Convergent synthesis, resolution, and chiroptical properties of dimethoxychromenoacridinium ions

Article abstract of DOI:10.1021/ol501692r

Cationic azaoxa[4]helicenes can be prepared in a single step from a common xanthenium precursor by addition of nucleophilic amines under monitored conditions (160°C, 2 min, MW). The (-)-(M) and (+)-(P) enantiomers can be separated by chiral stationary-phase chromatography. Determination of the absolute configuration and racemization barrier (ΔG ^a (433 K) 33.3 ± 1.3 kcal·mol ^-1) was achieved by VCD and ECD spectroscopy, respectively.

Full text of DOI:10.1021/ol501692r

Letter
pubs.acs.org/OrgLett
Convergent Synthesis, Resolution, and Chiroptical Properties of
Dimethoxychromenoacridinium Ions
Jerome Gouin,† Thomas Burgi,‡ Laure Guenee,§ and Jerome Lacour*,†
́
̂
́
́
́
̂
̈
‡
†Department of Organic Chemistry, Department of Physical Chemistry, and §Laboratory of Crystallography, University of Geneva,
Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland
S
* Supporting Information
ABSTRACT: Cationic azaoxa[4]helicenes can be prepared in a
single step from a common xanthenium precursor by addition of
nucleophilic amines under monitored conditions (160 °C, 2 min,
MW). The (−)-(M) and (+)-(P) enantiomers can be separated by
chiral stationary-phase chromatography. Determination of the
absolute configuration and racemization barrier (ΔG⧧ (433 K)
33.3 1.3 kcal·mol−1) was achieved by VCD and ECD spectroscopy, respectively.
ationic helicenes related to the family of triangulene dyes
and fluorophores are investigated for their unusually high
stability under basic conditions and for applications in the fields
of chirality, physical organic chemistry, catalysis, photophysics
and biology.1,2 Two families of derivatives have been reported
so far, the [4] and [6]helicenes respectively (Figure 1). They
Scheme 1. Preparation of Dimethoxychromenoacridinium
Ions 3
C
Figure 1. Cationic [4]- and [6]helicenes (P enantiomers shown). X, Y
= O, NR.
are characterized by a (formally) central positive charge flanked
by two neighboring donor heteroatoms that tame the reactivity
of the electrophilic center. While two nitrogen, two oxygen or a
combination of both atoms can be relatively easily introduced
into the [6]helicene framework,3 achieving such a diversity in
the [4]helicene series has been less trivial. Diaza derivative 1
was for a long time the only known member of the [4] family;4
isolation of chromenoacridinium ions 3 (Scheme 1, eq 2).
Xanthenium salt 6 is used as a common precursor for all
derivatives 3. Under optimized conditions (rapid RNH2
addition, chemo- and stereoselective reduction, novel photo-
chemical reoxidation), salts 3 are isolated in yields up to 46%
for four combined steps. Interestingly, this procedure is
amenable to acid-sensitive residues and some important
mechanistic information is afforded by the isolation in high
yields of initial leuco intermediates. Compound 3a (R = Pr)
was furthermore separated into single enantiomers by chiral
stationary phase (CSP) chromatography. The P and M
enantiomers were identified by vibrational circular dichroism
(VCD) and they present a rather large barrier of racemization
(ΔG⧧ 33.3 1.3 kcal·mol−1 at 433 K).
5
and azaoxa 36 being reported quite later.7
4l,
dioxa 2
In fact, the synthesis of dimethoxychromenoacridinium ions
3 was reported only recently by Laursen and collaborators
(Scheme 1, eq 1).6 Several acridiniums 4 were prepared by
reactions of tris(2,6-dimethoxybenzene)methyl cation 5
(Scheme 2) with primary amines.4a,b Then, treatment in
concentrated H2SO4/AcOH afforded the targeted azaoxa[4]-
helicenes in moderate to excellent yields. Compounds 3 were
+
characterized by their pKR value (13.0). Absorption and
As just mentioned, helical dimethoxychromenoacridinium
ions have been recently reported by the group of Laursen.6 In
this study, compounds 3 were prepared in two main steps by
reactions of tris(2,6-dimethoxybenzene)methyl cation 5 with
emission properties were also examined and discussed. The
reactivity toward nucleophiles such as hydrides (NaBH4) or
organolithium reagents (MeLi) was investigated demonstrating
good levels of facial selectivity in the nucleophilic attacks to the
central carbon.
Herein, in a complementary study, we present a chemically
orthogonal and convergent procedure for the preparation and
Received: June 11, 2014
Published: July 7, 2014
© 2014 American Chemical Society
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Scheme 2. Convergent Synthesis of Azaoxa[4]helicenes 3
Scheme 3. Chemoselective Reduction and Photochemical
Reoxidation of Neutral Adducts 9
the reactivity−selectivity principle under kinetic control.13
Finally, reoxidation of compounds 9 to salts [3][BF4] was
afforded by a photochemical irradiation of MeOH solutions in
the presence of air and of NaBF4 or HBF4.14,15
With this procedure in hand, a variety of side chains were
introduced. Yields are low to moderate, from 7 to 46%, but they
correspond to the combined yields of four consecutive steps−
the last three being performed in a row. Alkyl residues from
propyl to hexadecyl are introduced readily; yields of the
corresponding cations 3a to 3e decreasing however constantly
with the longer side-chains. The reason for the decrease is
unknown at the moment. Less nucleophilic aniline reacted
nevertheless to afford 3f in 15% yield. To our satisfaction, it was
possible to introduce acid-sensitive allylamine and tert-butyl (2-
aminoethyl)carbamate. The corresponding tetrafluoroborate
salts [3g][BF4]and [3h][BF4] were isolated in 27% and 19%
respectively.
primary amines and then treatment of the resulting acridinium
salts 4 in strongly acidic conditions (Scheme 1, eq 1). Despite
the efficiency of this method,8 we saw an advantage in
developing of an alternative protocol which would be
convergent and allow the use of acid-sensitive side chains
(e.g., NHBoc, allyl). This approach would use xanthenium salt
[6][BF4] as a common precursor for all derivatives 3 (Schemes
1 and 2). We considered that 6 ought to react with primary
amines under controlled conditions and afford the dimethox-
ychromenoacridinium ions by nucleophilic aromatic substitu-
tions of two neighboring MeO substituents by the aza-
nucleophiles.
At that stage, to shed some light on the mechanism, it was
decided to investigate further the addition of amines to salt
[6][BF4]. Reactions were performed in CH3CN at 20 °C. In all
instances (Table 1), a rapid discoloration was achieved and
a
Table 1. Isolation of the Triarylammonium salts [10][BF4]
In practice, [6][BF4] was prepared using conditions
described by Martin and Smith.9 A solution of [5][BF4] in
aqueous HCl was heated at reflux for 12 h to obtain, after
workup and acidification with HBF4, salt [6][BF4] in
quantitative yield. Then, solutions in dry NMP of primary
amines and [6][BF4] were heated at 160 °C in a microwave
apparatus. Care was taken to use a short reaction time (2 min)
and a relatively modest quantity of amine (3 equiv) since large
amounts of base and prolonged reaction times provoke further
reactions and favor the formation of triangulene products.10 To
our satisfaction, analysis of the reaction crude revealed the rapid
consumption of 6 (see the mechanistic discussion) and the
formation of desired products [3][BF4] which were extracted
from the organic layers after the addition of EtOAc and brine,
along with traces of the corresponding ADOTA adducts 8
(typically 1−10%, ADOTA = azadioxatriangulenium ions,
Scheme 3). While it was impossible to separate 3 from 8 by
column chromatography or precipitation, a chemo and
stereoselective reduction afforded a rapid solution to the
problem.11 Treatment of the mixtures with NaBH3CN led to
the exclusive reduction of 3 (Scheme 3).12 Resulting neutral
triarylmethanes 9 were then easily separated from cationic 8 by
filtration over silica gel plugs. Of interest, compounds 9 were
isolated in quite better diastereomeric ratios (35:1, HPLC)
using NaBH3CN as hydride source instead of NaBH4 (10.1:1).6
Clearly, the milder nature of the cyano-containing reagent is
beneficial; the higher selectivity being then possibly the result of
entry
compd
R
yield (%)
1
2
3
4
5
10a
10b
10c
10d
10e
propyl
hexyl
95
80
70
69
70
octyl
decyl
hexadecyl
a
Anisotropic displacement ellipsoids plot of the crystal structure of
[10a][BF4]. Thermal ellipsoids are drawn at 50% probability. For
clarity, most hydrogen atoms have been removed and the propyl side
chain was truncated.
NMR spectroscopic analyses revealed the predominant
formation of 1:1 adducts between 6 and the amines. These
leuco products were isolated by precipitation upon addition of
Et2O and a further cooling to 4 °C. Only a motif with an
ammonium moiety bound directly to the central carbon atom
was consistent with the 1H, 13C, IR, and MS analyses; the motif
was confirmed by the X-ray diffraction study of [10a][BF4]
(see Table 1 and the Supporting Information).16 Interestingly
and a bit surprisingly, these ammonium salts are highly stable as
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evidenced by their lack of reactivity when heated to 160 °C in
solution in NMP (MW, 2 min). In fact, the reactions remain
essentially colorless and salts [10][BF4] are recovered
quantitatively.17
i
However, additions of 1.5 equiv of base (Et3N, Pr2NEt,
DBU, or the primary amines themselves) to the NMP solutions
of salts [10][BF4] result in an immediate red color. After
heating (MW, 160 °C, 2 min) and workup, the corresponding
[3][BF4] salts can be isolated (yields 11−15%). To characterize
this transformation, salts [10a][BF4] (R = Pr) and [10b][BF4]
(R = Hex) were reacted with hexylamine and propylamine,
respectively (1.5 equiv). In both experiments (Scheme 4),
Scheme 4. Evidence for a Dissociative Intermolecular
Mechanism
Figure 2. Experimental VCD spectra (CD2Cl2, 298 K) of
(−)-[3a][BF4] (blue) and (+)-[3a][BF4] (red). Calculated spectrum
of (P)-3a (green).
products [3a][BF4] and [3b][BF4] were obtained in a statistical
mixture; the ratios reflecting the stoichiometry between the
propyl and hexyl components in each crude. Clearly, these
results indicate that a base is required to transform ammonium
derivatives [10][BF4] into products 3 and that a dissociative
intermolecular mechanism is at play.18
barrier was performed by ECD, monitoring a single wavelength
every second (410 nm, see the Supporting Information). It was
necessary to heat DMSO solutions of (+)-[3a][BF4] at 160 °C
to start observing a relatively rapid decrease of the Cotton
effect. After 1000 s, a 28% loss of enantiomeric purity was
observed at that temperature. Samples were then heated at 170,
180, and 190 °C and analyzed for the same period of time. The
kinetic constants were calculated (e.g., k (433 K) 1.75 × 10−4 s·
mol−1) and the activation parameters determined (ΔH⧧ (433
K) 24.9 2.4 kcal·mol−1 and ΔS⧧ (433 K) −19.4 2.5 cal·
K−1·mol−1). Not surprisingly, the racemization barrier of
With these results in hand, the resolution of 3a was tackled.
The enantiomeric separation was, however, performed by CSP
chromatography on neutral compound 9a rather than on the
charged moiety; the high diastereomeric purity of 9a (dr 35:1)
obviously helped the separation process. In fact, the resolution
of rac-9a was achieved on a semipreparative scale using a
Chiralpak IC column and a mixture of n-hexane:i-PrOH 99:1 as
eluent. From 50 mg of rac-9a, after several runs, two major
separated fractions were afforded, 9 mg (ee > 99%, 18%) of
(−)-9a and 9 mg (ee>99%, 18%) of (+)-9a (see the Supporting
Information for details). Upon photochemical oxidation
(Scheme 3), the corresponding enantiopure salts
(−)-[3a][BF4] and the (+)-[3a][BF4] were afforded. Electronic
circular dichroism (ECD) spectra display totally symmetrical
curves in the 250−650 nm domain. The spectra are reported in
Figure S2 (Supporting Information).
[3a][BF4] (ΔG⧧ (433 K) 33.3
1.3 kcal·mol−1) is lower
than that of diaza[1][BF4] (ΔG⧧ 41.3 kcal·mol−1) and higher
than dioxo [2][BF4] (ΔG⧧ 27.7 kcal·mol−1). Clearly, as
observed before,5,20 the presence of an oxygen atom at a
bridging position causes a higher degree of flexibility leading to
an easier racemization. Recently, Elm and co-workers reported
a calculated estimation of 35.4 kcal·mol−1 for the racemization
barrier of 3 showing a good agreement between experimental
and theoretical values.21
In conclusion, using xanthenium ion 6 as precursor, a series
of dimethoxychromenoacridinium ions 3 was afforded. This
route is convergent and presents an interesting orthogonality to
that reported by Laursen and co-workers.6 Products 10 of initial
addition of the amines to the central carbon atom of 6 were
furthermore characterized and shown to be possible inter-
mediates if treated under basic conditions. Upon resolution by
CSP chromatography, single enantiomers were obtained of
which racemization barriers and absolute configurations were
determined by ECD and VCD spectroscopy, giving then a
complete description of the chiroptical properties of this novel
class of cationic helicenes.
The absolute configuration of helicene 3a was established by
vibrational circular dichroism (VCD).19 IR absorption and
VCD spectra were measured for solutions (CD2Cl2) of both
(+)- and (−)-[3a][BF4] and compared to the most stable
conformer of (P)-3a (Figure 2), thus accounting for about 90%
according its Boltzmann weight. Overall, a good agreement
between the experimental and theoretical spectra is observed
allowing the assignment of a P and M configurations for the
carbenium ion in salts (+)- and (−)-[3a][BF4] respectively.
With the enantiopure salt in hand, the determination of the
kinetic barrier for the interconversion between the enantiomers
of 3a was examined. The determination of the racemization
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(10) Typically, 25 equiv of RNH2 is used for the formation of
cationic diaza[4]- and -[6]helicenes. See refs 3 and 4a,c for details.
(11) We had initially considered using the procedure developed for
the purification of dioxo[4]helicene 2, i.e., the reduction with NaBH4
of all cationic derivatives followed by a separation of the resulting
neutral triarylmethane adducts (see reference 5). However, in our
hands, a satisfactory separation of the reduced products could not be
achieved.
(12) The chemoselectivity can be rationalized by the higher
electrophilicity of cations 3 over 8 (pKR+ 13 vs 14.5, respectively).
This difference may be related to the skeleton deformation that occurs
upon the addition of nucleophiles to the central carbon of the
carbenium ions. This leads to change of hybridization from sp2 to sp3
and the resulting strain seems to be better accommodated by the
helical framework of 3 than the rigid planar geometry of triangulene 8.
(13) The relative configuration of compounds 9 was not determined
in the course of this study but everything indicates that the major
diastereoisomer obtained with NaBH4 remains the same with
NaBH3CN. Its nature and the origin of the stereoselectivity are
discussed in ref 6.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jerome.lacour@unige.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Geneva and the Swiss National
Science Foundation for financial support. We acknowledge the
contributions of the Sciences Mass Spectrometry (SMS)
platform at the Faculty of Sciences, University of Geneva.
(14) Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46,
4605−4608.
(15) This procedure was preferred over the I2 oxidation protocol that
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