), 316 (3.76), 304 (3.77), 281 (4.20), 260 (4.20), 213
(4.18) nm; dH (300 MHz, CDCl3) 7.35 (1H, dd, 3J 7.6 Hz, 3J 7.6 Hz, 3-
H), 7.16 (1H, s, 8-H), 6.96 (1H, s, 5-H), 6.95 (1H, d, 3J 7.6 Hz, 4-H),
6.75 (1H, d, 3J 7.6 Hz, 2-H), 3.98 (3H, s, 6-OCH3), 3.95 (3H, s, 7-
OCH3), 3.91 (3H, s, 1-OCH3); dC (300 MHz, CDCl3) 191.7 (C]O),
158.1 (C-1), 154.2 (C-6), 150.2 (C-7), 146.4 (C-4a), 138.1 (C-4b),
136.6 (C-3), 127.5 (C-8a), 120.4 (C-9a), 112.9 (C-2), 112.3 (C-4),
107.1 (C-8), 103.7 (C-5), 56.6 (6-OCH3), 56.5 (7-OCH3), 56.2 (1-
OCH3); m/z (EI, 70 eV) 270 (100, Mþ), 255 (16), 239 (Mþ-OCH3)
(36), 227 (12), 212 (14%); HRMS (EI, 70 eV): Mþ, found 270.2917.
C16H14O4 requires 270.2908.
nmax (ATR) 3358, 1684, 1595, 1468, 1437, 1283 cmꢂ1
; lmax (MeCN)
(log ε) 352 (3.04), 250 (4.12), 205 (3.81) nm; dH (300 MHz, CDCl3)
8.44 (1H, br s, 1-OH), 7.63 (1H, d, 3J 7.1 Hz, 8-H), 7.49 (1 H, over-
lapped, 3J 7.1 Hz, 5-H), 7.48 (1 H, overlapped, 3J 7.1 Hz, 6-H), 7.36
(1H, dd, 3J 8.0 Hz, 3J 8.0 Hz, 3-H), 7.30 (1H, dt, 3J 7.1 Hz, 4J 1.9 Hz, 7-
H), 7.03 (1H, d, 3J 7.2 Hz, 2-H), 6.76 (1H, d, 3J 8.0 Hz, 4-H); dH
(300 MHz, CDCl3, H/D-exchange) 7.63 (1H, d, 3J 7.1 Hz, 8-H), 7.49
(1H, overlapped, 3J 7.1 Hz, 5-H), 7.48 (1H, overlapped, 3J 7.1 Hz, 6-H),
7.36 (1H, dd, 3J 8.0 Hz, 3J 8.0 Hz, 3-H), 7.30 (1H, dt, 3J 7.1 Hz, 4J 1.9 Hz,
7-H), 7.03 (1H, d, 3J 7.2 Hz, 2-H), 6.76 (1H, d, 3J 8.0 Hz, 4-H); dC
(300 MHz, CDCl3) 196.4 (C]O), 157.4 (C-1), 144.2 (C-8a), 143.9 (C-
4a), 137.5 (C-3), 134.7 (C-6), 134.3 (C-4b), 129.1 (C-7), 124.1 (C-8),
121.1 (C-5), 118.2 (C-4), 117.5 (C-9a), 112.9 (C-2); m/z (EI, 70 eV) 196
(40, Mþ), 168 (MþꢂCO) (26), 139 (17), 44 (10), 32 (24), 28
(MþꢂC12H8O) (100%).
4.3.5. 1,4,6,7-Tetramethoxyfluoren-9-one (5e). According to the
general procedure (20,50-dimethoxyphenyl)(2-iodo-4,5-dimeth-
oxyphenyl)methanone (2e) (0.43 g, 1.00 mmol), CuI (0.03 g,
0.15 mmol) and K3PO4 (0.64 g, 3.00 mmol) were reacted in DMF
(6 mL) in a sealed vial in an argon atmosphere at 155 ꢀC for 48 h.
After column chromatography over silica gel (cyclohexane/
EtOAc¼1:1), the title compound 5e (0.27 g, 91%) was isolated as
yellow orange crystals; mp 135e136 ꢀC; [found: C, 67.86; H, 5.08.
C17H16O5 requires C, 67.98; H, 5.27%]; Rf (cyclohexane/EtOAc¼1:2)
0.42; nmax (ATR) 2947, 2825,1694,1583,1488, 1475,1255 cmꢂ1
;
lmax
4.4.2. 1,4-Dihydroxyfluoren-9-one (6c).16 According to the general
procedure 1,4-dimethoxyfluoren-9-one (5c) (0.16 g, 0.67 mmol)
was treated with boron tribromide 1 M in DCM (1.33 mL,
1.33 mmol). After column chromatography over silica gel (cyclo-
hexane/EtOAc¼2:1) the title compound 6c (0.97 g, 68%) was iso-
lated as dark red crystals; mp 268e269 ꢀC; Rf (cyclohexane/
EtOAc¼2:1) 0.29; IR (ATR) 3300e3000, 1673, 1595, 1485,
(MeCN) (log ε) 487 (2.96), 325 (2.84), 312 (2.89), 279 (3.73), 264
(3.80) nm; dH (300 MHz, CDCl3) 7.36 (1H, s, 5-H), 7.16 (1H, s, 8-H),
6.96 (1H, d, 3J 9.1 Hz, 3-H), 6.71 (1H, d, 3J 9.1 Hz, 2-H), 3.98 (3H, s, 6-
OCH3), 3.91 (9H, s, 1-OCH3, 4-OCH3 and 7-OCH3); dC (300 MHz,
CDCl3) 191.7 (C]O),153.9 (C-6),152.4 (C-4),149.3 (C-1),149.0 (C-7),
134.7 (C-8a), 132.0 (C-9a), 127.0 (C-4b), 121.6 (C-4a), 120.4 (C-3),
114.0 (C-2), 107.8 (C-5), 107.1 (C-8), 56.50 (6-OCH3), 56.46 (1-OCH3
and 7-OCH3), 56.3 (4-OCH3); m/z (EI, 70 eV) 300 (100, Mþ), 269
(MþꢂOCH3) (35), 242 (14), 150 (7%); HRMS (EI, 70 eV): Mþ, found
300.0960. C17H16O5 requires 300.0996.
1282 cmꢂ1
; lmax (MeCN) (log ε) 442 (2.99), 368 (2.96), 250
(3.19) nm; dH (300 MHz, CDCl3) 9.83 (1H, s, 4-OH), 9.79 (1H, s, 1-
OH), 7.82 (1H, d, 3J 7.7 Hz, 5-H), 7.50e7.55 (2H, m, 7-H and 8-H),
7.28 (1H, dd, 3J 7.3 Hz, 3J 7.7 Hz, 6-H), 6.95 (1H, d, 3J 8.9 Hz, 3-H),
6.68 (1H, d, 3J 8.9 Hz, 2-H); dH (300 MHz, CDCl3, H/D-exchange) 7.82
(1H, d, 3J 7.7 Hz, 5-H), 7.50e7.55 (2H, m, 7-H and 8-H), 7.28 (1H, dd,
3J 7.3 Hz, 3J 7.7 Hz, 6-H), 6.95 (1H, d, 3J 8.9 Hz, 3-H), 6.68 (1H, d, 3J
8.9 Hz, 2-H); dC (300 MHz, CDCl3) 192.4 (C]O),150.7 (C-1),147.0 (C-
4), 143.5 (C-8a), 135.0 (C-8), 134.2 (C-4b), 128.4 (C-6), 127.4 (C-4a),
127.2 (C-3),124.4 (C-5),123.7 (C-7),121.1 (C-2), 118.6 (C-9a); m/z (EI,
70 eV) 212 (100, Mþ), 184 (13), 183 (7), 128 (11), 59 (10%); HRMS (EI,
70 eV): Mþ, found 212.0464. C13H8O3 requires 212.0467.
4.3.6. 1,4,5,8-Tetramethoxyfluoren-9-one (5f). According to the
general procedure (2,5-dimethoxyphenyl)(20-iodo-30,60-dimethox-
yphenyl)methanone (2f) (0.43 g, 1.00 mmol), CuI (0.03 g,
0.15 mmol) and K3PO4 (0.64 g, 3.00 mmol) were reacted in DMF
(6 mL) in a sealed vial in an argon atmosphere at 155 ꢀC for 48 h.
After column chromatography over silica gel (cyclohexane/
EtOAc¼1:1), the title compound 5f (0.25 g, 84%) was isolated as
yellow orange crystals; mp 134e135 ꢀC; Rf (CH2Cl2/EtOAc¼1:1)
0.29; nmax (ATR) 2939, 2836, 1692, 1587, 1577, 1493, 1265 cmꢂ1
;
lmax
4.4.3. 1,6,7-Trihydroxyfluoren-9-one (6d). According to the general
procedure 1,6,7-trimethoxyfluoren-9-one (5d) (0.18 g, 0.67 mmol)
was treated with boron tribromide 1 M in DCM (1.33 mL,
1.33 mmol). After column chromatography over silica gel (cyclo-
hexane/EtOAc¼1:1), the title compound 6d (0.13 g, 84%) was iso-
lated as dark red crystals; mp 282e283 ꢀC; Rf (cyclohexane/
EtOAc¼1:1) 0.30; nmax (ATR) 3446, 3251, 1665, 1600, 1595, 1469,
(MeCN) (log ε) 443 (3.83), 360 (3.53), 245 (3.82), 214 (3.80) nm; dH
(300 MHz, CDCl3) 7.10 (2H, d, 3J 8.9 Hz, 3-H and 6-H), 6.86 (2H, d, 3J
8.9 Hz, 2-H and 7-H), 3.96 (6H, s, 4-OCH3 and 5-OCH3), 3.91 (6H, s,
1-OCH3 and 8-OCH3); dC (300 MHz, CDCl3) 189.9 (C]O), 153.7 (C-4
and C-5), 149.3 (C-1 and C-8), 131.8 (C-4a and C-4b), 124.0 (C-3 and
C-60), 122.0 (C-8a and C-9a), 115.3 (C-2 and C-7), 58.8 (4-OCH3 and
5-OCH3), 56.8 (1-OCH3 and 8-OCH3); m/z (EI, 70 eV) 300 (60, Mþ),
285 (MþꢂCH3) (100), 242 (16), 227 (10), 71 (20%); HRMS (EI, 70 eV):
Mþ, found 300.0996. C17H16O5 requires 300.0993.
1274 cmꢂ1
; lmax (MeCN) (log ε) 364 (2.56), 316 (2.50), 304 (2.48),
271 (2.43), 211 (2.32) nm; dH (300 MHz, CDCl3) 10.05e9.71 (3H, br,
1-OH, 6-OH and 7-OH), 7.26 (1H, t, 3J 7.8 Hz, 3-H), 7.03 (1H, s, 5-H),
6.94 (1H, d, 3J 7.8 Hz, 4-H), 6.90 (1H, s, 8-H), 6.65 (1H, d, 3J 7.8 Hz, 2-
H); dH (300 MHz, CDCl3, H/D-exchange) 7.26 (1H, t, 3J 7.8 Hz, 3-H),
7.03 (1H, s, 5-H), 6.94 (1H, d, 3J 7.8 Hz, 4-H), 6.90 (1H, s, 8-H), 6.65
(1H, d, 3J 7.8 Hz, 2-H); dC (300 MHz, CDCl3) 191.8 (C]O),156.4 (C-1),
152.0 (C-6), 146.8 (C-7), 145.9 (C-4a), 137.1 (C-4b), 136.8 (C-3), 126.5
(C-8a), 118.7 (C-9a), 118.5 (C-2), 111.7 (C-4), 111.3 (C-8), 109.1 (C-5);
m/z (EI, 70 eV) 228 (100, Mþ), 200 (MþꢂCO) (40), 171 (8), 154 (7),
126 (9), 100 (11%); HRMS (EI, 70 eV): Mþ, found 228.0420. C13H8O4
requires 228.0420.
4.4. General procedure for the deprotection of the methoxy-
substituted fluoren-9-ones 5bef
Boron tribromide 1 M in DCM (1.33 mL, 1.33 mmol) was added
dropwise to a solution of the methoxy-substituted fluoren-9-ones
5bef (0.67 mmol) in CH2Cl2 (15 mL) at ꢂ78 ꢀC. The reaction mix-
ture was allowed to warm to room temperature and stirred for 24 h.
After quenching with water at 0 ꢀC the precipitate was filtered. The
filtrate was extracted with tert-butylmethyl ether (4ꢁ50 mL). The
combined organic layers were washed with water (1ꢁ50 mL) and
brine (2ꢁ50 mL), dried over anhydrous MgSO4 and concentrated in
vacuo. The crude product was purified by column chromatography
over silica gel (cyclohexane/EtOAc).
4.4.4. 1,4,6,7-Tetrahydroxyfluoren-9-one (6e). According to the
general
procedure
1,4,6,7-tetramethoxyfluoren-9-one
(5e)
(200 mg, 0.67 mmol) was treated with boron tribromide 1 M in
DCM (1.33 mL, 1.33 mmol). After column chromatography over

6494
R.A. Haggam / Tetrahedron 69 (2013) 6488e6494
silica gel (cyclohexane/EtOAc¼2:3), the title compound 6e (0.14 g,
83%) was isolated as dark red crystals; mp 270e271 ꢀC; Rf (cyclo-
hexane/EtOAc¼2:3) 0.25; nmax (ATR) 3350e2900, 1648, 1600, 1579,
References and notes
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1480, 1277 cmꢂ1
; lmax (MeCN) (log ε) 474 (3.22), 364 (2.95), 243
(3.98), 217 (3.72) nm; dH (300 MHz, CDCl3) 9.88 (1H, s, 6-OH), 9.53
(1H, s, 4-OH), 9.33 (1H, s,1-OH), 9.28 (1H, s, 7-OH), 7.23 (1H, s, 5-H),
6.88 (1H, s, 8-H), 6.84 (1H, d, 3J 8.8 Hz, 3-H), 6.51 (1H, d, 3J 8.8 Hz, 2-
H); dH (300 MHz, CDCl3, H/D-exchange) 7.23 (1H, s, 5-H), 6.88 (1H, s,
8-H), 6.84 (1H, d, 3J 8.8 Hz, 3-H), 6.51 (1H, d, 3J 8.8 Hz, 2-H); dC
(300 MHz, CDCl3) 192.3 (C]O), 151.8 (C-7), 149.9 (C-1), 145.6 (C-4),
145.5 (C-6),137.1 (C-4b),127.5 (C-4a),126.5 (C-3),125.9 (C-8a),119.7
(C-2),119.2 (C-9a),112.2 (C-5),111.44 (C-8); m/z (EI, 70 eV) 244 (100,
Mþ), 216 (9), 170 (6), 99 (5%); HRMS (EI, 70 eV): Mþ, found
244.0357. C13H8O5 requires 244.0339.
4.4.5. 1,4,5,8-Tetrahydroxyfluoren-9-one (6f). According to the
general procedure 1,4,5,8-tetramethoxyfluoren-9-one (5f) (200
mg, 0.67 mmol) was treated with boron tribromide (1.33 mL,
1.33 mmol). After column chromatography over silica gel (cyclo-
hexane/EtOAc¼1:3) the title compound 6f (0.14 g, 80%) was iso-
lated as dark red crystals; mp 238e239 ꢀC; Rf (cyclohexane/
EtOAc¼2:3) 0.62; nmax (ATR) 3300e2980, 1659, 1601, 1492, 1449,
1259 cmꢂ1
; lmax (MeCN) (log ε) 474 (3.22), 364 (2.95), 243 (3.98),
217 (3.72) nm; dH (300 MHz, CDCl3) 10.69 (2H, s, 1-OH and 8-OH),
9.62 (2H, s, 4-OH and 5-OH), 6.89 (2H, d, 3J 8.9 Hz, 3-H and 6-H),
6.68 (2H, d, 3J 8.9 Hz, 2-H and 7-H); dH (300 MHz, CDCl3, H/D-
exchange) 6.89 (2H, d, 3J 8.9 Hz, 3-H and 6-H), 6.68 (2H, d, 3J
8.9 Hz, 2-H and 7-H); dC (300 MHz, CDCl3) 191.2 (C]O), 151.3 (C-1
and C-8), 143.8 (C-4 and C-5), 126.3 (C-3 and C-6), 126.0 (C-4a and
C-4b),120.6 (C-2 and C-7),118.2 (C-8a and C-9a); m/z (EI, 70 eV) 244
(100, Mþ), 222 (75), 177 (18), 150 (15), 28 (Mþ-C12H8O4) (100%);
HRMS (EI, 70 eV): Mþ, found 244.0331. C13H8O5 requires 244.0339.
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4.5. General procedure for the Cu(I)-catalyzed synthesis of
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conditions 5aef
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A dry microwave glass vial (10 mL) with magnetic stirrer bar
was charged with (2-iodophenyl)(phenyl)methanones 2aef
(1.00 mmol), CuI (0.30 g, 0.15 mmol) and potassium phosphate
(0.64 g, 3.00 mmol) under air. The vial was sealed, evacuated and
backfilled with argon three times, then freshly distilled dry DMF
(6 mL) were added. The sealed vial was irradiated with microwaves
(DiscoverÔ by CEM, 2450 MHz, 250 W,160 ꢀC) for 20e60 min. After
cooling to room temperature the reaction mixture was partitioned
between 60 mL EtOAc and 30 mL brine. The aqueous phase was
extracted with EtOAc (3ꢁ50 mL). The combined organic layers were
dried over anhydrous MgSO4 and concentrated in vacuo. The crude
products isolated was purified by flash column chromatography
over silica gel. The yields of the products are given in Table 6.
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The author is grateful to Hohenheim University, Germany and
Institute of Organic and Biomolecular Chemistry, Gottingen Uni-
versity, Germany, for providing facilities to perform the analyses
were described in this publication.