Alkyl aluminum halide promoted intramolecular cyclization of ω-allyl-cycloalk-2-enones: Access to bridged bi- and tricyclic compounds

Full text of DOI:10.1002/anie.200461207

Angewandte
Chemie
Lewis Acids in Organic Synthesis
While investigating novel syntheses of functionalized
odorants,[8] we observed a novel and unexpected EtAlCl2
promoted cyclization of cyclohexenone 6a to bicyclo[3.2.1]oc-
tenone 7a (see Table 1,entry 1) which displays a pleasant
woody vetiver-like odor.[9] To better understand this reaction,
labeled substrate [D2]-6a was prepared by a selective
deuteration of unstable trienone 5[10] which was accessible
by C-alkylation of phenol 4 (Scheme 2).[11] After cyclization,
Alkyl Aluminum Halide Promoted
Intramolecular Cyclization of w-Allyl-cycloalk-2-
enones: Access to Bridged Bi- and Tricyclic
Compounds
Andreas Goeke,* Daniel Mertl, and Gerhard Brunner
Dedicated to Professor Günter Helmchen
The cationic cyclization of olefins has been developed as an
important methodology in organic synthesis.[1] Since Stork
and Burgstahler and Eschenmoser et al. rationalized the
proton-catalyzed biological cyclization of polyprenoids,[2]
a
variety of different initiators of this and related reactions have
been developed.[3] Intramolecular Lewis acid promoted con-
jugate additions of olefins to a,b-unsaturated ketones or
aldehydes belong to this category,[4] although,depending on
the Lewis acid,the course of such cyclizations can be
different. Snider et al. demonstrated that cyclohexenone 1
reacted in the presence of SnCl4 to compound 2 which is the
product of a concerted Lewis acid induced ene reaction,[5]
while treatment of 1 with two equivalents of MeAlCl2 (or
EtAlCl2) resulted in naphthalenone 3 (Scheme 1).[6] It was
deduced that this compound was generated by two consec-
utive 1,2-H shifts of zwitterionic intermediates A and B rather
than by one 1,3-H shift as the relative configuration of the
stereogenic centers C4a and C8 was determined to be anti.
This unique behavior of alkyl aluminum halides as Lewis
acids was partially explained by their Brønsted base-like
character: Any adventitious water will be scavenged by
forming an alkane and a new Lewis acid.[7]
Scheme 2. Synthesis of [D2]-7a by deuteration of trienone 5.
Conditions: a) NaH, toluene, prenyl chloride; b) MeOH, Pd/C, D2;
c) 1.5 equiv EtAlCl2, toluene.
the overall deuterium incorporation of [D2]-6a was retained
in [D2]-7a,which indicates a) the methylene-bridge in 7a
stems from the prenyl group and b) the deuterated positions
of the cyclohexenone unit of 6a are not the locations of
intermediate zwitterions.
Scheme 1. Ene reaction versus cationic cyclization of 1.[6]
Further investigation (Table 1) revealed that the cycliza-
tion tolerates cycloalkenones of different substitution at R1–
R6 and also of different ring sizes,although yields decrease
with increasing steric strain (entries 3,4) and increasing ring
size (entries 8,9). Additional unsaturation in substituents
[*] Dr. A. Goeke, D. Mertl, Dr. G. Brunner
Givaudan Schweiz AG, Fragrance Research
Überlandstrasse 138
8600 Dübendorf (Switzerland)
Fax (+41)44-824-2926
E-mail: andreas.goeke@givaudan.com
6
R2,R4,and R (entries 5,6,7) neither disturbed the cationic
cyclization,nor was a competitive or subsequent cyclization
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
observed in these cases.[12] The yields dramatically decreased
Angew. Chem. Int. Ed. 2005, 44, 99 –101
DOI: 10.1002/anie.200461207
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99

Communications
Table 1: Cyclization of allyl cycloalkenones 6 to bicyclic compounds 7.
Entry
R1
R2
R3
R4
R5
R6
n
d.r.
Product [%][a]
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
HH HH
HH HH
Me
Me
HHH
HMe
Me
Me
HH
Me
Me
1
-
-
7a 95
7b 86
7c 67
7d 54
7e 90
7 f 75
7 g 71
7h 64
7i 45
Me
Me
1
-
Me
H
HH
HH
Me
Me C(CH CH
Me
Me
1
)
-
H
c-C6H13
1
1
-
1.6:1
3
2
prenyl
HCH(CH
Me
Me
1
Me
2)CH3
Me
1
7:3[b]
Me
Me
Me
Me
HH
HH
2
3
-
-
1
10
11
Me
Me
HMe
Me
-
7j 30[c]
7k 86[c,d]
Me
(CH
2)2CO2Me
1
1.5:1
[a] Products isolated by chromatography. [b] Endo:exo-isomers at 7-position. [c] Reaction was carried out at 808C. [d] 3 equiv EtAlCl2, 8 h.
with R5 or R6 = H,which reflects the necessity of cation
stabilization at the 3’ position of the allylic substituent in
ketone 6 (Table 1,entry 10). Entry 11 shows that an addi-
tional ester group in substrate 6k consumes at least one
equivalent of the Lewis acid by a competitive complexation,
although esters were shown to be less basic than ketones.[13]
The outcome of the cyclization does change completely
with different substitution patterns of ketones 8[10] (Table 2).
In these cases,mixtures of tricyclic compounds 9 and 10 were
usually obtained,in ratios not very much influenced by
varying steric demand of the substituents R3 and R4. How-
ever,cyclization of compound 8a (R3, R4 = H) led to a
mixture of 9a and 11a (see Scheme 3) while the trans-
formation of homoallylic derivative 8 f provided compound
10 f exclusively.
The conversion of compounds 6 (and 8a) follows path A.
The initially formed zwitterion results from cyclization of the
enone–EtAlCl2 complex with the allyl side chain being in an s-
trans conformation. Subsequent 1,2-H (or methyl) shift
followed by intramolecular alkyl migration generates com-
pounds 7 (11a). In path B,the allyl side chain of compounds 8
may be sterically (R3,R4 = alkyl,R 7 = Me) pushed into a s-cis
conformation which gives,after the initial cyclization,the
cation close to the enolate. This effect may also be caused by
angular strain that occurs during the cyclization of homo-
allylic derivative 8 f. The quenching of charges in the
zwitterionic intermediate at this stage results in compounds
9. However,the 1,2-R 7 shift is rapid enough to allow path B to
be partially terminated by the formation of compounds 10.
In summary,the novel EtAlCl -induced cyclization of 6-
2
These observations are in accordance with the proposed
mechanism in Scheme 3. It can be explained by a sequence of
1,2-H and alkyl shifts that were proposed by Snider et al.[6,7]
allyl cyclohexenones is a flexible tool for the synthesis of bi-
and tricyclic compounds. The scope and limitations were
investigated with respect to substitution patterns.
Table 2: Cyclization of cyclohexenones 8 to tricyclic compounds 9, 10, and 11.
Entry
Compound
R1
R2
R3
R4
1
R7
n
Ratio
Yield [%][a]
1
2
3
4
5
6
8a
8b
8c
8d
8e
8 f
Me
HMe
Me
HMe
Me
Me
Me
Me
Me
HHMe
9a:11a[b] (1:1)
9b:10b (1.4:1)
9c:10c (1:1.4)
9d:10d (1.1:1)
9e:10e (1.5:1)
10 f
61
74
52
78
86
60
Me
H1
Me
Me
2(CH2)3CH2
CH2(CH2)2CH2
Me
H
H
1
1
1
CH
Me
Me
HH2H
only
[a] Products isolated by chromatography. [b] For compound 11a see Scheme 3; 10a was not detected.
100
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Angewandte
Chemie
Scheme 3. Mechanistic considerations.
[12] A single case of a domino-cyclization of geranylcyclohexenone
Received: July 6,2004
Revised: August 13,2004
12 to tricyclic ketone 13 was observed. The terminating step is a
1,5-hydride shift leading to an exo-methylene group [Eq. (1)].
Keywords: aluminum · cyclization · hydride shifts · Lewis acids ·
.
rearrangement
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[8] For a recent review of fragrance chemistry see: P. Kraft,J. A.
Bajgrowicz,C. Denis,G. Frꢀter, Angew. Chem. 2000, 112,3106;
Angew. Chem. Int. Ed. 2000, 39,2980.
[9] The odor descriptions of compounds 7, 8,and 10 are given in the
Supporting Information.
[10] Selective hydrogenation of trienones 5 to compounds 6 and 8: A.
Goeke (Givaudan Schweiz AG) EP 1213276, 2002[Chem.
Abstr. 2002, 137,19737].
[11] For C-alkylation of phenols see: H. Greuter,H. Schmid,G.
Frꢀter, Helv. Chim. Acta 1977, 60,1701.
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