Ba-catalyzed direct mannich-type reactions of a β,γ-unsaturated ester providing β-methyl aza-Morita - Baylis - Hillman-type products

Article abstract of DOI:10.1021/ol071380x

Barium-catalyzed direct Mannich-type reactions of a β,γ- unsaturated ester are described. The Ba-catalyst not only promoted the Mannich-type reactions, but also isomerized Mannich adducts to afford β-methyl aza-Morita - Baylis - Hillman-type products in 6

Full text of DOI:10.1021/ol071380x

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3387-3390
Ba-Catalyzed Direct Mannich-Type
Reactions of a -Unsaturated Ester
-Methyl
Baylis
â,γ
Providing
aza-Morita
Products
â
−
−Hillman-Type
Akitake Yamaguchi, Naohiro Aoyama, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo 7-3-1,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Received June 11, 2007
ABSTRACT
Barium-catalyzed direct Mannich-type reactions of a
reactions, but also isomerized Mannich adducts to afford
aryl, heteroaryl, and alkyl imines. Preliminary trials on enantioselective variants with a chiral biaryldiol ligand gave products in up to 80% ee.
â
,
γ
-unsaturated ester are described. The Ba-catalyst not only promoted the Mannich-type
â
-methyl aza-Morita Baylis Hillman-type products in 61 88% yield from various
−
−
−
â-Amino carbonyl compounds are important building blocks
for the syntheses of natural products and pharmaceuticals.
Therefore, tremendous effort has been devoted to the
development of synthetic methods for â-amino carbonyl
compounds, including enantioselective variants.1 Of these
methods, direct catalytic Mannich-type reactions are attrac-
tive in terms of atom economy.2,3 Many excellent direct
catalytic enantio- and diastereoselective Mannich(-type)
reactions with ketones and aldehydes as donors have been
reported.3,4 The use of esters as nucleophiles, however, is
limited to a glycine Schiff-base5 and active methylene
compounds such as â-keto esters and malonates.6 Recently,
the utility of activated ester equivalent donors such as
N-acylpyrroles,7 trichloromethylketones,8 and N-Boc-anilides9
in direct catalytic Mannich-type reactions was also reported.
There remains room for improvement, however, when using
esters themselves as donors. Herein, we describe the utility
(4) Selected recent direct Mannich-type reactions of ketones and alde-
hydes: Metal catalysts: (a) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul,
V. J. Am. Chem. Soc. 2006, 128, 2778. (b) Matsunaga, S.; Yoshida, T.;
Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
8777. Organocatalysts: (c) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288. (d) Yang, J. W.; Stadler,
M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609. (e) Kano, T.; Yamaguchi,
Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 16408. For
other examples, see reviews in ref 3 and references therein.
(1) Reviews: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (b)
Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
(2) Trost, B. M. Science 1991, 254, 1471.
(5) (a) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2003, 68, 2583. (b) Ooi, T.; Kameda, M.; Fujii, J.-i.; Maruoka,
K. Org. Lett. 2004, 6, 2397. (c) Shibuguchi, T.; Mihara, H.; Kuramochi,
A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794 and references
cited therein.
(3) Recent reviews on direct Mannich-type reactions: (a) Marques, M.
M. B. Angew. Chem., Int. Ed. 2006, 45, 348. (b) Shibasaki, M.; Matsunaga,
S. J. Organomet. Chem. 2006, 691, 2089. (c) Co´rdova, A. Acc. Chem. Res.
2004, 37, 102.
10.1021/ol071380x CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/26/2007

of a â,γ-unsaturated ester as a new donor class in direct
catalytic Mannich-type reactions.10,11 The Ba-catalyst not only
promoted the Mannich-type reactions of the â,γ-unsaturated
ester, but also isomerized Mannich adducts to afford â-meth-
yl aza-Morita-Baylis-Hillman-type products in up to 88%
yield.12 Preliminary studies on enantioselective reactions are
also described.
metal catalyst would readily generate a dienolate in situ from
1. The dienolate reacts with imine 2 at the R- and/or
γ-position. If the catalyst further deprotonates the R-proton
from the R-adduct, the C-C double bond would isomerize
to give a â-amino ester 3 bearing an R-alkylidene group.
Despite recent progress in aza-Morita-Baylis-Hillman (aza-
MBH) reactions including enantioselective variants,13,14 ap-
plicable substrates in aza-MBH reactions are mostly limited
to cyclic enones, â-unsubstituted acyclic enones, and related
esters. aza-MBH reactions with â-substituted R,â-unsaturated
esters are rare due to their low reactivity.15 Thus, we decided
to search for a suitable catalyst to selectively promote the
R-addition/isomerization sequence using â,γ-unsaturated
ester 1 to provide an alternative approach for â-substituted
aza-MBH adducts.16
Possible reaction pathways with use of a â,γ-unsaturated
ester 1 are shown in Scheme 1. The acidity of the proton at
Scheme 1. Mannich-Type Reaction/Isomerization Sequence
with a â,γ-Unsaturated Ester
We screened several metal aryloxides for racemic reactions
using N-diphenylphosphinoyl (N-Dpp) imine17 2a and 1.3
equiv of benzyl ester 1 (Table 1, entries 1-5).18 LiOAr (Ar
) 4-MeO-C6H4) and Ba(OAr)2 promoted both the Mannich-
type R-addition and desired isomerization at 0 °C to afford
product (E)-3a in 51% (entry 1) and 74% (entry 3) yield,
respectively. Considering the extension to an asymmetric
variant, Ba(OAr)2 was selected for further studies.19 The use
of another alkaline earth metal (entry 2: Ca), and rare earth
metals (entries 4 and 5: Sc and La) gave trace, if any, product
3a. The first Mannich-type reaction was problematic in
(13) For recent reviews on MBH reaction and aza-MBH reactions, see:
(a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
4614. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811.
(14) For selected leading references: (a) Shi, M.; Xu, Y.-M. Angew.
Chem., Int. Ed. 2002, 41, 4507. (b) Kawahara, S.; Nakano, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103. (c) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521. (d) Shi, M.; Xu, Y.-M.;
Shi, Y.-L. Chem. Eur. J. 2005, 11, 1794. (e) Raheem, I. T.; Jacobsen, E.
N. AdV. Synth. Catal. 2005, 347, 1701. (f) Matsui, K.; Takizawa, S.; Sasai,
H. J. Am. Chem. Soc. 2005, 127, 3680 and references cited therein. For
other examples, see ref 13 and references cited therein.
(15) Racemic aza-MBH reactions with acyclic â-substituted esters. (a)
Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62, 461. For the use of an acyclic
â-substituted ester in racemic MBH reactions: (b) Krishna, P. R.;
Narsingam, M.; Reddy, P. S.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron
Lett. 2005, 46, 8885. (c) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org.
Chem. 2003, 68, 692.
(16) For alternative approaches to R-alkylidene-â-amino esters, nitriles,
and ketones, see: Pd-catalyzed allylic aminations: (a) Trost, B. M.; Oslob,
J. D. J. Am. Chem. Soc. 1999, 121, 3057. (b) Mori, M.; Nakanishi, M.;
Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801. (c) Nemoto,
T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.;
Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927. Phosphine-catalyzed
allylic aminations: (d) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett.
2004, 6, 1337. Vanadium-catalyzed isomerization/addition sequence of
propargyl alcohols to imines: (e) Trost, B. M.; Chung, C. K. J. Am. Chem.
Soc. 2006, 128, 10358. For other approaches, see also: (f) Wei, H.-X.;
Hook, J. D.; Fitzgerald, K. A.; Li, G. Tetrahedron: Asymmetry 1999, 10,
661. (g) Li, G.; Wei, H. X.; Whittlesey, B. R.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061. (h) Reginato, G.; Mordini, A.; Valacchi, M.; Piccardi, R.
Tetrahedron: Asymmetry 2002, 13, 595.
the R-position of the ester group is increased due to the
neighboring C-C double bond. Therefore, a Brønsted basic
(6) For selected recent examples, see: (a) Marigo, M.; Kjærsgaard, A.;
Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.
(b) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005,
127, 11256. (c) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.;
Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525. (d)
Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 2896. (e) Song, J.; Wang, Y.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 6048. (f) Sasamoto, N.; Dubs, C.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010. (g) Tillman, A. L.; Ye,
J.; Dixon, D. J. Chem. Commun. 2006, 1191. (h) Ting, A.; Lou, S.; Schaus,
S. E. Org. Lett. 2006, 8, 2003. (i) Fini, F.; Bernardi, L.; Herrera, R. P.;
Pettersen, D.; Ricci, A.; Sgarzani, V. AdV. Synth. Catal. 2006, 348, 2043.
(j) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603. For related
reactions with a diketone, see also: (k) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356.
(7) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4365.
(8) Racemic reactions: (a) Morimoto, H.; Wiedemann, S. H.; Yamaguchi,
A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2006, 45, 3146. Asymmetric reactions: (b) Morimoto, H.; Lu, G.;
Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc., published
online July 14, http://dx.doi.org/10.1021/ja073285p.
(9) Racemic reactions: Saito, S.; Tsubogo, T.; Kobayashi, S. Chem.
Commun. 2007, 1236.
(10) â,γ-Unsaturated nitriles and a â,γ-unsaturated ester were utilized
in direct catalytic aldol reactions. The isomerization step to afford MBH-
type adducts was, however, problematic when using the â,γ-unsaturated
ester: Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2002, 67, 426.
(11) Diastereoselective addition of a dienolate from a â,γ-unsaturated
ester to imines with chiral auxiliary afforded R-alkylidene-â-amino esters;
however, stoichiometric amounts of LDA were required in the method:
Garcia Ruano, J. L.; Ferna´ndez, I.; del Prado Catalina, M.; Hermoso, J. A.;
Sanz-Aparicio, J.; Mart´ınez-Ripoll, M. J. Org. Chem. 1998, 63, 7157.
(12) Recently, an elegant organocatalytic enantioselective Mannich-type
reaction/isomerization sequence using R,â-unsaturated aldehydes and
R-imino esters to produce chiral R-alkylidene-â-amino aldehydes was
reported. Excellent enantioselectivity (99% ee) and stereoselectivity were
achieved; however, 5 equiv of donor and 1 equiv of imidazole were used
in the system to obtain isomerized adducts in good yield: Utsumi, N.; Zhang,
H.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int. Ed. 2007, 46, 1878.
(17) A review on the utility of N-Dpp-imines: (a) Weinreb, A. M.; Orr,
R. K. Synthesis 2005, 1205. For the use of N-Dpp-imines in direct Mannich-
type reactions, see: (b) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 4712. (c) Sugita, M.; Yamaguchi, A.;
Yamagiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2005,
7, 5339. See also ref 4a.
(18) Benzyl ester 1 was selected in this study because benzyl ester is
easily detected on TLC and is less volatile than methyl ester.
(19) For chiral Ba-aryloxide catalysts: (a) Yamada, Y. M. A.; Shibasaki,
M. Tetrahedron Lett. 1998, 39, 5561. (b) Saito, S.; Kobayashi, S. J. Am.
Chem. Soc. 2006, 128, 8704. For the utility of Ba-aryloxides in racemic
direct catalytic Mannich-type reactions, see ref 9.
3388
Org. Lett., Vol. 9, No. 17, 2007

Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scopes and Limitations of Mannich-Type
Reaction/Isomerization Sequence
imine
2
cat.
(mol %)
time yield
entry
imine
M(OAr)n
time (h)
yield (%)
R/γa
entry
imine 2: R )
Ph
(h)
(%)
R/γa
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2b
2c
LiOAr
21
21
17
21
21
21
21
51
trace
74
>15:1
NDb
1
2
3
4
5
2a
2d
2e
2f
2f
2f
2g
2g
2h
2i
2j
2k
2l
10
10
10
10
5
0.5
10
10
10
10
10
10
10
10
10
17
17
17
17
19
24
21
17
19
17
19
17
17
17
19
74
82
81
84
81
75
55
64
61
76
88
75
61
27
53
>15:1
>15:1
>15:1
>15:1
>15:1
>15:1
7:1
13:1
>15:1
11:1
>15:1
>15:1
>15:1
>15:1
>15:1
Ca(OAr)2
Ba(OAr)2
Sc(OAr)3
La(OAr)3
Ba(OAr)2
Ba(OAr)2
4-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Cl-C6H4
2-furyl
>15:1
0
NDb
trace
tracec
39d
NDb
NDb
6
7
>15:1
a Ratio of 3/γ-adduct determined by 1H NMR analysis. b Not determined.
c Trace amount of unisomerized R-adduct was obtained. d Mixture of
R-adduct and isomerized adduct 3c.
8b
9b
10
11
12b
13b
14b
2-thienyl
cyclopropyl
cyclohexyl
(CH3)2CHCH2-
n-butyl
entries 2, 4, and 5. Imines with other protective groups were
not suitable (entries 6 and 7). N-Ts-imine 2b gave trace of
unisomerized Mannich-adduct (entry 6). N-Boc-imine 2c
gave a mixture of the desired aza-MBH-type adduct and
unisomerized Mannich-adduct in low yield (entry 7, 39%).
Ba(OAr)2 was applicable to various aryl, heteroaryl, and
alkyl N-Dpp-imines to afford (E)-products (Table 2).20 No
(Z)-adduct was observed in all entries. Aryl imines 2d-f
with an electron-donating group at either the 4- or the
2-position afforded the desired (E)-products in 81-84% yield
and high R/γ selectivity (entries 2-4, R/γ >15/1). Catalyst
loading was successfully reduced to 5 and 0.5 mol % while
maintaining high R/γ selectivity (entries 5 and 6). The
turnover number of the catalyst reached as high as 150 (entry
6; 75% yield). Imine 2g with an electron-withdrawing group
gave a less satisfactory yield and R/γ selectivity under
standard conditions (entry 7, 55% yield, R/γ 7/1). The
moderate yield of the desired product was partially due to a
sequential R-addition/γ-addition reaction, giving a side-
product containing one ester and two imine units. Slow
addition of both imine 2g and ester 1 over 2 h improved
R/γ selectivity as well as yield to some extent (entry 8, 64%,
R/γ 13/1). Heteroaryl imines 2h,i were also applicable
(entries 9 and 10). Slow addition was required for imine 2h
(entry 10). Not only nonisomerizable alkyl imine 2j, but also
isomerizable alkyl imines 2k and 2l with an R-proton were
applicable,21 giving 3k and 3l in 75% and 61% yield,
respectively (entries 12 and 13). The results implied that the
Ba-catalyst chemoselectively deprotonated the R-proton from
ester 1 over alkyl imines 2k and 2l. In the case of linear
alkyl imine 2m, however, the desired product 3m was
obtained in only 27% yield (entry 14), possibly because
2m
2m
15b,c n-butyl
a Ratio of 3/γ-adduct determined by crude 1H NMR analysis. b Imine 2
and ester 1 were added slowly over 2 h. c 3 equiv of ester 1 was used.
undesired isomerization of the imine to enamide was
competitive with the desired reaction pathway. By using
excess ester 1 (3 equiv), 3m was obtained in 53% yield (entry
15).
The postulated catalytic cycle is shown in Scheme 2. A
Brønsted basic Ba-OAr moiety deprotonates the R-proton
in â,γ-unsaturated ester 1 to form dienolate A. The dienolate
reacts with N-Dpp-imine 2 selectively at the R-position to
give intermediate B. Dienolate C would be derived from
intramolecular proton transfer from B and/or deprotonation
Scheme 2. Postulated Catalytic Cycle
(20) For determination of stereochemistry of products, see the Supporting
Information.
(21) For synthesis of isomerizable alkyl N-Dpp-imines, see ref 4a. See
also: Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2006,
47, 3985.
Org. Lett., Vol. 9, No. 17, 2007
3389

of Mannich adduct D by the Ba-catalyst. Protonation of C
at the γ-position gives the desired product 3 and regenerates
the Ba-catalyst. We assume that the high E-selectivity shown
in Table 2 would be due to the preference of an s-trans
conformation of intermediate C over an s-cis conformation.
Further studies to clarify the precise reaction mechanism as
well as the origin of high stereoselectivity are ongoing.
An initial trial with the Ba(O-iPr)2/(S)-BINOL 4a ) 1/1
complex resulted in 14% ee (entry 1). After screening of
chiral ligands, the Ba(O-iPr)2/(S)-biaryldiol 4b22 ) 1/1
complex showed good selectivity. The biaryldiol complex
promoted the Mannich-type reaction/isomerization sequence
of imines 2a, 2d, and 2i, giving the desired adducts in 69-
78% yield, 9:1 to >15:1 R/γ-selectivity, and 77-80% ee
(entries 2-4).20
In summary, we have developed a Ba-catalyzed direct
Mannich-type reaction/isomerization sequence of a â,γ-
unsaturated ester to give â-methyl aza-MBH-type products
in moderate to good yield. Preliminary trials on asymmetric
variants with use of a Ba(O-iPr)2/biaryldiol 4b complex
afforded products in up to 80% ee. Further investigations to
improve enantioselectivity and ester generality23 are ongoing.
Acknowledgment. This work was supported by Grant-
in-Aid for Specially Promoted Research, Grant-in-Aid for
Encouragements for Young Scientists (B), and the Sumitomo
Foundation. A.Y. thanks the JSPS Fellowship for Young
Scientists. We thank Dr. H. Kakei at the University of Tokyo
for his kind help with chiral ligand synthesis.
Figure 1. Structures of (S)-BINOL 4a and (S)-biaryldiol 4b.
Preliminary results of catalytic enantioselective reactions
with chiral ligands 4 (Figure 1) are summarized in Table 3.
Supporting Information Available: Experimental pro-
cedures, spectral data of products, determination of stereo-
chemistry of products, and synthesis of biaryldiol 4b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Table 3. Catalytic Enantioselective Mannich-Type Reaction/
Isomerization Sequence with (S)-Ligands 4a and 4b
OL071380X
(22) Synthesis and use of chiral biaryldiols in asymmetric catalysis: (a)
Harada, T.; Tuyet, T. M. T.; Oku, A. Org. Lett. 2000, 2, 1319. (b) Tosaki,
S.-y.; Hara, K.; Gnanadesikan, V.; Morimoto, H.; Harada, S.; Sugita, M.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
11776. (c) Kakei, H.; Tsuji, R.; Ohshima, T.; Morimoto, H.; Matsunaga,
S.; Shibasaki, M. Chem. Asian J. 2007, 2, 257 and references cited therein.
(23) At present, only γ-unsubstituted ester 1 gave satisfactory results in
the Ba-catalyzed R-addition/isomerization sequence. For example, the Ba-
catalyst promoted Mannich-type reaction (R-addition) of γ-substituted ester
5; however, the second isomerization step to produce an aza-MBH-type
adduct did not proceed in the case of ester 5.
imine time yield
eeb
(%)
entry
ligand
2
(h)
(%)
R/γa
1
2
3
4
(S)-BINOL 4a
2a
2a
2d
2i
19
17
19
17
58
69
78
73
>15:1
9:1
>15:1
>15:1
14
77
80
78
(S)-biaryldiol 4b
(S)-biaryldiol 4b
(S)-biaryldiol 4b
a Ratio of 3/γ-adduct determined by crude 1H NMR analysis. b Deter-
mined by chiral HPLC analysis.
3390
Org. Lett., Vol. 9, No. 17, 2007