Palladium(ii) acetate mediated oxidative cyclization of ω-unsaturated α-cyano ketones for facile construction of methylenecyclohexane ring system

Article abstract of DOI:10.1039/c2ob25161b

A highly efficient annulative approach towards the construction of the structurally attractive methylenecyclohexane ring was developed through a convenient 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2- cycloalkenones followed by a Pd(ii)-mediated oxidative cyclization of the resulting ω-unsaturated α-cyano ketones. Based on this newly developed protocol, polycyclic adducts bearing various ring sizes and substitutions can be prepared in moderate to high yields.

Full text of DOI:10.1039/c2ob25161b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4609
www.rsc.org/obc
PAPER
Palladium(II) acetate mediated oxidative cyclization of ω-unsaturated α-cyano
ketones for facile construction of methylenecyclohexane ring system†
Min-Tsang Hsieh,*a Kak-Shan Shia,b Hsing-Jang Liuc and Sheng-Chu Kuo*d
Received 20th January 2012, Accepted 10th April 2012
DOI: 10.1039/c2ob25161b
A highly efficient annulative approach towards the construction of the structurally attractive
methylenecyclohexane ring was developed through a convenient 1,4-addition of 4-pentenylmagnesium
bromide to 2-cyano-2-cycloalkenones followed by a Pd(II)-mediated oxidative cyclization of the resulting
ω-unsaturated α-cyano ketones. Based on this newly developed protocol, polycyclic adducts bearing
various ring sizes and substitutions can be prepared in moderate to high yields.
Cyclic motifs containing a methylene appendage, such as
methylenecyclohexane and methylenecyclopentane systems, are
found in high abundance in naturally occurring products,1 the
construction of which is typically a rather complex process.2
During the past decade, our long-term efforts to discover a facile
annulation process have developed several convenient synthetic
protocols,3 part of which has been employed as a key operation
for the synthesis of natural products.4 Our previous research not
only showed that the α-cyano moiety could serve as a versatile
directing group in facilitating the methylenecyclopentane annula-
tive process,3a but also disclosed the unique nature of the
α-cyano group in a hitherto unknown autoxidative annulation as
shown in Scheme 1.3c
more powerful directing group than the ester functionality to
facilitate the methylenecyclohexane annulative process. As such,
being an extension of our previous work, the objective of the fol-
lowing investigation is to develop a facile methylenecyclohexane
annulative approach of the title system containing an α-cyano
moiety as an activating group instead.
Our investigation began with the preparation of structurally
diverse 2-cyano-2-cycloalkenones as substrates, via a two-step
sequence, involving Thorpe–Ziegler condensation6 of the corre-
sponding alkanedinitriles followed by phenylselenenylation-oxi-
dative elimination or a four-step synthetic sequence, involving
formylation, isoxazole formation and its subsequent rearrange-
ment,7 and phenylselenenylation-oxidative elimination.8 2-
Cyano-2-cycloalkenones thus formed, except 7 and 9, are
Regarding transition metal catalyzed methylenecyclohexane
annulation,5 it has been well documented that a quaternary
center adjacent to the ester functional group (Scheme 2, eqn (1))
and the vinyl center β to the silyl enol ether moiety (Scheme 2,
eqn (2)) would completely hamper the occurrence of a methyle-
necyclohexane annulative process, presumably due to the steric
congestion encountered during the carbon–carbon bond
formation.
As demonstrated previously,3 the cyano group represented a
vital functionality in our previous intramolecular annulative
cases. We thus speculated that the cyano group might serve a
Scheme 1
aChinese Medicinal Research and Development Center, China Medical
University Hospital, 2 Yude Road, Taichung 40447, Taiwan, R.O.C.
E-mail: d917410@alumni.nthu.edu.tw; Tel: +886-4-22053366 ext: 5605
bInstitute of Biotechnology and Pharmaceutical Research, National
Health Research Institutes, Miaoli County 35053, Taiwan, R.O.C.
cDepartment of Chemistry, National Tsing Hua University, Hsinchu,
Taiwan 30013, R.O.C.
dGraduate Institute of Pharmaceutical Chemistry, China Medical
University, Taiwan, R.O.C.
†Electronic supplementary information (ESI) available: 1H and 13C
spectra for all new compounds and X-ray crystallographic analysis of
24a13 and 2814. CCDC 851795 and 851796. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2ob25161b
Scheme 2
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4609–4617 | 4609

View Article Online
Table 1 1,4-Addition of 4-pentenylmagnesium bromide to 2-cyano-2-
cycloalkenones
unstable under air atmosphere and must be freshly prepared and
used for subsequent 1,4-addition. Sterically uncongested 2-
cyano-2-cycloalkenones 1–9 are highly reactive Michael accep-
tors and able to undergo 1,4-addition with Grignard reagents
without any assistance with metal catalysts (e.g., Mn(II) and
Cu(I)).9–11 For the present studies, an array of structurally diverse
ω-unsaturated α-cyano ketones 12–22, as compiled in Table 1,
were readily provided in moderate to good yields by treating sub-
strates 1–11 with excess freshly prepared 4-pentenylmagnesium
bromide (1.5 equiv.) at −78 °C. In most cases, the catalyst-free
conjugate addition took place effectively within 2 h, with the
exception that compounds 10 and 11 required an addition of a
catalytic amount of CuI–Me2S12 complex (0.5 equiv.) to
promote the 1,4-addition.
With these ω-unsaturated α-cyano ketones in hand, the methylene-
cyclohexane annulation of the title system was then examined
under catalysis with Pd(OAc)2. As expected, the annulation reac-
tion was found to be remarkably facile under mild reaction con-
ditions. Results are listed in Table 2. As a typical example, upon
treatment with 1 equiv. of Pd(OAc)2 in THF at ambient tempera-
ture for 20 min, cyano ketone 13 underwent intramolecular annu-
lation smoothly in a regio- and stereocontrol manner to afford
bicyclic adduct 24 as a sole product in 82% yield. Similarly, sub-
strates 14–22, irrespective of the parent ring size, could readily
undergo cyclization to afford products 25–33 in fair to good
yields (59–86%). It is noteworthy that α-cyano ketone 22
(Table 2; entry 11), in sharp contrast to its α-ester counterpart
(Scheme 2, eqn (1)), could undergo annulation smoothly to give
bicyclic product 33 in 68% yield. This distinct difference in reac-
tion activity again demonstrates that the α-cyano group appears
superior to the α-ester in serving as an auxiliary functionality for
above annulation.
Substrate
Product
Yielda (%)
71 (cis : trans = 1 : 5.2)b
76 (cis : trans = 1 : 1.8)b
73 (cis : trans = 1 : 2.8)b
75 (cis : trans = 1 : 4)b
75 (cis : trans = 1 : 3)b
73 (cis : trans = 1 : 1.3)b
76 (cis : trans = 1 : 1.2)b
The spectral data of 24 are in full agreement with the assigned
structure and its relative configuration was confirmed by a single
crystal X-ray analysis of its corresponding hydrazone derivative
24a,13 readily produced by treating 24 with 2,4-dinitrophenyl
hydrazine and a catalytic amount of p-TSA in refluxing toluene
(Scheme 3). In addition, the structure of product 28 was deter-
mined unambiguously by an X-ray analysis,14 further implying
that other 6/6 fused bicyclic ketones 29a and 30–33 are very
likely to possess a cis ring junction as well. On the other hand,
the stereochemistry of macrobicyclic adducts 25–27 remains
to be determined in that all efforts to grow desirable crystals for
X-ray analyses turned out to be fruitless. Intriguingly, as α-cyano
ketone 12 was employed as a substrate (Table 2; entry 1), enone
product 23 was isolated as a major component instead of the
anticipated 5/6 fused adduct, indicating that the oxidative elimi-
nation might occur rapidly on the cyclopentanone core.
Similar results are also observed with substrate 18, in which
an equal amount of bicyclic product 29a and enone 29b were
obtained. A possible explanation for these could be that for sub-
strates 12 and 18, the carbon center β to both carbonyl and
cyano groups is somehow activated, rendering the initial oxo-
π-allyl palladium(II) complex to undergo oxidative elimination
more easily than the regular cyclization process for expected
products.
79 (cis : trans = 1 : 1.1)b
69 (cis : trans = 1 : 1.5)b,c
82 (cis : trans = 1 : 1.5)b,d
71 (cis : trans = 1 : 1.7)b,d
a Yields refer to isolated, chromatographically pure products. b The ratio
of the keto : keto diastereomeric forms. c The stereochemistry was
confirmed by NOE experiments. d The reactions were performed at
−40 °C in the presence of CuI–Me2S (0.5 equiv.) for 3 h.
chosen as a co-oxidant to regenerate the active Pd(II) species so
that the loading of Pd(OAc)2 could be dramatically reduced to
0.25 equiv.15 The cyclization did occur to afford the expected
products, but yields were lower than those of stoichiometric con-
ditions by 10–15% as indicated in Table 3.
In light of the high price of palladium reagents, a more econ-
omic alternative for the annulation reaction of the title system
was then explored. Accordingly, the inexpensive Cu(OAc)2 was
4610 | Org. Biomol. Chem., 2012, 10, 4609–4617
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Palladium(II) acetate mediated methylenecyclohexane
annulation process
Entry
1
Substrate
Producta (% Yield)
Time
12
10 min
Scheme 3
Table 3 Palladium(II) acetate mediated methylenecyclohexane
annulation process with a co-oxidant copper(II) acetate
2
13
20 min
3
4
14
15
18 min
25 min
Substrate
Time (h)
Product
Yielda (%)
12
13
14
15
16
19
3.5
7
7.5
8.5
10
8
23
24
25
26
27
30
65
67
73
69
72
63
5
16
20 min
a Yields refer to isolated, chromatographically pure products.
6
7
17
18
45 min
2 h
Scheme 4
metal could be further reduced to 0.1 equiv., but yields remained
inferior to those subject to the stoichiometric amount
(Scheme 4). Other catalytic systems combining milder oxidizing
agents, including benzoquinone and copper chloride, were also
explored, but all resulted in lower yields relative to the current
reaction system.16d–f
8
9
19
20
25 min
3 h
As illustrated in Scheme 5, the annulative process is proposed
to proceed in a 6-exo-trig fashion, wherein the olefinic terminus
first coordinates with Pd(II) to form oxo-π-allyl palladium(II)
complex A followed by intramolecular insertion to generate
complex B and finally, β-elimination takes place to provide
cyclic products and Pd(0), which can be re-oxidized by
Cu(OAc)2 to Pd(II) species to initiate the catalytic cycle again.
Adducts thus obtained in Table 2 were further applied to
reductive decyanation process according to established proto-
cols.17,18 Treatment with lithium naphthalenide (LN) followed
by capturing the enolates with appropriate electrophiles resulted
in the formation of the corresponding decyanated products in
moderate to good yields. As shown in Table 4, the angular cyano
group in 24, 25 and 27 was protonated to give rise to products
34–36 with concomitant transposition of the exocyclic olefin to
the fully conjugated position. Alternatively, the reductive decya-
nation alkylation could take place in a stereoselective manner to
10
11
21
22
5 h
6.5 h
a Yields refer to isolated, chromatographically pure products. b The cis
configuration is tentatively assigned based on other structurally related
products 24 and 28.
Nevertheless, when the above catalytic systems were carried
out under one atmosphere of oxygen,16a–c the amount of Pd
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4609–4617 | 4611

View Article Online
Table 4 LN induced reductive decyanation of 24, 25 and 27
Substrate
Electrophile
H2O
Time
Product/Yielda (%)
24
15 min
25
27
H2O
H2O
15 min
15 min
Scheme 5
give a single trans adduct with the exo double bond intact as
demonstrated by treating substrate 24 with LN and benzyl
bromide.
24
BnBr
6 h
In conclusion, an efficient methylenecyclohexane annulative
process has been developed, which involves a highly facile 1,4-
addition of 4-pentenylmagnesium bromide to 2-cyano-2-
cycloalkenones followed by a Pd(II)-mediated cyclization of the
resulting ω-unsaturated α-cyano ketones to give various bicyclic
products with an exocyclic double bond in a stereo- and regio-
selective manner.
a Yields refer to isolated, chromatographically pure products. b The trans
configuration is proposed on the basis of NOE experiment.
2-Oxo-5-pent-4-enylcyclopentanecarbonitrile
(12). Freshly
Experimental
prepared 4-pentenylmagnesium bromide solution (8.0 mL,
0.65 M in THF, 5.16 mmol) was added dropwise to a stirred sol-
ution of compound 1 (0.368 g, 3.44 mmol) in THF (10 mL) at
−78 °C. The resulting mixture was stirred for another 2 h at the
same temperature. Saturated NH4Cl solution (8 mL) was added
to quench the reaction. The aqueous layer was separated and
extracted with EA (2 × 15 mL). The combined organic extracts
were washed with brine, dried over MgSO4, filtered and concen-
trated to give the crude residue, which was purified by flash
chromatography on silical gel with EtOAc–n-hexane (1 : 5) to
afford compound 12 [432 mg, 71% yield, a mixture of keto
isomers in a ratio of 1 : 5.2 (cis : trans)] as a yellow oil.
General
All reactions were performed under an atmosphere of argon or
nitrogen unless otherwise stated. All solvents were dried prior to
use and reagents were employed as revived. Analytical thin layer
chromatography was performed on SiO2 60 F-254 plates and
flash column chromatography was carried out using SiO2 60
(particle size 0.040–0.055 mm, 230–400 mesh), both of which
are available from E. Merck. Visualization was performed under
UV irradiation at 254 nm followed by staining with vanillin
(60 g of vanillin in 1 L of 95% ethanol containing 10 mL of
conc. H2SO4) and charring by heat gun. Fourier transform infra-
red spectra (IR) were recorded on Bomen MR-100 and expressed
IR (CH2Cl2 cast, cm−1) ν max 2925, 2854, 2236, 1749; H
1
NMR (CDCl3, 600 MHz) major isomer: δ 5.81–5.74 (m, 1H),
5.03–4.96 (m, 2H), 2.81 (d, J = 12.1 Hz, 1H), 2.49 (dd, J =
18.8, 8.2 Hz, 1H), 2.45–2.25 (m, 3H), 2.12–2.08 (m, 2H),
1.79–1.75 (m, 1H), 1.58–1.48 (m, 4H); minor isomer: δ 3.32 (s,
1H); 13C NMR (CDCl3, 150 MHz) major isomer: δ 206.5 (C),
137.8 (CH), 116.4 (C), 115.3 (CH2), 46.3 (CH), 42.6 (CH), 37.2
(CH2), 33.8 (CH2), 33.4 (CH2), 27.6 (CH2), 26.0 (CH2); HRMS
(EI) calcd for C11H15NO: 177.1154; found: 177.1159.
in cm−1 1H and 13C NMR spectra were recorded on Bruker
.
Avance EX 400 FT NMR or Bruker DMX-600. Chloroform-d
was used as the solvent and TMS (δ = 0.00 ppm) as an internal
standard. Chemical shifts are reported as δ values in ppm as
referenced to TMS. Multiplicities are recorded as s (singlet),
d (doublet), t (triplet), q (quartet), quint (quintet), sext (sextet),
sept (septet), dd (doublet of doublet), dt (doublet of triplet), br
(broadened), m (multiplet). Coupling constants (J) are expressed
in Hz. HRMS were measured by JEOL JMS-HX110 spec-
trometer and spectral data were recorded as m/z values.
2-Oxo-6-pent-4-enylcyclohexanecarbonitrile (13). A mixture
of keto isomers in a ratio of 1 : 1.8 (cis : trans) was obtained as a
yellow oil (76% yield).
General procedure for 1,4-addition in the synthesis of com-
pounds 12–22. The general procedure is illustrated immediately
below with compound 12 as a specific example.
IR (CH2Cl2 cast, cm−1) ν max 2954, 2825, 2238, 1710, 1460;
1H NMR (CDCl3, 600 MHz) major isomer: δ 5.79–5.70 (m,
1H), 5.00–4.93 (m, 2H), 3.23 (d, J = 11.6 Hz, 1H), 2.57–2.54
4612 | Org. Biomol. Chem., 2012, 10, 4609–4617
This journal is © The Royal Society of Chemistry 2012

View Article Online
(m, 1H), 2.27 (dt, J = 14.4, 5.9 Hz, 1H), 2.12–1.92 (m, 4H),
1.81 (m, 2H), 1.53 (m, 5H), minor isomer: δ 3.45 (d, J = 3.4 Hz,
1H), 2.71–2.68 (m, 1H), 2.39–2.34 (m, 1H); 13C NMR (CDCl3,
150 MHz) major isomer: δ 200.3 (C), 137.9 (CH), 115.9 (C),
115.1 (CH2), 49.9 (CH), 43.2 (CH), 40.4 (CH2), 34.2 (CH2),
33.4 (CH2), 29.4 (CH2), 25.3 (CH2), 24.9 (CH2), minor isomer:
δ 201.3 (C), 137.8 (CH), 115.6 (C), 115.1 (CH2), 47.9 (CH),
42.0 (CH), 38.9 (CH2), 33.3 (CH2), 31.6 (CH2), 27.4 (CH2),
25.7 (CH2), 24.7 (CH2); HRMS (EI) calcd for C12H17NO:
191.1310; found: 191.1307.
IR (CH2Cl2 cast, cm−1) ν max 2953, 2248, 1718, 1640;
1H NMR (CDCl3, 600 MHz): δ 5.77–5.73 (m, 1H), 5.02–4.92
(m, 2H), 3.50–3.34 (m, 1H), 2.53–2.48 (m, 1H), 2.41–2.30 (m,
1H), 2.10 (m, 3H), 1.74–1.60 (m, 3H), 1.50–1.34 (m, 4H),
1.07–0.99 (m, 3H); 13C NMR (CDCl3, 150 MHz) major isomer:
δ 200.7 (C), 137.8 (CH), 115.7 (C), 115.2 (CH2), 47.6 (CH),
45.4 (CH), 40.3 (CH2), 33.4 (CH2), 33.2 (CH), 29.9 (CH2), 25.5
(CH2), 22.2 (CH2), 18.5 (CH3), minor isomer: δ 201.5 (C),
137.7 (CH), 116.4 (C), 115.2 (CH2), 47.3 (CH), 38.0 (CH2),
32.1 (CH), 18.3 (CH3); HRMS (EI) calcd for C13H19NO:
205.1467; found: 205.1468.
2-Oxo-7-pent-4-enylcycloheptanecarbonitrile (14). A mixture
of keto isomers in a ratio of 1 : 2.8 (cis : trans) was obtained as a
yellow oil (73% yield).
5,5-Dimethyl-2-oxo-6-pent-4-enylcyclohex-3-enecarbonitrile (18).
A mixture of keto isomers in a ratio of 1 : 1.2 (cis : trans) was
obtained as a yellow oil (76% yield).
IR (CH2Cl2 cast, cm−1) ν max 2935, 2863, 2236, 1709, 1451;
1H NMR (CDCl3, 600 MHz) major isomer: δ 5.79–5.72 (m,
1H), 5.01–4.94 (m, 2H), 3.61 (d, J = 3.1 Hz, 1H), 2.74–2.69 (m,
1H), 2.58–2.52 (m, 1H), 2.06 (m, 2H), 1.97–1.84 (m, 4H),
1.65–1.59 (m, 2H), 1.49–1.39 (m, 5H), minor isomer: 3.45 (d,
J = 8.4 Hz, 1H), 2.81–2.77 (m, 1H); 13C NMR (CDCl3,
150 MHz) major isomer: δ 203.3 (C), 137.9 (CH), 116.3 (C),
115.1 (CH2), 50.1 (CH), 42.3 (CH2), 39.9 (CH), 33.6 (CH2),
33.3 (CH2 × 2), 26.3 (CH2), 22.7 (CH2), 26.0 (CH2), minor
isomer: 137.9 (CH), 49.8 (CH), 42.0 (CH2), 39.3 (CH), 32.4
(CH2), 25.9 (CH2), 25.6 (CH2), 23.9 (CH2); HRMS (EI) calcd
for C13H19NO: 205.1467; found: 205.1468.
IR (CH2Cl2 cast, cm−1) ν max 2943, 2862, 2246, 1694, 1468;
1H NMR (CDCl3, 600 MHz) major isomer: δ 6.69 (d, J = 10.2
Hz, 1H), 5.92 (d, J = 10.2 Hz, 1H), 5.80–5.74 (m, 1H),
5.03–4.96 (m, 2H), 3.45 (d, J = 13.2 Hz, 1H), 2.11–2.07 (m,
2H), 2.05–1.97 (m, 1H), 1.90–1.83 (m, 1H), 1.68–1.41 (m, 3H),
1.25 (s, 3H), 1.18 (s, 3H), minor isomer: δ 6.72 (d, J = 10.2 Hz,
1H), 5.96 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 4.8 Hz, 1H);
13C NMR (CDCl3, 150 MHz) major isomer: δ 189.3 (C), 161.3
(CH), 137.9 (CH), 124.3 (CH), 116.6 (C), 115.2 (CH2), 46.2
(CH), 43.9 (CH), 37.2 (C), 33.8 (CH2), 29.8 (CH2), 27.6 (CH3),
27.1 (CH2), 19.8 (CH3), minor isomer: δ 188.6 (C), 162.2 (CH),
137.7 (CH), 124.2 (CH), 116.2 (C), 115.4 (CH2), 44.6 (CH),
36.6 (C), 33.4 (CH2), 28.5 (CH2), 26.5 (CH2); HRMS (EI) calcd
for C14H19NO: 217.1467; found: 217.1467.
2-Oxo-8-pent-4-enylcyclooctanecarbonitrile (15). A mixture
of keto isomers in a ratio of 1 : 4 (cis : trans) was obtained as a
yellow oil (75% yield).
4,4-Dimethyl-2-oxo-6-pent-4-enylcyclohexanecarbonitrile (19).
A mixture of keto isomers in a ratio of 1 : 1.1 (cis : trans) was
obtained as a yellow oil (79% yield).
IR (CH2Cl2 cast, cm−1) ν max 2933, 2860, 2239, 1708, 1448;
1H NMR (CDCl3, 600 MHz) major isomer: δ 5.79–5.75 (m,
1H), 5.02–4.95 (m, 2H), 3.53 (d, J = 3.5 Hz, 1H), 2.58–2.51 (m,
2H), 2.41–2.38 (m, 1H), 2.09 (m, 2H), 1.97–1.87 (m, 2H),
1.80–1.74 (m, 2H), 1.62–1.43 (m, 6H), 1.35–1.31 (m, 1H),
1.22–1.18 (m, 1H), minor isomer: 3.51 (d, J = 10.5 Hz, 1H);
13C NMR (CDCl3, 150 MHz): δ 206.2 (C), 137.9 (CH), 115.5
(C), 115.2 (CH2), 50.5 (CH), 40.0 (CH2), 38.0 (CH), 34.4
(CH2), 33.4 (CH2), 31.2 (CH2), 27.7 (CH2), 26.4 (CH2), 26.2
(CH2), 23.9 (CH2); HRMS (EI) calcd for C14H21NO: 219.1623;
found: 219.1618.
1
IR (CH2Cl2 cast, cm−1) ν max 2241, 1715, 1642; H NMR
(CDCl3, 600 MHz) major isomer: δ 5.79–5.75 (m, 1H),
5.03–4.96 (m, 2H), 3.14 (d, J = 12.2, 1H), 2.28–2.26 (m, 1H),
2.2–2.18 (m, 1H), 2.16–2.02 (m, 2H), 1.82–1.76 (m, 2H), 1.68
(m, 1H), 1.58–1.49 (m, 3H), 1.43–1.37 (m, 1H), 1.11–1.06 (m,
3H), 0.93–0.88 (m, 3H); minor isomer: δ 2.76–0.272 (m, 1H);
13C NMR (CDCl3, 150 MHz) major isomer: δ 200.0 (C), 137.8
(CH), 115.9 (C), 115.1 (CH2), 53.3 (CH2), 49.5 (CH), 43.2
(CH2), 38.7 (CH), 35.3 (C), 34.5 (CH2), 33.4 (CH2), 31.7 (CH3),
25.6 (CH2), 25.3 (CH3) minor isomer: δ 137.9 (CH), 115.0
(CH2), 48.5 (CH2), 37.8 (CH2), 31.2 (CH3), 29.2 (CH2), 26.7
(CH2), 26.6 (CH3), 25.3 (CH2); HRMS (EI) calcd for
C14H21NO: 219.1623; found: 219.1615.
2-Oxo-12-pent-4-enylcyclododecanecarbonitrile (16). A mixture
of keto isomers in a ratio of 1 : 3 (cis : trans) was obtained as a
yellow oil (75% yield).
IR (CH2Cl2 cast, cm−1) ν max 2963, 2236, 1709, 1641, 1457;
1H NMR (CDCl3, 600 MHz): δ 5.83–5.72 (m, 1H), 5.04–4.97
(m, 2H), 3.68–3.66 (m, 1H), 2.89–2.80 (m, 1H), 2.47–2.40 (m,
1H), 2.13 (m, 4H), 2.03–1.98 (m, 2H), 1.71–1.65 (m, 2H),
1.57–1.51 (m, 3H), 1.39–1.19 (m, 12H); 13C NMR (CDCl3,
150 MHz): δ 201.6 (C), 137.9 (CH), 115.7 (C), 115.2 (CH2),
49.6 (CH), 37.6 (CH2), 37.5 (CH), 33.5 (CH2), 31.7 (CH2), 27.9
(CH2), 26.5 (CH2), 26.0 (CH2), 24.3 (CH2), 23.5 (CH2), 23.4
(CH2), 22.9 (CH2), 22.5 (CH2), 21.1 (CH2); HRMS (EI) calcd
for C18H29NO: 275.2249; found: 275.2252.
(3aS*,7aR*)-Octahydro-3a-methyl-6-oxo-4-(pent-4-enyl) ben-
zofuran-5-carbonitrile (20). A mixture of keto isomers in a ratio
of 1 : 1.5 (cis : trans) was obtained as a yellow oil (69% yield).
IR (CH2Cl2 cast, cm−1) ν max 2938, 2241, 1712, 1638, 1458;
1H NMR (CDCl3, 600 MHz) major isomer: δ 5.78–5.74 (m,
1H), 5.01–4.96 (m, 2H), 3.85–3.80 (m, 2H), 3.75–3.73 (m, 1H),
3.41 (d, J = 12.7 Hz, 1H), 2.76 (dd, J = 15.5, 4.3 Hz, 1H), 2.55
(dd, J = 15.5, 4.3 Hz, 1H), 2.09–1.99 (m, 6H), 1.87–1.84 (m,
1H), 1.78–1.68 (m, 2H), 1.63–1.46 (m, 4H), 1.12 (s, 3H), minor
isomer: δ 3.43 (d, J = 4.2 Hz, 1H), 1.29 (s, 3H); 13C NMR
(CDCl3, 150 MHz) major isomer: δ 198.3 (C), 137.8 (CH),
115.9 (C), 115.3 (CH2), 84.8 (CH), 64.7 (CH2), 53.6 (C), 45.7
(CH), 42.3 (CH), 40.4 (CH2), 37.4 (CH2), 33.7 (CH2), 30.8
3-Methyl-6-oxo-2-pent-4-enylcyclohexanecarbonitrile (17). A
mixture of keto isomers in a ratio of 1 : 1.3 (cis : trans) was
obtained as a yellow oil (73% yield).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4609–4617 | 4613

View Article Online
(4aS*,8aR*)-4-Methylene-5-oxooctahydronaphthalene-4a-car-
bonitrile (24). Pd(OAc)2 (105 mg, 0.47 mmol) was added to a
solution of compound 13 (89 mg, 0.47 mmol) in THF (5 mL) at
room temperature. The resulting mixture was stirred at the same
temperature for 20 min. Silica gel (2g) was added and the
mixture was concentrated to give crude residue which was
purified by flash chromatography on silica gel with EtOAc–n-
hexane (1 : 5) to afford compound 24 (63 mg, 82% yield) as a
colorless oil.
(CH2), 28.5 (CH2), 16.0 (CH3), minor isomer: δ 199.2 (C),
137.6 (CH), 115.9 (C), 115.4 (CH2), 85.5 (CH), 65.0 (CH2),
42.0 (CH), 39.3 (CH2), 27.8 (CH2), 26.2 (CH2), 17.9 (CH3);
HRMS (EI) calcd for C15H21NO2: 247.1572; found: 247.1573.
General procedure for 1,4-addition in the synthesis of com-
pounds 21 and 22. The general procedure is illustrated immedi-
ately below with compound 21 as a specific example.
2-Methyl-6-oxo-2-pent-4-enylcyclohexanecarbonitrile (21).
Freshly prepared 4-pentenylmagnesium bromide solution
(4.2 mL, 0.65 M in THF, 2.73 mmol) was added to a solution of
copper(I) iodide dimethyl sulfide complex (0.229 g, 0.91 mmol)
in anhydrous THF (5 mL) dropwise at −78 °C. The resulting
mixture was stirred at the same temperature for 30 min, after
which time a solution of compound 21 (0.25 g, 1.82 mmol) in
anhydrous THF (5 mL) was introduced dropwise. Then the
resulting mixture was warmed and stirred at −40 °C for 3 h.
H2O (5 mL) and saturated NH4Cl solution (5 mL) was added to
quench the reaction. The aqueous layer was separated and
extracted with EA (3 × 15 mL). The combined organic extracts
were washed with brine, dried over MgSO4, filtered and concen-
trated to give the crude residue, which was purified by flash
chromatography on silica gel with EtOAc–n-hexane (1 : 9) to
afford compound 21 [0.331 g, 79% yield, a mixture of keto
isomers in a ratio of 1 : 1.5 (cis : trans)] as a colorless oil.
IR (CH2Cl2 cast, cm−1) ν max 2967, 2866, 2233, 1730, 1645;
1H NMR (CDCl3, 600 MHz): δ 5.06 (s, 1H), 5.04 (s, 1H), 2.75
(ddd, J = 14.4, 10.4, 6.7 Hz, 1H), 2.38–2.43 (m, 1H), 2.28–2.34
(m, 2H), 2.18–2.14 (m, 2H), 1.92–1.85 (m, 2H), 1.72–1.67 (m,
2H), 1.64–1.59 (m, 1H), 1.43–1.27 (m, 2H); 13C NMR (CDCl3,
150 MHz): δ 201.9 (C), 140.7 (C), 118.6 (C), 114.9 (CH2), 58.7
(C), 46.2 (CH), 39.2 (CH2), 31.9 (CH2), 27.4 (CH2), 27.2 (CH2),
24.6 (CH2), 23.1 (CH2); HRMS (EI) calcd for C12H15NO:
189.1154; found: 189.1155.
5-Oxo-2-pent-4-enylcyclopent-1-enecarbonitrile
(23). Com-
pound 23 was obtained as a yellow oil (70% yield).
IR (CH2Cl2 cast, cm−1) ν max 3028, 2947, 2233, 1685, 1637;
1H NMR (CDCl3, 600 MHz): δ 5.79–5.72 (m, 1H), 5.06–5.01
(m, 2H), 2.78–2.74 (m, 2H), 2.71–2.68 (m, 2H), 2.54–2.52 (m,
2H), 2.13 (dd, J = 14.1, 7.0 Hz, 2H), 1.77–1.72 (m, 2H); 13C
NMR (CDCl3, 150 MHz): δ 201.3 (C), 193.3 (C), 136.7 (CH2),
117.3 (C), 116.2 (CH2), 111.9 (C), 34.6 (CH2), 33.2 (CH2), 32.9
(CH2), 31.1 (CH2), 26.3 (CH2); HRMS (EI) calcd for
C11H13NO: 175.0997; found: 175.0993.
IR (CH2Cl2 cast, cm−1) ν max 2938, 2241, 1712, 1643, 1458;
1H NMR (CDCl3, 600 MHz) major isomer: δ 5.78–5.72 (m,
1H), 5.01–4.93 (m, 2H), 3.30 (s, 1H), 2.58–2.51 (m, 1H),
2.30–2.23 (m, 1H), 2.06–1.62 (m, 6H), 1.53–1.24 (m, 4H), 1.02
(s, 3H), minor isomer: δ 3.36 (s, 1H), 1.12 (s, 3H); 13C NMR
(CDCl3, 150 MHz) major isomer: δ 201.1 (C), 137.9 (CH),
115.3 (CH2), 115.2 (C), 53.9 (CH), 42.6 (C), 40.9 (CH2), 39.8
(CH2), 34.5 (CH2), 33.8 (CH2), 22.7 (CH2), 21.7 (CH2), 21.0
(CH3), minor isomer: δ 55.5 (CH), 39.5 (CH2), 33.6 (CH2), 25.0
(CH3), 22.3 (CH2), 21.5 (CH2); HRMS (EI) calcd for
C13H19NO: 205.1467; found: 205.1469.
(4aS*,9aR*)-4-Methylene-5-oxodecahydrobenzocycloheptene-
4a-carbonitrile (25). Compound 25 was obtained as a yellow oil
(86% yield).
IR (CH2Cl2 cast, cm−1) ν max 2935, 2860, 2235, 1712, 1645,
1
1450; H NMR (CDCl3, 600 MHz): δ 4.94 (d, J = 1.8 Hz, 1H),
4.47 (d, J = 1.2 Hz, 1H), 2.80 (dt, J = 11.6, 3.9 Hz, 1H),
2.58–2.54 (m, 1H), 2.43–2.35 (m, 2H), 2.02–1.98 (m, 2H),
1.91–1.88 (m, 1H), 1.85–1.82 (m, 1H), 1.79–1.75 (m, 2H),
1.71–1.67 (m, 1H), 1.62–1.43 (m, 4H); 13C NMR (CDCl3,
150 MHz): δ 206.5 (C), 143.6 (C), 117.4 (C), 111.1 (CH2), 63.9
(C), 45.1 (CH), 40.6 (CH2), 33.5 (CH2), 32.4 (CH2), 30.7 (CH2),
28.1 (CH2), 26.7 (CH2), 20.2 (CH2); HRMS (EI) calcd for
C13H17NO: 203.1310; found: 203.1308.
5-Isopropyl-2-methyl-6-oxo-2-(pent-4-enyl) cyclohexanecarbo-
nitrile (22). A mixture of keto isomers in a ratio of 1 : 1.2 (cis :
trans) was obtained as a yellow oil (76% yield).
1
IR (CH2Cl2 cast, cm−1) ν max 2963, 2875, 2241, 1704; H
NMR (CDCl3, 600 MHz) major isomer: δ 5.76–5.69 (m, 1H),
5.00–4.92 (m, 2H), 3.37 (s, 1H), 2.34–2.31 (m, 1H), 2.07–2.00
(m, 1H), 1.98–1.89 (m, 3H), 1.72–1.66 (m, 1H), 1.53–1.31 (m,
5H), 1.19 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz,
3H), minor isomer: δ 3.26 (s, 1H), 2.16–2.11 (m, 1H), 0.85 (d,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 150 MHz) major isomer +
minor isomer: δ 203.4 (C), 201.1 (C), 137.9 (CH), 137.8 (CH),
116.1 (C), 115.2 (CH2 × 2), 57.1 (CH), 55.4 (CH), 54.3 (CH),
52.4 (CH), 43.1 (C), 38.6 (CH2), 33.9 (CH2), 33.8 (CH2), 32.0
(CH2), 31.1 (CH2), 26.7 (CH2), 26.5 (CH3), 26.2 (CH2), 23.9
(CH2), 22.7 (CH2), 22.9 (CH3), 22.5 (CH2), 22.3 (CH2), 20.8
(CH3), 20.8 (CH3), 19.4 (CH3), 18.4 (CH3); HRMS (EI) calcd
for C16H25NO: 247.1936; found: 247.1935.
4-Methylene-5-oxodecahydrobenzocyclooctene-4a-carbonitrile
(26). Compound 26 was obtained as a colorless oil (82% yield).
IR (CH2Cl2 cast, cm−1) ν max 2942, 2846, 2239, 1710, 1641;
1H NMR (CDCl3, 600 MHz): δ 5.02 (d, J = 1.9 Hz, 1H), 4.49
(d, J = 1.1 Hz, 1H), 2.74 (dt, J = 12.9, 3.3 Hz, 1H), 2.42–2.31
(m, 4H), 1.92–1.83 (m, 3H), 1.78–1.72 (m, 4H), 1.55–1.42 (m,
3H), 1.22–1.18 (m, 1H), 1.05–1.01 (m, 1H); 13C NMR (CDCl3,
150 MHz): δ 208.5 (C), 142.1 (C), 116.2 (C), 113.5 (CH2), 63.4
(C), 39.2 (CH), 38.9 (CH2), 34.2 (CH2), 33.9 (CH2), 30.9 (CH2),
29.8 (CH2), 25.9 (CH2), 25.8 (CH2), 23.3 (CH2); HRMS (EI)
calcd for C14H19NO: 217.1467; found: 217.1466.
The general procedure for Pd(II) mediated annulation in the
synthesis of compounds 23–33. The general procedure is illus-
trated immediately below with compound 24 as a specific
example.
4-Methylene-5-oxotetradecahydrobenzocyclododecene-4a-car-
bonitrile (27). Compound 27 was obtained as a colorless oil
(81% yield).
4614 | Org. Biomol. Chem., 2012, 10, 4609–4617
This journal is © The Royal Society of Chemistry 2012

View Article Online
IR (CH2Cl2 cast, cm−1) ν max 2974, 2937, 2875, 2229, 1712,
(s, 3H); 13C NMR (CDCl3, 150 MHz): δ 203.2 (C), 139.9 (C),
118.4 (C), 116.4 (CH2), 58.3 (C), 51.4 (CH2), 38.9 (CH), 38.8
(CH2), 34.9 (C), 32.6 (CH2), 31.9 (CH3), 27.7 (CH2), 25.6
(CH3), 20.5 (CH2); HRMS (EI) calcd for C14H19NO: 217.1467;
found: 217.1464.
1
1649 cm−1; H NMR (CDCl3, 600 MHz): δ 5.00 (dd, J = 1.5
Hz, 1H), 4.60 (d, J = 0.9 Hz, 1H), 2.74–2.72 (m, 2H), 2.38–2.34
(m, 2H), 2.09–2.03 (m, 1H), 1.96–1.92 (m, 2H), 1.85–1.82 (m,
1H), 1.42–1.40 (m, 16H), 1.55–1.62 (m, 1H); 13C NMR
(CDCl3, 150 MHz): δ 204.1 (C), 142.8 (C), 117.9 (C), 113.8
(CH2), 63.9 (C), 43.2 (CH), 37.1 (CH2), 32.5 (CH2), 30.6 (CH2),
27.9 (CH2), 26.1 (CH2), 25.6 (CH2), 25.3 (CH2), 25.2 (CH2),
24.4 (CH2), 23.9 (CH2), 22.7 (CH2), 21.8 (CH2); HRMS (EI)
calcd for C18H27NO: 273.2093; found: 273.2090.
(3aR*,5aS*,9aR*,9bS*)-Dodecahydro-9b-methyl-6-methylene-
5-oxonaphtho[2,1-b]furan-5a-carbonitrile (31). Compound 31
was obtained as a colorless oil (59% yield).
1
IR (CH2Cl2 cast, cm−1) ν max 2236, 1723, 1640 cm−1; H
NMR (CDCl3, 600 MHz): δ 4.95 (d, J = 1.9 Hz, 1H), 4.66 (d,
J = 1.9 Hz, 1H), 3.95 (ddd, J = 9.1, 6.6, 3.0 Hz, 1H), 3.69–3.65
(m, 2H), 2.59 (m, 1H), 2.51 (d, J = 13.8 Hz, 1H), 2.43–2.41 (m,
2H), 2.23 (dd, J = 13.8, 2.6 Hz, 1H), 2.10–2.04 (m, 1H), 1.85 (t,
J = 13.6 Hz, 1H), 1.71–1.65 (m, 3H), 1.31–1.27 (m, 1H), 1.04
(s, 3H), 0.92 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 203.2 (C),
139.9 (C), 118.4 (C), 116.4 (CH2), 58.3 (C), 51.4 (CH2), 38.9
(CH), 38.8 (CH2), 34.9 (C), 32.6 (CH2), 31.9 (CH3), 27.7 (CH2),
25.6 (CH3), 20.5 (CH2); HRMS (EI) calcd for C14H19NO:
245.1416; found: 245.1416.
(1S*,4aS*,8aR*)-Decahydro-1-methyl-5-methylene-4-oxonaph-
thalene-4a-carbonitrile (28). Compound 28 was obtained as
white solid (79% yield), which was further recrystallized from
ethyl acetate and n-hexane to afford a crystalline compound in
white color.
Mp 133–136 °C; IR (CH2Cl2 cast, cm−1) ν max 2236, 1728,
1
1640; H NMR (CDCl3, 600 MHz): δ 5.15 (d, J = 2.0 Hz, 1H),
4.63 (d, J = 1.7 Hz, 1H), 2.67 (dt, J = 13.7, 6.1 Hz, 1H),
2.59–2.55 (m, 1H), 2.50–2.41 (m, 2H), 2.00–1.89 (m, 2H),
1.69–1.63 (m, 2H), 1.62–1.54 (m, 2H), 1.49–1.37 (m, 2H), 0.98
(d, J = 5.9 Hz, 3H); 13C NMR (CDCl3, 150 MHz): δ 202.9 (C),
140.5 (C), 118.3 (C), 115.8 (CH2), 59.5 (C), 49.2 (CH), 39.1
(CH2), 34.0 (CH2), 32.7 (CH2), 28.3 (CH), 24.6 (CH2), 20.9
(CH2), 18.5 (CH3); HRMS (EI) calcd for C13H17NO: 203.1310;
found: 203.1309.
(4aR*,8aR*)-Decahydro-8a-methyl-4-methylene-5-oxonaphtha-
lene-4a-carbonitrile (32). Compound 32 was obtained as a color-
less oil (62% yield).
IR (CH2Cl2 cast, cm−1) ν max 2934, 2234, 1711, 1640,
1
1457 cm−1; H NMR (CDCl3, 600 MHz): δ 5.19 (s, 1H), 5.14
(s, 1H), 2.83 (m, 1H), 2.52–2.49 (m, 1H), 2.36–2.33 (m, 1H),
2.29–2.27 (m, 1H), 1.98–1.94 (m, 3H), 1.74–1.71 (m, 1H), 1.64
(m, 3H), 1.38–1.35 (m, 1H), 1.17 (s, 3H); 13C NMR (CDCl3,
150 MHz): δ 202.5 (C), 140.3 (C), 117.5 (C), 115.9 (CH2), 63.3
(C), 43.4 (C), 38.2 (CH2), 33.6 (CH2), 33.0 (CH2), 31.2 (CH2),
24.3 (CH3), 21.1 (CH2 × 2); HRMS (EI) calcd for C13H17NO:
203.1310; found: 203.1314.
8,8-Dimethyl-4-methylene-5-oxo-1,3,4,5,8,8a-hexahydro-2H-
naphthalene-4a-carbonitrile (29a) and 3,3-dimethyl-6-oxo-2-
pent-4-enylcyclohexa-1,4-dienecarbonitrile
(29b). Compound
29a was obtained as a colorless oil (41% yield) and Compound
29b was obtained as a colorless oil (45% yield).
Compound 29a IR (CH2Cl2 cast, cm−1) ν max 2237, 1697,
1
1638; H NMR (CDCl3, 600 MHz): δ 6.59 (d, J = 8.7 Hz, 1H),
(4aR*,8aR*)-Decahydro-3-isopropyl-8a-methyl-5-methylene-4-
oxonaphthalene-4a-carbonitrile (33). Compound 33 was
obtained as a colorless oil (68% yield).
6.02 (d, J = 8.1 Hz, 1H), 5.34 (d, J = 0.9 Hz, 1H), 5.21 (d,
J = 1.4 Hz, 1H), 2.42 (m, 1H), 2.28–2.25 (m, 1H), 2.04–1.82
(m, 3H), 1.33–1.23 (m, 2H), 1.16 (s, 3H), 1.15 (m, 3H);
13C NMR (CDCl3, 150 MHz): δ 189.3 (C), 158.3 (CH), 141.4
(C), 124.2 (CH), 118.2 (C), 115.4 (CH2), 54.5 (C), 50.7 (CH),
37.3 (C), 32.0 (CH2), 29.0 (CH3), 28.5 (CH3), 26.0 (CH2), 25.5
(CH2); HRMS (EI) calcd for C14H17NO: 215.1310; found:
215.1309.
IR (CH2Cl2 cast, cm−1) ν max 2954, 2232, 1727, 1645 cm−1
;
1H NMR (CDCl3, 600 MHz): δ 5.26 (s, 1H), 5.17 (t, J = 7.2 Hz,
1H), 2.77–2.73 (m, 1H), 2.32–2.29 (m, 2H), 2.21–2.16 (m, 1H),
2.12–2.08 (m, 1H), 2.00–1.95 (m, 1H), 1.77–1.63 (m, 2H),
1.60–1.46 (m, 1H), 1.16 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.87
(d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz): δ 202.9 (C),
139.8 (C), 118.4 (C), 115.2 (CH2), 63.9 (C), 52.7 (CH), 44.1
(CH2), 36.7 (CH2), 31.6 (CH2), 31.1 (CH2), 26.3 (CH), 24.2
(CH3), 23.4 (CH2), 21.2 (CH2), 20.7 (CH3), 18.4 (CH3); HRMS
(EI) calcd for C16H23NO: 245.1780; found: 245.1782.
Compound 29b IR (CH2Cl2 cast, cm−1) ν max 2238, 1691,
1640 cm−1; 1H NMR (CDCl3, 600 MHz): δ 6.79 (d, J = 7.9 Hz,
1H), 6.23 (d, J = 6.8 Hz, 1H), 5.56 (m, 1H), 5.08–5.02 (m, 2H),
2.62 (m, 1H), 2.55 (m, 1H), 2.23–2.20 (m, 2H), 1.78–1.73 (m,
2H), 1.65–1.63 (m, 2H), 1.33 (s, 3H), 1.32 (s, 3H); 13C NMR
(CDCl3, 150 MHz): δ 181.2 (C), 179.9 (C), 156.9 (CH), 136.9
(CH), 127.2 (C), 125.2 (CH), 116.2 (C), 113.9 (CH2), 41.7 (C),
41.2 (CH2), 32.2 (CH2), 28.5 (CH2), 25.6 (CH3 × 2); HRMS
(EI) calcd for C14H17NO: 215.1310; found: 215.1308.
(4aR*,8aR*)-4-[(2,4-Dinitro-phenyl)-hydrazono]-5-methylene-
octahydro-naphthalene-4a-carbonitrile (24a). A two-neck round
bottom flask equipped with a Dean-Stark and a condenser was
charged with compound 24 (48 mg, 0.40 mmol), p-TSA (2 mg,
0.01 mmol), 2,4-dinitrophenylhydrazine (0.104 g, 0.80 mmol)
and toluene (10 mL). The reaction mixture was heated to reflux
for 40 hours with azeotropic removal of water and then cooled to
room temperature. Saturated NaHCO3 solution (5 mL) was
added. The resulting aqueous solution was extracted with Et2O
(3 × 10 mL). The combined organic extracts were washed with
brine, dried over MgSO4, filtered and concentrated to give the
crude product, which was purified by flash chromatography on
(4aS*,8aR*)-Decahydro-2,2-dimethyl-5-methylene-4-oxonaph-
thalene-4a-carbonitrile (30). Compound 30 was obtained as a
colorless oil (76% yield).
IR (CH2Cl2 cast, cm−1) ν max 2236, 1728, 1643 cm−1
;
1H NMR (CDCl3, 600 MHz): δ 5.16 (s, 1H), 4.63 (s, 1H), 2.59
(m, 1H), 2.51 (d, J = 13.8 Hz, 1H), 2.43–2.41 (m, 2H), 2.23 (dd,
J = 13.8, 2.6 Hz, 1H), 2.10–2.04 (m, 1H), 1.85 (t, J = 13.6 Hz,
1H), 1.71–1.65 (m, 3H), 1.31–1.27 (m, 1H), 1.04 (s, 3H), 0.92
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4609–4617 | 4615

View Article Online
silical gel with EtOAc–n-hexane (1 : 9) to afford compound 24a
(48 mg, 52% yield) as an orange solid, which was further recrys-
tallized from ethyl acetate and n-hexane to afford a crystalline
compound in bright-orange color.
2.11–2.04 (m, 2H), 1.97–1.93 (m, 2H), 1.63–1.50 (m, 7H),
1.36–1.23 (m, 15H); 13C NMR (CDCl3, 150 MHz): δ 210.3 (C),
140.2 (C), 133.8 (C), 37.9 (CH2), 32.9 (CH), 31.7 (CH2), 30.2
(CH2), 26.5 (CH2), 26.2 (CH2), 24.7 (CH2), 23.9 (CH2), 23.6
(CH2), 23.3 (CH2), 22.4 (CH2), 21.7 (CH2), 20.8 (CH3), 19.1
(CH2); HRMS (EI) calcd for C17H28O: 248.2140; found:
248.2146.
Mp 233–236 °C; IR (CH2Cl2 cast, cm−1) ν max 2938, 2829,
1
2342, 1702, 1636, 1592; H NMR (CDCl3, 600 MHz): δ 11.18
(s, 1H), 9.11 (d, J = 2.6 Hz, 1H), 8.33 (dd, J = 9.6, 2.5 Hz, 1H),
8.01 (d, J = 9.5 Hz, 1H), 5.19 (s, 1H), 4.95 (s, 1H), 2.73–2.69
(m, 1H), 2.54–2.50 (m, 2H), 2.45–2.41 (m, 1H), 2.35–2.32 (m,
1H), 1.97–1.89 (m, 3H), 1.80–1.70 (m, 3H), 1.66–1.59 (m, 2H);
13C NMR (CDCl3, 150 MHz): δ 152.6 (C), 145.2 (C), 142.1
(C), 138.7 (C), 130.4 (CH), 129.8 (C), 123.2 (CH), 119.5 (C),
116.8 (CH), 115.3 (CH2), 53.4 (C), 44.0 (CH), 32.5 (CH2), 27.8
(CH2), 26.7 (CH2), 24.2 (CH2), 23.1 (CH2), 22.5 (CH2); HRMS
(EI) calcd for C18H19N5O4: 369.1437; found: 369.1441.
(4aS*,9aR*)-4a-Benzyl-4-methylenedecahydrobenzo-cyclo-
hepten-5-one (37). Freshly prepared LN reagent was slowly
added to a stirred solution of compound 24 (55 mg, 0.27 mmol)
in THF (8 mL) at −78 °C until the resulting solution become
deep green color. The reaction was stirred at the same tempera-
ture for another 45 min, at which time benzyl bromide (70 mg,
0.40 mmol) was introduced dropwise. Then the resulting
mixture was warmed and kept stirring at 0 °C for 6 h. H2O
(10 mL) was added to quench the reaction. The aqueous layer
was separated and extracted with EA (2 × 10 mL). The com-
bined organic extracts were washed brine, dried over MgSO4,
filtered and concentrated to give the crude residue, which
was purified by flash chromatography on silical gel with EtOAc–
n-hexane (1 : 4) to afford compound 37 (49 mg, 71%) as color-
less oil.
The general procedure for LN induced reductive decyanation
in the synthesis of compounds 34–36. The general procedure is
illustrated immediately below with compound 34 as a specific
example.
8-Methyl-3,4,4a,5,6,7-hexahydro-2H-naphthalen-1-one
(34). Freshly prepared LN18 reagent was slowly added to a
stirred solution of compound 24 (52 mg, 0.26 mmol) in THF
(8 mL) at −78 °C until the resulting solution become deep green
color. The reaction was stirred at same temperature for another
15 min, at which time H2O (10 mL) was introduced to quench
the reaction. The aqueous layer was separated and extracted with
EA (2 × 10 mL). The combined organic extracts were washed
brine, dried over MgSO4, filtered and concentrated to give the
crude residue, which was purified by flash chromatography on
silical gel with EtOAc–n-hexane (1 : 4) to afford compound 34
(36 mg, 85%) as a colorless oil.
IR (CH2Cl2 cast, cm−1) ν max 2971, 2953, 1714, 1638, 1595;
1H NMR (CDCl3, 600 MHz): 7.21–7.18 (m, 2H), 7.16–7.13 (m,
1H), 7.09–7.07 (m, 2H), 5.00 (s, 1H), 4.82 (s, 1H), 3.35 (d, J =
13.3 Hz, 1H), 2.87 (d, J = 13.3 Hz, 1H), 2.41–2.36 (m, 1H),
2.19–2.14 (m, 3H), 2.11–2.07 (m, 1H), 1.74 (td, J = 11.5, 2.4
Hz, 1H), 1.69–1.64 (m, 2H), 1.56–1.52 (m, 4H), 1.41–1.26 (m
3H); 13C NMR (CDCl3, 150 MHz): δ 215.3 (C), 146.8 (C),
137.3 (C), 130.5 (C × 2), 128.0 (C × 2), 126.4 (C), 113.2 (CH2),
62.4 (C), 44.5 (CH2), 42.6 (CH2), 37.6 (CH), 33.2 (CH2), 32.5
(CH2), 29.9 (CH2), 28.5 (CH2), 25.2 (CH2), 22.7 (CH2); HRMS
(EI) calcd for C19H24O: 268.1827; found: 268.1830.
1
IR (CH2Cl2 cast, cm−1) ν max 2962, 2933, 1675; H NMR
(CDCl3, 600 MHz): δ 2.50–2.45 (m, 1H), 2.49 (dq, J = 13.7, 6.5
Hz, 2H), 2.09–2.06 (m, 2H), 1.97–1.93 (m, 1H), 1.90–1.84 (m,
2H), 1.83 (t, J = 1.1 Hz, 1H), 2.07–2.02 (m, 1H), 1.75–1.66 (m,
3H), 1.48–1.32 (m, 2H), 1.24–1.18 (m, 1H); 13C NMR (CDCl3,
150 MHz): δ 204.6 (C), 143.4 (C), 134.8 (C), 43.0 (CH2), 39.1
(CH), 33.8 (CH2), 33.0 (CH2), 30.8 (CH2), 23.7 (CH2), 21.8
(CH3), 21.3 (CH2); HRMS (EI) calcd for C11H16O: 164.1201;
found: 164.1200.
Acknowledgements
We are grateful to China Medical University Hospital
(DMR-101-104) and National Science Council of Republic of
China for financial support.
4-Methyl-1,2,3,6,7,8,9,9a-octahydrobenzocyclohepten-5-one
Notes and references
(35). Compound 35 was obtained as a colorless oil (81% yield).
1
IR (CH2Cl2 cast, cm−1) ν max 2951, 2943, 1677; H NMR
1 (a) J. K. Stille, G. T. Crisp and W. J. Scott, J. Am. Chem. Soc., 1984,
106, 7500; (b) D. Hart and A. C. Guevel, J. Org. Chem., 1991, 61, 473;
(c) G. Mehta and A. Srikrishna, Chem. Rev., 1997, 97, 671;
(d) D. G. I. Kingston, V. S. P. Chaturvedula, A. Farooq, J. K. Schilling,
S. Malone, I. Derveld, M. C. M. Werkhoven and J. H. Wisse, J. Nat.
Prod., 2004, 67, 2053; (e) Y. L. Kuo, M. Dhanasekaran and C. K. Sha,
J. Org. Chem., 2009, 74, 2033.
2 For examples, see: (a) W. P. Jackson and S. V. Ley, J. Chem. Soc., Perkin
Trans. 1, 1981, 1516; (b) N. Iwasawa, K. Maeyama and H. Kusama, Org.
Lett., 2001, 3, 3871; (c) F. D. Toste, J. J. Kennedy-Smith and
S. T. Staben, J. Am. Chem. Soc., 2004, 126, 4527; (d) C. H. Jiang,
A. Bhattacharyya and C. K. Sha, Org. Lett., 2007, 17, 3241; (e) Q. Gao,
B. F. Zheng, J. H. Li and D. Yang, Org. Lett., 2005, 7, 2158; (f) C.
L. Deng, T. Zou, Z. Q. Wang, R. J. Song and J. H. Li, J. Org. Chem.,
2009, 74, 412.
(CDCl3, 600 MHz): 2.57 (td, J = 12.4, 2.8 Hz, 1H), 2.43–2.40
(m, 1H), 2.35–2.31 (m, 1H), 2.10–2.05 (m, 2H), 1.90–1.85 (m,
1H), 1.84 (t, J = 0.8 Hz, 3H), 1.72–1.66 (m, 4H), 1.53–1.46 (m,
3H), 1.40–1.33 (m, 2H); 13C NMR (CDCl3, 150 MHz): δ 208.5
(C), 141.1 (C), 137.8 (C), 44.0 (CH2), 36.9 (CH2), 36.6 (CH),
33.0 (CH2), 31.6 (CH2), 30.2 (CH2), 26.1 (CH2), 21.5 (CH3),
20.3 (CH2); HRMS (EI) calcd for C12H18O: 178.1358; found:
178.1356.
4-Methyl-1,2,3,6,7,8,9,10,11,12,13,13a-dodecahydrobenzo-
cycloundecen-5-one (36). Compound 36 was obtained as a color-
less oil (86% yield).
3 (a) L. R. Kung, C. H. Tu, K. S. Shia and H. J. Liu, Chem. Commun.,
2003, 2490; (b) C. L. Chin, C. F. Liao, H. J. Liu, Y. C. Wong,
M. T. Hsieh, P. K. Amancha, C. P. Chang and K. S. Shia, Org. Biomol.
Chem., 2011, 9, 4778; (c) Y. C. Wong, M. T. Hsieh, P. K. Amancha,
1
IR (CH2Cl2 cast, cm−1) ν max 2971, 2953, 1682; H NMR
(CDCl3, 600 MHz): 3.06–3.02 (m, 1H), 2.54–2.52 (m, 1H),
4616 | Org. Biomol. Chem., 2012, 10, 4609–4617
This journal is © The Royal Society of Chemistry 2012

View Article Online
C. L. Chin, C. F. Liao, C. W. Kuo and K. S. Shia, Org. Lett., 2011, 13,
896.
4 M. T. Hsieh, H. J. Liu, T. W. Ly and K. S. Shia, Org. Biomol. Chem.,
2009, 7, 3285.
5 K. Chen, Y. Ishihara, M. M. Galan and P. S. Baran, Tetrahedron, 2010,
66, 4738.
6 J. A. Marshall, J. C. Peterson and L. Lebioda, J. Am. Chem. Soc., 1984,
106, 6006.
7 J. L. Zhu, K. S. Shia and H. J. Liu, Chem. Commun., 2000, 1599.
8 D. Liotta, C. Barnum, R. Puleo, G. Zima, C. Bayer and H. S. Kezar,
J. Org. Chem., 1981, 46, 2920.
9 F. F. Fleming, V. A. Vu, B. C. Shook, M. Rahman and O. W. Sterward,
J. Org. Chem., 2007, 72, 1431.
10 T. Sato, M. Takeuchi, T. Ito, M. Kawashima and T. Fujisawa, Tetrahedron
Lett., 1981, 22, 1817.
11 S. Marquais, M. Alami and G. Cahiez, Org. Synth., 1995, 72, 135.
12 P. Perlmutter, Conjugate Addition Reaction in Organic Synthesis, Perga-
mon, New York, 1992.
14 Crystal data for 28: C13H17NO, M = 203.28; Triclinic, space group P2(1)/
n; a = 9.7923(14), b = 8.0377(11), c = 14.520(2) Å, V= 93.817(2)°, V =
1140.3(3) Å3, T = 273(2) K; Z = 4; μ = 0.074 mm−1; reflections: total =
8265, unique = 2874 (Rint = 0.0270); R indices (all data): R1 = 0.0699,
wR2 = 0.1905. CCDC 851795.
15 For a review, see: W. L. Thomas and S. S. Melanie, Chem. Rev., 2010,
110, 1147.
16 (a) K. T. Yip and D. Yang, Org. Lett., 2011, 13, 2134;
(b) J. W. Wrigglesworth, B. Cox, G. C. Lloyd-Jones and K. I. Booker-
Milburn, Org. Lett., 2011, 13, 5326; (c) G. Broggini, E. M. Beccalli,
E. Borsini, A. Fasana and G. Zecchi, Synlett, 2011, 227; (d) G. Yang and
W. Zhang, Org. Lett., 2012, 14, 268; (e) G. Broggini, V. Barbera, E.
M. Beccalli, E. Borsini, S. Galli, G. Lanza and G. Zecchi, Adv. Synth. Catal.,
2012, 354, 227; (f) Z. B. Zhu and M. Shi, Org. Lett., 2009, 11, 5278.
17 (a) H. J. Liu, K. S. Shia, X. Shang and B. Y. Zhu, Tetrahedron, 1999, 55,
3803; (b) H. J. Liu, Y. L. Ho, J. D. Wu and K. S. Shia, Synlett, 2001,
1805; (c) J. D. Wu, K. S. Shia and H. J. Liu, Tetrahedron Lett., 2001, 42,
4207; (d) P. K. Amancha, Y. C. Lai, I. C. Chen, H. J. Liu and J. L. Zhu,
Tetrahedron, 2010, 66, 871; (e) Y. K. Wu, T. W. Ly and K. S. Shia, Curr.
Org. Synth., 2010, 7, 78; (f) P. K. Amancha, H. J. Liu, T. W. Ly and
K. S. Shia, Eur. J. Org. Chem., 2010, 3473.
13 Crystal data for 24a: C18H19N5O4, M = 369.38; monoclinic, space group
P2(1)/n; a = 13.1764(14), b = 7.0909(7), c = 19.046(2) Å, V = 92.154
(3)°, V = 1778.3(3) Å3, T = 295(2) K; Z = 4; μ = 0.101 mm−1; reflections:
total = 12 845,unique = 4419 (Rint = 0.0836); R indices (all data): R1
0.1310, wR2 = 0.1289. CCDC 851796.
=
18 For preparation of LN reagent, see: H. J. Liu, J. Yip and K. S. Shia, Tetra-
hedron Lett., 1997, 38, 2253.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4609–4617 | 4617