4-Chromenesulphones: Synthesis and transformation to isoflavonoid models

Article abstract of DOI:10.1016/S0040-4039(02)01653-2

Novel sulphones derived from chromenes through substitution at C-4 were prepared. It has been shown that, after conjugate addition of phenyl lithium and sulphone function manipulation on the adducts, these molecules lead to isoflavan, isoflavene and isoflavanone models.

Full text of DOI:10.1016/S0040-4039(02)01653-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6893–6895
4-Chromenesulphones: synthesis and transformation to
isoflavonoid models†
Alessandro Bolis C. Simas,* Luis F. O. Furtado and Paulo R. R. Costa
Universidade Federal do Rio de Janeiro, Nu´cleo de Pesquisas de Produtos Naturais, Ilha da Cidade Universita´ria, CCS, bloco H,
Rio de Janeiro, RJ, 21941-590, Brazil
Received 22 July 2002; accepted 6 August 2002
Abstract—Novel sulphones derived from chromenes through substitution at C-4 were prepared. It has been shown that, after
conjugate addition of phenyl lithium and sulphone function manipulation on the adducts, these molecules lead to isoflavan,
isoflavene and isoflavanone models. © 2002 Elsevier Science Ltd. All rights reserved.
Isoflavonoids constitute quite a large family of natural
products.1,2 Some of these molecules are biosynthesized
de novo by plants as a consequence of microorganism
invasion. Induced substances which carry antimicrobial
activity are known as phytoalexins. Regardless of func-
tional group composition, most isoflavonoids bear basic
backbone 1 (Scheme 1).
We set resorcinol-related chromenes 2 as starting mate-
rials (Scheme 2). Among the literature alternatives,4 we
chose to obtain these compounds via acetals 6,4a mainly
due to the availability of materials employed in their
synthesis. Nevertheless, the initial experiments making
use of such a route indicated the opportunity of further
development. Firstly, we managed to increase the yields
of acrolein-derived acetal chain incorporation on phe-
nols 5 by changing the solvent to DMF. The reaction
times were also much shorter (1.5 h) and reaction
conditions milder. With regard to preparation of sub-
stances 2, control over the amount of p-TsOH (0.05
mol equiv.) and reaction dilution (0.1–0.2 M) was
found to be essential to suppress the formation of
inseparable 4-methoxy ether, an especially important
problem at larger scales, and to bestow a more consis-
tent reaction profile. We observed that, under these
conditions, cyclization to chromenes 2 could be accom-
plished at higher rates (reaction taking 1.5 h instead of
3–6 h). Moreover, we were able to prepare unavailable
3-benzyloxy phenol 5a from resorcinol 4 in a more
straightforward manner.5 Notwithstanding the moder-
We wondered whether skeleton 1 might be constructed
from chromene 2. This structure could arguably be
harnessed to accept a phenyl nucleophile at C-3. Thus,
a temporary electron-withdrawing group (EWG), prop-
erly located (as shown by 3), would render the required
electrophlilicity to 2. Sulphones are well suited for this
task. Furthermore, they are recognizably versatile func-
tional groups3 and could accommodate introduction of
different functions at C-4 and/or C-3. Herein, we
describe the synthesis of novel substances 3 and report
chemical transformations effected on them.
1
O
O
2
3
4
3
4
R
1
2, R = H
3, R = EWG = PhSO2
RO
O
RO
O
RO
OH
iii
ii
O
O
2a, R = Bn, 75%
2b, R = Me, 73%
4, R = H
5a, R = Bn, 55%
5b, R = Me
i
Scheme 1.
6a, R = Bn, 93%
6b, R = Me, 96%
Scheme 2. Reagents and conditions: (i) a. BnCl (0.5 mol.
equiv.), DMSO, rt; then, 40% aq. KOH (1.3 mol. equiv.),
90°C, 16 h, b. aq. NH4Cl, rt. (ii) a. NaH, DMF, 0°C, rt, b.
I(CH2)2CH(OCH3)2, rt. (iii) p-TsOH, dioxane, 110°C.
* Corresponding author. Fax: 21-2270-2683; e-mail: abcsimas@
nppn.ufrj.br
We dedicate this work to the memory of Professor Roderick A.
†
Barnes, a pioneer in Natural Products Chemistry in Brazil.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01653-2

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A. B. C. Simas et al. / Tetrahedron Letters 43 (2002) 6893–6895
ate yield of 5a that it provided,6 this homogeneous-
medium procedure made the preparation of multigram
quantities (10–20 g) of 5a easier.
Conjugate addition of phenyllithium to vinylsulphones
3 occurred quite cleanly (Scheme 4).‡ Data from NOE
diff experiments (6.0–7.7% enhancements following
irradiations of C3/C4-hydrogens) on adduct 7a are con-
sistent with the shown cis diastereomer.8 Thus, during
work-up (addition of aq. NH4Cl at −30°C), the proton
source approaches the conjugate base of sulphones 7
anti to the phenyl group producing kinetic product 7.
Once the electrophilic ability of substances 3 had been
established, we set out to study potential manipulations
of the sulphone function. Desulphinylation of 7a was
easily accomplished by metal reduction.9 Isoflavan
model structure 1a was obtained.
With compounds 2 in hand, we investigated phenylsul-
phinyl group incorporation and found that Sas-
Inomata’s procedure7 proceeded regioselectively to 3
(Scheme 3). By this, chromenes 2 were transformed into
b-chloromercury sulphones. Such intermediates were
isolated and, in crude form, subjected to rapid HgCl (as
Hg0 and Cl−) group elimination (20 min). Reproduction
of literature stoichiometry (condition A) resulted in
slow reaction (24 h) and incomplete conversion to the
organomercurial intermediate (55% yield after demercu-
ration). However, we found that higher rates (3 h) and
(slightly higher) yields (60%) are attained when a 1.0
mol. equiv. excess of HgCl2 (condition B) is employed.
At large scales, condition A is indicated because it
prevents final product contamination by mercurial
species.
Moreover, elimination reaction10 provided 3-phenyl
chromene 8, a model for isoflavenes (Scheme 5). We
also studied conversion of adduct 7a into its respective
ketone via hydrolyzable a-thiosulphone 9.11 Attempts
to react the conjugate base of 7a (LDA or LHMDS as
base) with (PhS)2 resulted mainly in recovered starting
material. Conversely, application of condition ii
(Scheme 5) brought about conversion of sulphone 7a
into a high-absorbance (UV) compound in low yield
which we identified as methylthiochromene 10. Natu-
rally, 10 results from the fast in situ elimination of
sulphinate from product 9 (R=Me) which leads to a
conjugated tetrasubstituted olefin. Hydrolysis of 10
could possibly provide the desired ketone, but because
of the low yields of 10, we sought another means for
achieving this transformation.
RO
O
RO
O
A or B
2a, R = Bn
2b, R = Me
SO2Ph
3a, R = Bn
3b, R = Me
Scheme 3. Reagents and conditions: (A) i. PhSO2Na, CH3OH,
CH2Cl2; then, HgCl2 (1.0 equiv.), rt, ii. DBU, THF, rt. (B) i.
idem, except for: HgCl2 (2.0 equiv.), ii. idem.
BnO
O
RO
O
RO
O
ii
i
3
4
SO2Ph
SO2Ph
1a, 80% (from 7a)
3a, R = Bn
3b, R = Me
7a, R = Bn, 53%
7b, R = Me, 60%
Scheme 4. Reagents and conditions: (i) [PhBr–BuLi], THF, −78°C, −30°C. (ii) Na(Hg), MeOH, THF, rt.
BnO
O
9
BnO
O
BnO
O
SR
PhO2S
i
ii
BnO
O
10, 36%
8, 89%
SO2Ph
7a
S
t
Scheme 5. Reagents and conditions: (i) BuOK, THF, 0°C, rt. (ii) a. LHMDS, THF, −78°C, b. (MeS)2, THF, HMPA, −78°C,
−30°C.
‡ Representative procedure: A stirred solution of PhBr (0.124 g; 0.79 mmol) in THF (1.0 mL) at −78°C under Ar was slowly treated with BuLi
in hexanes (1.42 M, 0.55 mL). After 20 min, sulphone 3b (0.16 g; 0.53 mmol) in THF (1.3 mL) was added dropwise to the resulting mixture.
The reaction mixture was kept under the same conditions for 30 min and then it was slowly warmed to −30°C. After 2.5 h at −30°C, satd aq.
NH4Cl was added and the cold bath was removed. Product extraction with AcOEt, followed by the usual work-up procedures, led to a brown
residue. This material was purified by medium-pressure column chromatography on silica gel (eluting with 10–30% AcOEt/hexanes) to afford
pure 7b.

A. B. C. Simas et al. / Tetrahedron Letters 43 (2002) 6893–6895
6895
BnO
O
BnO
O
O
BnO
OH
O
ii
i
7a
O
PhO2S
12, quant.
11, 70%
O
M
13
M = Molybdenum complex
Scheme 6. Reagents and conditions: (i) a. LHMDS, THF, −78°C, b. MoOPH, THF, −78°C. (ii) DBU, THF, rt.
Use of Vedejs’ reagent12 produced a,b-unsaturated
ketone 11 (Scheme 6) instead of the desired cyclic
compound 12. After treatment with DBU (but not with
either pyridine or Et3N), enone 11 was converted to 12.
Interestingly, it appears that, during the first reaction,
formation of less polar product 11 occurs in the reac-
tion medium (TLC) before the usual reductive work-up.
Thus, apparently, the metal peroxide13 intermediate 13
disproportionates spontaneously in situ producing 12,
which suffers retro-Michael-type ring opening under
the basic conditions. Ketone 12 represents an isofla-
vanone model structure.
References
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ing materials. It renders unnecessary the employment of
2-functionalized phenols, a common feature of the
alternative synthetic methodologies.14
8. These were the highest values for signal effects on vicinal
hydrogen atoms of the dihydropyran ring system.
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13. In their original work dealing with oxidation of enolates,
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13.
In summary, a practical synthesis of chromene-based
vinyl sulphones has been developed. These novel struc-
tures have proven to be quite versatile. Phenyl adducts
resulting from these structures may have their sulphone
group manipulated to yield isoflavan, isoflavene and
isoflavanone models.
Acknowledgements
We thank CNPq (PIBIC-fellowship to LFOF), Central
Anal´ıtica-NPPN and Centro Nacional de RMN-UFRJ
for analytical data, Instituto de Qu´ımica-UFRJ for IR
spectra.
14. Dean, F. M. In The Total Synthesis of Natural Products;
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