Design and synthesis of violet odorants with bicyclo[6.4.0]dodecene and bicyclo[5.4.0]undecene skeletons

Article abstract of DOI:10.1055/s-1999-3444

The Diels-Alder reaction of 1,2-bis(methylene)cyclooctane (13), 4- methylenespiro[2.7]decane (29), 4-methylenespiro[2.6]nonane (40) and 4- methylenespiro[2.7]dec-8-ene (46) with different α,β-unsaturated carbonyl compounds afforded various derivatives 16, 18, 20, 22, 24, 26, 32, 36, 38, 41, 42 and 47 of a molecular-modeled lead compound 9. These less flexible β- ionone-mimics with bicyclo[6.4.0]dodecene and bicyclo[5.4.0]undecene skeletons possess interesting fruity-woody-floral odor notes and provide insight into the structure-odor correlation of violet odorants. 5-(2- Methylcycloalk-1-en-1-yl)hex-3-en-2-ones (e.g. 35) were identified as byproducts of the Rh(I)-catalyzed reactions of the vinylcyclopropanes 29 and 40.

Full text of DOI:10.1055/s-1999-3444

PAPER
695
Design and Synthesis of Violet Odorants with Bicyclo[6.4.0]dodecene and
Bicyclo[5.4.0]undecene Skeletons
Philip Kraft
Givaudan Roure Fragrance Research Ltd., CH-8600 Dübendorf, Switzerland
Fax +41(1)8242926; E-mail philip.kraft@roche.com
Received 15 September 1998; revised 16 November 1998
Dedicated with best wishes to Professor Werner Tochtermann on the occasion of his 65th birthday
Abstract: The Diels–Alder reaction of 1,2-bis(methylene)cyclooc-
tane (13), 4-methylenespiro[2.7]decane (29), 4-methylene-
spiro[2.6]nonane (40) and 4-methylenespiro[2.7]dec-8-ene (46)
with different a,b-unsaturated carbonyl compounds afforded vari-
ous derivatives 16, 18, 20, 22, 24, 26, 32, 36, 38, 41, 42 and 47 of
a molecular-modeled lead compound 9. These less flexible b-ion-
one-mimics with bicyclo[6.4.0]dodecene and bicyclo[5.4.0]un-
decene skeletons possess interesting fruity-woody-floral odor notes
and provide insight into the structure-odor correlation of violet
odorants. 5-(2-Methylcycloalk-1-en-1-yl)hex-3-en-2-ones (e.g. 35)
were identified as byproducts of the Rh(I)-catalyzed reactions of the
vinylcyclopropanes 29 and 40.
Key words: cycloadditions, ionones, molecular modeling, vinylcy-
clopropanes, Wilkinson’s catalyst
About hundred years ago, violet flower oil (Viola odorata
L., fam. Violaceae) was one of the most valuable perfum-
1
ery materials, and v. Soden estimated the production cost
of this highly esteemed essential oil to exceed 80 000 Ger-
man gold marks per kg. On the assumption that their odor
was due to the same natural product, Tiemann and
2
Krüger used the similarly smelling but much cheaper or-
ris root oil (Iris pallida Lam., fam. Iridaceae) in their
search for the odorous principle of violets. The odor of a
mixture of a-ionone (1) and b-ionone (2) (Figure 1) ob-
tained by acid-catalyzed cyclization of pseudoionone pos-
sessed the typical odor of violets in bloom. Thus, in
combination with incorrect elemental analyses, Tiemann
and Krügerbelieved the isolated irone to be a double-bond
Figure 1. Survey of diverse violet odorants
that of Oncidium tigrinum La Llave et Lex. even 14.5% of
b-ionone (2). In modern perfumery, 8-methylionone (4),
which is more intense than 1/2 and possesses a very fine
odor reminiscent of orris and violets with a slightly
woody-vetiver tonality, became the most popular violet
odorant, and one can find up to 20% of it in some cre-
ations.10
2
isomer of ionone (1/2). The correct constitution of the
irones was established only 54 years later in 1947,3 and
–5
6
the stereochemistry was elucidated as late as 1971. In
7
terms of odor, (+)-(2R,6S)-cis-a-irone (3) with its intense
and very fine orris character is the most important irone
isomer of orris root oil. However, in 1972 an in-depth
8
analysis of violet flower oil showed a mixture of a- and
Interestingly, the constitutional irone-isomer 5 with a
seven-membered ring was said to be reminiscent of 8-
methylionone (4) with a pronounced floral character,11
while the constitutional ionone-isomer 6 is more reminis-
cent of irone (3) with an additional fruity raspberry note.12
Two seco ionones, 5-tert-butyl-6-methylhepta-3,5-dien-
b-ionone (1/2) to be indeed responsible for the odor of
violets. Although, Tiemann and Krüger had inaccurately
analyzed orris root oil in search of the odorous principle
of violets, they had actually discovered what they were
initially looking for.
2
-one (7)13 and (3E)-3,4,5,6,6-pentamethylhept-3-en-2-
b-Ionone (2) was not only found in Viola odorata L., it
®
14
9
one (8, Koavone ) (Figure 1), are known to possess the
odor characteristics of ionone (1/2) and 8-methylionone
also occurs in a great variety of floral scents. In the Or-
chidaceae family, the headspace of Encyclica adenocarpa
(4), respectively. Yet, no attempts have been made to con-
(
2
La Llave et Lex.) Schltr. for example contains 10.0% of
, that of Maxillaria nigrescens Lindl. 13.6% of 2, and
struct conformationally more rigid violet odorants that
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

6
96
P. Kraft
PAPER
would provide insight into the structural requirements of ly, and since methylated ionones are also important odor-
this highly interesting odor.
ants (e.g. 4 and 8), we were aiming at the synthesis of
methylated analogs of 9 and the related cyclo-derivatives
20 and 22.
For this purpose, we carried out in-depth molecular-mod-
1
5
eling calculations, and not surprisingly found the anti-
periplanar s-trans conformation of the two conjugated
double bonds that is depicted in Figure 2 to be the global
energy minimum of b-ionone (2). This led to the idea of
mimicking the steric bulk of the dimethyl substitution by
fusing a six-membered ring. The remaining 5-methyl
group was then found to be best superimposed by a cy-
clooctene structure. Combination of these structural fea-
tures gave the bicyclic ketone 9, our first molecular target.
A local minimum 0.236 kcal/mol above the lowest energy
conformer showed the best overlap with b-ionone (2).
This is illustrated with a stereoplot in Figure 2.
Scheme 1
Compounds 16, 18, 20, 22, 24 and 26 (Scheme 2) were
synthesized in good yield by analogous Diels–Alder reac-
tions of bis(methylene)cyclooctane (13) with pent-1-en-3-
one (15), (3E)-pent-3-en-2-one (17), cyclopent-2-en-1-
one (19), cyclohex-2-en-1-one (21), acrolein (23), and
methacrolein (25), respectively. While the 10-(1-oxo)pro-
pyl substitution of 16 did not change the typical ionone
odor, the trans 11-methyl group of 18 diminished the in-
tensity and shifted the odor towards a more woody, cof-
fee-like character. The violet note was, however,
completely absent in the cyclo-derivatives 20 and 22, as
well as in the aldehydes 24 and 26.
The synthesis of the compounds 32, 36, 38, 41, 42 and 47,
methylated in a-position to the bridgehead, was carried
out in an unexpected way by a novel Rh(I)-mediated
Figure 2. Molecular-modeling calculations
[
4+2] cycloaddition of the corresponding dienophiles to
The molecular target 9 is easily accessible by Diels–Alder
reaction of but-3-en-2-one (14) with bis(methylene)cy-
vinylcyclopropanes (e.g. 29, 40) (Scheme 3). These were
synthesized from cyclooctanone (10), cyclooct-4-en-1-
one (44) and cycloheptanone (39) by spiroannullation
clooctane (13, Scheme 1). We synthesized the latter diene
19
20
according to a modified sequence of Bickelhaupt et al.,16
21
with 2-chloroethyl methyl sulfonium iodide (27) and
subsequent Wittig methylenation.18 Employing this two-
step sequence, 4-methylenespiro[2.7]decane (29) was ob-
tained from cyclooctanone (10) on a 30 g scale in 62% iso-
lated overall yield. Methylenespiro[2.7]decane (29)
reacted with but-3-en-2-one (14) in the presence of
Wilkinson's catalyst not by means of a [5+2] cycloaddi-
starting from cyclooctanone (10). Mannich reaction em-
1
7
ploying Eschenmoser salt, followed by a Wittig reaction
using potassium tert-butoxide18 provided 11 in 70% iso-
lated overall yield. This was then quaternized quantita-
tively by the action of methyl iodide to yield 12. A
1
6
classical Hofmann degradation of 12 in the next step fur-
nished the diene 13 in 54% yield. This circuitous route to
2
2
tion, discovered by Wender et al. and recently applied by
1
3 is necessary, because direct Wittig methylenation of 2-
23
1
6
Binger, de Meijere et al.; instead, the diastereoisomeric
-methylated bicyclo[6.4.0]dodecenylethanones 32 (E/Z
1:4) were isolated in 45% yield. (3E,1'E)-5-(2'-Methyl-
methylenecyclooctan-1-one is not possible. The Diels–
Alder reaction of 13 with the dienophile 14 in the presence
of aluminum trichloride was straightforward, and gave the
target molecule 9 in 84% yield. The fruity-woody odor of
the tailored molecular target 9 was indeed found to be
very close to that of the parent b-ionone (9). Consequent-
9
=
cyclooct-1'-en-1'-yl)hex-3-en-2-one (35) was the only
byproduct isolated, no regioisomers to 32 nor any com-
pounds with seven-membered ring systems were ob-
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Design and Synthesis of Violet Odorants
697
Scheme 3
reactions of vinylcyclopropanes in Scheme 3 have not
been described before. Compounds 36, 38, 41 and 42 were
prepared in analogy to the synthesis of 32 employing
Scheme 2
(3E)-pent-3-en-2-one (17), 3-methylbut-3-en-2-one (37),
and but-3-en-2-one (14) as dienophiles in the presence of
Wilkinson’s catalyst (Scheme 4). Corresponding 5-(2-
methylcycloalk-1-en-1-yl)hex-3-en-2-ones were again
identified as byproducts, and became main products in the
presence of silver triflate.
tained. However, in the presence of one equivalent of
silver triflate used by Wender et al.2 to accelerate the
2
+
[
(
(
5+2] cycloaddition by formation of the [Rh(PPh ) ] ion,
3
3
3E,1’E)-5-(2’-methylcyclooct-1’-en-1’-yl)hex-3-en-2-one
35) became the only product and was isolated in 66%
The odor of both diastereoisomeric 9-methylated bicyc-
lo[6.4.0]dodecenylethanones 32 was described as being
reminiscent to b-ionone (2) with pronounced woody as-
pects and a vetiver tonality. The odor of 32 is however
more intense than that of compounds 9 or 16. As with 18,
the additional methyl group of 36 at C-11 diminishes
again both the ionone tonality and odor intensity, resulting
in a relatively weak woody-fruity, balsamic note. Trans-
position of the 11-methyl group of 36 into the 10-position
in compound 38 strongly increases the odor intensity, but
this goes with a complete loss of the b-ionone (2) charac-
ter. Instead, the interesting woody-ambery, incense-like
yield.
The formal mechanism presented in Scheme 3 might ac-
count for the observed reaction products. Though 32 ob-
viously is the Diels–Alder adduct of but-3-en-2-one (14)
and 1-ethylidene-2-methylenecyclooctane, we were not
able to detect this reactive intermediate. This could be due
to a fast cycloaddition step or to the formation of rhodium
complexes. However, 2-methyl-1-vinylcyclooct-1-ene
was found to be present in rather large quantity. The catal-
ysis of [4+2] cycloadditions by low valent rhodium com-
2
4
plexes was described by Livinghouse et al. and Wender
10
odor of 38 is close to that of Iso E super. The odors of the
2
5
et al., but to our best knowledge the rhodium-catalyzed
ring-contracted compounds 41 and 42, synthesized from
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

6
98
P. Kraft
PAPER
much weaker than that of compound 38, with a pro-
nounced cedarwood tonality and a juniper nuance.
Scheme 5
Reagents and solvents (puriss. or purum) were purchased from Flu-
ka and used without further purification. Flash chromatography
(FC): Merck Kieselgel 60 (0.040–0.063 mm). IR: Nicolet 510 FT-
IR (neat). NMR: Bruker AVANCE DPX-400 (CDCl , TMS). MS:
3
Finnigan MAT 95 and MAT 212 (EI: 70 eV). ESI: Finnigan SSQ
7
10C (H O/MeOH, 1:1, + 1% AcOH). Elemental analyses: F. Hoff-
2
Scheme 4
mann-La Roche AG, Basel, PRPI-S.
2
-(Dimethylaminomethyl)-1-methylenecyclooctane (11)
N,N-Dimethylmethyleneammonium chloride (75 g, 0.80 mol) was
4
-methylenespiro[2.6]nonane, were quite similar to that
added under N to a solution of cyclooctanone (100 g, 0.79 mmol)
2
of their parent compounds 32 and 38. However, 41 is in MeCN (250 mL) at 0 °C. The cooling bath was removed, and the
more floral, jasmone-like than 32 and less reminiscent of mixture was stirred at r.t. for 3 d prior to the addition of 2 N aq
NaOH (500 mL). The product was extracted with t-BuOMe (3 î
violets, and 42 in contrast to 38 inclines to a sandalwood
5
00 mL), and the combined organic extracts were dried (Na SO )
2 4
direction.
and evaporated to provide 144 g (99%) of 2-(dimethylamino)meth-
Finally, we wanted to see if double-bonds would be ylcyclooctan-1-one. With mechanical stirring under N , methyl
2
tolerated by the reaction conditions of the rhodium-cata- triphenylphosphonium bromide (336 g, 0.941 mol) was added to a
solution of t-BuOK (100 g, 0.891 mol) in THF (2 L), and the mix-
ture was heated to reflux. At this temperature, 2-(dimethylami-
no)methylcyclooctan-1-one (144 g, 786 mmol) was added
dropwise, and the mixture was stirred for 3 h under reflux and 14 h
lyzed vinylcyclopropane addition. Scheme 5 shows the
synthesis of 1-{r-9,c-10-dimethylbicyclo[6.4.0]dodec-
1
1
(8),6(7)-diene-10-yl}ethan-1-one (47) from cycloocta-
,5-diene (43). Cyclooct-4-en-1-one (44) was synthesized
at r.t. prior to pouring into a mixture of t-BuOMe/H O (1:1, 2 L).
2
in 40% overall yield following a sequence of Meier, May-
The organic layer was separated, the aqueous layer extracted with t-
1
9
26
er and Kolshorn, but using Dess–Martin periodinane in BuOMe (3 î 500 mL), and the combined organic extracts were
the oxidation step. Spiroannullation of 44 with 2-chloro- dried (Na
SO
), concentrated in vacuo and purified by silica gel FC
2
4
2
0,21
(
pentane/t-BuOMe, 1:1, R 0.23) to provide 100 g (71%) of 11 as a
ethyl dimethyl sulfonium iodide
yet spiro[2.7]dec-8-en-4-one (45) was obtained in a mod-
erate to low yield of 35% only. Wittig methylenation in IR: n = 2763 (n N–CH
was regioselective,
f
colorless liquid.
18
), 1457, 1447 (d H–C–H), 888 (w C
C=CH ),
2
2
2
–
1
1
028, 1043 (n C–N), 1636 (n C=C), 3066 cm (n C=C–H).
the next step gave 4-methylenespiro[2.7]dec-8-ene (46) in
7% yield. This was then reacted in the rhodium(I)-medi-
ated [4+2] cycloaddition with 3-methylbut-3-en-2-one
37) to afford 47 in 43% yield, the double bond being
1
8
H NMR: d = 1.38–1.68 (m, 10 H, 4'-H to 8'-H ), 2.07–2.18 (m, 2
2 2
H, 3'-H ), 2.20 [s, 6 H, N(CH ) ], 2.21–2.25 (m, 2 H, 1-H ), 2.34
2
3 2
2
(
m , 1 H, 1'-H), 4.85 (d, J = 4.0 Hz, 2 H, =CH ).
(
c
2
1
3
shifted into conjugation in the course of the reaction. Con-
nectivity and relative stereochemistry were assigned by
two-dimensional NMR experiments. The odor of 47 was
C NMR: d = 26.0, 26.4, 26.5 (t, C-4', 7', 8'), 28.8, 30.5 (t, C-5', 6'),
3
3.5 (t, C-3'), 43.4 (d, C-1'), 45.8 [2 q, N(CH ) ], 66.0 (t, C-1), 111.7
3 2
(
t, =CH ), 153.2 (s, C-2').
2
+
+
MS: m/z (%) = 58 (C H N , 100), 181 (M , 1).
3
8
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Design and Synthesis of Violet Odorants
699
N,N,N-Trimethyl 1-(2-methylenecyclooct-1-yl)methyl Ammo-
nium Iodide (12)
FC on silica gel (pentane/t-BuOMe, 50:1, R 0.41), 4.21 g (76%) of
16 as a colorless liquid.
f
MeI (78.0 mL, 1.25 mol) was added to a stirred solution of 11 (90.7
g, 0.50 mol) in Et O (1.5 L) at r.t. under N , and the stirring was con-
tinued for 4 h. The precipitate was filtered, washed thoroughly with
–1
IR: n = 1711 cm (n C=O).
1
2
2
H NMR: d = 1.06 (t, J = 7.0 Hz, 3 H, CH ), 1.35–1.58 (m, 10 H, 3'-
3
H to 6'-H , 11'-H ), 1.99–2.18 (m, 8 H, 2' ,7', 9', 12'-H ), 2.48 (dq,
Et O (1.5 L), and dried on a vacuum line to provide 164 g (100 %)
2
2
2
2
2
J = 17.5, 7.5 Hz, 1 H, 2-H ), 2.54 (dq, J = 17.5, 7.5 Hz, 1 H, 2-H ),
.57 (dddd, J = 11.5, 10.5, 5.0, 3.0 Hz, 1 H, 10'-H).
of 12 as a colorless solid.
b
a
2
–
1
IR: n = 926, 916 (n C–N), 1481, 1441, 1414 (d C–H), 1635 cm (nas
1
3
+
C NMR: d = 7.68 (q, C-3), 25.5 (t, C-11'), 26.5, 26.5 (t, C-3', 6'),
8.7, 28.8 (t, C-4', 5'), 29.1, 31.3 (t, C-2', 7'), 31.5, 31.7 (t, C-9', 12'),
3.7 (t, C-2), 47.2 (d, C-10'), 128.9 (s, C-1'), 130.2 (s, C-8'), 214.3
NR ).
4
2
3
+
+
+
MS: m/z (%) = 58 (C H N , 100), 127 (I , 8), 142 (CH I , 32).
3
8
3
+
+
ESI: m/z (%) = 151 (C H N , 3), 196 (C H N , 100).
(s, C-1).
1
0
17
13 26
+
+
+
MS: m/z (%) = 29 (C H , 33), 57 (C H O , 40), 67 (C H ,100), 81
2
5
3
5
5
7
1
,2-Bis(methylene)cyclooctane (13)
Compound 12 (132 g, 0.408 mol) and AgO (185 g, 0.800 mol) were
suspended in H O (1 L) under N . After stirring at r.t. for 1 h, the
mixture was concentrated on a rotary evaporator at 60 °C/100 mbar.
The resulting residue was pyrolyzed for 3 h at 140 °C/10 mbar with
a distillation temperature of 39–40 °C and condensation of the prod-
uct in a cold trap at –78 °C. The pyrolysis product was added to a
+
+
+
(
C H , 81), 91 (C H , 29), 107 (13), 121 (15), 135 (5) [C H
series], 163 (M – C H – CO, 49), 191 (M – C H , 16), 220 (M ,
-
6
9
7
7
n
(2n–5)
+
+
+
2
5
2
5
2
2
18).
Anal. C H O (220.4): calcd C 81.76, H 10.98; found C 81.80, H
1
5
24
1
0.90.
(r-10, t-11)-1-{11-Methylbicyclo[6.4.0]dodec-1(8)-en-10-
mixture of H O/t-BuOMe (2:1, 600 mL), the organic layer was sep-
2
yl}ethan-1-one (18)
arated, the aqueous phase extracted with t-BuOMe (3 î 200 mL).
Following the procedure described for the preparation of 9, (3E)-
pent-3-en-2-one (17; 7.30 mL, 75.0 mmol) and 1,2-bis(methyl-
ene)cyclooctane (13; 3.50 g, 25.0 mmol) were reacted together to
give, after FC on silica gel (pentane/t-BuOMe, 20:1, R 0.53), 2.32
g (42%) of 18 as a colorless liquid.
The combined organic extracts were dried (Na SO ) and concentrat-
2
4
ed in vacuo to provide 30.1 g (54%) of 13 as a colorless liquid.
IR: n = 2921, 2849 (n C–H), 1467, 1446 (d H–C–H), 891 (d C=C–
H), 1629 cm–1 (n C=C).
f
1
H NMR: d = 1.53–1.55 (m, 4 H, 5, 6-H ), 1.59–1.61 (m, 4 H, 4, 7-
–1
2
IR: n = 1710 cm (n C=O).
H ), 2.32 (dd, J = 6.5, 6.0 Hz, 4 H, 3, 8-H ), 4.76 (m, 2 H, 9, 10-H ),
2
2
b
1
H NMR: d = 0.93 (d, J = 6.5 Hz, 3 H, 11’-CH ), 1.35–1.55 (m, 8 H,
5
.08 (d, 2 H, J = 2.5 Hz, 9, 10-Ha).
3
3
3
'-H to 6'-H ), 1.76–2.16 (m, 9 H, 2', 7', 9', 12'-H , 11'-H ), 2.17 (s,
1
3
2
2
2
a
x
C NMR: d = 25.9 (t, C-4, 7), 30.7 (t, C-5, 6), 33.5 (t, C-3, 8), 110.7
H, COCH ), 2.36 [ddd, J = 10.5, 10.5, 5.5 Hz, 1 H, 10'-H ). J(10'-
3
ax
(
t, C-9, 10), 152.0 (s, C-1, 2).
H, 11'-H) ≈ J(10'-H, 9'-H ) ≈ 10.5 Hz, i.e. 2 î ax–ax coupling,
J(10'-H, 9'-H ) ≈ 5.5 Hz].
ax
+
MS: m/z (%) = 67 (C H , 80), 79 (100), 93 (100), 107 (58), 121 (38)
5
7
eq
+
+
[
C H
-series], 136 (M , 23).
13
n
(2n–5)
C NMR: d = 19.5 (q, 11'-CH ), 26.4, 26.3 (t, C-3', 6'), 28.7, 28.7
3
(
t, C-4', 5'), 29.2 (q, C-2), 30.8 (d, C-11'), 31.3, 31.4, 32.5 (t, C-2',
1
-{Bicyclo[6.4.0]dodec-1(8)-en-10-yl}ethan-1-one (9); Typical
7
2
', 9'), 37.8 (t, C-12'), 55.2 (d, C-10'), 128.3 (s, C-1'), 130.0 (s, C-8'),
13.0 (s, C-1).
Procedure
AlCl (160 mg, 1.20 mmol) was added to a stirred solution of 13
3
MS: m/z (%) = 43 (C H O , 61), 67 (C H , 100), 95 (C H +, 63),
+
+
2
3
5
7
7
11
(2.00 g, 14.7 mmol) and but-3-en-2-one (1.46 mL, 17.8 mmol) in
+
+
+
1
77 (M – C H O, 52), 205 (M – CH , 5), 220 (M , 19).
2
3
3
toluene (20 mL) at 0 °C. The mixture was allowed to warm to r.t.,
stirred for 60 h, and poured into t-BuOMe/H O (1:1, 400 mL). The
Anal. C H O (220.4): calcd C 81.76, H 10.98; found C 81.46, H
2
15 24
organic layer was separated, the aqueous phase extracted with t-
BuOMe (3 î 200 mL). The combined organic extracts were dried
10.95.
(
Na SO ), concentrated in vacuo, and purified by silica gel FC (pen-
3,7
2
4
Tricyclo[7.6.0.0 ]pentadec-1(9)-en-4-one (20)
tane/t-BuOMe, 20:1, R 0.58) to provide 2.54 g (84%) of 9 as a col-
f
Following the procedure described for the preparation of 9, cyclo-
pent-2-en-1-one (19; 1.35 mL, 16.7 mmol) and 1,2-bis(methyl-
ene)cyclooctane (13; 1.70 g, 12.5 mmol) were reacted together to
orless liquid.
–
1
IR: n = 1711 cm (n C=O).
furnish, after FC on silica gel (pentane/t-BuOMe, 20:1, R 0.33),
1
f
H NMR: d = 1.35–1.57 (m, 10 H, 3'-H to 6'-H , 11'-H ), 2.18 (s, 3
2
2
2
1
6
.39 g (51%) of 20 as a colorless product; diastereomeric ratio,
5:35.
H, CH ), 1.93–2.14 (m, 8 H, 2', 7', 9', 12'-H ), 2.55 (dddd, J = 11.5,
3
2
1
0.0, 5.5, 3.0 Hz, 1 H, 10'-H).
–
1
IR: n = 1741 cm (n C=O).
1
3
C NMR: d = 25.3 (t, C-11'), 26.5, 26.5 (t, C-3', 6'), 27.9 (q, C-2),
8.7, 28.8 (t, C-4', 5'), 29.1, 31.1 (t, C-2', 7'), 31.5, 31.7 (t, C-9', 12'),
8.2 (d, C-10'), 128.8 (s, C-1'), 130.3 (s, C-8'), 211.9 (s, C-1).
1
H NMR: d = 1.30–1.55 (m, 8 H, 11-H to 14-H ), 1.66–1.87 (m, 2
2
4
2
2
H, 7, 8-H ), 2.00–2.47 (m, 12 H, 7, 8-H and 2, 5, 6, 10, 15-H ).
b
a
2
1
3
+
+
+
C NMR: d = 25.7, 26.3, 26.4, 26.5, 26.5, 26.6, 27.7, 28.6, 28.8,
MS: m/z (%) = 43 (C H O , 87), 67 (C H , 100), 81 (C H , 68), 93
2
3
5
7
6
9
+
28.8, 28.8, 29.1, 30.7, 31.6, 31.9, 31.9, 32.9, 34.2 (t, C-2, 6, 8 and
C-10 to C-15), 36.8, 37.6 (t, C-5), 32.0, 39.5 (d, C-7), 47.6, 52.0 (d,
C-3), 128.4, 128.8, 129.9, 130.7 (s, C-1, 9), 219.1, 219.7 (s, C-4).
(
20), 107 (15), 121 (15), 135 (7), 149 (5) [C H
-series], 163
n
(2n–5)
+
+
+
(
M – C H O, 49), 191 (M – CH , 4), 206 (M , 23).
2
3
3
Anal. C H O (206.3): calcd C 81.50, H 10.75; found C 81.49, H
14
22
+
+
+
MS: m/z (%) = 41 (C H , 60), 79 (C H O , 55), 91 (C H , 93), 105
1
0.57.
3
5
5
3
7
7
+
+
(46), 133 (29), 147 (17), 161 (19) [C H
-series], 174 (C H
,
n
(2n-7)
13 18
+
+
+
2
9), 190 (M – CO, 15), 200 (M – H O, 5), 218 (M , 100).
2
1
-{Bicyclo[6.4.0]dodec-1(8)-en-10-yl}propan-1-one (16)
Following the procedure described for the preparation of 9, pent-1-
en-3-one (15; 7.40 mL, 75.0 mmol) and 1,2-bis(methylene)cyclooc-
tane (13; 3.50 g, 25.0 mmol) were reacted together to afford, after
Anal. C H O (218.3): calcd C 82.52, H 10.16; found C 82.19, H
15 22
10.16.
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

7
00
P. Kraft
PAPER
-series], 177 (M – CHO, 70), 191 (M – CH , 9), 206
3
,8
+
+
+
Tricyclo[8.6.0.0 ]hexadec-1(10)-en-4-one (22)
[C H
n (2n–5)
(M , 31).
3
+
Following the procedure described for the preparation of 9, cyclo-
hex-2-en-1-one (21; 1.60 mL, 16.6 mmol) and 1,2-bis(methyl-
ene)cyclooctane (13; 1.70 g, 12.5 mmol) were reacted together to
afford, after FC on silica gel (pentane/t-BuOMe, 20:1, R 0.44), 2.49
g (86%) of 22 as a colorless liquid.
2-Chloroethyl Dimethyl Sulfonium Iodide (27)
To a stirred solution of 2-chloroethyl methyl sulfide (25 mL, 0.25
mol) in anhyd MeOH (75 mL) was added MeI (31 mL, 0.50 mol) at
f
–
1
r.t. under N . Stirring was continued at r.t. for 18 h, then the reaction
IR: n = 1711 cm (n C=O).
2
was quenched by the addition of anhyd Et O (250 mL). The result-
1
2
H NMR: d = 1.26–1.71 (m, 11 H, 8-H, 7-H and 12-H to 15-H ),
2
2
2
ing precipitate was filtered, washed thoroughly with Et O, and dried
2
1
.88–2.10 (m, 8 H, 6, 9, 11, 16-H ), 2.15–2.26 (m, 3 H, 3-H and 2-
2
on a vacuum line to provide 49 g (78%) of 27 as a dark yellow pow-
der. This reagent was sufficiently pure for the following transforma-
tions, it should, however, be stored at –18 °C under argon.
H ), 2.35–2.42 (m, 2 H, 5-H ).
2
2
1
3
C NMR: d = 26.1, 26.5, 26.6, 28.7, 28.8, 28.8, 31.3, 31.5, 32.4 (t,
C-2, 6, 7 and C-11 to C-16), 38.1 (t, C-9), 40.9 (d, C-8), 41.9 (t, C-
), 51.1 (d, C-3), 128.9, 129.4 (s, C-1, 10), 212.6 (s, C-4).
–1
IR (KBr): n = 669 (n C–S), 869 cm (n C–Cl).
5
1
H NMR (CD OD): d = 3.12 [s, 6 H, S(CH ) ], 3.94 (t, J = 6.5 Hz,
+
+
+
3
3 2
MS: m/z (%) = 41 (C H , 25), 79 (C H O , 26), 91 (C H , 63), 105
3
5
5
3
7
7
2
H, 1-H ), 4.13 (t, J = 6.5 Hz, 2 H, 2-H ).
+
+
2
2
(
(
(
29), 147 (38), 161 (17) [C H
M – C H O, 15), 203 (M – CHO, 18), 214 (M – H O, 5), 232
M , 100).
-series], 173 (C H , 38), 186
(2n-7) 13 17
n
+
1
3
+
+
C NMR (CD OD): d = 26.1 [q, S(CH ) ], 38.9 (t, C-2), 47.1 (t, C-
3 3 2
2
6
2
+
1).
+
+
+
MS: m/z (%) = 61 (C H S , 100), 75 (C H S , 33), 110 (C H ClS ,
Anal. C H O (232.4): calcd C 82.70, H 10.41; found C 82.69, H
2
5
3
7
3
7
16
24
+
+
3
7), 127 (I , 26), 142 (CH I , 88).
1
0.37.
3
+
+
+
ESI: m/z (%) = 63 (C H Cl , 2), 97 (C H ClS , 6), 125 (C H ClS ,
2
4
2
6
4
10
1
-{Bicyclo[6.4.0]dodec-1(8)-en-10-yl}methanal (24)
100).
Acrolein (23, 13.4 mL, 202 mmol) was added to a stirred solution
of 13 (22.9 g, 168 mmol) in toluene (200 mL) under N . The mixture
Spiro[2.7]decan-4-one (28); Typical Procedure
2
was cooled to 0 °C, and a 1.0 M solution of dimethylaluminum
chloride in hexanes (14 mL, 14 mmol) was added via a syringe. Af-
ter stirring for 5 min at this temperature, the cooling bath was re-
moved and stirring was continued at r.t. for 5 d with renewed
addition of acrolein (13.4 mL, 202 mmol) and 1.0 M solution of
dimethylaluminum chloride in hexanes (14 mL, 14 mmol) after 3 d.
KOt-Bu (47.6 g, 0.424 mol) was dissolved in t-BuOH (0.5 L) with
mechanical stirring at 60 °C under N . To this solution was added
2
cyclooctanone (27.0 g, 212 mmol). After 5 min of stirring at r.t., 2-
chloroethyl dimethyl sulfonium iodide (27; 49.0 g, 0.194 mol) was
added in small portions within 15 min, and the stirring was contin-
ued at r.t. for 22 h. The mixture was poured into H O (0.5 L), and
2
The mixture was then poured into H O/t-BuOMe (1:1, 1 L), and the
extracted with t-BuOMe (3 î 0.5 L). The combined organic extracts
2
organic layer was separated. The aqueous layer was extracted with
t-BuOMe (3 î 250 mL), the combined organic extracts were dried
were dried (Na SO ), concentrated in vacuo, and purified by FC on
2
4
silica gel (pentane/t-BuOMe, 10:1, R 0.69) to provide 24.8 g (85%)
f
(
Na SO ), and the solvent was removed on a rotary evaporator. FC
2 4
of 28 as a colorless liquid.
on silica gel (pentane/t-BuOMe, 40:1, R 0.41) provided 20.9 g
f
–1
IR: n = 1684 (n C=O), 1113, 1075 cm (n C–C–C).
as
(65%) of 24 as a colorless oil.
1
H NMR: d = 0.67 (dd, J = 6.5, 3.6 Hz, 2 H, 1, 2-H ), 1.22 (dd, J =
–
1
b
IR: n = 1726 cm (n HC=O).
6
.5, 3.2 Hz, 2 H, 1, 2-H ), 1.45–1.49 (m, 2 H, 9-H ), 1.54–1.60 (m,
a
2
1
H NMR: d = 1.41–1.65 (m, 10 H, 3'-H to 6'-H , 11'-H ), 1.93–2.13
2
2
2
4 H, 7, 8-H ), 1.71–1.76 (m, 2 H, 10-H ), 1.91 (m , 2 H, 6-H ), 2.67
2
2
c
2
(
m, 8 H, 2', 7', 9', 12'-H ), 2.47 (m , 1 H, 10'-H), 9.69 (d, J = 1.0 Hz,
(m , 2 H, 5-H ).
2
c
c
2
1
H, CHO).
1
3
C NMR: d = 18.1 (2 t, C-1, 2), 25.3, 26.0 (t, C-6, 9), 28.4, 29.5 (t,
C-7, 8), 31.3 (s, C-3), 32.1 (t, C-5), 38.9 (t, C-10), 216.3 (s, C-4).
1
3
C NMR: d = 22.8 (t, C-11'), 26.5, 26.5 (t, C-3', 6'), 28.0, 28.5 (t,
C-4', 5'), 28.8, 28.8 (t, C-2', 7'), 31.7, 31.8 (t, C-9', 12'), 46.8 (d, C-
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 87), 67 (C H , 69), 97
3
5
4
+
7
5
7
1
0'), 128.4 (s, C-1'), 130.8 (s, C-8'), 204.8 (d, C-1).
+
+
+
(
C H , 68), 109 (C H , 63), 124 (M – CO, 44), 137 (M – CH ,
7 13 8 13 3
+
+
+
MS : m/z (%) = 29 (CHO, 33), 41 (C H , 72), 67 (C H , 90), 91
6), 152 (M , 7).
3
5
5
7
+
+
(
C H , 98), 107 (51), 121 (34), 135 (29), 149 (12) [C H
-se-
7
7
n
(2n–5)
+
+
ries], 164 (M – CO, 31), 192 (M , 100).
4
-Methylenespiro[2.7]decane (29); Typical Procedure
Methyl triphenyl phosphonium bromide (124 g, 347 mmol) was
added to a mechanically stirred solution of KOt-Bu (37.0 g, 0.330
mol) in THF (750 mL) and the mixture was heated to reflux. At this
reflux temperature was added dropwise 28 (44.0 g, 289 mmol) with
vigorous stirring, and heating was continued for 2 h. After addition-
1
-{10’-Methylbicyclo[6.4.0]dodec-1’(8’)-en-10’-yl}methanal
(26)
Following the procedure described for the preparation of 9, 2-meth-
ylprop-2-en-1-al (25; 1.45 mL, 17.7 mmol) and 1,2-bis(methyl-
ene)cyclooctane (13; 2.00 g, 14.7 mmol) were reacted together to
afford, after FC on silica gel (pentane/t-BuOMe, 50:1, R 0.44) 2.06
g (68%) of 26 as a colorless oil.
al 14 h of stirring at r.t., the mixture was poured into H O (1 L), and
2
f
the product extracted with t-BuOMe (3 î 1 L). The combined or-
ganic extracts were dried (Na SO ), concentrated on a rotary evap-
2
4
–
1
orator and purified by FC on silica gel (pentane, R 1.00) to provide
IR: n = 1727 cm (n HC=O).
f
3
1.8 g (73%) of 29 as a colorless liquid.
1
H NMR: d = 1.04 (s, 3 H’, 10-CH ), 1.37–1.54 (m, 10 H, 3'-H to
3
2
IR: n = 2922, 2851, 2997, 3076 (n C–H), 1444 (d H–C–H), 879,
6
2
'-H , 11'-H ), 1.78 (d, J = 16.0 Hz, 1 H, 9'-H ), 2.01–2.12 (m, 6 H,
2
2
b
–
1
1
014 (d C=C–H), 1632 cm (n C=C).
', 7'-,12'-H ), 2.29 (d, J = 16.0 Hz, 1 H, 9'-H ), 9.47 (s, 1 H, CHO).
2
a
1
1
3
H NMR: d = 0.45 (dd, J = 6.0, 4.0 Hz, 2 H, 1, 2-H ), 0.59 (dd, J =
C NMR: d = 20.7 (q, 10'-CH ), 26.4, 26.5, 26.6 (t, C-3', 6', 11'),
b
3
6
.0, 4.0 Hz, 2 H, 1, 2-H ), 1.45–1.59 (m, 8 H, 7-H to 10-H ), 1.67–
2
8.8, 28.9 (t, C-4', 5'), 29.1 (t, C-12'), 31.6, 31.9 (t, C-2', 7'), 35.9 (t,
a
2
2
1
.73 (m, 2 H, 6-H ), 2.25 (ddd, J = 14.5, 6.5, 1.0 Hz, 2 H, 5-H ), 4.71
2 2
C-9'), 45.1 (s, C-10'), 128.2 (s, C-1'), 130.1 (s, C-8'), 206.2 (d, C-1).
(
dd, J = 3.5, 1.0 Hz, 2 H, 11-H2).
+
+
MS: m/z (%) = 29 (CHO, 36), 41 (C H , 78), 67 (C H , 65), 81
3
5
5
7
+
+
(C H , 100), 95 (C H , 61), 121 (39), 135 (29), 149 (20), 163 (28)
6 9 7 11
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Design and Synthesis of Violet Odorants
701
1
3
MS: m/z (%) = 43 (C H O , 100), 81 (C H , 38), 95 (C H11+, 39),
+
+
C NMR: d = 14.9 (2 t, C-1,-2), 25.0 (s, C-3), 25.2 (t, C-6), 26.4,
2
3
6
9
7
+
+
+
2
6.4 (t, C-7, 8), 29.5 (t, C-9), 34.4 (t, C-5), 37.1 (t, C-10), 108.9 (t,
177 (M – C H O, 26), 205 (M – CH , 4), 220 (M , 5).
2 3 3
C-11), 155.8 (s, C-4).
+
(3E,1’E)-5-(2’-Methylcyclooct-1’-en-1’-yl)hex-3-en-2-one (35)
Chlorotris(triphenylphosphine)rhodium(I) (1.66 g, 1.79 mmol) was
added to a stirred solution of 29 (5.00 g, 33.3 mmol) and but-3-en-
MS: m/z (%) = 67 (C H , 85), 79 (100), 93 (61), 107 (29), 121 (21),
5
7
+
+
1
35 (13) [C H
-series], 150 (M , 3).
n
(2n–5)
2
-one (3.30 mL, 40 mmol) in toluene (50 mL) under N . AgOTf
2
1
-{9-Methylbicyclo[6.4.0]dodec-1(8)-en-10-yl}ethan-1-one (32)
(462 mg, 1.80 mmol) was added and the mixture was refluxed for
and (3E,1’E)-5-(2’-Methylcyclooct-1’-en-1’-yl)hex-3-en-2-one
35)
2
3 h, filtered through a pad of silica gel, and poured into t-BuOMe/
(
H O (1:1, 900 mL). The organic layer was separated, the aqueous
layer extracted with t-BuOMe (3 î 500 mL). The combined organic
extracts were dried (Na SO ), concentrated in vacuo, and purified
2
Chlorotris(triphenylphosphine)rhodium(I) (1.10 g, 1.19 mmol) was
added to a stirred solution of 29 (2.21 g, 14.7 mmol) and but-3-en-
2
ture was refluxed for 20 h, filtered through a pad of silica gel, and
poured into t- BuOMe/H O (1:1, 400 mL). The organic layer was
separated, the aqueous layer extracted with t-BuOMe (3 î 200 mL).
2
4
-one (1.45 mL, 17.8 mmol) in toluene (20 mL) under N . The mix-
2
by FC on silica gel (pentane/t-BuOMe, 20:1) to provide 4.87 g
66%) of 35 (R 0.22) as a colorless liquid. For spectroscopic data,
(
f
2
see above.
The combined organic extracts were dried (Na SO ), concentrated
in vacuo, and purified by FC on silica gel (pentane/t-BuOMe, 20:1)
2
4
(
1
r-9, c-10, t-11)-1-{9,11-Dimethylbicyclo[6.4.0]dodec-1(8)-en-
0-yl}ethan-1-one (36)
to provide 288 mg (9%) of (r-9,t-10)-32 (R 0.46), 1.15 g (36%) of
f
Following the procedure described for the preparation of 32, (3E)-
pent-3en-2-one (17; 3.00 mL, 30.8 mmol) and 4-methyle-
nespiro[2.7]decane (29, 3.75 g, 25.0 mmol) were reacted together to
afford, after FC on silica gel (pentane/t-BuOMe, 20:1), 2.32 g
(42%) of 36 as a colorless liquid.
(
r-9,c-10)-32 (R 0.38), and 714 mg (22%) of 35 (R 0.22) as color-
f
f
less liquids.
(r-9,t-10)-32:
–
1
IR: n = 1710 cm (n C=O).
1
–1
H NMR: d = 1.03 (J = 7.0 Hz, 3 H, 9’-CH ), 1.34–1.57 (m, 9 H, 3'-
IR: n = 1710 cm (n C=O).
3
H to 6'-H , 11'-H ), 1.75 (m , 1 H, 11'-H ), 1.87–2.00 (m, 4 H, 2'-
1
2
2
b
c
a
H NMR: d = 0.84 (d, J = 7.0 Hz, 3 H, 11’-CH ), 0.91 (d, J = 6.0 Hz,
3
H , 7', 12'-H ), 2.17 (s, 3 H, COCH ), 2.21–2.26 (m, 2 H, 7', 12'-H ),
2
and 9'-H.
1
2
b
3
a
3
H, 9’-CH ), 1.42–1.55 (m, 8 H, 3'-H to 6'-H ), 1.67 (dd, J = 17.0,
3
2
2
.38 (m , 1 H, 10'-H), 2.52 (m , 1 H, 9'-H). No NOE between 10'-H
c
c
1
0.5 Hz, 1 H, 12-H ), 1.89–2.27 (m, 5 H, 2'-H , 7'-H , 12'-H ), 2.09
b 2 2 a
(
m ,1 H, 11'-H ), 2.15 (s, 3 H, COCH ), 2.37 (qd, J = 6.0, 5.0 Hz,
c ax 3
3
C NMR: d = 19.5 (q, 9'-CH ), 22.9 (t, C-11'), 26.3, 26.5 (t, C-3',
1 H, 9'-H ), 2.45 (dd, J = 11.0, 5.0 Hz, 1 H, 10'-H ). J (9'-H , 10'-
3
eq ax eq
6
'), 28.1, 28.6 (t, C-4', 5'), 28.2 (q, C-2), 28.8, 29.5 (t, C-2', 7'), 32.1
H ) = 5.0 Hz (ax–eq), J (10'-H ,11'-H ) = 11.0 Hz (ax–ax).
ax ax ax
(
2
t, C-12'), 33.1 (d, C-9'), 55.1 (d, C-10'), 130.3, 133.3 (s, C-1', 8'),
11.4 (s, C-1).
13
C NMR: d = 15.3 (q, 9'-CH ), 19.9 (q, 11'-CH ), 23.9 (d, C-11'),
3
3
2
6.4, 26.9 (t, C-3', 6'), 28.4 (t, C-5'), 30.1 (t, C-4'), 30.5 (q, C-2),
+
+
+
MS: m/z (%) = 43 (C H O , 32), 81 (C H , 100), 95 (C H , 41),
1
CH , 1), 220 (M , 6).
30.7 (t, C-7'), 31.2 (t, C-2'), 35.3 (d, C-9'), 38.5 (t, C-12'), 59.1 (d,
C-10'), 129.9 (s, C-1'), 134.1 (s, C-8'), 211.1 (s, C-1)
MS: m/z (%) = 43 (C H O , 68), 95 (C H , 100), 109 (C H +, 45),
191.1797 (M – C H O, 38), 219 (M – CH , 5), 234.1971 (11).
[M ]; calcd for C16
2
3
6
+
9
7
11
+
+
21 (M – C H O – C H , 17), 177 (M – C H O, 37), 205 (M –
2 3 4 8 2 3
+
3
+
+
2
3
7
11
8
13
+
+
(
r-9,c-10)-32:
2
3
3
+
–
1
H26O: 234.1983.
IR: n = 1709 cm (n C=O).
1
H NMR: d = 0.84 (J = 7.0 Hz, 3 H, 9’-CH ), 1.39–1.61 (m, 8 H, 3'-
3
(
r-9, c-10)-1-{9,10-Dimethylbicyclo[6.4.0]dodec-1(8)-en-10-
yl}ethan-1-one (38); Typical Procedure
-Methylbut-3-en-2-one (37; 60 mL, 600 mmol) and chloro-
H to 6'-H ),1.72 (m , 2 H, 11'-H ), 1.93–2.08 (m, 4 H, 2'-H , 7', 12'-
2
2
c
2
2
H ), 2.16 (s, 3 H, COCH ), 2.19–2.31 (m, 2 H, 7'-,12'-H ), 2.52 (m ,
b
3
a
c
3
1
H, 10'-H), 2.56 (m , 1 H, 9'-H).
c
tris(triphenylphosphine)rhodium(I) (10.0 g, 10.8 mmol) were added
in turn to a stirred solution of 17 (31.8 g, 212 mmol) in toluene (0.5
L). The mixture was refluxed for 3 d, filtered through a pad of silica
1
3
C NMR: d = 14.7 (q, 9'-CH ), 18.1 (t, C-11'), 26.4, 26.9 (t, C-3',
3
6
'), 28.4 (q, C-2), 28.5, 29.2 (t, C-4', 5'), 30.2, 30.8 (t, C-2', 7'), 31.4
(
2
t, C-12'), 34.5 (d, C-9'), 52.6 (d, C-10'), 130.5, 134.4 (s, C-1', 8'),
11.5 (s, C-1).
MS: m/z (%) = 43 (C H O , 65), 81 (C H , 100), 95 (C H +, 50),
gel, washed with H
on a rotary evaporator. The residue was purified by FC on silica gel
(pentane/t-BuOMe, 40:1, R 0.41) to give 38 (23.9 g, 48%) as a col-
orless waxy solid; mp 56.3 °C.
2
O (200 mL), dried (Na SO ) and concentrated
2
4
+
+
f
2
3
6
9
7
11
+
+
+
1
77 (M – C H O, 38), 205 (M – CH , 3), 220 (M , 14).
2
3
3
–
1
IR: n = 1704 cm (n C=O).
Anal. C H O (220.4): calcd C 81.76, H 10.98; found C 81.60, H
1
15
24
1
0.87.
H NMR: d = 0.83 (d, J = 7.0 Hz, 3 H, 9’-CH ),1.10 (s, 3 H, 10’-
3
CH ), 1.42–2.06 (m, 15 H, 2', 7'-H , 3'-H to 6'-H , 9'-H, 11', 12'-
3
b
2
2
3
5:
H ), 2.14 (s, 3 H, COCH ), 2.23–2.40 (m, 2 H, 2', 7'-H ).
2
3
a
–1
IR: n = 982 cm (d C=C, trans), 1254 (d COCH ), 1359 (d CH ),
1
3
3
13
C NMR: d = 17.1 (q, 9'-CH ), 21.0 (q, 10'-CH ), 22.7 (t, C-11'),
3
3
620 (n C=CCO),1676 (n C=O), 1697 (n C=C).
2
5.4 (q, C-2), 26.6, 26.7 (t, C-3', 6'), 27.0 (t, C-4'), 28.8 (t, C-5'),
1
H NMR: d = 1.17 (d, J = 7.0 Hz, 3 H, 5-CH ), 1.41–1.54 (m, 8 H,
3
29.7 (t, C-12'), 30.8 (t, C-7'), 31.7 (t, C-2'), 40.7 (d, C-9'), 49.9 (s,
C-10'), 128.9 (s, C-1'), 133.1 (s, C-8'), 214.2 (s, C-1).
4
2
(
'-H to 7'-H ), 1.71 (s, 3 H, 2'-CH ), 2.03–2.23 (m, 4 H, 3', 8'-H ),
2
2
3
2
.25 (s, 3 H, COCH ), 3.59 (qdd, J = 7.0, 6.0, 1.5 Hz, 1 H, 5-H), 6.02
3
+
+
MS: m/z (%) = 95 (C H , 31), 191.1800 (M – C H O, 100), 219
7
11
2
3
dd, J = 16.5, 1.5 Hz, 1 H, 3-H), 6.80 (dd, J = 16.5, 6.0 Hz, 1 H, 4-
+
+
(
M – CH , 3), 234.2020 (M , 12).
3
H).
1
3
Anal. C16H26O (234.4): calcd C 81.99, H 11.18, O 6.83; found C
C NMR: d = 17.1 (q, C-6), 18.3 (q, 2'-CH ), 26.1 (t, C-4'), 26.6 (q,
3
81.68, H 11.15, O 6.89.
C-1), 26.7 (t, C-7'), 27.2, 27.7 (t, C-5', 6'), 31.4 (t, C-8'), 33.0 (t, C-
3
1
'), 39.1 (d, C-5), 129.1 (d, C-3), 131.1 (s, C-2'), 132.8 (s, C-1'),
52.2 (d, C-4), 198.8 (s, C-2).
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

7
02
P. Kraft
PAPER
4
-Methylenespiro[2.6]nonane (40)
and a standard Dess–Martin oxidation26 (scale: 0.48 mol) afforded
First spiro[2.6]nonan-4-one was prepared from 39 (20.0 g, 0.792
mol), following the procedure for the preparation of the homolog 28
after FC on silica gel (pentane/t-BuOMe, 10:1, R 0.46) 39.4 g
(66%) of 44 as a colorless liquid.
f
and purified by FC on silica-gel (pentane/t-BuOMe, 10:1, R 0.58);
–1
f
IR: n = 1705 cm (n C=O).
yield: 5.86 g (54%). Spiro[2.6]nonan-4-one (2.95 g, 42.0 mmol)
was then transformed to 40 according to the procedure described for
the preparation of 29 and purified by FC on silica gel (pentane, Rf
1
H NMR: d = 1.61 (m , 2 H, 7-H ), 2.19 (m , 2 H, 6-H ), 2.43–2.52
c
2
c
2
(
13
m, 6 H, 2, 3, 8-H ), 5.70, 5.73 (m , 2 H, 4, 5-H).
2
c
1
.00).
C NMR: d = 21.7, 23.8 (t, C-3, 7), 26.2 (t, C-6), 40.1, 47.1 (t, C-2,
8), 130.1, 130.6 (d, C-4, 5), 214.5 (s, C-1).
–
1
IR: n = 872, 1015 (d C=C–H), 1628 cm (n C=C), 2852, 2924,
2
997 (n C–H), 3076.
+
+
+
MS: m/z (%) = 27 (C H , 30), 39 (C H , 65), 54 (C H , 84), 67
(C H , 100), 96 (M – C H , 84), 109 (M – CH , 33), 124 (M , 18).
2
4
3
3
4
6
+
+
+
+
1
H NMR: d = 0.52 (dd, J = 6.0, 4.0 Hz, 2 H, 1, 2-H ), 0.66 (dd, J =
5
7
2
4
3
b
6
.0, 4.0 Hz, 2 H, 1, 2-H ), 1.46–1.49 (m, 2 H, 9-H ), 1.55–1.59 (m,
a
2
4
H, 7, 8-H ), 1.61–1.66 (m, 2 H, 6-H ), 2.35 (m , 2 H, 5-H ), 4.44
Spiro[2.7]dec-8-en-4-one (45)
2
2
c
2
(
d, J = 1.5 Hz, 1 H, 10-H ), 4.58 (d, J = 1.5 Hz, 1 H, 10-H ).
3
Following the procedure described for the preparation of 28, cy-
clooct-4-en-1-one (44; 20.0 g, 0.161 mol) and 2-chloroethyl dime-
thyl sulfonium iodide (27; 34.5 g, 0.136 mol) were reacted together
b
a
1
C NMR: d = 17.2, 17.2 (t, C-1, 2), 24.7 (s, C-3), 28.0, 29.3, 29.7
t, C-6, 7, 8), 36.9 (t, C-5), 38.7 (t, C-9), 106.3 (t, C-10), 156.3 (s,
(
to give, after FC on silica gel (pentane/t-BuOMe, 50:1, R 0.27),
f
C-4).
7
.15 g (35%) of 45 as a colorless liquid.
+
MS: m/z (%) = 67 (C H , 68), 79 (100), 93 (57), 107 (22), 121 (18)
5
7
–1
IR: n = 1687 (n C=O), 1098 cm (n C–C–C).
+
+
as
[C H
-series], 136 (M , 3).
n
(2n–5)
1
H NMR: d = 0.69 (dd, J = 6.5, 4.0 Hz, 2 H, 1, 2-H ), 1.17 (dd, J =
b
6
2
8
.5, 4.0 Hz, 2 H, 1, 2-H ), 1.72 (m , 2 H, 6-H ), 2.30 (m , 2 H, 7-H ),
(r-8, c-9)-1-{8-Methylbicyclo[5.4.0]undec-1(7)-en-9-yl}ethan-1-
a c 2 c 2
.41 (d, J 5.5 Hz, 2 H, 10-H ), 2.70 (m , 2 H, 5-H ), 5.73 (m , 2 H,
one (41)
2
c
2
c
, 9-H).
Following the procedure described for the preparation of 38, but-3-
en-2-one (14; 1.0 mL, 12 mmol) and 40 (1.36 g, 10.0 mmol) were
reacted together to give, after FC on silica gel (pentane/t-BuOMe,
13
C NMR: d = 16.3, 16.3 (t, C-1, 2), 26.0, 26.8 (t, C-6, 7), 33.0 (s,
C-3), 33.9 (t, C-5), 40.7 (t, C-10), 129.3, 130.1 (d, C-8, 9), 214.2 (s,
C-4).
2
0:1, R 0.43), 519 mg (25%) of 41 as a colorless liquid.
f
–
1
IR: n = 1709 (n C=O), 1353, 1376 cm (d CH3).
+
+
MS: m/z (%) = 39 (C H , 54), 67 (C H , 31), 79 (100), 107 (23),
3
3
5
7
+
+
1
121 (39), 135 (37) [C H
-series], 150 (M , 7).
H NMR: d = 0.80 (d, J = 7.0 Hz, 3 H, 8’-CH ), 1.34–1.76 (m, 8 H,
n
(2n–5)
3
3
'-H to 5'-H ,10'-H ), 1.99–2.15 (m, 6 H, 2', 6', 11'-H ), 2.16 (s, 3
2
2
2
2
H, COCH ), 2.45 (qd, J = 6.0, 6.0 Hz, 1 H, 8'-H), 2.58 (ddd, J = 12.0,
4-Methylenespiro[2.7]dec-8-ene (46)
3
6
.0, 3.0 Hz, 1 H, 9'-H). J(9'-H, 8'-H) ≈ J(8'-H, 8'-CH ) ≈ 6.0 Hz.
Following the procedure described for the preparation of 29,
spiro[2.7]dec-8-en-4-one (45; 4.30 g, 28.6 mmol) and methyltri-
phenylphosphonium bromide (12.3 g, 34.4 mmol) were reacted to-
3
1
3
C NMR: d = 14.1 (q, 8'-CH ), 18.3 (t, C-10'), 26.2, 27.3 (t, C-
3
3
3
1
',,5'), 28.4 (q, C-2), 31.6, 32.7 (t, C-2', 6'), 34.1, 34.7 (t, C-4', 11'),
gether to afford, after FC on silica gel (pentane, R 0.91), 3.71 g
f
6.8 (d, C-8'), 52.3 (d, C-9'), 134.0, 137.3 (s, C-1', 7'), 211.5 (s, C-
).
(87%) of 46 as a colorless liquid.
–
1
IR: n = 899, 1015 (d C=C–H), 1461 (d H–C–H), 1636 cm (n C=C),
+
+
+
MS: m/z (%) = 28 (CO , 38), 43 (C H O , 68), 81 (C H , 100), 91
2
3
6
9
2
853, 2926, 3016, 3075 (n C–H).
+
+
+
+
(C H , 34), 105 (C H O , 24),121 (C H , 13), 163 (M – C H O,
7 7 7 7 9 13 2 3
+
+
1
3
8), 191 (M – CH , 2), 206 (M , 7).
H NMR: d = 0.44 (dd, J = 6.0, 4.0 Hz, 2 H, 1, 2-H
b
), 0.59 (dd, J =
3
6
2
.0, 4.0 Hz, 2 H, 1, 2-H ), 1.60 (m , 2 H, 6-H ), 2.07 (d, J = 7.5 Hz,
a
c
2
H, 10-H ), 2.14–2.22 (m, 4 H, 5, 7-H ), 4.74 (d, J = 2.0 Hz, 11-
(r-8, c-9)-1-{8,9-Dimethylbicyclo[5.4.0]undec-1(7)-en-9-
2
2
H ), 4.81 (d, 1 H, J = 2.0 Hz, 11-H ), 5.68 (m , 2 H, 8, 9-H).
yl}ethan-1-one (42)
b
a
c
Following the procedure described for the preparation of 38, 3-me-
thylbut-3-en-2-one (37, 1.2 mL, 12 mmol) and 40 (1.36 g, 10.0
mmol) were reacted together to give, after FC on silica gel (pentane/
13
C NMR: d = 12.4 (2 t, C-1, 2), 25.5 (t, C-6), 28.7 (s, C-3), 30.0 (t,
C-7), 33.3 (t, C-5), 35.6 (t, C-10), 111.2 (t), 129.2, 130.4 (d, C-8, 9),
54.2 (s, C-4).
1
t-BuOMe, 20:1, R 0.39), 1.14 g (52%) of 42 as a colorless liquid.
f
+
+
+
MS: m/z (%) = 39 (C H , 35), 79 (C H , 80), 91 (C H , 100), 105
(
3
3
6
7
7
7
–
1
IR: n = 1703 cm (n C=O).
+
+
+
+
M – C H , 54), 119 (M – C H , 23), 133 (M – CH , 19), 148 (M ,
3 7 2 5 3
1
1).
H NMR: d = 0.77 (d, J = 7.0 Hz, 3 H, 8’-CH ), 1.06 (s, 3 H, 9’-CH ),
3
3
1
.34–1.44 (m, 5 H, 4'-H , 8'-H, 10'-H ), 1.68–1.75 (m, 4 H, 3', 5'-
2 2
Anal. C H (148.24): calcd C 89.12, H 10.88; found C 88.93, H
11 16
10.84.
H ), 1.93–2-08 (m, 6 H, 2', 6', 11'-H ), 2.11 (s, 3 H, COCH ).
2
2
3
1
3
C NMR: d = 16.3 (q, 8'-CH ), 20.6 (q, 9'-CH ), 23.0 (t, C-10'), 25.4
3
3
(
3
(
q, C-2), 26.3, 26.8 (t, C-3', 5'), 28.8 (t, C-4'), 32.8 (t, C-11'), 34.4,
4.6 (t, C-2', 6'), 43.3 (d, C-8'), 49.5 (s, C-9'), 132.1 (s, C-1'), 135.5
s, C-7'), 214.1 (s, C-1).
(r-9, c-10)-1-{9,10-Dimethylbicyclo[6.4.0]dodec-1(8),6(7)-dien-
10-yl}ethan-1-one (47)
Following the procedure described for the preparation of 32, 4-me-
thylenespiro[2.7]dec-8-ene (46; 3.20 g, 21.6 mmol) and 3-methyl-
but-3-en-2-one (37; 6.5 mL, 29.1 mmol) were reacted together to
+
+
MS: m/z (%) = 43 (C H O , 52), 95 (C H , 100), 107 (40), 121
2
+
3
7
11
+
+
(
32), 149 (4) [C H
-series], 177 (M – C H O, 81), 220 (M , 7).
n
(2n–5) 2 3
afford, after FC on silica gel (pentane/t-BuOMe, 100:1, R 0.18),
f
2
.17 g (43%) of 47 as a colorless liquid.
Cyclooct-4-en-1-one (44)
–
1
IR: n = 1704 cm (n C=O).
Prepared according to the procedure of Meier, Mayer and
Kolshorn19 by epoxidation of cycloocta-1,5-diene (43; 86.6 g, 0.800
mol) with 3-chloroperoxybenzoic acid (207 g, 0.840 mol; yield:
1
H NMR: d = 0.79 (d, J = 7.0 Hz, 3 H, 9’-CH -ax), 1.14 (s, 3 H, 10’-
3
CH -ax), 1.23–1.30 (m, 2 H, 3', 11'-H ), 1.48–1.67 (m, 3 H, 3', 11'-
3
b
6
0.0 g, 60%, FC on silica gel: pentane/t-BuOMe, 10:1, R 0.63),
f
H and 4'-H ), 1.78–2.18 (m, 7 H, 4'-H and 2', 5', 12'-H ), 2.09 (q,
J = 7.0 Hz, 1 H, 9'-H ), 2.15 (s, 3 H, COCH ), 5.59–5.73 (m, 2 H,
eq 3
a
b
a
2
LiAlH reduction (scale: 0.48 mol; crude yield: 60.5 g, ca 100%),
4
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Design and Synthesis of Violet Odorants
703
6
’, 7’-H). NOEs from 9’-H to 9’-CH -ax, 7-H, 10’-CH -ax, 10’-Ac
eq
(11) Stoll, M.; Scherrer, W. Helv. Chim. Acta 1940, 23, 941.
eq
3
3
and 12-Hax.
(12) Hoffmann, W.; Pasedach, H.; Pommer, H.; Reif, W. Liebigs
Ann. Chem. 1971, 747, 60.
1
3
C NMR: d = 17.0 (q, 9’-CH ), 20.7 (q, 10’-CH ), 23.1 (t, C-4’), 23.3
3
3
(
(
13) Sestanj, K. Croat. Chem. Acta 1962, 43, 211.
14) Warren, C. B.; Brugger, W. E.; Zander, G. S. Chem. Ind.
(
t, C-3’), 23.9 (t, C-11’), 25.3 (q, C-2), 27.0 (t, C-12’), 28.9 (t, C-5’),
3
1
2.6 (t, C-2’), 40.2 (d, C-9’), 49.2 (s, C-10’), 129.4 (d, C-7’), 131.0,
30.6 (s, C-1’, 8’), 131.6 (d, C-6’), 213.7 (s, C-1).
(London) 1983, 36.
(
15) (a) Gerber, P. Biopolymers 1992, 32, 1003.
(b) Gerber, P.; Müller, K. J. Comput.-Aided Mol. Design
1995, 9, 251.
+
MS: m/z (%) = 43 (C H O , 50), 91 (57), 105 (43), 119 (52), 133
2
3
+
+
+
(
2
39) [C H
32 (M , 28).
-series], 189 (M – C H O, 100), 217 (M – CH , 9),
n
+
(2n–7) 2 3 3
(
(
c) Gerber, P. R. J. Comput.-Aided Mol. Design 1998, 12, 37.
d) Moloc, Molecular Modeling on Silicon Graphics
Anal. C H O (232.37): calcd C 82.70, H 10.41; found C 82.68, H
1
6
24
Workstations, dated 06/17/96, F. Hoffmann-La Roche Ltd.,
996.
1
0.30.
1
(
16) van Straten, J. W.; van Norden, J. J.; van Schaik, T. A. M.;
Franke, G. T.; de Wolf, W. H.; Bickelhaupt, F. Recl. Trav.
Chim. Pays-Bas 1978, 97, 105.
Acknowledgement
Thanks are due to D. Lebeau and C. Charmoille for composition of
demo perfumes and olfactory descriptions, to G. Fráter and J. A. Ba-
jgrowicz for valuable discussions, to G. Brunner and J. Schmid for
spectroscopic data, and to R. Rueher of HLR for elemental analyses.
(
(
(
17) Winterfeld, E. J. Prakt. Chem. 1994, 336, 91.
18) Fitjer, L.; Quabeck, U. Synth. Commun. 1985, 15, 855.
19) Meier, H.; Mayer, W.; Kolshorn, H. Chem. Ber. 1987, 120,
685.
(
(
20) Ruder, S. M.; Ronald, R. C. Tetrahedron Lett. 1984, 25, 5501.
21) Doering, W. von E.; Schreiber, K. C. J. Am. Chem. Soc. 1955,
References
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(
(
1) von Soden, H. J. Prakt. Chem. 1904, 69, 256.
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2
675.
(b) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.
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(
(
3) Schinz, H. Fortschr. Chem. Org. Naturst. 1951, 8, 146.
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Acta 1947, 30, 1599.
(
5) Schinz, H.; Ruzicka, L.; Seidel, C. F.; Tavel, C. Helv. Chim.
Acta 1947, 30, 1810.
(23) Binger, P.; Wedemann, P.; Kozhushkov, S. I.; de Meijere, A.
Eur. J. Org. Chem. 1998, 113.
(
6) (a) Rautenstrauch, V.; Ohloff, G. Helv. Chim. Acta 1971, 54,
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Am. Chem. Soc. 1990, 112, 4965.
1776; Erratum 1972, 55, 2686.
(
b) Rautenstrauch, V.; Willhalm, B.; Thommen, W.; Ohloff,
(b) Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y. Angew.
Chem. 1998, 110, 2362; Angew. Chem., Int. Ed. Engl. 1998,
37, 2248.
G. Helv. Chim. Acta 1984, 67, 325.
(
7) For a stereoselective synthesis of (±)-cis-a-irone, see:
Nussbaumer, C.; Fráter, G. J. Org. Chem. 1987, 52, 2096.
8) Uhde, G.; Ohloff, G. Helv. Chim. Acta 1972, 55, 2621.
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(26) (a) Dess, B. D.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, B. D.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
(
(
1
993; Engl. Ed.: Kaiser, R. The Scent of Orchids; Elsevier:
Amsterdam, 1993.
10) Fráter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54,
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(
(c) Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996,
338, 588.
7
Synthesis 1999, No. 4, 695–703 ISSN 0039-7881 © Thieme Stuttgart · New York