Synthesis of 1,2,2a,3-tetrahydro-1,4,7b-triazacyclopenta[cd]indenes

Article abstract of DOI:10.1055/s-2005-918409

1,2,2a,3-Tetrahydro-1,4,7b-triazacyclopenta[cd]indenes 12 were obtained from 3-halomethyl-5-chloro-6- or 8-nitropyridines in a novel reaction sequence which comprises a nucleophilic aromatic substitution followed by an intramolecular nucleophilic substitu

Full text of DOI:10.1055/s-2005-918409

PAPER
3107
Synthesis of 1,2,2a,3-Tetrahydro-1,4,7b-triazacyclopenta[cd]indenes
T
riazacyclope
y
c
d
]inden
l
Abteilung Organische Chemie II, Universität Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
E-mail: volkhard.austel@chemie.uni-ulm.de
Received 13 May 2005; revised 13 June 2005
Abstract: 1,2,2a,3-Tetrahydro-1,4,7b-triazacyclopenta[cd]indenes
12 were obtained from 3-halomethyl-5-chloro-6- or 8-nitropy-
ridines in a novel reaction sequence which comprises a nucleophilic
aromatic substitution followed by an intramolecular nucleophilic
substitution. The starting material for this reaction (9a) can be pre-
pared in good yields by halocyclization of the easily accessible 2-
allylamino-6-chloro-3-nitropyridine (4a). Aliphatic as well as aro-
matic amines are suitable unless they are strongly deactivated. The
tricyclic compounds are relatively reactive electrophiles and may
serve as interesting intermediates for combinatorial syntheses.
Key words: polycycles, ring closure, nucleophilic aromatic substi-
tutions, halogenation, amines
For an investigation of structure-conformation relation-
ships of 2,6-bis-anilino-3-nitropyridines (1, Figure 1) we
Figure 1
needed conformationally rigid analogues in which either
R1 or R2 form a bridge between their aniline nitrogen at-
oms and the pyridine nitrogen (2, 3, Figure 1).
The halomethyl sidechain formed in the halocyclization
offers a further possibility of increasing structural diversi-
ty, e.g., via nucleophilic replacement of the halogen atom
by amines.
The main objective, however, was using these compounds
as new, non-planar scaffolds and intermediates for combi-
natorial syntheses of potential new drug molecules.
Therefore, we were interested in compounds of type 2 or
3 in which the R1 or R2 bridges carry reactive groups that
can be further structurally modified with readily accessi-
ble reagents.
Halocyclizations have been successfully applied to the
synthesis of a great variety of (partially) saturated hetero-
cycles. Thus, allyl ureas2–6 or O-alkyl isoureas7 were con-
verted to the corresponding imidazole derivatives with
iodine, 3-allyl-2-amino-3,5-dihydroimidazol-4-ones to 2-
iodomethyltetrahydroimidazo[1,2-a]imidazolones,8
3-
Under these considerations, halocyclization of allylamino
pyridines 4 to 5 followed by nucleophilic replacement of
the chlorine in 6-position (6-Cl) (6) seemed to us an at-
tractive synthetic approach to compounds of type 2
(Scheme 1).
acylamino-4-methallyl-1,2,4-triazoles to the correspond-
ing 2-bromomethylimidazo[2,1-c]-1,2,4-triazoles,9 3-al-
lylamino-5-phenyl-1,2,4-triazine to 3-bromomethyl-7-
phenyl-2,3-dihydro-1H-imidazo[1,2-b]-1,2,4-triazinium
bromide,10 3-allyl-4-imino-3,4-dihydroquinazoline-
Scheme 1 Halocyclization as an approach to compounds of type 2 with a chemically reactive side chain
SYNTHESIS 2005, No. 18, pp 3107–3118
x
x.
x
x
.
2
0
0
5
Advanced online publication: 29.09.2005
DOI: 10.1055/s-2005-918409; Art ID: Z09405SS
© Georg Thieme Verlag Stuttgart · New York

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2(1H)-ones and -thiones to imidazo[1,2-c]quinazoline- present in the precipitate by DMSO.17 A spectrum record-
5(6H)-ones and -thiones,11 4-allylamino-2-methylthio- ed in CDCl3 [the precipitate itself is insoluble but addition
quinazoline to 3-bromomethyl-5-methylthio-2,3-dihydro- of some N,N-diisopropylethylamine (DIPEA) gives a suf-
imidazo[1,2-c]quinazoline,11,12 3-allylamino-4H-1,2,4- ficiently concentrated solution] as well as a mass spec-
benzothiadiazine-1,1-dioxide to 3-bromomethyl-2,3-di- trum and the elemental analysis indicated clearly that the
hydro-1H-imidazo[1,2-b]-1,2,4-benzothiadiazine-5,5-di-
precipitate is in fact the primary cyclization product 9a
oxide,13 2-allylaminopteridin-4(3H)-ones to 1-iodomethyl- (Scheme 2). The lactam 7 originates from a hydrolysis by
1,2-dihydroimidazo[1,2-a]pteridin-5(4H)-ones,14 and 3- the water content of the solvents used to prepare the NMR
allyl-2-anilinopteridin-4(3H)-ones to 7,8-dihydro-7-io- samples.
domethyl-6-phenylimidazo[2,1-b]pteridin-10(6H)-ones.15
Considering the apparent ease of nucleophilic replace-
There is also one report on the successful application to 2-
ment of the chlorine, a great variety of 6-(substituted anili-
allylaminopyridine to give 3-bromomethyl-2,3-dihy-
no) derivatives of type 2 ought to be readily accessible
from 9a or 9b. However, when 9a was treated with aniline
droimidazo[1,2-a]pyridine.16
The starting material in ref.16 differs from the one that is in CH2Cl2 in the presence of DIPEA, a product precipitat-
needed for the present purpose (4b) by the absence of ed which in the 1H NMR spectrum showed coupling pat-
electron-withdrawing groups, which may seriously im- terns of the aliphatic hydrogen atoms that differed
pede halocyclization. As a means of clarifying this point, remarkably from those of the imidazo[1,2-a]pyridines
we applied the reaction in a first attempt to 4a, which cov- discussed above (e.g., 7) and from those reported in the
ers the electronic effects of the nitro group and the chlo- literature for the related imidazolidinone 107 both of
rine but not yet the electron-withdrawing mesomeric which show very similar coupling patterns (Scheme 3).
effect of the phenyl group.
When 4a was treated with bromine in anhydrous CH2Cl2
or chlorobenzene a precipitate formed the 1H NMR spec-
trum of which in DMSO-d6 indicated the presence of
mainly two components (7, 8, Figure 2) in variable ratios.
Scheme 3 Correspondence between the coupling pattern of 7
(DMSO) and a reference compound 10 (CDCl3)7
Except for Hb each of these hydrogen atoms has only one
coupling constant in the area of 10 Hz (for 10 Jcd and Jdd
Figure 2
were not given). On the contrary, the coupling constants
However, a spectrum of the same precipitate in DMF-d7
shows only signals of 7. Therefore, the observed bromina-
tion must be attributed to an oxidation of the bromide ions
of the aliphatic hydrogen atoms of the new product all
ranged from 9.1 to 12.5 Hz (DMSO). Taking this pattern
together with mechanistic aspects leaves 12a as the only
Scheme 2 Halocyclization of 4a and origin of products 7 and 8
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Triazacyclopenta[cd]indenes
3109
plausible structure for the new product. Conceivably, the
expected nucleophilic aromatic substitution had taken
place (11a) but was rapidly followed by ring closure
(Scheme 4).
To our knowledge, neither 1,2,2a,3-tetrahdro-1,4,7b-tri-
aza-cyclopent[cd]indenes nor the present synthetic ap-
proach to the parent tricyclic system or its hydrogenated
analogs have so far been reported in the literature. The
unsubsituted18 and the 2,3-dimethylated19 fully aromatic
tricyclic system (13, Figure 3) and the 1,2-dihydro- and 2-
oxo-1H-derivatives of the former18 have, however, been
synthesized previously from 5-amino-3-ethoxycarbon-
ylimidazo[1,2-a]pyridine18 and 3-acetyl-5-acetylamino-
2-methylimidazo[1,2-a]pyridine respectively. Variously
1-substituted 3-methyl-1,2-dihydro-1,4,7b-triazacyclo-
pent[cd]indenes (14a, Figure 3)20 and their 2-oxo-deriva-
tives (14b, Figure 3)20,21 have been synthesized and
exerted kinase inhibiting,21a chemokine receptor antago-
nist,21b and platelet-derived growth factor inhibiting20,21c,d
activities.
Figure 3
mainly the expected products but we were unable to puri-
fy them sufficiently.
With aliphatic amines, the second step of the reaction
seems to be rate limiting which made it possible to deter-
mine the more or less complete 1H NMR spectra of the in-
termediates 11h–j. Secondary amines 15a,b also reacted
with 9a but in this case the intermediates 16a,b did not un-
dergo ring formation (Scheme 6).
Solutions of 4b in CH2Cl2 or chlorobenzene also reacted
with bromine but no precipitation formed in CH2Cl2,
whilst in chlorobenzene an oily lower phase appeared. On
evaporation of the solvent a glassy material remained
which is most likely 9b (Scheme 7). Attempts to charac-
terize the material spectroscopically at least in crude form
failed because DMSO solutions decomposed rapidly
while in CDCl3; only the aryl hydrogens gave well-re-
solved signals. However, on treatment of a sample of the
material with aniline a solid product was obtained, which
according to the 1H NMR spectrum was a 9:1 mixture of
In order to examine the scope of the new reaction, a num-
ber of diverse aromatic amines as well as some aliphatic
amines were reacted with 9a (Scheme 5). The tricyclic
system forms readily with aromatic amines including ster-
ically hindered ones. However, there seem to be limita-
tions with respect to the electron-withdrawing character
of the aromatic system. 2-Nitro-aniline did not react
whereas 2-aminopyridine and 4-aminobenzamide yielded
Scheme 4
Scheme 5
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3110
S. Schmid et al.
PAPER
Scheme 6
the tricyclic compound 17 and a derivative of it in which The reaction of 9a with amines gives good results only if
one of the phenyl rings is brominated in para position the latter are added in equimolar amounts. Excess amine
(Scheme 7).
leads to product mixtures due to nucleophilic ring open-
ing. This limitation makes it inconvenient to synthesize
the unsubstituted 5-nitro-1,2,2a,3-tetrahydro-1,4,7b-tri-
azacyclopenta[cd]indene 20 from 9a and NH3. Therefore,
an alternative synthesis strategy was developed. An obvi-
ous possibility consists of exchanging the chlorine in 6-
position of 4a prior to halocyclization, i.e., starting the
synthesis of 20 from the 6-amino derivative 21
(Scheme 9). Unfortunately, such an approach always led
to side products due to 5-bromination of the pyridine.
Acylation of the amino groups would solve this problem
provided the acylation products still undergo halocycliza-
tion. In the present case double acylation (22) was re-
quired in order to avoid the side reaction. Treatment of
This side product may arise from bromine that remains
absorbed in the crude 9b probably in the form of a tribro-
mide.
Since separation from the side product turned out to be
very difficult, we looked for a more satisfactory alterna-
tive. We found that the easily accessible 2-anilino-6-(N-
allylanilino)-3-nitropyridine (18) can be cyclized with
iodine without formation of halogenated side products.
The intermediate 19 cyclizes when dissolved in DMSO
whilst the subsequent reduction of the triiodide to the io-
dide was necessary to obtain a product with a reproducible
salt form (Scheme 8).
Scheme 7
Scheme 8
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Triazacyclopenta[cd]indenes
3111
this product with bromine in CH2Cl2 resulted in a mixture form and therefore would have to be used as crude mate-
the 1H NMR spectrum of which suggested that it is mainly rial in the next step. In addition, it turned out to be impor-
composed of the addition product 23 and the imidazo[1,2- tant to reduce the triiodide to iodide before ring closure to
a]pyridine 24 in a ratio of 2:1 (Scheme 9). Apparently, the 20.
double acylation reduced the nucleophilicity of the ring
nitrogen to such an extent that bromine addition to the
double bond was now able to compete successfully with
ring formation.
A more satisfactory way of synthesizing 20 became pos-
sible when we found that 26 can be obtained directly and
without side reactions from 21 with 1.5 equivalents of io-
dine (Scheme 11). The excess iodine was removed by
In principle, it is possible to solve this latter problem by heating with DMF to 60 °C. Treatment of 26 with base af-
using iodine as a cyclization reagent. The Boc groups can forded the N-unsubstituted tricyclic system 20
be removed by heating the resulting imidazo[1,2-a]pyri- (Scheme 11).
dine 25 to 60 °C for 12 hours to afford the fully deprotect-
ed amino derivative 26 (Scheme 10).
This latter route turned out to be also the most suitable one
for the preparation of the 7-nitro-1-phenyl-1,2,2a,3-tet-
The temperature at which this deprotection occurs is sur- rahydro-1,4,7b-triazacyclopenta[cd]indene (27) from 6-
prisingly low considering reports on the thermal cleavage allylamino-2-anilino-3-nitropyridine (28; Scheme 12). In
of Boc groups in which much higher temperatures (reflux- the first step it was, however, necessary to use two equiv-
ing quinoline or diphenyl,22 or heating at 185 °C23) were alents of iodine. Due to the higher lipophilicity of the in-
necessary.
termediate 29 it was possible to reduce the excess iodine
with aqueous sodium disulfite.
However, the procedure was still not ideal because the in-
termediate 25 is not stable enough to be isolated in pure
Scheme 9
Scheme 10
Scheme 11
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3112
S. Schmid et al.
PAPER
Scheme 12
13C NMR: d = 155.0, 151.4, 138.6, 134.4, 126.8, 115.8, 111.6, 43.1.
MS (CI): m/z = 214 [M + H]+, 216.
Despite the presence of two electronegative groups, 2-al-
lylamino-6-chloro-3-nitropyridine can undergo a halocy-
clization reaction with bromine. If the electron-
withdrawing character of the substituents increases (e.g.
22) the competing addition of bromine to the allylic dou-
ble bond becomes more important and can even gain the
upper hand. A clean halocyclization may, however, still
be achieved if iodine is used as a cyclization reagent.
Anal. Calcd for C8H8ClN3O2: C, 44.99; H, 3.77; N, 19.67. Found:
C, 45.07; H, 3.79; N, 19.70.
2-N-Allylanilino-6-chloro-3-nitropyridine (4b)
A mixture of 2-anilino-6-chloro-3-nitropyridine24 (1000 mg, 4
mmol), ally bromide (725 mg, 0.51 mL, 6 mmol), K2CO3 (702 mg,
6 mmol) and DMF (5 mL) was stirred at r.t. After 1 d another por-
tion of allyl bromide (72 mg, 0.05 mL, 0.6 mmol) was added and
stirring continued for 1 d. Water was added and the resulting mix-
ture was extracted with EtOAc. In order to separate the product
from unreacted starting material, the solvent was evaporated and the
residue dissolved in EtOH (3 mL). o-Phenylenediamine (20 mg)
and DIPEA (0.02 mL) were added and the solution was warmed to
40 °C for 2 d. After evaporation of the solvent the residue was pu-
rified by column chromatography on silica gel (n-hexane–EtOAc,
4:1).
The imidazo[1,2-a]pyridines formed in the reaction con-
tain two electrophilic centers, one in 5-position and the
other one in the side chain. The former one is considerably
more reactive but when primary amines are used as nu-
cleophiles the second center can undergo a subsequent in-
tramolecular nucleophilic substitution to form a new
tricyclic structure, i.e., a 1,2,2a,3-tetrahydro-1,4,7b-tri-
aza-cyclopenta[cd]indene. The sensitivity to nucleophiles
such as water and amines could make these compounds
interesting candidates for intermediates in combinatorial
syntheses.
Yield: 701 mg (60%); orange solid; mp 36 °C.
1H NMR: d = 4.66 (dt, J1 = 5.1 Hz, J2 = 1.5 Hz, 2 H, CH2), 5.12 (dq,
J1 = 10.4 Hz, J2 = 1.5 Hz, 1 H, H3¢ trans to CH2), 5.23 (dq, J1 = 17.2
Hz, J2 = 1.6 Hz, 1 H, H3¢ cis to CH2), 5.96 (ddt, J1 = 17.2 Hz, J2 =
10.4 Hz, J3 = 5.2 Hz, 1 H, H2¢), 7.08 (d, J = 8.3 Hz, 1 H, H5), 7.09
(m, 2 H, ortho-H), 7.12 (m, 1 H, para-H), 7.28 (m, 2 H, meta-H),
8.16 (d, J = 8.3 Hz, 1 H, H4).
13C NMR: d = 150.9, 149.4, 144.3, 138.7, 133.6, 133.5, 129.6,
125.6, 122.4, 117.2, 114.8, 54.4.
MS (CI): m/z = 290 [M + H]+, 292.
For chromatography, silica gel 60 (230–400 mesh) from Fluka was
used. Melting points were measured on a Büchi B-545 melting point
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
corded on a Bruker Avance 400 spectrometer, in DMSO-d6 (400
1
MHz for H, 100 MHz for 13C) unless stated otherwise. Chemical
1
shifts are expressed in ppm with d (DMSO-d6) = 2.49 ppm for H
and 39.5 ppm for 13C as internal standards. 2D-NMR spectra were
recorded in DMSO at 303 K on a Bruker DPX400 spectrometer
Anal. Calcd for C14H12ClN3O2: C, 58.04; H, 4.17; N, 14.50. Found:
C, 58.03; H, 4.22; N, 14.44.
1
(400 MHz for H, 100 MHz for 13C; internal reference: TMS d =
0.00 ppm for 1H and 13C-DMSO d = 39.5 ppm for 13C). CI and EI
mass spectra were recorded on a Finnigan SSQ7000 mass spectrom-
eter. High-resolution ESI mass spectra were recorded on a Micro-
mass QTOF-2 instrument. Elemental analyses were done with an
Elementar Analysensysteme Vario EL analyzer. Petroleum ether
used had a boiling range of 35–60 °C.
3-Bromomethyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyri-
din-5-one (7)
Compound 9a (150 mg, 0.4 mmol) was added to a stirred mixture
of EtOAc (50 mL) and sat. aq NaHCO3 solution (50 mL). After 3 h
at r.t., the organic phase was concentrated in vacuo and the residue
crystallized from toluene.
2-Allylamino-6-chloro-3-nitropyridine (4a)
Yield: 87 mg (89%); pale yellow crystals; mp 172 °C.
To a solution of 2,6-dichloro-3-nitropyridine (4.82 g, 25 mmol) in
CH2Cl2 (100 mL) were added at –15 °C Et3N (2.63 g, 3.60 mL, 26
mmol) and subsequently dropwise within 8 h allyl amine (1.48 g,
1.95 mL, 26 mmol). After another 8 h at r.t., the solution was
washed with 0.2 M aq citric acid and sat. aq NaHCO3 and evaporat-
ed. The crude product was crystallized from EtOH.
1H NMR: d = 3.67 (ddd, J1 = 11.6 Hz, J2 = 4.8 Hz, J3 = 1.0 Hz, 1 H,
H2 trans to H3), 3.83 (dd, J1 = 10.6 Hz, J2 = 2.0 Hz, 1 H, CH2), 4.03
(t, J = 11.1 Hz, 1 H, H2 cis to H3), 4.13 (dd, J1 = 10.6 Hz, J2 = 4.6
Hz, 1 H, CH2), 5.03 (dtd, J1 = 10.6 Hz, J2 = 4.8 Hz, J3 = 2.0 Hz, 1
H, H3), 5.70 (d, J = 10.1 Hz, 1 H, H6), 7.96 (d, J = 10.1 Hz, 1 H,
H7), 9.52 (br s, 1 H, NH).
13C NMR: d = 160.2, 151.6, 135.8, 112.3, 107.0, 56.0, 47.8, 34.7.
MS (CI): m/z = 274 [M + H]+, 276.
Yield: 4.90 g (92%); yellow needles; mp 58–59 °C.
1H NMR: d = 4.14 (t, J = 5.3 Hz, 2 H, CH2), 5.10 (m, 1 H, H3¢ trans
to CH2), 5.17 (m, 1 H, H3¢ cis to CH2), 5.93 (ddt, J1 = 17.2 Hz, J2 =
10.4 Hz, J3 = 5.1 Hz, 1 H, H2¢), 6.78 (d, J = 8.6 Hz, 1 H, H5), 8.43
(d, J = 8.6 Hz, 1 H, H4), 8.78 (br t, J = 5 Hz, 1 H, NH).
Anal. Calcd for C8H8BrN3O3: C, 35.06; H, 2.94; N, 15.33. Found:
C, 34.85; H, 2.94; N, 15.19.
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Triazacyclopenta[cd]indenes
MS (CI): m/z = 269 [M + H]+.
3113
6-Bromo-3-bromomethyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-
a]pyridin-5-one (8)
To a suspension of 7 (240 mg, 0.87 mmol) in CH2Cl2 (5 mL) was
added dropwise at r.t. a solution of bromine (139 mg, 0.044 mL,
0.87 mmol) in CH2Cl2 (5 mL). After the addition was completed the
mixture was stirred for 4 h and evaporated. The residue was crystal-
lized from n-hexane–EtOAc (4:1).
Anal. Calcd for C14H12N4O2·HBr: C, 48.16; H, 3.75; N, 16.04.
Found: C, 48.05; H, 3.81; N, 16.12.
Analogously were prepared:
1-(2-Methylphenyl)-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-triaza-
cyclopent[cd]indene Hydrobromide, Hydrochloride (12b)
Prepared from 9a (187 mg, 0.5 mmol) and 2-methylaniline (54 mg,
0.5 mmol) with DIPEA (65 mg, 0.5 mmol).
Yield: 200 mg (65%); pale yellow powder; mp 220 °C (decomp.).
1H NMR: d = 3.70 (ddd, J1 = 11.6 Hz, J2 = 5.1 Hz, J3 = 1.0 Hz, 1 H,
H2 trans to H3), 3.84 (dd, J1 = 10.9 Hz, J2 = 2.0 Hz, 1 H, CH2), 4.05
(t, J = 11.2 Hz, 1 H, H2 cis to H3), 4.11 (dd, J1 = 10.8 Hz, J2 = 4.8
Hz, 1 H, CH2), 5.07 (dtd, J1 = 10.8 Hz, J2 = 4.9 Hz, J3 = 2.0 Hz, 1
H, H3), 8.32 (s, 1 H, H7), 9.65 (s, 1 H, NH).
13C NMR: d = 156.3, 151.0, 136.8, 112.4, 99.1, 57.0, 48.2, 34.3.
MS (CI): m/z = 352 [M + H]+, 354, 356.
Yield: 175 mg (69%); yellow solid; mp 225 °C (decomp.).
1H NMR: d = 2.33 (s, 3 H, CH3), 4.28 (t, J = 11 Hz, 1 H, H3 cis to
H2a), 4.36 (t, J = 10 Hz, 1 H, H3 trans to 2a-H), 4.57 (dd, J1 = 10.2
Hz, J2 = 9.6 Hz, 1 H, H2 trans to H2a), 4.73 (dd, J1 = 12.3 Hz, J2 =
10.2 Hz, 1 H, H2 cis to H2a), 5.54 (m, 1 H, H2a), 5.84 (d, J = 9.2
Hz, 1 H, H7), 7.43 (m, 4 H, H4¢, H5¢, H6¢), 8.30 (d, J = 9.2 Hz, 1 H,
H6), 10.15 (br s, 1 H, NH).
Anal. Calcd for C8H8Br2N3O3: C, 27.22; H, 2.00; N, 11.90. Found:
C, 27.07; H, 1.99; N, 11.89.
13C NMR: d = 155.4, 150.0, 143.1, 135.1, 134.4, 131.8, 129.7,
127.5, 119.7, 95.0, 62.6, 55.8, 54.5 17.2.
3-Bromomethyl-5-chloro-8-nitro-2,3-dihydroimidazo[1,2-a]py-
ridine Hydrobromide (9a)
MS (CI): m/z = 283 [M + H]+.
Anal. Calcd for C15H14N4O2·HBr·HCl: C, 45.08; H, 4.04; N, 14.02.
Found: C, 45.21; H, 3.88; N, 14.23.
To a solution of 4a (4.62 g, 23 mmol) in chlorobenzene (100 mL)
was added dropwise within 2 h a solution of bromine (3.44 g, 23
mmol) in chlorobenzene (20 mL). The mixture from which a solid
precipitated was stirred for 15 h at r.t. and then treated with cyclo-
hexene (0.6 mL). Stirring was continued for 2 h and the precipitate
was collected by filtration, washed with CH2Cl2 and dried over par-
affin.
1-(2,6-Dimethylphenyl)-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-tri-
azacyclopent[cd]indene Hydrobromide (12c)
Prepared from 9a (94 mg, 0.25 mmol) and 2,6-dimethylaniline (30
mg, 0.25 mmol) with 2,4,6-trimethylpyridine (61 mg, 0.5 mmol) in
chlorobenzene (2.5 mL).
Yield: 6.58 g (77%); yellowish crystals; mp 217–219 °C (decomp.).
Yield: 89 mg (92%); yellow solid; mp 225 °C (decomp.).
1H NMR (CDCl3 + 9 equiv DIPEA): d = 3.53 (dd, J1 = 10.6 Hz,
J2 = 2.8 Hz, 1 H, CH2Br), 3.62 (dd, J1 = 10.6 Hz, J2 = 7.6Hz, 1 H,
CH2Br), 4.11 (dd, J1 = 15.7 Hz, J2 = 3.9 Hz, 1 H, H2 trans to H3),
4.25 (dd, J1 = 15.7 Hz, J2 = 10.0 Hz, 1 H, H2 cis to H3), 4.76 (dddd,
J1 = 10.0 Hz, J2 = 7.6 Hz, J3 = 3.9 Hz, J4 = 2.8 Hz, 1 H, H3), 5.79
(d, J = 8.1 Hz, 1 H, H6), 8.06 (d, J = 8.1 Hz, 1 H, H7); the assign-
ment of the H-atoms in position 2 is based on the coupling constants
and is in agreement with the assignment reported for equivalent pro-
tons in iodomethylimidazolinones (ref.7).
1H NMR: d = 2.26 (s, 3 H, CH3), 2.32 (s, 3 H, CH3), 4.34 (m, 2 H,
H3), 4.48 (dd, J1 = 10.5 Hz, J2 = 9.2 Hz, 1 H, H2 trans to H2a), 4.65
(dd, J1 = 12.8 Hz, J2 = 10.6 Hz, 1 H, H2 cis to H2a), 5.62 (m, 1 H,
H2a), 5.76 (d, J = 9.4 Hz, 1 H, H7), 7.24 (br d, J = 7.6 Hz, 1 H, H3¢),
7.28 (br d, J = 7.6 Hz, 1 H, H5¢), 7.35 (t, J = 7.6 Hz, 1 H, H4¢), 8.32
(d, J = 9.4 Hz, 1 H, H6), 10.14 (br s, 1 H, NH).
13C NMR: d = 153.7, 149.4, 143.4, 136.8, 135.9, 132.1, 130.0,
129.2, 129.0, 120.1, 94.2, 60.4, 56.2, 54.4 17.48, 17.45.
MS (EI): m/z = 291 [M]+, 293, 295; due to a replacement of chlorine
by bromine which (considering the analytical data) occurs during
recording of the MS data [m/z = 335 [M(Br)]+, 337, 339].
HRMS: m/z [M + H]+ calcd for C16H16N4O2: 297.1352; found:
297.1348.
Anal. Calcd for C16H16N4O2·HBr·0.25HCl: C, 49.74; H, 4.50; N,
14.50. Found: C, 49.79; H, 4.74; N, 14.38.
Anal. Calcd for C8H7BrClN3O2·HBr: C, 25.73; H, 2.16; N, 11.25.
Found: C, 25.51; H, 2.28; N, 11.03.
1-(2-Methoxyphenyl)-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-tri-
azacyclopent[cd]indene Hydrobromide (12d)
Prepared from 9a (187 mg, 0.5 mmol) and 2-methoxyaniline (62
5-Nitro-1-phenyl-1,2,2a,3-tetrahydro-1,4,7b-triazacyclo-
pent[cd]indene Hydrobromide (12a)
To a mixture of 9a (1.50 g, 4.0 mmol) in CH2Cl2 (40 mL) and
DIPEA (1.03 g, 1.37 mL, 8.0 mmol) was added a solution of aniline
(0.37 g, 4.0 mmol) in CH2Cl2 (3 mL). The mixture was stirred at r.t.
for 24 h, the precipitate collected by filtration, washed with CH2Cl2
and dried.
mg, 0.5 mmol) with DIPEA (129 mg, 1.0 mmol).
Yield: 162 mg (85%); yellow solid; mp from 140 °C (decomp.).
1H NMR: d = 3.89 (s, 3 H, OCH3), 4.26 (dd, J1 = 12.2 Hz, J2 = 10.6
Hz, 1 H, H3 cis to H2a), 4.34 (dd, J1 = 10.4 Hz, J2 = 9.4 Hz, 1 H, H3
trans to H2a), 4.55 (dd, J1 = 9.9 Hz, J2 = 9.1 Hz, 1 H, H2 trans to
H2a), 4.91 (dd, J1 = 12.6 Hz, J2 = 10.2 Hz, 1 H, H2 cis to H2a), 5.51
(tt, J1 = 12.3 Hz, J2 = 9.1 Hz, 1 H, H2a), 6.02 (d, J = 9.4 Hz, 1 H,
H7), 7.12 (m, 1 H, H5¢), 7.30 (m, 1 H, H3¢), 7.45 (m, 1 H, H6¢), 7.47
(m, 1 H, H4¢), 8.32 (d, J = 9.3 Hz, 1 H, H6), 10.11 (br s, 1 H, NH).
13C NMR: d = 154.5, 152.9, 149.9, 142.6, 130.0, 124.3, 124.1,
121.0, 119.8, 113.2, 96.1, 61.7, 55.9, 55.7, 54.3. In an HC–HMBC
experiment strong cross peaks were observed between 3-H (trans to
2a-H) and C-4a and between 2-H (trans to 2a-H) and C-7a; weak
cross peaks between these two carbon atoms and 2-H (cis) or 3-H
(cis) respectively; no cross peak between the two carbons and 2a-H.
Yield: 1.17 g (84%); yellow solid; mp 275–277 °C.
1H NMR: d = 4.26 (dd, J1 = 12.2 Hz, J2 = 10.6 Hz, 1 H, H3 cis to
H2a), 4.37 (dd, J1 = 10.4 Hz, J2 = 9.3 Hz, 1 H, H3 trans to H2a),
4.65 (dd, J1 = 9.7 Hz, 9.2 Hz, 1 H, H2 trans to H2a), 4.96 (dd, J1 =
12.5 Hz, J2 = 10.0 Hz, 1 H, H2 cis to H2a), 5.51 (tt, J1 = 12.3 Hz,
J2 = 9.2 Hz, 1 H, H2a), 6.49 (d, J = 9.4 Hz, 1 H, H7), 7.41 (m, 1 H,
H4¢), 7.48 (m, 2 H, H2¢), 7.58 (m, 2 H, H3¢), 8.39 (d, J = 9.4 Hz, 1
H, H6), 10.16 (br s, 1 H, NH).
13C NMR: d = 153.3, 149.8, 143.2, 136.3, 130.0, 127.4, 120.7,
120.3, 95.4, 60.9, 55.6, 54.2. In an HC–HMBC experiment cross
peaks were observed between 3-H (trans to 2a-H) and C-4a and be-
tween 2-H (trans to 2a-H) and C-7a but not between these two car-
bon atoms and 2a-H, 2-H (cis), or 3-H (cis).
MS (CI): m/z = 299 [M + H]+.
Synthesis 2005, No. 18, 3107–3118 © Thieme Stuttgart · New York

3114
S. Schmid et al.
PAPER
Anal. Calcd for C15H14N4O3·HBr: C, 47.51; H, 3.99; N, 14.77.
Found: C, 47.43; H, 4.04; N, 14.83.
13C NMR: d = 151.8, 149.7, 148.1, 143.6, 142.2, 133.5, 128.7,
124.6, 120.8, 95.3, 60.9, 56.0, 54.2.
MS (CI): m/z = 270 [M + H]+, 135.5 [M + 2 H]2+.
1-(3-Methoxyphenyl)-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-tri-
azacyclopent[cd]indene Hydrobromide (12e)
Prepared from 9a (187 mg, 0.5 mmol) and 3-methoxyaniline (62
Anal. Calcd for C13H11N5O2·HBr: C, 44.59; H, 3.45; N, 20.00.
Found: C, 44.49; H, 3.63; N, 19.85.
mg, 0.5 mmol) with DIPEA (129 mg, 1.0 mmol).
1-Benzyl-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-triazacyclo-
pent[cd]indene Hydrobromide (12h)
Yield: 157 mg (83%); yellow solid; mp 302–303 °C.
1H NMR: d = 3.82 (s, 3 H, OCH3), 4.21 (dd, J1 = 12.0 Hz, J2 = 10.5
Hz, 1 H, H3 cis to H2a), 4.35 (dd, J1 = 10.5 Hz, J2 = 9.3 Hz, 1 H, 3-
H trans to 2a-H), 4.62 (dd, J1 = 9.9 Hz, J2 = 9.3 Hz, 1 H, H2 trans
to H2a), 4.90 (dd, J1 = 12.4 Hz, J2 = 9.9 Hz, 1 H, H2 cis to H2a),
5.46 (m, 1 H, H2a), 6.50 (d, J = 9.4 Hz, 1 H, H7), 6.98 (m, 2 H, H2¢,
H6¢), 7.02 (m, 1 H, H4¢), 7.47 (m, 1 H, H5¢), 8.36 (d, J = 9.4 Hz, 1
H, H6), 10.15 (br s, 1 H, NH).
13C NMR: d = 160.2, 153.4, 149.8, 143.2, 137.5, 131.0, 120.4,
113.0, 112.9, 106.8, 95.6, 61.0, 55.6, 55.6, 54.2.
MS (CI): m/z = 299 [M+H]+.
To a suspension of 9a (748 mg, 2.0 mmol) in CH2Cl2 (25 mL) were
added dropwise DIPEA (412 mg, 0.545 mL; 3.2 mmol) and subse-
quently benzylamine (214 mg, 0.229 mL; 2.0 mmol). The mixture
was stirred at r.t. for 16 h, DIPEA (0.02 mL, 0.12 mmol) was added
and stirring was continued at 30 °C for 2 h. The precipitate was col-
lected by filtration.
Yield: 359 mg (51%, based on a 2:1 mixture of hydrobromide and
hydrochloride); light yellow solid; mp 271 °C (decomp.).
1H NMR: d = 4.12 (dd, J1 = 12.1 Hz, J2 = 10.5 Hz, 1 H, H3 cis to
H2a), 4.13 (dd, J1 = 12.3 Hz, J2 = 10.6 Hz, 1 H, H2 cis to H2a), 4.18
(dd, J1 = 10.6 Hz, 9.5 Hz, 1 H, H2 trans to H2a), 4.22 (dd, J1 = 10.5
Hz, J2 = 9.4 Hz, 1 H, H3 trans to H2a), 4.81 (s, 2 H, CH2), 5.30
(dddd, J1 = 12.3 Hz, J2 = 12.1 Hz, J3 = 9.5 Hz, J4 = 9.4 Hz, 1 H,
H2a), 6.56 (d, J = 9.5 Hz, 1 H, H7), 7.34–7.43 (m, 5 H, Ph), 8.35 (d,
J = 9.5 Hz, 1 H, H6), 9.97 (br s, 1 H, NH).
13C NMR: d = 156.1, 150.1, 142.4, 133.8, 128.8, 128.3, 118.8, 94.9,
58.7, 55.5, 54.6, 44.5.
HRMS: m/z [M + H]+ calcd for C15H14N4O2: 283.1195; found:
283.1194.
Anal. Calcd for C15H14N4O3·HBr: C, 47.51; H, 3.99; N, 14.77.
Found: C, 47.49; H, 4.08; N, 14.83.
1-(3-Aminocarbonylphenyl)-5-nitro-1,2,2a,3-tetrahydro-
1,4,7b-triazacyclopent[cd]indene Hydrobromide (12f)
Prepared from 9a (374 mg, 1.0 mmol) and 3-aminobenzamide (137
mg, 1.0 mmol) with DIPEA (260 mg, 2.0 mmol). The precipitate
was separated by filtration, immediately transferred into a glass
dish, triturated after drying and stirred at 42 °C for 18 h in CH2Cl2
to which one drop of DIPEA was added.
Anal. Calcd for C15H14N4O2·0.67HBr·0.33HCl: C, 51.66; H, 4.43;
N, 16.07. Found: C, 51.51; H, 4.45; N, 16.00.
Yield: 143 mg (36%); yellow solid; mp 200 °C (decomp.).
1H NMR: d = 4.24 (dd, J1 = 12.1 Hz, J2 = 10.5 Hz, 1 H, H3 cis to
H2a), 4.36 (dd, J1 = 10.5 Hz, J2 = 9.6 Hz, 1 H, H3 trans to H2a),
4.66 (t, J = 10.1 Hz, 1 H, H2 trans to H2a), 4.96 (dd, J1 = 12.5 Hz,
J2 = 10.1 Hz, 1 H, H2 cis to H2a), 5.50 (m, 1 H, H2a), 6.51 (d, J =
9.4 Hz, 1 H, H7), 7.57 (br s, 1 H, CONH), 7.60–7.67 (m, 2 H, H2¢,
H6¢), 7.86–7.90 (m, 2 H, H4¢, H6¢), 8.19 (br s, 1 H, CONH), 8.40 (d,
J = 9.4 Hz, 1 H, H6), 10.17 (br s, 1 H, NH).
1H NMR [intermediate 11h (protonated) from a reaction mixture]:
d = 3.91 (m, 1 H, H2 trans to H3), 3.93 (m, 1 H, CH2Br), 4.16 (dd,
J1 = 11.9 Hz, 4.0 Hz, 1 H, CH2Br), 4.24 (dd, J1 = 11.4 Hz, J2 = 10.6
Hz, 1 H, H2 cis to H3), 4.74 (s, 2 H, CH2), 5.69 (m, 1 H, H3), 6.32
(d, J = 9.9 Hz, 1 H, H6), 7.28 (m, 1 H, H4¢), 7.35 (m, 2 H, H3¢), 7.41
(m, 2 H, H2¢), 8.33 (d, J = 9.9 Hz, 1 H, H7), 10.21 (br s, 1 H, NH1).
13C NMR: d = 166.7, 153.4, 149.8, 143.5, 136.6, 136.0, 130.2,
126.2, 123.6, 120.6, 119.8, 95.5, 61.1, 55.8, 54.3.
5-Nitro-1-(3-phenyl-1-propyl)-1,2,2a,3-tetrahydro-1,4,7b-tri-
azacyclopent[cd]indene Hydrobromide (12i)
Prepared from 9a (374 mg, 1.0 mmol) and 3-phenyl-1-propylamine
(135 mg, 1.0 mmol) with DIPEA (220 mg, 1.7 mmol).
MS (CI): m/z = 312 [M + H]+.
Anal. Calcd for C15H13N5O3·HBr: C, 45.94; H, 3.60; N, 17.86.
Found: C, 45.61; H, 3.80; N, 17.65.
Yield: 165 mg (42%); light yellow solid; mp 215–216 °C.
1H NMR: d = 1.91 [m, 2 H, CH2(2)], 2.66 [m, 2 H, CH2(3)], 3.54 [dt,
J1 = 14.2 Hz, J2 = 7.1 Hz, 1 H, CH2(1)], 3.63 [dt, J1 = 14.2 Hz, J2 =
7.1 Hz, 1 H, CH2(1)], 4.15 (dd, J1 = 12.1 Hz, J2 = 10.6 Hz, 1 H, H3
cis to H2a), 4.24 (dd, J1 = 12.1 Hz, J2 = 10.6 Hz, 1 H, H2 cis to H2a),
4.28 (dd, J1 = 10.6, J2 = 9.4 Hz, 1 H, H2 trans to H2a), 4.30 (dd, J1 =
10.6 Hz, J2 = 9.4 Hz, 1 H, H3 trans to H2a), 5.25 (tt, J1 = 12.3 Hz,
J2 = 9.4, 1 H, H2a), 6.40 (d, J = 9.4 Hz, 1 H, H7), 7.19 (m, 1 H, H4¢),
7.23 (m, 2 H, H2¢), 7.29 (m, 2 H, H3¢), 8.28 (d, J = 9.6 Hz, 1 H, H6),
9.94 (br s, 1 H, NH).
5-Nitro-1-(3-pyridyl)-1,2,2a,3-tetrahydro-1,4,7b-triazacyclo-
pent[cd]indene Hydrobromide (12g)
To a suspension of 9a (150 mg, 0.4 mmol) in CH2Cl2 (2 mL) were
added 2,4-dimethylpyridine (86 mg, 0.05 mL, 0.4 mmol) and sub-
sequently dropwise a solution of 3-aminopyridine (38 mg, 0.4
mmol) and 2,4-dimethylpyridine (86 mg, 0.05 mL, 0.4 mmol) in
CH2Cl2 (2 mL). After stirring at r.t. for 24 h 2,4-dimethylpyridine
(0.1 mL) was added and stirring was continued for 24 h. The precip-
itate was collected by filtration.
13C NMR: d = 156.2, 150.3, 141.9, 141.0, 128.4, 128.2, 125.9,
118.3, 95.0, 58.6, 55.4, 54.6, 44.8, 31.8, 28.3.
Yield: 89 mg (63%); yellow solid; mp 200–210 °C.
1H NMR: d = 4.24 (dd, J1 = 12.3 Hz, J2 = 10.6 Hz, 1 H, H3 cis to
H2a), 4.37 (dd, J1 = 10.6 Hz, J2 = 9.4 Hz, 1 H, H3 trans to H2a),
4.70 (dd, J1 = 9.6 Hz, J2 = 9.2 Hz, 1 H, H2 trans to H2a), 4.96 (dd,
J1 = 12.4 Hz, J2 = 10.0 Hz, 1 H, H2 cis to H2a), 5.51 (tt, J1 = 12.3
Hz, J2 = 9.1 Hz, 1 H, H2a), 6.57 (d, J = 9.4 Hz, 1 H, H7), 7.60 (ddd,
J1 = 8.3 Hz, J2 = 4.7 Hz, J3 = 0.5 Hz, 1 H, 5¢-H¢), 7.95 (ddd, J1 = 8.3
Hz, J2 = 2.8 Hz, J3 = 1.3 Hz, 1 H, H4¢), 8.41 (d, J = 9.4 Hz, 1 H, H6),
8.59 (dd, J1 = 4.7 Hz, J2 = 1.3 Hz, 1 H, H6¢), 8.75 (br d, J = 2.5 Hz,
1 H, H2¢) 10.21 (br d, 1 H, NH).
MS (CI): m/z = 311 [M + H]+.
Anal. Calcd for C17H18N4O2·HBr: C, 52.19; H, 4.89; N, 14.32.
Found: C, 52.20; H, 4.91; N, 14.29.
1H NMR [intermediate 11i (protonated) which in one case precipi-
tated in crude form]: d = 1.91 [m, 2 H, CH2(2)], 2.66 [m, 2 H,
CH2(3)], 3.53 [br m, 2 H, CH2(1)], 3.87 (m, 2 H, H2 trans to H3,
CH2Br), 4.04 (dd, J1 = 11.8 Hz, J2 = 4.7 Hz, 1 H, CH2Br), 4.19 (dd,
J1 = 11.4, J2 = 10.5 Hz, 1 H, H2 cis to H3), 5.48 (m, 1 H, H3), 6.45
(d, J = 10.0 Hz, 1 H, H6), 7.18 (m, 1 H, H4¢), 7.21 (m, 2 H, H2¢),
Synthesis 2005, No. 18, 3107–3118 © Thieme Stuttgart · New York

PAPER
Triazacyclopenta[cd]indenes
3115
7.29 (m, 2 H, H3¢), 8.28 (d, J = 9.9 Hz, 1 H, H7), 9.48 [br t, J = 5.5
MS (CI): m/z = 363 [M +H ]+, 365, 443 [M + HBr + H]+, 445, 447.
Hz, 1 H, NH (5)], 10.19 (br s, 1 H, NH1).
Anal. Calcd for C15H15BrN4O2·HBr: C, 40.57; H, 3.63; N, 12.62.
Found: C, 40.69; H, 3.71; N, 12.64.
1-Cyclohexyl-5-nitro-1,2,2a,3-tetrahydro-1,4,7b-triazacyclo-
pent[cd]indene Hydrobromide (12j)
Prepared from 9a (748 mg, 2.0 mmol) and cyclohexyl amine (198
mg, 0.23 mL, 2.0 mmol) with DIPEA (439 mg, 0.58 mL, 3.4 mmol);
3 d; crystallized from CH2Cl2.
5-Nitro-1,4-diphenyl-2,2a,3,4-tetrahydro-4,7b-diaza-1-azonia-
cyclopent[cd]indene Iodide (17)
Compound 19 (80 mg, 0.09 mmol) of was dissolved in DMSO (2
mL). After 20 min at r.t. water (10 mL) was added and the solution
was extracted with CH2Cl2 (10 mL). The organic phase was washed
with water (10 mL) and was then stirred with a 0.2 M aq solution of
sodium disulfite (15 mL) for 30 min at r.t. The organic layer was
separated and evaporated, the residual material crystallized from
CH2Cl2–petroleum ether.
Yield: 281 mg (39%); light yellow solid; mp 225 °C (decomp.).
1H NMR: d = 1.12 (qt, J1 = 12.8 Hz, J2 = 3.5 Hz, 1 H, H4a-cy), 1.28–
1.90 (m, 9 H, cy), 3.86 (tt, J1 = 11.5 Hz, J2 = 3.7 Hz, 1 H, H1-cy),
4.13 (dd, J1 = 11.9 Hz, J2 = 10.6 Hz, 1 H, H2 cis to H2a), 4.18 (dd,
J1 = 12.4 Hz, J2 = 10.6 Hz, 1 H, H3 cis to H2a), 4.26 (dd, J1 = 10.6
Hz, J2 = 9.4 Hz, 1 H, H2 trans to H2a), 4.29 (dd, J1 = 10.6 Hz, J2 =
9.4 Hz, 1 H, H3 trans to H2a), 5.22 (tt, J1 = 12.3 Hz, J2 = 9.4 Hz, 1
H, H2a), 6.47 (d, J = 9.4 Hz, 1 H, H7), 8.26 (d, J = 9.4 Hz, 1 H, H6),
9.94 (br s, 1 H, NH).
13C NMR: d = 155.3, 150.5, 141.6, 118.2, 95.4, 55.1, 55.0, 54.6,
30.6, 28.6, 24.5, 24.4, 24.3.
MS (CI): m/z = 275 [M + H]+.
Yield: 55 mg (100%); yellow solid; mp 250 °C.
1H NMR: d = 4.67 (t, J = 9.6 Hz, 1 H, H2 trans to H2a), 4.71 (dd,
J1 = 12.6 Hz, J2 = 9.9 Hz, 1 H, H3 cis to H2a), 4.76 (dd, J1 = 9.9 Hz,
J2 = 9.6 Hz, 1 H, H3 trans to H2a), 4.97 (dd, J1 = 12.6 Hz, J2 = 9.6
Hz, 1 H, H2 cis to H2a), 5.68 (m, 1 H, H2a), 6.68 (d, J = 9.4 Hz, 1
H, H7), 7.35 (m, 2 H, H2¢¢), 7.40 (m, 1 H, H4¢¢), 7.42 (m, 1 H, H4¢),
7.48 (m, 2 H, H3¢¢), 7.51 (m, 2 H, H2¢), 7.59 (m, 2 H, H3¢), 8.46 (d,
J = 9.4 Hz, 1 H, H6).
13C NMR: d = 152.7, 145.8, 144.9, 139.4, 136.4, 130.1, 129.1,
128.0, 127.4, 122.3, 120.7, 96.6, 64.3, 60.2, 55.4.
MS (CI): m/z = 345 [M+], 473 [M + HI]+.
Anal. Calcd for C14H18N4O2·HBr: C, 47.34; H, 5.39; N, 15.77.
Found: C, 47.63; H, 5.71; N, 15.40.
1H NMR [characteristic signals of the intermediate 11j (protonated)
from a reaction mixture]: d = 5.73 (br m, 1 H, H3), 6.58 (d, J = 9.9
Hz, 1 H, H6), 8.36 (d, J = 9.9 Hz, 1 H, H7), 9.05 [br d, J = 7.8 Hz,
1 H, NH (5)], 10.21 (br s, 1 H, NH1).
Anal. Calcd for C20H17N4O2I: C, 50.86; H, 3.63; N, 11.86. Found:
C, 50.73; H, 3.61; N, 11.69.
3-Bromomethyl-5-morpholino-8-nitro-2,3-dihydroimidazo[1,2-
a]pyridine Hydrobromide (16a)
To a suspension of 9a (374 mg, 1.0 mmol) in CH2Cl2 (5 mL) were
added Et3N (152 mg, 0.207 mL, 1.5 mmol), and subsequently 15a
(87 mg, 0.87 mL, 1.0 mmol). The mixture was stirred at r.t. for 16
h and the precipitate was collected by filtration.
2-Anilino-6-(N-allylanilino)-3-nitropyridine (18)
To a solution of 2,6-bisanilino-3-nitropyridine22 (495 mg, 1.5
mmol) in DMF (3 mL) were added K2CO3 (270 mg, 2.0 mmol) and
allyl bromide (240 mg, 0.17 mL, 2.0 mmol). The mixture was
stirred at r.t. for 16 h. Another portion of allyl bromide (240 mg)
was added and stirring was continued for 16 h. Water (75 mL) was
added and the mixture was extracted with EtOAc (45 mL). The or-
ganic layer was separated and concentrated under vacuum. The res-
idue was purified by column chromatography on silica gel (n-
hexane–EtOAc, 4:1).
Yield: 235 mg (55%); yellow solid; mp 212–218 °C (decomp.).
1H NMR: d = 3.59–3.84 (m, 8 H, morph.), 3.87 (dd, J1 = 11.9 Hz,
J2 = 2.8 Hz, 1 H, H2 trans to H3), 3.90 (dd, J1 = 11.9 Hz, J2 = 2.5
Hz, 1 H, one of CH2), 4.05 (dd, J1 = 11.9 Hz, J2 = 4.6 Hz, 1 H, CH2),
4.20 (dd, J1 = 11.9 Hz, J2 = 9.9 Hz, 1 H, H2 cis to H3), 5.70–5.77
(m, 1 H, H3), 6.71 (d, J = 9.6 Hz, 1 H, H6), 8.55 (d, J = 9.6 Hz, 1 H,
H7), 10.38 (s, 1 H, NH).
13C NMR: d = 156.0, 150.7, 140.0, 119.5, 102.9, 65.4, 62.2, 50.0,
47.9, 33.1.
MS (CI): m/z = 343 [M + H]+, 345, 423[M + HBr + H]+, 425, 427.
Yield: 407 mg (64%); orange crystals; mp 104–105 °C.
1H NMR: d = 4.51 (dt, J1 = 5.3 Hz, J2 = 1.4 Hz, 2 H, H1-allyl), 5.11
(dq, J1 = 16.4 Hz, J2 = 1.4 Hz, 1 H, H3-allyl-cis), 5.12 (dq, J1 = 10.6
Hz, J2 = 1.4 Hz, 1 H, H3-allyl-trans), 5.90 (br, 1 H, H5), 5.91 (ddt,
J1 = 16.4 Hz, J2 = 10.6 Hz, J3 = 5.3 Hz, 1 H, H2-allyl), 7.09 (m, 1
H, H4¢), 7.28 (m, 2 H, H3¢), 7.35 (m, 2 H, H2¢¢), 7.41 (m, 1 H, H4¢¢),
7.51 (m, 2 H, H3¢¢), 7.59 (m, 2 H, H2¢9), 8.17 (d, J = 9.5 Hz, 1 H,
H4), 10.60 (s, 1 H, NH).
13C NMR: d = 159.3, 150.4, 142.7, 138.1, 136.3, 132.9, 130.0,
128.5, 127.8, 124.0, 122.2, 119.3, 117.3, 101.0, 53.6.
MS (EI): m/z = 346 [M]+.
Anal. Calcd for C12H15BrN4O3·HBr: C, 33.99; H, 3.80; N, 13.21.
Found: C, 33.86; H, 3.90; N, 13.33.
3-Bromomethyl-5-(N-methylanilino)-8-nitro-2,3-dihydroimi-
dazo[1,2-a]pyridine Hydrobromide (16b)
To a suspension of 9a (150 mg, 0.4 mmol) in CH2Cl2 (4 mL) was
added DIPEA (83 mg, 0.11 mL, 0.64 mmol) upon which a dark red
solution was formed. Compound 15 (43 mg, 0.043 mL, 0.4 mmol)
was added and the mixture was left at r.t. for 24 h. The precipitate
was collected by filtration.
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.27; H, 5.28; N, 16.05.
3-Iodomethyl-6-nitro-1-phenyl-5-phenylimino-2,3-dihydro-1H-
imidazo[1,2-a]pyridine Hydrotriiodide (19)
To a solution of 18 (162 mg, 0.47 mmol) in CH2Cl2 (10 mL) was
added iodine (119 mg, 0.47 mmol). The solution was stirred at r.t.
for 2 h and another portion of iodine (119 mg, 0.47 mmol) was add-
ed. After another 4 h at r.t. the dark colored crystalline product was
collected by filtration.
Yield: 111 mg (76%); yellow solid; mp 205 °C.
1H NMR: d = 3.64 (s, 3 H, Me), 3.67 (dd, J1 = 11.9 Hz, J2 = 3.0 Hz,
1 H, H2 trans to H3), 3.69 (dd, J1 = 11.4 Hz, J2 = 2.3 Hz, 1 H, CH2),
3.90 (dd, J1 = 11.9 Hz, J2 = 9.9 Hz, 1 H, H2 cis to H3), 3.90 (dd,
J1 = 11.4 Hz, J2 = 5.6 Hz, 1 H, CH2), 4.02 (m, 1 H, H3), 6.78 (d,
J = 9.6 Hz, 1 H, H6), 7.48 (m, 1 H, H4¢), 7.56 (m, 2 H, H3¢), 7.59
(m, 2 H, H2¢), 8.67 (d, J = 9.6 Hz, 1 H, H7), 10.37 (s, 1 H, NH).
Yield: 400 mg (99%); mp 78 °C.
1H NMR (CDCl3): d = 3.23 (dd, J1 = 11.9 Hz, J2 = 2 Hz, 1 H, CH2),
3.69 (dd, J1 = 11.9 Hz, J2 = 4.6 Hz, 1 H, CH2), 3.92 (dd, J1 = 11.6
Hz, J2 = 3.3 Hz, 1 H, H2 trans to H3), 4.77 (br, 1 H, H3), 5.16 (dd,
13C NMR: d = 154.2, 150.8, 142.3, 140.7, 130.7, 128.8, 125.0,
120.3, 103.1, 60.9, 47.5, 44.6, 32.5.
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S. Schmid et al.
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J1 = 11.6 Hz, J2 = 10.9 Hz, 1 H, H2 cis to H3), 6.32 (d, J = 9.9 Hz,
1 H, H8), 7.51–7.70 (m, 10 H, Ph), 8.68 (d, J = 9.9 Hz, 1 H, H6),
11.41 (br, 1 H, NH).
MS (CI): m/z = 473 [M + H]+.
HRMS: m/z [M + H]+ calcd for C8H9IN4O2: 320.9849; found:
320.9851.
Anal. Calcd for C8H9IN4O2·HI: C, 21.45; H, 2.25; N, 12.51. Found:
C, 21.53; H, 2.27; N, 12.50.
Anal. Calcd for C20H17IN4O2·HI3: C, 28.13; H, 2.12; N, 6.56.
Found: C, 28.08; H, 2.28; N, 6.54.
5-Nitro-1,2,2a,3-tetrahydro-1,4,7b-triazacyclopent[cd]indene
Hydroiodide (20)
A mixture of 26 (40 mg, 0.09 mmol), CH2Cl2 (1.8 mL), and DIPEA
(18 mg, 0.024 mL, 0.14 mmol) was stirred at r.t. for 4 d. The precip-
itate was collected and washed with CH2Cl2.
2-Allylamino-6-amino-3-nitropyridine (21)
Concd aq NH3 (15 mL) was added to a concd solution of 4a (5.0 g,
23.4 mmol) in EtOH and the mixture was heated in a closed vessel
to 50 °C for 5 d. The solution was evaporated to dryness and the res-
idue was distributed between water and EtOAc. Evaporation of the
organic phase gave 21 (4.53 g, 100%).
Yield: 23 mg (82%); amorphous orange solid; mp 140 °C (de-
comp.).
1H NMR: d = 4.13 (dd, J1 = 12.1 Hz, J2 = 10.4 Hz, 1 H, H2 cis to
H2a), 4.15 (dd, J1 = 12.4 Hz, J2 = 10.9 Hz, 1 H, H3 cis to H2a), 4.24
(dd, J1 = 10.4 Hz, J2 = 9.4 Hz, 1 H, H2 trans to H2a), 4.28 (dd, J1 =
10.9 Hz, J2 = 9.4 Hz, 1 H, H3 trans to H2a), 5.26 (tt, J1 = 12.3 Hz,
J2 = 9.4 Hz, 1 H, H2a), 6.19 (d, J = 9.4 Hz, 1 H, H7), 8.23 (d, J =
9.4 Hz, 1 H, H6), 9.89 (s, 1 H, NH).
13C NMR: d = 157.6, 150.1, 141.9, 118.3, 96.0, 56.4, 54.7, 54.5.
HRMS: m/z [M + H]+ calcd for C8H9N4O2: 193.0726; found:
Yellow crystals; mp 118–120 °C.
1H NMR: d = 4.14 (tt, J1 = 5.6 Hz, J2 = 1.6 Hz, 2 H, CH2), 5.10 (dq,
J1 = 10.4 Hz, J2 = 1.5 Hz, 1 H, H3-allyl-trans), 5.17 (dq, J1 = 17.2
Hz, J2 = 1.8 Hz, 1 H, H3-allyl-cis), 5.91 (d, J = 9.4 Hz, 1 H, H5),
5.96 (ddt, J1 = 17.2 Hz, J2 = 10.4 Hz, J3 = 5.3 Hz, 1 H, H2-allyl),
7.39 (br, 1 H, NH2), 7.50 (br, 1 H, NH2), 8.00 (d, J = 9.1 Hz, 1 H,
H4), 8.93 (br t, J = 5.7 Hz, 1 H, NH).
13C NMR: d = 162.4, 154.1, 135.7, 135.2, 117.8, 115.6, 101.2, 42.3.
MS (CI): m/z = 195 [M + H]+.
193.0729.
6-Allylamino-2-anilino-3-nitropyridine (28)
A solution of 2-anilino-6-chloro-3-nitropyridine22 (1000 mg, 4
mmol), allyl amine (286 mg, 0.375 mL, 5 mmol), and DIPEA (542
mg, 0.854 mL, 5 mmol) in CH2Cl2 (2 mL) was refluxed for 2 h. The
mixture was washed with 0.2 M aq citric acid (15 mL) and aq
NaHCO3 and evaporated. The residue was crystallized from n-hex-
ane–EtOAc (4:1).
Anal. Calcd for C8H10IN4O2: C, 49.48; H, 5.19; N, 28.85. Found: C,
49.58; H, 5.25; N, 28.85.
2-Allylamino-6-(bis-tert.-butoxycarbonylamino)-3-nitropyri-
dine (22)
To a solution of 21 (2.0 g, 10.3 mmol) in CH2Cl2 (25 mL) were add-
ed di-tert-butyldicarbonate (4.8 g, 22.0 mmol) and 4-(N,N-dimeth-
ylamino)pyridine (DMAP, 50 mg). After 20 min at r.t. the mixture
was evaporated to dryness and the residue crystallized from n-hex-
ane–EtOAc (6:1).
Yield: 800 mg (74%); light orange crystals; mp 146–148 °C.
1H NMR: d = 3.98 (br t, J = 5.3 Hz, 2 H, CH2), 5.11 (dq, J1 = 10.2
Hz, J2 = 1.5 Hz, 1 H, H-allyl-3 trans to CH2), 5.17 (dq, J1 = 17.2 Hz,
J2 = 1.5 Hz, 1 H, H-allyl-3 cis to CH2), 5.90 (ddt, J1 = 17.2 Hz, J2 =
10.2 Hz, J3 = 5.3 Hz, 1 H, H-allyl-2), 6.16 (d, J = 8.4 Hz, 1 H, H5),
7.11 (m, 1 H, H4¢), 7.34 (m, 2 H, H3¢), 7.70 (m, 2 H, H2¢), 8.10 (d,
J = 8.4 Hz, 1 H, H4), 8.44 (br t, J = 5.2 Hz, 1 H, 6-NH) 10.82 (br s,
1 H, 2-NH).
13C NMR: d = 160.1, 152.2, 138.2, 135.0, 134.5, 128.5, 123.8,
121.9, 118.1, 115.9, 103.2, 43.3.
MS (CI): m/z = 271 [M + H]+.
Yield: 2.45 g (69%); yellow crystals; mp 104–107 °C.
1H NMR: d = 1.48 (s, 18 H, t-Bu) 4.08 (tt, J1 = 5.7 Hz, J2 = 1.5 Hz,
2 H, CH2), 5.08 (dq, J1 = 10.4 Hz, J2 = 1.5 Hz, 1 H, H3-allyl-trans),
5.15 (dq, J1 = 17.2 Hz, J2 = 1.6 Hz, 1 H, H3-allyl-cis), 5.91 (ddt,
J1 = 17.2 Hz, J2 = 10.4 Hz, J3 = 5.3 Hz, 1 H, H2-allyl), 6.95 (d, J =
9.1 Hz, 1 H, H5), 8.46 (d, J = 9.1 Hz, 1 H, H4), 8.69 (br t, J = 5.8
Hz, 1 H, NH).
13C NMR: d = 154.7, 151.1, 149.8, 138.0, 134.7, 124.2, 115.8,
104.2, 84.2, 42.7, 27.3.
MS (CI): m/z = 395 [M + H]+.
Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C,
62.36; H, 5.29; N, 20.85.
Anal. Calcd for C18H26N4O6: C, 54.81; H, 6.64; N, 14.20. Found: C,
54.74; H, 6.61; N, 14.36.
3-Iodomethyl-5-phenylimino-6-nitro-2,3-dihydro-1H-imida-
zo[1,2-a]pyridine Hydroiodide (29)
To a solution of 28 (108 mg, 0.4 mmol) in CH2Cl2 (4 mL) was added
iodine (200 mg, 0.8 mmol). The mixture was stirred at r.t. for 1 d.
The dark precipitate was collected by filtration and stirred with a 0.2
M aq sodium disulfite solution (3 mL) for 30 min. The solid mate-
rial was separated by filtration and washed with acetone and
CH2Cl2.
5-Imino-3-iodomethyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-
a]pyridine Hydroiodide (26)
To a solution of 21 (360 mg, 1.8 mmol) in CH2Cl2 (15 mL) was add-
ed iodine (683 mg, 2.7 mmol). The mixture was stirred at r.t. for 2
d. The dark precipitate was dissolved in DMF (2.5 mL) and kept at
60 °C for 2 h. The solvent was removed under vacuum and the re-
maining material was triturated with boiling CH2Cl2 (15 mL). The
yellow precipitate was collected by filtration.
Yield: 210 mg (100%); yellow solid; mp 143 °C.
1H NMR (500 MHz, CD3OD internal standard CD3 = 3.31 ppm):
d = 3.39 (dd, J1 = 11.4 Hz, J2 = 2.3 Hz, 1 H, CH2), 3.61 (dd, J1 = 11.4
Hz, J2 = 6.6 Hz, 1 H, CH2), 3.77 (dd, J1 = 12.1 Hz, J2 = 3.3 Hz, 1 H,
H2 trans to H3), 4.07 (dd, J1 = 12.1 Hz, J2 = 9.9 Hz, 1 H, H2 cis to
H3), 4.43 (m, 1 H, H3), 6.54 (d, J = 9.6 Hz, 1 H, H8), 7.43 (m, 2 H,
ortho-H), 7.44 (m, 1 H, para-H), 7.55 (m, 2 H, meta-H), 8.67 (d,
J = 9.9 Hz, 1 H, H7).
Yield: 610 mg (75%); mp 155 °C (decomp.).
1H NMR: d = 3.59 (dd, J1 = 11.4 Hz, J2 = 2.5 Hz, 1 H, CH2), 3.73
(m, 2 H, H2 trans to H3, CH2), 4.17 (dd, J1 = 11.9 Hz, J2 = 10.1 Hz,
1 H, H2 cis to H3), 5.03 (m, 1 H, H3), 6.19 (d, J = 9.6 Hz, 1 H, H6),
+
8.32 (d, J = 9.6 Hz, 1 H, H7), 9.14 (br, 1 H, NH2 ), 9.72 (br, 1 H,
+
NH2 ), 10.16 (br, 1 H, H1).
13C NMR [CD3OD (internal standard 49.00 ppm)]: d = 159.4, 147.0,
143.4, 137.5, 131.6, 129.2, 125.2, 99.2, 63.4, 50.5, 49.5.
13C NMR: d = 153.7, 149.3, 138.5, 116.1, 100.1, 57.5, 54.9, 50.4.
Synthesis 2005, No. 18, 3107–3118 © Thieme Stuttgart · New York

PAPER
Triazacyclopenta[cd]indenes
3117
MS (CI) under the experimental conditions reduction to a de-iodi-
nated species occurs: 271 [M + H]+ and a peak for I2: 255 [I2 + H]+
appears.
This material (450 mg) was dissolved in CH2Cl2 (4 mL) and aniline
(93 mg, 0.09 mL, 1 mmol) was added dropwise followed by DIPEA
(129 mg, 0.171 mL, 1 mmol). The mixture was stirred for 4 h and
the formed precipitate (370 mg) was collected by filtration. The 1H
NMR spectrum of this product was identical with that of the iodide
of 17 (see above) except that it was contaminated with 10% of a 4-
bromophenyl analogue.
Anal. Calcd for C14H13IN4O2·HI: C, 32.08; H, 2.69; N, 10.69.
Found: C, 31.97; H, 2.63 N, 10.59.
7-Nitro-1-phenyl-1,2,2a,3-tetrahydro-1,4,7b-triazacyclopen-
ta[cd]indene Hydroiodide (27)
To a solution of 29 (105 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added
DIPEA (32.3 mg, 0.042 mL, 0.25 mmol) and the mixture was
stirred at r.t. for 1 h. The precipitate was collected by filtration.
1H NMR: d = 6.70 (d, J = 9.4 Hz, 1 H, H7), 7.77 (part of an AA¢BB¢
system, 2 H, BrPh), 8.50 (d, J = 9.4 Hz, 1 H, H6).
Acknowledgment
Yield: 62 mg (78%); pale yellow crystals; mp 240 °C (decomp.).
We would like to thank N. Mayr and M. Schmid (University of
Ulm) for technical assistance, W. Bolek, Boehringer Ingelheim
Pharma GmbH & Co. KG in Biberach, for assistance with the 2D-
NMR spectra, Dr. M. Wunderlin, Section Mass Spectrometry at the
University of Ulm, and E. Endris (Boehringer Ingelheim Pharma
GmbH & Co. KG, Biberach) for assistance with the MS spectra, and
Margit Lang, Department of Analytical Chemistry, University of
Ulm, for the elemental analyses. Sponsorship of a guest professor-
ship (V.A.) as well as additional support by Boehringer Ingelheim
Pharma GmbH & Co. KG is gratefully acknowledged. V.A. and
S.S. are grateful to Prof. Bäuerle, head of the Department of Orga-
nic Chemistry II, University of Ulm, for his generous support with
department resources.
1H NMR: d = 4.22 (dd, J1 = 12.6 Hz, J2 = 10.9 Hz, 1 H, H3 cis to
H2a), 4.32 (dd, J1 = 10.9 Hz, J2 = 9.4 Hz, 1 H, H3 trans to H2a),
4.64 (m, 2 H, H2), 5.47 (m, 1 H, H2a), 6.38 (d, J = 9.4 Hz, 1 H, H5),
7.32 (m, 2 H, ortho-H), 7.35 (m, 1 H, para-H), 7.44 (m, 2 H, meta-
H), 8.33 (d, J = 9.4 Hz, 1 H, H7), 9.90 (br, 1 H, NH).
13C NMR: d = 156.9, 145.8, 143.7, 139.6, 128.9, 127.8, 120.4, 97.2,
64.5, 56.2, 54.0.
HRMS: m/z [M + H]+ calcd for C14H13N4O2: 269.1039; found:
269.1034.
Bromination of 2-Allylamino-6-(bis-tert-butoxycarbonylami-
no)-3-nitropyridine
To a solution of 22 (394 mg, 1 mmol) in CH2Cl2 (3 mL) was added
dropwise at r.t. a solution of bromine (160 mg, 0.051 mL, 1 mmol).
After 20 min the solvent was removed under vacuum and a 1H NMR
spectrum (DMSO) of the residue was taken which showed the sig-
nals of a 2:1 mixture of 23 and 24.
1H NMR (DMSO): d = 1.44 (s, 9 H, t-Bu), 3.65 (dd, J1 = 12.1 Hz,
J2 = 3.8 Hz, 1 H, CH2), 3.97 (dd, J1 = 12.1 Hz, J2 = 2.0 Hz, 1 H,
CH2), 4.02 (dd, J1 = 12.4 Hz, J2 = 3.8 Hz, 1 H, H2 trans to H3), 4.34
(dd, J1 = 12.4 Hz, J2 = 10.6 Hz, 1 H, H2 cis to H3), 5.48 (m, 1 H,
H3), 7.50 (d, J = 8.6 Hz, 1 H, H6), 9.12 (d, J = 8.6 Hz, 1 H, H7),
10.78 (br s, 1 H, NH)].
References
(1) Schmid, S. PhD Thesis; University of Ulm: Germany, 2005.
(2) (a) Hunt, P. A.; Moody, C. J. Tetrahedron Lett. 1988, 29,
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Through chromatography on silica (n-hexane–EtOAc, 4:1) of half
of the material 23 (80 mg) was obtained as an orange solid.
1H NMR (DMSO): d = 1.50 (s, 9 H, t-Bu), 3.86 (dd, J1 = 11.4 Hz,
J2 = 6.3 Hz, 1 H, CH2Br), 3.94 (dd, J1 = 11.4 Hz, J2 = 5.6 Hz, 1 H,
CH2Br), 3.95 (m, 2 H, CH2), 4.66 [m (slightly distorted pent.), 1 H,
CHBr], 6.97 (d, J = 9.1 Hz, 1 H, H5), 8.48 (d, J = 9.1 Hz, 1 H, H4),
8.74 (t, J = 5.8 Hz, 1 H, NH).
13C NMR (DMSO): d = 154.5, 151.0, 149.9, 138.1, 124.9, 105.5,
84.3, 51.9, 45.7, 36.2, 27.4.
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Anal. Calcd for C18H26Br2N4O6: C, 39.01; H, 4.73; N, 10.11. Found:
C, 39.22; H, 4.85; N, 9.88.
Attempt to Prepare 17 via 9b
A solution of bromine (320 mg, 0.1 mL, 2.0 mmol) in chloroben-
zene (1 mL) was added dropwise at r.t. to a solution of 4b (580 mg)
in chlorobenzene (5 mL). An oily material precipitated which
adopted a glassy state. After 1 h cyclohexene (0.1 mL) was added
and after 20 min the solvent was decanted and the residue was
washed with petroleum ether and dissolved in CH2Cl2 (10 mL). The
solution was evaporated to dryness yielding a yellow material (867
mg).
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MS (CI): 368 [M]+, 370, 372, 448 [M + HBr]+, 450, 452.
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A replacement of chlorine by bromine takes place, which most like-
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MS: 412 [M(Br)]+, 414, 416, 492 [M(Br) + HBr]+, 494, 496.
Chem. Soc., Perkin Trans. 1 1998, 2277.
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3118
S. Schmid et al.
PAPER
(17) Brominations in DMSO in the presence of Br– have also
been observed in other cases, e.g.: (a) Majetich, G.; Hicks,
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Synthesis 2005, No. 18, 3107–3118 © Thieme Stuttgart · New York