DNMR, DFT and preparative study on the conformation of (Z)-4,5,6,7-tetrahydropyrazolo[1,5-e]benzo[g][1,5]diazonin-8-ones and (Z)-4,5-dihydropyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones

Article abstract of DOI:10.1016/j.tet.2008.09.020

By means of base-catalyzed ring enlargement of triazaindenoindenes and pentalenoindenes obtained from anhydride-induced ring transformation of 3,4-dihydro-2H-pyrimido- and 2,3-dihydroimidazo[2,1-a]phthalazinium-olates, respectively, a series of pyrazolo[1,5-e]benzo[g][1,5]diazonin-8-ones and pyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones were obtained. Alternative pathways and energetics for the?ring inversion of symmetrically substituted medium-size ring systems were determined by combined use of DNMR measurements and B3LYP/6-31G(d,p) calculations using the IEFPCM solvent model. One pyrazolobenzodiazonine carrying hydrogen at the C1 position was found to undergo facile ring inversion by a two-step mechanism, while 1-Me and 1-Ph substituents rendered complete rigidity to this ring system. A three-step mechanism was revealed for the ring inversion of the two studied pyrazolobenzodiazocines with energetics practically invariant to the investigated C1-substituents (H and Me). The attempted RCM of the N,O-diallyl derivative of a selected rigid model effected by Grubbs II catalyst led to deallylation and olefin isomerization avoiding the formation of bridged products with?enhanced skeletal strain. A tolerable degree of ring strain associated with negligible skeletal distortion could be introduced into the same benzodiazonine by N,O-dialkylation with 1,3-bis(bromomethyl)benzene.

Full text of DOI:10.1016/j.tet.2008.09.020

Tetrahedron 64 (2008) 10837–10848
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
DNMR, DFT and preparative study on the conformation
of (Z)-4,5,6,7-tetrahydropyrazolo[1,5-e]benzo[g][1,5]diazonin-
8-ones and (Z)-4,5-dihydropyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones
a
a
b
c
d
a,
*
´
a
´
¨
¨
´
´
´
´
´
Adam Gyomore , Zoltan Kovacs , Tibor Nagy , Veronika Kudar , Andras Szabo , Antal Csampai
´
Institute of Chemistry, Eo¨tvo¨s Lorand University, PO Box 32, H-1518 Budapest-112, Hungary
b
´
Research Group for Protein Modelling, Hungarian Academy of Sciences, Eo¨tvo¨s Lorand University, PO Box 32, H-1518 Budapest-112, Hungary
c Chemres Institute of Structural Chemistry Chemical Research Center, Hungarian Academy of Sciences, PO Box 17, H-1518 Budapest, Hungary
d Ubichem Research Ltd, PO Box 17, H-1518 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2008
Received in revised form 19 August 2008
Accepted 4 September 2008
Available online 17 September 2008
By means of base-catalyzed ring enlargement of triazaindenoindenes and pentalenoindenes obtained
from anhydride-induced ring transformation of 3,4-dihydro-2H-pyrimido- and 2,3-dihydroimidazo[2,1-a]
phthalazinium-olates, respectively, a series of pyrazolo[1,5-e]benzo[g][1,5]diazonin-8-ones and pyr-
azolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones were obtained. Alternative pathways and energetics for
the ring inversion of symmetrically substituted medium-size ring systems were determined by combined
use of DNMR measurements and B3LYP/6-31G(d,p) calculations using the IEFPCM solvent model. One
pyrazolobenzodiazonine carrying hydrogen at the C1 position was found to undergo facile ring inversion
by a two-step mechanism, while 1-Me and 1-Ph substituents rendered complete rigidity to this ring
Keywords:
Benzodiazonine
Benzodiazocine
Ring inversion
Conformational flexibility
DNMR
system.
A three-step mechanism was revealed for the ring inversion of the two studied pyr-
azolobenzodiazocines with energetics practically invariant to the investigated C1-substituents (H and
Me). The attempted RCM of the N,O-diallyl derivative of a selected rigid model effected by Grubbs II
catalyst led to deallylation and olefin isomerization avoiding the formation of bridged products
with enhanced skeletal strain. A tolerable degree of ring strain associated with negligible skeletal distortion
could be introduced into the same benzodiazonine by N,O-dialkylation with 1,3-bis(bromomethyl)benzene.
Ó 2008 Elsevier Ltd. All rights reserved.
DFT
1. Introduction
phenyl]azetidin-2-ones.6 On the other hand, the primary formation
of medium-size rings can be immediately followed by a variety of
Medium ring heterocycles are often encountered in biologically
active natural products as well as drug candidates. However, me-
dium-sized rings are difficult to prepare due to enthalpic and en-
tropic reasons, and direct cyclization methods are ineffective unless
certain conformational restraints are present in the acyclic pre-
cursor.1 Interesting structures containing medium-size heterorings
with valuable biological effects have also been obtained by a variety
of ring transformation reactions.2–11 Bicyclic benzo[g][1,5]diazo-
nines obtained by base-mediated ring enlargement of aryl-N-
methylpyrazolo[1,2-b]phthalazinium iodides2a have been shown to
display pronounced CNS-activity.2b Different benzodiazocines and
benzodiazonines are preferably obtained from oxidative ring ex-
pansion of polycyclic fused compounds often containing indole
trans-annular interactions leading to ring contraction. 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-tetrahydropyrrolo[3,4-b]quinolinones7a or
1,2,3,4-tetrahydropyrrolo [2,3-c]quinolinones.7b Another example
is the ring isomerization of pyridazino[1,2-c][1,3,4]thiadiazinones
into thiazolo[3,4-a][1,3]diazepinones proceeding by the cleavage of
the N–N bond followed by trans-annular recyclization of the in-
termediate 1,3,8-thiadiazecinones.8 In biological fluids the bi-
ological activity of medium-size heterocycles depends not only on
pharmacophoric grouping,9 but also on the conformation.10 By
means of combined use of NMR, X-ray analysis and molecular
modelling, the structural and energetic aspects of the ring inversion
of some benzodiazepine and benzotriazepine derivatives were
studied in detail establishing nonplanar, rapidly interconverting
(on the NMR time scale) boat shape conformation for the seven
membered ring in agreement with the results of X-ray analyses.9–15
unit3–5 or intramolecular transacylation of 1-[2-(
u-aminoalkyl)-
* Corresponding author. Tel.: þ36 01 209 0555; fax: þ36 01 372 2909.
´
E-mail address: csampai@chem.elte.hu (A. Csampai).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.020

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10838
Experimental and theoretical conformational studies of the more
flexible benzodiazocine and benzodiazonines have also been
reported,5,16–20 but there are a relatively low number of examples
of synthesis and structural analysis of their polycyclic hetero-con-
densed derivatives.21–27 To our knowledge no theoretical modelling
even on tricyclic benzodiazocines and benzodiazonines exists.
These facts impelled us to initiate comparative preparative, DNMR
and theoretical study on the conformation of pyr-
azolobenzodiazonines 5a,b27 and 5c (Scheme 1) and related diaz-
ocines 9e–i (Scheme 2). The preparation of 5c and 9e–i is also
described in this paper.
Since 2a,b, the potential precursors of medium-size ring sys-
tems, were prepared by ring transformation of pyrimido[2,1-
a]phthalazinium-olate 1 taking place with the incorporation of
RCH–CO motif of the anhydride component,28 we tried to employ
phenylacetic anhydride as reagent to extend the group of model
compounds with
a phenyl-substituted analogue. When the
reaction was conducted at 140 ꢀC, zwitterion 1 was directly trans-
formed into N,O-diacylated 1-phenylpyrazolo[1,5-d]benzodiazo-
nine 6c (Scheme 1). The facile conversion of triazaindenoindene 2c,
the assumed intermediate, is suggested to start with equilibrium
trans-annular ring enlargement to Ic retaining the lactam motif
with ‘E’ configuration, which is preformed in 2c. The propensity of
2c to undergo trans-annular ring opening can be ascribed to the
enhanced steric repulsion between the 1-phenyl substituent and
the condensed benzene ring, which interaction is decreased in Ic.
Following equilibrium rotation about the N6a–C7 bond and N/O
acyl migration (Ic/IIc/IIIc), the resulted ‘Z’-lactam IIIc is sup-
posed to undergo N-acylation yielding 6c, facile hydrazinolysis of
2. Results and discussion
2.1. Preparation of model compounds
In 1988 Ko¨rmendy et al. observed that, on treatment with
aqueous NaHCO3 at reflux temperature, tetracyclic tri-
azaindenoindenes 2a,b underwent trans-annular ring opening via
deacylated intermediates 4a,b affording 5a,b in maximum yields
ca. 50%.27 This limited yield was attributed to competitive hy-
drolytic fission of the N-acylated pyrazole ring leading to car-
boxylic acids 3a,b (Scheme 1) and other undefined products.27
Avoiding the undesirable conversions we selectively accomplished
the deacylation of N3 pyrazole nitrogen with hydrazinehydrate in
refluxing ethanol and obtained 4a,b in 80–88% yield. (Deacetyla-
tion leading to 4a in a maximum of 51% yield has been achieved by
heating 2a for ca. 10 min in aqueous NaHCO3.28) Ring enlargement
of 4a and 4b effected by aqueous NaHCO3 took place almost
quantitatively (92% and 96%, respectively) via the assumed
‘E’-lactams IVa,b. The treatment of 5a,b with boiling acetic anhy-
dride (Scheme 1) afforded 6a,b with aromatic pyrazole ring27
without reconstruction of tetracyclic system type 2. We found that
pyrazolobenzodiazonines 5a,b can easily be recovered by hydra-
zinolysis of 6a,b taking place without the cleavage of the nine-
membered lactam ring.
which afforded 5c. Diacyl derivatives 6a,b were analyzed by 1H, 13
C
and 15N NMR spectroscopy of which results were unambiguously
confirmed by single crystal X-ray diffraction providing indirect
evidence for the skeletal structure of the studied models 5a–c
(discussed later).
The view about the size-dependent effect of the group R on the
propensity of triazaindenoendene skeleton to undergo isomeri-
zation into the corresponding pyrazolobenzodiazonine was sup-
ported by monitoring thermal conversions 4a,b/5a,b by 1H NMR
spectroscopy in DMSO-d6 solution. The reaction of 4b could be
completed at 340 K in 1 h, while 4a proved to be stable at this
temperature. On heating its solution at 370 K, ca. 40% conversion
of 4a could be achieved in 30 min. In order to get comparable
theoretical results DFT calculations29 were also carried out for
relevant models (4a–c and 5a–c) at B3LYP level of theory30 using
31
6-31G(d,p) basis set
and IEFPCM solvent model,32 which ade-
quately represents the experimental conditions (solvent: DMSO,
3¼46.70). The free energy differences for the overall conversions
O
O
O
(RCH2CO)2O
140 °C, 3h
R = Ph
N
N
N
N
N
H
N
N
N
N
N
N
Ref. 28
O
O
H
H
R
COCH2R
Ph
COCH2Ph
HN
COCH2Ph
Ph
O
O
IIc
2a,b, [2c]
Ic
1
N2H4, EtOH
reflux 30 min
10% NaHCO3
reflux, 3 h
Ref. 27
O
N
N
H
N
N
N
O
7
8
O
5
NHCOCH2R
CO2H
H
R
Ph
+ undefined
N
max. ca. 50%
N
NH
products
OCOCH2Ph
11b
4
yield for 5a,b
11
3a,b
IIIc
(cf. Ref. 27)
1
(cf. Ref. 27)
H
R
O
4a (80%)
4b (88%)
O
4
8
N2H4, EtOH
reflux 30 min
12
N
N
10% NaHCO3
reflux, 3 h
N
H
N
5
COCH2R1
12b
N
N
N
N
O
O
N
(MeCO)2O
140 °C, 1h
H
R
R
3
1
OCOCH2R1
R
OH
OH
6a R = R1 = H (82% from 5a)
6b R = Me, R1 = H (90% from 5b)
6c R = R1 = Ph (38% from 1)
IVa,b
5a (92% from 4a, 82% from 6a)
5b (96% from 4b, 90% from 6b)
5c (94% from 6c)
For 2-5 and I -III: a R = H; b R = Me; c R = Ph.
Scheme 1. Synthetic routes to model pyrazolobenzodiazonines 5a–c.

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10839
O
O
O
O
R3
(RCH2CO)2O
140 °C, 2 h
N 2H4 , EtOH
reflux 15 min
R3
R3
R2
N
N
N
N
N
N
N
R2
COCH2R
N
R2
Ref. 33
R3
N
N
H
NH
H
R
H
HN
R2
R
R
O
O
OH
VIe-i
7b R2 = R3 = Me
8e-i
Ve-i
from 8f
7g R2 = Et, R3 = H
7h R2 = iso-Bu, R3 = H
62-77%
(EtCO)2O
140 °C, 8 h
42%
from 8e-i
R3
Me
(EtCO)2O
140 °C, 2 h
83%
For 8, 9, 10, 11 and V :
e: R2 = R3 = Me, R = H
4
4
R2
Me
7
7
11
11
N
N
f:
R
2 = R3 = R = Me
11b
N
11b
N
g: R2 = Et, R3 = R = H
O
H
O
H
N2H4 , EtOH
reflux 15 min
88%
N3
OCOCH2Me
N
Me
1
3
h: R2 = iso -Bu, R3 = R = H
R
1
i:
R
2 = Et, R3 = H, R = Me
OH
9e-i
10f
Scheme 2. Synthetic routes to model pyrazolobenzodiazocines 9e–i.
4a–c/5a–c obtained after geometry optimization and subsequent
frequency calculation show the expected R-group-dependence
with the pronounced effect of the phenyl substituent [DG(5–
4)¼ꢁ0.59 kcal/mol for a; ꢁ1.95 kcal/mol for b; ꢁ6.23 kcal/mol for
c]. Experimentally observable overall reactions (4/IV/5) are
related to the analogue unobservable process (2c/Ic/IIc/IIIc),
since both types of isomerizations presumably proceed via the
corresponding ‘E’-lactam formed directly from the tetracyclic
precursor.
hydrazinolysis without fission of the eight-membered lactam
(10f/9f). It must be pointed out here that the eight-membered
‘E’-lactams VIe,f are also assumed to be involved as intermediates
in the ring inversion of 9e,f associated with racemization (dis-
cussed later).
2.2. Structural analysis of pyrazolobenzodiazonines and
benzodiazocines
In order to elaborate an expedient route to an analogous novel
tricyclic ring system with eight-membered heterocycle we envi-
sioned the two-step protocol involving hydrazine-mediated
deacylation followed by base-catalyzed ring enlargement to the
transformation of triazapentalenoindenes 8e–i33 into the corre-
sponding pyrazolobenzodiazocine of type 9 (Scheme 2). The syn-
thesis of 8e–i was performed by the anhydride-induced ring
transformation of zwitterionic 2,3-dihydroimidazo[2,1-a]phthala-
zinium-olates 7b,g,h with sterically hindered N1 atom and steri-
cally accessible N5 atom of which primary acylation is the
prerequisite of the ring transformation of type 7/8.33 (This is the
circumstance, which prevents the formation of simpler pyr-
azolobenzodiazocine models unsubstituted on position 5.)
To our surprise the hydrazinolysis of 8e–i directly afforded 9e–i
in short time (15 min) with acceptable yields (62–77%) suggesting
that the primarily formed deacetylated intermediates Ve–i un-
dergo fast isomerization probably proceeding through trans lac-
tams VIe–i. In keeping with this observation, B3LYP/6-31G(d,p)/
The 1H, 13C and 15N NMR spectroscopic data measured in CDCl3
at 300 K for diacyl derivatives 6a,b are consistent with their solid
state structures determined by X-ray diffraction (Figs. 1 and 2). The
same skeletal structure was established for 6c on the basis of 1H, 13
C
and 15N NMR spectroscopic data, which are closely related to those
of 6a,b.
In 5a–c and 6a–c the chair-like fraction of the nine-membered
ring composed by N3a, C4, C5, C6 and N7 is unambiguously
reflected from the relatively large values (10–12 Hz) of vicinal
coupling constants 3J(H4ax,5Hax), 3J(H5ax,6Hax) and 3J(7NHax,6Hax
)
showing approximately anti-periplanar position for the relevant
atom pairs. The presence of this structural element was also sup-
ported by mutual NOEs (6–8%) detected between H4ax and H6ax
.
The 1H, 13C and 15N NMR parameters measured for 5a–c in DMSO-
d6 at 300 K indicate basically the same structural characteristics
with aromatic pyrazole ring. In the 1H–15N HMBC spectra the 15N
IEFPCM calculations (
3
¼46.70) revealed that even isomerization
VIe/9e (R¼H) is approximately as exothermic as that of the ring
opening postulated for its 1-phenyl-substituted ring homologue
(4c/5c), which was discussed above [
D
G(9e–Ve)¼ꢁ6.56 kcal/
mol,
DG(5c-4c)¼ꢁ6.23 kcal/mol]. The enhanced tendency of tet-
racycles Ve–i to undergo ring opening can be attributed to the
strain resulted from the annulation of three five-membered rings
and to the repulsive interaction of the endo-oriented R2 group and
H1 atom being in steric proximity.33 Indicating an additional
destabilizing effect exerted by the Me1-group on the tetracyclic
system, a more significant decrease in the free energy was cal-
culated by the same method for the trans-annular ring opening of
the assumed intermediate Vf [
D
G(9f–Vf)¼ꢁ11.07 kcal/mol]. Ac-
cordingly, on prolonged treatment with propinic anhydride, 8f
underwent partial isomerization affording monopropionyl com-
pound 10f in moderate yield (42%). Demonstrating the steric
hindrance of the N6 atom due to the adjacent methyl groups in
a control experiment, on heating with propionic anhydride 9f
underwent acylation exclusively on the hydroxypyrazole unit to
give 10f. The propionyl group can be removed by facile
Figure 1. ORTEP structure of 6a.

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10840
separated signals, showing that the bulky C1-substituents on the
pyrazole moiety highly enhance the rigidity of the whole skeleton.
In contrast to the studied nine-membered ring system, pyr-
azolobenzodiazocines 9e,f exhibited only a practically negligible
substituent-dependence in the conformational flexibility charac-
terized by very similar coalescence temperatures (355 K for 9e and
360 K for 9f). The Eyring equation34 using the coalescence tem-
perature and chemical shift difference of the most separated signal
pairs of geminal ring protons [Dn(H4ax–H4eq)¼300 Hz for 5a–c and
140 Hz for 9e,f] afforded 15.8 kcal/mol for 5a, 17.9 kcal/mol for 9e
andz 18.2 kcal/mol for 9f as experimental activation free energy
(
D
DGzexp, Table 1). In the absence of coalescence temperature no
Gexp could be obtained for 5b and 5c.
Theoretical modeling of the investigated ring inversions was
applied to reveal the mechanisms. One-step racemization of 5a–c
and 9e,f would proceed via transition states with internal mirror
plane, which are associated with fully planar ring systems. Since
such structures could not be located on the potential energy surface
(PES) by none of the applied methods (Berny analytical gradient
optimization,35 QST2 and QST3 analyses36), one-step inversion can
be ruled out as a possible mechanism for each investigated model.
Two further pathways involving two and three steps, respectively
(A and B), were taken into consideration and studied in detail
(Schemes 3 and 4). [The (þ) and (ꢁ) signs are arbitrary representa-
tions of the enantiomeric forms.] The stationary points were char-
acterized by frequency calculations in order to verify that minima
and transition structures have zero and one imaginary frequency,
respectively.37 The ring inversion along path A involves two separate
flips of the lactam and the condensed pyrazole motifs sweeping
through the plane of the benzene ring. Single local minimum con-
taining oppositely oriented lactam and pyrazole motifs (VIIa,
Scheme 3) could be localized exclusively for the racemization of
benzodiazonine 5a. In the first transition state (TS1/A/5a) the lactam
unit and the benzene ring and in the second transition state (TS2/A/
5a) the benzene and the pyrazole rings are nearly coplanar (inter-
Figure 2. ORTEP structure of 6b.
signals of N3 and N3a atoms can be identified from the intense
cross-peaks with H4ax and H5eq signals, respectively, showing
nearly anti-periplanar position of the strongly coupled nuclei. The
downfielded N3 and N3a shifts measured for 5a–c and 6a–c [266–
288 ppm for N3 and 180–184 ppm for N3a (relative to the signal of
liquid NH3)] indicate the aromatic character of the pyrazole ring,
while the upfield shift of the same signals obtained for 4a,b (159–
162 ppm for N3 and 98–103 ppm for N3a) points to the presence of
saturated pyrazolidine ring incorporating CONH motif. The domi-
nance of this tautomer was unequivocally evidenced by the one-
bond coupling between N3 and H3 nuclei via their satellite
cross-peaks (1JN–H¼95 Hz) detected in the 1H–15N HMBC spectra.
The lactam-acylation in 6a–c is spectacularly reflected from the
significantly downfield-shifted N7 resonance (172 ppm for each).
The analogous signals of 5a–c were detected at 122–124 ppm.
In 9e–i the presence of an aromatic hydroxypyrazole ring and
the ‘Z’-lactam is evidenced by the related 1H, 13C and 15N NMR data,
which are very similar to those obtained for the analogous ben-
zodiazonine derivatives (see Section 4). Considerable NOEs (9–11%)
were measured between the NH and the protons of the R2 group
pointing to their relative cis position on the exo side of the eight-
membered ring. Since the R2 group is endo-situated in tetracycles of
type 8,33 this configuration gives indirect support for the assumed
mechanism of the two-step conversion of unisolable tetracycles
Ve–i proceeding through VIe–i containing R2 and the pyrazole ring
in cis position relative to each other. As additional support for the
boat conformation of the eight-membered ring, in 9e,f mutual
NOEs (3–5%) were detected between the protons of the endo-po-
sitioned methyl group (R3¼Me) and the H8 proton of the con-
densed benzene ring.
planar angles
Q
¼4.4ꢀ and 0.1ꢀ, respectively). (The calculated TS
structures are collected on Fig. 3.) With bulky R-substituents neither
analogous saddle point structures (TS2/A/5b,c) nor local minimum
structures (VIIb,c) could be located on the PESs, indicating that
pathway A can be ruled out as a possible ring inversion mechanism
for the rigid benzodiazonines 5b,c. This mechanism must again be
discarded for the ring inversion of benzodiazocine models 9e,f as
structures IXe,f (Scheme 4) could not be located as local minima on
Table 1
Measured coalescence temperatures (Tcoal [K]) and experimental activation free
energy values (
of 5a–c and 10e,f, and theoretical activation free energy values (
D
Gzexp [kcal/mol])a for the alternative ring inversions (paths A and B)
D
Gz [kcal/mol])b
ꢂn
for the possible elementary steps (cf. Schemes 3 and 4, respectively)
Inv. of
Tcoal [K]
D
Gzexp
D
D
Gz1/A
Gzꢁ1/A
D
D
Gz2/A
Gzꢁ2/A
D
D
Gz1/B
Gzꢁ1/B
D
D
Gz2/B
Gzꢁ2/B
D
D
Gz3/B
Gzꢁ3/B
5a
333
dc
15.8
d
13.3
2.5
d
2.2
13.1
19.7
14.3
18.8
10.7
18.9
12.0
14.6
6.9
21.8
20.3
24.6
24.9
25.1
26.0
17.1
14.6
17.9
17.3
17.9
24.8
17.9
25.6
18.0
24.0
10.3
20.5
10.5
21.3
2.3. Ring inversion
5b
5c
The conformational flexibility of the model pyrazolobenzo-
diazonines 5a–c and selected pyrazolobenzodiazocines 9e,f with
symmetric substitution pattern was investigated by DNMR mea-
surements and DFT analysis of the potential energy surface. The
calculations were carried out at B3LYP/6-31G(d,p) level of theory
dc
d
d
d
d
d
d
d
10e
10f
355
360
17.9
18.2
16.5
6.3
using IEFPCM solvent model (solvent: DMSO,
3¼46.70). Ring in-
a
version associated with racemization was monitored by 1H NMR
spectroscopy employing DMSO-d6 as solvent. The separated signals
of diastereotopic skeletal protons completely coalesced at 333 K for
5a. By heating the solutions of 5b and 5c up to 370 K no coalescence
could be detected, even line broadening was not observable on the
Obtained by Eyring equation using the Tcoal and Dn values extracted from DNMR
measurements, which were carried out in DMSO-d6 solution.
b
Obtained by B3LYP/6-31G(d,p) level of DFT calculations using IEFPCM solvent
model (DMSO,
3
¼46.70) representing the experimental conditions.
c
No coalescence could be observed. For technical precaution the temperature was
not raised above 370 K, which was obviously far from the coalescence conditions.

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10841
O
H
N
N
TS1/A
path A
TS2/A
N
HO
O
ΔG ‡/A
1
R
ΔG ‡/A
R
2
N
N
OH
VIIa,[b,c]
H
N
N
N
H
O
N
R
HO
O
(+)-5a-c
TS3/B
TS1/B
O
N
OH
ΔG ‡/B
(-)-5a-c ΔG ‡/B
R
N
TS2/B
3
1
N
N
N
ΔG ‡/B
H
N
H
path B
2
a: R = H,
R = Me
R = Ph
R
IVa-c
b
OH
VIIIa-c
c
Scheme 3. Ring inversion pathways of model pyrazolobenzodiazonines 5a–c.
the PESs. When started from input structures of type IX having op-
representing a high barrier (
D
Gz2/B¼21.8 kcal/mol, Table 1), which
positely oriented ‘Z’-lactam and pyrazole units, geometry optimi-
zations ended up in global minima 9e,f. (Similarly, when started
frominputstructuresgenerated fromthe real localminimumVIIa by
replacing H1 for Me and Ph groups, respectively, geometry optimi-
zations resulted in global minima 5b,c.)
could be passed at around 450 K, path B cannot be taken intoaccount
for the observed facile racemization of 5a. The energetics calculated
for path A fit much better to the experimental activation free energy
of the racemization of 5a (Table 1) and suggest that the order of el-
ementary steps might be reversed as the two transition states are of
similar in energy. On the other hand, the activation free energies
calculated for the racemization of 9e,f along path B (Table 1) show
that the order of elementary steps cannot be reversed because lac-
tam isomerization step 9/X (Scheme 4) is prevented by high bar-
Pathway B comprising three separate steps with two local min-
ima and three transition states could be traced and analyzed for the
racemization of each studied model compound. The first step is the
Z/E isomerization of the lactam unit by the rotation of the oxo
group taking place through the exo side of the ring systems [(ꢁ)-5a–
c/IVa–c: Scheme 3; (ꢁ)-9e,f/VIe,f: Scheme 4]. In the subsequent
steps the flip of the pyrazole ring [IVa–c/VIIIa–c: Scheme 3;
VIe,f/Xe,f: Scheme 4] is followed by the E/Z isomerization of the
lactam unit taking place with the rotation of the NH group [VIIIa–
c/(þ)-5a–c: Scheme 3; Xe,f/(þ)-9e,f: Scheme 4]. The TS struc-
tures collected in Figure 3 (TS1/A, TS2/A for 5a and TS1/3/B for each
model) were obtained as QST3/B3LYP/6-31G(d,p)/IEFPCM re-
finements of input structures resulted from QST2 calculations car-
ried out at HF/6-31G level of ab initio theory. The final results of DFT
calculations (Table 1) showthat in the course of racemization of 5a–c
proceeding along path B the flip of the pyrazole ring has the highest
barrier with transition state of type TS2/B, which must be destabi-
lized by the repulsion between the C1-substituent and H12 situated
close to each other. Due to steric crowding associated with the
presence of bulky C1-methyl and phenyl substituents, TS2/B/5b and
rier (D
Gzꢁ3/B¼20.5 kcal/mol for 9e and 21.3 kcal/mol for 9f), which
could be passed at around 440–450 K. On the other hand, suggesting
that the ring inversion of 9e,f proceeds along path B, the experi-
mental energetic data match satisfactorily with the activation free
energy values calculated for the flip of pyrazole ring, the rate-lim-
iting second elementary step (Table 1). This step is associated with
much lower barrier for the racemization of 9e,f than calculated for
that of 5a–c. Due to the enhanced interatomic distance the repulsive
interaction between H1 and H11 is significantly smaller in TS2/B/9e
than the analogous interaction in TS2/B/5a involving H12 (dH1–
¼2.262 Å in TS2/B/9e, dH1–H12¼1.926 Å in TS2/B/5a). This is the
H11
consequence of the different interplanar angles between the ben-
zene and pyrazole motifs computed for TS2/B/9e (
Q
¼31.7ꢀ) and TS2/
B/5a (
corresponding
Q
¼16.9ꢀ), respectively. Accordingly, as reflected from the
D
Gz2/B values listed in Table 1, the degree of steric
crowding is almost equivalent in TS2/B/9e and TS2/B/9f, while the
replacement of H1 in TS2/B/5a for bulkier substituents significantly
enhances the energy of TS structures TS2/B/5b and TS2/B/5c.
In summary, comparison of experimental and calculated acti-
vation free energy values leads to the conclusion that the
TS2/B/5c represent very high barriers to this step (
D
Gz2/B¼24.6 kcal/
mol for 5b and 25.1 kcal/mol for 5c: Table 1), which could be over-
come at around 500 K. These calculated values are in accord with the
experimentally observed extreme rigidity of 5b,c. Since TS2/B/5a
H
N
O
Me
N
Me
path A
Me
N
OH
R
R
OH
N
Me
O
H
N
[IXe,f]
N
N
N
H
O
Me
Me
N
R
TS1/B
TS3/B
ΔG ‡/B
OH
OH
O
(-)-9e,f ΔG ‡/B
Me
Me
(+)-9e,f
1
3
R
N
N
Me
TS2/B
ΔG ‡/B
N
H
O
N
path B
Me
N
H
2
N
e: R = H
f: R = Me
R
OH
VIe,f
Xe,f
Scheme 4. Ring inversion pathways of model pyrazolobenzodiazocines 9e,f.

´
10842
A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
Figure 3. Transition state structures for the ring inversion of 5a–c and 9e,f calculated by B3LYP/6-31G(d,p)/IEFPCM (
3
¼46.70).
racemization of 5a proceeds via path A, but the racemization of
5b,c along this path is not an allowed process. The ring inversion
of these rigid models was found to progress along path B, but
could be effected only at highly elevated temperature because of
the high barrier calculated for the second step. On the other hand,
the racemization of 9e,f is allowed to take place along path
B with the rate determining flip of pyrazole ring, of which barrier
is almost invariant to the size of the investigated R groups (H
and Me).
2.4. Bridging reactions of the rigid pyrazolobenzo
diazonine 5b
We wondered whether the conformationally rigid, readily
available pyrazolobenzodiazonine 5b with sterically accessible
lactam NH group is capable of undergoing such bridging reactions,
which are accompanied by more or less skeletal distortion, so we
attempted its overbridging by olefin ring closing metathesis (RCM)
and dialkylation protocols, respectively.

´
A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10843
2.4.1. Allylation and attempted RCM reaction
1.) 1 eq.
Br
First, diallylation of 5b was performed in refluxing THF in the
presence of NaH resulting in selectively N,O-diallyl derivative 11b of
whichRCM38 wasattemptedby20 mol %ofsecondgenerationGrubbs
catalyst in benzene at reflux temperature (Scheme 5). Instead of the
formation of bridged compounds (XIb and XIIb), N7-deallylation39
and two types of olefin isomerization40 took place as evidenced by the
structures of isolated products 12b, 13b and 14b. A synchronous 1,3-
O/N-allyl migration must alsobepostulated for the formation of 14b
of which structure is evidenced by the following spectroscopic data:
(i) appearance of the two amide-I bands in the IR spectrum (1662 and
1651 cmꢁ1); (ii) the C2 and C11b resonances are downfield-shifted
(166.4 and 153.4 ppm, respectively) relative to those measured for
11b–13b containing aromatic pyrazole ring (160.0–160.7 and 139.8–
140.7 ppm, respectively); (iii) the N3 and N3a resonances are upfield-
shifted (153 and 105 ppm, respectively) relative to those obtained for
11b–13b (261–262 and 182 ppm, respectively).
Br
12
4
1 eq. NaH, THF,
reflux 30 min
8
N
5
N
N
12b
21
Me
20
18
5b
O
8
2.) 1 eq. NaH
,
17
1
19
reflux 1 h.
27%
16
1
13
O
14
15
15b
Scheme 6. Bridging of 5b by dialkylation without introducing significant strain into
the ring system.
The structure of 15b was evidenced by single crystal X-ray
analysis (Fig. 4) and also characterized by IR, 1H, 13C and 15N NMR
spectroscopy. The orientation of the bridging motif in CDCl3 solu-
tion was proved by DNOE experiment disclosing interaction be-
tween the protons of Me21 group and H19 (5%). A small distortion
was resulted from the bridging as reflected from the comparison of
the O1–N7 distance measured for 15b and the diacetyl derivative 6b
by X-ray analysis [5.345(2) Å and 5.260(2) Å, respectively, Table 2].
A smaller strain accumulated in 15b than in XIb and XIIb as it can
be estimated from the enthalpy change calculated by B3LYP/6-
31G(d,p) method for the entropically favoured hypothetic reaction
5bþ1,3-bis(hydroxymethyl)-benzene/15bþ2H2O involving co-
6
4
12
Grubbs II (20 mol%)
benzene, reflux, 5h
8
N
N
N
N
N
N
N
12b
13
Me
N
O
19
18
O
O
O
8
N
Me
Me
1
3
17
O
O
14
1
15
valent molecules (
D
H¼6.74 kcal/mol, G¼0.28 kcal/mol).
D
XIb
XIIb
16
11b
2.4.3. X-ray and DFT anylysis of 6a,b and 15b
It is worth pointing out that the bonding parameters obtained
from X-ray diffraction and B3LYP/6-31G(d,p) optimization are in
acceptable to good agreement (Table 2) indicating the sufficient
reliability of the applied DFT method. In the experimental and the
calculated structures of 6a,b and 15b the nine-membered ring
adopts a bent conformation with eight atoms forming a boat shape
(N3a, C4, C6, N7, C8, C8a, C12a and C12b) with the exception of C5
being on the tip (Figs. 1, 2 and 4). The planes of the pyrazole and
benzene rings are nearly perpendicular to each other [X-ray/DFT
interplanar angles defined by the torsion angle along the atomic
sequence C8a–C12a–C12b–C1: 91.2(2)ꢀ/92.5ꢀ for 6a, 87.9(2)ꢀ/88.9ꢀ
for 6b and 83.8(2)ꢀ/77.5ꢀ for 15b]. The planes of the benzene ring
and the carbonyl group of the N-substituted lactam moiety, defined
by the torsion angle along the atomic sequence C12a–C8a–C8–O8,
are not too far from being perpendicular (interplanar angles
obtained X-ray/DFT: ꢁ113.9(2)ꢀ/ꢁ115.2ꢀ for 6a, ꢁ118.2(2)ꢀ/ꢁ112.3ꢀ
for 6b and ꢁ101.6(2)ꢀ/ꢁ101.2ꢀ for 15b).
CH2=CHCH2Br
NaH, THF
reflux, 1 h.
6
6
6
4
4
4
12
12b
12
12
12b
13
Me
1
N
N
N
12b
13
N
N
N
19
19
5b
O
O
H
O
O
13
O
O
15
N
N
18
N
1
18
Me
Me
Me
1
3
3
3
Me
16
14
17
14
15
14
15
13b (18%)
17
16
16
12b (24%)
14b (11%)
Scheme 5. Conversions of diallyl compound 11b under the conditions of RCM.
The failure of RCM can be attributed to the high rigidity of the
pyrazolobenzodiazonine skeleton inclined to avoid the considerable
compression, which wouldbe introducedbylinking O1and N7atoms
with the relatively short CH2CH]CHCH2 chain having either Z or E
configuration. This assumption is in accord with the structural and
thermochemical parameters calculated for 11b, XIb and XIIb by
B3LYP/6-31G(d,p) method. The overall skeletal compression is most
spectacularly reflected from the change in the calculated O1–N7
distance, which is significantly shorter in XIb and XIIb than in 11b
(4.726 Å and 4.772 Å vs 5.465 Å). The changes in enthalpy for
the hypothetical RCM reactions (
D
H¼14.77 kcal/mol for 11b/
XIbþethene and 10.55 kcal/mol for 11b/XIIbþethene) can be con-
sidered as good measure of the strain associated with the compres-
sion of the nine-membered ring. Since these processes are favoured
from the aspect of entropy, the calculated changes in free energy are
significantly smaller (6.73 kcal/mol and 4.77 kcal/mol, respectively).
2.4.2. Bridging by dialkylation
In order to check the possibility to introduce a minimal degree
of strain into 5b we also attempted its bridging with 1,3-bis(bromo
methyl)benzene serving as a slightly more extended linker suitable
to connect O1 and N7 atoms without significant distortion of the
ring system. On treatment with this reagent and NaH in refluxing
THF, 5b partly underwent intramolecular dialkylation and the
bridged product 15b (Scheme 6) could be separated in 27% yield
from the polymer-like substances formed in the reaction.
Figure 4. ORTEP structure of 15b.

´
A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10844
Table 2
get DIFFNOE spectra was used with a selective pre-irradiation time.
Selected bonding parameters of 6a,b and 15b obtained by X-ray analysis and B3LYP/
6-31G(d,p) calculations
DEPT spectra were run in a standard manner, using only
Q
¼135ꢀ
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 programs. All calculations were
carried out with the Gaussian 03 suite of programs.41 Optimized
structures of all stationary points on PES’s are available from the
authors. All X-ray diffraction measurements were made on a Rigaku
R-AXIS Rapid IP diffractometer at low temperatures using an
X-Stream 2000 unit. Crystals were mounted in loops in high vis-
cosity oil droplet. Crystal data were collected using standard X-scan
6a/X-ray 6a/DFT 6b/X-ray 6b/DFT 15b/X-ray 15b/DFT
Bond lengths [Å]
C1–C2
N3–C2
N3–N3a
N3a–C12b
C1–C12b
N3a–C4
N7–C8
1.391(2)
1.320(2)
1.358(2)
1.356(2)
1.377(2)
1.456(2)
1.402(2)
1.409 1.389(3)
1.328 1.326(2)
1.355 1.360(2)
1.365 1.358(2)
1.387 1.384(3)
1.457 1.467(2)
1.405 1.401(2)
1.413 1.408(2)
1.328 1.328(2)
1.353 1.362(2)
1.367 1.359(2)
1.391 1.382(2)
1.457 1.455(2)
1.404 1.355(2)
1.418
1.325
1.361
1.369
1.388
1.455
1.375
Non-bonding
distance [Å]
O1/N7
procedures, with graphite monochromated Mo Ka radiation. Initial
structure model obtained by direct methods (SHELXS97)42 gave
most of the non-hydrogen atoms, rest of which were subsequently
located and refined to their final positions via full matrix least
squares (SHELXL97)43 following standard procedures. The hydro-
gen atoms were located from difference density maps and refined
by riding model. All crystallographic data are deposited at the
Cambridge Crystallographic Data Centre (deposit numbers: 687068
for 6a; 687069 for 6b; 687071 for 15b) and can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk. Crystal data and refinement param-
eters are listed in a table in Supplementary data.
5.295(2)
5.260(2)
5.345(2)
Bond angles [ꢀ]
N3–N3a–C12b
N3–N3a–C4
C4–N3a–C12b
C6–N7–C8
112.3(2) 112.5
118.4(2) 119.2
128.9(2) 128.2
115.8(2) 121.1
118.3(2) 117.8
112.2(2) 112.4
112.2(2) 111.9
119.2(2) 119.4
128.2(2) 127.9
120.1(2) 121.4
117.4(2) 117.6
119.1(2) 118.0
127.4(2) 127.1
124.4(2) 123.5
117.8(2) 118.3
N7–C8–C8a
Torsional angles [ꢀ]
C8–C8a–C12a–C12b
O8–C8–N7–C6
C8a–C12a–C12b–C1
C12a–C8a–C8–O8
ꢁ6.2(2) ꢁ3.2
ꢁ2.2(3)
ꢁ146.8(2) ꢁ155.8
87.9(2) 88.9
ꢁ118.2(2) ꢁ112.3
ꢁ2.6
ꢁ2.2(2)
ꢁ171.8(2) ꢁ170.2
83.8(2) 77.5
ꢁ101.6(2) ꢁ101.2
ꢁ4.5
ꢁ148.4(2) ꢁ151.0
91.2(2)
92.5
ꢁ113.9(2) ꢁ115.2
4.2. General procedure for the hydrazinolysis of tetracycles
2a,b, 8e–i and tricycles 6a–c and 10f
3. Conclusion
To a suspension of the corresponding precursor (1 mmol) in
EtOH (10 mL) was added 92% N2H4$H2O (100 mL dissolved in 1 mL
The facile formation of (Z)-4,5,6,7-tetrahydropyrazolo[1,5-e]
benzo[g][1,5]diazonin-8-ones and (Z)-4,5-dihydropyrazolo[1,5-d]
benzo[f][1,4]diazocin-7(6H)-ones by trans-annular ring enlarge-
ment of the appropriate fused tetracyclic compounds, their con-
formation as well as substituent- and ring-size-dependent
molecular dynamics determined by the combined use of X-ray
analysis, 1H, 13C, 15N NMR, DNMR and DFT molecular modelling
may contribute to understand the chemical reactivity and receptor-
binding properties of medium-size angularly condensed hetero-
cyclic compounds with potential biological interest. Since the
experimental and theoretical energetic data discussed in this con-
tribution are in good agreement and provide a possibility for de-
cision between alternative mechanisms, it seems that standard
B3LYP/6-31G(d,p) calculations employing polarizable continuum
model are reasonable and reliable methods for studying ring in-
version of related ring systems.
of EtOH) dropwise under Ar atmosphere at rt, and the mixture was
stirred and refluxed for 30 min (for 2a,b and 6a–c), or for 15 min
(for 8e–i and 10f). The resulted yellow solution was cooled by ice-
water, neutralized with a few drops of AcOH and after standing for
ca. 30 min the precipitated crystals were filtered off and washed
with a cooled 7:3 mixture of MeOH–water (5 mL). Analytical
samples were obtained by recrystallization: EtOH (4a,b); DMF–
EtOH (5a–c and 9e–i). After filtration from DMF–EtOH, 5a–c and
9e–i were washed with EtOH and dried over P2O5 at 78 ꢀC.
4.3. Data of triazaindeno[3,3a-a]indene-2(3H),7-diones,
pyrazolobenzodiazonones and pyrazolobenzodiazocines
4.3.1. 5,6-Dihydro-1H,4H,7H-3,3a,6a-triazaindeno[3,3a-a]indene-
2(3H),7-dione (4a)
Yield: white solid, 0.195 g, 80% (from 2a); mp 174–175 ꢀC (lit. 28
4. Experimental
4.1. General
173–174 ꢀC); nmax 3200, 1695, 1605 cmꢁ1 1H NMR (DMSO-d6)
;
d
10.08 (1H, s, NH), 7.72 (1H, br d, J¼7.3 Hz, H8), 7.64 (1H, td, J¼7.3,
1.2 Hz, H9), 7.54ꢁ7.56 (overlapping, 2H, m, H10 and H11), 4.19 (1H,
tdd, J¼12.7, 4.4, 1.7 Hz, H6eq), 3.62 (1H, d, J¼16.6 Hz, H1endo), 3.22
(1H, dt, J¼11.3, 3.4 Hz, H4eq), 3.15 (1H, td, J¼12.7, 3.4 Hz, H6ax), 2.92
(1H, td, J¼11.5, 2.7 Hz, H4ax), 2.18 (1H, d, J¼16.6 Hz, H1exo), 1.71 (1H,
br d, J¼12.7 Hz, H5eq), 1.42 (1H, qa, J¼12.7, 1.7 Hz, H5ax); 13C NMR
All chemicals were obtained from commercially available sour-
ces and used without further purification (Aldrich, Fluka). Benzene
and THF for the RCM and dialkylation reactions, respectively, were
freshly distilled and dried by standard methods. All solvents for the
crystallizations were used without additional purification. Each
flash silica gel column chromatography was carried out on Merck
Kieselgel 60 (230–400 mesh). Melting points were determined
with a Boethius microstage and are uncorrected. The IR spectra
were run in KBr disks on a Bruker IFS-55 FT-spectrometer con-
trolled 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 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 1H–15N HMBC spectra. The
standard Bruker microprogram NOEMULT to generate NOE and to
(DMSO-d6)
d 174.5 (C7), 167.0 (C2), 149.0 (C11a), 133.7 (C10), 130.5
(C9), 130.3 (C7a), 123.9 (C8), 122.1 (C11), 80.7 (C11b), 55.7 (C4), 35.9
(C6), 33.8 (C1), 24.5 (C5); 15N NMR (DMSO-d6)
d
162 (N3),128 (N6a),
103 (N3a). Anal. Calcd for C13H13N3O2 (243.26): C, 64.19; H, 5.39; N,
17.27. Found: C, 64.25; H 5.35; N, 17.30%.
4.3.2. (1R
*
,11bR )-5,6-Dihydro-1-methyl-1H,4H,7H-3,3a,6a-
*
triazaindeno[3,3a-a]indene-2(3H),7-dione (4b)
Yield: white solid, 0.226 g, 88% (from 2b); mp 184–186 ꢀC; nmax
3230, 1692, 1610 cmꢁ1; 1H NMR (DMSO-d6)
d 10.11 (1H, s, NH), 7.76
(1H, d, J¼7.5 Hz, H8), 7.63 (1H, t, J¼7.3 Hz, H10), 7.56 7.63 (1H, t,
J¼7.3 Hz, H9), 7.41 (1H, d, J¼7.5 Hz, H11), 4.21 (1H, br d, J¼12.8 Hz,
H6eq), 3.70 (1H, qa, J¼7.1 Hz, H1), 3.20–3.16 (2H, m, H4eq and
H6ax), 3.07 (1H, t, J¼11.3 Hz, H4ax), 1.72 (1H, br d, J¼13.2 Hz, H5eq),

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10845
1.43 (1H, qa, J¼13.1, 3.0 Hz, H5ax), 0.56 (3H, d, J¼7.1 Hz, 1-CH3); 13
C
(DMSO-d6) d 9.75 (1H, s, OH), 7.69 (1H, s, NH), 7.55–7.51 (over-
lapping, 3H, m, H8, H9 and H10), 7.23 (1H, m, H11), 5.70 (1H, s, H1),
NMR (DMSO-d6)
d
176.3 (C7), 167.1 (C2), 145.5 (C11a), 133.0 (C10),
131.4 (C7a), 130.4 (C9), 124.3 (C8), 123.3 (C11), 84.5 (C11b), 54.7
3.79 (1H, d, J¼15.4 Hz, H4exo), 3.51 (1H, J¼15.4 Hz, H4endo), 1.30 (3H,
(C4), 35.9 (C6), 34.8 (C1), 24.8 (C5), 8.9 (1-CH3); 15N NMR (DMSO-
s, 5-CH3endo),1.10 (3H, s, 5-CH3exo); 13C NMR (DMSO-d6)
d 170.9 (C7),
d6)
d
159 (N3), 127 (N6a), 98 (N3a). Anal. Calcd for C14H15N3O2
161.4 (C2), 143.3 (C11b), 139.2 (C7a), 130.8, 130.0 (two coalesced
lines), 129.6 (C8–11), 127.7 (C11a), 90.4 (C1), 56.1 (C4), 55.0 (C5),
(257.29): C, 65.35; H, 5.88; N, 16.33. Found: C, 65.30; H, 5.94; N,
16.40%.
29.8 (5-CH3endo), 29.1 (5-CH3exo); 15N NMR (DMSO-d6)
d 271 (N3),
185 (N3a), 137 (N6). Anal. Calcd for C14H15N3O2 (257.29): C, 65.35;
H, 5.88; N, 16.33. Found: C, 65.37; H, 5.94; N, 16.29%.
4.3.3. (Z)-4,5,6,7-Tetrahydro-2-hydroxypyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (5a)
Yield: white solid, 0.199 g, 82% (from 6a); mp 326–330 ꢀC sub-
4.3.7. (Z)-4,5-Dihydro-2-hydroxy-1,5,5-trimethylpyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (9f)
lim. (lit.27 >300 ꢀC); nmax 3200–2400 (br), 1669, 1615, 1550 cmꢁ1
;
1H NMR (DMSO-d6)
d
9.58 (1H, s, OH), 7.67 (1H, t, J¼7.2 Hz, NH),
Yield: white solid, 0.193 g, 71% (from 8f); 0.239 g, 88% (from 10f);
mp >360 ꢀC; nmax 3275, 3210–2350 (br),1669,1622,1538,1220,1177,
7.54 (1H, td, J¼7.3, 1.8 Hz, H10), 7.49 (1H, td, J¼7.3, 1.8 Hz, H11), 7.35
(1H, dd, J¼7.4, 2.0 Hz, H9), 7.33 (1H, dd, J¼7.3, 1.8 Hz, H12), 5.37
(1H, s, H1), 3.92 (1H, br d, J¼13.0 Hz, H4eq), 3.49 (1H, br t,
J¼12.8 Hz, H4ax), 3.17 (1H, br d, J¼14.3 Hz, H6eq), 2.79 (1H, m, H6ax),
1.66 (1H, qa, J¼13.7 Hz, H5ax), 1.50 (1H, br d, J¼13.7 Hz, H5eq); 13C
790 cmꢁ1 1H NMR (DMSO-d6)
; d 9.67 (1H, s, OH), 7.56 (1H, s, NH),
7.58–7.53 (overlapping, 3H, m, H8, H9 and H10), 7.28 (1H, m, H11),
3.74 (1H, d, J¼15.4 Hz, H4exo), 3.50 (1H, J¼15.4 Hz, H4endo),1.83 (3H, s,
1-CH3), 1.34 (3H, s, 5-CH3endo), 1.12 (3H, s, 5-CH3exo); 13C NMR
NMR (DMSO-d6)
d
171.1 (C8), 160.7 (C2), 141.4 (C12b), 140.3 (C8a),
(DMSO-d6)
130.01, 129.99, 129.7 (C8–11), 127.5 (C11a), 97.7 (C1), 56.1 (C4), 55.0
(C5), 29.6 (5-CH3endo), 29.2 (5-CH3exo); 15N NMR (DMSO-d6)
270
d 170.9 (C7), 160.0 (C2), 140.3 (C7a), 139.8 (C11b), 130.6,
130.5 (two coalesced lines, C10 and C12), 129.4 (C11), 128.9 (C12a),
126.3 (C9), 93.5 (C1), 50.7 (C4), 44.0 (C6), 31.0 (C5); 15N NMR
d
(DMSO-d6)
d
268 (N3), 182 (N3a), 124 (N7). Anal. Calcd for
(N3), 184 (N3a), 137 (N6). Anal. Calcd for C15H17N3O2 (271.31): C,
66.40; H, 6.32; N, 15.49. Found: C, 66.44; H, 6.39; N, 15.47%.
C13H13N3O2 (243.26): C, 64.19; H, 5.39; N, 17.27. Found: C, 64.15; H
5.44; N, 17.32%.
4.3.8. (Z)-(exo)-5-Ethyl-4,5-dihydo-2-hydroxypyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (9g)
4.3.4. (Z)-1-Methyl-4,5,6,7-tetrahydro-2-hydroxypyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (5b)
Yield: white solid, 0.160 g, 62% (from 8g); mp 300–304 ꢀC; nmax
Yield: white solid, 0.232 g, 90% (from 6b); mp 320–323 ꢀC
sublim. (lit.27 >310 ꢀC); nmax 3295, 3180–2300 (br), 1662, 1625,
3305, 3130–2300 (br), 1675, 1610, 1531, 1212, 1191, 800 cmꢁ1 1H
;
NMR (DMSO-d6)
d
9.26 (1H, s, OH), 8.06 (1H, d, J¼9.4 Hz, NH), 7.48–
1568 cmꢁ1
;
1H NMR (DMSO-d6)
d
9.44 (1H, s, OH), 7.61 (1H, dd,
7.44 (overlapping, 2H, m, H9 and H10), 7.36–7.32 (overlapping, 2H,
m, H8 and H11), 5.50 (1H, s, H1), 3.97 (1H, dd, J¼12.6, 3.0 Hz,
4Hendo), 3.78 (1H, t, J¼12.6, 4Hexo), 3.44 (1H, m, 5H), 1.43 (2H, qui,
J¼7.0 Hz, CH2CH3), 0.78 (3H, t, J¼7.0 Hz, CH2CH3); 13C NMR (DMSO-
J¼9.5, 4.9 Hz, NH), 7.54 (1H, td, J¼7.3, 1.5 Hz, H10), 7.50 (1H,
td, J¼7.3, 1.5 Hz, H11), 7.35 (1H, dd, J¼7.8, 1.5 Hz, H9), 7.30 (1H,
dd, J¼7.3, 1.5 Hz, H12), 3.88 (br d, J¼13.9 Hz, H4eq), 3.42 (1H, dd,
J¼13.9, 10.8 Hz, H4ax), 3.14 (1H, dt, J¼15.2, 4.9 Hz, H6eq), 2.74
(1H, dt, J¼15.2, 10.7 Hz, H6ax), 1.63 (1H, qa, J¼13.2 Hz, H5ax), 1.50
(3H, s, 1-CH3), 1.47 (1H, dt, J¼13.2, 4.3 Hz, H5eq); 13C NMR
d6) d 171.7 (C7),161.2 (C2),142.7 (C11b),136.2 (C7a), 130.6 and 130.5
(C9 and C10), 130.1 (C8), 129.1 (C11a), 128.0 (C8), 95.8 (C1), 58.1
(C4), 53.3 (C5), 25.8 (CH2CH3), 11.4 (CH2CH3); 15N NMR (DMSO-d6)
(DMSO-d6)
d
171.2 (C8), 159.2 (C2), 140.6 (C8a), 139.9 (C12b),
d 272 (N3), 183 (N3a), 128 (N6). Anal. Calcd for C14H15N3O2 (257.29):
130.7 (C12), 130.4 (C10), 129.6 (C11), 128.6 (C12a), 126.4 (C9),
C, 65.35; H, 5.88; N, 16.33. Found: C, 65.40; H, 5.90; N, 16.24%.
100.5 (C1), 50.7 (C4), 44.0 (C6), 31.6 (C5), 7.3 (1-CH3); 15N NMR
(DMSO-d6)
d
266 (N3), 180 (N3a), 124 (N7). Anal. Calcd for
4.3.9. (Z)-(exo)-5-iso-Butyl-4,5-dihydro-2-hydroxypyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (9h)
C14H15N3O2 (257.29): C, 65.35; H, 5.88; N, 16.33. Found: C, 65.41;
H, 5.90; N, 16.41%.
Yield: white solid, 0.194 g, 68% (from 8h); mp 285–287 ꢀC; nmax
3300, 3200–2300 (br), 1668, 1625, 1538, 1232, 1178, 776 cmꢁ1 1H
;
4.3.5. (Z)-4,5,6,7-Tetrahydro-2-hydroxy-1-phenylpyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (5c)
NMR (DMSO-d6)
d
9.25 (1H, br s, OH), 8.08 (1H, d, J¼9.6 Hz, NH),
7.49–7.45 (overlapping, 2H, m, H9 and H10), 7.37–7.33 (over-
lapping, 2H, m, H8 and H11), 5.53 (1H, s, H1), 3.93 (1H, dd, J¼13.5,
4.5 Hz, H4endo), 3.79 (1H, t, J¼13.5 Hz, H4exo), 3.58 (1H, m, H5), 1.64
[1H, m, CH2CH(CH3)2], 1.46 [1H, ddd, J¼14.5, 11.3, 4.7 Hz,
CH(H)CH(CH3)2], 1.09 [1H, ddd, J¼14.5, 10.3, 3.4 Hz, CH(H)CH(CH3)2],
0.79 [3H, d, J¼6.7 Hz, CH2CH(CH3)(CH3)], 0.55 [3H, d, J¼6.7 Hz,
Yield: white solid, 0.300 g, 94% (from 6c); mp >360 ꢀC; nmax
3260–2300 (br), 1662, 1611, 1573, 1221, 1184, 764 cmꢁ1 1H NMR
;
(DMSO-d6)
d
10.11 (1H, s, OH), 7.83 (1H, dd, J¼9.6, 4.9 Hz, NH), 7.58
(1H, td, J¼7.7, 1.5 Hz, H10), 7.47 (1H, td, J¼7.7, 1.5 Hz, H11), 7.43 (1H,
br d, J¼7.7 Hz, H9), 7.29 (1H, br d, J¼7.5 Hz, H12), 7.19 (2H, dd, J¼7.5,
1.3 Hz, H20 of 1-Ph), 7.09 (2H, t, J¼7.5 Hz, H30 of 1-Ph), 7.00 (1H, tt,
J¼7.7, 1.3 Hz, H40 of 1-Ph), 3.97 (1H, br d, J¼14.9 Hz, H4eq), 3.48 (1H,
dd, J¼14.9, 12.1 Hz, H4ax), 3.22 (1H, dt, J¼15.0, 4.6 Hz, H6eq), 2.89
(1H, dt, J¼15.0, 9.8 Hz, H6ax), 1.77 (1H, br qa, J¼13.0 Hz, H5ax), 1.58
CH2CH(CH3)(CH3)]; 13C NMR (DMSO-d6)
d 171.4 (C7), 161.0 (C2),
142.9 (C11b), 136.1 (C7a), 130.7 and 130.5 (C9 and C10), 130.1 (C8),
129.1 (C11a), 127.8 (C8), 95.7 (C1), 58.4 (C4), 49.6 (C5), 40.9
[CH2CH(CH3)2], 24.8 [CH2CH(CH3)2], 23.8 [CH2CH(CH3)(CH3)], 21.5
(1H, dt, J¼14.5, 4.7 Hz, H5eq); 13C NMR (DMSO-d6)
d
171.3 (C8),
[CH2CH(CH3)(CH3)]; 15N NMR (DMSO-d6)
d 272 (N3), 185 (N3a), 129
158.4 (C2), 141.0 (C8a), 138.6 (C12b), 133.4 (C10 of 1-Ph), 130.8 (two
coalesced lines, C10 and C12),129.8 (C11),128.6 (C12a),128.5 (C30 of
1-Ph),126.6 (C9), 125.7 (C40 of 1-Ph),106.0 (C1), 50.8 (C4), 44.0 (C6),
(N6). Anal. Calcd for C16H19N3O2 (285.34): C, 67.35; H, 6.71; N,14.73.
Found: C, 67.28; H, 6.65; N, 14.74%.
31.0 (C5); 15N NMR (DMSO-d6)
d
266 (N3),188 (N3a), 122 (N7). Anal.
4.3.10. (Z)-(exo)-5-Ethyl-4,5-dihydro-2-hydroxy-1-
Calcd for C19H17N3O2 (319.36): C, 71.46; H, 5.37; N, 13.16. Found: C,
71.42; H, 5.33; N, 13.21%.
methylpyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-one (9i)
Yield: white solid, 0.209 g, 77% (from 8i); mp 312–315 ꢀC; nmax
3295, 3180–2300 (br), 1662, 1625, 1545, 1210, 1158, 754 cmꢁ1 1H
;
4.3.6. (Z)-4,5-Dihydro-2-hydroxy-5,5-dimethylpyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (9e)
NMR (DMSO-d6)
d
9.57 (1H, br s, OH), 7.96 (1H, d, J¼9.4 Hz, NH),
7.49 (1H, t, J¼7.3 Hz, H10), 7.45 (1H, t, J¼7.3 Hz, H9), 7.34 (1H, d,
J¼7.3 Hz, H8), 7.27 (1H, d, J¼7.3 Hz, H11), 3.92 (1H, dd, J¼13.0,
5.0 Hz, H4endo), 3.43 (1H, t, J¼13.0 Hz, H4exo), 3.37 (1H, m, H5), 1.62
Yield: white solid, 0.196 g, 76% (from 8e); mp >360 ꢀC; nmax
3150–2200 (br), 1674, 1635, 1549, 1208, 1188, 782 cmꢁ1 1H NMR
;

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10846
(3H, s, 1-CH3), 1.42 (2H, qui, J¼7.0 Hz, CH2CH3), 0.78 (3H, t, J¼7.0 Hz,
CH2CH3); 13C NMR (DMSO-d6)
171.9 (C7), 159.8 (C2), 139.1 (C11b),
137.2 (C7a), 130.8 (C10), 130.2 (C9), 129.9 (C8), 129.6 (C11a), 127.9
1.7 Hz, H4ax), 3.01 (1H, dd, J¼14.7, 11.8 Hz, H6ax), 2.30 (3H, s,
OCOCH3), 2.23 (3H, s, NCOCH3) overlapping with 2.22 (1H, br qa,
J¼14.9 Hz, H5ax), 1.66 (3H, s, 1-CH3), 1.54 (1H, br d, J¼15.1 Hz, H5eq);
d
(C11), 101.6 (C1), 57.8 (C4), 53.6 (C5), 25.2 (CH2CH3), 11.5 (CH2CH3),
13C NMR (CDCl3)
d 173.6 (NCOCH3), 173.3 (C8), 168.6 (OCOCH3),
7.9 (1-CH3); 15N NMR (DMSO-d6)
d
270 (N3), 182 (N3a), 131 (N6).
153.6 (C2), 139.4 (C8a), 139.2 (C12b), 131.12 and 131.07 (C10 and
C11), 130.7 (C9), 127.6 (C12), 127.1 (C12a), 107.5 (C1), 50.1 (C4), 46.3
(C6), 27.3 (C5), 26.2 (NCOCH3), 20.9 (OCOCH3), 7.0 (1-CH3); 15N NMR
Anal. Calcd for C15H17N3O2 (271.31): C, 66.40; H, 6.32; N, 15.49.
Found: C, 66.33; H, 6.37; N, 15.44%.
(CDCl3)
d 279 (N3), 193 (N3a), 172 (N7). Anal. Calcd for C18H19N3O4
4.4. General procedure for base-catalyzed ring enlargement
reactions 4a,b/5a,b
(341.36): C, 63.33; H, 5.61; N, 12.31. Found: C, 63.40; H, 5.57; N,
12.28%.
The mixture of the appropriate precursor (1 mmol) and 10%
NaHCO3 (10 mL) was refluxed for 3 h. The resulted yellow solution
was cooled and its pH was adjusted to 5–6 by concd HCl. After
standing for 1 h in refrigerator the precipitated crystals were col-
lected, washed with water and dried. Yield: 0.224 g, 92% for 5a;
0.247 g, 96% for 5b. Analytical samples were obtained by re-
crystallization from EtOH. Within experimental error spectroscopic
and analytical data proved to be identical with those listed in
Sections 4.3.3 and 4.3.4, respectively.
4.6.3. (Z)-4,5-Dihydro-1-methyl-2-propionyloxypyrazolo[1,5-
d]benzo[f][1,4]diazocin-7(6H)-one (10f)
Yield: pale yellow solid, 0.137 g, 42% (from 8f) and 0.272 g, 83%
(from 9f); mp 215–217 ꢀC; nmax 3305, 1765, 1641, 1583, 1551, 1222,
1154, 744 cmꢁ1 1H NMR (CDCl3)
; d 7.69 (1H, m, H8), 7.57–7.51
(overlapping, m, 2H, H9–10), 7.31 (1H, m, H11), 5.77 (1H, s, NH),
3.93 (1H, d, J¼15.1 Hz, H4exo), 3.83 (1H, d, J¼15.1 Hz, H4endo), 2.64
(2H, qa, J¼7.6 Hz, OCOCH2CH3), 1.89 (3H, s, 1-CH3), 1.47 (3H, s,
5-CH3endo), 1.29 (3H, t, J¼7.6 Hz, OCOCH2CH3), 1.26 (3H, s, 5-CH3exo),
13C NMR (CDCl3)
d 172.5 (OCOCH2CH3), 171.6 (C7), 154.1 (C2), 141.0
4.5. General procedure for anhydride-induced
transformations of 5a,b, 8f and 9f
(C11b), 138.0 (C7a), 131.0 (C10), 130.3 (C9), 130.1 (C8), 130.0 (C11),
127.1 (C11a), 105.1 (C1), 56.4 (C4), 55.5 (C5), 30.1 (5-CH3endo), 29.5
(5-CH3exo), 27.7 (OCOCH2CH3), 9.5 (OCOCH2CH3), 7.5 (1-CH3). Anal.
Calcd for C18H21N3O3 (327.38): C, 66.04; H, 6.47; N, 12.84. Found: C,
65.99; H, 6.50; N, 12.80%.
A mixture of the corresponding precursor (1 mmol) and anhy-
dride (50 mmol) was heated at 140 ꢀC for the following periods of
time: 1 h (5a,bþacetic anhydride); 8 h (8fþpropionic anhydride);
2 h (9fþpropionic anhydride). The excess of the acetic or propionic
anhydride was distilled under reduced pressure (2–5 mBa; the
temperature of oil bath was kept at 90–110 ꢀC). The resulted
brownish solid was triturated with methanol, filtered off, thor-
oughly washed with water and extracted with DCM (30 mL). The
solution was dried over MgSO4 and evaporated to dryness. The
residue was subjected to column flash chromatography using n-
hexane–EtOAc (5:1) as eluent yielding 6a,b or the unreacted 8f. The
undissolved monopropionyl compound 10f (from 8f and 9f) con-
taminated by some tarry substances was purified by flash column
chromatography using DCM–MeOH (20:1) as eluent. Analytical
samples were recrystallized: 6a,b (DCM–cyclohexane); 10f (EtOH).
4.7. (Z)-4,5,6,7-Tetrahydro-1-phenyl-7-phenacetyl-2-
phenacetoxypyrazolo[1,5-e]benzo[g][1,5]diazonin-8-one (6c)
The mixture of 1a (2.01 g, 10 mmol) and phenylacetic anhy-
dride (12.70 g, 50 mmol) was kept at 140 ꢀC for 3 h. To the cooled
brownish mixture ethanol (40 mL) was added and the resulted
solution was stirred for 2 h at rt and kept overnight in refrigerator.
The precipitated colourless microcrystals were filtered off, washed
with cold EtOH (5 mL) and dried. Analytical sample was recrys-
tallized from DCM–cyclohexane. Yield: white small needles,
0.211 g, 38% (from 1a); mp 203–205 ꢀC; nmax 1761, 1689, 1578,
1525, 1220, 1164, 753 cmꢁ1 1H NMR (CDCl3)
; d 7.60–7.53 (over-
lapping, 3H, m, H9–11), 7.43 (1H, d, J¼7.3 Hz, H12), 7.30–7.18
(overlapping, 10H, m, OCOCH2Ph and NCOCH2Ph), 7.08–7.00
(overlapping, 3H, m, H30–50 of 1-Ph), 6.94 (2H, d, J¼7.7 Hz, H20 of
1-Ph), 4.24 (1H, br d, J¼12.0 Hz, H4eq), 4.17 (1H, br d, J¼12.8 Hz,
H6eq), 4.06 (1H, d, J¼16.7 Hz, NCOCHHC6H5), 3.83–3.77 (over-
lapping, m, 3H, H4ax and OCOCH2C6H5), 3.60 (1H, d, J¼16.7 Hz,
NCOCHHC6H5), 3.08 (1H, t, J¼12.8 Hz, H6ax), 2.31 (1H, br qa,
J¼15.3 Hz, H5ax), 1.55 (1H, br d, J¼15.3 Hz, H5eq); 13C NMR (CDCl3)
4.6. Data of the acylated medium-size heterocycles
4.6.1. (Z)-7-Acetyl-2-acetoxy-4,5,6,7-tetrahydropyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (6a)
Yield: white prisms, 0.268 g, 82% (from 5a); mp 153–155 ꢀC
(lit.27 154–155 ꢀC); nmax 1754, 1690, 1568, 1548, 1212, 1178,
772 cmꢁ1; 1H NMR (CDCl3)
d 7.64–7.56 (overlapping, m, 3H, H9–11),
7.43 (1H, m, H12), 6.13 (1H, s, H1), 4.17 (1H, br d, J¼15.3 Hz, H4eq
)
d 175.0 (C8), 169.2 (OCOCH2Ph), 152.4 (C2), 139.7 (C8a), 138.5
4.09 (1H, dd, J¼15.0, 4.5 Hz, H6eq), 3.85 (1H, br t, J¼14.1 Hz, H4ax),
3.01 (1H, dd, J¼14.5,11.4 Hz, H6ax), 2.29 (3H, s, OCOCH3), 2.23 (3H, s,
NCOCH3) overlapping with 2.21 (1H, br qa, J¼14.9 Hz, H5ax), 1.60
(C12b), 135.2 (C10 of NCOCH2Ph), 133.2 (C10 of OCOCH2Ph), 130.1
(C10 of 1-Ph), 131.33, 131.29, 131.25, 130.3, 129.9, 129.1, 128.9, 128.6
(two coalesced lines), 127.9 (two coalesced lines), 127.2, 127.1 (Ar–
CH signals), 50.5 (C4), 46.7 (C6), 44.5 (NCOCH2Ph), 41.5
(1H, br d, J¼15.0 Hz, H5eq); 13C NMR (CDCl3)
d 172.9 (NCOCH3),
172.7 (C8), 167.5 (OCOCH3), 154.3 (C2), 140.3 (C8a), 138.7 (C12b),
130.5 (C10), 130.4 (C11), 130.0 (C9), 127.2 (two coalesced lines, C12
and C12a), 98.5 (C1), 49.9 (C4), 46.0 (C6), 27.1 (C5), 26.1 (NCOCH3),
(OCOCH2Ph), 27.1 (C5); 15N NMR (CDCl3)
d 281 (N3), 196 (N3a), 172
(N7). Anal. Calcd for C35H29N3O4 (555.62): C, 75.66; H, 5.26; N,
7.56. Found: C, 75.59; H, 5.28; N, 7.60%.
20.7 (OCOCH3); 15N NMR (CDCl3)
d 278 (N3), 194 (N3a), 172 (N7).
Anal. Calcd for C17H17N3O4 (327.33): C, 62.38; H, 5.23; N, 12.84.
Found: C, 62.33; H, 5.26; N, 12.88%.
4.8. N,O-Diallylation of 5b: preparation of (Z)-7-allyl-2-
allyloxy-1-methyl-4,5,6,7-tetrahydropyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (11b)
4.6.2. (Z)-7-Acetyl-2-acetoxy-4,5,6,7-tetrahydro-1-
methylpyrazolo[1,5-e]benzo[g][1,5]diazonin-8-one (6b)
Yield: white plates, 0.307 g, 90% (from 5b); mp 179–181 ꢀC; nmax
Under Ar atmosphere to the mixture of NaH (0.48 g, 20 mmol)
and THF (50 mL), 5b (2.57 g, 10 mmol) was added in small portions.
The resulted yellowish suspension was stirred for ca. 5–10 min at
25 ꢀC until the hydrogen evolution was stopped. After dropwise
addition of allylbromide (2.42 g, 20 mmol) the reaction mixture
was refluxed for 1 h and evaporated to dryness. The oily residue
1771, 1683, 1567, 1513, 1224, 1172, 769 cmꢁ1 1H NMR (CDCl3)
;
d
7.66–7.61 (overlapping m, 2H, H10 and H11), 7.58 (1H, m, H9), 7.43
(1H, m, H12), 4.16 (1H, br d, J¼15.1 Hz, H4eq) slightly overlapping
with 4.11 (1H, dd, J¼15.1, 4.7 Hz, H6eq), 3.76 (1H, ddd, J¼15.1, 12.7,

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A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
10847
was dissolved in DCM (50 mL) and the undissolved salt was re-
4.10.2. (Z)-2-Allyloxy-1-methyl-7-[(E)-propen-1-yl]-4,5,6,7-
moved by filtration. The solution was extracted with water
(2ꢃ50 mL), dried over MgSO4 and evaporated. The oily residue was
subjected to flash column chromatography using n-hexane–EtOAc
(8:1) as eluent. The first band visible on UV-irradiation was col-
lected and evaporated. On standing overnight under n-hexane in
refrigerator the resulted pale yellow oil was solidified, filtered off
and dried to obtain 11b in analytically pure form. Yield: pale yellow
microcrystals, 2.292 g, 68%; mp 131–133 ꢀC; nmax 1643, 1498, 1464,
tetrahydropyrazolo[1,5-e]benzo[g][1,5]diazonin-8-one (13b)
Yield: pale yellow microcrystals, 0.061 g, 18%; mp 139–141 ꢀC;
nmax 1690, 1592, 1541, 1205, 1163, 779, 640 cmꢁ1
;
1H NMR (CDCl3)
d
7.51 (1H, td, J¼7.7,1.7 Hz, H10), 7.47 (1H, td, J¼7.7,1.7 Hz, H11), 7.41
(1H, dd, J¼7.6, 1.7 Hz, H9), 7.31 (1H, br d, J¼7.5 Hz, H12), 6.91 (1H, br
d, J¼14.7 Hz, H19), 6.04 (1H, ddt, J¼17.4, 10.4, 5.4 Hz, H15), 5.34 (1H,
dqa, J¼17.4, 1.7 Hz, H16trans), 5.21 (1H, dqa, J¼10.5, 1.7 Hz, H16cis),
4.98 (1H, dqa, J¼14.7, 6.3 Hz, H18), 4.69–4.63 (overlapping, m, 2H,
H14), 4.08 (1H, br d, J¼15.2 Hz, H4eq), 3.60 (1H, t, J¼13.8 Hz, H4ax),
3.54 (1H, dd, J¼14.9, 4.6 Hz, H6eq), 3.32 (1H, dd, J¼14.9, 9.8 Hz,
H6ax), 2.22 (1H, dqa, J¼15.0, 10.0 Hz, H5ax), 1.68 (overlapping, 6H, s,
H13 and dd, J¼6.3, 1.8 Hz, H17), 1.44 (1H, dt, J¼15.0, 4.5 Hz, H5eq);
1216, 1191, 786 cmꢁ1
;
1H NMR (CDCl3)
d
7.52 (1H, td, J¼7.7, 1.3 Hz,
H10), 7.48 (1H, td, J¼7.7, 1.3 Hz, H11), 7.44 (1H, dd, J¼7.7, 1.3 Hz, H9),
7.32 (1H, br d, J¼7.5 Hz, H12), 6.11 (1H, ddt, J¼17.3, 10.6, 5.3 Hz,
H15), 5.62 (1H, ddt, J¼16.9, 10.8, 5.5 Hz, H18), 5.42 (1H, dqa, J¼17.3,
1.7 Hz, H16trans), 5.26 (1H, dqa, J¼10.7, 1.7 Hz, H16cis), 5.14 (1H, dqa,
J¼17.0, 1.5 Hz, H17trans), 5.08 (1H, dqa, J¼10.8, 1.5 Hz, H17cis), 4.72
(2H, br d, J¼5.3 Hz, H14), 4.11 (1H, dt, J¼15.0, 3.2 Hz, H4eq), 4.03
(1H, br dd, J¼15.0, 5.3 Hz, H6eq), 3.69 (1H, dd, J¼15.0, 7.0 Hz, H6ax),
3.62 (1H, ddd, J¼15.0, 12.6, 2.1 Hz, H4ax), 3.25 (2H, br d, J¼5.5 Hz,
H19), 2.15 (1H, m, H5ax), 1.42 (1H, br d, J¼15.2 Hz, H5eq), 1.72 (3H, s,
13C NMR (CDCl3)
d 168.9 (C8), 161.0 (C2), 140.0 (C8a), 139.8 (C12b),
134.5 (C15), 130.0 (C12), 129.9 (C10), 129.7 (C11), 128.4 (C12a), 126.4
(C9), 125.7 (C19), 108.5 (C18), 102.6 (C1), 69.8 (C14), 50.3 (C4), 46.8
(C6), 26.8 (C5), 16.0 (C17), 6.5 (C13); 15N NMR (CDCl3)
d 261 (N3),
182 (N3a),149 (N7). Anal. Calcd for C20H23N3O2 (337.42): C, 71.19; H,
6.87; N, 12.45. Found: C, 71.27; H, 6.96; N, 12.48%.
H13); 13C NMR (CDCl3)
d 170.0 (C8), 160.7 (C2), 140.7 (C12a), 140.2
(C8a), 134.2 (C15), 133.7 (C18), 130.5 (C11), 130.3 (C10), 129.3 (C9),
128.5 (C12a), 126.1 (C12), 117.8 (C16), 117.4 (C17), 102.5 (C1), 69.7
(C14), 50.3 (C4), 49.4 (C19), 48.1 (C6), 27.8 (C5), 6.6 (C13); 15N NMR
4.10.3. (Z)-7-Allyl-1-methyl-3-[(E)-propen-1-yl]-4,5,6,7-
tetrahydro-3H-pyrazolo[1,5-e]benzo[g][1,5]diazonin-
3,8-dione (14b)
(CDCl3)
d
261 (N3), 182 (N3a), 125 (N7). Anal. Calcd for C20H23N3O2
Yield: white microcrystals, 0.037 g, 11%; mp 144–145 ꢀC; nmax
(337.42): C, 71.19; H, 6.87; N, 12.45. Found: C, 71.28; H, 6.88; N,
12.38%.
1662, 1651, 1565, 1483, 1215, 1177, 753, 648 cmꢁ1; 1H NMR (CDCl3)
d
7.59–7.50 (overlapping, m, 3H, H9–11), 7.39 (1H, br d, J¼7.39 Hz,
H12), 6.57 (1H, dqa, J¼14.3, 1.7 Hz, H14), 5.79 (1H, m, H18), 5.64
(1H, dqa, J¼14.4, 6.7 Hz, H15), 5.20 (1H, dqa, J¼10.4, 1.7 Hz, H17cis),
5.15 (1H, dqa, J¼17.4, 1.7 Hz, H17trans), 4.23 (1H, ddt, J¼15.2, 5.3,
1.7 Hz, H19exo), 3.84 (1H, br d, J¼15.8 Hz, H4eq), 3.58 (1H, ddt,
J¼15.2, 7.5,1.7 Hz, H19endo), 3.20–3.16 (overlapping, m, 2H, H4ax and
H6eq), 2.88 (1H, dd, J¼15.4,10.3 Hz, H6ax),1.84 (3H, dd, J¼6.8,1.7 Hz,
H16), 1.72 (3H, s, H13), 1.62 (1H, br qa, J¼14.9 Hz, H5ax), 1.27 (1H, dt,
4.9. Attempted RCM of 11b
To the solution of 11b (0.337 g, 1 mmol) in dry benzene (50 mL)
previously degassed by Ar, [Cl2RuP(C6H11)3(]CHC6H5)(1,3-dime-
sitylimidazol-2-ylene)] (0.187 g, 0.2 mmol) was added. The solu-
tion was stirred, refluxed for 5 h under Ar and evaporated to
dryness. The resulted deep red mixture was subjected to flash
column chromatography using n-hexane–EtOAc (4:1) as eluent.
The first eluting band was put aside and the second well-sepa-
rated fraction was collected, evaporated and the solid residue was
recrystallized from EtOH to obtain 12b in analytically pure form.
The first band containing the mixture of 13b and 14b was sepa-
rated as first and second bands, respectively, by repeated flash
column chromatography using n-hexane–Et2O (15:1) as eluent. On
standing overnight under n-hexane in refrigerator, 13b and 14b
were solidified, filtered off and dried to obtain analytically pure
samples.
J¼15.0, 4.5 Hz, H5eq); 13C NMR
d 170.4 (C8), 166.4 (C2), 153.4 (C12b),
138.9 (C8a), 132.9 (C18), 130.8 (C10), 129.8 (C11), 129.6 (C12), 127.5
(two coalesced lines, C9 and C12a), 121.5 (C14), 118.3 (C17), 116.1
(C15), 112.2 (C1), 50.5 (C4), 48.6 (C6), 48.4 (C19), 24.3 (C5), 15.5
(C16), 7.8 (C13); 15N NMR (CDCl3)
d 153 (N3), 105 (N3a), 124 (N7).
Anal. Calcd for C20H23N3O2 (337.42): C, 71.19; H, 6.87; N, 12.45.
Found: C, 71.24; H, 6.97; N, 12.38%.
4.11. Bridging of 5b by dialkylation with 1,3-bis(bromo
methyl)benzene: (Z)-1-methyl-2-O-7-(benzene-1,3-diyldi
methanediyl)-4,5,6,7-tetrahydropyrazolo[1,5-e]benzo
[g][1,5]diazonin-8-one (15b)
4.10. Data of the products obtained by attempted RCM of 11b
Under Ar atmosphere to the mixture of NaH (0.24 g, 10 mmol)
and THF (80 mL), 5b (2.57 g, 10 mmol) was added in small portions.
The resulted yellowish suspension was stirred for ca. 5 min at 25 ꢀC
until the hydrogen evolution was stopped. 1,3-Bis(bromo-
methyl)benzene (2.64 g, 10 mmol) was added in one portion to this
mixture, which was then refluxed for 30 min and cooled to 25 ꢀC.
After addition of the second portion of NaH (0.24 g, 10 mmol), the
mixture was stirred at 25 ꢀC for ca. 10 min, refluxed for 1 h and
evaporated to dryness. The solid residue was dissolved in DCM
(50 mL) and the undissolved salt was removed by filtration. The
solution was extracted with water (2ꢃ50 mL), dried over MgSO4
and evaporated. The resulted solid mixture was separated by flash
column chromatography using n-hexane–EtOAc (5:1) as eluent.
The first band visible on UV-irradiation was collected and evapo-
rated. The white crystals of 15b were washed with cold EtOH
(5 mL), filtered off and dried. Analytical sample was recrystallized
from EtOH. Yield: white cubic crystals, 0.970 g, 27%; mp 251–
4.10.1. (Z)-2-Allyloxy-1-methyl-4,5,6,7-tetrahydropyrazolo[1,5-
e]benzo[g][1,5]diazonin-8-one (12b)
Yield: pale yellow needles, 0.072 g, 24%; mp 254–256 ꢀC; nmax
3240, 1655, 1494, 1476, 1211, 1189, 780 cmꢁ1 1H NMR (DMSO-d6)
;
d
7.51 (1H, t, J¼7.7 Hz, H11), 7.47 (1H, t, J¼7.7 Hz, H10), 7.43 (1H, br
d, J¼7.5 Hz, H9), 7.30 (1H, d, J¼7.7 Hz, H12), 6.52 (1H, dd, J¼9.1,
4.9 Hz, NH), 6.06 (1H, ddt, J¼17.0, 10.5, 5.4 Hz, H15), 5.37 (1H, dqa,
J¼17.0, 1.5 Hz, H16trans), 5.21 (1H, br d, J¼10.5 Hz, H16cis), 4.68 (2H,
br d, J¼5.4 Hz, H14), 4.10 (1H, br d, J¼14.2 Hz, H4eq), 3.58 (1H, t,
J¼13.5 Hz, H4ax), 3.26 (1H, dt, J¼14.4, 4.9 Hz, H6eq), 2.95 (1H, dt,
J¼14.4, 9.3 Hz, H6ax), 1.91 (1H, br qa, J¼13.2 Hz, H5ax), 1.67 (3H, s,
H13), 1.50 (1H, dt, J¼15.0, 3.4 Hz, H5eq); 13C NMR (DMSO-d6)
d 173.0
(C8), 160.7 (C2), 140.0 (C12b), 139.1 (C8a), 134.1 (C15), 130.5 (C12),
130.3 (C11), 129.7 (C10), 128.5 (C12a), 126.3 (C9), 117.5 (C16), 102.6
(C1), 69.6 (C14), 50.6 (C4), 44.2 (C6), 31.4 (C5), 6.6 (C13); 15N NMR
(DMSO-d6)
d
262 (N3), 182 (N3a), 121 (N7). Anal. Calcd for
252 ꢀC; nmax 1639, 1480, 1419, 1196, 947, 760, 651 cmꢁ1
(CDCl3)
7.48 (1H, td, J¼7.7, 1.8 Hz, H10), 7.43–7.39 (overlapping, m,
2H, H9 and H11), 7.30 (1H, br d, J¼7.5 Hz, H17), 7.24 (1H, br d,
;
1H NMR
C17H19N3O2 (297.35): C, 68.67; H, 6.44; N, 14.13. Found: C, 68.60; H,
6.58; N, 14.09%.
d

´
A. Gyo¨mo¨re et al. / Tetrahedron 64 (2008) 10837–10848
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J¼7.6 Hz, H12), 7.21 (1H, t, J¼7.5 Hz, H16), 7.14 (br d, J¼7.5 Hz, H15),
6.74 (1H, br s, H19), 5.61 (1H, d, J¼14.3 Hz, H20exo), 5.03 (1H, d,
J¼10.9 Hz, H13exo), 4.88 (1H, d, J¼10.9 Hz, H13endo), 3.75 (1H, br d,
J¼14.5 Hz, H6eq), 3.42–3.38 (overlapping, m, 2H, H4ax and H6ax),
3.35 (1H, d, J¼14.3 Hz, H20endo), 3.28 (1H, dd, J¼15.4, 5.3 Hz, H4eq),
1.66 (3H, s, H20), 1.55 (1H, br qa, J¼14.5 Hz, H5ax), 1.30 (1H, dt,
J¼15.4, 4.5 Hz, H5eq); 13C NMR (CDCl3)
d 170.7 (C8),158.2 (C2),140.6
(C8a), 140.1 (C12b), 139.4 (C18), 136.1 (C14), 132.1 (C19), 130.5 (two
coalesced lines, C10 and C12), 129.6 (C17), 129.4 (C11), 128.8 (C15),
128.6 (C16), 128.0 (C12a), 108.9 (C1), 75.0 (C13), 53.7 (C4), 52.5
(C20), 50.0 (C6), 30.6 (C5), 7.0 (C21); 15N NMR (CDCl3)
d
282(N3),192(N3a), 135 (N7). Anal. Calcd for C22H21N3O2 (359.42):
C, 73.52; H, 5.89; N, 11.69. Found: C, 73.54; H, 5.94; N, 11.74%.
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Supplementary data
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