Chiral lithiothiophenes as non-transferable ligands in organocuprate conjugate addition reactions

Article abstract of DOI:10.1016/j.tetasy.2003.09.016

Non-transferable carbon bound homochiral ligands have been developed for the asymmetric transfer of an alkyl or an aryl group to a prochiral α,β-unsaturated enone with copper reagents. These ligands are based on thiophene and chiral amino alcohols derived from L-proline and ephedrine.

Full text of DOI:10.1016/j.tetasy.2003.09.016

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3281–3283
Chiral lithiothiophenes as non-transferable ligands in
organocuprate conjugate addition reactions
Craig A. Ogle* and Jason B. Human
Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
Received 7 August 2003; accepted 8 September 2003
Abstract—Non-transferable carbon bound homochiral ligands have been developed for the asymmetric transfer of an alkyl or an
aryl group to a prochiral a,b-unsaturated enone with copper reagents. These ligands are based on thiophene and chiral amino
alcohols derived from L-proline and ephedrine.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
able starting materials made this an attractive starting
material for 3-substituted thiophene ligands.18 A non-
transferable ligand based upon ephedrine and thio-
phene was prepared from reduction of 1 to the alcohol
and subsequent treatment with thionyl chloride to yield
the benzylic chloride, 2. The chloride was displaced
using the sodium alkoxide of (−)-N-methylephedrine19
to give 3.20 Similarly, the sodium alkoxide of (+)-N-
methylpseudoephedrine derivative was used in the place
of (−)-N-methylephedrine to give, the diastereomeric 5.
A second type of thiophene-based ligand was prepared
directly from the carboxaldehyde by reductive amina-
Organocuprates are some of the most important
reagents for CꢀC bond-forming reactions available to
synthetic chemists. Alkyl and aryl groups have been
transferred enantioselectively to prochiral a,b-unsatu-
rated enones using heterocuprates of the empirical for-
mulas RCu(OR)Li1–5 and RCu(NR*R%)Li6–9 where the
R* is a homochiral fragment. Several of these have
been reported to give excellent enantioselectivities.
These reagents are based upon earlier work using hete-
rocuprates formed from alkyl and aryl lithium reagents
and lithium alkoxides10 and amides,11,12 developed to
transfer selectively the alkyl and aryl groups to enones
as a way of conserving valuable carbanionic moieties.
This methodology has also been used with non-trans-
ferable carbon-bound ligands.13–16 One of the most
effective of these carbon-bound mixed cuprates is the
thienyl cuprate moiety, having both good reactivity17
and stability.15 The classic thiophene ligand developed
by Nilsson has had perhaps the widest usage because of
these advantages coupled with the low cost and ease of
preparation. With this in mind, we have begun to
develop chiral ligands based upon thiophene for enan-
tioselective additions to enones.
tion with 2-methoxymethylpyrrolidine, derived from L-
proline,21 to give 4 (Scheme 1).
2. Results and discussion
A recent description of a large scale preparation 3-thio-
phene carboxaldehyde, 1, from cheap and readily avail-
Scheme 1. Reagents: (a) LiAlH4; (b) SOCl2; (c) Ti(O-i-pr)4/
* Corresponding author. E-mail: cogle@email.uncc.edu
NaCHBH3.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.016

3282
C. A. Ogle, J. B. Human / Tetrahedron: Asymmetry 14 (2003) 3281–3283
Table 1. Yield of 6 at various times
Entry
R
Solvent
Yields (%) at time (s)
36 360 3600
4
1
2
3
4
5
6
n-Bu
n-Bu
THF
Et2O
THF
Et2O
THF
Et2O
10
99
9
82
8
24 68
99 99
32 57
84 89
22 59
81 95
86
99
75
92
87
97
2-Thienyl
2-Thienyl
Ara
Ara
33
a Ar is derived from lithiated 3. All reactions are carried out at
−78°C. Data for entries 1–4 were taken from Ref. 17.
chalcone was selected as the a-enone. The mixed
cuprates of 3, 4 and 5 were prepared by lithiating the
corresponding thiophene derivative in the desired sol-
vent. The freshly prepared the lithiothiophene was
treated with CuI·PBu3 at −78°C, annealed at 0°C,
treated with the alkyllithium at −78°C and finally
annealed again at 0°C. A solution of chalcone was
slowly introduced into the stirred reaction mixture at
−78°C and allowed to react overnight at that tempera-
ture. The reaction mixtures were quenched cold with
saturated aqueous ammonium chloride. Chemical yields
were determined by gas chromatography, using the
internal standard method. Enantiomeric excesses were
determined by chiral HPLC.26,27 These results are
shown in Table 2. Both the yields and selectivity were
found to be better in diethyl ether than THF.28
1
Figure 1. The H NMR spectra of the aromatic region of 3.
(a) Starting material. (b) After the lithiation-deuteration
sequence. Note that the resonance at 7.16 ppm corresponding
to hydrogen Ha, has disappeared.
These ligands were regioselectively lithiated at the 2-
position in THF or diethyl ether with n-BuLi at −20°C
in 1 h.22 The regioselectivity of the lithiation was deter-
mined by quenching the lithiated products with D2O
1
and comparing the H NMR spectra to those of the
original ligands. Using compound 3 as the example, the
1H NMR spectra for this reaction sequence are shown
in Figure 1. The hydrogen at 2-position of the thio-
phene ring (Ha) is assigned to the resonance at 7.16
ppm. The spectra of the lithiation and deuterium oxide
quench product shows the clean replacement of Ha with
a deuterium. Similar results were found with 4 and 5.
Because the coordination of the lithium by multi-den-
tate ligands can greatly retard the reactivity of
organocuprate reactions,23,24 we were interested in the
relative reactivity of these new mixed cuprates. As
shown in Table 1, logarithmic reactivity profiles were
used to gauge the reactivities of these new hetero-
cuprates (entries 5 and 6) against those of the di-n-butyl
homocuprate (entries 1 and 2) and the n-butyl(thienyl)
mixed cuprate (entries 3 and 4), using cyclohexenone as
the substrate at −78°C.17,25 The data in the table makes
it evident that the homocuprate in diethyl ether is the
most reactive combination. The new mixed cuprates in
THF were comparable in reactivity to the homocuprate
in THF and have nearly identical reactivity as Nilsson’s
unadulterated thienyl mixed cuprate in both THF and
diethyl ether. The observed yields for entry 6 suggests
that little if any of the thiophene ligand is being
transferred.
3. Conclusions
Thiophenes substituted with chiral b-amino ethers in
the 3-position are smoothly lithiated in the 2-position
with n-butyllithium in ether solvents. These ligands
Table 2. Yields and selectivities with chalcone
Entry
Ar
R
Solvent
7 (%)
Ee (%)
1
2
3
4
5
6
7
3
3
3
4
4
5
5
Bu
Bu
Me
Me
Bu
Me
Bu
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
16
96
89
78
59
62
76
30 (R)
78 (S)
60 (S)
79 (R)
75 (S)
40 (R)
46 (R)
To test the enantioselectivity of the transfer, methyl and
n-butyl were chosen as the transferable groups and
All reactions were run at −78°C for 24 h.

C. A. Ogle, J. B. Human / Tetrahedron: Asymmetry 14 (2003) 3281–3283
3283
were non-transferable and gave good to excellent chem-
16. Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127–130.
17. Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle, C. A.;
Seagle, P. Chem. Eur. J. 1999, 5, 2680–2691.
18. Huckabee, B. K.; Stuk, T. L. Synth. Commun. 2001, 31,
1527–1530.
19. The sodium salt of (−)-N-methylephedrine was prepared
from the alcohol and NaH. The Eschweiler–Clarke pro-
cedure on (−)-ephedrine gave (−)-N-methylephedrine.
20. All new compounds were characterized with high resolu-
tion mass spectra, proton and carbon NMR and optical
rotations. Purities were checked by gas chromatography.
21. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552–2554.
ical yields of the conjugate addition product with chal-
cone in diethyl ether. The enantiomeric excesses in ether
were promising, giving moderate to good enantioselec-
tivities. Further studies are underway with different
substrates and reaction conditions to determine the
generality of thiophene-based non-transferable chiral
ligands. Multi-nuclear NMR studies to characterize the
new mixed cuprates and their intermediate p-complexes
are also ongoing.29
Acknowledgements
22. A septum-sealed nitrogen filled test tube containing a
solution of 3 (0.5 mmol (138 mg) in 5 mL dry ether was
cooled to −78°C. A solution of n-BuLi (0.55 mmol; 260
mL of 2.1 M in hexane) was added slowly via syringe. The
reaction mixture was then placed in a −20°C freezer for 1
h before being used in further reactions.
23. Ouannes, C.; Dressaire, G.; Langlois, Y. Tetrahedron
Lett. 1977, 815–818.
24. Christenson, B.; Hallnemo, G.; Ullenius, C. Tetrahedron
1991, 47, 4739–4752.
25. Bertz, S. H.; Miao, G.; Eriksson, M. Chem. Commun.
1996, 815–816.
26. Kanai, M.; Koga, K.; Tomioka, K. Tetrahedron Lett.
1992, 33, 7193–7196.
27. Nakagawa, Y.; Kanai, M.; Nagaoka, Y.; Tomioka, K.
Tetrahedron 1998, 54, 10295–10307.
28. In a typical procedure, a small test tube was charged with
CuI·PBu3 (189 mg, 0.48 mmol) and a stir bar. The
septum-sealed tube was purged with argon and further
charged with 3 mL of ether and 50 mL of decane. The
mixture was cooled to −78°C. The freshly lithiated 3 (0.5
mmol) in ether22 was introduced via syringe and annealed
6 min at −78°C, 6 min at 0°C, then 6 additional min at
−78°C. The n-butyllithium (0.43 mmol, 210 mL of 2.1 M
in hexane) was introduced and annealed in the same
manner. The chalcone (0.40 mmol, 83 mg) was then
introduced slowly in 1 mL of ether to prevent localized
heating. The reaction was quenched after 24 h at −78°C
with 15 mL of a saturated solution of ammonium chlo-
ride, the chemical yield was determined to be 96% by gas
chromatography. The product, 7 (R=butyl), was isolated
on silica gel plates using a 50/50 mixture of ether and
hexane. Analysis on Chiralpak AD column determined
there to be a 89:11 ratio of S to R.26,27 The spectral data
were in agreement with that by Langer, W.; Seebach, D.
Helv. Chim. Acta 1979, 62, 1710–1722.
We would like to thank the Research Corporation for
partial financial support of this work and Dr. Steven
Bertz for many helpful discussions.
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