Synthesis of chiral 2-phospha[3]ferrocenophanes and their behaviour as organocatalysts in [3+2]Cyclization reactions

Article abstract of DOI:10.1002/adsc.200900193

Planar chiral 2-phospha[3]ferrocenophanes have been prepared via a stereoselective three-step synthesis. The key step is the lithiation of the l,1′-disubstituted ferrocene 11 bearing (S)-2-(methoxymethyl)pyrrolidines as the chiral ortho-directing groups.

Full text of DOI:10.1002/adsc.200900193

FULL PAPERS
DOI: 10.1002/adsc.200900193
Synthesis of Chiral 2-Phospha[3]ferrocenophanes and their
Behaviour as Organocatalysts in [3+2]Cyclization Reactions
Arnaud Voituriez,a Armen Panossian,a Nicolas Fleury-Brꢀgeot,a
Pascal Retailleau,a and Angela Marinettia,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 av. de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Fax : (+33)-01-6907-7247; phone: (+33)-01-6982-3036; e-mail: angela.marinetti@icsn.cnrs-gif.fr
Received: March 9, 2009; Published online: July 31, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900193.
Abstract: Planar chiral 2-phospha[3]ferrocenophanes 2-phospha[3]-ferrocenophanes with stereogenic a-
have been prepared via a stereoselective three-step carbons, the planar chiral derivatives 16 proved to be
synthesis. The key step is the lithiation of the 1,1’-di- suitable catalysts for these processes. Thus, for in-
ACHTUNGTRENNUNGsubstituted ferrocene 11 bearing (S)-2-(methoxyme- stance, phosphine 16c successfully promotes the
thyl)pyrrolidines as the chiral ortho-directing groups. enantioselective [3+2]annulations of allenes and
The diastereoselectivity of these reactions has been enones into functionalized cyclopentenes (ees up to
mastered by an appropriate choice of the metallating 96%). Among others, spirocyclic derivatives have
agent, so as to afford a suitable access to C2-symmet- been obtained in good yields and ees in the range
rical, tetrasubstituted ferrocenes. These compounds 77–85%. The robustness of this catalyst has been
have been converted into the enantiomerically pure demonstrated by recycling experiments.
2-phospha[3]-ferrocenophanes 16, via the corre-
sponding acetates and their reactions with primary
phosphines. Phosphines 16 have been used as nucleo- Keywords: cyclization; enantioselective organocatal-
philic catalysts in model cyclization reactions. Unlike ysis; ferrocenophanes; ortho-metallation; phosphines
Introduction
phosphine 5[10] and the phosphinothiourea 6[5d] have
been highlighted as outstandingly efficient Lewis
In the field of organocatalysis, phosphines represent bases nucleophilic catalysts.
efficient auxiliaries,[1] whose peculiar reactivity often
complements that of nitrogen-based[2] nucleophilic
promoters. Since a number of synthetically useful pro-
cesses have been highlighted, the development of
asymmetric variants of phosphine-promoted transfor-
mations represents today a highly valuable challenge.
Significant advances in this field have been reported
mainly during the last decade: after the seminal work
of Vedejs on enantioselective acylations,[3] several
groups have investigated the use of chiral phosphines
in Morita–Baylis–Hillman reactions,[4] [3+2]annula-
tions of electron-poor unsaturated substrates (olefins,
allenes and alkynes) with enones, unsaturated esters
or imines,[5] [4+2]annulations with imines[6] and other
miscellaneous reactions.[7] From these studies, only a
few structural motifs have emerged as efficient scaf-
folds for phosphorus-based catalysts. Notably, the bi-
Given the reaction-catalyst and substrate-catalyst
cyclic phospholanes 1[8] and 2,[5a] the binaphthyl-based specificity which are usually distinctive for most cata-
phosphines 3[9] and 4,[6] the a-amino acid-derived lytic transformations, it seems essential to further
1968
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1968 – 1976

Synthesis of Chiral 2-Phospha[3]ferrocenophanes
FULL PAPERS
expand the present range of efficient phosphines for
enantioselective organocatalytic processes.
Despite the highly successful uses of many chiral
phosphines with ferrocene backbones,[13] ferroceno-
Our efforts toward this goal and the development phane derivatives have been seldom considered for
of 2-phospha[3]ferrocenophanes as new scaffolds for applications in catalytic processes. As far as we know,
Lewis base-type chiral organocatalysts are summar- only chiral ferrocenophanes bearing carbon tethers
ized herein. Part of this work has been reported previ- between the Cp rings and attached R2P functions,
ously as a preliminary communication.[11]
have been used so far in asymmetric catalysis.[14]
We started our study by considering the use as cata-
lysts of 2-phospha[3]ferrocenophanes with stereogenic
carbon atoms in the tethering chain (I).[12] Their pre-
liminary evaluations in a model organocatalytic reac-
Results and Discussion
In our search for new phosphine organocatalysts, we tion (Scheme 1) have highlighted, however, a major
targeted 2-phospha[3]ferrocenophane derivatives, drawback of the targeted structures.
with either stereogenic carbons (I)[12] or planar chirali-
Indeed, when the racemic phosphane dl-7 has been
ty (II),[11] since these ferrocenophane scaffolds display used as catalyst in the [3+2]cyclization reaction of
some peculiar structural features that are, a priori, ethyl 2,3-butadienoate with N-tosyl-1-naphthaldim-
amenable to enantioselective organocatalysis.
ine[5c,d,15] under the usual conditions, TLC monitoring
ACHTUNGTRENNUNG
showed that a significant amount of the putative cata-
lyst was still present in the reaction mixture, after
completion of the reaction. After isolation, this com-
pound was shown to be the anti-anti (meso) isomer of
the 2-phospha[3]ferrocenophane 7 initially employed.
This experiment thus highlighted that the phosphafer-
rocenophane structure is remarkably stable in the
conditions of the catalytic reactions which induce,
however, inversion of the relative stereochemistry of
the stereogenic centers.
A first key point is that 2-phospha[3]ferroceno-
A tentative rational for the observed isomerization
phanes are dialkyl- or trialkylphosphines, which credit process is shown in Scheme 1. According to the gener-
them with an electron-rich nature and potentially nu- ally accepted mechanism,[16] the phosphane-promoted
cleophilic character, a crucial requisite for good cata- [3+2]cyclizations involve zwitterionic intermediates
lytic activity. Secondly, their cyclic structures, with the such as the phosphonium salt 8 which is generated by
related restricted conformational freedom, are expect- addition of the nucleophilic phosphane to the elec-
ed to favour chiral induction in catalytic processes. Fi- tron-poor allene. The zwitterionic phosphonium salt
nally, the bulky ferrocene moiety is expected to par- might very likely undergo reversible intra- or inter-
ticipate in steric discriminations as well as to increase molecular proton exchange reactions[17] leading to
the air-stability and ease of handling of these phos- phosphorus ylides such as 9. This proton exchange re-
phines.
action can account for the isomerization process, in so
Scheme 1. Phosphine-promoted synthesis of pyrrolines. Proposed mechanism for the epimerization of dl-7 into meso-7
during the organocatalytic process.
Adv. Synth. Catal. 2009, 351, 1968 – 1976
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1969

Arnaud Voituriez et al.
FULL PAPERS
far as the anti-anti isomer, meso-7, is expected to be
The major issue of this synthetic approach was to
the thermodynamically favoured isomer of the ferro- identify a suitable chiral auxiliary as well as the exper-
cenophane catalyst. imental conditions allowing highly diastereoselective
Analogous epimerization or racemization processes dilithiations of the disubstituted ferrocene.
via transient phosphorus ylides might take place, in Although a number of ferrocenes bearing chiral
principle, for other phosphines bearing stereogenic a- ortho-directing groups are known to undergo diaste-
carbons. This might advise against using phosphines reoselective metallation-substitution reactions,[20] di-
of this class as chiral auxiliaries, although some of ortho-metallations have been comparatively less con-
them have already been applied to enantioselective sidered.[21,22] The 1,1’-bis[(2-methoxymethylpyrrolidin-
organocatalytic processes.[5a,b,6,7a,18,19] No mention was 1-yl)methyl]ferrocene, (S,S)-11 introduced by Pugin
made about possible racemization processes, but cata- et al.,[21f] retained our attention as a suitable substrate
lyst recovering was not mentioned either.
because of the easy availability of the chiral auxiliary
The observed epimerization of ferrocenophane 7 and its subsequent easy removal procedure, that will
during the catalytic cyclization reactions mentioned give a direct access to the desired ferrocenylmethyl
above led us to consider planar chirality as a more re- units (see above).
liable stereogenic element and ferrocenophanes II as
a priori more convenient organocatalysts.
The ferrocene derivative (S,S)-11 has been pre-
pared on a multigram scale by reductive amination of
The envisioned access to structures II is the three- the commercially available dialdehyde 10 with (S)-
step procedure shown in Scheme 2, which involves methoxymethylpyrrolidine (SMP) (Scheme 3).[23] This
the diastereoselective di-ortho-metallation of a 1,1’- synthetic procedure compares favourably with the
disubstituted ferrocene bearing chiral ortho-directing previously reported method based on the nucleophilic
groups (step a) as the key step.
substitution between SMP and (ferrocenylmethyl)-tri-
methylammonium iodide.[24]
A detailed study of the ortho-metallation of (S,S)-
11 (step a) was then conducted. The lithiation-bromi-
nation reaction shown in Table 1 has been selected as
Scheme 2. Strategy for the synthesis of 2-phospha[3]ferroce-
nophanes with planar chirality.
Scheme 3. Synthesis of (S,S)-11 by reductive amination.
Table 1. Diastereoselective di-ortho-lithiation/bromination of (S,S)-11: effect of base and reaction conditions on the products
ratio.
Entry
Base
Solvent
Products ratios
Yield[a] [%]
12a
13a
13b
1
2
3
4
n-BuLi[b]
s-BuLi[c]
s-BuLi
Et2O
Et2O
THF
Et2O
47
50
95
40
25
3
5
3
75
13a, 38
13a, 80
13a, 25
13b, 55
57
t-BuLi[d]
[a]
Reactions performed at 08C, on a 60 mg scale (0.15 mmol).
1.60M in hexane.
1.40M in cyclohexane.
[b]
[c]
[d]
1.7M in pentane.
1970
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1968 – 1976

Synthesis of Chiral 2-Phospha[3]ferrocenophanes
FULL PAPERS
the model sequence because structural assignment of
the final products could be easily performed in this
series, including assignment of the planar configura-
tion (see X-ray data below).
Lithiations have been performed with 2.5 equiva-
lents of the base and the resulting metallated ferro-
cene has been reacted then with an excess 1,2-dibro-
motetrachloroethane. After aqueous work-up, the
crude reaction mixture has been monitored by
1H NMR.
n-Butyllithium proved unsuitable for dilithiations,
as it led to a 1:1 mixture of the mono- and dibromo-
substituted ferrocenes 12 and 13.
With stronger bases such as s-BuLi or t-BuLi, 1,1’-
dibromoferrocenes were obtained efficiently, for reac-
tions performed in ether (entries 2 and 4). The two
metallating agents led, however, to preferential pro-
duction of two different isomers of the dibromoferro-
cene 13.[25] Spectroscopic data allowed assignment of
a C2-symmetrical structure (SP,SP or RP,RP planar con-
figurations) to the major isomer 13a which was ob-
tained with s-BuLi (entry 2), while the SP,RP epimer
13b was preferentially formed when using t-BuLi
(entry 4).[26] The first lithiation step might account for
this reversal of stereochemical control since opposite
senses of chiral induction are also observed when
(S,S)-11 undergoes mono-lithiation with s-BuLi and t-
BuLi, respectively.[27] A clear rational for the stereo-
chemical course of these reactions cannot be pro-
Figure 1. ORTEP diagram for the tetrasubstituted ferrocene
(S,S,SP,SP)-13a.
posed at present, particularly since lithium coordina- NMR analysis of the crude reaction mixtures shows
tion by either the vicinal and/or the remote pyrroli- formation of the C2-symmetrical silylated derivatives
dine units might occur here.
14 in >95:5 diastereomeric ratios. The final products
Data in Table 1 show that an appropriate choice of 14 have been obtained in diastereomerically pure
the metallating agent is crucial to direct the outcome form after purification by chromatography on silica
of these lithiations toward the desired tetrasubstituted gel. Yields are satisfying, although column chromatog-
C2-symmetrical stereoisomer 13a of the planar-chiral raphy may induce partial degradation of the product.
ferrocene. s-BuLi is the reagent of choice, giving 13a
with almost perfect diastereoselectivity.
The silylated ferrocenes 14 were then converted
into the corresponding 2-phospha[3]ferrocenophanes
The known sense of chiral induction from the (S)- 16 following the two-steps sequence in Scheme 4.
methoxymethylpyrrolidine unit in the lithiation of Step b, that is, removal of the chiral auxiliary, has
monosubstituted ferrocenes[20d] could not be reliably been performed following a known procedure,[20d,29]
used here to predict the stereochemical outcome of by heating 14 in acetic anhydride at 908C. The corre-
the di-metallations above, because these reactions sponding bis-acetates 15 were obtained in good yields
clearly display a rather intricate behaviour. Thus, the from 14a–c, while the dimethylsilyl-substituted deriva-
major epimer 13a, which was obtained from (S,S)-11 tive 14d afforded an inseparable mixture of the de-
by lithiation with s-BuLi (entry 2), has been submit- sired diacetate (15, R3Si=Me2HSi) and the corre-
ted to X-ray diffraction studies in order to determine sponding (acetoxy)dimethylsilyl-substituted ferrocene
the relative configuration of the planar chiral moiety. [15, R3Si=Me
2ACHTUNGTRENN(UNG OAc)Si].
As shown in Figure 1, the chiral tetrasubstituted The pyrrolidine removal method above is especially
ferrocene 13a displays an (SP,SP) configuration. The convenient since it directly generates the acetate leav-
pyrroline auxiliary displays here the same sense of ing groups which are required for the next step. In
chiral induction as that reported for the lithiations of step c, the bis-(acetoxymethyl)ferrocenes 15 were sub-
monosubstituted ferrocenes.[20d]
jected to nucleophilic substitution reactions[30] with
Dimetallation of (S,S)-11 with s-BuLi as the base equimolar amounts of primary phosphines, namely
was then used for the synthesis of the tetrasubstituted PhPH2, (À)-menthylPH2 or C6H11PH2, to afford the
ferrocenes 14a–d by quenching the reaction mixture corresponding 2-phospha[3]ferrocenophanes (S,S)-
with various silyl chlorides (step a in Scheme 4).[28] 16a–e (called FerroPHANEs).
Adv. Synth. Catal. 2009, 351, 1968 – 1976
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1971

Arnaud Voituriez et al.
FULL PAPERS
Scheme 4. Synthesis of (S,S)-R3Si-FerroPHANEs 16.
Phosphines 16a–c have been described in our previ- and diethyl fumarate.[16a] Results are reported in
ous communication.[11] The [Cy]-Et3Si-FerroPHANE Table 2.
16d and [Cy]-Me2PhSi-FerroPHANE 16e are orange
oils which have been purified by column chromatog-
raphy and fully characterized. Unlike FerroPHANE
Table 2. Cyclization of ethyl 2,3-butadienoate with diethyl
fumarate promoted by FerroPHANEs 16.[a]
16c which hardly oxidizes in solution at room temper-
ature (<5% oxidation after 24 h in CDCl3 solution, in
air), FerroPHANEs 16d and 16e are moderately air-
sensitive compounds which are better handled and
stored under inert atmospheres.
In an attempt to prepare FerroPHANEs with ste-
reogenic phosphorus atoms, the trisubstituted 2-trime-
thylsilyl-1,1’-bis(acetoxymethyl)ferrocene 18 was re-
acted with cyclohexylphosphine (step b in Scheme 5).
However, the cyclization reaction proved to be a non-
stereoselective process which led to an inseparable
mixture of the two diastereomeric FerroPHANEs 19
in about 1:1.6 ratios [31P NMR (CDCl3): d=13.6 and
10.7 ppm].
Entry Phosphine Solvent
T
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
16a
16b
16c
16d
16e
16c
16c
16c
16c
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
r.t.
908C 34
r.t.
r.t.
r.t.
r.t.
30
11 (À)
12 (+)
90 (+)
84 (+)
89 (+)
83
84
90
93
54
63
22
59
61
68
Acetone r.t.
Toluene[d] r.t.
Toluene[d] 08C 28
[a]
Reaction conditions: allene (0.2 mmol, 1 equiv.), fumarate
(2 equiv.), solvent (1 mL), degassed solvents, under
argon.
Catalytic Studies
[b]
[c]
As a preliminary study, the properties of Ferro-
PHANEs 16a–e as nucleophilic organocatalysts have
been evaluated in a model [3+2]cyclization reaction,
that is, the annulation between ethyl 2,3-butadienoate
Isolated yield after flash chromatography.
Enantiomeric excesses were measured using chiral
HPLC.
[d]
Reactions performed at a 0.3 mmolmLÀ1 concentration.
Scheme 5. Attempted synthesis of P-stereogenic FerroPHANEs
1972
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1968 – 1976

Synthesis of Chiral 2-Phospha[3]ferrocenophanes
FULL PAPERS
In the presence of a 10% amount of the chiral tion between butadienoate and fumarate leading to
phosphines, these reactions yield the trans-stereoiso- 20 had been carried out by Zhang[5a] with the bicyclic
mer of cyclopentene 20 as the single product, imply- phosphine 2 as the catalyst: the yield (49%) and en-
ing that the process takes place, as expected, with re- antiomeric excess (79%) were slightly lower than
tention of stereochemistry of the starting olefin.
those obtained with FerroPHANE 16c. For compari-
From the data in Table 2 the catalytic properties of son purposes, we also tested Binepine 4 in the same
phosphines 16a–c can be compared as a function of cyclization reaction, which afforded 20 in high yield
the phosphorus substituent (entries 1–3) as well as of (80%) and enantioselectivity (93% ee) under the re-
the nature of the silyl groups (entries 3–5).
action conditions of entry 8.
The P-cyclohexyl-FerroPHANE 16c afforded 20 in
The excellent catalytic behaviour of [Cy]-TMS-Fer-
54% yield after 24 h (entry 3) at room temperature, roPHANE 16c has been demonstrated also in the
while the P-phenyl-substituted phosphine 16a afford- enantioselective [3+2]cyclizations of ethyl 2,3-buta-
ed 20 in only 30% isolated yield under analogous con- dienoate with both ethyl acrylate and b-substituted
ditions. With the P-menthyl-FerroPHANE 16b, heat- enones. As disclosed in our preliminary communica-
ing at 908C was required to achieve a reasonable con- tion,[11] in these reactions FerroPHANE 16c performs
version rate (entry 2). The lower reactivity of 16a and as well as the best catalysts known so far,[5a,b] with ees
16b, compared to the P-cyclohexyl-FerroPHANE 16c, in the range of 84–96%. Moreover, a key property of
might be tentatively ascribed to a lower nucleophilic FerroPHANE 16c is its remarkable stability toward
character for 16a and to an increased steric hindrance air oxidation. This allows phosphane 16c to be stored
for 16b.
for an indefinite period of time and the catalytic reac-
The nature of the phosphorus substituent in 16 is a tions to be routinely performed under standard condi-
crucial structural factor also with regard to asymmet- tions (no glove-box required). Most importantly, we
ric induction: the P-cyclohexyl-FerroPHANE 16c also noticed that phosphane 16c can be recovered
gives indeed much higher enantioselectivity (90% ee) after completion of the organocatalytic reaction and
than phosphines 16a and 16b. It may be worth men- re-used then for a further run. This unprecedented re-
tioning that the P-phenyl-FerroPHANE 16a gives an cycling procedure of a chiral phosphane organocata-
opposite sense of chiral induction with albeit very low lyst is illustrated in Table 3.
ee (entry 1).
The cyclization reaction between ethyl 2,3-butadie-
The nature of the Cp-linked silyl groups modulates noate and 3-(1-naphthyl)-1-phenyl-2-propenone was
to some extent the enantioselectivity levels of the cyc- performed at room temperature for 24 h, with a 10%
lization reaction, with enantiomeric excesses varying amount of FerroPHANE 16c as the catalyst. At the
from 84 to 89 and 90% for FerroPHANES bearing end of the first run, the catalyst was isolated by chro-
Et3Si, Me2PhSi and Me3Si groups, respectively (en- matography and used again for a second run at the
tries 3–5).
same catalyst loading. A third run was performed
Thus, among the FerroPHANEs 16, the P-cyclohex- again in the same conditions. The three reactions led
yl, trimethylsilyl-substituted derivative 16c ([Cy]- to comparable ratios of regioisomers and enantiomer-
TMS-FerroPHANE) proved to be the most efficient ic excesses, showing that the unchanged catalyst oper-
catalyst, with respect to both conversion rates and ates in these reactions.
enantioselectivity. In the optimized conditions of
Alternatively, the cyclization reaction leading to 21
entry 8 (Table 2), 20 was obtained in 68% yield and has been carried out at an initial catalyst loading of
90% ee. Previously, the enantioselective [3+2]cycliza- 10%, and successive additions of the substrates have
Table 3. Recycling of catalyst 16c in the [3+2]cyclization between ethyl 2,3-butadienoate and 3-(1-naphthyl)-1-phenyl-2-pro-
penone.
Enone (mmol)
21/21’
Yield [%]
ee [%]
Initial run
0.50
0.26
0.13
20/1
20/1
20/1
87
76
80
96
96
95
1st catalyst recycling
2nd catalyst recycling
Adv. Synth. Catal. 2009, 351, 1968 – 1976
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1973

Arnaud Voituriez et al.
FULL PAPERS
Table 4. Asymmetric [3+2] annulations on exocyclic enones
promoted by FerroPHANE 16c.
been performed after 24 h and 48 h. A 76% conver-
sion rate (69% isolated yield) was observed after
70 h, which amounts to a product/catalyst ratio=23.
These results demonstrate the efficiency of the new
planar chiral 2-phospha[3]ferrocenophane scaffold in
enantioselective organocatalytic processes, as well as
the ease of handling, robustness and configurational
stability of 16c in the conditions of the catalytic reac-
tion. When starting this project, the configurational
stability of 2-phospha[3]ferrocenophane was confi-
dently predicted, however, the possibility of some ste-
reochemical scrambling could not be definitely ruled
out, since in ferrocenophane derivatives haptotropic
rearrangements of the cyclopentadienyl ligands may
take place. Such rearrangements have been especially
noticed with [1]- and [2]ferrocenophanes where ring
strain favours h3- and h1-coordination of the Cp rings
over the h5-bonding mode.[31] The negligible ring
strain of phospha[3]ferrocenophanes, where the three-
atom tether makes the Cp rings only slightly tilted
toward each other,[32] accounts for the strong prefer-
R1 Ar
R2
T
Product Yield [%] ee [%]
1
2
3
4
5
6
7
8
9
Et Ph
Cy Ph
Bn Ph
Br r.t.
Br r.t.
Br r.t.
23a
23b
23c
23d
85
80
73
45
82
30
87
44
35
84
80
77
84
83
80
85
77
82
84
77
Bn 1-Naphth Br r.t.
Bn 1-Naphth Br 808C 23d
Bn 4-Cl-C6H4 Br r.t. 23e
Bn 4-Cl-C6H4 Br 808C 23e
Bn Ph
Bn Ph
H
r.t.
23f
23g
Me r.t.
Me 808C 23g
10 Bn Ph
ence for h5-coordination and the subsequent configu- small decrease of the regioselectivity (10:1 isomers
rational stability of 16c.
ratio) is also observed in entry 7
In order to further explore the catalytic properties
The Br-substituted indanone (22, R2 =Br) turned
of FerroPHANE 16c in [3+2]cyclization reactions, out to be more reactive than unsubstituted (R2 =H,
we have considered the annulations between 2,3-buta- entry 8) or Me-substituted (R2 =Me, entry 9) inda-
dienoates and the cyclic enones 22 displaying exocy- nones which require heating to 808C to produce 23 in
clic double bonds (Table 4). These reactions had been high yields.
introduced by Fu during his studies on the (S)-Bine-
On the whole, the results in Table 4 show that con-
pine 4 promoted cyclizations.[5b] The expected prod- ditions have been found, for each single pair of
ucts are spirocyclic indanones with quaternary stereo- allene/enone substrates, where yields >80% and en-
genic centres.
antiomeric excesses of 77–86% can be obtained.
More exhaustive studies on the use of Ferro-
Under FerroPHANE catalysis, the annulation reac-
tions between 2,3-butadienoates and enones 22 af- PHANEs in enantioselective organocatalytic [3+
forded the g-cycloadducts 23[33] in high yields and 2]cyclizations are ongoing. Results will be reported in
enantioselectivity. Only small amounts of the putative due course.
a-adducts have been observed in some experiments
(entries 5, 7 and 8), which have never been unambigu-
ously characterized, however.
Conclusions
The scope and limitations of these [3+2]annulation
reactions have been considered, with respect to both In summary, this work shows that planar chiral, C2-
the nature of the allenic ester and the substitution symmetrical 2-phospha[3]ferrocenophanes are easily
pattern of the cyclic enone substrate.
available via a stereoselective approach allowing
Of the three 2,3-butadienoates checked so far (R1 = modulation of both the phosphorus and Cp rings sub-
Et, Cy and Bn), the benzyl ester was found to afford stituents. The [Cy]-TMS-FerroPHANE 16c represents
the highest enantioselectivity level (84%, entry 3). It a highly efficient nucleophilic promoter for enantiose-
was used then as the preferred allene in further ex- lective organocatalytic processes. It ranks among the
periments.
best catalysts known so far for the [3+2]annulation
Variation of the Ar group in 22 did not affect the reactions between allenoates and electron-poor ole-
enantioselectivity levels, while it may have a major fins. These good catalytic properties can be ascribed
impact on the reactivity, since low conversion rates to the electron-rich nature of 16c, the C2-symmetry of
were observed at room temperature when starting the chiral moiety, as well as to the bulk and restricted
from 1-naphthyl- and 4-chlorophenyl-substituted conformational freedom of the cyclic ferrocene unit.
enones (entries 4 and 6). Good conversion rates could The remarkable stability of these catalysts has been
be attained, however, for reactions run at 808C (en- demonstrated by recycling experiments.
tries 5 and 7), with only a small decrease of the enan-
Future studies on these new chiral phosphines will
tiomeric excesses to 80 and 77% ee, respectively. A involve exploring their behaviour in other organoca-
1974
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1968 – 1976

Synthesis of Chiral 2-Phospha[3]ferrocenophanes
FULL PAPERS
Cyclohexylphosphine (83 mL, 0.62 mmol, 1.1 equiv.) was
added dropwise to a solution of the diacetate (S,S)-15b
(0.31 g, 0.56 mmol) in degassed acetic acid (9 mL) at room
temperature. The reaction mixture was heated at 608C for
16 h. The solvent was evaporated under vacuum, the crude
product was taken up in dichloromethane and the solvent
was evaporated again. Purification by flash chromatography
on silica gel with heptane as the eluent afforded 16d; yield:
135 mg (43%). Rf =0.6 (1% EtOAc/heptane); 1H NMR
(500 MHz, CDCl3): d=4.54 (bs, 1H), 4.21 (bs, 1H), 4.18 (bs,
1H), 4.03 (bs, 1H), 4.01 (bs, 1H), 3.91 (bs, 1H), 2.39 (t,
JH,H ~JP,H =13.5 Hz, 1H, PCH2), 2.31 (t, JH,H ~JP, H =13.5 Hz,
1H, PCH2), 2.05–1.80 (m, 6H), 1.78–1.70 (m, 1H), 1.60–1.50
(m, 1H), 1.40–1.28 (m, 5H), 1.03 [t, J=8.0 Hz, 9H, Si-
talytic processes, as well as their properties as ligands
in transition metal-promoted reactions.
Experimental Section
General Procedure for the Synthesis of the Silyl-
Substituted Ferrocenes 14 from (S,S)-11 (Scheme 4)
s-Butyllithium (1.4M in cyclohexane, 2.5 equiv.) was added
dropwise to a solution of (S,S)-11 (1.0 equiv.) in anhydrous
Et2O, at À788C. The mixture was warmed then to À208C
for 1 h and cooled again to À788C. Neat chlorosilane
(3.0 equiv.) was added to the solution of lithiated ferrocene
and the mixture was allowed to stir at À788C for 10 min,
then at room temperature for 3 h. Water was added. The
layers were separated and the aqueous phase was extracted
twice with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered and concen-
trated. The residue was purified by flash chromatography on
silica gel (0.5% Et3N/Et2O)
(S,S,Sp ,Sp)-1,1’-Bis(triethylsilyl)-2,2’-bis[(2-methoxymeth-
ylpyrrolidin-1-yl)methyl]ferrocene (14b): Compound 14b
was prepared in 73% yield (0.78 g) from (S,S)-11 (1.6 mmol)
as an orange oil. Rf =0.7 (0.5% TEA/Et2O); 1H NMR
(500 MHz, CDCl3): d=4.20 (t, J=2.0 Hz, 2H), 4.03 (bs,
2H), 3.95 (d, J=12 Hz, 2H), 3.94 (bs, 2H), 3.49 (dd, J=9.0,
J=5.5 Hz, 2H), 3.37 (s, 6H), 3.24 (dd, J=9.0, J=6.5 Hz,
2H), 2.96 (d, J=12.5 Hz, 2H), 2.7–2.6 (m, 2H), 2.6–2.5 (m,
2H), 2.0–1.9 (m, 2H), 1.9–1.8 (m, 2H), 1.65–1.50 (m, 6H),
1.0–0.9 (m, 18H), 0.9–0.7 (m, 12H); 13C NMR (75 MHz,
CDCl3): d=89.8 (C), 77.1 (CH2), 76.4, 75.2, 70.9, 69.4 (C),
63.6, 59.1, 55.3 (CH2), 54.2 (CH2), 29.1 (CH2), 22.5 (CH2),
8.2 (Me), 4.9 (CH2); HR-MS (ESI): m/z=691.3748, calcd.
for C36H64FeN2NaO2Si2 [M+Na]+: 691.3753; [a]D24: À119 (c
1, CHCl3).
A
ACHTNUGTRNEN(UGN CH2CH3)3], 0.88 [q,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
69.7 (C), 69.0, 38.9 (d, JP, C =12.9 Hz, CH), 30.5 (d, JP, C
12.0 Hz, CH2), 30.0 (d, JP, C =10.6 Hz, CH2), 27.3 (d, JP, C
=
=
9.0 Hz, CH2), 27.2 (d, JP, C =8.0 Hz, CH2), 26.7 (CH2), 24.5
(d, JP,C =23.0 Hz, P-CH2), 22.8 (d, JP, C =18.5 Hz, P-CH2), 8.1
(Me), 7.8 (Me), 5.4 (CH2), 5.3 (CH2); 31P NMR (202 MHz,
CDCl3): d=11.4 ppm; HR-MS (ESI): m/z=555.2694, calcd.
for C30H52FePSi2 [M+H]+: 555.2695; [a]2D5: À55 (c 1,
CHCl3).
Catalytic Asymmetric [3+2]Annulations of Buta-2,3-
dienoates with Enones 22 (Table 4)
A mixture of enone 22 (0.15 mmol), buta-2,3-dienoate
(0.30 mmol) and phosphine 16c (10 mol%, 0.015 mmol,
7.1 mg) in degassed toluene (0.50 mL) was stirred at the
given temperature for 24 h under an argon atmosphere. The
crude mixture was concentrated under vacuum, and purified
by flash chromatography on silica gel (EtOAc/heptanes).
Enantiomeric excesses were measured by chiral HPLC (See
supporting information). The shown configurational assign-
ment for compounds 21 and 23 is based on [a]D values, by
comparison with known compounds from ref.[5b]
ACHTUNGTRENNUNG(S,S)-1,1’-bis(Triethylsilyl)-2,2’-bis(acetyloxymethyl)-
ferrocene (15b)
Compound 14b (730 mg, 1.1 mmol) was dissolved in 8 mL of
acetic anhydride. The solution was stirred at 908C for 16 h
in a sealed tube. After evaporation of the solvent under
vacuum, purification by column chromatography gave 15b
as an orange solid; yield: 340 mg (56%). Rf =0.48 (30%
References
[1] a) J. L. Methot, W. R. Roush, Adv. Synth. Catal. 2004,
346, 1035–1050; b) J. Seayad, B. List, Org. Biomol.
Chem. 2005, 3, 719–724; c) L.-W. Ye, J. Zhou, Y. Tang,
Chem. Soc. Rev. 2008, 37, 1140–1152.
[2] a) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. 2008, 120, 6232–6265; Angew. Chem.
Int. Ed. 2008, 47, 6138–6171; b) S. E. Denmark, G. L.
Beutner, Angew. Chem. 2008, 120, 1584–1663; Angew.
Chem. Int. Ed. 2008, 47, 1560–1638.
[3] a) E. Vedejs, O. Daugulis, S. T. Diver, J. Org. Chem.
1996, 61, 430–431; b) E. Vedejs, O. Daugulis, N. Tuttle,
J. Org. Chem. 2004, 69, 1389–1392; c) J. A. MacKay, E.
Vedejs, J. Org. Chem. 2006, 71, 498–503.
1
Et2O/heptane); H NMR (500 MHz, CDCl3): d=4.92 (d, J=
12.0 Hz, 2H), 4.77 (d, J=12.0 Hz, 2H), 4.35 (bs, 2H), 4.31
(bs, 2H), 4.08 (bs, 2H), 2.04 (s, 6H, Me), 1.01 (t, J=8.0 Hz,
18H, Me), 0.90–0.75 (m, 12H, CH2); 13C NMR (75 MHz,
CDCl3): d=170.6 (CO), 85.8 (C), 76.1, 74.4, 72.3, 71.1 (C),
63.4 (CH2), 21.0 (Me), 7.9 (Me), 5.0 (CH2); HR-MS (ESI):
m/z=581.2187, calcd. for C28H46FeNaO4Si2 [M+Na]+:
581.2182; [a]2D5: +46 (c 1, CHCl3).
ACHTUNGTRENNUNG(S,S)-1,1’-Bis(triethylsilyl)-2,2’-(2-cyclohexyl-2-phos-
phapropanediyl)ferrocene (16d)
[4] a) M. Shi, L.-H. Chen, C.-Q. Li, J. Am. Chem. Soc.
2005, 127, 3790–3800; b) Y.-L. Shi, M. Shi, Adv. Synth.
Catal. 2007, 349, 2129–2135; c) K. Yuan, H.-L. Song, Y.
Hu, X.-Y. Wu, Tetrahedron Lett. 2008, 49, 6262–6264.
[5] a) G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao, X.
Zhang, J. Am. Chem. Soc. 1997, 119, 3836–3837;
Adv. Synth. Catal. 2009, 351, 1968 – 1976
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1975

Arnaud Voituriez et al.
FULL PAPERS
b) J. E. Wilson, G. C. Fu, Angew. Chem. 2006, 118,
1454–1457; Angew. Chem. Int. Ed. 2006, 45, 1426–
1429; c) N. Fleury-Brꢀgeot, L. Jean, P. Retailleau, A.
Marinetti, Tetrahedron 2007, 63, 11920–11927; d) Y.-Q.
Fang, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130,
5660–5661.
Kagan, J. Am. Chem. Soc. 1993, 115, 5835–5836; oxa-
zolines: c) Y. Nishibayashi, S. Uemura, Synlett 1995,
79–81; pyrrolidines: d) C. Ganter, T. Wagner, Chem.
Ber. 1995, 128, 1157–1161; sulfoxides: e) F. Rebiꢃre, O.
Riant, L. Ricard, H. B. Kagan, Angew. Chem. 1993,
105, 644–646; Angew. Chem. Int. Ed. Engl. 1993, 32,
568–570; ephedrine derivatives: f) L. Xiao, R. Kitzler,
W. Weissensteiner, J. Org. Chem. 2001, 66, 8912–8919;
sulfoximines: g) C. Bolm, M. Kesselgruber, K. Muniz,
G. Raabe, Organometallics 2000, 19, 1648–1651, and
others.
[6] R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005, 127,
12234–12235.
[7] a) Z. Chen, G. Zhu, Q. Jiang, D. Xiao, P. Cao, X.
Zhang, J. Org. Chem. 1998, 63, 5631–5635; b) F. Seidel,
J. A. Gladysz, Synlett 2007, 986–988; c) Y.-Q. Jiang, Y.-
L. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130, 7202–
7203; d) C.-W. Cho, J.-R. Kong, M. J. Krische, Org.
Lett. 2004, 6, 1337–1339; e) Z. Pakulski, O. M. Dem-
chuk, J. Frelek, R. Luboradzki, K. M. Pietrusiewicz,
Eur. J. Org. Chem. 2004, 3913–3918; f) Y.-K. Chung,
G. C. Fu, Angew. Chem. 2009, 121, 2259–2261; Angew.
Chem. Int. Ed. 2009, 48, 2225–2227.
[8] E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 1999, 121,
5813–5814.
[9] M. Shi, L.-H. Chen, Chem. Commun. 2003, 1310–1311.
[10] B. J. Cowen, S. J. Miller, J. Am. Chem. Soc. 2007, 129,
10988–10989.
[11] A. Voituriez, A. Panossian, N. Fleury-Brꢀgeot, P. Re-
tailleau, A. Marinetti, J. Am. Chem. Soc. 2008, 130,
14030–14031.
[12] N. Fleury-Brꢀgeot, A. Panossian, A. Chiaroni, A. Ma-
rinetti, Eur. J. Inorg. Chem. 2007, 3853–3862.
[13] R. G. Arrayas, J. Adrio, J. C. Carretero, Angew. Chem.
2006, 118, 7836–7878; Angew. Chem. Int. Ed. 2006, 45,
7674–7715.
[14] a) T. Sturm, W. Weissensteiner, F. Spindler, K. Mereit-
er, A. M. Lopez-Agenjo, B. R. Manzano, F. A. Jalon,
Organometallics 2002, 21, 1766–1774; b) P. Liptau, L.
Tebben, G. Kehr, R. Frçhlich, G. Erker, F. Hollmann,
B. Rieger, Eur. J. Org. Chem. 2005, 1909–1918; c) T.
Sturm, B. Abad, W. Weissensteiner, K. Mereiter, B. R.
Manzano, F. A. Jalon, J. Mol. Catal. A 2006, 255, 209–
219; d) A. Almassy, K. Barta, G. Francio, R. Sebesta,
W. Leitner, S. Toma, Tetrahedron: Asymmetry 2007, 18,
1893–1898; e) R. Sebesta, F. Bilcik, B. Horvath, Eur. J.
Org. Chem. 2008, 5157–5161.
[21] a) L. Schwink, P. Knochel, Chem. Eur. J. 1998, 4, 950–
968; b) J. Kang, J.-H. Lee, S. H. Ahn, J-S. Choi, Tetra-
hedron Lett. 1998, 39, 5523–5526; c) W. Zhang, Y.
Adachi, T. Hirao, I. Ikeda, Tetrahedron: Asymmetry
1996, 7, 451–460; d) M. Raghunath, W. Gao and X.
Zhang, Tetrahedron: Asymmetry 2005, 16, 3676–3681;
e) D. Enders, T. Klumpen, J. Organomet. Chem. 2001,
637–639, 698–709; f) B. Pugin, X. D. Feng, M. Thom-
men, (Solvias AG, Switzerland), PCT Int. Appl. WO
2006/003195, 2006.
[22] Sparteine-mediated enantioselective ortho-lithiations of
diamidoferrocenes have been also reported: a) H. Jen-
dralla, E. Paulus, Synlett 1997, 471–472; b) R. S.
Laufer, U. Veith, N. J. Taylor, V. Snieckus, Org. Lett.
2000, 2, 629–631.
[23] D. Enders, P. Fey, H. Kipphardt, Org. Synth. Coll. Vol.
VIII 1993, 173–182.
[24] L. Xiao, K. Mereiter, W. Weissensteiner, M. Widhalm,
Synthesis 1999, 1354–1362.
[25] Analogous reversals of stereoselectivity as a result of
base effects have been mentioned before: a) J. Park, S.
Lee, K-H. Ahn, C-W. Cho, Tetrahedron Lett. 1995, 36,
7263–7266; b) C. Metallinos, V. Snieckus, Org. Lett.
2002, 4, 1935–1938.
[26] Assignment of an SP,RP configuration to 13b also relies
on the fact that removal of the chiral auxiliaries from
13a and 13b with acetic anhydride, according to the
procedure in Scheme 4, affords the dl and meso stereo-
isomers of the corresponding 1,1’-dibromo-2,2’-diace-
toxymethylferrocene, respectively.
[27] Both 12a (SP-configuration) and the epimeric complex
12b (RP-configuration), produced with t-BuLi have
been characterized: see supporting information.
[28] Other electrophiles such as MeI or DMF also afford
the corresponding tetrasubstituted ferrocenes in good
yields. Diastereomeric ratios are largely insensitive to
the nature of the electrophilic trapping reagent.
[29] M. Steurer, Y. Wang, K. Mereiter, W. Weissensteiner,
Organometallics 2007, 26, 3850–3859.
[30] a) T. Hayashi, T. Mise, M. Fukushima, M. Kagotani, N.
Nagashima, Y. Hamada, A. Matsumoto, S. Kawakami,
M. Konishi, K. Yamamoto, M. Kumada, Bull. Chem.
Soc. Jpn. 1980, 53, 1138–1151; b) P. Barbaro, C. Bian-
chini, A. Togni, Organometallics 1997, 16, 3004–3014.
[31] D. E. Herbert, M. Tanabe, S. C. Bourke, A. J. Lough, I.
Manners, J. Am. Chem. Soc. 2008, 130, 4166–4176.
[32] For instance, 16c displays a tilt angle of about 5.98 in its
solid state structure, see ref.[11]
[15] a) Z. Xu, X. Lu, J. Org. Chem. 1998, 63, 5031–5041;
b) L. Jean, A. Marinetti, Tetrahedron Lett. 2006, 47,
2141–2145.
[16] a) C. Zhang, X. Lu, J. Org. Chem. 1995, 60, 2906–2908;
b) T. Dudding, O. Kwon, E. Mercier, Org. Lett. 2006, 8,
3643–3646; c) Y. Liang, S. Liu, Y. Xia, Y. Li, Z.-X. Yu,
Chem. Eur. J. 2008, 14, 4361–4368.
[17] Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang,
S. Liu, Y. Li, Z.-X. Yu, J. Am. Chem. Soc. 2007, 129,
3470–3471.
[18] M. Couturier, F. Mꢀnard, J. A. Ragan, M. Riou, E.
Dauphin, B. M. Andresen, A. Ghosh, K. Dupont-
Gaudet, M. Girardin, Org. Lett. 2004, 6, 1857–1860.
[19] A notable exception was reported by Fu: ees of 72–
87% were obtained with BPE catalysts in a [4+2]cycli-
zation reaction: see ref.[6]
[20] Suitable substrates include the Ugiꢂs amine: a) D. Mar-
quarding, H. Klusacek, G. Gokel, P. Hoffmann, I. Ugi,
J. Am. Chem. Soc. 1970, 92, 5389–5393; ferrocenes
bearing chiral acetals: b) O. Riant, O. Samuel, H. B.
[33] The designation “g-” refers to the allene carbon atom
which adds to the b-carbon of the enone moiety.
1976
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1968 – 1976