Remarkable effects of additives to facilitate aza-Mannich type reaction: A rapid access to β-amino ketone O-alkyl oximes

Article abstract of DOI:10.1055/s-2006-944220

Aza-Mannich-type reaction proceeded between imines and the aza-enolates formed from α-iodomethyl ketone O-alkyl oximes with titanium tetraiodide to give β-amino ketone O-alkyl oximes in good to excellent yields. Remarkable effects of added silica gel or m

Full text of DOI:10.1055/s-2006-944220

LETTER
1687
Remarkable Effects of Additives to Facilitate Aza-Mannich Type Reaction:
A Rapid Access to b-Amino Ketone O-Alkyl Oximes
Synethesisof
b
-Amino
a
Ketone
O
-
k
A
lkyl Oxime
o
s
to Shimizu,* Mitsue Tanaka, Tomohiro Itoh, Iwao Hachiya
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Fax +81(59)2319413; E-mail: mshimizu@chem.mie-u.ac.jp
Received 14 March 2006
However, since the product yields were not satisfactory,
Abstract: Aza-Mannich-type reaction proceeded between imines
and the aza-enolates formed from a-iodomethyl ketone O-alkyl
oximes with titanium tetraiodide to give b-amino ketone O-alkyl
oximes in good to excellent yields. Remarkable effects of added
silica gel or molecular sieves (4 Å) were observed to promote the
addition reactions.
the effects of additives, solvents, and Ti(IV) species were
examined in detail to improve them, and Table 1 summa-
rizes the results.
a
Table 1 Aza-Mannich-Type Reaction Promoted by TiI4–Ti(OR)4
TiI4-Ti(OR)4 (2.5 equiv)
Key words: aza-Mannich-type reaction, titanium tetraiodide, iodo-
acetone O-benzyl oxime, b-amino ketone O-alkyl oximes
PMP
OBn
I
PMP
OBn
N
N
Additive
NH
N
+
12 h
Ph
H
Ph
1a
(2.5 equiv)
(PMP = p-MeOC6H4)
3a
Reductive formation of aza-enolates has enabled a rapid
access to b-hydroxy imino derivatives under non-basic
conditions, when the enolates are used for the Refor-
matsky-type additions.1 Metallo-enamines (aza-enolates)
are useful enolate derivatives which enhance the nucleo-
philicity as compared with their parent carbonyl com-
pounds.2 For the preparation of such an aza-enolate, we
have introduced reductive formation from a-iodomethyl
ketone O-alkyl oximes with titanium tetraiodide, which
eliminates use of strong bases for the deprotonation.3
However, difficulties were encountered when the aza-
enolate generated as above was subjected to the reaction
with imines, where low addition product yields were often
obtained. We have now found intriguing synergetic ef-
fects of titanium tetraiodide and silica gel or molecular
sieves to promote addition reaction of titanium aza-eno-
lates with imines.
(Z)-2
Entry R
TiI4:
Ti(OR)4
Additiveb Solvent Temp.
(°C)
Yield
(%)c
1
2
–
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
3:1
1:1
1:3
1:1
1:1
None
4 Å MS
Al2O3
Celite®
SiO2
THF
THF
THF
THF
THF
DME
Et2O
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–55 to r.t.
–78 to r.t.
35
43
54
57
69
25
0
–
3
–
4
–
5
–
6
–
SiO2
7
–
SiO2
8
–
SiO2
CH2Cl2 –78 to r.t.
MeCN –45 to r.t.
0
9
–
SiO2
0
The initial reaction was carried out using the addition
10
–
SiO2
EtCN
THF
THF
THF
THF
THF
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
7
reaction of (E)- or (Z)-iodoacetone O-benzyl oxime (2)4
with N-benzylidene-4-methoxyphenylamine (1a) in the 11
presence of TiI4. As can be seen from Scheme 1, (Z)-2
gave better product yield than the corresponding E-iso-
mer.
i-Pr
i-Pr
i-Pr
Et
n-Bu
SiO2
81
94
32
61
25
12
SiO2
13
14
15
SiO2
SiO2
PMP
Ph
OBn
PMP
OBn
I
NH
N
N
N
SiO2
TiI4 (2.5 equiv)
+
a The reaction was carried out according to the typical experimental
Ph
H
THF, –78 °C to r.t., 12 h
procedure.5
3a
(2.5 equiv)
(PMP = p-MeOC6H4)
b Additive (300 mg/mmol) was used.
c Isolated yield.
1a
2
Geometry of 2 = (E): 15% yield
(Z): 35% yield
As shown in Table 1, the additives examined here all
improved the product yields, and among them silica gel
was proved to be the most effective, giving the adduct 3a
in 69% yield (entries 2–5).6 Regarding the solvent, diethyl
ether, dichloromethane, and acetonitrile did not give the
desired adduct at all (entries 7–9). Although the product
Scheme 1 Influence of the geometry of the oxime ether
SYNLETT 2006, No. 11, pp 1687–1690
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944220; Art ID: U02606ST
© Georg Thieme Verlag Stuttgart · New York

1688
M. Shimizu et al.
LETTER
yields were not too bad in THF, a by-product always ac- 1–4). The present addition reaction appears to be sensitive
companied arising from the ring-opening iodination of to the steric bulk of the imines, and cyclohexyl and tert-
THF with titanium tetraiodide.7 In an effort to eliminate butyl derivatives recorded slightly decreased product
such a by-product formation, modification of the titanium yields (entries 5 and 6). While the cinnamylidene imine
species was examined. The presence of titanium tetra- was not a good substrate for the present aza-aldol reaction
alkoxide considerably altered the efficiency of the reduc- in which the hydrolyzed parent cinnamaldehyde was
tive enolate formation and improved the product yields recovered after work-up, its chlorinated derivative served
(entries 11–15). Among the titanium tetraalkoxides exam- as a good acceptor to give the adduct in moderate yield
ined, the tetraisopropoxide worked most effectively (entries 7–9).8 In the cases with the alkynyl derivatives,
(entries 11–13). The ratio of the teteraiodide to the tetra- the presence of titanium tetraisopropoxide was not neces-
isopropoxide was crucial, and the best result was obtained sary, but the use of titanium tetraiodide itself in the pres-
using a 1:1 mixture (entry 12). Use of the tetraethoxide ence of 4 Å MS effected the addition reaction to give the
and the tetra-n-butoxide was not effective (entries 14 and adduct 3 in good yield (entries 10–12). In contrast to their
15). Under the best conditions found for the formation of benzylidene analogues, the 2-methoxy, 2,4-dimethoxy,
the adduct 3a, a variety of imines were subjected to the and 4-chlorophenyl derivatives were not good substrates
addition reaction with (Z)-iodoacetone O-benzyl oxime as the electrophile (entries 11, 13, 14, and 15).
(2), and Table 2 summarizes the results.
Regarding the reaction mechanism, Scheme 2 may ex-
As shown in Table 2, the N-benzylidenearylamines exam- plain a possible reaction pathway.
ined here gave the adducts in good yields, whereas their
tert-butylimino derivative did not give the adduct (entries
OBn
N
I
TiI2(OiPr)2
1/2 TiI4 + 1/2 Ti(OiPr)4
Table 2 Aza-Mannich-Type Reaction of the Oxime Ether 2 with
Various Iminesa
4
R2
H
TiI4 (1.25 equiv)
N
Ti(OiPr)4 (1.25 equiv)
I
(iPrO)2ITi
R2
R1
R2
H
OBn
OBn
N
(iPrO)2ITi
OBn
N
SiO2 (300 mg/mmol)
NH
N
R1
OBn
I
N
–I2
+
1
N
I
THF, –78 °C to r.t.
12 h
R1
SiO2
(2.5 equiv)
1
5
3
(Z)-2
R2
R1
-O-Si-O-Si-O-
OBn
Entry
1
R1
R2
Yield (%)b
NH
N
OH
O
R2
H
N
Ph
Ph
Ph
Ph
Cy
2-MeOC6H4
88
75
89
0
3
OBn
R1
2
2,4-(MeO)2C6H3
N
TiI(OiPr)2
3
4-ClC6H4
t-Bu
Scheme 2 A possible reaction pathway
4
5
PMP
72
48
0
First, a 1:1 mixture of titanium tetraiodide and titanium
tetraisopropoxide may generate TiI2(Oi-Pr)2 species 4,9
which in turn effects the formation of the titanium enolate
5 from iodoacetone O-benzyl oxime (2). Addition of this
enolate is facilitated by the activation of the imine 1 on the
silica gel surface to give the aza-Mannich type adduct 3.
Thus, the synergetic effect of the titanium species to form
the titanium enolate and the silica gel surface to activate
the imine may be responsible for the success of the present
aza-Mannich type reaction.10
6
t-Bu
PMP
7c
(E)-PhCH=CH
(Z)-PhCH=CCl
(Z)-PhCH=CCl
PhC≡C
PMP
8c
PMP
47
65
75
84
72
14
53
16
9
PMP
10c
11c,d
12
13c,d
14c,d
15c,d
PMP
PhC≡C
PMP
In conclusion, we have found that the use of silica gel or
molecular sieves is very convenient to facilitate the addi-
tion of the titanium aza-enolates with imines, forming b-
amino imines that are important synthetic intermediates
for a variety of 1,3-diamines of biological importance.11
PhC≡C
PMP
PhC≡C
2-MeOC6H4
2,4-(MeO)2C6H3
4-ClC6H4
PhC≡C
PhC≡C
a The reaction was carried out according to the typical experimental
procedure.5
Acknowledgment
b Isolated yield.
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
c TiI4 (2.5 equiv) was used in place of TiI4–Ti(Oi-Pr)4.
d 4 Å MS (300 mg/mmol) were used in place of SiO2.
Synlett 2006, No. 11, 1687–1690 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Ketone O-Alkyl Oximes
1689
concentrated in vacuo. Purification on preparative silica gel
TLC (n-hexane–EtOAc = 4:1 as an eluent) gave 4-[N-(4-
methoxyphenyl)amino]-4-phenyl-2-butanone-O-benzyl
oxime (3a, 35.4 mg, 94%) as a pale brown oil. 1H NMR (270
MHz, CDCl3): d = 1.70 (s, 3 H), 2.41 (dd, J = 5.3, 13.1 Hz,
1 H), 3.20 (dd, J = 8.9, 13.1 Hz, 1H), 3.66 (s, 3 H), 4.30 (br
s, 1 H), 4.51 (dd, J = 5.3, 8.9 Hz, 1 H), 5.11 (d, J = 12.2 Hz,
1 H), 5.17 (d, J = 12.2 Hz, 1 H), 6.26–6.30 (m, 2 H), 6.57–
6.62 (m, 2 H), 7.22–7.46 (m, 10 H). 13C NMR (67.8 MHz,
CDCl3): d = 20.7, 38.8, 55.7, 56.6, 75.8, 114.2, 114.6, 126.2,
127.3, 128.0, 128.4, 128.5, 128.7, 137.7, 141.3, 143.4,
151.7, 156.0.
References and Notes
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Organomet. Chem. Rev. A 1972, 8, 183. (d) Harada, T.;
Mukaiyama, T. Chem. Lett. 1982, 161. (e) Kagoshima, H.;
Hashimoto, Y.; Oguro, D.; Saigo, K. J. Org. Chem. 1998, 63,
691. (f) Borah, H. N.; Boruah, R. C.; Sandhu, J. S. Chem.
Commun. 1991, 154. (g) Fukuzawa, S.; Matsuzaka, H.;
Yoshimitsu, S. J. Org. Chem. 2000, 65, 1702.
(h) Kagayama, A.; Igarashi, K.; Shiina, I.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 2000, 73, 2579.
(2) (a) Fustero, S.; Torre, M. G.; Pina, B.; Fuentes, A. S. J. Org.
Chem. 1999, 64, 5551. (b) Nakamura, E.; Kubota, K.;
Sakata, G. J. Am. Chem. Soc. 1997, 119, 5457. (c) Capriati,
V.; Florio, S.; Luisi, R. Eur. J. Org. Chem. 2001, 2035.
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H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905.
(3) (a) Shimizu, M.; Toyoda, T. Org. Biomol. Chem. 2004, 2,
2891. (b) Shimizu, M.; Kobayashi, F.; Hayakawa, R.
Tetrahedron 2001, 57, 9591. (c) Shimizu, M.; Takeuchi, Y.;
Sahara, T. Chem. Lett. 2001, 1196. (d) Shimizu, M.;
Inayoshi, K.; Sahara, T. Org. Biomol. Chem. 2005, 3, 2237.
(e) Shimizu, M.; Sahara, T. Chem. Lett. 2002, 888.
(6) (a) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishizawa,
H. J. Org. Chem. 1996, 61, 984. (b) Veselovsky, V. V.;
Gybin, A. S.; Lozanova, A. V.; Moiseenkov, A. M.; Smit,
W. A. Tetrahedron Lett. 1988, 29, 175. (c) Weinstein, R.
D.; Renslo, A. R.; Danheiser, R. L.; Tester, J. W. J. Phys.
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(7) (a) 4-Iodobutanol was obtained from the reaction of THF
with TiI4 (Scheme 3). Confer: (b) Breen, C. C. B.; Bautista,
M. T.; Schauer, C. K.; White, P. S. J. Am. Chem. Soc. 2000,
122, 3952. (c) Dufour, P.; Dartiguenave, M.; Dartiguenave,
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(f) Hayakawa, R.; Shimizu, M. Org. Lett. 2000, 2, 4079.
(4) To a solution of O-benzylhydroxylamine hydrochloride
(2.07 g, 13.0 mmol) in H2O (30.0 mL) was added
I
I
TiI3
+
TiI4
O
O
O
O
TiI3
chloroacetone (0.79 mL, 10.0 mmol) and NaHCO3 (0.84 g,
10.0 mmol) at ambient temperature for 5.0 h. Then, the
mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried over anhyd Na2SO4
and concentrated in vacuo to give chloroacetone O-benzyl
oxime (2.08 g, quant., E/Z-mixture) as a colorless oil. Under
an argon atmosphere, to a solution of chloroacetone O-
benzyl oxime (2.00 g, 10.1 mmol) in acetone (30.0 mL) was
added a NaI (2.11 g, 14.1 mmol) at ambient temperature for
14.5 h. The mixture was filtered through a Celite® pad, and
extracted with Et2O (3 × 10 mL). The organic phase was
washed with 10% aq NaHSO3, dried over anhyd Na2SO4,
and concentrated in vacuo. Purification by silica gel column
chromatography (n-hexane–EtOAc = 30:1) gave
H+
TiI4-n
I
I
OH
n
Scheme 3
(8) (a) Shimizu, M.; Goto, H.; Hayakawa, R. Org. Lett. 2002, 4,
4097. (b) Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.;
Maruoka, K. Org. Biomol. Chem. 2004, 2, 3312.
(c) Brocchini, S. J.; Eberle, M.; Lawton, R. G. J. Am. Chem.
Soc. 1988, 110, 5211.
iodoacetone O-benzyl oxime (2, 1.90 g, 65%, E:Z = 23:77,
E-isomer: Rf = 0.23; Z-isomer: Rf = 0.29) as a pale brown oil.
E-Isomer: 1H NMR (500 MHz, CDCl3): d = 2.03 (s, 3 H),
3.87 (s, 2 H), 5.15 (s, 2 H), 7.28–7.38 (m, 5 H). 13C NMR
(125.7 MHz, CDCl3): d = 6.0, 13.9, 76.0, 127.9, 128.0,
128.4, 137.6, 154.6. Z-Isomer: 1H NMR (500 MHz, CDCl3):
d = 2.34 (s, 3 H), 3.91 (s, 2 H), 5.10 (s, 2 H), 7.26-7.40 (m, 5
H). 13C NMR (125.7 MHz, CDCl3): d = –7.2, 18.5, 76.0,
127.8, 127.9, 128.3, 137.7, 153.5.
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(10) (a) The formation of the following species 6, 7 may be
excluded. See: Fraile, J. M.; Garcia, J.; Mayoral, J. A.;
Proietti, M. G.; Grazia, M.; Sanchez, M. C. J. Phys. Chem.
1996, 100, 19484. (b) Although there are several arguments
on the role of silica gel, e. g., scavenger of iodine or water,
its acidity may be responsible as part of the imine activation
on the surface (Scheme 4).6
(5) To a solution of TiI4 (69.4 mg, 0.125 mmol) and titanium
tetraisopropoxide (0.125 mL, 0.125 mmol, 1.0 M in CH2Cl2)
in THF (1.0 mL) was added a solution of (Z)-iodoacetone O-
benzyl oxime (2, 72.2 mg, 0.250 mmol) in THF (1.0 mL) at
0 °C under an argon atmosphere. After 30 min stirring, to the
resulting solution was added a THF (1.0 mL) solution of N-
benzylidene-4-methoxyphenylamine (1a, 21.1 mg, 0.100
mmol) and silica gel (dried, 300 mg/mmol) at –78 °C. The
mixture was allowed to warm to ambient temperature with
stirring for 12.0 h. The reaction was quenched with sat. aq
NaHCO3, and EtOAc and 10% aq NaHSO3 were added
successively. The mixture was filtered through a Celite®
pad, and extracted with EtOAc (3 × 10 mL). The combined
organic extracts were dried over anhyd Na2SO4 and
-O-Si-O-Si-O-
-O-Si-O-Si-O-
O
O
O
O
Ti
Ti
iPrO OiPr
I
I
6
7
Scheme 4
Synlett 2006, No. 11, 1687–1690 © Thieme Stuttgart · New York

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M. Shimizu et al.
LETTER
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Synlett 2006, No. 11, 1687–1690 © Thieme Stuttgart · New York