Structures of the reactive intermediates in organocatalysis with diarylprolinol ethers

Article abstract of DOI:10.1002/hlca.200900179

Structures of the reactive intermediates (enamines and iminium ions) of organocatalysis with diarylprolinol derivatives have been determined. To this end, diarylprolinol methyl and silyl ethers, 1, and aldehydes, Ph-CH ₂-CHO, ^tBu-CH<

Full text of DOI:10.1002/hlca.200900179

Helvetica Chimica Acta – Vol. 92 (2009)
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Structures of the Reactive Intermediates in Organocatalysis with
Diarylprolinol Ethers
by Urosˇ Grosˇelj1), Dieter Seebach*, D. Michael Badine2), W. Bernd Schweizer, and Albert K. Beck
Laboratorium fꢀr Organische Chemie, Departement fꢀr Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, Hçnggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(phone: þ 41-44-632-2990; fax: þ 41-44-632-1144; e-mail: seebach@org.chem.ethz.ch)
and Ingo Krossing and Petra Klose
Lehrstuhl fꢀr Molekꢀl- und Koordinationschemie, Institut fꢀr Anorganische und Analytische Chemie,
Albert-Ludwigs Universitꢁt Freiburg, Albertstrasse 21, D-79104 Freiburg i. Br.
(phone: þ 49-761-203-6122; e-mail: krossing@uni-freiburg.de)
and Yujiro Hayashi
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science,
1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan (phone: þ 81-3-5228-8318;
e-mail: hayashi@ci.kagu.tus.ac.jp)
and Tadafumi Uchimaru*
Research Institute for Computational Sciences, National Institute of Advanced Industrial Science and
Technology (AIST), Tsukuba, Ibaraki 305-8568, Japan (phone: þ 81-29-861-4800;
e-mail: t-uchimaru@aist.go.jp)
Structures of the reactive intermediates (enamines and iminium ions) of organocatalysis with
diarylprolinol derivatives have been determined. To this end, diarylprolinol methyl and silyl ethers, 1, and
t
aldehydes, PhꢀCH2ꢀCHO, BuꢀCH2ꢀCHO, PhꢀCH ¼ CHꢀCHO, are condensed to the correspond-
ing enamines, A and 3 (Scheme 2), and cinnamoylidene iminium salts, B and 4 (Scheme 3). These are
isolated and fully characterized by melting/decomposition points, [a]D, elemental analysis, IR and NMR
spectroscopy, and high-resolution mass spectrometry (HR-MS). Salts with BF4, PF6, SbF6, and the
weakly coordinating Al[OC(CF3)3]4 anion were prepared. X-Ray crystal structures of an enamine and of
six iminium salts have been obtained and are described herein (Figs. 2 and 4 – 8, and Tables 2 and 7) and
in a previous preliminary communication (Helv. Chim. Acta 2008, 91, 1999). According to the NMR
spectra (in CDCl3, (D6)DMSO, (D6)acetone, or CD3OD; Table 1), the major isomers 4 of the iminium
salts have (E)-configuration of the exocyclic N¼C(1’) bond, but there are up to 11% of the (Z)-isomer
present in these solutions (Fig. 1). In all crystal structures, the iminium ions have (E)-configuration, and
the conformation around the exocyclic N-CꢀC-O bond is synclinal-exo (cf. C and L), with one of the
phenyl groups over the pyrrolidine ring, and the RO group over the p-system. One of the meta-
substituents (Me in 4b, CF3 in 4c and 4e) on a 3,5-disubstituted phenyl group is also located in the space
above the p-system. DFT Calculations at various levels of theory (Tables 3 – 6) confirm that the
1
ˇ
ˇ
)
On leave from Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva
5, P.O. Box 537, 1000 Ljubljana, Slovenia; financed by Slovene Human Resources Development and
Scholarship Fund (Vilharjeva 27, 1000 Ljubljana, Slovenia) and by Novartis Pharma AG, Basel.
Postdoctoral Research Fellow at ETH-Zꢀrich (2006/2007), financed by Novartis Pharma AG, Basel.
Present address: BASF SE, GCl/P-M311, D-67056 Ludwigshafen.
2
)
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢀrich

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experimentally determined structures (cf. Fig. 10) are by far (up to 8.3 kcal/mol) the most stable ones.
Implications of the results with respect to the mechanism of organocatalysis by diarylprolinol derivatives
are discussed.
1. Introduction. – In the year 2005, the field of organocatalysis experienced a boost
when several groups started to use diarylprolinol3) (¼diarylpyrrolidine-2-methanol)
ethers 1 as catalysts [4]. Since then, the formulae of enamines A and of iminium ions B,
the reactive intermediates involved in activating nucleophilic a-carbonyl positions and
electrophilic b-carbonyl positions, have been presented in dozens of publications. The
big (ꢃobeseꢄ [5]) diarylmethanol-ether substituent was assumed a) to enforce an s-trans-
conformation around the exocyclic NꢀC(1’) bond of an enamine A, b) to secure (E)-
configuration of the iminium N¼C(1’) bond in B, and c) to direct incoming reactants to
approach the p-system of A and B from the face anti to the large substituent at C(2) of
the pyrrolidine, in agreement with the experimental results. For the (S)-forms, this
corresponds to a relative topicity4) like (lk) for reactions of the enamines A (Si on
C(2’)) and of the iminium ions B with R’ ¼ Arl (Si on C(3’)). Besides some in-situ NMR
spectra5), there were no experimental structural data of the reactive intermediates A
and B available, as of July 2008. On the other hand, DFT calculations of the structures
of a diarylprolinol-derived dienamine and of an iminium ion had been published in
2006 [7].
While there are only a few enamine structures recorded in the Cambridge
Crystallographic Data Base6), there is a rich history of isolation and structure
3
)
The parent compound rac-1, Arl ¼ Ph, R ¼ H was first described 75 years ago [1], the
enantiomerically pure form 45 years ago [2]. For further references, see Footnote 16 and Scheme 1
of [3].
4
5
6
)
)
)
For the definition of relative topicities of stereoselective reactions, see [6].
See Footnote 14 in our preliminary communication [3].
See Footnote 11 in [3] and discussion in Sect. 9, with Footnote 60 in [5].

Helvetica Chimica Acta – Vol. 92 (2009)
1227
determination of iminium salts7). As discussed in a seminal work by Bçhme et al. [9],
J. von Braun and E. Rçver were probably the first to isolate dimethyl(methylidene)-
iminium bromide (ꢃdimethyl-bromomethyl amineꢄ)8) in 1903 [14]. There are numerous
protocols for preparing and isolating iminium salts. We used a modified procedure of
Leonard and Paukstelis [15]9).
2. Preparation of the Enamines 3 and of the Iminium Salts 4, and Growing of Single
Crystals. – The diarylprolinol derivatives 1a – 1e are commercially available, and the
new compounds 1f – 1i were prepared as depicted in Scheme 110). From the Grignard
reaction with the N-(ethoxycarbonyl)proline ester substantial amounts of the
Scheme 1. Preparation of the Diarylprolinol Silyl Ethers 1f – 1i and Isolation of the Oxazolidine
Derivatives 2
7
)
A search in the Cambridge Structural Data File (CSD [8]) as of March 2009 provided the following
number of structures:
8
9
)
For the relationship a-halo-amines/dialkyl-iminium halide salts, see [10]. For a monograph and a
review on a-aminoalkylations (Mannich reactions), see [11][12]. The iminium salt Me2NCH2I
(Eschenmoser salt [13]) is very stable, sublimes at 1208/10ꢀ3 Torr, and decomposes at ca. 2408.
Besides our group [3][5][16], Mayr and co-workers [17], Tompkinson and co-workers [18], and
Gilmour and co-workers [19] have recently reported isolations and structural identifications of
iminium salts of relevance to organocatalysis.
)
10
)
For a discussion and leading references about the various methods of preparing diarylprolinols, see
Scheme 1 in [3].

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oxazolidinone 2a were isolated and subsequently hydrolyzed with NaOH in MeOH.
Trace amounts of the oxazolidine 2b were also obtained after this step11).
The enamines 3a and 3b were prepared as shown in Scheme 212). Suitable single
crystals for X-ray analysis could be prepared only of the enamine 3a. For character-
ization of the enamines, see data in the Exper. Part.
Scheme 2. Preparation of the Enamines 3a and 3b by Condensation of 2-Phenylacetaldehyde or 3,3-
Dimethylbutanal with the Diphenyl Prolinol Silyl Ethers 1d and 1h, Respectively
The preparation of cinnamaldehyde-derived13) iminium salts 4 is outlined in
Scheme 3. First, the ammonium salts 1 · HX were prepared from the prolinol ethers and
HCl or HBF414). With the hydrochloride, an anion exchange could be achieved by
adding a Ag salt (cf. 1c · HCl ! 1c · HPF6). The ammonium salts were allowed to react
with cinnamaldehyde in EtOH, in the presence of catalytic amounts of Et3N. This led to
precipitation of the iminium salts 4, X ¼ BF4, PF6, which, after filtering, washing with
Et2O and drying under high vacuum, gave correct elemental analyses.
The chlorides 4, X ¼ Cl, are converted to PF6, SbF6, and Al[OC(CF3)3]4 salts by
adding the corresponding Ag salt to the EtOH solution. The salts 4c and 4e derived
from the bis[3,5-bis(trifluoromethyl)phenyl]prolinols 1c and 1e do not precipitate.
Especially the salts with the complex aluminate anion, a so-called weakly-coordinating
anion [21]15), are extremely well soluble, even in a nonpolar solvent such as Et2O16). In
these cases, analytically pure samples are obtained by removing the AgCl precipitate by
suction of the supernatant solution through an HPLC filter, stripping off the EtOH
solvent, dissolving the residue in Et2O, precipitating with heptane, washing with
hexanes, and drying under high vacuum.
Single crystals were produced by the so-called diffusion method or by slow solvent
evaporation. Thus, vials with solutions of the salts, for instance, in THF/heptane, were
put in a sealed container, together with a reservoir of Et2O/petroleum ether (b.p. 30 –
11
)
It is not clear to us how the aromatic Grignard reagent could have caused the reduction to 2b;
maybe MeONa functioned as a hydride source in step 3.
For the setup with a molecular-sieve bag in the gas phase, see [20].
12
13
)
)
All attempts with unsaturated aliphatic aldehydes, such as crotonaldehyde, failed to produce
crystalline iminium salts of this type, which would have been suitable for crystal structure analysis.
In the salt-forming process with HBF4 and prolinol silyl ethers, up to 35% loss of the silyl group was
observed, which complicated the subsequent step of iminium-salt formation and isolation.
Positively charged counter-ions do not abstract a small anion ((CF3)3COꢀ) from the complex
aluminate anion Al[OC(CF3)3]4ꢀ, a process which can happen with BFꢀ4 , PF6ꢀ, or SbFꢀ6 anions by
transfer of Fꢀ.
14
15
)
)
)
On the other hand, these Al[OC(CF3)3]ꢀ4 salts have much higher melting/decomposition points than
the corresponding BF4ꢀ, PF6ꢀ, or SbFꢀ6 salts (see Exper. Part).
16

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Scheme 3. Preparation of the Ammonium Salts 1 · HX and of the Iminium Salts 4. The structure of the
ammonium salt 1a · HBF4 and of the iminium salt 4h, X ¼ BF4, have been published in [3].
508). One of the crystals which had grown on the wall of one of the vials was picked and
transferred to the X-ray diffractometer.
3. NMR Spectra of the Iminium Salts 4. – Selected NMR data are collected in
Table 1. Besides the signals from the iminium salts 4 of (E)-configuration around the
N¼C bond (cf. the crystal structures), the NMR spectra of the analytically pure
samples contain a set of signals that must arise from an isomer to which we assign the
(Z)-configuration ((Z)-4). The amount of this ꢃimpurityꢄ can be as high as 8% (see
Fig. 1; Table 1 contains only data of the major isomers 4). There are two noticeable
features of the chemical shift data in Table 1: i) The H-atoms at C(2) of the pyrrolidine
ring, and HꢀC(1’,2’,3’) in the iminium side chain of the bis(trifluoromethyl)phenyl-
substituted compounds 4c and 4e resonate at lower field (by up to 0.8 ppm) than those
of the other four compounds (4b, 4d, 4h, and 4i); comparison of spectra obtained with

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1
Table 1. Selected H-NMR Data of the Iminium Salts 4. The spectra were recorded on different NMR
instruments. Multiplicities and coupling constants could not be determined in the case of the starred (*)
signals because of overlap with signals from other H-atoms. 1H-NMR Chemical shifts of the overlapping
signals were extracted from the corresponding 2D-HSQC spectra recorded in the same solvent on the
same instrument. For NMR spectra of in situ observed iminium salts of type 4, see [4a][22]. For an NMR
and a high-resolution mass spectrum of 4d, X ¼ OSO2CF3, see supplementary material of [17a]; the
NMR spectra of this salt with BF4 and triflate anions are more or less identical.
Chemical shifts d [ppm], multiplicities, and coupling constants J [Hz]
Iminium salt
Solvent
CDCl3
HꢀC(2)
5.46 (d,
J ¼ 7.4)
HꢀC(1’) HꢀC(2’)
8.53 (d, 7.00 (dd,
J ¼ 10.6) J ¼ 10.7, 15.2)
HꢀC(3’)
ca. 7.70*
4d
(X-ray)
4h
(X-ray)
(D6)DMSO 5.61 (d,
J ¼ 8.2)
8.40 (d,
J ¼ 10.5)
ca. 7.14*
6.85 (d,
J ¼ 15.2)
4i
CDCl3
5.53 (d,
J ¼ 7.6)
8.33 (d,
6.88 (dd,
6.49 (d,
J ¼ 10.3) J ¼ 10.6, 15.0) J ¼ 15.1)
4b
CDCl3
5.27 (dd,
8.58 (d,
7.04 (dd,
8.00 (d,
(X-ray)
J ¼ 3.1, 8.9) J ¼ 10.5) J ¼ 10.5, 15.3) J ¼ 15.2)
4b
CDCl3
5.24 (dd,
8.51 (d,
6.93 (dd,
7.91 (d,
(X-ray)
J ¼ 3.7, 9.2) J ¼ 10.6) J ¼ 10.7, 15.2) J ¼ 15.2)

Helvetica Chimica Acta – Vol. 92 (2009)
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Table 1 (cont.)
Chemical shifts d [ppm], multiplicities, and coupling constants J [Hz]
Iminium salt Solvent HꢀC(1’) HꢀC(2’)
HꢀC(2)
(D6)DMSO 5.99 (dd, 8.91 (d, 7.46 (dd,
HꢀC(3’)
8.51 (d,
4c
(X-ray)
J ¼ 3.6, 9.0) J ¼ 10.4) J ¼ 10.5, 15.1) J ¼ 15.0)
4e
4e
(D6)Acetone 6.02 (dd,
9.05 (d,
ca. 7.59*
ca. 7.61*
ca. 7.65*
ca. 8.30*
J ¼ 3.1, 9.4) J ¼ 10.7)
(D6)Acetone 6.04 (dd,
9.07 (d,
ca. 8.31*
J ¼ 2.6, 9.1) J ¼ 10.7)
4e
(X-ray)
(D6)Acetone 6.11 (d,
J ¼ 6.6)
9.14 (d,
J ¼ 10.7)
8.34 (d,
J ¼ 15.2)
CDCl3, (D6)DMSO, and (D6)acetone solutions would suggest that this is not just a
solvent or counterion effect. ii) In the case of 4h and 4i, the signals from HꢀC(3’), the
C-atom of nucleophilic attack on such iminium ions, are shifted to higher fields (by up
to 2 ppm) as compared to those of the other salts 4; this effect is compatible with the X-
ray crystal structure of 4h, X ¼ BF4 [3], where the HꢀC(3’) resides in the shielding
cone of one of the Si-bound phenyl groups (Fig. 2).
4. Crystal Structures of the Ammonium Salt 1b · HBF4, of the Enamine 3a, and of
Five Iminium Salts 4. – The crystal structure of the ammonium salt 1b · HBF4 (Fig. 3),
precursor to the iminium salts 4, X ¼ BF4 and PF6, is shown in Fig. 3. While essentially
all known diarylprolinols 1, R ¼ H, have a sc(synclinal)-endo-conformation D around

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1
Fig. 1. Section of the H-NMR spectrum of the iminium salt 4e, X ¼ PF6, in (D6)acetone. The doublet
signal at 8.96 ppm, the doublet of doublet signal at 6.49 ppm, and the multiplet signal at 4.22 ppm are
assigned to the isomer of (Z)-configuration of the N¼C bond. A nuclear-Overhauser-effect was
observed between HꢀC(2) and HꢀC(1’), and between HꢀC(5) and HꢀC(2’) in 4e, and between
HꢀC(5) and HꢀC(1’) in (Z)-4e.
the exocyclic ethane bond17), all eight diarylprolinol ether derivatives, of which we
have determined crystal structures18), have a sc-exo-conformation C around this bond,
and so has the ammonium salt 1b · HBF4. The antiperiplanar (ap) conformation E has
17
)
)
See the result of a search in the Cambridge Structural Data File (CSD) as of May 2008 [3].
This work and [3].
18

Helvetica Chimica Acta – Vol. 92 (2009)
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Fig. 2. Space-filling model of the X-ray crystal structure of iminium salt 4h, X ¼ BF4. Cf. Fig. 2 in [3] and
the accompanying discussion. The shielding of HꢀC(3’) (green label) in the NMR spectrum of this salt
(Table 1) is compatible with the assumption that the conformation seen in the crystal is also populated in
(D6)DMSO solution.
Fig. 3. Crystal structure of the ammonium salt 1b · HBF4. The exocyclic CHꢀC bond has sc-exo-
conformation.

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been found only in hydrazones derived from N-amino-diphenylprolinol methyl ethers
[23]19).
The crystal structure of enamine 3a has been discussed in our previous work [3].
From a view at the face of the plane containing the PhꢀCH¼CHꢀN moiety of the
molecule (see F), it is apparent that a Me group of Me3Si and one of the phenyl groups
cause massive shielding of the enamine N¼C bond Re-face, while the Si-face is wide
open for electrophilic attack (see G)20).
The crystal structures of the iminium salts 4d, X ¼ BF4, 4b, X ¼ BF4 and PF6, 4c and
4e, X ¼ Al[OC(CF3)3]4, are shown in Figs. 4 – 7, and some selected structural data are
listed in Table 2 (for more details, see Table 7 in the Exper. Part). The iminium N-atoms
are slightly pyramidalized (0.02 – 0.04 ꢅ) towards the large substituent, the conforma-
tion of the pyrrolidine ring is such that the C(1’)¼NꢀC(2)ꢀC(2’’) torsion angle
becomes ꢃas large as possibleꢄ (ꢀ 73 to ꢀ 798), there is a slight distortion of the C¼N
bond (C(2’)ꢀC(1’)¼NꢀC(2): 174 – 1798)21). As mentioned above, the exocyclic CꢀC
bond has sc-exo conformation, with the R group (Me or R3Si) at the O-atom pointing
up and away (torsion angles C(2)ꢀC(2’’)ꢀOꢀR: 85 – 1708). These structural features
may be considered as the result of repulsion minimization between the two substituents
at N(1) and C(2) of the pyrrolidine ring. One of the aryl groups (the ArlRe in an (S)-
diarylprolinol, where it causes especially strong steric shielding in the enamine
intermediate) and the RO group are located above one face of the p-system.
Of special interest are the diarylprolinol derivatives with meta-substituted phenyl
groups, 3,5-(H3C)2C6H3 (Fig. 5) and 3,5-(F3C)2C6H3 (Figs. 6 and 7). Clearly, one of the
meta-substituents and (in the case of the trimethylsilyl ether) one of the Me groups at
19
)
If we could consider the nitrogen of the hydrazone a s-donor and the oxygen of the MeO group a s-
acceptor, a s ! s* interaction would be at work to stabilize the ap conformation E in these
derivatives; see entries 21 and 22 in Table 1 of [3].
20
21
)
)
Cf. Fig. 1 in [3] and the discussion in Sect. 2.1. of that work, and compare with the presentations of
three iminium salts in Fig. 8, below.
This is hardly caused by intramolecular forces, as the two extreme values are observed in the two
symmetry-independent molecules of the 4d crystal structure.

Helvetica Chimica Acta – Vol. 92 (2009)
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Fig. 4. Crystal structure of the iminium salt 4d, X ¼ BF4. The asymmetric unit contains two somewhat
different conformations of the cation. As can be seen from the overlay, in which the five-membered ring
and the p-system are superimposed as closely as possible, the torsion angle around the exocyclic CꢀC
bond differs by a few degrees in these two conformations.
the Si-atom are the major contributors to steric shielding of the iminium p-face
Si(C(1’))/Re(C(2’))/Re(C(3’)) (Fig. 8). The superior performance of the organocatalyst
1e with geminal 3,5-(F3C)2C6H3 groups is thus understandable, and it would appear
reasonable to suggest that the CF3 groups (volume of the hemisphere ca. 43 ꢅ3) [24] are

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Fig. 5. Crystal structures of the BF4 and PF6 salts of 4b. The crystal structures have the same spacegroup
P1 with very similar cell dimensions and are almost superimposable.
primarily acting as ꢃbigꢄ methyl groups (volume of the hemisphere ca. 17 ꢅ3), and that
electronic or ꢃlipophilicꢄ effects of the CF3 groups are of less importance22).
The role of the Al[OC(CF3)3]4 anion in the salts 4c and 4e warrants comments:
when going from 4e, X ¼ PF6 or SbF6, to 4e, X ¼ Al[OC(CF3)3]4, there is a jump
of the melting point by ca. 1008; while we could not prepare single crystals of
the phosphate and antimonate salts of 4c and 4e (carrying meta-CF3-substituents
on the phenyl groups), the aluminate salts gave nice crystals in the first attempt. Large
22
)
See, however, the low-field shifts observed in the NMR spectra of the CF3-substituted iminium salts
(Table 1 and Sect. 3, i, above).

Helvetica Chimica Acta – Vol. 92 (2009)
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Fig. 6. X-Ray crystal structure of the bis(trifluoromethyl)phenyl derivative 4c, X ¼ Al[OC(CF3)3]4. The
counter-anion is almost as large as the iminium ion! There is a massive disorder of all CF3 groups,
especially in the anion where two CF3 fragments could not be localized in the electron density map and
had to be included as rigid groups (cf. the Me3SiO analog in Fig. 7).
lipophilic anions, such as this aluminate, are called weakly-coordinating anions
(WCAs), and it has been suggested that their counterparts, the cations, attain
structures similar to gas-phase structures (which have no counter-ion at all);
such anions are thought to create pseudo-gas-phase conditions in condensed
phases [21]. Thus, the similarity of the iminium-ion structures with ꢃnormalꢄ counterions
(BFꢀ4 , PF6ꢀ, and SbF6ꢀ ) and with the WCA Al[OC(CF3)3]4 is compatible with the
assumption that there is at least no pronounced counterion effect to be con-
sidered in the structures reported herein (see NMR chemical shift ꢃsimilaritiesꢄ of
the selected NMR signals for the three 4e iminium salts in Table 1). If so, a comparison
with DFT-calculated (ꢃgas-phaseꢄ) structures appears to be appropriate at this
point.
5. Density-Functional Theory (DFT) Calculations of the Structures of [3,5-
(F3C)2C6H3]2-Substituted Prolinol-Derived Enamines and Iminium Ions. – DFT
Calculations of the diarylprolinol-derived dienamine 5 and of the iminium ion 6 (Fig. 9)
were first reported by Jørgensen and co-workers in 2006 and 2007 [7][25]. In these
calculated structures, the exocyclic CHꢀC bond has sc-endo-conformation D, which
leads to essentially complete coverage of the p-faces, syn to the large substituent at
C(2) of the pyrrolidine ring by a bis(trifluoromethyl)phenyl group (see the space-filling
representations23) in Fig. 9 and compare with Fig. 8). It looks like the sc-exo-
23
)
For another presentation, see Fig. 5 in [3].

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Fig. 7. Crystal structure of the bis[3,5-bis(trifluoromethyl)phenyl]prolinol trimethylsilyl ether-derived
iminium salt 4e, X ¼ Al[OC(CF3)3]4. a) Unit cell, b) cation/anion pair.
conformation, which we see in all diarylprolinol-ether crystal structures, has nowhere
been considered in these calculations.
We have now performed DFT calculations with the three possible conformations C,
D, and E of the exocyclic ethane bond for Jørgensenꢄs dienamine 5 and for our
cinnamoylidene iminium ion 4e24).
We first recalculated [27 – 31] Jørgensenꢄs dienamine structure 5 with s-trans-
conformation around the NꢀC-bond and sc-endo-conformation (type D) of the
exocyclic CꢀC bond at the B3LYP/6-31G(d) level: as can be seen from Table 3, the
energy, as well as the detailed structure [7], was completely reproduced (cf. Fig. 9). We
next calculated the structures of the dienamine 5 with sc-exo- and ap-conformations.
The results listed in Table 3 show that the conformation of type C with the N-atom and
the Me3SiO group in sc-exo-relationship is the most stable one and the ap-arrangement
24
)
We performed geometry optimizations at the same computational level, B3LYP/6-31G(d), as the
Jørgensen group, and then B3LYP and MP2 single-point energy evaluations using a little bit larger
basis set, 6-311G(d,p), were carried out at the optimized geometries. The B3LYP calculations do not
reproduce dispersion effects [26], but the MP2 calculations do consider them, at least partly. We
thank Prof. S. Grimme (Universitꢁt Mꢀnster) for pointing this out to us.

Helvetica Chimica Acta – Vol. 92 (2009)
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Fig. 8. View along the iminium p-plane in the salts a) 4b, X ¼ PF6, b) 4c, X ¼ Al[OC(CF3)3]4, c) and
d) 4e, X ¼ Al[OC(CF3)3]4. A meta-CH3 and a meta-CF3 group are sitting above one face of the p-plane,
with increasing steric shielding from a) (meta-Me/MeO) to b) (meta-CF3/MeO) to c) (meta-CF3/
Me3SiO). The pink plane in d is the average plane of the enoyliminium p-system in 4e; C(3’) is the atom
of nucleophilic attack (red arrow).
(type E) the least stable one of the three conformations. This conclusion remains
unchanged in single-point energy evaluations at the B3LYP/6-31G(d)-optimized
geometries. Thus, the most stable calculated structure of dienamine 5 and the X-ray
structure of enamine 3a have the same conformation around the exocyclic CꢀC bond
(Table 3, top). The order of calculated stabilities of the three enamine conformations is
the same in the gas phase and in toluene solution (Table 3, bottom). The dienamine 5

1240
Helvetica Chimica Acta – Vol. 92 (2009)

Helvetica Chimica Acta – Vol. 92 (2009)
1241

1242
Helvetica Chimica Acta – Vol. 92 (2009)
Fig. 9. Jørgensenꢀs DFT-calculated structures of the dienamine 5 (a), and of an iminium ion 6 (b) derived
from diarylprolinol 1e and pentenal. The coordinates for generating these pictures are taken from [7].
With the sc-endo-conformation around the OꢀCꢀCꢀN bond the (Si)-aryl group winds up right on top
of the dienamine and enoyliminium p-planes, with steric shielding much stronger than in the measured
structures with sc-exo-conformation (cf. Fig. 8).
structure with s-cis-conformation of the exocyclic NꢀC bond was also calculated. All s-
cis-structures are found to be less stable than the s-trans-sc-exo-form (by 1.6 – 5.9 kcal/
mol; see Table 4, and compare with Table 3).
We then calculated the structures of the (E)-iminium ion 4e with the three
conformations C, D, and E of the exocyclic CꢀC bond in the gas-phase, at the B3LYP
and MP2 levels, using 6-31G(d) and 6-311G(d,p) basis sets. Again, the sc-exo-
conformation is by far the most stable one: the sc-endo-conformation (cf. 6 in Fig. 9) is
up to 4 and the ap-conformation up to 8 kcal/mol less stable (Table 5).
An overlay of the calculated and measured sc-exo-structures of iminium ion 4e is
shown in Fig. 10. For comparison, the three conformations C, D, and E of the isomeric
(Z)-iminium ion 4e were also calculated. At all three levels of theory, all three
conformers came out at higher energies than those of the (E)-sc-exo-form (by 1.7 –
8.7 kcal/mol; see Table 6 and compare with Table 5).

Helvetica Chimica Acta – Vol. 92 (2009)
1243
Table 3. Selected Results of a Computational Search for the Most Stable Structure of Jørgensenꢀs
Dienamine 5 (cf. Fig. 9,a) with s-trans-NꢀC(1’) Conformation, and Conformations of Type C, D, and E of
the Exocyclic CꢀC Bond. Various basis functions were used. For further details, see Exper. Part. For a
comparison with the calculated structures of s-cis NꢀC(1’) conformation, see Table 4.
sc-exo
sc-endo
ap
Dihedral angle NꢀCꢀCꢀNO [8]
60.3
ꢀ 68.2
ꢀ 177.1
Gas-phase calculations:
B3LYP/6-31G(d)
Eelec [au]a)
ꢀ 2740.185713
0.00
ꢀ 2740.183693
1.27
ꢀ 2740.179526
3.88
Eelec [kcal/mol]b)
Eelec [au]a)
B3LYP/6-311G(d,p)c)
MP2/6-311G(d,p)c)
ꢀ 2740.899766
ꢀ 2740.897333
ꢀ 2740.893299
Eelec [kcal/mol]b)
Eelec [au]a)
0.00
1.53
4.06
ꢀ 2734.266005
0.00
ꢀ 2734.262795
2.01
ꢀ 2734.257087
5.60
Eelec [kcal/mol]b)
CPCM Calculations (toluene soln.):
B3LYP/6-31G(d)c)
Eelec [au]a)
ꢀ 2740.191460
0.00
ꢀ 2740.189261
1.38
ꢀ 2740.184696
4.24
Eelec [kcal/mol]b)
Eelec [au]a)
MP2/6-31G(d)c)
ꢀ 2732.861831
ꢀ 2732.859738
ꢀ 2732.853455
Eelec [kcal/mol]b)
0.00
1.31
5.26
a) Absolute energies for calculated compounds. b) Potential-energy differences between each conformer
and the sc-exo-conformer are given. c) Single-point calculations at the B3LYP/6-31G(d)-optimized
geometries.
6. Discussion and Conclusions. – The isolation and structural characterization,
supported by DFT calculations, of the diarylprolinol-ether derivatives 3 and 4, the
reactive intermediates in organocatalyses by (diarylpyrrolidin-2-yl)methanol ethers,
confirm the generally accepted assumption [4] that the large (ꢃobeseꢄ [5]) Arl2(RO)C
substituent at C(2) of the pyrrolidine ring a) sterically blocks one face of the
nucleophilic and electrophilic p-systems of these intermediates, and b) causes a
preference for the s-trans-conformation of the enamine and for the (E)-configuration
of the iminium ion. The thus derived topical attack of electrophiles and of nucleophiles,
as indicated in H and I, is compatible with the observed stereochemical course of the
corresponding reactions. There are, however, two new aspects concerning details of the
general mechanistic model.
a) The (E)/(Z) Ratio. When we dissolved the precipitated, analytically pure
iminium salts 4 in CDCl3, (D6)DMSO, or (D6)acetone, and recorded NMR spectra, we
detected between 3 and 8% of the (Z)-isomers, besides the major (E)-isomers (see
Exper. Part). To see whether the two geometrical isomers are in equilibrium with each
other, we dissolved the CF3-substituted iminium salt 4e, X ¼ PF6, in CD3OD, recorded
1H-NMR spectra at temperatures between ꢀ 15 and þ 458 and deduced the (E)/(Z)-

1244
Helvetica Chimica Acta – Vol. 92 (2009)
Table 4. Results of Calculations of the Dienamine 5 Structures with s-cis-Conformation around the
NꢀC(1’) Bond and sc-exo, sc-endo-, and ap-Conformations of the Exocyclic CꢀC Bond in the Gas Phase
and in Toluene Solution (cf. the corresponding s-trans-structures in Table 3). Note that, while all
structures of s-cis-conformation are less stable than that of the s-trans-sc-exo-form, the s-cis-sc-endo form
is slightly (0.1 – 0.6 kcal/mol) more stable than the s-cis-sc-exo-form in this calculation. While this small
energy difference is within the error limit of the calculation, it is consistent throughout all levels of theory,
in the gas phase as well as in toluene solution. More elaborate calculations (cf. Footnote 24) could
possibly clarify this issue and might very well lead to the conclusion that there is an interaction between
one of the CF3-substituted benzene rings and the electron-rich dienamine p-system in the s-cis-sc-endo-
form.
sc-exo
sc-endo
ap
Dihedral angle NꢀCꢀCꢀNO [8]
57.0
ꢀ 70.8
167.3
Gas-phase calculations:
B3LYP/6-31G(d)
Eelec [au]a)
ꢀ 2740.180850
3.05
ꢀ 2740.181521
2.63
ꢀ 2740.176885
5.54
Eelec [kcal/mol]b)
Eelec [au]a)
B3LYP/6-311G(d,p)c)
MP2/6-311G(d,p)c)
ꢀ 2740.894569
ꢀ 2740.895660
ꢀ 2740.891303
Eelec [kcal/mol]b)
Eelec [au]a)
3.26
2.58
5.31
ꢀ 2734.263245
1.73
ꢀ 2734.263474
1.59
ꢀ 2734.257871
5.10
Eelec [kcal/mol]b)
CPCM Calculations (toluene solution):
B3LYP/6-31G(d)c)
Eelec [au]a)
ꢀ 2740.186025
3.41
ꢀ 2740.186410
3.17
ꢀ 2740.182023
5.92
Eelec [kcal/mol]b)
Eelec [au]a)
MP2/6-31G(d)c)
ꢀ 2732.858173
ꢀ 2732.858865
ꢀ 2732.853681
Eelec [kcal/mol]b)
2.30
1.86
5.11
a) Absolute energies for calculated compounds. b) Potential-energy differences between each conformer
and the sc-exo-conformer with s-trans-conformation of the exocyclic NꢀC bond are given (cf. Table 3).
c) Single-point calculations at the B3LYP/6-31G(d)-optimized geometries.
ratios from the signals at 5.67 and 6.06 ppm (HꢀC(2); cf. Fig. 1). The content of (Z)-
isomer (11 ꢁ 1%) did not vary within the detection limit of NMR-peak integration.
Furthermore, inversion-transfer NMR experiments (a) with the same solution at 458 or

Helvetica Chimica Acta – Vol. 92 (2009)
1245
Table 5. Theoretical Structures Calculated at Various Levels of Theory for the sc-exo-, sc-endo-, and ap-
Conformations of the Iminium Ion 4e. For an overlay of the measured (cf. Fig. 8,c and d) and the lowest-
energy calculated structure, see Fig. 10. For a comparison with the analogous structures of (Z)-
configuration, see Table 6.
sc-exo
sc-endo
ap
Dihedral angle NꢀCꢀCꢀNO [8]
61.4
ꢀ 59.6
ꢀ 177.6
Gas-phase calculations:
B3LYP/6-31G(d)
Eelec [au]a)
ꢀ 2893.026143
0.00
ꢀ 2893.021057
3.19
ꢀ 2893.018802
4.61
Eelec [kcal/mol]b)
Eelec [au]a)
B3LYP/6-311G(d,p)c)
MP2/6-311G(d,p)c)
ꢀ 2893.764039
ꢀ 2893.757877
ꢀ 2893.754698
Eelec [kcal/mol]b)
Eelec [au]a)
Eelec [kcal/mol]b)
0.00
3.87
5.86
ꢀ 2886.685493
0.00
ꢀ 2886.679220
3.94
ꢀ 2886.672259
8.30
a) Absolute energies for calculated compounds. b) Potential-energy differences between each conformer
and the sc-exo-conformer are given. c) Single-point calculations at the B3LYP/6-31G(d)-optimized
geometries.
b) in the presence of Et3N at room temperature) showed that the rate constant of
equilibration must be ꢂ 0.05 sꢀ125). This means that we can not detect equilibration
(Scheme 4)26) between (E)- and (Z)-iminium salt 4 under these conditions and with
the experiments carried out so far27). If the (Z)-isomer would also be present in
organocatalytic applications of the CF3-substituded prolinol Me3Si ether 1e, we would
expect an erosion of the enantioselectivity (see I vs. J): with a 9 :1 (E)/(Z) ratio the
enantiomer excess of a compound produced in such a process would be 80%. This is
inconsistent with the generally observed [4] high enantioselectivities (er up to 99.5 :0.5)
of the reactions catalyzed by 1e (carried out in solvents such as CH2Cl2, MeCN,
dioxane, sometimes in the presence of a benzoic acid Arl-CO2H [4])27).
Three lines of rationalization come to mind: i) The (Z)-content in the samples of
the iminium salts 4 may be an ꢃartifactꢄ of our salt preparation in EtOH, in the presence
25
)
)
We thank Drs. G. Deniau, and M.-O. Ebert, as well as Prof. B. Jaun (ETH-Zꢀrich) for carrying out
and interpreting the temperature-dependent NMR measurements.
An energy difference of 1.4 kcal/mol corresponds to a 10:1 ratio at room temperature. The (E)/(Z)-
ratio of ca. 89:11 happens to be in reasonable agreement with the DFT-calculated 1.7 kcal/mol
energy difference between (E)-sc-exo- and (Z)-sc-exo-4e (cf. Tables 5 and 6).
It is intriguing that, according to NMR spectra, the iminium salt derived from 2-[fluoro(diphe-
nyl)methyl]pyrrolidine is present as a 1:1 mixture of (E)- and (Z)-forms in solution, while the
pyrrolidine itself catalyzes the epoxidation by H2O2 of a,b-unsaturated aldehydes with enantio-
selectivities ranging from er 90:10 to 98:2 [19].
26
27
)

1246
Helvetica Chimica Acta – Vol. 92 (2009)
Table 6. Theoretical Structures Calculated at Various Levels of Theory for the sc-exo-, sc-endo-, and ap-
Conformations of the Iminium Ion (Z)-4e of (Z)-Configuration of the Exocyclic N¼C Bond. For
comparison with the corresponding conformations with (E)-configuration, see Table 5.
sc-exo
sc-endo
ap
Dihedral angle NꢀCꢀCꢀNO [8]
64.6
ꢀ 62.5
179.0
Gas-phase calculations:
B3LYP/6-31G(d)
Eelec [au]a)
ꢀ 2893.020342
3.64
ꢀ 2893.019821
3.97
ꢀ 2893.013816
7.74
Eelec [kcal/mol]b)
Eelec [au]a)
B3LYP/6-311G(d,p)c)
MP2/6-311G(d,p)c)
ꢀ 2893.757508
ꢀ 2893.756427
ꢀ 2893.750149
Eelec [kcal/mol]b)
Eelec [au]a)
Eelec [kcal/mol]b)
4.10
4.78
8.72
ꢀ 2886.682738
1.73
ꢀ 2886.682497
1.88
ꢀ 2886.676750
5.49
a) Absolute energies for calculated compounds. b) Potential-energy differences between each conformer
and the sc-exo-conformer with (E)-configuration of the exocyclic N¼C bond (see Table 5) are given.
c) Single-point calculations at the B3LYP/6-31G(d)-optimized geometries.
Fig. 10. Overlay of the measured (green) and calculated
(red) structures of the iminium ion 4e
of Et3N, followed by precipitation from this solvent or from Et2O (see Sect. 2 and Exper.
Part). ii) Under the conditions of catalytic applications, the (E)-isomers 4 may be
generated preferentially, equilibrate slowly or not at all with the (Z)-isomer, and react
rapidly with nucleophiles (kinetic control) to give the precursors (see I) of the isolated
products. iii) Both (E)- and (Z)-isomer are formed in the catalytic process, and the
(E)-isomer is a much more reactive electrophile [17b] than the (Z)-isomer.
Detailed mechanistic and, possibly, theoretical investigations will be necessary in
order to elucidate the apparent discrepancy between our results and the high
performance of the diarylprolinol ethers as organocatalysts.

Helvetica Chimica Acta – Vol. 92 (2009)
1247
Scheme 4. Possible Modes of Iminium (E) > (Z) Equilibration. a) Iminium ions of type 4; b) an
iminium salt derived from crotonaldehyde (cf. Fig. 9 and Tables 3 – 6).
b) The sc-exo-Conformation. In the generally accepted mechanistic model, ꢃwishful
thinkingꢄ has placed an aryl group above the p-system in the reactive intermediates of
catalysis by diarylprolinol ethers (see, for instance, the presentation K used in a recent –
anonymous – publication on the subject and the calculation by the Jørgensen group
presented in Fig. 9). From the crystal structures and from the DFT calculations, we are
now led to assume that the CꢀC bond between the diaryl(methoxy)methyl or
diaryl(silyloxy)methyl group and the pyrrolidine-ring C-atom adopts preferentially
(ꢃ 3.2 kcal/mol) a sc-exo-conformation, C, in the reactive electrophilic intermediates,
such as the iminium ions 4 (see L)28). In this conformation, it is not so much the
benzene ring of the aryl group itself, but a meta-substituent on one of the aryl groups
and the RO group, which provide the major contributions to steric hindrance of
approach to one of the faces of the iminium p-system (see especially Fig. 8).
In conclusion, the structure determination of reactive intermediates of organo-
catalysis by diarylprolinol ethers has provided new insights and, at the same time, raised
some interesting questions concerning details of the mechanism.
28
)
We do not know the barrier to rotation around this bond, but we may assume that it is substancial
(cf. the discussion of the geminal-diaryl effect in stereoselective organic syntheses in [3] and [32]).

1248
Helvetica Chimica Acta – Vol. 92 (2009)
We thank P. Kꢁlin and M. Schneider (Elemental Analyses), R. Hꢁfliger, L. Bertschi, and O. Greter
(MS Service), Prof. B. Jaun, Dr. M.-O. Ebert, R. Frankenstein, and P. Zumbrunnen (NMR Service), and
M. Solar (X-Ray Service), as well as the Laboratory of Organic Chemistry (ETHZ) and the Novartis
Pharma AG for all their help and support.
Experimental Part
General. All reactions were performed under Argon in dried glassware using anh. solvents except
when using aq. reagents. All chemicals were of reagent grade and used as supplied, unless stated
otherwise. Solvents for extractions and chromatography were of technical grade and were distilled prior
to use. Sat. hydrocarbon solvents were kept over Na wire. Extracts were dried over technical grade
MgSO4. Anal. TLC: pre-coated Merck silica gel 60 F254 plates (0.25 mm). Column chromatography
(CC): Fluka silica gel 60 (230 – 400 mesh). M.p.: Bꢂchi 510 melting-point apparatus and are uncorrected.
Optical rotations: Jasco P-2000 polarimeter. IR Spectra: as neat solid/oil on a Perkin-Elmer precisely
Universal ATR Sampling Accessory; in cmꢀ1 1H- and 13C-NMR Spectra: Bruker AVANCE (1H:
.
300 MHz, 13C: 75 MHz), DRX (1H: 400 MHz, 13C: 101 MHz), and AV (1H: 400 MHz, 13C: 101 MHz)
spectrometer, or Varian Gemini-300 (1H: 300 MHz, 13C: 75 MHz) spectrometer; chemical shifts (d) are
reported in ppm rel. to Me4Si (0.00 ppm). High-resolution (HR) MS: IonSpecUltima 4.7-T-FT Ion
Cyclotron Resonance (ICR; HR-MALDI, in 2,5-dihydroxybenzoic acid matrix) spectrometer. Elemental
analyses: by the Microanalytical Laboratorium at the Laboratory for Organic Chemistry, ETH Zꢀrich.
Preparation of Diphenylprolinols 1 and Oxazolidines 2. (R)-Bis[4-tert-butyl)phenyl](pyrrolidin-2-
yl)methanol (1; Arl ¼ 4-tBuC6H4, R ¼ H) and (R)-1,1-bis[4-(tert-butyl)phenyl]tetrahydro-1H-pyrro-
lo[1,2-c][1,3]oxazol-3-one (2a). a) To a soln. of [4-(tert-butyl)phenyl]magnesium bromide (2m in Et2O,
50 ml, 100 mmol) at 08 was added a soln. of N-(ethoxycarbonyl)-d-proline methyl ester29) (6.3 g,
31.27 mmol) in anh. THF (40 ml, r.t.) during 40 min. After the addition, the mixture was stirred for 1 h at
08 and 24 h at r.t. The reaction of the ice-cold (08) mixture was carefully quenched by slow addition of aq.
sat. NH4Cl (30 ml). After stirring for 1 h at r.t., the mixture was filtered through a short plug of Celite and
thoroughly washed with CH2Cl2. Volatile components were evaporated in vacuo, and the residue was
treated with H2O (100 ml) and extracted with CH2Cl2 (4 ꢄ 100 ml). The combined org. phase was dried
(MgSO4), filtered, and volatile components were evaporated in vacuo. The residue was dissolved in
MeOH (120 ml), KOH (19 g) was added, and the resulting mixture was heated under reflux for 4 h.
Volatile components were carefully evaporated in vacuo. The residue was treated with CH2Cl2 (200 ml)
upon which a gel-like mixture was formed. The mixture was filtered through a short plug of Celite and
thoroughly washed with CH2Cl2 (4 ꢄ 100 ml). The filtrate was washed with H2O (100 ml) and brine
(100 ml), and dried (MgSO4), filtered, and volatile components were evaporated in vacuo. The residue
was purified by CC: 1st eluate: AcOEt/hexane 1:2 to elute 2a (ca. 10 – 15 mmol of 2a containing several
29
)
N-(Ethoxycarbonyl)-d-proline methyl ester was prepared from d-proline methyl ester according to
the literature procedure used for the preparation of its l-enantiomer, N-(ethoxycarbonyl)-l-proline
methyl ester [33].

Helvetica Chimica Acta – Vol. 92 (2009)
1249
other by-products, in tubes containing the highest concentration of the product, 2a tends to precipitate
from the soln.); 2nd eluate: AcOEt/Et3N 50 :1 to give 2.98 g of 1 (Arl ¼ 4-tBuC6H4, R ¼ H) as a white
solid containing ca. 20% of (R)-1,1-bis[4-(tert-butyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole
(2b), that could not be separated from 1 (Arl ¼ 4-tBuC6H4, R ¼ H) under these conditions. Fractions
containing the product were evaporated in vacuo to give crude 2a and 1 (Arl ¼ 4-tBuC6H4, R ¼ H). The
so isolated 2a was used for the preparation of anal. pure 1 (Arl ¼ 4-tBuC6H4, R ¼ H; see procedure b). A
small amount of 2a was purified by CC (two times CC, AcOEt/hexane 1:5) to obtain an anal. pure
sample of 2a. Crude 1 (Arl ¼ 4-tBuC6H4, R ¼ H) was used to prepare compound 1i and to isolate the side-
product 2b.
b) Crude 2a (4.5 g, ca. 10 mmol, see a, above) in MeOH (100 ml) and KOH (27 g) were heated under
reflux for 9 h. Volatile components were carefully evaporated in vacuo. The residue was treated with
CH2Cl2 (150 ml) upon which a gel-like mixture was formed. The mixture was filtered through a short plug
of Celite and thoroughly washed with CH2Cl2 (4 ꢄ 100 ml). The filtrate was washed with H2O (100 ml)
and brine (100 ml), and dried (MgSO4), filtered, and volatile components were evaporated in vacuo. To a
cold soln. of the residue in Et2O (200 ml, 08) was added a cold soln. of H2SO4 in Et2O (0.1m, 100 ml, 08)
during 10 min. The white precipitate was collected by filtration and washed with Et2O (300 ml) and H2O
(200 ml). The solid was suspended in a mixture of NaOH (aq., 2m, 150 ml) and THF (100 ml) and
vigorously stirred for 5 h at r.t. The bulk of the THF from the mixture was carefully evaporated in vacuo.
The remaining soln. was extracted with CH2Cl2 (4 ꢄ 100 ml), and the combined org. phase was washed
with brine (100 ml), dried (MgSO4), filtered, and volatile components were evaporated in vacuo to give 1
(Arl ¼ 4-tBuC6H4, R ¼ H). Yield: 2.47 g (ca. 70%).
Data of 1 (Arl ¼ 4-tBuC6H4, R ¼ H). White solid. M.p. 160 – 1628. [a]rD:t: ¼ þ52.2 (c ¼ 0.18, CH2Cl2).
IR: 2965m, 2866w, 2843w, 1508w, 1462w, 1403m, 1365m, 1324w, 1267m, 1203w, 1188w, 1110m, 1101m,
1019w, 997m, 915m, 874m, 844m, 836s, 823s, 810m, 707m, 693m, 655m, 637m. 1H-NMR (400 MHz,
(D6)DMSO): 1.23 (s, tBu); 1.24 (s, tBu); 1.41 – 1.55 (m, CH2); 1.57 – 1.68 (m, CH2); 2.81 – 2.94 (m, CH2);
3.30 (br. s, NH); 4.24 (t, J ¼ 7.7, H ꢀC(2)); 7.20 – 7.27 (m, 4 arom. H); 7.34 – 7.38 (m, 2 arom. H); 7.45 – 7.50
(m, 2 arom. H). 13C-NMR (101 MHz, (D6)DMSO): 25.3; 26.4; 31.0; 33.8; 46.7; 64.0; 76.7; 124.2; 124.3;
124.8; 125.6; 143.3; 144.9; 147.8; 148.0. HR-MS (MALDI): 366.2791 (100, [M þ H]þ, C25H36NOþ; calc.
366.27914). Anal. calc. for C25H35NO (365.55): C 82.14, H 9.65, N 3.83; found: C 81.87, H 9.72, N 3.83.
Data of 2a. White solid. M.p. 240 – 2438. [a]rD:t: ¼ þ124.5 (c ¼ 0.44, CH2Cl2). IR: 2961m, 2902w,
2869w, 1747s, 1510w, 1475w, 1462w, 1391m, 1362w, 1345w, 1325w, 1266m, 1230m, 1199w, 1110w, 1064m,
1021w, 999s, 969m, 861w, 843w, 823s, 771m, 720w, 709w. 1H-NMR (300 MHz, CDCl3): 1.05 – 1.21 (m, 1 H,
CH2); 1.29 (s, 2 tBu); 1.67 – 1.77 (m, 1 H, CH2); 1.78 – 2.04 (m, CH2); 3.22 (ddd, J ¼ 3.8; 9.3; 11.4, 1 H,
CH2); 3.71 (dt, J ¼ 8.1, 11.4, 1 H, CH2); 4.49 (dd, J ¼ 5.4, 10.5, CH); 7.26 – 7.38 (m, 6 arom. H); 7.41 – 7.46
(m, 2 arom. H). 13C-NMR (101 MHz, CDCl3): 25.1; 29.2; 31.39; 31.43; 34.63; 34.64; 46.1; 69.8; 86.1; 125.2;
125.3; 125.6; 125.7; 137.5; 140.8; 150.6; 151.2; 160.8. HR-MS (MALDI): 391.2510 (100, Mþ, C26H33NO2þ ;
calc. 391.2506). Anal. calc. for C26H33NO2 (391.55): C 79.76, H 8.49, N 3.58; found: C 79.64, H 8.57, N 3.55.
(S)-2-[{[Dimethyl(phenyl)silyl]oxy}(diphenyl)methyl]pyrrolidine (1f). According to a literature
procedure [34] Me2PhSiCl (392 ml, 2.37 mmol) was added to a soln. of the (S)-diphenyl(pyrrolidin-2-
yl)methanol (1a; 500 mg, 1.97 mmol), Et3N (550 ml, 3.97 mmol), and 4-(dimethylamino)pyridine
(DMAP; 17 mg, 5.9 mmol) in anh. CH2Cl2 (18 ml) under Ar in a 50-ml two-necked round-bottomed
flask fitted with stirrer bar, stopper, and gas inlet (dried by heat gun at 0.3 mbar). The resulting colorless
soln. was stirred for 20 h, after which it had become pink. TLC indicated the reaction was complete, and
the reaction was quenched by pouring into ice/H2O (25 ml). This mixture was extracted with AcOEt
(3 ꢄ 25 ml), and the org. layers were combined and washed with H2O (25 ml), resulting in an emulsion.
This was broken up by washing with brine (3 ꢄ 25 ml). The org. layer was dried (MgSO4) and
concentrated to give a yellow oil (ca. 860 mg). The crude material was purified by CC (3 ꢄ 25 cm;
AcOEt/hexane 1:1) to give a yellow oil which crystallized on standing to give 1f (682 mg, 89%). Large
yellow cubes. M.p. 59 – 618. [a]rD:t: ¼ ꢀ46.0 (c ¼ 1.27, CHCl3). IR (neat): 3017w, 2955m, 2872w, 1599w,
1490m, 1446m, 1428m, 1401m, 1290w, 1256m, 1243m, 1197m, 1141s, 1118s, 1074s, 936m, 920w. 1H-NMR
(300 MHz, CDCl3): 0.09 (s, Me2Si); 1.18 – 1.28 (m, 1 H, CH2); 1.40 – 1.80 (m, 3 H, CH2, NH); 2.64 – 2.71
(m, 1 H, CH2); 2.76 – 2.84 (m, 1 H, CH2); 4.02 (t, J ¼ 7.2, HꢀC(2)); 7.19 – 7.55 (m, 15 arom. H). 13C-NMR
(75 MHz, CDCl3): 1.13; 1.28; 24.8; 27.5; 47.1; 65.4; 83.6; 126.7; 127.0, 127.6 (2ꢄ); 128.2; 128.4; 128.9; 133.3;

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Helvetica Chimica Acta – Vol. 92 (2009)
140.5; 145.6; 146.6. ESI-MS: 107 (12); 149 (25); 310 (22); 181 (100); 207 (12); 236 (88); 310 (21); 388
(18); 391 (12). HR-ESI-MS: 388.2088 (C25H30NOSiþ; calc. 388.2091).
(S)-2-[{[Methyl(diphenyl)silyl]oxy}(diphenyl)methyl]pyrrolidine (1h). Same procedure as for the
synthesis of 1f (see above), except that MePh2SiCl (534 ml, 2.37 mmol) was used for the silylation. The
resulting colorless soln. was stirred for 16.5 h, after which it had become yellow. Workup gave a yellow
foam (1.10 g). The crude material was purified by CC (3 ꢄ 25 cm; AcOEt/hexane 1:1) to give 1h
(787 mg, 89%). Amorphous yellow solid. M.p. 88 – 908. [a]rD:t: ¼ ꢀ48.2 (c ¼ 1.02, CHCl3). IR (neat):
2867w, 1491m, 1448m, 1427s, 1400m, 1245m, 1196w, 1137s, 1115s, 1073s, 1020m, 930m. 1H-NMR
(300 MHz, CDCl3): 0.20 (s, MeSi); 0.92 – 1.05 (m, 1 H, CH2); 1.24 – 1.46 (m, CH2); 1.54 – 1.67 (m, 1 H,
CH2); 1.70 (br. s, NH); 2.55 (ddd, J ¼ 5.2; 7.6; 9.8, 1 H, CH2); 2.73 (dt, J ¼ 6.4; 9.8, 1 H, CH2); 4.00 (t, J ¼
7.4, HꢀC(2)); 7.18 – 7.39 (m, 14 arom. H); 7.48 – 7.54 (m, 6 arom. H). 13C-NMR (75 MHz, CDCl3): ꢀ 0.8;
24.3; 27.3; 46.8; 65.2; 83.9; 126.9; 127.2; 127.5; 127.6 (2ꢄ); 127.8 (2ꢄ); 128.5; 129.1; 134.3; 134.5; 139.2;
139.5; 145.7; 146.6. EI-MS: 70 (100); 165 (3); 197 (14); 434 (0.3). HR-EI-MS: 434.1935 ([M ꢀ Me]þ,
C29H28NOSiþ; calc. 434.1935).
Preparation of R12R2SiO-Protected Prolinole Derivatives 1g, 1i, and 2b. General Procedure 1
(GP 1)30). To a soln./suspension of diarylprolinol (1 equiv.) in anh. CH2Cl2 (V1) at r.t. under Ar were
added Et3N (2 equiv.), DMAP (0.06 equiv.) and R12R2SiCl (1.2 equiv.). After stirring at r.t. for hours (t1),
the reaction was quenched with ice cold H2O (25 – 50 ml), and the resulting mixture was extracted with
AcOEt (2 ꢄ 100 ml). The combined org. phase was dried (MgSO4), filtered, and volatile components
were evaporated in vacuo. The residue was purified by CC to give 1g and 1i (or 1i and 2b).
(R)-2-(Bis[(4-tert-butyl)phenyl]{[dimethyl(phenyl)silyl]oxy}methyl)pyrrolidine (1g). Prepared ac-
cording to GP 1 from 1 (Arl ¼ 4-tBuC6H4, R ¼ H; 215 mg, 0.59 mmol) and Me2PhSiCl (120 ml,
0.71 mmol): CH2Cl2 (6 ml), Et3N (164 ml, 1.18 mmol), DMAP (4 mg, 0.035 mmol); t1 ¼ 22 h; CC
(AcOEt/hexane 1:4). Yield: 224 mg (76%). Colorless oil. [a]rD:t: ¼ þ45.3 (c ¼ 0.15, CH2Cl2). IR: 2960m,
2904w, 2869w, 1509w, 1475w, 1461w, 1428w, 1403w, 1363w, 1268w, 1249m, 1202w, 1144w, 1112s, 1075m,
1037m, 1015m, 934w, 877m, 825s, 801m, 780s, 726m, 699s, 648m. 1H-NMR (400 MHz, CDCl3): 0.25 (s, 2
Me); 1.31 – 1.38 (m, 1 H, CH2); 1.44 (s, tBu); 1.45 (s, tBu); 1.56 – 1.67 (m, CH2); 1.70 – 1.80 (m, 1 H, CH2);
1.87 (br. s, NH); 2.78 – 2.86 (m, 1 H, CH2); 2.88 – 2.95 (m, 1 H, CH2); 4.15 (t, J ¼ 7.5, HꢀC(2)); 7.35 – 7.46
(m, 9 arom. H); 7.50 – 7.56 (m, 2 arom. H); 7.63 – 7.68 (m, 2 arom. H). 13C-NMR (101 MHz, CDCl3): 1.0;
1.1; 24.8; 27.4; 31.5; 34.43; 34.45; 47.0; 65.6; 83.4; 124.4; 124.5; 127.3; 127.6; 128.1; 128.9; 133.4; 140.8;
142.6; 143.5; 149.5; 149.7. HR-MS (MALDI): 499.3259 (100, Mþ, C33H45NOSiþ; calc. 499.3265). Anal.
calc. for C33H45NOSi (499.80): C 79.30, H 9.07, N 2.80; found: C 78.34, H 9.01, N 2.75.
(R)-2-(Bis[(4-tert-butyl)phenyl]{[methyl(diphenyl)silyl]oxy}methyl)pyrrolidine (1i) and 2b. Pre-
pared according to GP 1 from crude 1 (Arl ¼ 4-tBuC6H4, R ¼ H; 310 mg, ca. 0.700 mmol, containing ca.
20% of 2b) and MePh2SiCl (183 ml, 0.84 mmol): CH2Cl2 (7 ml), Et3N (195 ml, 1.4 mmol), DMAP (5 mg,
0.042 mmol); t1 ¼ 20 h; CC (AcOEt/hexane 1:4) afforded 1i (300 mg, 76%) and 2b (47 mg, ca. 88%).
Large-Scale Preparation of 1i. Prepared according to GP 1 from anal. pure 1 (Arl ¼ 4-tBuC6H4, R ¼
H; 1.65 g, 4.52 mmol) and MePh2SiCl (1.18 ml, 5.42 mmol) (GP 5): CH2Cl2 (45 ml), Et3N (1.26 ml,
9.03 mmol), DMAP (33 mg, 0.27 mmol); t1 ¼ 23 h; CC (AcOEt/hexane 1:4). Yield: 2.04 g (80%).
Data of 1i (elutes first). White solid. M.p. 61 – 658. [a]rD:t: ¼ þ61.0 (c ¼ 0.25, CH2Cl2). IR: 2961m,
2904w, 2867w, 1509w, 1475w, 1461w, 1428m, 1403w, 1363w, 1269w, 1251w, 1190w, 1143w, 1109s, 1063m,
1
1014m, 936w, 874m, 842w, 824m, 788s, 734s, 715s, 698s, 666m. H-NMR (400 MHz, CDCl3)31): 0.31 (s,
Me); 0.98 – 1.09 (m, 1 H, CH2); 1.34 (s, tBu); 1.34 (s, tBu); 1.38 – 1.47 (m, CH2); 1.60 – 1.73 (m, 2 H, CHH,
NH); 2.56 – 2.67 (m, 1 H, CH2); 2.70 – 2.79 (m, 1 H, CH2); 4.04 (t, J ¼ 7.2, HꢀC(2)); 7.22 – 7.37 (m, 12
arom. H); 7.45 – 7.49 (m, 2 arom. H); 7.52 – 7.58 (m, 4 arom. H). 13C-NMR (101 MHz, CDCl3): ꢀ 0.6;
24.3; 27.3; 31.51; 31.52; 34.40; 34.43; 46.7; 65.4; 83.7; 124.45; 124.46; 127.2; 127.47; 127.48; 128.1; 128.93;
128.95; 134.3; 134.5; 139.4; 139.6; 142.6; 143.4; 149.4; 149.7. HR-MS (MALDI): 561.3425 (100, Mþ,
30
)
)
The volumes (in ml) of H2O or solvents given in all General Procedures refer to the batch sizes (1 –
4 mmol) given in the corresponding individual procedures.
If one sees rotamers in NMR spectra recorded in CDCl3, one should record the same spectra in
DMSO to avoid that!
31

Helvetica Chimica Acta – Vol. 92 (2009)
1251
C38H47NOSiþ; calc. 561.3422). Anal. calc. for C38H47NOSi (561.87): C 81.23, H 8.43, N 2.49; found: C
81.10, H 8.56, N 2.46.
Data of 2b (elutes second). White solid. M.p. 162 – 1678. [a]rD:t: ¼ þ227.8 (c ¼ 0.53, CH2Cl2). IR:
2960m, 2867w, 1507m, 1475w, 1461w, 1404w, 1362w, 1268m, 1192w, 1172w, 1155w, 1131w, 1109m, 1091w,
1075w, 1023w, 1005s, 963m, 953m, 941m, 927m, 843m, 820s, 727w, 709m, 695m. 1H-NMR (400 MHz,
CDCl3): 1.16 – 1.23 (m, 1 H, CH2); 1.27 (s, tBu); 1.27 (s, tBu); 1.59 – 1.70 (m, 3 H, CH2); 2.74 – 2.83 (m, 1 H,
CH2); 3.19 – 3.27 (m, 1 H, CH2); 4.31 (d, J ¼ 6.1, 1 H, CH2); 4.36 (t, J ¼ 7.0, CH); 4.48 (d, J ¼ 6.1, 1 H,
CH2); 7.22 – 7.34 (m, 6 arom. H); 7.40 – 7.45 (m, 2 arom. H). 13C-NMR (101 MHz, CDCl3): 26.5; 30.6; 31.4;
31.5; 34.4; 34.5; 56.6; 71.4; 85.8; 88.1; 124.7; 125.1; 125.6; 126.7; 141.0; 141.8; 149.1; 149.8. HR-MS
(MALDI): 378.2791 (100, [M þ H]þ, C26H36NOþ; calc. 378.27914). Anal. calc. for C26H35NO (377.56): C
82.71, H 9.34, N 3.71; found: C 82.49, H 9.34, N 3.75.
Preparation of the Ammonium Salts 1 · HX. Preparation of BF4 Salts of the Secondary Amines 1a ·
HBF4 and 1b · HBF4. General Procedure 2 (GP 2)30). To a soln. of a secondary amine (1 equiv.) in anh.
Et2O (V1) at 08 under Ar was added a soln. of HBF4 · Et2O (1 equiv.) in anh. Et2O (V2) at r.t. during
10 min. The mixture was stirred for additional t1 min. at 08 and t2 min at r.t. The precipitate was collected
by filtration, washed with anh. Et2O (30 ml), and dried under high vacuum to give BF4 salts 1a · HBF4
and 1b · HBF4.
(S)-2-[Hydroxy(diphenyl)methyl]pyrrolidinium Tetrafluoroborate (1a · HBF4). Prepared according
to GP 2 from 1a (510 mg, 2.01 mmol) and HBF4 · Et2O (276 ml, 2.01 mmol): V1 ¼ 80 ml; V2 ¼ 30 ml; t1 ¼
60 min; t2 ¼ 10 min. Yield: 660 mg (96%). White solid. M.p. 207 – 2098. [a]rD:t: ¼ þ49.1 (c ¼ 0.33, EtOH).
IR: 3469w, 3233w, 3193w, 1578w, 1495w, 1450m, 1395w, 1361m, 1328w, 1268w, 1185m, 1162w, 1112s, 1065s,
1
1043s, 981s, 956s, 944s, 882m, 861w, 771s, 753s, 698s, 641s. H-NMR (400 MHz, (D6)DMSO): 1.79 – 1.98
(m, 2 CH2); 3.04 – 3.20 (m, CH2); 4.86 (deg. t, J ¼ 7.5; 7.8, CH); 6.58 (s, OH); 7.21 – 7.28 (m, 2 arom. H);
7.31 – 7.40 (m, 4 arom. H); 7.51 – 7.63 (m, 4 arom. H); 7.89 (s, 1 H, NHþ2 ); 8.85 (s, 1 H, NH2þ ). 13C-NMR
(101 MHz, (D6)DMSO): 23.9; 25.8; 46.7; 65.4; 76.9; 125.56; 125.59; 127.1; 127.2; 128.2; 128.4; 144.4;
144.9. HR-MS (MALDI): 254.1539 (100, Mþ, C17H20NOþ; calc. 254.15394). Anal. calc. for C17H20BF4NO
(341.15): C 59.85, H 5.91, N 4.11; found: C 59.98, H 5.99, N 4.05.
(S)-2-[Bis(3,5-dimethylphenyl)(methoxy)methyl]pyrrolidinium Tetrafluoroborate (1b · HBF4). Pre-
pared according to GP 2 from (S)-2-[bis(3,5-dimethylphenyl)(methoxy)methyl]pyrrolidine (1b;
1.39 mmol; which was quantitatively prepared from its HCl salt (500 mg, 1.39 mmol) by neutralization
(aq. Na2CO3) and extraction with CH2Cl2 sequence) and HBF4 · Et2O (191 ml, 1.39 mmol): V1 ¼ 60 ml;
V2 ¼ 10 ml; t1 ¼ 10 min; t2 ¼ 30 min. Yield: 460 mg (80%). White solid. M.p. 192 – 1958. [a]rD:t: ¼ ꢀ37.2 (c ¼
0.28, CH2Cl2). IR: 3118w, 1604m, 1457w, 1408w, 1371w, 1297w, 1270w, 1223w, 1177w, 1062s, 1021s, 922m,
865m, 857m, 811m, 760m, 720m, 700w. 1H-NMR (400 MHz, CDCl3): 1.16 – 1.28 (m, 1 H, CH2); 1.86 – 2.00
(m, CH2); 2.23 – 2.39 (m, 1 H, CH2); 2.31 (s, 2 Me); 2.32 (s, 2 Me); 2.67 – 2.80 (m, 1 H, CH2); 3.07 (s,
MeO); 3.37 – 3.48 (m, 1 H, CH2); 4.86 – 4.96 (m, HꢀC(2)); 6.54 (br. s, 1 H, NHþ2 ); 6.90 (s, 2 arom. H);
6.97 (s, 2 arom. H); 7.00 (s, 2 arom. H); 7.79 (br. s, 1 H, NHþ2 ). 13C-NMR (101 MHz, CDCl3): 21.5; 21.6;
24.0; 27.4; 47.4; 51.6; 63.4; 83.6; 126.1; 126.9; 130.4; 130.6; 138.1; 138.2; 138.5; 138.6. HR-MS (MALDI):
324.2322 (100, Mþ, C22H30NOþ; calc. 324.23219). Anal. calc. for C22H30BF4NO (411.28): C 64.25, H 7.35,
N 3.41; found: C 64.42, H 7.34, N 3.40.
Preparation of BF4 Salts of Secondary Amines 1d · HBF4, 1h · HBF4, and 1i · HBF4. General
Procedure 3 (GP 3)30). According to GP 2, the initially obtained precipitate (in case the desired product
did not precipitate readily, hexane (up to 50 ml) was added to the mixture, and vigorous stirring at 08 was
continued until a fine precipitate was formed) consisted of the desired R3SiO-protected prolinol-derived
BFꢀ4 salt (major product) and various amounts (ca. 5 – 36%) of undesired R3SiO-deprotected BF4ꢀ salt
(minor product). The precipitate was suspended in anh. CH2Cl2 (V3) or a mixture of anh. CHCl3/hexane
(V3), where only the desired R3SiO-protected prolinol-derived BFꢀ4 salt was soluble, and quickly filtered
and washed through a short plug of Celite with the same solvent or solvent mixture. Volatile components
were evaporated in vacuo, and the residue was dried under high vacuum. Et2O and hexane were added to
the residue, followed by intense ꢃscratching by spatulaꢄ until a nicely powdered, filterable solid was
formed. The so formed solid was collected by filtration, washed with Et2O (20 ml), and dried under high
vacuum to give salts 1d · HBF4, 1h · HBF4, and 1i · HBF4.

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Helvetica Chimica Acta – Vol. 92 (2009)
(S)-2-{Diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidinium Tetrafluoroborate (1d · HBF4). Prepared
according to GP 3 from (S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine (1d; 1250 mg,
3.84 mmol) and HBF4 · Et2O (527 ml, 3.84 mmol): V1 ¼ 60 ml; V2 ¼ 20 ml; t1 ¼ 60 min; V3 ¼ 40 ml CH2Cl2.
Yield: 860 mg (54%). White solid. M.p. 149 – 1508. [a]rD:t: ¼ ꢀ9.3 (c ¼ 0.19, CH2Cl2). IR: 3199w, 1590w,
1494w, 1392w, 1362w, 1252w, 1199w, 1182w, 1130m, 1110m, 1078s, 1066s, 1050s, 1033s, 1000s, 990s, 980s,
1
894w, 871s, 837s, 762s, 751s, 704s, 642m. H-NMR (400 MHz, CDCl3): ꢀ 0.08 (s, Me3Si); 1.41 – 1.53 (m,
1 H, CH2); 1.92 – 2.06 (m, CH2); 2.27 – 2.40 (m, 1 H, CH2); 2.70 – 2.82 (m, 1 H, CH2); 3.27 – 3.38 (m, 1 H,
CH2); 4.78 – 4.89 (m, HꢀC(2)); 6.32 (br. s, 1 H, NHþ2 ); 7.28 – 7.64 (m, 11 H, 10 arom. H, NHHþ).
13C-NMR (101 MHz, CDCl3): 1.7; 24.1; 27.0; 47.6; 67.9; 81.8; 128.3; 128.5; 128.8; 128.85; 128.90; 129.0;
140.7; 141.5. HR-MS (MALDI): 326.1935 (100, Mþ, C20H28NOSiþ; calc. 326.19347). Anal. calc. for
C20H28BF4NOSi (413.33): C 58.12, H 6.83, N 3.39; found: C 58.41, H 6.76, N 3.24.
(S)-2-({[Methyl(diphenyl)silyl]oxy}(diphenyl)methyl)pyrrolidinium Tetrafluoroborate (1h · HBF4).
Prepared according to GP 3 from (S)-2-({[methyl(diphenyl)silyl]oxy}(diphenyl)methyl)pyrrolidine (1h;
743 mg, 1.65 mmol) and HBF4 · Et2O (227 ml, 1.65 mmol): V1 ¼ 60 ml; V2 ¼ 10 ml; t1 ¼ 30 min; V3 ¼ 20 ml
of CHCl3/heptane 3 :2. Yield: 460 mg (51%). White solid. M.p. 139 – 1418. [a]rD:t: ¼ ꢀ8.7 (c ¼ 0.21,
CH2Cl2). IR: 3237w, 1590w, 1491w, 1446w, 1429w, 1374w, 1263w, 1195w, 1109m, 1092m, 1058s, 1016s,
1001s, 934w, 920w, 898w, 847m, 833m, 796m, 788m, 775m, 751m, 739s, 722s, 711m, 698s. 1H-NMR
(300 MHz, CDCl3): 0.32 (s, Me); 1.29 – 1.45 (m, 1 H, CH2); 1.80 – 2.03 (m, CH2); 2.18 – 2.34 (m, 1 H,
CH2); 2.46 – 2.61 (m, 1 H, CH2); 3.13 – 3.27 (m, 1 H, CH2); 4.77 – 4.90 (m, HꢀC(2)); 6.06 (br. s, 1 H,
NHþ2 ); 7.13 – 7.52 (m, 20 arom. H). 13C-NMR (101 MHz, (D6)DMSO): ꢀ 1.9; 23.7; 26.8; 46.2; 65.9; 82.6;
127.57; 127.68; 127.74; 128.15; 128.16; 128.24; 128.5; 128.6; 129.7; 133.8; 133.9; 136.7; 136.8; 141.1; 142.1.
HR-MS (MALDI): 450.2248 (100, Mþ, C30H32NOSiþ; calc. 450.22477). Anal. calc. for C30H32BF4NOSi
(537.47): C 67.04, H 6.00, N 2.61; found: C 66.90, H 6.12, N 2.64.
(R)-2-(Bis[4-tert-butyl)phenyl]{[methyl(diphenyl)silyl]oxy}methyl)pyrrolidinium Tetrafluorobo-
rate (1i · HBF4). Prepared according to GP 3 from (R)-2-(bis[(4-tert-butyl)phenyl]{[methyl(diphenyl)-
silyl]oxy}methyl)pyrrolidine (1i; 559 mg, 0.99 mmol) and HBF4 · Et2O (137 ml, 0.99 mmol): V1 ¼ 60 ml;
V2 ¼ 20 ml; t1 ¼ 30 min; only the desired product was formed (no R3SiO deprotection occurred). Yield:
560 mg (86%). White solid. M.p. 181 – 1838. [a]rD:t: ¼ þ24.7 (c ¼ 0.52, CH2Cl2). IR: 2965w, 1591w, 1512w,
1477w, 1462w, 1429w, 1393w, 1363w, 1262w, 1101m, 1054s, 1012s, 954w, 916w, 860m, 834m, 792m, 777m,
1
t
736m, 722m, 697m, 669w. H-NMR (400 MHz, CDCl3): 0.36 (s, Me); 1.27 (s, Bu); 1.24 – 1.39 (m, 1 H,
CH2); 1.31 (s, tBu); 1.82 – 2.00 (m, CH2); 2.16 – 2.28 (m, 1 H, CH2); 2.39 – 2.51 (m, 1 H, CH2); 3.22 – 3.35
(m, 1 H, CH2); 4.83 – 4.92 (m, HꢀC(2)); 5.98 (br. s, 1 H, NHþ2 ); 7.08 (d, J ¼ 8.6, 2 arom. H); 7.16 (d, J ¼
8.6, 2 arom. H); 7.23 – 7.41 (m, 14 arom. H); 7.81 (br. s, 1 H, NHþ2 ). 13C-NMR (101 MHz, CDCl3): ꢀ 0.9;
24.1; 27.1; 31.3; 31.4; 34.66; 34.74; 47.9; 67.9; 82.5; 125.5; 125.7; 128.00; 128.03; 128.1; 128.5; 129.9; 130.0;
134.26; 134.30; 136.4; 137.0; 137.1; 152.1; 152.2. HR-MS (MALDI): 562.3500 (100, Mþ, C38H48NOSiþ;
calc. 562.34997). Anal. calc. for C38H48BF4NOSi (649.68): C 70.25, H 7.45, N 2.16; found: C 69.97, H 7.37,
N 1.97.
(S)-2-[Bis(3,5-dimethylphenyl)(methoxy)methyl]pyrrolidinium Hexafluorophosphate (1b · HPF6).
To a soln. of (S)-2-[bis(3,5-dimethylphenyl)(methoxy)methyl]pyrrolidinium hydrochloride (1b · HCl;
474 mg, 1.32 mmol) in EtOH (5 ml) under Ar was added a soln. of AgPF6 (333 mg, 1.32 mmol) in H2O
(2 ml). Upon addition of AgPF6, a white precipitate formed immediately (AgCl). The mixture was
stirred at r.t. for 10 min, then filtered through a short plug of Celite and washed with EtOH (30 ml).
Volatile components were evaporated in vacuo, and the residue was dried under high vacuum. The solid
residue was dissolved/suspended in anh. CH2Cl2, filtered through a short plug of Celite, and washed with
anh. CH2Cl2. Volatile components were evaporated in vacuo, and the solid residue was dissolved in anh.
CH2Cl2 and filtered through an HPLC filter to remove traces of insoluble by-products. Volatile
components were evaporated in vacuo, and the residue was dried under high vacuum to give 1b · HPF6.
Yield: 590 mg (95%). Light yellow-brownish solid. M.p. 206 – 2088. [a]rD:t: ¼ ꢀ18.5 (c ¼ 0.22, EtOH). IR:
3246w, 2920w, 1599m, 1457w, 1382m, 1359w, 1333w, 1269w, 1186w, 1156w, 1096w, 1070m, 824s, 764m,
741m, 715m, 699m. 1H-NMR (400 MHz, CDCl3): 1.19 – 1.35 (m, 1 H, CH2); 1.84 – 2.02 (m, CH2); 2.19 –
2.42 (m, 1 H, CH2); 2.31 (s, 2 Me); 2.32 (s, 2 Me); 2.67 – 2.82 (m, 1 H, CH2); 3.06 (s, MeO); 3.30 – 3.44 (m,
1 H, CH2); 4.77 – 4.91 (m, HꢀC(2)); 6.47 (br. s, 1 H, NHþ2 ); 6.88 (s, 2 arom. H); 6.94 (s, 2 arom. H); 7.01
(s, 2 arom. H); 7.92 (br. s, 1 H, NHþ2 ). 13C-NMR (101 MHz, CDCl3): 21.5; 21.6; 24.0; 27.4; 47.4; 51.7; 63.9;

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83.6; 126.1; 126.8; 130.5; 130.7; 138.0; 138.26; 138.29; 138.7. HR-MS (MALDI): 324.2322 (100, Mþ,
C22H30NOþ; calc. 324.23219). Anal. calc. for C22H30F6NOP (469.44): C 56.29, H 6.44, N 2.98; found: C
56.48, H 6.38, N 2.97.
(S)-2-{Bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilyl)oxy]methyl}pyrrolidinium Hydrochloride
(1e · HCl). To a soln. of (S)-2-{bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilyl)oxy]methyl}pyrroli-
dine (1e; 1000 mg, 1.67 mmol) in anh. Et2O (50 ml) under Ar at 08 was added a soln. of HCl (1.7 ml, 1m in
anh. Et2O, 1.7 mmol) diluted in anh. Et2O (30 ml) during 20 min. Upon stirring at 08 for additional
15 min, volatile components were evaporated in vacuo, and the residue was dried under high vacuum to
give 1e · HCl in quant. yield. White solid. M.p. 85 – 938. [a]rD:t: ¼ þ3.4 (c ¼ 0.64, CH2Cl2). IR: 1370w, 1276s,
1171m, 1127s, 1051w, 905m, 866w, 843m, 756w, 708m, 681s. 1H-NMR (300 MHz, (D6)DMSO): ꢀ 0.03 (s,
Me3SiO); 1.68 – 1.89 (m, CH2); 1.90 – 2.03 (m, 1 H, CH2); 2.28 – 2.43 (m, 1 H, CH2); 2.84 – 2.99 (m, 1 H,
CH2); 3.03 – 3.18 (m, 1 H, CH2); 4.99 – 5.13 (m, HꢀC(2)); 7.94 – 8.29 (m, 7 H, 6 arom. H, NHHþ); 10.41
(br. s, 1 H, NHþ2 ). HR-MS (MALDI): 598.1430 (100, Mþ, C24H24F12NOSiþ; calc. 598.14301). Anal. calc.
for C24H24ClF12NOSi (633.97): C 45.47, H 3.82, N 2.21; found: C 45.48, H 3.90, N 2.15.
Preparation of Enamines 3. (S)-2-{Diphenyl[(trimethylsilyl)oxy]methyl}-1-[(E)-2-phenylethenyl]-
pyrrolidine (3a). 2-Phenylacetaldehyde (339 ml, 2.90 mmol) was added to a soln. of (S)-2-{diphenyl-
[(trimethylsilyl)oxy]methyl}pyrrolidine (1d; 944 mg, 2.90 mmol) in anh. benzene (20 ml) under Ar in a
two-necked flask fitted with a stirrer bar, stopper, and a Dean – Stark trap filled with freshly activated 4-ꢅ
mol. sieves. Soln. went cloudy, and, after stirring at r.t. for 30 min, a slight emulsion resulted. The mixture
was heated to reflux (1208 bath temp.), and an orange soln. developed. After 2 h of reflux, the soln. was
cooled to r.t., more anh. benzene (10 ml) was added, and the mixture was returned to reflux. After a
further 2 h of reflux, the heating was stopped, and the flask was cooled under Ar. The Dean – Stark
condenser was removed, and the mixture was concentrated under vacuum, resulting in a light orange
foam. Recrystallization under Ar from anh. Et2O gave 3a (440 mg, 35%). Light yellow cubes. M.p. 152 –
1548 (dec.). [a]Dr:t: ¼ ꢀ283.8 (c ¼ 0.76, CHCl3). IR (neat) 2962w, 1630s, 1595m, 1491w, 1447m, 1387s,
1307w, 1250m, 1176w, 1149m, 1089s, 1063s, 1031s, 923m. 1H-NMR (300 MHz, CDCl3): ꢀ 0.11 (s, Me3Si);
0.48 – 0.64 (m, 1 H, CH2); 1.42 – 1.54 (m, 1 H, CH2); 1.93 – 2.16 (m, CH2); 2.57 (td, J ¼ 2.8; 9.2, 1 H, CH2);
2.94 (q, J ¼ 9.2, 1 H, CH2); 4.62 (dd, J ¼ 2.2; 9.0, HꢀC(2)); 5.02 (d, J ¼ 13.8, HꢀC(1’)); 6.95 (tt, J ¼ 1.2;
7.4, 1 arom. H); 7.06 (br. d, J ¼ 7.4, 2 arom. H); 7.19 (t, J ¼ 7.4, 2 arom. H); 7.25 (d, J ¼ 13.8, HꢀC(2’));
7.33 – 7.43 (m, 6 arom. H); 7.48 – 7.54 (m, 4 arom. H). 13C-NMR (75 MHz, CDCl3): 2.2; 22.7; 28.0; 48.6;
70.0; 83.9; 97.2; 122.6; 123.1; 127.3; 127.6 (2ꢄ); 128.4 (2ꢄ); 129.5; 129.7; 137.4; 140.4; 142.2; 142.7. EI-MS:
172 (100); 173 (15); 255 (2.5); 338 (0.5); 412 (1); 427 (0.4). HR-EI-MS: 427.2328 (C28H33NOSiþ; calc.
427.2326).
(S)-1-[(1E)-3,3-Dimethylbut-1-en-1-yl)-2-({[methyl(diphenyl)silyl]oxy}(diphenyl)methyl)pyrro-
lidine (3b). To a soln. of (S)-2-({[methyl(diphenyl)silyl]oxy}(diphenyl)methyl)pyrrolidine (1h; 192 mg,
0.43 mmol) in anh. C6D6 (8 ml) under Ar was added 3,3-dimethylbutanal (56 ml, 0.43 mmol), and the
resulting mixture was heated under reflux under Dean – Stark condition using freshly activated 4-ꢅ mol.
sieves. After 1 h, ca. 87% conversion was achieved according to 1H-NMR analysis of the mixture (0.7-ml
aliquot). Additional 3,3-dimethylbutanal (56 ml, 0.43 mmol) was added to the mixture, and heating under
reflux was continued for further 3 h to give 100% conversion. Volatile components were evaporated in
vacuo, and the residue was dried under high vacuum to remove all traces of volatile compounds to give 3b
as an orange-yellow semisolid. The product was stored under Ar. The product 3b is highly sensitive to
hydrolysis and should, therefore, always (during the synthesis, reaction workup, storage etc.) be kept
under dry Ar in carefully dried glassware. 1H-NMR (300 MHz, C6D6): 0.22 (s, Me); 0.40 – 0.58 (m, 1 H,
t
CH2); 1.00 (s, Bu); 1.15 – 1.27 (m, 1 H, CH2); 1.80 – 1.93 (m, 1 H, CH2); 2.09 – 2.20 (m, 1 H, CH2); 2.72
(dd, J ¼ 5.0; 9.0, CH2); 4.26 (d, J ¼ 14.0, HꢀC(1’)); 4.43 (dd, J ¼ 1.8; 8.9, HꢀC(2)); 6.14 (d, J ¼ 14.0,
HꢀC(2’)); 6.91 – 7.00 (m, 3 arom. H); 7.01 – 7.07 (m, 3 arom. H); 7.12 – 7.22 (m, 6 arom. H); 7.41 – 7.46 (m,
2 arom. H); 7.47 – 7.57 (m, 4 arom. H); 7.63 – 7.68 (m, 2 arom. H). 13C-NMR (75 MHz, C6D6): ꢀ 0.8; 23.3;
28.8; 29.8; 32.0; 49.9; 70.5; 85.1; 110.3; 117.3; 127.3; 127.4; 127.7; 127.8; 128.0; 129.57; 129.62; 129.9; 130.4;
133.8; 134.56; 134.63; 138.6; 139.1; 142.1; 143.7.
Preparation of the Iminium Salts 4. Preparation of 4b · BF4, (E/Z)-4b · PF6, 4d · BF4, (E/Z)-4h ·
BF4, and 4i · BF4. General Procedure 4 (GP 4)30). To a soln./suspension of a PF6ꢀ or BFꢀ4 salt of a
secondary amine in anh. EtOH (V1) under Ar was added cinnamaldehyde (1.05 equiv.), followed by

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addition of Et3N (V2). The mixture was stirred vigorously at r.t. until a filterable precipitate was formed
(t1). The precipitate was collected on a dry ceramic frit under Ar and washed with anh. Et2O (20 ml) to
give iminium salts 4b · BF4, (E/Z)-4b · PF6, 4d · BF4, (E/Z)-4h · BF4, and 4i · BF4. The isolated products
were dried under high vacuum and stored under Ar.
(S)-2-[Bis(3,5-dimethylphenyl)(methoxy)methyl]-1-[(2E)-3-phenylprop-2-en-1-ylidene]pyrrolidini-
um Tetrafluoroborate (4b · BF4). Prepared according to GP 4 from (S)-2-[bis(3,5-dimethylphenyl)(me-
thoxy)methyl]pyrrolidinium tetrafluoroborate (1b · BF4; 330 mg, 0.80 mmol) and cinnamaldehyde
(108 ml, 0.84 mmol): V1 ¼ 2 ml; V2 ¼ 5 ml; t1 ¼ 3 h. Yield: 322 mg (76%). Light yellow solid. M.p. 232 –
2358. [a]rD:t: ¼ ꢀ194.6 (c ¼ 0.59, CH2Cl2). IR: 2960w, 1623m, 1608m, 1591m, 1450w, 1424w, 1330w,
1
1283w, 1189w, 1178m, 1075s, 1051s, 997m, 957w, 862w, 848m, 761s, 693m. H-NMR (400 MHz, CDCl3):
1.12 – 1.25 (m, 1 H, CH2); 1.67 – 1.81 (m, 1 H, CH2); 1.99 – 2.10 (m, 1 H, CH2); 2.34 – 2.49 (m, 1 H, CH2);
2.24 (s, 2 Me); 2.32 (s, 2 Me); 2.53 – 2.63 (m, 1 H, CH2); 2.99 (s, MeO); 3.86 – 3.96 (m, 1 H, CH2); 5.27 (dd,
J ¼ 3.1; 8.9, HꢀC(2)); 6.81 (s, 2 arom. H); 6.94 (s, 2 arom. H); 7.00 (d, J ¼ 14.8, 2 arom. H); 7.04 (dd, J ¼
10.5; 15.3, HꢀC(2’)); 7.42 – 7.54 (m, 3 arom. H); 7.81 (d, J ¼ 7.1, 2 arom. H); 8.00 (d, J ¼ 15.2, HꢀC(3’));
8.58 (d, J ¼ 10.5, HꢀC(1’)). 13C-NMR (101 MHz, CDCl3): 21.5; 21.6; 22.4; 26.8; 52.0; 52.8; 72.9; 86.0;
117.3; 126.8; 127.6; 129.5; 130.2; 130.4; 130.7; 133.6; 133.7; 136.9; 137.2; 137.8; 138.0; 161.9; 168.5. HR-MS
(MALDI): 438.2791 (100, Mþ, C31H36NOþ; calc. 438.27914). Anal. calc. for C31H36BF4NO (525.43): C
70.86, H 6.91, N 2.67; found: C 70.77, H 6.99, N 2.64.
(S)-2-[Bis(3,5-dimethylphenyl)(methoxy)methyl]-1-[(2E)-3-phenylprop-2-en-1-ylidene)pyrrolidini-
um Hexafluorophosphate (4b · PF6; (E)/(Z) 1:0.06). Prepared GP 4 from (S)-2-[bis(3,5-dimethylphe-
nyl)(methoxy)methyl]pyrrolidinium hexafluorophosphate (1b · PF6) (500 mg, 1.06 mmol) and cinnamal-
dehyde (144 ml, 1.12 mmol): V1 ¼ 1.5 ml; V2 ¼ 10 ml; t1 ¼ 2 h. Yield: 580 mg (93%; (E)/(Z) 1:0.06).
Yellowish solid. M.p. 242 – 2458. [a]rD:t: ¼ ꢀ178.8 (c ¼ 0.23, CH2Cl2). IR: 2956w, 1628m, 1608m, 1592m,
1454w, 1319w, 1281w, 1188w, 1177m, 1076m, 998w, 954w, 877w, 833s, 756m, 741w, 689m. 1H-NMR
(400 MHz, CDCl3): (E)-isomer: 1.16 – 1.29 (m, 1 H, CH2); 1.70 – 1.83 (m, 1 H, CH2); 2.01 – 2.11 (m, 1 H,
CH2); 2.25 (s, 2 Me); 2.32 (s, 2 Me); 2.38 – 2.50 (m, 1 H, CH2); 2.51 – 2.62 (m, 1 H, CH2); 2.97 (s, MeO);
3.77 – 3.89 (m, 1 H, CH2); 5.24 (dd, J ¼ 3.7; 9.2, HꢀC(2)); 6.82 (s, 2 arom. H); 6.93 (dd, J ¼ 10.7; 15.2,
HꢀC(2’)); 6.94 (s, 2 arom. H); 7.02 (d, J ¼ 9.9, 2 arom. H); 7.42 – 7.48 (m, 2 arom. H); 7.49 – 7.55 (m, 1
arom. H); 7.73 – 7.79 (m, 2 arom. H); 7.91 (d, J ¼ 15.2, HꢀC(3’)); 8.51 (d, J ¼ 10.6, HꢀC(1’)); (Z)-isomer:
2.88 (s, MeO); 3.61 – 3.68 (m, 1 H, CH2); 5.52 (dd, J ¼ 4.4; 9.1, HꢀC(2)). 13C-NMR (101 MHz, CDCl3):
(E)-isomer: 21.57; 21.63; 22.5; 26.8; 52.1; 52.8; 73.5; 86.2; 117.0; 126.9; 127.7; 129.6; 130.4; 130.6; 130.7;
133.6; 133.9; 136.7; 136.8; 138.0; 138.1; 162.1; 168.3. HR-MS (MALDI): 438.2791 (100, Mþ, C31H36NOþ;
calc. 438.27914). Anal. calc. for C31H36F6NOP (583.59): C 63.80, H 6.22, N 2.40; found: C 63.71, H 6.23, N
2.39.
(S)-2-{Diphenyl[(trimethylsilyl)oxy]methyl}-1-[(2E)-3-phenylprop-2-en-1-ylidene)pyrrolidinium
Tetrafluoroborate (4d · BF4). Prepared according to GP 4 from (S)-2-{diphenyl[(trimethylsilyl)oxy]me-
thyl}pyrrolidinium tetrafluoroborate (1d · BF4) (327 mg, 0.79 mmol) and cinnamaldehyde (107 ml,
0.83 mmol): V1 ¼ 1 ml; V2 ¼ 5 ml; t1 ¼ 24 h. Yield: 105 mg (25%). Light yellow solid. M.p. 155 – 1588.
[a]Dr:t: ¼ ꢀ110.9 (c ¼ 0.13, CH2Cl2). IR: 2953w, 1619m, 1608m, 1592m, 1446w, 1327w, 1288w, 1253w,
1182m, 1053s, 1001m, 928w, 915w, 870m, 839s, 764s, 704s, 690m. 1H-NMR (400 MHz, CDCl3): ꢀ 0.16 (s,
Me3Si); 1.15 – 1.29 (m, 1 H, CH2); 1.67 – 1.82 (m, 1 H, CH2); 1.99 – 2.09 (m, 1 H, CH2); 2.44 – 2.56 (m, 1 H,
CH2); 2.62 – 2.73 (m, 1 H, CH2); 3.85 – 3.95 (m, 1 H, CH2); 5.46 (d, J ¼ 7.4, HꢀC(2)); 7.00 (dd, J ¼ 10.7;
15.2, HꢀC(2’)); 7.25 – 7.54 (m, 13 arom. H); 7.67 – 7.75 (m, 3 H, 2 arom. H, HꢀC(3’)); 8.53 (d, J ¼ 10.6,
HꢀC(1’)). 13C-NMR (101 MHz, CDCl3): 1.6; 22.6; 26.2; 52.4; 76.3; 83.5; 117.2; 128.3; 128.75; 128.86;
128.88; 129.1; 129.5; 129.6; 130.7; 133.6; 133.8; 140.1; 140.4; 161.5; 168.4. HR-MS (MALDI): 440.2404
(100, Mþ, C29H34NOSiþ; calc. 440.24042). Anal. calc. for C29H34BF4NOSi (527.48): C 66.03, H 6.50, N
2.66; found: C 65.90, H 6.53, N 2.49.
(S)-2-({[Methyl(diphenyl)silyl]oxy}(diphenyl)methyl)-1-[(2E)-3-phenylprop-2-en-1-ylidene)pyrro-
lidinium Tetrafluoroborate (4h · BF4; (E)/(Z) 1:0.03). Prepared according to GP 4 from (S)-2-
({[methyl(diphenyl)silyl]oxy}(diphenyl)methyl)pyrrolidinium tetrafluoroborate (1h · BF4) (417 mg,
0.78 mmol) and cinnamaldehyde (105 ml, 0.82 mmol): V1 ¼ 3 ml; V2 ¼ 10 ml; t1 ¼ 20 h. Yield: 250 mg
(49%; (E)/(Z) 1:0.03). Light yellow solid. M.p. 196 – 1988. [a]rD:t: ¼ ꢀ160.2 (c ¼ 0.79, CH2Cl2). IR: 3071w,
1615m, 1589m, 1450w, 1430w, 1326w, 1285w, 1259w, 1181m, 1057s, 996s, 958w, 927w, 852m, 792m, 755m,