Stereoselective synthesis of tri- and tetrasubstituted alkenes by iron-catalyzed carbometalation ring-opening reactions of cyclopropenes

Article abstract of DOI:10.1002/anie.200802391

(Chemical Equation Presented) Open sesame: An iron-catalyzed cyclopropene carbometalation ring-opening sequence using trialkylaluminum reagents is described. The reactions proceed with high levels of regio- and stereo-control to provide a range of multisubstituted alkenes, including trisubstituted vinylsilanes, trisubstituted vinylstannanes, and all-carbon tetrasubstituted alkenes.

Full text of DOI:10.1002/anie.200802391

Communications
DOI: 10.1002/anie.200802391
Alkene Synthesis
Stereoselective Synthesis of Tri- and Tetrasubstituted Alkenes by Iron-
Catalyzed Carbometalation Ring-Opening Reactions of
Cyclopropenes**
Yi Wang, Euan A. F. Fordyce, Fung Yan Chen, and Hon Wai Lam*
Alkenes are one of the major classes of chemical building
blocks for organic synthesis. Although numerous methods
exist for the preparation of alkenes, the stereoselective
synthesis of tri- and tetrasubstituted[1] alkenes can still pose
a significant challenge. One method that has enjoyed consid-
erable success in this respect is the carbometalation of
alkynes.[1–5] In this approach, the key issue is regioselectivity,
which usually originates either from directing groups present
in the substrate,[2] or from significant differences in steric and/
or electronic properties between the two groups attached to
the alkyne.[3] Although internal alkynes lacking either of these
two features are a more challenging class of substrates from
both regioselectivity and reactivity standpoints, encouraging
progress has been documented in a number of recent
publications.[4] These successes notwithstanding, the develop-
ment of new carbometalation procedures[5] that tolerate an
increased range of substrates and organometallic reagents,
enabling access to a correspondingly broader array of alkenes,
remains an important challenge. In particular, the continued
development of methods that employ non-alkyne precursors
is an attractive goal. Herein, we describe a carbometalation
strategy that employs cyclopropenes as substrates, enabling
the preparation of tri- and tetrasubstituted alkenes with
excellent control of regio- and stereoselectivity. This process
leads to b,g-unsaturated ester building blocks, which can be
difficult to prepare using alternative methods owing to
possible migration of the alkene into conjugation.[6]
panes (Scheme 1, left).[7,8] We envisaged that development of
a cyclopropene carbometalation reaction that is followed by
ꢀ
cleavage of a C C s-bond could provide a powerful route to
multisubstituted alkenes (Scheme 1, right). Within this mani-
fold, critical selectivity issues that would need to be addressed
are: a) carbometalation regioselectivity with unsymmetrical
cyclopropenes (R1 ¼
6
R4), and b) E/Z stereoselectivity of the
alkene in the product.
5
ꢀ
Scheme 1. Addition of organometallic reagents (R M)to cyclopro-
penes.
Surprisingly, despite the potential utility of such a trans-
formation, relatively few examples have been described.[9]
The single existing report of catalytic cyclopropene addition
ring-opening reactions using carbon nucleophiles was
restricted to active methylene compounds and 3,3-dihexylcy-
clopropene as the substrates.[9d] Furthermore, issues of regio-
and stereoselectivity were not relevant in this case. The only
examples of cyclopropene addition ring-opening reactions
using hard organometallic reagents as nucleophiles were
uncatalyzed, and displayed low efficiencies and limited
scope.[9a–c] We speculated that synthetically more useful
processes using hard carbon nucleophiles might be realized
through the use of a catalyst to facilitate carbometalation, and
by the presence of anion-stabilizing substituents at R2 and R3
to promote ring-opening.
Our experiments began with a brief survey of reactions of
cyclopropenes with various organometallics in the presence of
substoichiometric quantities of first-row d-block metal salts.
These studies revealed that with cyclopropenes containing
two electron-withdrawing groups at C3,[10] [Fe(acac)3]
(5 mol%) is able to promote the desired carbometalation
ring-opening sequence using trialkylaluminum reagents.[11,12]
Under optimized conditions, cyclopropenes 1a–1h [13] reacted
smoothly to provide a variety of trisubstituted alkenes 2a–2r
in good to excellent yields with high stereoselectivities (>
19:1) (Table 1).[6] Tolerated functionality at C3 encompassed
a range of esters and a phenylsulfone, while both alkyl and
Owing to their highly strained nature, cyclopropenes
exhibit a diverse range of reactivities, which present unique
opportunities for organic synthesis.[7] Although cyclopropenes
are susceptible to a range of useful carbometalation (and
hydrometalation) reactions,[7,8] a significant majority of exam-
ples described to date result in preservation of the three-
membered ring to provide highly functionalized cyclopro-
[*] Y. Wang, E. A. F. Fordyce, F. Y. Chen, Dr. H. W. Lam
School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings
West Mains Road, Edinburgh EH93JJ (United Kingdom)
Fax: (+44)131-650-6453
E-mail: h.lam@ed.ac.uk
Homepage: http://homepages.ed.ac.uk/hlam/index.html
[**] This work was supported by EaStCHEM (The Edinburgh and
St. Andrews Research School of Chemistry)and Hoffmann-La Ro-
che. The EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea is thanked for providing high
resolution mass spectra.
=
aromatic substitution at the cyclopropene C C bond were
permitted. Regarding the scope of the organometallic
reagent, trialkylaluminum moieties ranging from linear
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802391.
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Table 1: Iron-catalyzed carbometalation ring-opening of cyclopropenes
1a–1h with trialkylaluminum reagents.
The more challenging task of tetrasubstituted alkene
synthesis was next addressed. Using conditions identical to
those employed in Table 1, a range of 1-trimethylsilylcyclo-
[13,15]
propenes 3a–3d
underwent carbometalation ring-open-
ing to provide a,b,b’-trisubstituted vinylsilanes 4a–4 f
(Table 2).[16] Importantly, the sense of regioselectivity
Using Me3Al:
Table 2: a,b,b’-Trisubstituted vinylsilane synthesis.
2a, 96%
2b, 78%
2e, 66%
2c, 83%
2 f, 61%
Using Me3Al:
Using Et3Al:
Using nPr3Al:
2d, 92%
Using Et3Al:
4a R1 =Ph, 89%
4b R1 =pTol, 71%
4d R1 =Ph, 73%
4 f, 88%
4e R1 =CH2CH2Ph,
4c R1 =nBu, 68%, 6:1 r.r.[a] 72%, 5:1 r.r.[a]
2g, 91%
2h, 72%
2k, 71%
2i, 70%
2l, 77%
TMS=trimethylsilyl. [a] r.r.=Regioisomeric ratio.
obtained in these reactions is opposite to that summarized
in Table 1, with the alkyl group delivered preferentially to the
TMS-bearing carbon. Regioselectivity was highest (> 19:1)
with aryl-substituted cyclopropenes (preparation of 4a, 4b,
4d, and 4 f). With alkyl-substituted cyclopropenes, formation
of the regioisomer was detected (preparation of 4c and 4e).
In similar fashion, the use of 1-stannylcyclopropenes
enabled the synthesis of a,b,b’-trisubstituted vinylstannanes
[Eq. (1) and Eq. (2)].
2j, 82% (67%)[a]
Using nPr3Al:
2m, 90%
2n, 72%
2q, 52%
2o, 63%
Using nHex3Al:
Using iBu3Al:
2p, 66%
2r, 62%
[a] Yield in parentheses refers to an experiment conducted using 0.5
equivalents of Et3Al.
Finally, this methodology was applied to preparation of
all-carbon tetrasubstituted alkenes [Equations (3)–(5)].[1]
Cyclopropenes 7 and 9 underwent efficient carbometalation
ring-opening to provide tetrasubstituted alkenes 8a, 8b, and
10. With unsymmetrical substrate 9, the alkyl group was
delivered preferentially to the methyl-substituted carbon of
the cyclopropene [Eq. (5)].
Scheme 2 illustrates a possible catalytic cycle for these
reactions. Reaction of [Fe(acac)3] with the trialkylaluminum
most likely generates a low-valent iron species 11. Syn-
carbometalation of the substrate 12 with 11 would generate
cyclopropyl iron species 13. b-Carbon elimination[17] of 13
(Me3Al, Et3Al, nPr3Al, and nHex3Al) to branched (iBu3Al)
were effective. The regioselectivities of these reactions were
also uniformly high (> 19:1), the sense of regioselection being
consistent with the majority of carbometalations of 1-
alkylcyclopropenes described previously,[7b] wherein the
alkyl nucleophile is delivered to the more substituted
carbon of the alkene. Notably, 1-arylcyclopropenes, which
have proven to be problematic substrates with respect to
regioselectivity using other carbometalation procedures,[7b,8a,h]
also underwent highly regioselective reactions under the
present conditions.[14] Although two equivalents of the
trialkylaluminum reagent were routinely used in our experi-
ments, smaller quantities are tolerated. For example, alkene
2j was isolated in 67% yield using only 0.5 equivalents of
Et3Al, demonstrating that transfer of more than one alkyl
group from aluminum is possible. This finding augurs well for
the use of more complex organoaluminum reagents in the
future.
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Communications
wave irradiation to provide b,g-unsaturated esters in good
yields [Eq. (8) and Eq. (9)].
In summary, an iron-catalyzed cyclopropene carbometa-
lation ring-opening sequence that enables the efficient syn-
thesis of tri- and tetrasubstituted alkenes has been developed.
The reactions proceed with high levels of regio- and
stereocontrol to produce a range of multisubstituted alkenes
that may be difficult to access by other means, including
a,b,b’-trisubstituted vinylsilanes, a,b,b’-trisubstituted vinyl-
stannanes, and all-carbon tetrasubstituted alkenes. In addi-
tion, the ring-opened products may be manipulated without
affecting the alkene. Further investigations into the interest-
ing reactivity of cyclopropenes will be reported in due course.
Scheme 2. Possible catalytic cycle. L=ligand.
with conservation of the cis-relationship between R2 and R3
would then provide iron enolate 14, which can undergo
transmetalation with an alkylaluminum species (L2AlR4) to
provide aluminum enolate 15 and regenerate 11. The
assistance of b-carbon elimination of 13 by Lewis acid
coordination of the trialkylaluminum to the malonate to
provide enolate 15 directly is a possibility that should also be
considered.
Although in situ functionalization of the aluminum eno-
lates 15 was an attractive possibility for obtaining other
compounds of interest, we found these species to be rather
unreactive,[18] and attempted trapping with various electro-
philes was unsuccessful. Therefore, our attention turned to
elaboration of the isolated ring-opened products. A major
concern with this approach was the potential sensitivity of
these compounds towards isomerization of the alkene into
conjugation with the esters, or scrambling of the E/Z
stereochemistry of the alkene. However, we have not found
these issues to be problematic. For example, Michael addition
or alkylation of the ring-opened products was accomplished
efficiently without compromising the integrity of the alkene
[Eq. (6) and Eq. (7)].
Received: May 22, 2008
Published online: August 13, 2008
Keywords: alkenes · iron · nucleophilic addition ·
.
small ring systems · strained molecules
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