Chemoselective reduction of α-imino carbonyl compounds into α-amino carbonyl compounds with titanium tetraiodide

Article abstract of DOI:10.1246/cl.2001.792

α-Imino carbonyl compounds are chemoselectively reduced with titanium tetraiodide to give α-amino carbonyl compounds in good to excellent yields.

Full text of DOI:10.1246/cl.2001.792

792
Chemistry Letters 2001
Chemoselective Reduction of α-Imino Carbonyl Compounds into α-Amino Carbonyl
Compounds with Titanium Tetraiodide
Makoto Shimizu,* Tetsuya Sahara, and Ryuuichirou Hayakawa
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507
(Received May 25, 2001; CL-010492)
α -Imino carbonyl compounds are chemoselectively
reduced with titanium tetraiodide to give α-amino carbonyl
compounds in good to excellent yields
In connection with exploration into new biologically active
compounds, it is highly desirable to develop ready methods for
the preparation of α-amino carbonyl compounds, since many of
targeted molecules in such field possess amino carbonyl and/or
amino alcohol moieties.1,2 For the introduction of amino groups,
reduction of imines is one of the most accessible methodologies,3
which involve metal borohydride reductions and hydrogenation in
the presence of transition metal catalysts. However, in terms of
chemoselectivity, such reductions have not been carried out readi-
ly in the presence of other functionalities. Among reduction
methodologies reported the use of chlorodibutylstannane or
hypervalent silanes enables the reduction of the imino groups in a
chemoselective manner.4–7 We have recently described that TiI4
is an excellent reagent for the pinacol coupling of aldehyde,8
selective reduction of 1,2-diketones to α-hydroxy ketones,9 that of
sufoxides to sulfides,10 and enolate formation from methoxyallene
oxide.11 We have now found that TiI4 effects the reduction of α-
imino carbonyl compounds 1 in a chemoselective manner to give
α-amino carbonyl derivatives 2 in good yields and wish to report
herein an efficient method for the preparation of α-amino car-
bonyl compounds.
indicating that even in the case of enolizable compounds, the
present method met with moderate success.
Next, we investigated the reduction of iminocarbonyl com-
pounds derived from phenylglyoxal and ethyl glyoxylate, and
results are summarized in Table 2. Although the reduction of
N-anisylimines did not proceed, the N-tosyl counterparts gave
α-amino ketone and ester in good yields. These examples indi-
cate that imines derived from aldehydes need relatively strong
The reduction was carried out as in the cases for 1,2-dike-
tones described earlier. The results of investigation into the
amount of TiI4, solvent, and N-substitient are summarized in
Table 1.12
The reduction using 1.0 equiv of TiI4 gave the α-amino
ketone 4 in 88% (entry 1). The best result was obtained using
2.0 equiv of TiI4 (entry 2). The use of more than 2.0 equiv of
TiI4 in acetonitrile afforded the reduction products in excellent
yields, whereas lower yields were observed using CH2Cl2 or
toluene as a solvent (entries 3–5). Under the optimum condi-
tions, reduction of several N-substitued imines derived from
benzil was carried out. When R was aryl group, the reductions
proceeded in good yields, whereas in the case of the benzyl
derivative, the reaction did not give the desired product (entries
6–9).
As shown below, reduction of the imines derived from
cyclodecane-1,2-dione 5 and camphorquinone 7 gave the corre-
sponding amino ketones in 49 and 55% yields, respectively,
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
793
activation with an electron-withdrawing N-substitutent.
4
I. Shibata, T. Moriuti-Kawakami, D. Tanizawa, T. Suwa,
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Kanematsu, T. Maki, and Y. Matsumura, Tetrahedron
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The following scheme shows a possible reaction pathway.
The present reaction appears to involve an initial attack of
iodide anion at the imino or carbonyl carbon and the subsequent
reaction with another iodide anion effects the formation of enol-
ates species.13 The enolates thus generated are protonated to
give α-amino carbonyl compounds chemoselectively. Another
possible mechanism involves reduction with a low-valent titani-
um species. However, our previous observation that the car-
bonyl next to the aliphatic substituent was more readily reduced
in the presence of the benzylic carbonyl which might be
reduced more readily under one-electron transfer reduction con-
ditions appears to support the above hypothesis.9 We are cur-
rently investigating into the true intermediate in more detail.
5
6
7
8
9
R. Hayakawa and M. Shimizu, Chem. Lett., 2000, 724.
R. Hayakawa, T. Sahara, and M. Shimizu, Tetrahedron
Lett., 41, 7939 (2000).
10 M. Shimizu, K. Shibuya, and R. Hayakawa, Synlett, 2000,
1437.
11 R. Hayakawa and M. Shimizu, Org. Lett., 2, 4079 (2000).
12 A typical procedure (Table 1, Entry 2) is as follows:
Acetonitrile (1.0 mL) was added to TiI4 (263.3 mg, 0.474
mmol) at ambient temperature under an argon atmosphere.
After stirring for 10 min, to the solution of TiI4 was added a
solution of 1,2-diphenyl-2-p-toluenesulfonyliminoethanone
(86.1 mg, 0.237 mmol) in acetonitrile (2 mL) at 0 °C. After
being stirred at 0 °C to room temperature for 21 h, the reac-
tion was quenched with sat. aq NaHCO3 and 10% aq
NaHSO3. 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 con-
centrated in vacuo. Purification by silica gel flash column
chromatography (n-hexane : ethyl acetate = 4 : 1 as an elu-
ent) gave 1,2-diphenyl-2-p-toluenesulfonylaminoethanone
(78.0 mg, 90%) as a colorless oil.
In conclusion, TiI4 reduces imines in the presence of car-
bonyl groups in good to excellent yields. Since titanium
tetraiodide is commercially available and inexpensive, and that
the experimental procedure is quite simple, this method offers a
convenient and practical method for α-amino carbonyl com-
pounds.
13 The reductive formation of the titanium enolate was attest-
ed using 1H NMR studies, and the subsequent reaction with
aldehyde actually gave an aldol product.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan.
References and Notes
1
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2
3
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