Alkylation of acetals using manganate-BF3·OEt2 mixed reagent

Article abstract of DOI:10.1016/j.tetlet.2004.04.050

A mixture of 'R₃MnMgBr' and BF₃·OEt ₂ prepared in advance only by stirring both reagents in ether converted acetals to alkylation products, where an alkoxy group of acetals was substituted by the alkyl group of manganese reagent used. Ketals also reacted with the 'mixed reagent' to afford the corresponding alkylation products in high yield. α-Alkoxy-substituted cyclic ethers and acetoxy-substituted cyclic ethers were selectively converted to ring-opening alkylation products and α-alkyl-substituted cyclic ethers, respectively.

Full text of DOI:10.1016/j.tetlet.2004.04.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4499–4501
Alkylation of acetals using manganate–BF ÆOEt mixed reagent
3
2
Makoto Hojo, Nobuo Ushioda and Akira Hosomi*
Department of Chemistry, 21st Century COE, Graduate School of Pure and Applied Sciences, University of Tsukuba, and CREST,
Japan Science and Technology Corporation (JST), Tsukuba, Ibaraki 305-8571, Japan
Received 11 March 2004; accepted 9 April 2004
3 3 2
Abstract—A mixture of ‘R MnMgBr’ and BF ÆOEt prepared in advance only by stirring both reagents in ether converted acetals to
alkylation products, where an alkoxy group of acetals was substituted by the alkyl group of manganese reagent used. Ketals also
reacted with the ‘mixed reagent’ to afford the corresponding alkylation products in high yield. a-Alkoxy-substituted cyclic ethers and
acetoxy-substituted cyclic ethers were selectively converted to ring-opening alkylation products and a-alkyl-substituted cyclic ethers,
respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
Introduction of a Lewis acid into the reactions using
organometallic reagents often promotes nucleophilic
ð1Þ
reaction of the organometallic reagent toward electro-
1
philes. Allylation with allylsilanes is representative.
2
Compared to reactions using less ionic organometallic
reagents, alkylation agents with more ionic carbon–
metal bond of higher reactivity are used for the nucleo-
philic introduction of simple alkyl groups. Use of a
Lewis acid in simple alkylation is limited because of
incompatibility of the simple and ionic alkylation agent
The above reaction suggests that organomanganese
reagents including ate-type reagents were ‘compatible’
with BF
by transmetalation were employed for preparation of
the pre-mixed reagent with BF ÆOEt to examine com-
3
2
ÆOEt . Manganese reagents that were generated
3
2
3
patibility of organomanganese reagents with BF ÆOEt2
3
with the Lewis acid.
in a more general manner. Thus-prepared ‘mixed
reagents’ based on mono-, di-butylmanganese, tri- and
tetra-butylmanganate were subjected to a reaction
with 3-phenylpropionaldehyde dimethyl acetal (1a,
We previously reported that manganese ate-type
reagents reacted with several electrophiles to generate
nucleophilic manganese reagents. Manganate reagents
served as a reductant in that process. Unfortunately,
thiomethylmanganese reagent that was generated
0
6
4
R @Ph(CH ) ). All mixed reagents for butylation
2
2
(R@Bu) that we examined afforded 2-phenylethyl butyl
carbinol methyl ether (2a) (Eq. 2). In the reaction with
‘
reductively from iodomethyl sulfide with ‘Bu MnLi’ did
3
not react with benzaldehyde. However, the correspond-
Bu Mn’–BF ÆOEt , acetal 1a remained (23% of 1a) after
2
3
2
8
h at )78 °C, whereas ‘Bu
3
MnMgBr’–BF
efficiently with 1a to give the substitution product 2a in
3
2
ÆOEt reacted
ing adduct was obtained in the presence of BF
Interestingly, even if the manganate reagent ‘Bu MnLi’
3
2
ÆOEt .
3
7
9
1% yield. This efficiency contrasts markedly with that
and BF
3
2
ÆOEt were mixed in advance, iodomethyl sulfide
was reduced to generate thiomethylmanganese reagent
without deactivation of the manganese-based reductant
by BF
nucleophilic reactivity of thus-generated thiomethylation
3
2
ÆOEt . Eventually, the Lewis acid enhanced
5
agent to the aldehyde (Eq. 1).
ð2Þ
Keywords: Alkylation; Acetal; Ketal; Lewis acid; Manganese.
*
Corresponding author. Tel.: +81-29-853-4237; fax: +81-29-853-6503;
e-mail: hosomi@chem.tsukuba.ac.jp
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.050

4500
M. Hojo et al. / Tetrahedron Letters 45 (2004) 4499–4501
a
Table 1. Reaction of organomanganate–BF
3
ÆOEt
2
mixed reagents with acetals 1
1
b
Entry
R
R
Conditions
Yield %
1
2
3
4
5
6
Ph(CH
1a
2
)
2
(1a)
Bu
)78 °C, 4 h
)50 °C, 4 h
)78 °C, 4 h
)78 °C, 4 h
)50 °C, 4 h
)78 °C, 4 h
2a 94
2b 90
2c 94
2d 71
2e 81
2f 80
Ph(CH
i-Pr
Ph
2 3
)
1a
1a
c-Hex (1b)
1b
Bu
i-Pr
a
3 2 3
BF ÆOEt was added to a solution of ‘R MnMgBr’ in ether at )78 °C. Then the mixture was stirred for 10 min. Acetal 1 (1 mmol) was added to the
mixture. The reaction was carried out under the conditions shown in the relevant column.
Isolated yield.
b
of the reaction in the absence of BF ÆOEt , where the
corresponding product 2a was not obtained.
rials with the action of the Lewis acid; activation of
methoxy group would engender production of alkylated
cyclic ethers. Notably, by merely changing the methoxy
group on the tetrahydropyran ring to i-propoxy group
affected the product selectivity: only ring-opening
product 2k was obtained (Eq. 7).
3
2
8
Table 1 summarizes other reactions of acetals 1 with
9
‘
R MnMgBr’–BF ÆOEt . Not only acetal 1a, but also
3
3
2
that of a-branched aldehyde 1b was alkylated to afford
c-hexyl butyl carbinol methyl ether (2e) in 81% (entry 5).
sec-Alkyl-manganese mixed reagents were also adapt-
able to the present reaction (entries 3 and 6): especially
0
in entry 6, where both R and R were sec-alkyl group,
c-hexyl i-propyl carbinol methyl ether (2f) was obtained
in 80% yield. Interestingly, even aromatic groups were
delivered onto acetal carbon (entry 4). The present
reaction seems not to have suffered from steric hin-
drance. Moreover, dibutyl ketone dimethyl acetal 1c was
converted to tert-alkyl ether 2h in 96% yield (Eq. 3).
ð5Þ
ð3Þ
This result suggested that cationic intermediates may
have been involved in these reactions and that the gen-
erated cationic intermediates were alkylated by the
manganate reagent in a stepwise manner. For those
reasons, we examined a reaction of acetal that generated
c-propyl carbinyl cation in the presence of a Lewis acid.
Interestingly, in the reaction of c-propanecarboxalde-
hyde dimethyl acetal (1d) with 3-phenylpropylmanga-
nese mixed reagent, c-propyl phenylpropyl carbinol
methyl ether (2i) was obtained in high yield without
ð6Þ
ð7Þ
10
cationic rearrangement (Eq. 4).
Lactol acetates also reacted with the present mixed re-
agents. In marked contrast to Eq. 7, we found that
alkyl-substituted cyclic ethers were obtained without
ring-opening products in reactions of cyclic ethers with
acetoxy group as a leaving group (Eqs. 8 and 9). sec-
Alkyl groups and even the phenyl group were able to be
introduced to cyclic ethers. A stereoisomeric mixture of
2-acetoxytetrahydrofuran 1h (syn/anti ¼ 1/1) gave 2,5-
disubstituted tetrahydrofurans 2l–n, whose ratio of syn/
anti varies from 46/54 to 62/38, depending on the R
group of manganese-mixed reagents.
ð4Þ
Reactions of unsymmetrical acetals were also examined.
When 2-methoxytetrahydrofuran (1e) was conducted to
the reaction, ring-opening product 2j and alkylated tet-
rahydrofuran 2j were produced in 55% and 36% yield,
respectively (Eq. 5). 2-Methoxytetrahydropyrane (1f)
also gave a mixture of ring-opening product 2k (33%)
and alkylated tetrahydropyran 2k (18%) (Eq. 6). In
these reactions, ring-opening products were formed
through the activation of ring-oxygen of starting mate-
0
0
A reaction of syn 2-acetoxytetrahydropyran 1i with
phenyl-mixed reagent afforded syn 2-phenyl-6-hexyl-
tetrahydropyran (2o) stereoselectively in 86% yield.

M. Hojo et al. / Tetrahedron Letters 45 (2004) 4499–4501
4501
acidic metal center, Reetz, M. T.; Westermann, J.;
Steinbach, R. Angew. Chem., Int. Ed. Engl. 1980, 19,
9
00–901; (c) Organocerium reagents exhibit unique
reactivity, Imamoto, T. In Lanthanides in Organic Synthe-
sis; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Academic: London, 1994.
. (a) Hojo, M.; Harada, H.; Ito, H.; Hosomi, A. J. Am.
Chem. Soc. 1997, 119, 5459–5460; (b) Hojo, M.; Harada,
H.; Ito, H.; Hosomi, A. J. Chem. Soc., Chem. Commun.
ð8Þ
4
5
1
997, 2077–2078; (c) For reviews on manganate reagents,
see: Oshima, K. J. Organomet. Chem. 1999, 575, 1–20;
Shinokubo, H.; Oshima, K. J. Synth. Org. Chem. Jpn.
1999, 57, 27–37.
. Hojo, M.; Sakuragi, R.; Murakami, Y.; Baba, Y.; Hos-
omi, A. Organometallics 2000, 19, 4941–4943.
6. The precise structures of the species expressed here as a
formula ‘R
ð9Þ
n
Mn(MgX)nꢀ2’ and terms ‘mono-, di-, and
trialkylmanganate’ are not clear at present and these are
tentatively used. For the structure of tetraethylmanganate,
see: (a) Morris, R. J.; Girolami, G. S. Organometallics
1
989, 8, 1478–1485; (b) Andersen, R. A.; Carmona-
Substitution by nonstabilized alkyl group at acetal
carbon center was attained using the ‘R MnMgBr’–
Guzman, E.; Gibson, J. F.; Wilkinson, G. J. Chem. Soc.,
Dalton Trans. 1976, 2204–2211.
. ‘Bu Mn’ and ‘Bu MnMgBr’ are possibly in equilibrium
2 3
through disproportionation. Such a disproportionation
would be the reason why clear difference between these
reactions was not observed.
. Previously, copper salt was co-used as a catalyst in
reactions of organomanganese reagents for conjugate
addition to a,b-unsaturated carbonyl compounds and
alkylation with alkyl bromides. In these reactions, trans-
metalation of alkyl group from manganese to copper may
possibly be involved. Therefore, these reactions are closely
related to copper chemistry (a) Cahiez, G.; Alami, M.
Tetrahedron Lett. 1989, 30, 3541–3544; (b) Cahiez, G.;
Alami, M. Tetrahedron Lett. 1989, 30, 7365–7368; (c)
Cahiez, G.; Alami, M. Tetrahedron Lett. 1990, 31, 7423–
3
BF
nate reagents with BF
trum of organomanganese reagents, but it remains
unclear whether manganate and BF ÆOEt is truly
3
ÆOEt
2
‘mixed reagent’. Such mixed-use of manga-
7
3
ÆOEt expands reactivity spec-
2
3
2
8
compatible, or whether both reagents form new species
for alkylation. Further study of ‘mixed reagents’ is now
in progress.
Acknowledgements
This work was partly supported by Grants-in-Aid for
Scientific Research from the Japan Society for the Pro-
motion of Science (JSPS), and Grants-in-Aid for Sci-
entific Research on Priority Areas from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
7
424; (d) Cahiez, G.; Marquais, S. Synlett 1993, 45–47,
Iron catalyst was also used for synthesis of ketones from
acid halides and coupling with vinyl halides; (e) Cahiez,
G.; Chavant, P.-Y.; Metais, E. Tetrahedron Lett. 1992, 33,
5
1
245–5248; (f) Cahiez, G.; Marquais, S. Tetrahedron Lett.
996, 37, 1773–1776.
9
2
. To a suspension of MnBr (1.1 mmol) and LiBr (2.2 mmol)
in ether (10 mL) was added Grignard reagent (3.3 mmol)
at )78 °C under argon. The mixture was stirred for 30 min.
BF ÆOEt (1.1 mmol) was added to the mixture at )78 °C.
References and notes
3
2
The resultant mixture was stirred for another 10 min.
Acetal (1.0 mmol) was added to the mixture at )78 °C; the
temperature was immediately raised to the reaction
1
2
. Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley: Weinheim, 2000; Vols. 1–2.
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4
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1
2
295–1298; (b) Hosomi, A. Acc. Chem. Res. 1988, 21, 200–
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Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev.
1992, 92, 69–95, and references cited therein.
3
. For organocopper–BF
K.; Yamamoto, Y. J. Am. Chem. Soc. 1977, 99, 8068–
070; (b) Organotitanium reagents are possessed of Lewis
3 2
ÆOEt reagents, see: (a) Maruyama,
8