Study on medium ring heterocycles: Synthesis and structure of novel condensed pyrazolo[1,4]diazocinones including single enantiomers

Article abstract of DOI:10.1016/j.tet.2011.02.034

By means of a base-catalysed ring enlargement of triazapentalenoindenes resulting from diasteroselective anhydride-induced ring transformation of chiral aminoalcohol-derived zwitterionic 2,3-dihydroimidazo[2,1-a]phthalazinium- olates, a series of pyrazolo[1,5-d][1,4]diazocin-7(6H)-ones with central and conformational chirality were obtained in enantiomerically pure form. The possible reasons of the characteristic substrate- and reagent-dependency observed for the diasteroselective ring transformations of the zwitterions were interpreted in terms of the relative energetics of the crucial alternative imidazolinium intermediates disclosed by B3LYP/6-31G(d,p) calculations. The trans-annular opening of three epimeric pairs of triazapentalenoindanones afforded identical pyrazolodiazonine products. This finding suggests that the primarily formed diastereomers, having different asymmetric conformations but the same element of central chirality, undergo ring inversions in one- and two steps, respectively, involved in pathways previously established for the facile racemisation of pyrazolodiazocines with conformational chirality and hydrogen- or methyl-substituent at C1-position. The ring enlargement of triazapentalenoindanones resulted from butyric anhydride-mediated ring transformation of zwitterions with symmetrical substitution pattern afforded highly rigid 1-ethylpyrazolodiazocines in racemic form potentially separable without thermal racemisation. The constitution, conformation and relative configuration of the novel compounds were determined by ¹H-, ¹³C- and ¹⁵N-NMR methods including 2D-HSQC, 2D-HMBC and DNOE measurements and the structure of a pyrazolodiazocine was supported by single crystal X-ray diffraction.

Full text of DOI:10.1016/j.tet.2011.02.034

Tetrahedron 67 (2011) 2979e2990
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study on medium ring heterocycles: synthesis and structure of novel condensed
pyrazolo[1,4]diazocinones including single enantiomers
a
a
,
b
b
ꢀ
*
ꢀ
€
€
ꢀ
ꢀ
ꢀ ꢀ
Adam Gyomore , Antal Csampai , Tamas Holzbauer , Matyas Czugler
a
€
€
ꢀ
Institute of Chemistry, Eotvos Lorand University, P.O. Box 32, H-1518 Budapest-112, Hungary
b Chemres Institute of Structural Chemistry Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri str. 59-67, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
By means of a base-catalysed ring enlargement of triazapentalenoindenes resulting from diasteroselective
anhydride-induced ring transformation of chiral aminoalcohol-derived zwitterionic 2,3-dihydroimidazo
[2,1-a]phthalazinium-olates, a series of pyrazolo[1,5-d][1,4]diazocin-7(6H)-ones with central and confor-
mational chirality were obtained in enantiomerically pure form. The possible reasons of the characteristic
substrate- and reagent-dependency observed for the diasteroselective ring transformations of the zwit-
terions were interpreted in terms of the relative energetics of the crucial alternative imidazolinium in-
termediates disclosed by B3LYP/6-31G(d,p) calculations. The trans-annular opening of three epimeric pairs
of triazapentalenoindanones afforded identical pyrazolodiazonine products. This finding suggests that the
primarily formed diastereomers, having different asymmetric conformations but the same element of
central chirality, undergo ring inversions in one- and two steps, respectively, involved in pathways pre-
viously established for the facile racemisation of pyrazolodiazocines with conformational chirality and
hydrogen- or methyl-substituent at C1-position. The ring enlargement of triazapentalenoindanones re-
sulted from butyric anhydride-mediated ring transformation of zwitterions with symmetrical substitution
pattern afforded highly rigid 1-ethylpyrazolodiazocines in racemic form potentially separable without
thermal racemisation. The constitution, conformation and relative configuration of the novel compounds
were determined by 1H-, 13C- and 15N-NMR methods including 2D-HSQC, 2D-HMBC and DNOE measure-
ments and the structure of a pyrazolodiazocine was supported by single crystal X-ray diffraction.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 December 2010
Received in revised form 21 January 2011
Accepted 14 February 2011
Available online 19 February 2011
Keywords:
Pyrazolodiazocine
trans-Annular ring enlargement
Ring inversion
Diastereoselectivity
Conformational chirality
DNMR
DFT
1. Introduction
tetrahydropyrrolo[3,4-b]quinolinones or6a 1,2,3,4-tetrahydro-
pyrrolo [2,3-c]quinolinones.6b Another characteristic example is the
Medium ring heterocycles are often present in biologically active
natural products and in a wide range of drug candidates. Their
synthesis by conventional direct ring closure methods may often be
difficult unless certain conformational restraints are present in the
acyclic precursor.1 Alternative synthetic approaches of structures
containing medium-size ring systems of potential biological interest
are based on diverse ring transformation reactions.2e10 Different
benzodiazocines- and benzodiazonines result from the oxidative
ring expansion of polycyclic fused compounds often containing in-
ring isomerisation of pyridazino[1,2-c][1,3,4]thiadiazinones into
thiazolo[3,4-a][1,3]diazepinones involving the cleavage of the NeN
bond followed by diastereoselective trans-annular recyclisation of
the intermediate 1,3,8-thiadiazecinones.7 The biological activity
associated with the receptor-binding properties of medium-size
heterocycles depends not only on pharmacophoric grouping,8 but
also on the conformation.9 By means of the combined use of NMR, X-
ray analysis and molecular modelling of some benzodiazepine and
benzotriazepine derivatives, a nonplanar rapidly interconverting
(on the NMR time scale) boat shape conformation were established
for the seven-membered ring in agreement with the results of X-ray
analyses.8e14 Experimental and theoretical conformational studies
of the more flexible benzodiazocine and benzodiazonines have also
been reported,4,15e19 but there are a relatively low number of ex-
amples of synthesis and structural analysis of their polycyclic hetero
condensed derivatives.20e26
dole unit2e4 or intramolecular transacylation of 1-[2-(
u-amino-
alkyl)-phenyl]-azetidin-2-ones.5 On the other hand, in certain cases
the transitionally formed medium-size rings cannot be isolated as
they immediately undergo trans-annular ring contraction to give
smaller condensed rings. For instance, alternative trans-annular
condensations of 3,4,5,6-tetrahydro-1H-benzo[e][1,4]diazonine-
2,7-diones transitionally formed by the oxidative ring fission of
1,2,3,4-tetrahydrocarbolines led to the formation of 1,2,3,4-
In our previous paper we reported on the synthesis and ring
inversion of the pyrazolo[1,5-e]benzo[g][1,5]diazonin-8(7H)-ones
1aec and pyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones 2a,b
(Fig. 1). These medium-size heterocycles with conformational
* Corresponding author. Tel.: þ36 01 209 0555; fax: þ36 01 209 0602; e-mail
ꢀ
address: csampai@chem.elte.hu (A. Csampai).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.034

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pyrazolodiazoninoses 2c and 7c, respectively. Upon heating di-
methyl-substituted zwitterions 328 and 4 with this reagent at reflux
the expected ring-transformations occurred producing 5c and 6c in
mediocre yields, as these reactions were accompanied by the for-
mation of substantial amounts of tarry materials. After a shorter
reaction with hydrazine hydrate in ethanol at reflux (method A), 5c
and 6c underwent N3-deacylation associated with trans-annular
ring opening leading to 2c and 7c, respectively, in low yields. By the
use of 10% NaHCO3 (reflux) as reagent (method B) higher yields
could be achieved (Scheme 2). The relatively low yields obtained by
method A suggest that the efficiency of hydrazine-mediated C1-
deprotonation seems to be more susceptible to the steric demand
of R1-substituent than that of the reactions with hydroxide ions.
This view is supported by the higher yields of 7a,b obtained by the
hydrazine-mediated ring enlargements of pentacycles 6a,b, which
were resulted from the reactions of 4 with acetic- and propionic
anhydride, respectively (Scheme 2).
In keeping with our expectations the 1H NMR analysis of the
novel pyrazolodiazocines carried out in DMSO-d6 solution at dif-
ferent temperatures disclosed that R1¼ethyl group renders com-
plete rigidity of the eight-membered ring as reflected by the fact
that even no line broadening could be detected when the solutions
of 2c and 7c were heated up to 390 K (for technical precaution the
temperature was not raised above this temperature.) This re-
sistance to undergo racemisation can obviously be due to a severe
repulsive interaction of the proximal H11(in 2c)/H13(in 7c) proton
and the intensively rotating methyl group inside the ethyl sub-
stituent, which prevents the crucial flip of the pyrazole ring on the
pathway revealed for the inversion of the pyrazolodiazocine scaf-
fold.27 Accordingly, by means of 1H NMR measurements 368 K and
376 K were measured as coalescence temperatures for the ring
inversions of 7a and 7b, respectively, exhibiting definite confor-
mational and consequently configurational flexibility.
Fig. 1. A 50% displacement representation of a single 7c molecule from the crystal
structure. Broken lines indicate minor disorder methyl terminus of the ethyl group
(plotted by the aid of PLATON32).
chirality were prepared in racemic form and their substituent-de-
pendent ring inversion associated with the change in chirality was
studied by DNMR and DFT calculations.27 It has been established
that the methyl-or the phenyl-group attached to the C1 position
affords complete rigidity to the pyrazolodiazonine skeleton (1b,c),
while the methyl-substituent in the same position of 2b has no
significant effect on the conformational stability of the pyr-
azolodiazocine ring system.27
As a continuation of our ongoing research on medium-size ring
systems we envisaged the synthesis of further representatives of
pyrazolodiazocines having potential interest in CNS-oriented as-
says, including 2-aminoalcohol-based derivatives in an enantio-
pure form. We also expected that the replacement of the methyl
group for an ethyl substituent in position 1 would result in a sig-
nificant decrease in the conformational flexibility of this ring sys-
tem (Scheme 1).
2.2. Preparation of single enantiomers of novel diazocines
with central and conformational chirality
Making use of this facile reaction sequence involving anhydride-
induced ring transformation and deacylation associated with ring
enlargement we undertook the synthesis of benzo- and naphtho-
condensed pyrazolodiazocines with central and conformational
chirality in enantiopure form (Scheme 3). First, valinol-based
zwitterion 828 was treated with anhydrides at reflux to get chiral
tetracycles 12a,b28 and 12c. Using acetic- and propionic anhydrides
zwitterions 9 and 10 were converted into chiral tetra- and penta-
cyclic compounds 13a,b, 14a and 15a with R2 group in endo position
2. Results and discussion
2.1. Preparation and conformational flexibility of the novel
diazocines without central chirality
as well as exo-substituted diastereomers 13a
*
and 15a considered
*
as potential precursors of further optically active pyr-
azolodiazocines containing the elements of central and conforma-
tional chirality. The ring enlargement of the tetra- and pentacyclic
intermediates was first attempted by hydrazine in ethanol at reflux
First we assessed the feasibility of incorporating butyric anhy-
dride in the tetra- and pentacyclic triazapentalenoindenones 5c
and 6c (Scheme 2), the potential precursors of 1-ethyl-substituted
HO
Me
HO
R1
R1
1a
Me
N
N
N
H
N
H
O
O
H
H
N
N
N
N
N
1b,c
O
O
N
Me
R1
N
N
R1
Me
OH
OH
(M)−2a R1 = H
(P)−2a R1 = H
(P)−1a R1 = H
(P)−1b R1 = Me
(P)−1c R1 = Ph
(M)−1a R1 = H
(M)−2b R1 = Me
(P)−2b R1 = Me
(M)−1b R1 = Me
(M)−1c R1 = Ph
The signs (P) and (M) are used arbitrarily for these compounds.
Scheme 1.

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OH
O
O
O
1
R1
11b/13b
11/13
3
(R1CH2CO)2O
reflux 5 h
Me
N
A: N2H4.H2O / EtOH
reflux 15 min.
7
6
N
N
H
N
5a
N
Me
N
B:10% NaHCO3
reflux 3 h.
4
Me
R1
N
1
4
5
HN
3
8
N
Me
O
Me
COCH2R1
Me
3 benzo
4 naphtho
5c (benzo): 49%
6a (naphtho): 92%
6b(naphtho): 65%
6c (naphtho): 63%
2c (benzo): 22% (A); 53% (B)
7a (naphtho): 48% (A); 58% (B)
7b (naphtho): 42% (A); 52% (B)
7c (naphtho): 20% (A); 49% (B)
a: R1 = H
b: R1 = Me
c: R1 = Et
For compounds 2c, 5c, 6a-c and 7a-c the relative configurations are represented on this Scheme.
Scheme 2.
Scheme 3.

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(method A), but the reactions of most endo diastereomers resulted
in pyrazolodiazocines contaminated by a number of undefined
side-products significantly decreasing the isolated yields (17e37%:
Scheme 3). Since acetone was employed for the workup for the
reaction mixtures obtained by method A, besides 21b (20%) and
a deacylated product (17b: 15%) hydrazone 26b could also be sep-
arated in low yield (12%) after the reaction of 12b. Imidazo[1,2-a]
isoindolone 20b, the precursor of 26b, was formed by the hydra-
zine-mediated fission of the pyrazole ring giving information on
the unwanted side reactions involving other amide/imide type
bonds present in the intermediates. The limited success of the
attempted reactions conducted under the conditions of method A
prompted us to resort to the application of 10% aqueous NaHCO3
(method B), which proved to be successful to effect ring enlarge-
ment of the optically active triazapentalenoindanones of types
21e24 in mediocre yields (Scheme 3), but the reaction of 12c gave
again a highly complex, practically unseparable mixture of prod-
ucts. The racemic mixtures of pentacycles 16a,b with slightly less
demanding R2¼ethyl group were also prepared by anhydride-in-
duced rearrangement reactions of zwitterion 11. Contrary to the
substrates with bulkier R2 substituents these models readily un-
derwent hydrazine-mediated deacylation by method A associated
with trans-annular ring opening affording 25a,b in quite good
yields (62% and 58%), and under the same conditions pentacycles
the complexes type B with smaller degree of steric crowdance the
hydrazine molecule anchored by hydrogen bond from the
hydroxypyrazoline moiety may promote the ring enlargement si-
multaneously operating as base- and acid catalyst to result in the
formation of intermediates type D.
The trans-annular ring enlargement of both endo- and exo-di-
astereomers gives identical pyrazolo-naphthodiazocine products as
the consequence of a single lactame-isomerisation by the rotation
of the C]O group in the intermediates type C, and the flip of the
pyrazole ring followed by lactame-isomerisation taking place by
the rotation of the NeH group in the diastereomeric intermediates
type D (Scheme 4). It is to be noted here that besides this proposed
mechanism involving hydrogen-bonded hydrazine-complexes of
deacylated triazapentalenoindanones other competitive reaction
pathways with simple proton transfers contributing to the forma-
tion of pyrazolodiazocines must also be taken into account for the
overall reactions affording isolable amount of the medium ring-size
products.
An interesting feature of the anhydride-induced ring trans-
formations of zwitterions is the characteristic substrate-, reagent-
and time dependent formation of endo- and exo diastereomers of
the tetra- and pentacyclic products of types 12e16 (Scheme 4).
Besides the corresponding endo-diastereomers (18e31%) some-
what higher yields (23e36%) of exo-diastereomers (13a
*
, 15a
*
and
13a
*
, 15a
*
and 16a
*
with exo-oriented R2 group got also converted
16a ) were obtained when naphtho-condensed zwitterions were
*
into the corresponding pyrazolo-naphthodiazonines (22a, 24a and
25a) in 78e86% yields.
treated with refluxing acetic anhydride employing shorter reaction
time (1.5 h). Prolonged treatment (5 h) with the same reagent
afforded endo diastereomers (13a, 15a and 16a) as only isolable
products referring to their possible formation under thermody-
namic control from the corresponding exo-isomer, the primarily
formed ‘kinetic products’. Since the preparative outcome of these
experiments apparently contradicted the general expectations, the
relative free energy values of the optimized structures of repre-
sentative diastereomeric model pairs with R2¼i-Pr substituent
The remarkable substrate-dependence observed in the re-
activity of diastereomer pairs 13a/13a
*
, 15a/15a
*
and 16a/16a to-
*
wards hydrazine suggests that these are the bulkier R2 groups
situated in endo position that may prevent the ring enlargement.
This experience can be explained by comparing the structures of
the assumed complexes types A and B composed of hydrazine and
the anchoring iminohydrine tautomer resulted from the deacety-
lation of the endo- and exo-diastereomers, respectively (Scheme 4).
It seems reasonable that too bulky R2-groups (i-Pr, Ph) may prevent
the formation of crowded complexes type A, the prerequisite of the
actual ring opening step. In these cases the ring fission leading to
complexes C can be effected by the sterically less demanding hy-
droxide ion present in the 10% NaHCO3 solution proved to be suc-
cessful reagent for most of our studied transformations affording
pyrazolodiazocines with central- and conformational chirality. In
(12a
*
/12a, 12b
*
/12b, 13a
*
/13a and 13b /13b) were calculated with
*
the dependence of the R1 group and the condensed aromatic ring.
The optimized structures and the thermodynamic parameters were
obtained by DFT calculations29 carried out at B3LYP/6-31G(d,p)
level of theory.30,31 In each case studied, the result was in agree-
ment with the experiments showing a somewhat higher thermo-
dynamic stability of the endo isomer and that the bulkier R1¼Me
group slightly facilitates the formation of endo products [DG
H
O
H
O
H
H2N
H
R1
NH2
H
N2H4 / EtOH
H
H
N
H
N
H
endo tetra-and
exo
N
N
N2H4 / EtOH
pentacycles
pentacycles
N
N
R2
H
N
N
R2
O
O
H
B
A
10% NaHCO3
-N2H4
OH
O
R1
N
H
O
H
H
N
O
H
N
R1
i.)
ii.)
H
R2
N
H
N
N
N
N
R2
H
H
N
R2
O
H
O
21a,b, 22a,b
23a, 24a
D
C
ii.) 1. flip of the pyrazole ring.
2. lactam isomerisation
i.) lactam isomerisation
by the rotation of the C=O group
by the rotation of the N-H group
Scheme 4.

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(exoꢀendo) calculated for 413 K and 440 K, respectively, repre-
senting the boiling points of the reagent anhydrides, which are
approximated to be identical with the reaction temperatures:
their thermodynamic parameters were obtained by B3LYP/6-31G
(d,p) (Table 1). The presence of the aforementioned non-bonding
C/O interaction in the intermediates type F is evidenced by the
distance between the atoms involved (Table 1). In keeping with the
general expectations the relative free energy values calculated for
the reaction temperatures (boiling points of the employed anhy-
drides: 413 K and 440 K, respectively) indicate that the fused
naphthalene ring facilitates cyclisations type F/G rather than does
þ2.65 kcal/mol (12a
*
/12a); þ3.60 kcal/mol (12b
*
/12b); þ2.70 kcal/
mol (13a
*
/13a); þ3.49 kcal/mol (13b
*
/13b), Table 1]. It is, however,
an important point that only the acetic anhydride-mediated re-
actions of naphtho-condensed zwitterions 9e11 afforded exo di-
astereomers in isolable amounts. In order to disclose the reason for
this substrate- and reagent-dependent diastereoselectivity first we
composed reaction pathways connecting the precursor zwitterions
with all the possible tetra- and pentacyclic products (Scheme 5),
and undertook again comparative B3LYP/6-31G(d,p) analysis of the
key intermediates of types G and F resulted from the protonation of
imidazoline ring (Q¼H) and involved in the conversions leading to
the benzene ring of less pronounced p-electron donating character,
opening the route to the exo-products. However, since cyclisations
of the type F/G are accompanied by a characteristic substituent-
dependent decrease in entropy (Table 1), R1¼Me suppresses this
step indirectly preventing the formation of exo-diastereomers,
particularly at higher temperatures.
our selected representative model pairs with R2¼i-Pr group (12a
*
/
12a, 12b
*
/12b, 13a
*
/13a and 13b /13b, cf. Table 1). The pathway
*
2.3. Structure determination
accounting for the formation of endo products comprises the re-
agent-mediated fission of the N-acylated pyridazinone ring (E/F)
and the crucial diastereoselective formation of the CeC bond in the
resulted imidazolium salt finally followed by the closure of the
pyrrolidone ring effected by the residual mixed anhydride moiety.
Since the cationic intermediates (type F) were supposed to be
stabilized by a non-bonding C/O interaction from the trans posi-
tion relative to the bulky R2 group allowing the enol-attack from
this side, we have previously proposed this mechanism for the
conversion of a series of benzo-condensed zwitterions affording
selectively endo-substituted tetracycles (e.g. 12a and 14a).28 On the
other hand, the ring closure of the mixed anhydride intermediates F
may also lead to cyclic imidazolium salts (G) of which alternative
cylisations are capable of affording either diastereomeric product.
The optimized structures of intermediate cations (G and F) and
The IR- 1H- 13C- and 15N-NMR data of the novel triazapenta-
lenoindanones and pyrazolodiazocines (see Experimental section)
are consistent with their structures and similar to those reported
for analogous compounds,27,28 however, the following remarks are
necessary.
The structure of pentacycles 13a , 15a and 16a was un-
ambiguously evidenced by mutual NOEs (2e4%) due to interactions
of H1endo with H4endo and H5, respectively. Due to the anisotropic
*
*
*
effect of the proximal 6-oxo group in 13a and 16a the CH- or CH2-
signals of R2 group are considerably downfield shifted (by
0.7e1.2 ppm) relative to those of 13a and 16a, respectively. In the
endo-diastereomers types 12e16 enhanced NOEs (4e8%) were
detected between H1endo and the protons of R2 group. Analogously,
in 5c, 6b,c, 12b,c, 13b, 16b and 17b the exo position of R1¼Me or Et
*
*
Table 1
Non-bonding C/O distance in representative intermediates type F (Q¼H) and thermodynamic parameters of their ring closure affording cyclic imidazolinium cations type G
calculated by B3LYP/6-31G(d,p) method
R1; condensed ring
d(C/O) in F [A]
D
G(exoeendo) at Treaction [kcal/mol]
DS(GeF) [cal/mol K]
DG(GeF) at Treaction [kcal/mol]
a
a
ꢁ
H; benzo
2.613
2.607
2.607
2.608
þ2.65
þ3.60
þ2.70
þ3.49
ꢀ27.68
ꢀ27.86
ꢀ34.92
ꢀ35.22
þ0.16
ꢀ1.96
þ1.72
ꢀ0.30
H; naphtho
Me; benzo
Me; naphtho
a
Boiling point of acetic- and propionic anhydrides (413 K and 440 K, respectively).
O
O
R2
N
13a*, 15a*, 16a*
N
N
[12a*, b*, c*, 13b*, 14a*, 16b*]
H
N
N
R1
HN
8−11
O
H
R2
G
(12a*, b*, c*, 13b*, 14a* and 16b* are
not detectable exo-diastereomers.)
O
R1
R1CH2CO2
Q = H or R1CH2CO
R1
O
N
R2
Q
N
N
N
O
O
N
R1
H
12a−c, 13a,b, 14a,
15a, 16a,b
N
O
O
O
O
H
E
R2
F
R1
R1CH2CO2
R1
Scheme 5.

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substituent was also evidenced by NOEs of similar intensity (5e9%)
detected between H1endo and the protons of R2 group.
The constitution of imidazo[1,2-a]indanone 26b was supported
by the C1 and C10b signals at 43.0 ppm and 97.2 ppm, respectively,
and by the presence of five nitrogen atoms of which positions could
unequivocally be located via the coupling patterns discernible in
the 1He15N-HMBC spectrum: e.g. the skeletal N3a atom can be
identified from the cross peaks with H1-, 3NH-, H4exo-, H4endo- and
H5eq signals (endo designates cis position relative to i-Pr group).
Accordingly, the 1He13C-HMBC spectrum reveals correlations be-
tween the aforementioned protons and C10b, which gives further
cross peaks with H10 and the protons of the 1-CH3 group. The
relative trans orientation of C1 and N3 atoms is reflected by the
mutual NOEs (4e9%) measured between H1 and the CH proton of i-
Pr group and resulted from the interaction involving 3NH- and
H4exo protons.
The structures of pyrazolodiazocines 2c, 7aec, 21a,b, 22a,b, 23a,
24a and 25a,b containing aromatic hydroxypyrazole ring and ‘Z’-
lactam moiety are consistent with the related 1H-,13C- and 15N-NMR
data (see Experimental section) and supported by the following NOE
experiments. Considerable NOEs (7e10%) were measured between
the lactam NH and the protons of the exo-positioned R2 group
pointing totheir relative cis position on the eight-membered ring. As
an additional evidence for the boat conformation of the eight-
membered ring mutual NOEs (4e6%) were detected between the
protons of the endo-positioned methyl group and the H8 proton of
the condensed aromatic ring (2c, 7aec). Smaller, but significant
NOEs (2e3%) could be obtained between the endo-positioned H5
proton and the H8 proton on the condensed aromatic ring in 21a,b,
22a,b, 23a, 24a and 25a,b. Providing further evidence for the boat
conformation of the eight-membered ring present in these com-
pounds diagnostic NOEs were measured between the proton pairs
H4endoeH5 (12e14%), H4endoeH11 (benzo-fused)/H13 (naphtho-
fused) (3e5%) and H4exoeNH (4e6%). The solid state structure of 7c
was determined by single crystal X-ray analysis (summary of data:
CCDC 801193).
Fig. 2. Different coloured type 1 (blue) and type 2 (light green, see text) residues with
their H-bridge contacts in broken lines, space filling representation of acetonitrile
solvent is also indicated in red (packing excerpt by the aid of mercury33).
3. Conclusion
Anhydride-induced diasteroselective ring transformation re-
actions of condensed zwitterionic imidazopyridazinium olates fol-
lowed by base-catalysed trans-annular ring enlargement were
utilized for the convenient synthesis of a series of novel optically
active pyrazolodiazocines with the elements of central- and con-
formational chirality of potential interest in biological test. Taking
into account the structureereactivity relationships established ex-
perimentally and partly interpreted by high-level DFT calculations,
the expedient procedures employed in the subsequent steps may
open up a way to a number of further representatives of this me-
dium-size ring system. It is a remarkable advantage of the synthetic
routes described in this contribution that the absolute configuration
of the target compounds can be determined by the configuration of
a particular enantiomer of the chiral aminoalcohol incorporated in
the easily available precursors. It was also established that, due to
subsequent ring inversion steps, the ring enlargement reactions of
both endo- and exo triazapentalenoindanones lead to identical
pyrazolodiazocines with conformational- and central chirality. From
the perspective of enantiomer-separation it may be of importance
that as ethyl group was found to be the sterically least demanding
substituent in position 1, which is capable of preventing the thermal
racemisation of pyrazolodiazocinones with symmetrical sub-
stitution pattern even at elevated temperatures. Accordingly, ex-
periments to achieve optical resolution of 2c and 7c are in progress.
2.4. Crystal structure description of pyrazolodiazocine 7c
Pyrazolodiazocinone 7c was also studied by single crystal X-ray
analysis. Its crystal structure, in spite of the nice looking crystals
poses some irregularities, interesting organization and stoichiom-
etry features. First of these is the involvement of a molecule of
acetonitrile crystallization solvent included in an apparently cen-
trosymmetric structure with half occupancy in the asymmetric
unit. Along with two 7c molecules in the asymmetric unit this then
yields to the overall 4/1 stoichiometry of the crystal. The 7c mo-
lecular structure alone (Fig.1) shows the disorder of the ethyl group
at C1. Peculiar ethyl disorder and the half occupancy might raise the
idea of reducing the space group symmetry to the chiral P1 space
group. However this hypothesis could not be verified convincingly.
Two kinds of functions of molecules 7c are seen in the crystal
(Fig. 2). Both types represent dimer associations of 7c molecules,
but these types involve differing ring involvements. The type 1
dimer placement for the molecules is at around in the cell linking
opposite facing diazocine NH/O]C functions across the symme-
try center at 1/2, 1/2, 1/2. The type 2 dimers, placed at the face
centers at 0, 1/2, 0 and through the 5-ring N3 atom as the acceptor
and the O1 HB donor function, serve for structure propagation
along the crystallographic ‘a’ axis. The connection between the two
dimer types as well as the structure propagation occurs via the
O1H/O2 hydrogen bridges along the c direction, together with
a slightly longer but geometrically regular N6/N3 hydrogen bridge
contact. The role of the solvent appears to be filling otherwise
empty space in the crystal and probably only contributing to the
crystal stabilization through non-specific weaker dispersion forces.
4. Experimental section
4.1. General
Melting points (uncorrected) were determined with a Boethius
microstage and are uncorrected. Flash silica gel column chroma-
tography was carried out on Merck Kieselgel 60 (230e400 mesh).
The IR spectra were run in KBr disks on a Bruker IFS-55 FT-spec-
trometer controlled by Opus 3.0 software. The 1H and 13C NMR
spectra were recorded in DMSO-d6 or CDCl3 solution in 5 mm tubes
at rt, on a Bruker DRX-500 spectrometer at 500.13 (1H) 125.76 (13C)
and 50.12 (15N) MHz, with the deuterium signal of the solvent as
the lock and TMS as the internal standard (for 1H and 13C NMR) and
NH3liq as external reference (15N NMR). The 15N NMR chemical
shifts were obtained and assigned from the 2D 1He15N HMBC
spectra. The standard Bruker microprogram NOEMULT to generate

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NOE and to get DIFFNOE spectra was used with a selective pre-ir-
radiation time. DEPT spectra were run in a standard manner, using
Analytical and spectroscopic data of 12a, 12b and 14a (yield: 59%,
55%, and 48% with reaction time of 2 h) are reported in Ref. 28.
only a
Q
¼135ꢁ pulse to separate the CH/CH3 and CH2 lines phased
‘up’ and ‘down’, respectively. The 2D-COSY-, HMQC- and HMBC
spectra were obtained by using the standard Bruker pulse pro-
grams. Optical rotations were measured with a Zeiss Polamat A
polarimeter. All calculations were carried out with the Gaussian 03
suite of programs.34 On request the optimized structures are
available from the authors.
4.3.1. 3-Butyryl-1-ethyl-1,2,3,3a,4,5,6,6a-octahydro-5,5-dimethyl-
3,3a,5a-triazapentaleno[3a,3-a]inden-2,6(3H,5aH)-dione (5c). Yield:
1.74 g, 49% (reaction time: 5 h); white solid, mp 114e115 ꢁC; Rf
(DCM/MeOH 80/1) 0.71; nmax 1753, 1699 (broad), 1640 cmꢀ1 1H
;
NMR (CDCl3)
d 7.76 (1H, m, H7), 7.54e7.49 (2H, m, H8,9), 7.20 (1H,
m, H10), 4.19 (1H, d, J 9.5 Hz, H4exo), 3.67 (1H, d, J 9.5 Hz, H4endo),
3.42 (1H, dd, J 8.3, 6.1 Hz, H1), 2.98 (2H, m, COCH2CH2CH3),
1.83e1.79 (3H, overlapping ms, COCH2CH2CH3 and 1-CHAHBCH3),
1.76 (3H, s, 5-CH3exo), 1.74 (3H, s, 5-CH3endo), 1.26 (1H, m, 1-
CHAHBCH3), 1.06 (3H, t, J 7.3 Hz, COCH2CH2CH3), 0.77 (3H, t, J 7.6 Hz,
4.2. Crystal structure determination of 7c
4.2.1. Crystal growth. Regular prism shaped transparent crystals of
7c were grown from a mixture of acetonitrile/ethanol (1/1) solution
by slow solvent evaporation. A crystal selected from the batch in
equilibrium with its mother liquor was used for the X-ray data
collection.
1-CH2CH3); 13C NMR (CDCl3)
d 173.5 (C6), 173.3 (C2), 170.5
(COCH2CH2CH3), 143.0 (10a), 134.1 (6a), 132.7 (C9), 130.7 (C8), 124.7
(C7), 122.2 (C10), 91.3 (10b), 73.1 (C4), 61.0 (C5), 49.1 (C1), 39.1
(COCH2CH2CH3), 29.9 (5-CH3exo), 26.3 (5-CH3endo), 19.8 (1-CH2CH3),
18.5 (COCH2CH2CH3), 14.1 (COCH2CH2CH3), 12.0 (1-CH2CH3). Anal.
Calcd for C20H25N3O3 (355.43): C, 67.58; H, 7.09; N, 11.82. Found: C,
67.64; H, 7.01; N, 11.77%.
4.2.2. Crystal structure determination. A selected single crystal
(0.2ꢂ0.3ꢂ0.5 mm) of 7c was mounted on a Rigaku R-AXIS RAPID
diffractometer. Data collection was performed at room tempera-
tures (T¼295 K). Crystal data for 7c: 4(C20H21N3O2)$C2H3N, F.W.
4.3.2. 3-Acetyl-1,2,3,3a,4,5,6,6a-octahydro-5,5-dimethyl-3,3a,5a-tri-
azabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione (6a). Yield:
3.21 g, 92% (reaction time: 5 h); white solid, mp 246e248 ꢁC; Rf
(DCM/MeOH 80/1) 0.44; nmax 1746,1707 (broad),1641 cmꢀ1; 1H NMR
ꢁ
ꢁ
1382.64, triclinic Pꢀ1 (No. 2), a¼11.0696(15) A, b¼12.6340(16) A,
ꢁ
c¼14.8683(19) A,
a
¼99.133(6)ꢁ,
b
¼98.061(5)ꢁ,
g
¼107.516(6)ꢁ,
V¼1918.4(4) A , Z¼1, D(calcd)¼1.197 [mg/m3]. Initial structure model
was obtained by SHELXS-97,35 completed by successive difference
Fourier syntheses and refined to convergence by SHELXL-97,35 final
R1¼0.0488, wR2¼0.1472, for 4857 observations. An alternative
model refinement proved to be futile in the acentric P1 space group.
Crystallographic data for 7c have been deposited at the Cambridge
Crystallographic Data centre under deposition no. CCDC 801193.
Copies of these data can be obtained free of charge upon applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: 00 44 (0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
3
ꢁ
(CDCl3)d 8.30(1H, s, H7), 8.00 (1H, d, J 8.3 Hz, H8), 7.91(1H, d, J 8.3 Hz,
H11), 7.80 (1H, s, H12), 7.63 (1H, t, J 8.3 Hz, H10), 7.59 (1H, t, J 8.3 Hz,
H9), 4.19 (1H, d, J 9.7 Hz, H4exo), 3.70 (1H, d, J 18.0 Hz, H1endo), 3.30
(1H, d, J 9.7 Hz, H4endo), 3.03 (1H, d, J 18.0 Hz, H1exo), 2.63 (3H, s,
COCH3),1.74 (3H, s, 5-CH3exo);1.72 (3H, s, 5-CH3endo);13C NMR (CDCl3)
d
171.4(C2),170.2(C6),167.0(COCH3),142.2 (C12a),136.1(C11a),134.2
(C7a),132.3(C6a),130.2(C8),129.0(C11),128.9(C10),127.8(C9),125.4
(C7), 120.1 (C12), 87.1 (C12b), 73.7 (C4), 61.5 (C5), 42.4 (C1), 29.6 (5-
CH3exo), 25.9 (5-CH3endo), 25.1 (COCH3). Anal. Calcd for C20H19N3O3
(349.38)C, 68.75; H, 5.48; N,12.03. Found: C, 68.79; H, 5.53; N,11.97%.
2,3-Dihydro-2,2-dimethylimidazo[2,1-a]phthalazin-4-ium-6-
olate (3) and (S)-2,3-dihydro-2-isopropyl-imidazo[2,1-a]phthala-
zin-4-ium-6-olate (8) are described compounds.28 2,3-Dihy-
drobenzo[g]imidazo[2,1-a]phthalazin-4-ium-6-olates (4, 9, 10 and
11) were synthesized in four steps (ieiv) starting from the anhy-
dride of naphthalene-2,3-dicarboxylic acid and the corresponding
aminoalcohol [2-amino-2-methylpropan-1-ol, (S)-2-amino-3-
methylbutan-1-ol and (S)-2-amino-2-phenylethanol and rac-2-
aminobutan-1-ol]. (The details are described in the Supplementary
data.)
4.3.3. (1R
*
,10bR )-1,2,3,3a,4,5,6,6a-Octahydro-1,5,5-trimethyl-3-
*
propanoyl-3,3a,5a-benzo[f]triazapentaleno[3a,3-a]inden-2,6
(3H,5aH)-dione (6b). Yield: 2.45 g, 65% (reaction time: 5 h); white
solid, mp 256e259 ꢁC; Rf (DCM/MeOH 80/1) 0.52; nmax 1777, 1698,
1639 cmꢀ1; 1H NMR (CDCl3)
d 8.32 (1H, s, H7), 8.02 (1H, d, J 8.3 Hz,
H8), 7.89 (1H, d, J 8.3 Hz, H11), 7.68 (1H, s, H12), 7.63 (1H, t, J 8.3 Hz,
H10), 7.59 (1H, t, J 8.3 Hz, H9), 4.27 (1H, d, J 9.7 Hz, H4exo), 3.67 (1H,
quartet, J 7.3 Hz, H1endo), 3.36 (1H, d, J 9.7 Hz, H4endo), 2.96 (2H, qu-
artet, J 7.2 Hz, COCH2CH3), 1.73 (6H, s, 5-CH3exo and 5-CH3endo), 1.21
(3H, t, J 7.2 Hz, COCH2CH3), 0.88 (3H, d, J 7.3 Hz, 1-CH3); 13C NMR
4.3. General procedure for the anhydride-induced
transformation of zwitterions
(CDCl3) d 173.6 (COCH2CH3),172.2 (C2),170.4 (C6),138.1 (C12a),135.8
(C11a), 134.4 (C7a), 132.0 (C6a), 130.2 (C8), 129.1 (C11), 128.9 (C10),
127.8 (C9), 125.6 (C7), 122.1 (C12); 91.2 (C12b), 73.2 (C4), 61.7 (C5),
43.9 (C1), 30.4 (COCH2CH3), 29.8 (5-CH3exo), 26.1 (5-CH3endo), 9.1
(COCH2CH3), 8.6 (1-CH3). Anal. Calcd for C22H23N3O3 (377.43) C,
70.01; H, 6.14; N, 11.13. Found: C, 70.12; H, 6.04; N, 11.08%.
A mixture of the zwitterion 3, 4, 9, 10 or 11 (10 mmol) and the
corresponding anhydride (100 mL) was heated to reflux for
1.5e5 h. The excess of the anhydride was distilled under reduced
pressure and the resulted brownish solid was stirred and triturated
with cold saturated NaHCO3 solution (20 mL), which was then
decanted. The residue was then triturated with ethanol to obtain
yellowish white powder, which was filtered off, thoroughly washed
with water and dried over P2O5 in a vacuum desiccator. The com-
position of the crude product was checked by TLC on silica plate
(DCM/MeOH 80/1) and 1H NMR spectroscopy. After the acetic an-
hydride-induced reactions of 9e11, which were conducted for 1.5 h,
4.3.4. (1R
*
,10bR )-3-Butyryl-1-ethyl-1,2,3,3a,4,5,6,6a-octahydro-5,5-
*
dimethyl-3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-
dione (6c). Yield: 2.55 g, 63% (reaction time: 5 h); white solid, mp
267e269 ꢁC; Rf (DCM/MeOH 80/1) 0.71; nmax 1774,1697,1636 cmꢀ1
;
1H NMR (CDCl3)
d 8.32 (1H, s, H7), 8.01 (1H, d, J 8.3 Hz, H8), 7.88 (1H,
d, J 8.3 Hz, H11), 7.63 (1H, s, H12) overlapped by 7.63 (1H, t, J 8.3 Hz,
H10), 7.59 (1H, t, J 8.3 Hz, H9), 4.23 (1H, d, J 9.7 Hz, H4exo), 3.41 (1H, d,
J 9.7 Hz, H4endo), 3.45 (1H, dd, J 8.3, 6.1 Hz, H1), 2.97 (2H, m,
COCH2CH2CH3), 1.83e1.79 (3H, overlapping ms, COCH2CH2CH3 and
1-CHAHBCH3), 1.76 (3H, s, 5-CH3exo), 1.75 (3H, s, 5-CH3endo), 1.22 (1H,
m, 1-CHAHBCH3), 1.06 (3H, t, J 7.3 Hz, COCH2CH2CH3), 0.79 (3H, t, J
two components (exo/endo diastereomeric pairs 13a
*
/13a, 15a
*
/15a
and 16a /16a) were clearly discernible in the primarily isolated
*
substances. Their separation was performed by flash column
chromatography on silica using DCM/MeOH 100/1 as eluent. After
the evaporation of the first and second bands the oily residues were
crystallized by water to obtain the exo- and endo products, re-
spectively. Analytical samples were recrystallized from EtOH.
7.6 Hz, 1-CH2CH3); 13C NMR (CDCl3)
(COCH2CH2CH3) 170.2 (C6), 137.5 (C12a), 135.3 (C11a), 134.3 (C7a),
d 173.3 (C2), 170.5

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131.7 (C6a),130.2 (C8),128.9 (two coalesced lines, C10,11),127.8 (C9),
125.5 (C7),121.5 (C12), 91.3 (12b), 72.9 (C4), 61.9 (C5), 49.7 (C1), 39.1
(COCH2CH2CH3), 29.9 (5-CH3exo), 26.5 (5-CH3endo), 19.8 (1-CH2CH3),
18.4 (COCH2CH2CH3), 14.1 (COCH2CH2CH3), 12.0 (1-CH2CH3). Anal.
Calcd for C24H27N3O3 (405.49) C, 71.09; H, 6.71; N, 10.36. Found: C,
71.00; H, 6.74; N, 10.46%.
(3H,5aH)-dione (13b). Yield: 1.72 g, 44% (reaction time: 1.5 h); pale
yellowish solid, 3.05 g, 78% (reaction time: 5 h); mp 234e236 ꢁC; Rf
(DCM/MeOH 80/1) 0.61; [
a
]
25 ꢀ86.0 (c 0.8, DMSO); nmax 1739, 1710
D
(broad), 1634 cmꢀ1; 1H NMR (CDCl3)
d
8.33 (1H, s, H7), 8.01 (1H, d, J
7.9 Hz, H8), 7.89 (1H, d, J 7.9 Hz, H11), 7.64 (1H, t, J 7.9 Hz, H10), 7.62
(1H, s, H12), 7.59 (1H, t, J 7.9 Hz, H9), 4.52 (1H, dd, J 10.0, 8.0 Hz,
H4exo), 4.06 (1H, dt, J 9.8, 8.1 Hz, H5), 3.57 (1H, quartet, J 7.2 Hz, H1),
3.12 (1H, dd, J 10.0, 8.0 Hz, H4endo), 3.00 (2H, quartet, J 7.6 Hz,
COCH2CH3), 1.96 [1H, m, CH(CH3)2], 1.26 (3H, t, J 7.6 Hz, COCH2CH3),
1.22 [3H, d, J 6.8 Hz, CH(CH3)(CH3)], 1.10 (3H, d, J 7.2 Hz, 1-CH3), 1.05
4.3.5. (5S,10bR)-3-Butyryl-1-ethyl-1,2,3,3a,4,5,6,6a-octahydro-5-iso-
propyl-3,3a,5a-triazapentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(12c). Yield: 1.59 g, 43% (reaction time: 2 h); white solid, mp
94e97 ꢁC; Rf (DCM/MeOH 80/1) 0.69; [
a]
25 ꢀ64.9 (c 0.6, EtOH); nmax
[3H, d, J 6.8 Hz, CH(CH3)(CH3)]; 13C NMR (CDCl3)
d 173.7 (C2), 173.5
D
1765, 1704, 1691, 1650 cmꢀ1
;
1H NMR (CDCl3)
d
7.81 (1H, m, H7),
(C6), 171.2 (COCH2CH3), 137.2 (C12a), 135.5 (C11a), 134.3 (C7a), 130.2
(C8),129.1 (C10), 129.7 (C6a),128.9 (C11), 127.8 (C9), 125.7 (C7), 120.7
(C12), 85.8 (C12b), 64.6 (C4), 62.9 (C5), 41.1 (C1), 35.7 [CH(CH3)2],
30.8 (COCH2CH3), 20.9 [CH(CH3)(CH3)], 19.5 CH(CH3)(CH3)], 9.5
(COCH2CH3), 8.7 (1-CH3). Anal. Calcd for C23H25N3O3 (391.46) C,
70.57; H, 6.44; N, 10.73. Found: C, 70.61; H, 6.37; N, 10.80%.
7.60e7.50 (2H, m, H8,9), 7.22 (1H, m, H10), 4.51 (1H, dd, J 10.1, 8.3 Hz,
H4exo), 3.98 (1H, dt, J 9.9, 8.3 Hz, H5), 3.34 (1H, dd, J 9.2, 5.3 Hz, H1),
3.09 (1H, dd, J 10.1, 8.3 Hz, H4endo), 2.90 (2H, m, COCH2CH2CH3), 1.97
[1H, m, CH(CH3)2], 1.92 (1H, m, 1-CHAHBCH3), 1.74 (2H, m,
COCH2CH2CH3), 1.33 (1H, m, 1-CHAHBCH3), 1.22 [3H, d, J 6.9 Hz, CH
(CH3)(CH3)], 1.04 [3H, d, J 6.9 Hz, CH(CH3)(CH3)], 1.01 (3H, t, J 7.3 Hz,
COCH2CH2CH3), 0.80 (3H, t, J 7.7 Hz, 1-CH2CH3); 13C NMR (CDCl3)
4.3.9. (5S,12bR)-3-Acetyl-1,2,3,3a,4,5,6,6a-octahydro-5-phenyl-
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(15a). Yield: 0.76 g,19% (reaction time: 1.5 h); yellowish solid 1.91 g,
48%(reaction time: 5 h);mp 252e255 ꢁC; Rf (DCM/MeOH80/1) 0.57;
d
173.7 (C6), 173.0 (C2), 170.3 (COCH2CH2CH3), 142.8 (C10a), 133.0
(C9),132.5 (C6a),130.9 (C8),125.3 (C7),122.5 (C10), 90.0 (C10b), 64.4
(C4), 62.8 (C5), 48.3 (C1), 39.0 (COCH2CH2CH3), 36.2 [CH(CH3)2],
20.8 CH(CH3)(CH3)], 20.0 CH(CH3)(CH3)], 19.4 (1-CH2CH3), 18.3
(COCH2CH2CH3),14.1 (COCH2CH2CH3),11.8 4 (1-CH2CH3). Anal. Calcd
for C21H27N3O3 (369.46): C, 68.27; H, 7.37; N, 11.37. Found: C, 68.39;
H, 7.44; N, 11.24%.
[
a
]
25 ꢀ15.9 (c 0.8, DMSO); nmax 1774,1705,1694,1648,1612 cmꢀ1; 1H
D
NMR (CDCl3) d 8.43 (1H, s, H7), 8.08 (1H, d, J 8.0 Hz, H8), 7.98 (1H, d, J
8.0 Hz, H11), 7.92 (1H, s, H12), 7.70 (1H, t, J 8.0 Hz, H10), 7.65 (1H, t, J
8.0 Hz, H9), 7.50e7.43 [4H, m, H20,30,50,60 (Ph)], 7.39 [1H, m, H40
(Ph)], 5.68 (1H, t, J 7.4 Hz, H5), 4.81 (1H, dd, J 9.9, 7.4 Hz, H4exo), 3.59
(1H, d, J 18.0 Hz, H1endo), 3.39 (1H, dd, J 9.9, 7.4 Hz, H4endo), 3.22 (1H,
4.3.6. (5S,12bR)-3-Acetyl-1,2,3,3a,4,5,6,6a-octahydro-5-iso-propyl-
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(13a). Yield: 1.13 g, 31% (reaction time: 1.5 h); pale yellowish solid,
d, J 18.0 Hz, H1exo), 2.60 (3H, s, COCH3); 13C NMR (CDCl3)
d 173.2 (C6),
171.0 (C2),167.1 (COCH3),141.6 (C12a),140.2 [C10, (Ph)],136.3 (C11a),
134.4 (C7a), 130.4 (C8), 129.5 [C3050, (Ph)], 129.3 (C10), 129.0 (C11),
128.5 (C6a), 128.4 [C40, (Ph)], 128.0 (C9), 126.1 (C7), 125.6 [C2060,
(Ph)], 121.1 (C12), 86.2 (C12b), 66.0 (C4), 58.6 (C5), 40.9 (C1), 25.1
(COCH3). Anal. Calcd for C24H19N3O3 (397.43) C, 72.53; H, 4.82; N,
10.57. Found: C, 72.58; H, 4.71; N, 10.68%.
2.23 g, 61% (reaction time: 5 h); mp 227e230 ꢁC; Rf (DCM/MeOH
25
80/1) 0.60; [
a
]
D
ꢀ70.1 (c 0.8, DMSO); nmax 1754, 1720, 1693,
1641 cmꢀ1; 1H NMR (CDCl3)
d
8.30 (1H, s, H7), 8.00 (1H, d, J 8.3 Hz,
H8), 7.92 (1H, d, J 8.3 Hz, H11), 7.80 (1H, s, H12), 7.63 (1H, t, J 8.3 Hz,
H10), 7.60 (1H, t, J 8.3 Hz, H9), 4.46 (1H, dd, J 10.5, 7.8 Hz, H4exo),
4.04 (1H, dt, J 10.4, 7.8 Hz, H5), 3.62 (1H, d, J 18.0 Hz, H1endo), 3.20
(1H, d, J 18.0 Hz, H1exo), 3.06 (1H, dd, J 10.5, 7.8 Hz, H4endo), 2.61 (3H,
s, COCH3), 1.96 [1H, m, CH(CH3)2], 1.22 [3H, d, J 6.8 Hz, CH(CH3)
4.3.10. (5S,12bS)-3-Acetyl-1,2,3,3a,4,5,6,6a-octahydro-5-phenyl-
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(CH3)], 1.05 [3H, d, J 6.8 Hz, CH(CH3)(CH3)]; 13C NMR (CDCl3)
d
173.3
(15a
240e243 ꢁC; Rf (DCM/MeOH 80/1) 0.41; [
nmax 1768, 1703 (broad), 1632, 1600 cmꢀ1
*
). Yield: 0.91 g, 23% (reaction time: 1.5 h); yellowish solid, mp
25
(C6), 171.5 (C2), 167.1 (COCH3), 141.8 (C12a), 136.2 (C11a), 134.4
(C7a), 130.3 (C8), 129.1 (C11), 128.9 (C10), 128.7 (C6a), 127.8 (C9),
125.7 (C7), 120.7 (C12), 85.8 (C12b), 64.6 (C4), 62.9 (C5), 41.1 (C1),
35.7 [CH(CH3)2], 25.1 (COCH3), 20.9 [CH(CH3)(CH3)], 19.5 CH(CH3)
(CH3)]. Anal. Calcd for C21H21N3O3 (363.41) C, 69.41; H, 5.82; N,
11.56. Found: C, 69.34; H, 5.88; N, 11.55%.
a
]
D
þ22.6 (c 1.1, CCl4);
;
1H NMR (CDCl3)
d 8.19
(1H, s, H7), 8.04 (1H, d, J 8.1 Hz, H8), 7.96 (1H, d, J 8.1 Hz, H11), 7.92
(1H, s, H12), 7.71 (1H, t, J 8.1 Hz, H10), 7.63 (1H, t, J 8.1 Hz, H9),
7.39e7.34 [5H, m, H20-60 (Ph)], 5.18 (1H, dd, J 7.7, 3.4 Hz, H5), 4.30
(1H, dd, J 10.5, 7.7 Hz, H4exo), 3.75 (1H, d, J 18.4 Hz, H1endo), 3.79 (1H,
dd, J 10.5, 3.4 Hz, H4endo), 3.14 (1H, d, J 18.4 Hz, H1exo), 2.65 (3H, s,
4.3.7. (5S,12bS)-3-Acetyl-1,2,3,3a,4,5,6,6a-octahydro-5-iso-propyl-
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
COCH3); 13C NMR (CDCl3)
d 171.3 (C2), 168.6 (C6), 167.0 (COCH3),
141.3 (C12a), 140.8 [C10, (Ph)], 136.4 (C11a), 134.1 (C7a), 130.2 (C8),
129.5 (C10), 129.3 [C3050, (Ph)], 129.8 (C6a), 129.1 (C11), 128.3 [C40,
(Ph)], 128.0 (C9), 125.2 (C7), 125.0 [C2060, (Ph)], 121.3 (C12); 86.9
(C12b), 67.7 (C5), 60.3 (C4), 41.8 (C1), 25.2 (COCH3). Anal. Calcd for
C24H19N3O3 (397.43) C, 72.53; H, 4.82; N, 10.57. Found: C, 72.64; H,
4.81; N, 10.49%.
(13a
213e215 ꢁC; Rf (DCM/MeOH 80/1) 0.50; [
nmax 1767, 1702, 1681, 1640 cmꢀ1; 1H NMR (CDCl3)
*
). Yield: 1.02 g, 28% (reaction time: 1.5 h); white solid, mp
25
a]
D
þ63.2 (c 0.6, EtOH);
d
8.27 (1H, s, H7),
7.99 (1H, d, J 8.3 Hz, H8), 7.92 (1H, d, J 8.3 Hz, H11), 7.87 (1H, s, H12),
7.62 (1H, t, J 8.3 Hz, H10), 7.58 (1H, t, J 8.3 Hz, H9), 3.73 (1H, dd, J 11.5,
7.1 Hz, H4exo), 3.84 (1H, quartet, J 7.6, H5), 3.56 (1H, d, J 18.6 Hz,
H1endo), 3.27 (1H, dd, J 11.5, 7.1 Hz, H4endo), 3.22 (1H, d, J 18.6 Hz,
H1exo), 3.09 [1H, m, CH(CH3)2], 2.62 (3H, s, COCH3), 1.27 [3H, d, J
6.9 Hz, CH(CH3)(CH3)], 0.89 [3H, d, J 6.8 Hz, CH(CH3)(CH3)]; 13C NMR
4.3.11. (5R
*
,12bS )-3-Acetyl-5-ethyl-1,2,3,3a,4,5,6,6a-octahydro-
*
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(16a). Yield: 0.98 g, 28% (reaction time: 1.5 h); pale yellowish solid
2.52 g, 72% (reaction time: 5 h); mp 249e251 ꢁC; Rf (DCM/MeOH
(CDCl3)
d 171.0 (C2), 169.0 (C6), 167.1 (COCH3), 141.3 (C12a), 136.2
(C11a), 134.2 (C7a), 130.2 (C8), 130.1 (C6a), 129.0 (C11), 128.9 (C10),
127.7 (C9), 125.2 (C7), 121.0 (C12), 86.5 (C12b), 63.6 (C5), 62.9 (C4),
41.1 (C1), 26.2 [CH(CH3)2], 25.1 (COCH3), 22.3 [CH(CH3)(CH3)], 18.6
CH(CH3)(CH3)]. Anal. Calcd for C21H21N3O3 (363.41) C, 69.41; H, 5.82;
N, 11.56. Found: C, 69.32; H, 5.90; N, 11.62%.
80/1) 0.58; nmax 1758, 1720, 1696, 1642 cmꢀ1 1H NMR (CDCl3)
;
d
8.32 (1H, s, H7), 7.98 (1H, d, J 8.1 Hz, H8), 7.92 (1H, d, J 8.1 Hz, H11),
7.82 (1H, s, H12), 7.62 (1H, t, J 8.1 Hz, H10), 7.57 (1H, t, J 8.1 Hz, H9),
4.54 (1H, dd, J 10.0, 8.0 Hz, H4exo), 4.29 (1H, quint, J 8.0 Hz, H5), 3.65
(1H, d, J 18.0 Hz, H1endo), 3.20 (1H, d, J 18.0 Hz, H1exo), 3.05 (1H, dd, J
10.0, 8.0 Hz, H4endo), 2.63 (3H, s, COCH3), 1.97 (1H, m, CHAHBCH3),
1.79 (1H, m, CHAHBCH3), 1.11 (3H, t, J 7.3 Hz, CH2CH3); 13C NMR
4.3.8. (1R,5S,12bR)-1,2,3,3a,4,5,6,6a-Octahydro-1-methyl-3-prop-
anoyl-5-iso-propyl-3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6
(CDCl3)
d 173.5 (C6), 171.5 (C2), 167.3 (COCH3), 141.9 (C12a), 136.5

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A. Gyomore et al. / Tetrahedron 67 (2011) 2979e2990
2987
(C11a), 134.6 (C7a), 130.3 (C8), 129.2 (C11), 128.9 (C10), 128.5 (C6a),
127.8 (C9), 125.9 (C7), 120.7 (C12); 85.7 (C12b), 65.5 (C4), 58.1 (C5),
41.3 (C1), 29.8 (CH2CH3), 25.3 (COCH3), 11.0 (CH2CH3). Anal. Calcd
for C20H19N3O3 (349.38) C, 68.75; H, 5.48; N, 12.03. Found: C, 68.72;
H, 5.59; N, 11.92%.
solidified by the trituration with water and filtered off to obtain 26b
as a white powder. The separation of 17b and 21b was performed by
flash column chromatography on silica using DCM/MeOH 30/1 as
eluent. Analytical samples were obtained by recrystallization from
EtOH and dried in a vacuum desiccator over P2O5.
4.3.12. (5R
3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(16a ). Yield: 1.26 g, 36% (reaction time: 1.5 h); pale yellowish
solid, mp 237e240 ꢁC; Rf (DCM/MeOH 80/1) 0.46; nmax 1770, 1704,
1680, 1642 cmꢀ1 1H NMR (CDCl3)
8.30 (1H, s, H7), 8.01 (1H, d,
*
,12bR
*
)-3-Acetyl-5-ethyl-1,2,3,3a,4,5,6,6a-octahydro-
4.4.1. (Z)-1-Ethyl-4,5-dihydro-2-hydroxy-5,5-dimethylpyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (2c). Yield: 0.126 g, 22%; white
solid, mp 242e246 ꢁC; Rf (DCM/MeOH 20/1) 0.18; nmax
*
w3300e2200, 1600, 1513 cmꢀ1; 1H NMR (DMSO-d6)
d 9.72 (1H, br
;
d
s, OH), 7.69 (1H, s, NH), 7.62e7.53 (3H, m, H8-10), 7.31 (1H, m, H11),
3.78 (1H, d, J 15.2 Hz, H4exo), 3.51 (1H, d, J 15.2 Hz, H4endo), 2.33 (1H,
dquartet, J 14.1, 7.5 Hz, 1-CHAHBCH3), 2.25 (1H, dquartet, J 14.1,
7.5 Hz, 1-CHAHBCH3), 1.38 (3H, s, 5-CH3exo), 1.15 (3H, s, 5-CH3endo),
J 8.3 Hz, H8), 7.91 (1H, d, J 8.2 Hz, H11), 7.88 (1H, s, H12), 7.63 (1H, t,
J 8.2 Hz, H10), 7.58 (1H, t, J 8.2 Hz, H9), 3.74 (1H, dd, J 11.0, 7.2 Hz,
H4exo), 3.86 (1H, quartet, J 7.2, H5), 3.58 (1H, d, J 18.3 Hz, H1endo),
3.27 (1H, dd, J 11.0, 7.2 Hz, H4endo), 3.22 (1H, d, J 18.3 Hz, H1exo), 2.60
(3H, s, COCH3), 2.57 (2H, quint, J 7.2 Hz, CH2CH3), 1.04 (2H, quint,
1.02 (3H, t, J 7.5 Hz, 1-CH2CH3); 13C NMR (DMSO-d6)
d 171.0 (C7),
159.2 (C2), 140.1 (C7a), 139.9 (C11b), 130.6 (C10), 130.1 (C9), 129.71,
129.65 (C8,11), 127.6 (C11a), 104.6 (C1), 56.2 (C4), 55.0 (C5), 29.7 (5-
CH3exo), 29.3 (5-CH3endo), 15.98 (1-CH2CH3), 15.92 (1-CH2CH3) (the
two latter hardly separated lines were identified by DEPT-135
measurement). Anal. Calcd for C16H19N3O2 (285.34) C, 67.35; H,
6.71; N, 14.73. Found: C, 67.30; H, 6.79; N, 14.85%.
J 7.2 Hz, CH2CH3); 13C NMR (CDCl3)
d 171.1 (C2), 169.3 (C6), 167.1
(COCH3), 141.6 (C12a), 136.3 (C11a), 134.2 (C7a), 130.4 (C8), 130.2
(C6a), 129.0 (C11), 128.8 (C10), 127.8 (C9), 125.4 (C7), 121.2 (C12),
86.6 (C12b), 62.1 (C4), 58.9 (C5), 41.4 (C1), 30.9 (CH2CH3), 25.3
(COCH3), 11.4 (CH2CH3). Anal. Calcd for C20H19N3O3 (349.38) C,
68.75; H, 5.48; N, 12.03. Found: C, 68.81; H, 5.54; N, 12.12%.
4.4.2. (Z)-4,5-Dihydro-2-hydroxy-5,5-dimethylpyrazolo[1,5-d]naph-
tho[2,3-f][1,4]diazocin-7(6H)-one (7a). Yield: 0.295 g, 48%; white
solid, mp 369e359 ꢁC; Rf (DCM/MeOH 20/1) 0.13; nmax 3270, 3204,
w3100e2400, 1643, 1568, 1510 cmꢀ1; 1H NMR (DMSO-d6) 9.92 (1H,
br s, OH), 8.10 (1H, s, H8), 8.05 (1H, s, NH), 8.07 (1H, m, H9), 8.02
(1H, m, H12), 7.85 (1H, s, H13), 7.63e7.59 (2H, m, H10,11), 5.64 (1H,
s, H1), 3.79 (1H, d, J 15.4 Hz, H4exo), 3.51 (1H, J 15.4 Hz, H4endo), 1.30
4.3.13. (1R
*
,5S
*
,12bR )-5-Ethyl-1,2,3,3a,4,5,6,6a-octahydro-1-
*
methyl-3-propanoyl-3,3a,5a-triazabenzo[f]pentaleno[3a,3-a]inden-
2,6(3H,5aH)-dione (16b). Yield: 1.40 g, 28% (reaction time: 1.5 h);
white solid 3.02 g, 80% (reaction time: 5 h); mp 268e261 ꢁC; Rf
(DCM/MeOH 80/1) 0.65; nmax 1741, 1710 (broad), 1631 cmꢀ1 1H
;
NMR (CDCl3) d 8.30 (1H, s, H7), 7.97 (1H, d, J 8.1 Hz, H8), 7.85 (1H, d,
J 8.1 Hz, H11), 7.59 (1H, t, J 8.1 Hz, H10), 7.56 (1H, s, H12), overlapped
with 7.55 (1H, t, J 8.1 Hz, H9), 4.53 (1H, dd, J 10.0, 8.2 Hz, H4exo), 4.29
(1H, quint, J 8.2 Hz, H5), 3.54 (1H, quartet, J 7.2 Hz, H1), 3.05 (1H,
dd, J 10.0, 8.2 Hz, H4endo), 2.96 (2H, quartet, J 7.4 Hz, COCH2CH3),
1.97 (1H, m, CHAHBCH3), 1.79 (1H, m, CHAHBCH3), 1.26 (3H, t, J
7.4 Hz, COCH2CH3), 1.11 (3H, t, J 7.3 Hz, CH2CH3), 1.04 (3H, d, J 7.2 Hz,
(3H, s, 5-CH3endo), 1.10 (3H, s, 5-CH3exo); 13C NMR (DMSO-d6)
d 171.6
(C7), 162.0 (C2), 142.0 (C13b), 134.8 (C7a), 134.0 (12a), 133.4 (C8a),
129.6 (C8), 129.1 (C9), 128.9 (12), 128.4 (C11), 128.1 (C10), 127.3
(C13), 126.9 (C13a), 96.4 (C1), 56.1 (C4), 55.0 (C5), 29.8 (5-CH3endo),
29.1 (5-CH3exo); 15N NMR (DMSO-d6)
d 272 (N3), 184 (N3a), 137
(N6). Anal. Calcd for C18H17N3O2 (307.35) C, 70.34; H, 5.58; N, 13.67.
Found: C, 70.39; H, 5.51; N, 13.58%.
1-CH3); 13C NMR (CDCl3)
d 173.9 (C6), 173.4 (C2), 171.4 (COCH2CH3),
137.7 (C12a), 135.8 (C11a), 134.3 (C7a), 130.0 (C8), 129.4 (C10), 129.6
(C6a), 128.5 (C11), 127.6 (C9), 125.2 (C7), 120.7 (C12), 85.3 (C12b),
65.4 (C4), 58.2 (C5), 41.5 (C1), 30.6 (COCH2CH3), 29.8 (CH2CH3), 9.5
(COCH2CH3), 8.8 (1-CH3). Anal. Calcd for C22H23N3O3 (377.44) C,
70.01; H, 6.14; N, 11.13. Found: C, 69.91; H, 6.22; N, 11.06%.
4.4.3. (Z)-4,5-Dihydro-2-hydroxy-1,5,5-trimethylpyrazolo[1,5-d]
naphtho[2,3-f][1,4]diazocin-7(6H)-one (7b). Yield: 0.270 g, 48%;
white solid, mp 356e359 ꢁC; Rf (DCM/MeOH 20/1) 0.15; nmax 3272,
3210, w3100e2400, 1645, 1556, 1509 cmꢀ1 1H NMR (DMSO-d6)
;
d
9.82 (1H, br s, OH), 8.11 (1H, s, H8), 8.07 (1H, m, H9), 8.05 (1H, m,
4.4. General procedure for the hydrazinolysis of tetra- and
H12), 7.94 (1H, s, NH), 7.82 (1H, s, H13), 7.63e7.59 (2H, m, H10,11),
3.74 (1H, d, J 15.4 Hz, H4exo), 3.50 (1H, J 15.4 Hz, H4endo), 1.67 (3H, s,
1-CH3), 1.34 (3H, s, 5-CH3exo), 1.12 (3H, s, 5-CH3endo); 13C NMR
pentacycles 5c, 6aec, 12aec, 13a,b, 14a, 15a, 16a,b, 13a
and 16a (method A)
*
, 15a
*
*
(DMSO-d6)
d 170.9 (C7), 160.0 (C2), 140.0 (C13b), 138.1 (C7a), 133.7
To a suspension of the corresponding precursor (2 mmol) in
EtOH (10 mL) was added 92% N2H4$H2O (200 L dissolved in 1 mL
(C12a), 133.4 (C8a), 129.5 (C8), 129.0 (two coalesced lines C9,13),
128.9 (C12), 128.4 (C10), 128.2 (C11), 125.6 (C13a), 102.0 (C1), 56.1
(C4), 55.0 (C5), 29.6 (5eCH3exo), 29.2 (5-CH3endo), 8.1 (1-CH3); 15N
NMR (DMSO-d6) 272 (N3), 183 (N3a), 138 (N6). Anal. Calcd for
C19H19N3O2 (321.37) C, 71.01; H, 5.96; N, 13.08. Found: C, 71.14; H,
6.16; N, 13.02%.
m
of EtOH) dropwise under Ar atmosphere at rt, and the mixture was
stirred and refluxed for 15 min. The resulted yellow solution was
cooled with ice-water, neutralized with a few drops of AcOH, and
after standing ca. 30 min in refrigerator the precipitated crystals
were filtered off and washed with water. The composition of
the crude product was checked by TLC on silica plate (DCM/MeOH
20/1) and 1H NMR spectroscopy. After the reactions of 13a and 15a
two components (18a/21a and 19a/24a) were clearly discernible in
the primarily isolated substances. Their separation was performed
by flash column chromatography on silica using DCM/MeOH 30/1
as eluent. After the evaporation of the first and second bands the
solid residues were washed with water and filtered off to obtain
the N3-deacylated- and diazocine products, respectively. Following
the reaction of 12b no any solid was precipitated from the neu-
tralized reaction mixture, which was then evaporated. The oily
residue was triturated with acetone to obtain a white solid com-
posed of 17b and 21b. After filtration of this mixture the evapora-
tion of the acetonic solution gave oily residue, which was slowly
4.4.4. (Z)-1-Ethyl-4,5-dihydro-2-hydroxy-5,5-dimethylpyrazolo[1,5-
d]naphtho[2,3-f][1,4]diazocin-7(6H)-one (7c). Yield: 0.134 g, 20%;
white solid, mp 310e312 ꢁC; Rf (DCM/MeOH 20/1) 0.17; nmax 3178,
3049, w2950e2300, 1646, 1558, 1508 cmꢀ1 1H NMR (DMSO-d6)
;
d
9.71 (1H, br s, OH), 8.11 (1H, s, H8), 8.07 (1H, m, H9), 8.04 (1H, m,
H12), 7.85 (1H, s, H13), 7.65 (1H, s, NH), 7.63e7.59 (2H, m, H10,11),
3.73 (1H, d, J 15.2 Hz, H4exo), 3.49 (1H, d, J 15.2 Hz, H4endo), 2.38 (1H,
dquartet, J 14.6, 7.5 Hz, 1-CHAHBCH3), 2.29 (1H, dquartet, J 14.6,
7.5 Hz, 1-CHAHBCH3), 1.37 (3H, s, 5-CH3exo), 1.13 (3H, s, 5-CH3endo),
1.01 (3H, t, J 7.5 Hz, 1-CH2CH3); 13C NMR (DMSO-d6)
d 171.1 (C7),
159.7 (C2), 140.0 (C13b), 137.9 (C7a), 133.6 (C12a), 133.4 (C8a), 129.4
(C8), 129.2 (C9), 129.0 (C13), 128.9 (C12), 128.4 (C10), 128.2 (C11),
125.5 (C13a), 104.9 (C1), 56.2 (C4), 54.8 (C5), 29.6 (5-CH3exo), 29.4

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(5-CH3endo), 16.07 (1-CH2CH3), 16.05 (1-CH2CH3) (the two latter
hardly separated lines were identified by DEPT-135 measurement);
15N NMR (DMSO-d6) 275 (N3), 181 (N3a), 137 (N6). Anal. Calcd for
C20H21N3O2 (335.40) C, 71.62; H, 6.31; N, 12.53. Found: C, 71.68; H,
6.40; N, 12.42%.
(C11b), 136.2 (C7a), 130.6 (C9) and 130.5 (C10), 130.1 (C8), 129.1
(C11a), 127.8 (C8), 96.3 (C1), 57.3 (C5), 56.5 (C4), 31.5 [CH(CH3)2],
20.1 [CH(CH3)(CH3)], 19.9 [CH(CH3)(CH3)]; 15N NMR (DMSO-d6)
d
272 (N3), 185 (N3a), 128 (N6). Anal. Calcd for C15H17N3O2 (271.31)
C, 66.40; H, 6.32; N, 15.49. Found: C, 66.37; H, 6.39; N, 15.56%.
4.4.5. (5S,10bR)-1,2,3,3a,4,5,6,6a-octahydro-1-methyl-5-iso-propyl-
3,3a,5a-triazapentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(17b). Yield: 0.090 g, 15%; white solid, mp 210e212 ꢁC; Rf (DCM/
4.4.9. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-1-methyl-5-iso-propylpyr-
azolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-one (21b). Yield: 0.114 g,
25
20%; white solid, mp 230e232 ꢁC; Rf (DCM/MeOH 20/1) 0.16; [
a
]
1DH
MeOH 20/1) 0.36; [
a
]
25 ꢀ26.4 (c 1.2, DMSO); nmax 3250, 1700, 1610,
ꢀ4.9 (c 0.5, DMSO); nmax 3400e2300, 1660, 1638, 1525 cmꢀ1
;
D
1544 cmꢀ1
;
1H NMR (DMSO-d6)
d
9.95 (1H, s, NH), 7.70 (1H, d, J
NMR (DMSO-d6) d 9.58 (1H, br s, OH), 8.01 (1H, d, J 9.5 Hz, NH), 7.54
7.6 Hz, H7), 7.66 (1H, t, J 7.6 Hz, H9), 7.59 (1H, t, J 7.6 Hz, H8), 3.97
(1H, dd, J 10.0, 8.1 Hz, H4exo), 3.67 (1H, m, H5), 3.46 (1H, qa, J 7.3 Hz,
H1), 3.29 (1H, dd, J 10.0, 8.9 Hz, H4endo), 2.02 [1H, m, CH(CH3)2], 1.07
[3H, d, J 6.5 Hz, CH(CH3)(CH3)], 0.91 [3H, d, J 6.5 Hz, CH(CH3)(CH3)],
(1H, t, J 7.8 Hz, H10), 7.50 (1H, t, J 7.8 Hz, H9), 7.38 (1H, d, J 7.8 Hz,
H8), 7.33 (1H, d, J 7.8 Hz, H11), 4.02 (1H, dd, J 13.2, 4.4 Hz, H4endo),
3.85 (1H, t, J 13.2 Hz, H4exo), 3.20 (1H, m, H5), 1.74 [1H, m, CH
(CH3)2], 1.66 (3H, s 1-CH3), 0.87 [3H, d, J 6.9 Hz, CH(CH3)(CH3)], 0.79
0.79 (1H, d, J 7.3 Hz, 1-CH3); 13C NMR (DMSO-d6)
d
176.5 (C2), 173.8
[3H, d, J 6.9 Hz, CH(CH3)(CH3)]; 13C NMR (DMSO-d6)
d 171.9 (C7),
(C6), 144.4 (C10a), 133.5 (C9), 131.9 (C6a), 131.0 (C8), 124.8 (C7),
123.5 (C10), 94.4 (C10b), 65.8 (C4), 63.4 (C5), 38.9 (C1), 34.8 [CH
(CH3)2], 21.6 [CH(CH3)(CH3)], 19.8 [CH(CH3)(CH3)], 9.5 (1-CH3).
Anal. Calcd for C16H19N3O2 (285.34) C, 67.35; H, 6.71; N, 14.73.
Found: C, 67.46; H, 6.79; N, 14.67%.
159.7 (C2), 139.1 (C11b), 137.2 (C7a), 130.8 (C10), 130.3 (C9), 130.0
(C8), 128.5 (C11a), 127.7 (C11), 101.7 (C1), 57.7 (C5), 56.4 (C4), 31.7
[CH(CH3)2], 20.3 [CH(CH3)(CH3)], 19.8 [CH(CH3)(CH3)], 7.9 (1-CH3);
15N NMR (DMSO-d6)
d 271 (N3), 183 (N3a), 127 (N6). Anal. Calcd for
C15H17N3O2 (285.34) C, 67.35; H, 6.71; N, 14.73. Found: C, 67.49; H,
6.78; N, 14.62%.
4.4.6. (5S,10bR)-1,2,3,3a,4,5,6,6a-octahydro-5-iso-propyl-3,3a,5a-
triazabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione
(18a). Yield: 0.244 g, 38%; pale yellow solid, mp 270e274 ꢁC; Rf
4.4.10. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-5-iso-propylpyrazolo[1,5-
d]naphtho[2,3-f][1,4]diazocin-7(6H)-one (22a). Yield: 0.244 g, 38%
(DCM/MeOH 20/1) 0.32; [
a
]
25 ꢀ17.7 (c 1.0, DMSO); nmax 3260, 1698,
(from 13a); 0.514 g, 86% (from 13a
*
); white solid, mp 176e179 ꢁC; Rf
ꢀ60.7 (c 0.8, DMSO); nmax
D
1605, 1572 cmꢀ1; 1H NMR (DMSO-d6)
d
10.03 (1H, s, NH), 8.31 (1H,
(DCM/MeOH 20/1) 0.12; [a]
25
D
s, H7), 8.14 (1H, d, J 8.1 Hz, H8), 8.11 (1H, d, J 8.1 Hz, H11), 7.99 (1H, s,
H12), 7.64 (1H, t, J 8.1 Hz, H10), 7.59 (1H, t, J 8.1 Hz, H9), 3.81 (1H,
dd, J 10.7, 7.2 Hz, H4exo), 3.72 (1H, dt, J 10.0, 7.2 Hz, H5), 3.35 (1H, d, J
17.6 Hz, H1endo), 3.12 (1H, dd, J 10.7, 7.2 Hz, H4endo), 2.76 (1H, d, J
17.6 Hz, H1exo), 2.01 [1H, m, CH(CH3)2], 1.06 [3H, d, J 6.5 Hz, CH(CH3)
(CH3)], 0.92 [3H, d, J 6.5 Hz, CH(CH3)(CH3)]; 13C NMR (DMSO-d6)
w3400e2500, 1650 (broad), 1640, 1530 cmꢀ1; 1H NMR (DMSO-d6)
d
9.90 (1H, br s, OH), 8.10 (1H, d, J 9.8 Hz, NH), 8.04 (1H, m, H9), 8.00
(1H, m, H12), 7.97 (1H, s, H8), 7.94 (1H, s, H13), 7.64e7.60 (2H, m,
H10,11), 5.59 (1H, s, H1), 4.04 (1H, dd, J 13.2, 4.7 Hz, H4endo), 3.90
(1H, t, J 13.2 Hz, H4exo), 3.24 (1H, m, H5), 1.75 [1H, m, CH(CH3)2],
0.87 [3H, d, J 6.9 Hz, CH(CH3)(CH3)], 0.78 [3H, d, J 6.9 Hz, CH(CH3)
d
173.6 (C2), 173.2 (C6), 143.6 (C12a), 136.3 (C11a), 134.2 (C7a), 130.6
(CH3)]; 13C NMR (DMSO-d6)
d 171.6 (C7), 162.2 (C2), 142.4 (C13b),
(C8), 129.50, 129.44 (C10,C11), 129.0 (C6a), 128.0 (C9), 124.9 (C7),
121.6 (C12), 90.2 (C12b), 65.7 (C4), 63.6 (C5), 39.2 (C1), 34.1 [CH
(CH3)2], 21.7 [CH(CH3)(CH3)], 19.9 [CH(CH3)(CH3)]. Anal. Calcd for
C19H19N3O2 (321.37) C, 71.01; H, 5.96; N, 13.08. Found: C, 71.10; H,
6.06; N, 13.01%.
134.6 (C7a), 133.7 (12a), 133.3 (C8a), 129.6 (C8), 128.9 (two co-
alesced lines, C9,12), 128.4 (C11), 128.1 (C10), 127.4 (C13), 127.1
(C13a), 96.8 (C1), 57.2 (C5), 56.5 (C4), 31.7 [CH(CH3)2], 20.1 [CH(CH3)
(CH3)], 19.8 [CH(CH3)(CH3)]; 15N NMR (DMSO-d6)
d 274 (N3), 185
(N3a), 127 (N6). Anal. Calcd for C19H19N3O2 (321.37) C, 71.01; H,
5.96; N, 13.08. Found: C, 70.90; H, 6.04; N, 13.02%.
4.4.7. (5S,10bR)-1,2,3,3a,4,5,6,6a-octahydro-5-phenyl-3,3a,5a-tri-
azabenzo[f]pentaleno[3a,3-a]inden-2,6(3H,5aH)-dione (19a). Yield:
4.4.11. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-1-methyl-5-iso-pro-
pylpyrazolo[1,5-d]naphtho[2,3-f][1,4]diazocin-7(6H)-one
0.121 g, 17%; yellowish solid, mp 288e292 ꢁC; Rf (DCM/MeOH 20/1)
25
0.27; [
a
]
D
ꢀ22.5 (c 1.0, DMSO); nmax 3276, 1703, 1615, 1588 cmꢀ1
;
(22b). Yield: 0.244 g, 38%; white solid, mp 188e190 ꢁC; Rf (DCM/
25
1H NMR (DMSO-d6)
d
9.97 (1H, s, NH), 8.44 (1H, s, H7), 8.21 (1H, d, J
MeOH 20/1) 0.19; [
a
]
D
ꢀ31.0 (c 0.6, DMSO); nmax w3500e2500,
7.8 Hz, H8), 8.17 (1H, d, J 7.8 Hz, H11), 8.06 (1H, s, H12), 7.70 (1H, t, J
7.8 Hz, H10), 7.65 (1H, t, J 7.8 Hz, H9), 7.45e7.36 [5H, m, H20-60 (Ph)],
5.39 (1H, t, J 7.6 Hz, H5), 4.16 (1H, dd, J 10.2, 7.6 Hz, H4exo), 3.32 (1H,
d, J 18.0 Hz, H1endo), 3.15 (1H, d, J 18.0 Hz, H1exo), 3.01 (1H, dd, J 10.2,
1652 (broad), 1632, 1539 cmꢀ1; 1H NMR (DMSO-d6)
d 9.70 (1H, br s,
OH), 8.06 (1H, d, J 9.5 Hz, NH), 8.06e8.02 (2H, m, H9,12), 7.99 (1H, s,
H8), 7.87 (1H, s, H13), 7.64e7.60 (2H, m, H10,11), 4.02 (1H, dd, J 13.0,
4.4 Hz, H4endo), 3.85 (1H, t, J 13.0 Hz, H4exo), 3.21 (1H, m, H5), 1.74
[1H, m, CH(CH3)2], 1.66 (3H, s 1-CH3), 0.87 [3H, d, J 6.9 Hz, CH(CH3)
(CH3)], 0.79 [3H, d, J 6.9 Hz, CH(CH3)(CH3)]; 13C NMR (DMSO-d6)
7.6 Hz, H4endo); 13C NMR (CDCl3)
d 173.3 (C2), 172.9 (C2), 143.5
(C12a), 139.7 [C10, (Ph)], 136.3 (C11a), 134.5 (C7a), 130.3 (C8), 129.7
[C3050, (Ph)], 129.2 (C10), 128.9 (C11), 128.7 (C6a), 128.2 [C40, (Ph)],
128.0 (C9), 125.4 (C7), 125.9 [C2060, (Ph)], 122.1 (C12), 90.7 (C12b),
67.1 (C4), 59.4 (C5), 39.0 (C1). Anal. Calcd for C22H17N3O2 (355.39) C,
74.35; H, 4.82; N, 11.82. Found: C, 74.21; H, 4.88; N, 11.91%.
d
171.8 (C7), 160.2 (C2), 139.0 (C13b), 135.4 (C7a), 133.6 (12a), 133.2
(C8a), 130.3 (C8), 128.9 (two coalesced lines, C9,12), 128.3 (C10),
128.2 (C11),127.3 (C13),126.3 (C13a),102.2 (C1), 57.5 (C5), 56.5 (C4),
31.5 [CH(CH3)2], 20.3 [CH(CH3)(CH3)], 19.8 [CH(CH3)(CH3)], 8.1 (1-
CH3); 15N NMR (DMSO-d6) 272 (N3),182 (N3a),127 (N6). Anal. Calcd
for C20H21N3O2 (335.40) C, 71.62; H, 6.31; N, 12.53. Found: C, 71.58;
H, 6.37; N, 12.61%.
4.4.8. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-5-iso-propylpyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (21a). Yield: 0.200 g, 37%; white
solid, mp 244e248 ꢁC; Rf (DCM/MeOH 20/1) 0.16; [
a]
25 ꢀ11.8 (c 0.6,
D
DMSO); nmax w3400e2300, 1658, 1627, 1520 cmꢀ1
;
1H NMR
4.4.12. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-5-phenylpyrazolo[1,5-d]
(DMSO-d6)
d
9.58 (1H, br s, OH), 7.94 (1H, d, J 9.5 Hz, NH), 7.49 (1H,
benzo[f][1,4]diazocin-7(6H)-one (23a). Yield: 0.171 g, 28%; white
t, J 7.3 Hz, H10), 7.45 (1H, t, J 7.3 Hz, H9), 7.34 (1H, d, J 7.3 Hz, H8),
7.27 (1H, d, J 7.3 Hz, H11), 5.58 (1H, s, H1), 4.06 (1H, dd, J 13.1, 4.6 Hz,
H4endo), 3.91 (1H, t, J 13.1 Hz, H4exo), 3.24 (1H, m, H5), 1.77 [1H, m,
CH(CH3)2], 0.88 [3H, d, J 6.8 Hz, CH(CH3)(CH3)], 0.76 [3H, d, J 6.8 Hz,
solid, mp 222e225 ꢁC; Rf (DCM/MeOH 20/1) 0.16; [
a
]
25 þ52.7 (c 0.9,
D
DMSO); nmax 3325, w3300e2300, 1662, 1607, 1528 cmꢀ1
;
1H NMR
(DMSO-d6) d 9.80 (1H, br s, OH), 8.24 (1H, d, J 10.5 Hz, NH), 7.54 (1H,
t, J 7.8 Hz, H10), 7.50 (1H, t, J 7.8 Hz, H9), 7.42 [2H, d, J 7.6 Hz, H20,60
(Ph)], 7.38 (1H, d, J 7.8 Hz, H8), 7.36e7.32 [3H, m, H30,50 (Ph) and
CH(CH3)(CH3)]; 13C NMR (DMSO-d6)
d 171.9 (C7), 161.0 (C2), 142.7

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€
€
A. Gyomore et al. / Tetrahedron 67 (2011) 2979e2990
2989
H11], 7.29 [1H, t, J 7.6 Hz, H40 (Ph)], 5.69 (1H, s, H1), 4.93 (1H, ddd, J
13.2, 10.5, 4.9 Hz, H5), 4.33 (1H, dd, J 13.2, 4.9 Hz, H4endo), 4.24 (1H,
7.57e7.49 (2H, m, H8,9), 7.18 (1H, m, H10), 4.07 (1H, dd, J 13.9, 8.5 Hz,
H4exo), 3.83 (1H, m, H5), 3.64 (1H, dd, J 13.9, 7.6 Hz, H4endo), 3.30 (1H,
quartet, J 7.0 Hz, H1), 2.02 [3H, s, (CH3)(CH3)C]NeNH (‘E’ relative to
NH)], 1.96 [3H, s, (CH3)(CH3)C]NeNH (‘Z’ relative to NH)], 1.69 [1H,
m, CH(CH3)2], 1.55 (1H, dquartet, J 14.1, 7.6 Hz, COCHAHBCH3), 1.43
(1H, dquartet, J 14.1, 7.6 Hz, COCHAHBCH3), 1.11 [3H, d, J 7.6 Hz, CH
(CH3)(CH3)], 0.87 [3H, d, J 7.6 Hz, CH(CH3)(CH3)], 0.67 (3H, d, J 7.0 Hz,
t, J 13.0 Hz, H4exo); 13C NMR (DMSO-d6)
d 171.8 (C7), 160.2 (C2),
142.1 [C10,(Ph)], 139.1 (C11b), 137.2 (C7a), 130.8 (C10), 130.3 (C9),
130.0 (C8), 129.7 [C3050, (Ph)], 128.5128.3 [C40, (Ph)], (C11a), 127.7
(C11), 126.0 [C2060, (Ph)], 101.7 (C1), 58.2 (C5), 52.5 (C4); 15N NMR
(DMSO-d6) 275 (N3), 184 (N3a), 130 (N6). Anal. Calcd for
C18H15N3O2 (305.33) C, 70.81; H, 4.95; N, 13.76. Found: C, 70.94; H,
5.04; N, 13.72%.
1-CH3), 0.37 (3H, t, J 7.6 Hz, COCH2CH3); 13C NMR (DMSO-d6)
d 171.7
(COCH2CH3), 171.0 (C6), 167.1 (C2), 158.4 [(CH3)2C]NeNH], 141.3
(C10a),135.3 (C6a), 132.7 (C9),131.0 (C8), 124.6 (C10), 123.6 (C7), 97.2
(C10b), 63.2 (C4), 60.1 (C5), 43.0 (C1), 34.4 [CH(CH3)2], 27.2
(COCH2CH3), 26.0, [(CH3)(CH3)C]NeNH (‘E’ relative to NH)], 22.5
[CH(CH3)(CH3)], 19.9 [CH(CH3)(CH3)], 18.8, [(CH3)(CH3)C]NeNH (‘Z’
relative to NH)], 11.6 (1-CH3), 10.6 (COCH2CH3); 15N NMR (DMSO-d6)
d 308 [(]NeNH)], 171 [(]NeNH)], 153 (N3), 125 (N5a), 99 (N3a).
Anal. Calcd for C22H31N5O3 (413.51) C, 63.90; H, 7.56; N,16.94. Found:
C, 64.02; H, 7.52; N, 16.87%.
4.4.13. (Rp,5S)-(Z)-4,5-Dihydro-2-hydroxy-5-phenylpyrazolo[1,5-d]
naphtho[2,3-f][1,4]diazocin-7(6H)-one (24a). Yield: 0.121 g, 17%
(from 15a); 0.583 g, 81% (from 15a
300e303 ꢁC; Rf (DCM/MeOH 20/1) 0.12; [
nmax 3305, w3150e2300, 1659 (broad), 1610, 1533 cmꢀ1
(DMSO-d6) 9.89 (1H, br s, OH), 8.22 (1H, d, J 10.7 Hz, NH), 8.09e8.06
*
); pale yellowish solid, mp
25
a]
D
þ73.8 (c 0.6, DMSO);
;
1H NMR
d
(2H, m, H9,12), 8.05 (1H, s, H8), 8.04 (1H, s, H13), 7.66e7.60 (2H, m,
H10,11), 7.40 [2H, d, J 7.7 Hz, H20,60 (Ph)], 7.33 [2H, t, J 7.7 Hz, H30,50
(Ph)], 7.29 [1H, t, J 7.7 Hz, H40 (Ph)], 5.70 (1H, s, H1), 4.94 (1H, ddd, J
13.0,10.7, 4.9 Hz, H5), 4.33 (1H, dd, J 13.0, 4.9 Hz, H4endo), 4.24 (1H, t, J
4.5. General procedure for the ring enlargement of tetra- and
pentacycles 5c, 6aec, 12a,b, 13a,b, 14a and 15a effected by
NaHCO3 (method B)
13.0 Hz, H4exo); 13C NMR (DMSO-d6)
d 171.6 (C7), 160.0 (C2), 142.2
[C10,(Ph)], 139.1 (C13b), 135.2 (C7a), 133.6 (12a), 133.4 (C8a), 130.4
(C8), 129.6 [C3050, (Ph)], 129.0 (C9), 128.8 (C12), 128.5 (C10), 128.3
[C40, (Ph)], 128.0 (11), 127.3 (C13), 126.5 (C13a), 125.9 [C2060, (Ph)],
101.8 (C1), 58.3 (C5), 52.5 (C4); 15N NMR (DMSO-d6) 273 (N3), 183
(N3a),129 (N6). Anal. Calcd for C22H17N3O2 (355.39) C, 74.35; H, 4.82;
N, 11.82. Found: C, 74.28; H, 4.88; N, 11.93%.
A mixture of the appropriate precursor (1 mmol) and 10%
NaHCO3 (10 mL) was heated at reflux for 3 h. The resultant yellow
solution was cooled and its pH was adjusted to 7e8 by concd HCl.
After standing for 1 h in the refrigerator the precipitated crystals
were collected, washed with water and dried in a vacuum desic-
cator over P2O5. Yield: 0.151 g, 53% for 2c; 0.178 g, 58% for 7a;
0.167 g, 52% for 7b; 0.164 g, 49% for 7c; 0.149 g, 55% for 21a; 0.140 g,
49% for 21b; 0.161 g, 50% for 22a; 0.164 g, 49% for 22b; 0.159 g, 52%
for 23a; 0.114 g, 32% for 24a. Analytical samples were obtained by
recrystallization from EtOH. Within experimental error spectro-
scopic and analytical data proved to be identical listed in the par-
agraphs above.
4.4.14. (Rp
naphtho[2,3-f][1,4]diazocin-7(6H)-one (25a). Yield: 0.381 g, 62%
(from 16a); 0.479 g, 78% (from 16a
); white solid, mp 243e246 ꢁC;
Rf (DCM/MeOH 20/1) 0.16; nmax 3305, w3150e2300, 1665, 1610,
1531 cmꢀ1 1H NMR (DMSO-d6)
9.94 (1H, br s, OH), 8.15 (1H, d, J
*
,5S
*
)-(Z)-4,5-Dihydro-2-hydroxy-5-ethylpyrazolo[1,5-d]
*
;
d
9.5 Hz, NH), 8.04 (1H, m, H9), 8.02 (1H, m, H12), 7.97 (1H, s, H8),
7.93 (1H, s, H13), 7.64e7.60 (2H, m, H10,11), 5.60 (1H, s, H1), 4.00
(1H, dd, J 12.3, 3.9 Hz, 4Hendo), 3.79 (1H, t, J 12.3, 4Hexo), 3.46 (1H, m,
5H), 1.46 (2H, quint, J 7.0 Hz, CH2CH3), 0.80 (3H, t, J 7.0 Hz, CH2CH3);
Acknowledgements
13C NMR (DMSOed6)
d 171.7 (C7), 162.0 (C2), 128.9 (two coalesced
This work was financially supported by the Hungarian Scientific
lines, C9,12), 128.4 (C11), 128.1 (C10), 127.4 (C13), 127.3 (C13a), 96.5
(C1), 58.0 (C4), 53.5 (C5), 25.8 (CH2CH3), 11.4 (CH2CH3); 15N NMR
(DMSO-d6) 273 (N3), 183 (N3a), 127 (N6). Anal. Calcd for
C18H17N3O2 (307.35) C, 70.34; H, 5.58; N, 13.67. Found: C, 70.31; H,
5.65; N, 13.77%.
Research Fund (OTKA K-68887) and the European Union and the
European Social Fund (grant agreement No. TAMOP 4.2.1/B-09/
KMR-2010-0003). X-ray costs of these investigations were in part
defrayed by OTKA-K-75869.
ꢀ
Supplementary data
4.4.15. (Rp
*
,5S )-(Z)-4,5-Dihydro-2-hydroxy-5-ethyl-1-methylpyr-
*
azolo[1,5-d]naphtho[2,3-f][1,4]diazocin-7(6H)-one (25b). Yield: 0.373 g,
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.034. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
58%; white solid, mp 258e261 ꢁC; Rf (DCM/MeOH 20/1) 0.20; nmax
3290, w3250e2300,1660,1612,1538 cmꢀ1; 1H NMR (DMSO-d6)
d 9.72
(1H, br s, OH), 8.10 (1H, d, J 9.7 Hz, NH), 8.06e8.01 (2H, m, H9,12), 7.97
(1H, s, H8), 7.88 (1H, s, H13), 7.64e7.60 (2H, m, H10,11), 3.97 (1H, dd, J
12.0, 4.0 Hz, H4endo), 3.76 (1H, t, J 12.0 Hz, H4exo), 3.37 (1H, m, H5), 1.62
(3H, s, 1-CH3), 1.42 (2H, quint, J 7.0 Hz, CH2CH3), 0.78 (3H, t, J 7.0 Hz,
References and notes
CH2CH3); 13C NMR (DMSO-d6)
d 171.8 (C7), 159.9 (C2), 139.2 (C13b),
1. Reviews: (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125e196; (b) Maier, M. E.
Angew. Chem., Int. Ed. 2000, 39, 2073e2077; (c) Evans, P. A.; Holmes, B. Tetrahedron
135.6 (C7a), 134.0 (12a), 133.4 (C8a), 130.3 (C8), 128.9 (two coalesced
lines, C9,12), 128.5 (C10), 128.2 (C11), 127.3 (C13), 126.2 (C13a), 102.4
€
1991, 47, 9131e9166 Selected examples; (d) Lindstrom, U. M.; Somfai, P. Chem.
€
dEur. J. 2001, 7, 94e98; (e) Bieraugel, H.; Jansen, T. P.; Shoemaker, H. E.; Hiemstra,
(C1), 57.8 (C4), 53.6 (C5), 25.4 (CH2CH3), 11.5 (CH2CH3), 8.0 (1-CH3); 15
N
H.; van Maarseveen, J. H. Org. Lett. 2002, 4, 2673e2674; (f) Derrer, S.; Feeder, N.;
Teat, S. J.; Davies, J. E.; Holmes, A. B. Tetrahedron Lett. 1998, 39, 9309e9312.
2. Bengelmans, R.; Herlem, D.; Husson, H.-P.; Khoung-Hun, F.; Le Goff, M.-T. Tet-
rahedron Lett. 1976, 17, 435e438.
3. Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa, S.; Yoneda, R. Chem.
Pharm. Bull. 1995, 43, 1089e1095.
NMR (DMSO-d6) 270 (N3), 182 (N3a), 131 (N6). Anal. Calcd for
C19H19N3O2 (321.37) C, 71.01; H, 5.96; N, 13.08. Found: C, 71.11; H, 6.07;
N, 12.99%.
4. McDonald, I. M.; Dunstone, D. J.; Kalindjian, S. B.; Linney, I. D.; Low, C. M. R.;
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a
;
]
25 ꢀ44.8 (c 1.3, DMSO)
D
nmax 3202, 3047, 1667 (broad), 1533 cmꢀ1
1H NMR (DMSO-d6)
d
11.75 [1H, s, (]NeNH)], 9.20 (1H, s, 3-NH), 7.61 (1H, m, H7),

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