Cyclization of 1,5-dienes: An efficient synthesis of β-Georgywood

Article abstract of DOI:10.1021/jo061668k

(Chemical Equation Presented) In the acid-promoted 1,5-diene cyclization of pseudo- to β-Georgywood, the cyclization product is obtained with high selectivity in spite of an unfavorable substituent at the C(2)-position of the diene precursor. Preisomeriza

Full text of DOI:10.1021/jo061668k

Cyclization of 1,5-Dienes: An Efficient Synthesis of â-Georgywood
Georg Fr a´ ter and Fridtjof Schr o¨ der*
Research Chemistry Department, GiVaudan Schweiz AG, CH-8600 D u¨ bendorf, Switzerland
fridtjof.schroeder@giVaudan.com
ReceiVed August 11, 2006
In the acid-promoted 1,5-diene cyclization of pseudo- to â-Georgywood, the cyclization product is obtained
with high selectivity in spite of an unfavorable substituent at the C(2)-position of the diene precursor.
Preisomerization of the cyclohexene double bond, which occurs in the presence of Brønsted acids, is
suppressed with >1 equiv of MX
n 2
-type Lewis acids, whereas RAlX -type Lewis acids such as >2 equiv
of MeAlCl have the additional benefit of steering the double bond of the cyclized product into the
2
desired â-position. Mechanistic studies revealed a crucial participation or nonparticipation of the carbonyl
group in the cyclization reaction, depending on the acid family employed, and allowed finally the
2
development of a cyclization reaction catalyzed by MeAlCl that can be generated in situ from precatalyst
1
3
AlMe .
More than 50 years ago, Eschenmoser, Stork, and others
published their fundamental investigations on the mechanism
of cationic 1,5-diene cyclization reactions. Fragrance chemists
111) 2a, and Iso E Super 2b (Figure 1). The latter compound
(2b) ultimately became one of the most important fragrance
ingredients of the woody-ambery family.
2
6
first used 1,5-diene cyclization reactions at the end of the 19th
3
century (e.g., for the synthesis of Ionone or Geranitrile) and
4
their use continues up to the present time. Also in the fifties,
Ohloff communicated the acid-promoted 1,5-diene cyclization
of 1-[4-(isohexenylcyclohex-3-enyl]alkan-1-ones 1. The cy-
clization products 2 had interesting woody-ambery odor proper-
ties (Scheme 1), depending on the substitution pattern at C(6)
5
and C(7).
SCHEME 1a
FIGURE 1. Commercialized compounds prepared via the cyclization
of Scheme 1. Compound 2b contains ca. 3% of impurity 4.
Inspired by the finding that the olfactorily most powerful
vector of Iso E Super is not an isomer of 2b, but impurity 4,7
Fr a´ ter et al. examined 1,5-diene 5 as a cyclization precursor
that contains (in contrast to 1) an additional methyl group at its
a
Reagents and conditions: R ) H or alkyl. R′ ) H, alkyl, or OR. The
R,â,γ denotation of the double bond isomers of 2 goes back to ref 5.
Some of these products (2) or their derivatives were com-
mercialized, e.g., Lactoscatone 3, Cyclemone A (or Aldehyde
(
3) Tiemann, F.; Kr u¨ ger, P.; Semmler, F. H. Ber. Dtsch. Chem. Ges.
893, 26, 2675-2729.
4) (a) Johnson, W. S. Angew. Chem., Int. Ed. Engl. 1976, 15, 9-17.
1
(
(1) Parts of this investigation were presented at the 11th International
(b) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1982; Vol. III, pp 341-409. (c) Gnonlonfoun, N. Bull.
Chem. Soc. Fr. 1988, 862-869. (d) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131-163. (e) De la Torre, M. C.; Sierra, M. A.
Angew. Chem., Int. Ed. 2004, 43, 160-181. (f) Yoder, R. A.; Johnston, J.
N. Chem. ReV. 2005, 105, 4730-4756.
(5) (a) Ohloff, G. Riechstoffe Aromen 1957, 38-40. (b) Ohloff, G. DE
1057108, 1957, Dragoco Spezialfabrik konz. Riech- und Aromastoffe
Gerberding & Co., G.m.b.H. [Chem. Abstr. 55, 48611].
Conference of Organic Process Research & Development, Barcelona, Spain,
April 25-28, 2005, and at the XVI Fechem Conference on Organometallic
Chemistry, Budapest, Hungary, September 3-8, 2005.
(
2) (a) Eschenmoser, A.; Arigoni, D. HelV. Chim. Acta 2005, 88, 3011-
3
5
354. (b) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068-
077 and literature cited therein. (c) Eschenmoser, A.; Ruzicka, L.; Jeger,
O.; Arigoni, D. HelV. Chim. Acta 1955, 38, 1890-1904 and literature cited
therein.
10.1021/jo061668k CCC: $37.00 © 2007 American Chemical Society
1
112
J. Org. Chem. 2007, 72, 1112-1120
Published on Web 01/20/2007

Cyclization of 1,5-Dienes
SCHEME 2. Givaudan Synthesis of Georgywood from
TABLE 1. Cyclization of Precursor 5 Promoted by Brønsted
Precursor 5a
Acidsd
equiv
temp time yield ratio
a
entry
acid
(molar) solvent [°C]
[h]
[%]
7/8
1
2
3
4
5
6
7
8
9
85% H
99% H
3
PO
PO
4
0.1
1.5
0.1
0.1
0.1
0.1
0.6
xylene
toluene 120
xylene
xylene
xylene
145
1
88
38:62
41:59
43:57
45:55
54:46
66:34
64:26
71:29
71:29
72:28
74:26
76:24
76:24
76:24
78:22
78:22
3
4
0.5 87
1.5 86
1
24
20
20
0.5 58
48
15
4
2.5 65
2.5 77
b
polyphosphoric acid
PO
65% HPO
96% H SO
Me-P(O)(OH)
SO /Ac
Amberlite H
Ph-PdO(OH)
PhO-PdO(OH)
CF CO
MsOH
145
145
145
110
140
125
145
130
130
H
3
3
85
84
89
80
3
2
4
2
H
2
4
2
O
1/1
HOAc
xylene
+
b
c
c
c
5
70
78
70
10
2
0.4
1.2
0.2
0.2
0.3
0.2
6
2
11
3
2
H
toluene 100
toluene 100
a
Reagents and conditions: (a) H3PO4, toluene, 115 °C, 1 h, 74%.9
12
3
14
b
c
1
Nafion-H
TosOH
100 120
76
8
toluene 100
3.5 78
C(2) position. Phosphoric acid-catalyzed cyclization yielded
15
2
HCO H
HCO
2
H
50 129
81
the isomers 7 and 8 in about equal amounts. As an olfactory
agent Georgywood 8 was by a factor of >10 000 more powerful
than 7 (Scheme 2).9
a
Products isolated by Kugelrohr distillation. b Weight equivalents. c GC-
conversions. d Representative assortment of ca. 80 experiments.
The formation of regioisomer 7 can be explained by a
preisomerization of the endocyclic double bond of 5, giving
intermediate 6, that readily undergoes cyclization to 7 (Scheme
Results and Discussion
Brønsted Acid-Promoted Cyclization. At the onset of our
investigations, the cyclization of 5 was screened with organic
or inorganic Brønsted acids at different temperatures and
concentrations. The influence of solvents, emulsifiers, or phase-
transfer catalysts was also checked, as well as pyrolysis over
different supports at temperatures up to 500 °C. Representative
experiments that gave good cyclization yields are listed in Table
2
). Steric constraints between the methyl group at C(2) and the
methyl groups of the 4-methylpent-4-enyl side chain of 5 were
thereby circumvented, in contrast to Ohloff’s cyclohexenes 1
(
Scheme 1, R ) alkyl), where such a preisomerization was much
5
,7
less predominant. The cyclization of a 1,5-diene such as 5,
where the new bond at C(3) of the cyclohexene ring must be
formed despite steric constraints of a substituent at C(2), is
1
. Selectivities in favor of â-Georgywood 8 over the undesired
unique in the literature dealing with polyprenoid cyclization
reactions,2,4,5 and has only recently been attempted on the trans-
isomer 7 were observed only in those cases where phosphorous
acids were employed (Table 1, entries 1-5).
10
diastereomer of 5.
An important question was whether or not regioisomer 7 was
formed from Georgywood 8 under the above-mentioned condi-
tions (Scheme 2). Such a conversion would proceed via ring
opening of 8 to 5 (1,5-diene retrocyclization), and equilibration
of 7 and 8 consistent with the reversibility of cationic 1,5-diene
Because the elegant, warm-woody, sweet-powdery smelling
Georgywood represents an important alternative to the classic
6
Iso-E Super 2b in perfumery applications, alternative syntheses
of 8 were reported, e.g., by Piancatelli et al.11 The enantiomers
1
2
of Georgywood 8 have been synthesized at Givaudan and by
1
5
1
3
cyclizations.
Corey et al. Here we communicate our investigations that
In a control experiment using H3PO4, we observed a slowly
increasing ratio of the product mixture 7/8 upon prolonged
heating. Isolation and structure elucidation of byproduct 9
explained the erosion of the isomer ratio under these conditions
(Scheme 3), which is probably due to a higher instability of 8
relative to 7. Similarly substituted ethers have been obtained
avoid the preisomerization from 5 to 6 and result in a highly
regioselective cyclization of precursor 5 to â-Georgywood 8.
1
4
(
6) (a) Fr a´ ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54,
7
633-7703. (b) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Fr a´ ter, G. Angew.
Chem., Int. Ed. 2000, 39, 2980-3010. (c) Gautschi, M.; Bajgrowicz, J. A.;
Kraft, P. Chimia 2001, 55, 379-387.
16
from related precursors under the same conditions, with the
(7) Etzweiler, F.; Helmlinger, D.; Nussbaumer, C.; Pesaro, M. EP
crucial carbocationic cyclization of γ,δ-unsaturated carbonyl
0
464357, priority 2.6.1990 to Givaudan [Chem. Abstr. 116, 194638w]. See
also: Nussbaumer, C.; Fr a´ ter, G.; Kraft, P. HelV. Chim. Acta 1999, 82,
016-1024.
8) Mousseron-Canet, M.; Mousseron, M.; Boch, J. J. Bull. Chem. Soc.
Chim. Fr. 1959, 601-606.
9) Bajgrowicz, J; Bringhen, A; Fr a´ ter, G; M u¨ ller, U. EP 0743297,
priority 16.5.1995 to Givaudan [Chem. Abstr. 126, 103856h].
10) (a) Erman, M. B.; Hoffmann, H. M.; Cardenas, C. G. EP 0985651,
priority 16.8.1998 to Millenium Speciality Chemicals, Inc. [Chem. Abstr.
1
7
compounds described by Baldwin.
1
At high temperatures (150 °C) and with pure Georgywood 8
as substrate, a slow conversion to isomer 7 (12% in 48 h) was
observed. We conclude that, at normal cyclization temperatures
(
(
(100-120 °C) with H3PO4 (Table 1, entries 1 and 2), the mixture
(
1
2
32, 207981k]. (b) Erman, M. B.; Williams, M. J.; Cardenas, C. G. WO
00160777, priority 18.2.2000 to Millenium Speciality Chemicals, Inc.
(15) (a) Stadler, P. A.; Nechvatal, A.; Frey, A. J; Eschenmoser, A. HelV.
Chim. Acta 1957, 40, 1373-1490. (b) Stadler, P. A.; Eschenmoser, A.;
Schinz, H.; Stork, G. HelV. Chim. Acta 1957, 40, 2191-2198. (c)
Eschenmoser, A.; Felix, D.; Gut, M.; Meier, J.; Stadler, P. in CIBA
Foundation Symposium on the Biosynthesis of Terpenes and Steroids;
Wolstenholme, G. E. W., O’Connor, M., Eds.; J. & A. Churchill: London,
UK, 1959; p 217.
[
Chem. Abstr. 135, 197197e]. (c) Erman, M. B.; Williams, M. J.; Whelan,
P.; Cardenas, C. G.; Antipin, M. Perfum. FlaVor. 2001, 26, 18-21.
11) Bella, M.; Cianflone, M.; Montemurro, G.; Passacantilli, G.;
Piancatelli, G. Tetrahedron 2004, 60, 4821-4827.
12) (a) Fr a´ ter, G.; M u¨ ller, U.; Nussbaumer, C. Book of Abstracts; 213th
National Meeting of the American Chemical Society, San Francisco, April
3-17, 1997; American Chemical Society: Washington, D.C., 1997. (b)
Fr a´ ter, G.; M u¨ ller, U.; Schr o¨ der, F. Tetrahedron: Asymmetry 2004, 15,
(
(
(16) (a) Kron, A. A.; Burdin, E. A.; Fedotova, Z. M.; Novikov, N. A.
Russ. J. Org. Chem. 1994, 30, 1035-1038. (b) Andreev, V. M.; Cherkaev,
G. V.; Ratnikova, E. V.; Andreeva, L. K.; Formchenko, Z. V. Zh. Org.
Khim. 1991, 27, 413-414.
(17) (a) Baldwin, J. E.; Lusch, M. J. J. Org. Chem. 1979, 44, 1923-
1927.( b) Snider, B. B.; Cartaya-Marin, C. P. J. Org. Chem. 1984, 49, 153-
157.
1
3
967-3972.
(
(
13) Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 1346-1352.
14) Barras, J.-P.; Schr o¨ der, F. WO 2005016938, priority 18.8.2003 to
Givaudan [Chem. Abstr. 142, 219409z].
J. Org. Chem, Vol. 72, No. 4, 2007 1113

Fr a´ ter and Schr o¨ der
SCHEME 3. Formation of Byproduct 9 from 8a
a
Reagents and conditions: 7/8 (1:1), 1 equiv of H3PO4, 100 °C, 48 h,
1
0% (GC/MS).
FIGURE 2. Classification of type MX
n
Lewis acids (X ) F, Cl, Br)
by reactivity and selectivity toward â-isomer 8, enol ether 12, and
γ-isomer 13. Lewis acids giving isomers of this mixture are shadowed.
Lewis acids with strong â-Georgywood 8 preference are shown in bold.
Lewis acids shown in italic gave larger amounts or predominantly
isomer 7. The other Lewis acids were ineffective. 1.5 equiv of Lewis
acid in toluene, xylene, cyclohexane, dichloromethane, or nitroalkanes
SCHEME 4. Formic Acid Addition to Precursor 5a
between 0 and 25 °C, except for BBr at -50 °C.
3
SCHEME 5a
a
Reagents and conditions: (a) HCO2H, 3-7 d, 25 °C, 40%. (b) MeOH,
cat. NaOMe, 1.5 h, 25 °C, 50%.
7/8 is formed directly from pre-equilibrium 5 T 6 and does
not further interconvert.
Preisomerization of 5 to 6 (Scheme 2) at the beginning of
the cyclization reactions was followed by GC. The accumulation
(k1 > k3) of 6 was with some acids hardly detectible but with
others very pronounced. In the H2SO4-catalyzed cyclization
reaction (Table 1, entry 6) quenching at the highest concentration
of 6 allowed preparative GC separation and NMR analysis of
this intermediate.
a
Reagents and conditions: (a) > 1 equiv of MXn, between -50 and
5 °C, several hours, 40-60% (dist). MXn ) BBr3, BCL3, gaseous BF3,
2
AlBr , AlCl , ZrCl , TiCl or TiBr in toluene, CH Cl or nitropropane,
workup. (b) 0.2 equiv of pTSA, toluene, 100 °C, 4 h, 72% (dist).
3
3
4
4
4
2
2
When the formic acid-promoted cyclization (Table 1, entry
1
1
1
5) was carried out at lower temperatures, the formate adducts
0 were isolated (Scheme 4) and characterized as their alcohols
1. Because all Brønsted acids should be capable of covalently
It is interesting that H3PO4 (Table 1, entry 1) gave the best
/7 selectivities (i.e., 62:32) at high temperatures. Further
8
blocking the sterically less hindered acyclic double bond with
improvements, however, were not possible and other Brønsted
acid systems promoted also the unwanted shift of the endocyclic
double bond of 5. With the goal of avoiding this preisomer-
ization, screening experiments with aprotic cyclization reagents,
e.g., Lewis acids, were examined next.
18
different addition and re-elimination rates, such an effect can
favor the isomerization of the cyclohexenyl double bond (for a
possible neighboring effect of the acetyl group in this pre-
isomerization, see Figure 3 and Scheme 11).19
Cyclization reaction promoted by MXn-Type Lewis Acids.
To overcome complex formation with the carbonyl group or
solvent, more than 1 equiv of a Lewis acid was employed in
noncomplexing solvents. Under these conditions we were
gratified to obtain a mixture containing mainly 8, 12, and 13 in
varying amounts (Scheme 5) using strong MXn-type Lewis acids
(
18) (a) Markovnikov addition of formic acid to trisubstituted double
bonds and re-elimination: Baird, K. J.; Grundon, M. F.; Harrison, D. M.;
Magee, M. G. Heterocycles 1981, 713-717. (b) Addition of phosphoric
acid: Julia, M.; Mestdagh, H.; Rolando, C. Tetrahedron 1986, 42, 3841-
3
849. HX addition and re-elimination was observed by us when bubbling
HCl or HBr through precursor 5 (GC/MS), where after attempted isolation
of these halides the partially isomerized mixtures 7, 8 were obtained after
chromatography or distillation.
(Figure 2, shadowed). The Georgywood isomers 12 and 13 were
(
19) This hypothesis represents so far the best answer to the important
isolated by preparative GC, and their structures were elucidated
by NMR in C6D6. In these mixtures, the â- and γ-isomers 8
and 13 were the main components. The corresponding R-isomer
question, why Brønsted acids induce preisomerization and strong, active
LA’s do not. We also considered an inductive deactivation of the
cyclohexenyl double bond depending on the strength of the carbonyl group/
acid complex. Although we could not find a well-proven precedent for a
deactivation over three σ-bonds, such an effect cannot be excluded.
1
0c
was not detected.
In contrast to the Brønsted acid-promoted cyclization, which
needed temperatures of at least 80-100 °C (Table 1), the
corresponding Lewis acid-promoted cyclization occurred readily
at 25 °C or below and gaVe for the first time no iso-Georgywood
(20) (a) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin
Trans. 1 1999, 2087-2094. (b) K u¨ rti, L.; Czak o´ , B. Strategic Applications
of Named Reactions in Organic Synthesis; Elsevier Academic Press: New
York, 2005.
1114 J. Org. Chem., Vol. 72, No. 4, 2007

Cyclization of 1,5-Dienes
SCHEME 6. Formal Mechanism for the Formation of
Dimer 14 from 12 and 13a
SCHEME 7. Enol Ether 15 from Precursor 5 and Further
Conversion to Enol Ether 12a
a
Reagents and conditions: (a) 1.5 equiv of FeCl3 in toluene, 25 °C, 1.5
h. (b) Same conditions but 30 h. 12 was contaminated by the â- and
γ-isomers 8 and 13 according to Scheme 5.
SCHEME 8. Screening of Alkylaluminum Chlorides
a
n
R AlCl
m
a
An analogous tentative mechanism can be designed for the formation
of 14 from 12 and 8.
7! The absence of this compound verified our hypothesis that
Lewis acids would activate selectively the exocyclic double bond
of 5 for cyclization, thus circumventing preisomerization to 6.
BBr3, AlBr3, and ZrCl4 (Figure 2, bold) gave the best
selectivities for the â-isomer 8, which were, unfortunately, not
perfectly reproducible. When <1 equiv of these Lewis acids
a
Reagents and conditions: (a) 2 equiv of MeAlCl2, hexane, 16 h, 75
°
(
C, 86% (dist). (b) 2 equiv of EtAlCl2, toluene, hexane, 9 d, 25 °C, 54%
dist). (c) 3 equiv of Me2AlCl, hexane, 70 °C, 30 d, 30% (FC). (d) 1.5
equiv of AlMe3, 4 h, 60 °C, 93% (dist). (e) 2 equiv of AlEt3, toluene, hexane,
5 h, 25 °C, 94% (dist). (f) 1.5 equiv of Et2AlCl, toluene, hexane, 2 d, 60
(Figure 2, shadowed) was employed, temperatures of above 100
1
°C were necessary to achieve cyclization. Isomer 7, derived from
°C, 90% (dist).
preisomerized intermediate 6, was again the main cyclization
product. Catalytic or stoichiometric amounts of metal triflates
M(O2CCF3)n or mesylates M(O3SCF3)n were ineffective. Al-
coholates such as Al(OEt)3, Ti(OEt)4, and (iPrO3TiCl) did not
promote cyclization, but gave partial reduction of the carbonyl
group instead. Typical weak Lewis acids such as LiCl or MgCl2
and some of the metal fluorides (Figure 2) gave no conversion
at all.
Enol ether 12 and γ-isomer 13 are unstable and convert to
â-Georgywood 8 during aqueous acidic workup, over silica,
during distillation and even in acidic CDCl3. For preparative
purposes, the product mixture of 8, 12, and 13 was converted
to the desired â-isomer 8 with catalytic amounts of pTSA in
toluene (Scheme 5). On the other hand, pure â-Georgywood 8
was reconverted to enol ether 12 with 1.5 equiv of AlCl3 in
toluene. These results indicate that the equilibrium among 8,
times converted 15 further to 12, probably via 5 as intermediate
(Scheme 7).
6-Membered endocyclic enol ethers (3,4-dihydropyrane type)
have been selectively obtained through cyclization of γ,δ-
unsaturated ketones in the presence of electrophilic reagents
4
c
(
6
Lewis acids), e.g., from Geranylacetone. One example of a
-membered exocyclic enol ether, obtained through Lewis acid-
promoted cyclization of γ,δ-unsaturated ketones, has been
2
1
mentioned.
Cyclization promoted by Alkylaluminum Chlorides, Es-
pecially MeAlCl2. During the search for an “ideal cyclization
reagent”, organometallic homologues of the MXn-type Lewis
acids (Figure 2, shadowed) were tested, to minimize the
tendency of these Lewis acids to induce postequilibration
(Scheme 5). The systematic screening of alkylaluminum reagents
RnAlXm was very rewarding (Scheme 8), and â-Georgywood 8
was obtained in excellent yield and selectivity by using
stoichiometric amounts (g2 equiv) of methylaluminum dichlo-
ride (MeAlCl2), the first alkyl homologue of AlCl3. For the next
higher homologue, ethylaluminum dichloride, the window
between effective cyclization temperature and undesired po-
lymerization was narrowed considerably, and with di- or
trialkylaluminum compounds, other reactions predominated,
resulting from the reducing ability or the higher nucleophilicity
of the alkyl substituents. Organoaluminum alkoxides were
similarly ineffective: MeOAlCl2 gave predominantly 7 and
methylaluminoxane (MAO) converted substrate 5 to 17 under
more drastic conditions, as observed also with AlMe3.
1
2, and 13 is determined by the Lewis acid reagent (system)
and is accompanied by side reactions such as cyclization,
dimerization, or polymerization. A quantitative conversion of
the isomeric mixture 8, 12, and 13 to â-isomer 8 was not
achieved.
Upon standing at ambient temperature for several weeks, a
crystalline precipitate was collected from the distilled mixtures
of 8, 12, and 13 and was characterized by NMR as dimer 14
(Scheme 6). Dimer 14 was also detected in the mass spectra of
the distillation residues. This explains the inferior yields obtained
from the MXn cyclization, and also why increased amounts of
enol ether 12 in the crude product mixtures correlated with
decreased amounts of product after distillation.
Intramolecular enol ether 15 was normally detected in
amounts of less than 10% but was formed as the main product
during the FeCl3-promoted cyclization of 5. Prolonged reaction
(
21) Baddeley, G.; Heaton, B. G; Rasburn, J. W. J. Chem. Soc. 1960,
4
713 -4719. As in our case (12, 15) the formation of an endocyclic enol
ether was not possible, due to the fully substituted endocyclic R-position.
J. Org. Chem, Vol. 72, No. 4, 2007 1115

Fr a´ ter and Schr o¨ der
SCHEME 9. Cyclization of Carbonyl-Free Hydrocarbon 20a
Whereas >1 equiv of the “active” MXn-type Lewis acids
Figure 2, shadowed) was necessary to obtain Georgywood 8
(
and its isomers 12 and 13, g2 equiv of the alkylaluminum
dihalides MeAlCl2 and EtAlCl2 was needed to achieve a
quantitative and clean cyclization of 5 to 8. Less than 2 equiv
of the alkylaluminum dichlorides gave decreased reaction rates
and increased side reactions such as polymerization or decom-
position, e.g., to 1,1,7-trimethyltetraline. The use of g2 equiv
of MeAlCl2 provided â-Georgywood 8 in excellent yield (86%)
and purity (92%, GC). Less than 0.3% iso-Georgywood 7 was
detected and less than 2% of the isomers 12 and 13.
A less expensive and more readily available Lewis acid than
MeAlCl2 was still desired. The use of g2.5 equiv of the
corresponding sesquichloride Me3Al2Cl3 promoted the selective
cyclization of 5 to 8 nearly as well (70 °C, 2 h, >70% yield) as
a
Reagents and conditions: (a) Hydrazin hydrate, NaOH, digly, 195 °C,
2
.5 equiv of MeAlCl2 (Scheme 8). Because Me3Al2Cl3 is a
7
h (95%). (b) cat. H3PO4, 145 °C, 14 h (75%).
2
2
complex of 1 equiv ofMeAlCl2 × 1 equiv of Me2AlCl, the
use of 2.5 equiv of Me3Al2Cl3 would give twice as much
aluminum waste and an even higher amount of gaseous methane
after quenching the reaction.
The same NMR experiment was not possible with the
heterogeneous H3PO4 cyclization reaction. Consequently, we
removed the carbonyl group of 5 by Wolff-Kishner reduction
Scheme 9). Hydrocarbon 20 gave, after H3PO4-promoted
cyclization, the isomers 21/22 in nearly the same good ratio as
the one of 7/8 obtained from the corresponding cyclization
reaction with precursor 5 (Table 1, entry 1), but only after a
very prolonged reaction time. From this, we conclude that a
pre-equilibrium 20 T 23 exists in analogy to that of 7 T 8
Because MeAlCl2 was by far the best Lewis acid for the
synthesis of 8 from 5, we have recently disclosed a procedure
for the preparation of MeAlCl2 and its use in the subsequent
cyclization of 5 that has the advantage that the pyrophoric
(
14
MeAlCl2 is prepared and destroyed in one vessel. To elucidate
the unique role of the reagent MeAlCl2, however, an in-depth
mechanistic study of this reaction was undertaken.
(
Scheme 2).
Mechanistic Investigations. The Lewis acids that promote
the cyclization of 5 to 8 and its isomers 12 and 13 (Figure 2)
correlate partially with the criteria “strong” or “active” estab-
lished by of Pearson23 and others.
24,25
The most striking
difference between the different acid families employed was
that enol ether 12 was detected only in the presence of MXn-
type Lewis acids, but not during or after the Brønsted acid- or
RAlCl2-promoted (R ) Me, Et) cyclization. However, cycliza-
tion transition state 19, which could lead to enol ether 12, is
possible with every acid employed. A σ-orbital of the carbonyl-
oxygen overlaps with the π-orbitals of the cyclohexenyl alkene,
which in turn overlap with the π-orbitals of the exocyclic double
bond (Figure 3). This would give the carbon framework of
Georgywood 8 and its enol ether 12 under stereoelectronic
control.
FIGURE 4. Deuterated precursors 24 and 25. D-grades >95%.
To gain further insight into the mechanism, the deuterated
precursors 24 and 25 were prepared (Figure 4). Ketone 24, fully
deuterated at the acetyl group, was prepared from 5 by using
K CO in D O. Precursor 25 was prepared with a deuteration
2
3
2
grade of >95% and in good yields from alkynol 26 (Scheme
2
6
10). Deuterium was introduced by hydroxy group-assisted
27
selective LAD-deuteration giving allyl alcohol 27, which was
converted to the (partially rearranged) carbonates 28 and 29
(
1
isomer ratio 2:1) that were subjected to a palladium-catalyzed
,4-elimination to give, via the same η -allylpalladium transition
3
state, the dienes 30 and 31 (isomer ratio 3:1). In this mixture,
only the reactive diene 30 underwent an endo-selective Diels-
Alder reaction with methylisopropenyl ketone to give the
cyclization precursor 25 in analogy to the reported Givaudan
9
procedure.
FIGURE 3. Transition state 19 for the cyclization of precursor 5. Q
The deuterated precursors 24 and 25 were cyclized with the
representative acids H3PO4, BBr3, and MeAlCl2. Regarding the
H3PO4-catalyzed cyclization of 24, no insights different from
those from previous observations (Scheme 2) were obtained.
+
)
H
or Lewis acid.
When the MeAlCl2-promoted cyclization of 5 to 8 was run
in an NMR tube, no intermediate was observed. Not surpris-
ingly, the carbonyl groups of 5 and 8 were complexed by an
aluminum species, as evidenced by the shift of acetyl signals
(24) Olah, G. A.; Kobayashi, S.; Tashiro, M. J. Am. Chem. Soc. 1972,
94, 7448-7461.
1
13
(25) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 6,
from ∼2 to 3 ppm ( H NMR) and from ∼210 to 245 ppm ( C
3
491-3494.
26) Pasedach, H. DE 2228333, BASF, 1972 [Chem. Abstr. 142,
19409z]. Alkynol 26 also can be prepared from Dehydro-â-linalol (CAS
NMR).
(
2
(
(
22) Brandt, J.; Hoffmann, E. G. Brennst. Chem. 1964, 7, 200-206.
23) (a) Pearson, R. G. Hard and Soft Acids and Bases. J. Am. Chem.
29171-20.-8) by using the 3-step procedure described by Gl a¨ nzer: Gl a¨ nzer,
B. I.; Faber, K.; Griengl, H. Tetrahedron 1978, 43, 5791-5796.
(27) Damm, L. G.; Hartshorn, M. P.; Vaughan, J. Aust. J. Chem. 1976,
29, 1017-1021.
Soc. 1962, 85, 3533-3539. (b) Santelli, M.; Pons, J.-M. Lewis acids and
SelectiVity in Organic Synthesis; CRC Press: Boca Raton, FL, 1996.
1116 J. Org. Chem., Vol. 72, No. 4, 2007

Cyclization of 1,5-Dienes
SCHEME 10. Synthesis of the Deuterated Precursor 25a
SCHEME 12. Cyclization of the Precursors 5, 24, and 25
with the MX -Type Lewis Acid BBr
n 3
a
a
Reagents and conditions: (a) 1.5 equiv of BBr3, toluene, -50 °C, 7 h.
b) 0.2 equiv of pTSA, toluene, 100 °C, 4 h, ca. 50% (dist). D-grade of 37
(
a
Reagents and conditions: (a) LiAlD4, THF, 65 °C, 3 h, 80%. (b) BuLi,
∼40%. Epimer ratio at C(2) of 37 ∼1:1. D-grade of 33 ∼50%. Error of the
13
hexane, 25 °C, then -50 °C, ClCO2Et, 25 °C, 90%. (c) 100 °C, 0.35 mol
dpppe, 0.14 mol % Pd(OAc)2, 30 min, 65%. (d) Methyl isopropenyl
D-grades (15% ( C NMR analysis). The boron intermediates 35 or 36
%
also can be present as higher complexes, e.g., dimers.
ketone, toluene, cat. BF3OEt2, 0 °C, 2 h, 85%.
of 33 and 34 arise from D+ abstraction from intermediate 32
and enolization.
Cyclization of the deuterated precursors 24 and 25 with the
representative MXn-type Lewis acid BBr3 gave a â-, γ-, and
enol ether isomer mixture (deuterated analogues of 8, 12, and
SCHEME 11. Cyclization of the Deuterated Precursor 25
with the Brønsted Acid H PO
3 4
a
1
3
3) that was converted with pTSA to the Georgywood analogues
3 and 37, respectively (Scheme 12), to allow a better analysis
13
of the deuterated positions by C NMR. The deuterium at C(2)
of 37 may result from an intermediate C(2)-boron bond as in
3
5 or 36 that gives after (an intermolecular) deuterium quench
the C-2 epimers of 37 in equal amounts. The relatively low
deuteration grade in 33 and 37 can be explained by enolization
2
9
during reaction or workup.
No enolization at all occurs with MeAlCl2 (Scheme 13), in
contrast to the cyclization with H3PO4 or BBr3, based on the
fact that 38 was obtained without any deuterium loss from 24
+
after H quench. Accordingly, nondeuterated 8 was obtained
from 5 after D2O quench. The C(2)-Al bond of 39, which is
more basic than the Al-Me bond, was presumably quenched
by DCl, as discussed for BBr3 (Scheme 12). In the complex
formation with the acetyl group, MeAlCl2 is a weaker Lewis
acid than the strong MXn-type Lewis acids (Figure 2).
Accordingly, no methane evolved during cyclization, but exactly
a
Reagents and conditions: (a) 3-8% H3PO4, xylene, 145 °C, 1 h, 70%.
Isomer ratio 33/34 ) 60:40. Epimer ratio at C(5) of 34 ) 82:18, D-grade
at C(5) of 34 ∼75%. D-grade at the acetyl groups of 33 and 34 <25%.
30
1
3
Error of the D-grades (15% ( C NMR analysis).
2
.5 equiv (100%) was collected after an aqueous quench of the
reaction mixture. The 2.5 equiv of CH3D obtained after D2O
Only the deuterium of the acetyl group was partially washed
out and reintroduced (at C(2) of 33) due to enolization. The
H3PO4-catalyzed cyclization of 25 deserves additional comment,
because of the interesting fact that the configuration at C(5) of
quench of the 5 f 8 reaction mixture and the 2.5 equiv of
+
nondeuterated methane obtained after H quench of the 24 f
38 or 25 f 37 mixtures confirmed our observations. This result
showed also that 2.5 equiv of unaltered MeAlCl2 was present
3
2
4 (Scheme 11) arises from preferential protonation at C(3) of
5 from the more hindered â-face. This outcome is guided by
after cyclization and no other species (i.e., Al-CH2-Al would
3
1
have given CH2D2).
the carbonyl group or an intramolecular enol ether intermediate
(
deuterated analogue of 15).28 This would explain the faster
(
29) According to the enolization equilibrium RCOMe + MXn T
reaction rate in the cyclization of 5 than that of the deoxygenated
precursor 20 (Scheme 9). The partial deuterated acetyl groups
RC(dCH)2OMXn-1 + HX, Brønsted acid HBr can be generated from
precursor 25 and BBr3.
(30) Strong Lewis acids are capable of enhancing the acidities of
R-carbonyl-protons by 20-25 pKa units: (a) Yamamoto, H.; Futatsugi, K.
Angew. Chem., Int. Ed. 2005, 44, 1924-1942. (b) Ren, H.; Cramer, C. J.;
Squires, R. R. J. Am. Chem. Soc. 1999, 121, 2633-2634.
(
28) We cannot exclude that backside shielding of the R-face of 25 by
the isohexenyl side chain, probably favored by π-stacking (in analogy to
Figure 3), is solely responsible for this preference.
(31) Anet, F. L.; O’Leary, D. J. Tetrahedron Lett. 1989, 30, 2755-2758.
J. Org. Chem, Vol. 72, No. 4, 2007 1117

Fr a´ ter and Schr o¨ der
SCHEME 13. Cyclization of the Precursors 5, 24, and 25
SCHEME 14. Disproportionation of >2 equiv of MeAlCl
in the Presence of Precursor 5 and Complex Formation of
AlCl and MeAlCl with the Lewis Basic Sites of 40
3 2
2
a
with MeAlCl
2
a
a
The aluminum species of 40 also can be also present as higher
complexes, e.g., dimers.
(b) Any AlCl3 formed in such a disproportionation should
preferentially complex with the carbonyl group, because AlCl3
gives a stronger Lewis acid-carbonyl complex than Me2AlCl
3
7
or MeAlCl2 (eq 2). The carbonyl group would be preferred
as a complexing partner over the less electron-donating double
bonds of 5 (eq 3), as confirmed in the above cyclization
experiment with >2 equiv of MeAlCl2 in an NMR tube.
AlCl > MeAlCl > Me AlCl > AlMe
3
2
2
3
(strength of the Lewis acids) (2)
R(CO)Me . exocyclic CdC > endocyclic CdC
(strength of Lewis basic basic sites in 5) (3)
a
Reagents and conditions: (a) 2.5 equiv of MeAlCl2, hexane, 2 h, 70
°
3
C, 80%. D-grade of 38 >95%. D-grade of 8 0%. Epimer ratio at C(2) of
(
c) The MeAlCl2 left over from disproportionation catalyzes
7 ∼1:1. D-grade of 37 >65%. The aluminum intermediate 39 also can be
present as higher complex, e.g., as dimer.
the desired cyclization.
On the basis of these suppositions, it should be possible to
effect the cyclization of 5 by adding ∼1 equiv of AlCl3 together
with catalytic amounts of MeAlCl2. As a prerequisite for this
endeavor, precursor 7 is fortunately inert in the presence of e1
equiv of AlCl3 up to 100 °C. With >1 equiv of AlCl3, as shown
above, surplus AlCl3 accelerates the cyclization at 25 °C but
also induces postisomerization. The necessity of e1 equiv of
AlCl3 per carbonyl group, which decreases the activity of this
Lewis acid by complex formation, is also known in certain
Diels-Alder reactions, where polymerization was observed with
The relevance of the above deuteration experiments can be
summarized as follows:
(a) Brønsted acids such as H3PO4 induce enolization and
preisomerization. The acetyl group seems to assist preisomer-
ization (Scheme 11).
(
b) Enolization occurs also with MXn-type Lewis acids
Scheme 12). The intermediate C(2)-B bond is quenched during
reaction (36 f 37 in Scheme 12).
c) MeAlCl2 gives no enolization. This explains why no
(
(
postisomerization and fewer side reactions occur with this
reagent (Scheme 13). The intermediate C(2)-Al bond is
quenched during reaction (39 f 37 in Scheme 13).
38
g1 equiv of AlCl3. In the optimized realization of this idea
(Table 2, entry 4), 0.95 equiv of AlCl3 and 0.15 equiv of
(
d) No other aluminum species arise from MeAlCl2. It
(
32) The use of g2 equiv of MeAlCl2/carbonyl group in C-C-coupling
remains unchanged after cyclization (Scheme 13) and raises the
possibility of a catalytic version of this reaction.
reactions is not mandatory. Ca. 1 equiv or catalytic amounts of MeAlCl2
have also been used successfully in reactions such as Cycloalkylation,
intramolecular Diels-Alder, epoxide-initiated cation-olefin cyclization,
aldol condensation, carbocationic cyclization of unsaturated carbonyl
compounds, and carbonyl ene reactions. See, for example: (a) Abouabdellah,
A.; Bonnet-Delpon, D. Tetrahedron 1994, 50 11921-11932. (b) Rogers,
C.; Keay, B. Can. J. Chem. 1993, 71, 611-622. (c) Corey, E. J.; Sodeoka,
M. Tetrahedron Lett. 1991, 32, 7005-7008. (d) Naruse, Y.; Ukai, J.; Ikeda,
N.; Yamamoto, H. Chem. Lett. 1985, 1451-1452. (e) Goeke, A.; Mertl,
D.; Brunner, G. Angew. Chem., Int. Ed. 2004, 44, 99-101.
Cyclization with Catalytic Amounts of MeAlCl2 and Its
Mechanism. Similar C-C-coupling reactions have been re-
3
2
ported that require 2 equiv of MeAlCl2 per carbonyl group,
e.g., certain intermolecular Diels-Alder reactions33 or carboca-
tionic cyclization reactions of unsaturated carbonyl com-
pounds.34 Snider proposed that carbonyl groups trigger the
34a
(33) (a) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett.
999, 40, 4457-4460. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am.
Chem. Soc. 1988, 110, 1238-1256.
disproportionation of MeAlCl2, as is known to happen in the
presence of other donor molecules (eq 1).35 Evidence for this
1
carbonyl-induced disproportionation was noted in the behavior
(34) (a) Snider, B. B.; Cartaya-Marin, C. P. J. Org. Chem. 1984, 49,
153-157. (b) Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J. J. Org.
Chem. 1982, 47, 4538-4545. (c) Karras, M.; Snider, B. B. J. Am. Chem.
Soc. 1980, 102, 7951-7953. (d) Snider, B. B.; Rodini, D. J.; van Straten,
J. J. Am. Chem. Soc. 1980, 102, 5872-5880. See also ref 32e.
of MeAlCl2 in the presence of methyl benzoate.36
donor + 2RAlCl f R AlCl + [donor‚AlCl ]
2
2
3
(35) (a) Lehmkuhl, H.; Ziegler, K. In Houben-Weyl, Methoden der
(R ) Me, Et) (1)
organischen Chemie; M u¨ ller, E., Ed.; Georg Thieme Verlag: Stuttgart,
Germany, 1970; pp 51-55, 59-78, and 95-101 and refs 2-5 on p 71. (b)
Tarao, R.; Takeda, S. Bull. Chem. Soc. Jpn. 1967, 40, 650-655. (c)
Lehmkuhl, H.; Kobs, H. D. Tetrahedron Lett. 1965, 29, 2505-2510.
(36) Starowieyski, K. B.; Pasynkiewicz, S.; Sporzynski, A. J. Organomet.
Chem. 1976, 117, 117-128.
If one considers the disproportionation of MeAlCl2 in the
presence of precursor 5, the following conclusions must be
drawn (Scheme 14):
(a) The 1 equiv of Me2AlCl generated is superfluous waste,
(37) See, for example: Smith, C. A.; Wallbridge, G. H. J. Chem. Soc.
because Me2AlCl cannot promote the cyclization of 5 under
these conditions (e.g., to 16, Scheme 8).
A 1967, 7-12.
(38) Inukai, T.; Michio, K. J. Org. Chem. 1965, 30, 3567-3569.
1118 J. Org. Chem., Vol. 72, No. 4, 2007

Cyclization of 1,5-Dienes
TABLE 2. Cyclization of Precursor 5 Promoted by Different
more than 0.1 equiv of AlMe3 was used. This is understandable
if one considers disproportionation and complexing as discussed
above, with the consequence that no MeAlCl2 is available for
activation of the exocyclic double bond. The combination of
a,b
AlCl3/MeAlCl2 Combinations
effectivec
yield of 8 or
other
d
AlCl
3
MeAlCl
2
MeAlCl
[equiv]
2
temp time
entry [equiv] [equiv]
[°C]
[h]
products
purity
1
.6 equiv of AlCl3 and 0.8 equiv of AlMe3, which should
1
2
3
4
5
6
7
8
0.95
0.5
0.95
0.95
0.95
0.9
55
55
65
55
65
40
60
70
18
18
6, 7, 8
5, 6
sluggish conversion
1:1:1
1:1
generate 2.4 equiv of MeAlCl2 in situ, gave similar results (Table
3, entry 5) as 2.5 equiv of MeAlCl2 alone (Table 2, entry 8).
Without catalyst AlMe3, preisomerization, and enolization
occurred as expected (Table 3, entry 1).
0.25
0.1
0.15
0.25
0.5
0
0.05
0.15
0.3
0.5
0.5
18
2
7
1
2
61%
65%
72%
70%
80%
77%
74%
71%
80%
92%
Summary. Pre-equilibration of the endocyclic double bond
of cyclization precursor 5, which occurs in the presence of
Brønsted acids, was avoided by using the organoaluminum
reagent, MeAlCl2. This also circumvented postequilibration of
the carbocationic cyclization product, which occurred in the
presence of MXn-type Lewis acids. â-Georgywood 8 was
obtained with high selectivity and good yields with use of
MeAlCl2 in stoichiometric or even catalytic amounts. Both
versions presumably proceed via carbonyl blocking effected by
AlCl3 generated from MeAlCl2. Stoichiometric amounts of AlCl3
have to be added, if MeAlCl2 is used catalytically. The catalyst
MeAlCl2 can also be generated in situ from AlMe3. Although
the yield of the catalytic version is slightly lower than the
stoichiometric reaction, the process advantages are obvious: less
pyrophoric reagent, less aluminum waste, and less generation
of gaseous methane. It can be expected that AlCl3 carbonyl
blocking and catalytic MeAlCl2 activation will also find its
application in similar C-C coupling reactions that were
previously carried out with stoichiometric amounts of MeAlCl2.
0.8
0.9
2.5
a
b
Substrate 5 and reagents (in toluene) mixed at -20 °C. 55 °C, 20 h,
+
c
H -quench. MeAlCl2 leftover for activation of the exocyclic double bond
d
after disproportionation according to eqs 1-3 and Scheme 14. Yield (after
distillation) corrected by purity.
TABLE 3. In Situ Generation of Catalyst MeAlCl2 from AlMe3a,b
e
effective effective
yield of 8
or other
d
AlCl
3
AlMe
3
MeAlCl
2
AlCl
3
time
purity
[%]
entry [equiv] [equiv] [equiv]c [equiv] [h]
products
1
1.05
1.05
24 mixture of
, 6, 8, 15
5
2
3
4
5
6
1.05
1.1
0.95
1.1
0.05
0.1
0.3
0.3
0.8
0.05
0.1
1.0
1.0
0.8
0.95
1.0
24 69%
24 56%
24 low conversion
24 not reproducible
84
73
1.6
0.4
4
70%
87
a
b
AlCl3, AlMe3, toluene, 100 °C, 1 h. Addition of substrate 5 at -10
+
c
°
C, then 55 °C, 20 h, H quench. MeAlCl2 leftover for activation of the
exocyclic double bond after disproportionation of the employed AlMe3
d
according to eqs 1-4 and Scheme 14. AlCl3, generated according to eqs
1
-4, that is partially or completely consumed for complex formation with
Experimental Section
e
the carbonyl group. Yield (after distillation) corrected by purity.
1
-(cis-1,2,3,4,5,6,7,8-Octahydro-1,1,7,8-tetramethylnaphtha-
len-7-yl)ethanone (8). For the preparation of cyclization precursor
see refs 8 and 9. Analytical data for 8: 1H NMR δ 0.85 (d, 3 H,
MeAlCl2 effected the cyclization of 5 to â-isomer 8 in good
yield (83%).
5
J ) 6.9 Hz), 0.99 (s, 3H), 1.02 (s, 3H), 1.06 (s, 3H), 1.4-2.2 (10
H), 2.15 (s, 3 H,), 2.36 (q, 1 H, J ) 6.9 Hz). 13C NMR δ 19.15 (t),
19.7 (q), 21.1 (q), 22.5 (t), 24.9 (q), 27.7 (t), 28.4 (q), 29.4 (q),
Without MeAlCl2 under otherwise identical conditions, pre-
isomerization of 5 to 6 was observed (Table 2, entry 1). The
cyclization also does not take place properly with AlCl3/
MeAlCl2 combinations, where after MeAlCl2 disproportionation
and complexing MeAlCl2 is no longer available for activation
of the exocyclic double bond (Table 2, entries 1-3). In the case
where MeAlCl2 is available for this activation (Table 2, entries
3
2
0.8 (t), 34.0 (s), 35.4 (d), 40.1 (t), 50.7 (s), 125.9 (s), 136.95 (s),
14.5 (s). MS (EI) m/z (%) 234 (M , 25), 219 (15), 191 (100), 161
+
(
1
20), 135 (65), 121 (40), 105 (40), 91 (30). IR (film) ν 2930 (m),
700 (s), 1460 (m), 1377 (m), 1357 (m), 1240 (w), 1220 (w), 1090
-1
(
m) cm . HRMS calcd for C16
For further analytical data, see ref 12b.
Method A: H PO (85%, 10 g, 85 mmol) is added dropwise to
H26O: 234.1984. Found: 234.1981.
4-8), the cyclization rate increases as more catalyst is left over
3
4
for cyclization. The reaction, however, works best with >2 equiv
of MeAlCl2 alone (Table 2, entry 8). Once again the higher
alkyl homologues of MeAlCl2 (Scheme 8) could not replace
MeAlCl2, consistent with the catalytic role of MeAlCl2 (Scheme
precursor 5 (200 g, 0.85 mol) in xylene (200 g) at 145 °C. After 2
h at this temperature, the reaction mixture is cooled to 20 °C and
treated with 0.5% aqueous Na
of the aqueous phase with xylene, washing of the organic phase to
pH 7, drying over MgSO , filtration, and evaporation of the solvent
2 3
CO . Phase separation, extraction
1
4) and inconsistent with MeAlCl2 solely providing water-free
4
gives an oily residue, which is short-path distilled. After addition
of 24 g of paraffin to the distillate (202 g) and a second distillation
conditions for an AlCl3-promoted cyclization.
AlMe3-Catalyzed Cyclization. It was known that MeAlCl2
can be generated from AlCl3 and AlMe3 (eq 4),35a but we were
pleased when we could use this equilibrium also in the presence
of donor molecules such as the carbonyl group of 5 for the in
situ generation of MeAlCl2.
(
4
30 cm, glass coil) 184 g of a 7/8 mixture (84% purity, ratio
0:60) is obtained at 105 °C/0.1 mbar. Yield of 8 corrected by
purity: 45%.
Method B: Precursor 5 (2 g, 8.5 mmol) in toluene (10 mL) is
cooled under nitrogen and stirring to -50 °C, where BBr (3.2 g,
3
1
3 mmol) is added dropwise via syringe. After 7 h at -50 °C, 2 M
AlMe + 2AlCl T 3MeAlCl
2
(4)
HCl is added at this temperature. Warmed again to 25 °C, the
mixture is extracted with tert-butyl methyl ether. The organic phase
3
3
is washed with concentrated NaCl, dried over MgSO
concentrated under reduced pressure. Bulb-to-bulb distillation at
30 °C/0.1 mbar gives 1.1 g of a 8/12 mixture, which is dissolved
in toluene (5 mL) and treated with p-toluenesulfonic acid (40 mg,
.2 mmol). After 4 h at 100 °C the organic phase is washed with
Na CO and water until pH 7, dried, and concentrated under reduced
pressure giving 1.2 g of a brown oil, which is bulb-to-bulb distilled
at 120 °C/0.05 Torr giving 0.8 g (40%) of 8 with ∼90% purity.
4
, and
After optimization, the combination AlCl3/AlMe3 worked as
well as the previous combination AlCl3/MeAlCl2 (Table 3,
entry 2).
Because 1 equiv of AlMe3 should generate 3 equiv of
MeAlCl2 in the presence of an excess of AlCl3 (eq 4), even
less AlMe3 could be employed than MeAlCl2. The cyclization
was blocked or not reproducible (Table 3, entries 3 and 4) when
1
0
2
3
J. Org. Chem, Vol. 72, No. 4, 2007 1119

Fr a´ ter and Schr o¨ der
powder (9 g, 67 mmol) and AlMe (2 M in
heptane, 1.6 mL, 3 mmol) in toluene (25 mL) are heated under
nitrogen and stirring to 100 °C. After 1 h at this temperature, the
suspension is cooled to -10 °C, where precursor 5 (15 g, 64 mmol)
in toluene (60 g) is added within 30 min. The solution is stirred at
55 °C for 24 h, then cooled to room temperature, poured upon ice/
water (200 mL), and extracted with hexane. The combined organic
layers are washed with NaHCO and water until pH 7, dried over
3
MgSO , filtered, and concentrated under reduced pressure. The
residue (16.1 g) is purified by bulb-to-bulb distillation giving 11.8
g of â-Georgywood 8 (69%) at 125 °C/0.1 Torr with a GC purity
of 84%.
Method C: γ-Georgywood 13 (1.3 g, 5.6 mmol) and p-
toluenesulfonic acid (0.25 g, 1.4 mmol) in toluene (3 mL) are stirred
for 4 h at 100 °C. After cooling to 20 °C the organic phase is
Method F: AlCl
3
3
2 3
washed with Na CO and water until pH 7, dried, and concentrated
under reduced pressure. Bulb-to-bulb distillation gives 0.95 g (47%)
of 8 with ∼90% purity.
Method D: Precursor 5 (20 g, 85 mmol) in toluene (100 g) is
added under ice cooling to methylaluminum dichloride (1 M in
hexane, 157 g, 0.21 mol). The mixture is heated to 70 °C for 2-3
h, then quenched under ice-cooling with ethanol (40 g), then with
4
2
M HCl. The organic phase is separated and the aqueous phase
extracted with tert-butyl methyl ether. The combined organic layers
are washed with concentrated NaCl, then with water until pH 7.
The organic phase is dried over MgSO
4
, filtered, and concentrated
Acknowledgment. Special thanks to the laboratory as-
sistants, technicians, and analysts at Givaudan: L. Hesse, P.
Aebersold, M. Mathys, C. Oberholzer, S. Elmer, J. Weibel, and
T. Reinmann (preparative work), M. Jocher (preparative GC),
J. Schmid (GC/MS, HRMS), and G. Brunner (NMR). We thank
A. Gabbai, A. Goeke, and P. Gygax (Givaudan), Prof. Sir Jack
Baldwin (University of Oxford), Prof. A. Vasella (ETH Z u¨ rich),
and Prof. P. Chen (ETH Z u¨ rich) for interesting discussions. For
proofreading we thank T. McStea.
under reduced pressure. The residue is distilled giving 16 g (80%)
of â-Georgywood 8 at 124 °C/0.1 Torr as a colorless liquid and
with a purity of ∼90% according to GC and NMR.
Method E: Precursor 5 (15 g, 64 mmol) in toluene (60 g) is
3
added at -10 °C to a suspension of anhydrous AlCl powder (8.4
g, 61 mmol) in toluene (25 mL) under nitrogen and stirring. After
addition of methylaluminum dichloride (9.6 g, 9.6 mmol) in hexane
(
1 M), the brown-red solution is heated at 55 °C for 18 h. The
solution is poured upon ice/water (300 g) and extracted with hexane.
The combined organic layers are washed with NaHCO and water
until pH 7, dried over MgSO , filtered, and concentrated under
3
Supporting Information Available: Experimental procedures
and analytical data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
4
reduced pressure. The residue (18 g) is purified by bulb-to-bulb
distillation, giving 10 g of â-Georgywood 8 (61%) at 125 °C/0.1
Torr with a GC purity of 87% according to GC and NMR.
JO061668K
1120 J. Org. Chem., Vol. 72, No. 4, 2007