Benzothiazines in organic synthesis. Synthesis of fluorescent 7-amino-2,1-benzothiazines

Article abstract of DOI:10.1039/c1ob06051a

Fluorescent 7-amino-2,1-benzothiazines were prepared in high yields using the palladium-catalyzed reaction of 4-amino-2-chlorobenzaldehydes with a sulfoximine or the reaction of 7-fluoro-2,1-benzothiazines with amines. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06051a

Organic &
Biomolecular
Chemistry
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Volume 9 | Number 23 | 7 December 2011 | Pages 7953–8204
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Michael Harmata et al.
Benzothiazines in organic synthesis. Synthesis
of fluorescent 7-amino-2,1-benzothiazines

Organic &
Biomolecular
Chemistry
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Benzothiazines in organic synthesis. Synthesis of fluorescent
7-amino-2,1-benzothiazines†
Nattawut Yongpruksa, Siddharth Pandey, Gary A. Baker and Michael Harmata*
Received 30th June 2011, Accepted 11th August 2011
DOI: 10.1039/c1ob06051a
Fluorescent 7-amino-2,1-benzothiazines were prepared in
high yields using the palladium-catalyzed reaction of 4-
amino-2-chlorobenzaldehydes with a sulfoximine or the re-
action of 7-fluoro-2,1-benzothiazines with amines.
The development of new fluorescent materials is mandated by
Fig. 2 Generic, fluorescent 2,1-benzothiazine.
the continuing and growing interest in the application of optical
devices and sensors, particularly in the context of materials
development and biological chemistry.1 Fluorescent species that
are properly functionalized can potentially serve as sensors for
detecting anything from the occurrence of biological metabolites
to tumors and as components in electronic materials.2 Our interest
in this area arose from our long-standing involvement in the
synthesis and application of various 2,1-benzothiazines3 and the
fact that we have known for quite some time that many of these
compounds are fluorescent.
In the present study, we decided to attempt to emulate certain
coumarins that have been developed in the context of fluorescent
sensors.4 For example, 1 (Fig. 1) has recently been introduced as
a fluorescent probe for the detection of Cu(II).5 We thought that
benzothiazines generically represented by 2 (Fig. 2) would exhibit
enhanced and useful fluorescent properties and thus decided to
synthesize several examples of such species.
Fig. 3 The sulfoximine used in this study.
a Pd source and the ligand RuPhos afforded the benzothiazine
5 in 77% yield (Scheme 1). Though we were not certain that
the methodology would be applicable to synthesis of aminoben-
zothiazines, we decided to attempt to expand the scope of the
methodology in this direction.
Scheme 1 Benzothiazine synthesis from a chloroarene.
The aldehydes used in this study were prepared from 2-chloro-4-
fluorobenzaldehyde via simple, but effective, nucleophilic aromatic
substitution. Thus, heating aldehyde 6 with an amine in DMF in
the presence of K2CO3 afforded 4-amino-2-chlorobenzaldehydes
in excellent yield, as summarized in Table 1. In general, only
secondary amines were effective in this reaction. Primary amines
such as benzylamine and n-propylamine appeared to give imines
in the process, and the latter were unreactive with respect to the
desired nucleophilic aromatic substitution.
With the aminobenzaldehydes 7 in hand, we proceeded to
examine their ability to participate in our benzothiazine synthesis.
Under conditions that were essentially the same as those developed
recently, almost all of the aminobenzaldehydes afforded benzoth-
iazines upon reaction with 3 in the presence of a Pd source and
RuPhos as the ligand. The results are summarized in Table 2.
However, aldehyde 7e, in which the amino group bore two allyl
substituents, did not work well in this reaction. Switching to
Fig. 1 A coumarin-based fluorescent sensor.
Typically, our approach to benzothiazine synthesis has involved
the Buchwald–Hartwig coupling of ortho-bromobenzaldehydes
with sulfoximines such as 3 (Fig. 3).6 We recently reported a new
approach to sulfoximines and benzothiazines that conveniently
made use of chloroarenes.7 For example, heating of a toluene
solution of o-chlorobenzophenone (4) with 3 in the presence of
Department of Chemistry, University of Missouri-Columbia, Columbia,
Missouri 65211, USA. E-mail: harmatam@missouri.edu; Fax: +1 (573)-
882-2754; Tel: +1 (573)-882-1097
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all new compounds. See DOI:
10.1039/c1ob06051a
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7979–7982 | 7979
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Table 1 Preparation of aminobenzaldehydes
Table 2 Synthesis of benzothiazines from aminobenzaldehydes
Entry
Substrate
Product
Yield (%)
Entry
1
Amine
Product
Yield (%)
87
1
7a
7b
7c
7d
7e
9ed
9ed
7f
8a
8b
8c
8d
8e
8e
8e
8f
98
93
82
62
0b
morpholine
2a
3
4
5a
6a
7a,c
8
0b
83
88
2
3
pyrrolidine
piperidine
97
87
a Racemic sulfoximine was used. b Complete conversion of the aryl halide
was observed, but none of the expected product was obtained. c A
combination of 5% Pd(OAc)2 and 7.5% BINAP was used as catalyst. d
at 100 ◦C in DMF. The results of this study are shown in Table 3.
Overall, the yields for the benozothiazines were good-to-excellent.
Diallylamine failed to give rise to 8e under these conditions for
reasons that are not yet clear. In addition, both diphenylamine
and dicyclohexylamine were not competent nucleophiles in this
process, perhaps due to a steric effect.
4
azepine
85
With the benzothiazines in hand, we measured both their
absorption and emission properties in chloroform. As can be
seen from the entries given in Table 4, Stokes shifts were in
the 100–130 nm range for the series of compounds 8a–8g.
Such shifts, coupled with the possibility of modification of the
benzothiazine framework, suggest that compounds of this class
might be manipulated to yield tailored emissions. Toward that end,
we deprotonated 8b8 at the 3 position and trapped the resulting
organolithium with DMF to give aldehyde 11 in 60% unoptimized
yield (Scheme 2). Whilst changes in the spectral data for 11
were not dramatic, this modification produced clear bathochromic
5
6
diallylamine
diethylamine
98
94
Table 3 Nucleophilic aromatic substitution reactions of 10a
the bromo analogue of 7e, namely 9e, was also not productive.
Consumption of the starting material was observed in this case,
but none of the desired product was obtained. However, the yield
of 8e could be increased to 83% with 9e by conducting the reaction
employing “old” reaction conditions, using Pd(OAc)2 as the Pd
source and racemic BINAP as the ligand. It would appear that this
catalyst system is still competent to perform oxidative addition on
the carbon–bromine bond of 9e but is less suited for the formation
of a p-allyl intermediate arising from oxidative addition into the
carbon–nitrogen bond of the latter. This assumes that the problems
with 7e and 9e involved deallylation, something that still must be
determined.
Entry
Amine
Product
Yield (%)
1b
2
3
4
5
6
7
8
9
morpholine
morpholine
pyrrolidine
piperidine
azepine
diallylamine
diethylamine
benzylamine
diphenylamine
dicyclohexylamine
8a
8a
8b
8c
8d
8e
8f
8g
8h
8i
50c
98
97
90
72
0
88
75
0
Another route to the target benzothiazines was also considered.
We earlier reported the synthesis of 10,7 and decided to explore its
ability to undergo simple aromatic nucleophilic substitution. Thus,
10 was treated with a variety of amines in the presence of K2CO3
10
0
a Most reactions were performed with enantiomerically pure (R)-10. b The
reaction was performed for only 36 h. c A 36% yield of 10 was recovered.
7980 | Org. Biomol. Chem., 2011, 9, 7979–7982
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Table 4 Absorption and fluorescence data for benzothiazinesa
proper manipulation of the chromophore in benzothiazines of this
class should produce interesting and useful fluorophores.
To provide more quantitative information about the photolu-
minescence efficiencies of benzothiazines 8a–8g and 11, fluores-
cence quantum yields (UF) were determined for the fluorophores
dissolved in chloroform under ambient conditions using quinine
sulfate in 0.1 M H2SO4 as the fluorescence quantum yield standard
(UF = 0.577;9 see Supporting Information (SI) for details†). The
obtained UF values for 8a–8g and 11 are presented in Table 4.
Benzothiazines 8a–8g and 11 show fair-to-good fluorescence
efficiency as evident by these values. In fact, the mean value of UF
is 0.053 for 8a–8g compared to 0.070 for 11, illustrating that the
aldehyde moiety does appear to enhance the fluorescence efficiency
to any extent. Most noteworthy, the aldehyde functionality of 11
significantly red shifts both absorbance and fluorescence emission
bands as shown in Fig. 5. This we attribute to the extended
conjugation which simply results in a narrowing of the energy
gap between the ground and excited states. In a practical sense,
the excitation profile for 11 is moved away from the UV to become
well matched to inexpensive visible light sources, particularly light-
emitting diodes (LEDs), a boon for future applications in sensing
and imaging.10
Entry
benzothiazine
eb
labs (nm)
lem (nm)
UFsc
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
1.82
2.52
2.26
3.20
1.67
2.65
1.54
5.67
356
370
364
373
364
370
355
430
487
472
480
474
477
474
483
504
0.035
0.069
0.040
0.065
0.058
0.053
0.050
0.070
8g
11
a Benzothiazines (10 mM) in chloroform were studied at 25 ◦C. b Molar
absorptivity in units of 104 M-1 cm-1. c Fluorescence quantum yields ( 6–
8%).
Scheme 2 Modification of benzothiazine 8b.
shifts, accompanied by a marked reduction in the Stokes shift
to 74 nm (Table 4, entry 8). It is thus quite conceivable that a
combination of reasoned analysis and empirical observation will
allow us to build a library of fluorophores from this benzothiazine
scaffold that could prove useful for various applications.
To further illustrate the fluorescence features of these com-
pounds, we show images of the benzothiazines under ambient
and long-wavelength UV (365 nm) lighting (Fig. 4). As would be
expected from the values in Table 4, benzothiazines 8a–g fluoresce
blue, while 11 emits blueish-green light. As intimated previously,
Fig. 5 Normalized UV-vis absorbance (dashed lines) and fluorescence
emission spectra of 8a (blue curves) and 11 (green curves) in chloroform.
Photoluminescence spectra were acquired for excitation at 350 nm.
In a preliminary exploration of the solvatochromic behavior of
these benzothiazines using a Lippert–Mataga treatment, which
determines general solvent effects (i.e., static dielectric constant, e,
and refractive index, n) on the Stokes shift (refer to SI†), we found a
noteworthy and unanticipated lack of correlation between Stokes
shifts for the representative benzothiazine 8a and the orientational
polarizability of the solubilizing milieu. This strongly hints at the
notable absence of solvent effect on the photophysical properties of
our benzothiazines. The fluorescence emission maxima of 8a were
found to marginally red shifted; however, in hexane (493 nm), a
nonpolar solvent, as compared to methanol (480 nm), a polar-
protic solvent or acetonitrile (485 nm), a polar-aprotic solvent.
This may suggest an uncommon (but small) decrease in the dipole
moment of the fluorophore in the excited-state as compared to
that in the ground state. In a larger sense, these results hint
at an intriguing role for the –S+–O- moiety in controlling the
fluorescence characteristics of the benzothiazines.
In summary, we have synthesized 7-amino-2,1-benzothiazines
using two different approaches and demonstrated that these
compounds exhibit fluorescent properties in combination with
large Stokes shifts. We further modified one of the benzothiazines
Fig. 4 10 mM CHCl3 solutions of 8a–8g in normal light (A) and under UV
lamp excitation (B). Images of 11 (10 mM in CHCl3) under these respective
conditions (C).
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via metalation chemistry, showing strongly red shifted spectral
features as a result. Further studies expanding the palette of
benzothiazine-based fluorophores and their application are in
progress and will be reported in due course.
This work was supported by the National Science Foundation
to whom we are grateful. We thank Professor Timothy E. Glass
and his coworkers Mr. Zhang Shaohui and Mr. Kenneth Hetti for
assistance with obtaining fluorescence data.
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7982 | Org. Biomol. Chem., 2011, 9, 7979–7982
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