Amine-salt-controlled, catalytic asymmetric conjugate addition of various amines and asymmetric protonation

Article abstract of DOI:10.1021/ol0493711

Matrix presented. The combined use of chiral Pd complex 2 and amine salt enabled completely regulated release of free nucleophilic amine. Under these conditions, an efficient catalytic asymmetric conjugate addition of various amines was achieved to afford

Full text of DOI:10.1021/ol0493711

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1861-1864
Amine-Salt-Controlled, Catalytic
Asymmetric Conjugate Addition of
Various Amines and Asymmetric
Protonation
Yoshitaka Hamashima, Hidenori Somei, Yuta Shimura, Toshihiro Tamura, and
Mikiko Sodeoka*
Institute of Multidisciplinary Research for AdVanced Materials (IMRAM),
Tohoku UniVersity, Katahira, Sendai, Miyagi 980-8577, Japan, and PRESTO,
Japan Science and Technology Agency (JST)
sodeoka@tagen.tohoku.ac.jp
Received April 7, 2004
ABSTRACT
The combined use of chiral Pd complex 2 and amine salt enabled completely regulated release of free nucleophilic amine. Under these
conditions, an efficient catalytic asymmetric conjugate addition of various amines was achieved to afford â-amino acid derivatives in high
chemical yields with up to 98% ee. Furthermore, a highly enantioselective protonation in 1,4-addition of amine was also developed.
The catalytic asymmetric conjugate addition of nitrogen
nucleophiles is a useful reaction in synthetic organic chem-
istry because the products are generally recognized as key
compounds for the synthesis of not only chiral natural and
unnatural â-amino acids but also clinically important â-lac-
tams.1 Therefore, considerable efforts to develop efficient
methods for this transformation have been made, and ex-
cellent enantioselectivity was achieved in several examples
using hydroxylamine or azide as a nitrogen source.2 In con-
trast, the reaction with simple amines is still difficult.
Although the products are extremely useful for the synthesis
of chiral dihydroquinoline derivatives via the intramolecular
Friedel-Crafts-type acylation,3 the usage of aromatic amines
has not been thoroughly investigated.4 Furthermore, only a
little work has been done on the use of alkylamines.4b,5 To
address this issue, we began to examine the catalytic asym-
metric conjugate addition of amines using the chiral Pd-
aqua complex 1, which was developed by us and performed
as an excellent catalyst in various reactions.6 However, the
(2) (a) Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1996,
2823-2826. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 1998, 120, 6615-6616. (c) Myers, J. K.; Jacobsen, E. N. J.
Am. Chem. Soc. 1999, 121, 8959-8960. (d) Horstmann, T. E.; Guerin, D.
J.; Miller, S. J. Angew. Chem., Int. Ed. 2000, 39, 3635-3638. (e) Guerin,
D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134-2136. (f) Sibi, M.
P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem. Soc.
2003, 125, 11796-11797. For a recent example in the case of enones: (g)
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
16178-16179 and references therein.
(3) Paradisi, M. P.; Romeo, A. J. Chem. Soc., Perkin Trans. 1 1977,
596-600.
(4) (a) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun.
2001, 1240-1241. (b) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-
31. (c) Li, K.; Hii, K. K. Chem. Commun. 2003, 1132-1133.
(1) (a) Juaristi, E., Ed. EnantioselectiVe Synthesis of â-Amino Acids;
Wiley-VHC: New York, 1997. (b) Magriotis, P. A. Angew. Chem., Int.
Ed. 2001, 40, 4377-4379. (c) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58,
7991-8035. (d) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-4299.
(e) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794-5795.
10.1021/ol0493711 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/05/2004

results were found to depend strongly on the nature of the
amine used.7 For example, while aromatic amine bearing
an electron-deficient group on the aromatic ring (p-CF3-
C6H4NH2) afforded high enantioselectivity (83% ee), neg-
ligible asymmetric induction (∼2% ee) was observed in the
case of amines of higher nucleophilicity such as anisidine
and benzylamine (2.5 mol % 1 in toluene).7 Independently,
Hii et al. reported a similar reaction last year,4c and their
most recent work described excellent enantioselectivity using
aromatic amines.8 However, they also found a tendency
similar to that seen in our results, and the reaction with
electron-rich amines did not achieve a synthetically useful
level. We speculated that this phenomenon is due to the basic
character of amines, causing deactivation of Lewis acid
catalysts by coordination to the metal center, while amines
of higher nucleophilicity react spontaneously, resulting in
uncontrolled reactions (Scheme 1). Thus, a novel reaction
Table 1. Optimization of Reaction Conditions
catalyst
(mol %)
TfOH
time
(h)
yield
(%)
ee
entry
(equiv to 4a )
(%)
1
2
3a
4
5a
1 (2)
-
1 (2)
1 (1)
2 (1)
-
-
24
24
24
24
12
35
41
25
98
92
2
-
88
4
98
TfOH (1.0), 6a
TfOH (0.5)
TfOH (1.0), 6a
a TfOH was added as a salt of 4a (6a).
1 reacted with excess amine, and several less active pal-
ladium complexes were formed.
Scheme 1
Furthermore, the control experiment revealed that spon-
taneous reaction proceeded at a comparable rate (entry 2).
These may be the reasons poor results were obtained in entry
1. On the basis of our finding that the cationic Pd complexes
1 and 2 work well in the presence of a Brønsted acid,6 we
envisaged that the usage of a salt to block the lone pair of
amines with a proton might be effective to suppress such
unfavorable side reactions (Scheme 1). Among the protic
acids examined, TfOH was found to be effective.9,10 When
the isolated salt 6a (4a/TfOH) was used, the reaction of 3a
proceeded slowly (25% after 24 h), probably because the
formation of 4a from 6a was not favorable (entry 3).11
Encouragingly, however, the enantioselectivity was greatly
improved to 88%. In entry 4, it was found that the addition
of a 0.5 equiv of TfOH to 4a accelerated the reaction, but
only negligible asymmetric induction was observed.12 Thus,
we considered that the generation of an appropriate amount
of free amine would be necessary. For this purpose, the Pd
complex 2, in which the hydroxyl group shows a basic
character,6f,g was employed instead of 1 (entry 5). The
reaction of 2 with 6a adequately regulated the generation of
free amine, thus avoiding unfavorable side reactions. As
shown in entry 5, the reaction of 3a with 6a was carried out
in THF using 1 mol % 2. Gratifyingly, the reaction
proceeded smoothly, and the desired product was obtained
in 92% yield and 98% ee (rt, 12 h).
system is required to realize a generally effective reaction
using various amines. Herein, we report a novel reaction
system for catalytic asymmetric conjugate addition of various
amines to alkenoyl oxazolidinones 3, in which the combined
use of the Pd complex 2 and amine salt is the key to suc-
cessful results. In addition, preliminary experiments on cata-
lytic enantioselective protonation in the conjugate addition
of amines are also described.
Initially, anisidine 4a was chosen as a nucleophile because
electron-rich amines gave poor results as described above.
The reaction of 3a with 4a was carried out using 2 mol %
Pd aqua complex 1 (Table 1, entry 1). Unfortunately, the
reaction was sluggish, and the ee of the product 5aa was
only 2%. As we speculated, NMR experiments indicated that
This method was also applicable to other starting materials,
as depicted in Table 2.13 The reaction with simple aniline or
(5) A recent example of the addition of Li amide of BnNHSiMe3 using
a chiral ether ligand: Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka,
K. J. Am. Chem. Soc. 2003, 125, 2886-2887.
(8) Li, K.; Cheng, X.; Hii, K. K. Eur. J. Org. Chem. 2004, 959-964.
This paper appeared during the preparation of our manuscript.
(9) AcOH, HCl, and MsOH gave less satisfactory results.
(10) An interesting proton effect was reported previously: Seligson, A.
L.; Trogler, W. C. Organometallics 1993, 12, 744-751.
(11) A trace amount of the product was formed in toluene, probably
because the salt was not dissolved.
(12) Recently, Spencer et al. reported that the proton itself can be an
active achiral catalyst for aza-Michael reaction. See: Wabnitz, T. C.; Yu,
J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484-493. In contrast, high
enantioselectivity was observed under our optimized conditions even in the
presence of a stoichiometric amount of proton source (Table 1, entry 5).
(6) (a) Sodeoka, M.; Ohrai, M.; Shibasaki, M. J. Org. Chem. 1995, 60,
2648-2649. (b) Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara, E.;
Shibasaki, M. Synlett 1997, 463-466. (c) Sodeoka, M.; Shibasaki, M. Pure
Appl. Chem. 1998, 70, 411-414. (d) Hagiwara, E.; Fujii, A.; Sodeoka, M.
J. Am. Chem. Soc. 1998, 120, 2474-2475. (e) Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450-5458. (f) Hamashima,
Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241.
(g) Hamashima, Y.; Yagi, K.; Takano, H.; Tama´s, L.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 14530-14531. (h) Hamashima, Y.; Takano, H.;
Hotta, D.; Sodeoka, M. Org. Lett. 2003, 5, 3225-3228.
(7) Unpublished results. See Supporting Information.
1862
Org. Lett., Vol. 6, No. 11, 2004

Scheme 2. Catalytic Asymmetric Conjugate Addition of
Table 2. Catalytic Asymmetric Conjugate Addition of Amines
Benzylamine
catalyst temp time yield ee
entry
1a
R
X
(mol %) (°C) (h) (%) (%)
Me (3a )
H (6b)
CF3 (6c)
OMe (6a )
6b
1
20
40
40
40
20
20
20
20
20
36
24
24
24
72
6
83 96
77 97
80 94
98 95
49 85
98 97
76 96
98 94
98 96
2b 3a
2
2
2
4
3
4
5c
6
7
8c
9
Et (3b )
3b
3b
6c
Scheme 3. Proposed Catalytic Cycle
BnOCH2 (3c ) 6a
2
3c
3c
3a
6b
6c
6a
2
4
0.2
12
16
16
a Absolute configuration was determined to be S after conversion of the
product to the known carboxylic acid.14 b THF/toluene ) 1/2. c 4c (1 equiv
to Pd) was added.
electron-deficient CF3-substituted aniline (6b,c) gave the
Michael adducts with high enantioselectivity (entries 1, 2).
The absolute configuration of 5ab was determined to be S
after conversion to the known carboxylic acid.14 The ethyl-
substituted oxazolidinone 3b reacted with 6a and 6b,
affording the corresponding products in excellent yields and
ees (entries 3, 4). Although the reaction of 3b with 6c was
relatively slow, probably due to the lower nucleophilicity
of the amine, the desired product was obtained in moderate
yield and high ee by the addition of a catalytic amount of
free amine 4c (entry 5). In addition, substrate 3c bearing the
benzyloxymethyl group, which is useful for the later
transformation, was also a good substrate. For all the amines
tested, the conjugate addition proceeded smoothly, and
excellent ees were obtained (94-97% ee, entries 6-8). For
entry 9, the catalyst amount was reduced to 0.2 mol %, and
comparable enantioselectivity was obtained (96% ee). In
these reactions, no double addition product, which is a
possible byproduct of the reaction with primary amine, was
formed. Also, it is noteworthy that these reactions were not
sensitive to either air or water and could be conducted
without any particular precautions.15
Further examples are as follows (Scheme 2). Benzylamine
reacted with 3a in the presence of 2 mol % Pd complex 2 in
THF (40 °C, 60 h). Because the product was rather unstable,
the corresponding methyl ester 8a was isolated in 75% yield
(two steps), with 86% ee. The reaction of 3c afforded the
desired â-benzylamino ester with good enantioselectivity
(80% ee). Since the catalytic reaction with alkylamines is
still an unsolved problem,16 the considerable potential of this
reaction system is indicated by these examples.
3 in a bidentate fashion (I). Then, the concomitantly formed
free amine would attack the activated double bond. Because
the re-face of the double bond was blocked preferentially
by one of the phenyl groups of (R)-BINAP, the addition of
(13) Representative Procedure (entry 9, Table 2): The palladium
complex 2 (1.8 mg, 1 µmol), 3a (77.6 mg, 0.5 mmol), and amine salt 6a
(205 mg, 0.75 mmol) were placed in a reaction vessel. THF (0.5 mL) was
added, and the reaction mixture was stirred at room temperature. After 16
h, saturated aqueous NaHCO3 was added on an ice bath for quenching.
Extraction with EtOAc, followed by flash column chromatography on SiO2,
gave the pure product 5aa. The ee of the product was determined by chiral
HPLC.
(14) See Supporting Information for details.
(15) Generally, a tedious anhydrous condition is required to avoid
hydrolysis of the metal catalyst. See ref 12.
(16) In ref 5, a catalytic amount of chiral ether ligand (0.3 equiv) afforded
the product in 75% yield and 70% ee (-78 °C, 17 h). For substoichiometric
reaction (50 mol %): Sundararajan, G.; Prabagaran, N. Org. Lett. 2001, 3,
389-392.
Although the exact reaction mechanism has not been
established, we speculate that the following catalytic cycle
may occur (Scheme 3). NMR experiments suggested that
the reaction of 2 with excess salt 6 would afford the
monomeric Pd complex 1′. The generated 1′ could activate
Org. Lett., Vol. 6, No. 11, 2004
1863

amine proceeded from the si-face in a highly enantioselective
manner, and the Pd enolate was formed (II). Subsequent
protonation of this Pd enolate, followed by dissociation of
the product as the salt, would complete the catalytic cycle.
In this step, protonation of the product might contribute to
preventing the product from coordinating to the metal center.
The observed absolute stereochemistry of the product was
in accord with the transition state model depicted in Scheme
3. Even though this mechanism seems to be plausible, we
should also consider a second possibility, which involves
the generation of Pd amide III as a nucleophile. Studies to
clarify the mechanism are under way.
the product was determined to be 94% by chiral HPLC. It
is noteworthy that the small proton approached the transient
Pd enolate with high enantioselectivity. The scope of this
reaction and the basis of this significantly controlled reaction
path will be described in detail elsewhere.
In conclusion, we have developed a novel and highly enan-
tioselective catalytic conjugate addition of various amines
to R,â-unsaturated carbonyl compounds. In this reaction,
appropriate regulation of the amino functionality was achieved
by the combined use of 2 and salt. As a result, both de-
composition of the catalyst by amine and uncontrolled spon-
taneous reaction were considerably suppressed. This reaction,
with both aromatic and alkylamines, should be extremely
useful in synthetic organic chemistry. In addition, highly
enantioselective protonation was also achieved using this
novel reaction system. Further details and extension of this
work will be reported in due course. Finally, we believe that
this salt effect in metal catalysis may allow the development
of other catalytic asymmetric reactions involving amine
participation.
In this catalytic cycle, it is expected that protonation of
the intermediate II should occur stereoselectively. To ex-
amine this hypothesis, we next planned the catalytic enan-
tioselective protonation of Pd enolate accompanied with the
conjugate addition of amines (Scheme 4).17,18 Thus, the
Scheme 4. Catalytic Asymmetric Protonation in the Conjugate
Addition of Anisidine
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Encouragement of Young Scientists (B)
from JSPS. We thank Mr. Takashi Matsumoto and Dr. Takao
Saito of Takasago International Corporation for fruitful
discussions.
Supporting Information Available: Experimental details
of the reactions and results of spectroscopic characterization
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
methacrylate derivative 9 was treated with 6a in the presence
of Pd complex 2 (5 mol %). The reaction was completed
after 8 h, and the desired â-amino acid derivative 10 with a
newly formed chirality at the R-position of the carbonyl
group was isolated in 80% yield. To our surprise, the ee of
OL0493711
(18) Recent examples of catalytic enantioselctive protonation of transient
metal enolate in Michael addition: (a) Emori, E.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043-4044. (b) Nishimura,
K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem., Int. Ed. 2001, 40,
440-442. (c) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed.
2004, 43, 719-723. Radical-based reaction: (d) Sibi, M.; Patil, K. Angew.
Chem., Int. Ed. 2004, 43, 1235-1238.
(17) A partially successful example was reported in ref 4b. The reaction
of methacrylonitrile with morpholine afforded the corresponding product
in 69% ee.
1864
Org. Lett., Vol. 6, No. 11, 2004