7-Pyridylindoles: Synthesis, structure, and properties

Article abstract of DOI:10.1021/jo061011z

(Chemical Equation Presented) A series of three isomeric 7-pyridylindoles (7-PIs) are prepared where the pyridine attachment is through C2, C3, or C4. These systems are prepared by a combination of the Bartoli reaction and the Stille coupling with an appropriate pyridyl stannane. By treatment with CH ₃I, the 7-PIs can be converted to their pyridinium salts. Deprotonation at the NH of these salts leads to a zwitterion which, in the 4-pyridyl system, also exists as a neutral isomer. The photophysical and NMR properties of these systems are discussed. All three pyridylindoles are analyzed by X-ray crystallography and shown to exist in different states of aggregation dictated by the formation of intra- and intermolecular H-bonds.

Full text of DOI:10.1021/jo061011z

7-Pyridylindoles: Synthesis, Structure, and Properties
Maria Salvatora Mudadu, Ajay Singh, and Randolph P. Thummel*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
thummel@uh.edu
ReceiVed May 16, 2006
A series of three isomeric 7-pyridylindoles (7-PIs) are prepared where the pyridine attachment is through
C2, C3, or C4. These systems are prepared by a combination of the Bartoli reaction and the Stille coupling
with an appropriate pyridyl stannane. By treatment with CH3I, the 7-PIs can be converted to their
pyridinium salts. Deprotonation at the NH of these salts leads to a zwitterion which, in the 4-pyridyl
system, also exists as a neutral isomer. The photophysical and NMR properties of these systems are
discussed. All three pyridylindoles are analyzed by X-ray crystallography and shown to exist in different
states of aggregation dictated by the formation of intra- and intermolecular H-bonds.
Introduction
which is quenched by the addition of alcohol, providing the
tautomer 2-ROH which exhibits a much weaker, lower energy
emission. The direct involvement of the alcohol complex
1-ROH in this process has been well established.3a
In earlier work, we have reported the preparation, properties,
and tautomeric behavior of compounds related to 2-(pyrid-2′-
yl)indole (1).1,2 This molecule is unique for a variety of reasons,
perhaps the most of important of which is that it juxtaposes a
pyridine and a pyrrole. The former heterocycle is π-deficient
but a good Lewis base. It also is a good H-bond acceptor.
Pyrrole, on the other hand, is π-excessive, a moderate Bronsted
acid, and a good H-bond donor.
Tautomerization can be inhibited by the methylation of 1 to
provide the salt 3. With the basic pyridine site blocked, this
system no longer undergoes phototautomerization. Rather treat-
ment with base deprotonates the indole to provide 4 as a stable,
well characterized species. Substituted and bridged derivatives
of 3 behave in a similar fashion.2
The molecule 7-(pyrid-2′-yl)indole (5) is an isomer of 1 that
is also capable of forming a proton-shifted tautomer; however,
in this system, the two nitrogens have a 1,5-relationship, and the
orientation of the pyridine lone pair and the pyrrole N-H is
much more favorable for intramolecular H-bonding. In this study,
In a series of papers with Waluk and co-workers, we have
examined the excited state properties of this system,3 finding
that in the excited state the basicity of the pyridine and the
acidity of the pyrrole both are increased substantially. Direct
photoexcited proton transfer from pyrrole to pyridine apparently
does not occur largely due to the unfavorable orientation of these
two moieties. Rather this process is mediated by added alcohol
so that, in nonprotic solvents, 1 shows intense fluorescence
(3) (a) Kyrychenko, A.; Herbich, J.; Wu, F.; Thummel, R. P.; Waluk, J.
J. Am. Chem. Soc. 2000, 122, 2818-2827. (b) Herbich, J.; Hung, C.;
Thummel, R. P.; Waluk, J. J. Am. Chem. Soc. 1996, 118, 3508-3518. (c)
Herbich, J.; Hung, C.; Thummel, R. P.; Waluk, J. J. Photochem. Photobiol.
A: Chem. 1994, 80, 157-160. (d) Kyrychenko, A.; Herbich, J.; Izydorzak,
M.; Gil, M.; Dobkowski, J.; Wu, F. Y.; Thummel, R. P.; Waluk, J. Isr. J.
Chem. 1999, 39, 309-318. (e) Nosenko, Y.; Thummel, R. P.; Mordzinski,
A. Phys. Chem. Chem. Phys. 2004, 6, 363-367.
(1) Thummel, R. P.; Hedge, V. J. Org. Chem. 1989, 54, 1720-1725.
(2) (a) Wu, F.; Hardesty, J.; Thummel, R. P. J. Org. Chem. 1998, 63,
4055-4061. (b) Wu, F.; Chamchoumis, C. M.; Thummel, R. P. Inorg.
Chem. 2000, 39, 584-590.
10.1021/jo061011z CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7611-7617
7611

Mudadu et al.
TABLE 1. 1H NMR Data for 7-Pyridylindoles and Their N-Methyl
we have prepared and examined the series of isomeric com-
pounds where the point of attachment of the 7-pyridyl substituent
varies from 2′-pyridyl (5) to 3′-pyridyl (6) to 4′-pyridyl (7).
Saltsa
H2 H3
7.42 6.52 7.66 7.13 7.79
11 7.52 6.64 ∼7.24 ∼7.24 7.86
7.34 6.54 7.60 ∼7.14 ∼7.14 8.84
12 7.51 6.62 7.74 7.20 7.31 9.35
H4
H5
H6 H2′ H3′ H4′ H5′ H6′ CH3
5
8.13 7.91 7.35 8.76
8.15 8.66 8.22 9.22 4.00
8.03 7.54 8.62
6
8.78 8.24 8.99 4.42
7
7.36 6.55 7.65 7.13 7.23 8.67 7.66
7.66 8.67
13 7.50 6.65 7.83 7.24 7.48 9.01 8.41
14 7.46 6.33 7.63 6.78 7.58 8.65 9.43
8.41 9.01 4.37
9.43 8.65 4.19
a Recorded in DMSO-d6 at room temperature.
Results and Discussion
Synthesis and Characterization. The 2-(pyrid-2′-yl)indole
(1) could be readily prepared by the Fisher cyclization of the
phenylhydrazone of 2-acetylpyridine.4 This route could not be
applied to the isomeric 7-pyridyl indoles, and thus we resorted
to coupling methodologies. Both the 2′-pyridyl5 and 4′-pyridyl
systems could be prepared in good yield by the Stille coupling6
between the corresponding tri-n-butylstannane and 7-bromo-
indole7 (8), which was prepared by the Bartoli reaction on 2-
bromonitrobenzene.8 This coupling, however, was unsuccessful
for 3-pyridyl tri-n-butylstannane. Alternatively, a Suzuki cou-
pling was attempted.9 This reaction was also unsuccessful using
either 7-indolylboronic acid and 3-bromopyridine or 3-pyridyl-
boronic acid10 and 7-bromoindole as the coupling partners.
FIGURE 1. Emission spectra of 1 and 5-7 in CH3CN (10-5 M) at
room temperature with excitation at absorbance 0.12: 1 (black), 5 × 20
(brown), 6 (blue), 7 (red). Blue peak at 450 is an excitation overtone.
The synthesis of 6 was finally accomplished by carrying out
the Stille coupling before the Bartoli reaction. Thus 3-pyridyl
tri-n-butylstannane was coupled with 2-bromonitrobenzene to
afford 10, which was then cyclized with vinylmagnesium
bromide to provide 6.
separate and easily identifiable spin systems for each of the three
aromatic rings (Table 1). The H3 proton on the indole ring was
always the highest field signal, appearing at 6.52-6.55 ppm as
a doublet with a very small coupling (J ) 2.4-2.7 Hz) to H2.
The proton adjacent to nitrogen on the pyridine ring, H6′, shows
a characteristically small (J ) 4.2-4.5 Hz) coupling constant
and thus is also readily identified, allowing one to make the
remaining assignments in this ring through 2D connectivities.
H4 and H6 in the benzo-ring are somewhat ambiguous and are
only tentatively assigned.
Properties and Chemistry. The most noteworthy property
of the 2-(pyrid-2′-yl)indoles is their strong fluorescence in
aprotic solvents.3 This fluorescence is quenched by the addition
of alcohols which form a cyclic H-bonded complex and thus
assist the proton transfer step required for phototautomerization.
The isomeric 7-pyridylindoles show different emissive proper-
ties. The 3′-pyridyl and 4′-pyridyl isomers 6 and 7 emit strongly
at 386 and 401 nm with quantum yields of 0.25 and 0.55,
respectively. The 2′-pyridyl system 5, on the other hand, emits
very weakly at 390 nm with a quantum yield of only 0.006.
For this system, the fluorescence is quenched by formation of
the phototautomer which is facilitated by strong intramolecular
H-bonding that is impossible for the other two isomers (Figure
1). In a separate study, the detailed photophysical behavior of
the three isomeric 7-pyridylindoles was examined, and the
involvement of alcohol solvents in promoting fluorescence
quenching of 6 and 7 has been pointed out.11
The pyridylindoles 5-7 were readily characterized by careful
1
examination of their H NMR spectra, which evidenced three
(4) (a) Robinson, B. The Fischer Indole Synthesis; Wiley: Chichester
and New York, 1982. (b) Sundberg, R. J. The Chemistry of Indole; Academic
Press: New York, 1970. (c) Thummel, R. P. Synlett 1992, 1-12.
(5) Seki, K.-I.; Ohkura, K.; Terashima, M.; Kanaoka, Y. Chem Pharm.
Bull. 1988, 36, 940-944.
(6) (a) Schubert, U. S.; Eschbaumer, C.; Heller, M. Org. Lett. 2000, 2,
3373-3376. (b) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 6343-6348. (c) Fujita, M.; Oka, H. Ogura, K. Tetrahedron Lett.
1995, 36, 5247-5250.
(7) (a) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51,
5106-5110. (b) Leggetter, B. E.; Brown, R. K. Can. J. Chem. 1960, 38,
1467-1471. (c) Pappalardo, G.; Vitali, T. Gazz. Chim. Ital. 1958, 88, 1147.
(8) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129-2132. (b) Bosco, M.; Dalpozzo, R.; Bartoli, G.;
Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657-663.
(c) Dobbs, A. J. Org. Chem. 2001, 66, 638-641.
(9) (a) Carbonnelle, A.-C.; Zamora, E. G.; Beugelmans, R.; Roussi, G.
Tetrahedron Lett. 1998, 39, 4467-4470. (b) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457-2483.
(10) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43,
4285-4287.
(11) Wiosna, G.; Petkova, I.; Mudadu, M. S.; Thummel, R. P.; Waluk,
J. Chem. Phys. Lett. 2004, 400, 379-383.
7612 J. Org. Chem., Vol. 71, No. 20, 2006

7-Pyridylindoles: Synthesis, Structure, and Properties
To more carefully examine the possible tautomeric behavior
of these three species, we prepared their N-methyl salts in the
same manner as for the conversion of 1 to 3.2 Treatment with
a large excess of iodomethane in acetonitrile at reflux afforded
the salts 11-13 in yields of 99, 72, and 91%, respectively. While
the reaction to form 12 and 13 proceeded smoothly in 3 h, 48
h reflux was required for the formation of 11, due to the
disruption of the strong intramolecular H-bond.
FIGURE 2. Emission spectra of 5 (black), 11 (red), and 11 + base
(blue) 10-5 M in CH3CN at 25 °C.
When a dichloromethane solution of 13 is treated with 25%
NaOH for 20 min at room temperature, a deep red solid
identified as the tautomer 14 is obtained in 99% yield. This
observation is consistent with what was observed for the
analogous 2-(pyrid-4′-yl)indole system.2a Treatment of 11 or
12 under similar or more severe basic conditions leads to the
formation of a red solution, but a stable neutral species cannot
be isolated. In all three cases, it seems likely that deprotonation
occurs to initially form a zwitterion, but only in the case of 13
can the zwitterion 14a readily undergo the electronic reorgan-
ization required to afford the isomer 14b. For the 3′-pyridyl
isomer 12, a reasonable valence bond structure for this analogous
isomer is not available. For 11, steric interference between the
N-methyl group and H6 or H1 causes twisting about the C7-
C2′ bond that disfavors the planarity required to produce the
neutral isomer.
FIGURE 3. Electronic absorption spectra of 11 in CH3CN, 10-5
M
(black line); after the addition of excess KOH, 10 min (red); 20 min
(blue); 30 min (dark blue); 40 min (turquoise).
solution, and the spectrum is re-measured at 10 min intervals.
The absorbance of the salt at 380 nm disappears, and two new
bands at 290 and 510 nm appear with clear isosbestic points,
indicating a concerted conversion to the neutral species.
The same interconversion can also be monitored by 1H NMR.
By observing the time-dependent changes in the NMR spectrum
of a DMSO-d6 solution of the salt 13 treated with KOH, one
can follow the conversion of 13, first to the zwitterion 14a,
and then to the neutral species 14b. At room temperature, the
two pairs of pyridinium ring protons, H3′/H5′ and H2′/H6′,
appear equivalent since the isomers 14a and 14b are rapidly
interconverting. Immediately after addition of the base, the
solution becomes deep red, and the NH signal at 11.54 ppm
disappears. The spectrum changes gradually with time, the most
notable change being the downfield shift of H3′/H5′ and the
upfield shift of H2′/H6′ (Figure 4). For the salt 13, the
pyridinium ring is twisted so that H3′ and H5′ are held over
the shielding region of the adjacent indole ring and appear at
higher field (8.4 ppm). Conversely, H2′ and H6′ are adjacent
to the pyridinium nitrogen and are deshielded, appearing at lower
field (9.0 ppm). As the salt is converted to the zwitterion 14a
and ultimately the neutral species 14b, H3′ and H5′ move more
into the deshielding region of the indole ring and downfield,
At first glance it appears that 14a and 14b are resonance
forms; however, due to the very different geometries of these
two species, they are instead a rapidly interconverting mixture
of two isomeric species. For the zwitterion 14a, a coplanar
arrangement of the indole and N-methylpyridinium ring would
cause unfavorable steric interaction between H6 and H3′. Twist-
ing around the 7,4′-bond relieves this interaction but also de-
creases conjugative interaction between the two aromatic rings.
For the 2′-pyridyl isomer 11, this effect is magnified by the
N-methyl group which amplifies the steric interference between
the rings. The changes in the emission spectra of the 2′-pyridyl
isomer 11 upon methylation and subsequent deprotonation are
illustrated in Figure 2. As mentioned earlier, the normally strong
indole emission is quenched in compound 5 due to the
intramolecular H-bond. When this H-bond is interrupted by
N-methylation, the emission increases. Deprotonation results in
the appearance of a second lower energy emission band which
may be attributed to the zwitterion.
These changes are even more clearly illustrated for the 4′-
pyridyl isomer 13. Figure 3 (black line) shows the absorption
spectrum of an acetonitrile solution of 13. Base is added to this
J. Org. Chem, Vol. 71, No. 20, 2006 7613

Mudadu et al.
The length of the C8-C10 bond also shows some significant
variation for the three structures. Two opposing effects are at
work. Coplanarity of the two rings would tend to increase the
steric interactions mentioned earlier and thus lengthen the C8-
C10 bond. At the same time, coplanarity would favor conjuga-
tive interaction between the rings which would tend to shorten
the bond. It appears that the steric interactions are more
influential, and thus the shortest connecting bond is found for
the least planar system 7 (1.465 Å) and the longest connecting
bond is for the most planar molecule 5 (1.493 Å).
The most interesting structural feature for this family of
compounds is their degree of aggregation in the crystal state.
This aggregation is controlled by interaction between the indole
H-bond donor site and the pyridine H-bond acceptor site. For
5, these sites are well disposed for the formation of an
intramolecular H-bond, and the system is monomeric in the solid
state. For 7, the two sites are arranged in an approximate parallel
fashion, and thus the molecule forms an H-bonded dimer (Figure
6, top). This dimerization leads to a large dihedral angle about
the C8-C10 bond which in turn allows the two pyridine rings
to lie in a stacked parallel arrangement with an interplanar
distance between the two pyridines of 3.25 Å. For molecule 6,
the H-bond donor and acceptor sites are less well organized for
mutual interaction, and thus the molecule forms a zigzag,
polymeric H-bonded network (Figure 6, bottom).
The melting points of 5-7 reflect these differences in aggre-
gation. The monomeric 5 has a relatively low mp ) 65-66
°C; dimeric 7 has the highest mp ) 207-208 °C, while poly-
meric 6 is almost exactly intermediate with mp ) 130-132
°C. The shortest (1.97 Å) and most linear (174.4°) H-bond is
for the polymeric system which is best able to arrange itself
for favorable H-bonding, while the longest H-bond (2.08 Å)
with the most acute angle (127°) is for 5 whose geometry is
much more restricted.
FIGURE 4. 1H NMR spectra of the downfield region of 13 in DMSO-
d6 at room temperature, t ) 0 min (top trace) and at time intervals
after the addition of KOH.
while H2′ and H6′ experience less deshielding from the
diminishing positive charge on pyridine and move upfield.
X-ray Structures. The structures of 5-7 were examined by
single-crystal X-ray diffraction. Figure 5 shows the ORTEP
diagrams for all three molecules, and some pertinent geometric
features are summarized in Table 2. The most obvious difference
between these three molecules is the dihedral angle about the
C8-C10 bond which connects the two aromatic rings. For 5,
this angle is only about 3° and is explained by the strong
intramolecular H-bond between N11 and N1-H, which tends
to hold the two rings coplanar. Such an intramolecular H-bond
is not possible for 6 and 7, and the two aromatic rings twist out
of coplanarity (ca. 54 and 65°, respectively) to relieve interac-
tions of C7-H and N1-H with C11-H and C15-H.
It is well documented that H-bonding, either inter- or
intramolecular, will quench the excited state emission of
pyridylindoles.12 Therefore, if the H-bonded aggregation which
FIGURE 5. ORTEP plots of 5-7 with atom numbering scheme for X-ray discussion.
TABLE 2. Selected Geometric Data for 7-PIs
bonda
7-(pyrid-2′-yl)indole
7-(pyrid-3′-yl)indole
7-(pyrid-4′-yl)indole
C8-C10
1.493(4)
0.90(3)
2.08(3)
2.719(4)
127°(2)
-3.0°(4)
-3.1°(4)
1.484(4)
0.94(3)
1.97(3)
2.882(3)
162°(2)
55.0°(4)
52.8°(4)
1.465(6)
0.87
2.06
2.925(5)
174.4°
-65.4°(7)
-65.3°(6)
D-H
A‚‚‚H
D-A
DHA
C9-C8-C10-X11
C7-C8-C10-X15
a D refers to H-bond donor (indole N), and A refers to H-bond acceptor (pyridine N).
7614 J. Org. Chem., Vol. 71, No. 20, 2006

7-Pyridylindoles: Synthesis, Structure, and Properties
1
hexane: mp 130-132 °C; H NMR (CDCl3) δ 10.26 (br s, 1H),
8.97 (d, 1H, J ) 2.1 Hz), 8.30 (dd, 1H, J ) 5.1, 1.8 Hz), 7.78 (dt,
1H, J ) 8.1, 1.8 Hz), 7.61 (d, 1H, J ) 7.8 Hz), 7.22 (dd, 1H, J )
7.8, 5.1 Hz), 7.18 (t, 1H, J ) 2.7 Hz), 7.11 (d, 1H, J ) 7.8 Hz),
7.07 (dd, 1H, J ) 7.2, 1.2 Hz), 6.54 (dd, 1H, J ) 3.6, 2.1 Hz); 1H
NMR (DMSO-d6) δ 11.18 (br s, 1H), 8.84 (d, 1H, J ) 1.2 Hz),
8.62 (dd, 1H, J ) 4.5, 1.2 Hz), 8.03 (dt, 1H, J ) 8.1, 2.1 Hz), 7.60
(dd, 1H, J ) 7.5, 1.5 Hz), 7.54 (dd, 1H, J ) 7.8, 5.1 Hz), 7.34 (t,
1H, J ) 2.7 Hz), 7.09-7.16 (overlapping m, 2H), 7.13 (t, 1H, J )
7.8 Hz), 6.254 (dd, 1H, J ) 2.4, 1.5 Hz); 13C NMR (CDCl3) δ 149.2,
147.9, 136.4, 135.8, 134.1, 129.0, 125.5, 124.2, 122.2, 122.0, 121.1,
120.3 (one carbon hidden). Anal. Calcd for C13H10N2(1/4H2O): C,
78.59; H, 5.07; N, 14.10. Found: C, 78.82; H, 5.07; N, 13.71.
7-(Pyrid-4′-yl)indole (7). A mixture of 4-tri(n-butylstannyl)-
pyridine (90%, 1.27 g, 3.1 mmol), 7-bromoindole (8, 0.80 g, 4.1
mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mol %, 18.4
mg, 0.16 mmol) in dry toluene (3 mL) was refluxed under Ar for
24 h. After cooling to room temperature, water (1 mL) was added
and the mixture was concentrated under reduced pressure. Part of
the product precipitated, and it was washed with CH2Cl2/hexane
(1:5) and collected as a white solid (0.10 g). Chromatography of
the residue on alumina, eluting with CH2Cl2 and followed by
EtOAc, provided 7 as a white solid which was washed with hexane
and joined to the former precipitate (0.15 g, 25%): mp 207-208
FIGURE 6. Organization of 6 (bottom) and 7 (top) in the crystal state.
1
°C; H NMR (DMSO-d6) δ 11.19 (br s, 1H), 8.67 (dd, 2H, J )
we observe for 6 and 7 in the solid state (Figure 6) was
maintained in solution, one would expect to see a similar
quenching effect which might vary as a function of concentra-
tion. For 6 and 7 in acetonitrile, we observe that the emission
intensity increases linearly as the concentration of the solution
is increased. If H-bonded aggregation was important in solution,
then we would expect to see more quenching as the concentra-
tion was increased. Apparently 6 and 7 do not aggregate
significantly in relatively dilute solution.
4.2, 1.8 Hz), 7.63-7.67 (overlapping m, 3H), 7.36 (t, 1H, J ) 3.0
Hz), 7.22 (dd, 1H, J ) 7.5, 0.9 Hz), 7.13 (t, 1H, J ) 8.1 Hz), 6.55
(dd, 1H, J ) 2.7, 1.5 Hz); 13C NMR (CDCl3) δ 150.1, 146.2, 132.7,
129.0, 126.4, 123.1, 122.4, 121.4, 121.1, 119.5, 101.9. Anal. Calcd
for C13H10N2(1/4H2O): C, 78.59; H, 5.29; N, 14.11. Found: C,
78.31; H, 5.02; N, 13.72.
7-Bromoindole (8). The 2-nitrobromobenzene (9, 1.01 g, 5.0
mmol) was placed in a two-necked round-bottom flask fitted with
a gas inlet and rubber septum. The flask was purged several times
with Ar before adding dry THF (50 mL) and cooling to -40 to -45
°C. Vinylmagnesium bromide (1 M, 15 mL, 15 mmol) was then
added rapidly to the THF solution, and stirring continued for 1 h.
Saturated NH4Cl was added to the reaction mixture at ca. -40 °C,
and the mixture was allowed to warm to room temperature. The
mixture was extracted with Et2O (3 × 70 mL). The combined organic
phase was washed with NH4Cl (100 mL), water (100 mL), and
brine (100 mL), dried (MgSO4), and concentrated. Chromatography
on SiO2, eluting with CH2Cl2, provided 8 as a white solid (0.52 g,
53%): mp 42-44 °C (lit.6b mp 42-43 °C); 1H NMR (CDCl3) δ 8.33
(s, 1H), 7.58 (d, 1H, J ) 7.8 Hz), 7.34 (d, 1H, J ) 7.8 Hz), 7.25
(m, 1H), 7.00 (t, 1H, J ) 7.8 Hz), 6.63 (dd, 1H, J ) 3.3, 2.4 Hz).
2-(Pyrid-3′-yl)nitrobenzene (10). A mixture of 3-tri(n-butyl-
stannyl)pyridine (0.42 g, 1.1 mmol), 2-nitrobromobenzene (9, 0.20
g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mol
%, 57.8 mg, 0.05 mmol) in dry toluene (3 mL) was refluxed under
Ar for 21 h. After cooling to room temperature, water (1 mL) was
added. The solvent was removed under reduced pressure. Chro-
matography on alumina, eluting with hexane, then with CH2Cl2
furnished 10 as a yellow oil (0.17 g, 83%): 1H NMR (CDCl3) δ
8.68 (dd, 1H, J ) 5.1, 1.5 Hz), 8.62 (d, 1H, J ) 1.8 Hz), 8.03 (dd,
1H, J ) 8.1, 0.9 Hz), 7.69-7.74 (overlapping m, 2H), 8.68 (td,
1H, J ) 8.1, 1.5 Hz), 8.62 (d, 1H, J ) 1.8 Hz), 7.42-7.46
(overlapping m, 2H).13
Experimental Section
7-(Pyrid-2′-yl)indole (5). A mixture of 2-tri(n-butylstannyl)-
pyridine (80%, 5.52 g, 12.0 mmol), 7-bromoindole (8, 1.96 g, 10.0
mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mol %, 0.58
mg, 0.50 mmol) in dry toluene (30 mL) was refluxed under Ar for
4 h. After cooling to room temperature, water (1 mL) was added
and the mixture was concentrated under reduced pressure. Chro-
matography on silica gel, eluting with hexane, followed by CH2-
Cl2/hexane (1:1) provided a mixture of 5 and tri(n-butylstannyl)-
chloride. This mixture was stored overnight in the freezer. The solid
obtained was washed with hexane to provide 5 (1.62 g, 83%): mp
1
65-66 °C (lit.5 mp 65-66 °C); H NMR (CDCl3) δ 11.37 (br s,
1H), 8.71 (ddd, 1H, J ) 4.8, 2.4, 0.9 Hz), 7.03 (d, 1H, J ) 8.4
Hz), 7.73-7.81 (overlapping m, 3H), 7.37 (t, 1H, J ) 2.7 Hz),
7.19-7.25 (overlapping m, 2H), 6.61 (t, 1H, J ) 2.7 Hz); 1H NMR
(DMSO-d6) δ 11.62 (br s, 1H), 8.76 (d, 1H, J ) 4.2 Hz), 8.14 (d,
1H, J ) 8.4 Hz), 7.91 (td, 1H, J ) 8.1, 1.5 Hz), 7.80 (d, 1H, J )
6.9 Hz), 7.66 (d, 1H, J ) 7.8 Hz), 7.42 (t, 1H, J ) 3.0 Hz), 7.35
(ddd, 1H, J ) 7.5, 4.8, 1.2 Hz), 7.13 (t, 1H, J ) 7.8 Hz), 6.25 (t,
1H, J ) 2.4 Hz); 13C NMR (CDCl3) δ 158.0, 148.6, 136.8, 134.6,
129.6, 125.0, 122.6, 121.4, 120.9, 120.1, 119.5, 102.1 (one carbon
hidden). Anal. Calcd for C13H10N2: C, 80.41; H, 5.15; N, 14.43.
Found: C, 80.28; H, 5.13; N, 14.36.
1-Methyl-2-(indol-7′-yl)pyridinium iodide (11). A solution of
iodomethane (1.6 mL, 25.7 mmol) in CH3CN (3 mL) was added
dropwise, during a period of 6 h, to a boiling solution of 7-(pyrid-
2′-yl)indole (5, 0.49 g, 2.5 mmol) in CH3CN (3 mL) under Ar.
The yellow mixture was refluxed for 48 h. After cooling to room
temperature, the solvent was evaporated and the yellowish solid
dried to furnish pure 11 (0.85 g, 99%): mp 205-207 °C; 1H NMR
(DMSO-d6) δ 11.31 (br s, 1H), 9.22 (d, 1H, J ) 5.7 Hz), 8.66 (dd,
7-(Pyrid-3′-yl)indole (6). In the same manner as described for
8, a mixture of 2-(pyrid-3′-yl)nitrobenzene (10, 0.32 g, 1.6 mmol),
vinylmagnesium bromide (1 M, 5.3 mL, 5.3 mmol), and dry THF
(17 mL) provided a crude material. Chromatography on alumina,
eluting with CH2Cl2, followed by EtOAc provided 6 as a yellow
solid (0.18 g, 58%), which was recrystallized from CH2Cl2/
(12) (a) Herbich, J.; Rettig, W.; Thummel, R. P.; Waluk, J. Chem. Phys.
Lett. 1992, 195, 556-562. (b) Herbich, J.; Waluk, J.; Thummel, R. P.; Hung,
C.-Y. J. Photochem. Photobiol. A: Chem. 1994, 80, 157-160.
(13) Cioffi, C. L.; Spencer, W. T.; Richards, J. J.; Herr, R. J. J. Org.
Chem. 2004, 69, 2210-2212 (S24).
J. Org. Chem, Vol. 71, No. 20, 2006 7615

Mudadu et al.
TABLE 3. Data Collection and Processing Parameters for 7-Pyridylindoles
compound
7-(pyrid-2′-yl)indole
7-(pyrid-3′-yl)indole
7-(pyrid-4′-yl)indole
molecular formula
formula weight
space group
C13H10N2
194.23
C13H10N2
194.23
C13H10N2
194.23
P21/c (orthorhombic)
A ) 9.7196(7) Å
B ) 17.4764(13) Å
C ) 11.7484(9) Å
R ) 90.00°
â ) 90.00°
γ ) 90.00°
Z ) 8
P1h (triclinic)
A ) 7.3185(11) Å
B ) 10.6790(15) Å
C ) 14.4363(21) Å
R ) 72.415(2)°
â ) 87.546(2)°
γ ) 70.876(2)°
Z ) 4
P21/c (monoclinic)
A ) 15.3107(14) Å
B ) 7.6895(7) Å
C ) 18.4142(18) Å
R ) 90.00°
â ) 112.269(2)
γ ) 90.00°
Z ) 8
cell constants
formula units per cell
volume
density
absorption coefficient
temperature
1995.6(3) Å3
F ) 1.293 mg/m3
µ ) 0.078 mm-1
223(2) K
1014.2(3) Å3
F ) 1.272 mg/m3
µ ) 0.077 mm-1
223(2) K
2006.2(3) Å3
F ) 1.286 mg/m3
µ ) 0.078 mm-1
223(2) K
radiation (Mo KR)
scan speed range
total data collected
independent data
total variables
R1
λ ) 0.71073 Å
1.17-22.51° min-1
8483
2473
278
λ ) 0.71073 Å
1.48-23.56° min-1
4675
2976
278
λ ) 0.71073 Å
1.44-23.49° min-1
9312
3229
278
0.0259
0.0494
0.0658
wR or wR2
0.0660
0.1299
0.1765
1H, J ) 7.8, 6.9 Hz), 8.22 (t, 1H, J ) 5.7 Hz), 8.15 (d, 1H, J )
7.8 Hz), 7.22 (dd, 1H, J ) 7.8, 5.1 Hz), 7.85 (dd, 1H, J ) 7.2, 2.1
Hz), 7.52 (t, 1H, J ) 2.4 Hz), 7.21-7.29 (overlapping m, 2H),
6.64 (dd, 1H, J ) 3.6, 2.1 Hz), 4.01 (s, 3H); 1H NMR (CD3CN) δ
9.97 (br s, 1H), 8.87 (d, 1H, J ) 6.0 Hz), 8.54 (td, 1H, J ) 7.8,
0.9 Hz), 8.07 (t, 1H, J ) 5.7 Hz), 8.04 (d, 1H, J ) 7.5 Hz), 7.90
(d, 1H, J ) 6.9 Hz), 7.37 (t, 1H, J ) 3.0 Hz), 7.28 (t, 1H, J ) 6.9
Hz), 7.23 (dd, 2H, J ) 7.5, 1.5 Hz), 6.67 (dd, 1H, J ) 3.0, 1.5
Hz), 4.03 (s, 3H); 13C NMR (CDCl3) δ 148.0, 146.8, 133.8, 132.0,
130.2, 128.1, 127.5, 125.0, 123.8, 120.5, 118.1, 115.9, 103.6, 47.5.
X-ray Structure Determinations. All measurements were made
with a Siemens SMART platform diffractometer equipped with a
1K CCD area detector. A hemisphere of data (1271 frames at 5
cm detector distance) was collected using a narrow-frame method
with scan widths of 0.30° in omega and an exposure time of 30
s/frame. The first 50 frames were re-measured at the end of data
collection to monitor instrument and crystal stability, and the
maximum correction on I was <1%. The data were integrated using
the Siemens SAINT program, with the intensities corrected for
Lorentz factor, polarization, air absorption, and absorption due to
variation in the path length through the detector faceplate. A psi
scan absorption correction was applied based on the entire data
set. Redundant reflections were averaged.
1-Methyl-3-(indol-7′-yl)pyridinium iodide (12). In the same
manner described above for 11, a solution of iodomethane (1.13 g,
8.0 mmol) in CH3CN (2 mL) and a solution of 7-(pyrid-3′-yl)-
indole (6, 0.15 g, 0.8 mmol) in CH3CN (2 mL) provided a crude
material after refluxing for 3 h. Chromatography on alumina, eluting
with CH3CN, provided a yellow solid, which was washed with
7-(Pyrid-2′-yl)indole (5). Final cell constants were refined using
3739 reflections having I > 10σ(I), and these, along with other
information pertinent to data collection and refinement, are listed
in Table 3. The Laue symmetry was determined to be mmm, and
from the systematic absences noted the space group was shown to
be either Pca2(1) or Pbcm. The asymmetric unit consists of two
independent molecules. The hydrogens attached to N were allowed
to refine freely.
1
hexane to furnish 12 (0.19 g, 72%): mp 209-211 °C; H NMR
(DMSO-d6) δ 11.46 (br s, 1H), 9.35 (s, 1H), 8.99 (d, 1H, J ) 6.0
Hz), 8.79 (d, 1H, J ) 8.4 Hz), 8.24 (t, 1H, J ) 7.2 Hz), 7.74 (d,
1H, J ) 7.8 Hz), 7.51 (t, 1H, J ) 3.0 Hz), 7.31 (d, 1H, J ) 7.2
Hz), 7.21 (t, 1H, J ) 8.1 Hz), 7.51 (s, 1H), 4.42 (s, 3H); 13C NMR
(DMSO-d6) δ 145.1, 144.2, 143.4, 138.0, 132.8, 129.0, 127.7, 126.7,
122.2, 122.1, 119.6, 118.0, 102.1, 48.03.
7-(Pyrid-3′-yl)indole (6). Final cell constants were refined using
2195 reflections having I > 10σ(I), and these, along with other
information pertinent to data collection and refinement, are listed
in Table 3. The Laue symmetry was determined to be -1, and the
space group was shown to be either P1 or P1h. The asymmetric
unit consists of two independent molecules having small but
significant differences in geometry. Hydrogens attached to nitrogen
were refined independently.
1-Methyl-4-(indol-7′-yl)pyridinium iodide (13). In the same
manner described above for 11, a solution of iodomethane (0.85 g,
6.0 mmol) in CH3CN (2 mL) and a solution of 7-(pyrid-4′-yl)-
indole (7, 0.12 g, 0.6 mmol) in CH3CN (6 mL) provided a yellow
pure 13 after refluxing for 3 h (0.18 g, 91%): mp 213-215 °C; 1H
NMR (DMSO-d6) δ 11.54 (br s, 1H), 9.02 (d, 2H, J ) 6.9 Hz),
8.41 (d, 2H, J ) 6.6 Hz), 7.83 (t, 1H, J ) 8.1 Hz), 7.47-7.50
(overlapping m, 2H), 7.24 (t, 1H, J ) 8.1 Hz), 6.65 (m, 1H), 4.37
(s, 3H); 13C NMR (CDCl3) δ 153.8, 145.2, 132.5, 129.6, 127.2,
126.1, 124.2, 123.1, 119.8, 119.1, 102.4, 47.1.
7-(Pyrid-4′-yl)indole (7). Final cell constants were refined using
2831 reflections having I > 10σ(I), and these, along with other
information pertinent to data collection and refinement, are listed
in Table 3. The Laue symmetry was determined to be 2/m, and
from the systematic absences noted the space group was shown
unambiguously to be P2(1)/c. There are two independent molecules
per asymmetric unit, both forming hydrogen-bonded pairs with their
symmetry relative across an inversion center. One of the molecules
was found to be disordered approximately 5:1 with its mirror image
(ignoring the torsional twist of the pyridyl ring), and this was treated
by refinement of two ideal rigid bodies for the minor component.
Due to the close proximity of many of the atoms in the two
orientations, all atoms were refined isotropically.
1-Methyl-4-(indolen-4′-ylene)-1,2-dihydropyridine (14). A sus-
pension of 13 (80 mg, 2.4 mmol) in CH2Cl2 (10 mL) and 25%
NaOH (10 mL) was stirred at room temperature for 20 min. The
two phases were separated, and the aqueous phase was extracted
with CH2Cl2 (4 × 20 mL). The combined phase was washed with
10% NaOH (5 mL), dried (Na2CO3) under vigorous stirring for 30
min, and concentrated to provide 14c as a deep red solid (50 mg,
1
99%): mp 84-86 °C; H NMR (DMSO-d6) δ 9.43 (d, 2H, J )
7.5 Hz), 8.64 (d, 2H, J ) 6.6 Hz), 7.63 (d, 1H, J ) 7.5 Hz), 7.58
(d, 1H, J ) 6.9 Hz), 7.46 (d, 1H, J ) 1.8 Hz), 6.78 (t, 1H, J ) 8.1
Hz), 6.33 (d, 1H, J ) 2.4 Hz), 4.19 (s, 3H).
7616 J. Org. Chem., Vol. 71, No. 20, 2006

7-Pyridylindoles: Synthesis, Structure, and Properties
Supporting Information Available: X-ray crystallographic
Acknowledgment. We thank the Robert A. Welch Founda-
tion (E-621) and the National Science Foundation (CHE-
0352617) for financial support. We would also like to thank
Dr. James Korp for assistance with the X-ray determinations
which made use of MRSEC/TCSUH shared facilities supported
by the NSF (DMR-9632667) and the Texas Center for Super-
conductivity at the University of Houston.
1
data (CIF files) for 5-7, general experimental methods, H and
13C NMR spectra for 11-13, and 1H NMR spectrum for 14.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JO061011Z
J. Org. Chem, Vol. 71, No. 20, 2006 7617