Cyclization of N,N-diethylgeranylamine N-oxide in one-pot operation: preparation of cyclic terpenoid-aroma chemicals

Article abstract of DOI:10.1016/j.tetlet.2008.08.001

Acid promoted cyclization of the geranylamine N-oxide (E)-4 followed by base-catalyzed intramolecular aldol condensation afforded 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in one-pot operation. Reduction of 7, which possess strong fruity odor, followed by lipase-catalyzed kinetic resolution furnished the acetate (R)-26 (>49.9% yield, >99% ee) and the recovered alcohol (S)-25 (>49.9% yield, >99% ee, herbal odor).

Full text of DOI:10.1016/j.tetlet.2008.08.001

Tetrahedron Letters 49 (2008) 6016–6018
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclization of N,N-diethylgeranylamine N-oxide in one-pot operation:
preparation of cyclic terpenoid-aroma chemicals
*
Kunihiko Takabe , Takashi Yamada, Takenori Miyamoto, Nobuyuki Mase
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Acid promoted cyclization of the geranylamine N-oxide (E)-4 followed by base-catalyzed intramolecular
aldol condensation afforded 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in one-pot operation. Reduction of
7, which possess strong fruity odor, followed by lipase-catalyzed kinetic resolution furnished the acetate
(R)-26 (>49.9% yield, >99% ee) and the recovered alcohol (S)-25 (>49.9% yield, >99% ee, herbal odor).
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 July 2008
Revised 25 July 2008
Accepted 1 August 2008
Available online 7 August 2008
N,N-Diethylgeranylamine ((E)-1)1a,b and N,N-diethylnerylamine
((Z)-1)1c are key intermediates for the preparation of industrially
important acyclic and cyclic monoterpenes such as linalool,2 gera-
niol,3 citral,4 citronellal,5 l-menthol,6 and liral.7 Previously, we
reported sulfuric acid promoted regioselective cyclization of (Z)-1
to N,N-diethyl b-cyclogeranylamine (2), in contrast, cyclization of
NEt2
a
b
NEt2
(54%)
NEt2
3
1
(91%)
2
α : γ = 20 : 80
3
+
(22%)
c
(E)-1 with BF3ÁOEt2 afforded a 20:80 mixture of N,N-diethyl
a-
O
and
c
-cyclogeranylamine (3) (Scheme 1).8 As a continuation of
Cyclyzation
our studies into the use of 1 in organic syntheses,9 we wondered
whether N,N-diethylgeranylamine N-oxide (4) could behave like
1. Although terpenoid N-oxides are well known as a good substrate
for Meisenheimer rearrangement,10 to our best knowledge, cycliza-
tion involving C–C bond formation as well as C–C bond fission has
not been studied previously. Herein, we report an acid promoted
cyclization of the N-oxide 4 and lipase-catalyzed kinetic resolution
of the odorous cyclized derivative 7.
NEt2
4
Scheme 1. Reagents and conditions: (a) 40% H2SO4, 120 °C, 20 h; (b) BF3ÁOEt2,
AcOH, 30 °C, 6 h; (c) H2O2, MeOH, rt, 48 h, then PtO2, rt, 24 h.
a
N,N-Diethylgeranylamine ((E)-1)11 and N,N-diethylnerylamine
((Z)-1)12 were stereoselectively prepared by a simple, one-step
procedure from myrcene (5) and isoprene (6), respectively
(Scheme 2). Oxidation of (E)-1 with 31% H2O2 followed by addition
of PtO2 to decompose excess oxidizing agent gave the N-oxide 4.
Cyclization of the crude N-oxide 4 was carried out by the following
manner.13 To a colorless solution of the crude N-oxide 4 in H2O was
added 50% H2SO4 aq, then the mixture changed from colorless to
pink. After the acidic reaction mixture was made strongly basic
with NaOH pellets, the mixture gradually separated into pale yel-
low aqueous layer and dark brown organic layer. Interestingly, this
dark brown liquid gave off good fruity odor. The structure of prod-
uct was confirmed as 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in
comparison with alternatively synthetic enone 7.14 Similarly, the
enone 7 was obtained from N,N-diethylnerylamine ((Z)-1) in 55%
yield. Both of regioisomers 1 resulted in the formation of the same
c
5
NEt2
b
(E )-1 from 5 (77%)
(Z )-1 from 6 (86%)
6
O
O
d
NEt2
4
7
(67% from (E)-1)
(55% from (Z)-1)
Scheme 2. Reagents and conditions: (a) Et2NH, Li, 55 °C, 5 h; (b) Et2NH, n-BuLi,
5–65 °C, 13 h; (c) H2O2, MeOH, rt, 48 h, then PtO2, rt, 24 h; (d) (i) H2SO4, H2O, 100 °C,
24 h; (ii) NaOH, H2O, 100 °C, 24 h.
enone 7. This outcome indicated that cyclization progressed
through the same intermediate.
Cyclization of N,N-diethylfarnesylamine (8) was also examined.
The crude N-oxide 9 was obtained by oxidation of 8 with 31% H2O2.
* Corresponding author. Tel./fax: +81 53 478 1148.
E-mail address: tcktaka@ipc.shizuoka.ac.jp (K. Takabe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.001

K. Takabe et al. / Tetrahedron Letters 49 (2008) 6016–6018
6017
O
a
Δ
18
NEt2
NEt2
8
20
19
H+
17
O
slow
b
O
O
NEt2
H+
7
O
9
NEt2 fast
NEt2
10 (33%)
11
12
Scheme 6. Proposed reaction sequence.
Scheme 3. Reagents and conditions: (a) H2O2, MeOH, rt, 48 h, then PtO2, rt, 24 h;
(b) (i) H2SO4, H2O, 100 °C, 24 h; (ii) NaOH, H2O, 100 °C, 24 h.
One-pot operation under the same procedure gave the bicyclic
enone 10 in 33% yield as a single diastereomer (Scheme 3).15
The proposed reaction mechanism for cyclization of the N-oxide
4 is shown in Scheme 4. Acid promoted cyclization of the N-oxide 4
20. Aromatization of the cyclic end group with concomitant regio-
selective migration of one methyl group from the geminal
dimethyl functionality afforded the product 18 (Scheme 6).16 On
the other hand, in the case of
the cyclic enone 7 was formed in 41% yield (Scheme 5). These
results indicate that the cyclization progressed through - and
-cyclogeranylamine N-oxide intermediate 11 not through b-inter-
mediate 17.
a- and c-cyclogeranylamine 11,
formed a mixture of N,N-diethyl
a- and c-cyclogeranylamine N-
oxide (11), which readily protonated to give the cation intermedi-
ate 12. Nucleophilic cyclization of 12 furnished the bicyclic inter-
mediate 13, which was transformed to the keto-enamine
intermediate 14 with C–C bond fission. Hydrolysis and base-cata-
lyzed intramolecular aldol condensation of keto-aldehyde 15 affor-
ded the desired enone 7.
Following experiments have been performed to prove the above
proposed reaction mechanism. The N-oxide 17 derived from
b-cyclogeranylamine 2 was reacted in the same way to cyclization
of the N-oxide 4 to give 1,2,3,4-tetramethylbenzene (18) in 53%
yield through sequential elimination, isomerization, and migration
(Scheme 5). Thermal elimination of 17 gave 1,1-dimethyl-2,3-di-
methylenecyclohexane (19),9b which was isomerized to the diene
a
c
The reactive difference between N-oxide 11 and 17 was illus-
trated by the protonation ability. Terminal and/or trisubstituted
olefin intermediate 11 is better proton acceptor than tetrasubsti-
tuted olefin intermediate 17. Therefore, the N-oxide 11 was easily
protonated to give the cyclized product 7 through the intermediate
12, in contrast, thermal elimination preferentially proceeded in the
case of 17 (Scheme 6).
Cyclization of the terminal olefin 21 and/or internal olefin 22
gave the same ketone 24 in 34–35% yields; therefore, location of
double bond did not affect the reactivity (Scheme 7). In addition,
C–C bond fission proceeded selectively at between b and
c position
to the nitrogen atom. These experiments (Schemes 5 and 7) sup-
port that the cyclization of the N-oxide 4 includes (1) acid pro-
moted cyclization, (2) nucleophilic cyclization of N-oxide, and (3)
selective C–C bond fission as shown in Scheme 4.
O
O
O
H+
NEt2
NEt2
NEt2
4
Since the cyclic enone 7 is strong fruity, odor of the derivatives
from 7 should be interesting. Sodium borohydride reduction of 7
gave the racemic alcohol 25 in 99% yield. Lipase-catalyzed kinetic
resolutions of 25 were carried out using 0.5 equiv of vinyl acetate
in diisopropyl ether at 25 °C. All of lipase tested except M-10 and
Newlase F provided the enantiomerically pure acetate 26 with R
configuration and the recovered alcohol 25 with S configuration
determined by derivation to the Mosher ester.17 Especially, lipase
AK (Pseudomonas fluorescens, Amano Enzyme Co, Ltd) was the best
catalyst to afford (R)-26 in >49.9% yield with excellent E value.18,19
Both enantiomers of the acetate 26 and alcohol 25 were prepared
11
12
O
O
O
H2O
NEt2
O
NEt2
H
13
14
15
O
O
OH-
OH
16
7
O
O
Scheme 4. Proposed reaction mechanism for cyclization of the N-oxide 4.
NEt2
NEt2
21
22
a
a
O
a
a
b
b
O
NEt2
NEt2
NEt2
NEt2
2
3
18
(53%)
17
11
23
O
O
NEt2
O
24
7 (41%)
(34% from 21, 35% from 22)
Scheme 5. Reagents and conditions: (a) H2O2, MeOH, rt, 48 h, then PtO2, rt, 24 h;
(b) (i) H2SO4, H2O, 100 °C, 24 h; (ii) NaOH, H2O, 100 °C, 24 h.
Scheme 7. Reagents and conditions: (a) (i) 40% H2SO4, 100 °C, 24 h; (ii) NaOH, H2O,
100 °C, 24 h.

6018
K. Takabe et al. / Tetrahedron Letters 49 (2008) 6016–6018
S. J. Am. Chem. Soc. 1984, 106, 5208–5217; (c) Tani, K.; Yamagata, T.; Otsuka, S.;
Table 1
Kumobayashi, H.; Akutagawa, S. Org. Synth. 1989, 67, 33–43.
6. (a) Akutagawa, S. Organic Synthesis in Japan: Past, Present, and future: in
Commemoration of the 50th Anniversary of the Society of Synthetic Organic
Chemistry, Japan; Noyori, R. (Ed.), Tokyo Kagaku Dojin, 1992; pp 75–82; (b)
Otsuka, S. Acta Chem. Scand. 1996, 50, 353–360.
7. Kumobayashi, H.; Mitsuhashi, S.; Akutagawa, S.; Ohtsuka, S. Chem. Lett. 1986,
157–160.
8. (a) Takabe, K.; Yamada, T.; Sato, T.; Katagiri, T. Nippon Kagaku Kaishi 1980, 776–
778; (b) Takabe, K.; Yamada, T.; Katagiri, T. Chem. Ind. (London, U.K.) 1980, 13,
540. see also Ref. 9b.
Lipase-catalyzed kinetic resolution of the racemic alcohol 25
AcO
c
25
(R)- (63%)
HO
O
26
(R)-
a
b
+
lipase
9. (a) Takabe, K. Koryo 1983, 139, 41–45; (b) Yamada, T.; Takabe, K. Chem. Lett.
1993, 29–30. See also references cited therein.
HO
10. Albini, A. Synthesis 1993, 263–277. See also references cited therein.
11. Takabe, K.; Katagiri, T.; Tanaka, J.; Fujita, T.; Watanabe, S.; Suga, K. Org. Synth.
1989, 67, 44–47.
7
25 (99%)
d
(S)-26 (51%)
12. Takabe, K.; Yamada, T.; Katagiri, T.; Tanaka, J. Org. Synth. 1989, 67, 48–51.
13. Typical procedure: To
a solution of N,N-diethylgeranylamine ((E)-1, 2.1 g,
25
(S)-
10 mmol, 1.0 equiv)) in methanol (10 mL) was added 31% H2O2 aq (3.3 mL) at
room temperature. The mixture was stirred for 48 h, and then PtO2 (3 mg) was
added to decompose excess oxidizing agent. The reaction mixture was filtrated
through the Celite and washed with MeOH. The filtrate was evaporated under
reduced pressure to give the crude N-oxide 4. To a colorless solution of the
crude N-oxide 4 in H2O was added 50% H2SO4 aq (V/V, 9.8 mL). The mixture
changed from colorless to pink during stirring for 24 h at 100 °C. After cooling to
0 °C, NaOH pellets (10 g) and crushed ice (10 g) were added to the reaction
vessel. Stirred for 24 h at 100 °C, the mixture was gradually separated into pale
yellow aqueous layer and dark brown organic layer. The mixture was quenched
with 10% HCl aq (10 mL). The aqueous layer was extracted with Et2O (3 Â 5 mL).
The organic extracts were concentrated to give the crude enone 7, which was
purified by flash column chromatography (silica gel 60 g, hexanes
only ? hexanes/ethylacetate = 80:20) to give 1-(4,4-dimethylcyclohex-1-
enyl)ethanone (7, 0.96 g, 63%) as a pale yellow liquid: registry number 5773-
37-5; Rf = 0.61 (hexane/AcOEt = 70:30); 1H NMR (300 MHz, CDCl3) d = 6.84
(ddd, J = 5.4, 3.7, 1.4 Hz, 1 H, –CH@C–), 2.29 (s, 3H, CH3CO–), 2.21–2.32 (m, 2 H,
–CH2–), 2.04 (td, J = 4.2, 2.3 Hz, 2H, –CH2–), 1.40 (t, J = 6.5 Hz, 2 H, –CH2–), 0.92
(s, 6H, 2 Â –CH3); 13C NMR (75 MHz, CDCl3) d = 199.24 (C@O), 140.04 (CH),
138.46 (C), 39.89 (CH2), 34.68 (CH2), 28.21 (C), 27.93 (CH3), 25.08 (CH3), 20.64
(CH2).
Entry
Lipase
M-10
Newlase F
A-6
PEG
MY
Conversion (%)
(R)-26 ee (%)
E value
1
2
3
4
5
6
7
8
9
0
0
4.4
4.5
—
—
—
—
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
208
208
221
232
308
344
373
374
738
992
9.7
OF
13.8
30.9
35.4
38.2
38.3
48.9
>49.9
CHIRAZYMEÒ L-2
PSA-30
PS-D
10
11
12
NOVOZYMEÒ
PL
AK
Reagents and conditions: (a) NaBH4, CeCl3Á7H2O, MeOH, 0 °C, 2 h; (b) vinyl acetate
(0.5 equiv), lipase (100 mg/mmol), i-Pr2O, 25 °C; (c) K2CO3, MeOH, 25 °C, 6 h; (d)
Ac2O, Et3N, DMAP, Et2O, rt, 2.5 h.
14. The cyclic enone 7 was prepared from commercially available enone 27 in four
step transformations: Fleming, I.; Pearce, A. J. Chem. Soc., Perkin Trans. 1 1980,
2485–2489.
by standard hydrolysis ((R)-26 ? (R)-25) or acetylation ((S)-
25 ? (S)-26). Interestingly, odor of (S)-isomers 25 and 26 is stron-
ger and more sensory active than those of (R)-isomers, particularly,
(S)-alcohol 25 shows good herbal odor (see Table 1).20
O
O
O
Cl
TMS
H2
PCl5
Na
TMSCl
AlCl3
AcCl
In summary, we have developed acid promoted cyclization of
geranylamine N-oxide (E)-4 followed by base-catalyzed intramo-
lecular aldol condensation afforded the cyclic enone 7 in one-pot
operation. Reduction of 7, which possess strong fruity odor, fol-
lowed by lipase-catalyzed kinetic resolution furnished the acetate
(R)-26 (>49.9% yield, >99% ee) and the recovered herbal alcohol (S)-
25 (>49.9% yield, >99% ee). Further studies focusing on the use of
acid promoted cyclization of N-oxide derivatives are currently
under investigation and will be reported in due course.
28
29
30
(40%)
27
(67%)
(40%)
7
(79%)
.
15. Acid promoted cyclization of farnesyl derivatives generally gave trans-decalyl
derivatives. See: (a) Ohloff, G.; Näf, F.; Decorzant, R.; Thommen, W.; Sundt, E.
Helv. Chim. Acta 1973, 56, 1414–1448; (b) Corbier, B.; Ehret, C.; Giraudi, E.;
Pelerin, G. Dev. Food Sci. 1988, 18, 483–494.
16. Valla, A.; Andriamialisoa, Z.; Valla, B.; Labia, R.; Le Guillou, R.; Dufosse, L.;
Cartier, D. Eur. J. Org. Chem. 2007, 711–715.
17. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
18. The enantiomeric ratio E is generally accepted as an adequate parameter to
quantify the enantioselectivity in biochemical kinetic resolutions: Chen, C. S.;
Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–
7299.
19. Enantioselectivities of the acetate 26 were determined by chiral capillary GC
using InertCap CHIRAMIX. (130–180 °C, 2 °C/min, Rt: 20.953 min for (S)-26,
22.008 min for (R)-26.
Acknowledgments
We gratefully acknowledge Takasago International Corporation
for odor evaluations. We would like to thank Amano Enzyme Co.,
Ltd, Meito Sangyo Co., Novo Nordisk, and Roche Molecular
Biochemicals for a generous gift of enzymes.
20. We further synthesized ester derivatives 31 using DCC coupling agent. All of
ester derivatives possessed sweet odor; however, odor of 31 was weaker than
that of 26.
References and notes
HO
R
O
1. (a) Takabe, K.; Katagiri, T.; Tanaka, J. Bull. Chem. Soc. Jpn. 1973, 46, 222–225; (b)
Fujita, T.; Suga, K.; Watanabe, S. Chem. Ind. (London, U.K.) 1973, 231–232; (c)
Takabe, K.; Katagiri, T.; Tanaka, J. Tetrahedron Lett. 1972, 13, 4009–4012.
2. Takabe, K.; Katagiri, T.; Tanaka, J. Tetrahedron Lett. 1975, 3005–3006.
3. Takabe, K.; Katagiri, T.; Tanaka, J. Chem. Lett. 1977, 1025–1026.
DCC
DMAP
O
+
RCO2H
CH2Cl2
0 o
C
4. Takabe, K.; Yamada, T.; Katagiri, T. Chem. Lett. 1982, 1987–1988.
25
R = Et (85%), Pr (81%),
31
5. (a) Tani, K.; Yamagata, T.; Otsuka, S.; Akutagawa, S.; Kumobayashi, H.;
Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R. J. Chem. Soc., Chem.
Commun. 1982, 600–601; (b) Tani, K.; Yamagata, T.; Akutagawa, S.;
Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka,
i-Pr (94%), (R)-sec-Bu (98%)