Selective reduction of acyl aziridines to Mannich bases using silyllithium reagents

Article abstract of DOI:10.1016/j.tetlet.2013.05.005

Mannich bases are prepared from the selective α-reduction of acyl aziridines using silyllithium reagents. The reaction proceeds via an aziridine ring-opening assisted Brook rearrangement.

Full text of DOI:10.1016/j.tetlet.2013.05.005

Tetrahedron Letters 54 (2013) 3673–3674
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Tetrahedron Letters
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Selective reduction of acyl aziridines to Mannich bases using
silyllithium reagents
⇑
Amanda L. Davis, Arthur A. Korous, Aaron M. Hartel
Department of Chemistry, Winthrop University, Rock Hill, SC 29733, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Mannich bases are prepared from the selective a-reduction of acyl aziridines using silyllithium reagents.
The reaction proceeds via an aziridine ring-opening assisted Brook rearrangement.
Received 13 February 2013
Revised 25 April 2013
Accepted 2 May 2013
Available online 11 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Mannich base
Aziridine
Brook rearrangement
Silyllithium
Reduction
Introduction
of the desired Mannich base. The lower yield is attributed to an
inability to stabilize the developing negative charge on carbon (3
in Scheme 1). By contrast, the phenyl substituent of the benzoyl azi-
ridine allows for the formation of a resonance-stabilized benzylic
anion, thus promoting the necessary Brook rearrangement.
Believing that the disappointing yield from the reaction of the
acyl aziridine was due at least in part to a slower Brook rearrange-
ment, we next explored the use of methyldiphenylsilyllithium in
place of dimethylphenylsilyllithium. The methyldiphenylsilyl
group has been reported to promote Brook rearrangement relative
to the dimethylphenylsilyl group,10b and its use has improved yields
in similar reactions.6,7 Thus, treatment of the acyl aziridine (entry 2)
with 2.5 equiv of methyldiphenylsilyllithium in THF at À50 °C gave
the desired Mannich base with a greatly improved yield of 64%. We
were pleased to find that similar treatment of the benzoyl aziridine
(entry 1) with methyldiphenylsilyllithium provided the corre-
sponding Mannich base with an improved yield of 70%.
The regioselective
a-reduction of acyl aziridines is a syntheti-
cally useful transformation, providing an alternative to the Man-
nich reaction for the formation of b-aminoketones. The few
reducing agents that have been reported to effect this transforma-
tion include samarium iodide,1 magnesium metal,2 tributyltinhy-
dride,3 and titanium tetraiodide.4
A
ruthenium catalyzed
photoreduction using the Hantzsch ester has also been developed.5
Based on our success with the selective
-reduction of acyloins6
and
,b-epoxyketones,7 we envisioned that the preparation of
a
a
Mannich bases from acyl aziridines using silyllithium reagents
could be similarly achieved (Scheme 1). A key step in this process
is a Brook rearrangement, which has found recent synthetic util-
ity,8 particularly in the anion relay chemistry (ARC) of Smith.9
The reaction proceeds via an initial nucleophilic attack of the
silyllithium reagent on the carbonyl of 1, triggering a Brook rear-
rangement on 2. Concomitant
p
-bond formation and aziridine ring
A number of acyl aziridines were then subjected to reduction
with methyldiphenylsilyllithium in order to determine the scope
of the reaction. These results are summarized in Table 2. An unpro-
tected aziridine (entry 1) gave none of the desired Mannich base,
resulting in recovery of starting material. This is likely due to the
acidity of the aziridine hydrogen, resulting in deprotonation by
the silyllithium reagent and preventing any further reaction. An al-
kyl protected aziridine (entry 2) gave only a trace of the expected
Mannich base, likely due to the poor stabilization of the developing
negative charge on nitrogen. Substrates with electron withdrawing
protecting groups were more successful. An acetyl protected aziri-
dine (entry 3) gave good results, but the electrophilic nature of this
opening would then give silyl enol ether intermediate 4. Desilylation
of 4 by a second equivalent of silyllithium reagent10 would form
dianion 5, providing Mannich base 6 upon acidic aqueous work-up.
We began with the two representative substrates, shown in
Table 1. The benzoyl aziridine (entry 1) was treated with 2.5 equiv
of dimethylphenylsilyllithium in THF at À50 °C, which provided the
corresponding Mannich base with a modest yield of 56%. Similar
reaction with an acyl aziridine (entry 2) resulted in only a 28% yield
⇑
Corresponding author. Tel.: +1 803 323 4942; fax: +1 803 323 2246.
E-mail address: hartela@winthrop.edu (A.M. Hartel).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
10.1016/j.tetlet.2013.05.005

3674
A. L. Davis et al. / Tetrahedron Letters 54 (2013) 3673–3674
O
R3SiO
R1
O
R3Si
NX
NX
NX
R3SiLi
Brook
Rearrangement
R1
R2
R1
R2
O
R2
1
2
3
R3SiO
R1
NX
NX
O
NHX
R2
R3SiLi
H3O+
R2
R1
R2
R1
4
5
6
Scheme 1.
group resulted in some deprotection by the silyllithium reagent.
More robust protecting groups (entries 4 and 5) gave excellent
yields of Mannich base and no deprotection was observed. The
reaction of enolizable acyl aziridines often resulted in the recovery
of some amount of starting material. This is attributed to the par-
tial enolization of the substrate by the powerfully basic silyllithium
reagent, and subsequent reprotonation upon workup.
In conclusion, a new method for the selective reduction of acyl
aziridines to Mannich bases using silyllithium reducing agents
has been developed. Use of methyldiphenylsilyllithium provided
Table 1
Reduction of acyl aziridines with dimethylphenyl- and methyldiphenylsilyllithium
(2.5–3.0 equiv) in THF at À50 °C
Entry Substrate
Silyllithium Product
Yielda (%)
Me2PhSiLi
MePh2SiLi
56
70
O
O
NHTs
NTs
1
Ph
Ph
Me2PhSiLi
MePh2SiLi
28
64
O
O
NHTs
NTs
2
significantly
dimethylphenylsilyllithium.
higher
yields
than
the
more
common
a
Yields determined by 1H NMR using hexamethylbenzene as an internal
standard.
Typical procedure: A solution of acyl aziridine (1.0 mmol) in
5 mL of dry THF was cooled to À50 °C under argon. A solution of
methyldiphenylsilyllithium (ꢀ0.7 M, 2.5–3.0 equiv) in THF was
added drop-wise with stirring. The reaction was quenched after
10 min with saturated aqueous NH4Cl and warmed to room tem-
perature. The mixture was extracted with CH2Cl2 (3 Â 10 mL) and
the combined organic layers dried over anhydrous Na2SO4. The
dried solution was concentrated in vacuo and the residue purified
by flash chromatography (silica gel, ethyl acetate/petroleum ether)
to give the Mannich base.
Table 2
Reduction of acyl aziridines with methyldiphenylsilyllithium (2.5–3.0 equiv) in THF
at À50 °C
Entry Substrate
Product
Yield
(%)
O
O
NH2
NH
N
1
0
Ph
Ph
O
O
HN
Acknowledgments
2
Trace
Ph
Ph
O
Acknowledgment is made to the Donors of the American Chem-
ical Society Petroleum Research Fund for support (47986-B1) of
this research. We also thank Michael Walla, University of South
Carolina, for acquisition of mass spectra.
O
NHAc
NHCBz
NHTs
NAc
3
67
88
89
98
60
Ph
Ph
O
O
NCBz
NTs
4
Supplementary data
Ph
Ph
O
O
Supplementary data associated (experimental procedures and
spectral data for products) with this article can be found, in the on-
line version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.005.
5
Ph
Ph
O
O
NHTs
Ph
NTs
O
6
References and notes
Ph
Ph
Ph
O
NHTs
Ph
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7
4-ClC6H4
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Quant
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O
O
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NHTs
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NTs
9
10
11
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37a
59a
O
NTs
O
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NTs
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Yields determined by 1H NMR using hexamethylbenzene as an internal stan-
dard due to decomposition during purification via chromatography.
a