Novel chiral 1,3-diamines by a highly modular Umpolung strategy employing a diastereoselective fluorination-nucleophilic aromatic substitution sequence

Article abstract of DOI:10.1002/ejoc.200700764

A new highly modular synthesis for the rare class of chiral 1,3-diamines has been devised. It is accessible through nucleophilic aromatic ipso-substitution of fluorine in [(R,R)-1-fluoro-2-{(1-dimethylamino)ethyl} benzene]tricarbonylchromium and related complexes by secondary as well as primary amines. The precursor is accessible by a new diastereoselective electrophilic fluorination using N-fluorobenzenesulfonimide (NFSI), and the method is of potential interest for the synthesis of fluorinated pharmaceuticals. The protocol allows for the straightforward, modular synthesis of a broad library of diamines. A stock of 21 diamines has been synthesized. Primary amines bearing a stereogenic α-center can be introduced without loss of optical purity, yielding planar-chiral diamines with two stereogenic centers in close proximity. An extended number of X-ray structures of these diamines is presented and discussed along with NMR experiments which show them to be chiral proton-donors . The 1,3-diaminoarene moiety can easily be liberated from the chromium complex by decomplexation with I2 as exemplified in four examples. The new methodology adds a powerful tool to the synthesis of organic diamines, and opens a new way to the formerly difficult-to-access class of chiral 1,3-diamines. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700764

FULL PAPER
DOI: 10.1002/ejoc.200700764
Novel Chiral 1,3-Diamines by a Highly Modular Umpolung Strategy
Employing a Diastereoselective Fluorination–Nucleophilic Aromatic
Substitution Sequence
Wolfgang Braun,*[a] Beatrice Calmuschi-Cula,[a] Ulli Englert,[a] Karola Höfener,[a]
Elisabetta Alberico,[b] and Albrecht Salzer*[a]
Dedicated to the memory of our friend and colleague Prof. Dr. Birgit Drießen-Hölscher
Keywords: Amines / Chirality / Aromatic substitution / Nucleophilic substitution / Halogenation / Chromium / Asymmetric
synthesis / Umpolung
A new highly modular synthesis for the rare class of chiral
1,3-diamines has been devised. It is accessible through nu-
cleophilic aromatic ipso-substitution of fluorine in [(R,R)-1-
fluoro-2-{(1-dimethylamino)ethyl}benzene]tricarbonylchro-
mium and related complexes by secondary as well as primary
amines. The precursor is accessible by a new diastereoselec-
tive electrophilic fluorination using N-fluorobenzenesulfon-
imide (NFSI), and the method is of potential interest for the
synthesis of fluorinated pharmaceuticals. The protocol allows
for the straightforward, modular synthesis of a broad library
of diamines. A stock of 21 diamines has been synthesized.
Primary amines bearing a stereogenic α-center can be intro-
duced without loss of optical purity, yielding planar-chiral di-
amines with two stereogenic centers in close proximity. An
extended number of X-ray structures of these diamines is
presented and discussed along with NMR experiments which
show them to be “chiral proton-donors”. The 1,3-diaminoar-
ene moiety can easily be liberated from the chromium com-
plex by decomplexation with I2 as exemplified in four exam-
ples. The new methodology adds a powerful tool to the syn-
thesis of organic diamines, and opens a new way to the for-
merly difficult-to-access class of chiral 1,3-diamines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
cyclohexane (dach),[2] diphenylethylenediamine (dpen)[3] or
diaminobis(naphthalene) (binam).[4] A search using Sci-
Finder, on the other hand, gives just 3 hits when inquiring
for “chiral 1,3-diamines”: a ferrocene derivative,[5] a class of
anilines[6] useful as a chiral proton source, and some di-
aminopropanes derived from chiral aziridines.[7]
Chiral diamines have gained considerable importance in
pharmaceutical chemistry, mostly 1,2-diamines, as in the
synthesis of tamiflu;[8a,8b] in addition, examples of 1,3-di-
amines of pharmaceutical importance are known.[8c]
Chiral fluorinated compounds have gathered importance
in chemistry in recent years,[9] as intermediates for further
functionalization as well as target structures in pharmaco-
logical research.[10] Fluorine groups can replace C–H
groups with relatively inert moieties with respect to human
metabolism, increase lipophilicity (especially Ar–F) and
acidity, act as bioisosteric mimics for other potentially more
labile groups, contribute to peptidomimetics, and be valu-
able analytical probes involving the 19F nucleus. In 1970,
not more than 2% of pharmaceuticals contained fluorine
compared to 18% in 2006. In the same year, 9 out of 31
drugs approved in the U.S.A. contained fluorine. Because
the fluorine atom has to be introduced stereoselectively, en-
Introduction
Since the discovery by Alfred Werner that chelating di-
amines can enhance the kinetic stability of metal com-
plexes[1] and the first isolation of chiral-at-metal complexes,
chelating ligands, especially diamines, have become an inte-
gral part of coordination chemistry. Applications of chelat-
ing ligands range from detergents to biochemistry, from
cancer therapy to metallurgy to new polymerization meth-
ods. Chiral derivatives have also found entry into homogen-
eous catalysis as rivals to phosphane ligands. A survey of
the known and widely applied ligands shows most of them
to be either 1,2-diamines or 1,4-diamines, the majority of
which display C2-symmetry, for example, diamino-
[a] Institut für Anorganische Chemie, RWTH Aachen University,
52056 Aachen, Germany
Fax: +49-241-8092288
E-mail: wolfgang.braun@ac.rwth-aachen.de
albrecht.salzer@ac.rwth-aachen.de
[b] Istituto di Chimica Biomolecolare, Consiglio Nazionale delle
Ricerche,
07040 Sassari, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author
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antio- and diastereoselective fluoro-functionalization re-
mains a field of continuing chemical research.[11]
We have recently investigated the chemistry of chiral di-
phosphanes (the “Daniphos” ligands),[12] based on an op-
tically active [η6-arene]tricarbonylchromium backbone,[13]
and have found many applications for them in homogen-
eous catalysis, where they rival the better-known and indus-
trially important Josiphos ligands.[12j,12k,12m] Both ligand
classes are based on the same structural principle of com-
bining central and planar chirality and reveal C1-symmetry.
We have now found a new highly modular method to pre-
pare C1-symmetric chiral 1,3-diamines based on the same
chiral organometallic framework.
Results and Discussion
Figure 1. 19F NMR spectrum of the crude reaction mixture of the
electrophilic fluorination.
In some of our recent contributions, we reported on the
synthesis and application of the modularly built planar-
chiral Daniphos ligand for stereoselective catalysis.[12]
The starting material for the synthesis of Daniphos is [(R)-
(1-phenyl)ethyldimethylamine]tricarbonylchromium (1).[14]
Our approach to chiral 1,3-diphosphanes or similar deriva-
tives employed a successive electrophilic exchange of the
ring proton in the 2-position followed by a nucleophilic ex-
change of the dimethylamino group via a chloro intermedi-
ate. This method was only limited by the availability of suit-
able electrophiles or nucleophiles, and enabled us to build
a whole library of new ligands.[12j,12l] This methodogy has
also been successfully applied by Bolm and Knochel to
other organometallic frameworks.[15]
We have now discovered that after diastereoselective elec-
trophilic fluorination[11] employing N-fluoro-benzenesul-
fonimide (NFSI), the resulting 2-fluoro derivative 2 can be
isolated in good yields (77%) (Scheme 1).
Figure 2. Displacement ellipsoid plot (30% probability) of one in-
dependent molecule in the asymmetric unit of fluoroarene complex
2.
best plane defined by coordinated arene [2.2(3) pm and
0.3(4) pm].
Fluorinated compound 2 was easily decomplexed from
the chromium tricarbonyl fragment by reaction with iodine
in air in an ethereal solution, yielding the free ortho-fluori-
nated benzylamine in 76% yield (Scheme 2).
Scheme 1. Diastereospecific electrophilic ortho-fluorination.
The reaction proved to be diastereoselectiveϪthe other
diastereomer could not be detected. The 19F NMR spec-
trum of the crude reaction mixture showed only a single
resonance at δ = –135.5 ppm (Figure 1). The fluoroarene
complex was characterized by X-ray structure analysis (Fig-
ure 2; single crystals were obtained by slow evaporation of
an ethereal solution).
Scheme 2. Liberation of the ortho-fluorinated benzylamine.
The crystal structure of 2 contains two independent
molecules in the asymmetric unit. These molecules are re-
(Fluorobenzene)tricarbonylchromium complexes are well
lated to each other by pseudosymmetry, which confirms the known to undergo nucleophilic exchange reactions on the
envisaged course of the reaction, displaying the ortho-fluori- arene ring (SNAr reactions) by common nucleophiles like
nated complex in the expected (R,R)-configuration. The C– amines, alkoxides, phosphides or nucleophilic carbon equiv-
F bond lengths are 134.0(8) and 135.3(9) pm, which are alents. The substitution reaction is facilitated by the elec-
typical values for fluoroarene chromium tricarbonyl com- tron-withdrawing nature of the chromium tricarbonyl moi-
plexes.[16,17] The fluoro substituent is situated almost in the ety, which switches the nucleophilic nature of the aromatic
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Chiral 1,3-Diamines by a Highly Modular Umpolung Strategy
ring to an electrophilic character.[18] An elegant recent ex- tion by a trap-to-trap distillation. Both secondary and pri-
ample by Imamoto demonstrated that an optically active mary amines, as well as some inorganic derivatives such as
BH3-protected secondary phosphide could be attached to ethanolamine, hydroxylamine and hydrazine, could be used,
benzenetricarbonylchromium in this manner.[19] By the time and we have not yet found any limitation to this reaction.[21]
Imamoto’s paper appeared, we had also found that com- In summary, the reaction sequence lithiation–fluorination–
pound 2 could be employed for the synthesis of planar-chi- substitution represents an example of an Umpolung strat-
ral 1,3-P,N-ligands by nucleophilic substitution with lith- egy, in which the original reactivity of the arene is reversed.
ium phosphides, especially those bearing unusual phos-
phane moieties which cannot be introduced via the classic
electrophilic route[12] due to the lack of availability of the
appropriate chlorophosphane (e.g. the phobane isomers).
Essential for this finding was the ipso-specific course of the
reaction (vide infra).[20]
Even more interesting was the discovery that amines can
react in a similar manner. Simple stirring of 2 in an excess
of amine at room temperature generates the 2-substituted
arenetricarbonylchromium complexes in a straightforward
and almost quantitative manner (Scheme 3). The reaction
Scheme 3. Substitution of the fluorine for an amine.
was performed without solvent in order to facilitate an easy
procedure and a quantitative and benign reaction; precious
To date, 18 diamines (plus another 3, see below) have
chiral amines were recovered after completion of the reac- been synthesized; they are depicted in Figure 3.
Figure 3. Depiction of the diamines derived from complex 2.
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The library of diamines includes simple alkyl- and aryl-
substituted candidates (3–7), as well as derivatives bearing
chiral sidechains in the amino groups (11–18). Compounds
8–10 incorporate unusual amines (ethanolamine, hydroxyl-
amine, hydrazine), two of them (8 and 10) bearing ambident
nucleophiles, which were found to coordinate via the more
nucleophilic N-atom, obeying Kornblum’s rule. We also
tried to introduce amino groups with sterically demanding
substituents like tert-butyl and (R)-1-(tert-butyl)ethyl, but
even after repeated attempts, no diamine product could be
detected. With these moieties, the tolerance of steric bulk
in the ortho-position is over-extended, an observation which
we also had made in the preparation of the analogous di-
phosphanes, where we found it still possible to introduce
diisopropylphosphane but not bis(tert-butyl)phosphane.
Because NFSI is a relatively expensive reagent, we
searched for a potentially cheaper alternative. We reasoned
that the nucleophilic substitution should also be possible
via a chloro-substituted chromium complex. Therefore an
appropriate chlorinating agent for the lithiated chromium
complex was needed, and we envisioned the use of hexa-
chloroethane. The ortho-chlorination worked excellently,
giving the ortho-chlorinated complex 21 in 96% yield as a
single diastereomer (Scheme 4), yet the subsequent substitu-
tion with isopropylamine failed under standard reaction
conditions, as well as at elevated temperature and prolonged
reaction time (65 °C, 24 h, Scheme 5).
Figure 4. Displacement ellipsoid plot (30% probability) of chlo-
roarene complex 21.
whereas that of complex 21 is pointing in the opposite di-
rection of the chlorine atom, whereby the two molecules
exhibit significant conformational differences. The torsion
angles between C1–N–C2 and C3 of complexes 21 and 2
have been calculated to be 179° in the case of the chloro
derivative and –65.3° and –61.7° for the fluoro derivative
(for the two independent molecules in the asymmetric unit
cell), respectively (Figure 5). The C–Cl bond length in com-
plex 21 is 1.739(5) pm.
An X-ray analysis of compound 21 was conducted (sin-
gle crystals were grown from an ethereal solution); a dis-
placement ellipsoids plot is depicted in Figure 4.
Complex 21 crystallizes in the orthorhombic space group
P212121 with similar lattice parameters as its related F-sub-
stituted complex 2, which crystallizes in the subspace group
P21 of the former with two independent molecules in the
asymmetric unit. Despite their resemblance with regard to
unit cell parameters (see Table 2), no obvious analogous
packing is observed. This might be ascribed to the fact that
Figure 5. Assignment of atoms for the calculation of the torsion
angles in the halo derivatives.
Not less than ten of the diamines have also been charac-
the free electron pair of the nitrogen atom of the complex 2 terized by X-ray crystallography as well. In all cases, the
points almost exactly in the direction of the Cipso–Cα bond, course of the substitution reaction was specifically ipso with
Scheme 4. Diastereospecific ortho-chlorination.
Scheme 5. Failed amination with chloro complex 21.
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Chiral 1,3-Diamines by a Highly Modular Umpolung Strategy
regard to the fluorine atom, and no side products of pos- group, each proton showed an independent resonance at δ
sible cine- and tele-substitutions were observed.[22] Some = 3.33 and 3.21 ppm respectively. It seems likely that the
representative examples of these X-ray structures are shown hydrogen bond formed by NH-group induces a hindrance
in Figure 6.
with respect to the free rotation of that methylene group on
An interesting difference emerged between the structures the NMR time scale, resulting in a different environment
similar to complex 3, with two tertiary amines, which for each proton (which in fact cannot be due to dia-
showed no interaction between the 2 nitrogen atoms, and stereotopicity of the protons, as the other set of dia-
those like complex 6, with the combination of a tertiary and stereotopic methylene protons shows only one resonance at
a secondary amino group, in which a hydrogen bond ap- δ = 2.57 ppm). In the solid, the ethanolamine side group is
pears to be formed between the NH group and the dimeth- disordered over two different conformations, which both al-
ylamino group. This causes the side chain bearing the di- low for the intramolecular hydrogen bond. In Figure 6 the
methylamino group to undergo a conformational rotation major conformer is shown. In the cases of the secondary-
towards the inner sphere of the complex, a phenomenon tertiary diamines forming such a hydrogen bond, it seems
which we also observed for the diphosphane class of com- justified to speak of a “chelated hydrogen”, resembling an-
pounds on coordination to a metal centre forming a six- other example of the rare class of a “chiral hydrogen”, sim-
membered chelate.[12h]
ilar to the one recently described by Johnston.[23] In order
An interesting case in this respect is also complex 10, to further investigate this aspect, we carried out a proton-
incorporating the ethanolamine moiety. In the analysis of ation experiment with the isopropyl-substituted diamine 5
its 1H NMR spectrum, it was found that for one methylene using trifluoromethane sulfonic acid. We anticipated that
Figure 6. X-ray structures of compounds 3, 6, 10, 11 and 13.
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this additional proton should be captured between the two
As expected, the most pronounced effects occur for those
amino groups to form the ammonium cation, and therefore protons in close proximity to the protonated nitrogens. The
cause significant changes in the 1H NMR spectrum. An NH proton (11-H) is shifted downfield by almost 2.6 ppm,
evaluation of the 1H NMR spectra of the unprotonated and while the CH protons on the side chains (7-H and 12-H)
protonated species showed remarkable differences. In are both shifted by roughly 1 ppm. Also, the protons on the
Table 1, a detailed comparison is presented of the NMR methyl group of the chiral α-chain (8-H) undergo a down-
spectra of compound 5 in its unprotonated and protonated field shift of 0.6 ppm. The most interesting effect, however,
forms, respectively.
is associated with the two methyl groups of the NMe2-moi-
ety: while in the unprotonated form they can freely rotate
and thus give only one resonance in the NMR, in the pro-
tonated form of the molecule, their free rotation is stopped
by the hydrogen bond formed by the additional proton and
its positive charge. The two methyl groups become fixed in
their positions and therefore chemically inequivalent and
magnetically anisochronous, which results in an indepen-
dent resonance for each methyl group. Moreover, both sig-
nals are shifted more than 0.6 ppm downfield. This phe-
nomenon of hydrogen bonding and consecutive con-
formative adjustment of the side chain was already ob-
served in the solid state of these diamines (compare the X-
ray structures mentioned above), yet in solution it proved
not to be strong enough to maintain this rigidity. An ad-
ditional proton and its positive charge amplified this effect
in order to yield a fixed side chain in solution as well as in
the solid state. This finding strengthens the argument for a
“chelated proton” mentioned above.
Table 1. NMR spectroscopic data of compound 5 (unprotonated
and protonated as [5H]O3SCF3).
Especially interesting in terms of applications in transi-
tion-metal catalyzed transformations or organocatalysis are
the derivatives bearing an α-chiral side chain in the substi-
tuted amine. They combine two stereogenic centers with
planar chirality in the same molecule, along with the advan-
tage of an easy and straightforward modular synthesis of
the whole diamine. This reveals a promising prospect for a
future application in asymmetric catalysis. The employment
Scheme 6. Decomplexation to liberate the free diamines 22–25.
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Chiral 1,3-Diamines by a Highly Modular Umpolung Strategy
Scheme 7. Diastereoselective ortho-fluorination of alternative chromium complexes and liberation of the free fluorinated benzylamines.
Scheme 8. Amination of alternative ortho-fluorinated chromium complexes to form diamines with different substitution patterns on the
aromatic ring and the chiral side chain.
of these compounds in organocatalytic aldol reactions[24,25] (Scheme 7 and Scheme 8). Again, our method proved to be
and other enamine/iminium catalytic transformations is highly effective with regard to stereoselectivity (no other
currently investigated in our labs. It should be noted that diastereomer was detectable in the fluorination or the sub-
diamines of this kind represent the first example of a stitution reaction) and yield (ortho-fluorination: 90–93%,
planar-chiral organocatalyst next to the impressive example decomplexation: 89–97%, amination: 87–89%, 70–80%
of a planar-chiral nucleophilic catalyst presented by Fu[26]
.
overall).
As representative examples compounds 3, 5, 6 and 11
were decomplexed by reaction with iodine in air in order to
liberate the free organic diamines 22–25 (Scheme 6).
In order to prove the general applicability of our new
method, some additional benzylamine(tricarbonyl)chro-
Conclusions
Starting from the readily available precursor [(R)-(1-
mium complexes[12l,12n,12o] were subjected to the same syn- phenyl)ethyldimethylamine]chromium tricarbonyl and re-
thetic protocol. This allows for the stereoselective synthesis lated benzylamine complexes, the ortho-fluoro derivative
of ortho-fluorinated benzylic amines as well as diamines was synthesized by a new diastereospecific electrophilic flu-
bearing additional substituents on the aromatic ring and in orination protocol. Successive decomplexation delivered the
the side chain bearing the stereogenic carbon atom free ortho-fluorinated benzylamines. This new method exhi-
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slurry was filtered through a pad of Celite. The ether was evapo-
rated, and the clean product was obtained as a colourless oil. Yield
75 mg (0.449 mmol, 76%). MS (EI): m/z (%) = 167 (9) [M+·]. 1H
NMR (400 MHz, CDCl3): δ = 1.38 (d, J = 6.8 Hz, 3 H, CHMe),
2.21 (s, 6 H, NMe2), 3.74 (q, J = 6.8 Hz, 1 H, CHMe), 7.01 (m, 1
H, Har), 7.11 (td, J = 7.5, 1.3 Hz, 1 H, Har), 7.20 (m, 1 H, Har),
7.39 (td, J = 7.5, 2.0 Hz, 1 H, Har) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.5 (CHMe), 42.8 (NMe2), 57.4 (d, JCF = 1.8 Hz,
CHMe), 115.3 (d, JCF = 23.5 Hz, CCFortho), 123.9 (d, JCF = 3.4 Hz,
Car), 128.2 (d, JCF = 7.5 Hz, CCFmeta), 128.8 (d, JCF = 5.0 Hz, Car),
bits great potential for the use in the stereoselective synthe-
sis of fluorinated pharmaceuticals. The new protocol was
used to generate a library of a new class of the rare chiral
1,3-diamines by a straightforward, high-yield and stereo-
conservative nucleophilic aromatic substitution reaction
employing various kinds of primary, secondary and “inor-
ganic” amines. Chiral amines can also be employed without
loss of optical purity, yielding a new valuable class of
planar-chiral diamines with two stereogenic centers in close
proximity. The whole reaction sequence represents an exam- 130.20 (d, JCF = 13.8 Hz, CCCipso), 160.66 (d, JCF = 245.0 Hz,
CCFipso) ppm. 19F NMR (188 MHz, CDCl3): δ = –118.49 ppm.
C10H14FN (167.21): calcd. H 8.44, C 71.83; found H 8.38, C 71.11.
ple of an Umpolung strategy. The resulting diamines can
be synthesized in a highly modular way, allowing for the
synthesis of a broad library of diamines, which exhibit a
valuable prospect for the use in asymmetric catalysis, both
transition-metal-mediated and organocatalytic.
General Procedure for the Substitution of Fluorine by an Amino
Group: In a small Schlenk tube, fluoro complex 2 (1.0 mmol,
303 mg) was dissolved in the respective amine (2 mL). For com-
plexes 11–13, a mixture of H2O/THF was added until all solids
were dissolved. The solutions were degassed by three freeze/purge
cycles, and were allowed to stir at room temperature for three days.
All liquids were removed under reduced pressure (in cases where
chiral amines were used they could be easily recovered by con-
desation into a cooling trap), and the residue was purified by col-
umn chromatography (alumina/ether). The resulting diamines were
easily be recrystallized from ether, with slow evaporation yielding
single crystals suitable for X-ray analysis in most cases. All com-
pounds melted at a melting point higher than 150 °C with decom-
position.
Experimental Section
General Remarks: All manipulations were carried out under nitro-
gen using standard Schlenk techniques. Solvents were dried and
deoxygenated by standard procedures. Chromatography was car-
ried out with Merck alumina 90. NMR spectra were recorded with
a
Varian Mercury 200 (1H: 200 MHz, 13C: 50 MHz, 19F:
188 MHz), a Varian Unity 500 (1H: 500 MHz, 13C: 125 MHz) or a
Bruker 400 MHz (1H: 400 MHz, 13C: 100 MHz) spectrometer at
ambient temperature. IR spectra were recorded with a Perkin–
Elmer FT-IR model 1720 X spectrometer. Mass spectra were ob-
tained with a Finnigan MAT 95 spectrometer, using the CI (isobut-
ane as reactand gas) and EI recording techniques. Complexes 1 and
26–28 were synthesized according to the literature.[12] (PhSO2)2NF
was purchased from ABCR; amines were commercially available
used without further purification. Chiral amines were generously
donated by BASF AG (Dr. Ditrich).
(R,R)-[η6-(Me2NCHMe)C6H4N(CH2)4]Cr(CO)3 (3): Yield 344 mg
(0.97 mmol, 97%). IR (CHCl ): ν
= 1896, 1975 (CO) cm–1. MS
max
˜
3
(CI): m/z (%) = 354 (17) [M+·], 355 (7) [M + 1+·]. 1H NMR
(500 MHz, C6D6): δ = 1.23 (d, J = 6.8 Hz, 3 H, CHMe), 1.40 (m,
4 H, CH2), 1.87 (s, 6 H, NMe2), 2.78–2.95 (br. m, 4 H, NCH2),
3.50 (q, J = 6.6 Hz, 1 H, CHMe), 4.29 (m, 1 H, Har) 4.34 (m, 1 H,
Har), 4.87 (m, 1 H, Har), 5.39 (m, 1 H, Har) ppm. 13C NMR
(125 MHz, C6D6): δ = 15.56 (CHMe), 25.63 (2 C, CH2), 41.37
(NMe2), 52.25 (2 C, NCH2), 57.94 (CHMe), 80.69 (Car), 83.23
(Car), 96.15 (Car), 97.24 (Car), 102.13 (Caripso), 132.38 (Caripso),
235.14 (CO) ppm. C17H22CrN2O3 (360.4): calcd. H 6.27, C 57.62;
found H 6.29, C 57.84.
[(R,R)-1-Fluoro-2-(1-dimethylaminoethyl)benzene]tricarbonylchro-
mium (2): In a Schlenk tube, [(R)-(1-phenyl)ethyldimethylamine]tri-
carbonylchromium (1, 5.35 g, 18.8 mmol) was dissolved in ether
(150 mL), cooled to –80 °C, and tBuLi (1.5 , 15 mL, 22.6 mmol,
1.15 equiv.) was added dropwise over 1 h. The solution was stirred
for 1 h, after which it was warmed to –60°C, and a yellowish pre-
cipitate occurred. The solution was re-cooled to –80 °C, and the
precipitate was redissolved by adding THF (20 mL) dropwise. A
solution of N-fluorobenzenesulfonimide (7.13 g, 22.6 mmol,
1.15 equiv.) dissolved in THF (40 mL) was added dropwise over
0.5 h. The solution was warmed to room temperature overnight.
The resulting precipitate was filtered through celite, the solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (alumina/diethyl ether). The product was
recrystallized from diethyl ether at –30 °C. Yield 4.40 g (14.5 mmol,
X-ray Structure Determinations: Crystal data and details of the
structure determinations are listed in Table 2. Data collections were
performed with a Bruker Smart CCD (Mo-Kα radiation, λ =
0.71073 Å, graphite monochromator) area detector. All data were
collected at 110 K except for 6, which was collected at 293 K. The
structures were solved by direct methods (SHELXS-97)[27] and re-
fined by full-matrix least-squares procedures based on F2 with all
measured reflections (SHELXL-97)[28] The SADABS[29] program
was used for absorption correction of the structures. All non-hydro-
gen atoms with the exception of the disordered ethanolamines in
10 were refined anisotropically. All H atom positions were intro-
duced at their idealized positions [d(CH) = 0.98 Å, d(NH) =
0.95 Å] and were refined using a riding model. The absolute config-
uration was confirmed by evaluation of the Flack[30] parameter.
The crystal structure of 2 is highly pseudosymmetric, the match of
electron density corresponding with its centrosymmetric space
group is 84%. The crystal structure of 10 presents disorder for the
ethanolamine fragment, which can occupy two different positions
in the solid state.
77%). IR (CHCl ): ν
= 1978, 1818 (CO) cm–1. MS (CI): m/z
˜
3
max
(%) = 304 (81) [M + 1+·]. 1H NMR (200 MHz, C6D6): δ = 0.92 (d,
3 H, CHCH3), 1.84 (s, 6 H, NMe2), 3.65 (q, 1 H, CHCH3), 3.81
(dd, 1 H, Har), 4.38 (m, 2 H, Har), 4.81 (d, 1 H, Har) ppm. 13C
NMR (200 MHz, C6D6): δ = 12.22 (CHCH3), 40.60 (NMe2), 61.47
(CHCH3), 84.87 (Car), 91.83 (Car), 93.36 (Caripso), 93.51 (Car), 95.65
(Car), 138.06 (Caripso), 232.28 (CO) ppm. 19F NMR (188 MHz): δ
= –132.5 ppm. C13H14CrFNO3 (303.23): calcd. H 4.65, C 51.49;
found H 4.67, C 51.74.
1-F-2-[(R)-Me2NCHMe]C6H4 (2a): Compound
0.594 mmol) was dissolved in ether and some crystals of iodine
were added. The solution was stirred under air overnight. The
5
(180 mg,
CCDC-615999 (for 2), -616000 (for 3), -616001 (for 6), -616002 (for
10), -616003 (for 11), -616004 (for 13), and -679639 (for 21) contain
the supplementary crystallographic data for this paper. These data
2072
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2065–2074

Chiral 1,3-Diamines by a Highly Modular Umpolung Strategy
Table 2. Experimental X-ray diffraction parameters and crystal data.
Complex
2
3
6
10
11
13
21
Empirical formula
Formula weight
Crystal size [mm]
Crystal habit, color
C
303.25
13H14CrFNO3
C17H22CrN2O3
354.37
C19H26CrN2O3
382.41
C15H21CrN2O4
345.34
C21H24CrN2O3
404.42
C22H24CrN2O3
416.43
C13H14CrClNO3
319.70
0.05ϫ0.25ϫ0.24 0.17ϫ0.17ϫ0.67 0.22ϫ0.29ϫ0.52 0.21ϫ0.21ϫ0.75 0.07ϫ0.13ϫ0.60 0.30ϫ0.57ϫ0.63 0.12ϫ0.15ϫ0.54
plate, light yellow rod, light yellow
block, light yel-
low
rod, light yellow
plate, light yellow rod, light yellow
rod, light yellow
Crystal system
Space group
a [Å]
b [Å]
c [Å]
monoclinic
P21
6.7652(9)
13.6312(19)
14.708(2)
orthorhombic
P212121
8.5469(16)
16.907(3)
23.850(5)
orthorhombic
P212121
9.471(3)
12.081(4)
17.375(5)
orthorhombic
P212121
6.5545(13)
12.428(3)
19.735(4)
monoclinic
P21
8.4286(16)
9.6196(18)
12.639(2)
orthorhombic
P212121
8.3252(15)
10.2597(19)
23.991(4)
orthorhombic
P212121
7.125(11)
12.79(2)
15.39(2)
α [°]
β [°]
92.294(3)
92.062(4)
γ [°]
V [Å3]
1355.3(3)
1.486
3446.4(11)
1.366
1988.0(11)
1.278
1607.6(5)
1.427
1024.1(3)
1.312
2049.2(6)
1.350
1402(4)
1.514
D [gcm–3
]
Z
4
8
4
4
2
4
4
µ (Mo-Kα) [mm–1
F(000)
]
0.858
624
0.679
1488
0.594
808
0.730
724
0.581
424
0.583
872
1.008
656
θ range [°]
Reflections collected
Rint
Unique refl. in refin.
Refl. with IϾ2σ(I)
Param. refined
R1 [2σ(I)]
R1 (all data)
wR2
Flack parameters
Goodness of fit
Diff. peak/hole [e/Å3]
2. 40–27.45
17491
0.0836
6181
4177
253
0.0696
0.1098
0.1500
–0.02(4)
1.052
2.41–27.45
56050
0.0474
7861
7138
421
0.0418
0.0487
0.1120
–0.013(16)
1.036
2.05–28.40
41536
0.0397
4976
4607
229
0.0448
0.0487
0.1123
–0.01(2)
1.089
2.06–5.00
15396
0.0397
2829
2687
201
0.0550
0.0578
0.1457
0.02(4)
1.029
2.66–28.33
7071
0.0179
4989
4712
248
0.0368
0.0393
0.0951
0.000(16)
1.053
2.16–28.47
37365
0.0470
5155
5002
256
0.0290
0.0301
0.0771
0.009(13)
1.064
2.65–25.99
15603
0.0869
2741
2479
175
0.0546
0.0620
0.1106
0.09(4)
1.084
0.66/–0.47
–0.23/0.52
–0.19/0.41
–0.49/1.49
–0.23/0.43
–0.36/0.42
–0.43/0.49
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Supporting Information (see also the footnote on the first page of
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14.
[8]
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Acknowledgments
The authors gratefully acknowledge financial support by the Deut-
sche Forschungsgemeinschaft (DFG) within the Collaborative Re-
search Centre (SFB 380) “Asymmetric Synthesis with Chemical
and Biological Methods”. B. C.-C. is grateful to the Graduierten-
kolleg “Methods in Asymmetric Synthesis” for a scholarship. We
thank BASF AG (Dr. Ditrich) for a generous gift of enantiomer-
ically pure chiral primary amines and Mrs. Ziyun Zhang and Mr.
Roy Dolmans for preparative and Mr. Michael Stauten for graphi-
cal assistance.
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Received: August 16, 2007
Published Online: March 10, 2008
2074
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2065–2074