Endo-selective Diels-Alder reaction of methacrylonitrile: application to the synthesis of Georgywood

Article abstract of DOI:10.1016/j.tet.2009.09.089

Diels-Alder reactions of alkyl-substituted dienes with acrylonitriles give good yields and endo-selectivities if catalyzed by (organo)aluminum, (organo)boron or gallium halides. The activity of these group IIIa Lewis acids in this reaction correlates with

Full text of DOI:10.1016/j.tet.2009.09.089

Tetrahedron 65 (2009) 10495–10505
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Endo-selective Diels–Alder reaction of methacrylonitrile: application to the
synthesis of Georgywood
*
Andras Borosy, Georg Frater, Urs Mu¨ller, Fridtjof Schro¨der
Research Chemistry Department, Givaudan Schweiz AG, CH-8600 Du¨bendorf, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Diels–Alder reactions of alkyl-substituted dienes with acrylonitriles give good yields and endo-selec-
tivities if catalyzed by (organo)aluminum, (organo)boron or gallium halides. The activity of these group
IIIa Lewis acids in this reaction correlates with the coordination strength of their nitrile complexes,
which deactivate Lewis acids sufficiently, so that the subsequently added diene partner undergoes the
Diels–Alder reaction without serious side-reactions. Boron trichloride is the most effective catalyst for
this purpose. This method gives the best endo/exo-ratios reported so far for these components and was
applied in the selective synthesis of the olfactory vector of GeorgywoodÒ.
Received 14 August 2009
Received in revised form
21 September 2009
Accepted 23 September 2009
Available online 25 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
selective Diels–Alder (DA) reaction with methacrylonitrile (MAN)
(Scheme 2).
Isomer 1a is the powerful olfactory vector of GeorgywoodÒ
(Fig. 1),1 an isomer mixture (1a/1c) produced at Givaudan and used
as a woody, ambery fragrance ingredient in perfumery applica-
tions.2 Since its first synthesis3 various routes have been realized,
which give the desired 1a with higher selectivity.4
As part of the search for new fragrance molecules, cis-configured
nitrile 4a has been recently prepared from aldehyde 3a1b in our
laboratories. Upon treatment with H3PO4, diene 4a underwent
carbocationic 1,5-cyclization giving bicyclic nitrile 5a with excellent
selectivity (Scheme 1).
The exclusive formation of 5a from 4a raised our attention be-
cause the corresponding Brønsted acid promoted cyclization of
ketone 6a gives mixtures of ketones 1a and 1c, which have their
origin in a pre-isomerization of the endocyclic double bond of
cyclization precursor 6a.4b Instead of preparing cyclization pre-
cursor 4a from aldehyde 3a (Scheme 1) we envisioned that 4a could
be more efficiently accessed from homomyrcene 2a3,4a by an endo-
Endo/exo-selectivities for DA reactions of acrylonitriles with
alkyl-substituted dienes,5 however, have been only reported from
endocyclic6 dienes so far, and in case of methacrylonitrile only for
the DA reaction with cyclopentadiene, where none- or exo-selec-
tivities have been obtained, either thermally7 or in the presence of
zeolites.8 In DA reactions with other dienes such as butadiene or
furan, MAN has been reported as being much less reactive or even
unreactive.9 In his fundamental study on the thermal DA reaction of
alkyl-substituted endocyclic dienes with
Mellor has found that endo/exo ratios and reaction rates decrease
with the bulk of the
-alkyl-substituent R (Fig. 2).7c,d Mellor has
a-alkyl-acrylonitriles,
a
attributed this effect to the centrosymmetric nature of the nitrile
group, which has less freedom for secondary orbital overlap. Hence,
with increasing bulk of R and R0 in endo-transition state 8a non-
bonding repulsive steric interactions between the bridging alkyli-
dene group R0 of the endocyclic diene and the
a-alkyl-substituent R
of the acrylonitrile become predominant. From this we expected
that methacrylonitrile and acyclic dienes such as homomyrcene 2a
would preferentially react via endo-transition state 9a, due to the
lack of the bridging alkylidene group R0 of the diene.
Other authors have reported slightly increased reaction rates
and endo/exo-ratios for the DA reaction of cyclopentadiene with
acrylonitrile in the presence of Lewis acids.10 Similar effects were
observed in Lewis acid/ionic liquid systems.11 Although endo/exo
ratios obtained from this transformation did not exceed 71:29,10d,11a
this hinted at the possibility that Lewis acids could also increase the
endo-ratios in methacrylonitrile Diels–Alder (MANDA) reactions of
homomyrcene 2a, via transition state 10a, to access cis-product 4a
and to exploit such a product for a selective synthesis of 1a.
O
O
45:55
1a (30 pg / L)
1c (500 ng / L)
Figure 1. Main isomers of GeorgywoodÒ (olfactory thresholds in brackets). Isomer
ratio 1a/1b¼45:55.
* Corresponding author.
E-mail address: fridtjof.schroeder@givaudan.com (F. Schro¨der).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.089

10496
A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
a) 1.5 equiv NH2OH x HCl,
Na2CO3, H2O, EtOH,
1 h, 60 °C, 99%
H3PO4,
60 -110 °C,
CN
CN
CHO
ref.1b
b) 4 equiv Ac2O, toluene,
reflux, 60%
75%
3a
4a
5a
2a
Scheme 1. Synthesis of nitrile 5a from aldehyde 3a.
CN
CN
O
O
5a
+
2a
MAN
6a
1a
4a
Scheme 2. Retrosynthesis of Georgywood vector 1a.
endocyclic
dienes
alkyl-subst.
nitrile - MXn
complexes
acyclic dienes
R''
R''
R''
R''
R''
R''
R''
R''
XnM
R'
N
R'
MXn
N
N
N
N
9b
R
N
R
R
R
R
R
10a
8a
8b
9a
10b
endo-TS
(disfavored)
exo-TS
exo-TS
endo-TS
exo-TS
endo-TS
(favored)
(favored)
Figure 2. Transitions states (TS) of endocyclic (R0¼alkylidene) and acyclic dienes, depending on nonbonding repulsive interactions of the bridging group R0 or the absence of this
7d
group with acrylonitriles. R0¼methylidene, 1,1-cyclopropylidene, and ethylidene according to Ref.
R00¼methyl, alkyl. M¼metal, X¼halide.
2. Results and discussion
superimposiblewith the ones obtained already for this compound via
the oxime route (Scheme 1). The structure of trans-isomer 4b was
determined after preparative GC separation from the 4a/4b mixture
and NMR-analysis.
Solvent-free DA reaction of homomyrcene 2a and methacryloni-
trile at reflux gave the diastereomer mixture 4a/4b with slight
exo-preference (Scheme 3). NMR-data of cis-diastereomer 4a were
A Lewis acid screening12 of this reaction at 60 ꢀC showed that
especially metal halides MX3 of the IIIa group (BX3, AlX3, and GaX3
with X¼Cl, Br) gave good reaction rates and endo/exo-ratios (Table 1,
entries 1–7). GaCl3, however, gave a much lower yield (run 7) and
InCl3 was inactive. EtAlCl2 and especially MeAlCl2 were similarly
effective (runs 4–5) but organoaluminum reagents of weaker Lewis
acidity such as AlF3, AlEt3, Al(iBu)3 or Me2AlCl gave very poor con-
versions. Methylaluminoxane (MAO) or Al(OTf)3 gave only traces of
DA adduct. The corresponding ZnX2 salts (X¼Cl, Br) were also re-
active but needed longer reaction times and gave inferior endo/exo-
ratios (runs 8–9).
1.3 equiv MAN,
CN
CN
105 - 120 °C, 24 h,
59%
46:54
4b
4a
2a
Scheme 3. Thermal DA reaction of homomyrcene 2a with methacrylonitrile (MAN).
Table 1
Lewis acid screening of the MANDA reaction of homomyrcene 2a at 60 ꢀC
15 - 20 mol% LA,
CN
Table 2
MAN, 0 °C,
Lewis acid screening of the MANDA reaction of homomyrcene 2a at 25 ꢀC
then 2a, 25 °C
15 - 20 mol% LA,
CN
4a
2a
MAN, 0 °C,
then 2a, 25 °C
Entry Lewis acid
mol % Solvent Time Yielda cis/trans Other
LAc
[h]
dienesb
4a
2a
(LA)
1
2
3
4
5
6
7
8
9
AlCl3
20%
Toluene 4 h
51%
63%
62%
73%
73%
64%
43%
81:19
77:23
78:22
64:36
81:19
84:16
79:21
66:34
70:30
20%
29%
20%
10%
5%
AlCl3/n-PrNO2 1:2d 15%
None
4 h
Entry Lewis acid mol % Solvent
Time Yielda cis /trans Other
[h]
(LA)
LA
dienesb
AlBr3
20%
20%
20%
10%
20%
20%
20%
Toluene 4 h
Toluene 4 h
Tol, hex 1 h
Xylene 1 h
Toluene 3 h
EtAlCl2
MeAlCl2
BCl3
GaCl3
ZnCl2
ZnBr2
1
2
3
4
5
6
7
AlCl3
AlCl3
MeAlCl2
BCl3
BBr3
20%
15%
15%
20%
20%
20%
20%
CH2Cl2
None
Toluene 22 h
Xylene 3 h
Toluene 3 h
72 h
44 h
39%
60%
51%
65%
63%
43%
54%
79:21
73:27
82:18
85:15
85:15
85:15
85:15
3%
20%
24%
10%
12%
7%
9%
26%
33%
27%
Toluene 21 h 58%
Toluene 48 h 54%
n-Bu-BCl2
Ph-BCl2
Hexane
Toluene 18 h
24 h
8%
Conditions: Homomyrcene 2a added to 10–25 mol % Lewis acid and 1.2 equiv
methacrolynitrile under cooling, stirring and nitrogen, then heated to 60 ꢀC until
complete conversion of the diene.
Conditions: Homomyrcene 2a added to 0.15–0.2 equiv Lewis acid and 1.2 equiv
methacrolynitrile under cooling, stirring and nitrogen, then stirred at 25 ꢀC until
complete conversion of the diene.
a
Yields (exoþendo) after distillation and corrected by purity of substrate 2a and
product 4.
CH2Cl2 instead of toluene gave similar results.
b
a
Mainly unconverted terminal dienes 2b and 2d and methyllimonene 2c before
Yields (exoþendo) after distillation and corrected by purity of substrate 2a and
distillation.
product 4.
c
b
Molar ratio relative to substrate in %.
Molar ratio.
Mainly unconverted terminal dienes 2b and 2d and methyllimonene 2c before
d
distillation.

A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
10497
The most reactive of these Lewis acids (Table 1) could be effi-
ciently employed at 25 ꢀC (Table 2). AlCl3 (runs 1–2)13 and MeAlCl2
(run 3), however, gave the DA adduct 4 only after prolonged re-
action times and with decreased yields and endo/exo-ratios,
whereas BCl3 and BBr3 (runs 4–5) catalyzed this reaction with best
efficiency at this temperature. n-BuBCl2 and PhBCl2 were less re-
active but also gave an endo/exo ratio of 85:15 (runs 6–7). Reactivity
(Scheme 4).22 Replacing homomyrcene 2a by cyclopentadiene gave
no DA product at all under these conditions, whereas in the pres-
ence of BCl3 the desired 13 was obtained readily (vide infra).
MAN, toluene,
10% BA, then
14
was drastically reduced with BEt3$ B(C6F5)3 catalyzed this re-
E
2a, 60-100 °C
action with good endo/exo selectivity but much slower. Corey’s
o-Tolyl-CBS-oxazaborolidine triflimide catalyst4c was inactive as
was gaseous BF3 or BF3(MeCN). Similar reaction rates were obtained
in xylene, toluene, and CH2Cl2. Ether solvents are inhibiting.15
Attempts to decrease the catalyst load of MeAlCl2 and BCl3 be-
low 15% were not successful, higher temperatures are then neces-
sary for complete conversion, which come close to the temperature
of the unselective thermal reaction (run 6).
2a
2c
2e
Scheme 4. Cyclization of homomyrcene 2a in the presence of Brønsted acids.
BA¼H2SO4, pTSA, TFA (all with 0.1 equiv) or formic acid (5 equiv).
2.1. Discussion
The observed catalytic activity of the boron and aluminum halides
(Tables 1 and 2) correlates with the strength of the methacrylonitrile
-orbital coordination to the boron and aluminum center as known
Homomyrcene 2a, produced as described,3 contains the isomers
2b and 2d as main impurities,16 which are eluted closely to 2a in the
GC (Fig. 3). Selective DA reaction of 2a with methacrylonitrile (under
the conditions of Tables 1 and 2) leave the less reactive 2b and
unreactive methyllimonene 2c (at GC-retention times close to 2a)
untouched. No defined byproducts are formed. With some less ef-
ficient catalysts such as Cu(OTf)2/BINAP, MAO, and TiCl4 slow
isomerization of 2a to 2b, 2c, and 2e was observed by GC. With
Bi(OTf)3 in CH2Cl2 competitive cyclization/isomerization to 2e be-
came predominant.
s
from the literature. The order BBr3ꢁBCl3>>BF3 has been reported
fromcoordinationstudies withacetonitrile,23 formationconstantsfor
complexes with p-fluorobenzonitrile have been reported to follow
the order BBr3wBCl3>>BF3>pFC6H4BCl2, BMe3.24 In a more recent
study of methacrylonitrile coordination with a series of strong Lewis
acids MCln (M¼Ti(IV), Sn(IV), B(III), Sb(V)) by far the most stable complex
of methacrylonitrile was formed with BCl3.25 The order of activity
AlCl3wMeAlCl2>EtAlCl2>>AlEt3, Al(iBu)3, Me2AlCl>MAO was ob-
served in reactions promoted by ketone Lewis acid complexation.4a
From another study it has been reported that especially group III
metal chlorides MX3 undergo strong coordination with saturated
nitriles and the order Al>Ga>Zn>Fe>Sn>Ti was observed.26
Z
E
E
2b
2c
2a
2d
2e
2f
A reliable quantitative structure–activity relationship (QSAR)
was established between the log t values (log10 of Time [h] in Tables
1 and 2) and the molecular structures of 22 catalysts, including the
ones employed and some others. The root mean square error
(RMSE) of prediction of the best model is 1.15 in log units.27 This
QSAR explains, for example, why Brønsted acids don’t promote
MANDA reactions: the coordination of MAN with a proton is as
weak as coordination with boron trifluoride, for example, therefore
Brønsted acids simply don’t activate MAN for DA reaction.28
The calculation of coordination complexes of 4 with AlCl3 and
BCl3 shows, that these complexes (B) are only 2–3 kcal lower in
Gibbs free energy than the corresponding complexes of meth-
acrylonitrile (A).29 This can be explained by an increased electron
Figure 3. Homomyrcene 2a and C11H18 isomers 2b–f (order of elution on a DB5 column).
Preparation of reference compounds: 2a (Ref. 3), 2b (Ref. 16), 2c (from Citral, MeMgCl,
THF, 0 ꢀC, then FeCl3, tetraethyleneglycol dimethylether, 80 ꢀC), 2d (Ref. 16), 2e (from
homomyrcene 2a, methacrylonitrile, 10% Bi(OTf)3, CH2Cl2, 64%, dist), 2f (Refs. 4a–b).
Silver salts slightly increased endo/exo-ratios under the conditions
of Table 1, e.g., up to 62:38 with AgBF4, but the reaction run very
sluggishly.17 Copper18 and zinc19 complexes were less effective and
other Lewis acids were found to be inactive,20 i.e., lanthanide triflates.21
It should also be mentioned that Brønsted acids did not promote
a Diels–Alder reaction of homomyrcene and MAN but gave mainly
mixtures of methyllimonenes 2c and 2e with moderate yields
M
M
CN
CN - X3
CN - X3
CN
+
+
4
A
MAN
B
Scheme 5.
Figure 4. Ab initio calculation of Diels–Alder transition 10a (endo): top view (left) and side view (right).

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A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
density at the nitrile lone pair orbital of 4 versus the more delo-
calized electron density in methacrylonitrile. The relatively low
energy difference allows equilibration and a catalytic activity of
these Lewis acids on methacrylonitrile (Scheme 5). The endo/exo
ratios are independent from the progress of the reaction and the
amount of catalyst used.
The enhanced endo-selectivities can be explained by the de-
creased LUMO of the methacrylonitrile–MX3 complex, thus
Table 3
DA reactions of various dienes with acrylonitrile (AN) and methacrylonitrile (MAN)
Entry
Dienesa
Dienophile
T [ꢀC]
t [h]
DA adduct
(main isomers)
Yieldb
89%d
endo /exoc
CN
1
MAN
25 ꢀ
C
C
3 h
85:15
4a
12
2a
CN
2
3
2a
AN
25 ꢀ
1 h
66%
68%
87:13
86:14
Cyclopentadiene
MAN
25 ꢀC
18 h
CN
CN
13
4
5
6
7
8
Cyclopentadiene
E-1,3-Pentadiene
E-1,3-Pentadiene
AN
25 ꢀ
C
C
1 h
69%
58%
71%
50%
91%
69:31
78:22
92:8c
76:24
85:15
14
CN
MAN
AN
70 ꢀ
1 h
15
16
CN
25 ꢀC
1 h
CN
MAN
AN
60 ꢀ
C
C
72 h
72 h
17
19
CN
17
25 ꢀ
20
CN
9
MAN
AN
60 ꢀ
25 ꢀ
C
C
1 h
1 h
47%
84%
57:22:14:7e
18
21
CN
10
18
64:12:12:12e
22
E/Z 3:2
CN
CN
11
12
MAN
AN
25 ꢀ
25 ꢀ
C
C
5 h
5 h
59%
78:19:3
E
2f
23
24
2f
82%f
88:4:4:4e
Conditions: Diene added to 0.15–0.2 equiv BCl3 in xylene and 1.2 equiv acrylonitrile or methacrolynitrile under cooling, stirring and nitrogen, then stirred at indicated
temperature until complete conversion of the diene.
a
Diene substrates: cyclopentadiene was obtained by distillative cracking of commercial dicyclopentadiene, E-1,3-Pentadiene is commercially available, 17 was prepared
from Artemol39 by Pd-cat. elimination. 1833 and 2f4a-b were prepared according to the literature.
b
Yields not optimized, after distillation or flash chromatography.
Endo/exo ratio of the crude before distillation or FC.
Yield optimized.
Isomer ratio by NMR analysis.
c
d
e
f
Yield based on the E-isomer (62%) of methylocimene 2f.

A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
10499
allowing tighter secondary orbital interaction with the HOMO of the
diene in endo-transition state 10a. Primary and secondary orbital
interaction were visualized by ab initio calculation (Fig. 4), with
activation energies of 80.5 and 82.5 kJ/mol for the uncomplexed
endo and exo transition states 9a and 9b (Fig. 2) and 26.9 and 34.6 kJ/
mol for the BCl3-complexed transition states 10a and 10b, re-
spectively. This is in accordance with increased reaction rates and
endo/exo selectivities in the BCl3 promoted DA reaction of homo-
myrcene 2a with MAN.
The ab initio calculation of transition state 10a shows also that
the C–CN group maintains its centrosymmetric geometry with only
minimal distortion in coordination complex 10a. The more
ionic coordination complex 11b would have higher freedom for
secondary orbital interaction (Scheme 6).
the DA reaction, in contrast to the less reactive 2E,4Z-isomer,32
giving mainly the all-cis cyclohex-3-enecarbonitriles 23 and 24.
The relative configuration of the main isomers of the DA re-
action (Table 3) was confirmed by NMR-analysis or by comparison
with literature data (13, 14, 16). To obtain more reliable NMR-data
on 23 this nitrile was further converted to aldehyde 25, whose
relative configuration was analyzed by NMR. The relative configu-
ration of 23 was also confirmed by methylation of secondary nitrile
24, which occurs preferentially at the less hindered side of the
corresponding carbanion (Scheme 7).7b
The cis- and trans isomers have generally superimposable MS
spectra, with the cis-isomers having lower GC-retention times in the
case of the MAN-derived
a-trisubstituted DA adducts 4a, 13, 15, 19,
21, and 23, whereas in the case of acrylonitrile-derived
a-di-
substituted DA adducts 12, 14, 16, and 24 this order is reversed. The
main diastereomers of the secondary nitriles 20 and 22, which could
not be analyzed by NMR, are also eluted at higher rT and are therefore
likely to be cis-configurated. Minor amounts of regioisomers were
only detected in the case of the DA adducts (21–24) derived from
dienes 18 and 2f.
δ-
MX3
MX3
δ+
N
N
N
+ MX3
MAN
11a
11b
Scheme 6. Formation of methacrylonitrile/MX3 complexes. M¼Al, B, Zn. X¼Cl, Br.
2.2. Scope of the endo-selective MANDA reaction
2.3. Application to the synthesis of Georgywood
The cis-configured DA adducts 4a, 12–19, 21, and 23–24 were
obtained with moderate to good yields and cis/trans-ratios by BCl3-
catalyzed reaction of dienes 2a, cyclopentadiene, E-1,3-pentadiene,
17–18, and 2f with acrylonitrile or methacrylonitrile (Table 3). The
cis-selectivities were comparable to the one already obtained for
DA adduct 4a (run 1). Furan did not undergo DA reaction with MAN
under these conditions.
Endo/exo-selectivities have been reported from DA reactions of
cyclopentadiene or E-1,3-pentadiene with acrylonitrile or meth-
acrylonitrile. Whilst the moderate cis/trans ratio of 14 was com-
parable to the ratios obtained for this compound from DA reactions
in the literature,10,11 13 and 16 were obtained with much better
endo-selectivities. As expected, MAN is less reactive than acrylo-
nitrile in these reactions. 1,2-Dialkylsubstituted dienes such as 17
and 18 underwent the (meth)acrylonitrile DA reaction with the
same regioselectivity, as reported by Nazarov for the thermal DA
reaction of 1,2-dimethylbutadiene or 1-vinylcyclohexene with
acrylonitrile,30 giving cyclohex-3-ene-1-carbonitriles substituted
in their 1,2,3- or 2,3-positions (19–22). The high temperatures
(ꢁ200 ꢀC) required for the thermal DA reactions,30 are decreased to
20–60 ꢀC under BCl3 catalysis. DA reactions of acrylonitriles with
1,2,4-trialkylsubstituted butadienes such as 2f have not been
reported so far.31 Here the E,E-isomer of 2f selectively underwent
Further conversion of the above obtained cis-diene 4a to cis-b-
Georgywood 1a was carried out as depicted in Scheme 8. The yield
of 4a was improved by using freshly distilled homomyrcene 2a in
the MANDA step (a). Cyclization of 4a upon exposure to cryst.
H3PO4 at 110 ꢀC readily gives 5a. Grignard-addition to this relatively
hindered nitrile (5a) went smoothly after distillative removal of
diethyl ether from the Grignard reagent and running the Grignard-
addition at 100 ꢀC in toluene.34 Hydrolysis of the intermediate
imine with concd H3PO4 gave Georgywood 1a with very good
chemical and good olfactory yield (77%) after distillation.
The H3PO4-catalyzed cyclization to 5a proceeds via g-isomer 5c,
which was isolated after cyclization of 4a with less concentrated
H3PO4 (85%) at lower temperatures and, which can be further
converted to 5a under more drastic conditions (Scheme 9). Cycli-
zation of 4a occurs from the less hindered
steric interaction with the C(2)-methyl group shielding the
a
-face, thus avoiding
-face,
b
giving 5c with r-1,c-2,t-8a-configuration.35 This is in agreement
with studies on the cyclization of the corresponding acetyl-pre-
cursor 6a to 1a.4b The nitrile group of 4a, however, cannot interact
intramolecularly with the endocyclic double bond of the molecule
(as 6a does, thus facilitating pre-isomerization by intramolecular
enolization),4b which results in a highly selective cyclization of 4a
to 5a.
then MeI,
CN
CN
CN
cat. HMPA,
99%
LDA, THF,
-78 °C
CHO
DiBAH
24
23
25
Scheme 7. Relative stereochemistry of 23.
Methacrylonitrile, -10 °C,
15% BCl3, xylene,
MeMgBr, Et2O
toluene, 4 h, 100 °C
10% cryst, H3PO4,
CN
CN
2
O
1
110 °C, 30 min,
90%
25 °C, 3 h, 89%
conc. H3PO4, 1 h,100 °C
94%
2
4a dr = 86 : 14
5a dr = 87 : 13
1a dr = 90:10
Scheme 8. Synthesis of Georgywood 1a via nitrile 4a. The (slightly) higher yield and diastereomer ratio (dr) of 4a (compared to the one of Table 3, entry 1) is probably due to
a better quality of homomyrcene 2a, which was freshly distilled before use. The dr’s were found to be gradually improved through the sequence, due to enrichment of the
cis-isomers by distillation.

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A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
N
H
CN
85% H3PO4,
eq
cryst H3PO4
H
2
8a
4a
5a
eq
40-60 °C, 15 min,
61%
110 °C, 30 min
5c
H
H
Scheme 9. H3PO4 promoted cyclization of 4a to 5a via g-isomer 5c.
3. Conclusion
work-up gave a yellow liquid (12 g), which was distilled at 45 ꢀC/
0.15 Torr giving 7.2 g (64%) of a yellow liquid, which consisted of
65% 2c (cis/trans 14:86) and 27% 2e. Analytical data of trans-2c:
Diels–Alder reactions of alkyl-substituted dienes and acryloni-
triles give good yields and endo/exo-ratios if catalyzed by (orga-
no)boron or aluminum halides with borontrichloride being the
most effective Lewis acid for this purpose. The activity of these
group IIIa Lewis acids in this reaction correlates with the co-
ordination strength of their complexes with nitriles, as this is well
known in the literature. Therefore, it is surprising that their use in
Diels–Alder reactions with acrylonitriles has not yet been reported.
This method gives the best endo/exo-ratios reported so far for these
dienophiles and was applied in the selective synthesis of the ol-
factory vector 1a of GeorgywoodÒ. After Diels–Alder reaction
a highly selective 1,5-diene cyclization gave the bicyclic tertiary
nitrile 5a, which was efficiently transformed to the corresponding
tert-alkyl methyl ketone 1a.
1H NMR (CDCl3):
d
0.7 (d, 3H), 1.67 (s, 3H), 1.73 (s, 3H), 1.55–1.65
(2H), 1.9–2.05 (2H), 2.2 (1H), 2.35 (1H), 4.6 (m, 1H), 4.8 (m, 1H), 5.4
(d, 1H) ppm. 13C NMR:
15.3 (q), 21.7 (t), 22.5 (q), 23.4 (q), 31.0 (d),
d
31.1 (t), 43.65 (d), 109.1 (t), 127.6 (d), 132.7 (s), 148.2 (s). MS (EI): m/z
(%) 150 (Mþ, 12), 135 (11), 121 (10), 107 (27), 82 (100), 67 (82). IR
(film):
n
¼2964 (m), 2928 (m), 1646 (w), 1449 (m), 1374 (m), 1179
(w), 1157 (w), 1037 (w), 963 (w), 887 (s), 842 (m), 808 (w) cmꢂ1
.
HRMS calcd for C11H18: 150.1408; found 150.1404.
4.2.2. 1,3-Dimethyl-4-(propan-2-ylidene)cyclohex-1-ene
2e. Homomyrcene (2a) of 76% purity (5 g, 25 mmol)3 was added
dropwise to Bi(OTf)3 (0.5 g, 2.5 mmol) and methacrylonitrile (1.7 g,
25 mmol) in dichloromethane (20 ml) at 5 ꢀC. After 5 h at 25 ꢀC
water was added. Extraction with pentane and standard work-up
gave 4.6 g of a residue, which was bulb-to-bulb distilled at 45 ꢀC/
0.15 Torr giving 3.3 g (55%, corr) of a liquid, which contains 62% 2e
and 17% 2c (cis/trans 43:57). Analytical data of 2e: 1H NMR (CDCl3):
4. Experimental
4.1. General
d
1.0 (d, 3H),1.67 (10H),1.95 (s, 3H), 2.6 (m,1H), 3.05 (m,1H), 5.3 (m,
1H) ppm. 13C NMR:
d
19.7 (q),19.8 (q), 20.6 (q), 23.0 (t), 23.4 (q), 31.7
Reagents and solvents were purchased from commercial
suppliers and used without further purification. Solvents for mois-
ture-sensitive reactions contained <0.1% water. Moisture-sensitive
reactions were conducted in oven-dried (130 ꢀC) glassware under
nitrogen and stirring. The given temperatures refer to reaction
thermometers. All reactions were carried out under stirring. The
silica gel used for flash chromatography was Sorbsil, 0.04–0.063 mm
(Merck). Standard work-up includes phase separation, extraction of
the aqueous phase with tert-butyl methyl ether (pentane, hexane),
washing of the combined organic phase to pH 7, drying over MgSO4,
filtration, and evaporation of the solvent under reduced pressure.
1H- and 13C NMR: Bruker-DPX-400 MHz spectrometer; all spectra
(t), 33.3 (d), 121.4 (s), 127.3 (d), 132.7 (s), 133.4 (s). MS (EI): m/z (%)
150 (Mþ, 50), 135 (100), 119 (10), 107 (79), 93 (40), 91 (44), 79 (20),
77 (21). IR (film):
n
¼2962 (s), 2911 (s), 2964 (m), 1449 (s), 1373 (s),
1180 (m), 1085 (m), 1053 (m), 967 (m), 838 (s) cmꢂ1. HRMS calcd for
C11H18: 150.14085; found 150.1408.
4.2.3. Preparation of 2e by Brønsted-acid promoted cycliza-
tion. Homomyrcene (2a) of 76% purity (5 g, 24 mmol)3 was added
dropwise to methacrylonitrile (1.9 g, 28 mmol) in formic acid (5 ml)
at 25 ꢀC. After 2 h at 60 ꢀC the reaction mixture was poured onto
satd NaHCO3 (100 ml). Extraction with tert-butyl methyl ether and
standard work-up gave 5.1 g of a residue, which was bulb-to-bulb
distilled at 45 ꢀC/0.15 Torr giving 3 g (68%) of a liquid, which con-
tains 59% 2e and 23% 2c. Analytical data: see above.
were recorded at 400 MHz and in CDCl3;
d in ppm rel to SiMe4;
coupling constants J in Hertz. GC/MS: Agilent 5973 MSD with 6890
GC; relative intensities in % of the base peak. High Resolution GC/MS:
Finnigan MAT95 with HP 5890 series II GC. IR: Bruker FT-IRVector 22
spectrometer, n
w in cmꢂ1. Peak intensities assigned as strong (s),
middle (m), and weak (w).
4.3. Procedure A
The Georgywood isomers 1a,1b 1b,36 and 1c1b are known from
the literature.
4.3.1. Preparation of 4a by BCl3-catalyzed MANDA reaction. Meth-
acrylonitrile (111 g, 1.65 mol) was added dropwise at 10–20 ꢀC to
boron trichloride 1 M in xylene (225 ml, 0.22 mol). Freshly distilled
homomyrcene (2a) of 76% purity (225 g, 1.1 mol)3 was added at 10–
20 ꢀC over 40 min. The reaction was kept for another 40 min at 10–
20 ꢀC, then for 3 h at 25 ꢀC. After complete conversion the reaction
mass was poured onto ice-cold NaHCO3 and extracted with tert-
butyl methyl ether. Standard work-up gave 306 g of a red oil. After
addition of 65 g paraffin oil, 15 g Na2CO3 and 0.2 g hydroquinone
the residue was short-path-distilled giving pre-fractions at 69 ꢀC/
0.05 Torr and 214 g of 4a at 105 ꢀC/0.05 Torr. Yield: 89% (dist, corr,
based on purity of the homomyrcene and the cis-isomer). RT¼8.4
(86%, cis-isomer 4a), 8.6 (14%, trans-isomer 4b) min (GC). MS of
trans-isomer 4b identical to the one of cis-isomer 4a. The analytical
data of the cis-isomer were identical with the ones obtained for 4a
synthesized below from cis-aldehyde 3a.
4.2. Procedures for the preparation of compounds 2
Homomyrcene 2a was prepared as described.3 The terminal
dienes 2b and 2d were prepared for reference purposes.16 E/Z-
Methylocimene 2f4a–b was prepared as described.
4.2.1. 1,3-Dimethyl-4-(prop-1-en-2-yl)cyclohex-1-ene
2c. Citral
(11.4 g, 75 mmol) in tetraethyleneglycol dimethylether (13 ml) was
added dropwise over 1 h to methylmagnesium chloride 3 M in THF
(26 ml, 80 mol) and tetraethyleneglycol dimethylether (27 ml) at
5 ꢀC. The mixture was stirred for 1 h at 25 ꢀC, then FeCl3 (12.2 g,
75 mmol) was added portion wise under cooling (0–20 ꢀC). The
reaction was heated at 80 ꢀC for 2 h, cooled to 5 ꢀC and poured onto
H2O/pentane. Extraction with tert-butyl methyl ether and standard

A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
10501
4.4. Methods and data
preparative GC. Its structure was proven by NMR-analysis (HSQC,
HMBC, COSY, NOESY comparison with 4a) in C6D6. Analytical data
4.4.1. cis-1,2-Dimethyl-4-(4-methylpent-3-enyl)cyclohex-3-ene-
carbonitrile 4a from aldehyde 3a. Cis-1,2-Dimethyl-4-(4-methyl-
pent-3-enyl)cyclohex-3-enecarbaldehyde 3a (50 g, 0.23 mol)1b in
ethanol (250 ml) was added slowly to NH2OHꢃHCl (24 g, 0.35 mol)
and Na2CO3 (24 g, 0.23 mol) in water (60 ml). The mixture was
heated to 60–70 ꢀC for 1 h, then poured onto water (0.5 l). Extrac-
tion with tert-butyl methyl ether and standard work-up gave the
crude oxime (62 g). For analytical measurements 2 g of the crude
were purified by bulb-to-bulb distillation giving 1.75 g (99%) of
pure oxime. Analytical data of the oxime: 1H NMR (CDCl3,
of 4b: 1H NMR (C6D6, 500 MHz):
d
0.72 (d, J¼7.05 Hz, 3H), 0.82
(s, 3H), 1.36 (m, 1H), 1.48 (m, 3H), 1.5 (s, 3H), 1.55 (m, 1H), 1.65
(d, J¼1.07 Hz, 3H), 1.78 (m, 1H), 1.84 (t, J¼7.48 Hz, 2H), 2.03
(m, 2H), 2.28 (dd, J¼7.05, 1.71 Hz, 1H), 4.94 (m, 1H), 5.11 (m, 1H)
ppm. 13C NMR (C6D6, 500 MHz):
d 16.2 (q), 17.7 (q), 18.5 (q), 25.0
(t), 25.8 (q), 26.6 (t), 31.5 (t), 34.4 (s), 37.4 (d), 37.4 (t), 123.9 (d),
124.4 (d), 125.2 (s), 131.5 (s), 136.2 (s) ppm. GC/MS: 217 (4%, Mþ),
202 (5%, [M–15]þ), 174 (15%), 149 (5%), 134 (7%), 121 (5%), 107
(14%), 69 (100%), 41 (29%). HRMS calcd for C15H23N: 217.1830;
found 217.1829.
400 MHz): d 0.9 (d, 3H), 1.1 (s, 3H), 1.6 (s, 3H), 1.6 (m, 1H), 1.7 (s, 3H),
1.75 (m, 1H), 2.9 (4H), 2.1 (3H), 5.1 (m, 1H), 5.2 (s, 1H), 8.8 (br, 1H)
ppm. 13C NMR (CDCl3, 400 MHz): 17.1 (q), 17.7 (q), 23.3 (q), 25.7 (q),
25.7 (t), 26.4 (t), 32.8 (t), 37.2 (t), 38.2 (s), 39.3 (d), 124.15 (d), 125.6
(d), 131.5 (s), 136.3 (s), 137.1 (s), 156.5 (d) ppm. GC/MS: 218 (2%, [M–
OH]þ), 217 (1%, [MꢂH2O]þ), 202 (3%, [MꢂH2OꢂCH3]þ, 174 (8%), 161
(4%), 149 (5%), 134 (6%), 121 (5%), 107 (20%), 69 (100%), 53 (12%), 41
(70%). IR (film): 3318 (br), 2965 (m), 2916 (m), 1449 (m), 1374 (m),
1305 (w), 1102 (w), 943 (s), 836 (w), 748 (w).
The crude oxime (60 g, 0.22 mol) in toluene (20 ml) was
added dropwise over 20 min to acetanhydride (102 g, 1 mol) and
toluene (130 ml) at reflux. Then water (20 ml) was added at 70–
80 ꢀC. Extraction with hexane and standard work-up gave
a residue, which was purified by flash chromatography over
1.2 kg silica gel using hexane/tert-butyl methyl ether 4:1 as el-
uent. After evaporation of the solvents the residue was purified
by distillation giving 31 g (65%) of 4a as an oil. Odor: anisic,
earthy, calamus, agrestic.
4.4.4. cis-1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-
2-carbonitrile 5a. Cis-1,2-dimethyl-4-(4-methylpent-3-enyl)cyclo-
hex-3-enecarbonitrile 4a (cis/trans 86:14, 55 g, 0.25 mol) was
added over 10 min to molten crystalline H3PO4 (22 g, 0.22 mol) at
105ꢀ–120 ꢀC under stirring and nitrogen. After another 15 min at
this temperature the mixture was cooled and water (150 ml)
added at 80 ꢀC. Extraction with hexane and standard work-up gave
55 g of an orange oil, which was short-path-distilled giving 51.5 g
of 5a at 84 ꢀC/0.04 Torr. Yield: 90% (dist, corr). Odor: woody,
cedarwood with a sweet floral touch, earthy. Analytical data of 5a:
1H NMR (CDCl3, 400 MHz): 0.96 (s, 3H), 1.07 (s, 3H), 1.28 (s, 3H), 1.3
(s, 3H), 1.47 (m, 2H), 1.66 (m. 2H), 1.65–1.95 (4H), 2.01 (m, 1H), 2.15
(ddd, 1H), 2.27 (m, 1H) ppm. 13C NMR (CDCl3, 400 MHz):
d 19.05 (t),
20.62 (q), 22.65 (q), 26.25 (t), 26.30 (t), 28.31 (q), 29.47 (q), 30.82
(t), 34.04 (s), 36.13 (d), 36.44 (s), 40.05 (t), 125.44 (s), 125.67 (s),
135.93 (s) ppm. Relative configuration proven by conversion to 1a.
GC/MS: 217 (11%, Mþ), 202 (100%, [M–15]þ), 175 (21%), 135 (28%),
121 (10%), 107 (12%), 105 (10%), 91 (14%), 79 (7%), 77 (11%), 75
(10%). RT¼8.74 (12%, trans-isomer 5b), 8.9 (6%, 5c), 9.0 (81%,
cis-isomer 5a) min (GC). IR (film): 2930 (s), 2836 (m), 2231 (w),
1459 (s), 1379 (s), 1361 (w), 1281 (w), 1261 (w), 1235 (w), 1204 (w),
1180 (w), 1166 (w), 1114 (w), 1068 (w), 1029 (w), 995 (w), 945 (w),
874 (w), 843 (w), 645 (w). HRMS calcd for C15H23N: 217.1830;
found 217.1828.
CN
CN
Me
=
H
Me
H
NOE's
4a
H
4.4.1.1. Analytical data of 4a. 1H NMR (CDCl3, 400 MHz): 1.2
4.4.5. cis-1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-
2-carbonitrile 5c. Diels–Alder adduct 4a (3.5 g, 11 mmol, cis/trans
86:14) and 85% H3PO4 (1.4 g, 14 mmol) were stirred for 5 days at
25 ꢀC, then the reaction mass was poured onto satd NaHCO3. Ex-
traction with tert-butyl methyl ether and standard work-up gave
3.3 g of a yellow oil, which was purified by flash-chromatography
over silica gel using hexane/tert-butyl methyl ether 98:2 as eluent
giving after evaporation of the solvents 2.8 g (80%) of 5c. Analytical
(d, 3H), 1.4 (s, 3H), 1.6 (s, 3H), 1.7 (s, 3H), 2.0 (5H), 2.1 (3H), 2.3 (1H),
5.1 (2H) ppm. 13C NMR (CDCl3, 400 MHz):
d 17.4 (q), 17.7 (q), 24.7
(q), 25.65 (q), 26.1 (t), 26.3 (t), 33.7 (t), 37.05 (t), 37.1 (s), 38.95 (d),
122.8 (s), 123.9 (d), 124.0 (d), 131.6 (s), 137.1 (s) ppm. Relative
configuration determined by NMR-analysis (HSQC, HMBC, COSY,
and NOESY) in C6D6. It was also deduced from the relative config-
uration of precursor 3a and proven by conversion to 1a. GC/MS: 217
(5%, Mþ), 202 (6%, [M–15]þ), 174 (13%), 149 (7%), 134 (7%), 107 (13%),
69 (100%), 41 (28%). IR (film): 2969 (s), 2926 (s), 2857 (w), 2233 (w,
CN), 1669 (w), 1453 (s), 1376 (m), 1343 (w), 1287 (w), 1173 (w), 1145
(w), 1105 (w), 984 (w), 885 (w), 829 (m), 635 (w), 611 (w), 603 (w).
HRMS calcd for C15H23N: 217.1830; found 217.1829.
data of 5c: 1H NMR (CDCl3, 400 MHz):
1.27 (d, 3H), 1.4 (s, 3H), 1.4–2.1 (10H), 5.55 (d, 1H) ppm. 13H NMR
(CDCl3, 400 MHz): 19.70 (q), 19.90 (q), 24.09 (t), 25.40 (q), 31.20
d 0.76 (s, 3H), 1.03 (s, 3H),
d
(q), 36.21 (t), 36.43 (t), 37.63 (s), 38.75 (d), 39.01 (s), 42.76 (t), 53.64
(d), 117.14 (d), 123.94 (s), 142.08 (s) ppm. Relative configuration
proven by NMR-analysis (HSQC, HMBC, COSY, and NOESY) in C6D6.
GC/MS: 217 (12%, Mþ), 202 (42%, [M–15]þ), 174 (32%),161 (14%), 149
(14%), 134 (11%), 107 (19%), 91 (20%), 69 (100%), 55 (12%). RT¼8.7
(8%, 5b), 8.9 (70%, 5c), 9.0 (19%, trans-isomer of 5c) min. IR (film):
2926 (s), 2869 (m), 2843 (m), 2231 (w), 1455 (m), 1385 (m), 1364
(m), 1338 (w), 1263 (w), 1221 (w), 1188 (w), 1146 (w), 1115 (w), 1060
(w), 1046 (w), 970 (w), 932 (w), 841 (m), 799 (w), 608 (w). HRMS
calcd for C15H23N: 217.1830; found 217.1829.
4.4.2. Preparation of 4a/4b by thermal DA reaction. Methacrylo-
nitrile (44 g, 0.66 mol), freshly distilled homomyrcene (2a) of 76%
purity (100 g, 0.51 mol), and hydroquinone monomethyl ether
(0.1 g) are heated at reflux (130 ꢀC) for 36 h. After cooling to rt
the reaction mass is distilled at 0.05 mbar giving 22 g pre-frac-
tions at 25–75 ꢀC and 71 g (65% d. Th.) of 4a/4b at 130 ꢀC. RT¼8.4
(53% 4a), 8.6 (47% 4b) min (GC). MS of trans-isomer 4b identical
to the one of cis-isomer 4a. The analytical data of the cis-isomer
were identical with the ones obtained for 4a synthesized from
aldehyde 3a.
NOE's
H
H
4.4.3. trans-1,2-Dimethyl-4-(4-methylpent-3-enyl)cyclohex-3-ene-
carbonitrile 4b. For configurational analysis the trans-isomer 4b
was separated from the 4a/4b mixture (prepared above) by
CN
5c

10502
A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
4.4.6. cis-2-Methyl-4-(4-methylpent-3-enyl)cyclohex-3-enecarboni-
trile 12. Prepared according to Procedure A from Homomyrcene
(2a) of 76% purity (3 g, 15 mmol),3 acrylonitrile (1.3 g, 24 mmol),
and boron trichloride 1 M in xylene (3 ml, 3 mmol) at 25 ꢀC in 1 h.
Standard work-up and flash-chromatography (silica gel, hexane/
tert-butyl methyl ether 95:5) gave 2 g (66%) of 12 as colorless oil.
Analytical data of the cis-isomer: 1H NMR (CDCl3, 400 MHz): 1.18 (d,
3H), 1.6 (s, 3H), 1.7 (s, 3H), 1.85 (m, 1H), 1.95–2.1 (6H), 2.2 (m, 1H),
2.45 (m, 1H), 2.9 (m, 1H), 5.08 (m, 1H), 5.2 (m, 1H) ppm. 13C NMR
and trans-isomers are identical. Analytical data for these isomers
have been reported.38
4.4.11. 3,3-Dimethyl-1-vinylcyclohex-1-ene 17. Ethyl chloroformate
(4.2 g, 39 mmol) was added dropwise to 1-(3,3-dimethylcyclohex-
1-enyl)ethanol (Artemol)39 (5 g, 32 mmol) in toluene (20 ml) and
pyridine (3.3 g, 42 mmol) under cooling. The mixture was stirred at
25 ꢀC until complete conversion was detected by GC or TLC. Stan-
dard work-up, filtration over silica gel, and evaporation of the sol-
vent gave 7 g (97%) of the mixed carbonate as yellow oil. Under
solvent-free conditions and stirring 1,5-bis(diphenylphosphino)-
pentane (dpppe) (0.15 g, 0.35 mmol) was added at 60 ꢀC, followed
by Pd(OAc)2 (31 mg, 0.14 mmol). After further heating distillation/
elimination set in at 90ꢀ–105 ꢀC, methanol was distilled off, until
complete conversion to 17 was detected by TLC or GC. Further
distillation gave 5 g (95%) of 17 as colorless oil (92% purity). Ana-
lytical data of 17: 1H NMR (CDCl3, 400 MHz): 1.0 (s, 6H), 1.4 (m, 2H),
1.7 (m, 2H), 2.05 (m, 2H), 4.9 (d, 1H), 5.1 (d, 2H), 5.45 (1H), 6.3
(CDCl3, 400 MHz):
d 17.7 (q), 18.8 (q), 24.3 (t), 25.57 (t), 25.65 (q),
26.2 (t), 31.2 (d), 31.5 (d), 37.3 (t), 120.75 (s), 123.77 (d), 123.82 (d),
131.7 (s), 137.2 (s) ppm. Relative configuration determined by NMR-
analysis: NOESY, HSQC, COSY, HMBC. GC/MS: 203 (3%, Mþ), 188 (4%,
[M–15]þ), 160 (12%), 135 (4%), 107 (5%), 91 (6%), 69 (100%). RT¼8.6
(13%, trans-isomer), 8.7 (87%, cis-isomer) min (GC). MS of trans-
isomer identical to the one of the cis-isomer. Anal. Calcd for
C14H21N: C, 82.70; H, 10.41; N, 6.89. Found: C, 82.41; H, 10.51;
N, 6.68.
(m, 1H) ppm. 13C NMR (CDCl3, 400 MHz):
d 19.35 (t), 23.8 (t), 29.7
H
NOE's
CN
H
H
H
(q, 2C), 32.1 (s), 37.2 (t), 110.2 (t), 133.7 (s), 140.0 (d), 140.4 (d) ppm.
GC/MS: 136 (40%, Mþ), 121 (100%, [M–15]þ), 107 (27%), 93 (78%), 91
(36%), 79 (48%), 77 (30%). IR (film): 2954 (m), 2929 (s), 2864 (m),
1747 (m), 1639 (w), 1604 (w), 1453 (m), 1359 (w), 1267 (s), 1208 (w),
1182 (w), 1036 (w), 988 (m), 940 (w), 893 (s), 869 (s). HRMS calcd
for C10H16: 136.1252; found 136.1252.
CN
=
12
4.4.7. endo-2-Methylbicyclo[2.2.1]hept-5-ene-2-carbonitrile
13. Prepared according to Procedure A from freshly distilled cyclo-
pentadiene (1.3 g, 20 mmol), methacrylonitrile (1.6 g, 24 mmol), and
boron trichloride 1 M in xylene (3 ml, 3 mmol) at 25 ꢀC in 18 h.
Standard work-up and bulb-to-bulb distillation gave 1.8 g (68%) of 13
as a solid. RT¼5.0 (86%, cis-isomer), 5.2 (14%, trans-isomer) min (GC).
Analytical data for these isomers have been reported.7c
4.4.12. cis-1,8,8-Trimethyl-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-
carbonitrile 19. Prepared according to Procedure A from diene 17
(1 g, 7 mmol), methacrylonitrile (0.6 g, 8.4 mmol), and boron tri-
chloride 1 M in xylene (1 ml, 1 mmol) at 60 ꢀC in 72 h. Standard
work-up with tert-butyl methyl ether and bulb-to-bulb distillation
gave 0.7 g (50%) of 19 as colorless oil. Analytical data of the cis-
isomer: 1H NMR (CDCl3, 400 MHz): 1.05 (s, 3H), 1.4 (s, 3H), 1.45 (s,
3H), 0.8–2.3 (10H), 5.5 (m, 1H) ppm. 13C NMR (C6D6, 400 MHz):
4.4.8. endo-Bicyclo[2.2.1]hept-5-ene-2-carbonitrile
14. Prepared
d
20.8 (t), 21.4 (q), 24.0 (t), 28.0 (q), 31.3 (q), 32.8 (s), 32.9 (t), 37.4
according to Procedure A from freshly distilled cyclopentadiene
(1 g, 15 mmol), acrylonitrile (0.9 g, 18 mmol), and boron trichloride
1 M in xylene (3 ml, 3 mmol) at 25 ꢀC in 1 h. Standard work-up and
bulb-to-bulb distillation gave 1.2 g (58%) of 14. RT¼4.4 (31%, trans-
isomer), 4.7 (69%, cis-isomer) min (GC). Analytical data for these
isomers have been reported.37
(s), 37.7 (t), 45.6 (t), 54.9 (d), 120.0 (d), 126.5 (s), 136.2 (s) ppm.
Relative configuration tentatively assigned by NMR-analysis:
NOESY, HSQC, COSY, HMBC. GC/MS: 203 (11%, Mþ), 188 (11%, [M–
NOE's
H
CN
4.4.9. cis-1,2-Dimethylcyclohex-3-enecarbonitrile 15. Prepared acc-
ording to Procedure A from freshly distilled E-1,3-pentadiene (1.4 g,
20 mmol), methacrylonitrile (2 ml, 24 mmol), and boron trichloride
1 M in xylene (3 ml, 3 mmol) at 60 ꢀC in 1 h. Standard work-up and
flash chromatography (silica gel, hexane) gave 1.4 g (50%) of 15.
Analytical data of 15: 1H NMR (CDCl3, 400 MHz): 1.2 (d, 3H), 1.4 (s,
3H), 1.6 (m, 1H), 2.0 (m, 1H), 2.1–2.2 (2H), 2.35 (m, 1H), 5.4 (m, 1H),
19
15]þ), 160 (21%), 147 (5%), 133 (21%), 108 (36%), 93 (16%), 91 (19%),
69 (100%). RT¼8.2 (76%, cis-isomer), 8.5 (24%, trans-isomer) min
(GC). The mass spectra of the cis- and trans-isomers are identical.
IR (film): 2954 (m), 2929 (s), 2864 (m), 1747 (m), 1639 (w), 1604
(w), 1453 (m), 1359 (w), 1267 (s), 1208 (w), 1182 (w), 1036 (w), 988
(m), 940 (w), 893 (s), 869 (s). HRMS calcd for C14H21N: 203.1674;
found 203.1665.
5.75 (m,1H) ppm.13C NMR (CDCl3, 400 MHz):
d 17.1 (q), 22.9 (t), 24.8
(q), 33.2 (t), 37.0 (s), 38.8 (d), 122.7 (s), 126.1 (d), 129.9 (d) ppm.
Relative configuration determined by NMR-correlation with 4a. GC/
MS: 135 (11%, Mþ), 120 (3%, [M–15]þ), 108 (3%), 93 (10%), 68 (100%),
67 (34%), 53 (12%). RT¼5.1 (78%, cis-isomer), 5.2 (22%, trans-isomer)
min (GC). The mass spectra of the cis- and trans-isomers are iden-
tical. IR (film): 3025 (w), 2971 (m), 2935 (m), 2879 (w), 2232 (w, CN),
1455 (s), 1434 (m), 1378 (m), 1164 (w), 1115 (w), 954 (w), 758 (m),
697 (s), 656 (m), 634 (m). Anal. Calcd for C19H13N: C, 79.95; H, 9.69;
N, 10.36. Found: C, 80.10; H, 9.94; N, 10.07.
4.4.13. (1SR,8aRS)-8,8-Dimethyl-1,2,3,5,6,7,8,8a-octahydronaphthal-
ene-1-carbonitrile 20. Prepared according to Procedure A from di-
ene 17 (1 g, 7 mmol), acrylonitrile (0.4 g, 8 mmol), and boron
trichloride 1 M in xylene (1.4 ml, 1.4 mmol) at 25 ꢀC in 72 h. Stan-
dard work-up and bulb-to-bulb distillation gave 1.2 g (91%) of 20 as
colorless oil. Analytical data of the main-isomer: 1H NMR (CDCl3,
400 MHz): 1.1 (s, 3H), 1.15 (s, 3H), 0.9–2.4 (11H), 3.1 (m, 1H), 5.5 (m,
4.4.10. cis-2-Methylcyclohex-3-enecarbonitrile 16. Prepared accord-
ing to Procedure A from freshly distilled E-1,3-pentadiene (1 g,
14 mmol), acrylonitrile (0.83 g, 17 mmol), and boron trichloride 1 M
in xylene (2.8 ml, 2.8 mmol) at 25 ꢀC in 1 h. Standard work-up and
bulb-to-bulb distillation gave 1.35 g (71%) of 15. RT¼4.4 (8%, trans-
isomer), 4.6 (92%, cis-isomer) min (GC). The mass spectra of the cis-
1H) ppm. 13C NMR (CDCl3, 400 MHz):
26.75 (t), 27.0 (d), 29.9 (q), 34.8 (t), 35.3 (s), 44.0 (t), 48.5 (d), 121.2
(d),122.9 (s),135.9 (s) ppm. GC/MS: 189 (7%, Mþ),174 (5%, [M–15]þ),
146 (20%), 133 (4%), 121 (4%), 119 (5%), 91 (10%), 79 (7%), 77 (6%), 69
d 21.6 (t), 21.7 (q), 22.4 (t),

A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
10503
temperature. After another 40 min methyl iodide (1.3 g, 9.3 mmol)
and hexamethylphosphoramide (0.3 ml, 1.7 mmol) were added at
ꢂ78 ꢀC. The reactionwas allowed to warm up to 25 ꢀC overnight and
poured onto a 2 M HCl/ice mixture. Extraction with tert-butyl
methyl ether, washing of the combined organic phases with concd
NaHCO3 and water, drying over MgSO4, filtration, and evaporation of
the solvents gave 1 g of crude 23 (99%) as an oil (isomer ratio
78:19:3).
H
CN
NOE's
21
H
(100%), 41 (24%). RT¼8.1 (15%, trans-isomer), 8.2 (85%, cis-isomer)
min (GC). Relative configurations of these isomers deduced from
their retention times (comparison with 12, 14, 16, and 24). The mass
spectra of the cis- and trans-isomers are identical. IR (film): 2929
(s), 2867 (m), 2846 (m), 2234 (w),1454 (m),1440 (m),1367 (m), 868
(m), 809 (m). HRMS calcd for C14H21N: 189.1517; found 189.1525.
HRMS calcd for C13H18N: 174.1283; found 174.1295.
4.4.16.1. Analytical data of the main isomer. 1H NMR (CDCl3,
400 MHz): 1.2 (d, 3H), 1.35 (s, 3H), 1.65 (s, 3H), 1.7 (s, 3H), 1.73 (s,
3H), 1.9 (m, 1H), 2.0–2.1 (3H), 2.2 (m, 1H), 2.3 (m, 1H), 5.0 (m, 1H),
5.3 (1H) ppm. 13C NMR (CHCl3, 400 MHz):
d 17.95 (q), 18.0 (q), 21.3
(q), 24.4 (q), 25.8 (q), 30.2 (t), 34.4 (t), 34.9 (s), 36.4 (d), 38.0 (d),
121.8 (d), 124.8 (s), 125.3 (d), 133.5 (s), 134.8 (s) ppm. The minor
isomer (19%) is a diastereomer (NMR-analysis). GC/MS: 217 (8%,
Mþ), 202 (2%, [M–15]þ), 149 (12%), 148 (7%), 134 (7%), 122 (6%), 121
(7%), 107 (13%), 94 (18%), 91 (10%), 69 (100%). Analytical data of the
4.4.14. cis-1-Methyl-1,2,3,5,6,7,8,9,10,10a-decahydrobenzo[8]annul-
ene-1-carbonitrile 21. Prepared according to Procedure A from diene
18 (5 g, 32 mmol),33 methacrylonitrile (2.55 g, 38 mmol), and boron
trichloride 1 M in xylene (4.7 ml, 4.7 mmol) at 60 ꢀC in 1 h. Standard
work-up with tert-butyl methyl ether and bulb-to-bulb distillation
gave 2.7 g (42%) of 21 as colorless oil, which slowly crystallized upon
standing. Analytical data of the cis-isomer: 1H NMR (CDCl3,
400 MHz): 1.3 (s, 3H),1.4–1.5 (3H),1.5–1.7 (6H),1.85 (m,1H),1.95–2.1
(4H), 2.25 (m, 1H), 2.4 (m, 1H), 5.4 (m, 1H) ppm. 13C NMR (CHCl3,
minor isomer: 13C NMR (CHCl3, 400 MHz):
d 15.6 (q), 18.0 (q), 18.7
(q), 21.0 (q), 28.8 (q), 30.1 (t), 33.6 (t), 35.0 (s), 37.5 (d), 37.65 (d),
121.1 (d), 125.7 (s), 126.9 (d), 133.35 (s), 135.65 (s) ppm. GC/MS: 217
(2%, Mþ), 202 (2%, [M–15]þ), 151 (13%), 148 (10%), 134 (5%), 121
(12%), 107 (11%), 106 (9%), 94 (13%), 91 (11%), 69 (100%). The relative
configuration of 23 was proven by a-methylation of nitrile 24, and
400 MHz): d 21.9 (t), 24.1 (q), 26.3 (t), 26.5 (t), 26.8 (t), 27.5 (t), 30.2 (t),
by conversion of 23 to aldehyde 25 and NMR-analysis of the latter.
IR (film): 2968 (s), 2932 (s), 2917 (s), 2875 (m), 2858 (m), 2232 (w),
1668 (w), 1451 (s), 1377 (s), 1297 (w), 1167 (w), 1108 (w), 1093 (w),
1070 (w), 985 (w), 840 (m), 779 (w). HRMS calcd for C15H23N:
217.1831; found 217.1833.
30.8 (t), 35.8 (t), 37.0 (s), 46.1 (d), 121.2 (d), 124.7 (s), 138.7 (s) ppm.
Relative configuration of the isomers determined by NMR-analysis
(NOESY, HSQC, COSY, HMBC): 57% (cis-isomer), 22% (trans-isomer),
14% and 7% (2 regioisomers). GC/MS: 203 (32%, Mþ), 188 (19%, [M–
15]þ), 175 (19%), 174 (14%), 161 (16%), 160 (17%), 148 (16%), 136 (53%),
121 (62%), 108 (100%), 107 (56%), 95 (46%), 94 (67%), 93 (68%), 91
(58%), 81 (39%), 80 (44%), 79 (79%), 77 (44%), 68 (62%), 67% (50%).
RT¼8.88 (63%, cis-isomer), 8.93 (37%) min (GC). IR (film): 2921 (s),
2850 (m), 2230 (w), 1445 (m), 1379 (w), 1019 (w), 851 (w), 812 (w),
746 (w). HRMS calcd for C14H21N: 203.1647; found 203.1657.
4.4.17. (1RS,2SR,5SR)-2,4-Dimethyl-5-(3-methylbut-2-enyl)cyclohex-
3-enecarbonitrile 24. Prepared according to Procedure A from
methylocimene 2f (E/Z 3:2, 10 g, 63 mmol),4a–b acrylonitrile (3.7 g,
76 mmol), and boron trichloride 1 M in xylene (12.6 ml, 13 mmol)
at 25 ꢀC in 5 h. Standard work-up with tert-butyl methyl ether and
bulb-to-bulb distillation at 110 ꢀC/0.1 mbar gave 5.9 g (82%, based
on the E,E-isomer of 2f) of 24 as colorless oil. Analytical data of the
main isomer: 1H NMR (CDCl3, 400 MHz): 1.15 (d, 3H), 1.55–1.7 (1H),
1.65 (s, 3H), 1.7 (s, 3H), 1.72 (s, 3H), 1.9 (m, 1H), 2.0–2.2 (2H), 2.3 (m,
1H), 2.45 (m, 1H), 2.8 (m, 1H), 5.0 (m, 1H), 5.4 (1H) ppm. 13C NMR
4.4.15. 1,2,3,5,6,7,8,9,10,10a-decahydrobenzo[8]annulene-1-carbo-
nitrile 22. Prepared according to Procedure A from diene 18 (1 g,
6.3 mmol),33 acrylonitrile (0.36 g, 7.6 mmol), and boron trichloride
1 M in xylene (1.3 ml, 1.26 mmol) at 25 ꢀC in 1 h. Standard work-up
with tert-butyl methyl ether and bulb-to-bulb distillation at 135 ꢀC/
0.1 mbar gave 1 g (81%) of 22 as colorless oil. Analytical data of the
main isomer: 1H NMR (CDCl3, 400 MHz): 1.6 (s, 3H), 1.25–2.5 (17H),
1.5–1.7 (6H), 2.8 (m, 1H), 5.45 (m, 1H) ppm. 13C NMR (CHCl3,
(CHCl3, 400 MHz): d 17.4 (q), 18.0 (q), 21.3 (q), 25.8 (q), 27.3 (t), 30.1
(d), 30.5 (t), 30.7 (d), 38.6 (d), 121.2 (d), 122.0 (s), 126.4 (d), 133.7 (s),
135.8 (s) ppm. Relative configuration determined by NMR-analysis
in C6D6: NOESY, HSQC, COSY, HMBC. GC/MS: 203 (5%, Mþ), 188 (1%,
[M–15]þ), 135 (6%), 107 (5%), 81 (10%), 69 (100%), 41 (25%). RT¼7.8
(4%), 8.0 (4%), 8.1 (88%, cis-isomer), 8.2 (4%) min (GC). IR (film):
2965 (s), 2916 (m), 2873 (m), 2237 (m), 1447 (s), 1378 (s), 1325 (w),
1311 (w), 1285 (w), 1185 (w), 1132 (w), 1110 (w), 1061 (w), 1041 (w),
1018 (w), 986 (w), 920 (w), 839 (m), 805 (w), 776 (w). HRMS calcd
for C15H23N: 203.1674; found 203.1669.
400 MHz): d 22.5 (t), 23.6 (t), 25.8 (t), 26.2 (t), 26.8 (t), 27.3 (t), 30.7
(t), 32.5 (d), 35.7 (t), 39.3 (d), 121.9 (d), 139.95 (s) ppm. Isomer ratio
according to NMR: 64:12:12:12. GC/MS: 189 (61%, Mþ), 174 (18%,
[M–15]þ), 160 (51%), 146 (52%), 133 (47%), 121 (36%), 119 (58%), 106
(51%), 93 (70%), 91 (92%), 81 (52%), 77 (64%). RT¼8.8 (5%, trans-iso-
mer), 8.9 (68%, cis-isomer), 9.0 (25%, regioisomers) min. The mass
spectra of the cis- and trans-isomers are identical. IR (film): 3365
(br), 2921 (s), 2853 (m), 2237 (w), 1666 (w), 1446 (m), 1025 (w), 885
(w), 742 (w). HRMS calcd for C13H19N: 189.1518; found 189.1523.
H
H
H
CN
4.3.16. (1RS,2SR,5SR)-1,2,4-Trimethyl-5-(3-methylbut-2-enyl)cyclo-
hex-3-enecarbonitrile 23. Prepared according to Procedure A from
methylocimene 2f (E/Z 3:2, 10 g, 63 mmol),4a–b methacrylonitrile
(5.1 g, 76 mmol), and boron trichloride 1 M in xylene (12.6 ml,
13 mmol) at 25 ꢀC in 5 h. Standard work-up with tert-butyl methyl
ether and bulb-to-bulb distillation at 140 ꢀC/0.07 mbar gave 5.2 g
(59%, based on the E,E-isomer of 2f) of 23 as colorless oil. RT¼8.1
(78%, cis-isomer), 8.2 (19%, diastereomer) min (GC).
Alternatively, 23 was prepared from secondary nitrile 24:
n-butyllithium 1.6 M in hexane (3.5 ml, 5.6 mmol) was added
dropwise to diisopropylamine (0.56 g, 5.6 mmol) in tetrahydrofuran
(5 ml) at ꢂ78 ꢀC. After 30 min 24 (1 g, 4.6 mmol) was added at this
24
4.4.18. (1RS,2SR,5SR)-1,2,4-Trimethyl-5-(3-methylbut-2-enyl)cyclo-
hex-3-enecarbaldehyde 25. DiBAH 1.2 M in toluene (25 ml,
31 mmol) was added dropwise to nitrile 23 (4 g,18 mmol) in CH2Cl2
(160 ml) at ꢂ78 ꢀC. After 5 h at ꢂ78 ꢀC and 15 h at 25 ꢀC the reaction
was quenched with 2 M HCl. Extraction with tert-butyl methyl
ether, washing of the organic phase with satd NaCl, drying over
MgSO4, filtration, and evaporation of the filtrate gave 3.8 g of an oil,
which was purified by bulb-to-bulb-distillation (110 ꢀC, 0.2 mbar) to

10504
A. Borosy et al. / Tetrahedron 65 (2009) 10495–10505
from O Botica´rio. (k) Quasar Feminino (Desodorante Coloˆnia) from O Boticario. (l)
Men’s moon sparkle (shower gel) from Escada. (m) Hinoki (Eau) from Commes
des Garçons.
give 3 g (78%) of a colorless oil with 98% purity. Analytical data of the
main isomer: 1H NMR (CDCl3, 400 MHz): 0.9 (d, 3H), 1.1 (s, 3H), 1.5
(1H), 1.65 (s, 3H), 1.7 (s, 3H), 1.72 (s, 3H), 2.0–2.2 (3H), 2.3 (m, 1H),
5.05 (t,1H), 5.4 (d,1H), 9.55 (s,1H) ppm. 13C NMR (CHCl3, 400 MHz):
´
3. Bajgrowicz, J. A.; Bringhen, A.; Frater, G. EP 0743297, priority 16.5. 1995 to
Givaudan; Chem. Abstr. 126, 103856 h.
4. (a) Barras, J.-P.; Bourdin, B.; Schro¨der, F. Chimia 2006, 60, 574–579; (b) Frater, G.;
Schro¨der, F. J. Org. Chem. 2007, 72,1112–1120; (c) Hong, S.; Corey, E. J. J. Am. Chem.
Soc. 2006, 128, 1346–1352; (d) Bella, M.; Cianflone, M.; Montemuro, G.; Passa-
canilli, G.; Piancatelli, G. Tetrahedron 2004, 60, 4821–4827.
5. Tetracyclone (a), methyl coumalate (b) and furan (c) were not considered for
comparison with Homomyrcene 2 due to additional carbonyl, phenyl or oxygen
substituents in conjugation with the diene. Endo-selective DA reactions from
these dienes and (meth)acrylonitrile have been reported: (a) Khazaei, A.;
Zolfigol, M. A.; Manesh, A. A. J. Chin. Chem. Soc. (Taiwan) 2005, 52, 515–518; (b)
Shimo, T.; Yamasaki, S.; Date, K.; Uemura, H.; Somekawa, K. J. Heterocycl. Chem.
d
17.9 (q), 18.0 (q), 19.65 (q), 21.1 (q), 25.8 (q), 28.9 (t), 30.8 (t), 36.0
(d), 36.15 (d), 47.7 (s), 121.7 (d), 126.6 (d), 133.0 (s), 134.9 (s), 1207.0
(s) ppm. Relative configuration determined by NMR-analysis in
C6D6: NOESY, HSQC, COSY, HMBC. GC/MS: 220 (5%, Mþ), 202 (2%),
151 (12%), 133 (14%), 123 (45%), 121 (50%), 107 (100%), 91 (20%), 81
(29%), 69 (82%), 55 (15%), 41 (70%). RT (GC)¼7.85 (15%,
diastereomer), 7.9 (79%, all-cis-isomer), 8.25 (3%). The mass spectra
of thediastereomersare identical. IR(film):2963 (m), 2928 (m), 2970
(m), 2687 (w),1725 (s),1450 (m),1375 (m), 912 (w), 840 (m), 718 (w),
696 (w). HRMS calcd for C15H23N: 220.1827; found 220.1829.
´
1993, 30, 419–423; (c) Fraile, J. M.; Garcıa, J. I.; Massam, J.; Mayoral, J. A.; Pires,
E. J. Mol. Catal. A: Chem. 1997, 123 43–37.
6. All four carbon atoms of an endocyclic conjugated diene are part of a cyclic
structure, not to be confused with the endo/exo descriptors of the Diels–Alder
transition states. The endo/exo description of the obtained Diels–Alder adducts
is identical with the cis/trans description of the diastereomers
respectively.
a and b,
O
H
H
CHO
7. (a) Kas’yan, A. O.; Zlenko, E. T.; Okovityi, S. I.; Golodaeva, E. A.; Kas’yan, L. I. Russ.
J. Org. Chem. 2001, 37, 1564–1569; (b) Fermann, M.; Herpers, E.; Kirmse, W.;
Neubauer, R.; Renneke, F.-J.; Siegfried, R.; Wonner, A.; Zellmer, U. Chem. Ber.
1989, 122, 975–984; (c) Mellor, J. M.; Webb, C. F. J. Chem. Soc., Perkin Trans. 2
1974, 17–22; (d) Cantello, B. C. C.; Mellor, J. M.; Webb, C. F. J. Chem. Soc., Perkin
Trans. 2 1974, 22–25; (e) Mekhtiev, S. D.; Musaev, M. R.; Sakhnovskaya, E. B.;
Sultanov, V. T. Zh. Org. Khim. 1969, 5, 1364–1366; (f) Sauers, R. R. J. Am. Chem.
Soc. 1958, 81, 4873–4876.
H
H
25
H
NOE's
4.4.19. 1-((cis)-1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-octahydronaph-
thalen-2-yl)ethanone 1a. Water-free toluene (100 ml) was added
to methylmagnesium bromide 3 M in diethylether (73.4 ml,
0.22 mol) under nitrogen and stirring. At 60 ꢀC the diethyl ether
was distilled off in the nitrogen stream leaving a clear solution to
which nitrile 5a (cis/trans 87:13, 43.5 g, 0.2 mol) in toluene
(150 ml) was added. The solution was heated to reflux (120 ꢀC) for
4 h. Water (20 ml) was added at 90ꢀ–70 ꢀC, followed by 85%
H3PO4 (29 g, 0.3 mol) and the mixture was heated for 1 h at reflux
(100 ꢀC). The phases were separated at 80 ꢀC and the water phase
extracted with toluene at this temperature. The combined or-
ganic phase was washed with water and satd NaHCO3 to pH 8.
Concentration under reduced pressure gave 105 g of an oily res-
idue to which paraffin oil (30 g) and hydroquinone (0.5 g) were
added. Distillation gave 47 g of 1a at 90 ꢀC/0.05 Torr. Yield 91%
(dist, corr, based on cis-isomer 5a). Olfactory yield: 77% (corr).
RT¼8.9 (8.6%, trans-isomer 1b), 9.06 (78.4%, cis-isomer 5a) min
(GC). The analytical data of 1a were identical with the ones
reported for this compound.1b
8. (a) Imachi, S.; Onaka, M. Tetrahedron Lett. 2004, 45, 4943–4946; (b) Najafi-
Mahmoudi, H.; Ghandi, M.; Farzaneh, F. Chem. Lett. 2000, 358–359.
9. (a) MANþButadiene: Doucet, J.; Rumpf, P. Bull. Soc. Chim. Fr. 1954, 610–613; (b)
Moore, J. A.; Partain, E. M., III. J. Org. Chem. 1983, 48, 1105–1106.
10. (a) Neodymium complex [(THF)2Nd(MBMP)2Na(THF)2]: Xu, X.; Ma, M.; Yao, Y.;
Zhang, Y.; Shen, Q. Eur. J. Inorg. Chem. 2005, 676–684; (b) Pt(II)-NCN-Pincer
complex: Fossey, J. S.; Richards, C. J. Organometallics 2002, 21, 5259–5264; (c)
´
AlClEt2 or ZnCl2 on SiO2: Garcıa, J. I.; Mayoral, J. A.; Pires, E.; Brown, D. R.;
Massam. J. Catal. 1996, 37, 261–266; (d) AlMe3: Maruoka, K.; Imoto, H.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 12115–12116.
11. (a) Sc(OTf)3: Vidis, A.; Kusters, E.; Sedelmeier, G.; Dyson, P. J. J. Phys. Org. Chem.
2008, 21, 264–270; (b) [HMI][BF4]: Lo´pez, I.; Silvero, G.; Are´lavo, M. J.; Babiano, R.;
Palacios, J.-C.; Bravo, J.-L. Tetrahedron 2007, 63, 2901–2906; (c) Sc(OTf)3: Silvero,
´
G.; Are´lavo, M. J.; Bravo, J. L.; Avalos, M.; Jime´nez, J. L.; Lo´pez, I. Tetrahedron 2005,
61, 7105–7111; (d) ZnCl2: Sun, I.-W.; Wu, S.-Y.; Su, C.-H.; Shu, Y.-L.; Wu, P.-L. J. Chin.
Chem. Soc. (Taiwan) 2004, 51, 367–370.
12. Ion resins or acid clays gave no conversion. See Ref. 8 for the use of Zeolites in
the DA reaction of cyclopentadiene and methacrylonitrile.
13. AlCl3 has been reported to catalyze DA reactions of butadiene or isoprene with
(meth)acrylonitriles, but no data about endo/exo selectivities were given:
Efendiev, E. Kh.; Rasulbekova, T. I.; Akhmedov, R. M. Azerbaidzhanskii Khi-
micheskii Zhurnal 1979, 43–46.
14. For coordination chemistry of B(C6F5)3 with nitriles, see: Focante, F.; Mercan-
delli, P.; Sironi, A.; Resconi, L. Coord. Chem. Rev. 2006, 250, 170–188.
15. Probably due to competing complexation/inactivation of the Lewis acid as
experienced in other LA-promoted reactions, see for example Ref. 4b.
16. (a) Maurer, B.; Hauser, A.; Froidevaux, J.-C. Tetrahedron Lett. 1986, 27, 2111–2112;
(b) Leopold, E. J. Org. Synth. 1986, 64, 164–174.
Acknowledgements
For skillful experiments we thank S. Elmer, C. Luzi, J. Oetiker and
T. Reinmann, for GC/MS-, HRMS- and NMR measurements we
thank J. Schmid and G. Brunner and for preparative GC-separations
H. Koch (all Givaudan Du¨bendorf). For olfactory evaluation we
thank J.-J. Rouge (Givaudan Vernier), A. Alchenberger and R. Kaiser
(both Givaudan Du¨bendorf). For advice on transition state calcu-
lations we thank Prof. A.-C. Corminboeuf (Federal Institute of
Technology, Lausanne). For discussions we thank Prof. P. Chen (ETH
Zu¨rich), Prof. A. Hoveyda (Boston College) and Prof. A. Vasella (ETH
Zu¨rich). For proofreading we thank C. Furniss and
S. Derrer (both Givaudan Du¨bendorf).
17. Silver salts AgX were less- or ineffective: X¼CF3CO2, Cl, OAc, BF4, OTf, SbF6,
BARF.
18. Copper complexes were less- or ineffective: CuBr, Cu(OTf)2 with or without
BOX or BINAP, Cu(MeCN)4PF6 with or without BINAP, Cu(NO3)2 with or without
dimethyl-bispyridine.
19. Zinc salts ZnX2 were less or ineffective: X¼Br, I, OTf.
20. Other ineffective Lewis acids: LiBr, TiCl4 (decomposition), TiF3, CpTiCl3, FeCl3,
CpFe(CO)2BF4, CoCl2, H2Ru(PPh3)4, PdCl2, SnCl2, SnBr4, SbF6, AuCl3, BiCl3, SmI2.
21. Lanthanide and related triflates in CH2Cl2 were inactive: Yb(OTf)3, Sc(OTf)3 with
or without BINOL or in H2O, Y(OTf)3, Lu(OTf)3.
22. Acidic ion resins or clays gave no conversion up to 80 ꢀC. MANDA reaction of 2a
in ethanol showed no effect.
23. Shriver, D. F.; Swanson, B. Inorg. Chem. 1971, 10, 1354–1365.
24. Taft, R. W.; Carten, J. W. J. Am. Chem. Soc. 1964, 86 4199–4120.
25. El-Erian, M. A. I.; Huggett, P. G.; Wade, K. Polyhedron 1991, 18, 2131–2136.
26. Oikawa, Eizo; Kambara, Shu J. Polym. Sci. 1964, 2, 649–653.
27. Equations have been generated by using all the available molecular descriptors
and genetic function approximation of Molecular Operating Environment
(MOE), version 2007.09, Chemical Computing Group Inc. Montreal, Canada,
2007. The root mean square error of prediction could be probably improved
with more accurate experimental data.
References and notes
´
¨
1. (a) Frater, G.; Muller, U.; Nussbaumer, C. Book of Abstracts, 213th ACS National
Meeting, San Francisco, April 13–17, 1997, Publisher: American Chemical
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´
Cologne) from Christian Dior. (e) Attraction (Eau de Parfum) from L’Oreal /Lan-
coˆme. (f) Brit (Eau de Cologne) from Burberrys. (g) Golden Moments (Eau) from
Priscilla Presley. (h) Pour Femme (Eau de Parfum) from Yohji Yamamoto. (i) Love
ˆ
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