followed by radical bromination. Transformation of benzyl
bromide 4 to aldehyde 5 via Sommelet reaction, followed
by conversion to the oxime and dehydration with TFAA,9
provided 6 in an overall yield of 44%.
Table 1. Optical Properties and Association Constants for
1a,b,h
1x
εa
φb
Keq 1x·Hg2+ (I/I0)c
Keq 1x·Ag+ (I/I0)c
1a
1b
1h
5.91
5.83
5.79
0.01
0.01
0.01
1.97 (4.2)
5.42 (3.0)
17.50 (2.7)
8.05 (10.1)
1.10 (3.0)
2.45 (2.8)
Scheme 3
a For longest-wavelength λmax; ε, 103 cm-1 M-1
.
b Relative to pyrene
(φ ) 0.32). c Keq, 104 M-1; I/I0 ratiometric increase of emission at λmax(em);
1:1 DMSO/pH 7.4 MOPSaq solution.
Compounds 1a-k are only modestly water-soluble, and
thus titrations were carried out with 5 × 10-5 M solutions
of fluorophore in 1:1 DMSO/pH 7.4 MOPS buffer. Salts were
added as 10-3 M solutions in the same solvent mixture.
Somewhat surprisingly, the majority of titrations led to little
or no change in emission intensity. (This will be discussed
below.) However, three compounds, 1a, 1b, and 1h, showed
strong responses to the addition of Ag(I) and Hg(II) salts
(Table 1).14-17
The aromatic components 3 and 6 were combined via
Negishi coupling (Scheme 3).10 The hydrogenation of the
CN groups in 7 proved more reliable than our previous NiCl2/
NaBH4 reduction protocol,11 and in the presence of Boc
anhydride consistently provided reasonable yields of 8.
Removal of the TBS group and subsequent Swern oxidation,
followed by Wittig-Horner coupling with ethyl phospho-
noacetate, provided Boc protected diamine 9, which is a
stable and convenient precursor for 1. This represents an
overall net reduction of 3 steps relative to our original route.
The syntheses of 1a,d,e,j,k consist of two or three steps:
deprotection of 9 with HCl/dioxane and coupling with the
corresponding carboxylic acid, followed by deprotection as
needed. Compounds 1b and 1c were prepared from phenyl
isothiocyanate and isocyanate, respectively. For 1f-h, depro-
tected 9 was coupled with R-bromoacetic acid and then
alkylated with morpholine, thiomorpholine, or 7-aza-1,4-
dithiacyclononane.6c-e Compound 1i was prepared by depro-
tection of 9, coupling with N,N′-di-Boc-N′′-triflylguanidine.12
This collection of potential fluorescent chemosensors was
evaluated in the presence of ions chosen on the basis of
physiological or environmental relevance. The cations chosen
for titration were Li+, Na+, K+, Cs+, Ca2+, Ba2+, Sr2+, Cu2+,
Zn2+, Cd2+, Pb2+, Ni2+, Fe2+/3+, Ag+, and Hg2+. Anions used
Figure 3
.
Titration of 1a (5 × 10-5 M) in DMSO/pH 7.4 MOPSaq
solution with HgCl2. Inset: change of I430/I550
.
The response of 1a was anticipated, as this is a close
analogue of the Hg(II)-responsive chemosensors discovered
from the previous combinatorial library.2i Fluorescence
emission from 1a increased ca. 4-fold upon titration with
Hg(II) (Figure 3).18 In addition, it exhibited a significant (80
nm) blue-shift in emission. This allows for ratiometric Hg(II)
-
were F-, Cl-, Br-, I-, SO42-, CO32-, PO43-, ClO4 , acetate,
(14) For a review of Hg(II)-responsive fluorescent chemosensors, see:
malonate, and oxalate.8,13
Nolan, E. M.; Lippard, S. J. Chem. ReV. 2008, 108, 3443
.
(15) For recent examples of fluorescent chemosensors for Ag(I) recogni-
tion in aqueous solution, see ref 6b and. (a) Park, C. S.; Lee, Y.; Kang,
E.-J.; Lee, J.-E.; Lee, S. S. Tetrahedron Lett. 2009, 50, 671. (b) Iyoshi, S.;
(7) For a review of guanidine coordination chemistry, see: Bailey, P. J.;
Pace, S. Coord. Chem. ReV. 2001, 214, 91–141.
Taki, M.; Yamamoto, Y. Inorg. Chem. 2008, 47, 3946
.
(8) See Supporting Information for complete experimental details and
compound characterization.
(16) Binding constants were determined by non-linear least-squares
fitting of plots of emission intensity versus log[M] using the program Prism3
(Graphpad, Inc., San Diego, CA).
(9) Carotti, A.; Campagna, F. Synthesis 1979, 56.
(10) Negishi, E.-i.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. Metal-
Catalyzed Cross Coupling Reactions, 2nd ed.; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: New York, 1998; Chapter 15.
(11) Vergne, F.; Aitken, D. J.; Husson, H.-P. J. Org. Chem. 1992, 57,
6071.
(17) All ligand-Ag(I) complexes were of 1:1 stoichiometry, as deter-
mined by the method of continuous variation. We were not able to accurately
evaluate the stoichiometry of Hg(II) complex formation because the
increases in emission are almost completely offset by dilution. For purposes
of binding constant determination, we have treated them as 1:1 complexes,
although we suspect that multiple species are present.
(18) Three minor features in the emission spectra warrant comment. Two
invariant peaks at ca. 380 and 400 nm arise from impurities in the DMSO/
buffer solution that we were not able to remove despite repeated purification.
The small spike at ca. 450 nm is a Wood’s anomaly characteristic of our
fluorimeter.
(12) Feichtinger, F.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org. Chem.
1998, 63, 3804–3805.
(13) Li+, Na+, and K+ were added as perchlorate salts, and Ag+ as its
tosylate salt. All other metal ions were added as their chlorides. Anions
were added as Li+ salts except acetate, malonate and oxalate, which were
added as their Na+ salts.
942
Org. Lett., Vol. 12, No. 5, 2010