Unexpected ring transformation to pyrrolo[3.2-b]pyridine Derivatives. Fused azolium salts. 22

Article abstract of DOI:10.1021/jo034231a

2-Arylsulfanyl and 2-benzylsulfanylpyridinium N-arylimides (2) easily prepared from 3-aryltetrazolopyridinium salts (1) with aryl and benzylthiolates, respectively, reacted with various dipolarophiles yielding cycloadducts that underwent transformation to give tetrahydropyrrolo[3,2-b]pyridines (5, 6, and 8) in good yields. A similar rearrangement (formation of 15) was also observed in the case of parent derivatives being unsubstituted in position 2 (12). The abscence of any significant solvent effect, comparison of the sulfur and non-sulfur analogues, as well as the stereoselective nature of the observed ring transformation seem to support a sigmatropic mechanism. Structure elucidation of the products has been carried out by single-crystal X-ray diffraction and ¹H NMR experiments.

Full text of DOI:10.1021/jo034231a

Un exp ected Rin g Tr a n sfor m a tion to P yr r olo[3.2-b]p yr id in e
Der iva tives. F u sed Azoliu m Sa lts. 22‡
Zsuzsanna Riedl, Pe´ter Ko¨ve´r, Tibor Soo´s, Gyo¨rgy Hajo´s,* Orsolya Egyed, La´szlo´ Fa´bia´n, and
Andra´s Messmer
Chemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, P.O. Box 17,
H-1525 Budapest, Hungary
ghajos@chemres.hu
Received February 21, 2003
2-Arylsulfanyl and 2-benzylsulfanylpyridinium N-arylimides (2) easily prepared from 3-aryltetra-
zolopyridinium salts (1) with aryl and benzylthiolates, respectively, reacted with various dipolaro-
philes yielding cycloadducts that underwent transformation to give tetrahydropyrrolo[3,2-b]pyridines
(5, 6, and 8) in good yields. A similar rearrangement (formation of 15) was also observed in the
case of parent derivatives being unsubstituted in position 2 (12). The abscence of any significant
solvent effect, comparison of the sulfur and non-sulfur analogues, as well as the stereoselective
nature of the observed ring transformation seem to support a sigmatropic mechanism. Structure
1
elucidation of the products has been carried out by single-crystal X-ray diffraction and H NMR
experiments.
In tr od u ction
In continuation of our studies on ring-opening reactions
of fused azolium salts1 we have recently found that
tetrazolopyridinium salts (1) readily react with aryl and
benzylthiolates to yield 2-sulfanylpyridinium N-arylim-
ides (2). These stable red zwitterions can participate in
1,3-dipolar cycloaddition reactions.2 Thus, 2 reacted with
N-phenylmaleimide to give cycloadduct 3 (Scheme 1). As
the easily available zwitterion 2 is regarded as a valuable
starting material for further transformations, continua-
tion of these studies seemed of preparative importance.
We describe now that extension of the cycloaddition
reaction of 2 for additional dipolarophiles may result in
a dramatic change of the course of the reaction, and an
unexpected ring transformation following the earlier
experienced cycloaddition can occur.
F IGURE 1. ORTEP diagram of 5b.
the isolated product 5. The structure of this product was
1
supported by H NMR data; furthermore, unambiguous
proof was provided by the X-ray analysis of 5b (Figure
13) revealing the cis fusion of the pyrrole and pyridine
rings.
Resu lts a n d Discu ssion
Upon this observation the question arose if the ob-
served ring transformation can occur only in the par-
ticular case of fumaronitrile as a dipolarophile. To clarify
this, cycloadduct 3 obtained from 2 with N-phenylmale-
imide was refluxed in chloroform for 1 h. We found that
under these conditions (and also upon storage of a
solution of 2 in chloroform at room temperature for 3
days) the expected rearrangement did occur and the fused
tetrahydropyrrolopyridine 6 was obtained in excellent
yields (Scheme 3). Also in this case, the structure of one
In contrast to the previously reported results2 we found
that reaction of 2 with fumaronitrile did not afford the
expected [3+2] cycloadduct 4; instead, tetrahydropyrrolo-
[3,2-b]pyridine derivative 5 was obtained in moderate
yields (Scheme 2). This finding can be rationalized by the
primary formation of the expected cycloadduct 4 followed
by a ring transformation involving N-N cleavagesas
shown on the structuresand formation of a new bond
between aryl-N and C-6 of the pyridine ring providing
‡ Part 21: Ba´tori, S.; Bokotey, S.; Messmer, A. Tetrahedron, 2003,
59, 4297. For part 20, see ref 2.
(1) (a) Be´res, M.; Hajo´s, Gy.; Riedl, Zs.; Soo´s, T.; Tima´ri, G.;
Messmer, A. J . Org. Chem. 1999, 64, 5499. (b) Soo´s, T.; Hajo´s, Gy.;
Messmer, A. J . Org. Chem. 1997, 62, 1136. (c) Messmer, A.; Gelle´ri,
A.; Hajo´s, Gy. Tetrahedron 1986, 42, 4827.
(3) Compound 5b: C21H14Cl2N4S; Mr 425.32; light yellow prism; size
0.30 × 0.20 × 0.10 mm3; monoclinic; space group P21/c; a ) 10.904(1)
Å, b ) 18.298(1) Å, c ) 10.284(1) Å, â ) 99.305(8)°, V ) 2024.9(3) Å3,
Z ) 4, rcalcd ) 1.395 g/cm3, m ) 3.959 mm-1, T ) 293(2) K. The final
model (254 parameters) was refined to wR2 ) 0.1596 for all data (4217
reflections), R1 ) 0.0510 for reflections with I > 2σ(I) (3158), and GOF
) 1.066.
(2) Messmer, A.; Ko¨ve´r, P.; Riedl, Zs.; Go¨mo¨ry, AÄ .; Hajo´s, Gy.
Tetrahedron 2002, 58, 3613.
10.1021/jo034231a CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/12/2003
5652
J . Org. Chem. 2003, 68, 5652-5659

Transformation to Pyrrolo[3.2-b]pyridine Derivatives
SCHEME 1
SCHEME 2
SCHEME 3
F IGURE 2. ORTEP diagram of 6a .
F IGURE 3. A possible mechanism of the N-N bond fission
in a by neighboring group participation of the sulfanyl group
to form intermediate b.
can occur in different ways: Path A, homolytically
(radical pathway); Path B, heterolytically, forming an
arylnitrenium cation that adds as an electrophile onto
the negatively charged dihydropyridine ring; Path C,
inverse heterolytic cleavage with formation of an arylim-
ide moiety that undergoes ring closure by nucleophilic
attack of the positively charged dihydropyridine ring; and
Path D, [1,5]-sigmatropic shift of the N-aryl moiety from
the dihydropyridine N-atom to C-6 of this ring.
of the products (6a ) was determined by X-ray diffraction
(Figure 24) revealing the cis-fusion of the product.
Upon workup of the reaction mixture obtained with
zwitterion 2b and dimethyl acetylenedicarboxylate
(DMAD) the expected cycloadduct 7 was not obtained;
instead and in apparent analogy to the formation of 6
(vide supra), the rearranged product 8 was isolated
(Scheme 4).
Oxidation of compounds 5, 6, and 8 with DDQ readily
afforded the corresponding fully unsaturated heterocycles
9, 10, and 11, respectively (Scheme 5).
As discussed above, the obvious key step of the
observed rearrangement reaction (i.e. formation of 5, 6,
and 8) is the cleavage of the N,N bond, which conceivably
Since the reaction rate did not change in the presence
of a radical trap (N,N-dimethyl-4-nitrosoaniline),5a Path
(5) (a) Two solutions of 3d (50 mg, 0.1 mmol) in acetone (2 mL)s
with and without addition of N,N-dimethyl-4-nitrosoaniline (5 mL)s
were refluxed for 20 min. The reaction mixture was subjected to column
chromatography and 6d was separated; as a result, 21 and 23 mg of
product, respectively, were obtained. (b) Transformation of 3d to 6d
was monitored by 1H NMR spectroscopy. For this purpose, a solution
of 3d (20 mg) in 0.6 mL of DMSO-d6 and acetone-d6 was placed into
an NMR tube. The progress of the reaction was observed by diappear-
ance of the signal of H-9 in 3d (at 5.65 ppm in DMSO-d6 and 5.75
ppm in acetone-d6) and appearance of the signal of H-5 in 6d (at 5.32
ppm in DMSO-d6 and 6.45 ppm in acetone-d6). The following conver-
sions have been measured at room temperature: in 8 hsDMSO 16%,
acetone 16%; in 24 hsDMSO 32%, acetone 33%; in 50 hsDMSO 53%,
acetone 56%.
(4) Compound 6a : C28H22ClN3O2S; Mr 500.00; colorless prism; size
0.45 × 0.20 × 0.09 mm3; orthorhombic; space group P212121; a )
7.517(1) Å, b ) 15.096(2) Å, c ) 20.836(2) Å, V ) 2364.4(5) Å3, Z ) 4,
rcalcd ) 1.405 g/cm3, m ) 2.515 mm-1, T ) 293(2) K. The final model
(316 parameters) was refined to wR2 ) 0.1127 for all data (4875
reflections), R1 ) 0.0429 for reflections with I > 2σ(I) (4596), and GOF
) 1.051.
J . Org. Chem, Vol. 68, No. 14, 2003 5653

Riedl et al.
SCHEME 4
SCHEME 5
A seems rather improbable. As to Paths B and C
involving heterolytic N,N-bond cleavage, the latter path
appears more realistic because of the possibility of
neighboring group participation as shown in Figure 3:
The sulfur atom of the 2-sulfanyl substituent can attack
the adjacent C-3 of the pyridine ring forming a sulfonium
cation intermediate, which may induce the N,N-bond
fission. Both Paths B and C involve formation of a
zwitterion intermediate and, consequently, acceleration
of the reaction in more polar solvents is expected. To
check this anticipation the reaction was repeated in
acetone and in dimethyl sulfoxide solution. No significant
difference of the reaction rates in these solvents was
found;5b thus, Paths B and C are considered improbable
as well.
F IGURE 4. [1,5]-Sigmatropic rearrangement of the cycload-
duct 3 to 6 with participation of three electron pairs as shown
by the arrows.
On the other hand, the pericyclic route D (Figure 4) is
in line also with the observed stereospecifity of the
rearrangement reaction resulting in cis-fused pyridine
and pyrrole rings in 5 and 6 as proved by the X-ray
analysis. According to the Woodward-Hoffmann rules
this [1,5]-sigmatropic rearrangement should take place
in a suprafacial manner resulting in the cis orientation
of 3a-H and 7a-H (HA and HB in Tables 1 and 2) as
observed.
Detailed investigations have been carried out to de-
termine the configuration of the cycloadducts and rear-
ranged products based on the scalar H-H couplings and
NOE measurements on the protons attached to saturated
carbon atoms of these compounds. The vicinal couplings
in the five-membered ring showed unexpected values, but
taking into account the rigid structure of the fused six-
and five-membered rings, no deviation from the Karplus
rule has been found. In certain cases the dihedral angle
between the protons in the trans position was distorted
to approximately 70°, resulting in smaller scalar cou-
plings compared to those of cis protons, connected by a
dihedral angle close to 30°. It is worth mentioning that
measurements of NOE effects proved to be ambiguous
in some cases, as small NOEs of the adjacent trans
protons could also be observed. To compare these 1H
NMR parameters, the J values and appearance of the
F IGURE 5. 1,3-Dipolar cycloaddition of [1,2,3]triazoliumimide
I and rearrangement of the resulting cycloadduct II with N,N
bond breakage forming III.6,7
NOE effects on the protons in question are compiled in
Tables 1 and 2.
A literature search revealed a report by Butler et al.6,7
on the [3+2] cycloaddition reaction of 2,4,5-triphenyl-2H-
[1,2,3]triazol-1-ium-1-phenylimide I with dipolarophiles
X ) Y and the rearrangement reaction of the resulting
cycloadducts. Thus, 3a,4,5,6-tetrahydro-1H-pyrazolo[1,5-
c][1,2,3]triazole II is converted into 3,3a,4,5,6,6a-hexahy-
(6) Butler, R. N.; Evans, A. M.; Gillan, A. M.; J ames, J . P.; McNeela,
E. M.; Cunningham, D.; McArdle, D. J . Chem. Soc., Perkins Trans. 1
1990, 2537.
(7) Butler, R. N.; O’Shea, D. F. Heterocycles 1994, 37, 571.
5654 J . Org. Chem., Vol. 68, No. 14, 2003

Transformation to Pyrrolo[3.2-b]pyridine Derivatives
TABLE 1. Com p a r ison of Cou p lin g Con sta n ts a n d NOE
Effects of Cycloa d d u cts (3 a n d 17) a n d Rea r r a n gem en t
P r od u cts (6) Obta in ed w ith N-P h en ylm a leim id e
SCHEME 6
compd
J (Hz)
compd
J (Hz)
5-6-fused ring systems 3, 4, and 7 (vide supra): The
rearrangement reaction of II has been explained by a
thermally allowed sigmatropic shift involving N,N-bond
cleavage in the pyrazolidine ring and bond formation of
the phenyl-substituted N atom at 5-C of the [d]-fused
dihydro[1,2,3]triazole III, in close analogy to the [1,5]-
sigmatropic shift discussed above for the isoelectronic
[a]-fused tetrahydropyrrolopyridine systems (e.g. for 4).
For reaction Path C the neighboring group effect of the
2-sulfanyl substituent of 2 is essential, and the rear-
rangement reaction is expected to be impossible in the
absence of this group, whereas the pericyclic route D is
expected to be indifferent to the absence of the sulfanyl
group. Thus, the feasibility of a rearrangement reaction
of a cycloadduct derived from pyridinium-N-arylimide 128
(lacking C-substituents in the pyridinium ring; prepared
in situ from its hydrogen bromide salt9) was tackled.
Recently, Huisgen et al.10-12 have investigated this
reaction. Remarkably, these authors have found that the
reaction of 12a with fumaronitrile at room temperature
gives risesvia the cycloaddition routesto a bridged ring
system 13a (Scheme 6). This reactionsfound to take
place also with isoquinolinium arylimides13,14swas in-
terpreted as an aza-Cope sigmatropic shift followed by a
ring closure step.15 For structural comparison, we have
confirmed this finding by an X-ray structure elucidation
(Figure S1).16
Q ) SR
3a a
J AB ) 5.0
J BC ) 7.5
J DC ) 8.0
J AB ) 5.0
J BC ) 7.0
J DC ) 8.0
J AB ) 4.8
6a b
J AB ) 7.8
J BC ) 6.0
J DC ) 8.0
J AB ) 7.5
J BC ) 6.0
J DC ) 8.0
J AB ) not
measured
J BC ) 6.0
J DC ) 8.5
3d
3e
6d
6e
J BC ) 7.5
J DC) 8.0
Q ) H
17
J AB ) 5.0
J BC ) 8.2
J DC ) 7.5
a
The irradiation of HC produced similar NOE effects on HB and
HD, proving that these three protons are in the cis position to each
b
other. The irradiation of HB produced a large NOE effect on HA
while the effect on HC was negligible, proving that HA and HB are
in the cis relationship while HB and HC in the trans relationship.
TABLE 2. Com p a r ison of Cou p lin g Con sta n ts a n d NOE
Effects of Cycloa d d u cts (14) a n d Rea r r a n gem en t
P r od u cts (5 a n d 15) Obta in ed w ith F u m a r on itr ile
We repeated the same transformation with our deriva-
tive 12b and also found that the reaction with fumaroni-
trile at room temperature yields 13b. Also in accordance
with the cited literature we succeeded in isolating the
compd
J (Hz)
compd
J (Hz)
(8) Tamura, Y.; Tsujimoto, N.; Uchimura, M. Yakugaku Zasshi 1971,
91, 72.
(9) This salt was prepared according to the procedure elaborated
for an analoguous compound: Carceller, R.; Garcia-Navio, J . L.;
Izquierdo, M. L.; Alvarez-Builla, J .; Fajardo, M.; Gomez-Sal, P.; Gago,
F. Tetrahedron 1994, 50, 4995.
(10) Huisgen, R.; Temme, R. Heteroatom Chem. 1999, 10, 79.
(11) Bast, K.; Durst, T.; Huisgen, R.; Lindner, K.; Temme, R.
Tetrahedron 1998, 54, 3745.
(12) Bast, K.; Durst, T.; Huber, H.; Huisgen, R.; Lindner, K.;
Stephenson, D. S.; Temme, R. Tetrahedron 1998, 54, 8451.
(13) Huber, H.; Huisgen, R.; Polborn, K.; Stephenson, D. S.; Temme,
R. Tetrahedron 1998, 54, 3735.
Q ) SR
5a
J AB ) 10
J BC ) 7.0
J DC ) 2.0
J AB ) 10
J BC ) 7.0
J DC ) 2.0
J AB ) 9.0
J BC ) 7.0
J DC ) 2.5
5ba
5c
Q ) H
(14) Huisgen, R.; Grashey, R.; Krishke, R. Tetrahedron Lett. 1962,
387.
14
J AB ) 4.7
J BC ) 9.1
J DC ) 7.0
15
J AB )10.5
J BC ) 7.0
J DC ) 2.5
(15) Abramovitch et al. also observed a ring closure of this type with
related sulfoxides. These authors discussed the possible mechanism
of this transformation and could not decide between the concerted route
and heterolytic cleavage: Abramovitch, R. A.; Siani, A. C.; Huttner,
G.; Zsolnai, L.; Miller, J . J . Org. Chem. 1986, 51, 4741.
(16) Compound 13a : C15H12N4; Mr 248.29; colorless prism; size 0.50
× 0.35 × 0.15 mm3; monoclinic; space group P21/c; a ) 8.069(1) Å, b
) 9.488(1) Å, c ) 16.125(1) Å, â ) 103.17(1)°, V ) 1202.0(2) Å3, Z ) 4,
rcalcd ) 1.372 g/cm3, m ) 0.086 mm-1, T ) 293(2) K. The final model
(172 parameters) was refined to wR2 ) 0.1542 for all data (5264
reflections), R1 ) 0.0511 for reflections with I > 2σ(I) (2791), and GOF
) 0.946.
a
The irradiation of HB produced similar, large NOEs with HA
and HC, proving that all these protons are in the cis relationship
dropyrrolo[2,3-d][1,2,3]triazol-2-ium-1-ide III (Scheme 6).
The rearrangement reaction of the 5-5-fused ring system
II is reminiscent of the analogous rearrangement of the
J . Org. Chem, Vol. 68, No. 14, 2003 5655

Riedl et al.
SCHEME 7
SCHEME 8
ring transformation involving N-N bond fission provides
a new method to prepare the latter heterocyclic system.
To the best of our knowledge no paper on the N-aryl
derivative of the pyrrolo[3,2-b]pyridine ring system has
been published so far. Further studies on the sulfur-
containing zwitterions (e.g. 2) are in progress.
Exp er im en ta l Section
X-r a y Cr ysta llogr a p h y. The crystals of 5b, 6a , 13a , and
15b were mounted on glass fibers. Each data set was collected
on an Enraf-Nonius CAD4 diffractometer with graphite-
monochromated Cu KR (for 5a , 6a , and 15b) or Mo KR (for
13a ) radiation at room temperature. Lattice parameters were
determined by a least-squares fit for 25 reflections. The
intensities of three standard reflections were monitored every
hour, and correction was made for the indicated decay. All
reflections were corrected for Lorentz and polarization effects.18
Absorption correction was applied by using ψ-scan data.19 The
space groups were determined from the unit cell parameters
and systematic absences. The structures were solved by direct
methods (SHELXS-9720). All non-hydrogen atoms were mod-
eled anisotropically in the structure refinement (SHELXL-
9721). Hydrogen atoms were located in difference Fourier maps.
Since they were found close to ideal positions, they were
refined isotropically in the riding mode, using idealized
geometry.
crystalline primary cycloadduct 14b at 0 °C. When,
however, the same reaction was repeated under reflux
conditions, formation of a mixture of 13b and the
expected ring transformation product 15 (in a ratio of
approximately 1:1) was experienced (Scheme 7). When,
however, the crystalline cycloadduct 14 was added to
boiling toluene, the resulting product mixture contained
a higher portion of 15 (13b:15 ) 1:2). Workup of this
reaction mixture allowed the isolation of crystalline 15;
its structure has also been verified by X-ray crystal-
lography (Figure S2).17 This finding clearly shows that
14 besides rearranging to tetrahydro-1H-2,9-ethanopy-
rido[2,3-b]indole (13b) also undergoes the rearrangement
reaction to tetrahydropyrrolo[3,2-b]pyridine (15) despite
the pyridine ring being devoid of the sulfanyl substituent;
this disproves the assumed neighboring group participa-
tion involved in Path C. The rearrangement product 15
was also oxidized by DDQ to the heteroaromatic product
16 (Scheme 7).
Gen er a l Meth od s. IR spectra were obtained on a FT
spectrophotometer. NMR spectra were recorded on a spec-
trometer operating at 400 and 100 MHz for 1H and 13C,
respectively. Chemical shifts are reported in ppm downfield
from tetramethylsilane. Proton assignments are based on
To answer the question if 13b is the precursor of 15
the former product was heated in toluene for 24 h but
13b was recovered unchanged.
1
decoupling and homonuclear correlation experiments. NOE H
NMR enhancements were determined from 1D difference NOE
1H NMR spectra obtained by subtraction of two spectra
acquired at identical conditions except for irradiation fre-
quency. The HSQC method was used for the determination of
the one-bond proton carbon connectivities, while quaternary
carbons were assigned by using the HMBC method (two- and
three-bond proton carbon connectivities). HRMS was measered
with use of direct inlet spectrometers. All commercial grade
reagents were used without further purification.
Synthesis of 2-arylsulfanylpyridinium-N-arylimides 2b,c as
well as their cycloaddition with N-phenylmaleininmide has
been published earlier.1 Derivatives 2a ,d ,e and their cycload-
dition products (3a ,d ,e) have been prepared by these published
procedures2 starting from 6 mmol of the appropriate tetrazol-
opyridinium salt 1 or 1.5 mmol of the zwitterion 2, respectively.
2-Ben zylsu lfa n ylp yr id in iu m -N-(4-ch lor op h en yl)im id e
(2a ): red crystals, (1.66 g, 85%); mp 168-170 °C; 1H NMR
(CDCl3) δ 4.13 (s, 2H, H-CH2), 6.90 (m, 2H, H-2′, H-6′), 6.92
(ddd, J ) 8, 6.5, 1 Hz, 1H, H-5), 7.02 (ddd, J ) 8, 8, 1 Hz, 1H,
Azomethine imine 12b also reacted with N-phenylma-
leimide to give cycloadduct 17. However, this cycloadduct
did not rearrange via the aza-Cope reaction to the bridged
isomer, presumably because of the high rigidity of the
ring system. Applying more forced conditions to induce
the rearrangement led only to decomposition. However,
the treatment of the crude mixturesobtained from 12b
and N-phenylmaleimideswith DDQ and separation of
the reaction mixture by chromatography afforded the
heteroaromatic product 19, i.e., the oxidation product of
the anticipated fused rearrangement intermediate 18
(Scheme 8).
Con clu sion
The rearrangement of pyrazolo[2,3-a]pyridines to fused
pyrrolo[3,2-b]pyridines by a new type of stereospecific
(18) Harms, K. XCAD4, Data Reduction Program for CAD4 Diffrac-
tometers; Philipps-Universita¨t: Marburg, Germany, 1996.
(17) Compound 15b: C15H11ClN4; Mr 282.73; colorless prism; size
0.35 × 0.17 × 0.08 mm3, monoclinic; space group P21/c; a ) 11.913(1)
Å, b ) 13.827(1) Å, c ) 8.300(1) Å, â ) 90.51(1)°, V ) 1367.1(2) Å3, Z
) 4, Fcalc ) 1.374 g/cm3, µ ) 2.425 mm-1, T ) 293(2) K. The final model
(181 parameters) was refined to wR2 ) 0.1536 for all data (2846
reflections), R1 ) 0.0502 for reflections with I > 2σ(I) (2236), and GOF
) 1.123.
(19) Reibenspies, J . DATCOR, Program for Empirical Absorption
Correction; Texas A & M University: College Station, TX, 1989.
(20) Sheldrick, G. M. SHELXS-97, Program for Crystal Structure
Solution; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(21) Sheldrick, G. M. SHELXL-97, Program for Crystal Structure
Refinement; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
5656 J . Org. Chem., Vol. 68, No. 14, 2003

Transformation to Pyrrolo[3.2-b]pyridine Derivatives
H-4), 7.13 (m, 2H, H-3′, H-5′), 7.18 (dd, J ) 8, 1 Hz, 1H, H-3),
7.30 (m, 1H, H-4′′), 7.34 (m, 2H, H-3′′, H-5′′), 7.44 (m, 2H, H-2′′,
H-6′′), 8.57 (dd, J ) 6.5, 1 Hz, 1H, H-6); 13C NMR (CDCl3) δ
37.0 (C-CH2), 118.2 (C-2′, 6′), 120.0 (C-5), 122.7 (C-3), 123.5
(C-4′), 124.8 (C-4), 128.2 (C-1′′), 129.3 (C-3′, 5′), 129.5 (C-2′′,
6′′), 129.9 (C-3′′, 5′′), 133.9 (C-4′′), 135.0 (C-6), 150.3 (C-2), 151.2
(C-1′); HRMS calcd for C18H15ClN2S 327.0723, found 327.0714.
Anal. Calcd for C18H15ClN2S: C, 66.15; H, 4.63; N, 8.57; S,
9.81. Found: C, 66.03; H, 4.40; N, 8.35; S, 9.76.
2-[(4-Met h ylp h en yl)su lfa n yl]p yr id in iu m -N-(4-flu or o-
p h en yl)im id e (2d ): red crystals (1.52 g, 82%); mp 131-133
°C.
2-[(4-Meth ylp h en yl)su lfa n yl]p yr id in iu m -N-(4-isop r o-
p ylp h en yl)im id e (2e): red crystals (1.48 g, 74%); mp 93-
95 °C.
d in e-2,3-d ica r bon itr ile (5c): prepared from 2c as colorless
crystals (282 mg, 23%); mp 192-193 °C.
Gen er a l P r oced u r e for Isom er iza tion of th e Cycloa d -
d u ct 3 to 1H-P yr r olo[3′,4′:4,5]-1H-p yr r olo[3,2-b]p yr id in e-
1,3(2H)-d ion e Der iva tives (6). A solution of cycloadduct 3
(1.5 mmol) in chloroform (5 mL) was refluxed for 1 h. The
solvent was removed, the residue was treated with ether, and
the resulting solid was filtered off.
(3aR,4aS,8aS,8bS)-r el-7-Ben zylsu lfan yl-4-(4-ch lor oph e-
n yl)-2-p h en yl-3b ,4a ,8a ,8b -t et r a h yd r o-1H -p yr r olo[3′,4′:
4,5]-1H-p yr r olo[3,2-b]p yr id in e-1,3(2H)-d ion e (6a ): pre-
pared from 3a as colorless crystals (674 mg, 90%); mp 218-
219 °C; 1H NMR (DMSO-d6) δ 3.70 (dd, 1H, J ) 8, 6 Hz, H-8b),
4.29 (d, 1H, J ) 14 Hz, H-CH2), 4.47 (d, 1H, J ) 14 Hz,
H-CH2), 4.88 (dd, 1H, J ) 7.8, 6 Hz, H-8a), 4.98 (d, 1H, J )
8 Hz, H-3a), 5.01 (dd, 1H, J ) 7.8, 2 Hz, H-4a), 6.10 (d, 1H, J
) 9.6 Hz, H-6), 6.43 (dd, 1H, J ) 9.6, 2 Hz, H-5), 7.16 (m, 2H,
H-3′, H-5′), 7.32 (m, 2H, H-2′, H-6′), 7.30-7.44 (m, 5H, H-2′′,
H-3′′, H-4′′, H-5′′, H-6′′), 7.51 (m, 1H, H-4′′′), 7.52 (m, 2H, H-2′′′,
H-6′′′), 7.55 (m, 2H, H-3′′′, H-5′′′); 13C NMR (DMSO-d6) δ 31.9
C-CH2), 52.2 (C-8b), 54.9 (C-3a), 59.8 (C-4a), 60.4 (C-8a), 117.6
(C-2′, 6′), 122.5 (C-6), 122.6 (C-4′′′), 127.2 (C-4′′), 127.4 (C-2′′′,
6′′′), 128.5 (C-2′′, 6′′), 128.6 (C-5), 128.7 (C-3′′, 5′′), 129.0 (C-
3′′′, 5′′′), 129.2 (C-3′, 5′), 131.9 (C-4′), 132.1 (C-1′′′), 138.3 (C-
1′′), 143.7 (C-1′), 160.5 (C-7), 173.8 (C-3), 174.4 (C-1); HRMS
calcd for C28H22ClN3O2S 499.1121, found 499.1106. Anal. Calcd
for C28H22ClN3O2S: C, 67.26; H, 4.43; N, 8.40; S, 6.41. Found:
C, 67.04; H, 4.44; N, 8.22; S, 6.21.
(3a R,4a S,8a S,8b S)-r el-4-(4-Ch lor op h en yl)-7-[(4-ch lo-
r op h en yl)su lfa n yl]-2-p h en yl-3b,4a ,8a ,8b-tetr a h yd r o-1H-
p yr r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b ]p yr id in e-1,3(2H )-d i-
on e (6b): prepared from 3b as colorless crystals (717 mg,
92%); mp 129-131 °C.
(3a R,4a S,8a S,8b S)-r el-4-(4-Ch lor op h en yl)-7-[(4-m et h -
ylp h en yl)su lfa n yl]-2-p h en yl-3b,4a ,8a ,8b-tetr a h yd r o-1H-
p yr r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b]p yr id in e-1,3(2H )-d i-
on e (6c): prepared from 3c as colorless crystals (603 mg, 86%);
mp 140-141 °C.
(3a R,4a S,8a S,8b S)-r el-4-(4-F lu or op h en yl)-7-[(4-m et h -
ylp h en yl)su lfa n yl]-2-p h en yl-3b,4a ,8a ,8b-tetr a h yd r o-1H-
p yr r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b]p yr id in e-1,3(2H )-d i-
on e (6d ): prepared from 3d as colorless crystals (623 mg,
86%); mp 179-181 °C.
(3a R,4a S,8a S,8bS)-r el-4-(4-Isop r op ylp h en yl)-7-[(4-m e-
t h ylp h en yl)su lfa n yl]-2-p h en yl-3b ,4a ,8a ,8b -t et r a h yd r o-
1H -p yr r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b]p yr id in e-1,3(2H )-
d ion e (6e): prepared from 3e as colorless crystals (638 mg,
84%); mp 178-180 °C.
(3a S,7a S)-r el-Dim eth yl 1-(4-ch lor op h en yl)-5-[(4-ch lo-
r op h en yl)su lfa n yl]-3a ,7a -d ih yd r o-1H-p yr r olo[3,2-b]p yr i-
d in e 2,3-d ica r boxyla te (8). Dimethyl acetylenedicarboxylate
(0.5 mL, 0.578 g, 4.067 mmol) was added to a solution of 2b (1
g, 2.88 mmol) in CH2Cl2 (10 mL). The reaction mixture was
stirred at room temperature for 2 h. The solvent was removed,
the residue was treated with ether, and the resulting solid was
filtered off to yield the product (380 mg, 27%): mp 159-161
°C; 1H NMR (CDCl3) δ 3.69 (s, 3H, H-Me), 3.78 (s, 3H, H-Me),
4.68 (dd, J ) 12, 5, Hz, 1H, H-7a), 5.25 (d, J ) 12 Hz, 1H,
H-3a), 5.87 (d, J ) 9.9 Hz, 1H, H-6), 6.13 (dd, J ) 9.9, 5 Hz,
1H, H-7), 7.00-7.48 (m, 8H, H-2′, H-6′, H-3′, H-5′, H-2′′, H-6′′,
H-3′′, H-5′′); 13C NMR (CDCl3) δ 51.2 (Me), 53.1 (Me), 56.7 (C-
7a), 61.7 (C-3a), 107.1 (C-3), 123.2 (C-6), 125.2 (C-2′, 6′), 126.3
(C-7), 127.5 (C-1′′), 128.9 (C-3′, 5′), 129.7 (C-3′′, 5′′), 132.1 (C-
4′′), 135.0 (C-4′), 135.7 (C-2′′, 6′′), 137.2 (C-1′), 151.1 (C-2), 157.9
(3a S,9a S,9bR)-r el-6-Ben zylsu lfa n yl-4-(4-ch lor op h en yl)-
2-p h en yl-3a ,4,9a ,9b-tetr a h yd r o-1H-p yr r olo[3′4′:3,4]p yr a -
zolo[1,5-a ]p yr id in e-1,3(2H)-d ion e (3a ): colorless crystals,
1
(622 mg, 83%); mp 223-224 °C; H NMR (CDCl3) δ 3.60 (dd,
J ) 8, 7.5 Hz, 1H, H-9b), 3.72 (d, J ) 12.5 Hz, 1H, H-CH2),
3.76 (d, J ) 12.5 Hz, 1H, H-CH2), 4.36 (dd, J ) 7.5, 5 Hz, 1H,
H-9a), 4.60 (d, J ) 8 Hz, 1H, H-3a), 4.88 (dd, J ) 6 Hz, 1H,
H-7), 5.78 (ddd, J ) 9.5, 5, 1 Hz, 1H, H-9), 6.08 (dd, J ) 9.5,
6 Hz, 1H, H-8), 7.10-7.30 (m, 11H, H-2′, H-3′, H-5′, H-6′, H-2′′,
H-3′′, H-4′′, H-5′′, H-6′′, H-2′′′, H-6′′′), 7.36-7.50 (m, 3H, H-3′′′,
H-4′′′, H-5′′′); 13C NMR (DMSO-d6) δ 34.8, 53.8, 60.7, 64.5, 95.7,
114.7, 115.8 (2C), 123.6, 125.1, 126.3 (2C), 127.0, 127.2, 128.4
(2C), 128.8 (2C), 128.9, 129.0 (2C), 129.4 (2C), 132.4, 135.8,
148.2, 172.3, 172.4; HRMS calcd for C28H22ClN3O2S 499.1121,
found 499.1129. Anal. Calcd for C28H22ClN3O2S: C, 67.26; H,
4.43; N, 8.40; S, 6.41. Found: C, 67.11; H, 4.26; N, 8.29; S,
6.30.
(3a S,9a S,9bR)-r el-4-(4-F lu or op h en yl)- 6-[(4-m eth ylp h e-
n yl)su lfa n yl]-2-p h en yl-3a ,4,9a ,9b-tetr a h yd r o-1H-p yr r olo-
[3′4′:3,4]p yr a zolo[1,5-a ]p yr id in e-1,3(2H)-d ion e (3d ): col-
orless crystals (550 mg, 76%); mp 129-131 °C.
(3a S,9a S,9bR)-r el-4-(4-Isop r op ylp h en yl)-6-[(4-m eth yl-
p h en yl)su lfa n yl]-2-p h en yl-3a ,4,9a ,9b-tetr a h yd r o-1H-p yr -
r olo[3′4′:3,4]p yr a zolo[1,5-a ]p yr id in e-1,3(2H)-d ion e (3e):
colorless crystals (692 mg, 91%); mp 135-137 °C.
Gen er a l P r oced u r e for th e Rea ction of Zw itter ion 2
w ith F u m a r on itr ile to Tetr a h yd r o-P yr r olo[3,2-b]p yr i-
d in e Der iva tives (5). To a solution of the appropriate
pyridinium-N-arylimide (2, 2.97 mmol) in dichloromethane (10
mL) was added fumaronitrile (228 mg, 3.56 mmol). The
reaction mixture was stirred at room temperature for 1 day.
The solvent was removed, the residue was treated with ether,
the solid material was filtered off, and the resulting solid was
recrystallized from acetonitrile.
(2R,3R,3a S,7a S)-r el-5-Ben zylsu lfa n yl-1-(4-ch lor op h e-
n yl)-2,3,3a ,7a -tetr a h yd r o-1H-p yr r olo[3,2-b]p yr id in e-2,3-
d ica r bon itr ile (5a ): prepared from 2a as colorless crystals
(468 mg, 39%); mp 207-209 °C.
(2R,3R,3aS,7aS)-r el-1-(4-Ch lor oph en yl)-5-[(4-ch lor oph e-
n yl)su lfa n yl]-2,3,3a ,7a -tetr a h yd r o-1H-p yr r olo[3,2-b]p yr i-
d in e-2,3-d ica r bon itr ile (5b): prepared from 2b as colorless
crystals (358 mg, 29%); mp 189-190 °C; IR (KBr) νmax 2240,
1
1641, 1594, 1497 cm-1; H NMR (CDCl3 + DMSO-d6) δ 4.52
(dd, J ) 7, 2 Hz, 1H, H-3), 4.62 (ddd, J ) 10, 3, 2 Hz, 1H,
H-7a), 4.88 (dd, J ) 10, 7 Hz, 1H, H-3a), 5.44 (d, J ) 2 Hz,
1H, H-2), 6.00 (dd, J ) 10, 2 Hz, 1H, H-6), 6.40 (dd, J ) 10, 3
Hz, 1H, H-7), 6.96 (m, 2H, H-2′, H-6′), 7.33 (m, 2H, H-3′, H-5′),
7.45 (m, 2H, H-3′′, H-5′′), 7.54 (m, 2H, H-2′′, H-6′′); 13C NMR
(CDCl3 + DMSO-d6) δ 40.1 (C-3), 49.3 (C-7a), 50.4 (C-2), 59.4
(C-3a), 116.4 (CN), 117.0 (CN), 117.4 (C-2′, 6′), 120.7 (C-6),
125.2 (C-4′′), 127.2 (C-4′), 129.7 (C-3′, 5′), 129.8 (C-3′′, 5′′), 131.4
(C-7), 135.3 (C-1′′), 136.9 (C-2′′, 6′′), 142.4 (C-1′), 163.1 (C-5);
HRMS calcd for C21H14Cl2N4S 424.0316, found 424.0322. Anal.
Calcd for C21H14Cl2N4S: C, 59.30; H, 3.32; N, 13.17; S, 7.54.
Found: C, 59.09; H, 3.29; N, 13.11; S, 7.31.
(C-5), 162.9 (CdO), 164.8 (CdO); HRMS calcd for C23H18
Cl2N2O4S 488.0341, found 488.0364. Anal. Calcd for C23H18
-
-
Cl2N2O4S: C, 56.45; H, 3.71; N, 5.72; S, 6.55. Found: C, 56.22;
H, 3.69; N, 5.62; S, 6.33.
Gen er a l P r oced u r e for Oxid a tion of th e Rin g Tr a n s-
for m a tion P r od u cts 5 a n d 6 to P yr r olo[3,2-b]p yr id in e-
2,3-d ica r bon itr iles (9) a n d 1H-P yr r olo[3′,4′:4,5]-1H-p yr -
r olo[3,2-b]p yr id in es (10), Resp ectively. A suspension of 5
(2R,3R,3aS,7aS)-r el-1-(4-Ch lor oph en yl)-5-[(4-m eth ylph e-
n yl)su lfa n yl]-2,3,3a ,7a -tetr a h yd r o-1H-p yr r olo[3,2-b]p yr i-
J . Org. Chem, Vol. 68, No. 14, 2003 5657

Riedl et al.
or 6 (0.47 mmol) and DDQ (293 mg, 1.29 mmol) in toluene (10
mL) was refluxed for 3 h. The solvent was removed, the residue
was mixed with CH2Cl2 (40 mL), and the impurities were
removed by filtration. Alumina (2 g) was added to the filtrate,
the mixture was stirred for a few minutes, and the mixture
were filtered. The organic solvent was evaporated, and the
residue was purified as described below.
5-Ben zylsu lfa n yl-1-(4-ch lor op h en yl)-1H-p yr r olo[3,2-b]-
p yr id in e-2,3-d ica r bon itr ile (9a ). The residue was submitted
to column chromatography (silica/chloroform) to give yellow
crystals (102 mg, 54%): mp 175-177 °C.
C23H16Cl2N2O4S: C, 56.68; H, 3.31; N, 5.75; S, 6.58. Found:
C, 56.42; H, 3.31; N, 5.75; S, 6.28.
(2R ,3R ,4R ,5R ,10S ,10a R )-r el-8-Ch lor o-1,2,3,4,10,10a -
h exa h yd r o-2,10-eth en op yr im id o[1,2-a ]in d ole-3,4-d ica r -
bon itr ile (13b). Zwitterion7 12b prepared from N-(4-chlo-
rophenyl)-pyridinium bromide8 (700 mg, 2.45 mmol) was
dissolved in water (30 mL) and saturated potassium carbonate
solution (20 mL) was added. The mixture was then extracted
with CH2Cl2 (3 × 20 mL). The organic phase was dried over
Na2SO4 and concentrated to half if its volume, and fumaroni-
trile was added (210 mg, 2.7 mmol). The mixture was stirred
at room temperature for 1 d. The solvent was removed, the
residue was treated with ether, and the resulting solid was
filtered off to yield colorless crystals (310 mg, 44%): mp 184-
1-(4-Ch lor op h en yl)-5-[(4-ch lor op h en yl)su lfa n yl]-1H -
p yr r olo[3,2-b]p yr id in e-2,3-d ica r bon itr ile (9b). The residue
was crystallized from acetonitrile (148.4 mg, 75%): mp 233-
1
1
234 °C; IR(KBr) νmax 2225, 1518, 1496, 1422 cm-1; H NMR
185 °C (toluene); H NMR (CDCl3) δ 2.40 (d, J ) 4 Hz, 1H,
N-H), 3.43 (dd, J ) 9.3, 4.8 Hz, 1H, H-3), 3.53 (ddd, J ) 4.7,
2.8, 1.5 Hz, 1H, H-10), 4.07 (ddd, J ) 5, 4.8, 0.9 Hz, 1H, H-2),
4.12 (d, J ) 9.3 Hz, 1H, H-4), 4.94 (dd, J ) 4.7, 4 Hz, 1H,
H-10a), 6.04 (ddd, J ) 10, 5, 1.5 Hz, 1H, H-1′), 6.11 (ddd, J )
10, 2.8, 0.9 Hz, 1H, H-2′), 7.19 (d, J ) 8.5 Hz, 1H, H-6), 7.24
(dd, J ) 8.5, 2 Hz, 1H, H-7), 7.29 (d, J ) 2 Hz, 1H, H-9); 13C
NMR (CDCl3) δ 35.3 (C-3), 42.1 (C-10), 45.4 (C-2), 52.1 (C-4),
72.4 (C-10a), 115.8 (C-CN), 117.8 (C-CN), 119.0 (C-6), 123.8
(C-1′), 125.5 (C-9), 129.0 (C-7), 130.5 (C-8), 132.7 (C-2′), 137.2
(C-9a), 149.3 (C-6a); HRMS calcd for C15H11Cl N4 282.0672,
found 282.0676. Anal. Calcd for C15H11ClN4: C, 63.72; H, 3.92;
N, 19.82. Found: C, 63.52; H, 3.78; N, 19.52.
(CDCl3 + DMSO-d6) δ 7.19 (d, J ) 9 Hz, 1H, H-6), 7.48 (m,
2H, H-2′′, H-6′′), 7.59 (m, 2H, H-3′′, H-5′′), 7.66 (m, 2H, H-2′,
H-6′), 7.69 (m, 2H, H-3′, H-5′), 7.71 (d, J ) 9 Hz, 1H, H-7); 13
C
NMR (CDCl3 + DMSO-d6) δ 97.2 (C-3), 110.3 (CN), 111.6 (CN),
117.8 (C-2), 121.8 (C-6), 122.2 (C-7), 128.6 (C-2′, 6′), 129.3 (C-
1′′), 129.6 (C-4′′), 130.2 (C-3′, 5′), 130.9 (C-3′′, 5′′), 133.0 (C-
4′), 135.5 (C-3a), 136.3 (C-7a), 136.5 (C-2′′, 6′′) 142.4 (C-1′),
159.6 (C-5); HRMS calcd for C21H10Cl2N4S 420.0003, found
419.9991. Anal. Calcd for C21H10Cl2N4S: C, 59.87; H, 2.39; N,
13.30; S, 7.61. Found: C, 59.77; H, 2.23; N, 13.48; S, 7.44.
1-(4-Ch lor op h en yl)-5-[(4-m et h ylp h en yl)su lfa n yl]-1H -
p yr r olo[3,2-b]p yr id in e-2,3-d ica r bon itr ile (9c). The residue
was crystallized from acetonitrile (146.8 mg, 78%): mp 197-
199 °C.
(2R,3R,3a R)-r el-1-(4-Ch lor op h en yl)-1,2,3,3a -t et r a h y-
d r op yr a zolo[1,5-a ]p yr id in e-2,3-d ica r bon itr ile (14). To a
solution of 12b (480 mg, 2.35 mmol) in diethyl ether (10 mL)
was added fumaronitrile (220 mg, 2.82 mmol) at room tem-
perature. The mixture was stirred for 20 min and the
precipitated product was filterred off and washed with cold
diethyl ether (2 mL) to give gray crystals (0.35 g, 53%): mp
90-91 °C. The product proved to be unstable at room tem-
perature and was stored at - 20 °C for a few days or subjected
to further transformations immediately. IR (KBr) νmax 2930,
2252, 1572, 1489, 1243 cm-1; 1H NMR (CDCl3) δ 3.86 (dd, J )
9.1, 7 Hz, 1H, H-3), 4.02 (dd, J ) 9.1, 4.7 Hz, 1H, H-3a), 4.38
(d, J ) 7 Hz, 1H, H-2), 5.23 (d, J ) 6.5, 5.5 Hz, 1H, H-6), 5.88
(dd, J ) 5.8, 4.7 Hz, 1H, H-4), 6.17 (d, J ) 5.5 Hz, 1H, H-7),
6.20 (dd, J ) 6.5, 5.8 Hz, 1H, H-5), 6.90 (m, 2H, H-3′, H-5′),
7.31 (m, 2H, H2′, H6′); 13C NMR (CDCl3) δ 43.4, 54.5, 61.4,
102.6, 115.5 (2C), 116.6, 118.8, 119.0, 125.7, 126.2, 129.8 (2C),
137.5, 146.4.
(2R,3R,3a S,7a S)-r el-1-(4-Ch lor op h en yl)-2,3,3a ,7a -t et -
r ah ydr o-1H-pyr r olo[3,2-b]pyr idin e-2,3-dicar bon itr ile (15).
Crystals of 14 (100 mg, 0.35 mmol) were added to boiling
toluene (5 mL) and the mixture was stirred at 110 °C under
Argon for 2 h. The solvent was evaporated and the residue
was treated with diethyl ether (5 mL) to give the crude product
(70 mg) containing two main components. The more polar
component was separated by colomn chromatography (silica-
gel; eluent CHCl3:methanol ) 100:4) and recrystallized from
MeOH to yield colorless crystals (28 mg, 28%): mp 209-211
°C; IR (KBr) νmax 2944, 2246, 1595, 1497, 1330 cm-1; 1H NMR
(DMSO-d6) δ 4.63 (ddd, J ) 10.5, 3, 1.5 Hz, 1H, H-7a), 4.77
(dd, J ) 7, 2.5 Hz, 1H, H-3), 4.89 (ddd, J ) 10.5, 7, 2 Hz, 1H,
H-3a), 5.50 (d, J ) 2.5 Hz, 1H, H-2), 6.09 (ddd, J ) 10, 5, 1.5
Hz, 1H, H-6), 6.39 (dd, J ) 10, 3 Hz, 1H, H-7), 7.00 (m, 2H,
H-2′, H-6′), 7.40 (m. 2H, H-3′, H-5′), 8.04 (dd, J ) 5, 2 Hz, 1H,
H-5); 13C NMR (DMSO-d6) δ 38.8 (C-3), 47.9 (C-2), 49.2 (C-
7a), 57.1 (C-3a), 115.6 (CN), 116.2 (CN), 116.6 (C-2′, 6′), 119.1
(C-6), 123.5 (C-4′), 128.6 (C-3′, 5′), 129.6 (C-7), 141.6 (C-1′),
156.5 (C-5); HRMS calcd for C15H11ClN4 282.0672, found
282.0676. Anal. Calcd for C15H11ClN4: C, 63.72; H, 3.92; N,
19.82. Found: C, 63.54; H, 3.89; N, 19.62.
7-Ben zylsu lfa n yl-4-(4-ch lor op h en yl)-2-p h en yl-1H-p yr -
r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b]p yr id in e -1,3(2H )d ion e
(10a ): prepared from 6a as pale yellow crystals (583 mg,
78%);: mp 191-193 °C.
4-(4-Ch lor oph en yl)-7-[(4-ch lor oph en yl)su lfan yl]-2-ph en -
yl-1H-pyr r olo[3′,4′:4,5]-1H-pyr r olo[3,2-b]pyr idin e-1,3(2H)-
d ion e (10b): prepared from 6b as pale yellow crystals (580
mg, 75%); mp 255-256 °C; 1H NMR (DMSO-d6) δ 7.10 (d, J )
9 Hz, 1H, H-6), 7.36 (m, 2H, H-2′′′, H-6′′′), 7.38 (m, 1H, H-4′′′),
7.48 (m, 2H, H-3′′′, H-5′′′), 7.52 (m, 2H, H-2′′, H-6′′), 7.58 (m,
2H, H-3′′, H-5′′), 7.67 (m, 2H, H-3′, H-5′), 7.77 (m, 2H, H-2′,
H-6′), 7.92 (d, J ) 9 Hz, 1H, H-5); 13C NMR (DMSO-d6) δ 114.7
(C-8b), 120.4 (C-6), 123.6 (C-5), 128.1 (C-3′′′, 5′′′), 128.4 (C-2′,
6′), 128.5 (C-4′′′), 129.5 (2C), 130.4 (2C), 130.5 (C-2′′′, 6′′′), 130.7
(C-1′′), 132.6 (C-4′′), 133.7 (C-4′), 134.4 (C-8a), 134.8 (C-4a),
135.0 (C-1′′′), 136.3 (C-2′′, 6′′), 138.2 (C-3a), 142.1 (C-1′), 157.4
(C-7), 160.0 (C-3), 162.2 (C-1); HRMS calcd for C27H15Cl2N3O2S
515.0262, found 515.0261. Anal. Calcd for C27H15Cl2N3O2S: C,
65.25; H, 3.13; N, 5.44; S, 6.22. Found: C, 65.05; H, 3.11; N,
5.25; S, 6.10.
4-(4-Ch lor op h e n yl)-7-[(4-m e t h ylp h e n yl)su lfa n yl]-2-
p h en yl-1H -p yr r olo[3′,4′:4,5]-1H -p yr r olo[3,2-b]p yr id in e-
1,3(2H)d ion e (10c): prepared from 6c as pale yellow crystals
(579 mg, 78%); mp 262-264 °C.
1H-Dim eth yl 1-(4-Ch lor op h en yl)-5-[(4-ch lor op h en yl)-
su lfan yl]-1H-pyr r olo[3,2-b]pyr idin e-2,3-dicar boxylate (11).
A suspension of 8 (110 mg, 0.255 mmol) and DDQ (100 mg,
0.44 mmol) in toluene (10 mL) was refluxed for 2 h. The solvent
was removed, the residue was mixed with CH2Cl2 (40 mL),
and the impurities were removed by filtration. Alumina (2 g)
was added and, the mixture was stirred for a few minutes and
then filtered. The organic solvent was evaporated, and the
residue was crystallized from petroleum ether to yield yellow
crystals (80 mg, 73%): mp 124-125 °C; 1H NMR (CDCl3) δ
3.82 (s, 3H, H-Me), 3.93 (s, 3H, H-Me), 6.98 (d, J ) 9 Hz,
1H, H-6), 7.28 (d, J ) 9 Hz, 1H, H-7), 7.29 (m, 2H, H-2′′, H-6′′),
7.38 (m, 2H, H-2′, H-6′), 7.50 (m, 2H, H-3′, H-5′), 7.58 (m, 2H,
H-3′′, H-5′′); 13C NMR (CDCl3) δ 52.1 (Me), 53.1 (Me), 119.0
(C-6), 119.8 (C-7), 128.3 (C-2′, 6′), 129.1 (C-1′′), 129.4 (C-3′′,
5′′), 130.0 (C-3′, 5′), 130.6 (C-3), 134.2 (C-3a), 134.3 (C-7a),
134.8 (C-4′′), 135.5 (C-4′), 135.6 (C-2′′, 6′′), 136.0 (C-1′), 141.8
(C-2), 156.7 (C-5), 161.4 (CdO), 163.5 (CdO); HRMS calcd for
1-(4-Ch lor op h en yl)-1H -p yr r olo[3,2-b]p yr id in e-2,3-d i-
ca r bon itr ile (16). A suspension of 15 (100 mg, 0.35 mmol)
and DDQ (193 mg, 0.85 mmol) in toluene (10 mL) was refluxed
for 2 h. The solvent was removed, the residue was mixed with
dichloromethane (40 mL), and the impurities were removed
C
23H16Cl2N2O4S 486.0208, found 486.0318. Anal. Calcd for
5658 J . Org. Chem., Vol. 68, No. 14, 2003

Transformation to Pyrrolo[3.2-b]pyridine Derivatives
by filtration. Alumina (2 g) was added to the filtrate, and the
mixture was stirred for 10 min and filtered. The solvent was
evaporated, and the residue was crystallized from acetonitrile
to afford colorless crystals (85 mg, 86%): mp 235-237 °C; 1H
NMR (DMSO-d6) δ 7.58 (dd, J ) 8, 4 Hz, 1H, H-6), 7.75-7.85
(m, 4H, H-2′, H-3′, H-4′, H-5′), 7.95 (d, J ) 8 Hz, 1H, H-7),
8.78 (d, J ) 4 Hz, 1H, H-5); 13C NMR (DMSO-d6) δ 97.4 (C-3),
110.9 (CN), 112.6 (CN), 118.9 (C-2), 121.7 (C-6), 123.6 (C-7),
129.5 (C-3′, 5′), 131.0 (C-2′, 6′), 131.6 (C-4′), 133.6 (C-1′), 135.8
(C-7a), 142.5 (C-3a), 149.6 (C-5); HRMS calcd for C15H7ClN4
278.0359, found 278.0349. Anal. Calcd for C15H7ClN4: C, 64.64;
H, 2.53; N, 20.10. Found: C, 64.34; H, 2.38; N, 19.91.
(3a S,9a S,9b R)-r el-4-(4-Ch lor op h en yl)-2-p h en yl-3a ,4,-
9a ,9b-t et r a h yd r o-1H-p yr r olo[3′4′:3,4]p yr a zolo[1,5-a ]p y-
r id in e-1,3(2H)-d ion e (17). To a solution of 12b7 obtained
from N-(4-chlorophenyl)pyridinium bromide8 (700 mg, 2.45
mmol) in water (30 mL) was added saturated potassium
carbonate solution (20 mL) to give a red suspension. The
mixture was extracted with CH2Cl2 (3 × 20 mL). The organic
phase was dried and concentrated to half of its volume. To
this solution was added N-phenylmaleimide (450 mg, 2.6
mmol). The mixture was stirred at room temperature for 15
min. A fast reaction occurred indicated by the disappearance
of the red color. The solvent was removed, the residue was
treated with ether, and the resulting solid was filtered off (783
mg, 83%): mp 174-176 °C; 1H NMR (DMSO-d6) δ 3.83 (dd, J
) 8.2, 7.5 Hz, 1H, H-9b), 4.34 (dd, J ) 8.2, 5 Hz, 1H, H-9a),
4.92 (dd, J ) 7.5, 5 Hz, 1H, H-7), 5.07 (d, J ) 7.5 Hz, 1H,
H-3a), 5.75 (dd, J ) 9.5, 5 Hz, 1H, H-9), 6.00 (dd, J ) 9.5, 5
Hz, 1H, H-8), 6.12 (d, J ) 7.5 Hz, 1H, H-6), 7.13 (m, 2H, H-3′,
H-5′), 7.17 (m, 2H, H-2′′, H-6′′), 7.37 (m, 2H, H-2′, H-6′), 7.44
(m, 1H, H-4′′), 7.51 (m, 2H, H-3′′, H-5′′); 13C NMR (DMSO-d6)
δ 55.6 (C-9b), 58.9 (C-9a), 66.6 (C-3a), 100.3 (C-7), 116.8 (C-
3′′, 5′′), 118.5 (C-9), 123.8 (C-8), 126.0 (C-4′), 127.1(C-3′, 5′),
129.1 (C-4′′), 129.7 (C-2′, 6′), 129.8 (C-2′′, 6′′), 132.9 (C-1′′),
138.8 (C-6), 148.5 (C-1′), 173.6 (C-1), 174.4 (C-3); HRMS calcd
for C21H16ClN3O2 377.0931, found 377.0917. Anal. Calcd for
C
21H16ClN3O2: C, 66.76; H, 4.27; N, 11.12. Found: C, 66.54;
H, 4.19; N, 10.97.
4-(4-Ch lor op h en yl)-2-p h en yl-1H-p yr r olo[3′4′:3,4]p yr a -
zolo[1,5-a ]p yr id in e-1,3(2H)-d ion e (19). A suspension of 17
(330 mg, 0.87 mmol) and DDQ (440 mg, 1.9 mmol) in toluene
(10 mL) was refluxed for 1 h. The solvent was removed, the
residue was mixed with CH2Cl2 (40 mL), and the mixture was
filtered. Alumina (2 g) was added to the filtrateand the mixture
was stirred for 10 min and filtered. The organic solvent was
evaporated, and the residue was crystallized from 2-pro-
panol: yellow crystals (79 mg, 24%); mp 248-250 °C; 1H NMR
(CDCl3) δ 7.36 (dd, J ) 8.5, 4.5 Hz, 1H, H-6), 7.37 (m, 1H,
H-4′′), 7.40 (m, 2H, H-2′′, H-6′′), 7.47 (m, 2H, H-3′′, H-5′′), 7.58
(m, 4H, H-2′, H-3′, H-5′, H-6′), 7.86 (dd, J ) 8.5, 1 Hz, 1H,
H-5), 8.78 (dd, J ) 4.5, 1 Hz, 1H, H-7); 13C NMR (CDCl3) δ
116.7 (C-8b), 120.5 (C-6), 120.8 (C-5), 126.7 (C-3′, 5′), 126.8
(C-3′′, 5′′), 127.9 (C-4′′), 129.0 (C-2′, 6′), 130.1 (C-2′′, 6′′), 131.7
(C-8a), 132.8 (C-4a), 135.3 (C-4′), 136.5 (C-3a), 138.4 (C-1′′),
140.3 (C-1′), 148.3 (C-7), 160.0 (C-3), 161.5 (C-1); HRMS calcd
for C21H12ClN3O2 373.0618, found 373.0628. Anal. Calcd for
C
21H12ClN3O2: C, 67.48; H, 3.24; N, 11.24. Found: C, 67.22;
H, 3.24; N, 11.04.
Ack n ow led gm en t. The national funds OTKA 35176
and 1/047 NKFP MediChem, as well as the EU fund
QLK2-CT-2002-90436, are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
of 13a and 15, analytical data for 2b,e, 3d ,e, 5a ,c, 6b,d ,e, 9a ,c,
and 10 a ,c. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034231A
J . Org. Chem, Vol. 68, No. 14, 2003 5659