Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Article abstract of DOI:10.1016/j.tet.2008.05.062

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.

Full text of DOI:10.1016/j.tet.2008.05.062

Tetrahedron 64 (2008) 7626–7632
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]-
thienopyridazines
*
Vegar Stockmann, Anne Fiksdahl
Department of Chemistry, Sem Saelands v. 8, Norwegian University of Science and Technology, NTNU, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-amino-
pyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3-
and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The
Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyr-
idylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of
the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thi-
enyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the
Received 22 February 2008
Received in revised form 29 April 2008
Accepted 15 May 2008
Available online 18 May 2008
Keywords:
Pyrido[3,4-b]thieno[2,3-d]pyrrole
Pyrido[3,4-b]thieno[3,2-d]pyrrole
Pyrido[4,3-e]thieno[2,3-c]pyridazine
Pyrido[4,3-e]thieno[3,2-c]pyridazine
Suzuki cross coupling
Diazotization
previous order of reactions. The desired b-carboline thiophene analogues (1a,b) were obtained via the
nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intra-
molecular diazocoupling, the corresponding pyridazine products (72–83%, 2a,b) were afforded.
Ó 2008 Elsevier Ltd. All rights reserved.
Diazocoupling
Azide
Nitrene
Thermal decomposition
1. Introduction
1.1. Background
skeleton. By replacing the phenyl-ring of II by five-ring heterocy-
cles, the novel thieno-, furano- or pyrrolo-
b
-carboline analogues
(III, Scheme 1) would be constructed.
b-Carbolines (II, Scheme 1) are naturally occurring alkaloids that
exhibit diverse biological and pharmacological activities. The
carboline ring structure is thus incorporated into many natural
products and pharmaceuticals. Numerous studies of natural oc-
b
-
X
X
NH
NH
NH
NH
currence, identification and isolation of
have been reported and studies of properties, biological and phar-
macological effects of -carboline alkaloids and derivatives have
b-carboline derivatives
N
N
N
b
III X = S, O, NH
β-carboline analogues
I
II
been carried out for several decades. Some of the most recent re-
ports include studies of the antitumor/cytotoxic,1 anticancer,2 an-
timalaria,3 antioxidant,4 free radical scavenging and antithrombotic
carbazole
β-carboline
Scheme 1.
activities.5
b
-Carbolines have also been studied because of the
neuroprotection6 and photosensitiser abilities7 as well as for
treatment of ophthalmic/eye disorders.8
-Carbolines are N-ana-
Pyridazine (Scheme 2) compounds have also been shown to be
biologically active and the pyridazine moiety is incorporated in
a series of pharmaceuticals. Cinnolines (IV, Scheme 2)11 are im-
portant intermediates in the preparation of the antidepressant
Binodaline12 and the antibiotic Cinoxacin.13 A series of substituted
benzo[c]cinnolines (IVa) have herbicidal activity,14 while others are
found to be mutagenic substances,15 being identified as organic
aza-heterocyclic pollutants.16 The corresponding N-analogues pyr-
ido[3,4-c]cinnoline (IVb) ring structure has also been reported.17
Pyridopyridazines (V) have been studied for preventing and
b
logues of carbazoles (I, Scheme 1), which are incorporated into
a number of pharmaceutical agents as well. Both the Carvedilol9
and the Carazolol10
b-blockers are based on the carbazole tricyclic
* Corresponding author.
E-mail address: anne.fiksdahl@chem.ntnu.no (A. Fiksdahl).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.062

V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
7627
treating atherosclerosis18 and have been used for the preparation of
antiviral agents.19 Structure VI represents potential five-ring-fused
heterocyclic analogues.
phenylpyridine by photolysis21 or thermal decomposition22 via the
nitrene (Scheme 4). The nature of the aryl groups affects the cyc-
lisation reactivity. The decomposition of biphenyl azides (X¼CH) is
known to afford the carbazoles (I) in high yields,23,24 while the
introduction of pyridine azide in these reactions reduces the re-
activity towards cyclisation and the corresponding heterocyclic
X
X
N
N
N
N
N
N
N
N
phenylpyridine azide produces
b
-carboline (II, X¼N) in signifi-
N
N
cantly lower yield.25 Attempts to improve the yields of
b-carboline
by Lewis acid thermal cyclisation have met with no success.
N
N
N
X
pyridazines:
IV
V
VI X = S, O, NH
IVa X = CH;
pyrido[3,4-c]- thieno-/furano-pyrrolo-
Cyclisation
benzo[c]cinnoline pyridazine
IVb X = N
pyridopyridazine
NH
Δ
N3
pyrido[3,4-c]cinnoline
X
X
Scheme 2.
I
X = CH; Carbazole
II X = N; β−Carboline
X = CH, N
1.2. Objective
Scheme 4.
Referring to the biological activity, the therapeutic use and the
generally interesting properties discussed above, it would be of
interest to prepare new closely related heterocyclic analogues of
The lower yield obtained for b-carboline (II, Scheme 4) com-
pared to carbazole (I), may be caused by the electron-deficient
character of the pyridine moiety. To improve the reactivity and
compensate for the effect of the pyridine-ring, we wanted to re-
place the phenyl group in the biaryl system of the precursor by
more electron-rich heterocyclic groups, such as five-ring hetero-
cycles (thiophene/furan/pyrrole) to study whether more reactive
biaryl azido-intermediates could be obtained in order to give five-
both b-carbolines (III, Scheme 1) and fused pyridazines (VI, Scheme
2). Heterocycle-fused analogues of benzo-fused heterocycles may
in general offer some advantages from a medicinal chemistry point
of view, since the new heteroatom may provide better water sol-
ubility by offering an additional site for protonation or salt for-
mation or it might enhance intermolecular interactions by
formation of an additional hydrogen bond to target proteins. Many
drugs are derived from thiophene. Bioisosteric effects have been
observed, since the pharmacological effect of the thienyl moiety
often is similar to phenyl or benzyl.25,26
The thienyl-fused heterocycles shown in Scheme 3, the pyr-
ido[3,4-b]thienopyrroles (1a,b) and the pyrido[4,3-e]thienopyr-
idazines (2a,b), would therefore be promising target compounds,
due to their potential biological properties. We wanted to study the
preparation of these heterocyclic compounds.
ring
In the present work, we examined the preparation of the new
thieno- -carboline analogue compounds (1a,b) shown in Scheme
b-carboline analogues (III).
b
3. These pyrido[3,4-b]thienopyrroles products can be prepared
from 3-amino-4-bromopyridine by palladium catalysed Suzuki
cross-coupling with suitable 2-/3-thiphene boronic acids followed
by diazotization, azide substitution and thermal decomposition to
afford the new thieno-b-carboline analogue products (1a,b).
This strategy would also give access to the novel pyrido[3,4-
c]thienopyridazines 2a,b by intramolecular diazocoupling of the
diazonium intermediate.
Our results for the preparation of the new potential biologically
active pyridothienopyrroles (1a,b) and pyridothienopyridazines
(2a,b) are discussed below.
Br
NHCO-tBu
S
3
2
N
b- carboline analogues;
pyrido[3,4-b]-thienopyrroles
B(OH)2
S
Suzuki coupling,
hydrolysis
S
2. Results and discussion
2.1. Intermediates
NH
NH
diazot., NaN3
cyclisation
S
N
1b
N
1a
The synthetic sequences for the preparation of pyrido[3,4-b]-
thieno[2,3-/3,2-d]pyrroles 1a,b and pyrido[4,3-e]thieno[2,3-/3,2-c]-
pyridazines 2a,b are presented in Scheme 5. These two new
groups of tricyclic heterocycles were prepared from 3-nitropyridine
(6) through seven- and six-step pathways. Nitropyridines are now
readily available through an improved nitration method26,27 and an
investigation of the chemistry of nitropyridines is in progress in our
laboratories.
3
2
NH2
S
diazotization
diazo-coupling
S
N
N
N
N
N
N
2a
N
2b
3-Aminopyridine (7) and the pivaloyl amide intermediate (8)28
were obtained in high yields by nitro-reduction (91%) followed by
derivatisation with pivaloyl chloride (96%). Pivaloylaminopyridines
are known to undergo regioselective electrophilic substitution by
ortho-lithiation29 and the 4-bromo-3-amido compound 9 was
prepared from 8.30 However, by using the n-BuLi/TMEDA method
for lithiation, substantial quantities (22%) of the Ziegler alkylation
product (5) was formed,31 caused by nucleophilic attack at C-4 by
n-BuLi. This problem has been reported by others as well.32 The
problem was avoided by using t-BuLi and the 4-bromo-3-
pyrido[4,3-e]-thienopyridazines
Scheme 3.
1.3. Synthetic strategy
The synthetic preparation of b-carbolines has previously been
based on different strategies. The most frequently used methods
are, respectively, the reductive cyclisation of 3-nitro-4-phenyl-
20
pyridines with P(EtO)3 and the direct cyclisation of 3-azido-4-

7628
V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
n-Bu
H
H
N
n-BuLi, TMEDA,
THF, - 78 °C
NO2
NH2
N
H2/Pd
91 %
Me3CCOCl
96 %
O
O
22 %
N
N
7
N
N
5
8
6
i) t-BuLi, THF, - 78 °C
ii) BrCH2CH2Br, - 78 °C
55 %
Br
Pd(PPh3)4
Na2CO3
Pd(PPh3)4
Na2CO3
86%
H
N
S
3
S
2
85%
O
N
B(OH)2
B(OH)2
H2SO4
85%
9
4
3
S
S
Br
H
N
H
N
NH2
O
O
N
16
N
10
N
11
i) NOBF4
ii) NaN3
60%
H2SO4
98%
H2SO4
98%
S
2
S
3
Br
N3
NH2
NH2
N
17
N
12
N
13
4
*)
*)
2
Pd(PPh3)4
Na2CO3
63%
73%
72%
S
15%
*)
NaNO2, H2SO4,
0 oC, NaN3
S
Pyridazine
2a
Pyridazine
2b
3
N3
N3
N
14
N
15
n-decane,
reflux 30 min
14%
n-decane,
reflux 30 min
29%
S
S
3
2
NH
NH
+ by-product (23%)
N
N
1a
1b
Scheme 5.
aminopyridine derivative 9 was isolated (55%) after lithiation of 8
and subsequent reaction with the electrophilic ethylene dibromide.
In Suzuki couplings reactions, (i) electron-deficient aryl halides
and (ii) electron-rich boronic acids are the substrates of choice,
since those compounds are more reactive than the contrary in,
respectively, (i) the oxidative addition and (ii) the transmetallation
steps. The Suzuki coupling of 4-bromopyridine (9) with commer-
cially available 2- and 3-thienylboronic acids (3,4) afforded the
corresponding thien-2-/3-ylpyridine coupling products 10 and 11
in high yields (85–86%). The yields were not altered by reducing the
amount of Pd(PPh3)4 from 5 to 2.5 mol % or the reaction time (12–
6 h). Acidic hydrolysis afforded the aminopyridine intermediates 12
and 13 in quantitative yields.
intermediate 13, the azide product 15 was not observed at all, due
to the competing exclusive formation of the intramolecular diazo-
coupling compound (73%, 2b) (see Section 2.3 below). By ex-
changing the order of the Suzuki coupling, the hydrolysis and
diazotisation steps described above, an alternative method was
used for the preparation of the azide product 15 (Scheme 5). Hy-
drolysis of intermediate 9 (85%) followed by NOBF4 diazotisation/
azide substitution (60%) and subsequent Suzuki coupling (63%)
yielded the azide 15 via intermediates 16 and 17.
Cyclisation by thermal decomposition of azides 14 and 15 via the
nitrenes, afforded the desired b-carboline analogues 1a,b by C–H
insertion into the 3- and 2-positions of thethiophene, respectively.
As expected from the higher reactivity of the 2-position of the
thiophene compared to the 3-position, an increased yield was
obtained by cyclisation of azide 15 to give 1b (29%) compared to 14
for the formation of 1a (14%). However, the yields were re-
producibly low and was not changed or improved by altering the
reaction time (10 mind5 days), the solvent (n-nonane, n-decane,
and undecane), the reflux temperature (150–195 ꢀC) or by
2.2. Pyrido[3,4-b]thienopyrroles (1a,b)
Diazotisation of aminopyridine 12 and subsequent nucleophilic
substitution of the diazonium group with azide afforded the azide
product 14 in 72% yield. By the corresponding reaction of thien-3-yl

V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
7629
introducing a Lewis acid (Ti(O–i-Pr)4). Attempts at performing the
cyclisation by microwave irradiation offered no advantages com-
pared to conventional heating.
protonation of the pyridine moiety. As shown in Scheme 6, no such
activation was needed for diazocoupling of the thien-3-yl 13 to give
2b, since this reaction also took place using NOBF4/MeCN. Due to
the electron-deficient and hence more reactive thienopyridine di-
azonium ion, the obtained yields of the present pyridazines 2a,b are
considerably higher than reported for the corresponding thieno-
phenyl diazonium analogues for the formation of thieno[3,2- and
2,3-c]cinnolines (13–69%).40
The thermal decomposition of azide 15 also afforded an addi-
tional by-product. This new compound was isolated in equivalent
amounts (23%) as the desired cyclisation product 1b but was con-
siderably less polar. The nature of this compound is being in-
vestigated.43 In all reactions, small amounts of the corresponding
primary amine (<5% for azide 14 and <1% for azide 15) and tarry
inseparable products were formed. It is known that such competing
reactions may take place when ring closure is too difficult under the
conditions employed, since the nitrene may abstract hydrogens
from the solvent or similar molecules. Such azide reductions are
also reported to occur together with tar formation.33–36
3. Conclusion
Two new types of pyrido-fused tris-heterocycles have been
prepared from 3-aminopyridine in five/six steps. The novel b-car-
boline analogues pyrido[3,4-b]thieno[2,3/3,2-d]pyrroles (1a,b)
have been prepared by the Suzukidnitrene approach. Additionally,
this diazonium intermediate pathway allowed the synthesis of the
new pyrido[4,3-e]thieno[2,3/3,2-c]pyridazines (2a,b) products by
diazocoupling. The preparation of analogous furan and pyrrole
products is now in progress in our laboratories.
X-ray analysis of the tricyclic product 1b reveal that there are 16
molecules in an unusual cell packing structure.37
The present results show that replacing the phenyl group in the
biaryl azide precursor of
b-carboline (Scheme 4) by the more
electron-rich thiophene moiety did not improve or compensate for
the lower reactivity of the electron-deficient pyridine substrates.25
Thus, similar reactivity of the phenylpyridyl and thienopyridyl
azides (14,15) to give b-carboline and the thiophene analogues has
been demonstrated.
4. Experimental
4.1. General
2.3. Pyrido[4,3-e]thienopyridazines (2a,b)
Chemicals: 2- and 3-Thiophene boronic acid, n-BuLi, t-BuLi
(Sigma–Aldrich), NaNO2 (Merck), BF4NO, C2H4Br2, Pd(PPh3)4
(Fluka). Solvents: Pro analysi quality. THF and ether were distilled
from sodium metal and benzophenone and used directly. All
moisture or air sensitive reactions were performed under nitrogen
atmosphere in pre-dried glassware. Flash column chromatography;
Due to the electron-rich and electron-deficient character of the
thienyl and pyridine moieties, respectively, compounds 12 and 13
represent appropriate intermediates for the formation of intra-
molecular diazocoupling pyridazine products. Even if electrophilic
substitution at the 3-position of thiophene is known to be negli-
gible, minor amounts (15%) of thienopyrido[3,4-c]pyridazine 2a
was isolated from the diazotisation and azide substitution reaction
of aminopyridine 12 (Scheme 5), aiming at the azide product 14
(72%, Section 2.2). However, pyridazine product 2b was exclusively
formed (73%) from 13. Pyridazine 2b is a regioisomer of 2a, formed
by electrophilic substitution at the highly reactive 2-position of the
thiophene 13. As expected, no product due to reaction in the
thienyl-4-position of 13 was observed. In the absence of azide nu-
cleophile, in order to optimise diazocoupling, the pyridazine
products 2a and 2b were afforded in 72% and 83% yields, re-
spectively (Scheme 6). Their structures were confirmed by X-ray
analysis.38,39
SiO2 (SDS, 60 Å, 40–63 m
m). 1H and 13C NMR: Bruker Avance DPX
300 and 400 MHz spectrometers, chemical shifts are reported in
parts per million downfield from TMS. J values are given in hertz.
MS: Finnigan MAT 95 XL mass spectrometer (EI, 70 eV). IR spectra
were obtained with a Nicolet 20SXC FT-IR spectrophotometer,
recorded using a Smart Endurance reflexion cell, unless film or KBr
are specified. All melting points are uncorrected, measured on
a Stuart apparatus. Elemental analyses were done by the Laborator
Beller/Matties, Go¨ttingen, Germany. 3-Nitropyridine (6) was pre-
pared by nitration of pyridine.26,27 3-Aminopyridine (7)41 was
prepared by hydrogenation of 6, according to the literature42 or
purchased from Aldrich and used directly.
4.2. Pyrido[3,4-b]thieno[2,3-d]pyrrole (1a)
S
3
S
3
NaNO2
H2SO4
Thermal cyclisation of azide 14 was carried out by heating
a stirred solution of 14 (141 mg, 0.697 mmol) in n-decane (50 mL)
to above 170 ꢀC. The mixture was kept stirring at reflux until full
conversion of azide 14 (approx. 30 min, monitored by TLC). The
reaction was allowed to cool to room temperature and the decane
was distilled off. Flash chromatography (gradient; 0–10% MeOH/
CH2Cl2) afforded 1a as a white solid (17 mg, 14%), pure by NMR; Rf
0.20 (10% MeOH/CH2Cl2); mp 217–218 ꢀC; 1H NMR (300 MHz,
DMSO-d6) dH: 11.81 (1H, br s, NH), 8.83 (1H, s, J 0.9, pyr-H2), 8.20
(1H, d, J 5.4, pyr-H6), 7.84 (1H, d, J 5.4, thieno-H5), 7.74 (1H, dd, J 5.4,
0.9, pyr-H5), 7.29 (1H, d, J 5.4, thieno-H4); 1H NMR (400 MHz,
CDCl3) dH: 8.98 (1H, s), 8.31 (1H, d, J 5.6), 7.67 (1H, d, J 5.6), 7.60 (1H,
d, J 5.2), 7.17 (1H, d, J 5.2); 13C NMR (75 MHz, CDCl3) dC: 148.0
(thieno-C3), 137.8 (pyr-C2), 135.0 (pyr-C6), 133.0 (thieno-C4), 132.3
(pyr-C3), 127.8 (pyr-C4), 116.6 (thieno-C2), 113.4 (pyr-C5), 111.9
(thieno-C5); NMR assignments are based on HMBC experiments; IR
nmax: 2919, 2851, 1609, 1459, 1344, 1280, 1091, 1053, 986, 817, 806,
797, 762, 707, 667 cmꢁ1; MS m/z (%): 174 (Mþ,100),149 (12),129 (4),
87 (5), 57 (7), 43 (4), 28 (25); HRMS calcd for C9H6N2S: 174.0252;
obsd 174.0249.
N
N
NH2
0 - 20 °C
72%
N
12
N
2a
S
S
2
NOBF4
MeCN
N
N
NH2
0 °C
83%
N
N
2b
13
Scheme 6.
The higher reactivity of the 2-position compared to the 3-
position of the thiophene was also demonstrated by the fact that
strongly acidic conditions (NaNO2/H2SO4, see Scheme 6) were
definitely required for the conversion of thien-2-yl 12 to 2a to take
place. The strong acid would activate the diazonium group by

7630
V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
4.3. Pyrido[3,4-b]thieno[3,2-d]pyrrole (1b)
(22), 28 (8); HRMS calcd for C9H5N3S: 187.0204; obsd 187.0203.
X-ray analysis.39
The title compound was prepared from azide 15 (150 mg,
0.742 mmol) in n-decane (50 mL) as described above for the for-
mation of 1a from 14. Product 1b was obtained as a light grey solid
(38 mg, 0.218 mmol, 29%), pure by NMR. This procedure also
afforded a less polar by-product (23%) after flash chromatogra-
phy.43 Compound 1b: Rf 0.19 (10% MeOH/CH2Cl2); mp 225–226 ꢀC;
1H NMR (300 MHz, DMSO-d6) dH: 12.02 (1H, br s, NH), 8.80 (1H, s, J
5.4, pyr-H2), 8.21 (1H, d, J 5.4, pyr-H6), 7.76 (1H, d, J 5.4, pyr-H5),
7.47 (1H, d, J 5.4, thieno-H5), 7.17 (1H, d, J 5.4, thieno-H4); 13C NMR
(75 MHz, DMSO-d6) dC: 145.2, 138.8, 138.2, 133.8, 125.4, 122.9, 119.2,
117.9, 113.4; IR (KBr) nmax: 3102, 2586, 1608, 1575, 1491, 1477, 1276,
1110, 1035, 805, 715, 709, 667, 640, 594 cmꢁ1; MS m/z (%): 174 (Mþ,
18), 149 (9), 109 (19), 95 (31), 69 (42), 57 (48), 44 (100); HRMS calcd
for C9H6N2S: 174.0252; obsd 174.0250. Anal. Calcd for C9H6N2S: C,
62.05; H, 3.47; N, 16.08; S, 18.40. Found: C, 61.95; H, 3.40; N, 15.98;
S, 18.26. X-ray analysis.37
4.6. 4-Butyl-3-pivaloylaminopyridine (5)44
The title compound was formed31,32 in a reaction of 8, TMEDA
(tetramethyl-1,2-diaminoethane) and n-BuLi in THF, and was iso-
lated as a yellow solid (22%) by flash chromatography (4% Et3N in
EtOAc/pentane (2:1)), pure by NMR; Rf 0.26 (4% Et3N in EtOAc/
pentane (2:1)); 1H NMR (400 MHz, CDCl3) dH: 8.89 (1H, s, H1), 8.34
(1H, d, J 4.8, H6), 7.21 (1H, br s, NH), 7.12 (1H, d, J 4.8, H5), 2.55 (2H, t,
J 8.0, 10-CH2), 1.59 (2H, m, 20-CH2), 1.40 (2H, m, 30-CH2), 1.37 (9H, s,
t-Bu), 0.96 (3H, t, J 7.6, 40-CH3); MS m/z (%): 234 (Mþ, 66), 192 (33),
150 (17), 121 (23), 108 (42), 107 (19), 85 (12), 57 (100).
4.7. N-(Pyridin-3-yl)pivalamide (8)28
The title compound was prepared from amine 7 (1.37 g,
14.6 mmol) as described elsewhere.29 Product 8 was isolated as
a slightly yellow solid (2.50 g, 96%), pure by NMR; Rf 0.25 (4% Et3N
in EtOAc/pentane (2:1)); 1H NMR (400 MHz, CDCl3) dH: 8.58 (1H, d, J
2.8, H2), 8.32 (1H, dd, J 4.8, 1.2, H6), 8.15 (1H, ddd, J 8.4, 2.8, 1.2, H4),
4.4. Pyrido[4,3-e]thieno[3,2-c]pyridazine (2a)
To a stirred solution of amine 12 (106 mg, 0.602 mmol) in H2SO4
(10 mL) at 0 ꢀC was added NaNO2 (62 mg, 0.899 mmol) in H2O
(6 mL) dropwise during 30 min. The reaction was kept stirring for
30 min at 0 ꢀC and then allowed to warm to room temperature and
stirred overnight. The reaction was added to NaOH (90 mL, 5 M)
and ice. The aqueous solution was extracted with CH2Cl2 (3ꢂ30 mL)
and the combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography (4% Et3N in EtOAc/pentane (2:1))
affording 2a as a white solid (81 mg, 72%), pure by NMR; 2a (15%
yield) was also isolated from a 15:72% mixture with 14, (see
preparation of 14 below). Compound 2a: Rf 0.30 (4% Et3N in EtOAc/
pentane (2:1)); mp 178–179 ꢀC; 1H NMR (400 MHz, CDCl3) dH: 10.12
(1H, d, J 0.8, pyr-H2), 8.89 (1H, d, J 6.0, pyr-H6), 8.23 (1H, d, J 5.6,
thieno-H5), 7.99 (1H, d, J 5.6, thieno-H4), 7.93 (1H, dd, J 6.0, 0.8,
pyr-H5); 13C NMR (100 MHz, CDCl3) dC: 156.4 (thieno-C3), 156.1
(pyr-C2), 147.8 (pyr-C6), 139.9 (pyr-C3), 131.2 (thieno-C4), 130.2
(thieno-C2), 126.1 (thieno-C5), 125.7 (pyr-C4), 115.3 (pyr-C5); NMR
assignments are based on HMBC experiments; IR nmax: 3085, 1603,
1414, 1354, 1331, 1279, 1243, 1234, 1130, 1098, 991, 867, 829, 811,
804, 743, 690 cmꢁ1; MS m/z (%): 187 (Mþ, 100), 176 (59), 149 (33),
132 (91), 57 (78), 41 (52); HRMS calcd for C9H5N3S: 187.0204; obsd
187.0201. X-ray analysis.38
7.80 (1H, br s, NH), 7.25 (1H, dd, J 8.4, 4.8, H5), 1.32 (9H, s, t-Bu); 13
C
NMR (100 MHz, CDCl3) dC: 177.3 (C]O), 145.0 (C6), 141.5 (C2), 135.0
(C3), 127.6 (C4), 123.5 (C5), 39.6 (quart-C), 27.4 (CH3); NMR as-
signments are based on HSQC experiments; IR nmax: 3172w, 2968w,
1677s, 1584s, 1537s, 1475s, 1420s, 1397s, 1325s, 1282s, 1264s, 1162s,
801s, 747m, 704s cmꢁ1; MS m/z (%): 178 (Mþ, 6), 94 (20), 85 (10), 78
(4), 67 (5), 57 (100), 41 (25), 39 (16); HRMS calcd for C10H14N2O:
178.1106; obsd 178.1108.
4.8. N-(4-Bromo-3-pyridinyl)-2,2-dimethylpropanamide (9)30
t-BuLi (61 mL, 103.8 mmol, 1.7 M in pentane) was added drop-
wise in 30 min to a stirred solution of 8 (7.40 g, 41.51 mmol) in THF
(60 mL) and ether (110 mL) at ꢁ78 ꢀC. The reaction was stirred for
30 min at ꢁ78 ꢀC, 30 min at ꢁ20 ꢀC and 1.5 h at room temperature.
The reaction was cooled to ꢁ78 ꢀC and ethylene dibromide
(10.73 mL, 124.5 mmol) was added dropwise during 30 min. The
mixture was allowed to heat to room temperature and stirred
overnight before water (100 mL) was added. Extraction and flash
chromatography (1:1 EtOAc/pentane) afforded 9 as a light yellow
solid (5.85 g, 55%), pure by NMR; Rf 0.28 (EtOAc/pentane (1:1)); mp
94–95 ꢀC; 1H NMR (400 MHz, CDCl3) dH: 9.53 (1H, s, H2), 8.17 (1H,
d, J 5.2, H6), 7.83 (1H, br s, NH), 7.50 (1H, d, J 5.2, H5), 1.37 (9H, s, t-
Bu); 13C NMR (100 MHz, CDCl3) dC: 176.5 (C]O), 145.2 (C6), 143.5
(C2), 133.3 (C3), 127.0 (C5), 123.3 (C4), 40.1 (quart-C), 27.6 (CH3);
NMR assignments are based on HSQC experiments; IR nmax: 3282m,
2965w, 1654s, 1568s, 1555s, 1495s, 1466s, 1398s, 1289m, 1174s,
1074m, 1064m, 862m, 805s, 669s cmꢁ1; MS m/z (%): 256 (Mþ, 6),
172 (14), 85 (22), 57 (100), 41 (25), 39 (9); HRMS calcd for
4.5. Pyrido[4,3-e]thieno[2,3-c]pyridazine (2b)
To a stirred solution of NOBF4 in MeCN (5 mL) at 0 ꢀC, amine 13
(116 mg, 0.658 mmol) in MeCN (5 mL) was added over 15 min. The
reaction was kept stirring for 30 min at 0 ꢀC before NaOH (15 mL,
5 M) was added. The crude product obtained after extraction with
CH2Cl2 (3ꢂ20 mL), drying over Na2SO4 and concentration under
reduced pressure was purified by flash chromatography (4% Et3N in
EtOAc/pentane (2:1)) to give the product 2b as a yellow solid
(102 mg, 83%), pure by NMR; Rf 0.25 (4% Et3N in EtOAc/pentane
(2:1)); (alternatively, 2b was exclusively formed in 73% yield from
13 by the reaction conditions described for the formation of 14 and
minor amounts of 2a below); mp 203–204 ꢀC; 1H NMR (400 MHz,
CDCl3) dH: 10.09 (1H, s, pyr-H2), 8.91 (1H, d, J 5.6, pyr-H6), 8.13 (1H,
d, J 5.6, thieno-H5), 8.08 (1H, dd, J 5.6, 0.8, pyr-H5), 7.95 (1H, d, J 6.0,
thieno-H4); 13C NMR (100 MHz, CDCl3) dC: 161.8 (thieno-C2), 155.6
(pyr-C2), 147.7 (pyr-C6), 141.0 (pyr-C3), 134.2 (thieno-C5), 126.4
(thieno-C3), 125.2 (pyr-C4), 119.3 (thieno-C4), 115.3 (pyr-C5); NMR
assignments are based on HMBC experiments; IR nmax: 3039, 1604,
1429, 1389, 1337, 1277, 1260, 1198, 1141, 1079, 1025, 945, 839, 823,
809, 756, 678 cmꢁ1; MS m/z (%): 187 (Mþ, 100), 159 (7), 132 (45), 44
C10H13BrN2O: 256.0211; obsd 256.0209.
4.9. N-(4-(Thien-2-yl)pyridin-3-yl)pivalamide (10)
A solution of 9 (2.00 g, 7.78 mmol) and Pd(PPh3)4 (419 mg,
0.363 mmol) in toluene (15 mL) was stirred and added Na2CO3
(7.5 mL, 2 M) and 2-thienylboronic acid (1.19 g, 9.30 mmol) in
MeOH (5 mL).45 The reaction was heated to 80–90 ꢀC overnight.
The reaction was allowed to cool to room temperature before
CH2Cl2 (60 mL) and NH3 (4 mL, concd) in Na2CO2 (40 mL, 2 M) was
added. The white/yellow crude product, obtained by extraction,
was purified by flash chromatography (4% Et3N in EtOAc/pentane
(2:1)) to give 10 as a white solid (1.72 g, 6.61 mmol, 85%), pure by
NMR; Rf 0.31 (4% Et3N in EtOAc/pentane (2:1)); mp/decomp.120 ꢀC;
1H NMR (400 MHz, CDCl3) dH: 9.43 (1H, s, pyr-H2), 8.39 (1H, d, J 4.8,

V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
7631
pyr-H6), 7.72 (1H, br s, NH), 7.53 (1H, dd, J 4.8, 1.2, thieno-H5), 7.31
(1H, dd, J 4.8, pyr-H5), 7.26 (1H, dd, J 3.6, 1.2, thieno-H3), 7.20 (1H,
dd, J 4.8, 3.6, thieno-H4), 1.25 (9H, s, C(CH3)3); 13C NMR (100 MHz,
CDCl3) dC: 176.5 (C]O), 145.3 (pyr-C6), 144.6 (pyr-C2), 136.3
(thieno-C2), 132.6 (pyr-C4), 131.6 (pyr-C3), 128.1 (thieno-C5), 128.0
(thieno-C4), 127.8 (thieno-C3), 123.9 (pyr-C5), 39.8 (CMe3), 27.4
(C(CH3)3); IR nmax: 3094, 2966, 1670, 1603, 1555, 1512, 1475, 1429,
1410,1305,1164, 823, 806, 746, 729, 704, 689 cmꢁ1; MS m/z (%): 260
(Mþ, 90), 175 (42), 149 (14), 131 (16), 85 (16), 57 (100), 43 (26), 41
CDCl3) dH: 8.15 (1H, s, pyr-H2), 8.03 (1H, d, J 4.8, pyr-H6), 7.51 (1H,
dd, J 3.2, 1.2, thieno-H2), 7.46 (1H, dd, J 5.2, 3.2, thieno-H5), 7.29
(1H, dd, J 5.2, 1.2, thieno-H4), 7.09 (1H, d, J 4.8, pyr-H5), 3.94 (2H, br
s, NH2); 13C NMR (100 MHz, CDCl3) dC: 140.1 (pyr-C6), 139.9 (pyr-
C3), 138.3 (pyr-C2), 137.2 (thieno-C3), 128.5 (pyr-C4), 127.4 (thieno-
C4), 126.8 (thieno-C5), 123.7 (thieno-C2), 123.6 (pyr-C5); NMR
assignments are based on HMBC experiments; IR nmax: 3311, 3175,
1614, 1591, 1555, 1490, 1423, 1321, 1285, 1233, 1185, 1062, 1039, 842,
825, 788, 750 cmꢁ1; MS m/z (%): 176 (Mþ, 100), 131 (75), 77 (45), 51
(33), 45 (31), 41 (16); HRMS calcd for C9H8N2S: 176.0408; obsd
176.0407. Anal. Calcd for C9H8N2S: C, 61.34; H, 4.58; N, 15.90; S,
18.19. Found: C, 61.45; H, 4.58; N, 15.67; S, 18.09.
(17), 29 (10); HRMS calcd for
C14H16N2OS: 260.0983; obsd
260.0987. Anal. Calcd for C14H16N2OS: C, 64.58; H, 6.19; N, 10.76; S,
12.32. Found: C, 64.62; H, 6.20; N, 10.71; S, 12.20.
4.10. N-(4-(Thien-3-yl)pyridin-3-yl)pivalamide (11)
4.13. 3-Azido-4-(thien-2-yl)pyridine (14)
The title compound was prepared from 9 (5.02 g, 19.5 mmol)
and Pd(PPh3)4 (1.13 g, 0.977 mmol) in toluene (40 mL), Na2CO3
(20 mL, 2 M) and 3-thienylboronic acid (3.00 g, 23.4 mmol) in
MeOH (12 mL) as described above for the preparation of 10.45 The
crude product was purified by flash chromatography (EtOAc/pen-
tane (1:1)) to give 11 as a white solid (4.35 g, 16.7 mmol, 86%), pure
by NMR; Rf 0.18 (EtOAc/pentane (1:1)); mp/decomp. 126 ꢀC; 1H
NMR (400 MHz, CDCl3) dH: 9.50 (1H, s, pyr-H2), 8.39 (1H, d, J 4.8,
pyr-H6), 7.56 (1H, dd, J 4.8, 3.2, thieno-H5), 7.51 (1H, br s, NH), 7.43
(1H, d, J 2.4, thieno-H2), 7.22 (1H, d, J 5.2, thieno-H4), 7.18 (1H, d, J
To a stirred solution of 12 (256 mg, 1.45 mmol) in H2SO4 (13 mL)
at 0 ꢀC was added NaNO2 (150 mg, 2.18 mmol) in H2O (10 mL)
dropwise during 30 min. The reaction mixture was kept stirring for
20 min at 0 ꢀC before NaN3 (140 mg, 2.15 mmol) was added drop-
wise during 40 min at 0 ꢀC. The reaction mixture was stirred for
10 min at 0 ꢀC and then kept stirring overnight at room tempera-
ture. NaOH (100 mL, 5 M) was added slowly (pH¼14). After ex-
traction with CH2Cl2, the crude product was purified by flash
column chromatography (4% Et3N in EtOAc/pentane (2:1)). Azide
14 was isolated as a brown oil, crystallising from pentane (212 mg,
72%), pure by NMR. Pyridazine 2a (40.5 mg, 15%) was also isolated
as crystals. Compound 14: Rf 0.53 (4% Et3N in EtOAc/pentane (2:1));
1H NMR (400 MHz, CDCl3) dH: 8.58 (1H, s, pyr-H2), 8.37 (1H, d, J 5.2,
pyr-H6), 7.70 (1H, dd, J 4.0, 1.2, thieno-H5), 7.50 (2H, d, J 5.2, pyr-
H5þthieno-H3), 7.16 (1H, dd, J 5.2, 4.0, thieno-H4); 13C NMR
(100 MHz, CDCl3) dC: 145.7 (pyr-C2), 141.7 (pyr-C6), 136.1 (thieno-
C2), 132.4 (pyr-C4), 132.1 (pyr-C3), 128.6 (2ꢂC, thieno-C4/-C5),
127.6 (thieno-C3), 122.0 (pyr-C5); NMR assignments are based on
HMBC experiments; IR nmax: 3053, 2127, 2103, 1580, 1544, 1236,
1478, 1413, 1309, 1298, 1259, 1056, 855, 836, 825, 727, 712,
662 cmꢁ1; MS m/z (%): 202 (Mþ, 6), 174 (100), 146 (39), 120 (18), 103
(24), 96 (14), 69 (15), 45 (31), 39 (17), 28 (48); HRMS calcd for
C9H6N4S: 202.0313; obsd 202.0311.
4.8, pyr-H5), 1.24 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) dC
:
176.4 (C¼O), 145.2 (pyr-C6), 143.8 (pyr-C2), 135.8 (thieno-C3), 134.7
(pyr-C4), 131.9 (pyr-C3), 127.8 (thieno-C4), 127.4 (thieno-C5), 124.7
(thieno-C2), 123.7 (pyr-C5), 39.7 (CMe3), 27.4 (C(CH3)3); NMR as-
signments are based on HMBC experiments; IR nmax: 3105, 2965,
1668, 1558, 1513, 1475, 1417, 1398, 1303, 1171, 1160, 858, 830, 788,
747, 734, 671, 652 cmꢁ1; MS m/z (%): 260 (Mþ, 21), 176 (16), 131 (7),
85 (6), 57 (100), 41 (16); HRMS calcd for C14H16N2OS: 260.0983;
obsd 260.0986. Anal. Calcd for C14H16N2OS: C, 64.58; H, 6.19; N,
10.76; S, 12.32. Found: C, 64.77; H, 6.30; N, 10.58; S, 12.23.
4.11. 4-(Thien-2-yl)pyridin-3-amine (12)
A solution of amide 10 (1.87 g, 7.19 mmol) in H2SO4 (100 mL,
25%, aq) was heated to reflux and kept stirring for 3 h. The reaction
was allowed to cool to room temperature before a mixture of NH3
(150 mL, concd) and ice was added (pH¼11). Extraction afforded
the yellow/brown crude oily product. Flash chromatography (4%
Et3N in EtOAc/pentane (2:1)) afforded amine 12 as a pale yellow oil
(1.24 g, 98%), which soon turned brown: Rf 0.19 (4% Et3N in EtOAc/
pentane (2:1)); 1H NMR (400 MHz, CDCl3) dH: 8.17 (1H, s, pyr-H2),
8.03 (1H, d, J 4.8, pyr-H6), 7.43 (1H, dd, J 5.2, 1.2, thieno-H5), 7.35
(1H, dd, J 3.6, 1.2, thieno-H3), 7.16 (2H, m, J 5.2, 4.8, 3.6, pyr-H5),
4.08 (2H, br s, NH2); 13C NMR (100 MHz, CDCl3) dC: 140.1 (pyr-C6),
139.5 (pyr-C3), 138.7 (pyr-C2), 138.3 (thieno-C2), 127.9 (thieno-C5),
126.6 (thieno-C4), 126.5 (thieno-C3), 126.2 (pyr-C4), 123.7 (pyr-C5);
NMR assignments are based on HMBC experiments; IR nmax: 3307,
3169, 1615, 1588, 1550, 1488, 1432, 1418, 1323, 1289, 1237, 1193,
1063, 853, 816, 699 cmꢁ1; MS m/z (%): 176 (Mþ, 100), 131 (57), 77
(16), 51 (9), 39 (6); HRMS calcd for C9H8N2S: 176.0408; obsd
176.0407. Anal. Calcd for C9H8N2S: C, 61.34; H, 4.58; N,15.90. Found:
C, 61.31; H, 4.51; N, 15.85.
4.14. 3-Azido-4-(thiophen-3-yl)pyridine (15)
To a stirred solution of azide 17 (434 mg, 2.18 mmol) and
Pd(PPh3)4 (127 mg, 0.110 mmol) in toluene (20 mL) was added
Na2CO3 (10 mL, 2 M) and 3-thienylboronic acid (337 mg,
2.630 mmol) in MeOH (5 mL).45 The reaction was heated to 80 ꢀC
and kept stirring for 4 h. The reaction mixture was cooled to room
temperature, CH2Cl2 (40 mL) and NH3 (2 mL, concd) in Na2CO2
(20 mL, 2 M) added and extracted with CH2Cl2 (2ꢂ20 mL). The
brown, oily crude product was purified by flash chromatography
(1:2 EtOAc/pentane) to give 15 as a brown oil crystallising from
pentane (277 mg, 63%); Rf 0.38 (EtOAc/pentane (1:2)), pure by NMR;
1H NMR (300 MHz, CDCl3) dH: 8.57 (1H, s, pyr-H2), 8.39 (1H, d, J 5.1,
pyr-H6), 7.80 (1H, dd, J 2.7,1.5, pyr-H5), 7.45–7.40 (2H, m, thieno-H2/
H5), 7.38 (1H, d, J 5.1, thieno-H4); 13C NMR (75 MHz, CDCl3) dC: 146.1,
141.6, 135.3 134.3, 133.3, 127.6, 126.2, 125.9, 123.4; IR (film) nmax
:
2124, 2102, 1587, 1420, 1307, 791, 744, 695 cmꢁ1; MS m/z (%): 202
(Mþ, 5),174 (100),146 (47),120 (14),103 (17), 45 (16); HRMS calcd for
C9H6N4S: 202.0313; obsd 202.0312. Anal. Calcd for C9H6N4S: C,
53.45; H, 2.99; N, 27.70. Found: C, 53.39; H, 3.05; N, 27.78.
4.12. 4-(Thien-3-yl)pyridin-3-amine (13)
The title compound was prepared from 11 (4.11 g, 15.8 mmol) in
H2SO4 (200 mL, 25%, aq) as described above for the preparation of
12. Extraction afforded a yellow-brown crude oil and flash chro-
matography (4% Et3N in EtOAc/pentane (2:1)) gave amine 13 as
a transparent oil, which soon turned brown (2.72 g, 98%), pure by
NMR; Rf 0.19 (4% Et3N in EtOAc/pentane (2:1)); 1H NMR (400 MHz,
4.15. 3-Amino-4-bromopyridine (16)46
The title compound was prepared from 9 (7.00 g, 27.2 mmol) in
H2SO4 (120 mL, 20%, aq) as described above for the preparation of
12. Extraction afforded a yellow crude oil and flash chromatography
(4% Et3N in EtOAc/pentane (2:1)) gave 16 as a colourless oil, which

7632
V. Stockmann, A. Fiksdahl / Tetrahedron 64 (2008) 7626–7632
9. Wiedemann, F.; Kampe, W.; Thiel, M.; Sponer, G.; Roesch, E.; Dietmann, K.
Patent DE 2815926, 1979; Chem. Abstr. 1979, 92, 128716.
10. Leinert, H.; Popelak, A.; Thiel, M.; Bartsch, W.; Schaumann, W. Patent DE
2240599, 1974; Chem. Abstr. 1974, 80, 133455.
11. Lewgowd, W.; Stanczak, A. Arch. Pharm. Chem. Life Sci. 2007, 340, 65.
12. Fischer, J.; Jahn, U.; Schatz, F.; Stammbach, C.; Thiele, K.; Wagner-Jauregg, T. W.;
Zirngibl, L. U.S. Patent 4,204,998, 1980; Chem. Abstr. 1980, 93, 186162.
13. White, W. A. Patent DE 2065719, 1975; Chem. Abstr. 1975, 83, 58860.
14. Entwistle, I. D.; Gilkerson, T.; Barton, J. W. Patent GB 2059263, 1981; Chem.
Abstr. 1981, 95, 182265.
15. Leary, J. A.; Lafleur, A. L.; Liber, H. L.; Biemann, K. Anal. Chem. 1983, 55, 758.
16. Zhao, X.; Wang, X.; Niu, J.; Wang, J. Huanjing Kexue Xuebao 2001, 21, 444.
17. Barton, J. W.; Walker, R. B. Tetrahedron Lett. 1975, 569.
18. Wathen M. W.; Wathen, L. K. Patent WO 2004019933, 2004; Chem. Abstr. 2004,
140, 229445.
soon turned brown (3.98 g, 23.0 mmol, 85%), pure by NMR; Rf 0.24
(4% Et3N in EtOAc/pentane (2:1)); 1H NMR (400 MHz, CDCl3) dH: 8.09
(1H, s, H2), 7.76 (1H, d, J 5.2, H6), 7.31 (1H, d, J 5.2, H5); 13C NMR
(100 MHz, CDCl3) dC: 141.5 (C3),139.6/137.4 (C2/C6),127.4 (C5),117.9
(C4); IR (film) nmax: 3449, 3315, 3180, 1623, 1574, 1556, 1484, 1417,
1328, 1235, 1058, 811, 669 cmꢁ1; MS m/z (%): 174 (C5H581BrN2, Mþ,
44), 172 (C5H759BrN2, Mþ, 47), 147 (12), 145 (12), 93 (47), 66 (100), 39
(38); HRMS calcd for C5H759BrN2: 171.9636; obsd 171.9639.
4.16. 3-Azido-4-bromopyridine (17)
To a stirred solution of NOBF4 in MeCN (15 mL) at ꢁ10 ꢀC, amine
16 (2.42 g, 13.99 mmol) in MeCN (5 mL) was added over 15 min.
The reaction was allowed to heat to 0 ꢀC and then kept stirring for
30 min. The reaction was cooled to ꢁ10 ꢀC and NaN3 in H2O (5 mL)/
MeCN (2 mL) was added over 30 min. The reaction was kept stirring
for 30 min at 0 ꢀC before H2O (10 mL) was added. Extraction with
CH2Cl2 afforded an oily crude product. Purification by flash chro-
matography (1:5 EtOAc/pentane) gave 17 as a light brown oil (1.657,
8.33 mmol, 60%), pure by NMR; Rf 0.25 (1:5 EtOAc/pentane); 1H
NMR (400 MHz, CDCl3) dH: 8.46 (1H, s, C2), 8.19 (1H, d, J 5.2, C6),
19. Bundy, G. L.; Ciske, F. L.; Genin, M. J.; Heasley, S. E.; Larsen, S. D.; Lee, B. H.; May,
P. D.; Palmer, J. R.; Schnute, M. E.; Vaillancourt, V. A.; Thorarensen, A.; Wolf, A. J.;
Wicnienski, N.A.; Wilhite, D. Patent WO 2002004444, 2002; Chem. Abstr.
2002, 136, 118476.
20. Kametani, T.; Ogasawara, K.; Yamanaka, T. J. Chem. Soc. C 1968, 1006.
21. Schofield, J.; Smalley, R. K.; Scopes, D. I. C.; Patel, D. I. J. Chem. Res., Synop. 1987,
164.
22. Kibalny, A. V.; Nikolukin, Yu. A.; Dulenko, V. I. Fiziologichno Aktivni Rechovini
2002, 23; Chem. Abstr. 2003, 139, 101049.
23. Mendenhall, G. D.; Smith, P. A. S. Org. Synth. 1966, 46, 85.
24. Jian, H.; Tour, J. M. J. Org. Chem. 2003, 68, 5091.
25. Bakke, J.; Andresen, E., unpublished results.
26. Bakke, J. M.; Hegbom, I.; Øvreeide, K.; Aaby, K. Acta Chem. Scand. 1994, 48, 1001.
27. Bakke, J. M.; Ranes, E. Synthesis 1997, 281.
7.50 (1H, d, J 5.2, C5); 13C NMR (100 MHz, CDCl3)
d: 146.1, 141.2,
28. El-Zahraa, F.; El-Basil, S.; El-Sayed, M.; Ghoneim, K. M.; Khalifa, M. Pharmazie
1979, 34, 12.
29. Gungor, T.; Marsais, F.; Queguiner, G. Synthesis 1982, 499.
30. Reetz, M. T.; Kesseler, K. J. Org. Chem. 1985, 50, 5436.
31. Bryce-Smith, D.; Morris, P. J.; Wakefield, B. J. Chem. Ind. 1964, 495.
32. Turner, J. J. Org. Chem. 1983, 48, 3401.
136.3, 128.3, 123.6; IR (film) nmax: 2113, 1551, 1477, 1405, 1325, 1312,
1066, 824, 703 cmꢁ1; MS m/z (%): 200 (C5H581BrN4, Mþ, 4), 198
(C5H759BrN4, Mþ, 4), 172 (28), 170 (25), 91 (32), 64 (100) 37 (27);
HRMS calcd for C5H739BrN4: 197.9541; obsd 197.9548.
33. Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 2489.
34. Smith, P. A. S.; Hall, J. H. J. Am. Chem. Soc. 1961, 84, 480.
35. Smolinsky, G. J. Am. Chem. Soc. 1960, 82, 4717.
References and notes
36. Abramovitch, R. A.; Adams, K. A. H. Can. J. Chem. 1960, 39, 2152.
37. Hansen, L. K.; Stockmann, V; Fiksdahl, A., in preparation.
38. Hansen, L. K.; Stockmann, V.; Fiksdahl, A. Acta Crystallogr. 2007, E63, o3290.
39. Hansen, L. K.; Stockmann, V.; Fiksdahl, A. Acta Crystallogr. 2007, E63, o3896.
40. Barton, J. W.; Lapham, D. J.; Rowe, D. J. J. Chem. Soc., Perkin Trans. 1 1985,
131.
41. Martens, R. J.; den Hertog, H. J.; van Ammers, M. Tetrahedron Lett. 1964, 3207.
42. Bakke, J. M.; Riha, J. J. Heterocycl. Chem. 2001, 38, 99.
43. Stockmann, V.; Fiksdahl, A., in preparation.
1. Zhao, M.; Bi, L.; Wang, W.; Wang, C.; Baudy-Floc’h, M.; Ju, J.; Peng, S. Bioorg.
Med. Chem. 2006, 14, 6998.
2. Garcia, M. D.; Wilson, A. J.; Emmerson, D. P. G.; Jenkins, P. R.; Mahale, S.;
Chaudhuri, B. Org. Biomol. Chem. 2006, 4, 4478.
3. Winkler, J. D.; Londregan, A. T.; Hamann, M. T. Org. Lett. 2006, 8, 2591.
4. Ichikawa, M.; Yoshida, J.; Ide, N.; Sasaoka, T.; Yamaguchi, H.; Ono, K. J. Nutr.
2006, 136, 726S.
5. Bi, W.; Bi, L.; Cai, J.; Liu, S.; Peng, S.; Fischer, N. O.; Tok, J. B.-H.; Wang, G. Bioorg.
Med. Chem. Lett. 2006, 16, 4523.
44. Bonnet, V.; Mongin, F.; Trecourt, F.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1
2000, 4245.
45. Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237.
46. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1990, 1505.
6. Herraiz, T.; Chaparro, C. Life Sci. 2006, 78, 795.
7. Guan, H.; Liu, X.; Peng, W.; Cao, R.; Ma, Y.; Chen, H.; Xu, A. Biochem. Biophys. Res.
Commun. 2006, 342, 894.
8. Bartels, S. P. U.S. Patent 2,006,292,202, 2006; Chem. Abstr. 2006, 146, 107626.