Reductive aldol and mannich-type reactions of azetidin-3-ones promoted by titanium tetraiodide

Article abstract of DOI:10.1002/asia.200900457

A convenient method is described for the generation and reaction of the enolates of aminoacetone equivalents, which uses the reduction of azetidin-3-one with titanium tetraiodide and subsequent reactions with electrophiles. This methodology provides a str

Full text of DOI:10.1002/asia.200900457

DOI: 10.1002/asia.200900457
Reductive Aldol and Mannich-Type Reactions of Azetidin-3-ones Promoted
by Titanium Tetraiodide
Shingo Hata, Daisuke Fukuda, Iwao Hachiya, and Makoto Shimizu*[a]
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
1,4- and 1,3-Amino alcohols and diamines are widely used
as synthons and other fine chemicals.[1] Consequently, the
search for reliable methodologies for the construction of
such building blocks in a regio- and stereoselective manner
has received considerable attention. The most straightfor-
ward synthetic approach involves the use of aldol and Man-
nich-type reactions. However, there are some drawbacks as-
sociated with the enolate formations. As the conventional
preparations of enolates involve deprotonation of the parent
carbonyl compounds, there are some problems regarding
the regioselectivity on the deprotonation of unsymmetrically
substituted ketones. This problem on regiochemistry has re-
cently been circumvented by utilizing the Rh- or Ir-cata-
lyzed hydrogenation of unsaturated ketones.[2] Regarding
this regiochemical issue, we have recently found that titani-
um tetraiodide generates enolate derivatives by the reduc-
tion of a-haloketones in a regioselective fashion.[3,4]
There are only a few reports available for the regioselec-
À
tive C C bond formation using the enolate from aminoace-
tone derivatives.[7] Therefore, the application of our method-
ology to this subject would lead to a straightforward proce-
dure. Azetidin-3-one was chosen as a suitable precursor to
the enolate because of the ring-strain derived from its small
ring (Scheme 1). This paper describes a convenient method
for the generation and reaction of the enolates of aminoace-
tone equivalents, which uses the reduction of azetidin-3-one
with titanium tetraiodide and subsequent reactions with
electrophiles. We utilized azetidine-3-ones, which were pre-
pared easily from various a-amino acids.[8]
The applicability of the titanium tetraiodide-mediated
system would be greatly enhanced with more conventional
methods, avoiding the troubles caused by the use of a-halo-
ketones, for example, instability and tedious preparation.
These drawbacks led us to direct our studies toward the use
of fused heterocyclic substrates.[5] First, the 2-acylaziridines
were used as substrates, which would provide the latent a-
haloketones by the reductive approach with titanium tet-
raiodide. As a result, the aldol or Mannich-type products
were obtained by the treatment of 2-acetyl- or methoxycar-
bonyl-N-tosylaziridine derivatives with titanium tetraiodide
followed by the addition of aldehydes or imines.[6]
Scheme 1. The present strategy for the formation and reaction of enolate.
We initially examined the reducing ability of titanium tet-
raiodide using azetidin-3-one 1. Treatment of azetidin-3-one
with TiI4 (1.5 eq) in EtCN at À788C to room temperature
for 22.5 h cleanly gave the amino ketone 4 in moderate
yield as shown in Table 1 (Entry 1). The influence of several
N-protecting groups was next examined under various con-
ditions. Table 1 summarizes the results. The best result was
obtained by using p-tosylazetidin-3-one (p-Ts) as a protect-
ing group in CH2Cl2 at 08C to room temperature (Entry 3).
Titanium tetraiodide recorded a good result for generating
the enolates efficiently from azetidin-3-one derivatives,
whereas the use of other metal halides (MgI2,[9a,b] AlI3,
ZnI2[5i], TiCl4[9c–e]) did not give satisfactory results. The effect
of the protecting group is important. The ring-opening reac-
tion of the azetidin-3-one (R=Bn) did not take place with a
weak electron-donating substituent.
[a] S. Hata, D. Fukuda, Dr. I. Hachiya, Prof. Dr. M. Shimizu
Department of Chemistry for Materials
Mie University
Tsu, Mie 514-8507 (Japan)
Fax : (+81)59-231-9413
E-mail: mshimizu@chem.mie-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900457.
Chem. Asian J. 2010, 5, 473 – 477
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
473

COMMUNICATION
Table 1. Titanium tetraiodide-promoted ring-opening reaction of azeti-
din-3-ones.
Entry
R
Solvent
T [8C]
t [h]
Yield [%]
1
2
Ts
Ts
Ts
Ts
Cbz
Cbz
EtCN
À788C to RT
À788C to RT
08C to RT
À788C to RT
À788C to RT
À788C to RT
22.5
20
15
18
13.5
8
43
63
80
35
24
trace
CH2Cl2
CH2Cl2
DME
EtCN
CH2Cl2
3[a]
4[b]
5
6
Scheme 2. The regioselectivity on the ring-opening reaction of 2,2-disub-
stituted azetidin-3-one.
[a] TiI4 (1.5 eq) was used. [b] TiI4 (6.0 eq) was used.
Further studies were carried out to examine the regiose-
lectivity of the reductive ring-opening reaction. Reductive
ring-opening of various 2-substituted azetidin-3-ones is sum-
marized in Table 2. The reduction of azetidin-3-ones derived
Table 2. Regioselectivity of the reductive ring-opening reaction of vari-
ous 2-substituted azetidin-3-ones.
Scheme 3. An explanation for the complete regioselectivity of the reduc-
tive ring-opening reaction of 2,2-dimethyl-azetidin-3-one.
Entry
R1
TiI4[Eq]
T [8C]
Yield [%][a]
4:5
1
2
3
4
5
Me
Et
iPr
iBu
Bn
2.0
1.5
3.0
2.0
3.0
08C to RT
RT
RT
08C to RT
RT
89
66
76
97
82
95:5
83:17
77:23
63:37
92:8
one at the C-3 position gives a radical intermediate. A ring-
À
opening reaction proceeded by fragmentation at the N C(2)
À
À
or N C(4) bond. At this point, fragmentation at N C(2)
bond was favored because of the electronically stabilized
2,2-dimethyl substitution. Further reduction of azetidine
leads to the corresponding titanium enolate. Also, the ho-
[a] Each regioisomer was not separated.
À
from various a-amino acids gave mixtures of amino ketones
4 and 5 in moderate to good yields with good to high regio-
selectivities, in which the steric congestion at C-2 of the aze-
tidine ring affected the regioselectivity. Unfortunately, race-
mization of amino ketones 4 was observed to some extent
during the enolate formation.
The results of the reductive ring-opening reaction with
2,2-disubstituted azetidin-3-one are shown in Scheme 2.
Complete regioselectivity was observed on the reductive
ring-opening of 2,2-dimethyl-substituted azetidin-3-one. The
use of spirohexyl azetidin-3-one, a more sterically congested
substrate, also recorded high regioselectivity albeit in a de-
creased yield of the product. Regioselectivity of the reduc-
tive ring-opening reaction is controlled by electronic factors
as well as steric effects of the 2-substitution.
Although more detailed examinations appear to be
needed, at present we propose a plausible mechanism
shown in Scheme 3. The reduction of azetidin-3-one would
proceed though in two different pathways, and it seems that
an electron-transfer reaction would play a significant role.
Initially, the disproportion of titanium tetraiodide gives low-
valent titanium species. One electron transfer to azetidin-3-
molysis of N C(4) bond gives the less substituted enolate
À
(path A). Alternatively, the homolysis of N C(2) bond leads
to the more substituted enolate (path B). In path A, the
enolate could reverse to the azetidine by re-cyclization
under the equilibrium. However, path B may not involve
such a cyclization because of the steric hindrance. Finally,
the more thermodynamically stable enolate would predomi-
nate. The examination into a more precise mechanism is still
underway.
The reductive aldol reaction of azetidin-3-ones with alde-
hydes was next examined, and Table 3 summarizes the re-
sults. Unfortunately, treatment of azetidin-3-one 1a (R1 =H)
with benzaldehyde in the presence of TiI4 gave a trace
amount of the desired 1,4-amino alcohol 3a (R1 =H, R2 =
Ph) along with the aminoacetone derivative 4a (R1 =H) in
78% yield (Entry 1). Low Lewis acidity of titanium tetraio-
dide might be responsible for this result.
To improve the yield, the addition of various Lewis acids
was investigated. The presence of TiCl4 and InCl3 were
found to be effective. When TiCl4 was used as an additive,
the desired aldol adduct 3a (R1 =H, R2 =Ph) was obtained
in 12% yield (Entry 2). The use of chloral as a reactive alde-
474
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 473 – 477

Reductive Aldol and Mannich-Type Reactions of Azetidin-3-ones
Table 3. Reductive aldol reaction of azetidin-3-ones.[a]
acids (Entry 14). To investigate the scope of electrophiles, 3-
chlorobenzaldehyde was used in the presence of ZnCl2 as an
additive. The desired product (R1 =iPr, R2 =3-ClC6H4) was
formed along with the dehydration product in 57% com-
bined yield. The reaction of 1g (R1 =Bn) derived from l-
phenylalanine with chloral gave the aldol adduct 3g (R1 =
Bn, R2 =CCl3) in 41% yield (Entry 16).
Although there is much room for the examination of the
regioselectivity, one plausible explanation is shown in
Scheme 4. In the case of mono-substituted azetidin-3-ones,
Entry R1
R2
TiI4
[Eq]
L.A.
T
Yield
[%][b]
dr
[oC]
1
H
Ph
Ph
3.0
None
08C to RT Trace
(78)
08C to RT 12 (61)
08C to RT 41 (17)
08C to RT 11 (53) 50:50
08C to RT 33 (34) 50:50
08C to RT 46 (30) 50:50
–
2
3
4
5
6
7
H
H
1.5
TiCl4, 1.5
TiCl4, 1.5
TiCl4, 1.5
InCl3, 1.5
InCl3, 2.0
InCl3, 2.0
InCl3, 2.0
InCl3, 3.0
–
–
CCl3 1.5
Me CCl3 1.5
Me CCl3 1.5
Me CCl3 2.0
Me CCl3 2.0
Me CCl3 2.0
Me CCl3 3.0
Me CCl3 2.0
Me CCl3 2.0
Et
Et
iPr
iPr
Bn
RT
RT
RT
57 (30) 50:50
70 (30) 68:32
55 (30) 50:50
41 (55) 50:50
8[c]
9
10
11
12
13[c]
14[c]
15[d]
16[d]
InBr3, 2.0 RT
InI3, 2.0
InCl3, 2.0
InCl3, 2.0
InCl3, 2.0
None
RT
RT
RT
RT
30 (0)
51(49)
80(10)
28(26)
50:50
83:17
80:20
84:16
81:19
63:37
CCl3 2.0
CCl3 2.0
CCl3 2.0
CCl3 2.0
CCl3 2.0
08C to RT 43(35)
08C to RT 41(31)
None
[a] Reactions were performed with azetidin-3-one (0.10 mmol) in CH2Cl2
(3.0 mL), unless otherwise indicated. [b] Yields of the reduction products
are in parentheses. [c] Reactions were performed with azetidin-3-one
(0.20 mmol), chloral (0.40 mmol), TiI4 (0.40 mmol), and InCl3
(0.40 mmol) in CH2Cl2 (2.0 mL). [d] Reactions were performed with aze-
tidin-3-one (0.20 mmol), chloral (0.40 mmol), TiI4 (0.40 mmol), and InCl3
(0.40 mmol) in CH2Cl2 (2.5 mL).
Scheme 4. Plausible reaction mechanism.
hyde was next examined. The reaction of azetidine-3-one 1a
(R1 =H) with chloral gave the adduct 3b (R1 =H, R2 =
CCl3) in moderate yield (Entry 3). On the other hand, the
aldol reaction of 1c (R1 =Me) derived from l-alanine with
chloral in the presence of a mixture of TiI4–TiCl4 (each
1.5 equiv to 1c) gave the adduct 3c (R1 =Me, R2 =CCl3) in
11% yield (Entry 4). When InCl3 was used in place of TiCl4
as an additive, the adduct 3c (R1 =Me, R2 =CCl3) was ob-
tained in 33% yield (Entry 5). To improve the yield, the re-
action conditions were investigated regarding the indium
species, amounts of TiI4 and InX3, and reaction tempera-
tures (Entries 6–11). The reaction of 1c (R1 =Me) with chlo-
ral in the presence of a mixture of TiI4–InCl3 (each 2.0 equiv
to 1c) gave the aldol adduct 3c in 57% yield (Entry 7).
Also, an increase in the concentration of the reaction im-
proved the product yield (Entry 8). The aldol reaction of 1d
(R1 =Et) with chloral in the presence of a mixture of TiI4–
InCl3 (each 2.0 equiv to 1d) gave the adduct 3d (R1 =Et,
R2 =CCl3) in 51% yield (Entry 12). The increased yield of
the adduct 3d (80% yield) was obtained when a three-fold
concentration of substrate 1d (R1 =Et) was examined in the
presence of a mixture of TiI4–InCl3 (each 2.0 equiv to 1d).
The aldol reaction of 1e (R1 =iPr) derived from l-valine
with chloral in the presence of a mixture of TiI4–InCl3
(2.0 equiv each) gave the adduct 3e (R1 =iPr, R2 =CCl3) in
28% yield (Entry 14). The aldol adduct 3e (R1 =iPr, R2 =
CCl3) was obtained in 43% yield without the added Lewis
the reaction would prefer an SN2-like process rather than
one electron transfer, because radical stabilization is more
depressed compared with that of 2,2-disubstituted cases. Ini-
tially, a-iodoketone A is generated by the ring-opening of
azetidin-3-one. The formation of intermediary a-iodoke-
tones and the reductive formation of enolates have been
precedented.[3,6] At this point, attack at the less hindered
site by the iodide anion was favored. The requirement for
an additional Lewis acid may be explained by the formation
of a more reactive enolate D from the stable titania cycle B.
Finally, the aldol reaction with aldehyde furnishes the prod-
À
uct 3. We next examined the reductive C C bond-forming
reaction with 2,2-dimethyl-substituted azetidin-3-one and
various electrophiles (Table 4).
In contrast to monosubstituted azetidin-3-ones, chloral
was not a good electrophile. Among the other electrophiles
(MVK, acetal) tested, N-tosylimine derived from benzalde-
hyde afforded a Mannich-type adduct in moderate yield
(Entry 5).
In conclusion, we found that the enolates from aminoace-
tone derivatives were readily prepared using the reduction
of azetidin-3-ones with titanium tetraiodide, and that subse-
À
quent C C bond formation with aldehyde or imine proceed-
ed in poor to good yields. This methodology provides a
straightforward access to 1,4-amino alcohols or diamines in
a regioselective manner.
Chem. Asian J. 2010, 5, 473 – 477
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
475

M. Shimizu et al.
COMMUNICATION
À
Table 4. Reductive C C bond-forming reaction with various electro-
philes.
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Entry
1
Electrophile
Product
Yield [%]
0
2[a]
9[a]
3
0
4
0
5
52
[a] Decomposition involving a retro-aldol reaction was observed on TLC.
Experimental Section
A typical experimental procedure (Table 3, entry 7): A solution of N-p-
tosyl-2-methylazetidin-3-one 1c (23.9 mg, 0.10 mmol) in CH2Cl2 (1.0 mL)
and a solution of chloral (22.1 mg, 0.15 mmol) in CH2Cl2 (1.0 mL) were
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added successively to
a mixture of titanium tetraiodide (111.1 mg,
0.20 mmol) and indium trichloride (44.2 mg, 0.20 mmol) in CH2Cl2
(1.0 mL) at room temperature. After the mixture was stirred for 15 h, it
was quenched with a saturated aqueous solution of NaHCO3. The whole
mixture was diluted with AcOEt, followed by the addition of an aqueous
solution of NaHSO3 (10%). The mixture was filtered through a celite
pad. The layers were separated, and the aqueous layer was extracted
with ethyl acetate (10 mLꢁ3). The combined extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude product was purified by preparative TLC on silica gel (developed
twice with n-hexane/CH2Cl2/Et2O=5:3:2 and then twice with CH2Cl2) to
give 5,5,5-trichloro-4-hydroxy-1-(p-tosylamino)-pentan-2-one 3c (57%,
22.1 mg).
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research (B)
and Priority Areas from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, and the Japan Society for the Promotion of Sci-
ence.
Keywords: aldol reaction
ketones · reduction · regioselectivity
·
homogeneous catalysis
·
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 473 – 477

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Received: September 14, 2009
Published online: January 8, 2010
Chem. Asian J. 2010, 5, 473 – 477
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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