An enantioselective chiral Bronsted acid catalyzed imino-azaenamine reaction

Article abstract of DOI:10.1021/ol063112p

(Chemical Equation Presented) The enantioselective Bronsted acid catalyzed addition of methyleneaminopyrrolidine to N-Boc imines has been achieved in the presence of chiral phosphoric acids derived from 3,3′-di(phenanthryl)-H8-BINOL. The corresponding ami

Full text of DOI:10.1021/ol063112p

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1065-1068
An Enantioselective Chiral Brønsted
Acid Catalyzed Imino
Reaction
−Azaenamine
Magnus Rueping,*,† Erli Sugiono,† Thomas Theissmann,† Alexander Kuenkel,†
Angela Ko
1
ckritz,‡ Anahit Pews-Davtyan,‡ Navid Nemati,‡ and Matthias Beller‡
Degussa Endowed Professorship, Institute of Chemistry and Chemical Biology,
Johann-Wolfgang Goethe UniVersity Frankfurt am Main, Max-Von-Laue Strasse 7,
D-60438 Frankfurt, Germany, and Leibniz Institute for Catalysis,
Albert Einstein Str. 29a, D-18059 Rostock, Germany
m.rueping@chemie.uni-frankfurt.de
Received December 22, 2006
ABSTRACT
The enantioselective Brønsted acid catalyzed addition of methyleneaminopyrrolidine to N-Boc imines has been achieved in the presence of
chiral phosphoric acids derived from 3,3′-di(phenanthryl)-H8-BINOL. The corresponding aminohydrazones have been isolated in good yields
with enantiomeric excesses up to 90%.
The application of Brønsted acids in organic syntheses
continues to rise, and a number of catalytic asymmetric
transformations have been developed in recent years.1 The
major function of Brønsted acids in these reactions is the
protonation of the electrophile, which is thereby activated
to react with a corresponding nucleophile. Often catalytic
amounts of Brønsted acids are sufficient to achieve complete
product formation.
reactions, a proton is transferred from the Brønsted acid to
the substrate resulting in the formation of a chiral ion pair
which subsequently undergoes reaction with a nucleophile
(2) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804. (d) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K.
Org. Lett. 2005, 7, 2583. (e) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005,
127, 15696. (f) Hofmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int.
Ed. 2005, 44, 7424. (g) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.;
Fuchibe, K. Synlett 2006, 141. (h) Seayad, J.; Seayad, A. M.; List, B. J.
Am. Chem. Soc. 2006, 128, 1087. (i) Terada, M.; Machioka, K.; Sorimachi,
K. Angew. Chem., Int. Ed. 2006, 45, 2254. (j) Mayer, S.; List, B. Angew.
Chem., Int. Ed. 2006, 45, 4193. (k) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
Chem., Int. Ed. 2006, 45, 4796. (l) Nakashima, D.; Yamamoto, H. J. Am.
Chem. Soc. 2006, 128, 9626. (m) Hasegawa, A.; Naganawa, Y.; Fushimi,
M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 3175. (n) Chen, X.-H.;
Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2006, 128,
14802.
Recently, we and others reported on the application of
chiral BINOL-phosphates in the development of highly
enantioselective transformations.2-6 In the first step of these
† Johann-Wolfgang Goethe University Frankfurt am Main.
‡ Leibniz Institute for Catalysis Rostock.
(1) For reviews, see: (a) Schreiner, P. R. Chem. Soc. ReV. 2003, 32,
289. (b) Pihko, P. M. Angew. Chem. 2004, 116, 2110; Angew. Chem., Int.
Ed. 2004, 43, 2062. (c) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew.
Chem., Int. Ed. 2005, 44, 1758. (d) Yamamoto, H.; Futatsugi, K. Angew.
Chem., Int. Ed. 2005, 44, 1924. (e) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520. (f) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV.
Synth. Catal. 2006, 348, 999.
(3) (a) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T. Synlett 2005,
2367. (b) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M.
Org. Lett. 2005, 7, 3781. (c) Rueping, M.; Antonchick, A. P.; Theissmann,
T. Angew. Chem., Int. Ed. 2006, 45, 6751.
10.1021/ol063112p CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/17/2007

to form the corresponding amine and the regenerated
Brønsted acid (eq 1).
Initially, we started our investigations with the evaluation
of different methylene-hydrazines 1a-d which can simply
be prepared on a large scale.8a,9 The BINOL-phosphate
catalyzed reactions were perfomed with N-Boc aldimine 2a
in the presence of 5 mol % of Brønsted acid catalyst 4a
(Figure 2) in chloroform at 0 °C (Table 1).
On the basis of this concept of chiral ion pair catalysis,
we were recently successful in developing highly enantio-
selective reactions, such as the first Brønsted acid catalyzed
transfer hydrogenations,3 cascade reductions,4 hydrocyana-
tions,5 or domino Mannich-Michael reactions.6
Herein, we report the development of yet another highly
enantioselective Brønsted acid catalyzed transformation, an
asymmetric imino ene type reaction (eq 2). The reaction
Figure 2. Chiral Brønsted acid catalysts.
consists of a new BINOL-phosphate catalyzed addition of
methylene-hydrazines 1 to N-Boc-protected imines 2 to
afford chiral aminohydrazones 3 (eq 2).7
From this survey, the best reactivities and selectivities were
obtained when piperidine- and pyrrolidine-derived methyl-
Chiral hydrazones have proven to be important synthetic
intermediates that can be readily derivatized to many useful
chiral blocks, including amino-aldehydes, amino-nitriles, or
diamines, without any racemization (Figure 1).8
Table 1. Survey of Different Methylene-hydrazines
entrya
1
RRN
ee [%]b
14
1a
1b
2
61
3c
4c
1c
1d
Ph2N
Bn2N
-
-
a Reactions were performed with aldimine 2a (1.2 equiv) and methylene-
hydrazines 1a-d at 0.15 M concentration in chloroform at 0 °C for 16 h.
b Enantiomeric excess was determined by HPLC using Chiralcel OD-H or
c
Chiralpak AD-H columns. No product formation was observed.
Figure 1. Derivatization of chiral aminohydrazones.
ene-hydrazines 1a and 1b were employed, and the corre-
sponding products were obtained with 14% ee and 61% ee,
Given the value of these products, we decided to develop
an enantioselective Brønsted acid catalyzed synthesis of
aminohydrazones.
(7) (a) El Kaim, L.; Gautier, L.; Grimaud, L.; Michaut, V. Synlett 2003,
1844. (b) Dixon, D. J.; Tillman, A. L. Synlett 2005, 2635.
(8) (a) Pareja, C.; Martin-Zamora, E.; Fernandez, R.; Lassaletta, J. M.
J. Org. Chem. 1999, 64, 8846. (b) Enders, D.; Diez, E.; Fernandez, R.;
Martin-Zamora, E.; Munoz, J. M.; Pappalardo, R. R.; Lassaletta, J. M. J.
Org. Chem. 1999, 64, 6329. (c) Enders, D.; Schubert, H. Angew. Chem.,
Int. Ed. 1984, 23, 365. (d) Diez, E.; Fernandez, R.; Martin-Zamora, E.;
Pareja, C.; Prieto, A.; Lassaletta, J. M. Tetrahedron: Asymmetry 1999, 10,
1145. (e) Diez, E.; Lopez, A. M.; Pareja, C.; Martin, E.; Fernandez, R.;
Lassaletta, J. M. Tetrahedron Lett. 1998, 39, 7955. (f) Review: Job, A.;
Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253.
(4) (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Synlett 2006,
1071. (b) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
Int. Ed. 2006, 45, 3683.
(5) (a) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006,
45, 2617. (b) Rueping, M.; Sugiono, E.; Moreth, S. A. AdV. Synth. Catal.
2007, in print.
(6) (a) Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832.
(b) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem., Int. Ed. 2007, 46, in print.
1066
Org. Lett., Vol. 9, No. 6, 2007

respectively (Table 1, entries 1 and 2). Interestingly, no
reaction to the desired products occurred with methylene-
hydrazines 1c and 1d (Table 1, entries 3 and 4).
Encouraged by the successful additions, we decided to
evaluate various aldimines with different protecting groups10
in combination with methylene-hydrazines 1a and 1b in the
Brønsted acid catalyzed imino ene type reaction. The results
of this examination are summarized in Table 2. The highest
suggested that solvent effects can play a crucial role in
obtaining good yields and high enantioselectivities.3-6 Indeed,
the survey of the reaction media revealed that the Brønsted
acid catalyzed addition is strongly dependent on the solvent,
and better enantioselectivities were observed in halogenated
solvents (Table 3, entries 1, 2, and 4), as compared to
Table 3. Evaluation of Solvents
Table 2. Survey of Different Imines in Combination with 1a,b
entrya
solvent
yield [%]b
ee [%]c
entrya
R1
hydrazine
ee [%]b
1
2
3
4
CHCl3
98
88
99
99
77
50
12
50
t
1
2
3
4
5
6
7c
8c
9c
CO2 Bu
1a
1b
1a
1b
1a
1b
1b
1b
1b
14
61
rac
50
rac
15
-
CH2Cl2
CH3-Ph
CF3-Ph
t
CO2 Bu
CO2CH2Ph
CO2CH2Ph
C(O)Ph
C(O)Ph
PhCH2
a
Reactions were performed with 1b and aldimine 2d (1.2 equiv) at
0.15 M concentration at 0 °C for 16 h. Isolated yields after column
chromatography. Enantiomeric excess was determined by HPLC using
Chiracel OD-H columns.
b
c
4-F-PhCH2
4-BrPh
-
-
a
Reactions were performed with methylene-hydrazines 1a,b and
nonpolar aromatic ones (Table 3, entry 2). The best results
with respect to yields and enantioselectivities were obtained
when the reaction was conducted in chloroform at 0 °C
providing the product 3d in 77% ee (Table 3, entry 1).12
aldimines 2 (1.2 equiv) at 0.15 M concentration in chloroform at 0 °C for
b
16 h. Enantiomeric excesses were determined by HPLC using Chiralcel
c
OD-H or Chiralpak AD-H columns. Cross over product was isolated.11
enantioselectivities were obtained with N-Boc-protected
aldimine 2a and the pyrrolidine-derived hydrazine 1b (61%
ee, Table 2, entry 2). Application of N-benzyloxycarbonyl-
or N-benzoyl-protected aldimines resulted in the correspond-
ing products with 50% ee and 15% ee (Table 2, entries 4
and 6). In contrast, a dramatic decrease in enantioselectivity
was observed when the reaction was performed with the
piperidine-derived hydrazine 1a. For instance, reaction of
1a with the aldimine 2a gave the hydrazone 3 with 14% ee
(Table 2, entry 1). No enantioselection was observed with
N-benzyloxy-carbonyl- or N-benzoyl-protected aldimines
under the otherwise same reaction conditions (Table 2, entries
3 and 5). In the case of N-benzyl- and N-aryl-protected
aldimines (Table 2, entries 7-9), only cross over products
were isolated.11
Subsequently, our reaction optimization focused on the
catalyst architecture (Table 4). A comparison of various
Table 4. Survey of Chiral Catalysts
entrya
catalyst
yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
5a
5b
5c
92
52
32
72
65
68
73
62
78
61
61
54
25
22
rac
74
57
rac
Our further examination of this valuable transformation
concentrated on the solvents employed, as earlier experiments
(9) Larsen, C.; Harpp, D. N. J. Org. Chem. 1981, 46, 2465
(10) The aldimines were prepared according to the described proce-
dures: (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
127, 9360. (b) Aggarwal, V. K.; Vasse, J. Org. Lett. 2003, 5, 3987. (c)
Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59,
1238. (d) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964. (e) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867.
a
Reactions were performed with 1b and aldimine 2a (1.2 equiv) at
0.15 M concentration in chloroform at 0 °C for 16 h. b Isolated yields after
column chromatography. c Enantiomeric excess was determined by HPLC
using Chiralcel OD-H columns.
(11) The formation of the cross over products has been reported before:
Fernandez, R.; Martin-Zamora, E.; Lassaletta, J. M. Synlett 2001, 1158.
tested phosphoric acid catalysts 4a-f and 5a-c (Figure 2)
reveals that the highest enantioselectivities are obtained with
the sterically more demanding 3,3′-substituents (Table 4,
Org. Lett., Vol. 9, No. 6, 2007
1067

protected aldimines bearing electron-withdrawing or electron-
donating groups could be applied in the enantioselective
reaction with methyleneamino-pyrrolidine resulting in the
corresponding hydrazones 3a-h in good isolated yields and
with high enantioselectivities (77-90% ee).
Table 5. Scope of the Enantioselective Imino Ene Reaction
The absolute configuration of the products was obtained
from an X-ray crystal structure analysis of hydrazone 3d.
On the basis of this structure, the aminohydrazones 3 exhibit
the S-configuration, which is in agreement with our previ-
ously described observations for BINOL-phosphate catalyzed
reactions (Figure 3).3-6
Figure 3. X-ray crystal structure of 3d.
In summary, we have developed a new highly enantio-
selective Brønsted acid catalyzed imino-azaenamine reaction
of various N-Boc-protected aldimines and methylene-ami-
nopyrrolidine. The corresponding valuable aminohydrazones
have been isolated in good yields and with high enantio-
selectivities. The mild reaction conditions of this metal-free
process together with the operational simplicity and practi-
cability not only render this approach a useful procedure for
the synthesis of optically active aminohydrazones but also
further expand the repertoire of enantioselective BINOL-
phosphate catalyzed transformations.
a
Reactions were performed with 1b and aldimines 2 (1.2 equiv) at 0.15
b
M concentration in CHCl3 at 0 °C for 16 h. Isolated yields after column
chromatography. Enantiomeric excess was determined by HPLC using
Chiralcel OD-H or Chiralpak AD-H columns. Performed with 5 mol %
of catalyst. After one recrystallization from hexane-dichloromethane.
c
d
e
entries 1, 2, and 7), which is in agreement with our earlier
findings.3-6 The best selectivities were obtained with Brøn-
sted acid 5a which gave the product 3a in 73% yield with
74% ee (Table 4, entry 7).
With the optimized reaction conditions in hand, a variety
of N-Boc-protected imines 2 were prepared and tested in the
Brønsted acid catalyzed imino ene reaction. The results are
summarized in Table 5. In general, a series of N-Boc-
Acknowledgment. We are grateful to Degussa AG
Germany for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Selectivities did not improve when the reaction temperature was
lowered to -20 or -40 °C.
OL063112P
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Org. Lett., Vol. 9, No. 6, 2007