Synthesis of 1,3-Amino Alcohols by Hydroxy-Directed Aziridination and Aziridine Hydrosilylation

Article abstract of DOI:10.1002/anie.201808034

We describe an approach to N-tosyl 1,3-amino alcohols that consists of a diastereoselective aziridination reaction of acyclic allylic alcohols and an unprecedented regioselective hydrosilylation of α-hydroxy aziridines. The products contain up to three co

Full text of DOI:10.1002/anie.201808034

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Accepted Article
Title: Synthesis of 1,3-Amino Alcohols via Hydroxy-Directed
Aziridination and Aziridine Hydrosilylation
Authors: Andreas Gansäuer, Stefan Grimme, Yong-Qiang Zhang,
Robin Bleith, Fabian Bohle, and Gregor Schnakenburg
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808034
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10.1002/anie.201808034
Angewandte Chemie International Edition
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Synthesis of 1,3-Amino Alcohols by Hydroxy-Directed
Aziridination and Aziridine Hydrosilylation
Yong-Qiang Zhang,[a] Fabian Bohle,[b] Robin Bleith,[a] Gregor Schnakenburg,[c] Stefan Grimme,*[b] and
Andreas Gansäuer*[a]
Dedicated to Prof. M. T. Reetz on the occasion of his 75th birthday
Abstract: We describe an approach to N-tosyl 1,3-amino alcohols
that consists of a diastereoselective aziridination reaction of acyclic
allylic alcohols and an unprecedented regioselective hydrosilylation of
α-hydroxy aziridines. The products contain up to three contiguous
stereocenters. Computational studies outline key-aspects of the
aziridination mechanism that is more intricate and different than
anticipated.
The hydrosilylation of aziridines is, to the best of our
knowledge, unprecedented. The diastereoselectivity of the
aziridination of allylic alcohols has only been studied with cyclic
systems.[12] To investigate the aziridination of acyclic allylic
alcohols, we selected 1a as model substrate. The reaction
proceeds in high yield to provide 2a with a syn:anti-selectivity of
89:11 in CH3CN (entry 1).[10]
Table 1. Optimization of the diastereoselective aziridination of 1a and 1b.
1,3-amino alcohols are important structural units in natural
products,[1] pharmaceuticals,[2] ligands for catalysis,[3] and
synthetic intermediates.[4] The Mannich reaction as well as
additions of metalated N-sulfonyl imines to aldehydes, have, in
combination with reductions of ketones or imines, been utilized for
1,3-amino alcohol synthesis.[5,6] Recently, transition metal
catalyzed additions to allenes,[7] allylic aminations,[8] and C-H
aminations[9] emerged as alternative methods that mostly employ
tethered carbamates as substrates.
Entry
Substrate
Solvent
Conversion
(%)
Yield(%)[a]
d.r. [b]
1
2
3
4
1a
1a
1a
1a
CH3CN
Toluene
CH2Cl2
100
36
87
21
42
82
89:11
85:15
95:5
Here, we describe a complementary strategy to 1,3-amino
alcohols from readily accessible allylic alcohols. It consists of a
diastereoselective aziridination of acyclic allylic alcohols via the
70
CH2Cl2:CH3CN
(v/v 1:1)
100
93:7
excellent
Sharpless-protocol[10,11]
and
a
regioselective
hydrosilylation of the α-hydroxy N-tosyl aziridines. The products
may contain three contiguous stereocenters (Scheme 1).
5
6
1a
1b
CH2Cl2:CH3CN
(v/v 4:1)
100
<5
82(76[c]
)
95:5
-
CH2Cl2:CH3CN
(v/v 4:1)
-
Conditions: substrate (0.5 mmol), chloroamine-T (0.6 mmol), PTAB (10
mol%), solvent (2.5 mL), RT. [a] NMR yield. [b] By 1H-NMR of the reaction
mixture. [c] Isolated yield of the major isomer. PTAB = PhNMe3+ Br3 .
-
Scheme 1. The synthesis of 1,3-amino alcohols via diastereoselective
aziridination and regioselective hydrosilylation. Ts = tosyl.
In CH2Cl2 the selectivity is substantially higher (95:5) at the
expense of a lower yield (42%). A solvent mixture (CH2Cl2:
CH3CN = 80:20 v/v) combines the advantages of both solvents to
give 2a in high selectivity (95:5). The major isomer was isolated
in 76% yield. Its relative configuration was established by X-ray
crystallography.[13] The O-methylated 1b does not lead to product
formation. Thus, the free hydroxy group is essential for the
reaction. Other (Z)-2,3-disubstituted allylic alcohols are equally
suitable substrates (Table 2A).
2,3,3-trisubstituted allylic alcohols are aziridinated in excellent
selectivities (>96:<4) (Table 2B) while (E)-2,2,3-trisubstituted
allylic alcohols displayed low reactivity in CH2Cl2/CH3CN. In
CH3CN, the diastereoselectivity was in the range of 81:19 to 87:13
and the major anti-isomers were obtained in yields around 60%
(Table 2C).
[a]
[b]
[c]
Dr. Y.-Q. Zhang, R. Bleith, 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
F. Bohle, Prof. Dr. S. Grimme
Mulliken Center for Theoretical Chemistry
Institut für Physikalische Chemie und Theoretische Chemie
Universität Bonn
Beringstraße 4, 53115 Bonn, Germany
Dr. G. Schnakenburg
Institut für Anorganische Chemie
For the synthesis of the desired 1,3-amino alcohols a general
method for the reduction of the aziridines at the C2 is required. It
must be regioselective and has to occur at tertiary carbons.
Moreover, the reduction must provide a stereochemically uniform
Universität Bonn
Gerhard Domagk-Straße 1, 53121 Bonn, Germany
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808034
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product and should work with primary, secondary, and tertiary
alcohols in the aziridine substrates.
properties. Reaction pathways and initial guesses on the
transition states were prepared by employing the GSM[21] method
together with the robust and fast tight-binding quantum chemical
method GFN-xTB.[22] The resulting reaction paths were refined
with GSM at the PBEh-3c/DCOSMO-RS DFT-level. Free
energies are calculated on the optimized DFT geometries as the
sum of the electronic energy, thermo statistical and solvation
contributions to the free energy. The highest level electronic
energy is obtained with a hybrid density functional in a large basis
Table 2. Diastereoselective aziridination of acyclic allylic alcohols.[a]
set, including
a
dispersion correction PW6B95-D3/QZ.[23]
Thermostatistical contributions are included at the level of
geometry optimization and COSMO-RS[24] is applied as solvation
correction to free energy. Free barriers of activation are then
obtained as the difference between the free energy of the
transition state and the corresponding substrates. All ΔG values
were computed at 298.15 K and 1 bar pressure in the solvents
CHCl3, CH2Cl2 and CH3CN.
Table 3. Regioselective hydrosilylations of α-hydroxyaziridines.[a]
[a] Isolated yields of the major isomers. d.r. by 1H-NMR of the crude reaction
mixture. Conditions: allylic alcohol (0.5 mmol), chloramine-T (0.6 mmol),
PTAB (10 mol%), CH2Cl2/CH3CN (2.0/0.5 mL), RT. [b] CH3CN (2.5 mL). [c]
anti-configuration by x-ray of the minor diastereomer 10'. [d] Combined
yields of both isomers.
The methods employing LiAlH4[14] or Red-Al[14] are unsuitable
because reduction at tertiary C-atoms is not possible and
secondary or tertiary alcohols fail to act as directing groups.
Hydrosilylation reactions of epoxides are useful methods for
the preparation of alcohols as shown in recent years.[15] Our
fluoride mediated hydroxy-directed synthesis of 1,3-diols from
Sharpless epoxides is attractive for our purposes, because it
provides the 1,3-diols with a completely regioselective ring-
opening at C2 under inversion of configuration even at tertiary
carbon centers.[15b,d] Gratifyingly, it also provides the 1,3-amino
alcohols as single isomers from α–hydroxy aziridines (Table 3).
The substitution pattern at the alcohol does not affect the
outcome of the reaction and ring-opening reaction at tertiary C-
centers proceeds smoothly. This allows the preparation of 1,3-
amino alcohols with three contiguous stereocenters that are of
high synthetic value and difficult to access otherwise. The
deuteration experiments provide the diastereomeric products 35
[a] Conditions: aziridine (0.5 mmol), PhSiH3 (2.0 eq), TBAF (0.6 mmol), THF
(2.0 mL), RT. TBAF = n-Bu4NF. THF = tetrahydrofuran.
In olefin brominations, a π-complex of Br2 and the olefin is
initially formed that can fragment to give a bromonium ion.
Alternatively, in the presence of bromide, the π-complex can
directly react via attack of nucleophile to yield the 1,2-addition
product.[25a-c] For PTAB catalyzed aziridinations a bromonium ion
was postulated as key-intermediate in the catalytic cycle.[10,12]
Therefore, we started our computational investigation with 1aBr
and 1a’Br (Scheme 2). However, all reactions of 1aBr and 1a‘Br
with TsNCl- proceed barrierless (see SI for details). Thus, the
diastereoselectivity of the PTAB catalyzed aziridination of 1a
cannot be accounted for with bromonium ions as intermediates.
Experimental studies on brominations have shown that the
formation of bromonium ions only occurs in the absence of
and 36 stereospecifically. This is in line with an SN2 mechanism
[16]
and rules out Meinwald
and semipinacol rearrangements[17]
.
Therefore, the reaction constitutes an example of an SN2-reaction
at tertiary C-atoms.[18]
In order to understand the selectivities in the formation of the
α-hydroxy aziridines, we studied the aziridination of 1a
computationally employing an established multilevel ansatz[19]. All
geometries are optimized with the global hybrid PBEh-3c[20] in
combination with the implicit solvent model COSMO. PBEh-3c
yields reliable structures and offers good thermochemical
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10.1002/anie.201808034
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nucleophiles and requires a protic solvent or excess Br2 to
calculated next. TS2 and TS3 that feature hydrogen bonding of
TsNCl- are lower in energy than TS1 and TS4 because 1,3-attack
is more favorable than 1,2-attack (Scheme 3A). More polar
solvents lead to lower barriers for the nucleophilic attack. This can
be rationalized by less repulsive values for ΔδGsolv (see SI for
details). The trends for the reaction barriers are not affected.
For all solvents, TS2 is favored over TS3 isomer by 2.6-3.0
kcal mol-1. Thus, the formation of the preferred isomer is correctly
predicted (d.r. of 2a: 95:5 experimentally and 99:1
computationally). The repulsive 1,3-interaction between the
phenyl and the methyl group in TS3 seems responsible for the
difference in stability. The absence of hydrogen bonding leads to
substantially disfavored TS5-TS8 (Scheme 3B). This is because
of the lack of the attractive interaction between the hydroxy group
and TsNCl- ion and a repulsion between the hydroxy group and
the π-complexed Br2.
facilitate ionization of the π-complex.[25a-c]
Scheme 2. Bromonium ions 1aBr and 1a’Br and π-Complexes 1aπ and 1a’π from
1a.
Compared to Br2, the corresponding H-bonded transition
states with BrNTs(Cl), an oxidant formed from Br2 and TsNCl-, are
higher in energy by 4 – 9 kcal mol-1 due to increased steric
interactions (see SI for details).
As with Br2, with BrCl the reaction proceeds via hydrogen
bonded TsNCl- with a transition state similar to TS2 being most
favorable. The differences between the transition state energies
and, thus, the computed diastereoselectivity of the addition to the
olefin (99:1) are similar to the reactions with Br2 but all barriers
are lower by about 2 kcal mol-1 than for Br2. Therefore, the 1,2-
addition is faster with BrCl. This is due to the positive partial
charge on Br (see SI for details).
Scheme 3. A) Transition states for the aziridination of 1a with hydrogen bonding.
B) Transition states for the aziridination of 1a without hydrogen bonding in CHCl3.
Therefore, we investigated π-complexes as intermediates in
the aziridination. They have been proposed and discussed in the
PTAB catalyzed ring-opening of vinylcyclopropanes.[25e] 1aπ and
1a’π are almost identical in stability with 1a’π being favored by 0.3,
0.7, and 0.8 kcal mol-1 (CHCl3, CH2Cl2, CH3CN). The activation
barriers for the ring-opening of 1aπ and 1a’π with TsNCl- were
Scheme 4. Transition state models for the aziridination of allylic alcohols.
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governed by the 1,3-interaction (Scheme 4B). Therefore, the syn-
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interaction shown and the anti-product is formed preferentially.
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types above and, thus, the 1,2-interaction seems to be weaker
than the 1,3-interaction.
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2,2,3-trisubstituted can also be deduced from the transition state
models. In the former case, there are no destabilizing interactions
in both transition states and, thus, aziridination occurs with low
selectivity. In the latter case, in both transition states repulsive
interactions are operating and the aziridination proceeds without
selectivity and is noticeably slower than for the other substitution
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In summary, we have developed a novel method for the
synthesis of N-tosylated 1,3-amino alcohols from allylic alcohols
in a two-step procedure. In the first step, α-hydroxy N-tosylated
aziridines are obtained from acyclic allylic alcohols with
unprecedented diastereoselectivity via the PTAB catalyzed
aziridination. The computational analysis of the addition reveals
that π-complexes of Br2 or BrCl are intermediates in the
aziridination and not the previously proposed bromonium ions.
Hydrogen bonding of TsNCl- by the hydroxy group is essential.
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interactions between the substituents of the allylic alcohol in the
transition states of attack on the π-complex. The unprecedented
hydroxy directed hydrosilylation of the aziridines yields N-
tosylated 1,3-amino alcohols via an SN2-mechanism even at
tertiary C-atoms. The products may contain three contiguous
stereocenters. Such compounds are of high synthetic value and
difficult to prepare otherwise.
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Acknowledgements
We gratefully acknowledge generous support by the DFG in the
framework of the Leibniz prize to S.G.
Keywords: 1,3-amino alcohol • aziridination •
diastereoselectivity • hydrosilylation • reaction mechanism
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Entry for the Table of Contents
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Y.-Q. Zhang, F. Bohle, R. Bleith, G.
Schnakenburg, S. Grimme,* A.
Gansäuer*
Page No. – Page No.
Synthesis of 1,3-Amino Alcohols via
Hydroxy-Directed Aziridination and
Aziridine Hydrosilylation
We describe an approach to N-tosylated 1,3-amino alcohols via a
diastereoselective aziridination of acyclic allylic alcohols and a novel regioselective
hydrosilylation of α-hydroxy aziridines via SN2 even at tertiary C-atoms. Our
computational studies show that the previously proposed bromonium ions are not
involved in the aziridination but π-complexes of the olefins with Br2 or BrCl.
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