Oxidative C-C bond-forming reaction of electron-rich alkylbenzyl ether with trimethylvinyloxysilane

Article abstract of DOI:10.1021/ol036314j

Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.

Full text of DOI:10.1021/ol036314j

ORGANIC
LETTERS
2
004
Vol. 6, No. 10
523-1526
Oxidative C−C Bond-Forming Reaction
of Electron-Rich Alkylbenzyl Ether with
Trimethylvinyloxysilane
1
Bai-Ping Ying, Bridget G. Trogden, Daniel T. Kohlman, Sidney X. Liang, and
Yao-Chang Xu*
DiscoVery Chemistry Research, Lilly Research Laboratories, Lilly Corporate Center,
Eli Lilly and Company, Indianapolis, Indiana 46285
xu_yao-chang@lilly.com
Received November 27, 2003
ABSTRACT
Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C−C
bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol
ethers to give carbonyl products in yields ranging from 10 to 85%.
Since the initial report of using p-methoxybenzyl (MPM) to
protect the hydroxy functional group by Oikawa in 1982,
The reagent of 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) has been successfully used for the cleavage of MPM
and other electron-rich benzyl protecting groups.1 Opera-
tionally, treatment of MPM ether in dichloromethane and a
small amount of water with slightly more than 1 equiv of
DDQ at room temperature can liberate the alcohol in very
high yield (Scheme 1). Besides the formation of the
1
-3
this protection and deprotection methodology has been
extensively utilized in organic chemistry, particularly in
2
complicated natural product syntheses. The widespread use
of this technology in the organic chemistry community can
be attributed to the relative stability of the MPM ether in
both acidic and basic conditions and, more importantly, the
ease of removing the MPM group under oxidative conditions.
Many other electron-rich benzyl ethers, including 3,4-
dimethoxybenzyl (DMPM), 3-methoxybenzyl (3-MPM), and
Scheme 1
3
,5-dimethoxybenzyl (3,5-DMPM) have since been devel-
3
oped for use in alcohol protections.
(
1) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
3, 885-888.
2) (a) Dinh, T. Q.; Du, X.; Armstrong, R. W. J. Org. Chem. 1996, 61,
2
(
6
606-6616. (b) Hirschmann, R.; Ducry, L.; Smith, A. B., III. J. Org. Chem.
2
000, 65, 8307-8316. (c) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 10521-10532. (d) Gurjar, M. K.; Maheshwar, K.
J. Org. Chem. 2001, 66, 7552-7554.
(3) (a) Oikawa, Y.; Tanaka, T.; Horita, K.; Yoshioka, T.; Yonemitsu,
O. Tetrahedron Lett. 1984, 25, 5393-5396. (b) Nakajima, N.; Abe, R.;
Yonemitsu, O. Chem. Pharm. Bull. 1988, 36, 4244-4247.
1
0.1021/ol036314j CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/14/2004

byproduct dihydroquinone (DDQH
2
), which results from the
process was carried out under dry nitrogen at room temper-
ature, and workup after 1 h afforded 3-methoxy-3-(4-
methoxy-phenyl)-1-phenyl-propan-1-one 8c in 56% isolated
yield.
reduction of DDQ, the reaction always produces the p-
methoxybenzaldehyde 3 (Scheme 1). The formation of
aldehyde 3 is not the focus for this operation, and 3 is usually
removed by column flash chromatography.
The purpose of using molecular sieves is to remove water
that might be present in the reaction mixture. To obtain
higher yields, it is essential to use a dry agent for this reaction
because the presence of water can compete with the desired
C-C bond-forming process. Due to the practical difficulty
of running a reaction in truly anhydrous conditions, a
byproduct such as p-methoxybenzaldehyde, resulting from
the coupling reaction with water present, has always been
observed, albeit the yield for this byproduct is in the low
single digits depending upon conditions.
The mechanism for this process is presented in Scheme
1. It is known that electron-rich benzyl ethers such as 1 can
3a
react with DDQ to form a charge-transfer complex. A rapid
color change, usually from colorless to deep blue, is observed
when a solution of 1 is combined with DDQ, an indication
of the formation of the charge-transfer complex 4. The
positive charge of complex 4 is localized onto the oxygen
atom as shown, which can serve as an activated electrophile,
and is ready to be coupled with any potential nucleophiles.
In this particular case, water serves as a nucleophile that
couples with 4 to form hemiacetal 5 along with the formation
2
of DDQH byproduct. Hemiacetal is usually not stable, and
decomposition of 5 provides the desired alcohol 2 and
benzaldehyde 3.
Table 1. Study of DDQ-Assisted C-C Bond-Forming
Reaction with a Variety of Electron-Rich Benzyl Ethers
a
Understanding the mechanism, we asked which other
nucleophiles could be potentially used to couple with the
charge-transfer complex 4. Herein we report our initial
finding that centers on the C-C bond construction through
carbon nucleophiles. It is expected that the coupling reaction
of 4 or similar structures with a carbon nucleophile will lead
to a product, which, unlike hemiacetal 5, will be stable for
isolation and a potentially useful substrate for organic
synthesis.
On the basis of recent findings from our laboratory that
isochroman treated with DDQ can couple with silyl enol
4
ethers and many literature reports that in situ-generated
cations can react with silyl enol ethers to form carbonyl
5
products, we first selected the trimethylvinyloxysilanes to
test the proposed reaction. To our pleasant surprise, the C-C
bond-forming reaction worked very well, as hoped. As shown
in Scheme 2, p-methoxybenzyl methyl ether 6c, dissolved
Scheme 2
in dichloromethane, was treated with DDQ for 30 min in
4
the presence of a small amount of LiClO , followed by
addition of trimethyl-(1-phenyl-vinyloxy)-silane 7. The whole
(
4) (a) Xu, Y.-C.; Roy, C.; Lebeau, E. Tetrahedron Lett. 1993, 34, 8189-
8
1
192. (b) Xu, Y.-C.; Kohlman, D. T.; Liang, S. X.; Erikkson, C. Org. Lett.
999, 1, 1599-1602. (c) Xu, Y.-C. Recent Research DeVelopments in
Organic Chemistry; Transworld Research Network: India, 2000; Vol. 4,
pp 423-441.
a
All reactions were carried out in anhydrous conditions at room
temperature under nitrogen pressure with 0.1 M solution of compound 6 in
CH2Cl2. b Anhydrous dichloromethane purchased from Aldrich in a Sure/
c
d
(
5) (a) Hashimoto, Y.; Mukaiyama, T. Chem. Lett. 1986, 755-758. (b)
Seal bottle was used. Performed with about 0.2-0.5 equiv of LiClO4. All
1
Mukaiyama, T.; Hayashi, Y.; Hashimoto, Y. Chem. Lett. 1986, 1627-1630.
c) Hashimoto, Y.; Mukaiyama, T. Chem. Lett. 1986, 1623-1626. (d)
Hayashi, Y.; Wariishi, K.; Mukaiyama, T. Chem. Lett. 1987, 1243-1246.
products were characterized by H NMR, MS, and elemental analysis.
Isolated yield after flash chromatography separation.
e
(
1524
Org. Lett., Vol. 6, No. 10, 2004

prevents the occurrence of the initial hydrogen abstraction
step. This is consistent with the fact that no color change
Table 2. Study of DDQ-Assisted C-C Bond-Forming
(indicating no charge-transfer complex was formed) was
Reaction with 5-Alkoxymethyl and
a
observed when DDQ was added to the substrate.
5-Phenoxymethyl-benzo[1,3]dioxole
From the resonance structure, the electron-donating group
at the para position will provide a stronger stabilizing
3
a,8
effect.
The data in Table 1 support this principle. The
reactions of compounds 6c, 6d, and 6e, all possessing a para-
methoxy group, with trimethyl-(1-phenyl-vinyloxy)-silane
worked well to give products 8c, 8d, and 8e, respectively,
in moderate yields. The lower yield obtained for compound
8
b can be attributed to the less reactive starting material 6b
possessing two methoxy groups at the meta position of the
benzene ring. It is interesting to observe that in the case of
5
-methoxymethyl-benzo[1,3]dioxole (6f), the reaction with
DDQ followed by trimethyl-(1-phenyl-vinyloxy)-silane pro-
9
vided product 8f in the highest yield.
The next area that was explored for this C-C bond-
forming reaction concerned the “R” group attached to the
benzylic “O” atom. As shown in Table 2, 5-alkoxymethyl-
benzo[1,3]dioxole was used to study the effect of the “R”
group in this coupling reaction because of the high yield
achieved with this particular substrate. Following the typical
protocol described earlier, the reaction of 5-tert-butoxy-
methyl-benzo[1,3]dioxole (9a) with trimethyl-(1-phenyl-
vinyloxy)-silane did not produce any product 10a. Both
starting materials, however, were consumed, indicating that
the reaction might proceed via a different pathway. Replacing
the tert-butyl group by a cyclohexyl group, as in 5-cyclo-
hexyloxymethyl-benzo[1,3]dioxole 9b, worked very well in
this DDQ-assisted C-C bond-forming reaction and afforded
the coupling product 10b in 85% isolated yield. In a sharp
contrast to these data, the reaction of similar phenyl analogue
a
All reactions were carried out in anhydrous conditions at room
temperature under nitrogen pressure with 0.1 M solution of compound 6 or
in CH2Cl2. Anhydrous dichloromethane purchased from Aldrich in aSure/
Seal bottle was used. Performed with about 0.2-0.5 equiv of LiClO4. All
products were characterized by H NMR, MS, and elemental analysis.
b
9
c
d
1
e
Isolated yield after flash chromatography separation.
9c with the same silyl enol ether 7 did not produce the desired
product 10c.
A plausible mechanism was proposed in trying to explain
the results in Table 2. The DDQ-assisted hydrogen abstrac-
tion from benzyl ether leads to the formation of a cationic
intermediate 11. The relative stability of 11 is critical in
4
The addition of LiClO is important for improving the
efficiency for the coupling reaction. It is postulated that the
-
ClO
4
can undergo exchange of counterion with the charge-
transfer complex 4 to form a new ion pair. Such a new ion
pair usually serves as a better electrophile than the charge-
(
7) (a) Becker, H. In The Chemistry of Quinoid Compounds; Patai, S.,
6
transfer complex 4. Without LiClO
4
additive, the same
Ed.; Wiley: New York, 1974; p 335. (b) Becker, H.; Turner, A. B. In The
Chemistry of Quinoid Compounds; Patai, S., Rappoport, Z., Ed.; Wiley:
New York, 1988; Vol. II, p 1351.
reaction as indicated in Scheme 2 afforded product 8 in lower
chemical yield (45%).
(
8) Oikawa, Y.; Horita, K.; Yoshioka, T.; Tanaka, T.; Yonemitsu, O.
Tetrahedron 1986, 41, 3021-3028.
9) A detailed typical reaction procedure for benzyl ether 6f and silyl
enol ether 7 is as follows: To a stirred solution of compound 6f (404 mg,
To understand the scope of this interesting reaction, we
first tried to probe the electronic effect of the benzyl ring.
Treatment of unsubstituted benzyl methyl ether 6a with DDQ
and followed by addition of silyl enol ether 7 did not yield
any product 8a (Table 1). In this case, the starting material
(
2
4
2
.43 mmol) in 10 mL of anhydrous dichloromethane was added activated
Å molecular sieves (200 mg). After 15 min of stirring, DDQ (662 mg,
.91 mmol) and LiClO4 (55 mg, 0.52 mmol) were added. The stirring was
continued for 60 min, then trimethyl-(1-phenyl-vinyloxy)-silane (561 mg,
2.91 mmol) was added. After 1 h, 5% NaHCO3 solution (25 mL) and
dichloromethane (15 mL) were added. The organic layer was separated,
and the aqueous layer was extracted with dichloromethane (3 × 15 mL).
The combined organic layer was dried, filtered, and evaporated. The residue
was purified by flash chromatography to give compound 8f (580 mg, 2.04
mmol) in 84% yield. Compound 8f: 1H NMR (400 MHz, CDCl3) δ 7.94
6a was fully recovered. It is believed that the initial hydrogen
abstraction from the benzylic position to form the charge-
transfer complex is the rate-limiting step. Electron-donating
substituents such as a methoxy group can stabilize the
benzylic cationic species7,8 and hence will promote the
desired C-C bond-forming process. In the simple benzylic
case, the absence of such a stabilizing substitution group
(
2H, m), 7.53 (1H, m), 7.44 (2H, m), 6.93 (2H, m), 6.84 (1H, d, J ) 8.8
Hz), 4.81 (1H, dd, J ) 8.4, 4.4 Hz), 3.91 (3H, s), 3.88 (3H, s), 3.58 (1H,
1
3
dd, J ) 16.3, 8.4 Hz), 3.24 (3H, s), 3.10 (1H, dd, J ) 16.3, 4.4 Hz);
NMR (CDCl3) δ 197.37 (C), 148.93 (C), 148.34 (C), 136.65 (C), 133.67
CH), 132.82 (C), 133.01 (CH), 128.29 (2 x CH), 127.96 (2 x CH), 118.90
C
(
(
6) (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1984,
(CH), 110.84 (CH), 109.14 (CH), 79.32 (CH), 56.66 (CH3), 55.85 (CH3),
55.81 (CH3), 47.14 (CH); HRMS for C18H20O4 calcd 284.1049, found
284.1055.
1
1
759-1762. (b) Hayashi, Y.; Mukaiyama, T. Chem. Lett. 1987, 1811-
814.
Org. Lett., Vol. 6, No. 10, 2004
1525

Table 3. Study of DDQ-Assisted C-C Bond-Forming
Reaction of 5-Methoxymethyl-benzo[1,3]dioxole with a Variety
of Trimethylvinyloxysilanesa
Scheme 3
forming the desired C-C bond with a nucleophile. A
possible breakdown of 11 can lead to aldehyde 12 and
another cation species 13 as indicated in Scheme 3. In the
cases where R was the methyl or cyclohexyl, intermediate
1
1 is relatively stable, and therefore the desired C-C
coupling reaction indeed took place to form the products (8f,
0b) in good yield (Table 2). In the cases where the “R”
1
group was tert-butyl, the cascade mechanism shown in
Scheme 3 might occur because of the formation of the
relatively more stable tert-butyl cation 13. The fact that we
did not see the coupling product 10a and the isolation of
aldehyde 12 seem to be consistent with this explanation
(Table 2). However, the hydrolysis mechanism shown in
Scheme 1 with possible presence of water can lead to the
same aldehyde. This alternative mechanistic pathway can also
explain why the same reaction of compound 9c with 7 does
not offer the coupling product 10c (Table 2).
A variety of silyl enol ethers have been tested in order to
expand the scope and utility of this DDQ-assisted C-C bond-
forming reaction. As shown in Table 3, all the silyl enol
ethers (7, 14a-l) tested so far worked rather well with
5
-methoxymethylbenzo[1,3]dioxole to afford 3-methoxy-3-
phenyl-propionyl analogues 8a and 15a-l in isolated yield
ranging from 30 to 84%. Many functional groups such as
carbonyl (14g,j) and olefin (14f) can be tolerated under the
1 2
reaction conditions. When the R and R substituents of the
silyl enol ether are not the same, a mixture of two
diastereoisomers is formed (15h-j,l). Starting with readily
available electron-rich benzyl ether, this novel C-C bond-
forming reaction provides easy access to a variety of
â-alkoxycarbonyl derivatives, including 3-alkoxyl-3-phenyl-
propionaldehyde (15a), ketones (15b-j, 8f), propionic acid
methyl ester (15k), and lactone (15l).
In conclusion, we have demonstrated a relatively simple
and novel method for preparing protected aldols from benzyl
ether and silyl enol ether, by means of the readily available
reagent DDQ. The benzyl ether must have resonance
electron-donating groups in the para-position, and the benzyl
ether must be neither aromatic nor too bulky. When these
conditions are met, fair to excellent yields ranging from 30
to 85% can be obtained; otherwise, poor yields are to be
expected. The coupling reaction works well with a variety
of silyl enol ethers possessing different functionalities. Our
continuing efforts are aimed at expanding the scope of this
C-C bond-forming reaction and applications of this new
method to the organic synthesis of naturally occurring and
biologically active compounds. We shall report on such work
in due course.
a
All reactions were carried out in anhydrous conditions at room
temperature under nitrogen pressure with 0.1 M solution of compound 6f
in CH2Cl2 with about 0.2-0.5 equivalent of LiClO4 added to the reaction
mixture. All trimethylvinyloxysilanes were purchased from commercial
resources and used without further purification. All products were
characterized by H NMR, MS, and elemental analysis. Isolated yield after
flash chromatography separation.
b
c
1
d
OL036314J
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Org. Lett., Vol. 6, No. 10, 2004