Coupling-isomerization - N,S-ketene acetal-addition sequences - A three-component approach to highly fluorescent pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines

Article abstract of DOI:10.1021/jo0602726

Annelated 2-amino pyridines such as pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]-azepines can be synthesized in moderate to good yields in a consecutive one-pot three-component process by a coupling-isomerization-enamine-addition-cycloc

Full text of DOI:10.1021/jo0602726

Coupling-Isomerization-N,S-Ketene Acetal-Addition SequencessA
Three-Component Approach to Highly Fluorescent
Pyrrolo[2,3-b]pyridines, [1,8]Naphthyridines, and
Pyrido[2,3-b]azepines
Oana G. Schramm, ne´e Dediu, Thomas Oeser,† and Thomas J. J. Mu¨ller*
Organisch-Chemisches Institut der Ruprecht-Karls-UniVersita¨t Heidelberg, Im Neuenheimer Feld 270,
D-69120 Heidelberg, Germany
thomas_j.j.mueller@urz.uni-heidelberg.de
ReceiVed February 9, 2006
Annelated 2-amino pyridines such as pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]-
azepines can be synthesized in moderate to good yields in a consecutive one-pot three-component process
by a coupling-isomerization-enamine-addition-cyclocondensation sequence of an electron-poor (hetero)-
aryl halide, a terminal propargyl N-tosylamine, and an N,S-ketene acetal. After the coupling-isomerization
sequence, a Diels-Alder reaction with inverse electron demand of the intermediate enimine and the
N,S-ketene acetal and subsequent aromatization furnish annelated 2-amino pyridines 4 that were
unambiguously characterized by numerous X-ray structure analyses. These heterocycles are highly
fluorescent and partially pH sensitive, and their electronic structure was studied with spectroscopic and
computational methods.
Introduction
pharmaceuticals, catalysts, and even novel molecule-based
materials. As part of our program, designed to develop new
multicomponent methodologies initiated by transition-metal-
catalyzed C-C-bond formation, we have recently discovered
and developed an unusual mode of alkyne activation by a
detouring outcome of the Sonogashira coupling,5 that is, a
coupling-isomerization reaction (CIR).6 The CIR of electron-
deficient (hetero)aryl halides and (hetero)arylpropargyl alcohols
or N-tosylamines under the conditions of the Sonogashira
One-pot multicomponent processes address very fundamental
principles of synthetic efficiency and reaction design and,
therefore, have recently gained a considerable and steadily
increasing academic, economic, and ecological interest.1,2 They
are diversity-oriented syntheses3 that can be often developed
into combinatorial and solid-phase strategies,2d,4 promising
manifold opportunities for generating novel lead structures of
† X-ray structure analyses.
(1) For a recent monography, see for example: Multicomponent Reac-
tions; Zhu, J., Bienayme´, H., Eds., Wiley-VCH: Weinheim, Germany, 2005.
(2) For reviews, see for example: (a) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.sEur. J. 2000, 6, 3321-3329. (b) Do¨mling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (c) Ugi, I.; Do¨mling, A.;
Werner, B. J. Heterocycl. Chem. 2000, 37, 647-658. (d) Weber, L.; Illgen,
K.; Almstetter, M. Synlett 1999, 366-374. (e) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123-131. (f) Ugi, I.; Do¨mling, A.; Ho¨rl, W. EndeaVour 1994, 18, 115-
122. (g) Posner, G. H. Chem. ReV. 1986, 86, 831-844.
2001, 40, 339-346. (d) Cox, B.; Denyer, J. C.; Binnie, A.; Donnelly, M.
C.; Evans, B.; Green, D. V. S.; Lewis, J. A.; Mander, T. H.; Merritt, A. T.;
Valler, M. J.; Watson, S. P. Prog. Med. Chem. 2000, 37, 83-133. (e)
Schreiber, S. L. Science 2000, 287, 1964-1969.
(4) Kobayashi, S. Chem. Soc. ReV. 1999, 28, 1-15.
(5) For lead reviews on Sonogashira couplings, see for example: (a)
Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980,
627-630. (b) Sonogashira, K. In Metal Catalyzed Cross-coupling Reactions,
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998,
203-229. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653 (1-2), 46-
49. (d) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2018.
(6) Mu¨ller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed. 2000,
39, 1253-1256.
(3) For reviews on diversity-oriented syntheses, see for example: (a)
Schreiber, S. L.; Burke, M. D. Angew. Chem., Int. Ed. 2004, 43, 46-58.
(b) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-
618. (c) Arya, P.; Chou, D. T. H.; Baek, M. G. Angew. Chem., Int. Ed.
10.1021/jo0602726 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
3494
J. Org. Chem. 2006, 71, 3494-3500

Sequence Approach to Annelated 2-Amino Pyridines
SCHEME 1. Coupling-Isomerization Reaction (CIR), a
Novel Synthesis of Enones and Eniminesa
SCHEME 2. Retrosynthetic Concept of a Consecutive
One-Pot Three-Component Annelated 2-Amino Pyridine
Synthesisa
a EWG: electron-withdrawing group; X ) O, NTos.
coupling is a mild and efficient route to chalcones6 or enimines,7
respectively (Scheme 1).
a Ar1 ) EWG(het)aryl; Ar2 ) (het)aryl.
Mechanistically, the CIR can be rationalized as a rapid
palladium/copper-catalyzed alkynylation reaction, followed by
the slow base-catalyzed isomerization of a propargyl alcohol
into an enone. In the past years, this new chalcone synthesis
has been applied as an entry to novel three- and four-component
syntheses of pyrazolines,6 pyrimidines,8 dihydrobenzo[b][1,4]-
thiazepines and -diazepines,9 pyrrols and furans,10 and pyridines,
pyrindines, and tetrahydroquinolines11 in the sense of consecu-
tive one-pot processes. These syntheses are based on subsequent
Michael addition-cyclocondensations following the CIR. Be-
cause N-tosyl enimines can be well-considered as electron-
deficient heterodienes that are perfectly suited for Diels-Alder
reactions with inverse electron demand,12 we could recently
show that a CIR-cycloaddition sequence with a very electron-
rich dienophile such as diethyl ketene acetal readily furnishes
2-ethoxy pyridines.7 Here we report the extension of the one-
pot synthesis of annelated pyridines based on a CIR-cycload-
dition sequence with more nucleophilic N,S-ketene acetals as
well as the absorption and emission properties of the resulting
fluorescent pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and
pyrido[2,3-b]azepines.
SCHEME 3. One-Pot Three-Component Synthesis of
Annelated 2-Amino Pyridines
consecutive one-pot fashion (vide supra) and preliminary studies
on CIR-cycloaddition sequences,7,17 our retrosynthetic analysis
of five-, six-, and seven-membered annelated amino pyridines
based on the CI approach (Scheme 2) suggests enimines as key
intermediates. Because N,S-ketene acetals are fairly electron-
rich dienophiles18 for [4+2] cycloadditions with inverse electron
demand, a facile three-component CI-cycloaddition-aroma-
tization synthesis of annelated 2-amino pyridines can be easily
envisioned.
Thus, we submitted p-bromo benzonitrile (1a), 2-bromo
pyridine (1b), or 2-bromo pyrimidine (1c) and N-[1-aryl-prop-
2-ynyl] tosyl amides 2,7 and after some reaction time cyclic
N,S-ketene acetals 3,19 to the reaction conditions of the CIR in
a boiling mixture of THF and triethylamine. After aqueous
workup, the annelated 2-aminopyridines 4 were obtained in 31-
66% yield as light yellow crystalline solids (4a-e, 4g-i) or
brown oils (4f, 4j; Scheme 3, Table 1).
Results and Discussion
Annelated 2-amino pyridines, where the amino group is an
endo constituent of the annelated saturated ring, are pharma-
ceutically intriguing structures. In particular, pyrrolo[2,3-b]-
pyridines or 7-azaindolines,13 [1,8]naphthyridines,14 and pyrido-
[2,3-b]azepines15 have received considerable interest as a
consequence of their broad pharmacological activity. Just
recently, Zard has reported a fairly general synthetic access
based on tin-free radical cyclizations.16 On the basis of our
experience in diversity-oriented heterocycle syntheses in a
The structures of the annulation products 4 were unambigu-
1
ously assigned by H, 13C, COSY, and NOESY NMR experi-
(14) For a recent pharmaceutical use of this class of compounds, see for
example: (a) Hutchinson, J. H.; Halczenko, W.; Brashear, K. M.; Breslin,
M. J.; Coleman, P. J.; Duong, L. T.; Fernandez-Metzler, C.; Gentile, M.
A.; Fisher, J. E.; Hartman, G. D.; Huff, J. R.; Kimmel, D. B.; Leu, C. T.;
Meissner, R. S.; Merkle, K.; Nagy, R.; Pennypacker, B.; Perkins, J. J.;
Prueksaritanont, T.; Rodan, G. A.; Varga, S. L.; Wesolowski, G. A.;
Zartman, A. E.; Rodan, S. B.; Duggan, M. E. J. Med. Chem. 2003, 46,
4790-4798. (b) Thomas Leonard, J.; Anbalagan, N.; Sadish Kumar, S.;
Kishore Gnanasam, S.; Sridhar, S. Biol. Pharm. Bull. 2002, 25, 215-217.
(c) Badawneh, M.; Ferrarini, P. L.; Calderoni, V.; Manera, C.; Martinetti,
E.; Mori, C.; Saccomanni, G.; Testai, L. Eur. J. Med. Chem. 2001, 36,
925-934.
(15) Kavali, J. R.; Badani, B. V. Farmaco 2000, 55, 406-409.
(16) Bacque´, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671-
3674.
(17) D′Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int.
Ed. 2005, 44, 153-158.
(18) Mu¨ller, K.; Sauer, J. Tetrahedron Lett. 1984, 24, 2541-2544.
(19) The N,S-ketene acetals were synthesized in a three-step sequence
starting from the corresponding cyclic amides, according to: Yde, B.;
Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S.-O. Tetrahedron
1984, 40, 2047-2052. By thionation with Lawesson’s reagent, the amides
were converted into the thiocarbonyl compounds in excellent yields (85-
95%). After methylation with methyl iodide and recrystallisation from
acetone, S-alkylated iodide salts (75-90%) were treated with potassium
tert-butoxide to furnish the N,S-ketene acetals in moderate overall yields
(35-65%).
(7) Dediu, O. G.; Yehia, N. A. M.; Mu¨ller, T. J. J. Z. Naturforsch. B:
Chem. Sci. 2004, 59, 443-450.
(8) Mu¨ller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2, 1967-
1970.
(9) (a) Braun, R. U.; Mu¨ller, T. J. J. Tetrahedron 2004, 60, 9463-9469.
(b) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2000, 2, 4181-
4184.
(10) (a) Braun, R. U.; Mu¨ller, T. J. J. Synthesis 2004, 2391-2406. (b)
Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297-3300.
(11) (a) Dediu, O. G.; Yehia, N. A. M.; Oeser, T.; Polborn, K.; Mu¨ller,
T. J. J. Eur. J. Org. Chem. 2005, 1834-1848. (b) Yehia, N. A. M.; Polborn,
K.; Mu¨ller, T. J. J. Tetrahedron Lett. 2002, 43, 6907-6910.
(12) (a) Sauer, J.; Wiest, H. Angew. Chem., Int. Ed. Engl. 1962, 1, 268.
(b) Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779-
807. (c) Boger, D. L.; Patel, M. In Progress in Heterocyclic Chemistry;
Suschitzky, H., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1989,
Vol. 1.
(13) (a) Desarbre, E.; Me´rour, J.-Y. Tetrahedron Lett. 1996, 37, 43-46.
(b) Taylor, E. C.; Pont, J. L. Tetrahedron Lett. 1987, 28, 379-382. (c)
Beattie, D. E.; Crossley, R.; Curran, A. C. W.; Hill, D. G.; Lawrence, A.
E. J. Med. Chem. 1977, 20, 718-721. (d) Robison, M. M.; Robison, B. L.;
Butler, F. P. J. Am. Chem. Soc. 1959, 81, 743-747.
J. Org. Chem, Vol. 71, No. 9, 2006 3495

Schramm et al.
TABLE 1. One-Pot Synthesis of Annelated 2-amino Pyridines 4
3496 J. Org. Chem., Vol. 71, No. 9, 2006

Sequence Approach to Annelated 2-Amino Pyridines
SCHEME 4. Mechanistic Rationale of the CI-Diels-Alder-Aromatization Sequence
TABLE 2. Selected UV/Vis and Fluorescence Properties (Recorded
in Dichloromethane) of Annelated 2-Amino Pyridines 4
ments. Most characteristically, in the 1H NMR spectra of 4, the
appearance of the methine singlets at δ 6.87-7.81 can be clearly
attributed to the formation of pentasubstituted pyridyl core unit.
In addition, the N-methyl protons are found as singlets at δ
3.02-3.22. Furthermore, the mass spectrometric and IR spec-
troscopic data are in full agreement with structural assignments.
Finally, the structure of 4 was unambiguously supported by
X-ray crystal structure analyses of compounds 4a, 4c, 4e, 4h,
and 4i (for ORTEP plots and structural data, see Supporting
Information).20
Depending on the conformational bias of the annelated ring,
the steric interactions force the acceptor-substituted (hetero)-
aryl ring to twist out of coplanarity with the pyridyl core. The
interplanar angle of the p-cyano phenyl ring and the central
pyridine moiety increases from the pyrrolo[2,3-b]pyridine 4a
(43.5°) over the pyrido[2,3-b]azepine 4h (60.7°, average
between the independent molecules) to the [1,8]naphthyridine
4e (88.6°). However, 2-pyridyl (4i, 39.4°) and 2-pyrimidyl
substituents (4c, 6.8°) impose the least steric bias.
The tentative mechanism of this one-pot sequence can be
described as follows (Scheme 4). After the CIR of the electron-
deficient (hetero)aryl halide 1 and the propargyl tosyl amides 2
furnish an enimine 5, the added N,S-ketene acetal 3 readily
undergoes a [4+2] cycloaddition with inverse electron demand
with 5 to give the annelated tetrahydropyridine 6 as the expected
cycloadduct. However, under the reaction conditions, the 2-fold
base-assisted elimination of tolylsulfinate and methyl mercaptane
from 6 furnishes upon aromatization the annelated pyridine 4.
All annelated 2-amino pyridines 4 absorb in the UV between
338 and 392 nm (Table 2). As a consequence of steric
interactions between the annelated ring and the acceptor
substituents in the 4-position of the central pyridine ring, the
latter are twisted out of coplanarity with increasing conforma-
tional bias of the annulated moiety. Hence, the longest wave-
length maxima are found for the pyrrolo[2,3-b]pyridines 4a-
c. Furthermore, these longest wavelength π-π* transitions, also
reflecting the S0-S1 excitation, display dominant charge-transfer
absorption
λmax,abs
[nm] (ꢀ)
emission quantum
λmax,em
yield
∆νa
fluorescence
color
compound
[nm]
Φf [%] [cm-1
]
4a
372 (3200)
310 (4400)
258 (21 900)
360 (15 900)
276 (41 700)
248 (47 900)
392 (6500)
284 (12 900)
252 (40 700)
362 (5900)
306 (5900)
258 (31 600)
364 (6600)
312 (5200)
258 (38 000)
358 (6200)
256 (20 400)
338 (3500)
260 (18 200)
340 (6600)
258 (38 900)
338
469
32
53
63
12
17
5600
6300
4200
4800
5000
green
green
green
blue
4b
4c
4d
4e
466
512 sh
468
516 sh
438
512 sh
444
518 sh
blue
4f
445
513 sh
501
25
24
34
5500
9600
9200
blue
blue
blue
4g
4h
495
4i
4j
478
511
26
15
8700
9200
blue
green
348 (5500)
280 (14 800)
254 (23 400)
a ∆ν˜ ) 1/λmax, abs - 1/λmax, em [cm-1].
character with a significant mutual HOMO-LUMO overlap in
a conformationally flexible 4-acceptor pyridyl framework. This
is also nicely supported by calculations on the DFT level of
theory (B3LYP G-31** density functional)21 performed on the
2-pyrimidyl-substituted pyrrolo[2,3-b]pyridine 4c (Figure 1) and
the pyrido[2,3-b]azepine 4j (Figure 2). The increase of steric
bias upon enlarging the annelated five-membered ring to a
seven-membered ring affects the orbital overlap and correlates
with the absorption energy. Therefore, in all series the absorption
maxima are bathochromically shifted upon increasing the
acceptor strength of the substituent at the 4-position of the
pyridine moiety from 2-pyridyl over p-cyanophenyl to 2-py-
rimidyl.
(20) Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication nos. CCDC-297966
(4a), CCDC-297967 (4c), CCDC-297968 (4e), CCDC-297970 (4h), CCDC-
297969 (4i). Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: + 44-1223/
336-033; e-mail: deposit@ccdc.cam.ac.uk).
(21) As implemented in PC Spartan Pro, Wavefunction, Inc.: Irvine,
CA, 2002.
J. Org. Chem, Vol. 71, No. 9, 2006 3497

Schramm et al.
TABLE 3. Selected UV/Vis and Fluorescence Properties (Recorded
in 0.1 M Acetate-Buffered DMSO Solution, T ) 298 K) and
Calculated HOMO and LUMO Energies of Pyrrolo[2,3-b]pyridines
4c and Pyrido[2,3-b]azepine 4j
absorption emission
λmax,abs
λmax,em
∆νa HOMO LUMO
[cm-1
[eV] [eV]
∆
HOMO-LUMO
compound
[nm] (ꢀ)
[nm]
]
[eV]
4c
384 (2700)b
478b
482c
478b
5100 -4.889 -1.544
4800 -8.563 -5.269
6000 -4.911 -1.409
3.345
3.294
3.502
250 (8600)
4c-H+ 392 (10 900)c
280 (15 100)
4j
372 (9500)b
298 (11 800)
268 (12 300)
4j-H+ 380 (6300)d
512d
6800 -8.605 -5.224
3.381
282 (7600)
a ∆ν˜ ) 1/λmax, abs - 1/λmax, em [cm-1]. b At pH 9. c At pH 1. d At pH 4.
significantly higher quantum yields (Φf ) 32-63%) than those
of [1,8]naphthyridines (4d-f, Φf ) 12-25%) and pyrido[2,3-
b]azepines (4g-j, Φf ) 15-34%). The longest wavelength
emission maxima, however, are found in the series of pyrido-
[2,3-b]azepines. As pointed out before for the absorption
properties, the emission behavior is as well-affected by steric
biases that control the efficiency of the spontaneous emission.
Therefore, the charge-transfer character of the HOMO-LUMO
transition responsible for the electronic absorption spectra is
well-reflected in the torsion-dependent emission efficiency from
the excited S1 state.23
FIGURE 1. LUMO (top) and HOMO (bottom) of the pyrrolo[2,3-b]-
pyrimidine 4c.
The presence of a basic pyridyl nitrogen in the annelated
2-amino pyridines 4 invites a scrutinization of the pH depen-
dence of the absorption and emission properties (Table 3). A
discrete halochromicity can be detected for the 2-pyrimidyl-
substituted pyrrolo[2,3-b]pyridine 4c and the pyrido[2,3-b]-
azepine 4j, where bathochromic shifts of the longest wavelength
absorption maxima are found by lowering the pH from pH 9
(4c, 384 nm; 4j, 372 nm) to pH 1 (4c, 392 nm) or pH 4 (4j,
380 nm). This decrease of the HOMO-LUMO gap upon
protonation is also reproduced in DFT calculations (B3LYP
G-31** density functional)21 on 4c, 4c-H+, 4j, and 4j-H+.
For the couple 4c/4c-H+, the HOMO-LUMO gap reduces
slightly upon protonation (4c, ∆HOMO-LUMO 3.35 eV; 4c-H+,
∆
3.29 eV), whereas the decrease of the HOMO-
HOMO-LUMO
LUMO gap is larger for the couple 4j/4j-H+ (4j, ∆HOMO-LUMO
3.50 eV; 4j-H+, ∆HOMO-LUMO 3.38 eV). However, the emission
behavior is even more affected from protonation than from the
absorption properties. The emission spectra of the 2-pyrimidyl-
substituted pyrrolo[2,3-b]pyridine 4c (Figure 3) and the pyrido-
[2,3-b]azepine 4j (Figure 4) display a quite different behavior
upon altering the pH. Whereas for the pyrrolo[2,3-b]pyridine
4c, the emission maximum only shifts slightly upon protonation
(478 nm at pH 9; 482 nm at pH 1); for the pyrido[2,3-b]azepine
4j, a significant bathochromic shift from 478 nm at pH 9 to
512 nm at pH 4 is observed. In the latter case, protonation of
the pyridyl nitrogen is obviously occurring at higher pKa as a
consequence of an increase in basicity. Again, the steric bias
causes a twist out of coplanarity of the 2-pyridyl substituent
(vide supra) and, hence, exerts a diminished electron-withdraw-
ing effect. The appearance of the fluorescence spectra of 4c
and 4j, with shoulders at longer wavelengths, indicates that dual
FIGURE 2. LUMO (top) and HOMO (bottom) of the pyrido[2,3-b]-
azepine 4j.
Furthermore, all annelated 2-amino pyridines 4 emit blue
(4d-i) or green light (4a-c, 4j) upon excitation at the
corresponding absorption wavelengths (Table 2). The Stokes
shifts are rather pronounced and lie between 4200 and 9600
cm-1. For all representatives the quantum yields Φf were
determined.22 Pyrrolo[2,3-b]pyridines (4a-c) fluoresce with
(22) Determined with 7-diethylamino-4-methyl-chromen-2-one, couma-
rine 1, as a standard (Φf ) 0.73), see: Jones, G., II.; Jackson, W. R.; Choi,
C. Y.; Bergmark, W. R. J. Phys. Chem. 1985, 89, 294-300.
(23) Valeur, B. Molecular Fluorescence; Wiley-VCH: Weinheim,
Germany, 2002.
3498 J. Org. Chem., Vol. 71, No. 9, 2006

Sequence Approach to Annelated 2-Amino Pyridines
quence of mild reaction conditions and functional-group com-
patibility. All annelated 2-amino pyridines display pronounced
blue or green fluorescence that can be controlled by reversible
protonation in weakly acidic media for pyrido[2,3-b]azepines.
Therefore, the fluorescence dyes, synthesized in a modular
diversity-oriented fashion, can be ideal candidates for fluores-
cence labels for studying pH-dependent and pH-alternating
cellular processes. Further studies are directed to the method-
ological development of novel multicomponent reactions, and
the implementation of the fluorophores in biolabeling is currently
under progress.
Experimental Section
General Procedure for the Coupling-Isomerization-Cycload-
dition-Condensation Sequence to Annelated 2-Amino Py-
ridines, 4. A magnetically stirred solution of 1.00 mmol of halogen
compound 1, 1.05 mmol of propargyl tosyl amide 2, 20 mg (0.02
mmol) of (PPh3)2PdCl2, and 2 mg (0.01 mmol) of CuI in 3.5 mL
of degassed triethylamine and 5 mL THF under nitrogen was heated
to reflux temperature for 24 h (for a table with experimental details,
see Supporting Information). After cooling to room temperature, a
solution of 5 mmol of N,S-ketene acetals 3 in 1 mL of THF were
added, and the reaction mixture was heated to reflux temperature
for 12 h. After cooling to room temperature, 40 mL of ethyl acetate
and 40 mL of water were added and stirring was continued for 5
to 10 min. The aqueous layer was extracted with ethyl acetate (4
× 15 mL), and the combined organic phases were dried with
magnesium sulfate. After filtration, the solvents were removed in
vacuo, and the residue was chromatographed on silica gel and
recrystallized from a suitable solvent to give the analytically pure
annelated 2-amino pyridine derivatives 4.
FIGURE 3. Emission maxima λmax,em [nm] (arbitrary units) of 4c at
pH 1.00, 2.00, 3.00, 4.00, and 9.00 (recorded in 0.1 M acetate-buffered
DMSO solution, T ) 298 K, λmax, excitation ) 340 nm).
6-(4-Methoxy-phenyl)-1-methyl-4-pyrimidin-2-yl-2,3-1H-
pyrrolo[2,3-b]pyrimidine (4c). According to the GP, after chro-
matography on silica gel (hexane/acetone, 2.5:1) and recrystalli-
zation from diethyl ether, 210 mg (66%) of 4c was isolated as
1
yellow crystals: mp 190 °C. H NMR (acetone-d6, 300 MHz): δ
3.02 (s, 3H), 3.44-3.57 (m, 4H), 3.85 (s, 3H), 6.99 (d, J ) 9.0
Hz, 2H), 7.20 (t, 1H), 7.43 (t, J ) 4.8 Hz, 1H), 7.91 (s, 1H), 8.07
(d, J ) 8.9 Hz, 2H), 8.93 (d, J ) 5.0 Hz, 1H). 13C NMR (acetone-
d6, CDCl3, 75 MHz): δ 28.7 (CH2), 32.9 (CH3), 53.8 (CH2), 55.6
(CH3), 107.1 (CH), 114.6 (CH), 120.8 (CH), 122.7 (Cquat.), 128.4
(CH), 141.0 (Cquat.), 154.7 (Cquat.), 158.1 (CH), 160.9 (Cquat.), 161.0
(Cquat.), 165.8 (Cquat.). EI MS (70 eV, m/z (%)): 318.2 (M+, 100),
303.2 (M+ - CH3, 7). IR (KBr): ν˜ 3003, 2929, 2874, 2836, 1610,
1601, 1584, 1570, 1554, 1512, 1477, 1441, 1417, 1370, 1335, 1299,
1282, 1260, 1240, 1170, 1036, 807, 568 cm-1. UV/vis (CH2Cl2)
FIGURE 4. Emission maxima λmax,em [nm] (arbitrary units) of 4j at
pH 4.00, 5.00, 6.00, 7.00, 8.00, and 9.00 (recorded in 0.1 M acetate-
buffered DMSO solution, T ) 298 K, λmax, excitation ) 340 nm).
fluorescence of these donor-acceptor-substituted pyridines is
obviously responsible for the variable pH sensitivity. In the
former system, the 2-pyrimidyl substituent is already coplanar
with the pyridine in the ground state, and the geometrical
changes upon protonation are only minimal, whereas in the latter
fluorophore, the S0-S1 excitation from the pyridyl core to the
pyrimidine occurs with dominant charge-transfer character to
an excited state that is coplanar and has to relax to a twisted
state again. All this makes the pyrido[2,3-b]azepine 4j a pH-
sensitive fluorescence sensor that can be operative in neutral
and weakly acidic media.
λmax (ꢀ): 252 (40 700), 284 (12 900), 392 (6500). Anal. Calcd for
C19H18N4O (318.4): C, 71.68; H, 5.70; N, 17.60. Found: C, 71.58;
H, 5.70; N, 17.86.
4-[2-(4-Methoxy-phenyl)-8-methyl-5,6,7,8-tetrahydro-[1,8]-
naphthyridin-4-yl]pyridine (4f). According to the GP, after
chromatography on silica gel (hexane/acetone, 3:1), 160 mg (48%)
of 4f were isolated as a brown oil. 1H NMR (acetone-d6, 300
MHz): δ 1.88 (m, 2H), 2.74 (t, J ) 6.3 Hz, 2H), 3.24 (s, 3H),
3.45 (t, J ) 5.7 Hz, 2H), 3.82 (s, 3H), 6.95 (d, J ) 8.9 Hz, 2H),
7.05 (s, 1H), 7.35-7.37 (m, 1H), 7.51 (d, J ) 7.8 Hz, 1H), 7.84 (t,
J ) 7.9 Hz, 1H), 8.05 (d, J ) 8.9 Hz, 2H), 8.66-8.68 (m, 1H).
13C NMR (acetone-d6, 75 MHz): δ 22.3 (CH2), 26.2 (CH2), 37.1
(CH3), 50.5 (CH2), 55.5 (CH3), 108.8 (CH), 113.9 (Cquat.), 113.0
(Cquat.), 114.5 (CH), 123.2 (CH), 124.7 (CH), 128.0 (CH), 128.3
(CH), 133.5 (Cquat.), 137.2 (CH), 148.0 (Cquat.), 150.0 (CH), 157.1
(Cquat.), 159.5 (Cquat.), 160.9 (Cquat.). IR (KBr): ν˜ 2834, 1665, 1609,
1585, 1572, 1555, 1513, 1471, 1428, 1410, 1399, 1369, 1356, 1327,
1246, 1202, 1179, 1170, 1032, 831, 792 cm-1. UV/vis (CH2Cl2)
Conclusion
The mild reaction conditions of the CI sequence of electron-
poor (hetero)aryl halides with 1-aryl propargyl N-tosylamines
giving rise to enimines can be extended to a one-pot three-
component synthesis of annelated 2-amino pyridines, such as
pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]-
azepines, applying a cycloaddition with N,S-ketene acetals and
subsequent aromatization. This methodology combines modern
catalytic cross-coupling processes with pericyclic reactions and,
therefore, opens new one-pot synthetic strategies as a conse-
λ
max (ꢀ): 256 (20 400), 358 (6200). HRMS (70 eV, EI): calcd for
C21H21N3O, 331.1685; found, 331.1679.
2-(4-Methoxy-phenyl)-9-methyl-4-pyrimidin-2-yl-6,7,8,9-tet-
rahydro-5H-pyrido[2,3-b]azepine (4j). According to the GP, after
J. Org. Chem, Vol. 71, No. 9, 2006 3499

Schramm et al.
chromatography on silica gel (hexane/acetone, 4:1) and recrystal-
HRMS (70 eV, EI): calcd for C21H22N4O, 346.1794; found,
346.1797.
lization from diethyl ether, 194 mg (56%) of 4j was isolated as a
1
brown oil. H NMR (CDCl3, 300 MHz): δ 1.83-1.89 (m, 4H),
Acknowledgment. The financial support of the Deutsche
Forschungsgemeinschaft, the Morphochem AG, Munich, and
the Fonds der Chemischen Industrie is gratefully acknowledged.
2.73-2.77 (m, 2H), 3.15 (s, 3H), 3.27-3.30 (m, 2H), 3.79 (s, 3H),
6.92 (d, J ) 8.9 Hz, 2H), 7.17 (t, J ) 4.9 Hz, 1H), 7.47 (s, 1H),
8.04 (d, J ) 8.9 Hz, 2H), 8.78 (d, J ) 4.9 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): δ 24.3 (CH2), 27.3 (CH2), 28.3 (CH2), 40.4
(CH3), 53.7 (CH2), 55.1 (CH3), 111.1 (CH), 113.6 (CH), 119.1 (CH),
121.9 (Cquat.), 127.6 (CH), 132.3 (Cquat.), 147.1 (Cquat.), 151.3 (Cquat.),
156.8 (CH), 159.7 (Cquat.), 162.0 (Cquat.), 167.1 (Cquat.). IR (KBr):
ν˜ 2932, 1608, 1589, 1566, 1547, 1513, 1492, 1443, 1418, 1368,
1350, 1333, 1296, 1247, 1191, 1179, 1032, 838, 813 cm-1. UV/
vis (CH2Cl2) λmax (ꢀ): 254 (23 400), 280 (14 800), 348 (5500).
Supporting Information Available: Experimental details,
computational data of 4c, 4c-H+, 4j, and 4j-H+, 1H and 13C NMR
spectra of compounds 4, and X-ray structure data and ORTEP plots
of 4a, 4c, 4e, 4g, and 4i. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0602726
3500 J. Org. Chem., Vol. 71, No. 9, 2006