First and mild synthesis of fluorene-9-malonic acid and some substituted derivatives via the intramolecular hydroarylation of 2-phenylbenzylidenemalonic acids

Article abstract of DOI:10.1016/j.tet.2011.02.026

Hitherto unknown fluorene-9-malonic acid and some substituted derivatives were easily synthesized in very mild conditions through the intramolecular hydroarylation of 2-phenylbenzylidenemalonic acids issued from the corresponding biphenylcarboxaldehydes.

Full text of DOI:10.1016/j.tet.2011.02.026

Tetrahedron 67 (2011) 2548e2554
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First and mild synthesis of fluorene-9-malonic acid and some substituted
derivatives via the intramolecular hydroarylation of 2-phenylbenzylidenemalonic
acids
,
Elizabeth Chosson a b, Christophe Rochais a, Remi Legaya, Jana Sopkova de Oliveira Santos a,
,
Sylvain Rault a, Patrick Dallemagne a
*
a
ꢀ
ꢀ
Centre d’Etudes et de Recherche sur le Medicament de Normandie, UPRES EA 4258, INC3M FR-CNRS 3038, UFR des Sciences Pharmaceutiques, Universite de Caen Basse-Normandie,
Boulevard Becquerel 14032 Caen cedex, France
b
ꢀ
ꢁ
CNRS UMR 6014dC.O.B.R.A. & FR3038, I.R.C.O.F. Universite de Rouen, Rue Tesniere, 76130 Mont Saint-Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Hitherto unknown fluorene-9-malonic acid and some substituted derivatives were easily synthesized in
very mild conditions through the intramolecular hydroarylation of 2-phenylbenzylidenemalonic acids
issued from the corresponding biphenylcarboxaldehydes.
Received 30 November 2010
Received in revised form 8 February 2011
Accepted 11 February 2011
Available online 17 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
acidic media and are generally limited to electron-rich starting
materials. It was however very recently demonstrated that elec-
Recently, hydroarylation of cinnamic acids 1 was reported as an
efficient method to synthesize benzhydrylacetic acid derivatives.1
Using phenol, this reaction was also widely used for the synthesis
of dihydrocoumarin derivatives 2 with potential biological in-
terest (Scheme 1).2ꢀ13 However, such hydroarylations need highly
tron-deficient benzylidene-malonic esters, such as p-NO2 de-
rivative 3 can be involved with phenol in a Lewis acid-catalyzed
hydroarylationelactonization sequence to lead more easily to
methyl oxochromancarboxylates 4.14 In this case, hydroarylation
is facilitated by the activating part played by the pendant carboxyl
PhOH
R
OH
O
1
2
O
O
O2N
O2N
O2N
L A
PhOH
O
O
O
O
O
O
O
O
+
O
O
O
O
H
3
4
Scheme 1. Literature hydroarylation of cinnamic acids 1 and benzylidene-malonic esters 3.
* Corresponding author. Tel.: þ33 2 31 56 68 13; fax: þ33 2 31 56 68 03; e-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.026

E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
2549
group, liable to stabilize the protonated intermediate via an
intramolecular hydrogen bond.
We imagined adapting this method to achieve the intra-
molecular hydroarylation of 2-phenylbenzylidenemalonic acids 5
in order to perform the synthesis of unknown fluorene-9-malonic
acids 6 (Fig. 1).
Acyl chloride 11a, quantitatively obtained under treatment of 5a
in refluxed SOCl2, was first used to achieve the synthesis of 6a.
Reaction of 11a with 1.1 equiv of AlCl3 in refluxing CH2Cl2 led after
1.5 h to the synthesis of the expected fluorenemalonic acid 6a in
50% conversion rate (Table 1, entry 1). Prolonging the reaction time
in these conditions did not allow the total conversion into 6a. The
latter however took place using 2.2 equiv of the Lewis acid at room
temperature (entry 2). Nevertheless, activation through an acyl
chloride species appeared not necessary since the application of the
same treatment, starting this time directly from the diacid 5a, led to
the same result (entry 3).
R
R
O
OH
Table 1
O
Cyclization conditions for the synthesis of compounds 6a and 12
HO2C
CO2H
OH
6
5
Fig. 1. Retrosynthetic acess to fluorene-9-malonic acids 6.
+
OH
OH
R
R
HO
O
O
Fluorene-9-malonic acid 6a (R¼H) had not been hitherto
reported and its unique 1-carboxy-substituted derivative, pre-
viously described, was obtained through irradiation of 3-hydroxy-
fluoranthene-1-carboxylic acid.15 Nevertheless, we consider this
system as potentially interesting particularly because of its analogy
with indane-1-malonic acid whose structure was recently designed
as a useful scaffold for the synthesis of some PPAR ligands.16 For this
reason, we undertook the synthesis of 6a and we propose herein an
easy and extending pathway to lead to various substituted fluo-
rene-9-malonic acids 6.
O
O
O
6a
12
5a (R= OH)
11a (R = Cl)
SOCl2
Entry Start Reagent
Mat
Solvent Temp Time (h) Conversion
rate (%)
6a
50
12
1
2
3
4
5
6
7
11a
11a
5a
5a
5a
AlCl3 1.129 equiv
AlCl3 1.1 equiv
AlCl3 2.2 equiv
CH2Cl2 rflx
CH2Cl2 rt
CH2Cl2 rt
1.5
12
0
0
0
0
0
0
100
100
100
100
100
0
12
12
19
5
BF3, Et2O 2.2 equiv Et2O
rt
2. Results and discussion
TFA 70 equiv
TFA 70 equiv
TFA/TFA2O 70
equiv/70 equiv
TFA2O 70 equiv
CH2Cl2 rt
5a
5a
CH2Cl2 60 ꢁCa
CH2Cl2 60 ꢁCa
The synthesis of 2-phenylbenzylidenemalonic acid 5a was per-
formed according to a Rodionow procedure,17 we use extensively to
preparebeta-aminobeta-arylpropionicacidsfromarylaldehydeswith
considerable interest as building-blocks in medicinal chemistry.18
Applied to commercially available 2-phenylbenzaldehyde 7a, the
useof malonicacidandammoniumacetateinrefluxingethanolfor6h
did not lead to the expected aminoacid 2-phenyl-beta-homophenyl-
alanine 10a, whose only traces were recovered, but to a precipitate of
the mono ammonium salt of 2-phenyl-benzylidenemalonic acid 8a,
which was formed in 29% yield concomitantly with the decarboxy-
lated phenylcinnamic acid 9a remaining in solution (Scheme 2).
Reducing the time of the reaction to 30 min allowed however to
improve the yield for the synthesis of 8a (58%), whose treatment
with aqueous hydrochloric acid gave the diacid 5a.
8.5
100
8
5a
CH2Cl2 60 ꢁCa 24
0
0
a
Sealed tube.
Replacing AlCl3 by BF3.Et2O in Et2O or by TFA in CH2Cl2 at room
temperature yielded also the complete formation of 6a after 12 and
19 h, respectively (entries 4 and 5). Heating the trifluoracetic re-
action mixture at 60 ꢁC allowed the decrease of the reaction time
from 19 h to 5 h (entry 6).
On the other hand, the use of a mixture in equal part of TFA and
TFA2O led to the total decarboxylation of 6a into fluorene-9-acetic
acid 12 (entry 7)19 for which this sequence constitutes a novel
synthesis method. Finally, the treatment of 6a in pure TFA2O led
only to the degradation of the formed products (entry 8).
During all these attempts, none of the cyclized compounds,
belonging to indanone and dibenzocycloheptenone series and po-
tentially issued from the intramolecular acylation of one of the two
phenyl rings by one of the two carboxylic acid groups of 5a or 11a,
were observed.
Concerning the isolation of fluorene-9-malonic acid 6a, the best
results were obtained under treatment with BF3$Et2O, then
quenching the reaction with MeOH and evaporating the reaction
mixture under vacuum in order to eliminate borane derivatives
(entry 4). In these conditions, the process yielded 6a in quantitative
yield. Its structure was deduced from 2D NMR experiments but also
according to its X-ray resolution (Fig. 2).20
CH2(CO2H)2
H
AcONH4
-
O
O
OH
OH
EtOH
+NH4
O
O
O
7a
8a
9a
HCl / H2O
OH
The activating part played by the pendant carboxylic acid group
of 5a and 11a was finallyassessed through performing this sequence
starting from 2-phenylcinnamic acid 9a, which did not lead in these
conditions to fluorene-9-acetic acid 12. This roleis also in agreement
with the similar formation of a 2-cyano-2-(fluoren-9-yl)acetic acid
by cyclization of a 2-cyano-3-(biphenyl-2-yl)propenoic acid.21
HO
OH
NH2
O
O
O
10a
5a
Scheme 2. RodionoweJonhson synthesis of 2-phenylbenzylidene-malonic acid 5a and
2-phenylcinnamic acid 9a.

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E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
Table 3
Reaction conditions for the synthesis of compounds 5beh and 6bej
R2
R2
R2
R1
R3
R1
R1
R3
BF .Et O
1) CH (CO H)
R3
AcONH
Et O
RT
O
O
7b-h
EtOH Rflx
O
O
O
OH
OH
6b-h
2) HCl / H O
OH OH
5b-h
R3
R2
CO H
HO C
6i,j
R1
R2 R3
Steps 1þ2
Step 3
Fig. 2. X-ray structure of fluorene-9-malonic acid 6a.
Compound Rflx Time Yield Compoud Time Yield
(min)
(%)
(h)
(%)
NO2
H
H
H
H
H
H
H
H
CH3
OCH3
5b
5c
5d
5e
5f
30
30
15
45
30
45
30
39
22
43
16
30
25
10
6b
15
20
In order to study the scope and limitations of this method, we
undertook its applications starting from variously substituted 2-
phenylbenzaldehydes 7beh. Most of them (7bef,h) were already
described in literature,22ꢀ27 but 2-(4-tert-butyl-phenyl)benzalde-
hyde 7g was unknown. We synthesized all these starting materials
according to a microwave promoted SuzukieMiyaura cross cou-
pling reaction involving 2-bromo-benzaldehyde 13 and substituted
phenylboronic acids 14beh with Pd(PPh3)4 as catalyst in DME and
an aqueous solution of K3PO4 as a base. Under these conditions, 2-
phenylbenzaldehydes 7beh were isolated with yields ranging from
39 to 81% (Table 2).
CF3
Cl
H
H
H
6c/6i
6d/6j
6e
6f
6g
15
15
20
15
15
15
50/20
50/50
quant.
quant.
quant.
quant.
H
CH3
C(CH3)3 5g
CH3 5h
H
6h
Even 5c and 5d, substituted by electron-withdrawing groups,
lend themselves in these conditions to the cyclization reaction.
However in these cases, not only the expected fluorene derivatives
6c and 6d were synthesized, but also compounds 6i and 6j issued
from the cyclisation on the second ortho position of the starting
materials. Disappointingly, these isomers could not be separated
from the reaction mixture.
Only, the deactivated o-NO2 derivative 5b, appeared less re-
active towards this procedure, since it gave in only 20% yield the
corresponding fluorenemalonic acid 6b, which could not be sepa-
rated from the starting material.
Under treatment with malonic acid and ammonium acetate in
refluxing ethanol, 2-phenylbenzaldehydes 7beh gave, after dis-
placement of the ammonium salts by hydrochloric acid, the 2-
phenylbenzylidenemalonic acids 5beh in low to moderate global
yields (Steps 1þ2; Table 3).
The procedure selected for the synthesis of 6a was then applied
to 5beh. Treatment of the latter with BF3$Et2O in Et2O at room
temperature gave contrasted results (Step 3; Table 3).
Compounds 5eeh, bearing on their phenyl ring various elec-
tron-donating groups able to promote the aromatic electrophilic
substitution, were easily and completely cyclized into the novel 2-
substituted fluorene-9-malonic acids 6eeh, after a reaction time
ranging from 15 to 20 h. They were isolated in a similar manner as
described for 6a.
3. Conclusions
In conclusion, we have developed an easy and efficient synthesis
invery mild conditions of somenovel fluorene-9-malonic acids from
2-bromobenzaldehydes. The sequence involves SuzukieMiyaura
cross coupling with various phenylboronic acids, followed by
a RodionoweJohnson reaction and a subsequent intramolecular
hydroarylation of the 2-phenylbenzylidenemalonic acids obtained.
Five unknown fluorene-9-malonic acids were thus isolated. They
constitute useful scaffolds for medicinal chemistry. The application
of this sequence to heterocyclic analogs is furthermore currently
under investigation.
Table 2
SuzukieMiyaura cross coupling conditions for the synthesis of compounds 7beh
R2
R1
R3
1.3 equiv
HO
R2
B
OH
R1
R3
14b-h
Br
O
4. Experimental section
4.1. General methods
0.05 equiv Pd(PPh3)4
13
7b-h
O
3 equiv K3PO4
DME µw
All commercial solvents and reagents were used as-received.
The microwave reactions were performed using a Biotage Initiator
Microwave oven; temperatures were measured with an IR-sensor
and reaction times given as hold times. Flash chromatography was
realized on a spot 2 apparatus; column: EVF SiO2; eluent: cyclo-
hexane/methylene chloride, or cyclohexane/ethylacetate. Melting
points were determined on a Kofler melting point apparatus and
were uncorrected. IR spectra were recorded on KBr discs; only se-
lected absorbances were quoted. LC/MS (ESI) analyses were
Compound
R1
R2
R3
Temp
(ꢁC)
P
m
(W)
w
Time
(h)
Yield
(%)
(bars)
7b
7c
7d
7e
7f
NO2
H
H
H
H
H
H
H
H
150
150
150
150
137
150
150
5
6
5
6
4
6
6
270
40
1.5
1.5
1.5
1.5
2
39
48
74
42
81
39
65
CF3
Cl
H
H
H
60
60
CH3
OCH3
C(CH3)3
CH3
290
60
300
7g
7h
H
CH3
1.5
1.5
H

E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
2551
realized as separating module using the following gradient: A
(95%)/B (5%) to A (5%)/B (95%) in 10 min; this ratio was hold during
3 min before return to initial conditions in 1 min. Initial conditions
were then maintained for 5 min (A: H2O, B: CH3CN; each containing
HCOOH: 0.1%; Column: C18 MSC118/2.1_50 mm). MS detection was
performed by positive or negative ESI. High Resolution Mass
Spectra were performed at 70 eV by electronic impact (HRMS-EI) or
by negative electrospray ionization (HRMS-ESI). 1H and 13C NMR
spectra were recorded, respectively, at 400 and 100 MHz or at 500
and 125 MHz, using CDCl3, DMSO-d6 or CD3OD as solvents.
d 191.8 (CHO), 144.3 (C1), 139.6 (Cquat.), 134.5 (Cquat.), 133.7 (CH),
133.6 (Cquat.), 130.6 (CH), 129.9 (CH), 129.6 (CH), 128.4 (CH), 128.3
(CH), 128.2 (CH), 127.8 (CH); LCeMS tR¼12 min, [ESIþ] m/z
[MþHþCH3CN]þ 258, [MþH]þ 217.
4.2.4. 40-Methylbiphenyl-2-carbaldehyde 7e23. Starting from 2-bro-
mobenzaldehyde (1 mmol, 185 mg, 117 ml) and 4-(methylphenyl)
boronic acid (1.3 mmol, 177 mg), under the following conditions
(1 h 30 min; 150 ꢁC; 6 bar; 60 W), 7e was obtained as a clear oil
(82 mg, 42%); IR (KBr)
n
(cmꢀ1) 3436 (OH), 3024, 2922, 2846, 2748,
Chemical shifts
d are reported in parts per million with the solvent
1691 (CO), 1596, 1254, 1193, 823, 763; 1H NMR (400 MHz, CDCl3)
resonance as the internal standard; coupling constants J are given
in Hertz. Crystal structure determination: data were collected at
d
9.99 (s, 1H, CHO), 8.01 (d, 1H, Jortho¼7.8 Hz, H3), 7.63 (t, 1H, Jor-
¼7.8 Hz), 7.48 (t, 1H, Jortho¼7.8 Hz), 7.44 (d, 1H, Jortho¼7.8 Hz), 7.28
tho
296 K with graphite-monochromatized Mo K
a
radiation on a dif-
(bs, 4H) 2.43 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d 192.6 (CHO),
fractometer equipped with a CCD area detector. The crystal
structure was solved by direct methods using SHELX97 package. All
non-hydrogen atoms were refined anisotropically. All H atoms
were calculated and fixed on the heavy atoms in the ideal geometry.
147.6 (C1),138.0 (Cquat.),133.7 (Cquat.),133.5 (CH),132.4 (Cquat.),130.8
(CH), 130.0 (or C30,C50), 129.1 (C30,C50or C20,C60), 127.5 (2CH), 21.2
(CH3); LCeMS tR¼11 min, [ESIþ] m/z [MþCH3CN]þ 238 [MþH]þ 197.
4.2.5. 40-Methoxybiphenyl-2-carbaldehyde
2-bromobenzaldehyde (3 mmol, 555 mg, 351
7f25. Starting
l) and 4-(methox-
from
4.2. Synthesis of biphenyl-carbaldehydes
m
yphenyl)boronic acid (3.9 mmol, 593 mg), under the following
conditions (2 h 00 min; 137 ꢁC; 4 bar; 290 W), 7f was obtained as
a clear yellow solid (515 mg, 81%). Spectral data (1H, 13C NMR, IR,
MS) are in agreement with those found in the literature.
Biphenyl-2-carbaldehyde 7a was bought from chemical sup-
pliers; all other aldehydes (7beh) were obtained as followed: To
a degassed solution of 1 equiv of 2-bromobenzaldehyde in DME
were added 1.3 equiv of boronic species, 3 equiv of K3PO4$H2O and
0.05 equiv of Pd(PPh3)4; the suspension was heated under micro-
waves irradiation. The resulting mixture was filtrated (washed with
Et2O) and evaporated to dryness under vacuum pressure. The crude
product was then purified by flash chromatography.
4.2.6. 40-tert-Butylphenyl-2-carbaldehyde 7g. Starting from 2-bro-
mobenzaldehyde (2 mmol, 370 mg, 235
ml) and 4-(tert-butyl-
phenyl)boronic acid (2.6 mmol, 463 mg), under the following
conditions (1 h 30 min; 150 ꢁC; 6 bar; 60 W), 7g was obtained as
a clear oil (420 mg, 88%); IR (KBr)
2855, 1691 (CO), 1596, 1472, 1389, 1256, 1194, 836, 767; 1H NMR
(400 MHz, CDCl3)
10.01 (s, 1H, CHO), 8.02 (d,1H, Jortho¼7.8 Hz, H3),
n
(cmꢀ1) 3430 (OH), 2959, 2920,
4.2.1. 20-Nitrobiphenyl-2-carbaldehyde 7b26. Starting from 2-bro-
mobenzaldehyde (3 mmol, 555 mg, 351
ml) and 2-(nitrophenyl)bo-
d
ronic acid (3.9 mmol, 651 mg), under the following conditions (1 h
7.63 (t, 1H, Jortho¼7.8 Hz), 7.50e7.45 (m, 4H), 7.32 (d, 2H,
30 min; 150 ꢁC; 5 bar; 270 W), 7b was obtained as a clear yellow
Jortho¼7.8 Hz), 1.36 (s, 9H, CH3); 13C NMR (100 MHz, CDCl3)
d 192.8
solid (263 mg, 39%); mp 72e73 ꢁC; IR (KBr)
n
(cmꢀ1) 3433 (OH),
(CHO), 151.2 (Cquat.), 146.0 (C1), 134.7(Cquat.), 133.8 (Cquat.), 133.5
(CH), 130.8 (CH), 129.9 (2CH), 127.5 (2CH), 125.4 (2CH), 34.7 (þC
(CH3)3), 31.3 (3C, CH3); LCeMS tR¼13.5 min, [ESIþ] m/z [MþH]
239; HRESIMS [MþNa]þ 261.1252 (calcd for C17H18ONa 261.12499).
2923, 2852, 1692 (CO), 1522e1344 (PheNO2); 1H NMR (400 MHz,
CDCl3)
d
9.87 (s, 1H, CHO), 8.13 (d, 1H, Jortho¼7.8 Hz, H30), 8.01 (d, 1H,
Jortho¼7.8 Hz, H3), 7.65 (m, 4H), 7.36 (d, 1H, Jortho¼7.8 Hz), 7.26 (m, 1H
under svt residual peak); 13C NMR (100 MHz, CDCl3)
d 191.1 (CHO),
148.6 (C20), 140.3 (C1), 134.0 (Cquat.), 133.7 (CH), 133.6 (Cquat.), 132.7
(CH), 132.4 (CH), 130.1 (CH), 129.8 (CH), 129.1 (CH), 128.7 (CH), 124.5
(C30); LCeMS tR¼10.7 min, [ESIꢀ] m/z [MꢀH]ꢀ 226.
4.2.7. 20-40-Dimethylphenyl-2-carbaldehyde 7h24. Starting from 2-
bromobenzaldehyde (3 mmol, 555 mg, 351
ml) and (2-4-dime-
thylphenyl)boronic acid (3.9 mmol, 585 mg), under the following
conditions (1 h 30 min; 150 ꢁC; 6 bar; 300 W), 7h was obtained as
4.2.2. 30-(Trifluoromethyl)biphenyl-2-carbaldehyde
7c22. Starting
a yellow clear oil (412 mg, 65%); IR (KBr)
2850, 1695 (CO), 1622, 1597, 1447, 1255, 826, 766; 1H NMR
(400 MHz, CDCl3)
n
(cmꢀ1) 3433 (OH), 2922,
from 2-bromobenzaldehyde (1 mmol, 185 mg, 117
ml) and [3-(tri-
fluoromethyl)phenyl]boronic acid (1.3 mmol, 242 mg), under the
d
* 9.76 (s, 1H, CHO), 8.01 (d, 1H, Jortho¼7.8 Hz, H3),
following conditions (1 h 30 min; 150 ꢁC; 6 bar; 40 W), 7c was
7.62 (t, 1H, Jortho¼7.8 Hz, H5), 7.48 (t, 1H, Jortho¼7.8 Hz, H4), 7.29 (d,
obtained as a clear oil (119 mg, 48%); IR (KBr)
2926, 2852, 2753, 1696 (CO), 1598, 1335, 1167e1126e1074 (CF3),
n
(cmꢀ1) 3434, 3067,
1H, Jortho¼7.8 Hz, H6), 7.12 (s, 1H, H30), 7.08 (br s, 2H, H50&H60), 2.39
(s, 3H, CH3), 2.07 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d 192.5
*
765; 1H NMR (400 MHz, CDCl3)
d
9.96 (s, 1H, CHO), 8.06 (d, 1H,
(CHO), 145.8 (C1), 138.0 (C40), 135.9 (C20), 134.5 (C10), 133.9 (C2),
133.7 (C5), 130.9 (C6), 130.8 (C30), 130.2 (C60), 127.6 (C4), 127.0 (C3),
126.4 (C50), 21.1 (C40eCH3), 20.2 (C20eCH3); LCeMS tR¼12.5 min,
Jortho¼7.8 Hz, H3), 7.73e7.52 (m, 7H), 7.44 (d, 1H, Jortho¼7.8 Hz); 13
C
NMR (100 MHz, CDCl3)
d 190.5 (s, CHO), 143.0 (s, C1), 137.7 (s, C2),
132.8 (s, CH), 132.6 (s, C10), 132.4 (s, CH), 129.8 (s, CH), 127.8 (s, CH),
[ESIþ] m/z [MþH]þ 211.
*
Assignments according to 2D experiments
1
127.5 (s, CH), 127.1 (s, CH), 125.8 (d, JCF¼240.2 Hz, CF3), 125.4 (d,
(HMBC, HMQC).
3JCF¼5.8 Hz, C20or C40), 123.9 (d, JCF¼7.4 Hz, C20or C40); LCeMS
3
tR¼12 min, [ESIþ] m/z [MþHþCH3CN]þ 292, [MþH]þ 251.
4.3. Synthesis of orthophenylbenzylidene malonic acids
4.2.3. 30-Chlorobiphenyl-2-carbaldehyde 7d21. Starting from 2-bro-
mobenzaldehyde (1 mmol, 185 mg, 117 ml) and 3-(chlorophenyl)
All malonic acids where obtained as followed. Previous
substituted biphenyl-carbaldehydes 7bej were refluxed in EtOH for
15 mine60 min with 1 equiv of malonic acid and 2 equiv of am-
monium acetate. The resulting mixture was cooled to room tem-
perature and stirred for 30 min.
boronic acid (1.3 mmol, 202 mg), under the following conditions
(1 h 30 min; 150 ꢁC; 5 bar; 60 W), 7d was obtained as a yellowish oil
(160 mg, 74%); IR (KBr)
n
(cmꢀ1); 3432, 3061, 2852, 2752, 1694 (CO),
1596, 1196, 764; 1H NMR (400 MHz, CDCl3)
d
9.98 (s, 1H, CHO), 8.04
(dd, 1H, Jortho¼7.8 Hz Jmeta¼1.9 Hz, H3), 7.65 (td, 1H, Jortho¼7.8 Hz,
Jmeta¼1.9 Hz, H5), 7.53 (t, 1H, Jortho¼7.8 Hz, H4), 7.43e7.38 (m, 4H),
7.25 (m under svt residual peak, 1H); 13C NMR (100 MHz, CDCl3)
4.3.1. Purification. Conditions A: The formed precipitate was fil-
tered, suspended in water and then acidified with HCl 1 M. The
resulting precipitate was dried, washed with water, to give the

2552
E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
corresponding malonic acid; the filtrate was also extracted with
CH2Cl2 or Et2O; the organic phase was filtered and dried with an-
hydrous MgSO4 and evaporated under reduced pressure until
dryness to give the same pure substituted malonic acid.
1684 (CO), 1594, 1424, 1256, 761; 1H NMR (400 MHz, CD3OD)
d 7.62
(d, 1H, Jortho¼7.8 Hz, H3), 7.50e7.47 (m, 2H), 7.43e7.40 (m, 4H), 7.30
(dt, 1H, Jortho¼7.8 Hz, Jmeta¼1.9 Hz, H60); 13C NMR (100 MHz, CD3OD)
d
170.1 (CO2H), 166.7 (CO2H), 143.2 (C1), 142.6 (CH]C(CO2H)2),
Conditions B: To the mixture was added the same volume of HCl
1 M; after 1 h stirring, EtOH was evaporated, and the resulting
aqueous phase was extracted three times with Et2O; after drying
over anhydrous MgSO4, the combined organic phases were evap-
orated to dryness under vacuum and the resulting crude extract
was suspended into a saturated aqueous NaHCO3 solution. The
obtained aqueous phase was washed twice with CH2Cl2 and then
gently acidified with aqueous HCl 6 M; the resulting precipitate was
filtered washed with H2O and dried to give the corresponding
malonic acid. The filtrate was also extracted with CH2Cl2 or Et2O;
the organic phase was filtered and dried with anhydrous MgSO4
and evaporated under reduced pressure until dryness to give the
same pure substituted malonic acid, improving yields of about 20%.
142.3 (Cquat.),135.3 (Cquat.),133.3 (Cquat.),131.3 (CH),131.0 (CH),130.9
(CH), 130.5 (CH), 130.1 (Cquat.), 129.5 (CH), 129.3 (CH), 129.1 (CH),
128.9 (CH); LCeMS tR¼11.0 min, [ESIꢀ] m/z [MꢀH]ꢀ 303e301,
[MeHeCO2]ꢀ 259e257. HRESIMS [MꢀH] m/z 301.0273 (calcd for
C16H10ClO4 301.02731).
4.3.6. [(40-Methylbiphenyl-2-yl)methylidene]propanedioic acid 5e.
Starting from 7e (0.37 mmol, 82 mg), 5e was obtained after 45 min
refluxing time (conditions A), as a colourless solid (16 mg, 16%); mp
196e197 ꢁC; IR (KBr)
n
(cmꢀ1) 3436 (OH), 3151, 3024, 2926, 2852,
1720 (CO), 1683 (CO), 1616,1380, 1273, 819, 755; 1H NMR (400 MHz,
CD3OD)
d
7.61 (d, 1H, Jortho¼7.8 Hz, H3), 7.53 (s, 1H, CH]C(CO2H)2),
7.45 (t, 1H, Jortho¼7.8 Hz, H5), 7.40 (d, Jortho¼7.8 Hz, H6), 7.34 (t, 1H,
Jortho¼7.8 Hz, H4), 7.25 (br s, 4H, H20, H30, H50, H60), 2.39 (s, 3H, CH3);
4.3.2. (Biphenyl-2-ylmethylidene)propanedioic acid 5a. Starting
from (1,10-biphenyl)-carbaldehyde (7a, Sigma) (3 mmol, 546 mg,
13C NMR (100 MHz, CD3OD)
d 170.4 (CO2H),167.0 (CO2H),144.1 (C1),
143.4 (CH]C(CO2H)2), 143.4 (C2), 138.9 (C10 or C40), 138.3 (C10 or
C40), 133.2 (C(CO2H)2), 131.2 (C5), 131.0 (C6), 130.7 (C20, C60), 130.0
(C30, C50), 129.4 (C3), 128.3 (C4), 21.2 (CH3); LCeMS tR¼10.7 min,
[ESIꢀ] m/z [MꢀH]ꢀ 281, [MeHeCO2]ꢀ 237. HRESIMS [MꢀH] m/z
483
as a colourless powder (402 mg, 50%); mp 190e191 ꢁC; IR (KBr)
(cmꢀ1) 3430 (OH), 2927, 2585, 1755 (CO), 1683 (CO), 1424, 1274,
ml), 5a was obtained after 30 min refluxing time (conditions A),
n
1244; 1H NMR (400 MHz, DMSO-d6)
d
13.25 (br s, 2H, OH), 7.58 (d,
281.0818 (calcd for C17H13O4 281.08193).
to 2D experiments (COSY, HMQC).
*
Assignments according
1H, Jortho¼7.8 Hz, H3), 7.53e7.42 (m, 6H), 7.34e7.31 (m, 3H); 13C
NMR (100 MHz, DMSO-d6) d 167.7 (CO2H), 165.0 (CO2H), 141.8 (C1),
139.4 (Cquat.), 139.2 (Cquat.), 131.5 (Cquat.), 130.1 (CH), 130.0 (CH),
129.5 (2CH, C20, C60or C30, C50), 129.4 (CH), 128.5 (2CH, C20, C60or
C30, C50), 128.1 (CH), 127.9 (CH), 127.7 (CH); LCeMS tR¼10.1 min,
[ESIꢀ] m/z [MꢀH]ꢀ 267, [MꢀHꢀCO2]ꢀ 223; HREIMS [Mþ] m/z
268.0723 (calcd for C16H12O4 268.0735).
4.3.7. [(40-Methoxybiphenyl-2-yl)methylidene]propanedioic acid 5f.
Starting from 7f (2.3 mmol, 490 mg), 5f was obtained after 30 min
refluxing time (conditions A), as a colourless solid (221 mg, 32%);
mp 175e176 ꢁC; IR (KBr) (cmꢀ1) 3427 (OH), 3084, 2924, 2846,1740
n
(CO),1672 (CO),1608,1478,1270,1242, 827, 761; 1H NMR (400 MHz,
CD3OD)
d
7.61 (d, 1H, Jortho¼7.8 Hz, H3), 7.56 (s, 1H, CH]C(CO2H)2),
4.3.3. [(20-Nitrobiphenyl-2-yl)methylidene]propanedioic acid 5b.
Starting from 7b (1.16 mmol, 263 mg), 5b was obtained after 30 min
refluxing time (conditions A), as a pale yellow solid (131 mg, 39%);
7.46 (t, 1H, Jortho¼7.8 Hz H4 or H5), 7.41 (d, 1H, Jortho¼7.8 Hz, H6),
7.35 (t, 1H, Jortho¼7.8 Hz, H4 or H5), 7.30 (d, 2H, Jortho¼8.8 Hz, H20,
H60or H30, H50), 7.01 (d, 2H, Jortho¼8.8 Hz, H30, H50 or H20, H60), 3.84
mp 216e217 ꢁC; IR (KBr)
n
(cmꢀ1) 3401, 3062, 2929, 2659, 2544,
(s, 3H, OCH3); 13C NMR (100 MHz, CD3OD)
d 170.5 (CO2H), 167.1
1749 (CO), 1681 (CO), 1531, 1437e1360 (NO2), 1306, 1184; 1H NMR
(CO2H), 161.0 (C40), 143.8 (C1), 143.6 (CH]C(CO2H)2), 133.4 (Cquat.),
133.1 (Cquat.), 132.0 (C20, C60), 131.2 (CH), 131.0 (CH), 129.5 (CH),
129.1 (Cquat.), 128.1 (CH), 114.8 (C30, C50), 55.8 (OCH3); LCeMS
tR¼10.1 min, [ESIꢀ] m/z [MꢀH]ꢀ 297, [MꢀHꢀCO2]ꢀ 253. HRESIMS
[MꢀH] m/z 297.0768 (calcd for C17H13O5 297.07685).
(400 MHz, CD3OD)
d
8.04 (d, 1H, Jortho¼10.4 Hz, H30), 7.74e7.62 (m,
3H), 7.44e7.40 (m, 3H), 7.34 (s, 1H, CH]C(CO2H)2), 7.20 (q, 1H); 13
C
NMR (100 MHz, CD3OD)
d
169.9 (CO2H), 166.6 (CO2H), 150.5 (C20),
140.8 (CH]C(CO2H)2), 139.9 (Cquat.), 135.6 (Cquat.), 134.2 (CH), 133.7
(CH), 133.6 (Cquat.), 130.9 (CH), 130.6 (Cquat.), 130.5 (CH), 129.9 (CH),
129.5 (CH), 129.2 (CH), 125.3 (CH); LCeMS tR¼9.8 min, [ESIꢀ] m/z
[MꢀH]ꢀ 312. HRESIMS [MꢀH] m/z 312.0515 (calcd for C16H10NO6
312.05081).
4.3.8. [(40-tert-Butylbiphenyl-2-yl)methylidene]propanedioic acid 5g.
Starting from 7g (1.76 mmol, 420 mg), 5g was obtained after 45 min
refluxing time (conditions B), as a colourless solid (145 mg, 25%); mp
90e91 ꢁC; IR (KBr) (cmꢀ1) 3430 (OH), 2961, 2925, 2851, 1711 (CO),
n
4.3.4. {[30-(Trifluoromethyl)biphenyl-2-yl]methylidene}propanedioic
acid 5c. Starting from 7c (0.45 mmol, 112 mg), 5c was obtained
after 30 min refluxing time (conditions A), as a colourless solid
1693 (CO), 1620, 1479, 1264, 1198, 834, 764; 1H NMR (400 MHz,
CD3OD)
7.63 (d, 1H, Jortho¼7.8 Hz, H3), 7.58 (s, 1H, CH]C(CO2H)2),
7.50e7.41 (m, 4H), 7.37e7.30 (m, 3H), 1.36 (s, 9H, CH3); 13C NMR
(100 MHz, CD3OD) 170.6 (CO2H), 167.3 (CO2H), 162.5 (Cquat.), 152.0
d
(33 mg, 22%); mp 170e171 ꢁC; IR (KBr)
n
(cmꢀ1) 3323 (OH), 3074,
d
2653, 2546, 1750 (CO), 1680 (CO), 1620, 1431, 1335e1303e1257
(Cquat.), 143.9 (Cquat.), 143.7 (CH]C(CO2H)2), 138.3 (Cquat.), 133.3
(Cquat.), 131.1 (C5), 131.0 (C6), 130.6 (C20, C60or C30, C50), 129.6 (C3),
128.3 (C4), 126.3 (C30, C50 or C20, C60), 35.5 (C(CH3)3), 31.7 (3C, CH3);
LCeMS tR¼11.7 min, [ESIꢀ] m/z [MꢀH]ꢀ 323, [MeHeCO2]ꢀ 279.
HRESIMS [MꢀH] m/z 323.1289 (calcd for C20H19O4 323.12888).
(CF3), 1166, 1115; 1H NMR (400 MHz, CD3OD)
d
7.70 (dd, 1H, Jor-
¼7.8 Hz, Jmeta¼1.9 Hz, H3), 7.67e7.62 (m, 4H), 7.52 (t, 1H,
tho
Jortho¼7.8 Hz), 7.47e7.42 (m, 3H); 13C NMR (100 MHz, CD3OD)
d
170.0 (s, CO2H), 166.7 (s, CO2H), 142.5 (s, Cquat.), 142.2 (s, Cquat.),
2
142.0 (s, Cquat.), 134.5 (s, CH), 133.5 (s, Cquat.), 131.8 (d, JCF¼32 Hz,
C30), 131.4 (s, CH0), 131.0 (s, CH), 130.3 (s, CH), 129.6 (s, CH), 129.3 (s,
4.3.9. [(20,40-Dimethylbiphenyl-2-yl)methylidene]propanedioic acid
5h. Starting from 7h (1.95 mmol, 410 mg), 5h was obtained after
30 min refluxing time (conditions B), as a clear oil (57 mg, 10%); IR
3
3
CH), 127.4 (d, JCF¼3.3 Hz, C20 or C40), 125.5 (d, JCF¼3.3 Hz, C20 or
C40), 125.5 (d, JCF¼269 Hz, CF3); LCeMS tR¼9.7 min, [ESIþ] m/z
1
[MþH]þ 337. HRESIMS [MꢀH] m/z 335.0537 (calcd for C17H10 F3O4
(KBr)
n
(cmꢀ1) 3434 (OH), 2926, 2855, 1733 (CO), 1698 (CO), 1633,
335.05367).
1428, 1258, 1057; 1H NMR (400 MHz, CD3OD)
d
7.68 (d, 1H, Jortho
¼
7.8 Hz, H3), 7.44 (t,1H, Jortho¼7.8 Hz), 7.35 (t,1H, Jortho¼7.8 Hz), 7.33 (s,
1H, CH]C(CO2H)2), 7.22 (d, 1H, Jortho¼7.8 Hz), 7.10 (s, 1H, H30), 7.05
(d, 1H, Jortho¼7.8 Hz), 6.98 (d, 1H, Jortho¼7.8 Hz), 2.35 (s, 3H, CH3), 2.02
4.3.5. [(30-Chlorobiphenyl-2-yl)methylidene]propanedioic acid 5d.
Starting from 7d (0.74 mmol,160 mg), 5d was obtained after 15 min
refluxing time (conditions A), as a colourless powder (96 mg, 43%);
(s, 3H, CH3); 13C NMR (100 MHz, CD3OD)
d 170.4 (CO2H), 167.3
mp 191e192 ꢁC; IR (KBr)
n
(cmꢀ1) 3435 (OH), 2927, 2586, 1757 (CO),
(CO2H), 144.5 (C1), 141.8 (CH]C(CO2H)2), 138.9 (Cquat.), 137.9 (Cquat.),

E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
2553
137.2 (Cquat.), 133.7 (Cquat.), 131.8 (CH), 131.4 (CH), 131.0 (CH), 130.7
(CH), 129.2 (Cquat.), 128.9 (CH), 128.4 (CH), 127.4 (CH), 21.2 (CH3), 20.1
(CH3); LCeMS tR¼10.8 min, [ESIꢀ] m/z [MꢀH]ꢀ 295, [MꢀHꢀCO2]ꢀ
251. HRESIMS [MꢀH] m/z 295.0976 (calcd for C18H15O4 295.09758).
CO2H), 151.5 (Cquat.), 145.6 (Cquat.), 145.1 (Cquat.), 142.5 (Cquat.), 139.8
(Cquat.), 128.7 (CH), 127.6 (CH), 125.9 (CH), 123.1 (CH), 120.6 (CH),
120.3 (CH), 57.3 (CHaliph.), 47.4 (C9), 35.7 (C(CH3)3), 31.9 (3C, CH3);
LCeMS tR¼11.4 min, [ESIꢀ] m/z [MꢀH]ꢀ 323, [MꢀHꢀCO2]ꢀ 279.
HRESIMS [MꢀH] m/z 323.1292 (calcd for C20H19O4 323.12888).
4.4. Synthesis of fluorene-9-malonic acids
4.4.5. (2,4-Dimethyl-9H-fluoren-9-yl)propanedioic acid 6h. Starting
from 5h (0.15 mmol, 45 mg), 6h was obtained as a colourless
All fluorene derivatives were obtained as followed: previous
benzylidene-malonic acids were stirred in Et2O with 2.2 equiv of
BF3$Et2O at room temperature during 15 h (20 h for 6e). The reaction
was then quenched with MeOH and the medium was evaporated
under vacuum to dryness to eliminate borane derivatives.
powder (43 mg, quant.); mp 190e191 ꢁC; IR (KBr)
n
(cmꢀ1) 3422
(OH), 2923, 2852, 1744 (CO), 1708 (CO), 1635, 1123, 1083, 1062; 1H
NMR (400 MHz, CD3OD)
d
7.82 (d, 1H, Jortho¼7.8 Hz), 7.57 (d, 1H,
Jortho¼7.8 Hz), 7.34 (t, 1H, Jortho¼7.8 Hz), 7.24 (s, 1H), 7.21 (t, 1H,
Jortho¼7.8 Hz), 6.96 (s, 1H), 4.53 (d, 1H, J¼5.8 Hz, H9), 3.77 (d, 1H,
J¼5.8 Hz, CHaliph.), 2.62 (s, 3H, CH3), 2.35 (s, 3H, CH3); 13C NMR
4.4.1. 9H-Fluoren-9-ylpropanedioic acid 6a. Starting from 5a
(0.17 mmol, 45 mg), 6a was obtained as a colourless powder (45 mg,
(100 MHz, CD3OD) d 171.9 (CO2H), 171.7 (CO2H), 146.1 (Cquat.), 145.6
quant.); mp 190e191 ꢁC; IR (KBr)
n
(cmꢀ1) 3431(OH), 2923, 1729
(Cquat.), 143.5 (Cquat.), 137.7 (Cquat.), 137.7 (Cquat.), 133.7 (Cquat.), 131.8
(CH), 128.5 (CH), 128.5 (CH), 126.8 (CH), 125.8 (CH), 124.0 (CH),
123.6 (CH), 57.1 (CHaliph.), 47.0 (C9), 21.5 (CH3), 21.1 (CH3); LCeMS
tR¼11.8 min, [ESIꢀ] m/z [MꢀH]ꢀ 295, [MꢀHꢀCO2]ꢀ 251. HRESIMS
[MꢀH] m/z 295.0975 (calcd for C18H15O4 295.09758).
(CO), 1707 (CO), 1449, 1206, 743; 1H NMR (400 MHz, DMSO-d6)
d
*
12.80 (br s, OH), 7.84 (d, 2H, Jortho¼7.8 Hz, H4, H5), 7.59 (d, 2H,
Jortho¼7.8 Hz, H1, H8), 7.36 (t, 2H, Jortho¼7.8 Hz, H3, H6), 7,28 (t, 2H,
Jortho¼7.8 Hz, H2, H7), 4.51 (d, 1H, J¼5.9 Hz, H9), 3.94 (d, 1H,
J¼5.9 Hz, Haliph.); 13C NMR (100 MHz, DMSO-d6)
d 169.6 (2C, CO2H),
144.2 (C8a, C9a), 140.7 (C4a, C4b), 127.4 (C3, C6), 126.9 (C2, C7),
124.9 (C1, C8), 119.9 (C4, C5), 54.7 (CHaliph.), 53.2 (C9); LCeMS
tR¼9.8 min, [ESIꢀ] m/z [MꢀH]ꢀ 267, [MꢀHꢀCO2]ꢀ 223; HREIMS m/z
268.07395 (calcd for C16H12O4 268.07354). HREIMS [MꢀH] m/z
4.5. Synthesis 9H-fluoren-9-ylacetic acid 12
o-Phenylbenzylidene malonic acid 5a (0.35 mmol, 100 mg) was
stirred at 60 ꢁC in CH2Cl2 (5 mL) in a sealed tube with 70 equiv of
TFA (24.5 mmol, 1.9 mL) and 70 equiv of TFAA (24.5 mmol, 3.4 mL)
during 8.5 h. After evaporation under vacuum, the crude material
was purified by flash chromatography (CH2Cl2/MeOH, 100/80/
0/20) to give a colourless solid (47 mg, 60%). Spectral data (1H
NMR) are in agreement with those found in the literature.19
268.07395 (calcd for C16H12O4 268.07354).
to 2D experiments (HMQC, HMBC).
*
Assignments according
4.4.2. (2-Methyl-9H-fluoren-9-yl)propanedioic acid 6e. Starting
from 5e (0.04 mmol, 11 mg), 6e was obtained as a colourless
powder (10 mg, quant.); mp 220e221 ꢁC; IR (KBr)
n
(cmꢀ1) 3420
(OH), 2920, 2855, 1714 (CO), 1696 (CO), 1633, 1415, 1083; 1H NMR
(400 MHz, CD3OD)
7.67 (d, 1H, Jortho¼7.8 Hz), 7.60 (d, 1H, Jor-
Supplementary data
d
¼7.8 Hz), 7.51 (d, 1H, Jortho¼7.8 Hz), 7.36 (s, 1H, H1), 7.29 (t, 1H,
1H and 13C NMR spectra are available as Supplementary data.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.026. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
tho
Jortho¼7.8 Hz,), 7.18 (d, 1H, Jortho¼7.8 Hz), 7.16 (t, 1H, Jortho¼7.8 Hz),
4.52 (d, 1H, 3J¼6.8 Hz, H9), 3.70 (d, 1H, 3J¼6.8 Hz, CHaliph.), 2.34 (s,
3H, CH3); 13C NMR (100 MHz, CD3OD)
d 171.7 (CO2H), 145.7 (Cquat.),
145.3 (Cquat.), 142.6 (Cquat.), 139.9 (Cquat.), 138.0 (Cquat.), 129.5 (CH),
128.6 (CH), 127.5 (CH), 126.6 (CH), 126.0 (CH), 120.5 (CH), 120.4
(CH), 56.9 (CHaliph.), 47.2 (CHaliph.), 21.7 (CH3); LCeMS tR¼10.4 min,
[ESIꢀ] m/z [MꢀH]ꢀ 281, [MꢀHꢀCO2]ꢀ 237. HRESIMS [MꢀH] m/z
281.0819 (calcd for C17H13O4 281.08193).
References and notes
1. Posternak, A. G.; Garlyauskayte, R. Y.; Yagupolskii, L. M. J. Fluorine Chem. 2010,
131, 274e277.
2. Neugebauer, R. C.; Uchiechowska, U.; Meier, R.; Hruby, H.; Valkov, V.; Verdin, E.;
Sippl, W.; Jung, M. J. Med. Chem. 2008, 51, 1203e1213.
3. Li, K.; Tunge, J. A. J. Comb. Chem. 2008, 10, 170e174.
4.4.3. (2-Methoxy-9H-fluoren-9-yl)propanedioic acid 6f. Starting
from 5f (0.17 mmol, 50 mg), 6f was obtained as a colourless powder
(48 mg, quant.); mp 204e205 ꢁC; IR (KBr) (cmꢀ1) 3418 (OH), 3009,
n
4. Srinivas, K.; Srinivasan, N.; Reddy, K. S.; Ramakrishna, M.; Reddy, C. R.; Ar-
unagiri, M.; Kumari, R. L.; Venkataraman, S.; Mathad, V. T. Org. Process Res. Dev.
2005, 9, 314e318.
5. Awale, S.; Tezuka, Y.; Wang, S.; Kadota, S. Org. Lett. 2002, 4, 1707e1709.
6. Rodrigues-Santos, C. E.; Echevarria, A. Tetrahedron Lett. 2007, 48, 4505e4508.
7. Kelin, L.; Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881e2883.
8. Majumder, P. L.; Chatterjee, S.; Mukhoti, N. J. Indian Chem. Soc. 2001, 78,
743e755.
9. Dupin, J.-F. E.; Chenault, J. Heterocycles 1983, 20, 2401e2404.
10. Camps, F.; Coll, J.; Colomina, O.; Messeguer, A. J. Heterocycl. Chem. 1985, 22,
363e368.
11. Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Org. Lett.
2008, 10, 2581e2584.
2923, 2849, 1713 (CO), 1689 (CO), 1633, 1467, 1259, 1084; 1H NMR
(400 MHz, CD3OD)
7.66 (d, 2H, Jortho¼7.8 Hz), 7.53 (d, 1H, Jor-
d
¼7.8 Hz), 7.32 (t, 1H, Jortho¼7.8 Hz), 7.20e7.16 (m, 2H), 6.94 (dd,
tho
1H, Jortho¼7.8 Hz, Jmeta¼1.9 Hz), 4.57 (d, 1H, J¼6.8 Hz, H9), 3.83 (s,
3H, OCH3), 3.75 (d, 1H, J¼6.8 Hz, CHaliph.); 13C NMR (100 MHz,
CD3OD)
d 171.7 (2C, CO2H), 161.0 (Cquat.), 147.2 (2C, Cquat.), 145.0
(Cquat.), 142.5 (Cquat.), 135.4 (Cquat.), 128.7 (CH), 126.8 (CH), 125.8
(CH), 121.5 (CH), 119.9 (CH), 114.8 (CH), 111.8 (CH), 57.0 (CHaliph.),
55.9 (OCH3), 47.3 (C9); LCeMS tR¼9.8 min, [ESIꢀ] m/z [MꢀH]ꢀ 297,
[MꢀHꢀCO2]ꢀ 253, [MꢀHꢀ(CO2)2]ꢀ 209. HRESIMS [MꢀH] m/z
297.0768 (calcd for C17H13O5 297.07685).
12. Richardson, T. I.; Dodge, J. A.; Durst, G. L.; Pfeifer, L. A.; Shah, J.; Wang, Y.;
Durbin, J. D.; Krishnan, V.; Norman, B. H. Bioorg. Med. Chem. Lett. 2007, 17,
4824e4828.
13. Piao, C.-R.; Zhao, Y.-L.; Han, X.-D.; Liu, Q. J. Org. Chem. 2008, 73, 2264e2269.
14. Duan, S.; Jana, R.; Tunge, J. A. J. Org. Chem. 2009, 74, 4612e4614.
15. Sieglitz, A.; Troester, H.; Boehme, P. Chem. Ber. 1962, 95, 3013e3029.
16. Lowe, D. B.; Bifulco, N.; Bullock, W. H.; Claus, T.; Coish, P.; Dai, M.; Dela Cruz, F.
E.; Dickson, D.; Fan, D.; Hoover-Litty, H.; Li, T.; Ma, X.; Mannelly, G.; Monahan,
M.-K.; Muegge, I.; OConnor, S.; Rodriguez, M.; Shelekhin, T.; Stolle, A.; Sweet, L.;
Wang, M.; Wang, Y.; Zhang, C.; Zhang, H.-J.; Zhang, M.; Zhao, K.; Zhao, Q.; Zhu,
J.; Zhua, L.; Tsutsumib, M. Bioorg. Med. Chem. 2006, 16, 297e301.
17. Rodionow, W. M.; Postovskaja, E. A. J. Am. Chem. Soc. 1929, 51, 841e852.
18. Rochais, C.; Rault, S.; Dallemagne, P. Curr. Med. Chem. 2010, 17, 4342e4369.
19. Goehring, R. R. Org. Prep. Proced. Int. 1994, 26, 476e478.
4.4.4. (2-tert-Butyl-9H-fluoren-9-yl)propanedioic acid 6g. Starting
from 5g (0.15 mmol, 48 mg), 6g was obtained as a colourless powder
(48 mg, quant.); mp 100e101 ꢁC; IR (KBr) (cmꢀ1) 3433 (OH), 2925,
n
1733 (CO),1704 (CO),1631,1455,1413,1189,1084; 1H NMR (400 MHz,
CDCl3)
d
7.72 (d, 1H, Jortho¼7.8 Hz), 7.68e7.67 (m, 2H), 7.55 (d, 1H,
Jortho¼7.8 Hz), 7.42 (d,1H, Jortho¼7.8 Hz), 7.34 (t,1H, Jortho¼7.8 Hz), 7.22
(t, 1H, Jortho¼7.8 Hz), 4.59 (d, 1H, J¼6.8 Hz, H9), 3.62 (d, 1H, J¼6.8 Hz,
CHaliph.), 1.34 (s, 9H, CH3); 13C NMR (100 MHz, CD3OD)
d 171.7 (2C,

2554
E. Chosson et al. / Tetrahedron 67 (2011) 2548e2554
20. C16H12O4, 2(H2O), M¼304.29 g/mol, monoclinic, space group C2, a¼19.6286
22. Bernardon, J.-M.; Nedoncelle, P. Eur. Patent Appl. 1998, EP 879814 A119981125.
23. Dijcks, F.A.; Grove, S.J.A.; Carlyle, I.C.; Thorn, S.N.; Rae, D.R.; Ruigt, G.S.F.; Leysen,
D. Int. Appl. 1999, WO 9918941 A2 19990422.
24. Guo, X.; Zhou, J.; Li, X.; Sun, H. J. Organomet. Chem. 2008, 693, 3692e3696.
25. Praveen Ganesh, N.; Chavant, P.-Y. Eur. J. Org. Chem. 2008, 27, 4690e4696.
26. Wu, H. J.; Lin, C. F.; Lee, J. L.; Lu, W. D.; Lee, C. Y.; Chen, C. C.; Wu, M. J. Tetra-
hedron 2004, 60, 3927e3934.
3
ꢂ
ꢁ
ꢂ
ꢂ
ꢂ
(9) A, b¼4.9575(3) A, c¼15.0559(8) A, ¼94.869(3) , V¼1459.79(14) A , Z¼4, F
b
(000)¼640,
m
¼0.107 mmꢀ1, Dc¼1.385 mg/m3. The 12,451 reflections were
collected of which 3360 were unique [R(int)¼0.0263]; 2934 reflections were
observed [I>2
reflections. Goodness of fit¼1.080.
s
(I)]. The final refinement gave R1¼0.0530 and wR2¼0.1413 for all
21. Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. J. Med. Chem.
1986, 29, 852e855.
27. Iihama, T.; Fu, J.-M.; Bourguignon, M.; Snieckus, V. Synthesis 1989, 3, 184e187.