Direct assembly of aldehydes, amino esters, and anilines into chiral imidazolidines via Bronsted acid catalyzed asymmetric 1,3-dipolar cycloadditions

Article abstract of DOI:10.1021/ol802177s

(Chemical Equation Presented) A chiral Bransted acid catalyzed 1,3-dipolar cycloaddition reaction directly assembles aldehydes, amino esters, and anilines into synthetically useful chiral imidazolidines with high levels of stereoselectivity (up to 91/9 dr and 98% ee).

Full text of DOI:10.1021/ol802177s

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5357-5360
Direct Assembly of Aldehydes, Amino
Esters, and Anilines into Chiral
Imidazolidines via Brønsted Acid
Catalyzed Asymmetric 1,3-Dipolar
Cycloadditions
Wei-Jun Liu, Xiao-Hua Chen, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei 230026, China
gonglz@ustc.edu.cn
Received September 17, 2008
ABSTRACT
A chiral Brønsted acid catalyzed 1,3-dipolar cycloaddition reaction directly assembles aldehydes, amino esters, and anilines into synthetically
useful chiral imidazolidines with high levels of stereoselectivity (up to 91/9 dr and 98% ee).
Optically active imidazolidines are important intermediates
with broad applications in organic synthesis.1 The 1,3-dipolar
cycloaddition of azomethine ylides to imines with concomi-
tant creation of multiple stereogenic centers represents an
efficient and atom-economical method for the manufacture
of these compounds. Numerous highly enantioselective 1,3-
dipolar additions between azomethine ylides and electron-
deficient olefins have been developed through the use of
either the metal-based or organic catalysts.2-4 However, only
a few diastereoselective 1,3-dipolar cycloadditions of azome-
thine ylides with imines that utilized preformed chiral
reaction components to control stereoselectivities have been
available for furnishing enantioenriched imidazolidines.5 To
(3) For examples, see: (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am.
Chem. Soc. 2002, 124, 13400. (b) Gothelf, A. S.; Gothelf, K. V.; Hazell,
R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236. (c) Chen,
C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (d) Kno¨pfel,
T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew.
Chem, Int. Ed. 2004, 43, 5971. (e) Cabrera, S.; Arraya´s, R. G.; Carretero,
J. C. J. Am. Chem. Soc. 2005, 127, 16394. (f) Yan, X.-X.; Peng, Q.; Zhang,
Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed.
2006, 45, 1979. (g) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am.
Chem. Soc. 2007, 129, 750. (h) Lo´pez-Pe´rez, A.; Adrio, J.; Carretero, J. C.
J. Am. Chem. Soc. 2008, 130, 10084.
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Gosmini, R.; Raussou, S. Pure Appl. Chem. 1996, 68, 531. (b) Alexakis,
A.; Mangeney, P. In AdVanced Asymmetric Synthesis; Stephenson, G. R.,
Ed.; Chapman and Hall: London, 1996; Chapter 5, pp 93. (c) Erkkila, A.;
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Int. Ed. 200746, 5168. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Cordova, A
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10.1021/ol802177s CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society

date, the catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides to imines has not been reported, and we
believe this represents a considerable challenge.6 Herein, we
present the first asymmetric catalytic three-component 1,3-
dipolar cycloaddition between azomethine ylides and imines
that directly assembles aldehydes, amino esters, and anilines
into chiral imidazolidines with high levels of enantioselec-
tivity (eq 1).
captured by the chiral Brønsted acid activated dipole Ia or
Ib to thereby undergo an enantioselective [3 + 2] cycload-
dition (Scheme 1).
Scheme 1
. Proposed Phosphoric Acid Catalyzed 1,3-Dipolar
Cycloaddition of Imines with Azomethine Ylides
During our recent efforts to develop Brønsted acid
catalyzed asymmetric multicomponent reactions, we have
demonstrated that chiral phosphoric acids7 effectively furnish
Biginelli reactions, Mannich reactions, and cyclization of
enals with anilines and 1,3-dicarbonyls.8 Most recently, we
established a three-component 1,3-dipolar cycloaddition
reaction wherein the phosphoric acid controlled the stereo-
chemistry by presumably forming a chiral dipole, Ia or Ib,
with an azomethine ylide.9 An imine generated in situ from
an aldehyde and an amine could be activated by formation
of an iminium species, either IIa or IIb, with a Brønsted
acid and showed high reactivity toward nucleophiles.7,8 We
questioned whether the iminium intermediates would be
Figure 1. Catalysts evaluated in this study.
(6) For racemic reactions, see: (a) Nagao, Y.; Kim, K.; Komaki, Y.;
Sano, S.; Kihara, M.; Shiro, M. Heterocycles 1994, 38, 587. (b) Amornraksa,
K.; Barr, D.; Donegan, G.; Grigg, R.; Rarananukul, P.; Sridharan, V.
Tetrahedron 1989, 45, 4649. (c) Grigg, R.; Kemp, J. J. Chem. Soc., Chem.
Commun. 1978, 109.
In our initial experiments, the benzaldehyde (1a), diethyl
aminomalonate (2a), and p-anisidine (3a) smoothly under-
went 1,3-dipolar cycloaddition in toluene under the catalysis
of a phosphoric acid 5a, furnishing the desired imidazolidine
4a in 90% yield, but with unsatisfactory stereoselectivity
(Table 1, entry 1). A survey of various binol-based catalysts
demonstrated that the phosphoric acid 5g, bearing the most
sterically congested substituents, gave superior stereoselec-
tivity (entries 2-7). However, the bis-phosphoric acid 6,
which delivered high ee in the 1,3-dipolar cycloaddition of
azomethine ylides to maleates, exhibited poor stereoselec-
tivity (entry 8). Screening of solvents suggested that toluene
is most suitable for the reaction (entries 7 and 9-11). The
aniline substituent played a crucial role in the stereochemistry
(entries 12-16). Accordingly, excellent enantioselectivities
were observed with m-toluidine and 4-tert-butoxyaniline
(entries 14 and 16).
Having established the optimal conditions, we then
examined the scope of the aldehydes that could participate
in the cycloaddition reaction with either m-toluidine (3d) or
4-tert-butoxyaniline (3f). As shown in Table 2, electronically
poor and neutral aromatic aldehydes reacted smoothly with
4-tert-butoxyaniline (3f) to afford syn-imidazolidines in high
yields with excellent enantioselectivities (entries 1-7 and
10-14). Although electronically rich benzaldehydes showed
much less reactivity in the reaction involving the 4-tert-
butoxyaniline component, they underwent facile reactions
with m-toluidine (3d) in high enantioselectivities (entries 8
and 9). The diastereoselectvity was found highly dependent
on the substituent of aldehydes. Generally, para-substituted
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G.-L.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216.
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Chem. Soc. 2006, 128, 14802. (b) Guo, Q.-X.; Liu, H.; Luo, S.-W.; Guo,
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5358
Org. Lett., Vol. 10, No. 23, 2008

diastereomers (entries 12 and 13), opposite to those observed
with para- and meta-substituted benzaldehydes. 1-Naphthal-
dehyde was also a good reaction partner, giving a good
diastereomeric ratio and high enantioselectivity (entry 14).
Notably, the protocol is amenable to aliphatic aldehydes such
as cyclopropanecarboxaldehyde,10 albeit with a moderate
stereoselectivity (entry 15). Importantly, ynals, a class of
challenging reaction acceptors under organocatalytic condi-
tions, were tolerated in the dipolar cycloaddition catalyzed
by 5e favoring the anti-product as exemplified by phenyl-
propiolaldehyde (entry 16). The relative and absolute ster-
eochemistry of 4h was assigned by X-ray analysis (Figure
2), and the stereochemistry of the other products was
assigned by analogy.
Table 1. Optimization of Reaction Conditionsa
yield
solvent (%)b drc
ee
(%)d
entry catalyst
4 (Ar)
1
5a
5b
5c
5d
5e
5f
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
p-MeOC6H4 (4a)
Ph (4b)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
90 67/33 7e (6)
84 52/48 8 (15)
83 56/44 2 (6)
89 68/32 15 (1)
82 53/47 8 (41e)
85 82/18 5e (1)
98 73/27 82 (41)
84 48/52 40e (5)
94 39/61 23 (54)
97 52/48 61 (38)
2
3
4
5
6
7
5g
6
8
9
5g
5g
5g
5g
5g
5g
5g
5g
10
11
12
13
14
15
16
(CH2Cl)2 85 30/70 31 (50)
toluene
m-MeOC6H4 (4c) toluene
89 78/22 89 (42)
86 59/41 87 (57)
86 79/21 91 (36)
96 66/34 89 (62)
77 75/25 90 (46)f
m-MeC6H4 (4d)
p-ClC6H4 (4e)
p-(t-BuO)C6H4 (4f) toluene
toluene
toluene
a The reaction was carried out at 0.2 mmol scale in toluene (2 mL)
with 3 Å MS (200 mg) at -10 °C for 36 h, and the ratio of 1a/2a/3 was
3:1:1.2. b Isolated yield based on 2a. c Determined by 1HNMR. d Determined
by HPLC, the ee in parentheses is for the minor diastereomer. e The opposite
enantiomer was obtained. f Reaction time was 60 h.
Table 2. Scope of Aldehydesa
Figure 2
. X-ray crystal structure of 4h with ellipsoids set at 10%
probability. Hydrogen atoms are omitted for clarity.
yield
(%)b
ee
(%)d
entry
4
R
drc
1
4g
4h
4i
4-NO2C6H4
4-BrC6H4
4-CNC6H4
4-MeO2CC6H4
4-CF3C6H4
4-ClC6H4
4-FC6H4
4-CH3C6H4
3-CH3OC6H4
3-BrC6H4
2-BrC6H4
2-ClC6H4
2-FC6H4
73
85
90
89
84
91
89
85
99
82
87
76
78
99
63
86
91/9
82/18
90/10
91/9
98
2
95
3
98
4
4j
98
5
4k
4l
83/17
79/21
76/24
75/25
63/37
84/16
65/35
48/52
45/55
88/12
j
94
6
95 (20)
93 (33)e
88 (15)f,g
90 (15)f,g
95
7
4m
4n
4o
4p
4q
4r
4s
4t
8
9
10
11
12
13
14
15
16
90 (65)
85 (66)
89 (60)
90e
Figure 3. Relation between enantiomeric excess of 4h and that of
5g.
1-naphthyl
c-C3H5
Pht
40g h
,
4u
4vi
34/66
76 (58)f,g
a Unless indicated otherwise, the reaction involving 4-tert-butoxyaniline
(3f was carried out in 0.2 mmol scale in toluene (2 mL) with 3 Å MS (200
mg) at -10 °C for 60 h, and the ratio of 1/2a/3 was 3/1/1.2. b Isolated
A preliminary mechanistic study was conducted by
measuring the nonlinear effect (NLE). Plotting the ee of the
catalyst 5g versus that of the product 4h led to a negative
NLE (Figure 3), implying that two molecules of phosphoric
acids may participate in the catalysis via the pathway shown
in Scheme 1.11
c
yield based on 2a. Determined by HNMR. d Determined by HPLC, the
ee in parentheses is for the minor diastereomer. e Stirred for 100 h. f At
-20 °C. g Reactions with m-toluidine (3d). h The ratio of 1/2a/3 was 5:3:1.
i Using 5e as a catalyst. j The anti-diastereomer was not observed by
1HNMR.
1
(10) Cyclohexanecarboxaldehyde also reacted with m-toluene (3d) to
afford imidazoline in a 32% yield after 6 days, but we failed to resolve the
product by chiral HPLC and therefore the ee is not reported.
(11) (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922.
(b) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402.
benzaldehydes gave much higher diastereomeric ratios than
ortho-substituted ones (entries 1-8 and 11-13). Interest-
ingly, 2-fluoro- and 2-chlorobenzaldehydes favored anti-
Org. Lett., Vol. 10, No. 23, 2008
5359

followed by a one-pot hydrolysis with aqueous phosphoric
acid in THF, generated a chiral ꢀ,γ-diamino alcohol 7 in an
overall 50% yield.
Scheme 2. Synthetic Application of Imidazolidines
In summary, we have disclosed the first catalytic asym-
metric 1,3-dipolar cycloaddition that directly assembles
aldehydes, amino esters, and anilines into synthetically useful
chiral imidazolidines with high levels of stereoselectivity.
Two molecules of Brønsted acids participated in the catalysis
by the activation of both azomethine ylides and imines. This
reaction has further demonstrated that the chiral Brønsted
acid activated dipoles are versatile intermediates for the
creation of new enantioselective 1,3-dipolar cycloadditions.
Additional related studies will be reported in due course.
Optically pure vicinal diamines and amino alcohols have
been widely used in organic synthesis, either as chiral
auxiliaries or ligands,12 and the present 1,3-dipolar cycload-
dition reaction may be applied to the synthesis of these
compounds (Scheme 2). The exposure of imidazolidine 4h
to a combined reductive reagent of sodium borohydride and
lithium chloride in a solvent mixture of ethanol and THF,13
Acknowledgment. We are grateful for financial support
from NSFC (20732006), Chinese Academy of Sciences, and
Ministry of Education.
Supporting Information Available: Experimental details
and characterization of new compounds, including CIF files.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
835. (b) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580. (c) Kizirian, J.-C. Chem. ReV. 2008, 108, 140.
(13) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J. Org.
Chem. 1987, 52, 1252.
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