Near-infrared fluorophores containing benzo[c]heterocycle subunits

Article abstract of DOI:10.1021/ol800988w

(Chemical Equation Presented) The syntheses and spectroscopic properties of eight new push-pull-type near-infrared fluorophores that contain either isobenzofuran or isothianaphthene subunits are presented. The isobenzofuran dyes demonstrate significantly red-shifted absorption compared with their isothianaphthene counterparts, which is attributed to isobenzofuran's more potent pro-quinoidal character.

Full text of DOI:10.1021/ol800988w

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2991-2993
Near-Infrared Fluorophores Containing
Benzo[c]heterocycle Subunits
Scott T. Meek, Evgueni E. Nesterov, and Timothy M. Swager*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tswager@mit.edu
Received April 30, 2008
ABSTRACT
The syntheses and spectroscopic properties of eight new push-pull-type near-infrared fluorophores that contain either isobenzofuran or
isothianaphthene subunits are presented. The isobenzofuran dyes demonstrate significantly red-shifted absorption compared with their
isothianaphthene counterparts, which is attributed to isobenzofuran’s more potent pro-quinoidal character.
In ViVo near-infrared (NIR) fluorescence imaging is rapidly
emerging as a powerful diagnostic method.1 In the NIR
region (650-900 nm) biological chromophores exhibit low
absorption and autofluorescence,2 thus allowing photons to
pass through the tissue and rendering this technique relatively
noninvasive. With applications such as vascular mapping of
the heart3 and brain4 and visualization of various pathologies
including tumors,5 atherosclerosis,6 and ꢀ-amyloid plaques,7
the demand for new NIR fluorescent contrast agents is ever
increasing.
Our group recently reported the synthesis and in ViVo
imaging properties of NIAD-4 (1), NIM-1 (2), and NIM-2
(3), all donor-acceptor type dyes (Figure 1).7a,8 In the case
of 2 and 3, it was found that the incorporation of ben-
zo[c]heterocycle isothianaphthene (ITN) into the conjugated
bridge red-shifted both the absorption and emission substan-
tially. Herein we explore the use of benzo[c]heterocycle
isobenzofuran (IBF) in place of ITN as a molecular
component in this class of dyes.
Isothianaphthene has a relatively long history as a component
in functional materials, with examples in fluorophores,9 OLE-
Ds,10 photovoltaics,11 and low band gap polmyers, of which
polyisothianaphthene (PITN)12 is the progenitor. The smaller
band gap of these ITN-containing materials over similar
(1) (a) Frangioni, J. V. Curr. Opin. Chem. Biol. 2003, 7, 626. (b) Rao,
J; Dragulescu-Andrasi, A; Yao, H. Curr. Opin. Biotechnol. 2007, 18, 17.
(2) (a) Weissleder, R. Nat. Biotechnol. 2001, 19, 316. (b) Weissleder,
R. Nat. Biotechnol. 2001, 19, 316.
(3) Nakayama, A.; del Monte, F.; Hajjar, R. J.; Frangioni, J. V. Mol.
Imaging 2002, 1, 365.
(4) Sankatani, K.; Kashiwasake-Jibu, M.; Taka, Y.; Wang, S.; Zou, H.;
Yamamoto, K.; Shimizu, K. J. Neurosurg. 1997, 87, 738.
(5) Weissleder, R.; Tung, C.; Mahmood, U.; Weissleder, R.; Tung, C.;
Mahmood, U.; Bogdanov, A, Jr Nat. Biotechnol. 1999, 17, 375.
(6) Chen, J.; Tung, C. H.; Mahmood, U.; Ntziachristos, V.; Gyurko,
R.; Fishman, M. C.; Huang, P. L.; Weissleder, R. Circulation 2002, 105,
2766.
(8) Xiang, Z.; Nesterov, E. E.; Skoch, J.; Lin, T.; Hyman, B. T.; Swager,
T. M.; Bacskai, B. J.; Reeves, S. A. J. Histochem. Cytochem. 2005, 53,
1511
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(9) Mohanakrishnan, A. K.; Lakshmikantham, M. V.; McDougal, C.;
Cava, M. P.; Baldwin, J. M.; Metzger, R. M. J. Org. Chem. 1998, 63, 3105.
(10) Mitschke, U.; Bauerle, P. J. Chem. Soc., Perkin Trans. 1 2001, 7,
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(7) (a) Nesterov, E. E.; Skoch, J.; Hyman, B.; Klunk, W. E.; Bacskai,
B. J.; Swager, T. M. Angew. Chem., Int. Ed. 2005, 44, 5452. (b)
Hintersteiner, M.; Enz, A.; Jaton, A.; Kinzy, W.; Kneuer, R.; Neumann,
U.; Rudin, M.; Staufenbiel, M.; Stoeckli, M.; Wiederhold, K.; Gremlich,
H. Nat. Biotechnol. 2005, 23, 577.
(11) Vangeneugden, D. L.; Vanderzande, D. J. M.; Salbeck, J.; van Hal,
P. A.; Janssen, R. A. J.; Hummelen, J. C.; Brabec, C. J.; Shaheen, S. E.;
Sariciftci, N. S. J. Phys. Chem. B 2001, 105, 11106.
(12) Wudl, F.; Kobayashi, M.; Heeger, A. J. J. Org. Chem. 1984, 49,
3382.
10.1021/ol800988w CCC: $40.75
Published on Web 06/19/2008
2008 American Chemical Society

Scheme 1. Synthesis of IBF and ITN Dyes
Figure 1. Structures of NIAD-4, NIM-1, and NIM-2.
thiophene-containing materials is a result of the increased
contribution of the quinoid resonance structure (Figure 2) due
Figure 2. Aromatic and quinoid resonance structures of PITN and
ITN donor-acceptor dyes.
aa: R ) H-. b: R ) MeO-. c: R ) Me2N-. d: R ) TIPSO-. b5a is
comercially available, 5d synthesized as above.
to the stabilization achieved by aromatization of the benzene
ring.13
In contrast, only a few examples14 of functional materials
containing isobenzofuran are reported in the literature,
presumably because of its reduced stability.15 For this reason,
we predicted that IBF would prove even more pro-quinoidal
and that its incorporation into donor-acceptor dyes would
further reduce the band gap of these materials.
To test this principal, we synthesized a series of IBF and
ITN dyes similar to NIAD-4 (Scheme 1). Four different
electron-donating (R) groups, H-, MeO-, HO-, and Me2N-,
were incorporated in order to span a range of wavelengths.
Appropriately substituted aryl-lactones 5a-d were either
purchased or synthesized via acid-mediated condensation16
of 2-carboxybenzaldehyde and substituted benzenes. In the
case of the phenol group (R ) OH), TiPS protection was
employed. Initially, the IBF framework was constructed with
a free 5 position on the thiophene, which was subsequently
lithiated and then formylated with DMF.
However, these unsubstituted intermediate compounds
proved relatively difficult to isolate and purify, resulting in
poor yields for the formylation. Exploiting the acetal-
protected aldehydes allowed us to bypass these troublesome
intermediates. Protected aldehydes 7a-d were produced in
one step by reaction of the lactones with the lithio-derivative
of 617 followed by dehydration with acetic anhydride and
deprotection with aqueous acetic acid. Knoevenagal con-
densation of the aldehydes with malonitrile installed the
dicyanomethylene electron-withdrawing group to afford dyes
8a-d in moderate yields. Deprotection of 8d was achieved
under acidic conditions as fluoride was found to revert the
dicyanovinyl group to the aldehyde.
(13) Hoogmartens, I.; Adriaensens, P.; Vanderzande, D.; Gelan, J.;
Quattrocchi, C.; Lazzaroni, R.; Bredas, J. L. Macromolecules 1992, 25,
7347.
To access the ITN counterparts to dyes 10a-d, we decided
to explore methods by which the IBF dyes could be
converted directly. It was found that such a transformation
could be accomplished with good yields, in one pot, using a
(14) Li, J. Y.; Hong, Z. R.; Wang, P. F.; Lee, C. S.; Wong, N. B.;
Kwong, H. L.; Lee, S. T. Thin Solid Films 2004, 446, 111.
(15) Jursic, B. S. J. Heterocycl. Chem. 1996, 33, 1079.
(16) (a) Barili, P. L.; Scartoni, V. J. Heterocycl. Chem. 1985, 22, 1199.
(b) Al-Hamdany, R.; Al-Rawi, J. M.; Ibrahim, S. J. Prakt. Chem. 1987,
329, 126.
(17) Johnson, A. L. J. Org. Chem. 1976, 41, 1320.
Org. Lett., Vol. 10, No. 14, 2008
2992

Table 1. Spectroscopic Properties of IBF and ITN Dyesa
a Spectra available in Supporting Information. b Quantum yields calculated by comparison to standards; see Supporting Information. c MeOH as solvent.
d CHCl3 as solvent.
5-10-fold excess of Lawesson’s reagent in the presence of
air or anhydrous oxygen. A possible mechanism includes
the formation of an endoperoxide upon reaction of the IBF
and oxygen, which in turn rearranges into to a diketone18
followed by conversion of the diketone to the dithioketone
with Lawesson’s reagent and cyclization to form the ITN.19
In the case of 8c, the dicyanovinyl group was cleaved during
the procedure, presumably to a thioaldehyde by Lawesson’s
reagent,20 and thus treatment with excess malonitrile and base
was necessary to obtain 10c. Dye 10d was deprotected under
acid conditions in a similar manner as 8d.
The spectroscopic properties of 8a-c, 10a-c, 11, and 12
are listed in Table 1. In all cases, the IBF dyes exhibited
markedly red-shifted absorption from the corresponding ITN
moieties, thus demonstrating the narrower band gaps of the
IBF compounds. The degree of this effect increases as the
efficacy of the electron-donating group increases. The degree
of red shift in the emission proved only modest, especially
in the case of 8c and 10c, indicating that perhaps the quinoid
resonance structure stabilization does not factor as heavily
into the excited-state energies of these molecules.
In conclusion, we have demonstrated the greater effective-
ness of isobenzofuran over isothianaphthene as a red-shifting
component in donor-acceptor-type dyes, an effect attribut-
able to the great pro-quinoidal nature of IBF. Currently, these
compounds are being screened as NIR contrast agents for
biomedical applications, and future investigations will ex-
plore the use alternate electron-withdrawing groups and the
incorporation of different heterocycles into this fascinating
class of compounds.
Acknowledgment. This work was supported by a NIH
BRP grant (R01 AG026240-01A1).
(18) Haynes, R. K.; Peters, J. M.; Wilmot, I. D. Aust. J. Chem. 1980,
33, 2653.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Lorcey, D.; Cava, M. P. AdV. Mater. (Weinheim, Ger.) 1994, 4,
562.
(20) Paulussen, H.; Haitjema, H.; van Asselt, R.; Mylle, P.; Andriaens-
ens, P.; Gelan, J.; Vanderzande, D. Polymer 2000, 41, 3121.
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