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Mechanism of the Cyclopropane УWalkФ Rearrangement Synthesis and Properties of the 2-Diazopropane Adduct of Cyclooctatetraene.

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CAS Registry numbers:
1, 52253-32-4; 2, 88245-12-9; 3, 62917-71-9; 4, 88245-13-0.
111 E. Michael, B. Hennig, H. Kreisel: Handbuch f i r Pilzfreunde, Ed. 3,
VEB Gustav Fischer Verlag, Jena 1979,3rd Edit., p. 380, and other reference works on fungi.
[2] The FeS0, mentioned in the literature is much less effective, since Fe"
must first be oxidized to Fe"' for complexation with 1 and 2.
[31 Collected in October 1981 near the Karlburg, Karlstadt/Main (FRG).
141 G. Zinner, G. Isensee, Arch. Pharm. 307 (1974) 7.
IS] a) 2 : [ag& +28.5 ( c = 1, H20); MW 219 (cryoscopic); empirical formula
C8H17N304(FAB-MS); 'H-NMR (400 MHz, D20): 6=1.55 (m, 2H),
1.75 (m. 2H), 2.75 (s, 6H), 3.05 (t, J=7.5 Hz, 2H), 3.55 (t, J=5.5 Hz,
1H); "C-NMR (D20): 6=24.4 (tm, J =129+4 Hz, C-4), 30.2 (tm,
130+3, C-3), 40.0 (49, 140+3.5, C-7), 55.0 (tt, 140+3, (2-9, 57.0 (dt,
146+2, C-2), 168.4 (br. s, C-6), 177.0 (sdt, 4+4, (2-1); we thank Prof. Dr.
H. Kelker and Dr. B. Bogdoll, Hoechst AG, for the FAB-MS measurements; b) 4: IR (CCI,): 2979 (w), 1703 (vs), 1520 (s), 1430 (m), 1392 (s),
1349 (m), 1265 (m), 1155 (s), 550 cm-' (m); 'H-NMR (CDCI,): 6=2.88,
3.02,4.18 (each s, 9H); "C-NMR (CDCI,): 6=35.4 (qq, J = 140+3 Hz),
57.4 (q, J = 144 Hz), 158.2 (br. s); MS: m / z 131 ( M + , C4H9N302,5.7%),
72 (CpHGNO, 100).
[6] F. Weygand, W. Steglich, D. Mayer, W. von Philipsborn, Chem. Ber. 97
(1964) 2023.
[7] Y. Isowa, T. Takashima, M. Ohmori, H. Kurita, M. Sato, K. Mori, Bull.
Chem. Soc. Jpn. 45 (1972) 1464. We thank Prof. Dr. T. Anke, Kaiserslautern, for a sample of the substance.
[S] Y. Isowa, T. Takashima, M. Ohmori, H. Kurita, M. Sato, K. Mori, Bull.
Chem. SOC.Jpn. 45 (1972) 1461.
[9] J. B. Neilands in A. Jacobs, M. Worwood: Iron in Biochemistry and Medicine, Vol. 2, Academic Press, London 1980, p. 529.
[lo] V. Mortarini, R. Calvino, A. Gasco, B. Ferrarotti, A: Sanfilippo, G.
Schioppacassi, Eur. J. Med. Chem. Chim. Ther. 15 (1980) 475.
[Ill A. Gasco, A. Serafino, V. Mortarini, E. Menziani, M. A. Bianco, J. C.
Scurti, Tetrahedron Lett. 1974,3431; H. Umezawa, T. Takeuchi, H. Iinuma, M. Ito, M. Ishizuka, Y. Kurakata, Y. Umeda, Y. Nakanishi, T. Nakamura, A. Obayashi, 0. Tanabe, J . Antibiot. 28 (1975) 87.
[12] N. I. Sax: Dangerous Properties of Industrial Materials, Van NostrandReinhold, New York 1979, 5th Edit., p. 528.
[13] R. Schoental: "Toxins Anim. Plant Origin" in A. De Vries, E. Kochva:
Proc. 2nd Int. Symp. Anim. Plant Toxins, Vol. 2, Gordon and Breach
1972, p. 781; Chem. Absrr. 82 (1975) 119915k.
[14] See e.g. R. J. Yu, E. J. van Scott, J. Invest. Dermatol. 63 (1974) 279.
[l5] The components 1, 2 and 4 remain unchanged after boiling the fungi
for 30 min.
Mechanism of the
Cyclopropane "Walk" Rearrangement :
Synthesis and Properties of
the 2-Diazopropane Adduct of Cyclooctatetraene""
By Frank-Gerrit Klarner* and Volker Glock
Whether the stereospecific cyclopropane "walk" rearrangement of the vinylogous systems bicyclo[2.1.0]pent-2ene, bicyclo[4.1.0]hepta-2,4-diene (norcaradiene) and cisbicyclo[6.1.0]nona-2,4,6-trieneproceed concertedly or in
two steps via diradicals cannot be unequivocally decided
on the basis of the results of stereochemical and kinetic investigations alone"'. An attempt was therefore made to
generate the possible diradical intermediates via an independent route. We report here on the synthesis and thermolysis of 1, which is a suitable precursor for a diradical
of the type 2, the potential intermediate of the "walk"
rearrangement 3 --+ 3'.
Cyclooctatetraene reacts with diazopropane differently
than with diazomethane and diazoethane"]; even at
- 15°C the bicyclic dihydropyrazole 1 is primarily pro-
duced, which can be separated free of isomer from the tricyclic dihydropyrazole 4, formed concomitantly as byproduct, by reaction with N-phenylmaleimide and subsequent column chromatography (Fluorisil, ether-pentane
(1 :3), - 20 "C; yield 7.6% referred to 2-dia~opropane)[~].
Similarly, as in the case of other bicyclic cyclooctatriene
derivatives[41,the valence isomerization 1 -+4 already occurs at room temperature (25 "C: T , , =
~ 89 min).
- Nz
c H3 7
Scheme 1. k1,4=6.3 x 10" exp [(-21.4f0.4) kcal/RT]; K=[4], :[l]- 2100;
ka,s=2.7x l O I 5 exp I(-34.3f0.7) kcal/RT]; k6,,=7.4x l O I 5 exp [(-39.8*0.5)
On heating the tricyclic dihydropyrazole 4 at 110°C, up
to 95% N,-cleavage takes place to give the trans- and cis9,9-dimethylbicyclo[6.1.0]nona-2,4,6-triene
5 in a ratio of
149 : lLS1(gas chromatography). In addition, 5% cycloreversion to 3,3-dimethyl-3H-pyra~ole[~]
and benzene is also observed. The structure of the novel hydrocarbon trans-5[']
follows unambiguously from its spectral data[3]. From a
comparison of the activation parameters of the reactions
4 +5 and 6 + 7 given in Scheme 1, it emerges that the NZcleavage at 110°C is 500 times more rapid than in the
structurally related cyclobutene-diazopropane adduct 6.
This finding indicates that the N,-cleavage does not occur
from the tricycle 4 but from the valence isomeric bicycle
To gain further insight into the course of the reaction
4+5, the thermal behavior of [1,2-DZ]-4,obtainable from
C-1: 83.0% D
C - 2 : $7.170 D
[ l 1 2 - D z ]- 8
[ 1,2-D,1-4
[*] Prof. Dr. F.-G. KlBrner, Dip1.-Chem. V. Glock
Abteilung fur Chemie der Universitat
Postfach 102148, D-4630 Bochum 1 (FRG)
trans- [ 1,Z-D,] -5
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. Engl. 23 (1984) No. I
trans-[ 2 , 3 -D,] -5
Scheme 2. Ratio of trans-[1,2-Dz]-5 to trans-[2,3-D2]-5 at 110 "C: 50.8 :49.2
(2H-NMR), 51.9 :48.1 ('H-NMR); kH/kD=1.19f0.02.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0101-0073 $02.50/0
4 by base-induced H I D exchange in tetrahydrofuran
(THF), was investigated (KOt-C,H,, DzO-THF, room temperature, 16 h, yield 19%). The deuterium content quoted
in Scheme 2 derives from the 'H- and 'H-NMR spectra.
After partial thermolysis of 11,2-Dz]-4 (llO"C, 140 min,
conversion: 50%), the content and position of the deuterh m atoms in the recovered educt remain unchanged. According to the 'H- and 'H-NMR analyses, the main product consists of equal amounts of the regioisomers trans[1,2-Dz]-5 and trans-[2,3-Dz]-5.
The surprising formation of trans-5 from the cis-configurated dihydropyrazole 4 can be explained as follows: After
the valence-isomerization 4 + 1, N,-cleavage starts to take
place from the exo-conformation of 1 shown in Scheme 2;
this conformation of 1 is undoubtedly thermodynamically
preferred over the corresponding endo-conformation. The
structure of the likely diradical intermediates 8 and/or 2
resembles that of the homotropylium ion, and favors ringclosure to the trans-configurated bicyclo[6.1.O]nonatriene
system. For formation of the cis-bicyclo[6.1.O]nonatriene,
the intermediate must exist in the endo-conformation. Ring
inversion obviously competes only to a very limited extent,
if at all, with the ring-closure reaction. From the deuterium
labeling experiment it can be concluded that the ring-closure between C-9 and C-1 proceeds at the same rate as that
between C-9 and C-7. This finding can hardly be reconciled with the diazenyl diradical 8 as intermediate for the
ring-closure. For the rear attack on the C atom bearing the
diazenyl radical previously discussed in the literature, a
preferred ring-closure between C-9 and C-7 would be expected. The experimental result, however, rather requires
an intermediate having the symmetry properties of the N2free diradical 2. The observation that the cis-configuration
is preserved during the "walk" rearrangement in the cis-bicyclo[6.1.0]nonatriene system rules out the participation of
a diradical intermediate of type 2 in this process.
Received: September 16, 1983 [Z 552 IE]
revised: November 14, 1983
German version: Angew. Chem. 96 (1984) 78
[I1 Review: F.-G. Klarner, F. Adamsky, Chem. Eer. 116 (1983) 299. F.-G.
Klamer, Top. Stereochem. 15, in press.
[21 A. Calatroni, R. Gandolfi, Heterocycles 14 (1980) 1115.
[31 'H-NMR(250 MHz, CDC13, TMS): 1 (-23°C): 6=1.22, 1.50 (s, 2CH3);
2.47 (d*, 8-H, J1,8=7.6 Hz); 5.52 (dd*, 1-H, J1,2=6.3 Hz); 5.64-5.79,
5.88-6.20 (m, 2-H to 7-H).-4: 6=1.10, 1.61 (s, 2CH3); 2.48 (m, 8-H,
J1,a=5.5 Hz, J2,8=1.0 Hz, J7,8=6.3 Hz); 2.67 (m, 7-H, J1,,=1.0 Hz,
J2.7-9.3 HZ,J6,7=5.1 HZ); 3.05 (m, 2-H, J1,2=3.0 Hz, J2,3=3.0 Hz); 5.16
(m, 1-H); 5.47 (dd*, 6-H, J5,6=9.8 Hz); 5.73 (m, 3-, 5-H); 5.86 (m, 4-H).trans-5 (c6D6): 6=0.61 (d*, 1-, 8-H, Jl,z=J7,a=1.6 Hz); 1.15 (s, 2CH3);
5.91-6.36 (m, 2-H to 7-H).--The signals marked with an asterisk are
broadened by extensive coupling.
141 Review: G. I. Frey, R. G. Saxton: The Chemistry of Cyclo-octatetraene and
its Deriuatiues, Cambridge University Press, Cambridge (England) 1978,
p. 40ff.
151 a) cis-9,9-Dimethylbicyclo[6.I.O]nona-2,4,6-triene: S. W. Staley, T. J. Henr y , J . Am. Chem. SOC.91 (1969) 1239; b) GC: 70 m glass capillary column,
silicone oil OV 101, temperature 1OO"C, helium as carrier gas. trans-5 is
not entirely stable under the GC conditions; in some analyses it rearranges (up to cu. 3%) to a hydrocarbon which has the same retention time
as trans-1,l-dimethyl-7,7a-dihydroindene.
161 G. Snatzke, H. Langen, Chem. Eer. 102 (1969) 1865.
171 The parent compound trans-bicyclo[6.1.0]nona-2,4,6-trieneis formed,
inter alia, in the photolysis of cis-bicyclo[6.1.0]nona-2,4,6-triene.W.
Grimme, Habilitationsschrift, UniversitXt Koln 1968; G. Masamune, P.
M. Baker, K. Hojo, Chem. Commun. 1969, 1203.
[8] Review: P. S. Engel, Chem. Reu. 80 (1980) 99. For the case of the diazenyl
diradical 8 as an intermediate the rotation about the C8-C9 bond must
be assumed to precede the ring-closure reaction. According to the observed stereoselectivity, conformational processes seem to compete with
the ring-closure reaction to only a minor extent.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
Macrocycles by
Intramolecular Diels-Alder ReactionRegioselective Synthesis of Anthracycline
By Joaquin Tamariz and Pierre Vogel*
The intramolecular Diels-Alder reaction is a powerful
synthetic tool and has been applied widely"]. Usually, the
connective chain between diene and dienophile moieties
consists of three to five atoms; if longer, the intramolecular reactivity and regio- and stereoselectivity decrease. It is
therefore not surprising that this technique has not yet
been widely used for the synthesis of medium-ring and macrocyclic corn pound^^^^^^. We report here an unusual regioand stereoselective macrocyclic synthesis using an intramolecular Diels-Alder reaction. The method suggests a
new approach to the synthesis of anthracycline precursors
such as daun~mycinone[~~.
4, R = CcHSCO
R = (CH,),OH
R = (CH2)$dr
R = (CH,),jOCOCH=CH,
Mesylate 2, derived from 1IS1,furnished phenolate 3
upon treatment with KOtBu. Reaction with benzoyl chloride, followed by oxidation with dichlorodicyanobenzoquinone gave 4 (%yo, m. p. = 148-149°C). Inspection of
simple molecular models indicates that an intramolecular
Diels-Alder addition could be possible if, for example,
acrylic acid were linked to naphthol 5 through a threemembered chain. Transesterification of 4 (KZC03/
CH30H) furnishes 5 (m.p. = 194-195"C, 98%). The corresponding naphthoate generated in tetrahydrofuran (THF)
using NaH reacts with 3-bromopropanol (molar ratio 1 : 1,
70°C, 3 h) to give 6 (m.p.=134-135"C, 96%). Esterification with acrylic acid yields 7 (51.5%). When dilute solutions ( < 8 x l o p 3 M) of 7 in xylene (with or without ZnCI,
or BF3.EtzO) are heated to 140-240°C only polymerization was observed. The failure to observe macrocycle formation with 7 led us to choose a longer connecting chain
between diene and dienophile.
The sodium naphthoate of 5 , generated using NaH in a
mixture of THF and hexamethylphosphoric triamide (1 :2)
reacts with 1,6-dibromohexane (molar ratio 1 :4, O"C, 0.5
h) to yield bromide 8 (75?/0).Treatment with acrylic acid
and 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) (molar ratio
2.2 :2 :1) in benzene (SOOC, 2 h) afforded acrylate 9 as a
[*I Prof. Dr. P. Vogel, Dr. J. Tamariz
Institut de chimie organique, Universite de Lausanne
2, rue de la Barre, CH-1005 L.ausanne (Switzerland)
[**I This work was supported by the Swiss National Science Foundation, the
Commission Fedkale des Bourses, and Hoffmann-La Roche AG, Basel.
0570-0833/84/0101-0074 $02.50/0
Anyew. Chem. lnt. Ed. Engl. 23 (1984) No. I
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adduct, synthesis, properties, rearrangements, mechanism, cyclopropane, cyclooctatetraene, diazopropane, уwalkф
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