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Iterative Cyclopentane Annulation of -Enones.

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tation in 3 (AAG' > 6 kcal/mol). 8n-"Antiaromaticity" in
the cycloheptatrienide ion, on the other hand, cannot be of
much significance energetically, since the difference in barriers for 1 and 2 is only 3.5 kcal/mol. According to the Xray structure analysis, 1 . 2 T H F has a "pentadienide ion"
structure (long C2C3 and C4Cs bonds and a short C3C4
h
wart, T. H. Siddall, 111, Chem. Rev. 70 (1970) 517); C8N in 1 . 2 T H F :
1.435 A. X-ray structure analysis of 1 '2THF, W. Bauer, T. Laube, D.
Seebach, Chem. Ber.. in press. We thank Professor Seebach for a copy of
the manuscript.
151 a) M. J. S. Dewar, N. Trinajstic, Tetrahedron 26 (1970) 4269; b) A. W.
Zwaard, A. M. Brouwer, J. J . C. Mulder, Recl. Trau. Chim. Pays-Bas 101
(1982) 137; c) A. W. Zwaard, Ph. I). Thesis, Universitat Leiden 1983; d)
W. Thiel, G. Boche, unpublished results; see also R. Breslow, Acc. Chem.
Res. 6 (1973) 393.
[6] See, e.g., S. W. Staley, A. W. Orvedal, J . A m . Chem. SOC.95 (1973)
3382.
Iterative Cyclopentane Annulation of u,P-Enones**
II
By Maria Dorsch, Volker Jager*, and Wolfgang Sponlein
There is currently extensive interest in the synthesis of
polycyclopentanoidsf'l, primarily because this structural
moiety is present in a variety of biologically active natural
products and theoretically interesting molecules. However,
efficient protocol for iterative cyclopentane annulation is
rare[',21.The following communication reports a four-step
sequence of this kind, to convert substituted a,b-unsaturated carbonyl compounds into ring-homologous cyclopentenones. To-date, this has enabled the synthesis of several mono- and bicyclic enones, as well as a tricyclic derivative.
1.
5
L -6
Fig. I . 'H-NMR spectra (100 MHz) of 1 in [D,]tetrahydrofuran (THF) at 83,
70, and 39°C.
bond)[41.Likewise, MO calculations on diverse cycloheptatrienyl anions lead to similar
which is in accordance with the small AAG' value for 1 and 2. At the
same time, cycloheptatrienide ion derivatives show paratropic shifts of the signals in the 'H-NMR spectrum[2b.61.
Received: June 8, 1984;
revised: August 3, 1984 [Z 875 IE]
German version: Angew. Chem. 96 (1984) 788
CAS Registry numbers:
1 , 86233-66-1; 2, 92270-11-6; 3, 92270-12-7
[I] Lithium I-(dimethylamino)vinylate (lithium enolate of N,N-dimethylacetamide) e.g. is conformationally stable: R. P. Woodbury, M. W. Rathke, J .
Org. Chem. 42 (1977) 1688.
[2] a) K. M. Rapp, T. Burgemeister, J. Daub, Tetrahedron Let?. 1978, 2685;
W. Bauer, J. Daub, K. M. Rapp, Chem. Ber. 116 (1983) 1777, spectroscopic investigation of 1 in T H F at - 10°C; b) A. W. Zwaard, H. Kloosterziel, Recl. Trau. Chim. Pays-Bas 100 (1981) 126, investigated the potassium compound of 1 in NH, at -40°C.
131 The conformation of lithium (cyclopentadieny1idene)ethanolate (lithium
enolate of the methyl ketone) is stable at 55°C (AG+(55"C)> 18 kcal/
mol, while the rotation about C5C6 in lithium cyclopentadienylidene(meth0xy)methanolate (Li-enolate of the methyl ester) freezes in at - 14°C
( A G f ( - 14"C)= 13.0f0.2 kcal/mol): G. Boche, R. Eiben, W. Thiel, Angew. Chem. 94 (1982) 703; Angew. Chem. Int. Ed. Engl. 21 (1982) 688; Angew. Chem. Suppl. 1982, 1535; thus, this barrier depends considerably on
the strength of the acceptor substituents.
141 3 : The rotation about C6-N in 3 is also of interest. A broadening of the
N-methyl signal is first observable at - 100"C, a splitting first at - 106°C
(AG+ (- 106"C)=8 kcal/mol). The C6N bond should thus have considerably less double bond character than normal "amide bond". This is
consistent with bond lengths of = 1.34 A for C N in amides (W. E. Ste-
a
798
3
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
The new annulation sequence is summarized by formula
A . The key steps (see Scheme 1) are:
(1) Preparation of an allylic alcohol from an a,p-enone by
LiAIH4 reduction or Grignard addition;
(2) Claisen rearrangement of the allylic alcohol involving
Johnson's o r t h o e ~ t e r ~h1~ or
" . Ireland's ketene acetal
m o d i f i c a t i ~ n [ ~ ~followed
-~I,
by hydrolysis to 4-alkenoic
acids[3e1;
(3) Polyphosphoric acid (PPA)-induced cyclodehydrat i ~ n [ ' ,to
~ l cyclopentenones, with appropriate C = C migration.
Some of the results are given in Table 1. The synthesis of
the bicyclic enone 7cLSa1
(an intermediate in a synthesis of
isocomene by Paquetfe et al.['"') serves as an example to illustrate both the principle and the details of this sequence:
Reaction of methacrolein l c with ethylmagnesium bromide afforded 2-methyl-1-penten-3-01 2c in 88% yield, which
with triethyl orthoacetate, at ca. 140°C, was transformed
into the 4-methyl-4-heptenoate and subsequently hydrolyzed to 3c. Heating 3c in PPA led to the 2,3-dialkylcyclopentenone 4c, which was isolated in 96% yield (GC purity:
97%). The allylic alcohol required for the second cycle was
obtained cleanly and quantitatively by LiAIH4 reduction.
[*I Prof. Dr. V. Jager, DipLChem. M. Dorsch, Dipl.-Chem. W. Sponlein
Institut fur Organische Chemie der Universitat
Am Hubland, D-8700 Wurzburg (FRG)
I**]
We thank Dr. E. Guntrum and M . Treiber for carrying out some experiments. This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, Bayer AG, BASF AG,
Haarmann & Reimer GmbH, and Hoechst AG.
0570-0833/84/1010-0798 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 10
5
6
8d 'OH
9d
10d
Scheme I . Iterative cyclopentane annulations. a) R2CH2MgI, Et20, 0°C: dilute hydrochloric acid. b) R'CH,C(OEt),, EtCOOH, 135--140°C [3a]. c)
KOH, MeOH-H20, reflux [3e]. d) PPA (ca. 83.5%, n $ = 1.4721 [7]); 7a:
1 IO"C/7 h; 7b: 11S°C/8 h ; 7c-7e llO"C/3 h. e) LiAIH4, EtzO, - I O T , for
5b-5e: LiAIH(OMe),, tetrahydrofuran (THF), 0°C. 17 h for 5a. f) Ac20,
pyridine, 4-dimethylaminopyridine (DMAP) (cat.), room temperature. g)
LICA, THF-hexamethylphosphoric triamide (HMPT), fBuSiMezC1,
-78-60°C; AcOH [3d]. h) AcOH, PPh,, Et02C-N=N-C02Et, benzene,
room temperature [6].
Table I . Yields in the synthesis of monocyclic (1st cycle) and bicyclic (2nd
cycle) enones according to Scheme 1.
R'
a
b
C
d
e
H
CH,
CH3
CHS
CH,
R2
H
H
CH,
n Bu
nBu
Yield [%I
R3
H
H
H
H
CH3
1-4
4-7
24
49
69
75
67
4
25
45
69
-
[a1
[a] Not investigated.
However, the reaction of cyclopentenols with orthoacetate
either did not proceed as desired, or gave unsatisfactory
yields, as checked with 5a, 5b, and 5d. To overcome this
difficulty, 5c was acetylated (940/0)
and rearranged via the
ketene acetal (formed by lithium cyclohexylisopropylamide (LICA)/tert-butyldimethylchlorosilane~3d1)
to yield the
cyclopentenylacetic acid 6c (59%) containing one quaternary center. PPA cyclization proceeded smoothly and gave
the bicyclo[3.3.0]octenone 7c (82%). As anticipated, the
endo double bond of 6c first had been shifted into the ex0
position; the resulting isomer then had selectively been
trapped from the mixture by acylium ion attack.
How many times can one repeat this sequence? In order
to demonstrate the utility of this iterative process for a
third cycle, 7d was reduced by LiAIH,, to the bicycloocteno1 8d, with high stereoselectivity and in quantitative
yield. However, contrary to expectation (Dreiding models)
this turned out to be the endo alcohol (NOE difference
measurements), unsuitable for the Claisen rearrangement
to follow[5b'.
Obtaining the wrong stereoisomer (endo) was of no serious consequence, since it was readily converted into the
desired ex0 acetate via the azodicarboxylate method (MitAngew. Chem. Int. Ed. Engl. 23 (1984) No. I0
sunobu)I6l in 82% yield (ca. 80% purity according to 'Hand I3C-NMR). The ex0 acetate, obtained as above, was lithiated and silylated to afford the ketene a ~ e t a l [ ~which
~],
after isolation was subjected to the rearrangement and
gave the carboxylic acid 9d containing lwo uicinal quaternary centers in 42% yield[3f1.Reaction of the latter with
PPA, followed by MPLC purification of the crude product,
furnished the tricycle 10d in 60% yield, with an overall
yield of 21% for the third cycle.
The additional entries in Table I demonstrate the potential of this synthetic scheme. For example, dihydrojasmone
4d[4a3'1and the unnatural methyldihydrojasmone 4e are
now easily accessible on a log-scale. With less substituted
substrates, the PPA cyclization proved to be unsatisfactory; e.g., 2-methylcyclopentenone was obtained in 32%
yield from 3a14b1.
The crucial step in the annulations is the
Claisen-Ireland rearrangement which introduces the acetic
acid side chain. The remaining steps all proceed in good to
very good yield. Numerous applications of this methodology are conceivable, specifically when taking advantage
of the PPA-induced C = C isomerization/cyclodehydration
step.
Received: June 22, 1984 [Z 896 IE]
German version: Angew. Chem. 96 (1984) 815
111 Reviews: a) L. A. Paquette, Top. Ctrrr. Chem. 79 (1979) 41; 119 (1984) 1 ;
b) cf. e.g. Nachr. Chem. Tech. Lah. 2Y (1981) 220, 868: 31 (1983) 14, 262,
360, 638,710; 32 (1984) 429.
[2] B. M. Trost, M. J. Bogdanowicz, J. Am. Chem. Soc. 95 (1973) 289, 5311;
A. E. Greene, Tetrahedron Left. 21 (1980) 3059; J. Huguet, M. Karpf, A.
Dreiding, Helu. Chim. Acfa 65 (1982) 2413.~Cf. potentially iterative cyclopentenone annulations: C. Santelli-Rouvier, M. Santelli, Synfhesi.s
1983. 429; M. Miyashita, T. Yanami, T. Kumazawa, A. Yoshikoshi, J.
Am. Chem. SOC.106 (1984) 2149: G. Mehta, K. S. Rao, Tetrahedron Lett.
25 (1984) 1839, and references cited therein.
[3] a) W. S. Johnson, L. Werthemann, W. R. Rartlett, T. J. Brocksom, T. Li,
D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc. 92 (1970) 741 : b) Reviews: S. J. Rhoads, N. R. Raulins, Org. React 22 (1975) 1 ; G . Bennett,
Synfhesis 1977. 589; F. E. Ziegler, Arc. Chem. Re.s. 10 (1977) 227; c) R. E.
Ireland, R. H. Mueller, J. Am. Chem. Soc. 94 (1972) 5897; R. E. Ireland,
R. H. Mueller, A. K . Willard, ibid. Y8 (1976) 2868; d) J. A. Katzeneilenbogen, K. J. Christy, J. Urg. Chem. 39 (1974) 3315; e) V. Jager, H. J.
Giinther, Tetrahedron Left. 1977. 2543; H. J . Giinther, E. Guntrum, V.
Jager, Liebigs Ann. Chem. 1984, 15; I) S . E. Denmark, M. A. Harmata, Tefrahedron Left. 25 (1984) 1543, and references cited therein.
(41 a) S. Dev, Chem. Ind. 1954, 1071; C'. Rai, S. Dev, J. lnd. Chem. Soc. 34
(1957) 178; b) M. F. Ansell, J. E. Emmett, 13. E. Grimwood, J . Chem. SOC.
1969, 141, and references cited therein; c) T. Fujita, S. Watanabe, K.
Suga, T. Inaba, J. Chem. Techno/. Biotechnol. 29 (1979) 100; d) P. E. Eaton, G . R. Carlson, J . T. Lee, J . Or</.Chem. 38 (1973) 4071 ; P. E. Eaton,
R. H. Mueller, G. R. Carlson, D. A. Cullison, G. F. Cooper, T.-C. Chou,
E.-P.Krehs, J. Am. Chem. SOC.99 (1977) 275 I ; e) cf. C.-W. Schellhammer
in Houben-Weyl-Miiller: Mefhoden der Organirchen Chemie, Val. 7/2a.
Thieme, Stuttgart 1973, p. 447ff.
IS] a) All compounds gave correct elemental analyses and characteristic IR,
'H-NMR, and "C-NMR data; b) a DIHAH reduction, suggested by a
referee, afforded a mixture of Bd (as main product) and, at most, small
amounts of the ex0 isomer.
161 0. Mitsunobu, Synrhesis 1981, 1.
171 R. G. Downing, D. E. Pearson, J. Am. Chem. SOC.83 (1961) 1718.
Red a-Indium(m) Iodide**
By Riidiger Kniep* and Peter Blees
In13 is generally prepared from the elements, with subsequent purification by sublimation, and is obtained as yellow crystals. This yellow form of Inl,, namely p-In13, con[*] Prof. Dr. R. Kniep, DipLChem. 1'. Rlees
Institut fur Anorganische Chemie und Strukturchemie der Universitat
Universitatsstrasse 1, D-4000 Diisseldorf (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0 Verlag Chemie GmbH. 0-6940 Weinheim. 1984
0570-0833/84/1010-0799 $ 02.50/0
799
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