Asymmetric reduction of azirines; a new route to chiral aziridines

Article abstract of DOI:10.1039/b203932j

The first enantioselective reduction of aromatic 2H-azirines yields aziridines in up to 70% ee, using the aminoalcohol-[RuCl₂(p-cymene)]₂ catalyzed asymmetric transfer hydrogenation reaction.

Full text of DOI:10.1039/b203932j

Asymmetric reduction of azirines; a new route to chiral aziridines
a
a
b
Peter Roth, Pher G. Andersson* and Peter Somfai*
a
Institute of Chemistry, Department of Organic Chemistry, Box 531, SE-751 21 Uppsala, Sweden.
E-mail: phera@kemi.uu.se; Fax: +46-18-512524; Tel: +46-18-471 38 01
Organic Chemistry, Department of Chemistry, Royal Institute of Technology, SE-100 44 Stockholm,
Sweden. E-mail: somfai@kth.se; Fax: +46-8-791-2333; Tel: +46 8 790 6960
b
Received (in Cambridge, UK) 23rd April 2002, Accepted 27th May 2002
First published as an Advance Article on the web 11th July 2002
Table 1 Asymmetric transfer hydrogenation of 1 (R = H)a
The first enantioselective reduction of aromatic 2H-azirines
yields aziridines in up to 70% ee, using the aminoalcohol-
Entry
Metal complex
Timeb
Yield
Eec
[
RuCl
2 2
(p-cymene)] catalyzed asymmetric transfer hydro-
genation reaction.
1
2
3
4
5
[IrClCp*]
[RhClCp*]
2
15
15
2
120
—
60
2
5
2
5
2
51
41
80
34
—
56
93
70
85
83
86
3
10
70
43
—
78
64
70
67
65
50
2
Chiral aziridines are useful synthetic intermediates in organic
synthesis since large ring-strain can facilitate regio- and
stereoselective ring-opening of the three-membered hetero-
cycle.1 Many nitrogen containing biologically interesting
molecules can be synthesized from aziridines that are made
[RuCl
[RuCl
2
(p-cymene)]
(mesityl)]
2
2
2
[RuCl (HMB)]2
2
d
6
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
2
(p-cymene)]
2
(p-cymene)]
2
(p-cymene)]
2
(p-cymene)]
2
(p-cymene)]
2
(p-cymene)]
2
2
2
2
2
2
e
7
f
8
9
from either enantiomerically pure starting material or through
g
asymmetric synthesis.2,3 Catalytic enantioselective aziridina-
h
1
1
a
0
1
tion of alkenes and imines have been developed into useful
synthetic tools but high enantiomeric excess can only be
i
4
Reactions were performed on a 1.0 mmol scale in a 0.1 M i-PrOH solution
obtained for a limited set of substrates. An alternative route
b
with ligand+base+substrate+Ru 4+5+100+1 at room temperature. Reaction
from readily available starting materials to chiral aziridines is
therefore desirable. 3-Substituted 2H-azirines are highly
strained molecules with an unsaturated CNN moiety that can
c
times are in minutes as determined by TLC. Determined on Chiralcel OD-
H column. Performed at 0 °C. 1 M in i-PrOH. f 0.05 M in i-PrOH.
d
e
g
and 1 mL of i-PrOH. h Toluene+i-PrOH
CN+i-PrOH 9+1.
Performed in 9 mL of CH
+1. Performed in CH
2
Cl
2
5
react with nucleophiles. These prochiral substrates serve as
i
9
3
precursors to aziridines and can be synthesized on a multigram
6
scale, starting from the corresponding olefin. We here disclose
the first enantioselective reduction of azirines that introduces a
new route to chiral aziridines (Scheme 1).
To investigate concentration effects, reductions were run
with different substrate concentrations in i-PrOH. Surprisingly,
the stereoselectivity decreased in a 1 M solution but performing
the reaction in a 0.05 M solution did not have any effect on the
stereoselectivity (Table 1, entry 9,10). No racemization of 2 was
observed after stirring the reaction mixture overnight.
Since the reaction could be performed in a 1 M solution using
only 1 mL of i-PrOH, we investigated the possibility of diluting
the reaction mixture to a 0.1 M solution with another solvent to
study solvent effects. Toluene, acetonitrile and THF were tested
but the effect on reaction times and ees proved to be of limited
importance, and gave slightly lower enantiomeric excess (Table
1, entry 9–11).
Next, we studied the influence of substituents on reactivity
and selectivity. Compounds with substituents on the arene or in
the 2-position of the azirine moiety were synthesized and
reduced under the optimized conditions.
As seen in Table 2, the stereoselective outcome of the
reaction was strongly influenced by substituents on the aromatic
Chiral amines can be obtained from enantioselective reduc-
7
tion of prochiral imines. Attempts to reduce azirine 1 using
different transition metal complexes did not give the desired
aziridine 2. However, when experiments were performed using
the transfer hydrogenation reaction with i-PrOH as the hydro-
8
gen donor, the results were promising. This reaction has been
developed into an attractive complement to hydrogenation, and
aromatic ketones can be reduced in more than 95% enantio-
meric excess, using a number of catalysts.9 Cyclic imines can
be reduced with high stereoselectivity if the more potent formic
,10
11
acid–triethylamine (5+2) mixture is used. The presence of this
hydrogen donor was found to cause decomposition of azirine
1
.
We have previously reported that amino alcohol 3 is a very
active and selective ligand for aromatic ketone reduction.12 This
bicycle was used as the ligand for the stereoselective reduction
of azirine 1, catalyzed by the metal complexes shown in Table
1
.†
The catalyst derived from [RuCl
-phenylaziridine in 70% ee and was chosen for further
Table 2 Asymmetric transfer hydrogenation of azirinesa
2
(p-cymene)]
2
gave (S)-
2
Entry
Ar
R
Timeb
Yield
Eec
optimization (Table 1, entry 3). Using this catalyst, the reaction
could be performed at 0 °C giving 2 in 78% ee but with lower
yield because of by-product formation (Table 1, entry 4).
1
2
3
4
5
6
7
8
9
C
o-ClC
m-ClC
p-ClC
p-BrC
m-CH
p-CH
2,4,6-MeC
p-CH OC
2-Naphthyl
6
H
5
H
H
H
H
H
H
H
Me
H
2
2
2
2
2
5
5
5
80
83
78
81
92
75
83
89
72
92
—
70
56
58
44
50
65
72
57
0
6
H
4
6
H
4
H
6 4
6
H
4
3
C
6
H
H
4
3
C
6
4
6
H
2
3
6
H
4
10
10
—
1
1
a
0
1
H
Me
50
—
C
6
H
5
Reactions performed on a 1 mmol scale at room temperature for 2–10
minutes with S/C 100. b Minutes (TLC). Determined on Chiralcel OD-H
c
column.
Scheme 1 Asymmetric reduction of azirine 1.
1
752
CHEM. COMMUN., 2002, 1752–1753
This journal is © The Royal Society of Chemistry 2002

column with a UV detector and a flow rate of 0.5 mL min2 using hexane+i-
1
ring and by the bulkiness of the alkyl group. Chloro- and bromo-
substituted aromatic azirines were reduced in 44 to 58%
enantiomeric excess (Table 2, entries 2–5). Methyl substitution
at the m- and p-positions on the aromatic ring yielded aziridines
with 65 and 72% ee respectively (Table 2, entries 6,7).
Surprisingly, a methoxy substituent in the p-position has a
dramatic negative influence on selectivity and yields the
product as a racemate (Table 2, entry 9). As shown in entry 11,
increased steric hindrance on the aliphatic group inhibits
reduction. This is probably due to lack of flexibility in this type
of azirine. Our attempts to reduce aliphatic azirines have failed.
These substrates proved to be less stable and difficult to
isolate.
PrOH 90+10.
1
A. Mitsunobu, in Comprehensive Organic Synthesis, ed. B. M. Trost
and I. Flemming, 1st edn., Pergamon Press, 1991, vol. 6, ch. 1, p.
6
75.
2
3
D. Tanner, Angew. Chem., Int. Ed. Engl., 1994, 33, 599.
H. M. I. Osborn and J. Sweeney, Tetrahedron: Asymmetry, 1997, 8,
1693; R. S. Atkinson, Tetrahedron, 1999, 55, 1519; E. N. Jacobsen, in
Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer, Hamburg, 1999.
4
R. W. Quan, Z. Li and E. N. Jacobsen, J. Am. Chem. Soc., 1996, 118,
8
1
1
156; Z. Li, R. W. Quan and E. N. Jacobsen, J. Am. Chem. Soc., 1995,
17, 5889; Z. Li, K. R. Conser and E. N. Jacobsen, J. Am. Chem. Soc.,
993, 115, 5326; D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A.
Andersson and D. M. Barnes, J. Am. Chem. Soc., 1993, 115, 5328; C. J.
Sanders, K. M. Gillespie, D. Bell and P. Scott, J. Am. Chem. Soc., 2000,
In agreement with the Noyori mechanism, preliminary
mechanistic experiments indicate that a N–H moiety in the
ligand is necessary for reduction. Alkylation of the nitrogen
1
22, 7132; C. Loncaric and W. D. Wulff, Org. Lett., 2001, 3, 3675; J. C.
Antilla and W. D. Wulff, Angew. Chem., Int. Ed. Engl., 2000, 39,
(
Me) on 3 inhibits reaction. This suggests that a mechanism
involving a concerted addition of a proton and a hydride from
4518.
the catalyst is operating, as is the case in the asymmetric transfer
5 F. Palacios, A. M. O. de Retana, E. M. de Marigorta and J. M. de los
hydrogenation of aromatic ketones.13
Santos, Eur. J. Org. Chem., 2001, 2401.
6
A. G. Hortmann, D. A. Robertson and B. K. Gilliard, J. Org. Chem.,
972, 37, 322; W. K. Anderson and A. S. Milowsky, J. Med. Chem.,
986, 29, 2241.
T. Ohkuma, M. Kitamura and R. Noyori, in Catalytic Asymmetric
Synthesis, ed. I. Ojima, Wiley-VCH, 2000, pp. 83–95.
For reviews see: R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997,
30, 97; M. J. Palmer and M. Wills, Tetrahedron: Asymmetry, 1999, 10,
2045; G. Zassinovich, G. Mestroni and S. Gladiali, Chem. Rev., 1992,
92, 1051.
In conclusion, chiral aromatic aziridines can be obtained
from the asymmetric transfer hydrogenation of azirines. Azirine
1
1
1
is reduced with 70% enantiomeric excess which is comparable
7
8
4
to the stereoselectivity reported for aziridination of styrene.
Other methods to reduce 2H-azirines are currently under
investigation.
We thank the Swedish Natural Science Research Council
NFR), the Swedish Research Council for Engineering Science
TFR) and the Swedish Foundation for Strategic Research for
(
(
9
R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40.
1
1
0 S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1995, 117, 7562; Y. Jiang, Q. Jiang and X. Zhang, J. Am.
Chem. Soc., 1998, 120, 3817; Y. Nishibayashi, I. Takei, S. Uemura and
M. Hidai, Organometallics, 1999, 18, 2291; M. Palmer, T. Walsgrove
and M. Wills, J. Org. Chem., 1997, 62, 5226.
generous financial support. Christian Hedberg is thanked for
preparing ligand 3 and Erik Risberg is also acknowledged for
his assistance.
1 N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1996, 118, 4916.
Notes and references
†
A typical procedure: to a dry 25 mL Schlenk flask equipped with a
magnetic stirrer and Ar atmosphere, were added [RuCl (p-cymene)] (2.5
mmol, 1.53 mg) and amino alcohol 3 (20 mmol, 4.27 mg) followed by 2 mL
of i-PrOH (freshly distilled over CaH ). The reaction mixture was stirred for
5 min at rt and another 6 mL of i-PrOH was added followed by i-PrOK (25
12 J. M. Nordin, P. Roth, T. Tarnai, D. A. Alonso, P. Brandt and P. G.
Andersson, Chem. Eur. J., 2001, 7, 1431.
2
2
13 R. Noyori, M. Yamakawa and S. Hashiguchi, J. Org. Chem., 2001, 24,
7931; D. A. Alonso, P. Brandt, S. J. M. Nordin and P. G. Andersson, J.
Am. Chem. Soc., 1999, 121, 9580; M. Yamakawa, H. Ito and R. Noyori,
J. Am. Chem. Soc., 2000, 122, 1466; D. G. I. Pera, J. N. H. Reek, J-W.
Handgraaf, E. J. Meijer, P. Dierkes. P. C. J. Kamer, J. Brusse, H. E.
Shoemaker and P. W. N. W van Leeuwen, Chem. Eur. J., 2000, 6, 2818;
M. Yamakawa, I. Yamada and R. Noyori, Angew. Chem., Int. Ed., 2001,
40, 2818.
2
1
mmol, 25 mL, 1 M solution in i-PrOH). The substrate (1.0 mmol) in 2 mL of
i-PrOH was added dropwise and the reaction was followed by TLC. The
reaction was quenched by the addition of 2 drops of water and the solvent
removed by distillation. The red oil was filtered through a short plug of SiO
1 g) with pentane–Et O. The ee was determined on a Chiralcel OD-H
2
(
2
CHEM. COMMUN., 2002, 1752–1753
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