Photochemical eliminations involving zwitterionic intermediates generated via electrocyclic ring closure of benzothiophene carboxanilides

Article abstract of DOI:10.1021/ol102932y

Leaving groups such as carboxylate, thiolate, and phenolate are expelled via zwitterionic intermediates produced upon photochemical electrocyclic ring closure of benzothiophene carboxanilides in the triplet excited state. Chemical yields generally exceed 90%, while quantum yields vary with basicity of the released leaving group.(Figure Presented)

Full text of DOI:10.1021/ol102932y

ORGANIC
LETTERS
2011
Vol. 13, No. 5
872–875
Photochemical Eliminations Involving
Zwitterionic Intermediates Generated via
Electrocyclic Ring Closure of
Benzothiophene Carboxanilides
Majher Sarker, Tasnuva Shahrin, and Mark G. Steinmetz*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881,
United States
mark.steinmetz@marquette.edu
Received December 3, 2010
ABSTRACT
Leaving groups such as carboxylate, thiolate, and phenolate are expelled via zwitterionic intermediates produced upon photochemical
electrocyclic ring closure of benzothiophene carboxanilides in the triplet excited state. Chemical yields generally exceed 90%, while quantum
yields vary with basicity of the released leaving group.
Photochemical electrocyclic ring closure of R,β-unsatu-
rated anilides is thought to produce intermediates that
have zwitterionic character (Scheme 1).1-4 Such zwitter-
ionic intermediates as 2 should be capable of expelling
leaving group anions (LG-), such as carboxylate and
phenolate groups,5,6 which represent functionality present
in numerous biomolecules. The expectation is that the
photochemistry could constitute the basis for the design
of a new class of “cage” compounds, which are generally
used in biological applications for the photolytic genera-
tion of locally high concentrations of biological substrates
in cells and tissue.7
Our recent study used a photochemical electrocyclic ring
closure to generate zwitterionic intermediates from acrylic
anilides.3 The photochemical electrocyclization was 8-10%
efficient with respect to light utilization. However, the leaving
groups were evidently not expelled directly from the puta-
tive zwitterionic intermediate, unlike Scheme 1, but instead
(1) (a) Ninomiya, I.; Naito, T. Heterocycles 1981, 15, 1433–1462. (b)
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Synthesis 1987, 421–452.
(2) (a) Cleveland, P. G.; Chapman, O. L. Chem. Commun. 1967,
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D.; Sakamoto, M. Helv. Chim. Acta 2005, 88, 996–1003.
(3) (a) Jia, J.; Steinmetz, M. G.; Shukla, R.; Rathore, R. Tetrahedron
Lett. 2008, 49, 4621–4623. (b) Jia, J.; Sarker, M.; Steinmetz, M. G.;
Shukla, R.; Rathore, R. J. Org. Chem. 2008, 73, 8867–8879.
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Photobiol. Sci. 2009, 8, 751–754.
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2003, 5, 71–74. (b) Ma, C.; Steinmetz, M. G.; Kopatz, E. J.; Rathore, R.
Tetrahedron Lett. 2005, 46, 1045–1048. (c) Ma, C.; Steinmetz, M. G.;
Kopatz, E. J.; Rathore, R. J. Org. Chem. 2005, 70, 4431–4442.
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C.; Chen, Y.; Steinmetz, M. G. J. Org. Chem. 2006, 71, 4206–4215.
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Biology; Wiley-VCH: Weinheim, 2005. (c) Pellicioli, A. P.; Wirz, J. Photo-
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r
10.1021/ol102932y
Published on Web 01/26/2011
2011 American Chemical Society

Scheme 1
Scheme 3
Scheme 2
derivative 5 (LG- = HO-) or from the 3-chloro com-
pound 5 (LG- = Cl-) (Scheme 3). The latter compound is
synthesized via acylation of N-methylaniline with 7, which
is produced by refluxing cinnamic acid with SOCl2.9 After
conversion of 7 to the phenyl ester, the C-3 chloro group
can also be substituted by phenolate anion to obtain 9,10
were eliminated from an enolate formed upon deprotona-
tion of the zwitterion.3b
This deprotonation step had to compete with a 1,5-H
shift in the zwitterionic intermediate that gave a product,
which retained the leaving group, and thus, leaving group
expulsion did not represent 100% of the reaction. Further-
more, the quantum yields for leaving group release ap-
peared to be controlled by the competition between
deprotonation and 1,5-H shift and were largely indepen-
dent of leaving group basicity.3b
which then is readily converted into amide 5 (LG-
=
PhO-). Various thiolates are capable of directly displacing
the C-3 chloride in amide 5 (LG- = Cl-) under mild
conditions.11 Carboxylate groups such as PhCH2CO2- are
introduced via DCC coupling with the 3-hydroxy com-
pound 5 (LG- = HO-), obtained via an alkylation and
subsequent Dieckmann condensation.
Direct photolyses of 10-2 M benzothiophene carboxa-
nilides 5 in 20-30% H2O containing 100 mM phosphate
buffer (pH 7) in CH3CN with unfiltered light from a 450 W
medium pressure mercury lamp were taken to essentially
complete conversion. Nearly quantitative expulsion of the
leaving groups was observed in most cases. Product yields
were determined by 1H NMR spectroscopy for similar small
scale runs performed with samples prepared in deuterated
solvents (Table 1). The cleavage coproduct in all cases was 6.
No other photoproducts were observed by NMR spectros-
copy of the photolyzates for any of the LG-s.
We sought to replace the acrylamide moiety with an
aromatic ring system(ringA inScheme1) sothatexpulsion
of LG- from the zwitterionic intermediate would poten-
tially have a greater likelihood of competing with the
deprotonation and 1,5-H shift pathways. A previous
study8 showed that the incorporation of a benzothiophene
ring system as ring A in Scheme 1 led to high yields of
electrocyclic ring closure. Therefore, we studied the ben-
zothiophene carboxanilide 5, which incorporates various
LG-s at the C-3 position of such a benzothiophene ring
system (Scheme 2). We now report evidence in support of
leaving group expulsions that occur directly from a zwit-
terionic intermediate, generated photochemically via elec-
trocyclic ring closure of benzothiophene carboxanilide 5.
Benzothiophene carboxanilides bearing leaving groups
at C-3 can be synthesized from either the 3-hydroxy
(9) Wright, W. B.; Brabander, H. J. J. Heterocycl. Chem. 1971, 8,
711–714.
(10) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.; Sorenson,
R. J.; Unangst, P. C.; Weikert, R. J.; Adolphson, R. L.; Kennedy, J. A.;
Thueson, D. O.; Wright, C. D.; Conroy, M. C. J. Med. Chem. 1992, 35,
958–965.
(11) Boschelli, D. H.; Kramer, J. B.; Khatana, S. S.; Sorenson, R. J.;
Connor, D. T.; Ferin, M. A.; Wright, C. D.; Lesch, M. E.; Imre, K.;
Okonkwo, G. C.; Schrier, D. J.; Conroy, M. C.; Ferguson, E.; Woelle, J.;
Saxena, U. J. Med. Chem. 1995, 38, 4597–4614.
(8) Kanaoka, Y.; Itoh, K.; Hatanaka, Y.; Flippen, J. L.; Karle, I. L.;
Witkop, B. J. Org. Chem. 1975, 40, 3001–3003.
Org. Lett., Vol. 13, No. 5, 2011
873

Quantum yields at 310 nm for LG- expulsion and
formation of 6 decreased with increasing basicity of LG-
(Table 1), contrary to what was observed in our earlier
study of acrylanilide electrocyclizations. The dependence
of Φ on LG- basicity is consistent with a mechanism,
whereby photochemical electrocyclic ring closure results in
formation of a ground state intermediate, which expels the
leaving group (Scheme 1). The zwitterion 2 would be a
plausible ground state intermediate in such LG- expulsions.
However, in order for the quantum yields to decrease with
increasing LG- basicity, there must be a pathway that
competes with the LG- expulsion. In Scheme 1 the com-
peting pathway is considered to be ring-opening of the
zwitterionic intermediate to regenerate the photochemical
reactant; i.e., the cyclized imminium ion moiety of 2 would
be a good internal leaving group.
The photochemistry of 5 occurs in the triplet excited
state. Quantum yields decrease, when photolyses are con-
ducted in air-saturated solvent, and 1,3-pentadiene (a triplet
excited state quencher) is effective at quenching the photo-
reaction. The triplet multiplicity is further supported by the
observation of a significant heavy atom effect. Photolysis of
6-bromobenzothiophene carboxanilide 10 at 310 nm in
17% H2O containing 100 mM phosphate buffer in dioxane
at pH=7 under N2 gives 11 with Φ=0.32 (Scheme 4),
whereas, without the 6-bromo substituent, Φ=0.23 for
5 (LG- = Cl-) under similar conditions. The heavy atom
in this case is expected to promote intersystem crossing
and thus increase the quantum yield for the triplet photo-
reaction.
Table 1. Yields and Quantum Yieldsa,b
reactant, LG-
LG-H, %
product 6, %
Φ
Cl-
ndc
95
100
99
0.23
-
PhCH2CO2
0.16
PhS-
ndc
96
91d
99
0.10
PhO-
0.074
0.076
0.007
PhCH2S-
HO-
91
98
nd
93
a The solvent was 20-30% D2O containing 100 mM phosphate
buffer (pD = 7) in CD3CN for chemical yields, whereas 17% H2O
containing 100 mM phosphate buffer in CH3CN was used for quantum
yields. b Yields were determined by NMR with DMSO as the integration
standard. For the quantum yields photolyzates were extracted by CHCl3
and concentrated prior to NMR analyses. c Not determined. d 7.2%
unreacted starting material was present.
In the quenching by 1,3-pentadiene, linear Stern-Volmer
quenching plots are obtained for LG-=PhCH2CO2- and
PhO- (Figure 1A). The slopes (kqτ) for these plots are
essentially the same, within experimental error. The life-
time of the triplet excited state τ is found to be 932 ( 41 and
830 ( 122 ns for LG-=PhCH2CO2- and PhO-, respec-
tively. For the calculation of τ, the solvent was taken as
acetonitrile, for which kq=2 Â 1010 M-1 s-1, although the
photolyses at 310 nm were actually conducted with 17%
H2O containing 100 mM phosphate buffer in CH3CN as
the solvent.
Scheme 4
In terms of the mechanism, it is evident that the singlet
excited state intersystem crosses to generate the triplet
Figure 1. (A) Stern-Volmer plots for the quenching of 5 (LG- = PhCH2CO2-, b) and 5 (LG- = PhO-, 9) by 1,3-pentadiene as triplet
quencher in 17% H2O containing 100 mM phosphate buffer in CH3CN. (B) Plot of log Φ vs pKa of the LG- conjugate acid.
874
Org. Lett., Vol. 13, No. 5, 2011

determinations. The quantum yield of 12 at 365 nm was Φ
= 0.15 in N2 saturated 20% H2O containing 100 mM
phosphate buffer in dioxane.
Scheme 5
In this study we have shown that the benzothiophene
carboxanilides have considerable potential for use as cage
compounds in biological applications. A variety of leaving
groups, which are straightforwardly incorporated at the
C-3 position of the benzothiophene ring system by stan-
dard synthetic procedures, are photochemically expelled
completely without formation of side products, and the
quantum efficiencies for LG- expulsion vary with basicity
of the LG- over the range 0.007-0.2. The approximate
dependence of log Φ on the pKa of the leaving group
conjugate acid suggests that the LG- expulsion competes
with ring-opening of the zwitterionic intermediate to re-
generate starting material. The electrocyclic ring closure to
form the zwitterionic intermediate occurs in the triplet
excited state. The plan is to introduce other, longer wave-
length chromophoric groups by replacing the N-phenyl
group of the anilide. Our initial step in this direction is the
introduction of a benzophenone chromophore, which
allows photolyses to be conducted at 365 nm.
excited state, which cyclizes with a rate constant 1/τ = ca.
106 s-1. The plot of log Φ vs pKa (LG-H) (Figure 1B)
shows that quantum yields vary primarily with LG-
basicity. Significant scatter in such a plot would be ex-
pected, considering the rather different LG-s being corre-
lated. Figure 1A,B are consistent with lifetimes of the
reacting excited state and intersystem crossing efficiencies
that are not overly sensitive to variation of LG-; i.e., the
LG-s do not strongly affect either Φisc or τ. A reasonable
conclusion is that quantum yields vary primarily with LG-
basicity, which controls the rate of the LG- expulsion step
in competition with ring-opening of intermediate 2 to
regenerate the starting material.
Preliminary work was done toextend the absorption of 5
to longer wavelengths by introducing a benzoyl group at
the C-4 position of the N-phenyl group. N-Methyl 4-ami-
nobenzophenonewas acylatedby7tofurnish 12witha C-3
chloro group. Direct photolysis of 10-2 M 12 in 20% H2O
containing 100 mM phosphate buffer in CH3CN using a
450 W medium pressure mercury lamp under N2 produced
a nearly quantitative yield of 13 upon photoelectrocycliza-
tion with loss of LG- = Cl- (Scheme 5). To resolve
solubility problems with photoproduct 13, the aq CH3-
CN was replaced with dioxane for the quantum yield
Acknowledgment. Acknowledgement is made to the
donors of the Petroleum Research Fund, administered
by the American Chemical Society for partial support of
this research.
Supporting Information Available. Experimental proce-
dures for the synthesis of 5 (LG- = Cl-, PhCH2CO2
,
-
PhS-, PhCH2S-, PhO-, HO-), 8-10, and 12). Experimen-
tal procedures for photolyses, quantum yield determina-
tions, and isolation and characterization of photoproducts
6, 11, and 13. Spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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