Stereoselective preparation of highly functionalized (Z)-3-magnesiated enoates by an iodine - Magnesium exchange reaction

Article abstract of DOI:10.1039/b106195j

3-Iodoenoates are converted into the corresponding alkenylmagnesium species with complete retention of configuration of the double bond; both direct reaction and copper(I)-mediated reactions with various electrophiles provide polyfunctional enoates.

Full text of DOI:10.1039/b106195j

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Stereoselective preparation of highly functionalized (Z)-3-magnesiated
enoates by an iodine–magnesium exchange reaction
Ioannis Sapountzis, Wolfgang Dohle and Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandstr. 5-13, Haus F, D-81377
München, Germany. E-mail: Paul.Knochel@cup.uni-muenchen.de; Fax: +49-089-2180-7680;
Tel: +49-089-2180-7681
Received (in Cambridge, UK) 12th July 2001, Accepted 5th September 2001
First published as an Advance Article on the web 27th September 2001
Table 1 Stereoselective preparation of 3-substituted crotonates and
3-Iodoenoates are converted into the corresponding alke-
nylmagnesium species with complete retention of configura-
cinnamates of type 3 and 4 obtained by the reaction of the 3-magnesiated
crotonates 1a and 3-magnesiated cinnamates 2b with various electro-
philes
tion of the double bond; both direct reaction and copper( )-
I
mediated reactions with various electrophiles provide
polyfunctional enoates.
Grignard
Entry reagent
Yield
(%)a
Electrophile
Product of type 3 or 4
Functionalized organometallics are key intermediates for the
synthesis of complex polyfunctional molecules.1 Although
organozinc reagents have been proven to tolerate many
functional groups, their low reactivity precludes their reaction
with some electrophiles.1 Recently, we have shown that the
iodine–magnesium exchange reaction allows the preparation of
highly functionalized aryl and heteroaryl magnesium rea-
gents2,3 and this methodology has also been used to access
alkenylmagnesium compounds.4 Since the stereoselective prep-
aration of stereochemically well defined E- or Z-alkenylmagne-
sium compounds is not possible by the direct insertion of
magnesium into E- or Z-alkenyl halides, the iodine–magnesium
exchange reaction may be a unique way of preparing stereo-
chemically pure E- or Z-alkenylmagnesium derivatives.5 Espe-
cially useful for synthetic applications are organometallic
reagents bearing functional groups in close proximity to the
carbon–magnesium bond in an arrangement which provides an
umpolung of the standard reactivity.6 This led us to investigate
the stereoselective preparation of 3-magnesiated enoates7 of
type 1 displaying a d3-reactivity.6 The required 3-iodoenoates of
type 2 are readily available by literature procedures.8 Thus, the
reaction of (Z)-ethyl 3-iodocrotonate (2a) with isopropylmag-
nesium bromide in THF at 220 °C for 2 h leads to the desired
(Z)-ethyl 3-magnesiated crotonate (1a). After quenching with
an electrophile, products of type 3 are obtained in good yields
(Scheme 1, Table 1). (Z)-Ethyl 3-iodocinnamate (2b) behaves in
a similar fashion; the I/Mg-exchange reaction is complete
within 0.5 h as indicated by GC analysis of iodolized and
hydrolyzed reaction aliquots. Transmetalation of 1a or 1b with
the THF-soluble copper salt CuCN·2LiCl9 provides a function-
alized copper reagent with complete retention of the double
1
1a
69b
2
3
1a
1a
69b
72
Me3SnCl
4
5
6
1a
1a
1a
PhCHO
c-HexCHO
PhCOCH3
3d: R1 = H; R2 = Ph
3e: R1 = H; R2 = c-Hex
3f: R1 = Me; R2 = Ph
75
73
47
7
1b
92b
8
1b
90b
9
1b
1b
TosCN
75
10
PhCOCl
96b
11
12
1b
1b
PhCHO
c-HexCHO
4e: R = Ph
4f: R = c-Hex
72
68
a Yield of analytically pure products. b A transmetalation to a copper
reagent with CuCN·LiCl (1 equiv.) was performed prior to the addition of
the electrophile.
Scheme 1
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Chem. Commun., 2001, 2068–2069
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DOI: 10.1039/b106195j

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bond configuration. Reaction of the cuprate derived from 1a
with ethyl (2-bromomethyl)acrylate10 provides the (Z)-un-
saturated diester 3a in 69% yield ( > 99% Z). Similarly,
3-magnesiated cinnamate 1b furnishes after transmetalation
with copper E-4a (92% yield; > 99% E), thus showing in both
cases complete retention of configuration of the double bond
(entries 1 and 7 of Table 1).11 Additionally we have prepared
iodide 2a as a 2:7 E/Z mixture.12 We observed that both isomers
undergo the I/Mg-exchange. However, iodolysis experiments
indicate that the E-isomer of 1a is less stable (30 min at 260 °C)
which can be explained by the absence of chelation for this
Grignard species. Due to the difficulty of preparing pure E-2a
no additional experiments have been performed so far. The fact
that the E-isomer of 2a undergoes the I/Mg-exchange under
similar conditions as the corresponding Z-isomer seems to
indicate that chelation is not essential. The reaction of the
copper derivatives of 1a,b with 3-iodo-2-methylcyclopent-
2-enone (220 °C, 2 h) furnishes the dienic ketoesters 3b and 4b
in 69% and 92% yield respectively ( > 99% Z for 3b and > 99%
E for 4b; entries 2 and 8). Reactive electrophiles like Me3SnCl
and tosyl cyanide react directly with the functionalized
alkenylmagnesium reagents 1a,b providing the Z-organotin
derivative 3c (72% yield; > 99% Z) and the Z-1,2-cyanoester 4c
(92% yield; > 99% Z); entries 3 and 9. After transmetalation to
the copper derivative, 1b reacts with PhCOCl to give the
unsaturated 1,4-ketoester 4d (96% yield; > 99% Z). The
unsaturated Grignard reagent 1a,b adds directly to aldehydes
and ketones, furnishing the corresponding lactones in 47–75%
yield (entries 4–6 and 11–12). Finally, an additional cyano
group is also well tolerated. Thus, ethyl 3-iodo-p-cyanocinna-
mate 2c can be converted into the corresponding magnesium
derivative (1c) under our standard conditions (i-PrMgBr (1
equiv); THF; 220 °C; 0.5 h) in high yield. After transmetalation
with CuCN·2LiCl and reaction with ethyl (2-bromomethyl)-
acrylate, the expected allylation product 5 is obtained ( > 99%
E; 70% yield; Scheme 1).
Notes and references
1 A. Boudier, L. O. Bromm, M. Lotz and P. Knochel, Angew. Chem., Int.
Ed., 2000, 39, 4415.
2 M. Rottländer, L. Boymond, L. Bérillon, A. Leprêtre, G. Varchi, S.
Avolio, H. Laaziri, G. Quéguiner, A. Ricci, G. Cahiez and P. Knochel,
Chem. Eur. J., 2000, 6, 767; L. Boymond, M. Rottländer, G. Cahiez and
P. Knochel, Angew. Chem., Int. Ed., 1998, 37, 1701; L. Bérillon, A.
Leprêtre, A. Turck, N. Plé, G. Quéguiner, G. Cahiez and P. Knochel,
Synlett, 1998, 1359; G. Varchi, A. E. Jensen, W. Dohle, A. Ricci, G.
Cahiez and P. Knochel, Synlett, 2001, 477.
3 F. Trécourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais and G.
Quéguiner, Tetrahedron Lett., 1999, 40, 4339; K. Kitagawa, A. Inoue,
H. Shinokubo and K. Oshima, Angew. Chem., Int. Ed., 2000, 39, 2481;
P. M. Herrinton, C. E. Owen and J. R. Gage, Org. Process Res. Dev.,
2001, 5, 80.
4 (a) M. Rottländer, L. Boymond, G. Cahiez and P. Knochel, J. Org.
Chem., 1999, 64, 1080; (b) J. Thibonnet and P. Knochel, Tetrahedron
Lett., 2000, 41, 3319.
5 The direct insertion of magnesium into alkenyl halides is not
stereoselective. For example, the reaction of (Z)-1-bromooctene with
magnesium in THF produces a 15+85 E+Z mixture of 1-octenylmagne-
sium bromide. The same behaviour is observed for the insertion of zinc
dust into alkenyl iodides. In both cases, a radical mechanism operates.
T. N. Majid and P. Knochel, Tetrahedron Lett., 1990, 31, 4413.
6 D. Seebach, Angew. Chem., 1979, 91, 259.
7 T. Takahashi, C. Xi, Y. Ura and K. Nakajima, J. Am. Chem. Soc., 2000,
122, 3228.
8 E. Piers, T. Wong, P. D. Coish and C. Rogers, Can. J. Chem., 1994, 72,
1816.
9 P. Knochel, M. C. P. Yeh, S. C. Berk and J. Talbert, J. Org. Chem.,
1988, 53, 2390.
10 J. Villieras and M. Rambaud, Synthesis, 1982, 924.
11 The corresponding 3-zincated enoates obtained by the insertion of zinc
to the precursor 3-iodoenoates are obtained as E+Z mixtures; see P.
Knochel and C. Janakiram Rao, Tetrahedron, 1993, 49, 29. Compare
also with ref. 4a.
12 W. J. Le Noble, J. Am. Chem. Soc., 1961, 83, 3897.
13 Typical procedure: preparation of 5-cyclohexyl-4-methylfuran-2(5H)-
one: a dry and argon flushed 25 mL flask, equipped with a magnetic
stirrer and a septum, was charged with 2a (480 mg, 2 mmol). Dry THF
was added and the mixture cooled to 220 °C. i-PrMgBr (3.7 mL, 0.54
M in THF, 2 mmol) was added dropwise. The exchange was complete
after 2 h (checked by GC analysis of reaction aliquots) and the
magnesiated crotonate 1a was added via cannula to a solution of
cyclohexanecarboxaldehyde (168 mg, 1.5 mmol) in THF (1.5 mL)
cooled to 240 °C. After 30 min stirring at 240 °C the reaction was
quenched with saturated NH4Cl solution (2 mL) and poured into water
(50 mL). The aqueous phase was extracted with diethyl ether (2 3 60
mL). The organic fractions were washed with brine (40 mL) then dried
over MgSO4 and concentrated in vacuo. The crude product was purified
by flash chromatography (pentane–EtOAc 4+1) yielding the lactone 3e
as a pale colourless oil (200 mg, 73%).
In summary, we have demonstrated that new 3-magnesiated
enoates can be prepared with high stereoselectivity ( > 99%)
starting from isomerically pure Z-3-iodoenoates. These func-
tionalized alkenylmagnesium reagents react with a range of
electrophiles either directly or after transmetalation to the
corresponding alkenylcopper species.13 Extension of this
method to other polyfunctional iodoalkenes and related organic
halides is currently underway in our laboratories.
We thank Aventis Pharma and the Deutsche Forschungsge-
meinschaft (Leibniz program) for financial support. We also
thank BASF AG (Ludwigshafen), Chemetall GmbH (Frankfurt)
and Degussa AG (Hanau) for generous gifts of chemicals.
Chem. Commun., 2001, 2068–2069
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