Iron-catalyzed addition of Grignard reagents to activated vinyl cyclopropanes

Article abstract of DOI:10.1039/b918818e

A highly regioselective iron-catalyzed addition of branched primary, secondary or tertiary alkyl Grignard reagents to activated vinyl cyclopropanes is described, which likely proceeds by a direct addition mechanism as opposed to single electron transfer or an iron-allyl based process. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b918818e

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Iron-catalyzed addition of Grignard reagents to activated
vinyl cyclopropaneswz
Benjamin D. Sherry and Alois Furstner*
¨
Received (in Cambridge, UK) 10th September 2009, Accepted 5th October 2009
First published as an Advance Article on the web 29th October 2009
DOI: 10.1039/b918818e
A highly regioselective iron-catalyzed addition of branched
primary, secondary or tertiary alkyl Grignard reagents to
activated vinyl cyclopropanes is described, which likely proceeds
by a direct addition mechanism as opposed to single electron
transfer or an iron-allyl based process.
Table 1 Examination of Grignard reagents in iron-catalyzed addition
reactions
Yieldc
aE : Zb (%)
Iron-catalyzed reactions are gaining prominence in synthetic
chemistry due to the associated economic and environmental
benefits.1 Amongst the various transformations of p-bonds
effected by low-valent iron,1,2 alkene carbometalation3,4 and
allylic substitution reactions5 have received considerable
attention. A juxtaposition of the reported systems for these
two processes reveals several features unique to each reaction
class. In the recorded allylic substitution reactions, the leaving
group is a stabilized oxygen (phosphate, carboxylate, alkoxide)
or halide atom, and the unsaturated system is frequently an
a-olefin.5 In contrast, alkene carbometalation is generally
reported within the context of strained systems.3 The latter
reactions benefit, however, from the generation of a reactive
carbon–metal bond, allowing further functionalization after
the iron-catalyzed step. A desire to bridge these two systems,
and in so doing capitalize on the advantages of each, led us to
consider the reaction of suitably activated vinyl cyclopropanes
Entry RMgX, cosolvent
Product a : bb
1
2
3
4
5
6
7
8
9
PhMgCl, THF 2a,b
(Mesityl)MgBr, THF 3a,b
1.5 : 1
1.4 : 1
4.3 : 1
8.9 : 1
5.7 : 1
2.7 : 1
4.3 : 1
5.6 : 1
75
84
79
48
82
83
79
61
78
MeMgCl, THF
nPrMgCl, THF
iBuMgCl, THF
tBuCH2MgBr, THF
iPrMgCl, THF
4a,b
5a,b
6a,b
7a,b
8a
11.9 : 1 7.2 : 1
8.6 : 1 8.4 : 1
420 : 1 5.8 : 1
420 : 1 6.5 : 1
420 : 1 8.2 : 1
cC5H9MgCl, Et2O
tBuMgCl, Et2O
9a
10a
a
Fe(acac)3 (10 mol%, 99.9+% purity), RMgX (1.5 equiv.), toluene,
b
ꢀ30 1C, 30 min. Determined by 1H NMR analysis of the crude
c
reaction mixture. Yield of regio- and stereoisomeric mixture after
chromatography.
with low-valent iron-catalysts.6–9 Such
a process could
conceivably take place with simple unstrained alkenes, and
through scission of the carbon–carbon s-bond, provide
a reactive carbon nucleophile for additional bond-forming
reactions.
Scheme 1 Reagents and conditions: (a) Fe(acac)3 (10 mol%, 99.9+%
purity), iPrMgCl (1.5 equiv.), toluene, ꢀ30 1C, 30 min; (b) allyl
bromide (3 equiv.), DMPU, room temperature, 23 h; (c) propargyl
bromide (3 equiv.), DMPU, room temperature, 23 h.
The study commenced with an examination of the reaction
between vinyl cyclopropane 1 and organomagnesium reagents
(Table 1). Aryl nucleophiles reacted efficiently but displayed
poor regioselectivity (entries 1 and 2). Transitioning to primary
alkyl Grignard reagents resulted in an increase in the relative
amount of 1,7-addition (a), with a further enhancement in the
selectivity observed with more sterically hindered nucleophiles
(entries 3–6). Secondary and tertiary alkyl Grignard reagents
displayed excellent regioselectivity, affording the 1,7-addition
products in good yield as predominately the E-isomers
(entries 7–9).
As secondary alkyl Grignard reagents provided high levels
of regiocontrol, a more thorough study with this class
of nucleophiles was conducted. We initially sought to utilize
the putative magnesium enolate generated upon cleavage
of the cyclopropane. Addition of an alkyl halide and DMPU
to the reaction mixture once 1 was consumed allowed
telescoping of the iron-catalyzed process with traditional
malonate chemistry, and thereby opened convenient access
to dialkylated malonates via this two-step one-pot approach
(Scheme 1).
We next turned our attention to the iron-catalyzed bond-
forming event itself. Three potential mechanisms were
considered (Scheme 2): (a) single electron transfer from a
reduced iron complex to afford a malonate anion and delocalized
allyl radical, followed by recombination of the allyl radical
with an alkyl group from iron (b) nucleophilic displacement,
potentially involving an iron-ate type intermediate, (c) oxidative
insertion of iron into the strained carbon–carbon bond to afford
an iron-allyl intermediate with expulsion of the malonate anion,
followed by reductive elimination.
Max-Planck-Institut fur Kohlenforschung, D-45470 Mulheim/Ruhr,
¨ ¨
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chem-
istry. Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
section and characterization data for all new compounds. See DOI:
10.1039/b918818e
ꢁc
This journal is The Royal Society of Chemistry 2009
7116 | Chem. Commun., 2009, 7116–7118

Scheme 2 Three conceivable pathways for iron-catalyzed addition.
Scheme 5 Reagents and conditions: (a) Fe(acac)3 (10 mol%, 99.9+%
purity), iPrMgCl (1.5 equiv.), toluene, ꢀ30 1C, 30 min; bottom:
hypothetical reactive conformations.
tetrasubstituted olefins remains
synthetic technologies.13
a challenge to modern
Scheme 3 Reagents and conditions: (a) Fe(acac)3 (10 mol%, 99.9+%
purity), 13 (1.5 equiv.), toluene, ꢀ30 1C, 30 min.
The preceding observations, assuming alkene generation
is under kinetic control, are most consistent with a transition
state where overlap of the p-system with the cyclopropane
s-bond is required. Two reactive conformations, A and B,
fulfill this stereoelectronic constraint, and lead to opposite
alkene geometry (Scheme 5, bottom). In the unsubstituted
case (R1 = R2 = H), reaction through conformer A minimizes
non-bonding interactions; this conformation becomes progres-
sively less favorable relative to B upon substitution. In the
disubstituted system (R1 = R2 = Me), A1,3-strain resulting
from methyl substitution on the cyclopropane and an eclipsing
interaction between R2 and the cyclopropane ring apparently
destabilize A to the extent that the reaction occurs exclusively
through B.14
To interrogate pathway (a) the reaction was first conducted
in the presence of H-atom donor g-terpinene, the Grignard
addition proceeded unperturbed, and no reduced product was
1
detected by H NMR. Radical generation in the nucleophilic
component of the reaction was further investigated using
2-norbornylmagnesium bromide as a stereochemical probe
(Scheme 3).10 The addition of a diastereomeric mixture of
Grignard reagent 13 (1.4 : 1.0 endo : exo) afforded an essentially
identical mixture of diastereomers in the product malonate 14.
However, when diastereomerically enriched endo-2-norbornyl-
magnesium bromide was employed, a 420 : 1 mixture of
endo : exo diastereomers was generated, providing evidence
against alkyl radical generation during the reaction.
The correlation between the bulk of the incoming
nucleophile and the reaction selectivity provides further
evidence for a direct addition pathway (Table 1). Moreover,
the reversal in regioselectivity observed in reactions between
the slim and hence less selective MeMgBr and the differently
substituted vinyl cyclopropanes 1, 19 and 24 also speaks
against an allyl mechanism (Table 2). Should the reaction
proceed through an Z3-allyl-iron intermediate, the regio-
chemistry is not expected to be significantly altered by a
methyl group at the central carbon of the p-allyl unit;15 the
product distribution obtained with substrates 1 and 19, however,
shows that the absence or presence of a methyl branch at this
position exerts a strong effect. In line with the preceding
observations, this result argues against an allyl-iron based
process and single electron transfer, even though at present
no single mechanism can be completely excluded.
To examine radical generation in the vinyl cyclopropane
component, alkene tethered substrate 15 was examined.11 No
5-exo-trig radical cyclization was observed suggesting that if
single electron transfer occurs the delocalized radical is
trapped at a rate greater than intramolecular cyclization
(Scheme 4).
Alkene stereochemistry is not established in the iron-allyl
mechanism until after cleavage of the cyclopropane,12 whereas
non-bonding interactions in the substrate are expected to
influence the product alkene geometry in a direct addition
process. Therefore, substituent effects may allow one to
distinguish pathways b and c. Substrate 17, which bears a
methyl group on the cyclopropane, was found to be less
E-selective than the unsubstituted system 1 (Scheme 5). Reaction
of 19, carrying a methyl group at the internal alkene carbon,
resulted in a modest preference for the Z-olefin. As shown with
21, these substituent effects work in concert to provide tetra-
substituted alkene 22 solely as the Z-isomer in 65% yield. This
observation is noteworthy, as the stereoselective formation of
Although a limited number of catalytic reactions of vinyl
cyclopropanes with carbon nucleophiles have been reported,7
the present study is the first example of the catalytic addition
of a hard organometallic nucleophile, and benefits from the
use of a cheap and benign precatalyst. The iron-catalyzed
reaction effectively outcompetes the otherwise rapid 1,2-addition
of the Grignard reagent to the substrate,16 providing another
illustration of the kinetic competence of reactions catalyzed
by low-valent iron.1 Moreover, though the structural details
of the in situ generated catalyst are not known, the most
convincing support to date for a direct addition mechanism
is provided,11 representing a rare case of mechanistic insight
Scheme 4 Reagents and conditions: (a) Fe(acac)3 (10 mol%, 99.9+%
purity), iPrMgCl (1.5 equiv.), toluene, ꢀ30 1C, 30 min, 61%,
E : Z = 1 : 4.9.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7116–7118 | 7117

Table 2 Product distribution in the iron-catalyzed ring opening of
differently substituted vinyl cyclopropanes; E = COOMe unless stated
otherwiseb
(d) S. Okada, K. Arayama, R. Murayama, T. Ishizuka, K. Hara,
N. Hirone, T. Hata and H. Urabe, Angew. Chem., Int. Ed., 2008,
47, 6860.
´
5 (a) J. L. Roustan, J. Y. Merour and F. Houlihan, Tetrahedron
Lett., 1979, 20, 3721; (b) Y. Xu and B. Zhou, J. Org. Chem., 1987,
52, 974; (c) B. Akermark and M. P. T. Sjogren, Adv. Synth. Catal.,
¨
Substrate
Products
a : b
Yield (%)
2007, 349, 2641; (d) B. Plietker and A. Dieskau, Eur. J. Org. Chem.,
2009, 775; (e) for iron-catalyzed deallylation of allylated
malonates, see: D. Necas, M. Kotora and I. Cısarova, Eur. J.
´ ´
3.4 : 1c 79
Org. Chem., 2004, 1280.
6 For the stoichiometric addition of carbon nucleophiles to 1, see:
(a) R. W. Kierstead, R. P. Linstead and B. C. L. Weedon, J. Chem.
Soc., 1952, 3616; (b) S. Danishefsky, G. Rovnyak and
R. Cavanaugh, J. Chem. Soc. D, 1969, 636; (c) G. Daviaud and
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K. Oshima, K. Utimoto and H. Nozaki, Bull. Chem. Soc. Jpn.,
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Soc., Chem. Commun., 1988, 734; (g) S. Danishefsky, Acc. Chem.
Res., 1979, 12, 66.
1 : 2e
85
13 : 1d 85
a
b
E = COOEt. Fe(acac)3 (10 mol%, 99.9+% purity), MeMgBr
c
(1.5 equiv.), toluene, ꢀ30 1C, 30 min. a isomer, E : Z = 8.7 : 1.
7 For the catalytic addition of nucleophiles to 1, see: Pd(0):
(a) K. Burgess, J. Org. Chem., 1987, 52, 2046; (b) S. Sebelius,
V. J. Olsson, O. A. Wallner and K. J. Szabo, J. Am. Chem. Soc.,
´
d
e
a isomer, E : Z = 15.2 : 1. a isomer, E : Z = 1 : 1.7.
2006, 128, 8150; Yb(OTf)3; (c) D. B. England, T. D. O. Kuss,
R. G. Keddy and M. A. Kerr, J. Org. Chem., 2001, 66, 4704; Ni(0);
(d) H. Gong, R. S. Andrews, J. L. Zuccarello, S. J. Lee and
M. R. Gagne, Org. Lett., 2009, 11, 879.
´
8 For oxidative insertion of iron carbonyl complexes, see:
(a) S. Sarel, Acc. Chem. Res., 1978, 11, 204; (b) D. F. Taber,
K. Kanai, Q. Jiang and G. Bui, J. Am. Chem. Soc., 2000, 122, 6807.
9 General reviews pertaining to metal-catalyzed reactions of cyclo-
propanes: (a) R. I. Khusnutdinov and U. M. Dzhemilev,
J. Organomet. Chem., 1994, 471, 1; (b) M. Rubin, M. Rubina
and V. Gevorgyan, Chem. Rev., 2007, 107, 3117.
10 (a) F. R. Jensen and K. L. Nakamaye, J. Am. Chem. Soc., 1966, 88,
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1521.
Scheme 6 Reagents and conditions: (a) Fe(acac)3 (10 mol%, 99.9+%
purity), iPrMgCl (1.5 equiv.), toluene, ꢀ30 1C, 30 min, 60%.
into iron-catalyzed C–C-bond formations.2,12,17–19 Furthermore,
early studies indicate that this reaction can be extended to other
p-systems such as 26 (Scheme 6), which is reminiscent of the
syn-selective iron-catalyzed opening of propargyl epoxides
previously described by our group.20
11 For the use of intramolecular reactions to probe for radical anion
intermediates, see: H. O. House and P. D. Weeks, J. Am. Chem.
Soc., 1975, 97, 2778.
Financial support by the Fonds der Chemischen Industrie
and the Alexander-von-Humboldt Foundation (fellowship to
B.D.S.) is gratefully acknowledged. We thank Dr R. Mynott
and D. Bartels for assistance with NMR spectroscopy and
Mrs H. Krause for supporting experiments.
12 This implies Z3-hapticity, which is in line with a recent study:
A. Furstner, R. Martin, H. Krause, G. Seidel, R. Goddard and
¨
C. W. Lehmann, J. Am. Chem. Soc., 2008, 130, 8773.
13 A. B. Flynn and W. W. Ogilvie, Chem. Rev., 2007, 107, 4698.
14 This analysis is consistent with previous observations on the effect
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(a) K. Miura, N. Fujisawa and A. Hosomi, J. Org. Chem., 2004,
69, 2427; (b) Y. Sumida, H. Yorimitsu and K. Oshima, Org. Lett.,
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15 T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem.,
1986, 51, 5216.
16 In the absence of iron, the starting material is consumed within
30 min to give what appears to be a mixture of 1,2-addition
products.
Notes and references
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This journal is The Royal Society of Chemistry 2009
7118 | Chem. Commun., 2009, 7116–7118