Ambident effect of a p-sulfinyl group for the introduction of two carbon substituents to phenol rings: a convergent synthesis of diverse benzofuran neolignans.

Article abstract of DOI:10.1021/ol0001261

A convergent synthesis of diversely substituted benzofuran neolignans (8) is described employing a single p-sulfinyl group on the phenols (3) as an ambident functional group for two types of carbon-carbon bond-forming reactions: (i) the direct synthesis of the dihydrobenzofuran skeletons through an aromatic Pummerer-type reaction and (ii) the ipso-substitution of the sulfur functional group by carbon substituents through a ligand exchange reaction.

Full text of DOI:10.1021/ol0001261

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2279-2282
Ambident Effect of a p-Sulfinyl Group
for the Introduction of Two Carbon
Substituents to Phenol Rings: A
Convergent Synthesis of Diverse
Benzofuran Neolignans
Shuji Akai, Nobuyoshi Morita, Kiyosei Iio, Yuka Nakamura, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6, Yamada-oka,
Suita, Osaka 565-0871, Japan
kita@phs.osaka-u.ac.jp
Received May 11, 2000
ABSTRACT
A convergent synthesis of diversely substituted benzofuran neolignans (8) is described employing a single p-sulfinyl group on the phenols
(3) as an ambident functional group for two types of carbon−carbon bond-forming reactions: (i) the direct synthesis of the dihydrobenzofuran
skeletons through an aromatic Pummerer-type reaction and (ii) the ipso-substitution of the sulfur functional group by carbon substituents
through a ligand exchange reaction.
Naturally occurring benzofuran neolignans such as liliflol
B (1), obovatinol, and kadsurenone (2) show important
biological activities, i.e., cytotoxicity, inhibition of cell
proliferation, inhibition of the platelet-activating factor
(PAF)-induced effects, etc., and have attracted much attention
on their effective syntheses.1-5 The characteristic structure
of these compounds involves the substituted phenyl group
at the C-2 position, methyl or hydroxymethyl group at the
C-3 position, carbon substituents at the C-5 position, and an
oxygen functional group at the C-6 or C-7 position of the
benzofuran skeleton (Figure 1).
The reported syntheses of these compounds were primarily
performed through the [3 + 2] cycloaddition of 1-phenyl-
1-propenes to p-quinones and their derivatives.2-4 However,
they are not always efficient due to unsatisfactory yields of
the cycloadducts and/or the limitation of the substrates.
Especially, lack of an effective method for the introduction
of a variety of carbon substituents at the C-5 position of the
skeleton has been an obstacle for the synthesis of various
derivatives. In this Letter, we present a novel and general
synthesis of benzofuran neolignans (8) containing diverse
substituents which provides a solution to the above-
mentioned problems. Our method utilizes the ambident effect
of the sulfinyl group of p-sulfinylphenols, viz., (i) the direct
synthesis of the dihydrobenzofuran skeleton (5) from the
(1) For reviews, see: Ward, R. S. Nat. Prod. Rep. 1993, 10, 1-28. Ward,
R. S. Nat. Prod. Rep. 1995, 12, 183-205. Ward, R. S. Nat. Prod. Rep.
1997, 14, 43-74.
(2) Bu¨chi, G.; Mak, C.-P. J. Am. Chem. Soc. 1977, 99, 8073-8075.
Bu¨chi, G.; Chu, P.-S. J. Org. Chem. 1978, 43, 3717-3719. Horne, D. A.;
Yakushijin, K.; Bu¨chi, G. Tetrahedron Lett. 1999, 40, 5443-5447.
(3) (a) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O.,
Jr.; Ray, J. E. J. Org. Chem. 1994, 59, 6567-6587. (b) Engler, T. A.; Chai,
W. Tetrahedron Lett. 1996, 37, 6969-6970. (c) Engler, T. A.; Chai, W.;
LaTessa, K. O. J. Org. Chem. 1996, 61, 9297-9308.
(4) Wang, S.; Gates, B. D.; Swenton, J. S. J. Org. Chem. 1991, 56, 1979-
1981. Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton, J. S
J. Org. Chem. 1992, 57, 2135-2143.
(5) Ponpipom, M. M.; Bugianesi, R. L.; Brooker, D. R.; Yue, B. Z.;
Hwang, S. B.; Shen T. Y. J. Med. Chem. 1987, 30, 136-142.
10.1021/ol0001261 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/23/2000

type reaction to generate the quinone thionium intermediates
(A), to which 1,2-addition of the counteranion, X )
-
CF3CO2 , occurred to give p-quinones and/or p-quinone
mono-O,S-acetals.6 We anticipated that a similar reaction in
the presence of a carbon nucleophile (4) would bring about
carbon-carbon bond formation on the same intermediate (A).
In this case, the preferential 1,4-addition of 4 to the
conjugated CdS+ system was expected due to the stronger
electron-withdrawing nature of the CdS+ group than that
of the CdO group.7,8
At first, we examined the feasibility of this reaction using
a simple p-sulfinylphenol (3a; R1 ) R2 ) H) and a
nucleophile (4a; R3 ) R4 ) OMe, R5 ) H, R6 ) Me). After
several trials that involved changing the acid anhydrides,
solvents, and the addition order of the chemicals, we found
that the addition of 3a (1.0 equiv) to a solution of (CF3-
CO)2O (1.4 equiv) and 4a (1.05 equiv) in CH3CN at -40
°C caused regiospecific carbon-carbon bond formation
followed by spontaneous cyclization of the benzylic cation
intermediate to give the product 5a (81% yield) as a single
regio- and stereoisomer (Table 1, run 1).9 Formation of the
p-benzoquinone was not observed in this reaction.
Application of this method to the p-sulfinylphenols (3a-
f) with various substituents and styrene derivatives (4a-g)
(1.1-1.6 equiv to 3) readily afforded the corresponding
products (5a-k) (Table 1). Several aspects are worth
mentioning: (1) The reaction was generally completed below
0 °C within 60 min. (2) Products were obtained in good-to-
high yields via the regioselective 1,4-addition of 4 to the
less congested, conjugated CdS+ system of A, which was
independent of the substituents (R1 and R2); however, the
methoxymethyl (MOM) ether (5j) was an exception (run 10).
(3) The trans-adducts were exclusively obtained even from
a mixture of E- and Z-olefins (4a, 4c, and 4g). (4)
Introduction of typical substituents of the natural neolignans,
i.e., alkoxy- or hydroxyphenyl group to the C-2 position and
methyl or oxymethyl group to the C-3 position, was
successfully attained using the corresponding olefins (4). (5)
The naphthol (3f) was used to prepare the unnatural
neolignan skeleton (5k) (run 11).
Figure 1. Benzofuran neolignans.
p-sulfinylphenols (3) through an aromatic Pummerer-type
reaction and (ii) ipso-substitution of the sulfur group by a
carbon substituent through a ligand exchange reaction of the
sulfoxides (6) (Scheme 1).
Recently we have reported that treatment of p-sulfinylphe-
nols (3) with (CF3CO)2O caused the aromatic Pummerer-
Scheme 1. Synthesis of Substituted Dihydrobenzofurans (8)
Next, ipso-substitution of the sulfur groups of 5 by carbon
substituents was investigated by utilizing the ligand exchange
reaction of the sulfoxides (6), readily prepared from 5 in
high yields (Table 1). This reaction generates the arylmetal
intermediates (D) via the sulfurane intermediates (C),10 which
(6) (a) Akai, S.; Takeda, Y.; Iio, K.; Yoshida, Y.; Kita, Y. J. Chem.
Soc., Chem. Commun. 1995, 1013-1014. (b) Akai, S.; Takeda, Y.; Iio, K.;
Takahashi, K.; Fukuda, N.; Kita, Y. J. Org. Chem. 1997, 62, 5526-5536.
(c) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.; Murata, K.;
Akai, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 1529-1531. (d) Kita, Y.;
Akai, S.; Fujioka, H. J. Synth. Org. Chem. Jpn. (Special Issue in English)
1998, 56, 963-974. (e) Akai, S.; Kita, Y. Org. Prep. Proc. Int. 1998, 30,
603-629.
(7) For related reactions of the p-sulfinylphenol, see: King, R. R. J. Org.
Chem. 1978, 43, 3784-3785.
(8) For related reactions of the o-sulfinylphenols, see: Jung, M. E.; Kim,
C.; von dem Bussche, L. J. Org. Chem. 1994, 59, 3248-3249. Jung, M.
E.; Jachiet, D.; Khan, S. I.; Kim, C. Tetrahedron Lett. 1995, 36, 361-364.
(9) The addition of 4a or (CF3CO)2O as the last component and the use
of (CF3SO2)2O and (ClCH2CO)2O as an acid anhydride gave 5a in low
yields (trace-60%).
2280
Org. Lett., Vol. 2, No. 15, 2000

Table 1. Preparation of 5 from 3 and 4 and Oxidation of 5 to 6a
5
run
3b
4b
temp, °C
R1
)
R2
)
R3
)
R4
)
R5
)
R6
Me
)
% yield
6
% yield
94
1
2
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
-40
-40
-40
25
5a
5b
5c
5d
5e
5f
H
H
OMe
H
OMe
OMe
OH
H
H
H
H
H
81
88
55
58
78
85
83
90
67
46c
76
H
H
H
H
H
H
H
H
H
H
H
6b
3
H
OMe
H
4
H
H
5
-40
-40
-40
0
H
OMe
OMe
OCH2O
H
OMe
OMe
CH2OAc
H
6
H
OMe
H
7
4g
4b
4g
4a
4g
5g
5h
5i
OMe
allyl
H
Me
6g
98
8
OMe
OMe
H
Me
9
0
OMe
OCH2O
OMe
OCH2O
H
Me
6i
6j
6k
90
99
84
10
11
0
5j
H
OMOM
H
Me
-40
5k
CHdCHCHdCH
H
Me
a Typical procedure for the preparation of 5: into a solution of 4a (0.29 mmol) and (CF3CO)2O (0.35 mmol) in anhydrous CH3CN (5 mL) at -40 °C was
added a solution of 3a (0.23 mmol). The reaction mixture was stirred at the same temperature for 30 min and quenched with saturated NaHCO3. After the
usual workup, the product was isolated by flash column chromatography on SiO2. b R1 and R2 of 3 and R3-R6 of 4 are the same as those of the corresponding
product (5). c A regioisomer (5l) was obtained in 28% yield.
in turn react with a carbon electrophile (7) to give 8 (Scheme
2). The key in this transformation was the selective fission
(9), viz., PhLi for sulfoxides (6i and 6j) with oxygen
functional groups at their ortho-position and naphthylsul-
foxide (6k) and n-BuLi for other types of sulfoxides.12
Five types of sulfoxides (6b, g, i, j, and k) were treated
with an appropriate lithium reagent (9), and the resulting
intermediates (D) were reacted with 7 (Table 2). In the cases
of 6b and 6g, it was critical to add 7 immediately after the
addition of n-BuLi (runs 1 and 2), because a 10 min delay
caused exclusive formation of protonated products (8, E )
H). Carbonyl compounds such as DMF, ClCO2Me, EtCHO,
and acrylaldehyde were sufficiently employed to introduce
C1- or C3-groups. On the other hand, the use of allyl iodide
or allyl bromide for 6j did not yield any allylated product
(8je), and the iodinated product (8, E ) I) and/or the
protonated product were obtained. However, the reaction with
Scheme 2. Ligand Exchange Reaction of 6
(12) The selectivity of the breaking bonds a and b was estimated by the
ratio of the products, 8 (E ) H) and 10, obtained by quenching the reaction
mixture of 6 and 9 with MeOH. The use of PhLi (5 equiv) for 6i, 6j, and
6k exclusively provided 8 (E ) H) but did not cause any reaction for other
sulfoxides. The use of n-BuLi (5 equiv) resulted in moderate ratios (2.2-
3.4:1) for 6b, 6g, and 6k and a good ratio (>8:1) for 6i. MeMgBr and
PhMgBr brought about no reaction, and t-BuLi caused nonselective
formation of the products.
1
(13) All new compounds (5, 6, and 8) were fully characterized by H/
13C NMR and IR spectroscopic data as well as elemental analyses or high
resolution mass spectroscopies. The product (1) was identical (mp and 1H/
13C NMR) with the authentic sample.3a
of bond a in C bearing two similar phenyl ligands,11 and it
(14) For preparation of 3 by direct introduction of the p-sulfinyl groups
into the phenols, see: Chasar, D. W.; Pratt, T. M. Phosphorus Sulfur 1978,
5, 35-40. For the indirect preparation of 3, see ref 6b.
(15) The sulfinyl group is known as a strong directing group for the
ortho-lithiation of aromatic rings, see: Quesnelle, C.; Iihama, T.; Aubert,
T.; Perrier, H.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2625-2628 and
references therein.
(16) A dual use of a sulfinyl group for stereocontrolled C-C bond
formation and subsequent regiocontrolled enol generation was reported,
see: Posner, G. H.; Hulce, M.; Mallamo, J. P.; Drexler, S. A.; Clardy, J. J.
Org. Chem. 1981, 46, 5244-5246.
was attained by choice of a suitable organometallic reagent
(10) For reviews, see: Oae, S. ReV. Heteroatom Chem. 1991, 4, 195-
225. Satoh, T. J. Synth. Org. Chem. Jpn. 1996, 54, 481-489. Satoh, T.
Farumashia 1999, 35, 1225-1229.
(11) Little is known about the selectivity of bond fission on unsym-
metrical biphenyl sulfoxides, see: Furukawa, N.; Shibutani, T.; Fujihara,
H. Tetrahedron Lett. 1987, 28, 2727-2730. Ogawa, S.; Furukawa, N. J.
Org. Chem. 1991, 56, 5723-5726. Furukawa, N.; Ogawa, S.; Matsumura,
K.; Fujihara, H. J. Org. Chem. 1991, 56, 6341-6348.
Org. Lett., Vol. 2, No. 15, 2000
2281

Table 2. Reaction of 6 with Various Carbon Electrophiles (7)a
8
run
6
9 (equiv)
7
R1
)
R2
)
R3
)
R4
)
E )
% yield
1
2
3
4
5
6
7
8
9
6b
6g
6i
6j
6j
6j
6j
6j
6k
n-BuLi (5)
n-BuLi (5)
PhLi (5)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (5)
PhLi (5)
DMF
DMF
DMF
DMF
8ba
8ga
8ia
8ja
8jb
8jc
8jd
8je
8k a
H
H
H
OMe
CHO
CHO
CHO
CHO
CO2Me
61
OMe
H
H
OCH2O
OCH2O
OMe
56
OMe
93
H
OMOM
OMOM
OMOM
OMOM
OMOM
OMe
OMe
OMe
OMe
OMe
85
ClCO2Me
H
OMe
72
EtCHO
H
OMe
CH(OAc)Et
CH(OAc)CHdCH2
CH2CHdCH2
CHO
52b
65b
57c
90
CH2dCHCHO
CH2dCHCH2Br
DMF
H
OMe
H
OMe
CHdCHCHdCH
OCH2O
a General procedure: n-BuLi or PhLi was added to a THF solution of 6 at -78 °C, and 7 (5 equiv) was added immediately (for runs 1, 2) or after 15 min
(for runs 3-9). The crude reaction mixture was stirred at -78 °C for 30-60 min, quenched with saturated NaHCO3, and worked up as usual. The product
(8) was isolated by flash column chromatography on SiO2. b Isolated after acetylation. c A solution of CuI (5 equiv) and LiCl (5 equiv) in THF was added
to a solution of the lithiated substrate in THF at -78 °C, and the mixture was stirred at 0 °C for 15 min. Allyl bromide (5 equiv) was added, and the reaction
mixture was stirred at 0 °C for 60 min. The remainder of the procedure was same as the general procedure.
allyl bromide after metal exchange from lithium to copper
In conclusion, a new convergent synthesis of diverse
benzofuran neolignans (8) from three components, viz.,
p-sulfinylphenols (3),14 1-aryl-1-propenes (4), and carbon
electrophiles (7), was developed. This protocol features the
dual effect of the sulfinyl group for two types of carbon-
carbon bond-forming reactions and is unique from the
viewpoint that a single functional group can produce the
regiocontrolled introduction of multicarbon chains under the
selected conditions.15,16 The umpolung reactivity of the
phenols to the corresponding highly reactive p-quinone
thionium ions under nonoxidative, mild conditions is also
noteworthy. An extensive study of these methodologies is
now under investigation in our laboratory.
afforded 8je (run 8).13
Deprotection of the MOM group of 8je using Me3SiCl-
NaI gave (()-liliflol B (1) in 70% yield.13 Conversion of 1
to (()-kadsurenone (2), the PAF antagonist, has been
reported (Scheme 3).3a,5
Scheme 3. Synthesis of (()-Liliflol B (1) and
(()-Kadsurenone (2)
OL0001261
2282
Org. Lett., Vol. 2, No. 15, 2000