A Diels-Alder route to angularly functionalized bicyclic structures

Article abstract of DOI:10.1016/j.tet.2010.04.094

A Diels-Alder-based route to trans-fused angularly functionalized bicyclic structures has been developed. This transformation features the use of a tetrasubstituted dienophile in the cycloaddition step.

Full text of DOI:10.1016/j.tet.2010.04.094

Tetrahedron 66 (2010) 6391e6398
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A DielseAlder route to angularly functionalized bicyclic structures
,
,
,b,
Woo Han Kim a y, Jun Hee Lee b y, Baptiste Aussedat a, Samuel J. Danishefskya
*
a Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
b Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A DielseAlder-based route to trans-fused angularly functionalized bicyclic structures has been de-
veloped. This transformation features the use of a tetrasubstituted dienophile in the cycloaddition step.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 February 2010
Received in revised form 8 April 2010
Accepted 22 April 2010
Available online 5 May 2010
We dedicate this paper to Professor Steven
Ley on the occasion of his receipt of the
Tetrahedron Prize for Creativity in Organic
Chemistry, honoring his pioneering accom-
plishments in organic synthesis
NO2
H
H
1. Introduction
O2N
trans-DA
paradigm
+
n
n
n
n
The development of improved methods for the stereoselective
construction of substituted decalin and hydrindane systems re-
mains an important focus of organic synthesis.1 Over the years, our
laboratory has been exploring extensions of the DielseAlder re-
action, with a view to gaining access to substructural patterns,
which are not traditionally filed under DielseAlder logic. Toward
this end, we recently developed a two-step ‘trans-DielseAlder’
paradigm, which provides access to trans-fused decalin and
hydrindane systems from 1-nitrocycloalkene dienophiles (2) and
simple dienes (1). As is shown in Figure 1, cycloaddition provides
a cis-fused bicyclic adduct, bearing a nitro group in the ring junc-
tion (3). Subsequent radical denitration furnishes the target trans-
fused system (4) with good selectivity.2 In the case of the hydrin-
dane series, the DielseAlder step, per se, is even more straight-
forward; however, denitration results in nearly 1:1 mixtures of
diastereomeric products.
1
H
H
2
3
4
trans-DA
paradigm
NO2
O2N
A
7
+
n
n
A
A
NHR
6
1
5
nitro
A = CO2Me, CN
n = 0, 1
reduction
n
A
8
Figure 1.
could be converted to a cis-fused angular amine product (cf. 8)
through reduction of the nitro functionality. We were not un-
mindful of the challenges inherent in this proposed sequence. In-
deed, tetrasubstituted olefins are known to act as poor dienophiles
in the DielseAlder reaction,4 and relatively few examples of tet-
rasubstituted cyclic dienophiles bearing nitro functionality have
been reported.5 To our knowledge, compound 5 had not been
demonstrated to function as a competent DielseAlder dienophile.
We were hopeful that by installing a second electron-withdrawing
group (i.e., CN) as substituent A, we could realize the desired cy-
cloaddition. We describe herein the development of two-step,
DielseAlder-based routes to trans-fused adducts containing angu-
lar substitution, such as 7, and to disubstituted, cis-fused adducts of
the type 8.6
To further expand upon this concept, we considered the pos-
sibility of achieving cycloaddition between a tetrasubstituted
dienophile of the type 5 and a diene (1).3 It was hoped that the cis-
fused nitro-substituted DielseAlder adduct, 6, following radical-
induced denitration, might progress to a trans-fused system bear-
ing substitution (A) at the ring junction (cf. 7). Alternatively, 6
* Corresponding author. E-mail address: s-danishefsky@ski.mskcc.org (S.J.
Danishefsky).
y
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.094

6392
W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
2. Results and discussion
method. We also examined the denitration and hydrolysis of
hydrindane 22, arising from the DielseAlder reaction of 21 and 17.10
As shown in Scheme 2, it was observed that, when denitration
preceded hydrolysis, the trans-fused adduct (23) was obtained as
the predominant product, with only moderate selectivity. By con-
trast, when hydrolysis was carried out at the stage of compound 22,
denitration of the resultant ketone selectively delivered the cis-
fused adduct 24 (cis/trans¼7:1).11
We first examined the cycloadditionedenitration sequence in
the context of dienophile 117 (itself prepared in one step from 9, as
shown) and synergistic diene 10 (Scheme 1).8 In the event, 10 and
11 did undergo cycloaddition to afford a 1:1 (exo/endo) mixture of
the readily separable adducts 12 and 13. The structure of 13 (endo)
was confirmed by X-ray crystallographic analysis. Each adduct was
then separately subjected to conditions, which favor radical-me-
diated denitration.9 Following hydrolysis, trans-fused adduct 14
was isolated as the predominant product; its structure was also
unambiguously determined by X-ray crystallography. The slightly
higher levels of stereocontrol achieved in the denitration of exo
cycloadduct 12 (12:1 vs 10:1) can perhaps be attributed to the axial
disposition of the methoxy group, which serves to more effectively
shield the ‘front’ face of the transient free radical, leaving the back
face exposed to attack by the hydrogen-donor agent.
Having explored the cycloadditionedenitration sequence with
activated diene coupling partners, we next investigated the use of
less reactive hydrocarbon-based dienes in the DielseAlder step.
Our initial efforts to effect DielseAlder reaction between 2,3-di-
methyl-1,3-butadiene and dienophile 11 were unsuccessful. Under
moderate thermal conditions (<130 ꢀC), no reaction was observed
(Scheme 3). At higher temperatures (150 ꢀC), compound 25 was
formed in 25e40% yield.12 The structure of adduct 25 was con-
firmed by X-ray crystallography. It was eventually determined that
MeO
MeO
NO2
CN
NO2
CN
O2N
a
b
+
OMe
NC
TBSO
NC
TBSO
10
11
9
12 (exo)
13 (endo)
TBSO
c,d
c,d
H
H
+ 15
+ 15
O
O
CN
CN
14
14
14
84% for two steps
80% for two steps
13
trans (14): cis (15)
trans (14): cis (15)
= 12:1
= 10:1
Scheme 1. Reagents and conditions: (a) NaNO2, CAN, CH3CN, rt, 24 h, 56%; (b) toluene, 100 ꢀC, 80 h, 78%; (c) n-Bu3SnH, AIBN, benzene, reflux, 2 h; (d) HF, CH3CN, 1 h.
We next examined the two-step sequence in the context of
a cyclopentenyl dienophile. Here, the tetrasubstituted dienophile,
17, was prepared from compound 16, as shown (Scheme 2). Under
thermal conditions, 17 underwent cycloaddition with diene 10 to
afford the cis-fused adduct,18, as a mixture of endo and exo isomers,
in 95% yield. Upon denitration and subsequent hydrolysis, a 2:1
mixture of trans-fused 19 and cis-fused 20 was isolated. Obviously,
this lack of stereocontrol would compromise the value of the
cycloadduct 26 could be generated in moderate yield at 100 ꢀC,
through the addition of 5.0 M LiClO4 in THF,13 which serves to ac-
celerate the DielseAlder reaction (Table 1, entry 1). In contrast to
the moderate DielseAlder yields obtained with cyclohexenyl
dienophile, 11 (Table 1, entries 1 and 2), the cyclopentenyl dien-
ophile, 17, readily undergoes cycloaddition with hydrocarbon di-
enes, furnishing cis-fused hydrindane adducts in excellent yields
(Table 1, entries 3 and 4).
MeO
H
NO2
O2N
NC
a
c,d
b
+ 20
10
NC
O
TBSO
CN
16
17
18
19
CN
19
trans (19): cis (20)
= 2:1
52% for 2 steps
H
c,d
+
24
34 %
O
for 2 steps
NO2
CN
CN
23
O2N
NC
e
trans (23): cis (24)
= 2:1
+
TBSO
TBSO
H
21
17
22
f,g
+ 23
49 %
O
for 2 steps
CN
24
trans (23): cis (24)
= 1:7
Scheme 2. Reagents and conditions: (a) NaNO2, CAN, CH3CN, rt, 24 h, 61%; (b) toluene, 100 ꢀC, 10 h, 95%; (c) n-Bu3SnH, AIBN, benzene, reflux, 2 h; (d) HF, CH3CN, 1 h; (e) toluene,
100 ꢀC, 36 h, 63%, p-directed/m-directed ¼ 4:1; (f) HF, CH3CN, rt, 8 h; (g) n-Bu3SnH, AIBN, benzene, reflux, 1.5 h, 48% for two steps.

W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
6393
Table 2
a
b
No
Reaction
O2N
NC
Me
Me
H
NO2
CN
n-Bu3SnH
R1
R2
+
R1
O
N
AIBN
O
11
Me
Me
n
n
benzene
R2
reflux, 2 h
CN
H
25
trans = 30a–33a
cis = 30b–33b
26–29
25 25-40%
Scheme 3. Reagents and conditions: (a) 2,6-di-tert-butyl-4-methylphenol, toluene,
130 ꢀC, 24 h. (b) 2,6-di-tert-butyl-4-methylphenol, toluene, 150 ꢀC, 24 h.
Entry
1
Substrate
NO2
Product
Yield (%)
trans/cis (a/b)
H
Me
Me
Me
Table 1
89
>20:1
Me
CN
CN
H
26
30
Method A
NO2
R1
R2
R1
R2
or
O2N
NC
NO2
Method B
+
n
n
2
85
>20:1
CN
26–29
CN
CN
H
11 (n = 1)
27
31
17 (n = 0)
NO2
Me
Me
Me
Me
Entry
1
Diene
Me
Dienophile
Method
A
Adduct
NO2
Yield (%)
26
3
4
77
89
w1.5:1
w1.7:1
Me
Me
CN
CN
H
28
32
11
11
Me
CN
NO2
26
NO2
CN
CN
33
2
A
35
29
CN
27
NO2
Me
Me
Me
Me
rubber septa under a positive pressure of nitrogen or argon using
standard Schlenk techniques. Heating was accomplished by heating
mantle or silicon oil bath using a temperature controller. Organic
solutions were concentrated under reduced pressure using a Büchi
rotatory evaporator, unless otherwise noted. Reactions were mag-
netically stirred and monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60-F254) using UV
light as a visualizing agent and a KMnO4 solution, a vanillin solu-
tion, an anisaldehyde solution, or a ceric ammonium molybdate
(CAM) solution, and heat as developing agent. Flash chromatogra-
phy was carried out with EM silica gel 60 (230e240 mesh) or
3
4
17
17
B
B
95
91
CN
28
NO2
CN
29
Key: Method A: 2,6-di-tert-butyl-4-methylphenol, 5.0 M LiClO4 in THF, 100 ꢀC, 60 h;
Method B: 2,6-di-tert-butyl-4-methylphenol, toluene, 100 ꢀC, 24 h.
We now turned to an assessment of the feasibility of the deni-
tration step, which we hoped would provide access to substituted,
trans-fused hydrindane and decalin systems. As outlined in Table 2,
entries 1 and 2, the cis-fused decalin systems (26 and 27) un-
derwent radical-based denitration to provide the corresponding
trans-fused adducts in good yield and with excellent levels of dia-
stereocontrol (>20:1 trans/cis).14 However, denitration of hydrin-
danes 28 and 29 proceeded with quite poor levels of
stereoselectivity (Table 2, entries 3 and 4).15
Finally, we sought to accomplish reduction of the cis-fused
DielseAlder adducts (26 and 28), to provide the corresponding cis-
fused amine derivatives. As outlined in Scheme 4, treatment16 of
compounds 26 and 28 with zinc dust in the presence of AcOH,
followed by Alloc protection of the resultant angular amines, pro-
vided compounds 34 and 35 in good yield, and with the cyanide
functionality intact. The two-step DielseAlder/reduction sequence
represents a straightforward synthesis of angular amines.
Sorbent Technology silica gel 60 (particle size 32e63 mm) according
to the method of Still.17 Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless oth-
erwise stated. Unless otherwise noted, all reagents were purchased
at the highest commercial quality from commercial suppliers and
used without further purification. Lithium perchlorate (battery
grade, dry, 99.99%) was purchased from Aldrich and dried under
high vacuum at 130 ꢀC for at least 12 h just prior to use. Tetrahy-
drofuran (THF) was freshly distilled from sodium/benzophenone
ketyl under an atmosphere of argon. Benzene, dichloromethane
(CH2Cl2), and toluene were freshly distilled over CaH2 or filtered
O
HN
O
NO2
CN
Me
Me
Me
Me
a,b
n
3. Experimental section
3.1. General
n
CN
34, n = 1, 40% for 2 steps
35, n = 0, 52% for 2 steps
26, n = 1
28, n = 0
Scheme 4. Reagents and conditions: (a) Zn dust, THF/AcOH (2:1), ꢁ20 ꢀC, 3 h; (b)
Experiments involving moisture- and/or air-sensitive com-
pounds were performed in oven- or flame-dried glassware with
AllocCl, THF, satd NaHCO3, rt, 3 h.

6394
W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
through a column of activated alumina under an atmosphere of
argon. Diethyl ether was filtered through a column of activated
alumina under an atmosphere of argon. Microwave reactions were
performed on a Biotage microwave reactor. 1H and 13C NMR spectra
were recorded on a Bruker DRX-400, a Bruker DRX-500 or a Bruker
DRX-600 spectrometer at ambient temperature (300 K), unless
otherwise stated. Chemical shifts of the 1H NMR (CDCl3: 7.26 ppm)
and 13C NMR (CDCl3: 77.0 ppm) spectra were referenced to residual
solvent peaks. 1H NMR spectra are reported as follows: chemical
shift, multiplicity (br¼broad, s¼singlet, d¼doublet, m¼multiplet),
coupling constant, and integration. 13C NMR spectra were recorded
with 1H decoupling. The multiplicities of the carbons of trans-3,4-
dimethylbicyclo[4.4.0]dec-3-en-1-carbonitrile (30a) and trans-
1,2,3,4,4a,5,6,7,8,9,9a,10-dodecahydroanthracene-4a-carbonitrile
(31a) were determined by DEPT (Distortionless Enhancement by
Polarization Transfer) experiments. IR spectra were recorded on
a Jasco FT/IR-6100 or a Nicolet AVATAR 370 DTGS spectrometer and
are reported in terms of frequency of absorption (cmꢁ1). Melting
points were measured using MEL-TEMPÒ and are uncorrected. Low
resolution mass spectra were acquired on a ZQ Micromass spec-
trometer using the technique of ESI (electrospray ionization). High-
resolution mass spectra (HRMS) were obtained from the Columbia
University Mass Spectral Core Facility on a JEOL HX 110 mass
spectrometer using the technique of EI (electron impact ionization)
or FAB (fast atom bombardment).
3.2.2. General procedure for the DielseAlder reaction of 2-nitro-
cycloalkenecarbonitriles (11 and 17) with electron-rich dienes (10
and 21). A sealable vial reactor equipped with a magnetic stirring
bar was charged with 2-nitrocycloalkenecarbonitriles (1.0 equiv),
an electron-rich diene (2.0 equiv), and anhydrous toluene. The re-
actor was sealed and the mixture was stirred at 100 ꢀC in a pre-
heated oil bath for 10e80 h. At this point, the mixture was cooled to
room temperature and the solvent was evaporated. The resulting
residue was purified by flash column chromatography on silica gel
to afford the desired DielseAlder adduct as a mixture of endo and
exo diastereomers.
3.2.2.1. A 1:1 mixture of silyl enol ethers 12 and 13. Prepared
using 11 (200 mg, 1.31 mmol) and trans-2-(tert-butyldimethylsily-
loxy)-4-methoxy-1,3-butadiene (10, 564 mg, 2.63 mmol) in toluene
(3.0 mL) at 100 ꢀC for 80 h, an approximate 1:1 mixture of 12 and 13
was isolated as a pale yellow oil (350 mg, 78%) after column chro-
matography (hexanes/EtOAc¼12:1). Diastereomers 12 and 13 were
separated by careful column chromatography. exo Isomer 12: 1H
NMR (600 MHz, CDCl3)
d
5.14 (d, J¼4.7 Hz, 1H), 4.04 (d, J¼4.9 Hz,
1H), 3.32 (s, 3H), 2.61 (br s, 2H), 2.45e2.44 (m, 1H), 2.37e2.34 (m,
1H), 1.89e1.85 (m, 1H), 1.74e1.71 (m, 2H), 1.65e1.56 (m, 2H), 1.25
(br s, 1H), 0.94 (s, 9H), 0.23 (s, 3H), 0.21 (s, 3H); IR (neat) 2951, 2932,
2884, 2859, 2239, 1752, 1673, 1554, 1454, 1370, 1254, 1230, 1210,
1089 cmꢁ1; MS (ESI) 389.3 [MþNa]þ. endo Isomer 13: 1H NMR
(600 MHz, CDCl3)
d
4.93 (d, J¼1.7 Hz, 1H), 4.58 (s, 1H), 3.36 (s, 3H),
2.81 (d, J¼17.9 Hz, 1H), 2.66 (d, J¼15.4 Hz, 1H), 2.42 (d, J¼17.9 Hz,
1H), 1.93e1.90 (m, 2H), 1.77e1.75 (m, 1H), 1.67e1.58 (m, 3H),
1.52e1.46 (m, 1H), 0.93 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H); 13C NMR
3.2. General procedure
(125 MHz, CDCl3)
d 141.8, 121.8, 102.3, 92.1, 81.0, 58.5, 39.3, 38.1,
3.2.1. General procedure for the nitration of cyloalkenecarbonitriles
30.6, 29.5, 19.4, 18.5, 17.9, ꢁ4.4; IR (neat) 2953, 2932, 2884, 2858,
(9 and 16)7. To
a
stirred solution of cycloalkenecarbonitrile
2237, 1674, 1548, 1455, 1366, 1254, 1226, 1198, 1096, 914 cmꢁ1
;
(20.0 mmol, 1.0 equiv) in anhydrous CH3CN (100 mL) at 0 ꢀC was
added NaNO2 (4.14 g, 60.0 mmol, 3.0 equiv) followed by ammo-
nium cerium nitrate (32.8 g, 60.0 mmol, 3.0 equiv). The reaction
mixture was stirred at room temperature for 24 h, diluted with
H2O, and extracted with EtOAc (20 mLꢂ3). The organic layer was
treated with a saturated solution of NaHCO3 (100 mL) and the
resulting mixture was stirred at room temperature for 12 h. The
mixture was diluted with H2O and extracted with EtOAc
(20 mLꢂ3). The combined extract was dried over anhydrous
MgSO4, filtered, and concentrated on a rotatory evaporator. Purifi-
cation of the residue by flash column chromatography on silica gel
gave the title compound.
HRMS (FAB) exact mass calculated for [Mþ1]þ (C18H31N2O4Si) re-
quired m/z 367.2053, found m/z 367.2063. The structure of 13 was
also confirmed by X-ray crystallographic analysis (see
Supplementary data).
3.2.2.2. A 1.8:1 mixture of silyl enol ethers 18 and 180. Prepared
using 17 (500 mg, 3.62 mmol) and trans-2-(tert-butyldimethylsi-
lyloxy)-4-methoxy-1,3-butadiene (10, 1.55 g, 7.24 mmol) in toluene
(4.0 mL) at 100 ꢀC for 10 h, an approximate 1.8:1 mixture of 18 and
180 was isolated as a pale yellow oil (1.21 g, 95%) after column
chromatography (hexanes/EtOAc¼10:1). Diastereomers 18 and 180
were separated by careful column chromatography. Compound 18:
1H NMR (600 MHz, CDCl3)
d 4.96e4.93 (m, 1H), 4.91e4.88 (m, 1H),
3.2.1.1. 2-Nitrocyclohexenecarbonitrile (11). Prepared using
cyclohexenecarbonitrile (9, 2.14 g, 20.0 mmol), NaNO2 (4.14 g,
60.0 mmol) and ammonium cerium nitrate (32.8 g, 60.0 mmol) in
CH3CN (100 mL), 11 was isolated as a yellow oil (1.70 g, 56%) after
column chromatography (hexanes/EtOAc¼4:1). 1H NMR (500 MHz,
3.32 (s, 3H), 2.73e2.69 (m, 1H), 2.62e2.59 (m, 1H), 2.32e2.28 (m,
1H), 2.14e2.01 (m, 4H), 1.95e1.89 (m, 1H), 0.90 (s, 9H), 0.19 (s, 3H),
0.17 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 147.5, 119.7, 101.0, 100.7,
78.6, 57.7, 45.0, 38.3, 35.8, 28.6, 25.4, 20.0, 17.8, ꢁ4.6, ꢁ4.7; IR (neat)
2955, 2931, 2887, 2858, 2830, 2241, 1675, 1547, 1462, 1363, 1255,
1218, 1094, 835 cmꢁ1; HRMS (FAB) exact mass calculated for
[Mþ1]þ (C17H29N2O4Si) required m/z 353.1897, found m/z 353.1918.
CDCl3)
d 2.75e2.72 (m, 2H), 2.61e2.59 (m, 2H), 1.86e1.82 (m, 2H),
1.77e1.72 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
157.9, 115.1, 114.2,
29.4, 25.7, 20.7, 20.3; IR (neat) 2952, 2869, 2221, 1652, 1528, 1427,
1342, 1331 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ
(C7H8N2O2) required m/z 152.0586, found m/z 152.0583.
Compound 180: 1H NMR (600 MHz, CDCl3)
d
5.11 (d, J¼4.9 Hz, 1H),
4.26 (d, J¼5.0 Hz, 1H), 3.32 (s, 3H), 2.79 (d of AB pattern, J¼18.3 Hz,
1H), 2.62e2.51 (m, 2H), 2.26 (d of AB pattern, J¼18.3 Hz, 1H),
2.17e2.12 (m, 1H), 2.06e2.01 (m, 1H), 1.93e1.88 (m, 2H), 0.91 (s,
3.2.1.2. 2-Nitrocyclopentenecarbonitrile (17). Prepared using
cyclopentenecarbonitrile (16, 3.00 g, 32.2 mmol), NaNO2 (6.67 g,
96.6 mmol), and ammonium cerium nitrate (53.0 g, 96.6 mmol) in
CH3CN (200 mL), 17 was isolated as a yellow oil (2.70 g, 61%) after
column chromatography (hexanes/EtOAc¼4:1). 1H NMR (600 MHz,
9H), 0.20 (s, 3H), 0.18 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 149.7,
120.8, 99.2, 98.7, 75.6, 57.3, 40.9, 39.8, 35.7, 33.5, 25.4, 18.6, 17.8,
ꢁ4.6, ꢁ4.7; IR (neat) 2955, 2931, 2893, 2858, 2825, 2243, 1671,
1553, 1461, 1369, 1256, 1221, 1087, 835 cmꢁ1; HRMS (FAB) exact
mass calculated for [Mþ1]þ (C17H29N2O4Si) required m/z 353.1897,
found m/z 353.1880.
CDCl3)
d 3.08e3.04 (m, 2H), 2.96e2.92 (m, 2H), 2.24e2.19 (m, 2H);
13C NMR (150 MHz, CDCl3)
d
160.4, 117.2, 112.4, 34.6, 31.2, 20.7; IR
(neat) 2964, 2919, 2850, 2229, 1644, 1521, 1435, 1348, 1321,
1177 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ (C6H6N2O2)
required m/z 138.0429, found m/z 138.0432.
3.2.2.3. A 4:1 mixture of silyl enol ethers 22 and 220. Prepared
using 17 (75.0 mg, 0.543 mmol) and 2-(tert-butyldimethylsilyloxy)-
1,3-butadiene (21, 200 mg, 1.08 mmol) in toluene (1.0 mL) at 100 ꢀC

W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
6395
for 36 h, an approximate 4:1 regioisomeric mixture of 22 and 220
was isolated as a pale yellow oil (110 mg, 63%) after column chro-
matography (hexanes/EtOAc¼14:1). Regioisomers 22 and 220 were
inseparable and characterization was carried out in the next step.
1H and 13C NMR spectra of the mixture of 22 and 220 are available in
Supplementary data.
(m,1H),1.77e1.71 (m,1H); 13C NMR (150 MHz, CDCl3)
d
195.3,147.9,
130.8, 121.6, 48.1, 47.4, 47.4, 35.6, 26.2, 21.0; IR (neat) 2960, 2879,
2231, 1683, 1455, 1381, 1240, 1159 cmꢁ1; HRMS (EI) exact mass
calculated for [M]þ (C10H11NO) required m/z 161.0841, found m/z
161.0850. The structure of 19 was also confirmed by X-ray crystal-
lographic analysis (see Supplementary data). Compound 20: 1H
NMR (600 MHz, CDCl3)
d
6.73 (dd, J¼10.3, 3.7 Hz, 1H), 6.05 (dd,
3.2.3. General procedure for the preparation of bicyclic ketones (14,
15, 19, 20, 23, and 24). To a stirred solution of a cis-fused silyl enol
ether (1.0 equiv) in anhydrous benzene was added tri-n-butyltin
hydride (2.0 equiv) followed by azobisisobutyronitrile (0.5 equiv)
and the mixture was heated under reflux for 2 h. At this point, the
mixture was cooled to room temperature and the solvent was
evaporated. In a separate FalconÒ tube, the resulting residue was
dissolved in CH3CN and treated with HF (48% in H2O) and the
mixture was stirred at room temperature for 1 h. The mixture was
cooled in an ice-water bath and the reaction was quenched by
dropwise addition of saturated NaHCO3 solution. The precipitate
thus formed was filtered off and the filtrate was diluted with H2O
and extracted with CH2Cl2 (3ꢂ30 mL). The combined extract was
dried over anhydrous Na2SO4, filtered, and concentrated on a rota-
tory evaporator. The residue was purified by flash column chro-
matography on silica gel to give the title compound.
J¼10.3, 1.9 Hz, 1H), 3.17e3.14 (m, 1H), 2.83 (d of AB pattern,
J¼16.6 Hz, 1H), 2.73 (d of AB pattern, J¼16.6 Hz, 1H), 2.35e2.23 (m,
2H), 2.00e1.93 (m, 1H), 1.90e1.82 (m, 3H); 13C NMR (150 MHz,
CDCl3) d 193.8,149.5,128.5, 123.3, 44.8, 42.0, 41.9, 35.9, 31.0, 23.0; IR
(neat) 2923, 2853, 1679, 1446, 1386, 1244, 1151, 1055, 842 cmꢁ1
;
HRMS (EI) exact mass calculated for [M]þ (C10H11NO) required m/z
161.0841, found m/z 161.0836.
3.2.3.4. A 2:1 mixture of trans-3-oxobicyclo[4.3.0]non-
anecarbonitrile (23) and cis-3-oxobicyclo[4.3.0]nonanecarbonitrile
(24). Prepared using a silyl enol ether 22 (60.0 mg, 0.186 mmol),
tri-n-butyltin hydride (81.2 mg, 0.279 mmol), azobisisobutyroni-
trile (10.0 mg, 56.0 mmol) in benzene (3.0 mL), a 2:1 mixture of
trans-fused 23 and cis-fused 24 was isolated as a pale yellow oil
(10.3 mg, 34% over two steps) after column chromatography
(hexanes/EtOAc¼4:1). Diastereomers 23 and 24 were separated by
careful column chromatography. Compound 23: 1H NMR
3.2.3.1. A 12:1 mixture of trans-3-oxobicyclo[4.4.0]dec-4-ene-
carbonitrile (14) and cis-3-oxobicyclo[4.4.0]dec-4-enecarbonitrile
(600 MHz, CDCl3)
2.35e2.26 (m, 3H), 2.19e2.16 (m, 1H), 2.08e1.87 (m, 5H), 1.70e1.61
(m, 2H); 13C NMR (150 MHz, CDCl3)
206.3, 120.9, 49.7, 48.3, 47.7,
d 2.93e2.90 (m, 1H), 2.59e2.56 (m, 1H),
(15). Prepared using an exo isomer 12 (35.0 mg, 95.5
butyltin hydride (55.3 mg, 190 mol), azobisisobutyronitrile
(8.0 mg, 48 mol) in benzene (4.0 mL), a 12:1 mixture of trans-
mmol), tri-n-
d
m
39.8, 37.0, 27.6, 25.7, 21.9; IR (neat) 2960, 2873, 2229, 1715, 1457,
1423, 1187, 913 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ
(C10H13NO) required m/z 163.0997, found m/z 163.0988. Compound
m
fused 14 and cis-fused 15 was isolated as a pale yellow oil (13 mg,
78% over two steps) after column chromatography (hexanes/
EtOAc¼4:1). The trans-fused 14 was isolated in pure form by careful
column chromatography. Compound 14: 1H NMR (600 MHz, CDCl3)
24: 1H NMR (500 MHz, CDCl3)
1H), 2.65e2.60 (m, 1H), 2.53 (d of AB pattern, J¼18.0 Hz, 1H),
2.42e2.33 (m, 2H), 2.28e2.22 (m, 1H), 2.18e2.10 (m, 2H), 1.92e1.83
(m, 2H), 1.77e1.70 (m, 2H), 1.66e1.56 (m, 1H); 13C NMR (125 MHz,
d
2.71 (d of AB pattern, J¼18.0 Hz,
d
6.68 (dd, J¼10.1, 1.5 Hz, 1H), 6.14e6.12 (m, 1H), 2.79 (d of AB
pattern, J¼16.7 Hz, 1H), 2.41 (d of AB pattern, J¼16.7 Hz, 1H),
2.38e2.37 (m, 1H), 2.04e2.02 (m, 1H), 1.98e1.94 (m, 2H), 1.83e1.80
(m, 1H), 1.78e1.63 (m, 2H), 1.55e1.50 (m, 1H), 1.48e1.46 (m, 1H);
CDCl3) d 207.3, 124.3, 45.2, 43.5, 42.2, 38.2, 37.0, 30.4, 26.0, 23.0; IR
(neat) 2957, 2872, 2231, 1719, 1526, 1373, 1350, 1241, 1045 cmꢁ1
;
HRMS (EI) exact mass calculated for [M]þ (C10H13NO) required m/z
163.0997, found m/z 163.0988.
13C NMR (150 MHz, CDCl3)
d 194.4, 151.4, 130.0, 120.8, 48.3, 43.6,
43.6, 35.9, 28.2, 25.5, 22.0; IR (neat) 2936, 2861, 2232, 1683, 1448,
1384, 1244, 1159, 982 cmꢁ1; HRMS (EI) exact mass calculated for
[M]þ (C11H13NO) required m/z 175.0997, found m/z 175.0998. The
structure of 14 was also confirmed by X-ray crystallographic anal-
ysis (see Supplementary data).
3.2.3.5. Stereochemical confirmation of cis-3-oxobicyclo[4.3.0]
nonanecarbonitrile (24). To a solution of 20 (20.0 mg, 0.124 mmol)
in degassed CH3OH (4.0 mL) was added Pd(OH)2 (20.0 mg, 20% w/
w). A hydrogen-filled balloon (1 atm) was placed over the solution
and the mixture was stirred at room temperature for 2 h. At this
point, TLC analysis indicated that the reaction was completed. The
mixture was filtered through a pad of CeliteÒ, washed thoroughly
with EtOAc, and the solvents were evaporated. The crude mixture
was purified by flash column chromatography (hexanse/
EtOAc¼2:1) on silica gel to afford cis-fused 24 (19 mg, 94%), whose
spectroscopic properties were in complete accord with the au-
thentic sample.
3.2.3.2. A 10:1 mixture of trans-3-oxobicyclo[4.4.0]dec-4-ene-
carbonitrile (14) and cis-3-oxobicyclo[4.4.0]dec-4-enecarbonitrile
(15). Prepared using an endo isomer 13 (50.0 mg, 0.136 mmol), tri-
n-butyltin hydride (78.6 mg, 0.270 mmol), azobisisobutyronitrile
(11.0 mg, 68.0 mmol) in benzene (5.0 mL), a 10:1 mixture of trans-
fused 14 and cis-fused 15 was isolated as a pale yellow oil (19 mg,
80% over two steps) after column chromatography (hexanes/
EtOAc¼4:1).
3.2.4. Preparation of a 1:7 mixture of trans-3-oxobicyclo[4.3.0]non-
anecarbonitrile (23) and cis-3-oxobicyclo[4.3.0]nonanecarbonitrile
(24). A FalconÒ tube was charged with a silyl enol ether 22
3.2.3.3. A 2:1 mixture of trans-3-oxobicyclo[4.3.0]non-4-ene-
carbonitrile (19) and cis-3-oxobicyclo[4.3.0]non-4-enecarbonitrile
(20). Prepared using a distereomeric mixture of 18 and 180
(200 mg, 0.567 mmol), tri-n-butyltin hydride (329 mg, 1.13 mmol),
azobisisobutyronitrile (47.0 mg, 0.284 mmol) in benzene (6.0 mL),
a 2:1 mixture of trans-fused 19 and cis-fused 20 was isolated as
a pale yellow oil (47 mg, 51% over two steps) after column chro-
matography (hexanes/EtOAc¼8:1). Diastereomers 19 and 20 were
separated by careful column chromatography. Compound 19: 1H
(10.0 mg, 31.0 mmol) and CH3CN (2.0 mL) and HF (48% in H2O,
0.010 mL) was added dropwise. The mixture was stirred at room
temperature for 8 h. The mixture was cooled in an ice-water bath
and the reaction was quenched by dropwise addition of saturated
NaHCO3 solution. The mixture was diluted with H2O and extracted
with CH2Cl2 (3ꢂ4 mL). The combined extract was dried over an-
hydrous Na2SO4, filtered, and concentrated on a rotatory evapora-
tor. The residue was purified by flash column chromatography
(hexanes/EtOAc¼4:1) on silica gel to afford cis-6-nitro-3-oxobicy-
clo[4.3.0]nonanecarbonitrile (4.1 mg, 64%) as a pale yellow oil. cis-
6-Nitro-3-oxobicyclo[4.3.0]nonanecarbonitrile: 1H NMR (500 MHz,
NMR (600 MHz, CDCl3)
d
7.04 (dd, J¼10.0, 1.3 Hz, 1H), 6.14 (dd,
J¼10.0, 2.8 Hz, 1H), 3.05 (d of AB pattern, J¼16.7 Hz, 1H), 2.63e2.59
(m, 1H), 2.39 (d of AB pattern, J¼16.7 Hz, 1H), 2.30e2.26 (m, 1H),
2.18e2.12 (m, 1H), 2.11e2.05 (m, 1H), 2.01e1.93 (m, 1H), 1.86e1.80

6396
W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
CDCl3)
d
3.32 (d of AB pattern, J¼18.8 Hz, 1H), 2.84e2.78 (m, 1H),
mass calculated for [M]þ (C13H18NO2) required m/z 234.1368, found
m/z 234.1383.
2.72 (d of AB pattern, J¼18.8 Hz, 1H), 2.70e2.59 (m, 2H), 2.50e2.45
(m, 1H), 2.44e2.38 (m, 1H), 2.35e2.14 (m, 3H), 1.97e1.88 (m, 2H);
13C NMR (125 MHz, CDCl3)
d
203.0, 119.6, 93.5, 47.5, 43.9, 36.0, 35.7,
3.2.6.2. cis-9a-Nitro-1,2,3,4,4a,5,6,7,8,9,9a,10-dodecahydroan-
34.4, 32.3, 18.1; IR (neat) 2962, 2919, 2889, 2850, 2239, 1724,
1675, 1539, 1419 cmꢁ1; HRMS (EI) exact mass calculated for
[M]þ (C10H12N2O3) required m/z 208.0848, found m/z 208.0855.
thracene-4a-carbonitrile (27). Prepared using 11 (76.1 mg,
0.500 mmol)
and
1,2-dimethylenecyclohexane18
(270 mg,
2.50 mmol), 27 was isolated as an off-white solid (45.6 mg, 35%)
To
a
stirred solution of cis-6-nitro-3-oxobicyclo[4.3.0]non-
after careful column chromatography. 1H NMR (CDCl3, 400 MHz,
anecarbonitrile (27.0 mg, 0.130 mmol, 1.0 equiv) in anhydrous
benzene (2.0 mL) was added tri-n-butyltin hydride (75.7 mg,
0.260 mmol, 2.0 equiv) followed by azobisisobutyronitrile (11.0 mg,
333.15 K)
d
2.79 (d, J¼17.6 Hz, 1H), 2.68 (d of AB pattern, J¼18.8 Hz,
1H), 2.54 (d of AB pattern, J¼18.8 Hz, 1H), 2.31e2.24 (m, 1H), 2.20
(d, J¼18.0 Hz, 1H), 2.10e2.02 (m, 2H), 1.92e1.56 (m, 13H); 13C NMR
70.0
mmol, 0.5 equiv) and the mixture was heated under reflux for
(CDCl3,100 MHz, 333.15 K) d 124.2,123.1,121.5, 90.4, 39.7, 39.4, 36.1,
1.5 h. At this point, the mixture was cooled to room temperature
and the solvent was evaporated. The residue was purified by flash
column chromatography (hexanes/EtOAc¼6:1) on silica gel to give
a 1:7 mixture of trans-fused 23 and cis-fused 24 (16 mg, 75%).
34.0, 32.8, 29.7, 29.5, 29.3, 22.6, 22.1, 21.0; IR (KBr) 2930, 2236,1789,
1546, 1439, 851 cmꢁ1; HRMS (EI) exact mass calculated for [Mþ1]þ
(C15H21N2O2) required m/z 261.1603, found m/z 261.1607.
3.2.7. General procedure for the DielseAlder reaction of 2-nitro-
cyclopentenecarbonitriles (17) with simple dienes. A sealable vial
reactor equipped with a magnetic stirring bar was charged with 2-
3.2.5. Preparation of tricyclic compound 25. A sealable vial reactor
equipped with a magnetic stirring bar was charged with 2-
nitrocyclohexenecarbonitrile (11, 70.0 mg, 0.460 mmol, 1.0 equiv),
2,3-dimethyl-1,3-butadiene (379 mg, 4.60 mmol, 10 equiv), 2,6-
nitrocyclopentenecarbonitriles
1.0 equiv), a simple diene (0.750 mmol, 3.0 equiv), 2,6-di-tert-bu-
tyl-4-methylphenol (2.8 mg, 13 mol, 5.0 mol %), and anhydrous
(17,
34.5 mg,
0.250 mmol,
di-tert-butyl-4-methylphenol (10.1 mg, 46.0
m
mol, 0.1 equiv), and
m
anhydrous toluene (2.0 mL). The reactor was sealed and the
mixture was stirred at 150 ꢀC in a pre-heated oil bath for 24 h. At
this point, the mixture was cooled to room temperature and the
solvent was evaporated. The resulting residue was purified by
flash column chromatography (hexanes/EtOAc¼14:1) on silica gel
to afford the title compound (32.0 mg, 33%) as a tan/orange sticky
toluene (0.5 mL). The reactor was sealed and the mixture was
stirred at 100 ꢀC in a pre-heated oil bath for 24 h. At this point, the
mixture was cooled to room temperature and the solvent was
evaporated. The resulting residue was purified by column chro-
matography (hexanes/EtOAc¼9:1) on silica gel to afford the title
compound.
solid. 1H NMR (500 MHz, CDCl3)
(m, 1H), 2.41e2.29 (m, 2H), 2.12e1.88 (m, 5H), 1.70 (s, 3H), 1.65
(s, 3H), 1.56e1.54 (m, 2H); 13C NMR (125 MHz, CDCl3)
180.0,
d 2.81e2.74 (m, 1H), 2.67e2.64
3.2.7.1. cis-3,4-Dimethyl-6-nitrobicyclo[4.3.0]non-3-en-1-car-
bonitrile (28). Prepared using 17 (34.5 mg, 0.250 mmol) and 2,3-
dimethyl-1,3-butadiene (61.6 mg, 0.750 mmol), 28 was isolated
as a pale yellow oil (52.3 mg, 95%) after column chromatography.
d
172.2, 124.2, 117.1, 47.4, 38.3, 32.4, 30.5, 27.7, 26.3, 24.2, 19.4, 18.5;
IR (neat) 2931, 2863, 1785, 1715, 1452, 1386, 1086 cmꢁ1; mp
80e86 ꢀC; HRMS (EI) exact mass calculated for [M]þ (C13H17NO2)
required m/z 219.1259, found m/z 219.1250. The structure of 25
was also confirmed by X-ray crystallographic analysis (see
Supplementary data).
1H NMR (600 MHz, CDCl3)
d
2.80 (d of AB pattern, J¼18.4 Hz, 1H),
2.72 (d of AB pattern, J¼18.0 Hz, 1H), 2.64e2.60 (m, 1H), 2.49 (d
of AB pattern, J¼18.4 Hz, 1H), 2.35e2.31 (m, 1H), 2.28 (d of AB
pattern, J¼18.0 Hz, 1H), 2.15e2.10 (m, 1H), 2.09e1.02 (m, 1H),
1.99e1.94 (m, 1H), 1.91e1.85 (m, 1H), 1.66 (s, 6H); 13C NMR
3.2.6. General procedure for the DielseAlder reaction of 2-nitro-
cyclohexenecarbonitriles (11) with simple dienes. A sealable tube
equipped with a magnetic stirring bar was charged with 2-nitro-
cyclohexenecarbonitrile (11, 76.1 mg, 0.500 mmol, 1.0 equiv),
(150 MHz, CDCl3) d 121.4, 121.3, 121.2, 95.0, 43.4, 38.8, 37.6, 35.0,
34.5, 18.5, 18.3; IR (neat) 2986, 2964, 2915, 2891, 2861, 2237,
1537, 1457, 1431, 1354, 1133 cmꢁ1; HRMS (EI) exact mass calcu-
lated for [M]þ (C12H16N2O2) required m/z 220.1212, found m/z
220.1214.
a
simple diene (5e10 equiv), 2,6-di-tert-butyl-4-methylphenol
(5.5 mg, 25 mol, 5.0 mol %), and anhydrous lithium perchlorate
m
(532 mg, 5.00 mmol, 10 equiv). Under an atmosphere of argon, the
mixture was cooled at 0 ꢀC and anhydrous THF (1.0 mL) was added
slowly. After stirring of the mixture for 10 min, the cooling bath was
removed and the tube was sealed. The mixture was then stirred at
100 ꢀC in a pre-heated oil bath for 60 h. At this point, the mixture
was cooled to room temperature, diluted with H2O, and extracted
with CH2Cl2 (3ꢂ15 mL). The combined extract was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated on
a rotatory evaporator. The resulting residue was purified by gradi-
ent column chromatography (hexanes/EtOAc¼9:1/8:1) on silica
gel to afford the title compound.
3.2.7.2. cis-9a-Nitro-2,3,3a,4,5,6,7,8,9,9a-decahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (29). Prepared using 17
(34.5 mg,
0.250 mmol)
and
1,2-dimethylenecyclohexane18
(81.1 mg, 0.750 mmol), 29 was isolated as a pale yellow oil
(56.0 mg, 91%) after column chromatography. 1H NMR (CDCl3,
400 MHz)
d
2.75 (d of AB pattern, J¼18.0 Hz,1H), 2.70e2.60 (m, 2H),
2.44 (d of AB pattern, J¼18.0 Hz, 1H), 2.38e2.31 (m, 1H), 2.23 (d,
J¼17.6 Hz, 1H), 2.19e1.82 (m, 8H), 1.67e1.57 (m, 4H); 13C NMR
(CDCl3, 100 MHz)
d 123.6, 123.5, 121.3, 94.8, 43.2, 37.8, 36.6, 35.0,
34.5, 29.3, 29.2, 22.5, 22.5, 18.4; IR (neat) 2924, 2239, 1726, 1549,
1439, 1361, 845 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ
(C14H18N2O2) required m/z 246.1368, found m/z 246.1383.
3.2.6.1. cis-3,4-Dimethyl-6-nitrobicyclo[4.4.0]dec-3-en-1-carbon-
itrile (26). Prepared using 11 (76.1 mg, 0.500 mmol) and 2,3-di-
methyl-1,3-butadiene (410 mg, 5.00 mmol), 26 was isolated as an
off-white solid (30.5 mg, 26%) after careful column chromatogra-
3.2.8. General procedure for the radical denitration of cis-fused
decalin (26 and 27) and hydrindane (28 and 29) systems. A 15-mL
Schlenk-type flask equipped with a magnetic stirring bar and
a reflux condenser was charged with a cis-fused decalin or
hydrindane derivative (1.0 equiv), tri-n-butyltin hydride
(2.0 equiv), azobisisobutyronitrile (0.3e0.5 equiv), and anhydrous
benzene. The mixture was heated under reflux for 2 h. At this point,
the mixture was cooled to room temperature and the solvent was
evaporated. The resulting residue was purified by gradient column
phy. 1H NMR (CDCl3, 400 MHz, 333.15 K)
d
2.85 (d, J¼18.0 Hz, 1H),
2.76 (d of AB pattern, J¼18.8 Hz, 1H), 2.60 (d of AB pattern,
J¼18.8 Hz, 1H), 2.32e2.24 (m, 2H), 2.10e2.02 (m, 2H), 1.86e1.55 (m,
5H), 1.64 (s, 6H); 13C NMR (CDCl3, 100 MHz, 333.15 K)
d 121.8, 121.4,
120.8, 90.4, 40.5, 39.7, 37.1, 33.9, 32.7, 22.0, 20.9, 18.4, 18.2; IR (KBr)
2933, 2865, 2232, 1789, 1544, 1455, 851 cmꢁ1; HRMS (EI) exact

W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
6397
chromatography (hexanes/EtOAc¼1:0/97:3/19:1) on silica gel
(1:2, v/v) at ꢁ20 ꢀC was added Zn dust (10 equiv). After stirring for
3 h, the mixture was filtered through a pad of CeliteÒ and the fil-
trate was concentrated on a rotatory evaporator. The resulting
residue was dissolved in THF and the mixture was treated succes-
sively with a saturated solution of NaHCO3 and allyl chloroformate
(2.5 equiv). The mixture was stirred for 3 h, diluted with H2O, and
extracted with EtOAc (3ꢂ10 mL). The combined extract was
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated on a rotatory evaporator. The resulting residue was
purified by gradient column chromatography on silica gel to afford
the title compound.
to afford the title compound.
3.2.8.1. trans-3,4-Dimethylbicyclo[4.4.0]dec-3-en-1-carbonitrile
(30a). Prepared using 26 (41.0 mg, 0.175 mmol), tri-n-butyltin hy-
dride (102 mg, 0.350 mmol), and azobisisobutyronitrile (8.6 mg,
52
yellow oil (29.5 mg, 89%) after column chromatography. The minor
isomer, cis-fused 30b was not detected within the limits of 1H and 13
NMR. 1H NMR (CDCl3, 400 MHz)
2.21 (d, J¼16.8 Hz, 1H), 2.05e1.89
(m, 3H), 1.80e1.75 (m, 1H), 1.72e1.58 (m, 3H), 1.62 (s, 6H), 1.49e1.41
(m, 1H),1.37e1.23 (m, 4H); 13C NMR (CDCl3,100 MHz)
125.8,122.6,
mmol) in benzene (1.8 mL), trans-fused 30a was isolated as a pale
C
d
d
121.9, 43.2 (CH2), 39.9 (CH), 39.6, 36.9 (CH2), 36.6 (CH2), 29.9 (CH2),
25.5 (CH2), 23.1 (CH2), 18.7 (CH3), 18.6 (CH3); IR (neat) 2926, 2230,
1738, 1448, 1382 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ
(C13H19N) required m/z 189.1517, found m/z 189.1516.
3.2.9.1. cis-Allyl 8a-cyano-6,7-dimethyl-1,2,3,4,4a,5,8,8a-octahy-
dronaphthalen-4a-ylcarbamate (34). Prepared using 26 (20.0 mg,
85.4
(25.7 mg, 214
40%) after column chromatography. 1H NMR (600 MHz, CDCl3)
5.95e5.88 (m, 1H), 5.32e5.28 (m, 1H), 5.23e5.21 (m, 1H), 4.92 (s,
mmol), Zn dust (55.8 mg, 854
mmol), and allyl chloroformate
mmol), 34 was isolated as a pale yellow oil (10 mg,
3.2.8.2. trans-1,2,3,4,4a,5,6,7,8,9,9a,10-Dodecahydroanthracene-
d
4a-carbonitrile (31a). Prepared using 27 (21.0 mg, 80.7
butyltin hydride (47 mg, 161 mol), and azobisisobutyronitrile
(6.6 mg, 40 mol) in benzene (0.8 mL), trans-fused 31a was isolated
m
mol), tri-n-
1H), 4.54e4.48 (m, 2H), 2.67 (d of AB pattern, J¼17.9 Hz, 1H),
2.50e2.42 (m, 2H), 2.25 (d of AB pattern, J¼17.9 Hz, 1H), 2.12e1.98
(m, 2H), 1.81e1.77 (m, 1H), 1.72e1.62 (m, 4H), 1.63 (s, 3H), 1.62 (s,
m
m
as an off-white solid (14.8 mg, 85%) after column chromatography.
3H), 1.52e1.47 (m, 1H); 13C NMR (150 MHz, CDCl3)
d 154.4, 132.8,
The minor isomer, cis-fused 31b was not detected within the limits
123.2, 126.7, 119.3, 117.8, 65.3, 55.0, 41.5, 38.5, 36.2, 31.3, 30.2, 29.7,
21.2, 18.7, 18.3; IR (neat) 3346, 2933, 2865, 2232, 1724, 1509, 1450,
1294, 1231,1111,1046, 985 cmꢁ1; HRMS (FAB) exact mass calculated
for [Mþ1]þ (C17H25N2O2) required m/z 289.1916, found m/z
289.1919.
of 1H and 13C NMR. 1H NMR (CDCl3, 400 MHz)
d
2.15 (d, J¼16.8 Hz,
1H), 2.05e1.95 (m, 2H), 1.88e1.45 (m, 14H), 1.37e1.24 (m, 4H); 13C
NMR (CDCl3, 100 MHz) 128.0, 124.3, 122.7, 42.1 (CH2), 39.8 (CH),
d
39.4, 36.8 (CH2), 35.7 (CH2), 30.0 (CH2), 29.7 (CH2), 29.6 (CH2), 25.5
(CH2), 23.2 (CH2), 22.8 (CH2), 22.7 (CH2); IR (KBr) 2925, 2830, 2228,
1738, 1449, 1320 cmꢁ1; HRMS (EI) exact mass calculated for [M]þ
(C15H21N) required m/z 215.1674, found m/z 215.1658.
3.2.9.2. cis-Allyl 7a-cyano-5,6-dimethyl-2,3,3a,4,7,7a-hexahydro-
1H-inden-3a-ylcarbamate (35). Prepared using 28 (20.0 mg,
90.8
(27.4 mg, 227
52%) after column chromatography. 1H NMR (600 MHz, CDCl3)
m
mol), Zn dust (59.4 mg, 908
mmol), and allyl chloroformate
3.2.8.3. A 1.5:1 mixture of trans-3,4-dimethylbicyclo[4.3.0]non-
3-enecarbonitrile (32a) and cis-3,4-dimethylbicyclo[4.3.0]non-
3-enecarbonitrile (32b). Prepared using 28 (30.8 mg, 0.140 mmol),
tri-n-butyltin hydride (81.5 mg, 0.280 mmol), and azobisisobutyr-
mmol), 35 was isolated as a pale yellow oil (13 mg,
d
5.95e5.89 (m,1H), 5.33e5.30 (m,1H), 5.23 (dd, J¼10.4,1.3 Hz,1H),
5.01 (s,1H), 4.54 (d, J¼5.5 Hz, 2H), 2.50e2.39 (m, 4H), 2.25e2.16 (m,
2H), 2.05e1.91 (m, 2H), 1.88e1.75 (m, 2H), 1.63 (s, 3H), 1.62 (s, 3H);
onitrile (11.5 mg, 70.0 mmol) in benzene (1.4 mL), an inseparable
1.5:1 mixture of trans-fused 32a and cis-fused 32b was isolated as
an pale yellow oil (18.9 mg, 77%) after column chromatography. The
relative stereochemistry of the major isomers was assigned
according to Casadevall’s observation and our previous study.2 Di-
astereomeric ratios were estimated by the integration of the
methine carbon signals. 1H and 13C NMR spectra of the mixture of
32a and 32b are available in Supplementary data. IR (neat) 2959,
2914, 2836, 2231, 1727, 1452, 1275, 1124, 1073 cmꢁ1; HRMS (EI)
exact mass calculated for [M]þ (C12H17N) required m/z 175.1361,
found m/z 175.1358.
13C NMR (150 MHz, CDCl3)
d 155.0, 132.6, 123.9, 122.7, 119.8, 118.0,
65.5, 62.5, 45.2, 37.7, 37.6, 34.7, 29.7, 19.3, 18.8, 18.4; IR (neat) 3332,
2916, 2886, 2849, 2233, 1724, 1510, 1445, 1274, 1238, 1086,
916 cmꢁ1
;
HRMS (FAB) exact mass calculated for [Mþ1]þ
(C16H23N2O2) required m/z 275.1760, found m/z 275.1772.
Acknowledgements
Support was provided by the NIH (HL25848 to S.J.D.). W.H.K. is
grateful for a Korea Research Foundation Grant funded by the Ko-
rean government (KRF-2007-357-c00060). We thank Rebecca
Wilson for assistance with the preparation of the manuscript and
Dr. Peter K. Park (Columbia University), Dr. Bernhard Fasching
(MSKCC), Dr. Jennifer Stockdill (MSKCC), and Dr. Pavel Nagorny
(MSKCC) for helpful discussions. We also thank Dr. George Suke-
nick, Ms. Hui Fang, Sylvi Rusli (NMR Core Facility, Sloan-Kettering
Institute), and Dr. Yasuhiro Itagaki (Mass Spectral Core Facility,
Columbia University) for mass spectral and NMR.
3.2.8.4. A 1.7:1 mixture of trans-2,3,3a,4,5,6,7,8,9,9a-decahydro-
1H-cyclopenta[b]naphthalene-3a-carbonitrile (33a) and cis-2,3,3a,
4,5,6,7,8,9,9a-decahydro-1H-cyclopenta[b]naphthalene-3a-carbon-
itrile (33b). Prepared using 29 (34.5 mg, 0.140 mmol), tri-n-butyl-
tin hydride (81.5 mg, 0.280 mmol), and azobisisobutyronitrile
(11.5 mg, 70.0 mmol) in benzene (1.4 mL), an inseparable 1.7:1
mixture of trans-fused 33a and cis-fused 33b was isolated as an pale
yellow oil (25.2 mg, 89%) after column chromatography. The rela-
tive stereochemistry of the major isomers was assigned according
to Casadevall’s observation and our previous study.2 Di-
astereomeric ratios were estimated by the integration of the
methine carbon signals. 1H and 13C NMR spectra of the mixture of
32a and 32b are available in Supplementary data. IR (neat) 2927,
2833, 2230,1729,1440,1312 cmꢁ1; HRMS (EI) exact mass calculated
for [M]þ (C14H19N) required m/z 201.1517, found m/z 201.1523.
Supplementary data
1H and 13C NMR spectra of all new compounds are available.
Crystallographic data for the structures reported in this article have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC-763857 (13), CCDC-
763854 (14), CCDC-763855 (19), and CCDC-763856 (25). Copies of
the data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK [Tel.: þ44 1223 336
408, fax: þ44 1223 336 033 or e-mail: deposit@ccdc.cam.ac.uk].
3.2.9. General procedure for the preparation of cis-fused angular
amine derivatives. To a stirred solution of a cis-fused decalin or
hydrindane (1.0 equiv) in a mixture of glacial acetic acid and THF

6398
W.H. Kim et al. / Tetrahedron 66 (2010) 6391e6398
11. The relative stereochemistry of 24 was confirmed by its preparation through
the catalytic hydrogenation of cis-fused 20 (H2, Pd(OH)2, CH3OH, room tem-
perature, 2 h, 94%). For details, see Experimental section.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2010.04.094.
12. The operative dienophile formally corresponds to either (i) or (ii), in principle
derivable from the thermolysis of 11 via cyclization, tautomerization, and de-
hydration in a sequence, which has not been defined.
References and notes
+
1. For recent reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369e396; (b)
Douglas, C.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363e5367; (c)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388e401.
2. Kim, W. H.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 12576e12578.
3. For examples of DielseAlder reactions of cyclohexenecarboxaldehyde or its
corresponding acetal to obtain cis-fused bicyclic ring system with all-carbon
quaternary center on the bridgehead, see: (a) Szmuszkowicz, J.; Bergmann, E. D.
Bull. Res. Counc. Israel 1953, 3, 93e95; (b) Bergmann, E. D.; Becker, A. J. Am.
Chem. Soc. 1959, 81, 221e225; (c) Lee, J. H.; Kim, W. H.; Danishefsky, S. J. Tet-
rahedron Lett. 2010, 51, 1252e1253.
–O
O
O
N
N
N
X
C
(i) X = O
11
(ii) X = NH
4. Most examples of tetrasubstituted cyclic dienophiles are limited to quinone
and maleic anhydride derivatives. For examples, see: (a) Kwon, O.; Park, S. B.;
Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 13402e13404; (b) Nicolaou, K. C.;
ꢀ
ꢀ
13. (a) Koprowski, M.; Skowronska, A.; Glówka, M. L.; Fruzinski, A. Tetrahedron
2007, 63, 1211e1228; (b) Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc.
1990, 112, 4595e4596.
€
Vassilikogiannakis, G.; Magerlein, W.; Kranich, R. Angew. Chem., Int. Ed. 2001,
40, 2482e2486.
14. Comparison with authentic sample of the cis-isomers indicates the presence of
only the trans-isomers within the limits of 1H and 13C NMR. For the analytical
data of the cis-isomers, see Ref. 3c. In accord with Casadevall’s observation, the
ring junction carbons of trans-fused 30a and 31a are more deshielded than
those of cis-fused 30b and 31b: Metzger, P.; Casadevall, E.; Pouet, M. J. Org.
Magn. Reson. 1982, 19, 229e234.
5. (a) Fuji, K.; Tanaka, K.; Abe, H.; Matsumoto, K.; Taga, T.; Miwa, Y. Tetrahedron:
Asymmetry 1992, 3, 609e612; (b) Piaz, V. D.; Giovannoni, M. P.; Ciciani, G.;
Giomi, D.; Nesi, R. Tetrahedron Lett. 1993, 34, 161e162; (c) Nesi, R.; Giomi, D.;
Papaleo, S.; Corti, M. J. Org. Chem. 1990, 55, 1227e1230.
6. Our efforts to accomplish the DielseAlder reaction of methyl 2-nitro-
cyclohexenecarboxylate (i.e., 5, A¼CO2Me) with
a
range of dienes were
15. Hydrindanes 30 and 32 were obtained as inseparable mixtures of the cis- and
trans-isomers. The relative stereochemistry of the major isomers was assigned
according to Casadevall’s observation and our previous study.2 Diastereomeric
ratios were estimated by the integration of the methine carbon signals.
16. Corey, E. J.; Estreicher, H. J. J. Am. Chem. Soc. 1978, 100, 6294e6295.
17. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.
18. (a) Arenz, T.; Vostell, M.; Frauenrath, H. Synlett 1991, 23e24; (b) Block, E.;
Aslam, M. Org. Synth. 1987, 65, 90e97.
unsuccessful.
7. Jayakanthan, K.; Madhusudanan, K. P.; Vankar, Y. D. Tetrahedron 2004, 60,
397e403.
8. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807e7808.
9. Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.; Kaji, A. Tetra-
hedron 1985, 41, 4013e4023.
10. Jung, M. E.; McComb, C. A. Tetrahedron Lett. 1976, 17, 2935e2938.