Development of chiral phosphoric acids based on ferrocene-bridged paracyclophane frameworks

Article abstract of DOI:10.1002/adsc.201300697

This work deals with the development of a new family of planar chiral phosphoric acids based on a ferrocenophane/paracyclophane scaffold. The synthetic approach has been improved by taking advantage of a chiral phosphorylating agent to access enantiomerically enriched acids via diastereomers separation. These phosphoric acids have been used as catalysts for the enantioselective H-transfer reduction of α-substituted quinolines with Hantzsch esters. Optimization of both the catalyst and the Hantzsch reductant allowed ee values in the range 82-92% to be attained starting from α-arylquinolines. Copyright

Full text of DOI:10.1002/adsc.201300697

FULL PAPERS
DOI: 10.1002/adsc.201300697
Development of Chiral Phosphoric Acids based on Ferrocene-
Bridged Paracyclophane Frameworks
Jꢀrꢀmy Stemper,a Kꢀvin Isaac,a Julien Pastor,b Gilles Frison,b Pascal Retailleau,a
Arnaud Voituriez,a Jean-FranÅois Betzer,a,* and Angela Marinettia,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, 91198 Gif-sur-Yvette,
France
Fax : (+33)-1-6907-7247; e-mail: jean-francois.betzer@cnrs.fr or angela.marinetti@cnrs.fr
Laboratoire des Mꢀcanismes Rꢀactionnels, Department of Chemistry, Ecole Polytechnique and CNRS, 91128 Palaiseau,
b
France
Received: August 1, 2013; Published online: December 5, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300697.
Abstract: This work deals with the development of tion of a-substituted quinolines with Hantzsch esters.
a new family of planar chiral phosphoric acids based Optimization of both the catalyst and the Hantzsch
on a ferrocenophane/paracyclophane scaffold. The reductant allowed ee values in the range 82–92% to
synthetic approach has been improved by taking ad- be attained starting from a-arylquinolines.
vantage of a chiral phosphorylating agent to access
enantiomerically enriched acids via diastereomers Keywords: chiral phosphorodiamidites; organo-
separation. These phosphoric acids have been used
ACHTUNGTRENcNUGN atalysis; paracyclophanes; phosphoric acids; planar
as catalysts for the enantioselective H-transfer reduc- chirality
Introduction
and offer new opportunities for catalytic applications.
This hypothesis led us to design phosphoric acids
The use of chiral phosphoric acids in organocatalytic based on planar chiral paracyclophane scaffolds as po-
processes has experienced an exponential growth fol- tentially relevant targets. Preliminary results from
lowing the seminal work of Terada[1] and Akiyama[2] these studies have been disclosed in a short communi-
on enantioselective Mannich-type reactions. Among cation.[11] In this paper we present (i) more detailed
the most classical applications, Biginelli, Pictet–Spen- information on our design of planar chiral phosphoric
gler, Friedel–Crafts, ene-type and Diels–Alder reac- acids, (ii) an improved synthetic approach to optically
tions can be mentioned.[3] Moreover, several unprece- pure compounds, based on the use of a chiral phos-
dented uses have been reported recently which in- phorylating agent, (iii) more extensive investigations
clude the desymmetrization of tetrasubstituted biaryls on the use of the new acids as organocatalysts in the
by asymmetric bromination,[4] the oxyfluorination of enantioselective H-transfer reduction of a-substituted
enamides,[5] the asymmetric protonation of ketene di- quinolines.
thioacetals and silyl ketene imines[6] and others.[7] The
privileged phosphoric acids for these applications are
mainly based on chiral BINOL, SPINOL,[8] VANOL Results and Discussion
and VAPOL[9] derivatives, that is, C2-symmetrical, ax-
ially chiral diols. Surprisingly, planar chirality has not At the start of our studies, our aim was to develop
been exploited so far for building phosphoric acids, al- a new series of phosphoric acids, based on planar
though planar chiral structural units are known to chiral paracyclophane scaffolds. As far as we know,
afford efficient auxiliaries in other fields.[10] In the the literature reports only one compound of this class,
case of phosphoric acids, it can be expected that the Enders acid A (Figure 1), in which a phosphoric
planar chiral scaffolds would create completely differ- acid function is embedded in the five-atom chain teth-
ent asymmetric environments, with respect to axially ering an unsymmetrical [2.2]paracyclophane unit. This
chiral frameworks. They might generate, therefore, Brønsted acid catalyst had been evaluated in Man-
complementary properties in terms of stereoselection
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As mentioned in our preliminary communication,[11]
phosphoric acids of the general formula B can be ac-
cessed when the tethering chain “X” is a 1,1’-ferro-
AHCTUNGTREGcNNUN enediyl unit. This chain has been designed initially,
following on from calculations of the ring strain and
configurational stability for a range of phosphoric
acids of this class. Results of these calculations are re-
ported hereafter in Scheme 1.
Two factors have been initially identified as crucial
for the choice of the tethering chain. First, the strain
energy associated with the macrocyclic structure: the
Figure 1. Endersꢂ planar chiral phosphoric acid (A) and tar-
geted structures from this work (B).
nich-type reactions affording moderate enantiomeric longer the tethering chain “X” is, the easier the cycli-
excesses (ees up to 38%).[12]
zation process would be. Secondly, the configurational
Our target structures (B, Figure 1) differ from the stability of the planar chiral scaffold: a long linker
À À
Enders acid in as far as the O P O bridge itself “X” might induce loss of the configurational stability,
would be a constitutive fragment of the C2-symmetri- by allowing easy rotation of the phenylene rings of
À
À
cal paracyclophane framework. In B, planar chirality the paracyclophane moiety around the X Caryl
O
is generated by the two aryl substituents (Ar) on op- axis. The nature of the tethering chain must therefore
posite edges of the paracyclophane. The only previous be finely adjusted. DFT calculations have been run to
report on related paracyclophanes and ferroceno- estimate ring strain energies for paracyclophanic
phanes are due to Nifant’ev[13] and Herberhold[14] who acids, relative to the BINOL-derived phosphoric acid
synthesized racemic macrocyclic bis-phosphorami- (DERSE), according to the isodesmic reaction depicted
dites, and ferrocenic phosphonites and phosphates, re- in Scheme 1. The computed data, obtained at the
spectively. None of these compounds have been pre- M06/6-31GACTHUNRTGNEUNG(d,p) level are shown.
pared in enantiomerically enriched form, neither have
they been investigated for catalytic purposes.
A 2-atom chain (IIa) induces the larger ring strain
energy, whereas 3-atom (IId) and, to a larger extent,
Scheme 1. Isodesmic reaction used to compute the relative ring strain energy of IIa–f relative to the BINOL-derived phos-
phoric acid.
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Development of Chiral Phosphoric Acids based on Ferrocene-Bridged Paracyclophane Frameworks
4-atom chains (IIf) significantly reduce strain. The figurational stability. As described in our previous
1,1’-ferrocenediyl unit (IIe) decreases significantly the communication, the ferrocene-tethered phosphoric
ring strain with respect to the 3-atom chains of IIb–d. acids 7 could be obtained according to two general
This comparatively low ring strain likely relates to the strategies shown in Scheme 2.[11]
high flexibility of the ferrocene unit, a unique struc-
For both pathways, the key step is the macrocycli-
tural feature that has allowed previously the synthesis zation reaction of a 1,1’-bis(para-hydroxyphenyl)fer-
of ferrocenophanes of various ring sizes, including the rocene, 3, with bis(diisopropylamino)cyanoethoxy-
highly constrained phospha[1]- and phospha[2]ferro- phosphine 8a. The two pathways differ from each
cenophanes.[15]
other by the reaction sequence leading to the ferro-
Geometrical parameters of the macrocyclic struc- cenic diol 3. Pathway (a) involves the reaction of 1,1’-
tures IIa–f also correlate well with the computed ring diiodoferrocene with a preformed biarylboronate
strain energies: smaller and less flexible linkers in- [BPin=4,4,5,5-tetramethyl-1,3,2-dioxaborolane] in the
crease the deformation angles of the benzene ring of presence of a palladium catalyst, under Suzuki condi-
the paracyclophane unit (see sum of deformation tions. Path (b) entails the synthesis of the bis-boro-
angles, ꢀa+b in Table 3),[16] as well as the strain of the nate 2 as a common platform allowing introduction of
À À
O P O bridge, as shown by the increased O···O dis- various aryl substituents (Ar) at a later step of the re-
tance (Table 3).
action sequence. The aryl substituents are introduced
Concerning the configurational stability of paracy- here by a palladium-catalyzed Suzuki coupling on 2.
clophanes, it has been computed recently that the bar- In the final step of the reaction sequence, diols 3 have
rier for rotation of the p-phenylene ring in [3.3]- and been reacted with bis(diisopropylamino)cyanoethoxy-
[4.4]paracyclophanes are of about 300 and phosphine in the presence of four equivalents of 1H-
80 kJ·molÀ1, respectively,[17] indicating that this barrier tetrazole to afford the desired d,l-phosphites 4.[18]
could be overcome only for the larger macrocycles Phosphites 4 have been oxidized into the correspond-
and at high temperature. A similar trend is expected ing phosphates with tert-butyl hydroperoxide, then re-
to be found in the targeted macrocyclic phosphoric moval of the cyanoethyl chain by elimination of acryl-
acids. For the ferrocenic derivative IIe and the naph- onitrile under basic conditions (DBU) afforded the
thalene-derived macrocycle IIc, the energy barriers racemic acids 7. Pathway (a) has been applied to the
for the rotation of the p-phenylene units around the synthesis of the phenyl-substituted phosphoric acid 7a
À
À
X Caryl O axis have been calculated at about 216 and (Ar=Ph), while path (b) allowed the synthesis of the
387 kJ·molÀ1, respectively [at the M06/6-31G
AHCTUNGTRENNUNG
level] in accordance with the chain size and flexibility
of these structures.
The racemic mixtures of 7a and 7b have been sepa-
rated initially into enantiomerically pure acids by
The theoretical studies above have oriented our semipreparative HPLC on a CHIRALPAKꢃ ID
choice toward 1,1’-ferrocenediyl units as the key com- column.
ponents of phosphoric acids B, due to their low ring
However, the use of semi-preparative chiral HPLC
strain energy and high racemization barrier. Initial ex- as the resolution method is a potential drawback of
periments have demonstrated that ferrocene-based the synthetic approach above, as far as it might pre-
paracyclophanes of the general formula B can indeed vent suitable scale-up of the acids 7. On the other
be accessed and display acceptable chemical and con- hand, the strategy of resolving the diol precursors
Scheme 2. Synthetic approaches to the 1,1’-ferrocenediyl-tethered paracyclophanes 7.
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commonly applied to the synthesis of chiral phospho- as shown in Scheme 3. After a Cl/CN substitution
ric acids,[19] cannot be applied here because of the pe- step, the resulting (S)-3-hydroxy-3-phenylpropaneni-
culiar structural features of this series. Acids 7 differ trile[20] has been reacted with [(i-Pr)2N]2PCl at room
indeed from the BINOL- or SPINOL-derived ana- temperature in the presence of Et3N. The desired
logues in that chirality is generated at the phosphina- phosphorodiamidite (S)-8b has been isolated as
tion step, while the diol precursors are achiral. This a white solid after filtration on a silica gel column.
means that resolution must be performed at a later
step of the synthetic sequence.
Phosphorodiamidite (S)-8b has been used as the
phosphinating agent for the previously reported diols
Thus, in order to avoid chiral HPLC separation, we 3a (Ar=Ph) and 3b (Ar=meta-terphenyl), but also
have envisioned an original approach, that is, the use for the newly synthesized ferrocenic diols 3c, d [Ar=
of a chiral auxiliary as the phosphinating agent and para-biphenyl and 3,5-(CF3)2C6H3], as shown in
subsequent separation of diastereomeric pairs. We Scheme 4. Diol 3c has been prepared via palladium-
have developed (S)-8b as a chiral variant of the classi- catalyzed coupling of 1,1’-diiodoferrocene, 1, with the
cal cyanoethoxy-substituted phosphinating agent 8a. corresponding biarylboronate [path (a) in Scheme 2].
The new phosphorodiamidite (S)-8b contains a cya- Diol 3d has been obtained via path (b) in Scheme 2,
À
noethoxy moiety as a precursor for the acidic P OH that is, coupling of 1-bromo-3,5-bis(trifluoromethyl)-
function, but, unlike 8a, it displays a stereogenic benzene with the ferrocenic bisboronate 2 [PG=me-
carbon in close proximity to the phosphorus center. It thoxymethyl, catalyst=PdACHTNUTRGNE(UNG PPh3)4]. The experimental
is easily available in two steps, starting from the com- procedures for these reactions are given in the Sup-
mercially available (R)-(À)-2-chloro-1-phenylethanol, porting Information.
Diols 3a–d have been reacted with the chiral phos-
phorodiamidite (S)-8b in the presence of 1H-tetrazole
to afford the desired macrocyclic, paracyclophane-
type phosphites 5a–d (Scheme 4). In principle, the
cyclization step might afford both the meso- and d,l-
isomers of 5, but, gratifyingly, these reactions oc-
curred with high stereoselectivity leading to the de-
sired d,l-isomers as the only isolated products. We can
assume that steric effects are responsible for the ob-
served selectivity, as far as the steric hindrance of the
Ar substituents is expected to favor their positioning
on opposite faces of the paracyclophane ring. From
Scheme 3. Synthesis of the chiral phosphorodiamidite (S)-
8b.
Scheme 4. Use of the chiral phosphorodiamidite (S)-8b in the synthesis of phosphoric acids 7.
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Development of Chiral Phosphoric Acids based on Ferrocene-Bridged Paracyclophane Frameworks
Unlike the corresponding phosphates 6, acids 7 dis-
played moderate thermal stability giving non-identi-
fied decomposition products after heating at 608C in
toluene for several hours. For instance, 7a undergoes
an estimated 10% decomposition after heating for
18 h at 608C. Therefore, to ensure the integrity of
their molecular scaffold, these acids are stored rou-
tinely at À208C and used then in catalytic experi-
ments at room temperature.
In summary, we have demonstrated here that the
use of the chiral phosphorodiamidite (S)-8b as the
phosphinating agent provides an easier access to the
phosphoric acids 7, the first family of planar chiral
acids based on paracyclophane structures.
With suitable synthetic methods in hand, we have
then started a systematic investigation of the behavior
of acids 7 as Brønsted acid catalysts.
Our investigations have been focused on the trans-
fer hydrogenation of 2-substituted quinolines with the
Hantzsch ester as a benchmark reaction (Table 1).[21]
Figure 2. X-Ray crystal structure of (À)-(SP,S)-6c’.
these reactions, phosphites 5a–d have been isolated as We have compared the catalytic properties of the four
mixtures of two diastereomers in 1:1 to 7:3 ratios. The acids 7a–d which display aryl groups with various
mixtures have been oxidized with t-BuOOH to obtain steric bulk and long-arm effects. The shape and bulk
the corresponding phosphates 6a–d. The four phos- of these aryl substituents are expected to play a major
phates could be separated easily into pure diastereo- role in enantioselective catalysis, as impressively dem-
mers by either column chromatography (for 6b–d) or onstrated with the analogous BINOL-derived phos-
HPLC (for 6a). Thus, for instance, phosphates 6c, c’ phoric acids.[22]
(Ar=4-biphenyl) have been separated by flash chro-
At first, the behavior of 7a–d has been surveyed in
matography on silica gel (Combiflash) with a toluene/ the reduction of 2-phenylquinoline with the Hantzsch
heptane/THF gradient (from 60:30:0 to 60:30:2) as ester 9a (R=Et, entries 1–4). All catalytic experi-
the eluent {6c: Rf =0.39, [a]2D0: +1151 (c=0.5, CHCl3); ments have been run in toluene on a 0.05-mmol scale.
6c’: Rf =0.34, [a]20: À1138 (c=0.5, CHCl3)}.
Standard conditions involve toluene as the solvent,
An X-ray crysDtal study on 6c’ demonstrated an (S)- room temperature, 10 mol% of chiral catalyst.
configuration of its planar chiral scaffold (Figure 2).
Acids 7a–d displayed excellent catalytic activity at
Since 6c’ displays a negative rotatory power, we tenta- room temperature, as they give total conversion in
tively assume that, in the whole series, negative alpha less than 2 h. As anticipated, the nature of the aryl
values are associated to phosphates and phosphoric substituents of the acids strongly modulates the enan-
acids with (S)-configurations.
tioselectivity levels, with enantiomeric excesses going
The phosphates 6 are chemically and configuration- from 26%, for Ar=phenyl, to 60% for the bulky,
ally stable: neither decomposition nor interconversion meta-terphenyl-substituted acid 7b.
of isomeric derivatives has been observed after either
prolonged storage in air at room temperature or heat- the 9-phenanthryl-substituted acid 7e[24] (entry 5)
ing overnight at 808C. since 9-phenanthryl substituents are known to give
In addition to catalysts 7a–d, we have tested also
The last step of the reaction sequence in Scheme 4 the most efficient acid in the binaphthyl series.[21a]
is the removal of the chiral auxiliary. The 1-phenyl-2- Acid 7e afforded, however, a very low enantiomeric
cyanoethyl chain could be removed under the condi- excess. Generally speaking, we have observed that the
tions usually applied for removal of the analogous substituent effects do not follow the same trends in
achiral cyanoethyl chain: DBU easily induces depro- the binaphthyl-derived and paracyclophane-type
tonation and subsequent elimination of 3-phenylacry- phosphoric acids. Such divergent substituent effects
lonitrile, with concomitant generation of the desired can be easily understood as far as the two series dis-
phosphoric acid salt. Starting from single diastereo- play totally different structural features and, especial-
mers of phosphates 6, the enantiomerically enriched ly, different arrangements of the aryl groups around
acids 7a–d have been obtained as yellow-orange the phosphorus functions. Comparative views of the
solids after filtration on silica gel with a DCM/MeOH molecular structures of a BINOL-derived phosphoric
gradient (0 to 10% MeOH) and work-up with aque- acid and the corresponding paracyclophanic acid 7a,
ous HCl (6N). The enantiomeric excesses of the acids obtained from DFT calculations, are given in
have been measured by HPLC.
Figure 3.
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Table 1. Survey of phosphoric acids and Hantzsch esters for
the H-transfer hydrogenation of 2-phenylquinoline.[a]
Cata-
lyst
Hantzsch
ester
R
Time ee [%][c]
[h][b]
ACHTUNGTRENN(UNG config.)
1
2
3
4
5
6
7
8
9
(+)-7a 9a
(+)-7b 9a
(+)-7c 9a
(+)-7d 9a
(À)-7e 9a
(À)-7b 9b
(À)-7b 9c
(À)-7b 9d
(+)-7b 9e
Et
Et
Et
Et
Et
Me
t-Bu
CH2Ph
2
2
2
2
27 (S)[d]
60 (S)
55 (S)[e]
56 (S)
2
26 (R)[g]
50 (R)
70 (R)
74 (R)
85 (S)
16
20[f]
3
2
2
CH2(4-MeOC6H4)
CH2(4-BnOC6H4)
10 (À)-7b 9 f
87 (R)[d]
[a]
Reactions were run at a substrate concentration of 0.05
to 0.01M, depending on the solubility of the Hantzsch
ester in toluene.
[b]
[c]
Reaction times giving total conversion rates (NMR mon-
itoring of the crude mixtures).
The ees were determined by HPLC on CHIRALPACKꢃ
IB (i-PrOH/heptane 5:95). Configuration assigned from
[a]D values.[23]
Figure 3. DFT computed molecular structures of a BINOL-
derived phosphoric acid and the corresponding paracyclo-
phanic acid 7a.
[d]
[e]
The same conversion rate and ee were observed at a cata-
lyst loading of 5 mol%.
CH2Cl2 and THF were also used as solvents in this reac-
tion, they afforded however lower reaction rates and
enantioselectivity levels (ee=30%).
ity relationships in the two series. This obviously pre-
vents us from making predictive hypotheses, but, on
the other hand, the peculiar structural features of
acids 7 might hopefully give complementary applica-
tions, with respect to BINOL-derived acids and ana-
logues.
[f]
80% conversion rate.
5 mol% catalyst.
[g]
From the initial screening of chiral acids in Table 1,
entries 1–5, we retained 7b (Ar=terphenyl) as the
most promising catalyst for the H-transfer reduction
of 10a and we investigated then the role of the dihy-
dropyridine partner (entries 2, 6–10 in Table 1). Ac-
cording to recent theoretical studies on the reduction
of imines with Hantzsch esters, the esters are assumed
to give H-bonds with the catalyst in the stereodeter-
Most particularly, in 7a the eclipsed conformation mining H-transfer step.[25] Consequently, the nature of
of the ferrocene unit and the parallel arrangement of the ester should have effects on the reaction outcome
the para-phenylene groups cause a bent arrangement in terms of stereochemical control. Although so far
À À
of the O P -O function and subsequent loss of the the literature shows that the Hantzsch ester plays
C2 symmetry of the molecule. Therefore, while in the a minor role in analogous reactions,[21f,26] in our study
C2-symmetrical BINOL-derived acid the phenyl an extensive screening of esters has allowed a signifi-
groups are distributed symmetrically on opposite cant improvement of the enantioselectivity levels.
sides of the phosphorus function, in 7a one of the Several known and new Hantzsch esters [e.g., R=t-
phenyl substituents becomes closer to the phosphorus Bu, CH2Ph, CH2(4-MeOC6H4), CH2(4-BnO-C6H4)]
function and the second one is kept away considera- have been prepared from formaldehyde, ammonium
bly. Based on these significant structural differences, acetate and the desired acetoacetate, following
we cannot expect similar trends in the structure-activ- a usual procedure.[27]
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Development of Chiral Phosphoric Acids based on Ferrocene-Bridged Paracyclophane Frameworks
As shown in Table 1, in the reduction of 2-phenyl- cyclophane, while suitably positioned aromatic sub-
quinoline catalyzed by acid 7b, the enantiomeric stituents generate planar chirality. We have demon-
excess increased with the steric hindrance of the strated that the planar chiral phosphoric acids 7 dis-
Hantzsch esters (R=Me<Et<t-Bu). Finally, benzyl play high catalytic activity and promising enantiose-
esters afforded the highest enantioselectivity levels, lectivity levels in model H-transfer reductions (ees up
with an 87% ee obtained with ester 9f, R=CH2(4- to 92%). Their behavior as Brønsted acid organocata-
BnO-C6H4). In these reactions, the catalyst loading lysts will be further investigated. Given their peculiar
could be decreased to 5 mol% without decreasing the structural features, including the lack of C2-symmetry,
conversion rate and enantioselectivity.
it can be anticipated that these acids will have com-
With these improved conditions in hand (7b as the plementary application fields with respect to other
catalyst and 9f as the reducing agent) we have investi- known chiral phosphoric acids. Further studies of
gated the scope of the H-transfer reaction by varying their catalytic properties are ongoing in our group.
the quinoline substrates. The main results are sum-
marized in Table 2.
Experimental Section
Table 2. Survey of 2-substituted quinolines 10 in H-transfer
reductions promoted by 7b.
Computational Method
Calculations have been carried out with the Gaussian09
package of programs.[30] Full geometry optimizations for all
compounds were carried out with the use of the M06[31] den-
sity functional level of theory and the 6-31GACTHNURTGNEU(GN d,p) basis set
for all atoms. This level of calculation is known to produce
reasonable geometries and energies for molecules in which
non-covalent interactions, like p-p interactions in paracyclo-
phane-type systems, play a noticeable role. To get accurate
geometries and energies, the SCF convergence criterion has
been systematically tightened to 10À8 a.u., and the force
minimizations were carried out until the rms force becomes
smaller than (at least) 1ꢄ10À5 a.u. Frequency analyses were
Substrate R’
1 10a
Acid
Product[a] ee [%][b]
(config.)
Ph
4-MeO-C6H4 (+)-7b 11b
2-naphthyl (+)-7b 11c
para-biphenyl (À)-7b 1d
(À)-7b 11a
87 (R)
83 (S)
92 (S)
82 (R)
87 (+)
40 (R)
40 (R)
2 10b
3 10c
4 10d
5 10e
6 10f
7 10g
3,5ACHTUNGTRENNUNG
1-naphthyl
C6H11
Table 3. Computed relative ring strain energy and geometric
parameters for IIa–f.[a]
(À)-7b 11f[c]
(À)-7b 11g[c]
[a]
Conversion rates are quantitative.
[b]
Configuration assigned from [a]D values of known com-
pounds: 11a,b,c,[23] 11d,[21a] 11f,[28] 11g.[29]
Conversion rate 50%.
[c]
These experiments show that the new catalyst 7b
[b]
[c]
[c]
[c]
[c]
[d]
affords high levels of enantioselectivity (ee 82–92%)
in the reduction of various a-aryl-substituted quino-
lines (entries 1–5). Under the same conditions, alkyl-
substituted quinolines are reduced with lower conver-
sion rates and enantiomeric excess (entry 7: R’=cy-
clohexyl, 40% ee). Even so, the potential of planar
chiral paracyclophanic acids as an enantioselective or-
ganocatalyst is demonstrated here.
DERSE
aO
aC
bO
bC
ꢀa+b dOÀ
O
IIa
87
11.1
7.8
9.5
7.5
6.0
4.2
10.0 2.6
11.8 35.5
2.611
2.596
2.601
2.596
2.582
2.573
IIb 43
IIc 40
IId 35
6.2
8.2
6.7
4.4
3.0
2.1
2.5
2.2
2.1
2.3
6.3
0.9
5.7
2.8
4.7
22.4
21.1
22.1
15.3
14.2
IIe
IIf
17
13
[a]
Angle aO (aC) is defined by lines L1 and LO (LC). Angle
À
À
bO (bC) is defined by line LO (LC) and the C1 O7 (C4
À
C8) bond. L1 goes through the midpoints of C2 C6 and
Conclusions
À
À
C3 C5. LO (LC) goes through the midpoints of C2 C6
À
(C3 C5) and C1 (C4).
This work has disclosed phosphoric acids 7 as the first
series of enantiomerically enriched phosphoric acids
with paracyclophane structures. Their unprecedented
scaffolds display an O P O chain and a 1,1’-ferro-
ACHTUNGTRENNUNGcenediyl unit tethering the aromatic rings of the para-
[b]
Ring strain energy relative to the BINOL-derived phos-
phoric acid in kJmolÀ1.
[c]
[d]
Phenylene ring deformation angles in degrees.
O···O distance in ꢅ. dOÀO =2.536 ꢅ for the BINOL-de-
rived phosphoric acid.
À À
Adv. Synth. Catal. 2013, 355, 3613 – 3624
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3619

Jꢀrꢀmy Stemper et al.
FULL PAPERS
carried out to confirm that the reported structures are
2H);
HR-MS
(ESI):
m/z=698.1486,
calcd.
for
minima or transition states on the M06/6-31G
energy surface (Table 3).
ACHTUNGTREN(NGNU d,p) potential
C43H32FeNO3P [M+H]+: 698.1547.
(b) Phosphates 6a, 6a’: A mixture of phosphites 5a,a’
(140 mg, 0.20 mmol) was dissolved in DCM (6 mL). TBHP
(5.5M in decane, 110 mL, 0.60 mmol) was added to the solu-
tion at 08C. Then the reaction mixture was allowed to warm
to room temperature and stirred for 45 min. The reaction
was treated with saturated aqueous Na2S2O3. The layers
were separated, the organic layer was dried over MgSO4
and concentrated under vacuum. The crude mixture was pu-
rified by chromatography on silica gel (heptane/EtOAc 7:3,
Rf =0.2) to afford a mixture of 6a,a’ as an orange solid;
yield: 140 mg (98%). The mixture was separated by semi-
preparative HPLC, with heptane./toluene/THF 35:70:5. Re-
tention times: 6a, 21 min; 6a’, 24 min.
General Methods
Semipreparative HPLC was carried out on an SiO2 column
(250ꢄ10 mm, 5 mic). 31P NMR have been recorded at
202 MHz. Phosphoric acid (À)-7e (Ar=9-phenanthryl) has
been prepared according to Scheme 2b. Quinolines 10b–f[32]
and 10g[33] have been prepared according to reported meth-
ods.
Synthesis of (S)-(2-Cyano-1-phenylethyl) N,N,N’,N’-
Tetraisopropylphosphorodiamidite (S)-8b
6a: 31P NMR (CDCl3): d=À15; 1H NMR (500 MHz,
CDCl3): d=7.54 (m, 2H), 7.5–7.4 (m, 7H), 7.40 (t, J=
7.3 Hz, 1H), 7.3 (m, 3H), 7.14 (m, 2H), 6.98 (bs, 2H), 6.86
(d, J=8.6 Hz, 1H), 6.34 (dd, J=8.6, 2.3 Hz, 1H), 6.27 (dd,
(S)-2-Cyano-1-phenylethanol[34] (3.90 g, 26.5 mmol) was dis-
solved in dry diethyl ether (50 mL), treated with anhydrous
triethylamine (4.06 mL, 29.2 mmol) and cooled to 08C. A
solution of bis(diisopropylamino)chlorophosphine (7.50 g,
26.5 mmol) in dry ether (30 mL) was added dropwise, the
mixture was allowed to warm to room temperature and
stirred overnight. The white solid was filtered off, the solu-
tion was evaporated under reduced pressure. The final prod-
uct was purified by filtration on a short silica gel column
with heptane/ethyl acetate/Et3N 70:29:1 as the eluent to fur-
nish (S)-8b as a white solid. 31P NMR (CDCl3): d=114;
1H NMR (500 MHz, CDCl3): d=7.41 (d, J=7.8 Hz, 2H),
7.36 (t, J=7.8 Hz, 2H), 7.31 (t, J=7.8 Hz, 1H), 4.85 (dt, J=
11.4, 6 Hz, 1H), 3.6 (m, 2H), 3.5 (m, 2H), 2.85 (ddd, J=
16.3, 6.2 Hz, 1H), 2.78 (dd, J=16.3, 5.0 Hz, 1H), 1.27 (d, J=
6.8 Hz, 6H), 1.19 (d, J=6.8 Hz, 6H), 1.14 (d, J=6.8 Hz,
6H), 1.03 (d, J=6.8 Hz, 6H); 13C NMR (75.5 MHz, CDCl3):
d=141.1 (C), 128.5 (CH), 128.3 (CH), 126.2 (CH), 117.3
(CN), 71.3 (d, J=18.6 Hz, CH), 45.2 (d, J=13.1 Hz, CH),
44.8 (d, J=13.1 Hz, CH), 28.6 (d, J=4.4 Hz, CH2), 24.7
(CH3), 24.6 (CH3), 24.5 (CH3), 24.4 (CH3), 24.3 (CH3); HR-
MS (ESI): m/z=396.2809, calcd. for C21H36N3OP [M+
H2O+H]+: 396.2780; [a]D20: +60 (c=1, CHCl3).
J=8.3, 2.3 Hz, 1H), 6.17 (d, J=8.3 Hz, 1H), 5.32 (dt, JH,P
=
6.9, J=6.2 Hz, 1H), 4.62 (s, 1H), 4.59 (s, 1H), 4.53 (s, 1H),
4.48 (s, 1H), 4.40 (s, 2H), 4.37 (s, 2H), 2.83 (d, J=6.2 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=146.8 (d, J=6.4 Hz,
C), 145.9 (d, J=8.6 Hz, C), 137.2 (C), 136.5 (C), 133.9 (C),
132.4 (d, J=7.5 Hz, C), 131.3 (C), 130.5 (C), 129.6 (CH),
129.2 (CH), 129.0 (CH), 128.9 (CH), 128.8 (CH), 128.3
(CH), 128.1 (CH), 127.9 (CH), 127.2 (CH), 126.2 (CH),
125.6 (CH), 122.4 (CH), 120.1 (CH), 115.5 (CN), 85.8 (C),
76.6 (d, J=6.6 Hz, CH), 69.9 (CH), 69.8 (CH), 69.3 (CH),
66.6 (CH), 66.5 (CH), 65.6 (CH), 65.4 (CH), 27.6 (d, J=
8.8 Hz, CH2). IR: nmax =3031, 3057, 2961, 2925, 1732, 1599,
1574, 1512, 1495, 1457, 1412, 1303, 1261, 1211, 1055, 1036,
1022, 930 cmÀ1; HR-MS (ESI): m/z=714.1487, calcd. for
C43H33FeNO4P [M+H]+: 714.1497; [a]2D0: +877 (c=1,
CHCl3).
6a’: 31P NMR (CDCl3): d=À15; 1H NMR (300 MHz,
CDCl3): d=7.6–7.3 (m, 13H), 7.3–7.2 (m, 3H), 6.99 (bs,
2H), 6.62 (d, J=8.5 Hz, 1H), 6.34 (d, J=8.5 Hz, 1H), 6.26
(dd, J=8.5, 1.5 Hz, 1H), 6.22 (dd, J=8.5, 1.7 Hz, 1H), 5.50
(m, 1H), 4.61 (bs, 2H), 4.50 (bs, 2H), 4.40 (bs, 2H), 4.38 (bs,
2H), 2.67 (dd, J=16.5, 4.8 Hz, 1H), 2.46 (dd, J=16.5,
7.4 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=146.6 (C),
146.5 (C), 137.5 (C), 136.9 (C), 136.4 (C), 133.1 (C), 132.6
(C), 131.1 (C), 130.8 (C), 129.8 (CH), 129.5 (CH), 129.3
(CH), 129.0 (CH), 128.8 (CH), 128.0 (CH), 127.7 (CH),
126.4 (CH), 125.9 (CH), 125.4 (CH), 122.0 (CH), 120.5
(CH), 115.6 (CN), 85.8 (C), 76.2 (d, J=5.4 Hz, CH), 69.9
(CH), 69.3 (CH), 66.7 (CH), 66.6 (CH), 65.6 (CH), 65.5
(CH), 26.7 (d, J=6.5 Hz, CH2). IR: nmax =3056, 3031, 2926,
2854, 1732, 1600, 1574, 1512, 1495, 1457, 1412, 1294, 1262,
1211, 1129, 1037, 1014, 973, 936, 822 cmÀ1; HR-MS (ESI):
m/z=714.1498, calcd. for C43H33FeNO4P [M+H]+: 714.1497.
[a]20: À871 (c=1, CHCl3).
Representative Procedures for the Synthesis of the
Phosphoric Acids 7: Phosphoric Acid 7a (Ar=Ph)
(a) Phosphites 5a,a’: To a solution of 1,1’-bis-(4-hydroxy-3-
phenyl-1-phenyl)ferrocene 3a[11] (261 mg, 0.50 mmol) and
1H-tetrazole (147 mg, 2.00 mmol, 4 equiv.) in anhydrous
DCM (25 mL) was added dropwise via cannula a solution of
[(S)-2-cyanoethyl-1-phenyl]
N,N,N’,N’-tetraisopropylphos-
phorodiamidite (S)-8b (226 mg, 0.60 mmol, 1.2 equiv.) in an-
hydrous DCM (5 mL). The flask was then equipped with
a reflux condenser and the mixture was heated at 408C for
3 h. The reaction was then quenched by addition of saturat-
ed aqueous NaHCO3 (20 mL) and extracted twice with
DCM (2ꢄ20 mL). The organic phase was dried over MgSO4
and the solvents were removed under reduced pressure. Pu-
rification by flash chromatography on silica gel (eluent: hep-
tane/EtOAc 9:1) gave the desired macrocyclic phosphites
5a,a’ in a 1:1 ratio, as an orange solid; yield: 146 mg (42%).
Rf =0.6 (heptane/EtOAc 7:3). 31P NMR (CDCl3): d=131.2
and 130.9; 1H NMR (500 MHz, CDCl3): d=7.60–7.25 (m,
14H), 7.14–7.08 (m, 1H), 6.92–6.80 (m, 2H), 6.61–6.53 (m,
1H), 6.44–6.15 (m, 3H), 5.46–5.32 (m, 1H), 4.54 (bs, 1H),
4.50 (bs, 3H), 4.39 (bs, 2H), 4.35 (bs, 2H), 2.81–2.60 (m,
(Dc) Phosphoric acid (R)-7a: Phosphate (R)-6a (45 mg,
0.06 mmol) was dissolved in DCM (2 mL) and DBU (19 mL,
0.12 mmol) was added at room temperature. After 30 min,
the mixture was purified by column chromatography with
a DCM/MeOH gradient (100:0 to 90:10; Rf =0.2). The
crude 6a·DBU salt was diluted in DCM (10 mL) and treated
with HCl 6N (3ꢄ10 mL). The layers were separated and the
organic layer was concentrated under vacuum to afford the
chiral phosphoric acid (R)-7a;[11] yield: 35 mg (95%). [a]D20:
3620
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Adv. Synth. Catal. 2013, 355, 3613 – 3624

Development of Chiral Phosphoric Acids based on Ferrocene-Bridged Paracyclophane Frameworks
+931 (c=1, CHCl3). The enantiomeric excess of the acids
850.2173, calcd. for C55H40FeNO3P [M+H]+: found:
was measured by HPLC on an ID column.
850.2178. The starting diol 3c has been prepared according
to path (a) in Scheme 2 (see the Supporting Information).
(b) Phosphates 6c, 6c’: Separated on a CombiFlashꢃ
system using a silica gel column. Eluents: toluene/heptane/
THF gradient from 60:30:0 to 60:30:2; Rf =0.39 for 6c and
0.34 for 6c’ (toluene/heptane/THF=6:3:1).
Phosphoric acid 7b (Ar=(5’-meta-Terphenyl)
(a) Phosphites 5b,b’: Obtained from 3b[11] as a 6:4 mixture
of isomers; yield: 39% yield; Rf =0.7 in heptane/EtOAc 7:3.
31P NMR (CDCl3): d=133 and 131; HR-MS (ESI): m/z=
1002.2784, calcd. for C67H49FeNO3P [M+H]+: 1002.2799.
(b) Phosphates 6b, 6b’: Separated on a CombiFlashꢃ
system using a silica gel column. Eluents: toluene/heptane/
THF gradient from 65:35:0 to 65:35:1.5. Rf =0.41 for 6b
(major) and 0.38/for 6b’ (toluene/heptane/THF=6:3.5:1).
6b: 31P NMR (CDCl3): d=À15; 1H NMR (300 MHz,
CDCl3): d=7.93 (bs, 1H), 7.8–7.6 (m, 13H), 7.6–7.3 (m,
12H), 7.2–7.0 (m, 8H), 6.39 (d, J=8.5 Hz, 1H), 6.33 (bs,
2H), 5.35 (m, 1H), 4.63 (s, 1H), 4.60 (s, 1H), 4.54 (s, 1H),
4.51 (s, 1H), 4.39 (s, 2H), 4.36 (s, 2H), 2.64 (dd, J=16.0,
6.0 Hz, 1H), 2.53 (dd, J=16.0, 6.0 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=147.0 (d, J=6.9 Hz, C), 145.9 (d, J=
9.5 Hz, C), 142.5 (C), 142.1 (C), 141.4 (C), 140.7 (C), 138.3
(C), 138.1 (C), 136.3 (C), 133.5 (C), 132.1 (d, J=6.5 Hz, C),
131.5 (C), 130.9 (C), 129.5 (CH), 129.3 (CH), 129.0
(CH),128.9 (CH), 128.1 (CH), 128.0 (CH), 127.7 (CH), 127.5
(CH), 127.4 (CH), 127.2 (CH), 127.1 (CH), 126.2 (CH),
126.1 (CH), 125.9 (CH), 122.5 (CH), 120.5 (CH), 115.3
(CN), 85.9 (C), 85.8 (C), 76.8 (CH), 70.0 (CH), 69.3 (CH),
6c: 31P NMR (CDCl3): d=À15; 1H NMR (500 MHz,
CDCl3): d=7.8–7.6 (m, 8H), 7.6–7.3 (m, 13H), 7.1 (m, 2H),
7.04 (bs, 2H), 6.89 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.4 Hz,
1H), 6.27 (bs, 2H), 5.47 (m, 1H), 4.66 (bs, 2H), 4.58 (bs,
1H), 4.54 (bs, 1H), 4.44 (bs, 2H), 4.42 (bs, 2H), 2.87 (d, J=
5.9 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=147.0 (d, J=
7.3 Hz, C), 146.2 (d, J=10.5 Hz, C), 141.0 (C), 140.9 (C),
140.7 (C), 140.6 (C), 136.6 (C), 136.3 (C), 136.2 (C), 133.4
(C), 131.9 (d, J=7.9 Hz, C), 132.0 (C), 131.9 (C), 130.1
(CH), 129.7 (CH), 129.2 (CH), 129.0 (CH), 128.9 (CH),
128.0 (CH), 127.9 (CH), 127.5 (CH), 127.4 (CH), 126.2
(CH), 125.9 (CH), 122.3 (CH), 120.4 (CH), 115.6 (CN), 86.5
(C), 86.4 (C), 76.7 (C), 70.1 (CH), 69.5 (CH), 66.9 (CH),
66.7 (CH), 65.8 (CH), 65.7 (CH), 27.6 (d, J=7.3 Hz, CH2).
IR: nmax =3032, 2967, 2926, 2855, 1601, 1508, 1488, 1458,
1399, 1367, 1304, 1258, 1212, 1185, 1128, 1055, 1034, 1022,
978, 934, 842, 768 cmÀ1; HR-MS (ESI): m/z=866.2188,
calcd. for C55H40FeNO4P [M+H]+: 866.2123; [a]D20: +1151
(c=0.5, CHCl3).
6c’: 31P NMR (CDCl3): d=À15; 1H NMR (500 MHz,
CDCl3): d=7.8–7.6 (m, 9H), 7.6–7.3 (m, 11H), 7.2 (m, 2H),
7.07 (bs, 2H), 6.68 (d, J=8.0 Hz, 1H), 6.43 (d, J=8.0 Hz,
1H), 6.31 (dd, J=8.0, 2.1 Hz, 1H), 6.27 (dd, J=8.0, 2.1 Hz,
1H), 5.56 (m, 1H), 4.67 (s, 2H), 4.55 (s, 2H), 4.45 (s, 2H),
4.43 (s, 2H), 2.70 (dd, J=16.5, 4.8 Hz, 1H), 2.51 (dd, J=
16.5, 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=147.2 (d,
J=9.6 Hz, C), 147.0 (d, J=10.3 Hz, C), 141.4 (C), 141.3 (C),
141.2 (C), 140.9 (C), 136.9 (C), 136.3 (C), 133.2 (d, J=
6.9 Hz, C), 132.7 (d, J=6.0 Hz, C), 131.7 (C), 131.4 (C),
130.4 (CH), 130.2 (CH), 130.1 (CH), 129.7 (CH), 129.5
(CH), 129.4 (CH), 128.4 (CH), 128.1 (CH), 128.0 (CH),
127.8 (CH), 127.7 (CH), 126.8 (CH), 126.4 (CH), 126.0
(CH), 122.6 (CH), 120.9 (CH), 116.0 (CN), 86.5 (C), 86.4
(C), 76.8 (d, J=5.5 Hz, CH), 70.5 (CH), 69.9 (CH), 67.2
(CH), 67.1 (CH), 66.1 (CH), 27.2 (d, J=7.7 Hz, CH2). IR:
nmax =3030, 2925, 2853, 1730, 1600, 1508, 1488, 1457, 1294,
67.0 (CH), 66.8 (CH), 65.7 (CH), 65.5 (CH), 27.2 (d, JP, C
=
7.2 Hz, CH2); IR : nmax =3058, 2955, 2924, 2854, 1716, 1684,
1595, 1512, 1498, 1455, 1414, 1302, 1267, 1231, 1205, 1183,
1136, 1078, 1035, 934, 877 cmÀ1; HR-MS (ESI): m/z=
1018.2766, calcd. for C67H49FeNO4P [M+H]+: 1018.2749;
[a]2D0: +918 (c=1, CHCl3).
6b’: 31P NMR (CDCl3): d=À15; 1H NMR (300 MHz,
CDCl3): d=8.08 (bs, 1H), 7.9–7.7 (m, 13H), 7.7–7.4 (m,
12H), 7.3–7.2 (m, 7H), 6.88 (d, J=8.5 Hz, 1H), 6.46 (d, J=
8.5 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.34 (d, J=8.5 Hz,
1H), 5.69 (m, 1H), 4.73 (s, 1H), 4.71 (s, 1H), 4.61 (s, 1H),
4.59 (s, 1H), 4.50 (s, 2H), 4.48 (s, 2H), 2.80 (dd, J=16.5,
4.7 Hz, 1H), 2.52 (dd, J=16.5, 8.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=146.8 (d, J=9.9 Hz, C), 146.6 (d, J=
9.7 Hz, C), 142.6 (C), 142.4 (C), 141.3 (C), 140.7 (C), 138.5
(C), 137.8 (C), 136.0 (d, J=4.8 Hz, C), 132.7 (d, J=6.7 Hz,
C), 132.4 (d, J=4.6 Hz, C), 131.5 (C), 131.0 (C), 129.8 (CH),
129.4 (CH), 129.1 (CH), 128.2 (CH), 127.8 (CH), 127.7
(CH), 127.5 (CH), 127.1 (CH), 126.5 (CH), 126.2 (CH),
126.1 (CH), 125.7 (CH), 122.3 (CH), 120.4 (CH), 115.2
(CN), 85.7 (C), 85.6 (C), 76.2 (d, J=4.9 Hz, CH), 70.0 (CH),
69.4 (CH), 66.9 (CH), 66.7 (CH), 65.6 (CH), 26.3 (d, J=
5.6 Hz, CH2); IR: nmax =3035, 2926, 2855, 1595, 1513, 1456,
1414, 1297, 1232, 1206, 1036, 1009, 966, 937, 877 cmÀ1; HR-
MS (ESI): m/z=1018.2745, calcd. for C67H49FeNO4P [M+
H]+: 1018.2749; [a]20: À710 (c=1, CHCl3).
1254, 1211, 1184, 1130, 1034, 1007, 971, 934, 840, 820 cmÀ1
;
HR-MS (ESI): m/z=866.2147, calcd. for C55H40FeNO4P
[M+H]+: 866.2123; [a]D20: À1138 (c=0.5, CHCl3).
An S-planar configuration has been assigned to com-
pound 6c’ by X-ray diffraction studies: CCDC 951975 con-
tains the corresponding crystallographic data. These data
can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(c) Phosphoric Dacid (R)-7b: Obtained from (R)-6b
(81 mg); yield: 53 mg (67%). 31P (DMSO-d6): d À12; [a]D:
+775 (c=1, CH2Cl2); HPLC: ID column, THF/heptane/
TFA/Et3N 60:40:0.5:0.3.
(c) Phosphoric acid (R)-7c: Obtained from (R)-6c
(25mg); yield: 7 mg (33%). 31P NMR (DMSO-d6): d=À12;
1H NMR (600 MHz DMSO-d6): d=7.78 (d, J=8.0 Hz, 4H),
7.77 (d, J=7.3 Hz, 4H), 7.69 (d, J=8.0 Hz, 4H), 7.51 (t, J=
7.3 Hz, 4H), 7.40 (t, J=7.3 Hz, 2H), 7.09 (bs, 2H), 6.62 (d,
J=8.5 Hz, 2H), 6.50 (d, J=8.5 Hz, 2H), 4.86 (s, 2H), 4.74
(s, 2H), 4.45 (s, 2H), 4.41 (s, 2H); 13C NMR (150.7 MHz,
DMSO-d6): d=146.8 (d, JP, C =5.6 Hz, C), 139.9 (C), 138.7
(C), 137.0 (C), 131.6 (d, JP, C =5.2 Hz, C), 129.8 (CH), 129.5
(C), 129.0 (CH), 127.5 (CH), 127.1 (CH), 126.7 (CH), 126.5
Phosphoric Acid 7c (Ar=para-Biphenyl)
(a) Phosphites 5c,c’: Obtained from 3c[11] as a 1:1 mixture of
isomers; yield: 44%; Rf =0.5 in heptane/EtOAc 7:3.
31P NMR (CDCl3): d=132 and 131; HRMS (ESI): m/z=
Adv. Synth. Catal. 2013, 355, 3613 – 3624
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asc.wiley-vch.de
3621

Jꢀrꢀmy Stemper et al.
FULL PAPERS
(CH), 126.0 (CH), 121.2 (CH), 86.0 (C), 69.3 (CH), 68.7
(CH), 66.6 (CH), 65.5 (CH); IR: nmax =3029, 2923, 2852,
1600, 1507, 1488, 1457, 1398, 1379, 1259, 1216, 1190, 1089,
1017, 1007, 911, 838 cmÀ1; HR-MS (ESI): m/z=736.1485,
calcd. for C46H33FeO4P: 736.1466; [a]2D0: +966 (c=0.7,
CHCl3).
General Procedure for the Synthesis of the Hantzsch
Esters 9d–f[27]
Paraformaldehyde (1 equiv.), ammonium acetate (2 equiv.),
and the desired acetoacetate MeCOCH2CO2R (2 equiv.)
were refluxed under argon for 2 h under strong agitation.
After cooling, the product was recrystallized from ethanol.
9d is a known product.[27]
Bis-(4-methoxybenzyl) 2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (9e): H NMR (500 MHz, DMSO-d6): d=
Phosphoric Acid 7d [Ar=3,5-Bis(trifluoromethyl)-
phenyl]
1
8.37 (bs, 1H), 7.27 (d, J=8.5 Hz, 4H), 6.90 (d, J=8.5 Hz,
4H), 5.01 (s, 4H), 3.75 (s, 6H), 3.16 (s, 2H), 2.11 (s, 6H).
Bis-(4-benzyloxybenzyl) 2,6-dimethyl-1,4-dihydropyridine-
(a) Phosphites 5d,d’: Obtained from 3d[11] as a 7:3 mixture
of isomers; yield: 20%; Rf =0.7 in heptane/EtOAc 7:3.
31P NMR (CDCl3): d=136 and 133; HR-MS (ESI): m/z=
970.1098, calcd. for C47H28F12FeNO3P [M+H]+: 970.1043.
The starting diol 3d has been prepared according to path (b)
in Scheme 2 (see the Supporting Information).
1
3,5-dicarboxylate (9f): H NMR (300 MHz, DMSO-d6): d=
8.38 (bs, 1H), 7.44–7.29 (m, 14H), 6.98 (d, J=8.4 Hz, 4H),
5.09 (s, 4H), 5.01 (s, 4H), 3.75 (s, 6H), 3.16 (s, 2H), 2.11 (s,
6H); 13C NMR (75 MHz, DMSO-d6): d=166.9 (CO), 158.0
(C), 147.0 (C), 137.0 (C), 129.4 (CH), 129.1 (C), 128.4 (CH),
127.8 (CH), 127.6 (CH) 114.6 (CH), 96.9 (C), 69.2 (CH2),
64.4 (CH2), 24.7 (CH2), 18.0 (CH3); HR-MS (ESI): m/z=
590.2524, calcd. for C37H36NO6 [M+H]+: 590.2543.
(b) Phosphates 6d, 6d’: Separated on a CombiFlashꢃ
system using a silica gel column, eluents: toluene/heptane/
THF gradient from 70:30:0 to 70:30:1; Rf =0.38 for 6d
(major) and 0.34 for 6d’ (toluene/heptane/THF=7:3:1).
6d: 31P NMR (CDCl3): d=À12; 19F NMR (282.4 MHz,
1
CDCl3): d=À62.5 and À62.6; H NMR (500 MHz, CDCl3):
Representative Procedure for the Catalytic Reduction
of a-Arylquinolines
d=8.02 (s, 1H), 7.98 (s, 3H), 7.96 (s, 2H), 7.41 (m, 3H),
7.24 (m, 2H), 7.01 (bs, 2H), 6.94 (d, J=8.7 Hz, 1H), 6.46 (d,
J=8.7 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 6.23 (d, J=8.53 Hz,
1H), 5.56 (q, J=6.5 Hz, 1H), 4.67 (s, 1H), 4.66 (s, 1H), 4.64
(s, 1H), 4.57 (s, 1H), 4.51 (s, 2H), 4.47 (s, 1H), 2.96 (d, J=
6.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=146.6 (d,
A solution of 2-phenylquinoline 10a (11 mg, 0.05 mmol),
Hantzsch dihydropyridine 9a (0.12 mmol) and the acid cata-
lyst 7a (0.005 mmol) in toluene (1 mL) was stirred at room
temperature for 2 h. The solvent was removed under re-
duced pressure and the residue was purified on silica gel
with toluene as the eluent.
J
P, C =5.6 Hz, C), 145.2 (d, JP, C =8.7 Hz, C), 139.4 (C), 138.8
(C), 136.1 (C), 136.0 (C), 132.3 (q, JF,C =33.9 Hz, C), 132.7
(C), 132.0 (q, JF,C =33.6 Hz, C), 131.6 (C), 131.2 (C), 129.9
(CH), 129.3 (CH), 129.2 (CH), 127.5 (CH), 127.3 (CH),
2-Phenyl-1,2,3,4-tetrahydroquinoline (11a): Obtained as
a colorless oil. The ees were determined by HPLC using
a CHIRALPAKꢃ IB column, eluent: i-PrOH/n-heptane
5:95, at a flow rate of 1 mLminÀ1 [detection at 275 nm]: re-
tention times of 6.7 min for (À)-(S)-11a and 8.2 min
(+)-(R)-11a; {Lit.[23] (S)-11a: [a]D20: À35.7 (c=0.8, CHCl3)}.
127.2 (CH), 127.0 (CH), 125.7 (CH), 123.6 (q, JF,C
=
273.0 Hz, CF3), 123.5 (q, JF,C =273.0 Hz, CF3), 123.3 (CH),
121.8 (CH), 120.0 (CH), 115.1 (CN), 85.3 (C), 85.2 (C), 77.0
(d, JP, C =3.9 Hz, C), 70.4 (CH), 69.7 (CH), 67.4 (CH), 67.1
(CH), 65.7 (CH), 65.5 (CH), 27.5 (d, JP, C =7.7 Hz, CH2); IR:
nmax =3089, 2929, 1723, 1621, 1604, 1514, 1457, 1414, 1373,
1277, 1179, 1130, 1052, 1037, 1016, 931, 900 cmÀ1; HR-MS
(ESI): m/z=986.1035, calcd. for C47H28F12FeNO4P [M+H]+:
986.0992. [a]2D0: +722 (c=1, CHCl3).
2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline
(11b):
CHIRALPAKꢃ IB, eluent: i-PrOH/n-heptane, 5:95 at
a flow rate of 1 mLminÀ1 [detection at 250 nm]: retention
times of 7.7 min [(À)-(S)-11b] and 17.9 min [(+)-(R)-11b];
{Lit.[23] (S)-11b: [a]20: À26.1 (c=1, CHCl3), 86% ee}.
6d’: 31P NMR (CDCl3): d=À12.2; 19F NMR (282.4 MHz,
CDCl3): d=À62.57 and À62.53; 1H NMR (300 MHz,
CDCl3): d=8.01 (s, 2H), 7.98 (s, 1H), 7.88 (s, 1H), 7.80 (s,
2H), 7.43–7.38 (m, 3H), 7.35–7.30 (m, 2H), 7.02 (s, 1H),
6.96 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.43 (d, J=8.7 Hz,
1H), 6.29 (d, J=8.8 Hz, 1H), 6.21 (d, J=8.8 Hz, 1H), 5.67
(q, J=6.6 Hz, 1H), 4.65 (s, 1H), 4.61 (s, 2H), 4.52 (s, 1H),
4.47 (s, 2H), 4.44 (s, 2H), 2.94 (dd, J=16.7, 6.2 Hz, 1H),
2.84 (dd, J=16.7, 6.2 Hz, 1H): 13C NMR (75.5 MHz,
CDCl3): d=146.6 (d, JP, C =5.6 Hz, C), 145.4 (d, JP, C =8.7 Hz,
C), 139.3 (C), 138.8 (C), 136.1 (C), 136.0 (C), 132.7 (C),
132.3 (q, JF,C =33.3 Hz, C), 132.0 (q, JF,C =33.3 Hz, C), 131.7
(C), 131.2 (C), 131.1 (C), 130.1 (CH), 129.4 (CH), 129.3
(CH), 129.2 (CH), 129.1 (CH), 127.7 (CH), 127.2 (CH),
127.0 (CH), 126.1 (CH), 125.3 (C), 123.1 (CH), 121.8 (CH),
121.7 (CH), 120.2 (CH), 115.1 (CN), 85.3 (C), 85.2 (C), 76.7
(d, JP, C =3.3 Hz, C), 70.5 (CH), 70.4 (CH), 69.8 (CH), 67.3
2-(2-Naphthyl)-1D,2,3,4-tetrahydroquinoline (11c): CHIR-
ALPAKꢃ IB, eluent: i-PrOH/n-heptane, 5:95 at a flow rate
of 1 mLminÀ1 [detection at 250 nm]: retention times of
9.6 min [(À)-(S)-11c] and 15.5 min [(+)-(R)-11c]; {Lit.[23]
(S)-11c: [a]2D0: À27.5 (c=1, CHCl3), 91% ee].
2-(para-Biphenyl)-1,2,3,4-tetrahydroquinoline
(11d):
CHIRALPAKꢃ IB, eluent: i-PrOH/n-heptane, 5:95 at
a flow rate of 1 mLminÀ1 [detection at 250 nm]: retention
times of 9.4 min [(À)-(S)-11d] and 17.9 min [(+)-(R)-11d];
{Lit.[21a] (S)-11d: [a]20: À13.8 (c=1, CHCl3), >99% ee}.
2-[3,5-Bis(trifluorDomethyl)phenyl]-1,2,3,4-tetrahydroqui-
noline (11e): CHIRALPAKꢃ IB, eluent: i-PrOH/n-heptane,
5:95 at a flow rate of 1 mLminÀ1 [detection at 250 nm]: re-
tention times of 8.4 min [(À)-11e] and 17.2 min [(+)-11e].
2-(1-Naphthyl)-1,2,3,4-tetrahydroquinoline (11f): CHIR-
ALPAKꢃ IB, Eluent: i-PrOH/n-heptane, 5:95 at a flow rate
of 1 mLminÀ1 [detection at 250 nm]: retention times of
10.7 min [(À)-(S)-11f] and 18.1 min [(+)-(R)-11f]; {Lit.[28]
(R)-11c: [a]2D0: +117 (c=1, CHCl3), 88% ee}.
(CH), 67.1 (CH), 65.7 (CH), 65.6 (CH), 27.0 (d, JP, C
=
6.3 Hz, CH2); IR: nmax =3089, 2931, 1719, 1620, 1604, 1514,
1457, 1413, 1373, 1277, 1180, 1130, 1051, 1037, 1015, 934,
900 cmÀ1; [a]2D0: À737 (c=1, CHCl3).
2-(1-Cyclohexyl)-1,2,3,4-tetrahydroquinoline
CHIRALPAKꢃ IC, eluent: i-PrOH/n-heptane, 2:98 at
(11g):[21b]
3622
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3613 – 3624

Development of Chiral Phosphoric Acids based on Ferrocene-Bridged Paracyclophane Frameworks
a flow rate of 1 mLminÀ1 [detection at 250 nm]: retention
times of 4.4 min [(+)-(S)-11g] and 4.7 min [(À)-(R)-11g];
{Lit.[29] (S)-11g: [a]2D0: +48.3 (c=0.1, CHCl3), 96% ee}.
Fu, J. Am. Chem. Soc. 2012, 134, 15149–15153. Phane-
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Tsou, R. P. Volante, P. J. Reider, J. Am. Chem. Soc.
1997, 119, 6207–6208. Paracyclophane-based NHCs:
d) Y. Ma, C. Song, C. Ma, Z. Sun, Q. Chai, M. B.
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Chem. Int. Ed. 2003, 42, 5871–5874. Josiphos and analo-
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Acknowledgements
This work was supported by the Paris-Sud University, the
ICSN, the Agence Nationale de la Recherche (ANR Blanc
SIMI7 2011, project “Chiracid”) and the COST ORCA
action CM0905. This work was granted access to the HPC re-
sources of CINES under allocation x2013086894 made by
GENCI (Grand Equipment National de Calcul Intensif.
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