Titanocene-Catalyzed Radical Opening of N-Acylated Aziridines

Article abstract of DOI:10.1002/anie.201707673

Aziridines activated by N-acylation are opened to the higher substituted radical through electron transfer from titanocene(III) complexes in a novel catalytic reaction. This reaction is applicable in conjugate additions, reductions, and cyclizations and suited for the construction of quaternary carbon centers. The concerted mechanism of the ring opening is indicated by DFT calculations.

Full text of DOI:10.1002/anie.201707673

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Title: Titanocene-Catalyzed Radical Opening of N-Acylated Aziridines
Authors: Andreas Gansäuer, Yong-Qiang Zhang, Elisabeth Vogelsang,
Zheng-Wang Qu, and Stefan Grimme
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10.1002/anie.201707673
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Titanocene-Catalyzed Radical Opening of N-Acylated Aziridines
Yong-Qiang Zhang, Elisabeth Vogelsang, Zheng-Wang Qu, Stefan Grimme, and Andreas Gansäuer*
Abstract: Aziridines activated by N-acylation are opened to the higher
substituted radicals through electron transfer from titanocene(III)
complexes in a novel catalytic reaction. It is applicable in conjugate
additions, reductions, and cyclizations and suited for the constructions
of quaternary carbon centers. The concerted mechanism of ring-
opening was established by DFT-methods.
aminoketyl radicals B or in a concerted process. The potential of
the radicals C for the synthesis of functionalized amides is largely
untapped. As yet, they have been generated from N-benzoyl
aziridines with stoichiometric amounts of Bu3SnH or via electron
transfer from arene radical anions.[4] They were reduced either in
a radical chain reaction or by a second electron transfer and
protonation. In both cases, B was postulated as intermediate in
the ring-opening.
Aziridines are versatile building blocks for the preparation of
functionalized amines. Ring opening of N-activated aziridines via
SN2 reactions is widely used and usually occurs at the less
substituted carbon center.[1] Transition-metal catalyzed cross
couplings of N-sulfonylated aziridines with alkyl zinc reagents
have recently emerged as a versatile C-C bond forming reaction[2]
leading to the cleavage of either the benzylic C-N or the less
substituted C-N bond. To the best of our knowledge, a general
method for aziridine opening at the higher substituted carbon has
not been developed.
The key feature of N-acyl aziridines in our approach is their
reduced amide resonance[5] that should render electron transfer
in A more facile. Titanocene(III) complexes do not reduce typical
amides.[6] The diminution of the amide resonance by the
introduction of two electron withdrawing groups on N has recently
been used for the generation of amino ketyl radicals derived from
cyclic imides and related compounds.[7] This reaction uses
stoichiometric amounts of SmI2-containing water as an additive, a
process likely proceeding through PCET given the energetics of
a sequential process.[8]
We identified suitable conditions for the catalytic aziridine
opening by trapping the putative radicals with tbutyl acrylate
(Scheme 1, Table 1).[9]
Table 1. Identification of suitable conditions for catalytic radical opening of
N-acyl aziridines (Coll = 2,4,6-trimethyl pyridine).
Entry
Cat.
M-mol%
Coll∙HX
Coll∙HCl
Coll∙HCl
Coll∙HCl
Coll∙HBr
Coll∙HBr
Yield (%)
1
2
3
4
5
Cp2TiCl2
10
10
10
10
5
22
46
80
82
76
(C5H4Me)2TiCl2
(C5Me5)2TiCl2
(C5Me5)2TiCl2
(C5Me5)2TiCl2
Scheme 1. Proposed catalytic cycle for the trapping of N-acyl aziridine derived
radicals ([TiIV] = [(C5Me5)2TiX], X = Cl or Br).
Conditions: Catalyst (M-mol%), Mn (2.0 eq.), Coll∙HX (2.5 eq.), tbutyl
acrylate (5.0 eq.), 1 (0.125 M in THF), RT.
The standard conditions for titanocene catalyzed epoxide
opening (entry 1) failed to give a satisfactory yield of 2.[10] Instead,
the stronger reductant (C5Me5)2TiCl is required for efficient
electron transfer to the carbonyl group (entries 2-4).[11] Catalyst
loading can be reduced to 5 mol% without significant reduction in
the yield of 2. Coll•HCl and Coll•HBr are both suitable acids for
mediating catalytic turn-over.[12]
Here, we describe the first catalytic ring opening addressing this
issue. It employs N-acyl aziridines as substrates for the
generation of radicals C bearing β–amido substituents (Scheme
1). Electron transfer in the titanocene(III) substrate complex A[3] is
expected to result in the ring-opened carbon centered radicals C.
This can occur either in a stepwise opening via formation of
The generality of our reaction was investigated next (Table 2).
First, we explored the influence of the carbonyl substituent. Due
to a reduced stability of the substrates, the formyl group (entry 2)
is inferior. Gratifyingly, aziridinyl carbamates (entries 3 and 4)
were also efficient substrates at slightly higher temperature (50
°C) through unprecedented electron transfer to a carbamate. The
BOC-substituted substrate (entry 4) is of practical importance
because it allows a straightforward amine synthesis after acidic
removal of the protecting group.
[a]
[b]
Dr. Y.-Q. Zhang, E. Vogelsang, Prof. Dr. A. Gansäuer
Kekulé-Institut für Organische Chemie und Biochemie
Universität Bonn
Gerhard Domagk Strasse 1, 53121 Bonn, Germany
E-mail: andreas.gansaeuer@uni-bonn.de
Dr. Z.-W. Qu, Prof. Dr. S. Grimme
Mulliken Center for Theoretical Chemistry
Institut für Physikalische Chemie und Theoretische Chemie
Universität Bonn
Beringstrasse 4, 53115 Bonn, Germany
Supporting information for this article is given via a link at the end of
the document.
The catalytic opening can be carried out with mono-, di-, and
trisubstituted aziridines and results in the exclusive formation of
the products derived from ring opening at the higher substituted
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10.1002/anie.201707673
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carbon center. The functional group tolerance of the reaction is
high (entries 11-14). Thus, our method is a broadly applicable
method and highly efficient for the synthesis of quaternary alkyl
substituted carbon centers. With 17 no cyclic trapping product by
the alkyne was obtained.
The trapping of the aziridine-derived radicals is not confined to
tbutyl acrylate (Scheme 2). α–Methylene lactone, acrylamide, and
vinyl sulfone,[14] can be employed to deliver the products in
satisfactory yields. Interestingly, the use of ethyl (E)-penta-2,4-
dienoate results in the formation of the (E)-β,γ–unsaturated ester
as single isomer.
Table 2. Scope of the opening of N-acyl aziridines as function of their
substitution pattern.
To understand the mechanism of the ring-opening, we studied
the reaction of 1 by DFT calculations (Scheme 3) at the TPSS-
D3/def2-QZVP + COSMO-RS (THF)//TPSS-D3/def2-TZVP +
COSMO (THF) level.[15]
Scheme 2. Michael acceptors in the catalytic aziridine opening. Conditions:
(C5Me5)2TiCl2 (10 mol%), Mn (2.0 eq.), Coll∙HBr (2.5 eq.), activated olefin (5.0
eq.), THF, RT.
Scheme 3. TPSS-D3/def2-QZVP + COSMO-RS (THF) computed free energy
paths (in kcal/mol) for the opening of 1. Transition structures are shown with the
respective crucial Ti (white), Cl (green), O (red), C (grey) and N (blue) atoms.
TPSS-D3/def2-TZVP + COSMO (THF) computed Mulliken spin densities (>0.1e,
in italics) are indicated.
Conditions unless otherwise noted: (C5Me5)2TiCl2 (10 mol%), Mn (2.0 eq.),
Coll∙HBr (2.5 eq.), tert-butyl acrylate (5.0 eq.), aziridine (0.125 M in THF),
RT. [a] (C5Me5)2TiCl2 (15 mol%). [b] 50 °C. [c] (C5Me5)2TiCl2 (20 mol%). [d]
70 °C. Boc = tert-butyloxycarbonyl; Bz = benzoyl.
The formation of the two complexes A and A’ that differ in
structure by a rotation of the substrate by 180° from (C5Me5)2TiCl
and 1 is exothermic but endergonic due to unfavorable entropy
effects. Both complexes are similar in energy. The formation of
the primary radicals Cprim and Cprim’ is thermodynamically and
With the strained tricyclic substrate 19,[13] ring opening leads to
the spirobicyclic product 20 via the secondary radical. Consistent
with the experiment, a similar mechanism is found by DFT
calculations for the ring-opening of tricyclic substrate 19, but with
a slightly lower barrier for the formation of the secondary radical
due to ring strain effects (See SI for details).
kinetically disfavored. The transition states TSCprim and TSCprim
’
have a higher spin density (0.56 and 0.50 electrons, respectively)
at the developing primary radical explaining the high ΔG≠.
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The formation of the tertiary radicals is thermodynamically
unfavorable from A but slightly favored from A’. Moreover, TSCtert
is noticeably lower in energy than TSCtert. This is due to reduced
steric interactions, a lower spin density at the developing tertiary
with Crabtree’s catalyst[17] in high selectivity to furnish 41 that may
be of potential interest for the synthesis of biologically active
substances.[18]
’
In summary, we have developed the first catalytic radical
opening reaction of N-acylated aziridines. The reaction is highly
regioselective, has a broad substrate scope and functional group
tolerance, and can be used in cyclizations, reductions, and
additions to activated olefins. Through DFT calculations, we have
shown for the first time that the ring-opening of N-acyl aziridines
through electron transfer can proceed in a concerted manner.
radical, and a higher spin density at Ti. For both Ctert and Ctert
’
trapping by tbutyl acrylate has a lower ΔG≠ than closure to A and
A’ (see SI for details). This should result in an irreversible ring-
opening.
In none of the cases discussed above, we were able to locate a
structure for an aminoketyl radical B. Therefore, our data is
consistent with the titanocene catalyzed ring-opening of N-acyl
aziridines occurring through a concerted and not a step-wise
process as suggested for other cases. [4a-c]
Experimental Section
1,4-cyclohexadiene (CHD) is an efficient H-atom donor for the
reduction of N-acyl aziridine derived radicals (Table 3). The
regioselectivity of ring opening to yield the less substituted amide
or carbamate is complete except for 15 (entry 4), when a 90:10
mixture or regioisomers was obtained. The Bu3SnH-mediated
opening[4a] requires N-Benzoyl substitution and is less general.
A heat-dried Schlenk tube was charged with Coll•HBr (2.5 eq.) under Ar
and the Schlenk tube was gently heated under vacuum. Mn (2.0 eq.),
(C5Me5)2TiCl2 (0.1 eq.) and THF were added. The mixture was stirred for
10 min. tButyl acrylate (5.0 eq.) followed by the aziridine (1.0 eq, 0.125 M
in THF) was added. After stirring at indicated temperature for 16 h, the
reaction mixture was filtrated through a plug of SiO2 with EtOAc. The crude
product was purified by flash chromatography on silica gel.
Table 3. Reduction of aziridines through HAT.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (Gottfried-
Wilhelm-Leibniz prize to S. G., Ga 619/12-1), the Studienstiftung
des deutschen Volkes (E. V.), and the Alexander von Humboldt-
Stiftung (research fellowship to Y.-Q. Z.).
Keywords: Aziridine • Conjugate addition • Radical opening •
Reduction • Titanocene
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Entry for the Table of Contents
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Y.-Q. Zhang, E. Vogelsang, Z.-W. Qu, S.
Grimme, and A. Gansäuer*
Page No. – Page No.
Titanocene-Catalyzed Radical
Opening of N-Acylated Aziridines
The first catalytic generation of β-amido substituted radicals from N-acyl aziridines is
described. The radicals that are generated with excellent regioselectivity are useful
intermediates for intermolecular additions, reductions, and cyclizations to yield
functionalized amides. Through calculations we have shown that the ring opening is
concerted and not step-wise as previously postulated.
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