Catalytic addition of homoenolates to imines - The homo-Mannich reaction

Article abstract of DOI:10.1055/s-2005-862378

For the first time, homo-Mannich reactions with unmasked homoenolates have been achieved by adding homoenolate precursor 1 and imines 5. The key to this reaction is the right choice of the Lewis acids - Cu(OTf)₂ proved to be most suitable for p

Full text of DOI:10.1055/s-2005-862378

LETTER
473
Catalytic Addition of Homoenolates to Imines – The Homo-Mannich Reaction
C
atalytic
Addition of
H
u
omoenolate
h
s
to Imines ammad Abbas,a Christiane Neuhaus,a Birte Krebs,b Bernhard Westermann*a,b
a
b
Received 24 June 2004
Dedicated to Prof. Dr. Frank Seela on the occasion of his 65th birthday.
provide homoaldol products 3 (Scheme 1). Imines, which
tend to have a lower electrophilicity than their corre-
sponding aldehydes, can be activated efficiently by Lewis
acids. Therefore, one can assume that cleavage of cyclo-
Abstract: For the first time, homo-Mannich reactions with un-
masked homoenolates have been achieved by adding homoenolate
precursor 1 and imines 5. The key to this reaction is the right choice
of the Lewis acids – Cu(OTf)2 proved to be most suitable for pre-
paring the homoenolate and activation of the imine. An asymmetric propanone hemiacetals 1 and activation of imines can be
catalytic version of this reaction is provided by using chiral, non-
achieved by the same Lewis acid in one pot. For the nature
racemic phenyl-derived bisoxazolidine as ligand for the Lewis acid.
of the Lewis acids, we hoped that Cu(OTf)2 currently used
Key words: asymmetric catalysis, amino acids, Lewis acids, ho-
moenolates, Mannich reaction
very successfully in Mannich reactions would serve as
valuable catalysts to enforce the homo-Mannich reac-
tion.2e,8
The Mannich reaction is one of the basic reactions in or-
ganic synthesis which has served in numerous sequences
as the key reaction.1 If one considers the closely related al-
dol reaction as one of the cornerstones of stereoselective
synthesis, it is most striking that the development of
asymmetric, especially catalytic versions of Mannich re-
actions, have been successfully accomplished only recent-
ly.2 Amongst others, the use of chiral, non-racemic Lewis
acids has played an important role. To stay in comparison
of aldol- and Mannich reactions, the corresponding ho-
moaldol reactions have been studied in detail and have
been employed in various natural product syntheses.3
However, homo-Mannich reactions (addition of ho-
moenolates to imines or iminium anions) have not been
reported in the literature (Scheme 1). In connection with
our work on cyclopropanone hemiacetals 14 we became
very intrigued by the idea of employing homoenolates 2
generated from 1 in addition reactions to imines to
achieve the synthesis of g-amino acids 4.5 In this commu-
nication we are presenting results to demonstrate for the
first time that, in fact, homoenolates can be added to imi-
nes.6,7 These results may be considered as entering points
towards the development of homo-Mannich reactions. In
addition, we will provide a catalytic asymmetric version
of this reaction and demonstrate that diastereoselective
homo-Mannich reactions can be achieved by using chiral
imines.
OEt
1
OSiMe3
Lewis
acid
OEt
O
R2
2
O
H
O
N
R3
R1
O
R2
R1
R3
OEt
OEt
NH
OH
3
4
Scheme 1
In our initial studies, we have chosen N-protected a-imino
esters 5. As the N-protecting group we used the electron
rich p-methoxyphenyl (PMP) group, which additionally
permits easy removal under oxidative conditions.9 N-
Tosyl- and N-phenyl-derived imines proved to be of no
use for this reaction type, no reaction could be observed.
Therefore, PMP-protected imines have been used
throughout these studies (Scheme 2).
Since the pioneering work of Kuwajima and Nakamura
cyclopropanone hemiacetals 1 have been used to provide
direct access to ester homoenolates 2. They showed that
this can be achieved by various Lewis acids such as TiCl4
or ZnCl2. Homoenolates 2 can be added to aldehydes to
SYNLETT 2005, No. 3, pp 0473–0476
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862378; Art ID: G21304ST
© Georg Thieme Verlag Stuttgart · New York

474
M. Abbas et al.
LETTER
NHPMP
OEt
Kuwajima and Nakamura explored a great variety of
Lewis acids suitable for cleavage of 1. It seemed appropri-
ate to use these for the activation of imines, too. Although
homoenolate formation proceeded successfully in all cas-
es, most of these Lewis acids failed to activate the imine
to form homo-Mannich products in reasonable yields
(Table 1, run 7–25). TMSOTf failed to form the ho-
moenolate, instead it activated the imine (run 26). This
could be proven in experiments using 1 equivalent TiCl4
and 1 equivalent TMSOTf. In this case, the product could
be observed in high yields indicating the formation of the
homoenolate with TiCl4 and the activation of the imine
with TMSOTf. A similar pattern has been observed in
homoaldol reactions.3g
CO2Et
1, Lewis acid
EtO
N
other conditions
Table 1
PMP
O
O
5
6
Scheme 2
Table 1 Results for the Reaction of Imine 511 with Cyclopropanone
Hemiacetals 1 in the Presence of Various Lewis Acids
Entry
Lewis acid Catalyst
(mol%)
Solvent
Time (h) Yield (%)
1
2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr2
100
20
THF
48
72a
Turning to Cu(OTf)2, which has been shown to be a very
suitable imine-activating Lewis acid, we have been able to
achieve the formation of N-protected g-amino esters. In
all experiments employing Cu(OTf)2 only substoichio-
metric amounts had to be used. In CH2Cl2 20 mol% had to
be used to obtain 6 in 73% yield. Better results could be
obtained by carrying out the reaction in THF (86% yield,
10 mol% Lewis acid), but the yield decreased by lowering
the amount of Cu(OTf)2 (59% yield, 5 mol% Lewis acid).
Diethyl ether was not suitable as solvent. Even with a very
high amount of catalyst the yield dropped to 26%. Inter-
estingly, toluene as solvent gave also very good results. In
the presence of 20 mol% of the catalyst, 85% of the prod-
uct could be obtained.
Toluene 18
85a
3
20
CH2Cl2
THF
18
18
48
72
72
72
72
72
72
72
72
72
72
18
72
72
72
72
72
18
72
72
24
24
73a
4
10
86a
5
5
THF
60a
6
50
Et2O
28a
7
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
CH2Cl2
Et2O
10
8
CuBr2
Tracesb
Tracesb
Tracesb
Tracesb
N.r.c
27
9
CuBr2
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
In(OTf)3
In(OTf)3
In(OTf)3
BF3
CH2Cl2
THF
These very encouraging results gave rise to believe that
this reaction can be carried out in an asymmetric catalytic
version. Recently, it was demonstrated very successfully
that chiral, non-racemic bisoxazoline–copper(II) com-
plexes 7 and 8 act as effective catalysts in aldol- and Man-
nich reactions, amongst others.2e,8
Et2O
CH2Cl2
THF
Tracesb
Tracesb
26
We employed 7 and 8 (20 mol%) in the presence of
Cu(OTf)2 (20 mol%). The chemical yields with complex
8 were comparable to the ones reported in Table 1 (78%),
however, the enantiomeric excess obtained was only 44%
(as determined by chiral HPLC). To our surprise, complex
7 did not lead to any product formation. In this case the
formation of a homoenolate, which is catalyzed also by
the Lewis acid, could not be observed. However, heating
the reaction solution up to 50 °C, homoenolate formation
and subsequent product formation could be observed, but
without any stereoselectivity.
Et2O
CH2Cl2
THF
BF3
Tracesb
Tracesb
N.r.c
N.r.c
N.r.c
21
BF3
Et2O
CsF
CH2Cl2
THF
CsF
CsF
Et2O
BiCl3
CH2Cl2
THF
Assuming the chelating model previously proposed for
imides and glyoxylates, notable differences have been ob-
served while using tert-butyl 7 or phenyl-derived ligands
8 (Figure 1).8b In hetero-Diels–Alder reactions and glyox-
ylate-ene reactions, an opposite diastereoselectivity was
observed, which was explained by a change in metal cen-
ter geometry. Here, it can be concluded to some extend
that distortion at the metal center leads to productive bind-
ing of the imine to complex 8, whereas non-productive
binding of the imine to 7 can be accounted for the failure
of the reaction. Interestingly, the same negative outcome
can be observed in the case of isopropyl- (from valine)
BiCl3
23
BiCl3
Et2O
N.r.c
N.r.c
N.r.c
TiCl4
Et2O
TMSOTf
THF
a Yield of isolated products, otherwise yields determined by GLC of
the crude reaction mixture after passing through a plug of silica gel.
b Traces: yields < 10%.
c N.r.: no reaction.
Synlett 2005, No. 3, 473–476 © Thieme Stuttgart · New York

LETTER
Catalytic Addition of Homoenolates to Imines
475
and benzyl-derived (from phenylalanine) ligands. Further and thus preventing further cyclization. In the case of
studies have to be done to gain a reliable mechanistic in- ZnCl2, no silylation is possible, therefore, the formation of
sight into this reaction.
the lactam can be achieved.
After clarifying some chemoselectivity aspects of this
new reaction, problems concerning regioselectivity while
using substituted cyclopropyl hemiacetals have to be ad-
dressed. Future plans also include the utilization of other
chiral, non-racemic Lewis acids to achieve the asymmet-
ric synthesis of non-natural g-amino acids.
O
O
O
O
N
N
N
N
Cu
Cu
Ph
Ph
t-Bu
t-Bu
(OTf)2
(OTf)2
8
7
Acknowledgment
O
O
Me
Me
Me
Me
Financial support by the DFG (We 1826/2-2) and the Fonds der
Chemischen Industrie is highly appreciated.
H
H
N
N
O
O
O
OEt
Ph
Ph
t-Bu
O
t-Bu
OEt
Cu
Cu
N
N
N
N
H
H
PMP
References
PMP
Re face
(tetrahedral)
H
Si face
H
(1) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. 1998, 37, 1045; Angew. Chem. 1998, 110, 1097.
(b) Arend, M. Angew. Chem. Int. Ed. 1999, 38, 2873; Angew.
Chem. 1999, 111, 3047. (c) Denmark, S. E.; Nicaise, O. J. C.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Heidelberg, 1999,
923.
(square planar)
Figure 1 Transition states for the Mannich reaction and the homo-
Mannich reaction
To show the potential of this new reaction, we employed
menthone-derived chiral glycine equivalent 9 as the imine
(Scheme 3).10 It can certainly be assumed that the addition
of homoenolate 2 is governed by the chiral, non-racemic
auxiliary, and therefore, leading to products in high dias-
tereoselectivities. Compound 9 can be easily synthesized
by forming the N,N-acetal (menthone and N-methyl glyc-
inamide) first and subsequent oxidation with PDC.
(2) (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(b) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett.
1999, 40, 307. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J.
Am. Chem. Soc. 2000, 122, 8180. (d) List, B. J. Am. Chem.
Soc. 2000, 122, 9336. (e) Juhl, K.; Gathergood, N.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2001, 40, 2995;
Angew. Chem. 2001, 113, 3083;. (f) Notz, W.; Sakthivel,
K.; Bui, T.; Zhong, G. F.; Barbas, C. F. Tetrahedron Lett.
2001, 42, 199. (g) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (h) Trost,
B. M.; Terell, L. R. J. Am. Chem. Soc. 2003, 125, 338.
(3) (a) Review: Crimmins, M. T.; Nantermet, P. G. Org. Prep.
Proced. Int. 1993, 25, 41. (b) Review: Hoppe, D.; Hense, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2283; Angew. Chem.
1997, 109, 2377. (c) Review: Ahlbrecht, H.; Beyer, U.
Synthesis 1999, 365. (d) Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1985, 107, 2138. (e) McWilliams, J. C.;
Armstrong, J. D. III; Zheng, N.; Bhupathy, M.; Volante, R.
P.; Reider, P. J. J. Am. Chem. Soc. 1996, 118, 11970.
(f) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.;
Shinkai, I. Tetrahedron Lett. 1991, 32, 1867. (g) Burke, E.
D.; Lim, N. K.; Gleason, J. L. Synlett 2003, 390.
(4) Westermann, B.; Krebs, B. Org. Lett. 2001, 3, 189.
(5) g-Amino acids have gained considerable attention due to
their helix forming properties when incorporated in peptides.
See: (a) Hintermann, T.; Gademann, K.; Jaun, B.; Seebach,
D. Helv. Chim. Acta 1998, 81, 983. (b) Seebach, D.; Beck,
A. K.; Brenner, M.; Gaul, C.; Heckel, A. Chimia 2001, 55,
831.
(6) A formal homoamino methylation was described in: Reissig,
H.-U.; Lorey, H. Liebigs Ann. Chem. 1986, 1914.
(7) (a) Nakamura, E.; Shimada, J.; Kuwajima, I.
Organometallics 1985, 4, 641. (b) Nakamura, E.; Oshino,
H.; Kuwajima, I. J. Am. Chem. Soc. 1986, 108, 3745.
(c) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.;
Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056.
(8) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1. (b) Jørgensen, K. A.; Johannsen, M.;
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33, 325.
OEt
H
N
H
O
O
10
2
2
N
Me
N
O
11
N
O
Me
H
N
O
N
9
Me
Scheme 3
Indeed, by adding 1 to the chiral imine 9 in the presence
of Cu(OTf)2 only one addition product could be observed
in 41% yield. As revealed by NMR spectroscopy, product
10 was diastereomerically pure. In the presence of ZnCl2,
however, lactam formation can be observed exclusively
(yield 19%). The structure of cyclized 11 could be deter-
mined by NMR- and by X-ray spectroscopy. The products
obtained in these reactions clearly revealed that the nu-
cleophilic attack of the homoenolate 1 was controlled by
the isopropyl moiety of the chiral auxiliary, which is effi-
ciently shielding the back of the imine moiety. The forma-
tion of the non-cyclized 10 can be explained by the
formation of TMSOTf, which is silylating the amide ion
formed as an intermediate from the homoenolate addition
Synlett 2005, No. 3, 473–476 © Thieme Stuttgart · New York

476
M. Abbas et al.
LETTER
(9) (a) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K.
J. Org. Chem. 1998, 63, 9932. (b) Anderson, J. C.; Peace,
S.; Pih, S. Synlett 2000, 850.
(10) (a) Vogt, A.; Altenbach, H.-J.; Kirschbaum, M.; Hahn, M.
G.; Matthäus, M. S. P.; Herrmann, A. R. EP 976721, 2000;
Chem. Abstr. 2000, 132, 108296. (b) Altenbach, H.-J.;
Hahn, M. G.; Matthäus, M. S. P. 12thInternational
Conference on Organic Synthesis; Venice: Italy, 1998, OC-
68.
(silica gel, petrol ether–EtOAc, 1:1, TLC developed twice).
The separation of the enantiomers was carried out with a
Daicel Chiralcel OD-H column (hexane–i-PrOH, 8:2; canalyt
0.1 mg/mL; flow rate 0.5 mL/min, l 254 nm); tR1 = 14.87
min; tR2 = 16.28 min.
Procedure of the BOX-Catalyzed Reaction.
In an oven dried 50 mL flask equipped with a magnetic
stirring bar, Cu(OTf)2 (35.5 mg, 0.1 mmol) and (S,S)-2,2-
isopropylidene-bis-(4-phenyl-2-oxazoline) (8, 38 mg, 0.11
mmol) were added. The mixture was stirred under high
vacuum for 2 h and then filled with dry argon. Dry THF (5
mL, distilled over Na and LiAlH4) was added and the
solution was stirred for 4 h. Imine 5 (207 mg, 1.0 mmol) was
dissolved in 1–2 mL of dry THF and added dropwise
followed by hemiacetal 1 (250 mL, 1.21 mmol) at –78 °C.
Stirring was continued for 72 h at r.t. and then the reaction
was quenched with EtOH (1–2 mL), concentrated and the
residue dissolved in CH2Cl2 (2 mL), filtered over a small pad
of silica gel using CH2Cl2 (20 mL) as eluent. Evaporation of
the solvent under reduced pressure afforded the crude
product 6, which was purified by column chromatography
(silica gel, n-hexane–EtOAc, 1:1).
(11) Experimental Procedures;
Procedure for the Cu(OTf)2-Catalyzed Homoenolate
Addition to Imine 5.
In an inert atmosphere [(1-ethoxycyclopropyl)oxy]tri-
methylsilane (1, 250 mL, 1.21 mmol, 1.3 equiv) was added to
a stirred mixture of Cu(OTf)2 (37 mg, 0.7 mmol) in THF (3
mL) at –78 °C. Imine 5 (207 mg, 1.0 mmol) was dissolved in
1.0 mL of THF and added to the reaction mixture. Stirring
was continued for 18 h at r.t. The reaction was quenched
with EtOH (1–2 mL), concentrated, the residue dissolved in
CH2Cl2 (2 mL) and filtered over a small bed of silica gel
using CH2Cl2 (20 mL) as eluent. Evaporation of the solvent
under reduced pressure afforded the crude reaction product
6, which was purified by column chromatography. Rf = 0.6
Synlett 2005, No. 3, 473–476 © Thieme Stuttgart · New York