Synthesis of biologically active seven-membered-ring heterocycles

Article abstract of DOI:10.1055/s-0033-1338549

Seven-membered rings that contain one or more heteroatoms are interesting motifs for organic synthesis. In addition to their synthetic interest, they play an important role in industrial and pharmaceutical chemistry with generally increased central nervous system activity when flanked by aromatic rings. Herein we report a brief summary of some key methods of preparation for seven-membered-ring heterocycles and how they have been applied to the synthesis of commercially desirable products. We then detail new methods that we have developed for the synthesis of biologically active compounds containing this motif. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338549

FEATURE ARTICLE
▌3211
feature article
Synthesis of Biologically Active Seven-Membered-Ring Heterocycles
Biologically Active Seven-Membered-Ring Heterocycles
Tristan A. Reekie,a Madeline E. Kavanagh,a Mitchell Longworth,a Michael Kassiou*a,b,c
a
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
b
Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c
Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia
Received: 05.08.2013; Accepted after revision: 03.10.2013
Seven-Membered-Ring Heterocycles: Synthesis and
Biological Activity
Abstract: Seven-membered rings that contain one or more hetero-
atoms are interesting motifs for organic synthesis. In addition to
their synthetic interest, they play an important role in industrial and
pharmaceutical chemistry with generally increased central nervous
system activity when flanked by aromatic rings. Herein we report a
brief summary of some key methods of preparation for seven-mem-
bered-ring heterocycles and how they have been applied to the syn-
thesis of commercially desirable products. We then detail new
methods that we have developed for the synthesis of biologically
active compounds containing this motif.
Nitrogen-Containing Seven-Membered Rings
One of the simplest nitrogen-containing heterocycles is
caprolactam (1, azepan-2-one), which is used industrially
for the synthesis of Nylon-6. Approximately two billion
tonnes of 1 is produced annually, with the primary method
of synthesis involving a Beckman rearrangement of ox-
ime 2, derived from cyclohexanone (Scheme 1).2
Key words: Heterocycles, fused-ring systems, medicinal chemis-
try, polycycles, amines
O
NOH
i
NH
Introduction
>90%
2
1
Seven-membered-ring heterocycles have found wide
spread use in medicinal chemistry due to their diverse
biological activity in mammalian systems. In particular,
seven-membered-ring heterocycles that are flanked by ar-
omatic rings show interesting activity in the central ner-
vous system.1 Methods for synthesis of these heterocycles
are varied and depend on: (i) the number and type hetero-
atom to be incorporated in the ring, (ii) the groups at-
tached to the ring, (iii) the degree of unsaturation
associated with the seven-membered ring, and (iv) in the
case of multiple heteroatom-containing rings, their rela-
tionship to one another (1,2-, 1,3-, or 1,4-substitution).1
Herein we report a brief summary of some key seven-
membered-ring heterocyclic compounds and significant
methods of synthesis before detailing methods that we
have developed for the synthesis of this heterocyclic mo-
tif.
Scheme 1 Beckman rearrangement to produce caprolactam (1).
Reagents and conditions: (i) 3.0 M aq H2SO4 (0.6 equiv).
The Beckman rearrangement is a commonly employed
strategy for the synthesis of other azepanones or azepi-
nones and, through lactam reduction, the corresponding
azepanes or azepines.3 Alternative methods for azepine
synthesis include cyclization with an azide and loss of ni-
trogen to incorporate the nitrogen atom into the seven-
membered ring. An illustrative example is shown in
Scheme 2, where such a transformation was used to con-
vert azide 3 into imine 4 in a key step for the synthesis of
the diastereomeric natural product claviciptic acid (5) in a
further five steps.4
CO2Me
CO2Me
CO2Me
N
H
CO2Me
H
N3
N
CO2Me
i
5 steps
H
62%
N
H
N
N
H
H
3
4
claviciptic acid (5)
Scheme 2 The key azepine-forming step for the synthesis of claviciptic acid (5). Reagents and conditions: (i) 1,2-dichlorobenzene, reflux, 3.75 h.
SYNTHESIS 2013, 45, 3211–3227
Advanced online publication: 24.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338549; Art ID: SS-2013-Z0517-FA
© Georg Thieme Verlag Stuttgart · New York

3212
T. A. Reekie et al.
FEATURE ARTICLE
Conversely an appropriately substituted amine can under-
go transition-metal-catalyzed intramolecular cross-cou-
pling or ring-closing metathesis to give target azepines.5
H
N
H2N
NH2
Chemical modification of parent azepines also allows ac-
cess to important azepine pharmaceuticals. For example,
the dianiline 6 was first used to synthesize dibenzazepine
(7) in the late 19th century,6 which in recent times has
been used to produce the anticonvulsant drugs carbamaze-
pine (8) and oxcarbazepine (9) (Scheme 3).7
6
7
O
O
NH2
NH2
N
N
A number of clinically important pharmaceuticals contain
seven-membered rings with two nitrogen atoms. The most
common of these incorporate the heteroatoms in a 1,4-re-
lationship with an associated aromatic giving rise to 1,4-
benzodiazepinones. Examples include the anti-anxiety
medication diazepam (10), the HIV-1 reverse transcrip-
O
oxcarbazepine (9)
carbamazepine (8)
Scheme 3 Carbamazepine (8) and oxcarbazepine (9) derived from
dibenzazepine (7)
Biographical Sketches█
Tristan Reekie obtained his thesis under the supervision medicinal chemistry. He
B.Sc. (Hons.) from the Aus- of Prof. Martin Banwell. He currently works as a post-
tralian National University, then took up a postdoctoral doctoral fellow at ETH,
Canberra in 2007 where he research fellowship with Zurich with Prof. François
also completed his Ph.D. in Prof. Michael Kassiou at the Diederich.
2013 in natural product syn- University of Sydney in
Madeline Kavanagh com- tained her B.Sc. (Adv.) de- thesis of inhibitors of the
pleted her M.Sc. degree in gree from the University of LRRK2 kinase as novel
July 2013 under the supervi- Sydney after completing an therapeutics to treat Parkin-
sion of Prof. Michael Honours year in chemistry son’s disease and other neu-
Kassiou at the University of in 2012. Her work has fo- rological conditions.
Sydney. She previously ob- cused on the design and syn-
Mitchell Longworth com- Michael Kassiou. His hon- currently working for No-
pleted his B.Sc. (Adv.) with ours project was based on a vartis Pharmaceuticals in
Honours at the University of structure-activity relation- the Drug Safety and Epide-
Sydney in 2012 under the ship study of a novel oxyto- miology Department.
supervision
of
Prof. cin receptor agonist. He is
Michael Kassiou is Profes- obtain structure-activity re- University and a Fogarty
sor of Medicinal Chemistry lationships of bioactive Fellow at the National Insti-
at the University of Sydney CNS molecules, allowing tute of Drug Abuse, Nation-
and Head of the Drug Dis- the rational design of more al Institutes of Health in the
covery Research Unit at the efficacious treatments for USA. He serves on several
Brain and Mind Research diseases of the brain. He re- journal editorial boards fo-
Institute. His main research ceived his Ph.D. in chemis- cusing on medicinal chem-
interests are concerned with try from the University of istry,
pharmaceutical
the understanding of drug– New South Wales in 1992. design, and drug discovery.
protein and drug-binding He has been a Postdoctoral
site interactions in order to Fellow at Johns Hopkins
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3213
tase inhibitor nevirapine (11), and the sedative chlordiaz-
epoxide (12) (Figure 1).
O
H
N
NH2
i
O
N
15–75%
R1
R1
Me
H
O
N
N
N
Y
Me
H
O
N
Cl
Cl
N
R2
R2
N
N
O
N
13
14
N
30–70%
(3 steps)
ii
iv
diazepam (10)
nevirapine (11)
chlorodiazepoxide (12)
Figure 1 Biologically active 1,4-benzodiazepines diazepam (10),
nevirapine (11), and chlorodiazepoxide (12)
X
NH2
O
O
A widely applicable method for the synthesis of these
benzodiazepinone-type structures is shown in Scheme 4.8
A single-step method can be employed whereby an appro-
priately substituted o-aminobenzophenone 13 reacts with
a glycine ester hydrochloride (with the ethyl ester provid-
ing the best yields) to afford the target compounds 14 in
15–75% yields. Lower yields resulted when substituents
were located at position Y, most likely as a result of steric
hindrance. A three-step procedure has also been employed
starting from the same o-aminobenzophenone 13 with the
aniline first acylated with a haloacetyl halide to give
amides 15 and subsequent aminolysis affording α-amino-
amides 16. Subsequent intramolecular Schiff base con-
densation afforded the benzazepines 14 in 30–70% yields
from o-aminobenzophenone 13.
NH
NH
O
iii
O
R1
R1
R2
R2
15
16
Scheme 4 Two routes for the synthesis of variably substituted di-
azapinones of type 14. Reagents and conditions (varied depending on
substituents): (i) glycine ethyl ester hydrochloride (1.5 equiv), pyri-
dine, reflux, 15 h; (ii) α-haloacetyl halide (1.3 equiv), 3 M aq NaOH
(1.3 equiv), <10 °C, 0.5 h; (iii) liquid NH3 (excess), reflux, 5 h; (iv)
toluene, reflux, 1 h.
The original synthesis of asenapine is illustrative of one
route available to access this class of compounds com-
mencing from precursors pre-functionalized with the bi-
aryl ether that will form part of the oxepine ring (Scheme
5). Acid chloride 209 was converted into the amide 21 via
acylation with glycine ethyl ester hydrochloride followed
by cyclization to form the five-membered ring and thus
provide compound 22. Cyclization promoted by
H3PO4/P2O5 provides the oxepine 23 with subsequent lac-
tam reduction affording the target asenapine (18). Other
methods have been reported where forming the oxygen–
aromatic bond is used to construct the oxepine ring.10
Oxygen-Containing Seven-Membered Rings
Mono-oxygen seven-membered rings are less common in
pharmaceuticals compared to nitrogen-containing ana-
logues. Available examples are normally flanked by two
aromatic moieties, as seen in the CNS active compounds
doxepin (17), asenapine (18), and oxetorone (19) (Figure
2).
O
O
MeN
H
H
Compared to other seven-membered-ring heterocycles,
dioxepines have made little impact in synthetic or medic-
inal chemistry and are generally used as precursors rather
than final targets. Of this class, 1,3-dioxepines of type 24
have had the greatest utility, which is most likely a result
of their ease of synthesis. For example, a diol of type 25
and aldehyde or ketone 26 can cyclize under acidic condi-
tions to afford the target seven-membered ring (Scheme 6)
from simple starting materials.11
O
O
Cl
Me2N
doxepin (17)
Me2N
oxetorone (19)
asenapine (18)
Figure 2 Biologically active benzoxapines doxepin (17), asenapine
(18), and oxetorone (19)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3214
T. A. Reekie et al.
FEATURE ARTICLE
O
OEt
Cl
O
MeN
HN
i
ii
O
O
O
O
O
O
Cl
Cl
Cl
20
21
22
iii
MeN
O
iv
asenapine (18)
O
Cl
23
Scheme 5 Previously reported synthesis of asenapine (18). Reagents and conditions: (i) glycine ethyl ester hydrochloride, Et3N, DMF, r.t.,
time not reported; (ii) t-BuOK, toluene, 0 °C, 16 h; (iii) H3PO4/P2O5, 125 °C, 4 h; (iv) Na, i-PrOH, time and temperature not reported (yields
and reagent equivalents not reported).
R1
R2
The greater nucleophilicity of sulfur allows for S-alkyla-
O
O
H+
R1
R2
OH
OH
tion as a more viable method of thiepine synthesis, a chal-
lenge associated with other heteroatoms. The synthesis of
dosulepin (27) begins with the alkylation of thiophenol
(30) with 2-carboxybenzyl bromide (31) to give thioether
32 (Scheme 7).14 Cyclization of this last compound into
the thiepine 33 can be promoted by H3PO4/P2O5 and fol-
lowing addition of Grignard reagent 34 and dehydration,
dosulepin (27) is obtained. Cyclization to form a more
substituted thiepine is best performed under Friedel–
Crafts reaction conditions from the corresponding acid
chloride.12
O
+
25
26
24
Scheme 6 General method for the synthesis of 1,3-dioxapines of
type 24
Sulfur-Containing Seven-Membered Rings
In a similar manner to benzoxepines and benzazapines,
numerous biologically active benzothiepine-containing
compounds have found success as pharmaceuticals.12 Do-
sulepin (27) is sold as an antidepressant while the thio-
phene analogue bisulepin (28) acts as an antihistamine
(Figure 3). The sulfoxide Y-23684 (29) is an anxiolytic
and anticonvulsant that has yet to progress past animal tri-
als, but demonstrates that the multiple oxidation states of
sulfur can be utilized in drug development.13
Whilst dithiepines are uncommon scaffolds in medicinal
chemistry, they are readily accessible by a number of syn-
thetic routes. The synthesis of 1,3-dithiepines 35 or 36 can
follow a similar path to that of the dioxepines with a dithi-
ol 37 reacting with an appropriate aldehyde or ketone 26,
or alternatively, by reacting with an alkyl derivative such
as dibromomethane (Scheme 8).15 The improved ability to
alkylate the dithiols allows for better access to the 1,4-
dithiepines 38 by direct alkylation of a 1,2- or 1,3-dithio-
alkane 39 or 40, respectively, with an alkane with appro-
priate leaving group (LG) at the 1,3- or 1,2-position 41 or
42, respectively. 1,3-Dithianes 40 also react with alkynes
43 to form 1,4-dithiepines 44.16 A range of oxidative tech-
niques have been explored to convert thioethers, including
those contained in a cyclic system, into the corresponding
sulfoxide or sulfone.17
O
S
S
S
S
O
N
N
NMe2
dosulepin (27)
NMe2
bisulepin (28)
Cl
Y-23684 (29)
Figure 3 Biologically active benzothiepines dosulepin (27), bisule-
pin (28), and Y-23684 (29)
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3215
S
SH
+
S
i
ii
Br
O
OH
O
OH
O
30
31
32
33
Me
Me
iii
Cl Mg
N
34
dosulepin (27)
Scheme 7 Previously reported synthesis of dosulepin (27). Reagents and conditions: (i) 31 (1.1 equiv), K2CO3 (2.2 equiv), acetone, reflux,
1.5 h; (ii) H3PO4/P2O5, 115 °C, 0.75 h; (iii) (a) 34 (1.5 equiv), THF, reflux, 2.5 h; (b) concd HCl (excess), 100 °C, 3 h (yields not reported).
to treat hypertension and the 1,3-oxazepine amoxapine
S
S
S
S
CH2Br2
H+
R1
R1
R2
SH
SH
(46) prescribed as an antidepressant (Figure 4). The relat-
ed 1,3-oxazepine CR gas or dibenzoxazepine (47) has
been used as an incapacitating agent for riot control due to
its strong lachrymatory and skin irritant effects. The syn-
thesis of these mixed heterocycles is dependent on the het-
eroatoms and typically involves sequential nucleophilic
aromatic substitution or alkylation/acylation reactions to
afford the cyclized seven-membered ring. Seven-mem-
bered rings containing oxygen and sulfur heteroatoms are
less common. Reports have primarily focused on the syn-
thetic challenge and properties associated with this class
of compounds as opposed to their applications.15,16
O
R2
26
36
37
35
LG
LG
SH
SH
S
S
HS
HS
LG
+
+
LG
39
41
38
42
40
S
HS
+
R
S
HS
R
43
40
44
Synthesis of Oxytocin Mimetics
Scheme 8 General methods for the synthesis of 1,4-dithiepines
We have recently become interested in the synthesis of the
1,4-diazepine moiety, owing to its relevance in nonpeptid-
ic oxytocin receptor agonists18 47 (WAY 267,464)19 and
48 (Figure 5). Oxytocin has been associated with proso-
cial behaviour. Increased levels have been reported to im-
prove trust, alleviate symptoms related to autism and
social phobias, and reduce social anxiety.20
Mixed Heteroatom Seven-Membered Rings
Seven-membered rings incorporating two different het-
eroatoms generally combine a nitrogen atom with either
oxygen or sulfur, to give the oxazepine or thiazepine re-
spectively. These compounds have found application in a
range of areas including pharmaceuticals with the 1,3-thi-
azepine diltiazem (45) acting as a calcium channel blocker
OMe
NH
N
S
N
N
N
O
O
Cl
O
O
O
Me2N
diltiazem (45)
amoxapine (46)
CR gas (47)
Figure 4 Biologically active benzothiazepine diltiazem (45) and benzoxazepines amoxapine (46) and CR gas (47)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3216
T. A. Reekie et al.
FEATURE ARTICLE
been reported and proceeds through compound 49.21,22
When repeating the syntheses of 47 and 48 on a similar re-
action scale comparable yields were obtained to the work
outlined in Scheme 9. However, upon necessary scale up
(>10 g) the reaction sequence proved problematic with a
substantial reduction in yield and challenging procedures
on a large scale. Therefore, a new method of synthesis
amenable to large-scale production and, if possible, toler-
ant towards various aromatic substituents, was required to
access diazepine 49 and a library of analogues.
O
OH
N
N
HN
H
Me
N
N
N
OH
N
O
WAY 267,464 (47)
O
N
N
N
H
HN
S
Me
It was proposed (Scheme 10) that by inverting the nucleo-
philic aromatic substitution reaction so that the pyrazole
unit (of type 55) now acted as the electrophile, as opposed
to in Scheme 9, with a 1,2-phenylenediamine 56 as the nu-
cleophile, then both goals could potentially be achieved.
N
N
N
O
N
48
Me
Figure 5 Nonpeptidic oxytocin receptor agonists WAY 267,464
(47) and compound 48
X
The previously reported synthesis of the benzodiazepine
core 49 contained within compounds 47 and 48 is shown
in Scheme 9.21 It began with the reaction of compound 50
with N-methylhydrazine to give pyrazole 51 (85%),
followed by a nucleophilic aromatic substitution with
1-fluoro-2-nitrobenzene to give compound 52 (62%). Re-
duction of the nitro moiety then gave aniline 53 (92%) that
could undergo intramolecular aminolysis to give benzodi-
azepinone 54 (89%). Reduction of the lactam contained
within this last compound gave the benzodiazepine core
49 (86%) that could be elaborated into oxytocin agonists
47 and 48.21
Me
+
HN
H2N
N
N
Me
CHO
NH
NH2
N
N
55
X = Cl, Br, I
56
49
Scheme 10 Proposed new synthesis of diazapine 49
To explore the validity of this approach to diazepine 49-
like compounds we first pursued the reaction between the
simplest, unsubstituted pyrazole 55 (X = Cl) and 1,2-
phenylenediamine (56). Pyrazole 55 was synthesized
from methyl 3-methoxyacrylate (57) and N-methylhydra-
zine followed by a Vilsmeyer–Haack formylation reac-
tion and concomitant chlorination in 52% over two steps
(Scheme 11). Pyrazole 55 and 1,2-phenylenediamine
were subjected to a one-pot nucleophilic aromatic substi-
tution in refluxing ethanol with piperidine followed by
imine reduction with sodium borohydride using condi-
tions that had been successful on related systems.23 Unfor-
tunately aromatic substitution did not occur under these
conditions and only the product of reductive amination 58
(40%) was obtained. More forcing conditions were em-
ployed with potassium hydroxide in N,N-dimethylform-
amide at 120 °C24 and without the addition of sodium
borohydride, but only imine 59 was obtained. Attempts to
cyclize both amine 58 and imine 59 to give diazepine 49
were unsuccessful using a variety of bases and Buchwald–
Hartwig amination or Ullman reaction conditions. Chang-
ing the aryl halide electrophile to the bromo or iodo ana-
logues of pyrazole 55 (X = Br, or I) also failed to promote
the desired substitution.
R
NC
OEt
NH2
NH
i
ii
Me
Me
OEt
O
OEt
O
N
N
N
N
O
85%
62%
OEt
50
51
52 R = NO2
iii
53 R = NH2, 92%
iv 89%
v
HN
HN
Me
Me
NH
NH
N
86%
N
N
N
O
49
54
Scheme 9 Previously reported synthesis of the diazapine core 49 of
oxytocin agonists WAY 267,464 (47) and compound 48. Reagents
and conditions: (i) methylhydrazine (1.1 equiv), EtOH, reflux, 1 h;
(ii) NaH (1.4 equiv), 1-fluoro-2-nitrobenzene (1 equiv), THF, 0 °C to
r.t., 18 h; (iii) Pd/C (cat.), MeOH, r.t., 1 h; (iv) AcOH–i-PrOH (1:9),
160 °C, sealed tube, 48 h; (v) LiAlH4 (14 equiv), THF, reflux, 44 h.
Following these unsuccessful attempts it was perceived
that by forcing the nucleophilic aromatic substitution to
occur first, without the possibility of imine formation, that
product 49, or some suitable precursor, could be obtained.
By altering the electronics of the nucleophilic aniline we
hoped to improve the acidity of the nucleophilic nitrogen
and destabilize the imine intermediate 59, and thus limit
its formation. 2-Nitroaniline was chosen for this purpose
As part of our group’s research efforts, we required access
to large quantities of the nonpeptidic oxytocin receptor
agonists 47 and 48, the synthesis of which has already
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3217
X
Cl
MeO
i
ii
Me
Me
HN
N
N
N
N
O
CHO
52%
40%
H2N
OMe
57
55
X = Cl
58
iii
76%
Cl
HN
Me
N
Me
N
N
NH
N
N
H2N
59
49
Scheme 11 First generation approach to diazepine 49. Reagents and conditions: (i) (a) N-methylhydrazine (1.1 equiv), MeOH, reflux, 16 h;
(b) DMF (1.5 equiv), POCl3 (3 equiv), 0 to 80 °C, 7 h; (ii) 1,2-phenylenediamine (1.1 equiv), pyridine (0.1 equiv), EtOH, reflux, 3 h, then
NaBH4 (2.5 equiv), 0 °C to reflux, 1 h; (iii) 1,2-phenylenediamine (3 equiv), KOH (2 equiv), DMF, 120 °C, 2 h.
as the electron-withdrawing nature of the nitro group has
a significant impact on the electronics of the system while
X
i
Me
HN
still retaining an appropriately substituted, but masked,
second nitrogen atom. Thus, pyrazole 55 (X = Cl) and 2-
nitroaniline were exposed to potassium hydroxide in N,N-
dimethylformamide at 120 °C to give the targeted com-
pound 60 in 75% yield (Scheme 12). Under these condi-
tions no imine formation was observed, even following
substitution, despite the excess of nitroaniline used. To
validate our initial hypothesis that the electron-withdraw-
ing nitro moiety disfavoured imine formation two differ-
ent anilines were exposed to pyrazole 55 (X = Cl) under
the same reaction conditions. As expected the electron-
rich 2-methoxyaniline gave amine 61 following sodium
borohydride reduction (54%) (attempts to isolate the im-
ine were unsuccessful) while the electron-poor 2-amino-
benzonitrile resulted in substitution to give compound 62
(53%).
N
N
CHO
Me
75%
NO2
N
N
O
55
X = Cl
60
iii
53%
ii
54%
Cl
HN
Me
Me
HN
MeO
CN
N
N
N
N
O
61
62
Scheme 12 Revised method for nucleophilic aromatic substitution.
Reagents and conditions: (i) 2-nitroaniline (3 equiv), KOH (2 equiv),
DMF, 120 °C, 2 h; (ii) 2-methoxyaniline (3 equiv), KOH (2 equiv),
DMF, 120 °C, 2 h then NaBH4 (2 equiv), MeOH, 0 °C to r.t., 0.5 h;
(iii) 2-aminobenzonitrile (3 equiv), KOH (2 equiv), DMF, 120 °C, 2 h.
A range of different conditions were tested to determine
the scope of this reaction. The reaction solvent was altered
to ethanol, 1,4-dioxane, or THF all at refluxing tempera-
tures to give compound 60 in 41%, 31%, or 19% yields,
respectively. This showed that while the same transforma-
tion could be achieved in a number of solvents and, there-
fore, temperatures, N,N-dimethylformamide at 120 °C
remained the most effective. Refluxing acetonitrile was
unsuccessful at providing any of compound 60 with only
decomposition of pyrazole 55 being observed. Changing
the base from potassium hydroxide to triethylamine, N,N-
diisopropylethylamine (DIPEA), or potassium carbonate
did not result in any reaction when carried out in N,N-di-
methylformamide at 120 °C, while sodium ethoxide gave
compound 60 in a lower 52% yield.
nitro moiety to the corresponding aniline 63, which can
then undergo an intramolecular Schiff base condensation
to give imine 64. Under the reducing conditions em-
ployed, the imine was then reduced to give the target di-
azepine 49. The hydrogenation catalyst appeared to be
unimportant for this transformation with Pd/Al2O3, Pt/C,
and Raney Ni all effecting the same transformation in
>90% yield. A Zn/HCl reductive system was also success-
ful in providing diazepine 49, but in a reduced yield of
70%.
With a new route to the target diazepine 49 obtained, the
procedure was repeated to determine if these methods
would be amenable to large scale (0.1 mol) production.
While some reduction in yield was observed (62% and
91% cf. 75% and 95% respectively) in scale up, large
quantities of diazepine 49 could be obtained quickly and
With compound 60 in hand we proceeded with the rest of
our proposed synthetic route. Exposure of 60 to palladium
on carbon in methanol under an atmosphere of hydrogen
effected reduction of the aromatic nitro moiety and cycli-
zation to give target diazepine 49 in 95% yield (Scheme
13). The mechanism likely follows initial reduction of the
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3218
T. A. Reekie et al.
FEATURE ARTICLE
i
HN
HN
HN
Me
Me
Me
NO2
NH2
N
N
N
N
N
N
N
O
O
60
63
64
95%
NH
HN
HN
ii
quant.
Me
Me
NH
2HCl
49•2HCl
N
N
N
N
49
Scheme 13 Tandem reductive cyclization to form diazepine 49. Reagents and conditions: (i) Pd/C (cat.), H2 (1 atm), MeOH, r.t., 16 h; (ii)
4.0 M HCl in 1,4-dioxane (2 equiv), THF, r.t., 2 min.
easily for quantitative conversion to the crystalline hydro-
chloride salt 49·2HCl.
X
i
O
Me
The applicability of this method to the synthesis of ana-
logues of diazepine 49 was then explored with focus on
varying the heteroatoms contained within the seven-mem-
bered ring. Towards the synthesis of oxazepine 65, 2-ni-
trophenol was subjected to the same reaction conditions
with pyrazole 55 (X = Cl), but no reaction took place.
Changing from conventional heating to microwave irradi-
ation promoted the desired transformation to give com-
pound 66 albeit in a reduced 33% yield (Scheme 14).
Subjecting 66 to tandem reductive cyclization conditions
gave the target oxazepine 65 in 94% yield. When 2-ami-
nophenol was exposed to the same reaction conditions ini-
tially trialed for nitrogen analogue 56, in contrast to that
result (Scheme 11) the desired nucleophilic aromatic sub-
stitution took place along with concomitant Schiff base
condensation to give imine 67 (58%). While the order of
reaction was most likely nucleophilic aromatic substitu-
tion followed by intramolecular Schiff base condensation,
no intermediates were isolated to support or disprove this
proposal. Reduction of the imine contained within com-
pound 67 with sodium borohydride gave oxazepine 65 in
82% yield, which was identical, in all respects, to that ob-
tained via the nitro derivative.
N
N
Me
NO2
CHO
33%
N
N
O
55
X = Cl
66
iii
58%
ii
94%
iv
O
O
Me
Me
N
NH
82%
N
N
N
N
67
65
Scheme 14 Synthesis of oxazepine analogue 65. Reagents and con-
ditions: (i) 2-nitrophenol (3 equiv), KOH (2 equiv), DMF, micro-
wave, 120 °C, 0.5 h; (ii) Pd/C (cat.), H2 (1 atm), MeOH, r.t., 18 h; (iii)
2-aminophenol (3 equiv), KOH (2 equiv), DMF, 120 °C, 2 h; (iv)
NaBH4 (2 equiv), MeOH, 0 °C to r.t., 1.5 h.
the thioether 69 was achieved with one equivalent of hy-
drogen peroxide in acetic acid25 to afford the sulfoxide 70
in 68% yield (87% based on recovered starting material).
Nitrogen deprotection with potassium carbonate in meth-
anol gave the racemic thiazepine 71 in 94% yield. Com-
plete oxidation of the thioether 69 to the sulfone 72 could
be achieved with excess hydrogen peroxide in acetic acid
(80%) and subsequent nitrogen deprotection afforded
compound 73 (97%).
Following on from these results, a route to the thiazepine
68 was also investigated. Due to the greater nucleophilic-
ity of sulfur a one-pot method was utilized whereby pyr-
azole 55 (X = Cl) was combined with 2-aminothiophenol
and piperidine in refluxing ethanol and then treated with
sodium borohydride to afford the thiazepine 68 in 24%
yield (Scheme 15). The ability to alter the oxidation state
of the sulfur atom contained within thiazepine 68 was also
investigated as a way to provide a greater range of poten-
tially interesting analogues of the heterocyclic unit. To
achieve this goal the azepine nitrogen was first protected
as the trifluoroacetamide 69 (91%). Partial oxidation of
The final target to be investigated within this series was
the corresponding azepine 74, which was thought to be
obtained from the initial reaction between pyrazole 55
(X = Cl) and 2-nitrotoluene to give compound 75
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3219
O
S
X
iii
68%
Me
S
i
Me
NR
N
N
N
N
Me
NR
CHO
24%
N
N
70 R = C(O)CF3
71 R = H
iv
94%
55
X = Cl
68 R = H
ii
91%
69 R = C(O)CF3
O
O
S
v
Me
NR
N
80%
N
72 R = C(O)CF3
73 R = H
iv
97%
Scheme 15 Synthesis of thiazepine analogue 68 and subsequent oxidation of the thioether to give sulfoxide 71 and sulfone 73. Reagents and
conditions: (i) 2-aminothiophenol (1.1 equiv), piperidine, EtOH, reflux, 3 h, then NaBH4 (2.5 equiv), 0 °C to reflux, 1 h; (ii) TFAA (1.5 equiv),
Et3N (3.0 equiv), THF, 0 °C 3 h, r.t., 18 h; (iii) 30% aq H2O2 (1 equiv), AcOH, 80 °C, 2 h; (iv) K2CO3 (3 equiv), MeOH, r.t., 18 h; (v) 30% aq
H2O2 (3 equiv), AcOH, 80 °C, 4 h.
(Scheme 16). Unfortunately, under the previously defined
conditions (KOH, DMF, 120 °C), the starting pyrazole 55
was returned unreacted and compound 76, resulting from
Me
Me
NO2
NH
a dimerization of 2-nitrotoluene, was also isolated
(88%).26 The use of different bases (KOt-Bu or n-BuLi)
did not give any of the desired product 75. When the reac-
tion with potassium hydroxide in N,N-dimethylform-
amide was performed at room temperature for 18 hours
then a condensation reaction took place to yield com-
N
N
N
N
X
O
Me
75
74
N
N
i
CHO
NO2
1
55
X = Cl
pound 77 (74%). H NMR spectroscopy showed the two
olefinic protons as doublets at δ = 6.75 and 7.35 with the
coupling constant (J = 16.3 Hz) indicating a E-double
bond. Work towards the synthesis of azepine 74 is still on-
going, but to date this compound has remained elusive.
88%
O2N
ii
74%
76
Cl
Me
N
N
Synthesis of Leucine-Rich Repeat Kinase 2 (LRRK2)
Inhibitors
O2N
77
Mutations within the PARK8 gene have been implicated
in the increased risk of developing Parkinson’s disease in
humans.27 Mutant leucine-rich repeat kinase 2 (LRRK2)
isoforms commonly exhibit elevated kinase activity and
consequently compounds that inhibit LRRK2 have been
sought as potential therapeutic treatments for Parkinson’s
disease.28 LRRK2IN1 (78), incorporating a pyrimido-
benzodiazepinone moiety, was identified as a potent in-
hibitor of the LRRK2 by high throughput screening.29 The
previously reported synthesis of LRRK2IN1 (78)
(Scheme 17) began with a nucleophilic aromatic substitu-
tion between the pyrimidine 79 and aniline 80 to give
compound 81 in 93% yield.29 Reduction of the aromatic
nitro moiety was accompanied by intramolecular aminol-
ysis to form the diazepinone 82 (85%) that could then be
methylated to give 83 (77%). A Buchwald–Hartwig ami-
Scheme 16 Attempts to synthesize azepine 74. Regents and condi-
tions: (i) 2-nitrotoluene (3 equiv), KOH (2 equiv), DMF, 120 °C, 2 h;
(ii) 2-nitrotoluene (3 equiv), KOH (2 equiv), DMF, r.t., 18 h.
nation between the last compound and aniline 84 afforded
the target LRRK2 inhibitor LRRK2IN1 (78) in 45% yield.
While LRRK2N1 has been shown to be a potent inhibitor
of LRRK2 in vitro and in peripheral tissues in vivo it is not
biologically available in the brain. Using computer mod-
eling, our group predicted that metabolism and a poor
pharmacokinetic profile may be preventing LRRK2IN1
from crossing the blood-brain barrier.
Attempts have been made within the group to synthesize
analogues that retain the potency of LRRK2IN1 but pos-
sess more favourable pharmacokinetics by making minor
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3220
T. A. Reekie et al.
FEATURE ARTICLE
NO2
Me
H
N
O
N
Me
HN
OEt
NO2
Cl
N
i
ii
N
Cl
N
N
OEt
+
O
93%
85%
Cl
N
N
Cl
N
O
Me
82, R = H
iii
77%
79
80
81
83, R = Me
iv
45%
O
Me
O
O
N
N
N
N
N
NH2
N
N
N
N
H
N
OMe
N
OMe
Me
Me
84
Me
LRRK2IN1 (78)
Scheme 17 Previously reported synthesis of the LRRK2 inhibitor LRRK2IN1 (78). Reagents and conditions: (i) 25 (1.5 equiv), DIPEA (2
equiv), 1,4-dioxane, 50 °C, 6 h; (ii) Fe(0) powder (10 equiv), AcOH, 50 °C, 9 h; (iii) MeI (1.5 equiv), NaH (3.1 equiv), DMA, –10 to 0 °C, no
time reported; (iv) 30 (1 equiv), Pd2(dba)3 (cat.), X-Phos (cat.), K2CO3 (equiv), t-BuOH, 100 °C, 4 h.
modifications to the pyrimido-benzodiazepinone core
(Figure 6). Diazepinone 85 and oxazepinone 86 were se-
lected as our initial synthetic targets through which we
X
O
N
N
Y
foresaw to access the reduced azepine derivatives through
N
Z
carbonyl reduction.
LRRK2IN1 (78) X, Y = H, Z = NMe
85 X, Y = Cl, Z = NMe
Our initial synthetic route mimicked that described previ-
ously for lead compound LRRK2IN1 (Scheme 17). Ani-
line 87 or phenol 88 were reacted with 2,4,6-trichloro-5-
nitropyrimidine (89) to give the corresponding compound
90 or 91 in 33% or quantitative yield, respectively
(Scheme 18). Along with the isolation of compound 90 a
second compound arising from disubstitution, whereby
the aniline also substituted for the chloride at the 2-posi-
86 X = Cl, Y = H, Z = O
Figure 6 LRRK2IN1 and potentially metabolically stable analogues
85 and 86
tion, was isolated in 22% yield despite an excess of the py-
rimidine.
Cl
NO2
Z
Cl
N
Cl
H
N
O
N
Z
OEt
i
NO2
Cl
N
iii
33%
N
Cl
N
OEt
O
+
Cl
94%
or ii
quant.
Cl
N
H
Cl
N
O
Y
89
92
87 Y = Cl, Z = NH2
88 Y = H, Z = OH
Y
90 Y = Cl, Z = NH
91 Y = H, Z = O
Cl
Cl
iv
NH2
H
N
O
N
N
v
Cl
N
O
OEt
Cl
82%
(2 steps)
N
O
O
94
93
Scheme 18 The synthesis of LRRK2IN1 azepinone analogues 92 and 94. Reagents and conditions: (i) 87 (0.66 equiv), DIPEA (1.3 equiv),
1,4-dioxane, 55 °C, 3 h; (ii) 88 (0.66 equiv), DIPEA (1.3 equiv), 1,4-dioxane, r.t., 4 h; (iii) Fe powder (10 equiv), AcOH, 130 °C (sealed tube),
20 h; (iv) Fe powder (10 equiv), AcOH, 60 °C, 18 h: (v) Me3Al (1.6 equiv), CH2Cl2, 0 °C, 1 h, reflux, 18 h.
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3221
Attempts to reduce the aromatic nitro moiety and cyclize
were somewhat more problematic than that experienced
Conclusion
in the parent system (81 to 82, Scheme 17).29 For the ani- Seven-membered-ring heterocycles are a key motif in nu-
line derivative 90, higher temperatures (130 °C cf. 50 °C) merous commercially significant compounds across a
and sealed tube conditions were required to afford diaze- range of industries and in particular in pharmaceuticals.
pinone 92 (94%) though this transformation could still be Their methods of synthesis are widely variable depending
achieved in a single-pot procedure. The oxygen analogue on the heteroatom(s) and substitution patterns required.
91 was accessed through a two-step procedure whereby We have provided a brief review of some of the key com-
the nitro moiety was first reduced to the corresponding an- pounds in this area as well as methods for their synthesis.
iline 93 and then treated with trimethylaluminum to effect These procedures have been adapted to provide new
cyclization to give oxazepinone 94 (82% over 2 steps).
methods for the synthesis of key compounds to target the
oxytocin receptor and inhibit LRRK2, both of which have
been implicated in important neurological disorders.
Unfortunately, attempts to reduce the carbonyl associated
with compounds 92 and 94 to afford the corresponding di-
azepine 95 or oxazepine 96 were unsuccessful using a
range of standard reducing conditions including lithium
aluminum hydride or borane–tetrahydrofuran complex.
The halogen substituents decorating these scaffolds as
metabolic blocking groups or handles for further function-
alization via Buchwald–Hartwig chemistry prevented fur-
ther reductive conditions from being attempted.
Therefore, in an attempt to access the reduced systems,
our success with diazepine 49, described above, led us to
develop a similar synthetic route (Scheme 19). Thus, the
dichloropyridimine 97 was reacted with 2-aminobenzal-
dehyde (98) or 2-hydroxybenzaldehyde (99) to afford
compounds 100 and 101, respectively. The presence of
the chlorides proved somewhat problematic for the reduc-
tive cyclization step with their propensity to be cleaved in
the reaction. Consequently, reductive systems such as pal-
ladium on carbon were avoided. Mild reduction using a
Zn/H+ system was unsuccessful, as was initial reduction to
the corresponding aniline (with Fe/H+) and attempts at in-
tramolecular reductive animation. Finally, a successful
one-pot reduction of the nitro moiety and concomitant re-
ductive cyclization was achieved using catalytic plati-
num(IV) oxide under an atmosphere of hydrogen in
refluxing methanol without cleavage of the aromatic chlo-
rides. Thus, compounds 95 and 96 were obtained from
precursors 100 and 101 in 34% and 40% yields, respec-
tively, and thereby provided the diazepine and oxazepine
analogues of the parent compound 78. The synthesis of
All reactions were performed under an atmosphere of N2 or argon
unless otherwise specified. THF, toluene, and 1,4-dioxane were
dried over Na wire and distilled from, in the case of THF, sodium
benzophenone ketyl. CH2Cl2, MeOH, EtOH, and MeCN were dis-
tilled from CaH2. AR Grade acetone was used as purchased. Com-
mercially available chemicals were used as purchased. Analytical
TLC was performed using Merck aluminum-backed silica gel 60
F254 (0.2 mm) plates which were visualized using shortwave (254
nm) and/or longwave (365 nm) UV fluorescence. Flash chromatog-
raphy was performed using Merck Kieselgel 60 (230–400 mesh) sil-
ica gel. Melting points were measured in open capillaries using a
Stuart SMP10 melting point apparatus and are uncorrected. Infrared
absorption spectra were recorded on a Bruker Alpha FT-IR spectro-
photometer. Nuclear magnetic resonance spectra were recorded at
300 K using a Bruker Avance 200 NMR (300.1 MHz) spectrometer
relative to the residual protonated solvent resonance. Assignment of
signals was assisted by COSY, DEPT, HSQC, and HMBC experi-
ments where necessary. LRMS were recorded using electrospray
ionization (ESI) or atmospheric-pressure chemical ionization (AP-
CI) recorded on a Finnigan LCQ ion trap spectrometer.
5-Chloro-1-methyl-1H-pyrazole-4-carbaldehyde (55, X = Cl)
A magnetically stirred solution of methyl 3-methoxyacrylate (20.0
g, 172.2 mmol) in MeOH (100 mL) was treated slowly with N-
methylhydrazine (10.0 mL, 189.4 mmol) and then heated at reflux
for 16 h. The resulting mixture was cooled to r.t. then concentrated
under reduced pressure to afford an orange solid that was dissolved
in DMF (19.9 mL, 258.4 mmol) and cooled to 0 °C. The resulting
mixture was treated slowly with POCl3 (48.1 mL, 516.6 mmol) and
then heated at 80 °C for 7 h. It was cooled and poured slowly into
ice-cold 20% aq Na2CO3 soln (600 mL). The aqueous solution was
then extracted with CHCl3 (5 × 100 mL); the combined organic
these derivatives further validated the versatility of the phases were washed with brine (1 × 100 mL) and then dried
(MgSO4), filtered, and concentrated under reduced pressure to af-
ford an orange solid. Recrystallization (CH2Cl2–hexane) afforded
55 (X = Cl, 12.87 g, 52%) as yellow crystals, mp 77–78 °C;
synthetic route we have developed to access various het-
eroaromatic substituted seven-membered heterocycles.
Rf = 0.44 (EtOAc–hexane, 1:1).
NO2
H
N
N
Z
i
NO2
Cl
N
iii
78%
N
Cl
N
Z
+
O
34% or
40%
or ii
73%
Cl
N
Z
Cl
N
O
97
98 Z = NH2
99 Z = OH
100 Z = NH
101 Z = O
95 Z = NH
96 Z = O
Scheme 19 The synthesis of diazapine 95 and oxazepine 96. Reagents and conditions: (i) 98 (0.66 equiv), DIPEA (1.3 equiv), 1,4-dioxane,
55 °C, 2 h; (ii) 99 (0.66 equiv), DIPEA (1.3 equiv), 1,4-dioxane, 50 °C, 1.6 h, r.t., 3 h; (iii) PtO2 (cat.), H2 (1 atm), MeOH, reflux, 18 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3222
T. A. Reekie et al.
FEATURE ARTICLE
IR (ZnSe cell, film): 1683, 1529, 1424, 1390, 1196, 814, 770 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.82 (s, 1 H), 7.95 (s, 1 H), 3.89
EtOAc (3 × 200 mL). The combined organic phases were washed
with brine (1 × 100 mL) and then dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a yellow oil. This oil was
subjected to flash column chromatography (silica gel, EtOAc–hex-
ane, 1:4 → 1:1 gradient elution) and the relevant fractions were con-
centrated [Rf = 0.33 (EtOAc–hexane, 1:1)] to afford 60 (7.38 g,
75%) as a yellow, crystalline solid; mp 102–105 °C.
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 182.5 (CH), 140.1 (CH), 132.5
(C), 119.1 (C), 36.2 CH3).
LRMS (ESI+): m/z (%) = 145 ([M + H]+, 100).
IR (ZnSe cell, film): 3340, 1679, 1613, 1579, 1506, 1338, 1271,
1226, 1149, 742 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.74 (s, 1 H), 9.35 (s, 1 H), 8.22
(d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.46 (t, J = 8.1 Hz, 1 H), 6.98 (t,
J = 8.1 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 3.72 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 183.2 (CH), 140.9 (CH), 140.3
(C), 140.1 (C), 136.1 (CH), 134.6 (C), 126.6 (CH), 120.2 (CH),
116.2 (C, CH, 2 overlapping signals), 35.8 (CH3).
2-{[(5-Chloro-1-methyl-1H-pyrazol-4-yl)methyl]amino}aniline
(58)
A magnetically stirred solution of 55 (X = Cl, 150 mg, 1.04 mmol),
1,2-phenylenediamine (124 mg, 1.14 mmol), and piperidine (11 μL,
0.1 mmol) in EtOH (5 mL) was heated at reflux for 3 h (TLC mon-
itoring, no starting aldehyde 55 remained). The mixture was cooled
to 0 °C and treated, in portions, with NaBH4 (98 mg, 2.6 mmol) and
once all was dissolved, the mixture was heated to reflux for 1 h then
evaporated to afford a yellow residue. The residue was dissolved in
sat. NaHCO3 soln (15 mL) and extracted with Et2O (3 × 15 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a brown oil that so-
lidified upon standing. The residue was subjected to flash column
chromatography (silica gel, EtOAc–hexane, 3:7, gradient elution)
and the relevant fractions were concentrated [Rf = 0.65 (EtOAc–
hexane, 1:1)] to afford 58 (98 mg, 40%) as a light brown solid; mp
92–95 °C.
LRMS (ESI+): m/z (%) = 269 ([M + Na]+, 100).
HRMS (ESI+): m/z [M + Na]+ calcd for C11H10N4NaO3: 269.0651;
found: 269.0646.
N-[(5-Chloro-1-methyl-1H-pyrazol-4-yl)methyl]-2-methoxyan-
iline (61)
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 2-methoxyaniline (1.12 g, 10.38 mmol) in DMF
(4 mL) was treated with powdered KOH (388 mg, 6.92 mmol) and
then heated at 120 °C for 2 h. The resulting mixture was cooled to
0 °C and MeOH (30 mL) was added followed by NaBH4 (262 mg,
6.92). The resulting solution was warmed to r.t. and stirred for a fur-
ther 0.5 h then treated with sat. aq NH4Cl (50 mL) and extracted
with EtOAc (3 × 20 mL). The combined organic phases were
washed with brine (1 × 10 mL) and then dried (MgSO4), filtered,
and concentrated under reduced pressure to afford a yellow oil. The
oil was subjected to flash column chromatography (silica gel,
EtOAc–hexane, 1:4 → 1:1 gradient elution) and the relevant frac-
tions were concentrated [Rf = 0.42 (EtOAc–hexane, 1:1)] to afford
61 (470 mg, 54%) as a yellow oil.
IR (ZnSe cell, film): 3381, 3277, 3045, 2961, 1594, 1508, 1457,
1275 cm–1.
1H NMR (300 MHz, CD3OD): δ = 7.51 (s, 1 H), 6.59–6.73 (m, 4 H),
4.13 (s, 2 H), 3.81 (s, 3 H).
13C NMR (75 MHz, CD3OD): δ = 139.9 (CH), 138.1 (C), 137.8 (C),
127.3 (C), 120.9 (CH), 120.0 (CH), 117.8 (C), 117.4 (CH), 113.5
(CH), 39.0 (CH3), 36.4 (CH2).
LRMS (ESI+): m/z (%) = 237/239 ([M + H]+, 100/37).
(E)-2-{[(5-Chloro-1-methyl-1H-pyrazol-4-yl)methylene]ami-
no}aniline (59)
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 1,2-phenylenediamine (1.12 g, 10.38 mmol) in
DMF (4 mL) was treated with powdered KOH (388 mg,
6.92 mmol) and then heated at 120 °C for 2 h. The resulting mixture
was cooled to r.t. then treated with sat. aq NH4Cl (50 mL) and ex-
tracted with EtOAc (3 × 20 mL). The combined organic phases
were washed with brine (1 × 10 mL) and then dried (MgSO4), fil-
tered, and concentrated under reduced pressure to afford a yellow
oil. The oil was subjected to flash column chromatography (silica
gel, EtOAc–hexane, 1:4 → 1:1 gradient elution) and the relevant
fractions were concentrated [Rf = 0.44 (EtOAc–hexane, 1:1)] to af-
ford 59 (617 mg, 76%) as a yellow solid; mp 88–89 °C.
IR (ZnSe cell, film): 3200, 1601, 1509, 1454, 1428, 1413, 1396,
1341, 1301, 1288, 1244, 1220, 1177, 1125, 1049, 1026, 990, 847,
796, 735, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.41 (s, 1 H), 6.78 (dt, J = 1.5,
7.5 Hz, 1 H), 6.67 (d, J = 7.5 Hz, 1 H), 6.69 (m, 2 H), 4.27 (br s, 1
H), 4.05 (s, 2 H), 3.72 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 147.0 (C), 138.8 (CH), 137.8 (C),
125.9 (C), 121.3 (CH), 117.0 (CH), 115.9 (C), 110.2 (CH), 109.5
(CH), 55.4 (CH3), 37.8 (CH2), 36.4 (CH3).
LRMS (ESI+): m/z (%) = 252 ([M + H]+, 100).
HRMS (ESI+): m/z [M + Na]+ calcd for C12H1435ClN3NaO:
IR (ZnSe cell, film): 3319, 1625, 1603, 1543, 1491, 1458, 1413,
1397, 1330, 1283, 1268, 1250, 1188, 990 cm–1.
274.0723; found: 274.0717.
2-[(4-Formyl-1-methyl-1H-pyrazol-5-yl)amino]benzonitrile
(62)
1H NMR (300 MHz, CDCl3): δ = 8.28 (s, 1 H), 7.93 (s, 1 H), 6.94
(m, 2 H), 6.65 (m, 2 H), 4.22 (br s, 2 H), 3.79 (s, 3 H).
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 2-aminobenzonitrile (1.22 g, 10.38 mmol) in DMF
(4 mL) was treated with powdered KOH (388 mg, 6.92 mmol) and
then heated at 120 °C for 2 h. The resulting mixture was cooled to
r.t. then treated with sat. aq NH4Cl (50 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic phases were washed
with brine (1 × 10 mL) and then dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a yellow oil. The residue
was subjected to flash column chromatography (silica gel, EtOAc–
hexane, 1:4 → 1:1 gradient elution) and the relevant fractions were
concentrated [Rf = 0.41 (EtOAc–hexane, 1:1)] to afford 62 (415 mg,
53%) as a yellow oil.
13C NMR (75 MHz, CDCl3): δ = 147.6 (CH), 142.1 (C), 138.7
(CH), 137.4 (C), 129.3 (C), 127.5 (CH), 118.4 (CH), 117.6 (C),
116.9 (CH), 115.4 (CH), 36.3 (CH3).
LRMS (ESI+): m/z (%) = 235 ([M + H]+, 100).
HRMS (ESI+): m/z [M – H•]+ calcd for C11H1035ClN4: 233.0594;
found: 233.0589.
1-Methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carbalde-
hyde (60)
A magnetically stirred solution of pyrazole 55 (X = Cl, 5.78 g,
40.0 mmol) and 2-nitroaniline (16.56 g, 120.0 mmol) in DMF
(40 mL) was treated with powdered KOH (4.49 g, 80.0 mmol) and
then heated at 120 °C for 2 h. The resulting mixture was cooled to
r.t. then treated with sat. aq NH4Cl (500 mL) and extracted with
IR (ZnSe cell, film): 2222, 1672, 1636, 1602, 1582, 1559, 1542,
1517, 1506, 1497, 1454, 1395, 1290, 1191, 839, 830, 759 cm–1.
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3223
1H NMR (300 MHz, CDCl3): δ = 9.65 (s, 1 H), 7.80 (s, 1 H), 7.58
(s, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 6.97 (t,
J = 7.5 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 3.51 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 184.2 (CH), 145.2 (C), 142.7 (C),
140.9 (CH), 134.3 (CH), 133.5 (CH), 122.3 (CH), 116.8 (CH),
116.6 (C), 114.4 (C), 101.5 (C), 36.3 (CH3).
LRMS (ESI+): m/z (%) = 227 ([M + H]+, 100).
HRMS (ESI+): m/z [M + H]+ calcd for C12H11N4O: 227.0933;
IR (ZnSe cell, film): 1737, 1680, 1526, 1442, 1350, 1232, 874, 824,
760 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.44 (s, 1 H), 8.05 (d, J = 8.1 Hz,
1 H), 7.90 (s, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.34 (t, J = 7.9 Hz, 1
H), 7.03 (d, J = 8.1 Hz, 1 H), 3.82 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 181.4 (CH), 149.7 (C), 148.8 (C),
140.5 (CH), 139.9 (C), 134.7 (CH), 126.3 (CH), 125.2 (CH), 118.4
(CH), 109.8 (C), 34.8 (CH3).
found: 227.0927.
LRMS (ESI+): m/z (%) = 248 ([M + H]+, 100).
HRMS (ESI+): m/z [M + H]+ calcd for C11H10N3O4: 248. 0671;
found: 248.0666.
1-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]di-
azepine (49)
A suspension of pyrazole 60 (3.94 g, 16.0 mmol) and 10% Pd/C
(200 mg) in MeOH (160 mL) was stirred magnetically at r.t. under
an atmosphere of H2 (1 atm) for 16 h. The resulting mixture was fil-
tered through Celite and the solids thus retained were washed with
MeOH (3 × 20 mL). The combined filtrates were concentrated un-
der reduced pressure to afford a yellow powder. Recrystallization
(CH2Cl2–hexane) afforded 49 (3.04 g, 95%) as a white powder; mp
205–207 °C; Rf = 0.43 (MeOH–CH2Cl2, 1:9).
1-Methyl-4,5-dihydro-1H-benzo[b]pyrazolo[4,3-f][1,4]oxaze-
pine (65)
Method A: A suspension of pyrazole 66 (300 mg, 1.21 mmol) and
10% Pd/C (20 mg) in MeOH (15 mL) was stirred magnetically at
r.t. under an atmosphere of H2 (1 atm) for 18 h. The resulting mix-
ture was filtered through Celite and the solids thus retained were
washed with MeOH (3 × 20 mL). The combined filtrates were con-
centrated under reduced pressure to afford a white solid. Recrystal-
lization (CH2Cl2–hexane) afforded 65 (229 mg, 94%) as white
crystals; mp 143–145 °C; Rf = 0.50 (MeOH–CH2Cl2, 1:9).
IR (ZnSe cell, film): 3293, 1560, 1505, 1393, 1318, 761 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.99 (s, 1 H), 7.05 (d, J = 7.6
Hz, 1 H), 6.97 (s, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.73 (t, J = 7.6 Hz,
1 H), 6.64 (t, J = 7.6 Hz, 1 H), 5.36 (s, 1 H), 3.86 (s, 2 H), 3.67 (s, 3
H).
13C NMR (75 MHz, DMSO-d6): δ = 140.9 (C), 139.5 (C), 135.0
(CH), 133.0 (C), 121.7 (CH), 120.8 (CH), 120.2 (CH), 118.9 (CH),
101.5 (C), 43.4 (CH2), 35.0 (CH3).
IR (ZnSe cell, film): 3293, 1560, 1505, 1393, 1318, 761 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.99 (s, 1 H), 7.05 (d, J = 7.6
Hz, 1 H), 6.97 (s, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.73 (t, J = 7.6 Hz,
1 H), 6.64 (t, J = 7.6 Hz, 1 H), 5.36 (s, 1 H), 3.86 (s, 2 H), 3.67 (s, 3
H).
13C NMR (75 MHz, DMSO-d6): δ = 140.9 (C), 139.5 (C), 135.0
(CH), 133.0 (C), 121.7 (CH), 120.8 (CH), 120.2 (CH), 118.9 (CH),
101.5 (C), 43.4 (CH2), 35.0 (CH3).
LRMS (ESI+): m/z (%) = 201 ([M + H]+, 100).
1-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]di-
LRMS (ESI+): m/z (%) = 201 ([M + H]+, 100).
azepine Dihydrochloride (49·2HCl)
A
magnetically stirred solution of diazepine 49 (3.47 g,
Method B: A magnetically stirred solution of imine 67 (350 mg,
1.76 mmol) in MeOH (8.5 mL) at 0 °C was treated, portionwise
over 5 min, with NaBH4 (136 mg, 3.51 mmol). The resulting mix-
ture was warmed to r.t. and stirred for 1.5 h and treated carefully
with H2O (5 mL). Once H2 evolution had ceased the MeOH was re-
moved under reduced pressure and the resulting aqueous mixture
extracted with EtOAc (3 × 10 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure to afford 65 (288 mg, 82%) as a white powder. This material
was identical, in all respects, with that obtained via Method A de-
scribed immediately above.
17.33 mmol) in THF (57 mL) was treated with 4.0 M HCl in 1,4-
dioxane (8.6 mL, 34.6 mmol) and a white precipitate formed imme-
diately. The precipitate was collected and dried under reduced pres-
sure to afford 49·2HCl (4.1 g, quant.) as a white solid; mp >227 °C
(dec.).
IR (ZnSe cell, film): 3521, 2451, 1632, 1584, 1547, 1505, 1438,
1366, 1212, 1089, 885 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 9.51 (s, 1 H), 7.71 (d, J = 7.5
Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.46 (s, 1 H), 7.63 (t, J = 7.6 Hz,
1 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.36 (s, 2 H), 3.86 (s, 3 H); NH signal
not observed.
13C NMR (75 MHz, DMSO-d6): δ = 140.1 (C), 135.9 (C), 135.7
(CH), 129.4 (C), 125.8 (CH), 125.0 (CH), 121.3 (CH), 121.0 (CH),
96.9 (C), 45.6 (CH2), 35.6 (CH3).
1-Methyl-1H-benzo[b]pyrazolo[4,3-f][1,4]oxazepine (67)
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 2-aminophenol (1.13 g, 10.38 mmol) in DMF
(4 mL) was treated with powdered KOH (388 mg, 6.92 mmol) and
then heated at 120 °C for 2 h. The resulting mixture was cooled to
r.t. then treated with sat. aq NH4Cl (50 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic phases were washed
with brine (1 × 10 mL) and then dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a yellow oil. The oil was
subjected to flash column chromatography (silica gel, EtOAc–
hexane, 1:4 → 1:1 gradient elution) and the relevant fractions were
concentrated [Rf = 0.21 (EtOAc–hexane, 1:1)] to afford 67 (400 mg,
58%) as a brown oil.
IR (ZnSe cell, film): 1680, 1529, 1229, 1050, 895, 832, 760 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.91 (s, 1 H), 7.23 (s, 1 H), 7.22
(d, J = 4.05 Hz, 1 H), 7.08 (m, 2 H), 7.88 (m, 1 H), 3.62 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.8 (C), 153.2 (C), 149.7 (CH),
138.8 (C), 137.1 (CH), 132.2 (CH), 128.4 (CH), 126.0 (CH), 120.2
(CH), 104.0 (C), 35.5 (CH3).
LRMS (ESI+): m/z (%) = 201 ([M + H]+, 100).
Anal. Calcd for C11H13N4·2HCl: C, 48.37; H, 5.17; N, 20.51. Found:
C, 48.37; H, 5.13; N, 20.45.
1-Methyl-5-(2-nitrophenoxy)-1H-pyrazole-4-carbaldehyde (66)
A solution of pyrazole 55 (X = Cl, 500 mg, 3.46 mmol), 2-nitrophe-
nol (1.44 g, 10.38 mmol), and powdered KOH (388 mg,
6.92 mmol) in DMF (4 mL) was irradiated in a CEM Explorer™
microwave reactor at 120 °C for 0.5 h. The resulting mixture was
cooled to r.t. then treated with sat. aq NH4Cl (50 mL) and extracted
with EtOAc (3 × 20 mL). The combined organic phases were
washed with brine (1 × 10 mL) and then dried (MgSO4), filtered,
and concentrated under reduced pressure to afford a yellow oil. The
oil was subjected to flash column chromatography (silica gel,
EtOAc–hexane, 1:4 → 1:1 gradient elution) and the relevant frac-
tions were concentrated [Rf = 0.26 (EtOAc–hexane, 1:1)] to afford
66 (282 mg, 33%) as a yellow solid; mp 88–89 °C.
LRMS (ESI+): m/z (%) = 200 ([M + H]+, 100).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3224
T. A. Reekie et al.
FEATURE ARTICLE
HRMS (ESI+): m/z [M + H]+ calcd for C11H10N3O: 200.0824;
found: 200.0818.
Concentration of fraction B [Rf = 0.30 (EtOAc–hexane, 1:1)] af-
forded 70 (90 mg, 68%) as a yellow solid; mp 205–208 °C.
IR (ZnSe cell, film): 2924, 1707, 1477, 1209, 1149, 1057 cm–1.
1-Methyl-4,5-dihydro-1H-benzo[b]pyrazolo[4,3-f][1,4]thiaze-
pine (68)
1H NMR (300 MHz, CD3OD): δ = 7.97 (d, J = 7.8 Hz, 1 H), 7.83 (t,
J = 7.8 Hz, 1 H), 7.69 (m, 2 H), 7.55 (s, 1 H), 5.90 (d, J = 17.2 Hz,
1 H), 4.29 (d, J = 17.2 Hz, 1 H), 4.15 (s, 3 H).
13C NMR (75 MHz, CD3OD): δ = 156.3 (C), 140.1 (C), 139.7 (C),
139.3 (C), 138.2 (CH), 135.9 (CH), 131.9 (CH), 130.7 (CH), 121.4
(CH), 119.5 (CH), 115.7 (CF3), 45.7 (CH2), 37.9 (CH3).
A magnetically stirred solution of 55 (X = Cl, 150 mg, 1.0 mmol),
2-aminothiophenol (120 μL, 1.1 mmol), and piperidine (11 μL 0.1
mmol) in EtOH (5 mL) was heated at reflux for 3 h (TLC monitor-
ing, no starting aldehyde 55 remained). The mixture was cooled to
0 °C and treated, in portions, with NaBH4 (98 mg, 2.6 mmol, 2.5
equiv) and once all was dissolved, the mixture was reheated to re-
flux for 1 h then evaporated down to afford a yellow residue. This
was dissolved in sat. NaHCO3 soln (20 mL) and extracted with Et2O
(3 × 20 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated under reduced pressure to afford a yellow
solid. The solid was subjected to flash column chromatography (sil-
ica gel, EtOAc–hexane, 3:7 → 8:2 gradient elution) and the relevant
fractions were concentrated [Rf = 0.15 (EtOAc–hexane, 1:1)] to af-
ford 68 (54 mg, 24%) as a white solid; mp 134–137 °C.
LRMS (ESI+): m/z (%) = 330 ([M + H]+, 100).
1-Methyl-4,5-dihydro-1H-benzo[b]pyrazolo[4,3-f][1,4]thiaze-
pine 10-Oxide (71)
A solution of acetamide 70 (90 mg, 273 μmol), and K2CO3 (100 mg,
720 μmol) in MeOH (6 mL) was stirred magnetically at r.t. for 18
h. The resulting mixture was then concentrated under reduced pres-
sure followed by the addition of H2O (15 mL), which was then ex-
tracted with EtOAc (3 × 15 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure to afford 71 (60 mg, 94%) as a white solid; mp 192–194 °C;
Rf = 0.45 (MeOH–CH2Cl2, 1:9).
IR (ZnSe cell, film): 3358, 2937, 1479, 1417, 1312 cm–1.
1H NMR (300 MHz, CD3OD): δ = 7.37 (d, J = 7.8 Hz, 1 H), 7.29 (s,
1 H), 7.20 (dd, J = 7.8, 7.8 Hz, 1 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.89
(dd, J = 7.8, 7.8 Hz, 1 H), 4.25 (s, 2 H), 3.83 (s, 3 H).
IR (ZnSe cell, film): 3302, 3096, 2928, 1547, 1468, 1029 cm–1.
13C NMR (75 MHz, CD3OD): δ = 152.1 (C), 137.5 (CH), 132.8 (C),
132.5 (CH), 130.9 (CH), 124.0 (CH), 123.9 (C), 123.3 (CH), 120.6
(C), 44.7 (CH2), 36.5 (CH3).
1H NMR (200 MHz, MeOD-d4): δ = 7.62 (d, J = 8.2 Hz, 1 H), 7.47
(s 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.80 (m, 2 H), 4.77 (d, J = 15.6 Hz,
1 H), 4.29 (d, J = 15.6 Hz, 1 H), 4.03 (s, 3 H); the NH proton was
not observed.
LRMS (ESI+): m/z (%) = 218 ([M + H]+, 100).
13C NMR (75 MHz, CD3OD): δ = 148.3 (C), 140.0 (C), 137.3 (CH),
135.3 (CH), 134.0 (CH), 123.0 (C), 121.5 (CH), 120.2 (C), 117.9
(CH), 38.0 (CH3), 37.6 (CH2).
HRMS (ESI+): m/z [M + Na]+ calcd for C11H11N3NaS: 240.0566;
found: 240.0566.
2,2,2-Trifluoro-1-[1-methyl-1H-benzo[b]pyrazolo[4,3-
f][1,4]thiazepin-5(4H)-yl]ethanone (69)
LRMS (ESI+): m/z (%) = 234 ([M + H]+, 100).
HRMS (ESI+): m/z [M + Na]+ calcd C11H11N3NaOS: 256.0515;
A magnetically stirred solution of compound 68 (200 mg, 920
μmol) and Et3N (96 μL, 2.8 mmol) in THF (3 mL) at 0 °C was treat-
ed dropwise with TFAA (200 μL, 1.4 mmol). The resulting solution
was allowed to stir at 0 °C for 3 h and then at r.t. for a further 18 h.
The resulting mixture was then concentrated under reduced pres-
sure to afford a yellow oil that was subjected to flash column chro-
matography (silica gel, EtOAc–hexane, 1:7 ). Concentration of the
relevant fractions [Rf = 0.43 (EtOAc–hexane, 1:1] afforded 69 (262
mg, 91%) as a yellow solid; mp 115–118 °C.
found: 256.0515.
2,2,2-Trifluoro-1-[1-methyl-10,10-dioxido-1H-benzo[b]pyrazo-
lo[4,3-f][1,4]thiazepin-5(4H)-yl]ethanone (72)
A magnetically stirred solution of compound 69 (50 mg, 160 μmol)
in glacial AcOH (0.6 mL) was treated dropwise with 30% aq H2O2
(50 μL, 480 μmol) at r.t. and then heated to 80 °C for 4 h. The re-
sulting solution was cooled to r.t. and treated with H2O (15 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure to afford 72 (55 mg, 80%) as a yellow solid, mp 187–190 °C;
Rf = 0.25 (EtOAc–hexane, 1:1).
IR (ZnSe cell, film): 2939, 1697, 1475, 1203, 1180, 1146 cm–1.
1H NMR (300 MHz, CD3OD): δ = 7.73 (d, J = 8 Hz, 1 H), 7.45–
7.63 (m, 3 H), 7.40 (s, 1 H), 5.78 (d, J = 16 Hz, 1 H), 4.14 (d, J = 16
Hz, 1 H), 3.85 (s, 3 H).
IR (ZnSe cell, film): 3100, 2961, 1710, 1478, 1366, 1211, 1167 cm–1.
13C NMR (75 MHz, CD3OD): δ = 163.2 (C), 143.1 (CH), 133.7
(CH), 133.1 (CH), 132.0 (CH), 131.0 (CH), 129.8 (CH), 116.3 (C),
115.8 (CF3), 46.4 (CH2), 36.9 (CH3).
1H NMR (300 MHz, CD3OD): δ = 8.18 (dd, J = 1.4, 7.8 Hz, 1 H),
7.93 (dt, J = 1.2, 7.8 Hz, 1 H), 7.80 (dt, J = 1.4, 7.9 Hz, 1 H), 7.76
(dd, J = 1.2, 7.9 Hz, 1 H), 7.5 (s, 1 H), 5.93 (d, J = 17.2 Hz, 1 H),
4.36 (d, J = 17.2 Hz, 1 H), 4.20 (s, 3 H).
LRMS (ESI+): m/z (%) = 314 ([M + H]+, 100).
13C NMR (75 MHz, CD3OD): δ = 157.9 (C), 157.5 (C), 141.2 (C),
137.5 (CH), 137.3 (CH), 131.9 (CH), 131.4 (CH), 128.6 (CH),
118.9 (C), 116–118 (CF3, unresolved), 46.0 (CH2), 40.6 (CH3).
2,2,2-Trifluoro-1-[1-methyl-10-oxido-1H-benzo[b]pyrazo-
lo[4,3-f][1,4]thiazepin-5(4H)-yl]ethanone (70)
A magnetically stirred solution of compound 69 (130 mg, 400
μmol) in glacial AcOH (1 mL) was treated dropwise with 30% aq
H2O2 (40 μL, 400 μmol) at r.t. and then the mixture was heated to
80 °C for 2 h. The resulting solution was cooled to r.t. and treated
with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The com-
bined organic phases were dried (MgSO4), filtered, and concentrat-
ed under reduced pressure to give a yellow oil. The oil was
subjected to flash column chromatography (silica gel, EtOAc–
hexane, 1:1) to afford two fractions, A and B.
LRMS (ESI+): m/z (%) = 346 ([M + H]+, 100).
1-Methyl-4,5-dihydro-1H-benzo[b]pyrazolo[4,3-f][1,4]thiaze-
pine 10,10-Dioxide (73)
A solution of acetamide 72 (56 mg, 159 μmol), and K2CO3 (62 mg,
450 μmol) in MeOH (4 mL) was stirred magnetically at r.t. for 18
h. The resulting mixture was then concentrated under reduced pres-
sure followed by the addition of H2O (15 mL) which was then ex-
tracted with EtOAc (3 × 15 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure to afford 73 (39 mg, 97%) as a white solid; mp 172–174 °C;
Rf = 0.39 (MeOH–CH2Cl2, 1:9).
Concentration of fraction A [Rf = 0.43 (EtOAc–hexane, 1:1)] af-
forded the starting compound 69 (17 mg, 13% recovery) as a yellow
solid. This material was identical, in all respects, with an authentic
sample.
IR (ZnSe cell, film): 3398, 3078, 2958, 1602, 1447, 1312, 1164 cm–1.
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biologically Active Seven-Membered-Ring Heterocycles
3225
1H NMR (200 MHz, MeOD-d4): δ = 7.80 (d, J = 8.4 Hz, 1 H), 7.45
(s 1 H), 7.29 (t, J = 7.0 Hz, 1 H), 7.69 (m, 2 H), 4.57 (s, 2 H), 4.11
(s, 3 H); the NH proton was not observed.
13C NMR (75 MHz, CD3OD): δ = 146.0 (C), 140.0 (C), 137.0 (CH),
135.6 (CH), 126.8 (CH), 122.6 (C), 120.9 (CH), 117.1 (C), 116.7
(CH), 38.8 (CH2), 38.5 (CH3).
were concentrated [Rf = 0.60 (hexane–CH2Cl2, 1:3)] to afford 90
(500 mg, 33%) as a yellow solid; mp 83–85 °C.
IR (ZnSe cell, film): 3548, 2902, 1695, 1561, 1536, 1468, 1304,
1247, 1204, 1077, 1011, 783 cm–1.
1H NMR (300 MHz, CDCl3): δ = 12.0 (s, 1 H), 8.46 (d, J = 9.0 Hz,
1 H), 8.07 (d, J = 2.7 Hz, 1 H), 7.59 (dd, J = 2.7, 9.2 Hz, 1 H), 4.46
(q, J = 6.9 Hz, 2 H), 1.44 (t, J = 6.9 Hz, 3 H).
LRMS (ESI+): m/z (%) = 250 ([M + H]+, 100).
HRMS (ESI+): m/z [M + Na]+ calcd for C11H11N3O2NaS: 272.0454;
found: 272.0464.
13C NMR (75 MHz, CDCl3): δ = 166.7 (C), 159.4 (C), 155.2 (C),
153.5 (C), 137.4 (C), 134.0 (CH), 131.1 (CH), 130.2 (C), 123.9
(CH), 119.9 (C), 62.7 (CH2), 14.3 (CH3); one unresolved quaternary
carbon.
1,2-Bis(2-nitrophenyl)ethane (76)
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 2-nitrotoluene (1.42 g, 10.38 mmol) in DMF
(4 mL) was treated with powdered KOH (388 mg, 6.92 mmol) and
then heated at 120 °C for 2 h. The resulting mixture was cooled to
r.t. then treated with sat. aq NH4Cl (50 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic phases were washed
with brine (1 × 10 mL) and then dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a yellow oil. The residue
was subjected to flash column chromatography (silica gel, EtOAc–
hexane, 1:4 → 1:1 gradient elution) to afford two fractions, A and B.
LRMS (ESI+): m/z (%) = 391/393/395 ([M + H]+, 100/96/27).
2,4,8-Trichloro-5,11-dihydro-6H-benzo[e]pyrimido[5,4-
b][1,4]diazepin-6-one (92)
A magnetically stirred suspension of compound 90 (359 mg, 0.916
mmol) and Fe powder (512 mg, 9.16 mmol) in glacial AcOH (14
mL) was heated at 130 °C in a sealed tube for 20 h. The cooled mix-
ture was and treated with H2O (20 mL) and the aqueous solution
was extracted with CH2Cl2 (3 × 20 mL). The combined organic lay-
ers were washed with brine (50 mL) and then dried (MgSO4), fil-
tered, and concentrated under reduced pressure to afford 92 (273
mg, 94%) as a yellow solid; mp 272–274 °C; Rf = 0.15 (hexane–
CH2Cl2, 1:5).
Concentration of fraction A [Rf = 0.65 (EtOAc–hexane, 1:1)] af-
forded the starting pyrazole 55 (462 mg, 92% recovery) as yellow
crystals. This material was identical, in all respects, with an authen-
tic sample.
IR (ZnSe, solid): 3337, 3252, 3184, 3106, 2927, 1647, 1532, 1459,
1254, 1219, 1142 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.16 (br s, 1 H), 7.72 (d,
J1 = 2.4 Hz, 1 H), 7.53 (dd, J = 2.2, 8.8 Hz, 1 H), 7.18 (d, J = 8.8
Hz, 1 H).
Concentration of fraction B [Rf = 0.35 (EtOAc–hexane, 1:1)] af-
forded 76 (1.24 g, 88%) as a white solid. The spectral data was iden-
tical, in all respects, with those previously reported.26
(E)-5-Chloro-1-methyl-4-(2-nitrostyryl)-1H-pyrazole (77)
A magnetically stirred solution of pyrazole 55 (X = Cl, 500 mg,
3.46 mmol) and 2-nitrotoluene (1.42 g, 10.38 mmol) in DMF
(4 mL) was treated with powdered KOH (388 mg, 6.92 mmol) then
stirred at r.t. for 18 h. The resulting mixture was treated with sat. aq
NH4Cl (50 mL) and extracted with EtOAc (3 × 20 mL). The com-
bined organic phases were washed with brine (1 × 10 mL) and then
dried (MgSO4), filtered, and concentrated under reduced pressure to
afford a yellow oil. The residue was subjected to flash column chro-
matography (silica gel, EtOAc–hexane, 1:4 → 1:1 gradient elution)
and the relevant fractions were concentrated [Rf = 0.57 (EtOAc–
hexane, 1:1)] to afford 77 (675 mg, 74%) as a yellow solid; mp 71–
73 °C.
13C NMR (75 MHz, DMSO-d6): δ = 164.9 (C), 159.7 (C), 151.6 (C),
150.1 (C), 142.0 (C), 133.8 (CH), 131.6 (CH), 126.8 (C), 123.0 (C),
122.2 (CH), 117.4 (C).
LRMS (APCI+): m/z (%) = 315/317/319/321 ([M + H]+,
94/100/33/24).
HRMS (APCI+): m/z [M + H]+ calcd for C11H637Cl3N4O: 320.9519;
found: 320.9727.
Ethyl 2-[(2,6-Dichloro-5-nitropyrimidin-4-yl)oxy]benzoate (91)
and Ethyl 2-[(5-Amino-2,6-dichloropyrimidin-4-yl)oxy]benzo-
ate (93)
Step ii: A magnetically stirred solution of 2,4,6-trichloro-5-nitropy-
rimidine (89, 1.68 g, 7.36 mmol) and DIPEA (1.72 mL, 9.81 mmol)
in anhyd 1,4-dioxane (20 mL) at r.t. was treated dropwise with a so-
lution of ethyl 2-hydroxybenzoate (88, 722 μL, 4.91 mmol) in 1,4-
dioxane (10 mL). The resulting mixture was stirred at r.t. for 4 h
then diluted with EtOAc (150 mL) and washed with brine (2 × 50
mL) and then dried (MgSO4), filtered, and concentrated under re-
duced pressure to afford 91 as an orange solid [Rf = 0.56 (EtOAc–
hexane, 1:5)]. This material was subjected to the next step of the re-
action sequence without further purification.
1H NMR (300 MHz, acetone-d6): δ = 8.12 (d, J = 7.6 Hz, 1 H), 7.81
(dd, J = 7.2 Hz, 1 H), 7.57 (dd, J = 7.7 Hz, 1 H), 7.46 (d, J = 8.4 Hz,
1 H), 4.24 (q, J = 6.9 Hz, 2 H), 1.20 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 164.4 (C), 163.4 (C), 159.2
(C), 154.1 (C), 151.0 (C), 135.6 (CH), 133.0 (CH), 128.6 (CH),
128.0 (C), 124.4 (CH), 124.0 (C), 62.2 (CH2), 14.1 (CH3).
IR (ZnSe cell, film): 1635, 1604, 1519, 1475, 1389, 1343, 1254,
956, 785, 741 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 7.5 Hz, 1 H), 7.65 (s
1 H), 7.64 (d, J = 5.4 Hz, 1 H), 7.52 (t, J = 6.9 Hz, 1 H), 7.35 (d,
J = 16.3 Hz, 1 H), 7.31 (d, J = 6.9 Hz, 1 H), 6.75 (d, J = 16.3 Hz, 1
H), 3.77 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 147.7 (C), 137.1 (CH), 133.0
(CH), 128.3 (C), 127.8 (CH), 127.7 (CH), 126.3 (C), 124.8 (CH),
122.4 (CH), 121.9 (CH), 116.4 (C), 36.4 (CH3).
LRMS (ESI+): m/z (%) = 264 ([M + H]+, 100).
HRMS (ESI+): m/z [M + H]+ calcd for C12H1135ClN3O2: 264.0540;
found: 264.0534.
Ethyl 5-Chloro-2-[(2,6-dichloro-5-nitropyrimidin-4-yl)ami-
no]benzoate (90)
Step iv: A magnetically stirred suspension of compound 91 (from
the previous step) and Fe powder (2.73 g, 48.9 mmol) in glacial
AcOH (60 mL) was heated at 60 °C for 18 h. The resulting mixture
was filtered through Celite and the solids thus retained were washed
with acetone. The filtrate was then concentrated under reduced
pressure and treated with ice-cold water resulting in a brown precip-
itate that was then filtered, and washed further with ice-cold water.
The solid was then dried under reduced pressure to afford 93 (1.61
A magnetically stirred solution of 2,4,6-trichloro-5-nitropyrimidine
(89, 1.33 g, 5.81 mmol) and DIPEA (1.30 mL, 7.74 mmol) in anhyd
1,4-dioxane (15 mL) at r.t. was treated dropwise with a solution of
ethyl 2-amino-5-chlorobenzoate (87, 776 mg, 3.87 mmol) in anhyd
1,4-dioxane (5 mL). The resulting solution was heated to 50–55 °C
and stirred for 3 h then cooled to r.t. and concentrated under reduced
pressure. The residue was subjected to flash column chromatogra-
phy (silica gel, EtOAc–hexane, 1:30) and the relevant fractions
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227

3226
T. A. Reekie et al.
FEATURE ARTICLE
g, 100% over 2 steps) as a brown solid; mp 82–83 °C; Rf = 0.39
(EtOAc–hexane, 1:5).
reduced pressure. The resulting residue was subjected to flash col-
umn chromatography (silica gel, EtOAc–hexane, EtOAc–hexane,
1:10) and the relevant fractions were concentrated [Rf = 0.20
(EtOAc–hexane, 1:4)] to afford 101 (70 mg, 73%) as a red/black
solid; mp 130–132 °C.
IR (solid): 3467, 3351, 1728, 1607, 1404, 1240, 1206, 1075, 958,
871 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 8.04 (dd, J = 1.6, 7.8 Hz, 1 H),
7.74 (ddd, J = 1.6, 7.8, 7.8 Hz, 1 H), 7.45 (dd, J = 7.6, 7.6 Hz, 1 H),
7.39 (d, J = 8.2 Hz, 1 H), 5.41 (br s, 2 H), 4.17 (q, J = 7.1 Hz, 2 H),
1.14 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 165.0 (C), 161.9 (C), 159.3
(C), 152.3 (C), 143.1 (C), 141.2 (C), 135.0 (CH), 132.7 (CH), 128.0
(C), 127.3 (CH), 125.0 (CH), 61.8 (CH2), 14.1 (CH3).
IR (solid): 3078, 2880, 2761, 1695, 1587, 1555, 1415, 1331, 1291,
1201, 1100, 962, 849 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.02 (s, 1 H), 9.22 (s, 1 H), 7.94
(dd, J = 1.7, 7.8 Hz, 1 H), 7.75 (ddd, J = 1.7, 7.8, 7.8 Hz, 1 H), 7.56
(ddd, J = 0.7, 7.6, 7.6 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 188.7, 162.9, 162.2, 157.6, 150.7,
135.9, 133.6, 131.5, 127.8, 123.3; one unresolved quaternary car-
bon.
LRMS (APCI+): m/z (%) = 328/330 ([M + H]+, 100/62).
LRMS (APCI+): m/z (%) = 282, 280 ([M + H]+, 60/67).
2,4-Dichlorobenzo[f]pyrimido[4,5-b][1,4]oxazepin-6(5H)-one
(94)
A magnetically stirred solution of compound 93 (67 mg, 0.203
mmol) in CH2Cl2 (2 mL) at 0 °C was treated dropwise with 2.0 M
Me3Al in toluene (162 μL, 0.325 mmol). The resulting mixture was
stirred at this temperature for 0.5 h and then warmed to r.t. and
stirred for a further 1 h. The mixture was then heated at reflux and
stirred for a further 18 h. The cooled mixture was then treated with
1 M aq HCl (1 mL) and the separated organic phase was concentrat-
ed under reduced pressure. The residue was subjected to flash col-
umn chromatography (silica gel, hexane–CH2Cl2, 1:2 → 1:4,
gradient elution) and the relevant fractions were concentrated [Rf =
0.55 (10% ammonia in MeOH–CH2Cl2, 1:10)] to afford 94 (47 mg,
82%) as a brown solid; mp >260 °C (dec.).
2-Chloro-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diaze-
pine (95)
A magnetically stirred solution of compound 100 (48 mg, 0.17
mmol) and PtO2 (1.2 mg, 5 μmol) in MeOH (1.5 mL) under an at-
mosphere of H2 (1 atm) was heated at reflux for 18 h. The resulting
mixture was filtered through Celite and the solids thus retained were
washed with EtOAc (3 × 5 mL). The combined filtrates were con-
centrated under reduced pressure and the residue was purified by
flash column chromatography (silica gel, EtOAc–hexane, EtOAc–
hexane, 1:4). Concentration of the relevant fractions [Rf = 0.46
(EtOAc–hexane, 1:2)] afforded 95 (13 mg, 34%) as a brown pow-
der; mp >155 °C dec.
IR (ZnSe cell, solid): 3176, 3086, 2919, 1683, 1455, 1410, 1331,
1131 cm–1.
IR (solid): 3352, 3255, 3045, 2925, 2856, 1704, 1574, 1537, 1495,
1395, 1279, 1228, 1157, 1121, 1051, 982 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.65 (s, 1 H), 7.83 (d, J = 7.8
Hz, 1 H), 7.70 (ddd, J = 1.5, 7.8, 7.8 Hz, 1 H), 7.43 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 164.6 (C), 163.8 (C), 155.5 (C),
153.4 (C), 151.5 (C), 135.2 (CH), 131.8 (CH), 126.9 (CH), 124.3
(C), 122.7 (C), 121.2 (CH).
1H NMR (300 MHz, CD3OD): δ = 7.68 (s, 1 H), 7.19 (ddd, J = 1.5,
7.7, 7.7 Hz, 1 H), 7.07 (m, 2 H), 6.92 (ddd, 3J = 0.9, 7.5, 7.5 Hz, 1
H), 4.17 (s, 2 H); NH signal not observed.
13C NMR (125 MHz, CDCl3): δ = 154.8 (C), 151.3 (C), 143.9 (CH),
141.1 (C), 132.6 (C), 129.8 (CH), 129.6 (C), 129.3 (CH), 123.2
(CH), 120.4 (CH), 51.8 (CH2).
LRMS (APCI+): m/z (%) = 235, 233 ([M + H]+, 27/100).
HRMS (ESI+): m/z [M + Na]+ calcd for C11H937ClN4Na: 257.0384;
LRMS (APCI+): m/z (%) = 282/284 ([M + H]+, 100/74).
Anal. Calcd for C11H5Cl2N3O2: C, 46.84; H, 1.79; N, 14.90. Found:
C, 46.83; H, 2.35; N, 14.40.
found: 257.0378.
2-[(2-Chloro-5-nitropyrimidin-4-yl)amino]benzaldehyde (100)
2,4-Dichloro-5-nitropyrimidine (97, 100 mg, 0.52 mmol) and
DIPEA (120 μL, 0.69 mmol) in anhyd 1,4-dioxane (1.8 mL) were
treated with 2-aminobenzaldehyde (98, 42 mg, 0.34 mmol) and the
mixture was stirred at 50–55 °C for 2 h. The resulting mixture was
concentrated under reduced pressure and the residue subjected to
flash column chromatography (silica gel, EtOAc–hexane, 1:20 →
1:10 gradient elution). Concentration of the relevant fractions [Rf =
0.30 (EtOAc–hexane, 1:5)] afforded 100 (74 mg, 78%) as a yellow-
orange solid; mp 208–209 °C.
2-Chloro-5,6-dihydrobenzo[f]pyrimido[4,5-b][1,4]oxazepine
(96)
A magnetically stirred solution of compound 101 (74 mg, 0.265
mmol) and PtO2 (1.8 mg, 8 μmol) in MeOH (2.3 mL) under an at-
mosphere of H2 (1 atm) was heated at reflux for 18 h. The resulting
mixture was filtered through Celite and the solids thus retained were
washed with solvent MeOH–EtOAc (1:20, 3 × 5 mL). The com-
bined filtrates were concentrated under reduced pressure and the
residue was purified by flash column chromatography (silica gel,
MeOH–EtOAc–hexane, 0.1:10:30). Concentration of the relevant
fractions [Rf = 0.46 (EtOAc–hexane, 1:2)] afforded 96 (25 mg,
40%) as a white powder; mp 191–193 °C.
IR (solid): 3389, 2932, 1675, 1577, 1555, 1451, 1366, 1313, 1253,
1221, 1195 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.92 (s, 1 H), 10.04 (s, 1 H), 9.25
(s, 1 H), 8.82 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.74
(dd, J = 7.5 Hz, 1 H), 7.43 (dd, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 194.3 (CH), 163.6 (C), 157.8 (C),
153.5 (C), 137.9 (C), 136.4 (CH), 135.6 (CH), 127.9 (CH), 125.6
(CH), 124.7 (C), 122.7 (CH).
IR (solid): 3365, 2922, 1579, 1547, 1483, 1428, 1358, 1340, 1208,
1170, 1107, 1040, 938 cm–1.
1H NMR (500 MHz, CD3OD): δ = 7.97 (s, 1 H), 7.35 (d, J = 7.5 Hz,
1 H), 7.28 (d, J = 7.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.18 (d,
J = 7.0 Hz, 1 H), 4.44 (s, 2 H); NH signal not observed.
13C NMR (125 MHz, CD3OD): δ = 157.2 (C), 156.4 (C), 148.6
(CH), 147.2 (C), 134.9 (C), 132.3 (CH), 130.6 (CH), 129.7 (CH),
126.7 (C), 121.8 (CH), 46.9 (CH2).
LRMS (APCI+): m/z (%) = 285/281/279 ([M + H]+, 28/35/100).
2-[(2-Chloro-5-nitropyrimidin-4-yl)oxy]benzaldehyde (101)
A magnetically stirred solution of 2,4-dichloro-5-nitropyrimidine
(97, 100 mg, 0.52 mmol) and DIPEA (120 μL, 0.69 mmol) in anhyd
1,4-dioxane (1.8 mL) was treated dropwise with 2-hydroxybenzal-
dehyde (99, 36 μL, 0.34 mmol). The resulting mixture was stirred at
50 °C for 1.6 h followed by 3 h at r.t. and then concentrated under
LRMS (APCI+): m/z (%) = 237, 234 ([M + H]+, 27/100).
HRMS (ESI+): m/z [M + H]+ calcd for C11H935ClN3O: 234.0434;
found: 234.0429.
Synthesis 2013, 45, 3211–3227
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Acknowledgement
Biologically Active Seven-Membered-Ring Heterocycles
3227
(16) Frauenrath, H. 1,4-Dioxepanes, 1,4-Oxathiepanes, and 1,4-
Dithiepanes, In Comprehensive Heterocyclic Chemistry II;
Vol. 9; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 271.
This work has been supported by funding from the National Health
and Medical Research Council (NHMRC) and Parkinson’s NSW.
(17) Kowalski, P.; Mitka, K.; Ossowska, K.; Kolarska, Z.
Tetrahedron 2005, 61, 1933.
Supporting Information for this article is available online at
(18) (a) Ring, R. H.; Schechter, L. E.; Leonard, S. K.; Dwyer, J.
M.; Platt, B. J.; Graf, R.; Grauer, S.; Pulicicchio, C.;
Resnick, L.; Rahman, Z.; Sukoff Rizzo, S. J.; Luo, B.; Beyer,
C. E.; Logue, S. F.; Marquis, K. L.; Hughes, Z. A.;
Rosenzweig-Lipson, S. Neuropharmacology 2010, 58, 69.
(b) Hicks, C.; Jorgensen, W.; Brown, C.; Fardell, J.;
Koehbach, J.; Gruber, C. W.; Kassiou, M.; Hunt, G. E.;
McGregor, I. S. J. Neuroendocrinol. 2012, 24, 1012.
(19) Rahman, Z.; Resnick, L.; Rosenzweig-Lipson, S. J.; Ring, R.
H. US 2007,0,117,794, 2007.
(20) McGregor, I. S.; Callaghan, P. D.; Hunt, G. E. Brit. J.
Pharmacol. 2008, 154, 358.
(21) Frantz, M.-C. L.; Rodrigo, J.; Boudier, L.; Durroux, T.;
Mouillac, B.; Hibert, M. J. Med. Chem. 2010, 53, 1546.
(22) Hudson, P.; Pitt, G.; Batt, R.; Roe, M. WO 2005,023,812,
2005.
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
References
(1) Comprehensive Heterocyclic Chemistry II; Vol. 9;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996.
(2) Carraher, C. E. J. Chem. Educ. 1978, 55, 51.
(3) Tucker, H.; Le Count, D. J. 1,4-Azepines, In Comprehensive
Heterocyclic Chemistry II; Vol. 9; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996, 152.
(4) Kozikowski, A. P.; Greco, M. N. J. Org. Chem. 1984, 49,
2310.
(5) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am.
Chem. Soc. 1987, 109, 4335.
(6) Thiele, J.; Holzinger, O. Justus Liebigs Ann. Chem. 1899,
305, 96.
(7) (a) Schindler, W. US 2,948,718, 1960. (b) Schindler, W. DE
2,011,087, 1970.
(8) Sternbach, L. H.; Fryer, R. I.; Metlesics, W.; Reeder, E.;
Sach, G.; Saucy, G.; Stempel, A. J. Org. Chem. 1962, 27,
3788.
(9) van der Burg, W. J. US 4,145,434, 1977.
(10) Kemperman, G. J.; Stuk, T. L.; van der Linden, J. J. M. WO
2008,003,460, 2009.
(11) Cockerill, G. S.; Kocienski, P.; Treadgold, R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2093.
(12) Yamamoto, K.; Yamazaki, S. Thiepanes and Thiepines, In
Comprehensive Heterocyclic Chemistry II; Vol. 9;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 67.
(23) Abd El Latif, F. M. J. Heterocycl. Chem. 2000, 37, 1659.
(24) Park, M. S.; Park, H. J.; Park, K. H.; Lee, K. I. Synth.
Commun. 2004, 34, 1541.
(25) Potapov, A. S.; Chernova, N. P.; Ogorodnikov, V. D.;
Petrenko, T. V.; Khlebnikov, A. I. Beilstein J. Org. Chem.
2011, 7, 1526.
(26) (a) Russell, G. A.; Janzen, E. G. J. Am. Chem. Soc. 1967, 89,
300. (b) Gandhi, S. S.; Gibson, M. S.; Kaldas, M. L.; Vines,
S. M. J. Org. Chem. 1979, 44, 4705.
(27) Paisán-Ruíz, C.; Jain, S.; Evans, E. W.; Gilks, W. P.; Simón,
J.; van der Brug, M.; de Munain, A. L.; Aparicio, S.; Gil, A.
M.; Khan, N.; Johnson, J.; Martinez, J. R.; Nicholl, D.;
Carrera, I. M.; Peňa, A. S.; de Silva, R.; Lees, A.; Martí-
Massó, J. F.; Pérez-Tur, J.; Wood, N. W.; Singleton, A. B.
Neuron 2004, 44, 595.
(28) West, A. B.; Moore, D. J.; Biskup, S.; Bugayenko, A.;
Smith, W. W.; Ross, C. A.; Dawson, V. L.; Dawson, T. M.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 16842.
(29) Deng, X.; Dzamko, N.; Prescott, A.; Davies, P.; Liu, Q.;
Yang, Q.; Lee, J.-D.; Patricelli, M. P.; Nomanbhoy, T. K.;
Alessi, D. R.; Gray, N. S. Nat. Chem. Biol. 2011, 7, 203.
(13) Griebel, G.; Perrault, G.; Tan, S.; Schoemaker, H.; Sanger,
D. J. Behav. Pharmacol. 1999, 10, 483.
(14) Zirkle, C. L.; Pa, B. US 3,609,167, 1971.
(15) Frauenrath, H. 1,3-Dioxepanes, 1,3-Oxathiepanes, and 1,3-
Dithiepanes, In Comprehensive Heterocyclic Chemistry II;
Vol. 9; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 236.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3211–3227