Enantioselective synthesis of 1,2-diarylaziridines by the organocatalytic reductive amination of α-chloroketones

Article abstract of DOI:10.1002/anie.200700165

(Chemical Equation Presented) One-sided triangles: A simple protocol has been developed for the synthesis of highly useful single enantiomers of 1,2-diarylaziridines. The method involves conversion of the readily available α-chloroacetophenones into the c

Full text of DOI:10.1002/anie.200700165

Communications
DOI: 10.1002/anie.200700165
Chiral Aziridines
Enantioselective Synthesis of 1,2-Diarylaziridines by the
Organocatalytic Reductive Amination of a-Chloroketones
ˇ
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´
Andrei V. Malkov,* Sigitas Stoncius, and Pavel Kocovsky*
Aziridines constitute the key structural feature of several
classes of natural products and have served in synthesis as
chiral building blocks, intermediates, auxiliaries, and
ligands.[1] To some extent, the synthetic approaches to
enantiopure aziridines mirror those designed for epoxides,
but are often less developed or less general.[1] Aziridine
chemistry is further complicated as a result of the diversity
that is introduced by the N-substituent, a problem that does
not exist with epoxides. Chiral 1,2-disubstituted (terminal)
aziridines 4 (R2 = aryl, Scheme 1) represent a particularly
challenging synthetic target for catalytic protocols.
whole sequence requires five steps from a ketone. Enantio-
merically enriched aziridines can also be synthesized from
chloroaldimines with a chiral auxiliary on the nitrogen atom,
by using a diastereoselective alkylation, followed by a base-
induced cyclization.[8,9]
Among the terminal aziridines, 1,2-diaryl-substituted
derivatives 4 have received little attention despite the fact
that some of them constitute an interesting class of pesticides
with a very low oral mammalian toxicity. Their enantiopure
forms have never been synthesized[10] and early attempts at
asymmetric synthesis have resulted in poor enantioselectivi-
ty.[4a] Herein, we report on a new and practical synthesis of
1,2-diaryl aziridines 4 by the enantioselective reductive
amination of a-chloroketones 1.
We recently developed an efficient procedure for the
asymmetric reduction of prochiral N-aryl ketimines with
trichlorosilane (up to 94% ee), catalyzed by Lewis basic
formamides derived from N-methylvaline (for example, 6 and
7; Scheme 1).[11–13] We reasoned that an analogous reduction
of a-chloroimines 2 would represent an attractive approach to
N-aryl aziridines 4. Despite its apparent simplicity, this
methodology has never been explored in detail. One of the
reasons could be that reduction of a-chloroimines with
complex metal hydrides usually produces mixtures of the
corresponding a-chloroamines, aziridines, and dehalogenated
amines, which has hampered the development of practical
methods.[9] Furthermore, a-chloroketones 1, on reaction with
aliphatic amines, are known to undergo a substitution of the
chlorine atom rather than to form the desired imine.[7] By
contrast, and to our advantage, the less nucleophilic anilines
preferentially form imines 2.
The a-chloroimines 2a–g were prepared from the corre-
sponding a-chloroketones 1 and aniline derivatives (reflux in
toluene with molecular sieves, Scheme 1). Reduction of 2a–g
with Cl3SiH at room temperature, catalyzed by 7 (5 mol%),
proceeded successfully to afford the a-chloroamines (R)-3a–g
in good yields and with up to 96% ee (Table 1, entries 1–8,
method A).
The absolute configuration of the a-chloroamines 3 was
established by a chemical correlation (Scheme 2): (ꢀ)-3a was
deprotected by treatment with trichloroisocyanuric acid
(TCCA)[14] to afford the primary amine 8, which was then
acylated with benzoyl chloride to give the benzamide 9.
Benzamide 9 thus prepared was identical to the material
which was prepared from commercially available (R)-phenyl-
glycinol ((R)-10) by using the benzoylation/chlorination
sequence, and therefore (ꢀ)-3a must have an R configura-
tion. Since this stereogenic center is not affected by the ring
closure of (R)-3a, the absolute configuration of aziridine 4a
remains R. This assignment can be extrapolated to the whole
Scheme 1. Enantioselective synthesis of aziridines; for R1 and R2,see
Table 1. MS=molecular sieves.
To date, a number of approaches to aziridines with varying
degrees of success and limitations have been developed.[1h,2–5]
The most versatile and efficient route to aziridines 4 is the
SN2-type cyclization of enantiopure vicinal amino alcohols 5,
which can be conveniently synthesized by opening of the
corresponding epoxides.[6] An alternative route to 5 employs
an asymmetric reduction (for example, transfer hydrogena-
tion) of N-protected a-amino ketones, which were obtained
from the corresponding a-haloketones 1.[7] However, a-amino
ketones are a rather capricious class of compounds and the
ˇ
ˇ
´
[*] Dr. A. V. Malkov,Dr. S. Stonc ius,Prof. Dr. P. Koc ovsky
Department of Chemistry,WestChem
University of Glasgow,Joseph Black Building
Glasgow G12 8QQ (UK)
Fax : (+)44-141-33-488
http://www.chem.gla.ac.uk/staff/amalkov/
http://www.chem.gla.ac.uk/~pavelk/Homepage.html
E-mail: amalkov@chem.gla.ac.uk
pavelk@chem.gla.ac.uk
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 1: Synthesis of (R)-3 by reduction of 2 (method A)[a] and reductive amination of 1 (method B),[b]
and their cyclization to (R)-4.
and selectivity. Conversely, addition
of a Brønsted acid (for example, 10
mol% of triflic acid) to the original
reaction mixture did not affect the
conversion or enantioselectivity,
which suggests that a trace amount
of Brønsted acid plays a crucial role
in the catalytic cycle by activating
the imine by protonation of the
nitrogen atom. In an optimized
protocol for the reductive amina-
Entry Amine 3 R1
R2
a-Chloroamines
method B[b]
Aziridine 4[d]
yield [%]
method A[a]
yield [%] (ee [%])[c] yield [%] (ee [%])[c] (ee [%])[c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Ph
4-MeOC6H4 98 (96)
4-MeOC6H4 92 (94)
4-MeOC6H4 87 (91)
94 (89)
71 (82)
68 (91)
–
–
–
98 (95)[g]
98 (94)[g]
94[g,h]
92 (90)
–
4-FC6H4
4-ClC6H4
Ph
Ph
Ph
47 (91)
Ph
84 (91)[e]
4-FC6H4
4-ClC6H4
2-naphthyl
4-MeC6H4
Ph
Ph
Ph
78 (87)
94 (86)
69 (81)[e]
–
–
98 [h]
83 (90)[e]
92 (90)
96 (92)
76 [h]
tion,
a threefold excess of the
ketone was used to consume all of
the aniline derivative. Since the
ketones are almost inert to the
reducing agent,[13a] they could be
easily separated from the product.
The direct reductive amination pro-
tocol was employed for a wide
range of a-chloroketones 1, in
which the steric and electronic
properties of the aromatic group
9
4-MeOC6H4
–
–
–
–
–
–
–
–
–
65 (93)
86 (91)
88 (84)
92 (91)
80 (92)
84 (92)[f]
54 (96)[f]
87 (95)
86 (95)
10
11
12
13
14
15
16
17
4-MeOC6H4 4-MeOC6H4
4-CF3C6H4
2-naphthyl
3-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
73 [h]
91 [h]
97 (92)
94 (92)
96 (96)
97[h]
3-MeOC6H4 4-MeOC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
91[h]
[a] Reduction of the imine was carried out on a 0.4-mmol scale with Cl3SiH (2.0 equiv) at RT (188C) for
24 h with catalyst 7 (5 mol%),unless stated otherwise. [b] The reactions were performed with aniline
(0.2 mmol) and a-chloroacetophenone (3 equiv) for 24 h,followed by reduction with Cl 3SiH (2.0 equiv)
for 24 h,both at RT. [c] Determined by HPLC on a chiral stationary phase with a Chiralpak IB column.
[d] Cyclization was carried out in THF on a 0.15-mmol scale with tBuOK (2.0 equiv) at reflux for 0.5 h.
[e] Catalyst loading of 10 mol% was used. [f] The ee value was determined for the corresponding
aziridine. [g] The starting amine 3 was obtained by using method A. [h] The enantiopurity could not be
established,but is assumed to reflect that of the chloroamine employed.
were
systematically
varied
(Table 1). The reaction proved
very efficient and produced the a-
chloroamines (R)-3h–p in high
yield and with up to 96% ee
(Table 1, entries 9–17, method B).
Significantly, the a-chloroketones
underwent facile reductive amination in high yield even
with the less nucleophilic anilines (Table 1, entries 16 and 17).
The cyclization of all the a-chloroamines (R)-3a–p with
tBuOK in THF proceeded readily to furnish the correspond-
ing aziridines (R)-4a–p with no loss in stereochemical
integrity (Table 1).[16,17] Aziridines 4o and 4p represent
single enantiomers of the known racemic pesticides.[10]
In summary, we have developed a new, expedient protocol
for the synthesis of 1,2-diaryl aziridines 4 that have not been
prepared previously as pure enantiomers. The method relies
on an in situ conversion of the readily available a-chloro-
acetophenones 1 into the corresponding a-chloroimines 2 at
RT, followed by reduction of 2 with Cl3SiH, catalyzed by the
l-valine-derived formamide 7 (5 mol%), to afford the
corresponding vicinal a-chloroamines (R)-3 in good yields
and high enantioselectivity (ꢁ 96% ee). Base-mediated ring
closure of these a-chloroamines (R)-3 afforded the aziridines
(R)-4 with preservation of enantiopurity. This new method-
ology is characterized by the use of a metal-free catalyst (7)
and toluene as an environmentally friendly solvent in the key
steps.
Scheme 2. Chemical correlation of the absolute configuration of
(ꢀ)-3a with (R)-10. PMP=para-methoxyphenyl,DIPEA =N,N-diiso-
propylethylamine.
series of 3b–p and 4b–p. It is pertinent to note that for the
deprotection of the nitrogen atom (3!8), which features the
oxidative removal of the PMP group, use of TCCA[14] proved
to be superior to the known methods that employ CeIV or
PhI(OAc)2, which gave intractable mixtures.
In the case of the electron-rich a-chloroketones 1, the
isolation of the corresponding a-chloroimines proved difficult
to the extent that the subsequent reduction could not be
carried out. Therefore, we examined a direct reductive
amination protocol (Table 1, method B), which has never
been attempted before in the reductions with trichloro-
silane.[15] The a-chloroimines 2a–c were generated in situ
(toluene, 5-Š MS, RT) and, without isolation, treated with
trichlorosilane in the presence of the catalyst (Table 1,
entries 1–3, method B). Here, we observed a detrimental
effect caused by the unreacted amine that lowered both the
enantioselectivity and conversion. Model studies carried out
with preformed imines showed that addition of one equiv-
alent of a tertiary amine or proton sponge almost completely
stopped the reaction, thus resulting in a very low conversion
Experimental Section
General procedure for the asymmetric reduction of imines 2 with
trichlorosilane (method A): Trichlorosilane (80 mL, 0.8 mmol,
2.0 equiv) was added dropwise to
a solution of 7 (6.9 mg,
0.02 mmol, 5 mol%) and the corresponding imine 2 (0.4 mmol,
1.0 equiv) in dry toluene (4 mL), precooled to 08C. The reaction
mixture was stirred at room temperature for 24 h, after which time a
Angew. Chem. Int. Ed. 2007, 46, 3722 –3724
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Communications
saturated aqueous solution of NaHCO3 (5 mL) was added to quench
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[9] For the preparation of racemic terminal aziridines 4 by the
reduction of di-and trichloroketimines with complex metal
hydrides, see: a) N. De Kimpe, R. VerhØ, L. De Buyck, N.
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the reaction. The mixture was extracted with EtOAc (2 ” 20 mL) and
the combined organic extracts were dried over MgSO4. Concentration
in vacuo, followed by flash chromatography on silica gel with a
mixture of petroleum ether and ethyl acetate (95:5) afforded amines
3.
General procedure for the asymmetric reductive amination of
ketones 1 (method B): Molecular sieves (5 Š, 200 mg) were added to
a
solution of a-chloroketone 1 (0.6 mmol, 3.0 equiv) and the
corresponding aniline derivative (0.2 mmol) in dry toluene (2 mL)
and the reaction mixture was stirred at room temperature under
argon for 24 h. The reaction mixture was cooled to 08C and catalyst 7
(250 mL, 0.04m solution in dry toluene, 5 mol%) was added, followed
by trichlorosilane (40 mL, 0.4 mmol, 2.0 equiv). The reaction mixture
was stirred at room temperature for 24 h, after which time a saturated
aqueous solution of NaHCO3 (5 mL) was added to quench the
reaction. The mixture was extracted with EtOAc (2 ” 20 mL) and the
combined organic extracts were dried over MgSO4. Concentration
in vacuo, followed by flash chromatography on silica gel with a
mixture of petroleum ether and diethyl ether (97:3 to 90:10) furnished
the amines 3.
General procedure for the synthesis of aziridines 4: tBuOK
(33.5 mg, 0.30 mmol, 2.0 equiv) was added to a stirred solution of a-
chloroamine 3 (0.15 mmol, 1.0 equiv) in dry THF (1.5 mL) and the
resulting suspension was heated at 708C under argon for 0.5 h. The
reaction mixture was cooled to room temperature and filtered
through a pad of celite, the pad was washed with diethyl ether, and the
filtrate was evaporated to dryness. The residue was purified by
column chromatography on silica gel (7 g), pretreated overnight with
triethylamine (1.5 mL) in petroleum ether (50 mL), using a mixture of
petroleum ether and diethyl ether (90:10) as eluent to afford the
corresponding aziridines 4.
[10] P. K. Kadaba, D. L. Dahlman, US Patent 4,582,827, 1983.
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´
[11] a) A. V. Malkov, A. Mariani, K. N. MacDougall, P. Kocovsky,
ˇ
Org. Lett. 2004, 6, 2253 – 2256; b) A. V. Malkov, S. Stoncius, K. N.
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´
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[12] For chiral pyridyloxazolines as catalysts in the reduction of both
imines and ketones, see: A. V. Malkov, A. J. P. Stewart-Liddon,
ˇ
´
P. Ramírez-López, L. Bendovµ, D. Haigh, P. Kocovsky, Angew.
Chem. 2006, 118, 1460 – 1463; Angew. Chem. Int. Ed. 2006, 45,
1432 – 1435.
Received: January 13, 2007
Published online: April 5, 2007
[13] For the asymmetric reduction of imines with trichlorosilane, also
see: a) F. Iwasaki, O. Omonura, K. Mishima, T. Kanematsu, T.
Maki, Y. Matsumura, Tetrahedron Lett. 2001, 42, 2525 – 2527;
b) O. Onomura, Y. Kouchi, F. Iwasaki, Y. Matsumura, Tetrahe-
dron Lett. 2006, 47, 3751 – 3754; c) Z. Wang, X. Ye, S. Wei, P. Wu,
A. Zhang, J. Sun, Org. Lett. 2006, 8, 999 – 1001; d) Z. Wang, M.
Cheng, P. Wu, S. Wei, J. Sun, Org. Lett. 2006, 8, 3045 – 3048.
[14] J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
P. L. Alsters, F. L. van Delft, F. P. J. T. Rutjes, Tetrahedron Lett.
2006, 47, 8109 – 8113.
[15] For the reductive amination of ketones using Hantzsch esters,
see: a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005,
117, 7590 – 7593; Angew. Chem. Int. Ed. 2005, 44, 7424 – 7427;
b) R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am.
Chem. Soc. 2006, 128, 84 – 86.
[16] Under the conditions used, the competing elimination reaction
was largely suppressed. Conversely, the use of the known
protocol (see: T. Satoh, T. Sato, T. Oohara, K. Yamakawa, J. Org.
Chem. 1989, 54, 3973 – 3978) for an analogous ring closure that
employed a mixture of THF with tBuOH as the solvent resulted
in substantial elimination.
[17] On several occasions (Table 1, entries 3, 7, 10–12, 16, and 17), we
could not determine the enantiopurity of aziridines by using
HPLC on a chiral stationary phase. However, in all other cases,
we were able to show that the enantiopurity of 4 reflected that of
3 (Table 1, entries 1, 2, 4, 6, 8, 9, and 13); therefore, the same
behavior can be expected for the rest of the series. Conversely,
we could not establish the enantiopurity of the amines 3m and
3n, though this can be inferred from the enantiopurity of
aziridines 4m and 4n, obtained by their cyclization (Table 1,
entries 14 and 15).
Keywords: amination · asymmetric synthesis · aziridines ·
organocatalysis · reduction
.
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