Enantioselective protonation in the aza-Michael reaction using a combination of chiral Pd-μ-hydroxo complex with an amine salt

Article abstract of DOI:10.1055/s-0029-1217347

A highly enantioselective protonation of enolate intermediates in aza-Michael reaction was achieved by using the combination of a bifunctional chiral Pd-μ-hydroxo complex with aromatic amine salts. The reaction proceeded smoothly to give the desired β-ami

Full text of DOI:10.1055/s-0029-1217347

CLUSTER
1631
Enantioselective Protonation in the Aza-Michael Reaction Using a
Combination of Chiral Pd–m-Hydroxo Complex with an Amine Salt
A
Y
symmetric Proto
o
nation inthe
s
A
za-Mich
h
ael Reactio ni taka Hamashima, Toshihiro Tamura, Shoko Suzuki, Mikiko Sodeoka*
Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan
Fax +81(48)4624666; E-mail: sodeoka@riken.jp
Received 30 January 2009
comitant generation of free amine. Then, the generated 2
activated the substrate 3 to promote conjugate addition of
the free amine. This controlled generation of the nucleo-
philic amine was extremely effective to suppress undes-
Abstract: A highly enantioselective protonation of enolate inter-
mediates in aza-Michael reaction was achieved by using the combi-
nation of a bifunctional chiral Pd–m-hydroxo complex with
aromatic amine salts. The reaction proceeded smoothly to give the
desired b-amino carbonyl compounds bearing a stereogenic carbon ired reactions, such as catalyst deactivation by
center at the a-position in good yield with excellent enantioselectiv-
ity (up to 97% ee). Although reactions with salts of electron-defi-
cient amines were slow, the introduction of free amine as an
additive promoted the reaction to a synthetically useful level.
coordination of the amine compounds and the uncatalyzed
racemic pathway. Consequently, high chemical yield and
excellent enantioselectivity were achieved even with
highly nucleophilic amines, such as anisidine and benzyl-
amine.
Key words: asymmetric catalysis, protonations, palladium, aza-
Michael additions, b-amino acids
Pd cat. 1
ArNH2⋅HOTf
O
O
ArHN
R
O
O
*
Enantioselective protonation of enolates has been inten-
sively investigated, because it is a useful method to con-
struct a stereogenic carbon center at the a-position of
R
N
O
N
O
THF, r.t.
3
4
up to 98% ee
1
carbonyl compounds. The reaction of preformed metal
H
O
P
P
P
ArNH2⋅HOTf
enolates, including silyl enol ethers, with a chiral proton
P
P
Pd+ Pd+
2
*
*
*
Pd2+ 2TfO–
(Lewis acid)
+
ArNH2
*
source has been a main focus, but catalytic generation of
O
P
H
chiral enolates in situ, followed by their enantioselective
TfO–
H2O
2
2
3
1
protonation, is also an attractive approach. The conjugate
(Brønsted base)
addition of (pro)nucleophiles to a,b-unsaturated carbonyl
compounds seems to be a closely related reaction. Indeed,
excellent results were achieved in some tandem conjugate
addition–protonation sequences. Such reactions involve
3
P
= (R)-BINAP
4
⋅TfOH
P
ArNH2⋅HOTf
4
4c
the conjugate addition of sulfur, phosphorus, and car-
5
P
P
P
P
bon nucleophiles, including aryl boronic acids and sub-
Pd+ TfO–
ArNH2
Pd2+ 2TfO–
6
TfO–
ArH2N+
stituted pyroles.
O
O
O
O
As a part of our studies on synthetic methodologies for op-
*
7
tically active b-amino acid derivatives, which constitute
R
N
O
R
N
O
8
an important class of chiral building blocks, we previous-
chiral Pd enolate 5
ly reported a highly enantioselective aza-Michael reac-
tion. We devised a novel strategy that combines chiral Pd–
Scheme 1 Catalytic asymmetric aza-Michael reaction using Pd ca-
m-hydroxo complex 1 and trifluoromethanesulfonic acid talyst 1 and amine salts
salt of aromatic and benzyl amines, and obtained the de-
sired compounds having a stereogenic carbon center con-
Since the putative Pd enolate 5 is generated in a chiral en-
nected to a nitrogen atom in a highly enantioselective
vironment, it is anticipated that the final protonation of 5
should also occur stereoselectively. To examine this hy-
pothesis, we planned the reaction of a-substituted acrylate
derivatives under our standard reaction conditions
7
a
manner (Scheme 1). Also, several efficient conjugate
addition reactions using hydroxylamine or azide as a ni-
trogen nucleophile were developed by other groups.9
As shown in Scheme 1, the Pd complex 1 acted as a bi- (Scheme 2). Although tandem protonation reactions initi-
1
0
functional catalyst. First, the m-hydroxo complex react- ated by the conjugate addition of nitrogen nucleophiles
ed with amine salts as a Brønsted base, and a catalytically are extremely useful to prepare optically active a-substi-
active Lewis acidic Pd complex 2 was formed with con- tuted b-amino acids, quite few such reactions are
1
1
known. Herein we wish to describe the catalytic enantio-
selective protonation of chiral Pd enolates accompanied
with aza-Michael reaction.
SYNLETT 2009, No. 10, pp 1631–1634
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217347; Art ID: Y00509ST
x
x
.x
x
.2
0
0
9
©
Georg Thieme Verlag Stuttgart · New York

1
632
Y. Hamashima et al.
CLUSTER
this work:
This reaction was found to be applicable to other a-substi-
tuted substrates (Table 2).13 Ethyl-substituted compound
9b underwent the reaction under the standard conditions,
affording 10ba in 54% yield with 88% ee (entry 1). Fur-
ther optimization revealed that a better chemical yield was
obtained in a mixed solvent system of THF–CPME (1:1;
CPME = cyclopentyl methyl ether; entry 2). The reaction
of bulkier phenyl-substituted compound 9c proceeded
without difficulty to give the corresponding product 10ca
in good yield with excellent enantioselectivity (79%, 93%
ee; entry 3). In addition to 7a, aniline salt 7b was also
available, and the corresponding product 10ab was
formed in 65% yield with 97% ee (entry 4).
O
O
Pd cat. 1
ArNH2⋅HOTf
ArHN
O
O
*
N
R2
OR3
N
R2
OR3
R1
R1
Scheme 2 Enantioselective protonation in aza-Michael reaction
7
a
Based on our previous results, we initially examined the
reaction of oxazolidinone 6 with anisidine salt 7a in the
presence of 5 mol% of the Pd complex 1 (Scheme 3). Al-
though a promising enantioselectivity was observed, the
reaction was slow and afforded the product 8 in only 20%
yield. When 6 coordinates to the catalyst in a bidentate
fashion, intramolecular steric interactions would occur, so
that the carbonyl group and the olefin of the substrate are
prevented from being co-planar. This may be the main
reason for the low chemical yield in this reaction. There-
fore, we expected that the reaction rate would be increased
if such steric interaction was minimized. Consequently,
we selected N-benzyloxycarbonyl-protected methacryl-
amide 9a as a model substrate.12
Table 1 Optimization of Aza-Michael–Protonation Reaction
Pd cat. 1
PMP
O
O
(5 mol%)
NH
O
O
7
a (1.5 equiv)
*
N
H
OBn
N
OBn
solvent (0.5 M), r.t.
H
Me
Me
9a
10aa
Entry
Solvent
THF
Time (h)
Yield (%)
ee (%)
94
Pd cat. 1
1
8
80
31
79
82
18
n.r.
79
(
5 mol%)
PMPNH2⋅HOTf (7a)
1.5 equiv)
PMP
O
O
2a
3a
4
NH
O
O
THF
12
24
3.5
24
24
24
93
(
N
O
*
N
O
CH Cl
2
77
THF (1 M), 45 °C, 10 h
2
Me
Me
toluene
EtOH
DMF
THF
88
6
8
2
0%, 74% ee
5
65
Pd2+
Pd2+
O
O
O
O
O
O
6
–
Me
N
OBn
N
O
N
O
H
7b
94
Me
Me
9
a
a
Temp: 0 °C.
b
1
mol% of the Pd complex 1; n.r. = no reaction.
Scheme 3 An initial attempt using 6 as a substrate
Table 2 Catalytic Enantioselective Protonation in Aza-Michael
Reaction
As we had hoped, the reaction of 9a with 7a proceeded
smoothly in THF at room temperature (Table 1, entry 1).
The desired product 10aa was obtained in 80% yield after
basic aqueous workup. To our delight, the ee was deter-
mined to be 94% by chiral HPLC analysis. Reaction tem-
perature affected the reaction rate, and the reaction at 0 °C
resulted in low chemical yield even after 12 hours (entry
Pd cat. 1
(5 mol%)
Ar
1
3
O
O
ArNH ⋅HOTf (7)
2
NH
O
O
(
1.5 equiv)
*
N
OBn
N
H
OBn
H
THF (0.5 M), r.t., 24 h
R
R
9
a R = Me
b R = Et
7a Ar = 4-MeOC6H4
7b Ar = Ph
10
2
). Among the solvents tested, THF was found to be the
9
best. Less polar solvents such as CH Cl and toluene gave
9c R = Ph
2
2
decreased enantioselectivity (entries 3 and 4). In the case
of polar solvents, such as EtOH and DMF, the reactions
did not proceed well (entries 5 and 6). As shown in entry
Entry
Acceptor 9 Salt 7 Product
Yield (%)
ee (%)
88
1
9b
9b
9c
9a
7a
7a
7a
7b
10ba
10ba
10ca
10ab
54
78
79
65
7
, it was possible to reduce the catalyst amount to as little
2a
3
84
as 1 mol%. Although the reaction did not go to completion
after 12 hours, results comparable to those in entry 1 were
obtained after 24 hours. Hii and co-workers reported that
the slow addition of anisidine was effective to improve the
93
4
97
1
1
enantioselectivity in their reactions. In contrast, this was
not necessary in the present reaction. Since our catalytic
system can keep the concentration of the nucleophilic free
amine low during the reaction, high catalytic activity and
stereoselectivity were achieved.
a
Solvent: THF–CPME = 1:1.
Unfortunately, however, aromatic amines substituted with
electron-withdrawing groups, such as CF and Br, failed
3
Synlett 2009, No. 10, 1631–1634 © Thieme Stuttgart · New York

CLUSTER
Asymmetric Protonation in the Aza-Michael Reaction
1633
to react smoothly. For example, even though the reaction
of 9a with amine salt 7c was carried out at higher temper-
ature (40 °C) for a prolonged reaction time (50 h), the ad-
duct 10ac was obtained in only 11% yield (Table 3, entry
P
P
salt (H+)
9
, ArNH2
Pd2+ 2TfO–
active 2
10⋅HOTf
Ar
NH
O
O
1
). We speculated that the low chemical yield might be
2
salt (H+)
*
ArNH2
N
OBn
14
due to insufficient nucleophilicity of the parent 4-
F CC H NH (11). To address this issue, we next exam-
H
R
3
6
4
2
ined the addition of 11 as an additive with the expectation
that the first aza-Michael reaction might be accelerated.
As we had hoped, the chemical yield was improved to
P
NH Ar
P
P
2
NH Ar
2
Pd2+
Pd2+
NH2Ar
*
or
*
P
L
TfO–
2
2TfO–
5
5%, as the amount of 11 was increased to 0.5 equivalents
1
2
13
(
entries 2 and 3). But further addition of 11 was not effec-
tive, and the chemical yield was only 20%, when 1 equiv- Scheme 4 Critical roles of amine salt
alent of 11 was employed (entry 4). Interestingly, the ee
was in the range of 96–97% in these reactions.
Finally, to improve the chemical yield, we examined the
reaction using twice the amount of the reagents (3 equiv
of 7c and 1 equiv of 11) with their ratio being the same as
in the case of entry 3. In accordance with our speculation,
deactivation of the catalyst was effectively suppressed,
and the desired product was formed in a better chemical
yield with high enantioselectivity (76% yield, 95% ee; en-
try 5). Furthermore, when the concentration of the reac-
tion mixture was increased to 1 M, satisfactory results
were also obtained under the same conditions as shown in
entry 3 (entry 6).
Table 3 Reactions in the Presence of Additional Amine
Pd cat. 1
Ar
(
5 mol%)
F3C
+
NH
O
O
ArNH2 (11)
NH2⋅HOTf THF (0.5 M), r.t., 24 h
Ar = 4-F3CC6H4
9a
*
N
OBn
H
Me
7c
10ac
Entry Salt 7 (equiv) Amine 11 (equiv) Yield (%)
ee (%)
n.d.
97
1a
2
1.5
1.5
1.5
1.5
3.0
1.5
–
11
35
55
20
76
64
In summary, we have succeeded in developing a tandem
aza-Michael reaction–enantioselective protonation reac-
tion. Our novel strategy using the bifunctional Pd–m-
hydroxo complex and amine salts was the key to success.
The obtained chiral b-amino acid derivatives with a chiral
center at the a-position are expected to be useful in the
field of medicinal chemistry. Because catalytic enantio-
selective aminomethylation, namely classical Mannich
0.25
0.5
1.0
1.0
0.5
3
96
4
97
5
95
6b
94
reaction, is still difficult to achieve, the present work pro-
a
14,15
Conditions: 40 °C, 50 h.
Concentration: 1 M; n.d. = not determined.
vides an important alternative method.
Further studies
b
on the scope of the reaction and the reaction mechanism
will be reported in due course.
Our original conditions using the combination of the Pd
complex 1 and amine salts were optimized for the reac-
tions with electron-rich amines, such as anisidine, where
the concentration of the free amine must be kept low to
avoid uncatalyzed racemic reaction. However, such a pro-
cess is likely to be negligible in the case of a less nucleo-
philic amine such as 11, and a much higher concentration
Acknowledgment
This work was supported by a Grant-in-Aid for the Encouragement
of Young Scientists (B) (No. 18790005) and a Grant-in-Aid for Sci-
entific Research on Priority Areas (No. 19028065, ‘Chemistry of
Concerto Catalysis’), and Special Project Funding for Basic Sci-
ence. We also thank to NIPPON ZEON Corporation for the ge-
of the free amine is required for smooth reaction. Never- nerous gift of CPME.
theless, too much free amine would deactivate the catalyst
through the formation of unreactive complexes, such as
References and Notes
1
2–14, for example (Scheme 4). We considered that these
complexes were responsible for the decrease in the cata-
lyst turnover observed in entry 4 and that a precise balance
between the salt (proton source) and the amine would be
important to keep the Pd complex catalytically active by
decomposing inactive complexes via proton-exchange
reactions. Our reaction requires both the Lewis acidic
complex 2 and a free amine, and the optimum amine/salt
ratio would vary depending on the nature of the amine.
(1) (a) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C.
Tetrahedron: Asymmetry 2004, 15, 3653. (b) Yanagisawa,
A.; Yamamoto, H. In Comprehensive Asymmetric Catalysis,
Vol. 3; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999, 1295. (c) Yanagisawa, A. In
Comprehensive Asymmetric Catalysis, Suppl. 2; Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin,
2004, 125.
Synlett 2009, No. 10, 1631–1634 © Thieme Stuttgart · New York

1
634
(
Y. Hamashima et al.
CLUSTER
(9) A short review: (a) Xu, L.-W.; Xia, C.-G. Eur. J. Org.
2) For recent examples of protonation of preformed enolates,
see: (a) Nakamura, S.; Kaneeda, M.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8120.
Chem. 2005, 633. For more recent examples:
(b) Yamagiwa, N.; Qin, N.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13419. (c) Chen, Y. K.;
Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
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(
b) Vedejs, E.; Kruger, A. W.; Lee, N.; Sakata, S. T.; Stec,
M.; Suna, E. J. Am. Chem. Soc. 2000, 122, 4602.
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Int. Ed. 2007, 46, 7119; added in revision: after submission
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(
1
(10) (a) Sodeoka, M.; Hamashima, Y. Bull. Chem. Soc. Jpn.
2005, 78, 941. (b) Sodeoka, M.; Hamashima, Y. Pure Appl.
Chem. 2006, 78, 477.
(11) We previously reported one example (entry 1, Table 1) in
ref. 7a. Recently, Hii et al. also reported partially successful
results related to our reaction using a chiral cationic Pd
complex. See: Phua, P. H.; Mathew, S. P.; White, A. J. P.;
de Vries, J. G.; Blackmond, D. G.; Hii, K. K. (Mimi) Chem.
Eur. J. 2007, 13, 4602.
(12) The synthesis of the starting material was carried out based
on the reported procedure. See: Liu, X.; Hu, X. E.; Tian, X.;
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212.
(
g) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.;
Fujimori, I.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
009, 131, 3858.
2
(
3) Reactions starting from ketenes: (a) Hodous, B. L.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 10006. (b) Wiskur,
S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176.
(
4
c) Schaefer, C.; Fu, G. C. Angew. Chem. Int. Ed. 2005, 44,
606. Decarboxylative protonation starting from b-keto
esters: (d) Baur, M. A.; Riahi, A.; Hénin, F.; Muzart, J.
Tetrahedron: Asymmetry 2003, 14, 2755. (e) Marinescu,
S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett.
008, 10, 1039. Reactions using a chiral carbene catalyst:
f) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
6406.
(13) General Procedure
The starting material 9 (0.1 mmol), amine salts 7 (0.15
mmol), and the Pd complex 1 (5 mol%) were dissolved in
THF (0.2 mL). In the case of 7c, the additive 15 (0.05 mmol)
was included. The resulting solution was stirred at ambient
temperature for the time shown in Tables 1– 3. For quench-
2
(
1
(
(
4) (a) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am.
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3
cooling. Usual workup, followed by flash column chromato-
4
40. (c) Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan,
C.-H. Angew. Chem. Int. Ed. 2008, 47, 5641.
graphy (Si O, hexane–EtOAc system) gave the pure
2
products.
5) (a) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem. Int.
Ed. 2004, 43, 719. (b) Moss, R. J.; Wadsworth, K. J.;
Chapman, C. J.; Frost, C. G. Chem. Commun. 2004, 1984.
Analytical Data of 10ca
1
H NMR (400 MHz, CDCl ): d = 3.38 (dd, J = 5.5, 13.0 Hz,
3
1 H), 3.74 (s, 3 H), 3.84 (dd, J = 8.7, 13.0 Hz, 1 H), 4.48 (br
s, 1 H), 5.08 (s, 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 6.78 (d,
J = 8.8 Hz, 2 H), 7.26–7.39 (m, 10 H), 7.55 (br s, 1 H).
(
2
c) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7,
571. (d) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.;
Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556. (e) Frost,
C. G.; Penrose, S. D.; Lambshead, K.; Raithby, P. R.;
Warren, J. E.; Gleave, R. Org. Lett. 2007, 9, 2119.
f) Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am.
Chem. Soc. 2008, 130, 6159.
1
3
C NMR (100 MHz, CDCl ): d = 48.0, 51.2, 55.7, 67.9,
3
114.7, 115.0, 128.0, 128.4, 128.5, 128.6, 128.7, 129.1,
134.7, 136.0, 141.2, 150.6, 152.5, 172.4. LRMS–FAB
(mNBA): m/z = 404 [M ], 405 [M + H] . HRMS (PEG 400/
mNBA): m/z calcd for C H N O [M] 404.1736; found:
404.1739. [a]D +64.6 (c 0.82, CHCl ; 93% ee). HPLC
(DAICEL CHIRALPAK AD-H, hexane–2-PrOH = 3:1, 1.0
+
+
(
+
2
4
24
2
4
2
5
(
(
6) Sibi, M. P.; Coulomb, J.; Stanley, L. M. Angew. Chem. Int.
3
Ed. 2008, 47, 9913.
7) (a) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.;
Sodeoka, M. Org. Lett. 2004, 6, 1861. (b) Hamashima, Y.;
Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.;
Sodeoka, M. Angew. Chem. Int. Ed. 2005, 44, 1525.
mL/min, 254 mn): t (minor) = 17.2 min, t (major) = 20.9
R
R
min.
(14) Several practical aminomethylation reactions of aldehydes
using organocatalysts have been reported. See: (a) Chi, Y.;
Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
(b) Ibrahem, I.; Dziedzic, P.; Córdova, A. Synthesis 2006,
4060.
(15) Asymmetric three-component classical Mannich reactions:
(a) Ibrahem, I.; Casa, J.; Córdova, A. Angew. Chem. Int. Ed.
2004, 43, 6528. (b) Hamashima, Y.; Sasamoto, N.;
Umebayashi, N.; Sodeoka, M. Chem. Asian J. 2008, 3, 1443.
(
c) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M.
J. Am. Chem. Soc. 2006, 128, 14010.
(
8) (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
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Tetrahedron 2002, 58, 7991. (c) Ma, J.-A. Angew. Chem.
Int. Ed. 2003, 42, 4290.
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