Design and synthesis of chiral imidazolidine-pyridine ligands

Article abstract of DOI:10.1055/s-0029-1218311

Condensation of chiral diamines and aldehydes gave a series of chiral imidazolidine-pyridine compounds with high diastereoselectivities. The ability of these compounds to act as chiral ligands was examined in the catalytic Henry reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218311

LETTER
3167
Design and Synthesis of Chiral Imidazolidine-Pyridine Ligands
S
ynthesis of Ch
a
iral
I
midaz
k
olidine-Pyrid
a
ine
L
igand
y
oshi Arai,* Kuniko Suzuki
Graduate School of Science and Technology, Chiba University, Inage 263-8522, Japan
Fax +81(43)2902889; E-mail: tarai@faculty.chiba-u.jp
Received 3 September 2009
Uozumi reported elegant work on the stereoselective syn-
thesis of an imidazoindole ligand for asymmetric palladi-
um catalyses.7 Despite the prevailing applications as
organocatalysts,8 however, the challenges on the ligand
for the metal catalysts are rather limited.9,10
Abstract: Condensation of chiral diamines and aldehydes gave a
series of chiral imidazolidine-pyridine compounds with high diaste-
reoselectivities. The ability of these compounds to act as chiral
ligands was examined in the catalytic Henry reaction.
Key words : asymmetric catalysis, ligands, imidazolidine, copper,
Henry reaction
Table 1 Henry Reaction Catalyzed by Imidazoline-pyridine (L1)-
Cu(OAc)2
Ph
Ph
The synthesis of chiral molecules in a catalytic asymmet-
ric manner is essential for supplying fundamentally valu-
able organic compounds.1 Because the creation of a well-
organized reaction sphere using highly functionalized
chiral ligands is the key to controlling stereoselective met-
al catalysis, the design and development of new chiral
ligands is at the forefront of research on catalytic asym-
metric synthesis. In this communication, the quick and ef-
ficient stereoselective synthesis of imidazolidine
compounds is reported, and their ability to act as chiral
ligands is examined in the Cu(OAc)2-catalyzed Henry
reaction.2,3
O
OH
N
N
L1-Cu(OAc)2
(5 mol%)
NO2
R
H
MeNO
+
2
EtOH, r.t.
N
NO2
NO2
L1a R = H
L1b R = Bn
L1c R = Ts
L1d R = Bz
Entry
Ligand
L0
Time (h)
Yield (%)
ee (%)
94
1
2
3
4
5
40
24
24
24
24
98
57
55
97
49
As part of our research program for exploring efficient
asymmetric catalysts, we have succeeded in developing
imidazoline-containing chiral ligands for metal-catalyzed
reactions.4,5 For example, imidazoline-aminophenol (L0)-
Cu complexes have been realized as efficient catalysts for
the Henry reaction,4d the Friedel–Crafts reaction,4d,e and
the tandem Friedel–Crafts–Henry reaction.4f
L1a
L1b
L1c
26
14
44
L1d
19
Ph
Ph
R1
R1
R1
R1
Although the unique asymmetric reaction sphere pro-
duced by the imidazoline-aminophenol (L0)-metal com-
plex has potential for successful application to other
various asymmetric reactions, the simple imidazoline-
pyridine analogues (L1) were not effective for the
Cu(OAc)2-catalyzed Henry reaction (Table 1, entries 2–
5). We assumed that the relatively flat structure around the
Cu center in the square-planar L1-Cu(II) complex was not
sufficient to promote the stereoselective reactions [see
Figure 1, L1 and Figure 4, L1b-Cu(OAc)2]. To produce
more stereochemical complexity, we focused on the imid-
azolidine ring, in which the sp2-carbon of the imidazoline
ring is replaced by a sp3-carbon [Figure 1, L2 and
Figure 4, L2a-Cu(OAc)2].
N
N
N
N
N
sp2
N
NH
sp3
Ts
R2
R2
OH
Br
Br
N
N
Ph
R3
R3
imidazoline-pyridines imidazolidine-pyridines
(L1) (L2)
imidazoline-aminophenol
(L0)
Figure 1 Structurally simplified analogues (L1 and L2) of L0
Although the newly formed sp3-carbon is a stereogenic
center, we envisioned that the configuration of the product
would be controlled by the steric repulsion relayed from
the substituents of the chiral diamine. A DFT calculation
at the level of B3LYP/6-31G* suggested that L2 depicted
in Figure 2 is more stable than the epimer at the newly
formed asymmetric sp3-carbon by 5.7 kcal/mol.
Relatives of the imidazolidines, chiral imidazolidinones
are widely employed as organocatalysts for asymmetric
reactions, as pioneered by MacMillan.6 Furthermore,
The synthesis of imidazolidine-pyridine ligands was
readily achieved by a simple condensation of monoalkyl
chiral diamines and aldehydes using acetic acid
SYNLETT 2009, No. 19, pp 3167–3170
Advanced online publication: 23.10.2009
DOI: 10.1055/s-0029-1218311; Art ID: U08909ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

3168
T. Arai, K. Suzuki
LETTER
Cu(OAc)]+.12 The DFT calculation at the level of B3LYP/
6-31G* suggested a slightly twisted square-planar Cu(II)
complex with L2, though the L1-Cu(OAc)2 complex is
square-planar (Figure 4).
N
N
Ph
N
R
Figure 2 Stable isomer of imidazolidine-pyridines (L2)
Ph
Ph
O
H
N
Ph
N
NH
R1
R1
NH2
AcOH
+
N
CH2Cl2, r.t.
H
N
Ph
R2
R2
L2a R1 = Bn , R2 = H, 86%, dr = 17:1
L2b R1 = Bn , R2 = Ph, 71%, dr = 13:1
Figure 4 L1b-Cu(OAc)2 complex and L2a-Cu(OAc)2 complex
(Cu: orange; N: blue; O: red; C: gray; H: white)
L2c R1 = Bn , R2 = 2,5-diMe-C6H3, 77%, dr = 15:1
L2d R1 = Bn , R2 = 2-naphthyl, 76%, dr >99:1
L2e R1 = 2-Me-Bn, R2 = Ph, 51%, dr = 9:1
L2f R1 = H , R2 = H, 43%
The three-dimensional structure of the imidazoline-pyri-
dine ligand (L2) would have an obvious advantage over
L1 in constructing the reaction sphere to promote the
asymmetric reaction.
TsCl
DIPEA
L2g R1 = Ts , R2 = H, 60%, dr = 21:1
Scheme 1 Synthesis of imidazolidine-pyridine ligands (L2)
The ability of the imidazolidine-pyridines to act as chiral
ligands was examined and the results are shown in
Table 2. The Henry reaction of o-nitrobenzaldehyde with
nitromethane was smoothly catalyzed by the imidazoli-
dine-pyridine (L2a)-Cu(OAc)2 complex to give the
adduct in 98% yield with 59% ee. For cyclohexane-
carboxaldehyde, imidazolidine-phenylpyridine L2b
showed better selectivity to provide the adduct with 71%
ee (entry 4).
(Scheme 1). The tosyl-imidazoline analogue (L2g) was
prepared by tosylation after forming the imidazolidine
(L2f).
The highly diastereoselective construction of the imidazo-
1
lidine-pyridines was confirmed by H NMR analysis.
Moreover, the X-ray crystallographic analysis of a single
crystal of L2b revealed an all-trans stereochemical out-
come (Figure 3).11
Table 2 L2-Cu(OAc)2-Catalyzed Asymmetric Henry Reaction
L2-Cu(OAc)2
(5 mol%)
OH
O
MeNO2
+
NO2
EtOH, r.t.
R
R
H
Entry
Ligand
R
Yield (%)
ee (%)
59
1
2
3
4
5
6
7
8
9
L2a
L2a
L2b
L2b
L2c
L2d
L2e
L2f
2-O2NC6H4
cyclohexyl
2-O2NC6H4
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
98
75
46
>99
84
53
71
16
30
61
65
Figure 3 All-trans imidazolidine-pyridine (L2b)
81
70
76
2
The newly obtained imidazolidine-pyridine ligands are
stable to moisture at ambient temperature, and can be kept
under air. When L2 was added to Cu(OAc)2 in EtOH, the
solution immediately turned a green color. The formation
of the L2b-Cu(II) complex was strongly suggested by
ESI-TOF mass spectrometry by the observation of an
ion peak at m/z = 589.11 corresponding to [L2b +
L2g
31
30
The generality of the enantioselective Henry reaction us-
ing L2b-Cu(OAc)2 was next examined and the results are
shown in Table 3.
Synlett 2009, No. 19, 3167–3170 © Thieme Stuttgart · New York

LETTER
Synthesis of Chiral Imidazolidine-Pyridine Ligands
3169
Table 3 Asymmetric Henry Reaction Catalyzed by L2b-Cu(OAc)2
1 H), 5.11 (s, 1 H), 7.03–7.10 (m, 5 H, arom.), 7.22–7.61 (m, 17 H,
arom.), 8.03–8.06 (m, 1 H, arom.). 13C NMR (125 MHz, CDCl3):
d = 55.4, 69.4, 82.2, 119.3, 120.8, 126.6, 126.9, 127.1, 127.2, 127.5,
127.7, 128.2, 128.26, 128.30, 128.6, 128.8, 129.5, 136.8, 137.5,
139.5, 140.1, 141.6, 143.0, 156.3, 161.7. FT-IR: 3315, 2985, 2902,
1572, 1493, 1450, 1406, 1394, 1070, 758, 698 cm–1. [a]D20 +118.7
(c 1.38, CHCl3, dr = 17:1). HRMS (FAB+): m/z calcd for C33H30N3
[M+ + H]: 468.2440; found: 468.2400.
L2b-Cu(OAc)2
(5 mol%)
O
OH
MeNO2
+
NO2
EtOH, r.t., 24 h
R
H
R
Entry
R
Yield (%)
93
ee (%)
53
1
3
Ph
4-O2NC6H4
2-ClC6H4
92
47
Catalytic Asymmetric Henry Reaction
The catalyst was prepared by the complex formation of L2 (0.011
mmol) with Cu(OAc)2·H2O (2.0 mg, 0.01 mmol) in anhyd CH2Cl2
(1.0 mL) under Ar. After stirring overnight at r.t., the solvent was
removed under reduced pressure. Next, the residue was dissolved in
EtOH (400 mL). To the resulting clear green solution was added ni-
tromethane (432 mL, 8.0 mmol) and aldehyde (0.20 mmol) under
Ar. After stirring for a further 24 h at r.t., the solution was directly
purified by silica gel column chromatography to afford the adduct.
The ee of the product was determined by HPLC analysis.
4
99
64
5
2-MeOC6H4
Me(CH2)3
Me(CH2)4
Me2CHCH2
Me2CH
>99
>99
91
76
6
72
7
70
8
>99
98
75
9
76
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
11
PhCH2CH2
>99
74
Various aldehydes were smoothly converted to Henry ad-
ducts at room temperature, and in all cases, the R-enriched
products were obtained using the (S,S)-diphenylethylene-
diamine-derived ligand L2b. The simplest aromatic alde-
hyde, benzaldehyde, was converted to the Henry adduct in
93% yield with 53% ee. Typically, the use of aliphatic al-
dehydes provided the corresponding adducts with higher
enantioselectivities than those obtained using aromatic al-
dehydes. In particular, a-branched aliphatic aldehydes
such as pivalaldehyde and cyclohexanecarboxaldehyde
gave the adducts with good enantioselectivity (up to 76%
ee) without a significant decrease in reaction rate.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas (No. 19028007, ‘Chemistry of Concerto Cataly-
sis’) from the Ministry of Education, Science, Sports, Culture and
Technology of Japan. We thank Mr. Naota Yokoyama for his kind
technical support and helpful discussions.
References and Notes
(1) (a) Asymmetric Catalysis in Organic Synthesis; Noyori, R.,
Ed.; Wiley: New York, 1994. (b) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999. (c) Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M.; Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004.
In summary, we have succeeded in developing a concise
method for the synthesis of chiral imidazolidine-pyridine
ligands. The newly synthesized imidazolidine-pyridine
(L2b)-Cu(OAc)2 complex smoothly catalyzed the Henry
reaction, and the desired products were obtained in high
chemical yields with moderate to good enantiomeric ex-
cesses. Due to this fascinating, short synthetic route, fur-
ther study on the development of diverse imidazolidine-
containing ligands and their application to asymmetric ca-
talysis are in progress.
(2) Selected examples of catalytic enantioselective Henry
reaction: (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418.
(b) Trost, B. M.; Yeh, V. S. C. Angew. Chem. Int. Ed. 2002,
41, 861. (c) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 2054. (d) Kogami, Y.; Nakajima, T.;
Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem. Lett.
2004, 33, 614. (e) Palomo, C.; Oiarbide, M.; Laso, A.
Angew. Chem. Int. Ed. 2005, 44, 3881. (f) Marcelli, T.; van
der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem. Int. Ed. 2006, 45, 929. (g) Uraguchi, D.;
Sasaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392.
(3) Pioneering works on the Cu-catalyzed asymmetric Henry
reaction: (a) Christensen, C.; Juhl, K.; Jørgensen, K. A.
Chem. Commun. 2001, 2222. (b) Evans, D. A.; Seidel, D.;
Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W.
J. Am. Chem. Soc. 2003, 125, 12692. (c) Lu, S.-F.; Du,
D.-M.; Zang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2004,
15, 3433. (d) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou,
M.-M. Tetrahedron: Asymmetry 2006, 17, 725.
(4) (a) Arai, T.; Mizukami, T.; Yokoyama, N.; Nakazato, D.;
Yanagisawa, A. Synlett 2005, 2670. (b) Arai, T.; Mizukami,
T.; Yanagisawa, A. Org. Lett. 2007, 9, 1145. (c) Arai, T.;
Mizukami, T.; Mishiro, A.; Yanagisawa, A. Heterocycles
2008, 76, 995. (d) Arai, T.; Yokoyama, N.; Yanagisawa, A.
Chem. Eur. J. 2008, 14, 2052. (e) Yokoyama, N.; Arai, T.
Chem. Commun. 2009, 3285. (f) Arai, T.; Yokoyama, N.
Synthesis of Imidazolidine-Pyridine Compounds
A solution of the appropriate aldehyde (1.0 mmol) and diamine (0.7
mmol) in CH2Cl2 (10 mL) was stirred at 0 °C, and then AcOH (40
mL, 0.7 mmol) was added to the mixture. The resulting solution was
allowed to warm to r.t. and stirred overnight. Sat. NaHCO3 was add-
ed to the reaction mixture to make the solution alkaline. The mix-
ture was extracted with CH2Cl2. The organic layer was dried over
Na2SO4, and the solvent was removed in vacuo. The residue was pu-
rified by silica gel column chromatography to give the correspond-
ing imidazolidine-pyridine (L2). Recrystallization of L2 from
CH2Cl2–EtOH (1:5) is effective to remove the minor diastereomer.
Spectral Data of L2b
1H NMR (400 MHz, CDCl3): d = 3.71 (d, J = 13.7 Hz, 1 H), 3.88 (d,
J = 8.2 Hz, 1 H), 3.90 (d, J = 13.7 Hz, 1 H), 4.42 (d, J = 8.2 Hz,
Synlett 2009, No. 19, 3167–3170 © Thieme Stuttgart · New York

3170
T. Arai, K. Suzuki
LETTER
Jørgensen, K. A. Adv. Synth. Catal. 2004, 346, 1077.
Angew. Chem. Int. Ed. 2008, 47, 4989.
(5) Recent progresses on chiral ligands containing the
imidazoline motif: (a) Manges, F.; Neuburger, M.; Pfaltz, A.
Org. Lett. 2002, 4, 4713. (b) Busacca, C. A.; Grossbach, D.;
So, R. C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett. 2003, 5,
595. (c) Casey, M.; Smyth, M. P. Synlett 2003, 102.
(d) Guiu, E.; Claver, C.; Benet-Buchholz, J.; Castillón, S.
Tetrahedron: Asymmetry 2004, 15, 3365. (e) Bastero, A.;
Claver, C.; Ruiz, A.; Castillón, S.; Daura, E.; Bo, C.;
Zangrando, E. Chem. Eur. J. 2004, 10, 3747. (f) Bhor, S.;
Anilkumar, G.; Tse, M. K.; Klawonn, M.; Döbler, C.;
Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett. 2005, 7,
3393. (g) Weiss, M. E.; Fischer, D. F.; Xin, Z.-q.; Jautze, S.;
Schweizer, W. B.; Peters, R. Angew. Chem. Int. Ed. 2006,
45, 5694. (h) Ma, K.; You, J. Chem. Eur. J. 2007, 13, 1863.
(i) Enthaler, S.; Hagemann, B.; Bhor, S.; Anilkumar, G.;
Tse, M. K.; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M.
Adv. Synth. Catal. 2007, 349, 853. (j) Xin, Z.-q.; Fischer, D.
F.; Peters, R. Synlett 2008, 1495. (k) Nakamura, S.; Hyodo,
K.; Nakamura, Y.; Shibata, N.; Toru, T. Adv. Synth. Catal.
2008, 350, 1443. (l) Jautze, S.; Peters, R. Angew. Chem. Int.
Ed. 2008, 47, 9284.
(e) Ramachary, D. B.; Barbas, C. F. III. Chem. Eur. J. 2004,
10, 5323. (f) Halland, N.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2002, 67, 8331.
(9) Recent progresses on chiral ligands containing the
imidazolidine motif: (a) Jin, M.-J.; Takale, V. B.; Sarkar,
M. S.; Kim, Y.-M. Chem. Commun. 2006, 663. (b) Lee,
E.-K.; Kim, S.-H.; Jung, B.-H.; Ahn, W.-S.; Kim, G.-J.
Tetrahedron Lett. 2003, 44, 1971. (c) Braga, A. L.; Vargas,
F.; Silveira, C. C.; de Andrade, L. H. Tetrahedron Lett. 2002,
43, 2335.
(10) Examples of chiral imidazolidines as NHC ligands: (a) Lee,
Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160.
(b) Fournier, P.-A.; Collins, S. K. Organometallics 2007, 26,
2945. (c) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito,
N. Org. Lett. 2007, 9, 5597. (d) Funk, T. W.; Berlin, J. M.;
Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840.
(e) Chianese, A. R.; Crabtree, R. H. Organometallics 2005,
24, 4432. (f) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici,
R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877.
(g) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
8876. (h) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 14370. (i) Burstein, C.; Glorius, F. Angew.
Chem. Int. Ed. 2004, 43, 6205. (j) Suzuki, Y.; Yamaguchi,
K.; Muramatsu, K.; Sato, M. Chem. Commun. 2004, 2770.
(k) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem. Int. Ed.
2004, 43, 5130. (l) Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534. (m) Jansen, D. R.; Sigman, M. S. Org.
Lett. 2003, 5, 63.
(6) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (b) Nagib, D. A.; Scott, M. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875;
and references cited therein.
(7) (a) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123,
2919. (b) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada,
Y. M. A. Angew. Chem. Int. Ed. 2009, 48, 2708; and
references cited therein.
(11) Crystal Data
(8) Chiral imidazoline as organocatalyst: (a) Szanto, G.;
Bombicz, P.; Grun, A.; Kadas, I. Chirality 2008, 20, 5357.
(b) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.;
Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005,
4821. (c) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett.
2005, 7, 3897. (d) Pulkkinen, J.; Aburel, P. S.; Halland, N.;
Orthorhombic, space group: P2 (1)2 (1)2 (1), a = 6.3601 (3),
b = 8.1108 (4), c = 50.351 (3), V = 2597.4 (2), Z = 4, MoKa
radiation, R1 = 0.0456, wR2 = 0.1458.
(12) The MS value of m/z = 997.29 was also detected for [(L2b)2
– Cu]+. Although the mixing ratio of L2b and Cu(OAc)2 was
reexamined to superior formation of the 1:1 complex, the ee
of the Henry adduct was not improved.
Synlett 2009, No. 19, 3167–3170 © Thieme Stuttgart · New York