Single enantiomer, chiral donor-acceptor metal complexes from bisoxazoline pseudoracemates

Article abstract of DOI:10.1021/ol060836s

Single enantiomer, chiral donor-acceptor metal complexes were synthesized via the self-discriminating zinc(II) complexation of a pseudoracemic mixture of donor/acceptor-substituted bisoxazoline derivatives.

Full text of DOI:10.1021/ol060836s

ORGANIC
LETTERS
2
006
Vol. 8, No. 13
759-2762
Single Enantiomer, Chiral
Donor Acceptor Metal Complexes from
2
−
Bisoxazoline Pseudoracemates
Jeffery M. Atkins, Shin A. Moteki, Stephen G. DiMagno, and James M. Takacs*
Department of Chemistry and the Center for Materials Research and Analysis,
UniVersity of NebraskasLincoln, Lincoln, Nebraska 68588-0304
jtakacs1@unl.edu
Received April 6, 2006
ABSTRACT
Single enantiomer, chiral donor−acceptor metal complexes were synthesized via the self-discriminating zinc(II) complexation of a pseudoracemic
mixture of donor/acceptor-substituted bisoxazoline derivatives.
We recently reported the multicomponent self-assembly of
donor, π-bridge, and acceptor (D-π-A) subunits have
neutral, heteroleptic (box)
self-discrimination of enantiomeric bisoxazoline (box) ligands.
Combining a racemic mixture of phenyl-substituted box
2
Zn complexes directed via chiral
attracted much attention in large measure because of their
1
3
nonlinear optical properties and potential applications in
4
electrooptics and molecular photonics. Pseudoenantiomeric
ligands (R,R)-1 and (S,S)-1 with Zn(OAc)
complexes: the heterochiral complex (RR,SS)-2 (i.e., the
product of chiral self-discrimination) and the two homochiral
2
could afford three
donor/acceptor-substituted aryl-substituted box ligands, such
as 3 and 4, have the potential to form single enantiomer,
chiral donor-acceptor complexes (i.e., DA complex (RR,SS)-
5) in which the metal center is intended to function as a
π-bridge (Figure 2).
(RR,RR)- and (SS,SS)-complexes (i.e., the products of chiral
self-recognition). We find that steric interactions between
the pendant aryl groups lead to a strong preference for the
tetrahedral (RR,SS)-2 complex under reaction conditions that
allow rapid equilibration. X-ray quality crystals of (RR,SS)-2
were grown from CH Cl /EtOH solution by slow evapora-
2 2
tion; the crystal structure is shown in Figure 1.
A series of chiral monosubstituted aryl-box derivatives
bearing electron-donating and -accepting groups were syn-
thesized. Although a large number of chiral box derivatives
have been prepared for use as chiral ligands in asymmetric
5
catalysis, other than the commercially available cyano-
The self-discriminating zinc(II) complexation of a box
ligand racemate can be extended to pseudoracemates, that
is, pairs of (R,R)- and (S,S)-box derivatives bearing different
substituents, thereby providing a general strategy for coupling
two unique components via the formation of a chiral zinc
(
2) The combinatorial synthesis of chiral self-assembled ligands for
asymmetric catalysis via the box-directed coupling of bifunctional ligands
is an ongoing application of this strategy. See: Takacs, J. M.; Reddy, D.
S.; Moteki, S. A.; Wu, D.; Palencia, H. J. Am. Chem. Soc. 2004, 126, 4494-
4
495. Takacs, J. M.; Chaiseeda, K.; Moteki, S. A.; Reddy, D. S.; Wu, D.;
Chandra, K. Pure Appl. Chem. 2006, 78, 501-509.
2
complex. Metal-organic complexes comprising electron
(3) Long, N. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 21-38. Di Bella,
S. Chem. Soc. ReV. 2001, 30, 355-366. de la Torre, G.; Vazquez, P.; Agullo-
Lopez, F.; Torres, T. Chem. ReV. 2004, 104, 3723-3750.
(1) Takacs, J. M.; Hrvatin, P. M.; Atkins, J. M.; Reddy, D. S.; Clark, J.
(4) Coe, B.; Curati, N. Comments Inorg. Chem. 2004, 25, 147-184.
(5) Rechavi, D.; Lemaire, M. Chem. ReV. 2002, 102, 3467-3493.
L. New J. Chem. 2005, 29, 263-265.
1
0.1021/ol060836s CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/01/2006

1
Ph, R ) H), was fruitless; thus, the alternative route outlined
in Scheme 1 was pursued. Palladium-catalyzed coupling of
Scheme 1. Preparation of Donor/Acceptor-Substituted Box
Derivatives 11 and 12
Figure 1. Preparation and crystal structure of (RR,SS)-2.
6
substituted derivative 6, relatively few chiral monoalkyl-
7
substituted box derivatives (i.e., 7) are known; chiral
donor/acceptor-substituted aryl halides (i.e., 9) with sodium
malononitrile gives ready access to a variety of aryl-
8
substituted malononitriles 10. The well-known ZnCl
2
-
catalyzed condensation of a nitrile with an amino alcohol
has been used to prepare a variety of chiral oxazoline and
9
box derivatives. Adapting this method to the reaction of
arylmalononitriles proved problematic initially, because the
zinc complex 11 precipitated from solution under the reaction
conditions, removing the Lewis acid catalyst. However, use
(6) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004.
Kwak, Y.-S.; Corey, E. J. Org. Lett. 2004, 6, 3385-3388. Choi, H.-W.;
Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-
K.; Xie, C. Pure Appl. Chem. 2003, 75, 1-17. Ward, D. E.; Sales, M.;
Hrapchak, M. J. Can. J. Chem. 2001, 79, 1775-1785.
(
7) Dagorne, S.; Bellemin-Laponnaz, S.; Welter, R. Organometallics
2
3
3
004, 23, 3053-3061. Bayardon, J.; Sinou, D. J. Org. Chem. 2004, 69,
121-3128. Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301-
04. Zhou, J.; Tang, Y. Chem. Commun. 2004, 432-433. Bourguignon, J.;
Bremberg, U.; Dupas, G.; Hallman, K.; Hagberg, L.; Hortala, L.; Levacher,
V.; Lutsenko, S.; Macedo, E.; Moberg, C.; Queguiner, G.; Rahm, F.
Tetrahedron 2003, 59, 9583-9589. Sibi, M. P.; Chen, J. Org. Lett. 2002,
4
, 2933-2936. Bellemin-Laponnaz, S.; Gade, L. H. Angew. Chem., Int.
Ed. 2002, 41, 3473-3475. Burguete, M. I.; Fraile, J. M.; Garcia, J. I.;
Garcia-Verdugo, E.; Herrerias, C. I.; Luis, S. V.; Mayoral, J. A. J. Org.
Chem. 2001, 66, 8893-8901. Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F. Eur. J. Org. Chem. 2001, 1045-1048. Denmark, S. E.; Stiff, C.
M. J. Org. Chem. 2000, 65, 5875-5878. Schulze, V.; Hoffmann, R. W.
Chem.-Eur. J. 1999, 5, 337-344.
Figure 2. Chirality directed self-assembly of chiral (noncentrosym-
metric) DA complexes, i.e., (RR,SS)-5.
(8) Uno, M.; Seto, K.; Masuda, M.; Ueda, W.; Takahashi, S. Tetrahedron
Lett. 1985, 26, 1553-1556. Gao, C.; Tao, X.; Qian, Y.; Huang, J. Chem.
Commun. 2003, 1444-1445 and references therein.
monoaryl-substituted derivatives 8 have not been reported
previously.
A direct approach to 8, palladium-catalyzed arylation of
(
9) Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991,
124, 1173-1180. Makarycheva-Mikhailova, A. V.; Kukushkin, V. Y.;
Nazarov, A. A.; Garnovskii, D. A.; Pombeiro, A. J. L.; Haukka, M.; Keppler,
B. K.; Galanski, M. Inorg. Chem. 2003, 42, 2805-2813 and references
therein.
2,2′-methylenebis[(4S)-4-phenyl-2-oxazoline] (i.e., 7, R )
2760
Org. Lett., Vol. 8, No. 13, 2006

of efficient stirring and excess of ZnCl
overcome this difficulty. After aqueous workup, complex 11
was isolated by precipitation from CHCl with hexanes or
2
was sufficient to
Scheme 2. Preparation of the para-Nitro Derivative (S,S)-16
3
by chromatography. Despite the initial difficulties, good
yields of complex 11 were generally obtained (Table 1).
Table 1. Preparation of Donor/Acceptor-Substituted Box
Derivatives 10 and 11 via the Route in Scheme 1
entry
G
X
10 (%)
11 (%)
configuration
1
2
3
4
5
6
H
H
MeO
TBSO
Et2N
I
I
Br
Br
I
83
83
42
50
71
84
88
88
92
88
59
98
(RR,RR)
(SS,SS)
(RR,RR)
(RR,RR)
(RR,RR)
(SS,SS)
n
CO2 Bu
I
requisite pseudoracemates with Zn(OAc)
mentary pairs of (RR,RR)- and (SS,SS)-homochiral (box)
2
(Table 2). Comple-
Zn
2
Unlike the phenyl-substituted box complex (RR,SS)-2 or
the proposed DA complexes (RR,SS)-5, the isolated homo-
chiral complex 11 has two identical box subunits bound to
zinc. Although it has been noted that neutral zinc(II)
complexes form more readily for electron-poor chelating
complexes disproportionate rapidly in protic solution to give
the thermodynamically favored (RR,SS)-combination. For
1
example, the combination of (RR,RR)-11 (G ) NEt
2
) with
n
(SS,SS)-11 (G ) CO
2
n
Bu) gives zinc complex (RR,SS)-5b
(D ) Et
2
2
N, A ) CO Bu). Although the box subunits used
10
ligands, the homochiral complexes 11, bearing either donors
or acceptors, are accessible. Although the homochiral
complexes are thermodynamically less stable than the
corresponding heterochiral complexes, they are nonetheless
quite robust. For example, 11 survives the extractive workup
and chromatography on silica used in its isolation, and the
TBS ether 11 (G ) TBSO) is readily desilylated (TBAF,
THF, 0 °C, 72%) to the corresponding phenol derivative 11
to direct complex formation are of opposite chirality, the
donor-acceptor complexes (RR,SS)-5a-f are chiral and
single enantiomers. For example, diethylaminophenylnitro-
phenyl DA complex (RR,SS)-5e exhibits a strong optical
589
rotation, [R]
D
3
) -346° (c ) 0.5, CHCl ).
Table 2. Preparation of Zn(II) DA Complexes (RR,SS)-5a-f
and the Donor and Acceptor Reference Complexes (RR,SS)-5g,h
(G ) OH). The homochiral complexes themselves can be
used directly to prepare the desired donor-acceptor com-
plexes (vide infra). In some cases, zinc can be removed by
treating with dilute aqueous HCl, although this is ac-
companied by partial ligand hydrolysis. In solution, the free
aryl-substituted box derivative 12 exists as a tautomeric
mixture favoring tautomer 12a over 12b.
entry
5 (M ) Zn)
D
A
yield (%)a
n
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
TBSO
Et2N
HO
CO2 Bu
67
99
97
53
98
97
82
89
n
CO2 Bu
NO2
NO2
MeO
11
Et N
NO2
(
4-Nitrophenyl)malononitrile (13) is easily prepared via
2
Et2N
Et2N
NO2
CN
nucleophilic aromatic substitution. However, its ZnCl
2
-
5g
5h
Et2N
NO2
promoted reaction with (S)-phenylglycinol proceeds only to
the stage where one dihydrooxazole ring forms (i.e., 14,
Scheme 2). Finely ground KOH in pyridine12 promotes
substitution of 4-fluoronitrobenzene (15) with 2,2′-methyl-
enebis[(4S)-4-phenyl-2-oxazoline] to give (S,S)-16 as a red
solid (65% yield).
a
Isolated yield after chromatography on silica (0-2% gradient of MeOH
in CHCl3).
Figure 3 shows the UV/visible spectra of (RR,SS)-5e and
the symmetric diamino and dinitro complexes (RR,SS)-5g
and (RR,SS)-5h. The latter were prepared from racemic
Having prepared a series of donor-substituted aryl-box
derivatives (RR,RR)-11 (G ) OMe, OTBS, OH, and NEt
2
)
and the stereochemically complementary acceptor-substituted
mixtures of 11 (G ) NEt
2
) and 11 (G ) NO
2
), respectively
N/NO
n
aryl-box derivatives, (SS,SS)-11 (G ) CO
2
Bu) and (S,S)-
(Table 2, entries 7 and 8). The spectrum of the Et
2
2
16, as well as having purchased the commercially available
DA complex (RR,SS)-5e exhibits the expected nitroaromatic
transition band at roughly half the intensity of (RR,SS)-5h,
and the remainder of the spectrum in large part resembles a
sum of the two individual ligand absorption bands. However,
the slightly increased absorption intensity at the long
wavelength edge in the DA complex suggests a weak CT
transition. The weakness of the putative CT transition
suggests that ligand geometry and the filled d-orbital set of
cyano-substituted box (S,S)-6, we prepared a series of DA
complexes (RR,SS)-5a-f (M ) Zn) by combining the
(
10) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. J. Org.
Chem. 2002, 67, 5753-5772.
11) Suzuki, H.; Koide, H.; Ogawa, T. Bull. Chem. Soc. Jpn. 1988, 61,
01-504.
12) Leader, H.; Smejkal, R. M.; Payne, C. S.; Padilla, F. N.; Doctor, B.
(
5
(
P.; Gordon, R. K.; Chiang, P. K. J. Med. Chem. 1989, 32, 1522-1528.
Org. Lett., Vol. 8, No. 13, 2006
2761

larger N-Zn-N bite angle is seen for the aminophenyl-
substituted box subunit (93.85°) compared to the cyano-
substituted box subunit (91.94°). In addition, the N-Zn bond
lengths differ slightly for the two box derivatives; those for
the aminophenyl-substituted box are slightly shorter. The
angle defined by the central carbon of each box subunit and
the zinc deviates about 10° from linear, and one of the
dihydrooxazole rings in each ligand exhibits some disorder,
indicating that these nonplanar rings have some conforma-
tional flexibility in the crystal.
Perhaps the most notable feature in the crystal structure
of (RR,SS)-5f is that the aminophenyl ring is essentially
orthogonal to the box π-system. The relevant dihedral angle
is 96.96° indicating poor overlap in the ground state. Zn(II)-
induced ground-state π-deconjugation has also been observed
Figure 3. UV/vis spectra (240-800 nm) of DA complex 5e (Et
2
N/
14
in N,N-bis(2-pyridyl)amino-substituted arenes. Nonetheless,
close contacts between the 4-(diethylamino)phenyl ring and
an adjacent phenyl substituent within the crystal suggest
packing forces may also play a role in the crystal structure.
Furthermore, ground- and excited-state overlap are modulated
by conformational dynamics, and overlap in the excited
NO ) and complexes 5g (Et N/Et N) and 5h (NO /NO ).
2
2
2
2
2
the zinc ion lead to weak coupling of the aromatic donor
and acceptor orbitals.
Attempts were made to crystallize several of the DA
1
5
charge-transfer state is expected to increase.
2
complexes; however, only the crystals of (RR,SS)-5f (Et N/
In summary, the self-discriminating zinc(II) complexation
of a pseudoracemic mixture of substituted-box derivatives
was used to prepare a series of single enantiomer, chiral DA
complexes (RR,SS)-5a-f. The initial results suggest DA
coupling is weak in these zinc complexes. Further study
of their excited-state and solid-state properties and the
preparation of related DA complexes incorporating other
metal ions are in progress.
CN) gave a solvable diffraction pattern (Figure 4). The unit
1
6
Acknowledgment. Financial support from the University
of Nebraska Research Initiative is gratefully acknowledged.
We thank the NSF (CHE-0091975) and the UNL Center for
Materials Research and Analysis for purchase of the dif-
fractometer, the NSF (CHE-0091975, MRI-0079750) and
NIH (SIG-1-510-RR-06307) for purchases of the NMR
spectrometers, and Dr. Joanna L. Clark for determining the
crystal structures.
Supporting Information Available: Procedures, spectral
data, and cif files. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 4. Crystal structure of DA complex (RR,SS)-5f.
OL060836S
(
13) Saalfrank, R. W.; Struck, O.; Peters, K.; Georg von Schnering, H.
Z. Naturforsch., B: Chem. Sci. 1994, 49, 1415-1424.
14) Yang, J.-S.; Lin, Y.-D.; Lin, Y.-H.; Liao, F.-L. J. Org. Chem. 2004,
cell consists of four complexes, each radiating out from the
center of the cell. The structural features of (RR,SS)-5f are
largely consistent with those found for simpler complexes.
For example, the bond lengths and angles within the
aminophenyl-substituted box subunit are much like those of
the phenyl derivative (RR,SS)-2, and those for the cyano-
substituted box subunit are similar to those reported for a
related cyano-substituted semicorrin complex.13 A slightly
(
6
9, 3517-3525.
(15) Lin, V. S. Y.; Therien, M. J. Chem.-Eur. J. 1996, 1, 645-651.
(16) We appreciate the suggestion made by a reviewer that donor/acceptor
interaction may contribute to the selective formation of (RR,SS)-DA
complexes. However, we find that acid-catalyzed equilibration of an
equimolar mixture of (RR,SS)-5g and (RR,SS)-5h (trace HOAc in CDCl3)
leads to a near statistical 2.7:1:1 mixture of DA complex (RR,SS)-5e and
the two starting complexes, again suggesting that DA interaction in the
ground state is weak.
2762
Org. Lett., Vol. 8, No. 13, 2006