Synthesis of 7-azaserotonin: Its photophysical properties associated with excited state proton transfer reaction

Article abstract of DOI:10.1021/ja064310e

We report the synthesis of 3-(2-aminoethyl)-5-ol-1H-pyrrolo[2,3-b]pyridine (7-azaserotonin), which may potentially serve as an agonist or antagonist of serotonin receptors. In alcohols, the solvent (e.g., ethanol) catalyzed proton-transfer reaction takes place for 7-azaserotonin in the excited state, resulting in dual emission. Conversely, excited-state deprotonation takes place in neutral aqueous solution. The unique excitation behavior makes 7-azaserotonin versatile as a potential bioprobe. Copyright

Full text of DOI:10.1021/ja064310e

Published on Web 10/24/2006
Synthesis of 7-Azaserotonin: Its Photophysical Properties Associated with
Excited State Proton Transfer Reaction
Pei-Wen Wu,† Wan-Ting Hsieh,† Yi-Ming Cheng,† Ching-Yen Wei,‡ and Pi-Tai Chou*,†
Department of Chemistry, National Taiwan UniVersity, Taipei 106, Taiwan, and Industrial Technology Research
Institute, Chemical Engineering DiVision, Room 313, Building 17, 321, Kuang Fu Road, Section 2,
Hsin Chu 300, Taiwan
Received June 19, 2006; E-mail: chop@ntu.edu.tw
Scheme 1. (a) Synthesis of 7-Azaserotonin and (b) the Structure
of Serotonin
Introduction
Perhaps one of the most prominent neurotransmitters is serotonin
(3-(2-aminoethyl)-1H-indol-5-ol, 1a in Scheme 1), which is a
completely natural hormone1 and has a powerful effect on most
parts of the brain involved in controlling vital functions such as
behavior, movement, pain, sexual activity, and appetite. In many
neuropsychiatric disorders,2 the serotonin system may also play a
key modulatory role. Although the pathophysiology of many
neuropsychiatric disorders remains enigmatic, abnormalities in
serotonin signaling have been strongly implicated.
That such a small molecule like serotonin acts as a vital element
in brain function has attracted much attention in synthetic chemistry.
Focus on derivatization of serotonin has been one of the intensive
areas in medicinal chemistry.3 While most of the approaches lie in
the substitution effect on the parent serotonin, we are interested in
replacing the parent indole moiety with the 7-azaindole chromo-
phore, forming 7-azaserotonin (3-(2-aminoethyl)-5-ol-1H-pyrrolo-
[2,3-b]pyridine, 1 in Scheme 1). Studies have shown great
differences in both the physical and photophysical properties
between indole and azaindole systems. It has been well-established
that HOMO and LUMO for indole (azaindole) are ascribed to
pyrrole and benzene (pyridine) rings, respectively.4 In comparison
to indole, the electron withdrawing properties of pyridyl nitrogen
in azaindole should lead to a further decrease of the LUMO level,
resulting in a smaller energy gap. Furthermore, the lower LUMO
level prevents the electron ejection upon electronic excitation. As
a prototypical example, 7-azatryptophan has replaced tryptophan
in numerous biological applications5 owing to its longer wavelength
absorption (>300 nm), which can be free of the interference by
natural tryptophan or other biochromophores. Moreover, its single-
exponential decay dynamics makes it apparently superior to trypto-
phan, which normally gives rise to complications due to its
biexponential decay dynamics.6
In addition to the above advantages, in view of its biochemical
properties, 1 may possess an additional pyridyl nitrogen capable
of hydrogen-bonding that may be more affinitive to the receptor
of 1a, such that 1 may act as a potential agonist or antagonist of
1a receptors. Herein, we report the first synthesis of 1 and its
intriguing photophysical properties, namely the excited-state proton-
transfer reaction.
The 7-step synthetic route to 1 is depicted in Scheme 1, in which
commercially available 7-azaindole served as a starting material.
Step 1 involved halogenation with bromine in a mixture of t-butanol
and water at room temperature to provide the tribromo derivative
2 (85%).7 In step 2, 2 was then treated with zinc in acetic acid to
furnish 3 in 95% yield. Reduction of the amide function was realized
with the borane-tetrahydrofuran complex, and the resulting indoline
was oxidized with manganese triacetate in acetic acid at 75 °C to
give 4 with 50% yield. Subsequently, the 5-methoxy functional-
ization was established by step 4, in which compound 4 was treated
in a mixture of N,N-dimethylformamide and methanol with sodium
methoxide in the presence of copper(I) bromide, yielding 5 in 85%
yield. In step 5, to elaborate the derivatization of the 3-position of
7-azaindole moiety, 5 was subjected to the Vilsmeier’ reaction, and
6 was achieved successfully in 60% yield.
In step 6, 6 was first treated with sodium borohydride in binary
solvents and then reacted with KCN. Note that this step is strongly
solvent-mixture dependent. Among various mixtures, MeOH/NH2-
CHO (1:1, v/v) maximized the yield of 7 to 85%.
Subsequently, reduction of the cyano group to the corresponding
amine was performed. The first attempt, incorporating reduction
under hydrogen gas by Raney Ni catalyst, was not efficient.
Alternatively, reduction of the cyano group was realized with a
borane-THF complex. However, further purification of the result-
ing amine derivative was subject to decomposition. To avoid this,
without prepurification, we carried out the next step of the treatment
with BBr3 and successfully transformed the methoxy group to the
hydroxyl group, forming the target compound 7-azaserotonin (1).
1 was then purified by twice recrystallization from methanol. In
summary, via Scheme 1, 1 has been successfully prepared with an
overall yield of ∼10%. Detailed synthetic procedures as well as
characterization of the intermediates are elaborated in Supporting
Information.
Figure 1 depicts the absorption and emission spectra of 1a and
1 in ethanol. In comparison, the first S0-S1 absorption peak of
∼320 nm is apparently red-shifted by ∼15 nm with respect to that
of serotonin, supporting the lowering of LUMO and hence the
decrease of the HOMO-LUMO energy gap by replacing the fused
benzene ring (in 1a) with pyridine (in 1). Upon excitation, 1a
exhibits a normal emission band with peak wavelength at 333 nm
in ethanol, while in sharp contrast, dual emission appeared in 1,
† National Taiwan University.
‡ Industrial Technology Research Institute.
9
14426
J. AM. CHEM. SOC. 2006, 128, 14426-14427
10.1021/ja064310e CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
-OH (pKa ≈ 9.6) should be >95% (see Figure S1 in Supporting
Information), and found that the corresponding emission spectrum
(λmax ) 395 nm, see Figure S1) is the same of that in pH ) 7. In
view of the different absorption spectra with the same emission
profiles, we tentatively propose that the excited-state proton
dissociation takes place in pH ) 7, giving rise to a 395 nm anionic
1 emission. Given the evidence of large a Stokes-shifted 395 nm
emission for 1 in neutral water, it is reasonable to expect that such
an anionic species can be further stabilized by solvation, such that
the further proton transfer is highly thermally unfavorable (see
Figure 2). Studies in low pH (<5.0) are rather complicated owing
to the protonation at the pyridyl nitrogen site.
In conclusion, the first synthesis and spectroscopic studies of 1
are reported. The differentiation of photophysics between alcohol
(solvent catalyzed proton-transfer reaction) and water (deprotona-
tion) are intriguing. In view of bioapplications, we thus suspect
that once 1 is in certain hydrophilic medium, similar to that in
alcohol, a water catalyzed excited-state proton-transfer reaction may
take place, allowing it to serve as a suitable molecular probe. We
also performed the molecular dynamic approaches for 1 using a
homology model of human 5-HT1B serotonin receptor to investigate
the difference of interaction to the 5-HT1B receptor between 1a
and 1. Our preliminary data indicate that 1 has larger association
strength than that of 1a, exhibiting its great potential to serve as a
5-HT1B agonist or antagonist for the treatment of aggression or
depression. We thus believe that exploration of 1 may spark a broad
spectrum of interest in the fields of medicinal chemistry and
biophysics.
Figure 1. Absorption (dash) and emission (solid) spectra of 1a (gray) and
1 (black) in ethanol. Emission spectrum of 1 in pH ) 7 is shown by the
red solid line. The excitation wavelength is 300 nm. Inset shows the relax-
ation dynamics of 1 in ethanol, monitored at 340 nm (red) and 540 nm
(green).
Acknowledgment. This work is supported by the National
Science Council and National Center for High-Performance Com-
puting, Taiwan.
Figure 2. The proposed excited-state behavior of 1 in alcohol and water.
consisting of short wavelength (the F1 band) and long wavelength
(the F2 band) bands maximized at 365 (the F1 band) and 538 nm
(the F2 band), respectively. The fluorescence excitation spectra
monitored at the F1 and F2 bands are identical and are also the
same as the absorption profile. The result eliminates the possibility
that the dual emission is resulting from trace impurities. Further-
more, the ratio of the F2 versus the F1 band is concentration
independent from 10-5-10-3 M in ethanol, discarding a proposal
that the F2 band originates from aggregation. Alternatively, the
results can more plausibly be rationalized by the ethanol (or
methanol) catalyzed proton-transfer reaction for 1 depicted in Figure
2. Figure 2 depicts a two-step proton-transfer mechanism, in which
there exists a fast equilibrium between the 1:1 alcohol/1 cyclic HB
structure (C*) and other complexes generally described as 2:1
alcohol/1 noncyclic HB structure (N*). Proton-transfer thus takes
place from C*, resulting in a green proton-transfer tautomer (T*)
emission.
Supporting Information Available: Listing of experimental details
and characterization data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Barnes, N. M.; Sharp, T. Neuropharmacology 1999, 38, 1038. (b)
Svenningsson, P.; Chergui, K.; Rachleff, I.; Flajolet, M.; Zhang, X.;
Yacoubi, M. E.; Vaugeois, J. M.; Nomikos, G. G.; Greengard, P. Science
2006, 311, 77.
(2) (a) Gingrich, J. A.; Hen, R. Psychopharmacology (Berlin), 2001, 155, 1.
(b) Manji, H. K.; Drevets, W. C.; Charney, D. S. Nat. Med. 2001, 7, 541.
(3) (a) Flaugh, M. E.; Mullen, D. L.; Fuller, R. W.; Mason, N. R. J. Med.
Chem. 1988, 31, 1746. (b) Malleron, J. L.; Gueremy, C.; Mignani, S.;
Peyronel, J. F.; Truchon, A.; Blanchard, J. C.; Doble, A.; Laduron, P.;
Piot, O. J. Med. Chem. 1993, 36, 1194. (c) Mattson, R. J.; Catt, J. D.;
Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Higgins, M. A.; Marcin, L. R.;
Sloan, C. P.; Beno, B. R.; Gao, Q.; Cunningham, M. A.; Mattson, G. K.;
Molski, T. F.; Taber, M. T.; Lodge, N. J. J. Med. Chem. 2005, 48, 6023.
(4) (a) Brause, R.; Kru¨gler, D.; Schmitt, M.; Kleinermanns, K. J. Chem. Phys.
2005, 123, 224311. (b) Rogers, D. M.; Besley, N. A.; Hirst, J. D. J. Phys.
Chem. B 2005, 109, 23061. (c) Kang, C.; Yi, J. T.; Pratt, D. W. Chem.
Phys. Lett. 2006, 423, 7.
The scheme proposed above is based on a well-established
mechanism associated with 7-azaindole and its corresponding
analogues.8 Further support of this precursor-successor type of
proton-transfer mechanism is rendered by the relaxation dynamics,
in which a single-exponential decay time of 360 ( 30 ps for the
F1 band (monitored at 340 nm), within experimental error, correlates
well with the 385 ( 40 ps risetime of the F2 band (monitored at
540 nm, see the inset in Figure 1). Interestingly, however, a unique
emission maximized at 395 nm (τf ≈ 0.5 ns) was observed for 1 in
aqueous solution (pH ≈ 7, see Figure 1). The fact that we could
not resolve any steady-state emission and rise-decay dynamics of
the F2 band, in combination with the good fluorescence yield (0.15),
leads us to propose that H2O assisted excited-state proton transfer
may be prohibited in aqueous solution. We further carried out the
luminescence study at pH ) 11.5, in which the deprotonation of
(5) (a) Chen, Y.; Gai, F.; Petrich, J. W. J. Phys. Chem. 1994, 98, 2203. (b)
Rich, R. L.; Gai, F.; Lane, J. W.; Petrich, J. W.; Schwabacher, A. W. J.
Am. Chem. Soc. 1995, 117, 733. (c) Kelepouris, L.; Blanchard, G. J. J.
Phys. Chem. B 2002, 106, 6600.
(6) Chen, Y.; Rich, R. L.; Gai, F.; Petrich, J. W. J. Phys. Chem. 1993, 97,
1770.
(7) Maze´as, D.; Guillaumet, G.; Viaud, M. C. Heterocycles 1999, 50, 1065.
(8) (a) Chapman, C. F.; Maroncelli, M. J. Phys. Chem. 1992, 96, 8430. (b)
Stratt, R. M.; Maroncelli, M. J. Phys. Chem. 1996, 100, 12981. (c) Chou,
P. T.; Yu, W. S.; Wei, C. Y.; Cheng, Y. M.; Yang, C. Y. J. Am. Chem.
Soc. 2001, 123, 3599. (d) Chou, P. T.; Wu, G. R.; Wei, C. Y.; Shiao, M.
Y.; Liu, Y. I. J. Phys. Chem. A 2000, 104, 8863. (e) Chou, P. T.; Liao, J.
H.; Wei, C. Y.; Yang, C. Y.; Yu, W. S.; Chou, Y. H. J. Am. Chem. Soc.
2000, 122, 986. (f) Hung, F. T.; Hu, W. P.; Chou, P. T. J. Phys. Chem.
A 2001, 105, 10475. (g) Yu, W. S.; Cheng, C. C.; Chang, C. P.; Wu, G.
R.; Hsu, C. H.; Chou, P. T. J. Phys. Chem. A 2002, 106, 8006. (h) Chou,
P. T.; Cheng, Y. M.; Yu, W. S.; Pu, S. C. J. Phys. Chem. A 2003, 107,
5640. (i) Hu, W. P.; You, R. M.; Yen, S. Y.; Hung, F. T.; Chou, P. H.;
Chou, P. T. Chem. Phys. Lett. 2003, 370, 139.
JA064310E
9
J. AM. CHEM. SOC. VOL. 128, NO. 45, 2006 14427