A new route to chiral imidazolidine salts and its application in organometallic synthesis

Article abstract of DOI:10.1016/j.tetasy.2008.06.006

A cost-efficient and high-yielding synthesis of enantiomerically pure imidazolidine salts is presented in this work. Starting from non-chiral amines, chirality is introduced using a Grignard reagent. Separation by the formation of a diastereomeric salt and subsequent condensation of the separated material with HC(OEt)₃ and NH₄BF₄ leads to the desired chiral product. Transmetallation allows the attachment of the new imidazolidine ligand to organometallic metal precursors such as [Rh(COD)Cl]₂.

Full text of DOI:10.1016/j.tetasy.2008.06.006

Tetrahedron: Asymmetry 19 (2008) 1532–1535
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new route to chiral imidazolidine salts and its application
in organometallic synthesis
a,b,
Sandra C. Zinner a, Wolfgang A. Herrmann a, , Fritz E. Kühn
*
*
a Department of Chemistry, Chair of Inorganic Chemistry, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany
b Department of Chemistry, Molecular Catalysis, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A cost-efficient and high-yielding synthesis of enantiomerically pure imidazolidine salts is presented in
this work. Starting from non-chiral amines, chirality is introduced using a Grignard reagent. Separation
by the formation of a diastereomeric salt and subsequent condensation of the separated material with
HC(OEt)3 and NH4BF4 leads to the desired chiral product. Transmetallation allows the attachment of
the new imidazolidine ligand to organometallic metal precursors such as [Rh(COD)Cl]2.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 9 April 2008
Accepted 6 June 2008
Available online 14 July 2008
1. Introduction
R
R
R
R
ArBr
Nearly 40 years have passed since the first successful incorpora-
tion of N-heterocyclic carbenes (NHCs) as ligands in transition
Pd(OAc)2, BINAP
NH2
Ar
H2N
HN
Ar NH
NaO t-Bu
metal complexes.1 The strong
r-donor ability of NHCs to metals
and their high temperature-, air- and moisture-stability in compar-
ison to phosphines has led to a high interest in these compounds as
ligands in organometallic chemistry and catalysis.2 There are
numerous applications of NHC ligated transition metal complexes,
including reactions such as hydrosilylation, hydrogenation and
metathesis.3
R
N
R
-
BF4
NH4BF4
HC(OEt)3
N
Ar
Ar
Scheme 1.
Asymmetric transition metal catalysis is an emerging area for
the application of NHCs.4 So far, the most successful example of
a chiral monodentate non-chelating NHC–Ru complex applied in
asymmetric metathesis was published by Grubbs et al.5 The ob-
tained high enantiomeric excess (ee = 90%) furthered the interest
and belief in the potential of NHC complexes in enantioselective
synthesis. Accordingly, special syntheses were developed for NHCs
with stereogenic centres in their backbone. One widely applied
synthesis consists of a two-step reaction first presented by Grubbs
et al. (Scheme 1).5 An enantiomerically pure diamine is substituted
by a Pd-catalyzed cross coupling and subsequent condensation
with triethyl orthoformate and ammonium tetrafluoroborate,
resulting in the formation of a chiral imidazolidine salt.
such as manganese, magnesium or zinc as both reduction agent
and coupling agent for diimines (Scheme 2).6 The major drawback
of this method, however, is the high yield of the meso compound.
Ph
Ph
Ar
HN
Ar NH
xs Metal
xs TFA
(rac)
+
For bulkier groups at the nitrogen, which are particularly inter-
esting for chiral induction in asymmetric catalysis, unfortunately,
the coupling takes place with low or non-measurable yields. Sig-
man et al. described an alternative synthesis using different metals
N
Ph
Ph
Ph
HN Ar
Ar NH
* Corresponding authors. Tel.: +49 89 289 13080; fax: +49 89 289 13143 (F.E.K.).
E-mail addresses: wolfgang.herrmann@ch.tum.de (W. A. Herrmann), fritz.
kuehn@ch.tum.de (F. E. Kühn).
(meso)
Scheme 2.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.006

S. C. Zinner et al. / Tetrahedron: Asymmetry 19 (2008) 1532–1535
1533
An easy method of separation, especially for larger amounts, is not
available and therefore makes this procedure unattractive.
Recently several chiral rhodium and iridium complexes with re-
stricted ligand flexibility and their applications in catalysis have
been reported.7 In contrast to the usually advantageous application
of chiral diamines as starting materials, we herein report a differ-
ent approach towards asymmetric N-heterocyclic carbenes and
the application of such carbenes as ligands in chiral rhodium
complexes.
mation of this complex displays the C@N bonds in a coplanar fash-
ion. The stereochemistry of the first tBu group can be either (S) or
(R), whilst the direction of entry of the second tBu-moiety is deter-
mined by a 1,2-effect (from the newly established asymmetric
centre) (Fig. 1).9,10
A racemic mixture of both enantiomers 2 can be isolated by
extraction with diethyl ether in 91% yield. The enantiomers can
be quantitatively separated by stereoselective crystallization with
tartaric acid (Scheme 3).11 Therefore, (+)-tartaric acid or (ꢀ)-tar-
taric acid is added to a solution of compound 2 in hot ethanol to
yield a precipitate of the corresponding enantiomerically pure
diamine tartrate.
2. Results and discussion
Diamines 2a and 2b are liberated with NaOH, and the enantio-
meric purity is verified with a CDA in NMR (Scheme 4).12 The P-
complexes 4a and 4b of both chiral diamines can be identified by
their different shifts in 31P NMR. The separation with tartaric acid
is repeated until the compounds are enantiomerically pure.
2.1. Synthesis of chiral imidazolidine salts
The starting material for the chiral imidazoline salt, compound
1, was prepared according to literature procedures via the reaction
of 2 equiv of 2,6-diisopropylphenylamine with 1 equiv of glyoxal.8
Following the proposed mechanism by Simpkins et al., subsequent
Grignard addition of the tBu-moieties at the diimine proceeds in a
two-step reaction (Fig. 1). In these additions, a rigid five-mem-
bered chelate is generated, including the two nitrogen atoms that
lead to an activation of the imine double bonds. The stable confor-
Ar
N
S
P
O
N
Ar
4a
1.) PCl3
2.) (+)-Menthol
3.) S8
t
BuMgCl
R
Ar
t
BuMgCl
NH
+
R
N
NH
Ar
R
N
N
N
R
M
M
Ar
N
S
(rac)
Figure 1. Chelation during Grignard addition.
P
O
N
2
Ar
4b
Ar
N
N
Ar
1
Scheme 4.
t
BuMgCl
The reaction of the chiral diamine 2b to form the imidazolidine
salt 3b is carried out by condensation with triethyl orthoformate
and ammonium tetrafluoroborate.13 After extraction, evaporation
of the solvent and recrystallization in ethanol, the salt is obtained
as an off-white solid in 83% yield (Scheme 5). An equivalent reaction
of the (R,R)-enantiomer 2a yields the corresponding chiral salt 3a.
Ar
NH
HN
Ar
(rac)
2
NH4BF4
1.) (-)-tartaric acid
2.) NaOH
HC(OEt)3
1.) (+)-tartaric acid
2.) NaOH
Ar
NH
HN Ar
2b
N
N
Ar
Ar
-
BF4
3b
Scheme 5.
Ar
NH
Ar
HN
Ar
NH
HN
Ar
(R,R)
2a
2.2. Synthesis of [(4R,5R)-1,3-bis[2,6-diisopropylphenyl]-4,5-di-
tert-butylimidazolin-2-ylidene][(1,2,5,6-g)-1,5-cyclooctadiene]-
iodorhodium(I)
(S,S)
2b
Ar = 2,6-diisopropylphenyl
Amongst the various synthetic pathways for obtaining transi-
tion metal carbene complexes,3a a mild carbene transfer method
Scheme 3.

1534
S. C. Zinner et al. / Tetrahedron: Asymmetry 19 (2008) 1532–1535
Ag2O, NaI
[Rh(COD)Cl]2
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
Ar
-
BF4
Rh
I
Ag
I
3b
5
6
Scheme 6.
was developed by Wang and Lin.14 For the transmetallation, a sil-
ver carbene complex (compound 5) was prepared and subse-
quently reacted with [Rh(COD)Cl]2 as a metal precursor (Scheme
6).
The suspension was stirred for 16 h, after which the precipitate
was filtered over Celite and the complex recovered using gradient
column chromatography. In a first fraction using CH2Cl2 as an elu-
ent, small amounts of unreacted starting material were obtained.
Additional elutions with acetone were used to retrieve complex
6. Subsequent re-crystallization in a mixture of acetone and Et2O
led to air-stable, pale-yellow crystals.
tet and m = multiplet. MS spectra were measured at the TU Mün-
chen Mass Spectrometry Laboratory on a Finnigan MAT 90 mass
spectrometer using FAB and CI techniques. Optical rotations were
measured on a Perkin–Elmer 341. Elemental analyses were carried
out by the Microanalytic Laboratory at the TU München.
4.2. Synthesis of N,N0-bis-(2,6-diisopropyl-phenyl)-rac-1,2-
diamino-1,2-di-tert-butylethane 2
At first, 30 mL of tert-butylmagnesiumchloride (1.7 M in Et2O)
was suspended in 300 mL of n-hexane and heated to 50 °C. A solu-
tion of 8 g (21 mmol) of diimine 1 in 80 mL of n-hexane was then
added dropwise to the Grignard mixture, after which the suspen-
sion is stirred for 1 h under argon atmosphere.
The successful carbene transfer was confirmed by analytical
methods. The most indicative result is the carbene–carbon signal
at 224 ppm, observed by 13C NMR spectroscopy. The 103Rh–13
C
coupling constant is 1JRh,C = 47 Hz. Both findings are in good accor-
dance with results previously reported for saturated NHC-com-
plexes.7a Due to the high nucleophilicity of these types of
complexes compared to unsaturated NHC-complexes, a shift of
the carbene–carbon signal to lower field is usual. The preservation
of chirality was determined by polarimetry, which showed a spe-
cific rotation of ꢀ60.6°.
After cooling to room temperature, 120 mL of a saturated NH4Cl
solution and 100 mL of Et2O were added. The obtained reaction
mixture is stirred for another 30 min. The phases were subse-
quently separated and the water phase was extracted with Et2O
(2 ꢁ 100 mL). The combined organic phases were dried over
K2CO3. After evaporation of the solvent and recrystallization in eth-
anol, compound 2 (9.45 g, 90%) was isolated as a colourless solid.
dH (400 MHz, CDCl3): 0.89–0.93 (dd, J 6, 12H, CH(CH3)2), 1.17–
1.28 (dd + s, 30H, CH(CH3)2 + C(CH3)3), 2.25–3.31 (m, 2H,
CH(CH3)2), 3.29–3.36 (m, 2H, CH(CH3)2), 3.76 (br s, 2H, NH), 3.98
(d, J 6.2, 2H, NCH), 6.95–7.05 (m, 6H, CHphenyl); dC (100 MHz, CDCl3)
22.9, 24.1, 27.1, 28.1, 35.5, 71.4, 122.6, 123.7, 137.2, 140.3, 140.9,
148.8. m/z (CI): 491.3 ([M+], 39%), 435.3 (100), 377.3 (3). Anal.
Calcd for C104H174N6O: C, 81.93; H, 11.50; N, 5.51. Found: C,
82.03; H, 11.09; N, 5.76.
3. Conclusions
An inexpensive and high-yielding synthesis of chiral imidazo-
lidine salts is reported in this work. With this procedure new
substitution patterns on the backbone of the complex should be
possible, leading to a broadening of the range of chiral imidazoli-
dine salts. The use of the synthesized compound as a chiral ligand
in an asymmetric rhodium–NHC complex is also discussed. Their
potential application in asymmetric transition metal catalysis is
currently under investigation in our laboratories.
4.3. Enantiomer separation of N,N0-bis-(2,6-diisopropyl-
phenyl)-rac-1,2-diamino-1,2-di-tert-butylethane 2
At first, 9.45 g of diamine 2 (19.2 mmol) was dissolved in
110 mL of hot ethanol. A solution of 1.44 g L-(+)-tartaric acid
4. Experimental
4.1. General
(9.6 mmol) in the minimum volume of water was added. After
16 h the precipitate was filtered off and washed with cold ethanol.
For liberating the enantiomer, 40 mL of NaOH (4 M) and 40 mL of
Et2O were added and the suspension stirred for 30 min. The phases
were separated, and the water phase is extracted again with Et2O
(2 ꢁ 40 mL). The combined organic phases were dried over MgSO4.
After removing the solvent, 2a was obtained as a colourless
solid. 4.70 g (99%). The enantiomeric purity was verified by a
All reactions were carried out in an air atmosphere unless sta-
ted otherwise. N,N0-Bis(2,6-diisopropylphenyl)imine 1 was synthe-
sized in accordance with previously reported methods.8 All other
materials were obtained commercially and used without further
purification. All solvents, except for those used in extraction proce-
dures, were dried on an alumina-based solvent purification system.
NMR spectra were recorded on a JEOL JMX-GX 400 spectrometer
operating at 400 MHz (1H NMR), 100 MHz (13C NMR) and on a Bru-
ker AMX 400 operating at 400 MHz (1H NMR), 100 MHz (13C NMR).
The spectra were calibrated to the residual proton of the solvents.
Coupling constants J are given in Hertz. NMR multiplicities are
abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quar-
CDA according to literature procedures.12
Et2O).
½
a 2D0
ꢂ
¼ ꢀ16 (c 0.0063,
For obtaining the (S,S)-enantiomer 2b, the mother liquor and
the washing fractions of the separation mentioned above were col-
lected, and the solvent was evaporated. The obtained solid was
stirred in NaOH (4 M) and extracted with Et2O as described for

S. C. Zinner et al. / Tetrahedron: Asymmetry 19 (2008) 1532–1535
1535
the (R,R)-enantiomer. For chiral purification, the solid was dis-
solved in 110 mL of hot ethanol and 1.44 g (9.6 mmol) of
-(ꢀ)-tar-
(400 MHz, CDCl3): 1.11–1.25 (m, 30H, CH(CH3)2 + C(CH3)3), 1.76–
1.80 (m, 4H, COD–CH2), 2.36–2.53 (m, 4H, COD–CH2, 4H,
CH(CH3)2), 3.66 (m, 4H, COD–CH), 6,82 (d, 2H, NCH), 7.19–7.23
(d, 4H, CHphenyl), 7.38–7.46 (dd, 2H, CHphenyl); dC (100 MHz,CDCl3):
22.2, 24.3, 24.7, 27.2, 28.6, 29.1, 30.5, 68.0, 78.6, 120.0, 124.3,
124.5, 130.5, 130.9, 145.5, 146.3, 224.3. m/z (CI): 550.5
([M+ꢀ(COD+I+tBu)], 70%), 506.7 (46), 444.9 (100). Anal. Calcd for
D
taric acid, which is dissolved in a minimum volume of water, then
added. After 16 h, the crystallized diamine tartrate was filtered off,
washed in cold ethanol and stirred in 40 mL of NaOH (4 M) and
40 mL of Et2O for 30 min. The phases were then separated, and
the water phase is extracted again with Et2O (2 ꢁ 40 mL). The sol-
vent was removed and 4.72 g (100%) of the product as a colourless
solid was obtained. The enantiomeric purity was verified by a CDA
C
43H65N2RhIꢃCH3CN: C, 61.26; H, 8.00; N, 4.30. Found: C, 61.78;
H, 7.75; N, 4.65.
according to literature procedures.12
½
a 2D0
ꢂ
¼ þ16 (c 0.006, Et2O).
Acknowledgements
4.4. Synthesis of 1,3-bis-(2,6-diisopropylphenyl)-(4R,5R)-di-
tert-butyl-4,5-dihydro-imidazolin tetrafluoroborate 3a and 1,3-
bis-(2,6-diisopropylphenyl)-(4S,5S)-di-tert-butyl-4,5-dihydro-
imidazolin tetrafluoroborate 3b
This work was supported by the Bayerische Eliteförderung der
Universität Bayern e. V. (scholarship for S.C.Z.) and by the elite net-
work NanoCat.
At first, 2 g of diamine 2a or 2b (4.1 mmol) was dissolved in
5 mL of HC(OEt)3, after which 0.51 g of NH4BF4 (4.9 mmol) is added
and the suspension is refluxed for 5 h. After cooling to room tem-
perature, 5 mL of Et2O was added, and the phases were separated.
The water phase was extracted two more times with Et2O
(2 ꢁ 5 mL). The organic phases were combined, and the solvent is
evaporated. The residue is extracted with DCM, filtered, dried over
Na2SO4, and the solvent is evaporated. Then 1.99 g (83%) of a beige
References
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solid was finally obtained ½a D20
¼ ꢀ83:3 (c 0.0012, CH2Cl2). dH
ꢂ
(400 MHz, CDCl3): 1.08–1.33 (qd, 24H, CH(CH3)2), 1.23 (s, 18 H,
C(CH3)3), 2.31 (m, 4H, CH(CH3)2), 3.42 (m, 2H, NCH), 7.26–7.34
(m, 4H, CHphenyl), 7.50 (t, J 7.83, 1H, CHphenyl), 7.59 (t, J 7.84, 1H,
CHphenyl), 8.83 (s, 1H, NCH); dC (100 MHz, CDCl3): 21.5, 23.9, 24.2,
26.1, 29.0, 29.5, 32.7, 77.0, 121.7, 124.5, 124.8, 129.6, 129.8,
132.6, 138.9, 145.4, 145.6. m/z (FAB): 445.2 ([M+ꢀtBu], 100%). Anal.
Calcd for C35H55N2BF4: C, 71.17; H, 9.39; N, 4.74. Found: C, 71.01;
H, 9.06; N, 4.59.
3. (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290; (b) Jafarpour, L.;
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4.5. Synthesis of [(4R,5R)-1,3-bis[2,6-diisopropylphenyl]-4,5-di-
tert-butylimidazolin-2-ylidene][(1,2,5,6-g)-1,5-cyclooctadiene]-
iodorhodium(I) 6
To a solution of 3a (590 mg, 1.2 mmol) 15 mL of dry CH3CN,
Ag2O (301 mg, 1.3 mmol) and NaI (225 mg, 1.5 mmol) was added
in the dark. The mixture was refluxed for 1 h at 60 °C under argon.
The silver precipitate was removed by filtration over Celite. The
solvent was removed under vacuum and the complex used without
further purification. The solid was dissolved in 15 mL of CH2Cl2,
after which 301 mg of [Rh(COD)Cl]2 (0.6 mmol) was added. The
suspension was stirred for 16 h in the dark. Purification of the com-
plex was carried out by filtration over a pad of Celite and gradient
column chromatography over silica gel. Elution with CH2Cl2 led to
a [Rh(COD)Cl]2 fraction and subsequent elution with acetone
yielded compound 6. After evaporation of the solvent, the yellow
solid was recrystallized in a mixture of acetone and Et2O (1:1).
11. Corey, E. J.; Lee, D.-H.; Sarshar, S. Tetrahedron: Asymmetry 1995, 6, 3.
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Yield: 737 mg, 0.8 mmol, 73% ½a D20
¼ ꢀ60:6 (c 0.025, CH2Cl2). dH
ꢂ