Lithium amide assisted asymmetric Mannich-type reactions of menthyl acetate with PMP-aldimines

Article abstract of DOI:10.1021/ol049675n

Matrix presented. A lithium enolate of menthyl acetate added to PMP-imines, in the presence of an equimolar amount of lithium diisopropylamide, affords the Mannich-type addition products in high stereoselectivity.

Full text of DOI:10.1021/ol049675n

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1721-1723
Lithium Amide Assisted Asymmetric
Mannich-Type Reactions of Menthyl
Acetate with PMP-Aldimines
Seiji Hata, Mayu Iguchi, Tetsuo Iwasawa, Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received February 24, 2004
ABSTRACT
A lithium enolate of menthyl acetate added to PMP-imines, in the presence of an equimolar amount of lithium diisopropylamide, affords the
Mannich-type addition products in high stereoselectivity.
There have been few reports1,2 on the asymmetric Mannich-
type reactions of acetate lithium enolates with stable N-
substituted imines3,4 of poor electrophilicity.5 In contrast,
propionates and other R-substituted acetate analogues have
been used in the asymmetric Mannich-type reactions.6
Success of the Mannich reaction with a chiral acetate is
limited to the Yamamoto protocol, which uses 2-methoxy-
aniline-derived aldimines and Lewis acid additives.7 We have
been investigating the chiral-ligand-controlled asymmetric
addition reaction8 of lithium ester enolates with aldimines
derived from aldehydes and 4-methoxyaniline (PMP-NH2).9
Either the ternary complex reagent of R-substituted ester
lithium enolates having a chiral bidentate ligand and a lithium
amide as components or the binary reagent of a lithium
enolate coordinated by a tridentate ligand enhanced the
reactivity of an enolate toward PMP-imines, giving the
(1) Reviews: (a) Hart, D. J.; Ha, D.-C. Chem. ReV. 1989, 89, 1447-
1465. (b) Enantioselective Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (c) Kobayashi, S. Ishitani, H. Chem. ReV.
1999, 99, 1069-1094. (d) Denmark, S. E.; Nicaise, O. J.-C. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 2, pp 923-961. (e) Benaglia, M.;
Cinquini, M.; Cozzi, F. Eur. J. Org. Chem. 2000, 563-572.
(2) For asymmetric Mannich-type reactions using a chiral acetate
equivalent with achiral activated imines, see: (a) Liebeskind, L. S.; Welker,
M. E.; Fengl, R. W. J. Am. Chem. Soc. 1986, 108, 6328-6343. (b) Palomo,
C.; Oiarbide, M.; Gonza´lez-Rego, M. C.; Sharma, A. K.; Garc´ıa, J. M.;
Gonza´lez, A.; Landa, C.; Linden, A. Angew. Chem., Int. Ed. 2000, 39,
1063-1066 and references therein.
(6) For examples, see: (a) Ojima, I.; Habus, I. Tetrahedron Lett. 1990,
31, 4289-4292. (b) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org. Chem.
2001, 66, 9030-9032.
(7) (a) Saito, S.; Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891-
1894. (b) Saito, S.; Hatanaka, K.; Yamamoto, H. Tetrahedron 2001, 57,
875-887.
(3) Other than stable N-aryl imines, chiral sulfinyl imines have been the
good reaction partners. (a) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000,
1-15. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819-7832
and references therein.
(4) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044-1070.
(5) For recent asymmetric Mannich-type reactions using a ketene
derivative, see: (a) Mu¨ller, R.; Ro¨ttele, H.; Henke, H.; Waldmann, H. Chem.
Eur. J. 2000, 6, 2032-2043. (b) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D.
Angew. Chem., Int. Ed. 2001, 40, 2271-2274. (c) Taggi, A. E.; Hafez, A.
M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002,
124, 6626-6635. (d) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964-12965. (e) Kobayashi, S.; Matsubara, R.; Nakamura,
Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507-2515.
(8) (a) Tomioka, K. Synthesis 1990, 541-549. (b) Tomioka, K.; Nagaoka,
Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, pp 1105-1120. (c)
Tomioka, K. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Veinheim, 2000; Chapter 12. (d) Iguchi, M.; Yamada, K.; Tomioka, K. In
Organolithiums in EnantioselectiVe Synthesis; Hodgson, D. M., Ed.;
Springer-Verlag: Heidelberg, 2003; pp 37-59.
(9) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J.
Am. Chem Soc. 1997, 119, 2060-2061. (b) Kambara, T.; Hussein, M. A.;
Fujieda, H.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1998, 39, 9055-9058.
(c) Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999, 55, 11219-
11228. (d) Kambara, T.; Tomioka, K. J. Org. Chem. 1999, 64, 9282-9285.
(e) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.;
Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun. 1999, 715-716.
10.1021/ol049675n CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004

â-lactam products in high enantioselectivities. However, an
acetate itself, in place of R-substituted esters, was not a
reactive partner in the reaction, and PMP-imines were
recovered mostly unchanged. After many trials, we finally
reached a simple solution for this problematic reaction by
using a lithium amide as an assisting agent.
report,7 the reaction with 3g (R2 ) 2-MeO) proceeded under
the same conditions to give 4g in 86% yield and 84:16 dr
(entry 7).
Hammett σ-constants and pKa values of the 4-substituted
anilines are likely to be the key to the success and failure of
the Mannich reaction. For example, imines 3b-3f derived
from anilines bearing 4-NO2 (σ12 0.81), 4-CN (0.71), 4-CO2i-
Pr (0.68 for CO2Et), 4-CF3 (0.53), and 4-H (0) groups are
good reaction partners, and 3a bearing 4-MeO (-0.28) is
not. The pKa values13 of 4-NO2 (21), 4-CN (26), and 4-H
(31) anilines are smaller than or nearly equal to that (30 for
MeCO2t-Bu) of an acetate. These apparently indicate two
critical points: (1) electron-withdrawing groups (R2) at the
4-position of aniline increase the reactivity of the imine
functionality, and (2) the initially formed lithium amide
species of 4 plays the important role in the reaction (Figure
1). When the lithium amides of the products 4 are more stable
We systematically studied the influence of the para
substituents of the aniline-derived aldimines 3 (R1 ) Ph) on
the reaction efficiency using menthyl acetate 1 (Scheme 1).
Scheme 1. Mannich-Type Reaction of Imine 3 with Menthyl
Acetate 1 via Lithium Enolate 2, Giving 4
The lithium enolate 2 was generated by treatment of a THF
solution of 1 with a slight excess of lithium diisopropylamide
(LDA) at -78 °C for 1 h and was then treated with 3.
Contrary to the lack of the addition product 4a (R1 ) Ph,
R2 ) 4-MeO) with PMP-imine 3a (R1 ) Ph, R2 ) 4-MeO)
(Table 1, entry 1),10 imines 3b-3f of anilines bearing
Figure 1. Hammett σ-constant, yield (×) and dr (O) of the reaction.
Table 1. Mannich-Type Reaction of 1 with 3 (R1 ) Ph) at
-78 °C
as a result of the electron-withdrawing 4-R2 group or internal
coordination (2-MeO), the efficiency of the reaction is higher
and vice versa.
3
4
yield
(%)
entry (R1 ) Ph)
R2
t (h) (R1 ) Ph)
dr
1
2
3
4
5
6
7
a
b
c
d
e
f
4-MeO
4-H
4-CF3
4-CO2i-Pr
4-CN
5
5
a
b
c
d
e
f
0
62
87
80
95
98
86
The diastereoselectivity is inversely proportional to the
value of the Hammett σ-constants of R2, implying the
important role of the reactivity of the imine functionality
(Figure 1). The reaction with more reactive imines likely
proceeds through a looser organization of the transition state,
leading to lower diastereoselectivity down to 56:44 dr with
3f (R2 ) NO2). Less reactive imines react through a tighter
transition state to afford better diastereoselectivity up to 93:7
dr with 3b (R2 ) H).
93:7
0.3
0.3
0.3
0.3
3
80:20
72:28
60:40
56:44
84:16
4-NO2
2-MeO
g
g
electron-withdrawing substituents or no substituent at the
4-position were good partners for the Mannich-type reaction
at -78 °C for 0.3 h (5 h for 3b) to afford 4b-4f (R1 ) Ph)
in good to high yields [62% (93:7 diastereomer ratio (dr))
with 3b (R2 ) 4-H), 87% (80:20 dr) with 3c (R2 ) 4-CF3),
80% (72:28 dr) with 3d (R2 ) 4-CO2i-Pr), 95% (60:40 dr)
with 3e (R2 ) 4-CN), and 98% (56:44 dr) with 3f (R2 )
4-NO2) (entries 2-6)].11 As expected from Yamamoto’s
These experiments and analyses led us to the expectation
that the least activated imine 3a would provide the highest
diastereoselectivity if the reaction proceeded. As a simple
solution to the problem we applied the concept of ternary
reagent control9 that enables activation of a lithium ester
enolate by forming a complex with a lithium amide and a
(10) The reaction at higher temperature resulted in the production of a
messy mixture.
(12) March’s AdVanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 5th ed.; Smith, M. B., March, J., Eds.; John Wiley & Sons
Inc.: NY, 2001.
(11) The diastereomer ratio was determined by 1H NMR (doublet Me
protons appearing at around 1 ppm) of the crude product.
(13) The pKa values in DMSO quoted from the Bordwell pKa table.
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Org. Lett., Vol. 6, No. 11, 2004

chiral ligand. For the reaction in THF, a binary complex of
a lithium enolate with a lithium amide would be the reagent
of choice.14
Scheme 2. Stability of 4a upon Treatment with LDA
To our delight, the reaction at -30 °C for 4 h of a binary
complex of menthyl acetate enolate (2-LDA), generated by
treatment of 1 with 2.25 equiv of LDA in THF, converted
PMP imine 3a to the desired adduct 4a (R1 ) Ph, R2 )
4-MeO) in 76% yield and 96:4 dr (Table 2, entry 1). The
Table 2. Mannich-Type Reaction of Imine 3 with 1 via Binary
Reagent of 2-LDA
1,4-adduct 6 in 12% yield. These products seemed to arise
through elimination of 4-methoxyaniline from 4a via its
lithium enolate and subsequent 1,2-addition to a carbonyl
group of cinnamate followed by 1,4-addition.15 Thus the
stability of the lithium amide of 4a is also one of the
controlling factors of the reaction. It is important to note
that LDA plays a dual role in the activation of the lithium
enolate and the lithiation of the unstable initial adduct into
the stable dianion.
The PMP group of (-)-4a, diastereomerically enriched
to over 99:1 dr in 70% yield by recrystallization from
methanol, was easily removed by a CAN oxidation to afford
optically pure (R)-715 (Scheme 3).
LDA, 2.25 eq
1
THF, -78 °C, 1 h8 2-LDA + 3 -40 to -20 °C, 3-4 h8 4
entry
3
R1
R2
4
yield (%)
dr
1
2
3
4
5
6
a
b
h
i
j
k
Ph
Ph
4-MeO
H
4-MeO
4-MeO
4-MeO
4-MeO
a
b
h
i
j
k
76
58
74
56
65
83
96:4
96:4
97:3
96:4
82:18
94:6
4-CF3C6H4
4-MeOC6H4
1-Naph
2-Naph
use of other lithium amides, derived from dicyclohexylamine,
isopropylcyclohexylamine, or tetramethylpiperidine, had little
influence on the reaction to afford 4a with the same high
selectivity of 94:6-93:7 dr and 56-80% yields. The binary
reagent (2-LDA) also converted 3b in 3.5 h to 4b with 96:4
improved dr (entry 2). Under these conditions, no improve-
ment in the diastereoselectivity was observed in the reaction
with activated imines 3c-3f.
Scheme 3. Conversion of Enantiomerically Pure 4a to 7
The 4-substituents of benzaldehyde derivatives were not
so influential on the reaction. The 4-trifluoromethyl- and
4-methoxybenzaldehyde imines 3h and 3i (R1 ) 4-CF3C6H4,
4-MeOC6H4, R2 ) 4-MeO) were converted at -30 °C in
the presence of an excess of LDA to 4h in 74% yield and
97:3 dr and 4i in 56% yield and 96:4 dr (entries 3 and 4). In
the absence of an excess of LDA, the starting imines were
recovered without formation of detectable amount of the
adducts. Other than benzaldehyde imines, PMP imines of
1- and 2-naphthaldehydes 3j and 3k (R1 ) 1- and 2-Naph)
were converted at -40 °C for 3 h to 4j in 65% and 82:18 dr
and 4k in 83% and 94:6 dr (entries 5 and 6).
The deuterium oxide quench of the reaction with 3a
revealed that the R-position of ester 4a was deuterized at
80%, indicating the conversion of the initially formed lithium
amide of the adduct to its dianion. The stability of the dianion
of the adduct was confirmed by treatment of 4a with 3 equiv
of LDA to recover 4a in 90% yield without any loss of
diastereo-integrity (Scheme 2). On the other hand, treatment
of 4a with 1.2 equiv of LDA gave the recovery of 4a in a
trace amount, along with 4-methoxyaniline in 13% yield,
N-PMP cinnamoylamide 5 in 28% yield, and its PMP-amine
In conclusion, we have developed a new and simple
methodology for the Mannich-type reaction of a chiral acetate
with arylaldimines, in which the use of a binary reagent
composed of a lithium acetate enolate and a lithium amide
is key to the success. It is also important to note that a simple
chiral auxiliary, menthol, is operative as an efficient sto-
ichiometric stereocontrolling group.
Acknowledgment. This research was partially supported
by the 21st Century Center of Excellence Program “Knowl-
edge Information Infrastructure for Genome Science” and a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules”, from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan, and a grant from JSPS.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL049675N
(14) (a) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1990, 112,
8602-8604. (b) Galiano-Roth, A. S.; Kim, Y.-J.; Gilchrist, J. H.; Harrison,
A. T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 5053-
5055.
(15) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886-2887.
Org. Lett., Vol. 6, No. 11, 2004
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