Ti-mediated direct and highly stereoselective Mannich reactions between esters and oxime ethers

Article abstract of DOI:10.1039/b717318k

The first general method of direct and highly stereoselective Ti-mediated Mannich reaction between three types of simple esters and E and Z mixtures of oxime ethers (aliphatic and aromatic) is accomplished. The Royal Society of Chemistry.

Full text of DOI:10.1039/b717318k

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Ti-mediated direct and highly stereoselective Mannich reactions
between esters and oxime ethers{
Takashi Funatomi, Shogo Nakazawa, Kunshi Matsumoto, Ryohei Nagase and Yoo Tanabe*
Received (in Cambridge, UK) 9th November 2007, Accepted 28th November 2007
First published as an Advance Article on the web 14th December 2007
DOI: 10.1039/b717318k
(Table 1).{ The desired phenyl and 4-nitrophenyl 2-butyl-3-
methoxyamino esters 1 and 2 were successfully obtained in 63
and 90% yield, respectively, with high syn-selectivity5 (entries 1, 2).
The stereochemistry (E and Z) of the oxime ethers is speculated to
be of primary importance in this reaction. Surprisingly, the
reaction using PhCH2CH2CHNLOMe with three different E :
Z-ratios produced almost the same results in yield and syn/anti
selectivity (entries 3–5).
The first general method of direct and highly stereoselective Ti-
mediated Mannich reaction between three types of simple esters
and E and Z mixtures of oxime ethers (aliphatic and aromatic)
is accomplished.
The Mannich reaction is well recognized as a fundamental C–C
bond forming reaction for the preparation of useful b-amino
carbonyl compounds and b-lactams.1 Direct methods using simple
esters as nucleophiles are considerably limited compared with
those of ketones because of their lower enolization ability, and in
addition the Mannich reaction generally utilizes relatively unstable
imines for the counter electrophiles.2 Oxime ethers are well-known
superior isosters to imines due to easier preparation and inherently
higher stability, especially for reliable aliphatic aldoximes derived
from enolizable aldehydes. The reaction using oxime ethers,
therefore, has a clear advantage over that of imines, because of its
wide variation. As part of our continuing studies of Ti-Claisen
condensation3 and related reactions,4 we disclose here direct and
stereoselective (syn or anti) Ti-mediated Mannich-type reactions
between three types of esters and methyl oxime ethers (aldoximes
and aryloximes, E and Z mixtures) (Scheme 1). To the best of our
knowledge, this is the first reported general method of a Mannich
reaction between simple esters and oxime ethers.
Thus, O-methyloximes with inherent E : Z-ratios (unnecessary
for any specific separation) can be used for the present method.
Reactions using several O-methyloximes successfully produced the
corresponding b-amino esters 4, 6–11 with high syn-selectivity
(syn : anti = .90 : 10) (entries 6–13), except for cyclohexyl
analogue 5 (syn : anti = 74 : 26) (entry 7). Functionalities such as a
terminal double bond, a furan, and v-chloro groups were tolerated
(entries 6, 9, 11, 13).
With these results in hand, we next investigated the reaction of
several methyl a-alkoxy esters with O-methyloximes because of the
utility of a-hydroxy-b-aminoacids.2a,d Table 2{ lists the successful
results of anti-selective reactions (but not syn) under optimized
conditions.
The initial attempted reaction of methyl methoxyacetate with
CH3(CH2)6CHLNOMe proceeded smoothly to give the desired
The initial attempt was guided by the reaction of phenyl and
4-nitrophenyl hexanoates with the O-methyloxime of 1-octanal
utilizing a TiCl4–sBu2NH reagent,3i because aryl esters have an
advantage over alkyl esters in smoother Ti-enolate formation4e
Table 1 Ti-mediated direct syn-selective Mannich reaction between
aryl esters and O-methyloximesa
Yield
Product (%) syn : antic
Entry R1
R2
E : Zb
1
2
3
4
5
6
n-Bu
n-Oct
n-Oct
PhCH2CH2 .99 : 1
PhCH2CH2 1 : .99
PhCH2CH2 57 : 43
61 : 39
61 : 39
1
2
3
3
3
4
63d
90
81
80
80
85
90 : 10
94 : 6
95 : 5
94 : 5
95 : 5
96 : 4
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CH2L
CH(CH2)8
c-Hex
Ph
2-Furyl
n-Oct
60 : 40
7
8
9
10
11
12
13
a
n-Bu
n-Bu
n-Bu
Me
78 : 22
.99 : 1
78 : 22
61 : 39
61 : 39
5
6
7
8
9
86
74 : 26
84 .99 : 1
61 .99 : 1
57
82
69
74
Scheme 1
90 : 10
95 : 5
90 : 10
97 : 3
b
CH2LCHCH2 n-Oct
PhCH2
Cl(CH2)3
Department of Chemistry, School of Science and Technology, Kwansei
Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
E-mail: tanabe@kwansei.ac.jp; Fax: (+81) 79-565-9077;
Tel: (+81) 79-565-8394
{ Electronic supplementary information (ESI) available: General experi-
mental section and spectroscopic data. See DOI: 10.1039/b717318k
n-Oct
n-Oct
61 : 39 10
61 : 39 11
s
Ester : oxime ether : TiCl4 : Bu2NH = 1.0 : 1.4 : 3.0 : 2.5. E : Z
ratio of O-methyloxime. Determined by 1H NMR of the crude
product. Ar = Ph.
c
d
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Chem. Commun., 2008, 771–773 | 771

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Table 2 Ti-mediated direct anti-selective Mannich reaction between
methyl 2-alkoxy esters and O-methyloximesa
Yield
Product (%) syn : antic
Entry R3
R2
E : Zb
61 : 39
1
Me n-Oct
12
85 2 : 98
(1 : .99)
(51)
(13)d
14
15
16
2
3
4
5
6
7
8
9
a
Bn n-Oct
Ts
Allyl PhCH2CH2
Allyl PhCH2CH2
Allyl PhCH2CH2
Allyl CH2LCH(CH2)8 60 : 40
Allyl n-Oct
Allyl c-Hex
61 : 39
61 : 39
.99 : 1
83 4 : 96
83 9 : 91
81 1 : .99
81 1 : .99
81 1 : .99
78 1 : .99
80 1 : .99
81 1 : .99
b
n-Oct
1 : .99 16
57 : 43
16
17
18
19
61 : 39
61 : 39
s
Ester : Oxime ether : TiCl4 : Bu2NH = 1.0 : 1.4 : 2.0 : 2.5. E : Z
ratio of O-methyloxime. Determined by 1H NMR of the crude
product. Use of O-benzyloxime ether.
c
d
Scheme 2
product 12 in 85% yield with excellent anti-selectivity5 (syn : anti =
2 : 98) (entry 1).
possibility of deprotection into account. Thus, the desired
a-allyloxy-b-methoxyesters 14–19 were produced with almost
complete anti-selectivity (entries 4–9).
Three stereoisomeric substrates of PhCH2CH2CHLNOMe
(E-, Z- and E,Z-mixtures) also produced results similar to that
described in Table 1, entries 4–6. Our attention was focused on the
reaction using methyl allyloxyacetate (R3 = allyl), taking the
Scheme 2 illustrates a couple of proposed mechanisms for the
present switching mode of syn- and anti-selectivities. A basic
working hypothesis is that the TiCl4-coordinated E-oxime ether
Table 3 Reductive Mannich-type addition between methyl 2-bromo-2,2-dialkyl esters and O-methyloximes.a
Entry
a-Bromoester
R2
E : Zb
61 : 39
60 : 40
57 : 43
57 : 43
53 : 47
64 : 36
.99 : 1
98 : 2
Product
Yield (%)
syn : antic
1
2
3
4
5
6
7
8
n-Oct
20
21
22
23
24
25
26
27
28
29
30
31
87
72
71
75
81
91
92
70
80
76
79
59
—
—
—
—
—
—
—
—
—
—
—
—
CH2LCH(CH2)8
PhCH2CH2
(CH3)2CHCH2
Ph(CH3)CHCH2
BnO(CH2)4
Ph
2-Naph
9
m-ClC6H4
p-CF3C6H4
2-thiophenyl
n-Oct
96 : 4
97 : 3
—
10
11
12
61 : 39
13
14
n-Oct
n-Oct
61 : 39
61 : 39
32
33
91
96
54 : 46d
57 : 43d
15
n-Oct
61 : 39
34
60
96 : 4
16
17
18
a
n-Oct
BnO(CH2)4
Ph
61 : 39
64 : 36
.99 : 1
35
36
37
c
79
73
90
85 : 15
85 : 15
96 : 4
Ester : oxime ether : TiCl4 : Ph3P = 1.0 : 1.0 : 2.4 : 1.6. E : Z ratio of O-methyloxime. Determined by 1H NMR of the crude product.
b
d
Syn/anti was not assigned.
772 | Chem. Commun., 2008, 771–773
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O-methyloxime (0.70 mmol) and an methyl alkoxyacetate (0.70 mmol) in
CH2Cl2 (1.5 mL) at 250 to 240 uC under an Ar atmosphere. A similar
work up of Table 1 gave the desired methyl anti-3-(methoxyamino)-2-
alkoxy ester as a major product. (Note: sat. NaHCO3 aqueous solution was
used instead of water to ensure the basicity of the aqueous phase).
General procedure of Table 3: PPh3 (210 mg, 0.80 mmol) in CH2Cl2
(0.5 mL) and TiCl4 (228 mg, 1.2 mmol) were successively added to a
solution of an O-methyloxime (0.50 mmol) and an a,a-dialkyl-a-bromoe-
ster (0.50 mmol) in CH2Cl2 (1.0 mL) at 250 to 40 uC under Ar atmosphere.
A similar work up of Table 1 gave the desired syn-3-(methoxyamino)-2,2-
dialkyl ester as a major product.
has higher content and/or reactivity than the Z-oxime ether in situ.
For a simple aryl ester, Ti-monodendate enolate reacts with an
E-isomer to form the chair transition state (TS) A or B. Due to
double 1,3-diaxial repulsions between R2 and OAr, R1 and OMe
in TS-B, TS-A is preferentially formed to give the syn-adduct. For
a methyl alkoxyacetate, Ti-bidentate enolate forms the boat TS-C
or TS-D. Due to repulsion between R3O and R2, TS-D is
preferentially formed to give the anti-adduct.
As a notable extension, we focused our attention on an
alternative reductive Ti-Mannich reaction utilizing a TiCl4–PPh3
reagent.6 Table 3{ lists the successful results using a couple of
substrates, a,a-dialkyl-a-bromoesters and O-methylaldoximes or
aryloximes. A striking feature is the application to the preparation
of various a,a-dialkylated b-(methoxyamino)esters 20–37, because
these products could not be obtained (no reaction) for the reaction
by the aforementioned TiCl4–sBu2NH method. Note that the use
of a-methyl-c-butyrolactone and a-ethyl-a-phenyl ester analogues
provided good to excellent syn-selectivity (entries 15–18).
The obtained various b-O-methyloxime ester products were
readily converted to the corresponding b-amino esters using Zn–
AcOH reagent under mild conditions with retentive syn or anti
stereochemistry.7
1 For examples: (a) F. F. Blicke, Org. React., 1942, 1, 303; (b)
E. F. Kleinman, in Comprehensive Organic Synthesis, ed. B. M. Trost,
I. Fleming and C. H. Heathcock, Pergamon, Oxford, 1991, vol. 2, p. 893;
(c) M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed.,
1998, 37, 1045; (d) L. Ku¨rti and B. Czako´, Strategic Applications of
Named Reactions in Organic Synthesis, Elsevier, Burlington, 2005, p. 274;
(e) M. B. Smith and J. March, March’s Advanced Organic Chemistry,
Wiley, New York, 6th edn, 2007, p. 1292.
2 (a) J. C. Adrian, Jr., J. L. Barkin, R. J. Fox, J. E. Chick, A. D. Hunter
and R. A. Nicklow, J. Org. Chem., 2000, 65, 6264; (b) S. Saito,
K. Hatanaka and H. Yamamoto, Org. Lett., 2000, 2, 1891; (c) T. P. Tang
and J. A. Ellman, J. Org. Chem., 2002, 7819; (d) A. L. Joffe,
T. M. Thomas and J. C. Adrian, Jr., Tetrahedron Lett., 2004, 45, 5087;
(e) S. Hata, M. Iguchi, T. Iwasawa, K. Yamada and K. Tomioka, Org.
Lett., 2004, 6, 1721; (f) M. Periasamy, S. Suresh and S. S. Ganesan,
Tetrahedron Lett., 2005, 46, 5521; (g) S. Kikuchi, T. Kobayashi and
Y. Hashimoto, Tetrahedron Lett., 2006, 47, 1973.
In conclusion, we developed the first general method for highly
stereoselective Ti-mediated Mannich-type reactions between
readily available esters and oxime ethers to give a variety of
3-(methoxyamino)-2-substituted esters (all new compounds). The
present method provides a new avenue for the synthesis of various
new stereocontrolled b-amino ester derivatives.
3 (a) Y. Tanabe, Bull. Chem. Soc. Jpn., 1989, 62, 1917; (b) R. Hamasaki,
S. Funakoshi, T. Misaki and Y. Tanabe, Tetrahedron, 2000, 56, 7423; (c)
S. N. Crane and E. J. Corey, Org. Lett., 2001, 3, 1395; (d) Y. Tanabe,
R. Hamasaki and S. Funakoshi, Chem. Commun., 2001, 1674; (e)
Y. Tanabe, A. Makita, S. Funakoshi, R. Hamasaki and T. Kawakusu,
Adv. Synth. Catal., 2002, 344, 507; (f) Y. Tanabe, N. Manta, R. Nagase,
T. Misaki, Y. Nishii, M. Sunagawa and A. Sasaki, Adv. Synth. Catal.,
2003, 345, 967; (g) T. Misaki, R. Nagase, K. Matsumoto and
Y. Tanabe, J. Am. Chem. Soc., 2005, 127, 2854; (h) A. Iida,
S. Nakazawa, T. Okabayashi, A. Horii, T. Misaki and Y. Tanabe,
Org. Lett., 2006, 8, 5215; (i) R. Nagase, H. Gotoh, M. Katayama,
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Areas (B) ‘‘18350056’’, Priority Areas
(A) ‘‘17035087’’ and ‘‘18037068’’, and Exploratory Research
‘‘17655045’’ from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT). We thank Dr Tomonori Misaki
(University of Hyogo, Japan) for his helpful discussion.
s
N. Manta and Y. Tanabe, Heterocycles, 2007, 72, 697: Bu2NH was
specially used for the dehydration-type Ti-Claisen condensation as an
effective amine.
4 (a) Y. Tanabe, K. Mitarai, T. Higashi, T. Misaki and Y. Nishii, Chem.
Commun., 2002, 2542; (b) Y. Tanabe, N. Matsumoto, T. Higashi,
T. Misaki, T. Itoh, M. Yamamoto, K. Mitarai and Y. Nishii,
Tetrahedron, 2002, 58, 8269 (Symposium); (c) A. Iida, K. Takai,
T. Okabayashi, T. Misaki and Y. Tanabe, Chem. Commun., 2005,
3171; (d) M. Katayama, R. Nagase, K. Mitarai, T. Misaki and
Y. Tanabe, Synlett, 2006, 129; (e) R. Nagase, N. Matsumoto,
K. Hosomi, T. Higashi, S. Funakoshi, T. Misaki and Y. Tanabe, Org.
Biomol. Chem., 2007, 7, 151.
5 The syn or anti configuration was unambiguously determined on the
basis of vicinal JH coupling values of b-lactams, which were derived from
the obtained b-hydroxymethyl esters (ESI{).
6 A. Iida, S. Nakazawa, H. Nakatsuji, T. Misaki and Y. Tanabe, Chem.
Lett., 2007, 36, 48.
Notes and references
s
{ General procedure of Table 1: TiCl4 (142 mg, 0.75 mmol) and Bu2NH
(100 mg, 0.75 mmol) were successively added to a stirred solution of an
O-methyloxime (0.70 mmol) in CH2Cl2 (1.0 mL) at 278 uC under an Ar
atmosphere. After stirring at the same temperature for 10 min, an ester
(0.50 mmol) in CH2Cl2 (0.5 mL) and TiCl4 (47 mg, 0.25 mmol) was added
to the mixture, followed by being stirred at 250 to 240 uC for 0.5 h.
s
Additional TiCl4 (95 mg, 0.50 mmol) and Bu2NH (65 mg, 0.50 mmol)
were successively added to the mixture. After stirring at the same
temperature for 1.0 h, water was added to the mixture, with stirring,
which was extracted twice with ether. The combined organic phase was
washed with water, brine, dried (Na2SO4) and concentrated. The obtained
crude oil was purified by SiO2-column chromatography to give the desired
aryl syn-3-(methoxyamino)-2-alkylester as a major product.
7 Yields of the b-amino esters from 2, 18 and 28 were 85, 55, and 87%,
respectively. Experimental details are described in ESI.{ For other
methods, see: Comprehensive Organic Transformations, Wiley, New York,
2nd edn, 1999, p. 843.
s
General procedure of Table 2: TiCl4 (190 mg, 1.00 mmol) and Bu2NH
(162 mg, 1.25 mmol) were successively added to a stirred solution of an
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Chem. Commun., 2008, 771–773 | 773