Highly Selective One-Pot Synthesis of Polysubstituted Isoflavanes using Styryl Ethers and Electron-Withdrawing ortho -Quinone Methides Generated in Situ

Article abstract of DOI:10.1055/s-0037-1611361

A highly selective one-pot synthesis of polysubstituted isoflavanes has been developed. The reaction proceeds through the cycloaddition of methyl styryl ethers, derived from phenylacetaldehyde dimethyl acetals under acidic conditions, with electron-withdrawing ortho -quinone methides generated in situ. When phenylacetaldehyde dimethyl acetals were reacted with salicylaldehydes, the reaction proceeded smoothly to afford the corresponding isoflavanes stereoselectively in high yields and with excellent regioselectivities. The present reaction provides versatile access to functionalized isoflavanes, and constitutes a useful tool for the synthesis of biologically active molecules.

Full text of DOI:10.1055/s-0037-1611361

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
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K. Tanaka et al.
Letter
Synlett
Highly Selective One-Pot Synthesis of Polysubstituted Isoflavanes
using Styryl Ethers and Electron-Withdrawing ortho-Quinone
Methides Generated In Situ
Kenta Tanaka
0
0
0
0-0
0
0
1-8
2
5
3-3
5
6
1
Mami Kishimoto
Naoya Ohtsuka
Yoshinori Iwama
Hiroki Wada
R1
MeO
OMe
OMe
EWG
EWG
TfOH (20 mol%)
CHO
OH
CH(OMe)3 (2.0 equiv)
toluene, 40 °C, 1 h
R1
Yujiro Hoshino*
Kiyoshi Honda*
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0
0
0-0
0
0
2-
8
3
7
3-8
0
1
3
O
OMe
16 examples
OMe
up to 99% yield
dr 1:1 to 46:1
EWG
Ar
Graduate School of Environment and Information Sciences, Yokohama
National University, Tokiwadai, Hodogaya-ku, Yokohama 240-8501,
Japan
OMe
O
honda-kiyoshi-rb@ynu.ac.jp
in situ generation
hoshino-yujiro-hy@ynu.ac.jp
Received: 13.09.2018
OMe
Accepted after revision: 25.10.2018
Published online: 17.12.2018
OMe
OMe
DOI: 10.1055/s-0037-1611361; Art ID: st-2018-u0590-l
OH
OMe
HO
O
HO
O
Abstract A highly selective one-pot synthesis of polysubstituted iso-
flavanes has been developed. The reaction proceeds through the cy-
cloaddition of methyl styryl ethers, derived from phenylacetaldehyde
dimethyl acetals under acidic conditions, with electron-withdrawing or-
tho-quinone methides generated in situ. When phenylacetaldehyde di-
methyl acetals were reacted with salicylaldehydes, the reaction pro-
ceeded smoothly to afford the corresponding isoflavanes
stereoselectively in high yields and with excellent regioselectivities. The
present reaction provides versatile access to functionalized isoflavanes,
and constitutes a useful tool for the synthesis of biologically active mol-
ecules.
(a) sativan phytoalexin
(b) iconisoflavan antimicrobial
Cl
NC
Cl
O
O
(c) 6-cyanoisoflavan
antirhinovirus
(d) 4' 6-dichloroisoflavan
antirhinovirus
Figure 1 Selected examples of bioactive compounds of isoflavanes
Key words isoflavan, ortho-quinone methide, [4+2] cycloaddition,
stereoselective synthesis, regioselective synthesis
previous synthetic reports suffered from the requirement
of tedious reaction process;3 therefore, more convenient
synthetic methodology remains desirable.
Isoflavan is a prevalent structural motif found in nu-
merous natural products and pharmaceuticals, which dis-
play diverse biological activities such as antioxidant and an-
timicrobial action.1 Many biologically active isoflavanes
bear multiple substituents, and, in particular, have various
electron-donating groups such as methoxy groups (Figure
1a and 1b). Based on the structure of these compounds, a
number of research groups have developed methodologies
to synthesize isoflavanes possessing electron-donating
groups (Scheme 1a).2 In contrast, isoflavanes substituted
with electron-withdrawing groups have received little at-
tention in organic synthetic chemistry. Some isoflavanes
having electron-withdrawing substituents are known to ex-
hibit biological activity such as anti-rhinovirus action (Fig-
ure 1c and 1d).3 Despite the reports of these functionalities
of isoflavanes, the synthesis of such electron-withdrawing
compounds has been much less explored. In addition, a few
ortho-Quinone methide (o-QM) is a useful synthetic in-
termediate that is widely implicated in organic synthesis.4
In recent years, catalytic asymmetric reactions using o-QM
are rapidly growing areas and have been examined by sev-
eral research groups.5 Recently, we have been developing
the generation of o-QM from salicylaldehyde in the pres-
ence of acid catalyst and trimethyl orthoformate under
mild conditions.6 In the course of this study, we reported
that salicylaldehyde 1 reacted with unsaturated alcohol 2 in
benzene in the presence of p-TsOH and trimethyl orthofor-
mate to give trans-4 through intramolecular inverse-elec-
tron-demand [4+2] cycloaddition reaction of 3 (Scheme 2,
Equation (1)).7 In this context, when we attempted to use
acetal 5 instead of alcohol 2, which would be converted into
the unsaturated alcohol under acidic conditions, interest-
ingly, isoflavan 6 was obtained in 52% yield, and no flavan 7
was observed (Scheme 2, Equation (2)). It is considered that
the reaction would proceed through intermolecular [4+2]
cycloaddition of ortho-quinone methide with unsaturated
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
K. Tanaka et al.
Letter
Synlett
alcohol. The reaction prompted us to investigate a new
method giving a one-pot synthesis of isoflavanes bearing
electron-withdrawing groups. Herein, we report the highly
selective one-pot synthesis of polysubstituted isoflavanes
using styryl ethers and electron-withdrawing ortho-qui-
none methides generated in situ (Scheme 1b).
high polar solvent, CH3CN, was also suitable for the reaction
(entry 9). Decreasing the amount of catalyst did not im-
prove the yield (entry 10). Interestingly, the reaction with-
out trimethyl orthoformate also gave the desired product in
63% yield (entry 11). Clearly, an acetal exchange reaction
between salicylaldehyde 1a and acetal 8a proceeded to gen-
erate o-QM and vinyl ether, while trimethyl orthoformate
effectively generated o-QM from salicylaldehyde. The best
yield of the desired product was achieved with 1a (0.25
mmol), 8a (0.75 mmol), CH(OMe)3 (2.0 equiv), TfOH (20
mol%) in toluene at 40 °C (entry 6).
(a) Isoflavanes with electron-donating substituents (previous work)
CHO
OTBS
OTBS
TBSO
TBSO
O
1) morpholine
toluene, reflux
Table 1 Optimization of the Reaction Conditionsa
CHO
OH
OTBS
2) Et3SiH, BF3•Et2O
CH2Cl2, r.t.
TBSO
O
2-ene/3-ene = 1 : 3
MeO
OMe
8a
OMe
O
(b) Isoflavanes with electron-withdrawing substituents (this work)
catalyst (20 mol%)
CH(OMe)3 (2.0 equiv)
O2N
O2N
CHO
OH
OMe
OMe
solvent, 40 °C, 1 h
EWG
EWG
TfOH
CH(OMe)3
CHO
OH
1a
6a
R1
R1
O
OMe
MeO
OMe
toluene
Entry
Solvent
Catalyst
Yield (%)
one-pot
Scheme 1 The synthesis of isoflavanes
1
2
toluene
toluene
toluene
toluene
toluene
toluene
DCE
Pd(OAc)2
BF3·OE2
Sc(OTf)3
p-TsOH·H2O
HBF4·OEt2
TfOH
N.R.
N.R.
12
12
9
3b
4b
5b
6
O
O
O
HO
Me
p-TsOH
CH(OMe)3
H
CHO
OH
(1)
H
C6H6, r.t.
O
Me
84
82
73
74
73
63
1
2
3
4
7
TfOH
OMe
O
Ph
TfOH
H
8
THF
TfOH
CHO
OH
O
CH(OMe)3
(2)
+
H
O
O
9
CH3CN
toluene
toluene
TfOH
toluene, r.t.
O
OMe
O
Ph
10c
11d
TfOH
1
5
6
7
TfOH
OMe
O
Ph
a All reactions were carried out with 1a (0.25 mmol), 8a (0.75 mmol),
CH(OMe)3 (2.0 equiv), catalyst (20 mol%) in solvent (2.5 mL) at 40 °C for 1 h.
b Yield based on 1H NMR spectra.
O
O
OH
O
O
Ph
c The amount of TfOH was 10 mol%
d Without CH(OMe)3
intermolecular
[4+2] cycloaddition
intramolecular
[4+2] cycloaddition
Scheme 2 The reactions of salicylaldehyde 1 with alcohol 2 or acetal 5
With the optimal reaction conditions in hand, the gen-
erality of various salicylaldehydes and phenylacetaldehyde
dimethyl acetal was examined (Scheme 3). The phenylacet-
aldehyde dimethyl acetals possessing electron-donating
groups such as methyl, tert-butyl and methoxy groups af-
forded the target products 6a–c in good yields and diastere-
oselectivities. The substrates having halogen groups were
also suitable in the reaction (6d–f). The reaction of the par-
ent substrate phenylacetaldehyde dimethyl acetal proceed-
ed efficiently to give 6g. Fortunately, a good crystal for X-
ray analysis was obtained in this case. The relative stereo-
chemistry of the major diastereomer of isoflavan 6g was
determined by X-ray crystal structure analysis to be
We initially investigated the reaction of 5-nitrosalicylal-
dehyde (1a) with 2-(4-methylphenyl)acetaldehyde dimeth-
yl acetal (8a) using Lewis and Brønsted acid catalysts in var-
ious solvents at 40 °C. While a soft Lewis acid catalyst gave
no product (Table 1, entry 1), the use of Sc(OTf)3, a hard
Lewis acid catalyst, afforded the desired cycloadduct 6a
(entry 3). Although p-TsOH·H2O and HBF4·OEt2 gave low
yields (entries 4 and 5), a stronger Brønsted acid, TfOH,
smoothly led to the formation of the corresponding product
in high yield (dr 30:1, entry 6).8 The reaction in a medium
polar solvent such as 1,2-dichloroethane (DCE) and tetrahy-
drofuran (THF), afforded good yields (entries 7 and 8). A
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
K. Tanaka et al.
Letter
Synlett
R2
R2
OMe
R1
R1
TfOH (20 mol%)
CH(OMe)3 (2.0 equiv)
CHO
toluene, 40 °C, 1 h
OH
OMe
O2N
O
MeO
OMe
1
8
6
Me
tBu
OMe
F
OMe
OMe
OMe
O
OMe
O
O2N
O2N
O2N
OMe
OMe
OMe
OMe
O
O
6d 92% (dr 18:1)a
6a 88% (dr 30:1)
6b 89% (dr 45:1)
6c 87% (dr 22:1)
Cl
Br
OMe
OMe
OMe
OMe
O2N
TsO
O2N
O2N
OMe
O
OMe
OMe
O
O
OMe
O
6e 83% (dr 18:1)a
6f 79% (dr 46:1)a
6g 89% (dr 22:1)
6h 91% (dr 21:1)
OMe
OMe
OMe
OMe
Br
NC
MeO2C
TsO
Me
OMe
OMe
O
OMe
OMe
O
O
O
6i 76% (dr 22:1)
6j 97% (dr 15:1)
6k 77% (dr 37:1)
6l >99% (dr 6:1)
OMe
OMe
OMe
OMe
MeO
OMe
OMe
OMe
O
O
O
Br
OMe
O
6n 90% (dr 1:1)b
6o 75% (dr 1:1)a,c
6m 91% (dr 7:1)
6p 58% (dr 2:3)
Scheme 3 The reaction of salicylaldehydes 1 with phenylacetaldehyde dimethylacetal 8. The diastereomeric ratio was based on 1H NMR spectroscopic
analysis. a 24 h, b 2 h, c room temperature
nating groups usually suffer racemization at the 4-position
under acidic conditions. Therefore, 6o and 6p should be ob-
tained with lower diastereoselectivities through racemiza-
tion at 4-position. The reaction was well suitable for the use
of electron-withdrawing salicylaldehydes and various phe-
nylacetaldehyde dimethyl acetals.
A proposed mechanism for the present reaction is
shown in Scheme 4. o-QM C is generated from salicylalde-
hyde A and trimethyl orthoformate via acetal B under acidic
conditions. Elimination of methanol from dimethyl acetal D
generates methyl styryl ether E. According to previous
studies, [4+2] cycloaddition of vinyl ethers would be
through a concerted reaction mechanism.11 Based on the
above, the electron-rich vinyl ether E would react with o-
QM C through a concerted reaction to give the desired cyclic
product G with excellent regioselectivity.2b,2c As shown in
Scheme 2, high diastereoselectivities were observed when
salicylaldehydes having 5-substituted electron-withdraw-
ing groups were used, and it is considered that the observed
stereochemistry would be achieved via an endo transition-
state intermediate.11
In conclusion, we have developed a highly selective one-
pot synthesis of polysubstituted isoflavanes using styryl
ethers and electron-withdrawing ortho-quinone methides
generated in situ. When phenylacetaldehyde dimethyl ac-
etals were reacted with salicylaldehydes, the highly regio-
selective reaction proceeded to afford the corresponding
isoflavanes in high yields. In particular, a variety of salicyl-
Figure 2 ORTEP view of isoflavan 6g9
(2RS,3RS,4SR), as shown in Figure 2.9 When salicylalde-
hydes bearing the strong or medium electron-withdrawing
groups such as 5-tosyloxy, 5-nitrile, 5-methoxycarbonyl
and 5-bromo were used, the corresponding products 6h–k
were obtained in good yields. It is reported that 6-cyanoiso-
flavan exhibits antirhinovirus activity.3a While 4-tosyloxy,
4-bromo and parent salicylaldehydes gave high yields (6l
and 6m), diastereoselectivities were clearly decreased com-
pared with 5-substituted salicylaldehydes. When salicylal-
dehyde having electron-donating groups were used, mod-
erate yields and low diastereoselectivities were observed
(6o and 6p). According to the previous studies,10 4-hy-
droxy- or 4-methoxy-chromanes possessing electron-do-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
K. Tanaka et al.
Letter
Synlett
N. Antiviral Chem. Chemother. 1992, 3, 195. (d) Conti, C.;
Genovese, D.; Santoro, R.; Stein, M. L.; Orsi, N.; Fiore, L. Antimi-
crob. Agents Chemother. 1990, 34, 460.
H
O
OMe
O
OMe
H+
H
CH(OMe)3
OMe
(4) (a) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-L.;
Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655. (b) Pathak, T. P.;
Sigman, M. S. J. Org. Chem. 2011, 76, 9210.
– MeOH
– H+
OH
OH
– H2O
A
B
C
OMe
OMe
(5) Jaworski, A. A.; Scheidt, K. A. J. Org. Chem. 2016, 81, 10145.
(6) (a) Tanaka, K.; Sukekawa, M.; Shigematsu, Y.; Hoshino, Y.;
Honda, K. Tetrahedron 2017, 73, 6456. (b) Tanaka, K.; Hoshino,
Y.; Honda, K. Heterocycles 2017, 95, 474. (c) Tanaka, K.; Hoshino,
Y.; Honda, K. Tetrahedron Lett. 2016, 57, 2448. (d) Tanaka, K.;
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Kishimoto, M.; Hoshino, Y.; Honda, K. Heterocycles DOI:
10.3987/COM-18-S(F)5. (j) Tanaka, K.; Kishimoto, M.; Hoshino,
Y.; Honda, K. Tetrahedron Lett. 2018, 59, 1841.
Ph
Ph
Ph
H+
– MeOH
Ph
C
OMe
MeO
OMe
O
OMe
O
OMe
D
F
G
E
Scheme 4 The proposed reaction mechanism
aldehydes having electron-withdrawing groups with phe-
nylacetaldehyde dimethyl acetals gave good regio- and di-
astereoselectivities. The present reaction provides versatile
access to functionalized isoflavanes, and constitutes a use-
ful tool for the synthesis of biologically active molecules.
(7) Miyazaki, H.; Honda, K.; Asami, M.; Inoue, S. J. Org. Chem. 1999,
64, 9507.
Supporting Information
(8) Synthesis of Isoflavane 6; General Procedure: Salicylaldehyde
1 (0.25 mmol), phenylacetaldehyde dimethyl acetal 8 (0.75
mmol) and trimethyl orthoformate (0.50 mmol) were dissolved
in anhydrous toluene (2.5 mL) under nitrogen. Trifluorometh-
anesulfonic acid (20 mol%) was added into the reaction mixture.
After being stirred at 40 °C for 1 h, the reaction was quenched
with 5% aq. NaHCO3. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The combined
organic layer was dried over MgSO4, and filtered. The filtrate
was concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel (hexane/ethyl acetate,
50:1) to afford isoflavan 6. Characterization data for 2,4-dime-
thoxy-6-nitro-3-(p-tolyl)phenylchromane (6a): Yield: 0.1368 g
(84%); yellow solid; dr 30:1. 1H NMR (500 MHz, CDCl3): δ = 8.29
(dd, J = 2.7, 0.8 Hz, 1 H), 8.16 (dd, J = 8.7, 3.0 Hz, 1 H), 7.10 (d, J =
1.3 Hz, 4 H), 7.00 (d, J = 1.3 Hz, 1 H), 5.50–5.47 (m, 1 H), 4.59 (d,
J = 4.7 Hz, 1 H), 3.55 (s, 3 H), 3.48 (t, J = 5.0 Hz, 1 H), 3.38 (s, 3 H),
2.31 (s, 3 H); 13C NMR (126 MHz, CDCl3): δ = 157.5, 141.6, 137.1,
132.6, 129.1, 128.9, 125.4, 124.4, 123.8, 117.3, 103.3, 74.4, 57.1,
56.6, 45.1, 21.0; IR (ATR): 2916, 1516, 1338, 1107, 1061, 1030,
918, 753, 616 cm–1; HRMS (ESI+): m/z [M + H]+ calcd for
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611361.
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References and Notes
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C
18H20NO5: 330.1336; found: 330.1342.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D