Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π−σ−π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin−Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between β-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched−linear >99:1, up to 99% enantiomeric excess).
more »
« less
Palladium-catalyzed enantioselective (2-naphthyl)methylation of azaarylmethyl amines
Enantioenriched azaarylmethyl amine derivatives are useful building blocks in synthetic and medicinal chemistry. To access these valuable motifs, an enantioselective palladium-catalyzed benzylation of azaarylmethyl amine pronucleophiles is introduced. Of note, this is a rare application of asymmetric (2-naphthyl)methylation of pro-nucleophiles with high p K a values (p K a ≈ 34 in DMSO). Control experiments support the notion that the coordination of Li + to the azaaryl nitrogen plays a critical role in the substitution process. With this procedure, enantioenriched (2-naphthyl)methylene azaarylmethyl amines with a variety of azaaryl groups (pyridyl, pyrazine, quinoxaline and isoquinoline) and cyclic and acyclic amines are readily obtained with good yields and enantioselectivities up to 99%.
more »
« less
- Award ID(s):
- 1902509
- NSF-PAR ID:
- 10348009
- Date Published:
- Journal Name:
- Organic Chemistry Frontiers
- Volume:
- 9
- Issue:
- 10
- ISSN:
- 2052-4129
- Page Range / eLocation ID:
- 2721 to 2727
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
null (Ed.)Hydrogen bonding plays a critical role in maintaining order and structure in complex biological and synthetic systems. N -heterocyclic carbenes (NHCs) represent one of the most versatile tools in the synthetic chemistry toolbox, yet their potential as neutral carbon hydrogen bond acceptors remains underexplored. This report investigates this capability in a strategic manner, wherein carbene-based hydrogen bonding can be assessed by use of ditopic NH -containing molecules. N–H bonds are unique as there are three established reaction modes with carbenes: non-traditional hydrogen bonding adducts (X–H⋯:C), salts arising from proton transfer ([H–C] + [X] − ), or amines from insertion of the carbene into the N–H bond. Yet, there are no established rules to predict product distributions or the strength of these associations. Here we seek to correlate the hydrogen bond strength of symmetric and asymmetric ditopic secondary amines with 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene ( IPr , a representative NHC). In symmetric and asymmetric ditopic amine adducts both the solid-state (hydrogen bond lengths, NHC interior angles) and solution-state ( 1 H Δ δ of NH signals, 13 C signals of carbenic carbon) can be related to the p K a of the parent amine.more » « less
-
While new particle formation events have been observed worldwide, our fundamental understanding of the precursors remains uncertain. It has been previously shown that small alkylamines and ammonia (NH 3 ) are key actors in sub-3 nm particle formation through reactions with acids such as sulfuric acid (H 2 SO 4 ) and methanesulfonic acid (CH 3 S(O)(O)OH, MSA), and that water also plays a role. Because NH 3 and amines co-exist in air, we carried out combined experimental and theoretical studies examining the influence of the addition of NH 3 on particle formation from the reactions of MSA with methylamine (MA) and trimethylamine (TMA). Experiments were performed in a 1 m flow reactor at 1 atm and 296 K. Measurements using an ultrafine condensation particle counter (CPC) and a scanning mobility particle sizer (SMPS) show that new particle formation was systematically enhanced upon simultaneous addition of NH 3 to the MSA + amine binary system, with the magnitude depending on the amine investigated. For the MSA + TMA reaction system, the addition of NH 3 at ppb concentrations produced a much greater effect ( i.e. order of magnitude more particles) than the addition of ∼12 000 ppm water (corresponding to ∼45–50% relative humidity). The effect of NH 3 on the MSA + MA system, which is already very efficient in forming particles on its own, was present but modest. Calculations of energies, partial charges and structures of small cluster models of the multi-component particles likewise suggest synergistic effects due to NH 3 in the presence of MSA and amine. The local minimum structures and the interactions involved suggest mechanisms for this effect.more » « less
-
more » « less
Abstract Rationale Contaminants present in ambient air or in sampling lines can interfere with the target analysis through overlapping peaks or causing a high background. This study presents a positive outcome from the unexpected presence of
N ‐methyl‐2‐pyrrolidone, released from a PALL HEPA filter, in the analysis of atmospherically relevant gas‐phase amines using chemical ionization mass spectrometry.Methods Gas‐phase measurements were performed using a triple quadrupole mass spectrometer equipped with a modified atmospheric pressure gas chromatography (APGC) source which allows sampling of the headspace above pure amine standards. Gas‐phase
N ‐methyl‐2‐pyrrolidone (NMP) emitted from a PALL HEPA filter located in the inlet stream served as the ionizing agent.Results This study demonstrates that some alkylamines efficiently form a [NMP + amine+H]+cluster with NMP upon chemical ionization at atmospheric pressure. The extent of cluster formation depends largely on the proton affinity of the amine compared with that of NMP. Aromatic amines (aniline, pyridine) and diamines (putrescine) were shown not to form cluster ions with NMP.
Conclusions The use of NMP as an ionizing agent with stand‐alone APGC provided high sensitivity for ammonia and the smaller amines. The main advantages, in addition to sensitivity, are direct sampling into the APGC source and avoiding uptake on sampling lines which can be a significant problem with ammonia and amines.
-
The use of chiral square planar gold( iii ) complexes to access enantioenriched products has rarely been applied in asymmetric catalysis. In this context, we report a mechanistic and synthetic investigation into the use of N-heterocyclic (NHC) gold( iii ) complexes in γ,δ-Diels–Alder reactions of 2,4-dienals with cyclopentadiene. The optimal catalyst bearing a unique 2-chloro-1-naphthyl substituent allowed efficient synthesis of functionally rich carbocycles in good yields, diastereo- and enantioselectivities. Transition state and multivariate linear regression (MLR) analysis of both catalyst and substrate trends using molecular descriptors derived from designer parameter acquisition platforms, reveals attractive non-covalent interactions (NCIs) to be key selectivity determinates. These analyses demonstrate that a putative π–π interaction between the substrate proximal double bond and the catalyst aromatic group is an essential feature for high enantioselectivity.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D2QO00273F
