1
Introduction
Roly J. Armstrong (right) graduated with an MSci in Natural Sciences from Pembroke College, Cambridge
(2011). He subsequently moved to Merton College, Oxford to carry out a DPhil under
the supervision of Professor Martin Smith (2011–2015), followed by postdoctoral studies
with Professor Varinder Aggarwal FRS at the University of Bristol (2015–2017) and
Professor Timothy Donohoe at the University of Oxford (2017–2018). In 2018, he took
up a Junior Research Fellowship at University College, Oxford, and in 2021 he joined
Newcastle University as a lecturer in chemistry. His research interests include organic
synthesis, asymmetric catalysis and medicinal chemistry.
Aaron D. G. Campbell (left) graduated in 2021 from Newcastle University with an MChem degree in chemistry.
After a brief spell in the chemical industry, in 2022 he joined the Armstrong group
as a PhD student. His research involves developing new methods for the synthesis of
chiral amides.
Atropisomerism refers to the phenomenon by which slow rotation about a single bond
allows the different conformers of a molecule to be isolated as distinct chemical
entities.[1] The most widely studied examples are axially chiral biaryls and heterobiaryls, the
stereoisomerism of which results from the non-planar arrangement of two ring systems
connected by a single C–C or C–N bond (Scheme [1], top). Intensive research in this area has led to an extensive array of elegant
synthetic methods for the stereoselective preparation of such materials, which have
been shown to have powerful applications as chiral ligands and catalysts.[2] The high degree of conformational rigidity present within cyclic scaffolds leads
to predictable and often very high levels of configurational stability, but atropisomerism
is also possible with acyclic functional groups. Indeed, an increasing number of elegant
reports have emerged involving C–N atropisomerism in amines and amides where the nitrogen
atom is not part of a ring system.[3] This is the focus of this Short Review.
The challenge in such systems is that the higher degree of conformational flexibility
possible in acyclic functional groups can compromise the configurational stability
of the key stereogenic C–N axis. Nevertheless, elegant work has shown that a wide
variety of scaffolds can be prepared including diarylamines, carboxamides, thioamides,
ureas, sulfonamides, sulfinamides, and phosphamides, which display remarkably robust
configurational stability. The emerging potential of these scaffolds is highlighted
by a number of reports of C–N atropisomeric molecules in drug discovery and agrochemistry,
including the herbicide metolachlor as well as sulfonamide-based NMDA and BRS-3 agonists
(Scheme [1], bottom).[4]
Scheme 1 Atropisomerism in cyclic and acyclic scaffolds along with important examples of medically
relevant acyclic C–N atropisomeric molecules
This Short Review begins with a summary of the factors that influence configurational
stability in C–Nacyclic atropisomeric scaffolds, followed by a detailed synopsis of the methods available
for their stereoselective synthesis. A wide variety of different synthetic strategies
are included, from classical chiral-pool approaches to recent catalytic enantioselective
methods, including desymmetrization, electrophilic amination, C–H functionalization,
N–H functionalization and annulation.
2
Atropisomerism in Acyclic Amines and Amides
Conformational exchange and atropisomerism represent a continuum, with atropisomers
arbitrarily defined as conformers that interconvert with a racemization half-life
(t1/2
rac) of more than 1000 s at a given temperature, corresponding to a Gibbs activation
energy of enantiomerization (ΔG‡) > 22 kcal/mol at room temperature.[1] Clearly the rate of racemization of a potentially atropisomeric molecule is a crucial
consideration when considering its possible applications and designing an asymmetric
synthesis.
Scheme 2 Contrasting Gibbs activation energies of enantiomerization (ΔG‡) in a series of different amine (top) and amide (bottom) scaffolds
Aromatic amines typically do not display atropisomerism owing to the high degree of conformational
flexibility arising from rotation about two C–N bonds. For example, Clayden and co-workers
have reported that diarylamine 1, possessing two ortho-substituents, is non-atropisomeric, with enantiomerization occurring too rapidly
to be detected by 1H NMR spectroscopy (Scheme [2], top).[5] In general, the rate of racemization in atropisomeric molecules can be slowed by
introducing additional bulky ortho-substituents. For instance, Clayden and co-workers were able to resolve the enantiomers
of tetra-ortho-substituted diarylamines (e.g., 2), but even in this extremely hindered system, comparatively rapid racemization was
observed (ΔG‡ = 25.5 kcal/mol; t1/2
rac = 84 min at 60 °C).[6] An exception is diarylamines with restricted conformational flexibility about the
nitrogen atom. For example, Kitagawa and co-workers have also reported that tertiary
diarylamines bearing an electron-withdrawing group at the para position display particularly high configurational stability (e.g., 3, ΔG‡ = 29.4 kcal/mol), which was attributed to planarization of the electron-deficient
ring with the nitrogen atom, which must be overcome during racemization.[7] A related effect has been reported by Kawabata and co-workers who reported that
diarylamines such as 4 display high levels of configurational stability, which was attributed to an N–H–N
intramolecular hydrogen bond that preorganizes one of the C–N axes into a planar conformation,
leading to compounds which possess racemization barriers of up to 28.2 kcal/mol.[8] Several elegant asymmetric syntheses of hydrogen-bonded diarylamines featuring similar
configurational stabilization have been reported. Although such systems could be considered
formally cyclic, given that their ring system relies upon a non-covalent interaction,
they are included within the scope of this Short Review.
In contrast, aromatic amides often display robust configurational stability, which is a consequence of the planarity
of the amide linkage due to conjugation between the carbonyl and amine groups (Scheme
[2], bottom).[9] Even amides bearing a single bulky ortho substituent (e.g., 5) display reasonable levels of configurational stability,[10] and this can be enhanced further by increasing the level of steric bulk at the ortho positions (e.g., 6).[11] For similar reasons, atropisomerism is also possible for heteroatomic amide analogues
(e.g., sulfonamides, sulfinamides and phosphamides), and combining these effects can
produce scaffolds that display remarkably high configurational stability. For example,
N-sulfonyl anilides (e.g., 7) have been shown to possess racemization barriers of up to 35.0 kcal/mol, corresponding
to a room-temperature racemization half-life in the order of >104 years.[12]
4
Atropselective Synthesis
Whilst chiral auxiliaries can provide simple and scalable methods to access enantioenriched
axially chiral amides, the requirement to add and then remove the auxiliary reduces
the overall efficiency and yield of the process. Direct atropselective synthesis can
often provide a more efficient approach to enantiopure targets. In the context of
achiral C–N atropisomeric scaffolds, several synthetic strategies have been explored,
namely: (i) kinetic resolution/desymmetrization; (ii) electrophilic amination; (iii)
C–H functionalization; (iv) N-functionalization; and (v) annulation.
4.1
Kinetic Resolution and Desymmetrization
In 1996, Simpkins and co-workers reported a pioneering kinetic resolution reaction
to obtain enantioenriched axially chiral anilides (Scheme [4]).[17] In this process, the racemic anilide rac-15 was deprotonated with a substoichiometric quantity of a chiral lithium amide base,
and the resulting lithium enolate was alkylated with methyl iodide. The small quantity
of recovered starting material (–)-15 was shown to be highly enantioenriched (94:6 e.r.), establishing proof-of-concept
for the direct atropselective synthesis of axially chiral anilides.
Scheme 4 Kinetic resolution of atropisomeric amides by deprotonation with a chiral base
Clayden and Turner have reported a kinetic resolution approach to access enantioenriched
N,N′-diaryl ureas (Scheme [5]).[18] Oxidation of racemic ortho-substituted thioether precursors rac-17 in the presence of VO(acac)2 modified with (S)-tert-leucinol-derived ligand 19 afforded sulfoxides 18 with high levels of enantio- and diastereoselectivity (up to 63% conversion). The
unreacted starting materials displayed relatively high configurational stability and
could be recovered with high enantiopurity (up to 97:3 e.r.), allowing calculation
of selectivity (S) factors for the process, which ranged from 2 to 300 for different substrates. The
method was most effective for oxidation of ortho-tert-butyl anilides bearing aliphatic thioethers.
Scheme 5 Kinetic resolution of thioethers by asymmetric S-oxidation
Very recently, Gong and co-workers reported a kinetic resolution for the synthesis
of atropisomeric thioanilides based upon Pd-catalyzed sp3 C–H activation (Scheme [6]).[19] This process employed Pd2(dba)3 in conjunction with phosphoramidite ligand 22 and chiral Co(III) complex 23, allowing the isolation of C–H arylated products 21 in up to 95.5:0.5 e.r. Unreacted thioanilide 20 isolated from this reaction also proved to be highly enantioenriched, demonstrating
the process to be an efficient kinetic resolution (S factor up to 618).
Scheme 6 Kinetic resolution of atropisomeric thioamides via Pd-catalyzed sp3 C–H activation
Uemura and co-workers have developed an elegant desymmetrization of prochiral anilide
tricarbonyl chromium complexes 24 (Scheme [7]).[20] Treatment of these starting materials with a chiral lithium amide base resulted
in selective deprotonation of one of the enantiotopic methyl groups to afford a lithiated
intermediate which could be quenched with a variety of electrophiles. The resulting
axially chiral anilide chromium complexes 25 were obtained in good to excellent yields with high levels of enantioselectivity
(up to 98.5:1.5 e.r.). Upon exposure to sunlight in Et2O the decomplexed anilides 25′ could straightforwardly be accessed with almost no decrease in optical purity.
Scheme 7 Desymmetrization of prochiral arene chromium tricarbonyl complexes by asymmetric
deprotonation with a chiral lithium amide base
Very recently, Yang and Zhang reported a desymmetrizing Sonogashira reaction for the
synthesis of atropisomeric amides (Scheme [8]).[21] In this reaction, prochiral diiodides 26 (possessing a plane of symmetry) were efficiently desymmetrized employing Pd(OAc)2 modified by chiral Ming-Phos ligand 29. Both diastereoisomers of the ligand were evaluated, and the (R,R)-epimer was found to be optimal, delivering desymmetrized products 27 in high yields with excellent levels of enantioselectivity (up to 99:1 e.r.). On
the basis of control experiments, it was proposed that the enantioselectivity of the
initial desymmetrization reaction is augmented by a subsequent kinetic resolution
process, which removes small amounts of the minor enantiomer of 27 through conversion into doubly alkynylated anilide 28.
Scheme 8 Desymmetrizing Sonogashira coupling for the synthesis of atropisomeric amides
4.2
Electrophilic Amination
Scheme 9 Catalytic asymmetric amination of 8-amino-2-naphthols
Electrophilic amination is an attractive method for the formation of C–N atropisomers.
This approach aims to achieve direct stereoselective formation of the key Ar–N bond,
and several elegant examples have been developed. For example, Bella, Jørgensen and
co-workers reported an efficient method to access axially chiral N,N-disubstituted
1-naphthamides, via a Friedel–Crafts amination (Scheme [9]).[22] The reaction of 8-amino-2-naphthols 30 with di-tert-butyl azodicarboxylate in the presence of 20 mol% of chiral dihydroquinidine-derived
catalyst 32a afforded the corresponding aminated naphthols 31 in excellent yield and reasonable enantioselectivity (up to 88% e.e.). It was subsequently
discovered that the catalyst itself can be aminated (employing more forcing reaction
conditions), leading to new catalyst 32b, which possesses an additional element of axial chirality. This modified catalyst
proved even more effective for the atropselective amination of 30, allowing isolation of products in up to 98% e.e. The other enantiomer of the products
could be conveniently accessed with comparable levels of enantioselectivity by employing
diastereomeric catalyst 32c.
Zhang and co-workers have developed a highly enantioselective C–H amination procedure
for the synthesis of naphthylamine-1,2-diamine atropisomers 34 (Scheme [10]A).[23] Employing chiral phosphoric acid catalyst 35a, the aminated products were obtained with excellent yields and high levels of enantioselectivity.
It was observed that an aromatic substituent at the 3,3′-positions of the catalyst
(e.g., phenanthryl) was essential to achieve high enantioselectivity, and it was proposed
that this group is able to form a key π–π interaction with the NAr group in the substrate.
The relatively high configurational stability of the products (t1/2
rac >10 h) was attributed in part to an intramolecular hydrogen bond between the N–H
of the diarylamine and the carbonyl of the terminal Boc group (supported by X-ray
crystallographic analysis). Subsequently, Yang and co-workers reported a related chiral
phosphoric acid catalyzed amination of 1,3-benzenediamines 36 that proceeded with excellent levels of enantioselectivity (Scheme [10]B).[24] The configurational stability of the products depended strongly upon the nature
of the ortho substituent (R1), with products bearing a bulky t-Bu group at this position undergoing very slow racemization (more rapid racemization
was observed with secondary or primary aliphatic groups). A series of control experiments
revealed that the para-amino substituent is crucial to ensure reactivity in this process.
Zhu, Gong and co-workers have shown that it is also possible to access unique heteroaryl
atropisomers 39 via a gold-catalyzed cycloisomerization–amination reaction of 2-alkynyl phenyl boronic
acids with di-tert-butyl azodicarboxylate (Scheme [10]C).[25] This reaction was promoted by a combination of (R)-BINAP(AuCl)2 and AgNTf2 and was proposed to occur via a mechanism involving Au-mediated cycloisomerization
of 38 followed by amination of the resulting vinyl gold intermediate. The absolute configuration
of the unusual heteroarylated products was tentatively assigned by vibrational circular
dichroism analysis. Very recently, Liao, Zhong and co-workers reported an atropselective
electrophilic amination of indoles 41 using quinone diimines 40 (Scheme [10]D).[26] This process was promoted by a remarkably low loading (0.2 mol%) of chiral phosphoric
acid 35c, and afforded a broad scope of atropisomeric 3-aminoindoles 42 in excellent yields and enantioselectivities. Notably, very high regioselectivity
was observed for 1,6-addition to the quinone diimines, with no evidence of competing
1,4-addition (e.g., products 43) observed.
4.3
C–H Functionalization
The functionalization of C–H bonds has proved to be a powerful strategy for the asymmetric
synthesis of axially chiral amines and amides, and has been applied within both transition-metal
catalyzed and organocatalytic reaction manifolds. For example, in 2020, Hong, Shi
and co-workers reported an elegant approach in which configurationally unstable anilides
44 bearing a single ortho-substituent (R2) could undergo highly enantioselective Pd-catalyzed C–H olefination to form products
45 displaying robust axial chirality (ΔG‡ up to 33.5 kcal/mol) (Scheme [11]A).[27] The optimal ligand for this process proved to be commercially available l-pyroglutamic acid (46), and on the basis of a detailed experimental and computational studies it was proposed
that the enantiodetermining step involves concerted-metalation deprotonation directed
by the picolinamide group via transition state TS-49. Subsequently, the Shi group were able to expand upon this approach to develop Pd-catalyzed
C–H alkynylation and allylation reactions, targeting atropisomeric N-aryl peptoids
48a and 48b, respectively (Scheme [11]B).[28]
Scheme 10 Formation of C–N atropisomers by asymmetric amination
Recently, Yu and co-workers reported a diastereoselective C2-amination of indoles
with protected amino acids to access unusual sulfonamide atropisomers (Scheme [12]).[29a] Products 52, bearing an alkyl or halogen group at the C3-position, were obtained in high yields
with up to 15:1 d.r. This process was subsequently expanded to enable haloamidation
to directly convert C3-unsubstituted indoles (R1 = H) to chlorinated and brominated atropisomeric analogues 53.[29b]
Scheme 11 Pd-catalyzed atropselective C–H functionalization of pro-atropisomeric picolinamides
Scheme 12 Atropselective amidation and haloamidation reactions of indoles[29]
Gustafson and co-workers have developed an asymmetric halogenation reaction targeting
N-aryl quinoid atropisomers (Scheme [13]A).[30] Upon exposure to an electrophilic halogenating agent (NXS; X = Cl, Br or I) along
with chiral phosphoric acid catalyst 56, configurationally unstable precursors 54 could be efficiently converted into enantioenriched products 55 with up to 98:2 e.r. It was proposed that the surprisingly high configurational stability
of these products is a result of a strong intramolecular hydrogen bond, which prevents
rotation about the N–quinone bond, resulting in a high degree of structural rigidity.
Subsequently, Xue, Chen and co-workers reported that electrophilic sulfenylation can
also be achieved in high yields and enantioselectivity employing a novel SPINOL-derived
catalyst along with p-toluenesulfonic acid (Scheme [13]B).[31]
Scheme 13 Asymmetric synthesis of atropisomeric N-aryl aminoquinones
4.4
N-Functionalization
The most widely employed strategy for the synthesis of acyclic C–N atropisomers involves
asymmetric N-functionalization of secondary anilides. Due to the small steric influence
of the N–H group, these precursors are typically non-atropisomeric, but following
N-functionalization configurationally stable products can be obtained. This concept
was pioneered by Taguchi and Curran, who independently reported asymmetric syntheses
of axially chiral anilides 61 via enantioselective Pd-catalyzed N-allylation (Scheme [14]).[32]
[33] These reactions were mediated by [Pd(allyl)Cl]2 modified by a chiral bisphosphine ligand. Despite relatively low enantioselectivities,
this ground-breaking work paved the way for numerous future studies.
Scheme 14 Asymmetric Pd-catalyzed N-allylation of secondary anilides
Liu, Feng and Du subsequently reported that introducing a chiral P/olefin ligand 64 could overcome the issues of low enantiomeric excess that dominated the early methods
for Pd-catalyzed allylation (Scheme [15]A).[34] Under these conditions good levels of enantiomeric excess were observed for a variety
of allylic carbonates and anilides (up to 92:8 e.r.). In 2019, Kitagawa and co-workers
reported a related Pd-catalyzed reaction between secondary sulfonamides and allyl
acetate to access atropisomeric products 66 (Scheme [15]B).[35] The enantioselectivity of the process displayed a strong dependence upon the nature
of the sulfonyl group (R1), with high levels of enantioselectivity obtained for several examples (up to 97.5:2.5
e.r.). Analysis of the configurational stability of the C–N sulfonamide atropisomeric
products was carried out, revealing them to undergo somewhat more facile racemization
than the analogous carboxamides (values of ΔG‡ 2–4 kcal/mol lower).
Scheme 15 Asymmetric synthesis of C–N atropisomers via Pd-catalyzed N-allylation
Scheme 16 Pd-catalyzed asymmetric N-arylation of secondary anilides
Kitagawa, Taguchi and co-workers have also reported a method for the enantioselective
N-arylation of secondary anilides (Scheme [16]).[36] After optimization, it was found that a combination of Pd(OAc)2 and (R)-DTBM-SEGPHOS could effect Buchwald–Hartwig-type arylation in up to 98:2 e.r. The
reaction displayed broad scope with respect to the anilide component, but a notable
limitation was that a 4-NO2 group was required on the aryl iodide to observe reactivity. Although outside the
scope of this Short Review, subsequent elegant work by Taguchi, Gu and others has
shown that intramolecular variants of this transformation are possible with tethered
aromatic partners.[36]
[37]
In 2012, Maruoka and co-workers reported an efficient synthesis of axially chiral
anilides 71 via a phase-transfer-catalyzed alkylation reaction (Scheme [17]).[38] The selectivity in this process was proposed to originate from the tight-ion pair
formed between the deprotonated anilide and chiral ammonium cation in a non-polar
organic solvent (
i
Pr2O). This approach produced products with very high levels of enantioselectivity, implying
efficient recognition between the two ortho-substituents. This was rationalized on the basis of steric differentiation between
the bulky iodide and smaller R1 substituents (a clear trend was observed with the highest levels of enantioselectivity
observed for examples with small R1 substituents, e.g., R1 = Me). A transition state model was proposed to account for the observed selectivity,
with the ortho-iodo group of the anilide preferentially oriented away from the bulky C3/3′ aryl
groups on the catalyst. In a subsequent publication, the authors were able to expand
upon this approach to prepare enantioenriched anilides bearing a single bulky ortho substituent.[39]
Scheme 17 Atropselective phase-transfer-catalyzed alkylation of anilides
In 2018, Li and co-workers made use of achiral Morita–Baylis–Hillman (MBH) carbonates
to develop an atropselective allylic alkylation reaction to synthesize axially chiral
anilides (Scheme [18]).[40] In the presence of (DHQ)2PYR (76) as the organocatalyst, a variety of atropisomeric anilides 74 were obtained in high yields, with high levels of enantioselectivity and with a strong
preference for the cis-amide isomer. The mechanism and origins of selectivity in the reaction were probed
by detailed DFT calculations and linear free-energy relationship analysis. Notably,
treatment of the N-allylated products with diazomethane resulted in diastereoselective
cycloaddition to afford products 75 with no erosion of enantiomeric purity.
In 2019, Kürti, Zhao and co-workers reported that organocatalytic N-allylation can
also be applied to the synthesis of atropisomeric sulfonamides 78 (Scheme [19]A).[41] The configurational stability of these products proved to be slightly lower than
the analogous carboxamides, with products 78 bearing a single bulky ortho-substituent (e.g., R1 = R2 = H; X =
t
Bu) undergoing relatively rapid racemization at room temperature. However, products
possessing two ortho-substituents (e.g., R1 = R2 = Me; X = I) displayed robust configurational stability, and could be isolated with
very high levels of enantioselectivity (up to 97.5:2.5 e.r.). Notably, the presence
of an ortho-halogen substituent (X = I, Br, Cl) proved key in order to obtain efficient stereoinduction.
Chen and co-workers subsequently developed a similar approach enabling reactions of
allyl and allenyl electrophiles.[42] Li and co-workers have also shown that it is possible to target C–N axially chiral
phosphamide products 81 (Scheme [19]B).[43] In this case, commercially available hydroquinidine 82 was the optimal catalyst to promote N-allylation, enabling the synthesis of atropisomeric
phosphamides 81 in good yields and with enantioselectivities of up to 96.5:3.5 e.r. The reaction
could be executed on gram scale, and the utility of the ortho-iodinated atropisomeric phosphamide products was exemplified by applying them as
chiral hypervalent iodine(III) catalysts for the oxidative spirolactonization of phenol
derivatives. Li and co-workers have also employed a similar strategy to target atropisomeric
sulfinamides (Scheme [19]C).[44] In this case racemic starting materials 83 (point chiral at sulfur) underwent efficient kinetic resolution upon organocatalytic
allylation to access atropisomeric sulfinamides 84 with excellent levels of diastereo- and enantioselectivity. Very recently, Li and
Zhou reported that a similar strategy can be applied to target atropisomeric enamides
86 (Scheme [19]D).[45] The partially saturated products of this reaction displayed comparatively low barriers
to racemization (ΔG‡ = 25.9–28.4 kcal/mol), which is likely a reflection of their flexible skeletons leading
to a higher degree of rotational freedom. However, ultimately the authors were able
to overcome this challenge to access atropisomeric enamides with high yields and excellent
levels of enantioselectivity (up to 99:1 e.r.).
Scheme 18 Asymmetric allylic alkylation of anilides with Morita–Baylis–Hillman carbonates
Scheme 19 Asymmetric allylic alkylation reactions targeting novel atropisomeric scaffolds beyond
aromatic carboxamides
Liu and co-workers have reported an interesting N-functionalization reaction to access
N-aryl quinone atropisomers (Scheme [20]).[46] In the presence of the commercially available chiral phosphoric acid catalyst (R)-TRIP (90), primary anilines 87 reacted with quinone esters 88 to afford axially chiral products 89 in high yields and excellent enantioselectivities (up to 99.5:0.5 e.r.). The mechanism
of this process is believed to proceed via an initial enantioselective conjugate addition
reaction of the amine to form a hydroquinone intermediate, which is then oxidized
by a second equivalent of quinone ester (present in excess) to generate the corresponding
quinone product 89. The configurational stability of the products was probed by DFT calculations and
it was proposed that racemization is disfavored because of a planarizing H-bond between
the N–H and the ester carbonyl.
In 2020, two independent reports emerged from Dong and co-workers and Lu, Zhao and
co-workers describing the atropselective N-acylation of sulfonamides, catalyzed by
a chiral isothiourea (Scheme [21]).[47]
[48] The optimized conditions of these methods were similar, employing opposite enantiomers
of the same isothiourea catalyst 93, along with slightly different bases, solvents and temperatures. The substrate scopes
of the two methods were broadly complementary, with Dong’s method predominantly focused
upon acylated sulfonamides bearing a single bulky ortho substituent (e.g., 92a, where R3 =
t
Bu), and the method developed by Lu, Zhao and co-workers exemplified with a series
of doubly ortho-substituted targets (e.g., 92b, where R3 = Me; X = I/Br). A transition state TS-94 was proposed by Dong whereby the deprotonated sulfonamide attacks the acylisothiouronium
intermediate on the opposite face to the phenyl group, with the ortho-tert-butyl group oriented away from the catalyst to avoid an unfavorable interaction with
the Ph group.[47] An interaction between the oxygen of the sulfonyl group and the positively charged
thiouronium moiety was also suggested to play a key role in this transition state.
Scheme 20 Synthesis of N-arylated quinoids by asymmetric N-addition/oxidation
Scheme 21 Asymmetric isothiourea catalyzed N-acylation of sulfonamides
In 2021, Zhou, Zhang, Jiang and co-workers disclosed an efficient atropselective hydroamination
of allenes for the synthesis of axially chiral sulfonamides (Scheme [22]).[12] High enantioselectivity and diastereoselectivity were obtained using Pd2(dba)3 modified by C
2-symmetrical diaminocyclohexyl ligand 99. Excellent selectivity for the branched isomer was observed, in preference over the
linear isomer (B/L >25:1), and high enantioselectivities (up to 99.5:0.5 e.r.) were
obtained. The resulting N,O-acetals 96 could be oxidized with DDQ to yield atropisomeric N-sulfonyl anilides 98, which were shown to exhibit remarkably high configurational stability (ΔG‡ >35.0 kcal/mol). Treatment of the N,O-acetals with BF3·OEt2 and silylated nucleophiles led to the formation of γ-addition products 97 with good to excellent levels of enantiospecificity.
Scheme 22 Atropselective Pd-catalyzed hydroamination of allenes
The palladium-catalyzed carbonylation of aryl iodides with amides has been reported
by Teng, Sun, Li and co-workers (Scheme [23]).[49] The predominant focus of this work was upon carbonylative cyclization to access
heterocyclic atropisomers (outside the scope of this Short Review), but several intermolecular
reactions between anilides, aryl iodides and CO were also reported. This enabled the
synthesis of unusual doubly acylated anilide atropisomers 101 in good to excellent yields and with enantioselectivities of up to 94:6 e.r. Interestingly,
the intermolecular process required the addition of Hantzsch ester, which may increase
the yield by prolonging the lifetime of the catalyst.
Scheme 23 Asymmetric carbonylative coupling reactions to access doubly acylated anilide atropisomers
4.5
Annulation
Accessing axially chiral scaffolds by strategic formation of an aromatic ring is a
powerful strategy that has been widely employed for the synthesis of biaryl and heterobiaryl
atropisomers.[50] There have also been several elegant reports applying this strategy to the synthesis
of atropisomeric amides. For example, in 2006, Tanaka and co-workers reported a pioneering
Rh-catalyzed [2+2+2] cycloaddition reaction between 1,6-diynes 103 and ynamides 104 to afford bicyclic amides 105 (Scheme [24]).[51] The reaction proceeded with moderate to good yields, and excellent levels of enantioselectivity
were observed. It was proposed that the key step involved selective formation of Rh-complex
106, in which the R3 substituent is oriented away from the bulky PAr2 groups of the ligand. A final reductive elimination then delivered atropisomeric
products 105.
Scheme 24 Rh-catalyzed atropselective [2+2+2] cycloaddition between 1,6-diynes and ynamides
Very recently, Wang, Li and co-workers reported that sulfoxonium salts 107 can also serve as efficient precursors for Rh-catalyzed annulation with ynamides
108 (Scheme [25]).[52] The process was mediated by Cramer’s second generation Rh(III)-Cp catalyst 110, along with chiral acid 111, catalytic Zn(OTf)2 and TlPF6 as a halide scavenger. Under these conditions, atropisomeric sulfonamides 109 were obtained in high yields and excellent levels of enantioselectivity. The transition
state TS-112 was proposed that accounts for the regio- and enantioselectivity observed within
the process, which involves simultaneous activation of both the ynamide and sulfoxonium
ylide.
Scheme 25 Synthesis of chiral anilides via atropselective annulation
