Probing electronic and regioisomeric control in an asymmetric Henry reaction catalyzed by camphor-imidazoline ligands

Article abstract of DOI:10.1016/j.tetlet.2009.04.010

Starting from (R)-camphordiamine, 13 new camphor-annulated imidazoline ligands are synthesized in good yields as two regioisomeric series. Yields of up to 94% and good enantioselectivities up to 67% are achieved for the copper(II)-catalyzed Henry reaction

Full text of DOI:10.1016/j.tetlet.2009.04.010

Tetrahedron Letters 50 (2009) 3042–3045
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Probing electronic and regioisomeric control in an asymmetric Henry
reaction catalyzed by camphor-imidazoline ligands
a
b
Filip Bureš a, , Jirí Kulhánek , Aleš Ru˚ zicka
*
ˇ
ˇ ˇ
a
ˇ
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, nám. Cs. legií 565, Pardubice 532 10, Czech Republic
Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, nám. Cs. legií 565, Pardubice 532 10, Czech Republic
b
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from (R)-camphordiamine, 13 new camphor-annulated imidazoline ligands are synthesized in
good yields as two regioisomeric series. Yields of up to 94% and good enantioselectivities up to 67%
are achieved for the copper(II)-catalyzed Henry reaction giving the product stereoselectively according
to the regioisomer used.
Received 9 February 2009
Revised 17 March 2009
Accepted 3 April 2009
Available online 9 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Optically active compounds incorporating five-membered het-
erocycles such as oxazolines1 or related imidazolines2 and their
use as biomaterials3 or efficient transition metal N-coordinating
ligands, and their ability to catalyze various reactions have been
investigated. Whereas the application of chiral oxazoline ligands
in asymmetric reactions has been thoroughly examined and exten-
sively reviewed,4 chiral imidazolines are currently perhaps the
most often employed ligands in a wide range of asymmetric reac-
tions including allylation,5 epoxidation,6 copolymerization,7
hydrogenation,8 addition of diethylzinc to aldehydes,9 Diels–Alder
reactions,10 Heck reactions,11 Baylis–Hillman reactions,12 Friedel–
Crafts alkylations,13 and Henry reactions.14 Despite recent progress
in the preparation of imidazolines,15 the most common synthesis
involves condensation of readily available chiral 1,2-diamines such
as 1,2-diphenylethanediamine (DPEDA) or trans-1,2-diaminocy-
clohexane.16 However, in 2000, Busacca et al. reported the stereo-
selective synthesis of (1R,2S,3R)-camphordiamine17 and, more
recently, its application as a chiral building block for the construc-
tion of a camphor-annulated imidazoline ligand (BIPI) with utility
in the intramolecular asymmetric Heck reaction.18 We have
recently prepared several families of chiral imidazole ligands
The synthesis of the proposed ligands started with the prepara-
tion of camphordiamine 1 by condensation of (R)-camphorquinone
with (rac)-DPEDA yielding two camphorbisimine diastereoisomers
that were subsequently reduced with NaBH4/MeOH to the dia-
mines. It has been confirmed on the basis of NOESY experiments
that this stereoselective reduction takes place exclusively from
the a
-face.17 In addition, we were able to grow a single crystal of
the diamine hydrochloride suitable for X-ray analysis which con-
firmed unambiguously the stereochemical outcome of the above
reduction (see Supplementary data). Final removal of the chiral
DPEDA auxiliary afforded camphordiamine dihydrochloride 1 in
61% overall yield.
With the optically pure exo-camphordiamine dihydrochloride 1
in hand, we examined its reaction with the picolinimidate gener-
ated in situ from pyridine-2-carbonitrile and sodium methoxide.
The condensation was accomplished in methanol and triethyl-
amine to liberate the free camphordiamine base giving rise to
imidazoline 2 in 92% yield. Slow evaporation of 2 from methanol
furnished single crystals suitable for X-ray analysis which con-
firmed the molecular structure of 2 (Fig. 1, see also the Supplemen-
tary data).
derived from either
a
-amino acids or terpenes such as (R)-(+)-cam-
In contrast to oxazolines, imidazolines offer the possibility for
N-functionalization to fine tune their electronic properties in order
to achieve good enantioselectivities.20 Hence, we further examined
the N-modification of 2 by alkylation, acylation, benzoylation, and
sulfonylation with RX substrates possessing either electron-donat-
ing or electron-withdrawing substituents (Scheme 1, Table 1).
Whereas routine N-deprotonation of 2 with DMAP proved to be
sluggish and reaction with nBuLi caused decomposition of the imi-
dazoline even at ꢀ78 °C, treatment of 2 with LHMDS at 0 °C fol-
lowed by addition of the electrophile RX afforded N-substituted
imidazolines 3–11 in good yields (Scheme 1, Table 1). As the
starting camphor-imidazoline 2 underwent imidazoline tautomer-
ism, N-substitution yielded two regioisomers a and b. To our
phor, (1S)-(ꢀ)-b-pinene, and (1S,2S,3S,5R)-(+)-isopinocampheone
and have described their application in the asymmetric Henry
reaction.19 Inspired by Busacca’s camphordiamine 1 and moving
from terpene-annulated imidazoles to the closely related dihydro
analogs, imidazolines, we report herein a modular synthesis of
two camphor-imidazoline ligand series a and b bearing an addi-
tional N-chelating pyridyl auxiliary and their catalytic behavior
in the copper(II)-catalyzed enantioselective Henry reaction.
* Corresponding author. Tel.: +420 46 603 7099; fax: +420 46 603 7068.
E-mail address: filip.bures@upce.cz (F. Bureš).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.010

F. Bureš et al. / Tetrahedron Letters 50 (2009) 3042–3045
3043
Table 1
N-Modification of camphor-imidazoline 2
Entry
1
Product
RX/R1
CH3I
Yield (%)
95a
Ratio a/b
3a/3b
1:1a
2
3
4a/4b
5a/5b
91a
89a
1:1a
0:1a
4
5
6a/6b
7a/7b
78a
90a
0:1a
1:3a
6
7
8
9
8a/8b
98a
53b
51b
41b
1:4a
1:1c
1:1c
1:1c
9a/9b
10a/10b
11a/11b
Figure 1. ORTEP representation of 2. Vibrational ellipsoids obtained at 150 K are
shown at the 50% probability level (solvent omitted). CCDC 717407.
delight, both regioisomers were separable by simple column
chromatography. Their molecular structures were assigned on
the basis of 1H–1H COSY, HMQC, and HMBC NMR spectroscopy
(see Supplementary data). More importantly, the ratio of both
regioisomers differed considerably according to the nature of RX
(Table 1). Whereas alkylation of 2 with methyl iodide or benzyl
bromide afforded regioisomers a and b in approximate ratios of
1:1 (Table 1, entries 1 and 2), acylation with isobutyrylchloride
or benzoylation gave exclusively the less sterically demanding
regioisomers 5b and 6b with anti-arrangement of the camphor
1-methyl and R groups (Table 1, entries 3 and 4). Benzoylation
with 4-methoxy- and 4-nitrobenzoyl chloride also resulted in the
pronounced formation of regioisomers 7b and 8b (Table 1, entries
5 and 6). In contrast, sulfonylation of 2 gave both regioisomers in a
1:1 ratio. However, slow decomposition of regioisomers 9b–11b
occurred during purification by column chromatography to yield
N,N0-disubstituted camphordiamines 12–14 (Scheme 1, Table 1,
entries 7–12). The easy formation of such products was confirmed
by adding 0.5 M HCl (0.5 mL) to the crude reaction mixture of 9–11
resulting in immediate precipitation of insoluble 14 and the grad-
ual formation of 12 and 13 within 2 h.
10
11
12
12
13
14
R1 = Me
R
R
43d
46d
39d
—
—
—
1 = OMe
1 = NO2
a
Overall isolated yield.
Isolated yield of regioisomer a.
Estimated by comparing the isolated yields of regioisomers 9a–11a and 12–14,
b
c
respectively.
d
Isolated yields of N,N’-disubstituted camphordiamines after acidification.
product in 90% yield but with a very low 8% ee (Table 2, entry 1).
This was most probably due to imidazoline tautomerism that
allows complexation of the copper on both imidazoline coordina-
tion sites resulting in the formation of almost a racemate. This
explanation is also applied to the reactions with N-methyl and
N-benzyl imidazoline regioisomers 3a/3b and 4a/4b which affor-
ded the nitroaldol products in 92–94% yields and enantioselectivi-
ties up to 51% (Table 2, entries 2 and 3). More importantly, the use
of either regioisomer a or b enabled the formation of either the (R)-
or (S)-nitroaldol. With reaction times and yields similar to those
observed for N-alkylated ligands 3 and 4, the N-acylated or N-ben-
zoylated ligands 5b and 6b gave the (S)-nitroaldols in higher
enantioselectivities up to 60% (Table 2, entries 4 and 5). Moreover,
The camphor-imidazolines synthesized were tested as ligands
in the copper(II)-catalyzed enantioselective Henry reaction.21,22
The reactions were carried out on 4-nitrobenzaldehyde with
CH3NO2/Cu(OAc)2/ligand in ethanol on a 0.5 mmol scale (Table
2).19a The N-unsubstituted imidazoline 2 afforded the nitroaldol
Scheme 1. Synthesis of camphor-imidazoline ligands.

3044
F. Bureš et al. / Tetrahedron Letters 50 (2009) 3042–3045
Table 2
Acknowledgments
The asymmetric Henry reactiona
This work was supported by the Czech Science Foundation
(203/07/P013) and by the Ministry of Education, Youth, and Sport
of the Czech Republic (MSM002167501).
Timeb (h)
Yieldc (%)
ee (%) configurationd
Supplementary data
Entry
Ligand
1
2
3
4
5
6
7
8
9
2
24
90
8 (R)
Supplementary data (experimental procedures, 1H, 13C, 1H-1H
COSY, HMQC, and HMBC NMR spectra and representative GC/MS
or MALDI data for all new compounds as well as the X-ray struc-
tures of the diamine hydrochloride and imidazoline 2) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.04.010.
3a/3b
4a/4b
5b
36/36
36/36
36
92/94
94/92
87
21 (R)/46 (S)
43 (R)/51 (S)
45 (S)
6b
36
90
60 (S)
7a/7b
8a/8b
9a
10a
11a
24/24
54/54
36
24
48
92/89
81/76
92
89
87
41 (R)/67 (S)
29 (R)/46 (S)
17 (R)
18 (R)
17 (R)
10
References and notes
a
Reactions were performed on a 0.5 mmol scale with Cu(OAc)2 (10%) and ligands
(10.5%) with nitromethane (10 equiv) in ethanol (5 mL) under N2 at room
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In summary, starting from the optically pure camphordiamine,
13 new camphor-annulated imidazolines were synthesized involv-
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the asymmetric Henry reaction afforded (R)-nitroaldols, regioi-
somers b gave the (S)-products. The latter also gave higher ees of
up to 67%. The enantioselectivity of the N-benzoylated ligands
was strongly affected by the electronic nature of the benzoyl moi-
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