Acid-mediated electrocyclic domino transformations of 5,5-disubstituted 1-amino-1-azapenta-1,4-dien-3-ones into dihydrospiroindenepyrazole and dihydroindenodiazepine derivatives

Article abstract of DOI:10.1021/jo900270e

(Chemical Equation Presented) Trifluoromethyl-substituted 1-amino-1-azapenta-1,4-dien-3-ones 4, which are accessible in good yield from pyruvates 1 in a three-step procedure, undergo a cascade reaction involving inter alia two electrocyclizations upon tre

Full text of DOI:10.1021/jo900270e

Acid-Mediated Electrocyclic Domino Transformations of
5,5-Disubstituted 1-Amino-1-azapenta-1,4-dien-3-ones into
Dihydrospiroindenepyrazole and Dihydroindenodiazepine
Derivatives
Nugzar Ghavtadze, Roland Fro¨hlich, and Ernst-Ulrich Wu¨rthwein*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 40, 48149 Mu¨nster, Germany
wurthwe@uni-muenster.de
ReceiVed February 17, 2009
Trifluoromethyl-substituted 1-amino-1-azapenta-1,4-dien-3-ones 4, which are accessible in good yield
from pyruvates 1 in a three-step procedure, undergo a cascade reaction involving inter alia two
electrocyclizations upon treatment with a large excess of trifluoromethanesulfonic acid to give novel
dihydrospiroindenepyrazole 5a-o and dihydroindenodiazepine 6a-j. We interpret this sequence of
reactions on the basis of quantum chemical calculations as a dicationic cyclization of a pentadien-1-one
(“superelectrophilic solvation”), where one of the double bonds is part of an aromatic ring and a subsequent
rearrangement to form an (monocationic) iminium ion, which either cyclizes to give five-membered spiro
ring systems (compounds 5) or tricyclic dihydroindenodiazepine derivatives 6. Hu¨ckel- and Mo¨bius-type
transition states of the electrocyclization reactions are discussed considering the results of NICS
calculations. One 1-amino-1-penta-1,4-dien-3-one 4 and several dihydrospiroindenepyrazoles 5 and
dihydroindenodiazepines 6 could be characterized by X-ray diffraction.
Introduction
Cationic or even dicationic intermediates, which may be
generated under superelectrophilic conditions, are well suited
for this purpose.3 In this paper, we report on new experiments
to initiate multistep transformations by treatment of unsaturated
nitrogen compounds of the 1-azapenta-1,4-dien-3-one type with
the very strong Brønsted acid trifluormethanesulfonic acid.
The efficiency of the formation of several bonds in one
sequence without isolating the intermediates, changing the
reaction conditions, or adding reagents is the main reason why
domino transformations have received considerable attention
from the synthetic organic community.1 Molecules containing
heterocyclic substructures continue to be attractive targets for
domino transformations, since they often exhibit diverse and
important biological properties.2 Thus, the construction of
heterocyclic molecules by such sequences of reactions has been
extensively exploited during the last decades. The initiation of
domino transformations often requires reactive intermediates,
which are prone to undergo a series of subsequent reactions.
Recently, we were able to identify the electronic and
topological preconditions for a successful application of the aza-
Nazarov reaction4 in heterocyclic synthesis involving a conro-
tatory 4π electrocyclization reaction.5 We demonstrated that
1-azapenta-1,4-dien-3-ones can successfully be applied for the
(3) Scho¨tz, K.; Clark, T.; Schleyer, P.v.R. J. Am. Chem. Soc. 1988, 110,
1394.
* To whom correspondence should be addressed. Fax: (+)-(0)251/83-39772.
(1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Mueller, T. J. J.; D’Souza,
D. M. Pure Appl. Chem. 2008, 80, 609. (c) Tietze, L. F.; Modi, A. Med Res
ReV. 2000, 20, 304–322. (d) Enders, D.; Grondal, C.; Huetti, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. (e) Pellisier, H. Tetrahedron 2006, 62, 1619. (f)
Pellisier, H. Tetrahedron 2006, 62, 2143.
(4) (a) Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 53, 11049. (b)
Matoba, K.; Itoh, K.; Yamazaki, T.; Nagata, M. Chem. Pharm. Bull. 1981, 29,
2442. (c) Matoba, K.; Miyata, Y.; Yamazaki, T. Chem. Pharm. Bull. 1983, 31,
476. (d) Matoba, K.; Terada, T.; Sugiuara, M.; Yamazaki, T. Heterocycles 1987,
26, 55. (e) Aftfah, A.; Abu-Shuheil, M. Y.; Hill, J. Tetrahedron 1990, 46, 6483.
(f) Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Estevens, P. M.; Almeida, L. S.
Org. Lett. 2007, 16, 3085.
(2) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341. (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
4584 J. Org. Chem. 2009, 74, 4584–4591
10.1021/jo900270e CCC: $40.75 2009 American Chemical Society
Published on Web 05/21/2009

Acid-Mediated Electrocyclic Domino Transformations
SCHEME 1
SCHEME 2
synthesis of variably substituted 1H- and 2H-pyrroles via the
aza-Nazarov route if treated with strong Brønsted acids.5,6
Results and Discussion
In order to extend the scope of this acid-promoted reaction,
we now focused on 5,5-disubstituted 1-azapenta-1,4-dien-3-ones
4, which bear an additional very strong electron-withdrawing
substituent, a CF3 group, at the 5-position. In general, the CF3
group was expected to strongly destabilize the protonated
azadienones and thus facilitates their cyclization reactions. The
compounds 4 are accessible from the condensation of R-ke-
toesters 1 with hydrazines to give the corresponding hydrazones
2, their conversion into the corresponding phosphonates 3,7 and
subsequent Horner-Wadsworth-Emmons (HWE) reactions
using various trifluoromethyl ketones to give the 1-amino-5-
trifluoromethyl-1-azapenta-1,4-dien-3-ones 4 (Scheme 1).
Other activated ketones (trifluoromethyl ketones, 1,2-dike-
tones, R-ketoesters) also reacted successfully in the HWE
reaction, but in contrast to the trifluoromethyl ketone-derived
azadienones 1,2-diketone and R-ketoester derivatives did not
show any clean reaction upon treatment with acid. Probably,
the carbonyl or carboxyl groups are not inactive in those cases
and mixtures of unidentified products are obtained from the
reaction. Therefore, we concentrated in this work our efforts
on CF3-substituted 5,5-disubstituted aza-dienones 4.8
Surprisingly, these systems 4 do not show ring-closure
reactions involving C-N bond formation (aza-Nazarov reaction)
upon treatment with strong acids like trifluoromethanesulfonic
acid (triflic acid). Instead, an unexpected cascade of transforma-
tions takes place and dihydrospiroindenepyrazoles 5 and dihy-
droindenodiazepines 6 were obtained in moderate to good
overall yields (Scheme 2, Table 1). Spiropyrazolines have been
known since 1984, when Dhar and Ragunathan reported on the
1,3-dipolar cycloaddition reaction of fulvenes with 1,3-diphe-
nylnitrilimine.9
TABLE 1. Substitution Patterns for Compounds 4-6 and Yields
for Compounds 5 and 6
no.
R1
R2
aryl
product
yield (%)
4a
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
5f
32
36
34
16
44
24
41
11
26
28
31
18
34
66
37
4b
4c
4d
4e
4f
Et
iPr
nBu
Me
Me
2-thienyl
6f
4g
4h
4i
Me
Me
Me
Me
Me
Me
4-Me-Ph
2,4-di-Me-Ph
1-naphthyl
6g
6h
5g
isolation of stable end products (see below and compare with
previous studies5,6,10,11). Treatment of the reaction mixture with
water instead of anhydrides led to a variety of unidentified
species.
In the cases where a 1-methyl-1-alkylamino group (R1 )
alkyl) is present, both dihydrospiroindenepyrazoles 5 and
dihydroindenodiazepines 6 can be isolated from the same
experiment (Table 1). The alkyl fragment R1 can be Me, Et,
i-Pr, and n-Bu. All compounds are stable toward air and
moisture and do not show further transformations or equilibria
at room temperature.
The cyclization reactions of the 1-amino-1-azapenta-1,4-dien-
3-ones 4 were carried out in dichloromethane by treatment with
a 10-fold excess of triflic acid at -10 to 0 °C. When only 2
equiv of triflic acid was used, no reactions were observed.
Furthermore, addition of an anhydride is necessary for the
(5) (a) Dieker, J.; Fro¨hlich, R.; Wu¨rthwein, E.-U. Eur. J. Org. Chem. 2006,
5339. (b) Alickmann, D.; Fro¨hlich, R.; Maulitz, A. H.; Wu¨rthwein, E.-U. Eur.
J. Org. Chem. 2002, 1523.
Introduction of Me groups at the para-postion, or ortho- and
para-positions of the aryl fragment of the azadienone (4g,h)
(6) Ghavtadze, N.; Fro¨hlich, R.; Wu¨rthwein, E.-U. Eur. J. Org. Chem. 2008,
3656.
(7) Neidlein, R.; Feistauer, H. HelV. Chim. Acta 1996, 79, 895.
(8) Ghavtadze, N. Ph.D. thesis, University Mu¨nster, 2008.
(9) Dhar, D. N.; Ragunathan, R. Tetrahedron 1984, 40, 1585.
(10) Ghavtadze, N.; Fro¨hlich, R.; Wu¨rthwein, E.-U. Eur. J. Org. Chem. 2009,
1228.
(11) Ghavtadze, N.; Fro¨hlich, R.; Bergander, K.; Wu¨rthwein, E.-U. Synthesis
2008, 3397.
J. Org. Chem. Vol. 74, No. 12, 2009 4585

Ghavtadze et al.
SCHEME 3a b
,
b
a Mixture of diastereomers (R,S;S,R)/(R,R;S,S) ratio 1:3.6. Mixture of diastereomers (R,S;S,R)/(R,R;S,S) ratio 1:1.8 (determined in both cases from 19F
NMR spectra of the crude reaction mixtures).
SCHEME 4
FIGURE 1. Molecular structure of the hydrogen-bonded dimer of 6b
TABLE 2. Substitution Patterns for Compounds 4l-o and 5l-o
and Yields for Compounds 5l-o
in the solid state.12
no.
n
X
product ratio of diastereomersa R,R;S,S/R,S;S,R yield (%)
enones did not undergo clean cyclization reactions, probably
due to the stabilizing influence of the aryl fragment, thus
impeding the cyclization route.
An interesting feature of the novel dihydroindenodiazepines
6 is the relatively high barrier for the ring inversion as seen in
the NMR spectra, exemplified by broad signals for the diaste-
reotopic hydrogen atoms of the CH2 group at room temperature.
Obviously, the transformation of one enantiomer into another
requires several conformational changes of the relatively rigid
ring system.
Another interesting property characterizing dihydroindeno-
diazepines 6 is the formation of intermolecular hydrogen bonds
between the NH groups of one molecule and the nitrogen lone
pair of another molecule in the solid state leading to the
formation of dimeric aggregates (Figure 1).
For the transformations presented above we suggest the
following domino mechanisms resulting in the formation of the
tri- and tetracyclic products. In a similar manner to that proposed
for the oxime derivatives11 we emphasize the intermediacy of
dicationic superelectrophilic species13 for the in situ indenol
formation. A large excess of the very strong triflic acid provides
4l
0
1
2
1
CH2
CH2
CH2
O
5l
9:1
54
39
72
52
4m
4n
4o
5m
5n
5o
4.5:1
2.2:1
6:1
a The ratios were determined from 19F NMR spectra of the crude
reaction mixtures.
makes it more electron rich, and we expected preferred
formation of the diazepines. Indeed, 4g,h did not yield spiro-
compounds of type 5; the seven-membered ring compounds 6g
and 6h were the exclusive products of the reactions with yields
of 34 and 66%, respectively (for quantum chemical calculations
on these methyl-substituted systems, see the Supporting Infor-
mation). On the contrary, a derivative with a naphthyl group
instead of Ph (4i) produces the spiro compound 5g exclusively
in 37% yield. We have further noted that the reaction is
unsuccessful if the aryl fragment contains any deactivating
substituents. Reactions with p-Br-, p-Cl-, and m-CF3-containing
substrates give hints for the formation of indene derivatives,
but in complex mixtures and low yield, or only byproducts.
If the starting material contains the amino substituents R1 )
allyl or benzyl (4j,k) both these groups may be involved into
the cyclization reaction. Consequently, three products were
isolated in these two cases from the reaction mixtures (Scheme
3), two spiro compounds 5h,j (R ) vinyl) and 5i,k (R ) Ph),
but only each one derivate 6i (R ) vinyl) and 6j (R ) Ph)
could be identified. The diastereomeric mixtures 5j,k were
assigned from 2D (COSY, HSQC, HMBC) and NOE NMR
spectra.
(12) Data sets were collected with Enraf-Nonius CAD4 and Nonius Kap-
paCCD diffractometers in the case of Mo radiation equipped with a rotating
anode generator. Programs used: data collection EXPRESS (Nonius B.V., 1994)
and COLLECT (Nonius B.V., 1998), data reduction MolEN (Fair, K. Enraf-
Nonius B.V., 1990) and Denzo-SMN (Otwinowski, Z.; Minor, W. Methods
Enzymol. 1997, 276, 307.) Absorption correction for CCD-data SORTAV
(Blessing, R. H. Acta Crystallogr. 1995, A51, 33. Blessing, R. H. J. J. Appl.
Crystallogr. 1997, 30, 421) and Denzo (Otwinowski, Z.; Borek, D.; Majewski,
W.; Minor, W. Acta Crystallogr. 2003, A59, 228.) Structure solution SHELXS-
97 (Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.) Structure refinement
SHEXL-97 (Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.) Graphics
SCHAKAL (Keller, E. 1997). CCDC-693648 (6a), -693649 (3l), -693650
(5o), -693651 (4o), -693652 (6b), -693653 (6f), -693654 (6e) and-693655
(5e) contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (int) +44(1223)336-033, E-mail: deposit@ccdc.cam.ac.uk]
Azadienones 4l-o, derived from hydrazines of cyclic amines,
also give exclusively tetracyclic spiro compounds 5l-o as a
mixture of diastereomers (Scheme 4, Table 2).
In contrast to N,N-dialkyl-substituted compounds 4 N-methyl-
N-phenylamino- and N-(diphenylamino)-substituted 1-azadi-
4586 J. Org. Chem. Vol. 74, No. 12, 2009

Acid-Mediated Electrocyclic Domino Transformations
SCHEME 5
the favorable medium for superelectrophilic solvation and
consequently leads to a successful cyclization.
cyclization15 or 8π electrons in case of 1-(methyl,alkyl)amino-
1-azapenta-1,4-dien-3-ones 4 affording dihydroindenodiazepines
6 via a 1,7-electrocyclization (Scheme 5).
The proposed reaction sequence starts with 2-fold protonation
(at least in equilibrium) of the carbonyl function and of the N1-
hydrazone nitrogen atom, followed by subsequent 4π-1,5-
cyclization of the dicationic intermediated creating the indenol
moiety. This assumption is supported by the isolation of an
indenol species in case a sterically hindered hydrazone derivative
(an N-amino-2,6-dimethylpiperidine derivative) was employed,
thus blocking the subsequent steps of the reaction cascade.11
Sterically undemanding hydrazones, however, undergo a de-
hydration reaction of the in situ formed indenol, giving rise to
a diazenium intermediate. We assume that the dehydration step
is substantially promoted by the anhydride. Tautomerization of
the diazenium cation into an iminium cation,14 possibly via a
dicationic intermediate, and its further cyclization complete the
reaction. The last step may involve either 6π electrons affording
spiro derivatives of the dihydroindenepyrazole type 5 via a 1,5-
The proposed mechanism is supported by quantum chemical
calculations at the SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p)
level.16-19 Thus, quantum-chemical gas-phase protonation ener-
gies indicate a preferred first protonation of the carbonyl oxygen
atom, followed by a second protonation at the N1-hydrazone
nitrogen atom. (Oxygen protonation is preferred by ca. 4 kcal/
mol over protonation at the N1-hydrozone nitrogen atom and
ca. 6 kcal/mol at the N2-hydrazone nitrogen atom; see the
Supporting Information). For the next step, the 4π-1,5-cycliza-
(16) All computations in this study have been performed using the
Gaussian 03 suite of programs.17 The Becke three-parameter exchange
functional and the correlation functional of Lee, Yang, and Parr (B3LYP)
with the 6-311G(d,p) basis set were used to compute the geometries and the
normal mode vibration frequencies of the starting cations, the corresponding
transition structures, and the products. For single-point energy calculations
on DFT-optimized geometries the SCS-MP2 method was used.18 Transition
structures were localized starting with AM1, PM3 or PM6 reaction pathway
calculations using the MOPAC 2007 program.19 The transition structure were
further optimized at the DFT level with the Gaussian 03 package of programs
using the option “mndofc” (opt ) (ts, noeigentest, mndofc)), applying the
B3LYP/6-311G(d,p) basis set. In order to verify the character of the stationary
points, they were subjected to frequency analyses. In the following text, E
(0 K) energies are discussed, which contain zero-point corrections. The
vibration related to the imaginary frequency corresponds to the nuclear motion
along the reaction coordinate under study. In significant cases intrinsic
reaction coordinate (IRC) calculations were performed in order to unambigu-
ously connect transition structures with reactants and products. Bond orders
and atomic charges were calculated with the natural bond orbital (NBO)
method as implemented in the Gaussian 03 program.
(13) (a) Olah, G. A. Angew. Chem. 1993, 105, 805; Angew. Chem., Int. Ed.
Engl. 1993, 32, 767. (b) Lammertsma, K.; Schleyer, P. v. R.; Schwarz, H. Angew.
Chem. 1989, 101, 1313–1335; Angew. Chem.; Int. Ed. Engl. 1989, 28, 1321. (c)
Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211. (d) Olah, G. A.;
Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley: New York, 2007.
(14) (a) Snyder, J. P.; Heyman, M. L.; Gundestrup, M. J. Chem.Soc., Perkin
Trans. 1 1977, 13, 1551. (b) Wirschun, W. G.; Al-Soud, Y. A.; Nusser, K. A.;
Orama, O.; Maier, G.-M.; Jochims, J. C. J. Chem. Soc., Perkin Trans. 1 2000,
24, 4356.
(15) (a) Kamitori, Y.; Hojo, M.; Masuda, R.; Ohara, S.; Kawasaki, K.;
Yoshikawa, N. Tetrahedron Lett. 1988, 29 (41), 5281. (b) Kamitori, Y.; Hojo,
M.; Masuda, R.; Fujitani, T.; Ohara, S.; Yokoyama, T. J. Org. Chem. 1988, 53,
129. (c) Kamitori, Y.; Hojo, M.; Masuda, R.; Yoshida, T.; Ohara, S.; Yamada,
K.; Yoshikawa, N. J. Org. Chem. 1988, 53, 519.
J. Org. Chem. Vol. 74, No. 12, 2009 4587

Ghavtadze et al.
SCHEME 6. Calculated Relative Energies of Mono- (Upper
Line) and Dicationic Species (Lower Line) As Intermediates
in the 1,5-Cyclization (SCS-MP2/6-311G(d,p)//B3LYP/
6-311G(d,p) Including Zero-Point Correction (ZPE))
(kcal/mol)
tion to give the cationic indene intermediate,20 from many
calculations of various conformations and configurations we find
for the energy lowest dicationic route (see the Supporting
Information) a slightly endothermic (6.9 kcal/mol) reaction with
a relatively low activation barrier (15.7 kcal/mol)(Scheme 6,
lower line). In contrast, the unfavorable monocationic route is
predicted to be highly endothermic (27.8 kcal/mol) with a high
activation barrier (28.9 kcal/mol) (Scheme 6, upper line).
In order to discuss the aromatic character of the transition
structures of the electrocyclization reactions,21 the calculated
geometries and NICS values20c,22 (determined with respect to
an axis perpendicular to the center of the formed cyclic system
at B3LYP/6-311+G(d,p) level) are presented.
FIGURE 2. Calculated NICS values for the transition state of the
dicationic conrotatory 4π-ring closure reaction leading to the indenol
intermediate. The NICS values were calculated for a number of points
on a line perpendicular to the center of the forming ring (z-axis).
The transition structure of the conrotatory 4π electron
dicationic 1,5-cyclization process leading to the indenol cation
is calculated to be significantly nonplanar (deviation from
planarity 35°), indicating Mo¨bius aromaticity.23 The distance
between the terminal atoms of 2.05 Å is typical for C-C bond-
forming pericyclic reactions.24 The relatively low negative NICS
FIGURE 3. Molecular structure of the transition state for the first
(dicationic) 1,5-cyclization of 4a to 5a/6a (left); HOMO-2-plot (right,
isocontour value 0.03/0.03) (B3LYP/6-311G(d,p)).
value (lowest NICS value ) -5.2)25 and the large charge
separation between the terminal carbon atoms (0.65e) suggest
a high degree of ionic character for this step (Figure 2).20c The
binding interaction in this transition structure is dominated by
the HOMO-2 (Figure 3). The HOMO corresponds mainly to
the CdNH-N-system, while the HOMO-1 is localized at the
carbocyclic part of the cation.
Similarly, we investigated the monocationic second steps of
the cascade computationally, the 1,5-electrocyclization to the
spirocyclic compounds and the 1,7-electrocyclization to the
dihydrodiazepines. (Scheme 7).
(17) Gaussian 03: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji,
H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann,
R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, ReVision C.01; Gaussian, Inc.: Wallingford, CT, 2004. Details of
the quantum chemical calculations (Gaussian archive entries) may be obtained
from E.-U.W. upon request.
The reaction pathways start with two different conformations
of the iminium cation, necessary for 1,5- and 1,7-electrocy-
(18) Grimme, S. J. Chem. Phys. 2003, 118, 9095.
(19) (a) MOPAC2007: Stewart, J. J. P. Stewart Computational Chemistry,
Colorado Springs, CO, 2007, http://OpenMOPAC.net. (b) Stewart, J. J. P. J.
Mol. Modeling 2007, 13, 1173.
(23) (a) Heilbronner, E. Tetrahedron Lett. 1964, 1923. (b) Zimmerman, H. E.
J. Am. Chem. Soc. 1966, 88, 1564. (c) Zimmerman, H. E. Acc. Chem. Res. 1971,
4, 272. (d) Rzepa, H. S. Chem. ReV. 2005, 105, 3697. (e) Herges, R. Chem.
ReV. 2006, 106, 4820.
(20) (a) Kallel, E. A.; Houk, K. N. J. Org. Chem. 1989, 54, 6006. (b) Smith,
D. A.; Ulmer II, C. W. J. Org. Chem. 1997, 62, 5110. (c) Faza, O. N.; Lopez,
C. S.; Alvarez, R.; de Lera, A. R. Chem.sEur. J. 2004, 10, 4324.
(21) (a) Rzepa, H. S. J. Chem. Educ. 2007, 84, 1535. (b) Jiao, H.; Schleyer,
P.v.R. Angew. Chem. 1993, 105, 1833; Angew. Chem., Int. Ed. 1993, 32, 1763.
(22) (a) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema
Hommes, N. J. R. J. Am. Chem. Soc. 1996, 118, 6317. (b) Chen, Z.; Wannere,
C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. V. R. Chem. ReV. 2005, 105,
3842. (c) Stanger, A. J. Org. Chem. 2006, 71, 883.
(24) Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem. 1992, 104, 711;
Angew. Chem., Int. Ed. 1992, 31, 682.
(25) For the nucleus in dependent chemical shift (NICS) calculations the
gauge-independent atomic orbitals (GIAO) method using the 6-311+G(d,p) basis
set on the B3LYP/6-311G(d,p) geometries was applied. NICS values were
determined along an axis perpendicular to the center of the transition state
structure (15 points above and below the plane of the forming ring system with
a step width of 0.2 Å). The lowest value obtained is given in the text.
4588 J. Org. Chem. Vol. 74, No. 12, 2009

Acid-Mediated Electrocyclic Domino Transformations
SCHEME 7. Calculated Relative Energies for the Second
(Moncationic) 1,5-Cyclization Step (Upper Line) To Give 5a
and for the Second (Monocationic) 1,7-Cyclization Step
(Lower Line) To Give 6a (SCS-MP2/6-311G(d,p)//B3LYP/
6-311G(d,p) Including Zero-Point Correction (ZPE))
(kcal/mol)
SCHEME 8. Reaction Profiles for the Competing Second
Monocationic 1,5- (Right) and 1,7- (Left) Electrocyclization
Steps Leading to 5a and 6a (SCS-MP2/6-311G(d,p)//B3LYP/
6-311G(d,p) Including Zero-Point Correction (ZPE))
(kcal/mol)
(2.14 Å distance between the terminal atoms) corresponds to a
Mo¨bius type aromatic system (lowest NICS value ) -8.8,
charge separation between the terminal atoms ) 0.21e).25 The
binding interaction in this transition structure is dominated by
the HOMO-1 and the HOMO (Figure 5).
As the reaction profile (Scheme 8) shows, the spiro compound
can be considered the result of thermodynamic control with a
high activation barrier and significant exothermicity, while the
more energy-rich seven-membered ring formed via a lower
activation barrier is the result of kinetic control.
Inspired by these results, we tried to test this prediction
experimentally. Carrying out the cyclization of 4a at -40 °C,
we were pleased to observe besides some starting material the
exclusive formation of dihydroindenodiazepine 6a in 27% yield
without any spiro compound 5a. Carrying out the reaction at
higher temperatures compared to the standard one leads to the
formation of both products, but in lower yields, as at higher
temperatures much more complex mixtures are obtained.
Further, we were interested in computationally clarifing the
origin of the experimentally observed diastereoselectivity in
compounds 5j-o. For this purpose, the energy surface for the
formation of the spiro compounds from monocationic interme-
diates with asymmetric substitution at nitrogen atom N2 was
investigated on two examples. Indeed for the piperidine
compound there were two reaction channels detected, leading
either to the (R,S/S,R)- or (R,R/S,S) pairs of diastereomers
(Scheme 9). While the (R,S/S,R)-forms are predicted to be result
of kinetic control, the (R,R/S,S)-forms, which represent the major
isomers detected experimentally, result from pronounced ther-
modynamic control.
clization reactions, respectively. They were obtained from IRC
calculations starting from the transition structures and differ in
energy by about 1.7 kcal/mol.
The structure of the relatively early transition state of the
disrotatory 6π electron 1,5-electrocyclization (2.47 Å distance
between the terminal atoms) is essentially planar (deviation from
planarity 8°) as expected for a Hu¨ckel type system and has a
high negative NICS value (lowest NICS value ) -13.0)25 and
a small charge separation between terminal atoms (0.08e). These
data clearly support a pericyclic mechanism. The binding
interaction in this transition structure is dominated by the HOMO
(Figure 4).
The helical transition structure for the conrotatory 8π (or 12π
if the aryl moiety is included) electron 1,7-electrocyclization
FIGURE 4. Molecular structure of the transition state for the second,
monocationic 1,5-cyclization to give 5a (left); HOMO plot (right,
isocontour value 0.03/0.03) (B3LYP/6-311G(d,p)).
In contrast, the calculations for the morpholino system predict
a slight thermodynamic preference by only ca. 1 kcal/mol for
FIGURE 5. Molecular structure of the transition state for the second monocationic 1,7-cyclization step to give 6a (left); HOMO-1-plot (middle)
and HOMO-plot (right) (isocontour value 0.03/0.03) (B3LYP/6-311G(d,p)).
J. Org. Chem. Vol. 74, No. 12, 2009 4589

Ghavtadze et al.
SCHEME 9. Calculated Relative Energies for the
1,5-Cyclization Step (Monocationic) To Give R,S;S,R-5m
(Upper Line) and R,R;S,S-5m (Lower Line) (SCS-MP2/
6-311G(d,p)//B3LYP/6-311G(d,p) Including Zero-Point
Correction (ZPE)) (kcal/mol)
denodiazepine systems as the kinetically favored products of
the reaction, which was confirmed experimentally. Hu¨ckel- and
Mo¨bius-type aromatic transition structures of the electrocyclic
transformations were identified computationally. The novel
heterocyclic systems have unique structural features and may
possibly show interesting biological or pharmaceutical activities.
Experimental Section
General Procedure: Preparation of Hydrazones 2. Hydrazones
2 were prepared from R-ketoesters and the corresponding hydrazines.
R-Ketoester (1 equiv) was dissolved in absolute ethanol (1 mmol of
the compound in 2 mL of solvent), and hydrazine (1-1.1 equiv) in
absolute ethanol (1 mmol of the compound in 0.5 mL of solvent) was
added slowly at 0 °C. In the case of the synthesis of compounds 2e
and 2f, acetic acid (1 equiv) and a small amount of sodium acetate
were added to the reaction mixture in order to maintain pH 5-6. The
reaction mixture was stirred at rt for 4 h. The reaction mixture was
filtered, and the solvent was evaporated. The hydrazones 2 were
purified by distillation at reduced pressure.
Ethyl 2-(2-Ethyl-2-methylhydrazono)propanoate (2b). Com-
pound 2b was obtained from ethyl pyruvate (2.32 g, 20 mmol) and
N-ethyl-N-methylhydrazine (1.48 g, 20 mmol) according to the
general procedure. The subsequent distillation (0.3 mbar, 42-45
SCHEME 10. Calculated Relative Energies for the
1,5-Cyclization Step (Monocationic) To Give R,S;S,R-5o
(Upper Line) and R,R;S,S-5o (Lower Line) (SCS-MP2/
6-311G(d,p)//B3LYP/6-311G(d,p) Including Zero-Point
Correction (ZPE)) (kcal/mol)
1
°C) gave 2.81 g (16.33 mmol, 82%) 2b as a yellow oil: H NMR
(500 MHz, CDCl3) δ 1.15 (t, J ) 7.2 Hz, 3H, CH3CH2N), 1.34 (t,
J ) 7.1 Hz, 3H, CH3CH2O), 2.13 (s, 3H, CH3), 2.78 (s, 3H, CH3N),
3.14 (q, J ) 7.2 Hz, 2H, CH3CH2N), 4.29 (q, J ) 7.1 Hz, 2H,
CH3CH2O) ppm; 13C NMR (100 MHz, CDCl3) δ 12.8 (CH3CH2N),
14.2 (CH3CH2O), 15.7 (CH3), 43.2 (CH3N), 54.7 (CH3CH2N), 61.2
(CH3CH2O), 144.6 (CdN), 165.4 (COO) ppm. IR (film): ν˜ ) 3395
(w), 2937 (m), 2905 (w), 2870 (w), 2855 (w), 1734 (m), 1707 (s),
1580 (w), 1460 (m), 1447 (m), 1369 (m), 1310 (s), 1227 (m), 1173
(m), 1138 (s), 1096 (m), 1069 (m), 1036 (m), 995 (w), 939 (w),
860 (w), 797 (w), 754 (w), 708 (w), 665 (m) cm-1; HRMS (ESI)
calcd for C8H16N2O2Na 195.1104, found 195.1109. Anal. Calcd for
C8H16N2O2 (172.22): C, 55.79; H, 9.36; N, 16.27. Found: C, 55.44;
H, 9.60; N, 16.46.
General Procedure: Preparation of Ketophosphonates 3.
Dimethyl methylphosphonate (1 equiv) (d ) 1.161) was dissolved
in absolute THF (1 mmol of the compound in 1.5 mL of solvent)
and cooled to -78 °C, and n-BuLi (1.6 M in hexane, 1 equiv) was
added slowly. The reaction mixture was stirred for 1 h at -78 °C.
Then, hydrazone 2 (1 equiv) in absolute THF (1 mmol of the
compound in 0.5 mL) was added. The reaction mixture was stirred
for 4 h at -78 °C and then quenched with AcOH (1 equiv) and
water (∼10 equiv). After evaporation of the solvent, the residue
was dissolved in dichloromethane and washed first with water and
then with saturated aqueous NaHCO3 solution and again with water.
The residue was dried over MgSO4 and purified by column
chromatography.
the (R,S/S,R)-forms, which is in contrast to the observed results
(Scheme 10). However, kinetically, here the reaction channel
to the (R,R/S,S)-isomers is preferred. We conclude from these
calculated data that the imperfect diastereoselectivity in the
formation of five-membered ring is not due to deviation from
the Woodward-Hoffmann rules but has to be traced back to
an equilibrium of the monocationic chain compounds.
Dimethyl 3-(2,2-Dimethylhydrazono)-2-oxobutylphosphonate (3a).
Compound 3a was obtained from compound 2a (1.71 g, 10.81
mmol) and dimethyl methylphosphonate (1.34 g, 10.81 mmol)
according to the general procedure. The subsequent chromato-
graphic purification (Et2O/acetone, 2:1) gave 1.53 g (6.48 mmol,
1
60%) 3a as a yellow oil: H NMR (300 MHz, CDCl3) δ 2.06 (s,
Conclusion
3H, CH3), 3.11 (s, 6H, CH3N), 3.58 (d, J ) 22.2 Hz, 2H, CH2P),
3.77 (d, J ) 11.1 Hz, 6H, CH3O) ppm; 13C NMR (75 MHz, CDCl3)
δ 12.4 (CH3), 33.9 (d, J ) 132.3 Hz, CH2P), 46.7 (CH3N), 52.6
(d, J ) 6.2 Hz, CH3O), 141.9 (CdN), 191.2 (d, J ) 6.3 Hz, CO)
ppm; 31P NMR (121.5 MHz, CDCl3) δ 23.8 ppm; IR (film) ν˜ )
3532 (w), 3464 (w), 2990 (w), 2957 (m), 2876 (w), 2853 (w), 2795
(w), 1665 (s), 1557 (s), 1448 (m), 1387 (w), 1367 (w), 1259 (s),
1204 (w), 1148 (w), 1132 (w), 1063 (m), 1030 (s), 947 (w), 878
(w), 845 (w), 804 (m), 754 (w), 745 (w), 689 (w) cm-1; HRMS
(ESI) calcd for C8H17N2PO4Na 259.0818, found 259.0804. Anal.
Calcd for C8H17N2PO4 (236.21): C, 40.68; H, 7.25; N, 11.86. Found:
C, 40.66; H, 7.27; N, 11.89.
In summary, we have disclosed a novel transformation
cascade of 5,5-disubstituted 1-azapenta-1,4-dien-3-ones 4 under
the conditions of superelectrophilic solvation involving succes-
sive electrocyclization reactions affording two new classes of
heterocyclic productssdihydrospiroindenepyrazoles 5 and di-
hydroindenodiazepine derivatives 6. In the case of methyl- and
alkylhydrazine derived hydrazones both products were isolated
from the same experiment. Hydrazones derived from cyclic
hydrazines afford interesting tetracyclic products as a mixture
of diastereomers. Computational studies predicted dihydroin-
4590 J. Org. Chem. Vol. 74, No. 12, 2009

Acid-Mediated Electrocyclic Domino Transformations
General Procedure: Preparation of Azapentadienones 4.
t-BuOK (1 equiv) was dissolved in absolute THF (1 mmol of the
base in 10 mL of solvent), and ketophosphonate (1 equiv) 3 in
THF (1 mmol of the compound in 2 mL of solvent) was added.
The reaction mixture was stirred for 1 h at rt, and trifluoroacetylke-
tone (1 equiv) in THF was added. The reaction mixture was stirred
for 4 h at rt. Then, the solvent was evaporated. The residue was
dissolved in dichloromethane, washed with brine, dried over
MgSO4, concentrated, and purified using column chromatography.
(CH-arom), 128.8, 130.9, 135.5 (q, J ) 34.9 Hz, CCF3), 137.7,
138.1 (q, J ) 4.9 Hz, CH), 145.6 (CdN) ppm; 19F NMR (282
MHz, CDCl3) δ -64.7 ppm; IR (KBr) ν˜ ) 3431 (m), 3067 (s),
2999 (m), 2968 (m), 2916 (m), 2878 (m), 2862 (m), 2843 (s), 2828
(s), 2793 (m), 1975 (w), 1935 (w), 1898 (w), 1746 (w), 1719 (w),
1630 (s), 1612 (s), 1580 (m), 1543 (w), 1458 (s), 1381 (s), 1335
(m), 1313 (s), 1302 (s), 1275 (s), 1259 (m), 1234 (s), 1196 (s),
1177 (s), 1140 (s), 1111 (s), 1057 (s), 1040 (m), 1016 (m), 1007
(m), 964 (s), 907 (s), 878 (m), 851 (s), 770 (s), 706 (m), 652 (s),
638 (m), 621 (m), 606 (m), 561 (m), 546 (w), 521 (w), 488 (w)
cm-1; HRMS (ESI) calcd for C14H13F3N2H 267.1104, found
267.1094. Anal. Calcd for C14H13F3N2 (266.26): C, 63.15; H, 4.92;
N, 10.52. Found: C, 62.91; H, 5.09; N, 10.29.
1
In all cases, the E-isomers were the main products. H and 13C
signals are assigned for the main E-product. The stereochemistry
and the ratios of E- and Z-isomers were determined by comparing
the 19F chemical shifts to compounds with known stereochemistry
from the crude reaction mixtures.6
2,4-Dimethyl-6-(trifluoromethyl)-2,3-dihydro-1H-indeno[7,1-
de][1,2]diazepine (6a). Compound 6a was obtained from azadienone
4a (0.207 g, 0.73 mmol) according to the general procedure. The
subsequent chromatographic purification (TBME/pentane, 4:1) gave
0.070 g (0.26 mmol, 36%) 6a as a red solid: mp 125 °C (dec); 1H
NMR (600 MHz, CDCl3) δ 2.34 (s, 3H, CH3), 2.53 (s, 3H, CH3),
4.16 (br d, 1H, CH2), 4.33 (br d, 1H, CH2), 6.82 (s, 1H, NH), 6.93
(dd, J ) 7.3, 0.6 Hz, 1H, H-arom), 7.17 (t, J ) 7.6 Hz, 1H,
H-arom), 7.23 (q, J ) 1.4 Hz, 1H, CH), 7.55 (d, J ) 7.8 Hz, 1H,
H-arom) ppm; 13C NMR (150 MHz, CDCl3) δ 18.8 (CH3), 40.5
(CH3N), 62.1 (CH2), 109.1 (C-olef), 118.6 (CH-arom), 120.2 (q, J
) 34.3 Hz, CCF3), 122.2 (CH-arom), 123.2 (CH-arom), 124.5 (q,
J ) 281.9 Hz, CF3), 127.0 (q, J ) 4.9 Hz, CH), 131.6, 132.5, 134.2
(q, J ) 1.7 Hz), 154.0 (C-N) ppm; 19F NMR (282 MHz, CDCl3) δ
-59.8 ppm; IR (KBr) ν˜ ) 3256 (s), 3076 (m), 3022 (m), 2968
(m), 2928 (m), 2797 (w), 1697 (w), 1607 (s), 1595 (s), 1547 (s),
1514 (s),1483 (s), 1431 (s), 1387 (s), 1356 (s), 1337 (s), 1319 (s),
1261 (m), 1240 (s), 1221 (s), 1198 (s), 1169 (s), 1151 (s), 1124
(s), 1099 (s), 1084 (s), 1049 (s), 1034 (s), 957 (m), 943 (m), 889
(w), 851 (m), 795 (s), 766 (s), 708 (m), 689 (m), 671 (m), 660
(m), 629 (m), 604 (w), 565 (s), 511 (m), 482 (w) cm-1; HRMS
(ESI) calcd for C14H13F3N2H 267.1104, found 267.1110. Anal.
Calcd for C20H16F3N5O7 (picrate) (495.37): C, 48.49; H, 3.26; N,
14.14. Found: C, 48.51; H, 3.32; N, 13.82.
2-(2,2-Dimethylhydrazono)-6,6,6-trifluoro-5-phenylhex-4-en-3-
one (4a). Compund 4a was obtained from ketophosphonate 3a
(0.408 g, 1.72 mmol) according to the general procedure. The
subsequent chromatographic purification (TBME/pentane, 1:1) gave
0.372 g (1.31 mmol, 76%) 4a as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 1.94 (s, 3H, CH3), 3.08 (s, 6H, CH3N), 7.23-7.26 (m,
2H, H-arom), 7.31-7.35 (m, 3H, H-arom), 7.46 (q, J ) 1.45 Hz,
1H, H-olef) ppm; 13C NMR (75 MHz, CDCl3) δ 12.4 (CH3), 46.7
(CH3), 123.2 (q, J ) 273.9 Hz, CF3), 128.0 (CH-arom), 128.6 (CH-
arom), 129.0 (CH-arom), 130.8 (q, J ) 5.4 Hz, CH-olef), 132.4
(C-ipso), 136.2 (q, J ) 30.1 Hz, CCF3), 142.3 (CdN), 189.2 (CO)
ppm; 19F NMR (282 MHz, CDCl3) δ -66.9 ppm (E-isomer), -59.8
(Z-isomer), ratio 19:1; IR (film) ν˜ ) 3289 (w), 3088 (w), 3061
(m), 3026 (m), 2926 (m), 2878 (m), 2841 (m), 2795 (w), 1956
(w), 1882 (w), 1751 (w), 1715 (w), 1665 (s), 1555 (s), 1497 (s),
1445 (s), 1429 (s), 1404 (m), 1369 (s), 1269 (s), 1236 (s), 1171
(s), 1096 (s), 1080 (s), 1034 (s), 1003 (m), 970 (s), 945 (m), 914
(m), 878 (m), 837 (m), 808 (m), 779 (m), 756 (m), 700 (s), 646
(s), 615 (m) cm-1; MS (EI) m/z 284 [M]+, 215, 199, 151, 127, 85,
57. Anal. Calcd for C14H15F3N2O (284.28): C, 59.15; H, 5.32; N,
9.85. Found: C, 59.10; H, 5.21; N, 9.64.
General Procedure: Cyclization of Azapentadienones with
the Use of Trifluoromethanesulfonic Acid. A solution of trifluo-
romethanesulfonic acid (10 equiv) in dry dichloromethane (1 mL
of acid in 50 mL of solvent) was cooled to -10 °C. A solution of
the 1-azapenta-1,4-dienone 4 (1 equiv) in dry dichloromethane (1
mmol of the compound in 5 mL of solvent) was added dropwise
with stirring. After complete addition, stirring was continued for
1 h. The reaction mixture was then treated with acetic anhydride
(20 equiv) and stirred at 0 °C for 1 h. A saturated solution of sodium
hydrogen carbonate was added carefully for neutralization of the
acidic mixture. The organic layer was washed with saturated sodium
hydrogen carbonate solution until the aqueous layer became neutral.
Then the organic layer was washed with water and dried with
MgSO4, and the solvent was evaporated. The substances were
purified by column chromatography. The identity of the diastere-
omers was determined on the basis of NOE experiments. The ratio
of diastereomers was determined from 19F spectra for the crude
reaction mixtures.
X-ray crystal structure analysis of 6a:12 formula C14H18F3N2, M
) 266.26, colorless crystal 0.40 × 0.25 × 0.20 mm, a ) 21.159(1)
Å, b ) 8.921(1) Å, c ) 16.079(3) Å, ꢀ ) 123.22(1)°, V ) 2539.1(3)
Å3, Fcalc ) 1.393 g cm-3, µ ) 0.979 mm-1, empirical absorption
correction (0.640 e T e 0.828), Z ) 8, monoclinic, space group
C2/c (No. 15), λ ) 1.54178 Å, T ) 293(2) K, ω and ꢁ scans,
17000 reflections collected (( h, ( k, ( l), [(sin θ)/λ] ) 0.60 Å-1
,
2230 independent (Rint ) 0.031) and 2130 observed reflections
[I g 2σ(I)], 178 refined parameters, R ) 0.048, wR2 ) 0.130, max
(min) residual electron density 0.25 (-0.26) e Å-3, hydrogen atoms
calculated and refined as riding atoms.
Acknowledgment. This work was supported by the NRW
Graduate School of Chemistry Mu¨nster, the Deutsche Fors-
chungsgemeinschaft (DFG, Bad Godesberg) and the Fonds der
Chemischen Industrie (Frankfurt).
1′,3′-Dimethyl-3-(trifluoromethyl)-1′,5′-dihydrospiro(indene-1,4′-
pyrazole) (5a). Compound 5a was obtained from azadienone 4a
(0.207 g, 0.73 mmol) according to the general procedure. The
subsequent chromatographic purification (TBME/pentane, 4:1) gave
0.062 g (0.23 mmol, 32%) of 5a as a red solid: mp 52-53 °C; 1H
NMR (500 MHz, CDCl3) δ 1.48 (s, 3H, CH3), 2.92 (s, 3H, CH3N),
3.32 (d, J ) 9.7 Hz, 1H, CH2), 3.46 (d, J ) 9.7 Hz, 1H, CH2),
6.82 (q, J ) 1.65 Hz, 1H, CH), 7.35 (dt, J ) 7.4, 1.0 Hz, 1H,
H-arom), 7.40 (dt, J ) 7.5, 1.2 Hz, 1H, H-arom), 7.47-7.50 (m,
2H, H-arom) ppm; 13C NMR (125 MHz, CDCl3) δ 11.8 (CH3),
43.6 (CH3N), 64.0 (CH2), 69.0 (C-spiro), 121.0 (CH-arom), 122.0
(q, J ) 270.3 Hz, CF3), 123.3 (CH-arom), 127.6 (CH-arom), 128.4
Supporting Information Available: Detailed procedures for
the synthesis of the new compounds; spectral characteristics of
1
the synthesized compounds; H and 13C spectra for the new
compounds; Cartesian coordinates and SCS-MP2/6-311G(d,p)//
B3LYP/6-311G(d,p)+ZPE energies for the calculated structures
together with additional quantumchemical results and thermal
ellipsoid plots for the crystal structures (50% ellipsoid prob-
ability). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900270E
J. Org. Chem. Vol. 74, No. 12, 2009 4591