Base-induced cyclization of 1-benzyloxy-2,2,4,4-tetramethylpentan-3-ones: Intramolecular nucleophilic addition of an anion of a benzyl ether to the carbonyl moiety without the Wittig rearrangement or protophilic decomposition

Article abstract of DOI:10.1039/a706802f

Alkyl benzyl ethers bearing a carbonyl moiety in the alkyl chain (1) cyclize effectively, without the Wittig rearrangement or protophilic decomposition, to give hydroxytetrahydrofurans (trans-2) on treatment with Bu^tOK in DMSO at room temperatu

Full text of DOI:10.1039/a706802f

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Base-induced cyclization of 1-benzyloxy-2,2,4,4-tetramethylpentan-3-ones:
intramolecular nucleophilic addition of an anion of a benzyl ether to the
carbonyl moiety without the Wittig rearrangement or protophilic
decomposition
Masakatsu Matsumoto,* Nobuko Watanabe, Akio Ishikawa and Hiroyuki Murakami
Department of Materials Science, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-12, Japan
Table 1 Base-induced cyclization of alkyl benzyl ethers 1
Alkyl benzyl ethers bearing a carbonyl moiety in the alkyl
chain (1) cyclize effectively, without the Wittig rearrange-
Conversion
(%)c
Ratio
ment
or
protophilic
decomposition,
to
give
Entry
Systema
t/hb
trans:cisd
hydroxytetrahydrofurans (trans-2) on treatment with
ButOK in DMSO at room temperature, whereas LDA–THF
induces the cyclization of 1 to afford predominantly the
stereoisomer cis-2.
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
A
B
B
A
B
A
B
A
B
A
B
4
91
94
95
92
99
0
86
99
96
72
63g
2a 100:0
2a 80:82
2a 9:91
2b 100:0
2b 9:91
— —
2c 12:88
2d 100:0
2d 10:90
2e 93:7
2e 13:87
2
2e
4
The a-carbanion of an alkyl benzyl ether is unstable and
undergoes protophilic cleavage (elimination)1,2 or Wittig re-
arrangement3–5 even at low temperature (Scheme 1), so that
little is known of its nucleophilic addition or substitution
reactions, although extensive studies have been made on the
rearrangement and the decomposition.6 We report here that (i)
the a-carbanion of an alkyl benzyl ether is able to add
effectively to a carbonyl moiety in the alkyl chain via
intramolecular nucleophilic addition without Wittig rear-
rangement or protophilic decomposition, and (ii) the addition is
sterically controlled by the base–solvent system used.
When benzyl ether 1a (1.1 g, 4.0 mmol) was treated with
ButOK (8.0 mmol) in DMSO (12 ml) under N2 at room
temperature for 4 h, 1a was exclusively transformed into
tetrahydrofuran trans-2a (91%), which was isolated as a
colourless oil in 88% yield after chromatographic purification
(SiO2) (Table 1, entry 1). The structure of trans-2a was
determined by 1H NMR, NOESY, IR and mass spectral
analysis.† A combination of base and solvent, e.g. ButOK–THF
or MeONa–DMSO, was ineffective for the cyclization of 1a.
On the other hand, after treatment of 1a with LDA–THF at room
temperature for 2 h, the cyclization took place smoothly to
afford a stereoisomer cis-2a as colourless crystals (mp
83.0–83.5 °C) together with a small amount of trans-2a
(cis:trans = 82:18) (94%) (entry 2). When the cyclization was
carried out at 0 °C, the stereoselectivity was somewhat
improved (cis:trans = 91:9) (entry 3). The reaction of 1a with
LDA–THF proceeded sluggishly at 278 °C. The other benzyl
ethers 1b–d also underwent base-induced cyclization to afford
the corresponding tetrahydrofurans 2b–d with similar ster-
eoselectivities, as shown in Table 1. It is noteworthy that even
benzyl ether 1c bearing an electron-donating substituent at the
para-position underwent cyclization in LDA–THF, even
though ButOK–DMSO was ineffective (entries 6 and 7).
The present results showed that (i) an alkyl benzyl ether is
probably stable enough to undergo nucleophilic reaction
2
4
5f
4
2
4
5f
10
11
a
A: 1 (4.0 mmol), ButOK (8.0 mmol), DMSO (12 ml). B: 1 (4.0 mmol),
b
LDA (8.0 mmol), THF (12 ml). Carried out at room temp. unless stated
otherwise. c No product other than 2 was observed, unless stated otherwide.
d
e
Determined via 1H NMR analysis of the crude product. Reaction
performed at 0 °C. f Reaction performed at 278 °C for 2 h and then at room
temp. for 3 h. g trans-2e (5.5%), cis-2e (31%) and 1e (37%) recovered after
chromatography.
without Wittig rearrangement or decomposition, so long as an
electrophile such as a carbonyl moiety exists in a favourable
situation, and (ii) the stereoselectivity of cyclization is tightly
controlled by the base–solvent system used. The stereoselec-
tivity can probably be rationalized as follows: for the ButOK–
DMSO system, a naked anion of 1 attacks the carbonyl via
transition state T-1, in which interaction between the aryl and
tert-butyl groups is minimized, thus giving the sterically less
congested isomer trans-2 (Scheme 2). On the other hand, in the
R1
R2
HO
O
R1
R2
:B
trans-2
O
O
R1
R2
HO
1a R1 = m-MeO, R2 = Me
b R1 = H, R2 = Me
O
c R1 = p-MeO, R2 = Me
d R1 = p-Br, R2 = Me
e R1 = m-MeO, R2 = H
cis-2
O
–
+
Ar
OR
ArCH2O
+
Li
O
Ar
Ar
R′
O
–
R′
Ar
But
–
–
Ar
But
–
H
trans-2
cis-2
–
O
O
O
T-1
T-2
R
Scheme 1
Scheme 2
Chem. Commun., 1997
2395

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LDA–THF system a lithium ion might coordinate the carbonyl
oxygen and the benzyl a-carbanion in transition state T-2 to
afford cis-2 predominantly, even though the repulsive inter-
action between the aryl and tert-butyl moieties is thermodynam-
ically unfavourable. This rationalization is consistent with the
effect of temperature on the stereoselectivity in the cyclization
of 1a using LDA–THF. It is noteworthy that 18-crown-6
promoted the trans-selective cyclization of 1a with ButOK in
THF to give trans-2a exclusively (room temp. for 4.5 h;
87%).
Since the substrate 1 lacks a b-hydrogen on the alkyl chain, it
is not susceptible to protophilic decomposition to form a
terminal alkene (Scheme 1), but it should undergo [1,2]-Wittig
rearrangement. Thus, we examined the reaction of benzyl ether
3 as a representative ether bearing b-hydrogens on the alkyl
chain. Treatment of 3 with LDA in THF (278 °C to room
efficient chemiluminescent substrate7§ in high yield upon
treatment with SOCl2 and pyridine at room temperature. The
other furans 2 obtained here were similarly dehydrated to give
the corresponding dihydrofurans.
The present results show that the a-carbanion of an alkyl
benzyl ether such as 1 or 3 undergoes nucleophilic addition to a
carbonyl moiety existing in the same molecule without Wittig
rearrangement or protophilic decomposition. Furthermore, the
present cyclization should form a facile entry to sterically
crowded cyclic enol ethers.
The authors gratefully acknowledge financial assistance in
the form of a Grant-in-aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture of the
Japanese Government.
Footnotes and References
* E-mail: matsumo@info.kanagawa-u.ac.jp
MeO
MeO
MeO
† All products obtained here gave satisfactory NMR, IR and mass spectral
data.
‡ A single isomer, with stereochemistry tentatively assigned as cis-4 was
isolated in 90% yield.
O
But OH
But
But
§ Previously, the dihydrofuran 5 had been synthesized by the McMurry
reaction of 3-oxo-2,2,4,4-tetramethylpentyl 3-methoxybenzoate using Ti0
(ref. 7). However, this method is expensive and not suitable for large-scale
synthesis.
O
O
O
3
4
5
temp.) gave the expected cyclization product 4 in high yield,‡
while the use of ButOK–DMSO induced almost no reaction.
Thus, intramolecular nucleophilic addition of the a-carbanion
of an alkyl benzyl ether to the carbonyl of the alkyl site takes
place effectively even if it bears b-hydrogens. In addition, we
should note that benzyl ether 1e bearing an isobutyryl moiety
also gave the corresponding cyclization product 2e on treatment
with a base even though 1e possesses an acidic proton adjacent
to the carbonyl moiety (entries 10 and 11).
1 M. Maercker, Angew. Chem., Int. Ed. Engl., 1987, 26, 972.
2 M. Matsushita, Y. Nagaoka, H. Hioki, Y. Fukuyama and M. Kodama,
Chemistry Lett., 1996, 1039.
3 U. Scho¨llkopf, Angew. Chem., Int. Ed. Engl., 1970, 9, 763.
4 T. Nakai and K. Mikami, Chem. Rev., 1986, 86, 885.
5 J. A. Marshall, in Comprehensive Organic Synthesis, ed. G. Pattenden,
Pergamon, Oxford, 1991, vol. 3, p. 975.
6 J.-F. Biellmann and J.-B. Ducep, Org. React., 1982, 27, 1.
7 M. Matsumoto, N. Watanabe, N. C. Kasuga, H. Hamada and K. Tado-
koro, Tetrahedron Lett., 1997, 38, 2863.
Both isomeric hydroxytetrahydrofurans trans- and cis-2a
were easily dehydrated to give dihydrofuran 5, which is a key
intermediate for the synthesis of a dioxetane used as a highly
Received in Cambridge, UK, 19th September 1997; 7/06802F
2396
Chem. Commun., 1997