A Forgotten Chiral Spiro Compound Revisited: 3,3'-Dimethyl-3H,3'H-2,2'-spirobi[[1,3]benzothiazole]

Article abstract of DOI:10.1002/chir.22492

The title compound was obtained as a side product during dimerization-oxidation steps of the carbene generated from N-methylbenzothiazolium iodide. Chromatography on (S,S)-Whelk O1 column showed on cooling a typical plateau shape chromatogram indicating an exchange between two enantiomers on the column. The thermal barrier to racemization was determined (85 kJ.mol^-1 at 10 C) by dynamic high-performance liquid chromatography (DHPLC).The absolute configuration of the first (M) and second eluted (P) enantiomers on the (S, S)-Whelk O1 column was established by comparing the reconstructed circular dichroism (CD) spectra from the CD detector signal and the calculated CD spectrum of the (P) enantiomer. Mass spectrometry revealed that 3,3'-dimethyl-3H,3'H-2,2'-spirobi[[1,3]benzothiazole] can be viewed as a masked thiophenate attached to a benzothiazolium framework. Chirality 27:716-721, 2015.

Full text of DOI:10.1002/chir.22492

CHIRALITY 27:716–721 (2015)
Special Issue Article
A Forgotten Chiral Spiro Compound Revisited: 3,3’-Dimethyl-3H,3’H-
2,2’-spirobi[[1,3]benzothiazole]
ANGÉLIQUE LINDAMULAGE DE SILVA,1 VESNA RISSO,1 MARION JEAN,1 MICHEL GIORGI,2 VALÉRIE MONNIER,2
1
JEAN-VALÈRE NAUBRON,2 NICOLAS VANTHUYNE,1 DANIEL FARRAN,1 AND CHRISTIAN ROUSSEL
*
1Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
2Spectropôle, Aix Marseille Université, Marseille, France
ABSTRACT
The title compound was obtained as a side product during dimerization-
oxidation steps of the carbene generated from N-methylbenzothiazolium iodide. Chromatography
on (S,S)-Whelk O1 column showed on cooling a typical plateau shape chromatogram indica-
ting an exchange between two enantiomers on the column. The thermal barrier to race-
mization was determined (85 kJ.molÀ1 at 10 °C) by dynamic high-performance liquid
chromatography (DHPLC).The absolute configuration of the first (M) and second eluted
(P) enantiomers on the (S, S)-Whelk O1 column was established by comparing the recon-
structed circular dichroism (CD) spectra from the CD detector signal and the calculated CD
spectrum of the (P) enantiomer. Mass spectrometry revealed that 3,3’-dimethyl-3H,3’H-2,2’-
spirobi[[1,3]benzothiazole] can be viewed as a masked thiophenate attached to a
benzothiazolium framework. Chirality 27:716–721, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: axial chirality; racemization barrier; spiro heterocycle; carbene dimerization;
oxidation of carbene dimer
We targeted the synthesis of the 10-membered ring 1
(Scheme 1) through the dimerization of the carbene gene-
rated from N-methylbenzothiazolium iodide in the presence
of triethylamine followed by air oxidation according to
Murphy and coll. in 1999.1
The reaction is reported to be quantitative for the N-ethyl
analog but for unclear reasons the outcome of our reaction
was different, leading to three compounds we isolated in low
yields by column chromatography in addition to 1 (Scheme 2).
N-methyl benzothiazolinone 2, the spiro-compound 3, which
resulted from a partial oxidation of the dimerized carbene,
and a nice crystalline spiro compound 4 issuing from the
decarbonylation of 3 were identified.
The characterization of these three compounds with mod-
ern techniques followed by a literature search led us to the
conclusion we were “reinventing” an already described out-
come of that reaction long before the extraordinary develop-
ment of N-heterocyclic carbenes (NHCs) in chemistry.2,3
The spiro compound 4 was solely reported or mentioned
during a period ranging between 1964 and 1978 and was
recalled in a review in 2005.4–12 A possible mechanism for
the formation of 3 and 4 has been proposed.5 As a proof of
the memory loss for compounds issued from that reaction,
it was particularly frustrating to see that Metzger et al. were
the very first to describe compound 4 more than 50 years
ago in the laboratory where the present study was conducted
in Marseilles, long before the characterization of 1.4 During
our efforts to identify the spiro compound 4, some unprece-
dented features appeared; they are reported herein.
MATERIALS AND METHODS
General Information
Commercially reagent grade chemicals were used as received without
additional purification. All reactions were followed by thin-layer chroma-
tography (TLC) (Kieselgel 60 F-254). TLC spots were visualized with
UV (254 nm). Column chromatography was performed on silica gel (60–
200 mesh). Dichloromethane used for purification by column chromatog-
raphy contained amylene as stabilizer. Nuclear magnetic resonance
(NMR) spectra were recorded on Bruker Avance DRX-400 MHz or
Bruker Avance III - 600 MHz instruments. Chemicals shifts in 1H NMR
and 13C NMR spectra are reported as parts per million downshift from
tetramethylsilane and coupling constants are reported in Hertz. When
necessary, resonances were assigned using 2D experiments (COSY,
HMBC, HSQC). HRMS (ESI) were recorded on a Waters SYNAPT G2
HDMS mass spectrometer or a QStar Elite (Applied Biosystems, Foster
City, CA, SCIEX) equipped with a TOF analyzer. High-resolution mass
spectrometry (MS), tandem MS/MS, and traveling wave ion-mobility
mass spectrometry (TWIM MS) experiments were performed with a
Waters Synapt G2 HDMS quadrupole/time-of-flight (Q/ToF) tandem
mass spectrometer (Manchester, UK), using the following parameters:
ESI capillary voltage: +2.8 kV; sampling cone voltage: +20 V range;
[This article is part of the Thematic Issue: “Chirality in Separation Science
and Molecular Recognition Honoring Prof. F. Gasparrini.” See the first articles
for this special issue previously published in Volume 27:9. More special arti-
cles will be found in this issue as well as in those to come.]
*Correspondence to: Christian Roussel, Aix Marseille Université, Centrale
Marseille, CNRS, iSm2 UMR7313,13397, Marseille, France. E-mail: christian.
roussel@univ-amu.fr
Received for publication 14 June 2015; Accepted 9 July 2015
DOI: 10.1002/chir.22492
Published online 25 August 2015 in Wiley Online Library
(wileyonlinelibrary.com).
© 2015 Wiley Periodicals, Inc.

FORGOTTEN CHIRAL SPIRO COMPOUND REVISITED
717
Physical data for 3,3’-dimethyl-3H,3’H-2,2’-spirobi[[1,3]-
benzothiazole 4. White crystals, mp: 233 °C; Rf = 0.91 (CH2Cl2/MeOH
99.5/0.5); 1H NMR (400 MHz, CDCl3, δ): 2.87 (s, 6H; CH3), 6.45-6.49
(m, 2H; Ar H), 6.77 (td, J = 7.5 Hz, J = 1.0 Hz, 2H; Ar H), 7.03-7.08 (m,
4H; Ar H); 13C NMR (100 MHz, CDCl3, δ): 29.6 (CH3), 106.9 (CH),
118.7 (C), 119.5 (CH), 120.9 (CH), 123.5 (C), 125.7 (CH), 142.6 (C);
HRMS (ESI, m/z): [M + H]+ calcd for C16H15N2OS2, 287.0671; found,
287.0681.
Scheme 1. Preparation of 10-membered ring 1.
It is worth mentioning that compounds 3 and 4 were kept in the solid
state to prevent decomposition.
X-ray analysis of 4. CCDC-1404056 contains the supplementary crys-
tallographic data for this article. These data can be obtained free of
charge from the Cambridge Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Scheme 2. Side products isolated during the synthesis of 1.
Calculations. Based on B3LYP/6-311G(df,p) optimized geometry of
the unique conformation of 4, the ECD and UV spectra were calculated
using time-dependent Density Functional Theory (TD-DFT)14,15 with
CAM-B3LYP functional16 and 6-31++G(d,p) basis set. Calculations were
performed for vertical 1A singlet excitation using 30 states. For a compar-
ison between theoretical results and the experimental values, the calcu-
lated UV and ECD spectra have been modeled with a Gaussian
function, using a half-width of 0.31 eV. Due to the approximations of the
theoretical model used, an offset almost constant was observed between
measured and calculated frequencies. Using UV spectra, all frequencies
were calibrated by a factor of 1.1. All calculations were performed using
Gaussian 09 package.17
desolvation gas (N2) flow: 100 L hÀ1 ; transfer CE: 4 eV; trap gas flow:
2 mL minÀ1 (Ar); helium cell gas flow: 180 mL minÀ1; ion mobility cell
gas flow 90 mL minÀ1 (3.45 mbar N2); source temperature: 20 °C;
desolvation temperature: 35 °C; IM traveling-wave height: 40 V; and IM
traveling wave velocity: 650 m sÀ1. Data analyses were conducted using
the MassLynx 4.1 program provided by Waters. Chiral high-performance
liquid chromatography (HPLC) analyses were achieved on a unit com-
posed of a Merck D-7000 system manager, a Merck-Lachrom L-7100
pump, a Merck-Lachrom L-7200 autosampler, a Merck-Lachrom L-7360
oven, a Merck-Lachrom L-7400 UV-detector, and a Jasco CD-1595 detec-
tor. (S,S)-Whelk O1 column (250*4.6 mm) was purchased from Regis
Technologies (Morton Grove, IL).
RESULTS AND DISCUSSION
Synthesis
The spiro compound 4 is axially chiral. The first single
crystal x-ray structure determination of 4 revealed, as
expected, the M and P forms in the cell (Fig. 1).
To a solution of triethylamine (0.58 ml, 4.32 mmol) in acetonitrile
(9.30 ml) was added at 0 °C the N-methyl-benzothiazolium iodide
(0.600 g, 2.16 mmol). The mixture was allowed to warm to room tempe-
rature and stirred for 24 h. The solvent was then removed under reduced
pressure and dichloromethane (10 ml) was added. The organic layer was
washed with water (20 ml), dried on MgSO4, and evaporated under
reduced pressure. The crude product was purified by column chromato-
graphy (eluent: CH2Cl2/MeOH 99.5/0.5) allowing to isolate compounds
1 (15–40%), 2 (5–12%), 3 (5–15%), and 4 (5–15%).
Interestingly, the molecule that presents a noncrystallo-
graphic two-fold axis centered on the spirocarbon displays
unsymmetric behavior at the level of its intermolecular interac-
tions. The calculation of Hirshfeld surfaces18 reveals that the in-
teractions within the crystal are mainly dominated by CH/π and
π/π interactions: the fingerprint of compound 4 is very close to
that of polycyclic aromatic compounds (fig. 5 in Supporting
Information).19 However, one sulfur atom is in short contact
with a hydrogen of a symmetry-related molecule while the
other is in short contact with another sulfur atom in the
crystal, the latter being the stronger intermolecular interaction
Physical data for 5,8-dimethyldibenzo[c,i][1,2,5,8]-dithiadiazecine-
6,7(5H,8H)-dione 1. Yellow solid; Rf = 0.45 (CH2Cl2/MeOH 99.5/0.5); 1H
NMR (400 MHz, CDCl3, δ): 3.04 (s, 6H; CH3), 7.34-7.41 (m, 2H; Ar H), 7.48-
7.51 (m, 4H; Ar H), 7.70-7.75 (m, 2H; Ar H); 13C NMR (100 MHz, CDCl3, δ):
36.7 (CH3), 130.0 (CH), 132.0 (CH), 132.3 (CH), 136.4 (C), 138.3 (CH), 144.5
(C), 163.8 (C = O); HRMS (ESI, m/z): [M + H]+ calcd for C16H15N2O2S2,
331.0569; found, 331.0569.
Physical data for 3-methyl-1,3-benzothiazol-2(3H)-one 2. Yellow
oil; Rf = 0.73 (CH2Cl2/MeOH 99.5/0.5); 1H NMR (400 MHz, CDCl3, δ):
3.46 (s, 3H; CH3), 7.04 (d, J = 8.2 Hz, 1H; Ar H), 7.17 (td, J = 7.7 Hz,
J = 1.1 Hz,1H; Ar H), 7.34 (td, J = 7.8 Hz, J = 1.2 Hz, 1H; Ar H), 7.43 (dd,
J = 7.8 Hz, J = 0.9 Hz,1H; Ar H). 1H NMR data are consistent with a com-
mercial sample and the literature.13
Physical data for 3’,4-dimethyl-3’H-spiro[1,4-benzothiazine-2,2’-
[1,3]benzothiazol]-3(4H)-one 3. White solid, mp: 136 °C; Rf = 0.82
(CH2Cl2/MeOH 99.5/0.5); 1H NMR (400 MHz, CDCl3, δ): 3.15 (s, 3H;
CH3), 3.56 (s, 3H; CH3), 6.61 (d, J = 8.0 Hz, 1H; Ar H), 6.78 (td, J = 7.6 Hz,
J = 1.0 Hz, 1H; Ar H), 6.96 (dd, J = 7.6 Hz, J = 1.1 Hz,1H; Ar H), 7.08-7.13
(m, 2H; Ar H), 7.17 (dd, J = 8.2 Hz, J = 0.9 Hz,1H; Ar H), 7.30 (dd,
J = 7.7 Hz, J = 1.4 Hz,1H; Ar H), 7.33-7.38 (m, 1H; Ar H); 13C NMR
(150 MHz, CDCl3, δ): 32.7 (CH3), 34.0 (CH3), 89.3 (C), 108.3 (CH), 118.2
(CH), 120.3 (CH), 121.4 (C), 122.1 (CH), 122.6 (C), 124.4 (CH), 126.5
(CH), 128.0 (CH), 130.9 (CH), 139.1 (C), 145.9 (C), 162.0 (C = O); HRMS
(ESI, m/z): [M + H]+ calcd for C16H15N2OS2, 315.0620; found, 315.0631;
[M + Na]+ calcd for C16H14N2OS2Na, 337.0440; found, 337.0447.
Fig. 1. Single crystal x-ray of 4.
Chirality DOI 10.1002/chir

718
DE SILVA ET AL.
(figs. 6 and 7 in Supporting Information). That difference in the
nature of short contacts is probably at the origin of the diffe-
rence in length between the two sulfur-central carbon bonds
(1.85 and 1.88Å, respectively). This dissymmetry within the
crystal structure of 4 is also illustrated on the N-CH3 moieties,
as the two N-CH3 bond lengths are significantly different: 1.436
and 1.374 Å, respectively. The methyl group of the longer
N-CH3 bond and its connected aromatic ring are involved in
several intermolecular CH-π interactions with symmetry-
related molecules (fig. 8 in Supporting Information).
Spiro compound 4 was submitted to a screening on several
chiral stationary phases using various mobile phases. At room
temperature, a single peak was noticed on most of the coated
or immobilized polysaccharide stationary phases, while a
broad distorted peak was obtained on the so-called (S,S)-
Whelk O1 eluted with a mixture of heptane/2-PrOH. On
cooling, a typical plateau shape chromatogram was obtained,
indicating an exchange between two enantiomers on the col-
umn (Fig. 2).20–35
As usual, the plateau was composed of the racemate and thus
gave no signal during chiroptical detection. With the aid of the
Trapp and Schurig equation,36–38 a thermal barrier to racemiza-
tion of 85 kJ.molÀ1 at 10 °C was determined, indicating a rela-
tively fast exchange at room temperature and precluding
further easy isolation of the enantiomers. Compound 4 presents
a unique feature in which a carbon atom bears two nitrogen
atoms and two sulfur atoms. The breaking of one carbon-sulfur
bond may lead to the rather stabilized intermediate 5 (Scheme 3)
Scheme 3. Open form intermediate 5 on the racemization pathway of 4.
in which a fast rotation around the N-aryl bond and further
formation of the C-S bond from both sides of the achiral
benzothiazolium salt results in racemization.
The thermal barrier of 85 kJ.molÀ1 thus reflects the weak-
ness of the C-S bonds, the stabilization of the open form 5,
and includes a statistical contribution since the two C-S bond
are equivalently prone to break. According to barrier determi-
nation, the C-S bond is particularly weak in spiro compound 4.
Polarimetric detection with a Jasco OR-1590 detector, which
combines the signals between 300 and 900nm, did not produce
any signal for the front and back eluting aisles. On the other
hand, the circular dichroism (CD) detector set at 254nm
showed that the enantiomer presenting a negative CD sign at
that wavelength and in the mobile phase was the less retained
enantiomer on the (S,S)-Whelk O1 column. The first eluted en-
antiomer constantly gave a negative CD sign at 254nm when
different mobile phases were applied on the (S,S)-Whelk O1
column at 15°C. These mobile phases were composed of
heptane/chloroform (90:10 v:v), heptane/ethylacetate (90:10
or 95:5 v:v), heptane/THF (98:2 v:v), or heptane/tertiobutanol
(90:10 v:v). It was tempting to determine the order of elution
and thus the chiral recognition of the enantiomers by the
(S,S)-Whelk O1 chiral column through a calculation of the
CD spectrum for one enantiomer of 4.
The calculated CD spectra for (P)-4 (Fig. 3a) showed a
large positive band centered at ~260 nm and a large negative
band centered at ~300 nm after a calibration from the compar-
ison of the calculated and experimental UV spectra signal
(fig. 10 in Supporting Information). Since the region where
the CD detector was set (254 nm) is quite close to the maxi-
mum of the calculated band (260 nm), we were quite confi-
dent that the first eluted enantiomer is the (M) one.
In order to confirm the assignment, several injections from
the same vial, to ensure the same concentration, were per-
formed on the (S,S)-Whelk O1 at 15°C in a mobile phase
consisting of 90:10 v:v heptane/2-PrOH. The UV detector was
set at 254nm while the CD detector was set at different wave-
lengths (15 measurements), one for each injection. The UV
traces served to track any concentration changes or artifacts,
while the CD traces were collected for the first and second
eluted enantiomer in exchange (fig. 9 in Supporting Informa-
tion). It was thus possible to reconstruct the CD spectra of
the first and second aisles of the plateau which correspond to
the first and second eluted enantiomers (Fig. 3b). Comparison
of the reconstructed CD spectra with the calculated one for
(P)-4 nicely shows that the (P) enantiomer (second eluted)
has the higher affinity with the (S,S)-Whelk-O1 chiral selector.
The fitting between calculated and reconstructed CD spectra is
not as good for low wavelengths (<240nm) than for the two
major bands at longer wavelengths (>240nm).
The mass spectrometry results deserve some comments
since they were quite puzzling when we were trying to eluci-
date the structure of 4. The mass spectra after electrospray
ionization in positive mode (Fig. 4a) showed the presence of
Fig. 2. Chromatogram of 4 on (S,S)-Whelk-O1 column (90:10 v:v heptane/
2-PrOH, 1.5 ml.minÀ1, UV and CD traces at 254 nm at different temperatures.
ΔG = 85 kJ.molÀ1 at 10 °C).
Chirality DOI 10.1002/chir

FORGOTTEN CHIRAL SPIRO COMPOUND REVISITED
719
on m/z 287 ion showed that it corresponded to the ion
C15H15N2S+2 [exp. : m/z 287.0665, th : m/z 287.0671, delta :
À2.1 ppm] associated with [4 + H+]. Exact mass measurement
on m/z 286 ion showed that it corresponded to the doubly
charged ion C30H28N4S24+ [exp. : m/z 286.0595, th : 286.0593,
delta : +0.7 ppm]. This latter compound fitted with a dimeriza-
tion of 5 through a disulfide bond.
The occurrence of that dimer during
a very soft
electrospray ionization (or during the sample preparation) is
in the line of the low barrier to racemization occurring
through 5 which gained the status of intermediate after the
MS results. In the presence of methanol, the status of low
populated intermediate for 5 might be validated by the obser-
vation of an ion m/z 317 corresponding to C16H17N2OS+2 [exp.
: m/z 317.0781, th : m/z 317.0777, delta: +1.3 ppm] which
results from the addition of MeOÀ to 5. In the same way, in
the presence of IÀ, an m/z 413 ion is observed, corresponding
to C15H14N2S2I+ [exp.: m/z 412.9641, th : m/z 412.9638, delta:
+0.7 ppm] which results from the addition of IÀ to 5.
In the literature, several spiro compounds with two oxygen
and two unsaturated carbon atoms linked to the central car-
bon atom (such as in spiropyrans) have been intensively stud-
ied for their valuable thermochromic or(and) photochromic
properties (Scheme 4). The open forms are particularly stabi-
lized. Okamoto et al. resolved the enantiomers of compounds
6 by liquid chromatography on a chiral poly(triphenylmethyl
methacrylate) column and the resolved enantiomers were
racemized upon UV irradiation.39,40
Fig. 3. Calculated CD for the (P)-4 enantiomer in vacuum (a) and recon-
structed experimental CD for the first (dotted line) and second eluted enantio-
mers (plain line) from data generated on (S,S)-Whelk O1 in a mobile phase
composed of heptane/2-PrOH (90:10) at 15 °C (b).
Other examples in which the central carbon was linked to
two oxygen in 2,2’-spirochromene derivatives 7 and 2-
oxaindan spiropyrane derivatives
8 were reported by
Mannschreck and colleagues.41–43 Spirochromene 7 was se-
lected to illustrate the concept of enantiomeric enrichment
of stereolabile chiral compounds by dynamic (D)HPLC.44
Spiro(cyclohexadiene-indolines) provided examples in which
the central carbon was linked to three carbon atoms and a ni-
trogen.45 Cases in which the central carbon atom was linked
to a nitrogen, an oxygen, and two carbon atoms such as in
9 were reported.46–48 In all the previous cases, the enantio-
mers of 7, 8, and 9 were obtained by liquid chromatography
on chiral support. To the best of our knowledge, a single arti-
cle reported spiro compounds 10 in which the central carbon
atom was linked to a sulfur and two nitrogens. In 10, the bar-
riers were determined by DNMR.49 In contrast to compound
4, the ground state is dipolar in 10, while the open form is
neutral. Spiro compound 11 provided an example in which
Fig. 4. (a) Mass spectra of 4 in positive electrospray mode; (b) doubly
charged m/z 286 ion; and (c) singly charged m/z 287 ion extraction after ionic
mobility separation.
a doubly charge ion corresponding to m/z 286 (red spots) in
close vicinity of a singly charged ion m/z 287 (blue spots).
These differently charged ions were cleanly separated
thanks to ionic mobility (Fig. 4b,c). Exact mass measurements
Scheme 4. Structures of selected examples of spiro compounds which
have been resolved into enantiomers and thermally or photochemically
racemized in the literature (except compound 11)
Chirality DOI 10.1002/chir

720
DE SILVA ET AL.
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heterocyclic spirans. J Chem Res (Synopsis) 1978; 138–139.
12. Diaper CM. Other tetrahetero-substituted methanes. Sci Synth 2005; 18:
the central carbon was attached to three nitrogen atoms and a
carbonyl group.50,51 However, in contrast to the selected
examples 7–10, the chirality issues and racemization were
not addressed in 11.
1203–1282.
13. Yang Y, Zhang X, Zeng W, Huang H, Liang Y. Copper catalyzed three-
component synthesis of benzothiazoles from o-iodoanilines, DMF, and
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CONCLUSION
Spiro compound 4 was solely described during a 14-year
period between 1964 and 1978. According to Scifinder, it is
available for screening in three commercial libraries and from
the excellent synthesis of that compound which was
disclosed in 1968 from quaternized 2-chlorobenzothiazole
and 2-(methylamino)benzenethiol.7 The availability of spiro
compound 4 in large amounts justifies our efforts to study
that compound which was in our case a minor by-product dur-
ing the synthesis of 1. Our study shows that compound 4 and
probably other N-substituted analogs can be viewed as a
masked thiophenate attached to a benzothiazolium frame-
work. Several applications of that unique property can be
envisioned in material or labeling experiments after a fine
tuning of the substitution pattern. This work is in progress.
17. Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 09, Revision D.01.
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ACKNOWLEDGMENTS
Dedicated to Professor Jacques Metzger (1921-2014). The
Erasmus program is thanked for a grant (to V.R.). Aix-Marseille
University, CNRS, and Chirbase project are thanked for
funding. Paulina Jimenez Meneses is thanked for skillful
assistance.
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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