Intramolecular N-Me and N-H aminoetherification for the synthesis ofN-unprotected 3-amino-O-heterocycles

Article abstract of DOI:10.1039/d0ob02122a

A mild Rh-catalyzed method for synthesis of cyclic unprotected N-Me and N-H 2,3-aminoethers using an olefin aziridination-aziridine ring-opening domino reaction has been developed. The method is readily applicable to the stereocontrolled synthesis of a va

Full text of DOI:10.1039/d0ob02122a

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Intramolecular N–Me and N–H
aminoetherification for the synthesis of
N-unprotected 3-amino-O-heterocycles†
Cite this: Org. Biomol. Chem., 2021,
19, 557
Received 20th October 2020,
Accepted 17th December 2020
Mahesh P. Paudyal,‡a Mingliang Wang,‡b Juha H. Siitonen, c Yimin Hu,d
Muhammed Yousufuddin,e Hong C. Shen,*d John R. Falck *a and László Kürti
*
c
DOI: 10.1039/d0ob02122a
rsc.li/obc
A mild Rh-catalyzed method for synthesis of cyclic unprotected
N–Me and N–H 2,3-aminoethers using an olefin aziridination–
aziridine ring-opening domino reaction has been developed. The
method is readily applicable to the stereocontrolled synthesis of a
variety of 2,3-disubstituted aminoether O-heterocyclic scaffolds,
including tetrahydrofurans, tetrahydropyrans and chromanes.
The 2-aryl-3-amino-O-heterocyclic motif is present in several
alkaloids as well as active pharmaceutical ingredients
(Scheme 1A).1 Conceptually, the intramolecular ring-opening
of aziridines with O-nucleophiles is a very direct synthetic
approach for the construction of these 2-aryl-3-amino-O-
heterocycles (Scheme 1B). This type of an approach has been
studied by the Zhang, Weng and Dauban groups
(Scheme 1C).2 However, these previous synthetic approaches
result in sulfonamide-protected amines which either require
harsh deprotection conditions or suitable deprotection con-
ditions have not yet been developed.3 We envisioned that our
recently developed Rh-catalyzed N–H and N–Me olefin aziridi-
nation reaction could be used in combination with styryl alco-
hols. This would allow us to circumvent the issues pertaining
to the heavily protected amines and gain direct access
to readily functionalizable N–H heterocyclic scaffolds
aDivision of Chemistry, Departments of Biochemistry and Pharmacology,
University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
E-mail: j.falck@utsouthwestern.edu
bDepartment of Natural Products Chemistry, Fudan University, 826 Zhangheng Road,
Shanghai 201203, P. R. China
cDepartment of Chemistry, Rice University, 6500 Main Street, Houston, Texas 77030,
USA. E-mail: lk18@rice.edu
dRoche Pharma Research & Early Development, Roche Innovation Center Shanghai,
Roche R&D Center (China) Ltd, Building 5, No. 371, Lishizhen Road,
Shanghai 201203, P. R. China. E-mail: hong.shen.hs1@roche.com
eLife and Health Sciences Department, The University of North Texas at Dallas,
7400 University Hills Boulevard, Dallas, TX 75241, USA
Scheme 1 (A) 2-Aryl-3-amino-O-heterocyclic motifs present in alka-
loids and pharmaceuticals. (B) Conceptual approach to preparing 2-aryl-
3-amino-O-heterocyclic systems. (C) Literature precedent for ami-
noetherification of styrylethanols resulting in sulfonamide protected
compounds. Proposed approach to prepare N–H and N–Me aminoether
products.
†Electronic supplementary information (ESI) available: Synthetic procedures
and characterization data. CCDC 2038759. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d0ob02122a
‡Equal contributions.
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(Scheme 1C).4 Furthermore, we were interested in expanding p-F 3h 78%) as well as a variety of functional groups (p-CN 3i
to alternative O-nucleophilic partners such as phenols and 76%, p-CO2Me 3j 82%, p-S(vO)Me 3l 58%). The cyclization
extended styryl alcohols to access structurally more complex was also amenable for the synthesis of uncommon
O-heterocycles.
O-heterocyclic scaffolds. For example, tetrahydropyran 3m
The main challenge was to find a suitable aminating could be obtained in 76% isolated yield when trans-styryl-pro-
reagent for the Rh-catalyzed aziridination: (1) the aminating panol (1m) was used as the starting material.6 The reaction
reagent must be sufficiently active to generate the Rh-nitrenoid could also be carried out with a phenol as the internal nucleo-
and (2) the leaving group of the aminating reagent has to be phile, furnishing the corresponding aminochromane 3n.7
essentially non-nucleophilic. The low nucleophilicity of the Notably, aliphatic olefins 1o, 1p and 1q proved to be viable
leaving group would ensure that it will not compete with the substrates in this N–Me aminoetherification, yielding tetrahy-
desired intramolecular aziridine ring-opening.5
drofurans 3o and 3p and tetrahydropyran 3q (Scheme 3).8,9
With these two criteria in mind, we initiated the studies However, with these aliphatic olefin substrates, extended reac-
with O-tosyl hydroxylamines (TsOHN2 and TsONHMe) as elec- tion times were required (74 h for 3p vs. 6 h for 3a). No other
trophilic aminating reagents. After an optimization study with ring-size products apart from those shown in Scheme 3 were
trans-styryl ethanol (1a) as the model substrate (see ESI†), the isolated from these reactions.
highest-yielding conditions were found to use TsONHMe (2) as
With these results for N–Me aminoetherification in hand,
the nitrogen source with a 1 mol% loading of [Rh2(esp)2] in next we explored the corresponding N–H variant. In the initial
2,2,2-trifluoroethanol (CF3CH2OH, TFE) at 65 °C. This reaction screening TsONH2 was found to be too unstable as a practical
afforded the desired N–Me-2,3-trans-tetrahydrofuran 3a in 85% nitrogen source for the in situ N–H aziridination with 1a.
isolated yield as a single trans-diastereomer.
Further screening revealed that O-(4-nitrobenzoyl)-hydroxyl-
With the established optimized conditions in hand, we amine (4) (NbzONH2) was a suitable alternative to TsONH2.
screened the scope of substrates for the N–Me aminoetherifica- When styryl–ethanol 1a was reacted with NbzONH2 (4) and
tion–cyclization reaction using TsONHMe (2) as the nitrogen [Rh2(esp)2] (2 equivalents and 2 mol% respectively), introduced
source (Scheme 2). The reaction showed great tolerance toward to the reaction mixture in two equal portions, the corres-
electronically very different styrenes (compare p-OMe 3b 85%, ponding primary aminotetrahydrofuran 5 was isolated in 53%
yield (Scheme 3). For the most reproducible results, the
[Rh2(esp)2] catalyst is added directly to a vigorously (1400 rpm)
stirred solution of the styryl–alcohol substrate and NbzONH2
(4) in TFE as the solvent.
We expected that using Z-styryl alcohols as the starting
materials would allow us to directly prepare cis-2,3-aminotetra-
hydrofurans. However, the aziridination–cyclization reaction
using Z-styrylethanol (Z-1a) as the starting material yielded a
2 : 1 trans/cis mixture in a 67% combined isolated yield
Scheme 2 Substrate scope for aminoetherification protocol to furnish
tetrahydrofurans and tetrahydropyrans. Reaction conditions: Substrate
(1) (1.0 mmol), TsONHMe (2) (1.5 mmol), [Rh2(esp)2] (1 mol%) in 2,2,2-
trifluoroethanol (TFE).
Scheme 3 Extended scope of the aminoetherification reaction.
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development of substantial carbocationic character on the
benzylic carbon via an SN1 type pathway would explain the
observed stereochemical scrambling.12
In conclusion, we have developed a mild one-pot Rh-cata-
lyzed domino reaction for the stereocontrolled synthesis of
2-aryl (or alkyl)-3-amino-substituted tetrahydrofurans, tetra-
hydropyrans as well as chromanes. The method affords
N-unprotected products which may be directly taken into
further transformations without the need of any protecting
group manipulations.
Scheme 4 Unexpected scrambling and experimental proof of the
stereospesificity of the aziridination.
Conflicts of interest
There are no conflicts to declare.
(Scheme 4). As the aziridination step is stereospecific, the
observed scrambling to favour trans-3a over cis-3a must take
place either before or during the intramolecular cyclization
step. To gain further insight into this scrambling process, cis-
aziridine 6 was prepared separately and exposed to a range of
additives to probe the cyclization reaction.
Acknowledgements
The authors are grateful for the financial support received
from Rice University, the National Institutes of Health (R35
GM-136373 for L. K., HL-139793 for J. R. F.), the National
Science Foundation (CAREER:SusChEM CHE-1546097 for
L. K.), the Robert A. Welch Foundation (C-1764 for L. K., I-0011
for J. R. F.), Amgen (2014 Young Investigators’ Award for L. K.),
Biotage (2015 Young Principal Investigator Award for
L. K.). J. H. S. gratefully acknowledges the support from the
Osk. Huttunen Foundation.
Treating cis-aziridine 6 under Brønsted acidic conditions
(Table 1, entries 1–4) or with zinc chloride (Table 1, entry 5)
led to either exclusive or highly favoured (dr 1 : 5) formation of
the scrambled trans-3a product. This type of stereochemical
scrambling at benzylic stereogenic centers has also been pre-
viously reported.10 The undesired stereochemical scrambling
could be supressed by activating the cis-aziridine 6 with rare-
earth triflates. Especially Yb(OTf)3 (1.2 equiv.) in TFE
supressed the unwanted scrambling to a significant degree,
giving cis-3a 2,3-aminotetrahydrofuran as the major diastereo-
mer (66% yield, dr 7 : 1) (Table 1, entry 9).11 These results
seem to indicate that some solvent and activating agent combi-
nations, such as La(OTf)3 in TFE, invoke a more SN2-type
stereospecific ring-opening reaction on a Lewis acid co-
ordinated aziridine, whereas Brønsted-acidic activators (e.g.,
CSA) cannot be interpreted as simple SN2 reactions. Instead,
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DCM/hexane (1 : 1) 50 °C/3 d 0 : 1 78
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CSA (1.2 equiv.)
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560 | Org. Biomol. Chem., 2021, 19, 557–560
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