Aza-Reformatsky-type reaction of α-iodomethyl ketone O-alkyl oximes promoted by titanium tetraiodide

Article abstract of DOI:10.1039/b411127c

An aza-Reformatsky-type reaction of α-iodomethyl ketone O-alkyl oximes was investigated. Simple oximes gave the addition products in poor to moderate yields. The corresponding O-methyl oxime gave an excellent result with 3-phenylpropanal, where the adduct was obtained in 91% yield, while the reaction with cinnamaldehyde gave a poor result. The TiI₄ promoted the reaction of α-iodomethyl ketone O-alkyl oximes with aldehyde to give aza-aldol products in good to excellent yields, where the reductive formation of Ti aza-enolate without the use of low valent metal species is noteworthy.

Full text of DOI:10.1039/b411127c

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C O M M U N I C A T I O N
Aza-Reformatsky-type reaction of a-iodomethyl ketone O-alkyl
oximes promoted by titanium tetraiodide
Makoto Shimizu* and Tadahiro Toyoda
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan.
E-mail: mshimizu@chem.mie-u.ac.jp; Fax: +81 59 231 9413
Received 23rd July 2004, Accepted 3rd September 2004
First published as an Advance Article on the web 16th September 2004
Titanium tetraiodide promotes an aza-Reformatsky-type
reaction of a-iodomethyl ketone O-alkyl oximes with carbonyl
compounds to give b-hydroxy ketone O-alkyl oximes in good to
high yields
Scheme 2
Since the introduction of metallo-enamines (aza-enolate) by the
groups of Stork,1e,f Wittig,1g and Corey,1h,i the power of these
species has eliminated several drawbacks associated with the
alkylation of enolates.1 Aza-enolates are usually generated by
deprotonation of the parent imino species with strong bases.
Although reductive generation of enolates form a-halo carbonyl
compounds has eliminated some drawbacks as exemplified in the
Reformatsky-type reactions, e.g. the reaction can be conducted
in the absence of strong bases, the generation of aze-enolate
via the reduction of a-halo imino species2 has received little
attention. We have already reported a Reformatsky-type reac-
tion using TiI4 as a reducing reagent for a-iodo ketones.3 In
that reaction, the reducing ability and the Lewis acid character
of TiI4 effectively promoted the addition reaction of a-iodo
ketones to carbonyl compounds [see reaction (1) in Scheme 1].
We have now found that TiI4 also promotes the aza-analogue
of this type of reaction in an efficient manner to give b-hydroxy
imino compounds in good to excellent yields [reaction (2) in
Scheme 1]. This paper reports an aza-Reformatsky-type reac-
tion of a-iodomethyl ketone O-alkyl oximes.
result, where the adduct was obtained in 50% yield. Better
results were obtained, when the reaction was carried out with O-
benzyl oximes. Although, the reductive formation of the enolate
from the chloro derivative did not proceed, the iodo counterpart
gave good yields of the aza-aldol product, where no Beckmann
rearrangement was observed. Under the optimum conditions a
variety of a-iodomethyl ketone O-alkyl oximes and aldehydes
were subjected to the present aza-aldol reactions, and Table 2
summarizes the results.†
In the cases with the O-benzyl oxime derived from iodo-
acetone, the reductive aza-aldol reaction proceeded with
aromatic, a,b-unsaturated, and primary aliphatic aldehydes to
give the adducts in good yields, whereas secondary aliphatic
aldehydes were not good acceptors for the present reaction. The
O-benzyl oxime derived from a-iodoacetophenone underwent
similar addition reactions to give the adducts in good yields
except for the case with 3-phenylpropanal. Interestingly, the
corresponding O-methyl oxime gave an excellent result with
3-phenylpropanal, where the adduct was obtained in 91% yield,
while the reaction with cinnamaldehyde gave a poor result. Thus,
the O-methyl and O-benzyl oximes compensate each other in the
cases with cinnamaldehyde and 3-phenylpropanal.
The present reductive aza-aldol reaction has the following
limitations: (1) ketones such as acetone 11 cannot be used as the
acceptor; (2) aza-enolates cannot be generated under the pres-
ent conditions from a-halo ketone O-alkyl oximes derived from
secondary halo derivatives such as 7–10 (Fig. 1).
Scheme 1
We have recently found that TiI4 is an excellent reagent for
the reduction of a-diketones and/or sulfoxides, and that it also
induces the ring-opening aldol reaction of methoxyallene oxide
and pinacol coupling of aldehyhdes.4 In these reactions Ti(IV)
was thought to be responsible for such facile reductions. In par-
ticular, the ability of the iodide ion to displace the iodine a to
the carbonyl appears to enable the facile aldol-type reaction of
methoxyallene oxide and a-iodo ketones recently published,3,4e,f
and therefore, we focused on the applicability of titanium iodide
to the formation of aza-enolates from a-iodo imine derivatives
and subsequent addition reactions.
We initially examined the reducing ability of titanium tetra-
iodide using the reduction of iodoacetone O-benzyl oxime.
Treatment of iodoacetone O-benzyl oxime with TiI4 (1.2 equiv.)
in propionitrile at −78 to −60 °C for 1 h gave cleanly the
reduction product, acetone O-benzyl oxime, in quantitative yield
as shown in Scheme 2. Encouraged with this result, we carried
out the reductive aza-aldol reaction using a-halomethyl ketone
O-alkyl oximes, and Table 1 summarizes the results.
Fig. 1
Although there are several arguments on the reactive speceis,
the present reaction most probably proceeds as follows: TiI4
reduces a-iodomethyl O-alkyl oxime to form Ti-aza-enolate 12
via the attack of idodide anion to the iodine. The formation of
the metal enolate via attack of an iodide anion has been well
precedented.6 Subsequent reaction with aldehyde gives the aldol
adduct (Scheme 3).
In conclusion, although a-halogenated imino compounds have
been used as the protected derivatives of the parent carbonyl
compounds for selective functional group transformations at the
carbons bearing halogens,2 the present study demonstrates the
utility of such compounds for excellent precursors to aza-enolates.
Thus, TiI4 promoted the reaction of a-iodomethyl ketone O-alkyl
oximes with aldehyde to give aza-aldol products in good to excel-
lent yields, where the reductive formation of Ti aza-enolate with-
out the use of low valent metal species is noteworthy.
As can be seen from Table 1, simple oximes gave the addi-
tion products in poor to moderate yields. In particular, among
the halogens screened the bromine derivative recorded the best
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 9 1 – 2 8 9 2
2 8 9 1

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a
Table 1 Reaction of a-halomethyl ketone oximes or O-alkyl derivatives 4 with 4-chlorobenzaldehyde in the presence of TiX4
Entry
4/equiv.
X
R
TiI4/equiv.
5/equiv.
Temp./°C
6 (%)b
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.5
1.5
2.5
Cl
Br
I
Cl
Br
I
I
I
I
I
H
H
H
2.5
2.5
2.5
2.5
2.5
2.5
1.2
2.5
2.5
2.5
2.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.0
ca. 0–rt
ca. 0–rt
ca. 0–rt
20
50
18
0
25
66
36
40
48
66
50
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
ca. −78 to −60
10
11
I
a The reaction was carried out according to the typical experimental procedure.5 b Isolated yield.
1
(a) D. E. Bergbreiter, in Asymmetric Synthesis, J. D. Morrison,
ed., Academic Press, New York, 1983, vol. 2, part A, pp. 243–273;
Table 2 Reaction of a-iodomethyl ketone O-alkyl oximes 1 with
a
aldehydes in the presence of TiX4
(b) M. E. Kuehne, in Enamines:
A Synthesis, Structure, and
Reactions, G. A. Cook, ed., Marcel Dekker, New York, 1969, pp.
314–468; (c) P. W. Hickmott, Tetrahedron, 1982, 38, 1975–2050;
(d) P. W. Hickmott, Tetrahedron, 1982, 38, 3363–3446; (e) G. Stork,
A. Brizzolara, H. Landesman, J. Szmuskovicz and R. Terrell, J.
Am. Chem. Soc., 1963, 85, 207; ( f ) G. Stork and S. R. Dowd, J.
Am. Chem. Soc., 1963, 85, 2178; (g) G. Wittig, H. D. Frommeld
and P. Suchanek, Angew. Chem., 1963, 78, 978; (h) E. J. Corey and
D. Enders, Tetrahedron Lett., 1975, 3; (i) E. J. Corey and D. Enders,
Chem. Ber., 1978, 111, 1337; ( j) W. G. Kofron and M.-K. Yeh,
J. Org. Chem., 1976, 41, 439; (k) A. Q. Hussein, A. A. Jarrar and
A. S. Madi, Heterocycles, 1989, 29, 1681; (l) S. Shatzmiller and B.-Z.
Dolitzki, Liebigs Ann. Chem., 1991, 189; (m) M. Ortiz-Marciales,
M. De Jesus, L. Quinones, D. Figueroa, Y. L. Montes, C. Burgos
and B. Moctezuma, Tetrahedron, 1999, 55, 12275.
For the preparation of a-halogenated imines, see: N. de Kimpe,
R. Verhe, L. de Buyck, L. Moens and N. Schamp, Synthesis, 1982,
43; N. de Kimpe, W. de Cock and C. Stevens, Tetrahedron, 1992, 48,
2739.
M. Shimizu, F. Kobayashi and R. Hayakawa, Tetrahedron, 2001, 57,
9591.
(a) M. Shimizu, H. Goto and R. Hayakawa, Org. Lett., 2002,
4, 4097; (b) M. Shimizu and T. Sahara, Chem. Lett., 2002, 888;
(c) M. Shimizu, Y. Takeuchi and T. Sahara, Chem. Lett., 2001, 1196;
(d) M. Shimizu, T. Sahara and R. Hayakawa, Chem. Lett., 2001,
792; (e) R. Hayakawa, H. Makino and M. Shimizu, Chem. Lett.,
2001, 756; ( f ) R. Hayakawa and M. Shimizu, Org. Lett., 2000, 2,
4079; (g) R. Hayakawa, T. Sahara and M. Shimizu, Tetrahedron
Lett., 2000, 41, 7939; (h) M. Shimizu, K. Shibuya and R. Hayakawa,
Synlett., 2000, 1437; (i) R. Hayakawa and M. Shimizu, Chem. Lett.,
2000, 724.
Entry
R1
R2
R3
3 (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Ph
54
87
88
49
73
74
53
0
2-ClC6H4
3-ClC6H4
4-MeC6H4
4-MeOC6H4
(E)-PhCHCH
PhCH2CH2
cyclo-Hex
i-Pr
2
0
Ph
83
61
69
95
7
82
86
90
8
4-ClC6H4
4-MeOC6H4
(E)-PhCHCH
PhCH2CH2
Ph
4-ClC6H4
4-MeOC6H4
(E)-PhCHCH
PhCH2CH2
3
4
Ph
Ph
Ph
Ph
Ph
91
a The reaction was carried out according to the typical experimental
procedure.5 b Isolated yield.
5
A typical procedure for the reaction of an a-halomethyl ketone O-
alkyl oximes and a carbonyl compound in the presence of titanium
tetraiodide is as follows. To a solution of titanium tetraiodide
(139 mg, 0.25 mmol) in propionitrile (1.0 mL) was added a solu-
tion of 2-benzyloxyimino-1-iodopropane (57.8 mg, 0.2 mmol) in
propionitrile (1.0 mL) at −78 °C under an argon atmosphere. After
stirring, to the resulting solution was added a propionitrile (1.0 mL)
solution of 3-chlorobenzaldehyde (14.1 mg, 0.10 mmol) at −78 °C.
The reaction mixture was allowed to warm to −50 °C. After 1.5 h,
the reaction was quenched with saturated aq. NaHCO3 (10 mL),
and 10% aq. NaHSO3 and ethyl acetate were added successively.
The mixture was filtered through a Celite pad, and extracted with
ethyl acetate (10 mL × 3). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification on
preparative silica-gel TLC (n-hexane–ethyl acetate = 3:1 as eluent)
gave 3-benzyloxyimino-1-(3-chlorophenyl)butan-1-ol 3 (R1 = Me,
R2 = Bn, R3 = 3-ClC6H4) (20.3 mg, 88%) as a colorless oil.
C. Rener, W. Huayue and Z. Yongmin, J. Chem. Res. (S), 1999,
666; T. Tsuritani, S. Ito, H. Shinokubo and K. Oshima, J. Org.
Chem., 2000, 65, 5066; K. Maeda, H. Shinokubo and K. Oshima,
J. Org. Chem., 1998, 63, 4558; M. Z. Liu, Z. W. Guo and Y. Z. Hui,
Youji Huaxue, 1997, 17, 319; R. Lin, L. Chen and Y. Zhang, Youji
Huaxue, 1990, 10, 454; H. N. Borah, R. C. Boruah and J. S. Sandhu,
J. Chem. Soc., Chem. Commun., 1991, 154; S. Fukuzawa, T. Tsuruta,
T. Fujinami and S. Sakai, J. Chem. Soc., Perkin Trans 1, 1987,
1473.
Scheme 3
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, of the Japanese Government.
6
Notes and references
† a-Iodomethyl ketone O-alkyl oximes were usually obtained as
mixtures of (E)- and (Z)-isomers in ratios varing from 10:1 to ca. 2:1
where (E)-isomers predominated. The reactions were carried out using
these mixtures.
2 8 9 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 9 1 – 2 8 9 2