Synthetic studies towards 1,5-benzodiazocines

Article abstract of DOI:10.1016/j.tet.2013.01.018

Anthranilonitrile reacted with phenylmagnesium bromide to yield a dianion, which when heated (～120 °C) yielded the condensation product 2-(2-aminophenyl)-2,4-diphenyl-1,2-dihydroquinazoline 8. This heterocycle, when treated with palladium acetate, was converted into 6,12-diphenyldibenzo[b,f][1, 5]diazocine 9. Methylmagnesium bromide and anthranilonitrile, under similar conditions directly gave a nitrogen-bridged diazocine, whose structure was determined by X-ray crystallography and also proven to be an analogue of Tro?ger's base. Acid-induced condensation of 2-amino-3-methoxybenzaldehyde gave the trimeric product 45 rather than a dibenzo[b,f][1,5]diazocine.

Full text of DOI:10.1016/j.tet.2013.01.018

Tetrahedron 69 (2013) 2647e2654
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies towards 1,5-benzodiazocines
,
b,c
Birgitta Pettersson a, Jan Bergman a , Per H. Svensson
*
a Karolinska Institute, Department of Biosciences and Nutrition at Novum, Unit of Organic Chemistry, SE-141 57 Huddinge, Sweden
b
€
€
Pharmaceutical Development, AstraZeneca R&D, SE-151 85 Sodertalje, Sweden
c Department of Applied Physical Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2012
Received in revised form 21 December 2012
Accepted 8 January 2013
Available online 24 January 2013
Anthranilonitrile reacted with phenylmagnesium bromide to yield a dianion, which when heated
(w120 ꢀC) yielded the condensation product 2-(2-aminophenyl)-2,4-diphenyl-1,2-dihydroquinazoline 8.
This heterocycle, when treated with palladium acetate, was converted into 6,12-diphenyldibenzo[b,f][1,5]
diazocine 9. Methylmagnesium bromide and anthranilonitrile, under similar conditions directly gave
a nitrogen-bridged diazocine, whose structure was determined by X-ray crystallography and also proven
€
to be an analogue of Troger’s base. Acid-induced condensation of 2-amino-3-methoxybenzaldehyde gave
Keywords:
the trimeric product 45 rather than a dibenzo[b,f][1,5]diazocine.
Ó 2013 Elsevier Ltd. All rights reserved.
Benzo[b,f][1,5]diazocine
Iminodibenzodiazocine
Quinazoline
Nitrogen heterocycle
Grignard reagent
€
Troger’s base
1. Introduction
Several benzo[b,f][1,5]diazocines have shown pharmacologi-
cally useful properties such as antiviral, cholesterol-lowering and
hormone-like activity.1,2 Additionally, some members of the diaz-
ocine system have found applications as homologues of benzodi-
azepine drugs and as reversal agents in multidrug resistance.3,4 In
recent years, material chemists have explored the electrochemical
properties of diaryldibenzo[b,f][1,5]diazocines (1), which were
found to be useful as a basis for molecular machines and artificial
muscles (Fig. 1).5,6 Moreover, a bridged variant of a dibenzo[b,f][1,5]
€
diazocine, Troger’s base (2), has a chiral aromatic cleft structure
with a unique ability to host guests and as a result act as a supra-
molecular receptor.7 Although most applications of Troger’s base
€
are within the field of supramolecular chemistry, pharmacological
applications have also been reported.8 More recently, the interest in
€
Troger’s bases has extended to iminodibenzodiazocines 3 con-
Fig. 1. Examples of benzo[b,f][1,5]diazocine structures (1e4).
taining an additional nitrogen, available for further interactions and
modifications.9
€
In the context with Troger’s base we will in this paper describe
2. Results and discussion
the synthesis and structural determination of the dimeric product
4
obtained from 2-aminobenzonitrile and methylmagnesium
2-Aminobenzonitrile (5) is a readily available and versatile
starting material for the synthesis of various heterocyclic systems.10
This molecule (5) will react with Grignard reagents (e.g., C6H5MgBr)
to produce intermediates of type 6, which subsequently can be
converted into nitrogen heterocycles, e.g., substituted quinazolines
(7), as illustrated in Scheme 1.11e15
bromide.
* Corresponding author. Tel.: þ46 8 52481084; fax: þ46 8 31 11 01; e-mail
address: jan.bergman@ki.se (J. Bergman).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.018

2648
B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
Scheme 1. (R¼phenyl, alkyl, M¼MgBr).
However, when the intermediate 6 was heated at higher
temperatures (typically 140 ꢀC) it underwent self-condensation to
give 8, the structure of which has been corroborated by X-ray
crystallography (Scheme 2).16 The preparation and NMR spectro-
scopic data for this molecule are now given for the first time.
Scheme 3.
Scheme 2. (M¼MgBr).
In the presence of Pd(II)-compounds (or Hg-compounds) the
dimer 8 undergoes a ring expansion with elimination of NH3. This
series of events probably starts with complexation of the metal ion
with the nitrogen atom of the imine group. Subsequently the amino
group will attack the now activated imine function and the scene is
now set for elimination of ammonia, thus forming the well-known
eight-membered ring system 9.17e19 This compound is readily pre-
pared in excellent yields by condensation of 2-aminobenzophenone
(10) using AlCl3. Recently, more sophisticated methods, albeit more
complex, have been developed.20 A similar study has beenpublished
by Leganza et al.9a wherein the more complex imine 11 was heated
in xylene to yield 12, which could rearrange to give a sister com-
pound to 8, namely 13 (also confirmed by X-ray crystallography),9a
but still containing palladium as illustrated in Scheme 3.
In contrast to the events discussed in Scheme 2 the intermediate
14, prepared from 2-aminobenzonitrile and methylmagnesium
bromide, when heated gave no dimeric product of type 8. However,
a crystalline product with the composition C16H17N3 was isolated
and the 13C NMR spectrum of this compound featured a diagnostic
singlet at 63.4 ppm, indicating the presence of an N,N-substituted
aliphatic carbon atom. The 1H NMR spectrum featured an NH sin-
glet at 2.96 (1H) ppm and another one at 6.36 (2H) ppm. The
suggested structure 4 could be corroborated by an X-ray crystal-
lographic study (vide infra) (Scheme 4.). The somewhat related
oxygen heterocycle 15 featured two signals at 91.0 and 95.5 ppm,
respectively, from the aliphatic carbon atoms in the eight-mem-
bered ring.21
symmetrical dihydroxy derivative 20, which is stabilized by hy-
drogen bonds. The aliphatic carbon atoms in 20 resonated at
66.4 ppm. Compound 20 featured only one set of signals in the 13C
NMR spectrum and it is assumed to have trans stereochemistry.
Attempts to eliminate two molecules of water to yield 21 failed.
One can assume that this molecule is suffering from the absence of
stabilizing phenyl rings (as in 9). In some experiments NMR spec-
troscopic evidence for the formation of 22a or its chain tautomer
22b was obtained but this unstable molecule decomposed rather
than eliminated water to 21. The unsuccessful formation of 21 and
its parent molecule is precedented in the literature.9d,37
In this context we became interested in the recently reported
acid-induced condensation of 2-aminoacetophenone 23 as outlined
in Scheme 7.23,24 However, no eight-membered products are formed
under these conditions. The real structure of the purported mole-
cule 24 is in fact that of 25. Actually, it was shown already in 1883
that 2-aminoacetophenone readily undergoes self-condensation to
2-(2-aminophenyl) 4-methylquinoline.25e27 Attempts to similarly
condense 2-aminopropiophenone failed, presumably due to steric
hindrance. In a hot medium of hydrogen chloride in acetic acid only
the hydrochloride salt of the starting material could be isolated.
The unsubstituted diazocine 26 has been reported to be formed
by hydrogenation of the nitrobenzene derivative 27 (Scheme 8).28
However, in our hands, the simple 1,5-benzodiazocine 26 could
not be obtained and the predominating product was identified as
the acetamide derivative 28. In addition to 28 small amounts of
a molecule, which tentatively has been assigned structure 29, were
also isolated. In addition to eight aromatic CH signals and two
acetoxy singlets at 17.6 and 21.9 ppm molecule 29 featured a di-
agnostic CH signal at 88.9 ppm in the 13C NMR spectrum. The
similarities between 22 and 29 are evident. Paudler29 has in a pre-
liminary communication reported that compound 37 upon treat-
ment with cupric acetate was converted into 26. In our hands this
Interestingly, formation of oxygen-bridged dibenzo[b,f][1,5]
diazocines (e.g., 17 and 18) had previously been reported by Ste-
fanovic et al. (Scheme 5).22 The acid corresponding to 17 is unstable
and isatin 19 will quickly be formed.
In the presence of even weak acids (e.g., acetic acid) the diazo-
cine 4 underwent ring-opening and hydrolysis (Scheme 6) to the

B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
2649
Scheme 4. (M¼MgBr).
Scheme 5.
Scheme 6.
Scheme 7.

2650
B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
Scheme 8.
operation gave the cycloamide 30. In this context the cyclodiamide
30 was converted into the known cyclodiamine 31 by reduction
with diborane in hot diglyme. However, all attempts to de-
hydrogenate 31 to 26 failed. Recently, Harmata et al. have converted
€
Troger’s base (2) (Fig. 1) in a multi-step reaction to a tetrame-
thylderivative of 31 namely 36 (Scheme 8).30
At this point we decided to synthesize the diazocines 33 and 34
from the diamide 30,31e33 and then allow them into react with
methylmagnesium bromide. Although the dichloro compound 33
was described as early as 1919, and it has also been resynthesized
a few times over the years, we found that the conditions are quite
critical and trichloroethylene was found to be the solvent of
choice.32
Because of the difficulties in making 33, alternative methods were
explored and in this context it was found that Viehe’s reagent, Cl2C]
NMe2Cl, readily reacted with the diamide 30 to yield 38, a known
compound, that previously had been prepared in a multi-step oper-
ation starting with 2-(2-azidophenyl)-4H-3,1-benzoxazin-4-one.40
However the dichloro compound 33 was not obtained.
It is assumed that the transformation of 30 into 38 is initiated by
an attack of the reagent on the two nitrogen atoms in the eight-
membered ring followed by a ring-opening induced by attack of the
dimethylammonium ion leading to the intermediate 39. The next
step features a displacement of the chlorine atom after attack by
the nitrogen atom in the dimethylamino function. Finally, the
chloride ion generated will attack one of the methyl groups in the
now positively charged amide and thereby generate chloro-
methane and the observed product 38 (Scheme 9).
Scheme 9.
knowledge of this type of substitution, which gave the known
molecule 40.39 At room temperature this molecule features re-
stricted rotation of the dimethylamino groups. The barrier is,
however, of low energy as the point of coalescence was determined
to be 34.8 ꢀC.
Thionation of 30 as described in the literature,34 gave 41, which
upon methylation gave 34. Treatment of 34 with methyl-
magnesium bromide in the presence of Ni2þ salts under conditions
originally developed by Wenkert35 gave a product in obvious dis-
agreement with 4, 20 and 21, because the two aromatic rings gave
4þ4 signals from the methine carbon atoms. Treatment of the
dichloro derivative 33 with methylmagnesium bromide in hot
tetrahydrofuran (in the absence of Ni2þ) and a work-up procedure
involving treatment with aq ammonium chloride gave the identical
The bishydrazone 37 was prepared by nucleophilic displace-
ment of the dichloro derivative 33 with hydrazine. Initially this
reaction was fraught with problems and therefore displacement
with dimethylamine was studied in order to broaden the

B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
2651
€
product. Somewhat surprisingly both reactants gave the same
product, namely the monomethyl-substituted hydrated molecule
22a. Perhaps again, an illustration of the importance of hydrogen
bonds.
Finally it should be added that Friedlander was the first (1884)
to study the condensation of 2-aminobenzaldehyde and structure
48 was given rather than its ring tautomer 49.43,44 Over the years
a considerable amount of wrong structures were introduced in the
literature until 1966 when McGeachin clarified the situation.37
The structure of 4 was confirmed by X-ray analysis, the details of
which are given in the Experimental section, and an ORTEP rep-
resentation of the molecular structure is shown in Fig. 4. The
To this end, no established methods exist for the preparation of
either dibenzo[b,f][1,5]diazocines with aliphatic substituents in
positions 6 and 12 or the parent compound 26 (Scheme 8.). The
tert-butyl derivative 42 (Fig. 2), however, seems to be an excep-
tion.36 Recently, compound 43 (Fig. 3) has been reported as a side-
product when 2-amino-4-methoxybenzonitrile was allowed to
react with ethylmagnesium bromide. In this context also a con-
densation product of 2-amino-3-methoxybenzaldehyde prepared
molecules are linked together via hydrogen bonds and CHe
p
stacking interactions to form a 3D network. The packing coefficient
(percent filled van der Waals space in the unit-cell) is 68.8%, in-
dicating an efficient molecular framework in the solid state.
a long time ago by Troger et al.41,42 was of interest as this molecule
€
after several assignments was given structure 44. If correct this
would have been the first example of the elusive system 26. This
work has now been reinvestigated and as excellent NMR spectro-
scopic data could be obtained. This condensation product has now
been re-assigned as the trimeric molecule 45. Useful diagnostic
signals (CH doublets) in the 13C NMR spectrum appeared at 80.5,
63.5, 63.3 ppm. The parent molecule 46 had previously been cor-
rectly assigned by McGeachin37 in 1966 after detailed studies of its
chemical transformations as well as 1H NMR spectroscopic data.
McGeachin also established that if the condensation between 2-
aminobenzaldehyde was performed in presence of Ni2þ the tetra-
meric product 47 was formed. Later similar condensations have
been studied by a wide range of research workers.38
3. Conclusions
The dianion, formed by addition of Grignard reagents to
anthranilonitrile is a versatile synthon that can be converted into
quinazolines and benzodiazepines but also into NH-bridged 1,5-
benzodiazocines.
4. Experimental section
4.1. General techniques and apparatus
All starting materials and solvents were obtained from com-
mercial sources and used without further purification. THF was
Fig. 2. Structures of additional benzo[b,f][1,5]diazocines.
Fig. 3. Additional benzo[b,f][1,5]diazocines and some related molecules.

2652
B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
Fig. 4. (a) Molecular and (b) crystal structure (H-atoms omitted) of 4.
distilled from sodium and benzophenone. Chromatography was
reflux. After a reflux period of 4 h, toluene (200 mL) was added
whereupon most of the ether was distilled off and the residue
heated at reflux for 4 h. The mixture was allowed to cool and am-
monium chloride (aq 5%, 2ꢁ200 mL) was added. The organic phase
was separated, dried and evaporated. Treatment of the residue with
isopropyl ether/isopropanol (2:1) gave after a lag of w1 h crystals of
the title compound 8 (9.6 g, 51%), mp 185e187 ꢀC; IR nmax: 3437,
3378, 3322, 3045,1606,1450,1332,1156, 966, 754, 740, 697 cmꢂ1; 1H
NMR (DMSO-d6): 5.32 (s, 2H), 6.53e6.59 (m, 3H), 6.92e7.05 (m, 3H),
7.26e7.41 (m, 7H), 7.50e7.56 (m, 6H); 13C NMR (DMSO-d6): 77.1 (s),
114.4 (d), 114.6 (d), 114.7 (s), 116.0 (d), 116.3 (d), 126.9 (d), 127.0 (d),
127.1 (d),127.5 (s), 127.6 (d),127.9 (d),128.1 (2d),129.0 (d),129.3 (d),
133.1 (d), 138.3 (s), 145.6 (s), 145.7 (s), 146.2 (s), 163.2 (s). Anal. Calcd
C, 83.17; H, 5.64;, N, 11.19. Found: C, 82.90; H, 5.77; N, 11.02. The
structure of 8 has been confirmed by X-ray crystallography.16 The
crystals used at the time (1988) emanated from our laboratory.
performed using silica gel (40e63
m
m). Melting points were de-
€
termined in open capillary tubes on a Buchi-B545 melting point
apparatus. IR spectra were recorded on Thermo Nicolet Avatar 330
FT-IR instrument. NMR spectra were recorded on a Bruker DPX 300
operating at 300.1 MHz for 1H and 75.5 MHz for 13C in DMSO-d6.
Chemical shifts are reported downfield to TMS. The elemental
analyses were performed by H. Kolbe Microanalytisches Labo-
€
ratorium, Mulheim an der Ruhr, Germany.
4.2. Methods and analysis
4.2.1. 6,12-Dimethyl-6,12-imino-5,6,11,12-tetrahydrodibenzo[b,f][1,5]
diazocine (4). To a THF-solution (20 mL) of anthranilonitrile (2.36 g,
20 mmol), MeMgBr (23.3 mL, 70 mmol) was added-drop wise at
room temperature. After stirring for 30 min, the mixture was
heated at reflux for 23 h and then quenched with NH4Cl (40 mL,
20% aq). EtOAc (20 mL) was added to the mixture and the organic
layer was separated, washed with water (3ꢁ50 mL) and dried
(Na2SO4). Evaporation of the solvent gave a yellow oil that was
purified by flash chromatography (MeOH/toluene, 1:6) to afford 4
1.0 g (41%) as a white solid, mp 151e152 ꢀC. An analytically pure
version (as colourless prisms) of 4, suitable for X-ray crystallogra-
4.2.3. 6,12-Diphenyldibenzo[b,f][1,5]diazocine (9). The condensa-
tion dimer 8 (374 mg, 1 mmol) was dissolved in DMF (50 mL) and
palladium acetate (5 mg, 0.020 mmol) was added and the mixture
heated at 140 ꢀC for 1 h. After filtration and concentration the
residue was crystallized from ethanol to give the title compound as
bright-yellow needles (210 mg, 52%), mp 190e192 ꢀC (lit.18 mp
191e193 ꢀC); 1H NMR (DMSO-d6): 7.01e7.10 (m, 6H), 7.36e7.44 (m,
6H), 7.49e7.50 (m, 2H), 7.66e7.68 (m, 4H); 13C NMR (DMSO-d6):
120.6 (d), 124.1 (d), 126.6 (s), 127.8 (d), 129.0 (d), 129.3 (d), 130.4 (d),
131.9 (d), 137.6 (s), 151.8 (s), 169.1 (s). These data are in good
agreement with those in the literature.46 There are several methods
available in the literature for compound 9, which has been known45
since 1896. The by far synthetically most useful method is due to
Sternbach.17 This excellent procedure was repeated and the mate-
rial obtained was identical with the product obtained above. The
analytical sample was recrystallized from acetonitrile, mp
190e192 ꢀC. In a recent paper by Wang et al.20 a considerably
higher range, 226e227 ꢀC was reported, which might be due to
polymorphism.
phy, was obtained by recrystallization from 2-propanol; IR nmax
:
3345, 3287, 3236, 3026, 1601, 1469, 1134, 934, 829, 751 cmꢂ1 1H
;
NMR (DMSO-d6): 1.62 (s, 6H), 6.32 (s, 2H), 6.39 (d, 2H, J 7.5 Hz), 6.49
(t, 2H, J 7.5 Hz), 6.82 (t, 2H, J 7.5 Hz), 7.13 (d, 2H, J 7.5 Hz); 13C NMR
(DMSO-d6): 26.6 (q), 63.4 (s), 114.5 (d), 115.9 (d), 124.8 (d), 126.8 (d),
128.6 (s), 143.9 (s). Anal. Calcd C, 76.46; H, 6.82; N, 16.72. Found: C,
76.30; H, 6.86; N, 16.56.
Crystal data for 4: C16H17N3, Mr¼251.33 g/mol, monoclinic, space
ꢀ
ꢀ
ꢀ
group P21/c (No 14), a¼9.1320(6) A, b¼13.3771(8) A, c¼10.7692(7) A,
3
b
¼96.689(3) , V¼1306.61(14) A , Z¼4, Dcalcd¼1.278 g cmꢂ3
, m(Mo
ꢀ
ꢀ
Ka
)¼0.78 cmꢂ1, R¼0.035, wR2¼0.094, GOF¼1.08. The data were
collected at 200 K on a Bruker APEX-II CCD with graphite mono-
ꢀ
chromatized Mo
Ka
radiation
(
l
¼0.71073 A) and employing
a 0.08 mmꢁ0.12 mmꢁ0.18 mm crystal (Rint¼0.03). CCDC-886046
contains the supplementary crystallographic data for 4, re-
spectively. The data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4.2.4. Sodium-6,12-oxido-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazo-
cine-6,12-dicarboxylate (17). This compound was prepared accord-
ing to Stefanovic et al.22 Yield: 80%, mp 170e175 ꢀC (lit.22 mp 176 ꢀC);
1H NMR: 4.72 (br s, 4H), 6.56 (t, 2H, J¼7.5 Hz), 6.75 (d, 2H, J 7.5 Hz),
6.93 (t, 2H, J 7.5 Hz), 7.32 (d, 2H J 7.5 Hz); 13C NMR: 82.9 (s),116.4 (d),
117.6 (d), 124.5 (s), 126.0 (d), 128.4 (d), 142.3 (s), 171.5 (s).
4.2.2. 2-(2-Aminophenyl)-2,4-diphenyl-1,2-dihydroquinazoline
(8). 2-Aminobenzonitrile (5.9 g, 50 mmol) was added in portions to
a solution of phenylmagnesium bromide (prepared from bromo-
benzene (16.0 g, 0.1 mol and magnesium 2.7 g)) in ether (200 mL) at
4.2.5. Dimethyl-6,12-oxido-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diaz-
ocine-6,12-dicarboxylate (18). The acid 17 was treated with

B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
2653
diazomethane as described by Stefanovic et al.22 Yield 95%, mp
236e237 ꢀC (lit.22 mp 238 ꢀC); 1H NMR: 3.79 (s, 6H, 2OCH3), 6.68
(dd, 2H, J¼7.8), 6.85 (d, 2H, J¼7.8), 7.01e7.08 (m, 4H), 7.57 (s, 2H,
2NH); 13C NMR: 53.2 (q), 82.9 (s), 117.0 (d), 118.4 (d), 122.3 (s), 124.0
(d), 128.8 (d), 140.8 (s), 168.6 (s).
24.8 (q), 64.4 (t), 122.9 (d), 124.6 (d), 129.1 (d), 129.2 (d), 135.4 (s),
139.4 (s), 169.3 (s). The spectroscopic data are in good agreement
with those in the literature.47
Compound 29 was obtained as a minor product from the chro-
matographic procedure described above and isolated as a white
crystalline solid, 259 mg, 8.0%, 1H NMR (CDCl3): 1.94 (s, 3H), 2.01 (s,
3H), 4.31 (d, 1H), 6.65e6.70 (m, 2H), 6.87 (d, 1H), 6.93 (d, 1H),
6.98e7.04 (m, 1H), 7.16 (d, 1H), 7.20 (t, 1H), 7.67 (d, 1H); 13C NMR
(CDCl3): 17.6 (q), 21.9 (q), 88.9 (d),113.1 (d),114.6 (d),120.5 (d),123.2
(d), 124.1 (s), 124.8 (d), 124.9 (s), 126.8 (d), 127.3 (d), 130.5 (d), 130.7
(d), 137.6 (s), 142.0 (s), 167.0 (s). No good elemental analysis data
could be obtained for this unstable compound.
4.2.6. 6,12-Dimethyl-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocine-
6,12-diol (20). The transannular amine 4 (252 mg, 1.0 mmol) was
dissolved in acetic acid (1.5 mL) at 25 ꢀC and after 2 min diluted
with water containing two drops of hydrochloric acid. The white
solid formed was collected and dried. Yield (243 mg, 90%), mp
190e195 ꢀC dec; IR nmax: 3240 (w), 2940, 1611, 1559, 1493, 1249,
749, 582 cmꢂ1 1H NMR (DMSO-d6): 1.97 (s, 6H), 6.62 (d, 2H, J
;
7.7 Hz), 6.75 (t, 2H, J 7.7 Hz), 7.07 (t, 2H, J 7.7 Hz), 7.29 (d, 2H, J
7.7 Hz), 7.53 (s, 2H), 10.36 (br s, 2H); 13C NMR (DMSO-d6); 23.8 (q),
66.5 (s), 115.3 (d), 118.7 (d), 123.5 (s), 125.6 (d), 129.0 (d), 141.0 (s).
Anal. Calcd C, 71.09; H, 6.71; N, 10.36. Found: C, 70.88; H, 6.70; N,
10.22.
4.2.11. 5,11-Dihydro-6,12-dioxodibenzo[b,f][1,5]diazocine (30). Methyl
anthranilate (45.3 g, 0.30 mol) was dissolved in THF (450 mL) under
an atmosphere of dry nitrogen. Sodium hydride (19.3 g, 60% in oil)
was then intermittently added over 0.5 h to the stirred mixture at
30 ꢀC. This mixture was worked-up after 76 h at 25e30 ꢀC by ad-
dition of water (1.5 L), filtration and acidification with acetic acid
gave a precipitate of the title compound (28.9 g, 81%), which was
collected after 1 h at room temperature, mp 344 ꢀC (lit.31 mp 333 ꢀC);
4.2.7. 6,12-Dimethyl-5,6-dihydrodibenzo[b,f][1,5]diazocin-6-ol
(22a). The experiment just described was repeated but at the end
hydrochloric acid (0.1 mL, 1.0% in H2O) was added. The unstable
solid formed was collected, dried and studied with NMR-
spectroscopy yield (204 mg, 80%), mp 220e230 dec; 1H NMR
(DMSO-d6): 2.23 (s, 3H), 2.43 (s, 3H), 7.22 (t, 1H, J 6.9 Hz), 7.46e7.51
(m, 1H), 7.73 (t, 1H, J 7.1 Hz), 7.99e8.04 (m, 2H), 8.42 (d, 1H, J 7.1 Hz),
8.49e8.56 (m, 2H), 10.99 (s, 1H), 12.04 (s, 1H); 13C NMR (DMSO-d6):
24.7 (q), 25.1 (q), 114.2 (s), 121.6 (d), 122.8 (d), 124.1 (d), 124.3 (s),
127.3 (d), 127.9 (d), 130.7 (d), 131.0 (d), 134.7 (d), 139.1 (s), 150.4 (s),
156.3 (s), 159.4 (s), 168.7 (s), 170.2 (s).
IR nmax: 3035, 1654, 1640, 1603, 1378, 1262, 783, 752, 609, 535 cmꢂ1
;
1H NMR (DMSO-d6): 7.1e7.4 (m, 8H), 10.2 (s, 2H, NH); 13C NMR
(DMSO-d6): 125.7 (d),127.3 (d),128.2 (d),130.5 (d),133.6 (s),134.8 (s),
169.3 (s).
4.2.12. 5,6,11,12-Tetrahydrodibenzo[b,f][1,5]diazocine (31). The diamide
30 (4.76 g, 20 mmol) was heated under nitrogen, to 135 ꢀC in diglyme
(150 mL). After cooling to 70e80 ꢀC sodium borohydride (2.40 g,
6.0 mmol) was added followed by boron trifluoride etherate (5.0 mL).
After 45 min at this temperature it was increased to 90e110 ꢀC during
45 min whereupon the reaction mixture was allowed to cool and the
solvent distilled off. The residue was treated with water (100 mL) and
concd HCl (30 mL) at 35 ꢀC and stirred for 3 h. After filtration the
filtrate was treated with concd ammonia until pH 8e9 was reached
and after a stirring period of 2 h the white solid was collected and
dried to give the title compound (2.8 g, 65%), mp 138.5e139.5 ꢀC
(lit.32d mp 137.8 ꢀC); 1H NMR (DMSO-d6): 4.42 (d, 2H), 4.86 (d, 2H),
7.26 (d, 2H), 7.41 (m, 2H), 7.49 (m, 2H), 7.59 (m, 2H), 10.48 (br s, 2H);
13C NMR (DMSO-d6): 57.2 (t), 124.7 (d), 126.4 (s), 128.5 (d), 128.9 (d),
129.0 (d), 137.6 (s).
No good elemental analysis data could be obtained.
4.2.8. N-(2-(4-Methylquinolin-2-yl)phenyl)acetamide (25). 2-Amino-
acetophenone (1.35 g, 10.0 mmol) was dissolved in acetic acid
(12 mL) containing sulfuric acid (0.1 mL) and the solution was heated
at reflux for 3 h, whereupon acetic anhydride (3 mL) was added and
the heating was continued for 1 h. The cooled mixture was poured in
to water and the semi-solid formed was crystallized from ethanol to
give the title compound (0.80 g, 40%), mp 115e116 ꢀC (lit.27 mp
116 ꢀC); IR nmax: 3058 (w), 2922, 1682, 1001, 1583, 1533, 1440, 1307,
1122, 1109, 851, 760, 735 cmꢂ1; 1H NMR (DMSO-d6): 2.15 (s, 3H, CH3),
2.73 (s, 3H, CH3), 7.20 (dd, 1H, J1 7.7 Hz, J2 7.3 Hz), 7.41 (dd, 1H, J1
7.7 Hz, J2 7.3 Hz), 7.64 (dd, 1H, J1 7.7 Hz, J2 7.3 Hz), 7.82 (dd, 1H, J1
7.7 Hz, J2 7.3 Hz), 7.93 (s, 1H), 7.98e8.09 (m, 3H), 8.44 (d, 1H, J 7.3 Hz),
12.8 (s, 1H, NH); 13C NMR (DMSO-d6): 18.4 (q), 24.8 (q), 121.1 (d),
121.2 (d), 123.3 (d), 124.1 (d), 124.9 (s), 126.2 (s), 126.8 (d), 128.7 (d),
129.6 (d), 156.9 (s), 168.0 (s), 130.1 (d), 130.2 (d), 138.2 (s), 145.3 (s),
146.1 (s).
4.2.13. 6,12-Dichlorodibenzo[b,f][1,5]diazocine (33). A mixture of
5,11-dihydro-6,12-dioxodibenzo[b,f][1,5]diazocine (11.9 g, 50 mmol)
and phosphorous pentachloride (25.0 g) in trichloroethylene
(220 mL) was heated at reflux for 3 h. After filtration the filtrate was
concentrated to ca. 100 mL and the solution was allowed to stand for
24 h. Big crystals of 33 had now deposited (10.5 g, 77%), mp
219e221 ꢀC (lit.32a mp 220 ꢀC); IR nmax: 3063, 1649, 1593, 1477, 1212,
4.2.9. Acetylation of 2-(4-methylquinolin-2-yl)aniline. 2-(2-Amino-
phenyl)-4-methylquinoline (2.34 g, 10 mmol) was dissolved in
acetic anhydride (5 mL). After 30 min at 60 ꢀC the solvent was
evaporated and the residue crystallized from ethanol to give the
title compound (2.67 g, 95%). This material was identical with that
obtained in the previous experiment.
1119, 944, 924, 866, 816, 757, 696, 644 cmꢂ1 1H NMR (C2Cl4):
;
6.95e7.35 (m, 8H); 13C NMR (C2Cl4): 121.5 (s), 124.6 (d), 125.8 (d),
126.6 (d), 130.8 (d), 145.0 (s), 155.5 (s). This molecule has been
prepared on several occasions in the past and no 13C NMR data have
been published until now.
4.2.14. 6,12-Dithiomethoxydibenzo[b,f][1,5]diazocine (34). Thione
3633,34 (2.70 g, 10.0 mmol) was dissolved in dimethylformamide
(40 mL) and dimethyl sulfate (2.77 g, 21.0 mmol) was added to the
stirred solution at 40 ꢀC. A precipitate was quickly formed, which
was collected and treated with a solution of sodium carbonate
(4.0 g) in water (100 mL) and ethanol (10) mL. The yellow solid
formed was collected and dried to give the title compound (2.70 g,
90%), mp 212e216 ꢀC; IR nmax: 3149, 2920, 1606, 1592, 1508, 1474,
1374, 1216, 1017, 966, 760, 703 cmꢂ1; 1H NMR (DMSO-d6): 2.50 (6H,
s, 2SMe), 6.88 (d, 2H), 4.05 (t, 2H, J 7.5 Hz), 7.19 (d, 2H, J 7.5 Hz), 7.32
(t, 2H, J 7.5 Hz); 13C NMR (DMSO-d6): 14.0 (q), 121.9 (d), 123.8 (d),
4.2.10. N-(2-(Hydroxymethyl-phenyl))acetamide (28). Palladium (5%
on carbon, 1.0 g) was added to a solution of 27 (5.06 g, 20 mmol) in
ethanol (100 mL) and toluene (60 mL). After 6 h at room temper-
ature, the catalyst was removed by filtration and washed with
a small amount of toluene. Evaporation gave a white solid that was
purified by column chromatography (CHCl3). Compound 28 was
obtained as a white solid (1.8 g, 53%), mp 115e116 ꢀC (lit.47 mp
116 ꢀC); IR nmax: 3271, 3195, 1653, 1530, 1454, 1367, 1295, 1036, 983,
760, 534 cmꢂ1; 1H NMR: 2.16 (s, 3H), 4.67 (s, 2H), 7.06e7.10 (m, 1H),
7.18 (d, 1H), 7.27e7.33 (m, 1H), 7.97 (d, 1H), 8.65 (s, 1H); 13C NMR:

2654
B. Pettersson et al. / Tetrahedron 69 (2013) 2647e2654
6. Suga, T.; Wi, S.; Long, T. E. Macromolecules 2009, 42, 1526e1532 and refs
therein.
7. Sergeyev, S. Helv. Chim. Acta 2009, 92, 415e444; Dolensky, B.; Elguero, J.; Kral,
V.; Pardo, C.; Valik, M. Advances in Heterocyclic Chemistry; AP: New York, 2007;
Vol. 93, pp 1e56; Adrian, J. C.; Wilcox, C. S. J. Am. Chem. Soc. 1989, 111,
8055e8057.
8. Baldeyrou, B.; Tardy, C.; Bailly, C.; Colson, P.; Houssier, C.; Charmantray, F.;
Demeunynck, M. Eur. J. Med. Chem. 2002, 37, 315e322; Bailly, C.; Laine, W.;
Demeunynck, M.; Lhomme, J. Biochem. Biophys. Res. Commun. 2000, 273,
681e685; Johnson, R. A.; Gorman, R. J.; Wnuk, N. J.; Crittenden, N. J.; Aiken, J.
W. J. Med. Chem. 1993, 36, 3202e3206.
9. (a) Leganza, A.; Bezze, C.; Zonta, C.; Fabris, F.; De Lucci, O.; Linden, A. Eur. J. Org.
Chem. 2006, 2987e2990; (b) Ukhin, L. Y.; Kuzmina, L. G. Russ. Chem. Bull. 2004,
53, 2262e2268; (c) Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65, 655e666; (d)
Molina, P.; Arques, A.; Tarraga, A.; Obon, M.; Jagerovic, N.; Elguero, J. Tetrahe-
dron 1998, 54, 997e1004.
127.0 (s), 127.2 (d), 130.9 (d), 148.9 (s), 169.8 (s). Anal. Calcd C, 64.35;
H, 4.04; N, 4.69. Found: C, 64.26; H, 3.99; N, 4.49.
4.2.15. 6-Methyl-12H-quinazolino[3,2-a]-quinazoline-5[6H]-12-dione
(38). Dibenzo[b,f][1,5]diazocine-6,12-dione (2.38 g, 10.0 mmol) and
dichloromethyleneedimethyl-iminium chloride, Viehe’s reagent
(3.25 g, 20.0 mmol) were heated at reflux temperature in acetoni-
trile (50 mL) for 2 h. After concentration methanol (35 mL) was
added, which soon resulted in crystallization of the product (2.20g,
79%), mp 180e181 ꢀC (lit.40 mp 177e178 ꢀC); 13C NMR (DMSO-d6):
29.9 (q), 118.3 (s), 118.5 (s), 120.8 (d), 125.1 (d), 125.6 (d), 126.7 (d),
127.0 (d), 127.3 (d), 133.6 (d), 135.3 (d), 135.6 (s), 145.4 (s), 159.2 (s),
161.5 (s).
10. Brown, D. J. Quinazolines, Supplement I; Wiley: New York, NY, 1996; Kikelj, D.
Product Class 13: Quinazolines. Science of Synthesis; Thieme Verlag: Stuttgart,
2004; Vol. 16, pp 573e749; Undheim, K.; Benneche, T. Comprehensive Hetero-
cyclic Chemistry II; Pergamon: Oxford, UK, 1998; Vol. 6.
The 1H NMR data were in agreement with data reported in the
literature.40
11. Wiklund, P.; Bergman, J. Org. Biomol. Chem. 2002, 1, 367e372.
12. Pettersson, B.; Rydbeck, A.; Bergman, J. Org. Biomol. Chem. 2009, 7, 1184e1191.
13. Bergman, J.; Brynolf, A.; Elman, B.; Vuorinen, E. Tetrahedron 1986, 42, 3697e3706.
14. Bergman, J.; Brynolf, A.; Elman, B. Heterocycles 1983, 20, 2141e2144.
15. Bergman, J.; Brynolf, A.; Toernroos, K.-W.; Karlsson, B.; Werner, P. E. Heterocy-
cles 1983, 20, 2145e2148.
4.2.16. 6,12-Bis-Dimethylaminodibenzo[b,f][1,5]diazocine (40). The
dichloro compound 33 (550 mg, 2.0 mmol) was dissolved in di-
oxane (25 mL) at 80 ꢀC and a stream of dimethylamine was in-
troduced. After the reaction had gone to completion, evaporation of
the solvent gave a residue, which was treated with water to remove
salts. The remaining solid was treated with 2-propanol and diiso-
propylether and the solid formed was collected to give the title
compound (535 mg, 91%), mp 144e145 ꢀC (lit.39 mp 144e145 ꢀC);
IR nmax: 3073 (w), 2953 (w), 1705, 1693, 1600, 1590, 1559, 1465,
16. Toernroos, K.-W. Acta Crystallogr. 1988, C44, 543e545.
17. Metlesics, W.; Tavares, R.; Sternbach, L. H. J. Org. Chem. 1966, 31, 3356e3362.
18. Metlesics, W.; Resnick, T.; Silverman, G.; Tavares, R.; Sternbach, L. H. J. Med.
Chem. 1966, 9, 633e635.
19. Borzilleri, R. M. Science of Synthesis; Thieme Verlag: Stuttgart, 2004; Vol. 17, pp
979e1024; Perlmutter, H. D. Advances in Heterocyclic Chemistry; AP: New York,
1989; Vol. 46, pp 1e62.
20. Wang, X.; Li, J.; Zhao, N.; Wan, X. Org. Lett. 2011, 709e711.
21. Palacios-Grijalva,L.N.;Cruz-Gonzalez,D.Y.;Lomas-Romero,L.;Gonzalez-Zamora,E.;
Ulibarri, G.; Negron-Silva, G. E. Molecules 2009, 14, 4065e4078.
1423, 1359, 1287, 1159, 1051, 1015, 953, 767, 681 cmꢂ1 1H NMR
;
(35 ꢀC) (CDCl3): 2.96 (br s,12H), 6.84e7.35 (m, 8H); 1H NMR (25 ꢀC):
2.96 (d, Dn¼151.0 Hz); 13C NMR (CDCl3): 37.9 (q), 120.6 (d), 124.5
(d), 125.9 (d), 126.0 (s), 129.5 (s), 130.5 (d), 147.5 (s), 158.5 (s). The IR
spectral data are in good agreement with those in the literature
(obtained in Nujol).39
22. Stefanovic, G.; Lorenc, L.; Mamuzic, R. I.; Mihailovic, M. L. Tetrahedron 1959, 6,
304e311.
23. Vandana, T.; Prasad, K. J. R. Indian J. Heterocycl. Chem. 2004, 13, 315e318.
24. Sangeetha, V.; Prasad, K. J. R. Indian J. Chem. 2004, 43B, 2231e2234.
25. Besthorn, A.; Fischer, O. Ber. Dtsch. Chem. Ges. 1883, 16, 68e75.
26. Bischler, E.; Burkart, E. Ber. Dtsch. Chem. Ges. 1893, 26, 1349e1353.
27. Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006, 71, 3653e3655.
28. Yuan, B.; Song, L.; Jian, Y. Huaxue Shiji 2001, 23, 240e242.
29. Paudler, W.; Zeiler, A. G. J. Chem. Soc., Chem. Commun. 1967, 1077e1078.
30. Harmata, M.; Rayanil, K.-O.; Barnes, C. L. Supramol. Chem. 2006, 18, 581e586.
31. Ollis, D. W.; Stephanatou, J. S.; Stoddart, J. F. J. Chem. Soc., Perkin Trans. 1 1982,
1629e1699.
32. (a) Schroeter, G. Ber. Dtsch. Chem. Ges. 1919, 52, 2224e2237; (b) Cooper, F. C.;
Partridge, M. W. J. Chem. Soc. 1954, 3429e3435; (c) Schwartz, P. M.; Saggiomo,
A. J. J. Heterocycl. Chem. 1972, 9, 947e948; (d) Mahon, A. B.; Craig, D. C.; Try, A.
C. ARKIVOC 2008, 148e163.
33. Olszewska, T.; Gdaniec, M.; Polonski, T. J. Org. Chem. 2004, 69, 1248e1255.
34. Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H. J. Org. Chem. 2011,
76, 1546e1553.
4.2.17. Bisanhydro trimer (45). 2-Amino-3-methoxybenzaldehyde
(1.51 g, 10.0 mmol) was dissolved in acetic acid (30 mL) and heated
at reflux temperature for 1 h. The product has low solubility in the
medium and starts to precipitate within 5 min. Filtration gave the
title compound (1.40 g, 95%), mp 280e282 ꢀC; IR nmax: 3268, 2932,
1592, 1576, 1477, 1437, 1254, 1212, 1054, 1035, 750 cmꢂ1 1H NMR
;
(DMSO-d6): 3.74 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 5.42e5.44 (m,
2H), 5.47 (s, 1H), 6.38 (d, 1H), 6.61e6.65 (m, 1H), 6.69e6.72 (m, 2H),
6.80e6.88 (m, 5H), 6.97e6.99 (m, 1H); 13C NMR (DMSO-d6): 55.3
(q), 55.4 (q), 55.7 (q), 63.3 (d), 63.5 (d), 80.5 (d), 109.3 (d), 110.2 (d),
110.3 (d), 116.5 (d), 120.4 (d), 120.9 (s), 121.0 (d), 121.5 (d), 123.6 (d),
123.7 (d), 130.3 (s), 130.6 (s), 131.0 (s), 132.2 (s), 132.7 (s), 146.7 (s),
151.8 (s), 152.1 (s). Anal. Calcd C, 69.05; H, 5.55; N, 10.07. Found: C,
68.97; H, 5.36; N, 9.87. This molecule had a long time ago been
35. Wenkert, E. J. Org. Chem. 2004, 69, 1248e1255.
36. Dyall, L. K. Aust. J. Chem. 1977, 30, 2669e2678.
37. McGeachin, S. G. Can. J. Chem. 1966, 44, 2323e2328 and refs therein.
38. (a) Gugger, P. A.; Hockless, D. C. R.; Swiegers, G. F.; Wild, S. B. Inorg. Chem. 1994,
33, 5671e5677; (b) Melson, G. A.; Busch, D. H. J. Am. Chem. Soc. 1965, 87,
1706e1710; (c) Owston, P. G.; Shaw, L. S. Acta Crystallogr. 1988, B44, 39e50; (d)
Kolchinski, A. C.; Alcock, N. W. J. Org. Chem. 1998, 63, 4515e4517; (e)
Skuratowicz, J. S.; Madden, I. L.; Busch, D. H. Inorg. Chem. 1977, 16, 1721e1725;
(f) Cummings, S. C.; Busch, D. H. J. Am. Chem. Soc. 1970, 92, 1924e1929.
39. Osbirk, A.; Pedersen, E. B. Acta Chem. Scand. 1979, B33, 313e318.
40. Molina, P.; Alajarin, M.; Vidal, A.; de la Conception Foces-Foces, M.; Hernandez
Cano, F. Tetrahedron 1989, 45, 4263e4286; Xiong, X.-D.; Chen, W.-X.; Kuang, Y.-Y.;
Chen, F.-E. Org. Prep. Proced. Int. 2009, 41, 423e427.
41,42
€
prepared by the Troger group
with incorrect assignments.
on several occasions, however
References and notes
1. U.S. Patent 111,534, 2010.
2. Wakankar, D. M.; Hosangadi, B. D. Indian J. Chem. 1984, 23B, 136e139 and refs
therein.
3. Duncan, G. W.; Lyster, S. C.; Wright, J. B. Proc. Soc. Exp. Biol. Med. 1965, 120,
725e728; Howard, T. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New York, NY, 1996; Vol. 7,
pp 151e182.
4. Nonnenmacher, E.; Hever, A.; Mahamoud, A.; Aubert, C.; Molnar, J.; Barbe, J.
Org. Prep. Proced. Int. 1997, 29, 711e714.
€
41. Troger, J.; Sabewa, V. J. Prakt. Chem. 1927, 117, 117e141.
€
42. Troger, J.; Bohnekamp, J. J. Prakt. Chem. 1927, 117, 161e184.
€
€
43. Friedlander, P.; Gohring, C. F. Ber. Dtsch. Chem. Ges. 1884, 17, 456e461.
44. Freundler, P. Compt. Rend. 1902, 136, 370e373.
45. Sondheimer, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1272e1275.
46. Jung, D.-I.; Song, J.-H.; Lee, E.-J.; Kim, Y.-Y.; Lee, D.-H.; Lee, Y.-G.; Hahn, J.-T.
Tetrahedron Lett. 2009, 50, 5805e5807.
47. Glover, S. A.; Jones, K. M.; McNee, I. R.; Rowbottom, C. A. J. Chem. Soc., Perkin
Trans. 2 1996, 1367e1376.
5. Marsella, M. J. Acc. Chem. Res. 2002, 35, 944e951.