Preparation of cyclic alkenylmagnesium reagents via an iodine/magnesium exchange

Article abstract of DOI:10.1039/b415588b

The reaction of various cyclic alkenyl iodides with i-PrMgCl·LiCl produces the corresponding alkenylmagnesium reagents under mild conditions. After reaction with various electrophiles, like allylic halides, disulfides, aldehydes and acid chlorides, the ex

Full text of DOI:10.1039/b415588b

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Preparation of cyclic alkenylmagnesium reagents via an iodine/
magnesium exchange{
Hongjun Ren, Arkady Krasovskiy and Paul Knochel*
Received (in Cambridge, UK) 8th October 2004, Accepted 8th November 2004
First published as an Advance Article on the web 6th December 2004
DOI: 10.1039/b415588b
Thus, the allylation of 2a with allyl bromide proceeds readily in
the absence of copper additives leading to the protected
cyclopentanol 3a in 91% yield (entry 1 of Table 1). Similarly, the
reaction of the cyclohexenol derivative 2b with allyl bromide
furnishes the allylated product 3g in 81% yield (entry 7). All
reactions proceed with complete retention of chirality (proved for
allyl cyclohexenol derivative 3g, ee .98%). Diphenyl disulfide
reacts with 2a,b providing the thioethers 3b and 3h in 82 and 80%
yield respectively (entries 2 and 8). After the transmetalation with
CuCN?2LiCl,8 the addition–elimination with 3-iodo-2-cyclohexen-
1-one leads to the dienone 3c in 61% yield (entry 3). Aldehydes like
benzaldehyde lead to 1,3-diol derivatives such as 3d (89%) and 3i
(84%) as a mixture of diastereomers (for 3d and 3i: dr 5 80 : 20).
The acylation of the copper derivative of 2a proceeds in moderate
yields affording the unsaturated enone 3e in 53% yield (entry 5).
The opening of N-tosylaziridine9 provides the amino-alcohol
derivative 3f in 63% yield (entry 6).
The reaction of various cyclic alkenyl iodides with
i-PrMgCl?LiCl produces the corresponding alkenylmagnesium
reagents under mild conditions. After reaction with various
electrophiles, like allylic halides, disulfides, aldehydes and acid
chlorides, the expected products are obtained in 53–91% yield.
Remarkably, the mild conditions of the I/Mg-exchange tolerate
the presence of sensitive diene functionalities.
The preparation of functionalized organometallics is an important
synthetic task, since these reagents allow the preparation of
polyfunctional molecules.1 In recent years, it was found that the
iodine–magnesium exchange reaction2 is an excellent method for
the preparation of various aryl and heteroaryl Grignard reagents.3
It was found that the rate of the I/Mg-exchange was dependent on
the electron-density of the aromatic or the heterocyclic ring. The
more electron-poor the ring, the faster was the halogen–
magnesium exchange. Interestingly, the I/Mg-exchange of alkenyl
iodides was much slower and had to be performed at 25 uC with
i-Pr2Mg in order to obtain synthetically useful results.4 Recently,
we have found that the rate of the halogen/magnesium exchange
can be dramatically increased by using the complex reagent
i-PrMgCl?LiCl.{5 This reagent may be viewed as a magnesiate
reagent i-PrMgCl22Li+ and is therefore much more reactive
compared to i-PrMgCl.6 We have demonstrated that chiral
2-iodocycloalkenyl alcohol derivatives of type 1 undergo readily
substitution reactions with zinc–copper reagents (if OR is a leaving
group) giving chiral cycloalkene derivatives with good to excellent
ee.7 We have now found that i-PrMgCl?LiCl reacts at low
temperature with 1a (225 uC, 5 h) and 1b (240 uC, 12 h) leading
to the corresponding alkenylmagnesium species 2a and 2b. The
reaction with various electrophiles (E+) provides the corresponding
chiral products 3a–i§ in good to excellent yield (see Table 1 and
Scheme 1).
Interestingly, this approach can be extended to the cyclic exo-
methylene dienes 4 and 5." The iododiene 4 is converted smoothly
to the corresponding magnesium derivative 6 (240 uC, 4 h) in high
yield. Its reaction with propionaldehyde furnishes the dienic
alcohol 7 in 91% yield. The addition to N-tosylbenzaldimine gives
the diene sulfonamide 8 in 85% yield. After transmetalation with
ZnBr2, a Negishi cross-coupling reaction with methyl 4-iodo-
benzoate or 3-bromocyclohexenone in the presence of Pd(dba)2
Scheme 1
{ Electronic supplementary information (ESI) available: Experimental
details and NMR spectra of the compounds. See http://www.rsc.org/
suppdata/cc/b4/b415588b/
Scheme 2
*Paul.Knochel@cup.uni-muenchen.de
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Chem. Commun., 2005, 543–545 | 543

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Table 1 2-Magnesiated cycloalkenol derivatives and their reaction
with electrophiles
Grignard
Entry reagent
Product of
Electrophile type 3
Yield
(%)a
1
91
82
61
Scheme 3
2
3
2a
2a
PhSSPh
dienic Grignard reagent 11 which undergoes after transmetalation
with ZnBr2, a Pd-catalyzed cross-coupling with methyl 4-iodo-
benzoate leading to the expected product 12 in 90% yield
(Scheme 3).
In summary, we have reported that various cyclic alkenyl and
dienyl Grignard reagents can be readily prepared via an I/Mg-
exchange using the new reagent i-PrMgCl?LiCl. Further extensions
of this method are currently underway in our laboratory.
We thank the Fonds der Chemischen Industrie and for generous
financial support. We thank the BASF AG (Ludwigshafen),
Wacker-Chemie and Merck (MSD) for the gift of chemicals.
4
5
6
7
2a
2a
2a
PhCHO
PhCOCl
89
53
63
81
Hongjun Ren, Arkady Krasovskiy and Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377, Mu¨nchen, Germany.
E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: (+49)-89-2180-77680; Tel: (+49)-89-2180-77681
Notes and references
{ Preparation of the reagent i-PrMgCl?LiCl: Magnesium turnings
(110 mmol) and anhydrous LiCl (100 mmol) were placed in an Ar-flushed
flask and THF (25 mL) was added. A solution of i-PrCl (100 mmol) in
THF (25 mL) was slowly added at rt. The reaction starts within a few
minutes. After the addition, the reaction mixture was stirred for 12 h at rt.
The grey solution of i-PrMgCl?LiCl was transferred via cannula to another
flask under Ar and removed in this way from the excess of magnesium. A
yield of ca. 95–98% of i-PrMgCl?LiCl is obtained.
§ Typical procedure. Preparation of the allylated product 3a (entry 1 of
Table 1): To a THF solution of the cyclopentenyl iodide (1a) (268 mg,
1 mmol in THF (0.3 mL)) was slowly added i-PrMgCl?LiCl (0.51 mL,
1.1 mmol, 2.16 M in THF) at 225 uC. After 5 h, a complete conversion to
the Grignard reagent (2a) was observed as indicated by GC-analysis of
hydrolyzed reaction aliquots. Allyl bromide (133 mg, 1.1 mmol, in 1.0 ml of
THF) was added and the reaction mixture was warmed to 25 uC and
quenched as usual. Purification by flash chromatography (hexane : diethyl
ether 5 100 : 1) yielded the pure product 3a (165 mg, 91% yield).
" These dienes are readily obtained by the Wittig-olefination of respectively
3-iodo- and 2-iodo-cyclohexenone with CH2LPPh3 (rt, 12 h) in variable
yields (84% for 4 and 10% for 5).
8
9
2b
2b
PhSSPh
PhCHO
80
84
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a
Isolated yields of analytically pure products.
(5 mol%), tri(2-furyl)phosphine (tfp, 10 mol%) provides the aryl-
substituted diene 9 in 90% yield and the conjugated trienone 10 in
70% yield (Scheme 2).
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with i-PrMgCl?LiCl (240 uC, 4 h) provides the corresponding
544 | Chem. Commun., 2005, 543–545
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Chem. Commun., 2005, 543–545 | 545