Angewandte
Communications
Chemie
Aminohydroxylation
Direct Catalytic Synthesis of Unprotected 2-Amino-1-Phenylethanols
from Alkenes by Using Iron(II) Phthalocyanine
Luca Legnani and Bill Morandi*
Abstract: Aryl-substituted amino alcohols are privileged
scaffolds in medicinal chemistry and natural products.
Herein, we report that an exceptionally simple and inexpensive
FeII complex efficiently catalyzes the direct transformation of
simple alkenes into unprotected amino alcohols in good yield
and perfect regioselectivity. This new catalytic method was
applied in the expedient synthesis of bioactive molecules and
could be extended to aminoetherification.
T
he direct catalytic synthesis of amine-containing molecules
from simple alkenes is a critical challenge in the synthesis of
bioactive molecules.[1] 2-Amino-1-phenylethanol derivatives
are a particularly important subclass of amino alcohols
(Scheme 1) that is widely represented in marketed drugs
and bioactive compounds.[2,3] The rapid synthesis of this
structural motif is thus of outmost important to the drug
discovery process.
Scheme 2. Context of the work.
stituents (Me and Ar) have been documented.[6] No catalytic
reactions have been reported to date that are capable of
directly introducing the ideal unprotected amino alcohol
motif, despite the potential for such a reaction to dramatically
increase the step and atom economy of the aminohydrox-
ylation reaction and streamline the synthesis of bioactive
compounds.[6a,9] Herein, we report a novel and efficient iron-
catalyzed aminohydroxylation of alkenes that enables the
direct synthesis of unprotected amino alcohols (Scheme 2b).
The direct catalytic synthesis of unprotected amino
alcohols has remained challenging in part because the
products can strongly chelate the metal catalyst and inhibit
the catalytic cycle.[10] In our design, we reasoned that the use
of a protonated amino source should prevent any undesired
chelation of the catalyst and would likely favor the formation
of highly electrophilic nitrogen intermediates that can readily
react with alkenes. We therefore investigated a series of
various transition-metal catalysts with PivONH3OTf as an
easily accessible, shelf-stable aminating[11] reagent (Table 1
and Table S1 in the Supporting Information). Neither Mn nor
Cu complexes known to catalyze amination reactions initi-
ated by SET[5a,7b] afforded the desired product in more than
10% yield (Entries 1–2) and most of the styrene starting
material was left unreacted. Simple FeII salts proved more
effective (Entries 3–4), giving up to 42% yield of desired
product 2. However, in contrast to the Mn and Cu catalysts,
the styrene was completely consumed under Fe catalysis.[12]
The addition of bipyridine and phenanthroline to FeSO4
revealed a significant ligand effect (Entries 5–6).
Scheme 1. Medicinal importance of 2-amino-1-phenylethanols.[3]
Several catalytic approaches have been developed to
access 2-amino-1-phenylethanols from alkenes by using
different protecting-group strategies (Scheme 2a).[4–8] Many
transformations provide the amino alcohol bearing protecting
groups on both the N and O atoms,[4] including Fe- and Cu-
catalyzed reactions using alkenes and hydroxylamine-derived
reagents. Alternatively, methods have been developed to
introduce a protected form of the N atom only.[5] Among
them, Os-catalyzed aminohydroxylation is still the most
commonly employed method to access amino alcohol deriv-
atives from alkenes. More recently, a Mn-catalyzed two-step
process was reported that enables the preparation of azido
alcohols.[5a] Finally, a few scarce examples of the synthesis of
primary aminoethers bearing poorly cleavable O-atom sub-
[*] L. Legnani, Dr. B. Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: morandi@kofo.mpg.de
Supporting information and ORCID(s) from the author(s) for this
Ultimately, inexpensive and widely available FeII Phtha-
locyanine (FeIIPc) gave full conversion to a single regioisomer
2248
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2248 –2251