Reductive deamination of α-amino carbonyl compounds by means of samarium iodide

Article abstract of DOI:10.1039/a903073e

Reaction of α-amino carbonyl compounds with SmI₂ in THF-HMPA in the presence of a proton source afforded the deamination products, where the fragmentation occurred between the nitrogen and the carbon α to the carbonyl group.

Full text of DOI:10.1039/a903073e

Reductive deamination of a-amino carbonyl compounds by means of
samarium iodide
Toshio Honda* and Fumihiro Ishikawa
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8051, Japan.
E-mail: honda@hoshi.ac.jp
Received (in Cambridge, UK) 19th April 1999, Accepted 4th May 1999
Table 1 Reductive deamination of phenylalanine derivativesa
Reaction of a-amino carbonyl compounds with SmI2 in
THF–HMPA in the presence of a proton source afforded the
R1
CO2Me
deamination products, where the fragmentation occurred
Ph
N
between the nitrogen and the carbon a to the carbonyl
MeO2C
R2
Ph
group.
R1
R2
Proton source
Reaction time
Yield (%)
SmI2 was firstly, introduced as a useful synthetic tool in organic
synthesis by Kagan and co-workers,1 and thereafter, this reagent
rapidly became an established reagent for developing a variety
of useful and unique transformations.2 Although much effort
has been devoted to studying the reductive deoxygenation of a-
hydroxy or a-alkoxy carbonyl compounds employing SmI2 as a
powerful one-electron reducing reagent, its application to the
deamination of a-amino carbonyl compounds has received
relatively little attention. Attractive examples of the reductive
deamination reaction were reported by Molander and Stengel
using 2-acylaziridines and 4-acylazetidin-2-one as starting
materials [eqn. (1)],3 where the leaving amino groups were
H
H
H
H
Me
Bn
H
H
H
MeOH
Pivalic acid
MeOH
MeOH
MeOH
30 min
15 min
30 min
2.5 h
< 5 min
4 h
73
80
71
85
90
93
99
Me
Bn
Me
Bn
Ac
MeOH
MeOH
15 min
a
Reaction conditions: starting material (0.5 mmol); SmI2 (5 equiv.);
HMPA (5 equiv.); proton soruce (2.5 equiv.); solvent (THF); 0 °C to room
temperature.
of an a-amino ester (0.5 mmol) in THF (10 cm3) at 0 °C, and the
resulting solution was allowed to warm to room temperature. A
stream of air was bubbled through the solution, and an excess of
Celite in Et2O and saturated aqueous NaHCO3 (2 cm3) were
added. The solution was filtered and the filtrate was washed
with brine. The organic layer was separated, dried and
evaported to give a residue, which was subjected to column
chromatography on silica gel.
O
O
Sml2
(1)
THF, proton source
R
TsHN
R
TsN
R = Me, OEt
involved in highly strained three- or four-membered rings.
Similar SmI2-promoted carbon–nitrogen bond cleavage reac-
tions were also employed in the reductive removal of an N-
substituted benzotriazolyl group,4 and in the isonitrile–nitrile
rearrangement.5
In continuation of our work on the synthesis of biologically
active natural products using SmI2,6 we were interested in
researching a general deamination reaction of a-amino carbonyl
compounds [eqn. (2)], and here report our successful results
The reactions of proline derivatives8 (Table 2) and ethyl
pipecolinate derivatives9 (Table 3), where the leaving amino
groups were involved in the cyclic systems, under the same
reaction conditions as above gave the corresponding deamina-
tion products in good yields. The deamination could be applied
not only to a-amino esters but also to a-amino ketones. Thus,
treatment of a-acetylpiperidine derivatives10 with SmI2 also
Table 2 Reductive deamination of proline derivativesa
Sml2
R
R
(2)
N
THF, proton source
P
Proton
source
Reaction Yield
NHP
O
O
Starting material
Product
time
(%)
P = alkyl, acyl
R = alkyl, OR′
MeOH
Pivalic acid
30 min
10 min
62
73
CO2Me
N
H
N
O
concerning systematic investigation of SmI2-promoted re-
ductive deamination.
H
TBDMSO
TBDMSO
Initially, we applied the SmI2-promoted deamination reaction
to phenylalanine derivatives,7 and the results obtained are
summarised in Table 1. Based on the results, it was concluded
that reductive deamination with SmI2 is applicable to the wide
variety of amino functions including primary, secondary and
tertiary amines, and also amide groups. The deamination
usually took place within 30 min in the presence of a proton
source, such as MeOH or pivalic acid, to give methyl
dihydrocinnamate in high yields, although a relatively pro-
longed reaction time was required in the case of benzyl-
substituted amines as leaving groups. The reductive deamina-
tion was typically carried out as follows: a solution of SmI2 (2.5
mmol) and HMPA (2.5 mmol) in THF (12 cm3) and a solution
of proton source (MeOH or pivalic acid, 1.25 mmol) in THF
(5 cm2) were successively added dropwise to a stirred solution
CO2Pri
CO2Me
MeOH
MeOH
1.5 h
9 h
88
82
H2N
N
H
CO2Pri
CO2Me
BnHN
N
Bn
TBDMSO
TBDMSO
BnHN
MeOH
7.5 h
99
CO2Pri
N
CO2Pri
Bn
a Reaction conditions: starting material (0.5 mmol); SmI2 (5 equiv.); HMPA
(5 equiv.); proton source (2.5 equiv.); solvent (THF); 0 °C to room
temperature.
Chem. Commun., 1999, 1065–1066
1065

TBDMSO
H2N
Table 3 Reductive deamination of 2-acetylpiperidine and ethyl pipecolinate
TBDMSO
THF, reflux
derivatives, and a phthalimide derivativea
Reaction
time
Yield
(%)
N
O
CO2Pri
H
Starting material
Product
R
Scheme 1
Me
Bn
1 min
1 min
<5 min
<5 min
87
96
94
96
Ac
N
R
Ac
RHN
Boc
Ac
heating of isopropyl d-amino-g-tert-butyldimethylsiloxyvaler-
ate in THF for 2 days gave 5-tert-butyldimethylsiloxy-
2-piperidone in 75% yield (Scheme 1).
Me
Bn
Ac
<5 min
<5 min
45 min
86
89
78
N
R
CO2Et
RHN
In summary, we have described a general reductive deamina-
tion reaction employing SmI2 in THF–HMPA. This reaction
proceeds in relatively high yield under mild reaction conditions
and seems to be applicable to the wide variety of a-amino
carbonyl compounds. Utilisation of this reaction in the synthesis
of natural products is under investigation. This work was
supported by the Ministry of Education, Science, Sports and
Culture of Japan.
CO2Et
O
O
N
O
—
1 min
72
NH
Ac
O
a Reaction conditions: starting material (0.5 mmol); SmI2 (5 equiv.); HMPA
(5 equiv.); MeOH (2.5 equiv.) was used as a proton source; solvent (THF);
0 °C to room temperature.
Notes and references
1 P. Girard, J. L. Namy and H. B. Kagan, J. Am. Chem. Soc., 1980, 102,
2693.
2 Reviews: J. Inanaga, J. Org. Synth. Chem., 1989, 47, 200, J. A.
Soderquist, Aldrichim. Acta, 1991, 24, 15; D. P. Curran, T. L. Fevig,
C. P. Jasperse and M. J. Totleben, Synlett, 1992, 943; G. A. Molander,
Chem. Rev., 1992, 92, 29: G. A. Molander and C. R. Harris, Chem. Rev.,
1996, 96, 307; G. A. Molander and C. R. Harris, Tetrahedron, 1998, 54,
3321 and references cited therein.
provided the desired compounds, in high yields, in which both
alkyl and acyl derivatives of amines could be used as leaving
groups (Table 3). Interestingly, the reaction of N-(2-oxo-
propyl)phthalimide with SmI2 in THF–HMPA in the presence
of MeOH yielded phthalimide in 72% yield (Table 3). The
products obtained were well-characterised by spectroscopic
data including microanalysis, or by direct comparison with the
authentic samples.
We next investigated the effect of proton sources, and found
that N,N-dimethylaminoethanol (DMAE) was also effective for
this reaction as well as MeOH and pivalic acid (Table 4). It
should be noted that this reaction can be carried out under
neutral reaction conditions in the presence of other functional
groups, such as alkyl ester, alkyl ether, imide and amide groups.
Moreover, this reaction proceeded in the presence or absence of
HMPA, however, the presence of HMPA proved desirable in
terms of yields and reaction times (Tables 2, 3 and 4). These
results were in agreement with those observed in the reductive
deoxygenation reactions, since HMPA was recognised to
increase the rate of the reaction of SmI2.11
As can be seen in Table 2, the fragmentation product bearing
a primary amino function sometimes afforded the cyclisation
compound. This type of conversion will provide a useful route
for the synthesis of naturally occurring or biologically inter-
esting piperidine derivatives in optically active forms. Indeed,
3 G. A. Molander and P. J. Stengel, J. Org. Chem., 1995, 60, 6660; G. A.
Molander and P. J. Sangel, Tetrahedron, 1997, 53, 8887; N. H.
Kawahara and M. Goodman, Tetrahedron Lett., 1999, 40, 2271.
4 J. M. Aurrecoechea and A. Fernandez-Acebes, Tetrahedron Lett., 1993,
34, 549; J. M. Aurrecoechea and A. Fernandez-Acebes, Synlett, 1996,
39; A. R. Katritzky, M. Qi, D. Feng and D. A. Nichols, J. Org. Chem.,
1997, 62, 4121.
5 H.-Y. Kang, A. N. Pae, Y. S. Cho, H. Y. Koh and B. Y. Chung, Chem.
Commun., 1997, 821.
6 T. Honda, S. Yamane, K. Naito, K. and Y. Suzuki, Heterocycles, 1994,
37, 515; T. Honda, F. Ishikawa and S. Yamane, J. Chem. Soc., Chem.
Commun., 1994, 499; T. Honda, S. Yamane, K. Naito and Y. Suzuki,
Heterocycles, 1995, 40, 301; T. Honda, F. Ishikawa and S. Yamane,
J. Chem. Soc., Perkin Trans. 1, 1996, 1125; T. Honda, S. Yamane, F.
Ishikawa and M. Katoh, Tetrahedron, 1996, 37, 12177; T. Honda, M.
Katoh and S. Yamane, J. Chem. Soc., Perkin Trans. 1, 1996, 2219; T.
Honda and M. Katoh, Chem. Commun., 1997, 369.
7 The starting phenylalanine derivatives were prepared from the methyl
ester by the known procedures; N-methyl derivative: M. C. Allen, W.
Fuhrer, B. Tuck, R. Wade and J. M. Wood, J. Med. Chem., 1989, 32,
1652; N,N-dimethyl derivative: T. Hayashi, M. Konishi, M. Fukushima,
K. Kanehira, T. Hioki and M. Kumada, J. Org. Chem., 1983, 48, 2195;
N-benzyl derivative: F. Effenberger, U. Burkard and J. Willfahrt,
Liebigs Ann. Chem., 1986, 314; N,N-dibenzyl derivative: B. D. Gray and
P. W. Jeffs, J. Chem. Soc., Chem. Commun., 1987, 1329; N-acetyl
derivative: M. J. Burk, J. E. Feaster, E. H. Harlow and L. Richard,
Tetrahedron: Asymmetry, 1991, 2, 569; N-Boc derivative: M. Sakaitani
and Y. Ohfune, J. Org. Chem., 1990, 55, 870.
8 N-Benzylproline methyl ester was prepared from methyl prolinate: V.
Ferey, P. Vedrenne, L. Toupet, T. L. Gall and C. Mioskowski, J. Org.
Chem., 1996, 61, 7244; isopropyl 4-tert-butyldimethylsiloxyprolinate
was prepared by silylation of the corresponding ester, which on N-
benzylation with BnBr and NaH gave the N-benzyl derivative.
9 N-Substituted pipecolinates were prepared from ethyl pipecolinate by
alkylation with the suitable alkyl halide and Pri2NEt or by acetylation
with Ac2O.
10 2-Acetyl-N-alkylpiperidine derivatives were prepared from ethyl pipe-
colinate via four steps involving N-alkylation with alkyl halide,
hydrolysis of the ester, conversion of the acid to the Weinreb’s amide
(S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815), and
treatment of the amide with MeMgBr; the N-acetyl compound was
derived from the N-benzyl derivative by reductive debenzylation over
Pd/C in the presence of Ac2O; the N-Boc derivative was prepared
according to the known procedure: S. Aoyagi, T.-C. Wang and C.
Kibayashi, J. Am. Chem. Soc., 1993, 115, 11393.
Table 4 Investigation of the proton sources and the effect of HMPA in
reductive deaminationa
Reac-
Proton tion Addi- Yield
Starting material
Product
source
time tive
(%)
TBDMSO
TBDMSO
MeOH
5 h
none
65
Pivalic acid 40 min HMPA 82
DMAE
45 min HMPA 90
CO2Pri
H2N
CO2Pri
CO2Me
N
H
MeOH
Pivalic acid
DMAE
18 h
1 h
2 h
none 85
HMPA 92
HMPA 78
BnHN
CO2Me
CO2Pri
N
Bn
TBDMSO
TBDMSO
BnHN
MeOH
36 h
none
76
88
93
Pivalic acid 45 min HMPA
DMAE
1.5 h
HMPA
N
CO2Pri
Bn
MeOH
Pivalic acid
DMAE
12 h
none
50
86
71
<5 min HMPA
10 min HMPA
N
Ac
AcHN
Ac
Ac
a Reaction conditions: starting material (0.5 mmol); SmI2 (5 equiv.); proton
source (2.5 equiv.); additive (5 equiv.); solvent (THF); 0 °C to room
temperature.
11 J. Inanaga, M. Ishikawa and M. Yamaguchi, Chem. Lett., 1987, 1485.
Communication 9/03073E
1066
Chem. Commun., 1999, 1065–1066