Synthesis and dynamic study of new ortho-(alkylchalcogen)acetanilide atropisomers. A second look at the hydrolysis of quaternary 2-methylbenzazol-3- ium salts

Article abstract of DOI:10.1016/j.tetlet.2013.07.123

The base-catalysed hydrolysis of N-ethyl-2-methylbenzazol-3-ium iodides was re-examined performing the reaction in boiling 96% ethanol, in the presence of triethylamine. The resulting unstable intermediates were isolated as the corresponding ether, thioether or selenoether derivatives, depending on the starting benzazole salt, by trapping via alkylation with ethyl and hexyl iodides, in moderate to good yields. Reduction of the o-(alkylchalcogen) acetanilides so obtained afforded the corresponding o-(alkylchalcogen)anilines. This methodology provides potential access to o-(alkylchalcogen)anilines bearing up to three different N-alkyl groups introduced in an unambiguous and regioselective way. The o-(alkylchalcogen)acetanilides are axially chiral molecules due to restricted rotation around the N-aryl bond. The resulting atropisomerism has been studied using dynamic variable temperature NMR spectroscopy and the corresponding rotational barriers were determined for the first time in acetanilides bearing a single ortho-substituent other than the tert-butyl and iodine groups. The estimated free energy of activation of the interconversion of the rotamers ranged from 17.1 to 20.5 kcal/mol.

Full text of DOI:10.1016/j.tetlet.2013.07.123

Tetrahedron Letters 54 (2013) 5441–5444
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and dynamic study of new ortho-(alkylchalcogen)
acetanilide atropisomers. A second look at the hydrolysis
of quaternary 2-methylbenzazol-3-ium salts
Susana S. Ramos a, Lucinda V. Reis b, Renato E. F. Boto c, Paulo F. Santos b, Paulo Almeida c,
⇑
a UMTP and Department of Chemistry, University of Beira Interior, Rua Marquês d’Ávila e Bolama, 6200-001 Covilhã, Portugal
b Department of Chemistry and Centro de Química-Vila Real, University of Trás-os-Montes and Alto Douro, Apartado 1013, 5001-801 Vila Real, Portugal
c CICS–UBI, Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The base-catalysed hydrolysis of N-ethyl-2-methylbenzazol-3-ium iodides was re-examined performing
the reaction in boiling 96% ethanol, in the presence of triethylamine. The resulting unstable intermediates
were isolated as the corresponding ether, thioether or selenoether derivatives, depending on the starting
benzazole salt, by trapping via alkylation with ethyl and hexyl iodides, in moderate to good yields. Reduc-
tion of the o-(alkylchalcogen)acetanilides so obtained afforded the corresponding o-(alkylchalcogen)ani-
lines. This methodology provides potential access to o-(alkylchalcogen)anilines bearing up to three
different N-alkyl groups introduced in an unambiguous and regioselective way.
Received 24 June 2013
Revised 19 July 2013
Accepted 23 July 2013
Available online 29 July 2013
Keywords:
Atropisomers
The o-(alkylchalcogen)acetanilides are axially chiral molecules due to restricted rotation around the N-
aryl bond. The resulting atropisomerism has been studied using dynamic variable temperature NMR
spectroscopy and the corresponding rotational barriers were determined for the first time in acetanilides
bearing a single ortho-substituent other than the tert-butyl and iodine groups. The estimated free energy
of activation of the interconversion of the rotamers ranged from 17.1 to 20.5 kcal/mol.
Ó 2013 Elsevier Ltd. All rights reserved.
Dynamic NMR spectroscopy
VT NMR
Line shape simulation
Hydrolysis
2-Methylbenzazol-3-ium salts
In recent years, considerable research work has been carried out
on the synthesis of cyanine dyes,1 a well-known class of organic
compounds with relatively good stability, high molar absorption
coefficients, medium fluorescence intensities and narrow absorp-
tion bands. Furthermore, the wavelength of maximum absorption
of these dyes can be tuned accurately from the near-UV to the
near-IR by means of simple structural modifications. These unique
photophysical and photochemical properties have turned cyanine
dyes useful for numerous applications in many different areas.1k
At present, a promising future for cyanine dyes is foreseen through
the joint efforts of synthetic dye chemists, molecular biologists,
physicists and medical scientists.
N-Alkyl-2-methylbenzazolium salts are common precursors in
cyanine dye synthesis, and their ability to be substituted at the aro-
matic moiety and at the quaternary nitrogen atoms, is crucial for
the structural diversity found in this family of dyes.2
It has been observed that under basic conditions, as often used
in cyanine dye synthesis, N-alkyl-2-methylbenzazolium salts inter-
act with water, which turns the full understanding of this reaction
important to avoid potential undesirable side reactions in cyanine
dye preparation.3d
Herein we re-evaluated the base-catalysed hydrolysis of N-
ethyl-2-methylbenzazol-3-ium salts 1 as a model, in the presence
of residual water, resulting in the opening of the heterocyclic ring.
The reaction does not stop at the o-hydrochalcogen intermediates
2, as thought previously,3 but subsequent cleavage of the heterocy-
cle occurs and, under suitable alkylating conditions, the corre-
sponding o-(alkylchalcogen)-N-ethylacetanilides 4 are obtained
(Scheme 1).
Nevertheless some authors have previously mentioned the for-
mation of ring opened products from the hydrolysis of 2-meth-
ylbenzothiazolium salts,4 none was unequivocally isolated or
deliberately trapped. The only ring opened product isolated and
characterized was the disulfide dimer, generally obtained as the
main reaction product, resulting from the oxidative coupling of
two initially formed ring opened molecules. In such cases the
hydrolysis was performed under rather more basic conditions than
those used in our previous studies,3 namely in aqueous sodium
hydroxide5a or in piperidine in 96% ethanol.6 A report where the
action of a nucleophile on benzothiazolium salts led to an isolable
species other than the corresponding disulfides, involved the reac-
tion with sodium ethoxide, which afforded the alkoxybenzothiaz-
ole unopened product.4b To the best of our knowledge, only two
examples of aromatic thioethers produced by the hydrolysis of
benzothiazolium salts can be found in the literature, resulting from
⇑
Corresponding author. Tel.: +351 275329174; fax: +351 275319056.
E-mail address: paulo.almeida@ubi.pt (P. Almeida).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.123

5442
S. S. Ramos et al. / Tetrahedron Letters 54 (2013) 5441–5444
Tetrahedron Letters
R
X
R
X
XH
X
N
X
ii
OH
O
O
i
iii
N
N
N
N
I
3
4
1
2
5
a: X = O, R = Et; b: X = O, R = Hex; c: X= S, R = Et; d: X = S, R = Hex; e: X = Se, R = Et
Scheme 1. Reagents and conditions: (i) NEt3, 96% EtOH, reflux; (ii) EtOH, NaOH, RI, reflux; (iii) LiAlH4/AlCl3 (1/1), Et2O, 0 °C to rt.
Table 1
noticed in anilides bearing two ortho-groups, possessing very high
rotational barriers, typically from <20 to ꢀ30 kcal/mol,11 and in
anilides possessing a single bulky ortho-substituent, usually iodine
or a tert-butyl group, showing rotational barriers of <20 kcal/mol.12
Atropisomerism was also observed in o-hydrochalcogen-substi-
tuted acetanilides, formed in the basic hydrolysis of N-ethyl-2-
methylbenzoxazolium and -benzothiazolium iodides.5b In this case
the authors could establish by NMR that, in solution, the open
hydroxylated benzazole compounds consist of four mutually inter-
changeable species, resulting from hindered rotation around the N-
aryl bond (atropisomers) and around the N–CO bond (E/Z diastere-
oisomers). The later conformational isomerism is well known for
amides due to the partial double bond character of the N–CO
Reaction times and yields of the synthesis of acetanilides 4 and anilines 5
Compound Reaction
timea (h)
Yieldb
(%)
Compound Reaction
time (h)
Yieldb
(%)
4a
4b
4c
4d
4e
4.0
7.0
3.5
6.5
3.5
79
68
87
75
83
5a
5b
5c
5d
5e
1.5
2.0
1.5
2.0
1.5
87
84
92
88
93
a
Overall.
Isolated yield.
b
the trapping of the transient o-thiophenol by inter-7a and intramo-
lecular7b alkylation of the thiol group, under strongly basic
conditions.
bond.13 The
diastereoisomer.
E conformer was confirmed to be the major
Recently, it was described that under basic catalysis the effec-
tive intermediates from the hydroxylation of 2-methylbenzoxazo-
lium and 2-methylbenzothiazolium iodides are the ring opened
products, an evidence which was corroborated by 1H and 13C
NMR data obtained by 600 MHz NMR.5a In that study 2-hydroxy-
acetanilide and a disulfide dimer resulting from the hydrolysis of
2-methylbenzoxazolium and 2-methylbenzothiazolium iodides,
respectively, were unequivocally isolated and characterized. It
was suggested5 that the structures of several compounds arising
from the hydrolysis of benzazoles reported by our group3 should
be revised.
In general, atropisomerism is recognized in solution by the non-
equivalence of individual protons (namely CH2 and CH3 groups) in
the 1H NMR spectra.5b,14 In particular, for acetanilides possessing at
least one bulky ortho-substituent11b,c,15 the restricted rotation
around the N-aryl bond is responsible for the non-equivalence of
the diastereotopic methylene protons, a typical sign of the exis-
tence of non-biaryl atropisomerism.
The 1H NMR spectra of acetanilides 4, at room temperature, are
also consistent with the existence of four different interconvertible
isomers in equilibrium such as depicted for 4c, as a representative
example, in Scheme 2.
As part of our efforts to definitively clarify this subject, we
ended with an efficient and simple way to obtain asymmetrically
substituted o-(alkylchalcogen)anilines 5 (Scheme 1). Thus, the
hydrolysis of 3-ethyl-2-methylbenzazol-3-ium iodides 1, readily
accessible as previously described,8 was carried out in boiling
96% ethanol, in the presence of triethylamine. The intermediate
N-ethyl-(2-hydrochalcogen)acetanilides 3, resulting from the
cleavage of the 2-hydroxyazole moiety of the initially formed
intermediate 2, were alkylated in situ, to afford the corresponding
(2-alkylchalcogen)-N-ethylacetanilides 4, in moderate to good
yields9 (Table 1).
The alkylation step was used to trap the sulfur and the selenium
open intermediates 3, as well as the oxygen analogues, following a
previously described strategy.7 Subsequently, acetanilides 4 so ob-
tained were converted to the corresponding 2-(alkylchalcogen)-
N,N-diethylanilines 5 by reduction with lithium aluminium hy-
dride in the presence of aluminium chloride.10 The short overall
reaction time, together with the mild conditions used and the good
yields obtained, yet non optimized, make this reaction syntheti-
cally useful. All the obtained compounds showed spectral data,
including high-resolution mass spectra, fully consistent with the
assigned structures.
Evidence of slow rotation about the N-aryl bond is immediately
noticeable in the 1H NMR spectrum of acetanilides 4 by the appear-
ance of two pairs of equally intense signals (partially overlapped
Hc
Ha
CH3
O
N-CO
C
CH3
C
CH3
rotation
O
S
N
H3C
S
N
Hd
Hb
H5C2
H5C2
Sa
Sa
N-Ar
rotation
N-Ar
rotation
Hc
Ha
O
CH3
N-CO
rotation
H3C
C
H3C
C
N
CH3
N
O
S
Hb
Hd
S
C2H5
C2H5
Ra
Ra
Acetanilides 4 were found to behave as enantiomeric atropi-
somers at room temperature due to restricted rotation around
the N-aryl bond, responsible for the achiral properties. The word
atropisomer is derived from the greek a, meaning not, and tropos,
meaning turn, videlicet without rotation. This feature has been
E
Z
Scheme 2. Enantiomeric and diastereoisomeric forms of acetanilide 4c resulting
from rotation around the N-aryl and N–CO bonds, respectively.

S. S. Ramos et al. / Tetrahedron Letters 54 (2013) 5441–5444
5443
double quartets) generated by the geminal non-equivalent N-
methylene protons (Fig. 1), in accordance with the literature.5b
Considering the chemical shift difference between the non-equiv-
alent methylene protons of each diastereoisomeric form it is
apparent that the methylene protons of the E-conformation expe-
rience considerably more different magnetic local environments
than those of the Z-conformation (Fig. 1). The E/Z ratio for all ace-
tanilides 4 was found to be P96/4.
The conformational dynamic process of the E diastereoisomeric
form of acetanilides 4 was investigated by variable temperature
NMR (VT NMR) spectroscopy16 and the corresponding rotational
barriers were determined. This seems to be the first time that rota-
tional barriers are determined for acetanilides bearing an alkyl-
chalcogen group as ortho-substituent.
As an illustrative example, by increasing the temperature of a
DMSO-d6 solution of 4a, the two partially overlapped double quar-
tets of methylene protons Ha and Hb, at 3.63 and 3.43 ppm, respec-
tively, came together yielding a very broad signal at 3.60 ppm,
owing to the rapid interconversion of the two conformers at higher
temperature (Fig. 2). The corresponding rotational barrier was
determined by computer line shape simulation performed at differ-
ent temperatures, yielding a series of rate constants for the exchange
process. From that, an activation energy of 18.1 0.2 kcal/mol for
the free interconversion between the two conformers could be
obtained using the Eyring equation.17 The free energies of activation
for the interconversion of the rotamers of 4b–e were similarly
determined and found to range from 17.1 to 20.5 kcal/mol (Table 2),
being in accordance with the values disclosed in the literature for
anilides possessing a single bulky ortho-substituent.11b,c,12
temperature, both atropisomers have sufficient thermal energy to
overcome the N-aryl bond rotational barrier and, therefore, free
rotation occurs. Contrary to acetanilides 4a,b, the coalescence tem-
perature could not be ascertained for acetanilides 4c–e due to the
limitation of the spectrometer’s working temperature to 413.15 K,
preventing, consequently, the determination of rate constants
above that temperature. However, the line shape simulations for
4c–e provided a set of rate constants which was sufficient to allow
the accurate calculation of the activation energy. In fact, the linear
regression analysis performed for each compound 4a–e was ob-
tained from a set of eight to eleven data points, with correlation
coefficients between 0.9873 and 0.9918, showing consistently a
very high degree of linearity for the data obtained.
From the observation of Table 2, it is apparent that the esti-
mated free energy of activation increases with the size of the chal-
cogen atom and decreases with the length of the alkyl group
connected to it. Even though the first correlation may be easily
rationalized based on the increase of the bulkiness of the chalcogen
atom in the ortho-position (
steric hindrance must be involved to explain the opposite effect
originated by the length of the alkyl group (
Gà: Et > Hex) on the
D
Gà: Se > S > O), other features besides
D
restriction of rotation around the N-aryl bond. On the other hand,
Tc increases both with the size of the chalcogen atom and the
length of the alkyl group.
In conclusion, the synthesis of some new o-(alkylchalcogen)ace-
tanilides 4, resulting from the base-catalysed hydrolysis of 3-ethyl-
2-methylbenzazol-3-ium iodides, is presented as a regioselective,
efficient and expeditious synthetic route to o-(alkylchalcogen)ani-
lines 5. This methodology provides potential access to o-(alkylchal-
cogen)anilines bearing up to three different N-alkyl groups
introduced in an unambiguous and regioselective way.
The ring opened products resulting from the hydrolysis of N-al-
kyl-2-methylbenzazolium salts were unequivocally trapped and
isolated as the ether, thioether and selenoether derivatives, in
the form of the ortho-substituted acetanilides 4 and the ortho-
substituted anilines 5. Herein we revise the structures presented
previously by us concerning N-alkyl-2-hydroxy-2-methylbenzaz-
oles3b and heptamethinecyanines resulting from the nucleophilic
Coalescence temperature can be defined as the temperature at
which the appearance of the NMR spectrum changes from that of
two separate peaks to that of a single, flat-topped peak. At this
Table 2
Interconversion energy barriers (D
Gà) and coalescence temperatures (Tc) for com-
pounds 4
Compound
D
Gà (kcal/mol)
Tc (K)
4a
4b
4c
4d
4e
18.1 0.2
17.1 0.2
18.3 0.2
17.8 0.2
20.5 0.2
388.15
393.15
>413.15
>413.15
>413.15
2
2
Figure 1. NMR signals of the non-equivalent geminal methylene protons of the E
(Ha e Hb) and Z (Hc e Hd) diastereoisomeric forms of acetanilide 4c.
Figure 2. Left: temperature dependence of the 1H NMR (400 MHz) signals of non-equivalent N-methylene protons of 4a in DMSO-d6. Right: computer line shape simulation
from the rate constants obtained for same compound.

5444
S. S. Ramos et al. / Tetrahedron Letters 54 (2013) 5441–5444
addition of the latter3a,c,d and correct them, respectively, to the iso-
meric N-alkyl-o-hydroxy-, o-sulfanyl- and o-selenylacetanilides
and to the substituted heptamethinecyanines resulting from the
nucleophilic addition of the latter two.
Finally, the atropisomerism of acetanilides 4 was studied using
dynamic NMR spectroscopy and the corresponding rotational bar-
riers were determined for the first time in acetanilides bearing a
single o-alkylchalcogen substituent. Further studies involving the
synthesis and VT NMR studies of new o-(alkylchalcogen)acetani-
lides substituted with N-alkyl groups other than ethyl and/or pos-
sessing a second group in the other ortho-position, along with the
assessment of their biological properties are currently being
undertaken, the results of which will be reported elsewhere.
completion of the reaction, the solvent was removed under reduced pressure,
the crude residue was dissolved in CH2Cl2 and extracted sequentially with 10%
aqueous HCl and 10% aqueous NaOH. The organic layer was then washed with
water, dried over anhydrous Na2SO4 and evaporated to dryness. The resulting
pinky-red oil was purified by column chromatography using CH2Cl2/MeOH
(from 10/0 to 9/1) as the eluent. The pure brown-yellowish products were
obtained in moderate to good yields (Table 1). Selected data. N-Ethyl-N-[(2-
(hexylthio)phenyl)]acetamide (4d): IR (m
max/cmÀ1): 2954, 2928, 2857, 1658
(C@O), 1583, 1470, 1392, 1297, 759, 734. 1H NMR (400 Hz, DMSO-d6): d = 7.36–
7.37 (m, 2H), 7.22–7.23 (m, 2H), 3.94 (dq, 1H, J = 13.8, 7.0 Hz), 3.09 (dq, 1H,
J = 13.8, 7.0 Hz), 2.98 (q, 2H, J = 7.3 Hz), 1.62 (s, 3H), 1.56–1.62 (m, 2H), 1.36–
1.43 (m, 2H), 1.23–1.27 (m, 4H), 1.00 (t, 3H, J = 7.1 Hz), 0.84 (t, 3H, J = 7.1 Hz)
ppm. 13C NMR (100 MHz, DMSO-d6): d = 169.2, 139.6, 137.5, 130.3, 129.3,
126.6, 125.9, 41.9, 31.2, 30.5, 28.6, 28.4, 22.5, 22.4, 14.3, 13.4 ppm. HRMS (ESI-
TOF) m/z 280.17216 (280.17351 calcd for C16H26NSO, [M+H]+).
10. General procedure for the reduction of acetanilides 4: Finely powdered AlCl3
(2.66 g, 0.02 mol) was added to
a stirred suspension of LiAlH4 (760 mg,
0.02 mol) in anhydrous Et2O (50 mL), cooled in an ice-bath. To this mixture
was added a solution of 4 (0.01 mol) in anhydrous Et2O (100 mL) over a 30 min.
period. After the mixture was stirred at room temperature for 1.5–2.0 h, it was
cooled in an ice-bath, the excess of reducing agent was decomposed by the
carefully addition of ethyl acetate and then a saturated aqueous Rochelle’s salt
solution was added and the mixture vigorously stirred for 30 min. The organic
layer was separated and the aqueous phase was extracted with Et2O. The
combined organic layers were washed with water, dried over anhydrous
Na2SO4, and the solvent evaporated under reduced pressure. Selected data.
Acknowledgments
This work was financed by FCT (Project PTDC/QUI-QUI/100896/
2008) and COMPETE (Project Pest-C/SAU/UI0709/2011).
N,N-Diethyl-2-(hexylthio)aniline (5d): Brownish oil. IR (m
max/cmÀ1): 2962, 2927,
References and notes
2855, 1578, 1468, 1377, 757, 731. 1H NMR (400 Hz, DMSO-d6): d = 7.15-7.17
(m, 1H), 7.04–7.09 (m, 3H), 2.96 (q, 4H, J = 7.1 Hz), 2.83 (t, 2H, J = 7.2 Hz), 1.58
(qt, 2H, J = 7.3 Hz), 1.36–1.43 (m, 2H), 1.27–1.28 (m, 4H), 0.91 (t, 6H, J = 7.1 Hz),
0.86 (t, 3H, J = 6.6 Hz) ppm. 13C NMR (100 MHz, DMSO-d6): d = 147.4, 135.9,
125.4, 124.4, 124.3, 122.6, 46.5 (2Â), 30.7, 29.9, 28.0 (2Â), 21.9, 13.8, 12.1
(2Â) ppm. HRMS (ESI-TOF) m/z 266.19422 (266.19425 calcd for C16H28NS,
[M+H]+).
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9. General procedure for the hydrolysis of 3-alkyl-2-methylbenzazol-3-ium iodides 1:
A
solution of the 3-alkyl-2-methylbenzazolium iodide 1 (1.0 mmol) and
16. Variable-temperature spectra of 3 were obtained at 400 MHz. Temperature
triethylamine (1.1 mmol) in 96% ethanol (100 mL) was heated under reflux.
After the reaction was complete (30–60 min), the solvent was removed under
reduced pressure and the crude reaction product was dissolved in EtOH.
Following the addition of sodium hydroxide (1.2 mmol with reference to salt 1)
and the appropriate alkyl iodide (1.0 mmol with reference to salt 1), the
reaction mixture was heated under reflux for an additional 2–6 h. After
calibrations were performed before the experiments by means of
a
thermocouple whit an uncertainty not exceeding 2 K. The line shape
simulations were performed by means of the gNMR software (Cherwell
Scientific).
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