Dynamic Covalent Chemistry within Biphenyl Scaffolds: Effects from Endocyclic to Exocyclic Sulfonamides

Article abstract of DOI:10.1055/s-0037-1610207

There is unabated interest in developing new strategies for the control of atropisomers despite the rich history of atropisomerism. We recently introduced dynamic covalent reactions (DCRs) within biphenyl skeletons for the incorporation and chirality recognition of multiple classes of mononucleophiles. To expand the scope of this strategy, the sulfonamide unit was switched from an endocyclic to an exocyclic position, and the influence of the resulting DCRs on chiral induction was investigated. The intramolecular equilibrium between the open aldehyde and its cyclic hemiaminal favored the ring form, and excellent chirality transfer from the hemiaminal stereocenter to the helical twist of the biphenyl was revealed. The modulation of unique dual reactivity then allowed the realization of DCRs of a diverse set of amines and alcohols. The degree of chirality induction was further explored by employing chiral substrates, affording significant circular dichroism signals.

Full text of DOI:10.1055/s-0037-1610207

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Dynamic Covalent Chemistry within Biphenyl Scaffolds: Effects
from Endocyclic to Exocyclic Sulfonamides
Cailing Nia,b◊
Meng Wanga◊
Lei You*a,b
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a State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, P. R. of China
lyou@fjirsm.ac.cn
b University of Chinese of Academy of Sciences, Beijing 100049,
P. R. of China
◊ These authors contributed equally to this work.
Published as part of the Cluster Atropisomerism
Received: 27.04.2018
Accepted after revision: 12.06.2018
Published online: 17.07.2018
gen bonding8 or metal coordination9 have been used to
control atropisomers and the resulting molecular rotors. In
addition, the effect arising from bond rotation is closely as-
sociated with the function of molecular switches10 and
light-emitting materials.11
DOI: 10.1055/s-0037-1610207; Art ID: st-2018-d0262-c
Abstract There is unabated interest in developing new strategies for
the control of atropisomers despite the rich history of atropisomerism.
We recently introduced dynamic covalent reactions (DCRs) within bi-
phenyl skeletons for the incorporation and chirality recognition of mul-
tiple classes of mononucleophiles. To expand the scope of this strategy,
the sulfonamide unit was switched from an endocyclic to an exocyclic
position, and the influence of the resulting DCRs on chiral induction
was investigated. The intramolecular equilibrium between the open al-
dehyde and its cyclic hemiaminal favored the ring form, and excellent
chirality transfer from the hemiaminal stereocenter to the helical twist
of the biphenyl was revealed. The modulation of unique dual reactivity
then allowed the realization of DCRs of a diverse set of amines and alco-
hols. The degree of chirality induction was further explored by employ-
ing chiral substrates, affording significant circular dichroism signals.
The field of dynamic covalent chemistry (DCC) has been
blossoming over the past decade,12 as it has found broad
utility in the creation of assemblies,13 modulation of nano-
materials,14 and the development of sensors and catalysts,15
as well as in the regulation of physiological functions.16 The
creation and exchange of reversible covalent bonds, in the
form of dynamic covalent reactions (DCRs), can readily gen-
erate molecular diversity as compared with stepwise cova-
lent synthesis.12–16 Propelled by its paramount position in
enzymatic as well as organic catalysis,17 the addition of
amines to carbonyls to create imines,18 iminium ions,19 or
hemiaminals/aminals20 in reversible systems is gaining
popularity in DCC research. Despite their availability, DCRs
of aldehydes and alcohols suffer from poor thermodynamic
stability due to the weak nucleophilicity and coordinating
ability of alcohols.21 The incorporation of readily accessible
carbonyl and amino/oxo functions into biaryl skeletons
might provide ample opportunities for accessing atropiso-
mers through DCC.
We recently proposed a strategy of bridging together re-
search efforts on DCC and on axial chirality through an in-
tramolecular DCR between aldehyde and sulfonamide units
at the 2- and 2′-positions of a biphenyl (1; Figure 1a).22 Di-
verse intermolecular DCRs of biphenyls 1 with alcohols,
thiols, primary amines, and secondary amines were real-
ized based on the dual reactivity; chiroptical sensing of
chiral mononucleophiles was also achieved. Building upon
these results, we moved the sulfonyl group from an endo-
cyclic position in 1 to an exocyclic position in 2 to fine-tune
the structure–reactivity relationship of DCRs and the asso-
ciated physical organic features [Figure 1(b)]. Although a
Key words atropisomerism, biaryls, aldehydes, dynamic covalent
chemistry, chirality recognition
The stereoisomerism that governs chirality within a
molecule due to nonplanar spatial arrangement of groups
about a chiral axis is referred to as axial chirality and it is
found in atropisomers, chiral allenes, and spiranes.1 As the
most representative subclass compounds displaying axial
chirality, atropisomeric compounds are ubiquitous in natu-
ral and synthetic molecules,2 and they play crucial roles in
asymmetric catalysis,3 drug development,4 and supra-
molecular chemistry.5 As a result, the development of new
strategies and methodologies for the control of atropisom-
erism is an intensive area of research. For biaryls, restric-
tion of the free rotation about the sp2–sp2 C–C bond by
bulky substituents can permit the creation of atropisomers,
which is of significance for the discovery of chiral auxilia-
ries and ligands.3a,6 The manipulation of atropisomers pro-
vides a means for regulation of chiral molecular assem-
blies.7 Moreover, noncovalent interactions such as hydro-
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similar acidity would be expected for the sulfonamide
groups in 1 and 2, we postulated that the equilibrium be-
tween the open aldehyde and its cyclic hemiaminal would
be affected by the structural difference between 1 and 2,
which, accordingly, might dictate chirality induction from
the hemiaminal stereocenter (labelled * in Figure 1) to the
chirality of the biphenyl, as well as in DCRs with other
mononucleophiles.
a. Previous work
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= ROH, RNH2, R1R2NH or RSH
NuH
b. This work
Nu
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Figure 2 Equilibrium and structural feature of 2. (a) 1H NMR spectrum
of 2 in CD3CN. (b) Crystal structure of 4 (the enantiomeric structures
were chosen from the unit cell of 4).
2
Figure 1 Proposed strategy for DCRs and chirality sensing with
open/cyclic atropisomeric biaryls: the sulfonyl group is changed from
an endocyclic position in 1 (a) to an exocyclic position in 2 (b).
calculations. More importantly, to alleviate electronic re-
pulsion between the oxygen lone pairs, the hydroxy group
on the hemiaminal carbon is oriented away from the exo-
cyclic sulfonyl oxygen atoms. Moreover, close contacts were
detected between the sulfonyl oxygen atoms and the near-
by hydrogen atoms, respectively (2.40 and 2.53 Å, Figure
S8). Those two intramolecular CH…O hydrogen bonds fur-
ther rigidify the structure and thereby contribute to the
high diastereoselectivity, in addition to the electronic effect
described above. On the basis of the crystal structure, an
S-stereocenter favors a P-twist in 4, whereas an R-stereo-
center gives an M-twist.
With the interconverting open/cyclic atropisomeric sys-
tem in hand, we examined their DCRs with a series of N-
and O-mononucleophiles. We surmised that, as in case of 1,
the reaction of 2 with primary amines might proceed via
the open aldehyde 3 [Figure 3(a), Pathway a]. The assembly
of 2 with butylamine was therefore examined at r.t. in
CD3CN containing molecular sieves [Figure 3(b)]. The for-
mation of imine 5 was confirmed by the presence in the 1H
NMR spectrum of a peak at about δ = 8.02 ppm, corre-
sponding to the imine proton [Figure 3(b)]. Furthermore, a
doublet at about δ = 5.50 ppm was observed, indicative of
the formation of the cyclic aminal 6. The existence of 6 was
also supported by the presence of two doublets at δ = 3.82
and 4.54 ppm, which were assigned to the diastereotopic
methylene protons. The ratio of products 5 and 6 was about
1.0, which is markedly different from that obtained in DCRs
The biaryl was readily prepared through Suzuki cou-
pling (Scheme S1).23 Both the aldehyde form 3 and the
hemiaminal form 4 were observed in acetonitrile, with the
ring form dominant [Figure 2(a)]. The formation of the cy-
clic hemiaminal (88%) was supported by observation of the
methine proton (Ha) and the diastereotopic methylene pro-
1
tons (Hb and Hc) in the H NMR spectrum. This is in sharp
contrast to the case of 1, for which the open aldehyde ac-
counts for the majority of the population (66%). We ratio-
nalized these findings in terms of the release of steric strain
due to the significantly smaller size of CH2 compared with
SO2, and the resulting structural flexibility. The equilibrium
was also explored in CDCl3, and analogous results were ob-
tained (Figure S3). Furthermore, only one set of signals was
detected for 4 at room temperature [Figure 2(a)] or below
(Figures S6 and S7). These observations were interpreted as
resulting from excellent chirality transfer between the
hemiaminal stereocenter and the chirality of the biphenyl
moiety (dr > 20).
To shed additional light on the chirality-relay process,
X-ray quality crystals of 4 were obtained through slow
evaporation of a solution of 2 in dichloromethane–hexane
[Figure 2(b)].24 The biphenyl moiety had a torsion angle of
43°, which is comparable to the twist (45°) within the most
stable structure of 1, according to density functional theory
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of 1 with primary amines, for which the imine predomi-
nates. The difference in the ratio of the imine and its aminal
for endocyclic and exocyclic sulfonamides is consistent
with the trend of their corresponding parent aldehydes and
hemiaminals (Figure 2). An equilibrium between 5 and 6
was also observed for other primary amines (Figures S9–
S13).
We next set out to investigate the incorporation of
amines that were more sterically hindered. Analogously to
the nucleophilic addition of a primary amine to aldehyde 3
to give an imine and its cyclic aminal, with the loss of water
as a driving force, the combination of 3 with a secondary
amine should lead to an iminium ion 7 and, subsequently,
the aminal 8 upon ring closure [Figure 3(a), Pathway a].
Gratifyingly, a high yield (>90%) of the desired product was
obtained for the DCR of 2 with piperidine [Figure 3(b)]. Sev-
eral achiral amines were tested, and 8 was formed diastere-
oselectively in all cases [see the sharp singlet for the
methine proton in Figure 3(b) and Figures S16–S18], there-
by emphasizing the generality of our approach.
Encouraged by DCRs of 2 with both primary and sec-
ondary amines, we turned our attention to monoalcohols.
Unfortunately, no reaction was apparent when 2 was mixed
with 3.0 equivalents of propan-2-ol, probably due to the
low reactivity of the alcohol group. We postulated that,
rather than a direct attack on the carbonyl by an alcohol, a
sulfonyliminium ion25 9 might be formed from cyclic 4 in
the presence of a Brønsted acid [Figure 3(b), Pathway b].
Such a species should be highly electrophilic, and could
therefore be captured by an alcohol to afford a hemiaminal
ether 10. In the presence of methanesulfonic acid (MA), the
reaction of 2 with propan-2-ol did indeed give hemiaminal
ether 10 in a high yield [>90%; Figure 3(b)]. The broad scope
of the assembly was confirmed by the successful incorpora-
tion of a series of monoalcohols (Figures S23–S29). Again,
the formation of dynamic covalent adducts was stereose-
lective (dr > 20), even with methanol (Figure S23–S25). The
nearly perfect chirality induction from the hemiaminal
ether stereocenter to the chirality of the biphenyl moiety
was verified by X-ray crystallographic analysis of the meth-
anol-derived product 10 (Figures S32–S34).24 Except for the
change from a hydroxy to methoxy group, the structural
features of 10 closely resemble those of 4, and the interplay
between the hemiaminal central chirality and the helical
twist of the biphenyl was maintained.
Having achieved dynamic covalent bonding of amines
and alcohols by using atropisomeric receptors, we probed
the reversibility of the process. To this end, a series of in
situ component-exchange reactions was performed. For in-
stance, the reaction of 2 with piperidine was initially per-
formed and then N-methylpropan-1-amine was added. Af-
ter equilibrium had been reached, 1H NMR spectroscopy in-
dicated a decrease in the amount of the original assembly,
with the emergence of an N-methylpropan-1-amine-de-
rived product [Figure 4(A)]. An analogous exchange was
also found to occur with primary amines (Figure S35) or al-
cohols (Figure S37). It is worthwhile mentioning that both
imines and their associated aminals participated in the
scrambling of primary amines. These results confirm the
dynamic nature of our system. Isolated 10, incorporating
methanol, was dissolved in CD3CN and equilibrated on ad-
dition of propan-2-ol and MA. An exchange of alcohols was
detected [Figure 4(B)], corroborating the reversibility of this
process.
Our next goal was to test the chirality induction with
chiral amines or alcohols under thermodynamic control, for
the purpose of chirality recognition. Due to the diastereose-
lective chirality transfer between the hemiaminal stereo-
center and the chiral axis of the biphenyl moiety with achi-
ral substrates, we surmised that DCRs of 2 with an enantio-
merically pure chiral substrate might give a pair of cyclic
diastereomers, taking into consideration the central-to-
central asymmetric induction, which would be represented
Figure 3 DCRs of 2 (i.e., 3 and 4) with primary amines, secondary
amines, and alcohols. (a) Proposed reaction pathways. (b) 1H NMR
spectra of the reaction of 2 with mononucleophiles in CD3CN.
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Figure 4 The dynamic nature of the system. A. Component exchange
(c) of a piperidine-derived adduct (a) with N-methylpropan-1-amine
(b). B. Component exchange (d) of the isolated 10 incorporating meth-
anol (a) with propan-2-ol. The in situ reaction of 2 with methanol and
propan-2-ol in CD3CN is shown in (b) and (c), respectively.
by the dr value. A suite of chiral amines and alcohols with
various substitution patterns were used in DCRs, and mod-
est dr values were obtained (Figures S11–S13, S19–S20, and
S26–S29). The degree of diastereoselectivity is controlled
by the structure of the chiral substrates and is reflected by
the induced helical twist of the biphenyl moiety. We there-
fore recorded circular dichroism spectra of the adducts
(Figure 5).
Figure 5 Chirality recognition with 2 (i.e., 3 and 4). (a) Chirality induc-
tion for DCRs of 2 with mononucleophiles; (b) CD spectra of solutions
of DCRs of 2 with 1-phenylethanol, 3,3-dimethylbutan-2-amine, and 2-
(methoxymethyl)pyrrolidine (0.13 mM).
With the dilute solutions of the assemblies from 2 as
presented above, reproducible CD spectra were observed.
For example, a strong positive Cotton effect at 242 nm was
found for aminal 8 derived from (2S)-2-(methoxymeth-
yl)pyrrolidine, which gave a dr value of 3.1. With (1R)- or
(1S)-1-phenylethanol (dr ~1.4), a peak at about 250 nm was
found. For 3,3-dimethylbutan-2-amine, a mixture of the
imine and aminal (dr ~1.3) gave weaker CD signals at about
280 nm. The absolute magnitude of the CD peaks approxi-
mately fell in line with the trend in the dr values. Several
chiral alcohols and amines were tested, and CD responses
were detected for their corresponding assemblies (Figures
S39–S47). Because the reactants (racemic 2 and the chiral
substrates) show no interference above 220 nm, any CD sig-
nals above this wavelength are indicative of the induced he-
licity and, in turn, correlate with the chirality of the sub-
strates. As a result, the current platform should be suitable
for chiroptical sensing, as previously reported 1.22
In conclusion, we have developed an atropisomeric sys-
tem for the reversible covalent binding of a series of mono-
nucleophiles. The intramolecular equilibrium between an
open aldehyde and its cyclic hemiaminal was investigated
in detail, and the structural basis of the diastereoselectivity
was elucidated. The regulation of reactivity of those
open/ring species then permitted the development of dy-
namic covalent reactions of a broad range of primary
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amines, secondary amines, and alcohols. The dynamic na-
ture of the system was verified through component ex-
change. Finally, the extent of chirality induction was exam-
ined by using chiral substrates, and a significant CD effect
was observed. The current exocyclic sulfonamide system
complements our recently reported endocyclic platform,
and further establishes the value of dynamic covalent inter-
actions for controlling the chirality of atropisomers.
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Funding Information
We thank the National Natural Science Foundation of China
(21672214 and 21504094), the Recruitment Program of Global Youth
Experts, the Strategic Priority Research Program (XDB20000000), the
Key Research Program of Frontier Sciences (QYZDB-SSW-SLH030) of
the CAS, and the Natural Science Foundation of Fujian Province
(2016J05060) for financial support. We also thank the CAS/SAFEA In-
ternational Partnership Program for Creative Research Teams.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610207.
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The mixture was extracted with EtOAc (2 × 30 mL), and the
organic layers were combined, washed with water, dried (Na2-
SO4), filtered, concentrated, and purified by column chromatog-
raphy [silica gel, PE–EtOAc (4:1)] to give a white solid; yield:
0.51 g (88%); mp 92–94 °C. 1H NMR (CD3CN): δ = 9.72 (s, 1 H,
open form), 8.01 (d, J = 7.6 Hz, 1 H, open form), 7.73 (t, J = 7.6
Hz, 1 H, open form), 7.37–7.63 (m, 61 H, open form 5 H; ring
form 56 H), 7.25 (d, J = 7.6, 1 H, open form), 6.29 (d, J = 4.8 Hz, 7
H, ring form), 5.39 (br s, 1 H, open form), 4.58 (d, J = 14.4 Hz, 7
H, ring form), 4.00 (d, J = 6.0 Hz, 2 H, open form), 3.90 (d, J = 14.4
Hz, 7 H, ring form), 3.71 (d, J = 4.8 Hz, 7 H, ring form), 2.98 (s, 21
H, ring form), 2.68 (s, 3 H, open form). 13C NMR (CD3CN):
δ = 191.7, 143.5, 140.8, 139.7, 138.5, 137.6, 136.81, 135.6, 134.9,
134.1, 133.7, 131.1, 130.6, 129.8, 129.5, 129.0, 128.7, 128.7,
128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.4, 83.3, 47.5, 44.5,
41.1, 39.1. ESI-HRMS: m/z [M + Na]+ calcd for C15H15NNaO3S:
312.0670; found: 312.0667.
(24) CCDC 1840008 and 1840009 contain the supplementary crys-
tallographic data for compounds 4 and 10, respectively. These
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
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Angew. Chem. Int. Ed. 2018, 57, 1300.
(23) 6-Mesyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-ol (2)
Under an argon atmosphere, N-(2-bromobenzyl)methanesul-
fonamide (0.53 g, 2.0 mmol), (2-formylphenyl)boronic acid
(0.46 g, 3.0 mmol), and Pd(dppt)Cl2 (60 mg) were dissolved in
1,4-dioxane (20 mL). A 1 M aq solution of K3PO4 (6.0 mL) was
added, and the mixture was stirred at 86 °C overnight. The
mixture was then cooled to r.t. and brine (15 mL) was added.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F