New functionalized alkenylmagnesium reagents bearing an oxygen function in the β-position. Preparation and reaction of 5-magnesiated-1,3-dioxin-4-one derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01426-5

5-Magnesiated-1,3-dioxin-4-ones have been prepared by performing a low temperature iodine-magnesium exchange reaction. These alkenylmagnesium reagents bearing an alkoxy function in the β-position react directly with aldehydes or with other electrophiles such as acid chlorides, allylic bromides, aryl and alkenyl iodides in the presence of a copper or palladium transition metal catalyst.

Full text of DOI:10.1016/S0040-4039(01)01426-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6847–6850
New functionalized alkenylmagnesium reagents bearing an
oxygen function in the b-position. Preparation and reaction of
5-magnesiated-1,3-dioxin-4-one derivatives†
Viet Anh Vu, Laurent Be´rillon and Paul Knochel*
Ludwig-Maximilians-Universita¨t Mu¨nchen, Institut fu¨r Organische Chemie, Butenandtstraße 5-13, Haus F,
81377 Mu¨nchen, Germany
Received 11 July 2001; accepted 20 July 2001
Abstract—5-Magnesiated-1,3-dioxin-4-ones have been prepared by performing a low temperature iodine–magnesium exchange
reaction. These alkenylmagnesium reagents bearing an alkoxy function in the b-position react directly with aldehydes or with
other electrophiles such as acid chlorides, allylic bromides, aryl and alkenyl iodides in the presence of a copper or palladium
transition metal catalyst. © 2001 Elsevier Science Ltd. All rights reserved.
Organomagnesium reagents are key intermediates in
organic chemistry. Our recent use of a halogen–metal
exchange reaction allows the preparation of functional-
ized aryl-, alkenyl- and heteroaryl-magnesium species
bearing ester, nitrile or amide groups.1,2 Also, function-
alized arylmagnesium derivatives bearing amino groups
can be prepared in high yield by an iodine–magnesium
exchange.3 The synthesis of alkenylmagnesium halides
bearing an oxygen functionality in the b-position, such
as type 1, is usually not possible since a fast b-elimina-
tion occurs.4 The preparation of such organometallics is
possible only in special cases.5,6 Various functionalized
alkenylmagnesium7 compounds bearing an electrophilic
group in the a-position can be readily prepared via a
bromine–magnesium exchange at low temperature. We
anticipated that sensitive b-alkoxymagnesium com-
pounds could be accessed via a fast iodine–magnesium
exchange. As an initial target, we selected the b-alkoxy-
magnesium derivatives of type 2. The corresponding
5-magnesiated-1,3-oxazin-4-one derivatives are not only
interesting as examples of b-alkoxy-Grignard reagents,
but the functionalization of the position 5 of these
heterocycles with an electrophile leads to products hav-
ing a potential use as pharmaceutical and agrochemical
intermediates.8 Thus, the iodination of the readily avail-
able 1,3-dioxin-4-ones 3a,b with N-iodosuccinimide
(NIS) in acetic acid8,9 furnishes the 5-iodo-1,3-dioxin-4-
ones 4a–b in 70–85% yield. Treatment of 2a–b with
i-PrMgCl (1.1 equiv.) in THF at −30°C for 0.5 h results
in complete conversion to the corresponding Grignard
2a–b. Although the stability of 2a–b was found to be
limited (half-lives of 2a–b at −30°C were ca. 2 h and ca.
1 h, respectively) these b-alkoxy alkenylmagnesium spe-
cies could be reacted with a range of electrophiles
leading to products of type 5 (Scheme 1 and Table 1).
Thus, the reaction of 2a and 2b with benzaldehyde or
OR
i-PrMgCl
NIS, AcOH
rt, 18 h
O
O
O
O
O
O
O
O
-30 oC, 0.5 h
O
R
O
R
O
R
O
R
MgCl
MgCl
I
H
MgCl
4a: R = Ph : 85 %
3a: R = Ph
2a: R = Ph : > 90 %
1
2a: R = Ph
2b: R = Me
4b: R = Me : 70 %
3b: R = Me
2b: R = Me : ca. 85 %
E+
O
O
O
O
Keywords: iodine–magnesium exchange; functionalized Grignard
reagents; palladium; cross-coupling reaction.
O
R
O
R
MgCl
E
* Corresponding author. Tel.: +49-89-2180-7679; fax: +49-89-2180-
7680; e-mail: paul.knochel@cup.uni-muenchen.de
5
2a - b
†
Dedicated to Professor Jean-Franc¸ois Normant on the occasion of
his 65th birthday.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01426-5

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V. Anh Vu et al. / Tetrahedron Letters 42 (2001) 6847–6850
Table 1. 5-Substituted 1,3-dioxin-4-ones of type 5 obtained by the reaction of the Grignard reagent 2a–b with various
electrophiles
an aliphatic aldehyde such as cyclohexanecarbaldehyde
furnishes the expected addition products 5a–b and 5g–h
in 57–81% yield (entries 1, 2, 7 and 8 of Table 1). The
acylation of 2a is best performed by converting the
Grignard reagent 2a to the corresponding copper
reagent by transmetalation with the THF-soluble cop-
per salt10 CuCN·2LiCl (−30°C; 0.5 h) followed by the
addition of benzoyl chloride (−15°C; 3 h), leading to
the unsaturated ketoester 5c in 83% yield (entry 3). The
allylation of 2a–b can be performed simply by adding a
catalytic amount of CuCN·2LiCl (10 mol%), leading to
the expected allylated products 5f, 5i and 5j in 65–81%
yield (entries 6, 9 and 10). Finally, electrophiles such as
Me3SnCl and PhSSPh react smoothly, furnishing the
organotin derivative 5d (59%; entry 4) and the thioether
5e, respectively (68%; entry 5). A palladium(0)-cata-
lyzed cross-coupling11 with aryl or alkenyl iodides is
accomplished by transmetalating the sensitive organo-
magnesium derivatives 2a–b to the corresponding
organozinc species 6a–b by adding ZnBr2 (1.0 equiv.).
In the presence of Pd(dba)2 (5 mol%) and tris-o-
furylphosphine (tfp, 10 mol%), the cross-coupling prod-
ucts 7a–c are produced in acceptable yields (60°C; 12 h;
54–57%). Remarkably, the b-alkoxy-organozinc
reagents 6 do not significantly undergo an elimination
reaction at 60°C (12 h reaction time!) showing that the
elimination rate depends strongly on the ionic character
of the carbonꢀmetal bond12 (Scheme 2).
In summary, we have shown that the mild reaction
conditions required for the I/Mg exchange allow the
generation of a b-alkoxy alkenylmagnesium derivative

V. Anh Vu et al. / Tetrahedron Letters 42 (2001) 6847–6850
6849
O
O
O
R
CN
I
CN
7a : R = Ph; 57 %
7b : R = Me; 54 %
1) i-PrMgCl, -30 oC, 0.5 h
O
O
Pd(dba)2 (5 mol %)
tfp (10 mol %)
60 oC, 12 h
4
O
R
2) ZnBr2, -30 oC to rt, 1 h
ZnBr
6a : R = Ph
6b : R= Me
I
O
O
O
Ph
O
O
7c : 55 %
Scheme 2.
which is sufficiently stable at low temperature (−30°C)
to react with aldehydes. A copper-transmetalation
provides the corresponding copper reagent, which can
be smoothly acylated or allylated. Finally, by
transmetalating to the organozinc species, a very sta-
ble b-alkoxyalkenylzinc reagent is obtained, which
undergoes Negishi cross-coupling reactions at 60°C in
satisfactory yields. Extensions of these reactions, as
well as further applications of the halogen–magnesium
exchange reaction for generating new functionalized
organomagnesium reagents is currently underway in
our laboratories.13
Oshima, K. Angew. Chem., Int. Ed. 2000, 39, 2481; (c)
Herrinton, P. M.; Owen, C. E.; Gage, J. R. Org. Proc.
Res. Dev. 2001, 5, 80.
3. Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez,
G.; Knochel, P. Synlett 2001, 477.
4. (a) Gurien, H. J. Org. Chem. 1963, 28, 878; (b) Ficini,
J.; Depezay, J. C. Bull. Soc. Chim. Fr. 1966, 3878; (c)
Mann, F. G.; Stewart, F. H. C. J. Chem. Soc. 1954,
2826; (d) Reichstein, T.; Baud, J. Helv. Chim. Acta
1937, 20, 892.
5. For the behaviour of b-aminomagnesium reagents, see:
(a) Ficini, J.; Sarrade-Loucheaur, G.; Normant, H.
Bull. Soc. Chim. Fr. 1962, 1219; (b) Ficini, J.; Depezay,
J. C. Bull. Soc. Chim. Fr. 1966, 3878; (c) Calaza, M. I.;
Paleo, M. R.; Sardina, F. J. J. Am. Chem. Soc. 2001,
123, 2095; (d) Foubelo, F.; Gutierrez, A.; Yus, M. Syn-
thesis 1999, 503; (e) Schwerdtfeger, J.; Kolczewski, S.;
Weber, B.; Fro¨hlich, R.; Hoppe, D. Synthesis 1999,
1573.
Acknowledgements
We thank the DFG (Leibniz-Program) and the Fonds
der Chemischen Industrie for generous financial sup-
port. We thank Dr. Thorsten Volk of BASF AG for
his interest in this work. We thank Chemetall GmbH
(Frankfurt) and the Degussa AG (Hanau) and BASF
AG for the generous gift of chemicals.
6. (a) Ficini, J.; Depezay, J. C. Tetrahedron Lett. 1969, 54,
4795; (b) Rychnovsky, S. D.; Griesgraber, G.; Kim, J.
J. Am. Chem. Soc. 1994, 116, 2621.
7. Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319.
8. (a) Iwaoka, T.; Murohashi, T.; Katagiri, N.; Sato, M.;
Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1992, 1393;
(b) Hayashizaki, K.; Usui, Y.; Tsutsumi, Y.; Go, A.
Jpn. Kokai Tokkyo Koho 1995, 11 pp., CAN
123:256690.
9. Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem.
Pharm. Bull. 1983, 31, 1896.
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13. Typical procedure: preparation of 5-(hydroxy-phenyl-
methyl) - 2,2 - dimethyl - 6 - phenyl - [1,3]dioxin - 4 - one (5a,
entry 1 of Table 1): A dry two-necked flask equipped

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V. Anh Vu et al. / Tetrahedron Letters 42 (2001) 6847–6850
with a magnetic stirring bar and a septum was charged
up to rt. After 2 h, the reaction mixture was quenched
with brine (10 mL) and extracted with Et2O. The
organic layer was washed with brine, dried over MgSO4
and concentrated under vacuum. The crude residue was
purified by flash chromatography (pentane:EtOAc,
85:15), yielding the product 5a (90 mg, 81% yield) as a
white solid (mp=124°C).
with 4a (118 mg, 0.357 mmol) in THF (3 mL) under
argon. The reaction mixture was cooled to −30°C and
a solution of i-PrMgCl (0.24 mL, 0.393 mmol, 1.62 M
in THF) was added dropwise. After 30 min of stirring
at −30°C, benzaldehyde (55 mL, 0.536 mmol) was
added and the reaction mixture was allowed to warm