Diels-Alder reactions of masked o-benzoquinones with acrylonitrile

Article abstract of DOI:10.1016/S0040-4020(03)00585-4

Regioselective Diels-Alder reactions of masked o-benzoquinones (MOBs) 2a-i derived from the corresponding 2-methoxyphenols 1a-i with acrylonitrile leading to highly functionalized bicyclo[2.2.2]octenone derivatives in high yields are described.

Full text of DOI:10.1016/S0040-4020(03)00585-4

Tetrahedron 59 (2003) 4039–4046
Diels–Alder reactions of masked o-benzoquinones
with acrylonitrile
*
Santhosh Kumar Chittimalla and Chun-Chen Liao
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, ROC
Received 18 March 2003; revised 8 April 2003; accepted 10 April 2003
Abstract—Regioselective Diels–Alder reactions of masked o-benzoquinones (MOBs) 2a–i derived from the corresponding
2-methoxyphenols 1a–i with acrylonitrile leading to highly functionalized bicyclo[2.2.2]octenone derivatives in high yields are
described. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
laboratory and it was found that these cycloadditions
proceeded in highly regio- and stereoselective manner.
The Diels–Alder cycloaddition reaction occupies a
position of particular prominence among the carbon–
carbon bond forming reactions. Its widespread application
is the introduction of up to four new contiguous
asymmetric centers with good yields, high selectivity and
It is well known that a nitrile group, which is a useful and
important functionality in organic synthesis can be trans-
formed into various functional groups such as carboxylic
acid, amide, amine, aldehyde, ketone, alcohol, etc. A nitrile
1
predictability.
was transformed into a methyl group in the synthesis of
9
(
During the synthetic study of epolactaene, a nitrile was
þ/2)-scopadulin an antiviral aphidicolane diterpene.
Recently, the Diels–Alder reactions of 6,6-dialkoxycyclo-
hexa-2,4-dienones generically known as masked o-benzo-
1
0
transformed to an amide functionality. In the Diels–Alder
reaction of 2-cyano-2-cyclohexenone, a nitrile group was
used as an activating group which could be easily removed
or replaced by an alkyl group. This strategy was success-
fully used by Liu and co-workers in the synthesis of cis-
2
quinones (MOBs) are extensively studied. The excellent
selectivities observed in the Diels–Alder reactions of
MOBs coupled with the synthetic utility of the cycloadducts
made these MOBs very attractive Diels–Alder partners.
MOBs can be easily generated in situ by the oxidation of the
corresponding 2-methoxyphenols with hypervalent iodine
reagents such as (diacetoxy)iodobenzene (DAIB) and
phenyliodonium(III) bis(trifluoroacetate) in the presence
of an alcohol. In view of the high propensity of most of these
1
1
clerodane diterpenoids. A 1,3-dipolar cycloaddition
reaction of acrylonitrile to N-benzyl-3-hydroxypyridinium
bromide was used as a key step in the total synthesis of Bao
1
2
Gong Teng A, a natural antiglaucoma compound.
Intrigued by the synthetic potential of a nitrile functionality
and highly reactive MOB building blocks, we have
investigated the Diels–Alder reactions of acrylonitrile
with various MOBs and contemplated that their cyclo-
adducts would be of potentially useful synthetic inter-
mediates. Herein we report the details of our studies on
these Diels–Alder reactions.
3
MOBs to undergo facile dimerization, they are usually
trapped in situ by reactive p-components to provide various
highly functionalized bicyclic and tricyclic ring systems via
inter- and intramolecular Diels–Alder reactions,
2
respectively. The Diels–Alder reactions of MOBs with
several dienophiles including methyl acrylate, methyl
methacrylate, methyl vinyl ketone (dienophiles bearing
4
electron-withdrawing group), styrene, benzyl vinyl ether,
phenyl vinyl sulfide, dihydrofuran (dienophiles bearing
2. Results and discussion
5
6
electron-donating group) and heteroaromatics like furans,
7
pyrroles, thiophene were extensively studied in this
8
At the outset, the Diels–Alder reaction of the reactive MOB
2a, generated in situ from methyl vanillate (1a) was studied
as a representative example. Thus, MOB 2a was slowly
generated in the presence of acrylonitrile by adding DAIB
over a period of 6 h (Method A) to afford a 1.1:1 mixture of
endo–exo isomers 3a and 4a along with 45% of dimer 5a
(Scheme 1). However, when the in situ generation of MOB
Keywords: 2-methoxyphenols; masked o-benzoquinones; acrylonitrile;
Diels–Alder reactions; bicyclo[2.2.2]octenones.
*
Corresponding author. Tel.: þ886-3-5715131x3388; fax: þ886-3-
5728123; e-mail: ccliao@mx.nthu.edu.tw
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00585-4

4040
S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
Scheme 1.
2
a was attempted by adding 1a to a mixture of acrylonitrile
and DAIB in methanol (Method B), a white solid was
obtained, presumably due to the polymerization of
acrylonitrile.
Scheme 2.
To circumvent this problem, MOB 2a was first generated at
0
1
and acrylonitrile was then added in one portion. The
reaction was brought to room temperature (Method C) and
stirring was continued until the reaction was complete
8C, confirmed by the disappearance of the starting phenol
a on TLC that implies the complete consumption of DAIB,
The solvent was evaporated, dienophile (25 equiv.) was
added, and the reaction was performed at appropriate
temperature (Methods C–E) as shown in Table 2. In each
case, no dimers of MOBs were observed, and the two
stereoisomers 3 (ortho, endo-) and 4 (ortho, exo-) were
1
(
disappearance of MOB on TLC). However, the reaction
obtained as indicated by the H NMR (400 MHz) spectra of
was found to be sluggish. Alternatively, the same procedure
was repeated at 508C (Method D) and 1008C (Method E),
where enhancement in the reaction rate was observed in
both cases. Nevertheless, two stereoisomers 3a and 4a were
isolated in poor yields along with a considerable amount of
dimer 5a (Scheme 1, Table 1). For this reason we envisioned
that the isolable MOBs could be utilized in the present study
where (i) the propensity to dimerization of these MOBs is
less (ii) even the presence of traces of DAIB can be avoided
and also (iii) the Diels–Alder reaction can be carried out
without the solvent (neat) thereby enhancing the rate of the
reaction by increase of concentration. Accordingly, several
MOBs 2b–i were prepared from the corresponding
the crude products. The reactions proceeded regio-
selectively, 3 being the major products (Scheme 2,
Table 2). When MOBs 2a–d and 2i were used, the resulted
isomers could be separated by column chromatography
unlike in the cases of MOBs 2e–h which afforded an
inseparable mixtures. However, 4e (ortho, exo-), 3g (ortho,
endo-), 3h (ortho, endo-) could be obtained in their pure
states by recrystalization from their mixtures of stereo-
isomers. It is interesting to note that the non-dimerizing
MOB 2i gave two regioisomers ortho, endo-3i and meta,
endo-6i, respectively, 3i being the major adduct (Scheme 3).
The structures of all the products were assigned on the basis
1
13
2
-methoxyphenols 1b–i, following the procedure
3
of their IR, H and C NMR, DEPT, and low- and high-
resolution mass spectral analyses. For all the cycloadducts,
satisfactory elemental analyses were obtained. For most of
the high-resolution mass spectra recorded in electron impact
1
developed in our laboratory and purified by flash
chromatography (ethyl acetate–hexanes 1:4) (Scheme 2).
mode (70 eV), the peaks corresponding to the molecular ion
þ
Table 1. Diels–Alder reactions of MOB 2a with acrylonitrile
(M ) could not be seen; instead the peaks corresponding to
M 228 were observed, indicating the extrusion of CO
a
Method (temp)
b
Time (h)
þ
Entry
Adduct
resulted from facile fragmentation. All the cycloadducts
exhibited IR absorptions at 2240–2340 and 1745–
1
c
Yield (%)
d
Ratio
758 cm2 , due to the characteristic features of nitrile and
carbonyl functional groups, respectively. All the com-
1
3
a
4a
5a
3a–4a
1
3
1
2
3
4
5
A (08C)
B (08C)
C (rt)
D (508C)
E (1008C)
1
–
12
2
0.5
10
–
8
15
22
6
–
6
11
15
45
–
60
48
34
1.1:1
–
1.2:1
1.2:1
1.2:1
pounds showed C resonance at about d 194.5–197.8 and d
18.0–120.8 also revealing the presence of carbonyl and
nitrile groups, respectively. Further, the peak corresponding
e
1
to the CH attached to nitrile carbon was observed at about d
23.5–31.6 and the quarternary carbon with two methoxy
All the reactions were carried out at 1 mM of 1a and 25 mM of
acrylonitrile.
groups was found to be present at d 92.8–95.1. The olefinic
carbons were observed at d 119.0–147.0 depending on the
substitutions on the double bond.
a
See Section 3.
In entry 1, it indicates the reaction time after the addition of DAIB. In
b
entries 3–5, it indicates the reaction time after the addition acrylonitrile to
in situ generated MOB.
The yields are of isolated products.
The regiochemistry of 3c,3d,4c and 4d was confirmed by
NOE studies (Fig. 1). In the case of 3c, saturation of both the
c
d
1
The ratios are of the stereoisomers and were determined from the
NMR analysis of the crude reaction mixture.
Polymerization of acrylonitrile was observed.
H
–OMe gave rise to increase in the signal intensity of He
(0.18%) while saturation of H brought about a significant
e
d

S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
Table 2. Diels–Alder reactions of MOBs 2b–i with acrylonitrile
4041
a
Method (temp)
Entry
Phenol
MOB
Time
Adducts
b
c
Yield %
Ratio
endo-3
exo-4
endo-3–exo-4
1
2
3
4
5
6
7
8
9
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
C (rt)
18.5 h
8 h
1 h
6 h
25 min
5 min
12.5 h
4 h
35 min
17 h
4 h
1 h
21 h
6.5 h
2 h 40 min
14 h
2.5 h
7 min
8 h
3b/55
3b/61
3b/57
3c/60
3c/72
3c/72
3d/68
3d/56
3d/56
4b/29
4b/30
4b/30
4c/17
4c/19
4c/21
4d/25
4d/36
4d/32
1.9:1
2:1
2:1
3:1
3:1
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
E (1008C)
C (rt)
D (508C)
(1008C)
3:1
2.5:1
1.6:1
1.6:1
1.3:1
1.3:1
1.3:1
1.4:1
1.5:1
1.4:1
1:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3e14e/92
3e14e/95
3e14e/88
3f14f/92
3f14f/80
3f14f/92
3g14g/75
3g14g/80
3g14g/70
3h14h/85
3h14h/74
3h14h/70
1f
1f
2f
2f
1g
1g
1g
1h
1h
1h
1i
2g
2g
2g
2h
2h
2h
2i
1:1
1:1
5:1
2.7:1
2:1
1 h
10 min
48 h
48 h
d
d
–
–
d
d
1i
1i
2i
2i
–
–
3:1
e
f
3 Days
3i/68
6i/23
All the reactions were carried out at 1 mM of MOB 2 and 25 mM of acrylonitrile.
See Section 3.
a
b
The yields are of isolated products; and the yields in entries 10–21 represent the combined yields of inseparable endo- and exo-isomers.
1
The ratios of stereoisomers were determined from the H NMR of crude reaction mixture.
The starting material (85–90%) was recovered.
The reaction was carried out in a sealed tube.
The ratio of the regioisomers 3i and 6i, respectively.
c
d
e
f
NOE in H (1.85%) and H (2.03%). For 3d, saturation of
f
e
–
OMe gave rise to the increase in signal intensity of He
0.36%) that proves the assigned ortho-regio chemistry,
(
while saturation of H gave rise to the enhancement in signal
g
intensity of H (1.82%) and H (1.00%) thus confirming the
e
f
endo-stereochemistry. In the case of 4c, saturation of Hd
brought about significant NOE on the signal intensities of Hf
Scheme 3.
(0.43%) and H (0.63%) and for 4d, when H was saturated,
the increase in the signal intensity of H (0.84%) and H
e
d
f
e
(
0.70%) was observed proving them to be ortho-adducts.
1
The H NMR spectra of 3b,3c and 3i showed long range
coupling between Hb and Hg of 0.8, 0.4 and 0.8 Hz,
respectively, confirming the given ortho,endo-assignment.
The structures of all the other compounds were confirmed
by comparing the chemical shifts [d H (endo),d H (exo), d
f
f
H (endo).d H (exo) and d H (endo).d H (exo)] and
e
e
g
g
coupling constants [J /J
0
, J /J
0
and Jb,g] of a particular
e,g e,g f,g f,g
set of protons as shown in Table 3 and by decoupling
experiments. For the cases where isomers could not be
separated, the chemical shifts and coupling constants of H ,
e
1
H and H in the H NMR spectra of the mixture of isomers
f
g
were used for the characterization. Single crystal X-ray
1
4
15
crystallography studies of 3h (Fig. 2) and 4b (Fig. 3) are
fully in consonance with their assigned structures.
1
Similarly, in the H NMR spectra of 6i, a long range
coupling (J¼0.8 Hz) between H and H , the proton on the
c
e
carbon with a nitrile function was observed and H exhibited
a
coupling constants of 3.6 and 2.8 Hz with the methylene
1
Figure 1. H NMR studies of NOE (%) for 3c,4c,3d, and 4d.

4042
S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
Table 3. Selected chemical shifts (d) and coupling constants (J in Hz) of the adducts 3a–i and 4a–h
Adduct
H
b
H
e
H
f
H
g
/H
g
0
J
a,g
J
b,g/Jb,g
0
J
d,e
J
d,f
J
e,f
J
e,g/Je,g
0
J
f,g/Jf,g
0
a
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
7.16
6.26
6.32
6.43
–
2.55
2.50
2.50
2.58
2.55
2.51
2.48
2.53
2.58
2.47
2.41
2.40
2.32
2.46
2.43
2.41
2.45
1.69
1.67
1.77
1.95
1.75
1.91
1.91
1.98
1.92
1.88
1.86
1.95
2.12
1.91
2.09
3.21
3.12
3.18
2.0
2.0
–
–
2.8
2.8
2.8
3.2
2.8
2.8
2.8
2.8
–
3.2
2.8
3.2
3.2
2.8
2.8
3.2
3.2
–
13.6
12.4
13.2
13.2
13.2
13.2
13.6
13.6
12.4
13.2
13.2
13.2
13.2
13.2
13.6
13.2
13.2
8.8
5.6
6.0
5.6
5.6
6.0
5.6
5.2
5.6
5.2
0.8
0.4
10.0
10.4
10.2
10.0
10.0
9.6
10.0
10.4
4.0
4.0
4.0
4.4
3.6
a
3.30–3.33
3.17
3.14
3.13
2.84
3.19
2.85
2.82
2.95
3.11
3.01
2.91
2.89
2.73
–
–
–
–
–
2.0
2.0
2.0
–
2.0
3.6
3.2
–
a
6.43
–
a
6.06
6.21
7.05
6.15
6.26
6.47
–
6.30
–
5.97
–
0.8
a
–
–
–
–
–
–
–
–
2.8
2.8
3.2
2.8
3.2
3.2
3.2
2.8
3.2
3.2
2.8
2.8
12.0
12.0
12.4
12.0
11.6
12.0
a
a
a
–
3.6
3.6
a
3.2
b
–
3.2
b
b
b
b
b
g
h
–
2.16
–
–
3.2
–
2.8
–
12.0
a
–
a
No coupling was observed.
Could not be assigned from the H NMR of the mixture of two isomers.
b
1
3
,5,16
results due to the greater influence of the carbonyl
functionality than the two methoxy groups present on the
1
7
MOB moiety. Secondary orbital interactions, if present,
do not appear to be particularly important in the control of
the endo–exo selectivity even though in most of cases endo-
adduct was major. It is clear by comparing the chemical
yields as given in Tables 1 and 2 that the Diels–Alder
reactivity of MOBs depends on the substituents. It is worth
mentioning that MOB 2a, which exhibited high reactivity
3
,6,18
with many other dienophiles,
4
failed to produce 3a and
a in good yields in the cycloaddition with acrylonitrile.
The isolable MOBs 2b–h provided the Diels–Alder
cycloadducts in good yields. The non-dimerizing MOB 2i
required harsh conditions to proceed and furnished two
regioisomeric adducts; these results are in accordance with
our earlier studies. The less stereoselectivities observed in
the present study have literature precedents. For example,
both cyclopentadiene and 5-bromo-2-pyrone provided the
endo- and exo-isomers in equal amounts in their cyclo-
Figure 2. Crystal structure of 3h.
1
9
2
0,21
addition with acrylonitrile
underwent Diels–Alder cycloaddition with acrylonitrile to
while the o-quinodimethanes
2
2
give a 3:1 endo–exo mixture. Similarly, less selectivities
2
were observed in the reactions of furan, and furo[3,4-
b]1,4-benzodioxin with acrylonitrile. Recently, we also
observed poor stereoselectivity in the Diels–Alder reactions
between 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone
3
2
4
2
5
and acrylonitrile.
Figure 3. Crystal structure of 4b.
protons (H and H ) confirming the assigned regio- and
g
stereochemistry (see Scheme 3).
In conclusion, the Diels–Alder reactions of masked
o-benzoquinones with acrylonitrile provided an entry to
functionalized bicyclo[2.2.2]octenone derivatives in high
yields with excellent regioselectivity. Although the stereo-
selectivities are not up to the anticipated level, the
f
The regioselectivities of the cyloadditions were very high in
all the cases except for 2i, and are in accord with our earlier

S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
4043
stereoisomers can be separated in several cases in good
chemical yields.
Procedure D. The procedure C was repeated while the
reaction mixture was dipped in a 508C preheated oil bath
and the reaction was carried for a period of time as shown in
Table 1.
3
. Experimental
Procedure E. The procedure C was repeated while the
reaction mixture was dipped in a 1008C preheated oil bath
and the reaction was carried for a period of time as shown in
Table 1.
Acrylonitrile was distilled prior to use. All the reagents were
obtained from commercial sources and used without further
purification. All the reactions were performed under a
nitrogen atmosphere in anhydrous solvents, which were
dried prior to use following standard procedures. Reactions
were monitored by thin layer chromatography carried out on
p
p
p
3.1.1. (1S ,4R ,8S )-8-Cyano-6,6-dimethoxy-5-oxo-
bicyclo[2.2.2]oct-2-ene-2-carboxylate (3a). Mp 156.9–
1
157.38C; IR (film) 2952, 2840, 2242, 1749, 1716;
H
0
.25 mm E. Merck silica gel Plate (60F-254) using 7%
NMR (400 MHz, CDCl ) d 1.69 (ddd, J¼3.2, 5.2, 13.6 Hz,
3
ethanolic phosphomolybdic acid as developing agent. The
isomeric distribution of the adducts in each reaction was
determined by analyzing the H NMR (400 MHz) spectrum
of the crude reaction mixture. Standard column chromato-
graphy was performed using 230–400 mesh silica gel
obtained from E. Merck. Melting points are uncorrected. IR
spectra were recorded as films on NaCl plates. H and
spectra were recorded at 400 and 100 MHz, respectively, in
1H), 2.55 (ddd, J¼2.8, 10.0, 13.6 Hz, 1H), 3.21 (ddd, J¼2.0,
5.6, 8.8 Hz, 1H), 3.28 (s, 3H), 3.30 (s, 3H), 3.59 (dd, J¼2.0,
6.4 Hz, 1H), 3.81 (s, 3H), 3.83 (dd, J¼2.4, 5.2 Hz, 1H), 7.16
1
1
3
(dd, J¼2.0, 6.4 Hz, 1H); C NMR (100 MHz, CDCl ) d
3
24.84 (CH), 26.42 (CH ), 38.11 (CH), 50.24 (CH), 50.37
2
(CH ), 52.35 (CH ), 92.75 (C), 119.93 (C), 133.80 (CH),
3
3
1
13
C
139.86 (C), 163.54 (C), 197.27 (C); MS (EI, 75 eV) m/z
(relative intensity) 237 (100), 209 (16), 206 (19), 190 (98),
178 (19), 145 (8), 118 (6), 104 (6), 76 (10); HRMS (EI)
CDCl and chemical shifts are reported in d ppm, using
3
þ
solvent resonance as the internal reference. Mass spectra
were recorded in electron-impact mode (70 eV) at NSC
Instrumentation Center at Hsinchu, Taiwan. Elemental
analyses were performed at NSC Instrumentation Center
at Tainan, Taiwan.
calcd for C H NO (M 2CO) 237.1001, found 237.1001.
1
2
15
4
Anal. calcd for C H NO : C, 58.86; H, 5.70; N, 5.28.
5
1
3
15
Found: C, 58.83; H, 5.79; N, 5.19.
p
p
p
3.1.2. (1R ,2S ,4S )-5-(5,5-Dimethyl-1,3-dioxan-2-yl)-
,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-2-yl cyanide
(3b). Mp 156.8–157.28C; IR (film) 2954, 2341, 2359,
8
3
.1. General procedures for Diels–Alder reactions
1
1
745; H NMR (400 MHz, CDCl ) d 0.74 (s, 3H), 1.21 (s,
3
Procedure A. To a mixture of methyl vanillate (1a, 1 mM)
and acrylonitrile (25 mM) in MeOH (4 mL) was added
DAIB (1.1 mM) in MeOH (6 mL) during a period of 6 h
with the aid of a syringe pump at room temperature. The
reaction mixture was stirred further for additional 1 h at the
same temperature and then all the volatiles were removed
under reduced pressure and the residue was subjected to
purification by column chromatography on silica gel using a
mixture of ethyl acetate and hexanes as eluent to obtain the
desired cycloadducts.
3H), 1.67 (ddd, J¼2.8, 6.0, 12.4 Hz, 1H), 2.50 (ddd, J¼2.8,
10.0, 12.8 Hz, 1H), 3.12 (ddd, J¼2.0, 6.8, 10.0 Hz, 1H),
3.28 (s, 3H), 3.31 (s, 3H), 3.43–3.45 (m, 2H), 3.49 (dd,
J¼5.2, 10.4 Hz, 2H), 3.65 (d, J¼11.6 Hz, 2H), 4.96 (s, 1H),
1
3
6.26 (dd, J¼0.8, 6.8 Hz, 1H); C NMR (100 MHz, CDCl )
3
d 21.61 (CH ), 22.82 (CH ), 24.60 (CH), 27.19 (CH ), 30.03
3
3
2
(C), 37.95 (CH), 49.21 (CH ), 49.43 (CH), 50.09 (CH ),
3
3
76.75 (CH ), 77.09 (CH ), 92.85 (C), 99.59 (CH), 120.39
2
2
(C), 120.99 (CH), 146.98 (C), 197.60 (C); MS (EI, 75 eV)
m/z (relative intensity) 293 (100), 207 (32), 203 (25), 160
(28), 144 (17), 133 (30), 132 (23), 91 (30), 69 (46), 28 (30);
HRMS (EI) calcd for C H NO (M ) 321.1602, found
þ
320.1496. Anal. calcd for C H NO : C, 63.54; H, 7.21; N,
4.36. Found: C, 63.68; H, 7.17; N, 4.14.
Procedure B. To a mixture of acrylonitrile (25 mM) and
DAIB (1.1 mM) in MeOH (6 mL) was added methyl
vanillate (1a, 1 mM) in MeOH (4 mL) during a period of
1
7
23
5
1
7
23
5
1
h with the aid of a syringe pump.
p
p
p
3
.1.3. (1S ,2R ,4S )-5-(5,5-Dimethyl-1,3-dioxan-2-yl)-
1,8,8-trimethoxy-7-oxobicyclo[2.2.2]oct-5-en-2-yl cyanide
Procedure C. To a solution of appropriate 2-methoxyphenol
1
(
(
1a–i) in anyhydrous MeOH (10 mL) was added DAIB
1.1 mM) at 08C. After 10 min stirring, MeOH was
(3c). Mp 119.9–121.98C; IR (film) 2954, 2244, 1757; H
NMR (400 MHz, CDCl ) d 0.74 (s, 3H), 1.19 (s, 3H), 1.77
3
evaporated and flash column was performed using a mixture
of ethyl acetate and hexanes as eluent to obtain the MOB
(ddd, J¼3.2, 5.6, 13.2 Hz, 1H), 2.50 (ddd, J¼2.8, 10.4,
13.2 Hz, 1H), 3.18 (ddd, J¼0.4, 8.0, 10.4 Hz, 1H), 3.30 (s,
3H), 3.31 (s, 3H), 3.35 (apparent ddd, J¼0.8, 2.8, 7.6 Hz,
1H), 3.49 (dd, J¼4.8, 10.8 Hz, 2H), 3.61 (s, 3H), 3.64 (dd,
J¼8.8, 11.2 Hz, 2H), 4.96 (d, J¼0.8 Hz, 1H), 6.32 (d,
(
only in the reaction of phenol 1a, the MOB 2a was not
isolated due to its high propensity towards dimerization).
Solvents were evaporated and acrylonitrile 25 equiv. (acts
as solvent also) was added and the reaction mixture was
stirred at room temperature for an appropriate period of time
as shown in Table 1 and worked up as described in
procedure A. Special care should be taken that flash
chromatography, evaporation of solvent and addition of
acrylonitrile should be done fast (30–45 min duration) or
else the prolonged time may lead to the dimerization of
MOBs.
1
3
J¼0.8 Hz, 1H); C NMR (100 MHz, CDCl ) d 21.80
3
(CH ), 22.99 (CH ), 27.81 (CH ), 30.25 (C), 30.80 (CH),
3
3
2
37.38 (CH), 49.92 (CH ), 50.13 (CH ), 54.42 (CH ), 76.67
3
3
3
(CH ), 77.30 (CH ), 83.30 (C), 93.48 (C), 99.37 (CH),
2
2
119.11 (C), 122.92 (CH), 145.08 (C), 197.77 (C); MS (EI,
75 eV) m/z (relative intensity) 323 (26), 308 (18), 292 (53),
237 (28), 222 (70), 202 (42), 190 (73), 163 (78); HRMS (EI)
þ
calcd for C H NO (M 2CO) 323.1733, found 323.1735.
7
1
25
5

4044
S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
Anal. calcd for C H NO : C, 61.52; H, 7.17; N, 3.99.
25
Found: C, 61.21; H, 7.18; N, 3.85.
(100), 225 (17), 178 (64), 104 (19), 76 (34), 73 (15), 59 (46),
18
6
7
9
42 (15), 28 (16); HRMS (EI) calcd for C H
(
BrNO2
1
0
12
þ
M 2CO) 257.0051, found 257.0053, calcd for
81
p
p
p
3.1.4. (1S ,2S ,4R )-5-Bromo-1-(5,5-dimethyl-1,3-
dioxan-2-yl)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-
C H
BrNO2 259.0030, found 259.0036. Anal. calcd
12
1
0
for C H BrNO : C, 46.18; H, 4.23; N, 4.90. Found: C,
1
1
12
3
2
2
3
-yl cyanide (3d). Mp 116.3–117.38C; IR (film) 2955,
1
46.22; H, 4.29; N, 5.20.
243, 1748, 1611; H NMR (400 MHz, CDCl ) d 0.73 (s,
3
p
p
p
H), 1.30 (s, 3H), 1.95 (ddd, J¼3.2, 5.6, 13.2 Hz, 1H), 2.58
3.1.7. (1S ,2S ,4R )-5-Bromo-8,8-dimethoxy-6-methyl-7-
oxobicyclo[2.2.2]oct-5-en-2-yl cyanide (3g). Mp 82.9–
(
2
ddd, J¼3.2, 10.2, 13.2 Hz, 1H), 3.29 (s, 3H), 3.30–3.33 (m,
1
H), 3.68 (dd, J¼2.8, 11.2 Hz, 1H) 3.35 (s, 3H), 3.47 (d,
84.68C; IR (film) 2946, 2241, 2349, 1747; H NMR
(400 MHz, CDCl ) d 1.91 (ddd, J¼3.2, 5.2, 13.6 Hz, 1H),
J¼11.2 Hz, 1H), 3.55 (d, J¼10.8 Hz, 1H), 3.75 (dd, J¼2.4,
3
1
3
1
NMR (100 MHz, CDCl ) d 21.89 (CH ), 23.22 (CH ), 24.82
0.8 Hz, 1H), 4.99 (s, 1H), 6.43 (d, J¼2.4 Hz, 1H);
C
1.98 (s, 3H), 2.48 (ddd, J¼2.8, 9.6, 13.6 Hz, 1H), 3.13 (ddd,
J¼2.0, 5.2, 10.0 Hz, 1H), 3.28 (s, 3H), 3.30–3.35 (m, 5H);
3
3
3
1
3
(
CH), 27.92 (CH ), 30.44 (C), 48.26 (CH), 50.41 (CH ),
3
C NMR (100 MHz, CDCl ) d 20.19 (CH ), 24.86 (CH),
3 3
2
5
0.81 (CH ), 58.57 (C), 76.66 (CH ), 76.98 (CH ), 93.78
3
27.28 (CH ), 48.78 (CH), 50.40 (CH ), 50.58 (CH ), 56.56
2 3 3
2
2
(
1
(
2
3
3
C), 97.79 (CH), 120.01 (C), 125.64 (C), 125.79 (CH),
94.66 (C); MS (EI, 75 eV) m/z (relative intensity) 371
100), 285 (91), 256 (6), 206 (21), 115 (12), 69 (32), 43 (23),
(CH), 93.67 (C), 119.96 (C), 120.15 (C), 132.18 (C), 196.04
(C); MS (EI, 75 eV) m/z (relative intensity) 273 (100), 271
(95), 255 (41), 242 (20), 198 (15), 161 (17), 132 (36);
7
9
þ
þ
9 (8); HRMS (EI) calcd for C H
1
71.0732, found 371.0732, calcd for C H BrNO4
6 22
BrNO (M 2 CO)
4
HRMS (EI) calcd for C H BrNO (M 2CO) 273.0187,
11 14
6
22
2
81
found 273.0180.
1
73.0711, found 373.0708. Anal. calcd for C H BrNO :
5
1
7
22
p
3.1.8. (1R ,2S ,4R )-5-Bromo-8,8-dimethoxy-1-methyl-7-
p
p
C, 51.01; H, 5.54: N, 3.50. Found: C, 51.51: H, 5.71: N,
.43.
3
oxobicyclo[2.2.2]oct-5-en-2-yl cyanide (3h). Mp 130.7–
1
131.28C; IR (film) 2955, 2238, 1748; H NMR (400 MHz,
p
p
p
3
.1.5. (1R ,2S ,4S )-6-Bromo-5-(5,5-dimethyl-1,3-
dioxan-2-yl)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-
CDCl ) d 1.42 (s, 3H), 1.98 (ddd, J¼3.2, 5.6, 13.6 Hz, 1H),
3
2.53 (ddd, J¼2.8, 10.0, 13.2 Hz, 1H), 2.84 (dd, J¼5.6,
10.0 Hz, 1H), 3.29 (s, 3H), 3.32 (apparent dd, J¼1.6,
1
13
2
-yl cyanide (3e). (The selected H and C NMR data of 3e
1
3
presented here were taken from the spectra of isomeric
mixture of 3e and 4e. All the other data given here belong to
the mixture of 3e and 4e.)
3.2 Hz, 1H), 3.35 (s, 3H), 6.06 (d, J¼2.4 Hz, 1H); C NMR
(100 MHz, CDCl ) d 15.86 (CH ), 28.32 (CH ), 31.64 (CH),
3
3
2
48.47 (CH), 50.24 (CH ), 50.88 (CH ), 52.75 (C), 93.67 (C),
3
3
119.54 (C), 126.01 (C), 129.80 (CH), 197.99 (C); MS (EI,
75 eV) m/z (relative intensity) 271 (99), 242 (19), 198 (37),
Mp 127.4–128.58C; IR (film) 2960, 2859, 2242, 1749,
1
1
1
104, 1055; H NMR (400 MHz, CDCl ) d 0.75 (s, 3H),
3
.21 (s, 3H), 1.75 (ddd, J¼2.8, 6.0, 13.2 Hz, 1H), 2.55 (ddd,
192 (52), 161 (13), 132 (28), 117 (20), 91 (21), 59 (47), 28
7
9
þ
BrNO2 (M 2CO)
14
79
(14); HRMS (EI) calcd for C H
1
1
J¼2.8, 10.0, 12.8 Hz, 1H), 3.17 (ddd, J¼2.0, 6.0, 10.0 Hz,
271.0207, found 271.0206, calcd for C H
BrNO2
1
1
14
1
H), 3.58–3.69 (m, 5H), 3.72 (dd, J¼2.8, 2.8 Hz, 1H), 3.29
273.0187, found 273.0188.
1
3
(s, 3H), 3.33 (s, 3H), 5.30 (s, 1H); C NMR (100 MHz,
CDCl ) d 21.81 (CH ), 23.03 (CH ), 25.35 (CH), 27.55
p
p
p
3.1.9. (1R ,2S ,4R )-4,8,8-Trimethoxy-7-oxobicyclo-
[2.2.2]oct-5-en-2-yl cyanide (3i). Mp 83.6–84.78C; IR
3
3
3
(
CH ), 30.18 (C), 39.71 (CH), 48.87 (CH ), 50.52 (CH ),
2
3
3
1
5
9.40 (CH), 77.12 (CH ), 93.06 (C), 99.11 (CH), 114.19
2
(film) 2948, 2242, 1746; H NMR (400 MHz, CDCl ) d 1.92
3
(
(
2
C), 119.02 (C), 143.39 (C), 194.54 (C); MS (EI, 75 eV) m/z
relative intensity) 371 (91), 298 (19), 285 (66), 239 (41),
(dd, J¼5.2, 12.4 Hz, 1H), 2.58 (ddd, J¼0.8, 10.4, 12.0 Hz,
1H), 3.10 (dddd, J¼0.8, 2.0, 5.2, 7.2 Hz, 1H), 3.37 (ddd,
J¼1.2, 2.0, 6.0 Hz, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 3.50 (s,
02 (36), 144 (45), 132 (23), 69 (99), 43 (100); HRMS (EI)
þ
7
9
calcd for C H BrNO4 (M 2CO) 371.0732, found
6 22
3H), 6.21 (dd, J¼6.4, 8.8 Hz, 1H), 6.67 (ddd, J¼1.2, 1.2,
1
8
1
13
3
3
5
71.0734, calcd for C H
BrNO4 373.0711, found
73.0716. Anal. calcd for C H BrNO : C, 51.01; H,
8.8 Hz, 1H); C NMR (100 MHz, CDCl ) d 23.50 (CH),
3
1
6
22
29.85 (CH ), 48.54 (CH), 51.95 (CH ), 52.49 (CH ), 52.84
2
1
7
22
5
3
3
.54; N, 3.50. Found: C, 51.20; H, 5.52; N, 3.69.
(CH ), 60.33 (C), 82.52 (C), 120.27 (C), 122.63 (CH),
3
1
39.28 (CH), 196.58 (C); MS (EI, 75 eV) m/z (relative
p
.1.6. (1R ,2S ,4R )-5-Bromo-8,8-dimethoxy-7-oxo-
p
p
3
intensity) 237 (11), 222 (22), 209 (24), 194 (41), 178 (58),
162 (100), 135 (23), 74 (18), 59 (35); HRMS (EI) calcd for
1
bicyclo[2.2.2]oct-5-en-2-yl cyanide (3f). (The selected H
NMR data of 3f presented here was taken from the spectra
of isomeric mixture of 3f and 4f. All the other data given
here belong to the mixture of 3f and 4f.)
þ
for C H NO ; C, 60.75; H, 6.37; N, 5.90. Found: C, 61.00;
H, 6.71; N, 5.59.
C H NO (M ) 237.1001, found 237.1004. Anal. calcd
1
2
15
4
1
2
15
4
1
p
p
p
Mp 115.4–116.78C; IR (film) 2947, 2242, 1746; H NMR
(
3.1.10. (1S ,4R ,8R )-8-Cyano-6,6-dimethoxy-5-oxo-
bicyclo[2.2.2]oct-2-ene-2-carboxylate (4a). Mp 123.4–
400 MHz, CDCl ) d 1.91 (ddd, J¼2.8, 5.6, 13.6 Hz, 1H),
3
1
2
9
.51 (ddd, J¼2.8, 10.0, 13.2 Hz, 1H), 3.14 (ddd, J¼2.0, 5.6,
124.58C; IR (film) 2507, 1870, 1819; H NMR (400 MHz,
1
3
.6 Hz, 1H), 6.43 (dd, J¼2.4, 7.2 Hz, 1H). C NMR
CDCl ) d 1.88 (ddd, J¼2.8, 11.2, 13.2 Hz, 1H), 2.47 (ddd,
3
(
100 MHz, CDCl ) d 24.86 (CH), 26.15 (CH ), 26.82 (CH ),
3
J¼3.2, 3.6, 13.6 Hz, 1H), 2.85 (ddd, J¼3.6, 4.0, 12.0 Hz,
1H), 3.29 (s, 3H), 3.39 (s, 3H), 3.55 (dd, J¼3.2, 6.8 Hz, 1H),
3.78 (s, 3H), 3.85 (dd, J¼2.8, 5.2 Hz, 1H), 7.05 (dd, J¼2.0,
2
2
4
(
1
1
8.72 (CH), 48.87 (CH), 50.30 (CH ), 50.40 (CH ), 50.82
3 3
CH ), 51.59 (CH), 51.68 (CH), 93.21 (C), 93.49 (C),
3
19.17 (C), 119.93 (C), 124.48 (C), 125.43 (C), 126.87 (C),
96.28 (C); MS (EI, 75 eV) m/z (relative intensity) 257
1
3
6.8 Hz, 1H); C NMR (100 MHz, CDCl ) d 24.93 (CH),
3
25.78 (CH ), 38.03 (CH), 49.82 (CH ), 50.34 (CH ), 50.50
3
2
3

S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
4045
p
p
p
(
CH), 52.35 (CH ), 92.98 (C), 119.29 (C), 134.74 (CH),
3
3.1.14. (1R ,2R ,4S )-6-Bromo-5-(5,5-dimethyl-1,3-
dioxan-2-yl)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-
1
(
1
39.67 (C), 163.52 (C), 196.73 (C); MS (EI, 75 eV) m/z
relative intensity) 237 (46), 209 (14), 206 (17), 190 (100),
46 (10), 104 (8), 77 (19); HRMS (EI) calcd for C H NO
2-yl cyanide (4e). Mp 143.1–143.68C; IR (film) 2956,
1
2857, 2238, 1744, 1097, 1052; H NMR (400 MHz, CDCl )
3
1
2
15
4
þ
(
M 2CO) 237.1001, found 237.0996.
d 0.742 (s, 3H), 1.20 (s, 3H), 1.91 (ddd, J¼2.8, 11.6,
1
4.8 Hz, 1H), 2.46 (ddd, J¼3.2, 3.6, 13.2 Hz, 1H), 3.01
p
.1.11. (1R ,2R ,4S )-5-(5,5-Dimethyl-1,3-dioxan-2-yl)-
p
p
3
8
(ddd, J¼3.6, 3.6, 12.0 Hz, 1H), 3.33 (s, 3H), 3.37 (s, 3H),
3.56 (d, J¼2.8, 11.2, 17.6 Hz, 2H), 3.60–3.65 (m, 3H), 3.74
,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-2-yl cyanide
1
13
(
NMR (400 MHz, CDCl ) d 0.73 (s, 3H), 1.18 (s, 3H), 1.86
4b). Mp 143.7–144.48; IR (film) 2954, 2240, 1745; H
(t, J¼3.2 Hz, 1H), 5.22 (s, 1H); C NMR (100 MHz,
CDCl ) d 21.81 (CH ), 23.09 (CH ), 25.32 (CH), 28.10
3
3
3
3
(
1
3
(
ddd, J¼2.8, 12.0, 14.4 Hz, 1H), 2.41 (ddd, J¼2.8, 4.0,
(CH ), 30.21 (C), 39.71 (CH), 49.27 (CH ), 50.67 (CH ),
2 3 3
59.25 (CH), 77.09 (CH ), 77.21 (CH ), 92.75 (C), 99.17
2 2
3.2 Hz, 1H), 2.82 (ddd, J¼3.2, 3.6, 12.0 Hz, 1H), 3.32 (s,
H), 3.36 (s, 3H), 3.41 (dd, J¼3.2, 6.8 Hz, 1H), 3.45–3.50
(CH), 113.25 (C), 119.29 (C), 143.21 (C), 194.94 (C); MS
(EI, 75 eV) m/z (relative intensity) 371 (11), 370 (54), 287
(59), 267 (18), 240 (50), 145 (24); HRMS (EI) calcd for
m, 3H), 3.63 (ddd, J¼2.4, 4.0, 11.2 Hz, 2H), 4.91 (d,
1
3
J¼0.8 Hz, 1H), 6.15 (ddd, J¼1.2, 2.0 Hz, 1H); C NMR
7
9
þ
BrNO4 (M 2CO) 399.0681, found 399.0691,
16 22
81
(
2
100 MHz, CDCl ) d 21.78 (CH ), 22.96 (CH ), 25.09 (CH),
3
C H
3
3
6.59 (CH ), 30.20 (C), 38.08 (CH), 49.27 (CH ), 49.56
2
calcd for C H
BrNO5 401.0601, found 401.0616.
3
17 22
(
CH), 50.27 (CH ), 76.67 (CH ), 77.30 (CH ), 93.42 (C),
3
Anal. calcd for C H BrNO : C, 51.01; H, 5.54; N, 3.50.
17 22 5
2
2
9
(
9.79 (CH), 120.04 (C), 122.20 (CH), 146.87 (C), 197.48
C); MS (EI, 75 eV) m/z (relative intensity) 293 (100), 207
Found: C, 50.91; H, 5.57; N, 3.45.
p
p
p
(
47), 160 (38), 133 (25), 90 (18), 74 (15), 69 (34), 43 (36),
3.1.15. (1R ,2R ,4R )-5-Bromo-8,8-dimethoxy-7-oxo-
1
þ
20.1498, found 321.16. Anal. calcd for C H NO : C,
3.54; H, 7.21; N, 4.36. Found: C, 63.29; H, 7.18; N, 4.20.
3
3
6
2 (10), 28 (39); HRMS (EI) calcd for C H NO (M )
5
bicyclo[2.2.2]oct-5-en-2-yl cyanide (4f). (The selected H
NMR data of 4f presented here was taken from the spectra
of isomeric mixture of 3f and 4f.)
1
7
23
1
7
23
5
p
.1.12. (1S ,2S ,4S )-5-(5,5-Dimethyl-1,3-dioxan-2-yl)-
,8,8-trimethoxy-7-oxobicyclo[2.2.2]oct-5-en-2-yl
p
p
1
3
1
H NMR (400 MHz, CDCl ) d 2.09 (ddd, J¼2.8, 12.0,
3
14.4 Hz, 1H), 2.43 (ddd, J¼3.2, 3.2, 13.6 Hz, 1H), 2.91
(ddd, J¼3.6, 4.0, 12.0 Hz, 1H), 6.30 (dd, J¼2.4, 6.8 Hz,
1H).
cyanide (4c). Mp 115–116.88C; IR (film) 3020, 2959, 2348,
1
1
3
4
3
3
758; H NMR (400 MHz, CDCl ) d 0.74 (s, 3H), 1.18 (s,
3
H), 1.95 (ddd, J¼3.2, 12.4, 13.2 Hz, 1H), 2.40 (ddd, J¼3.2,
.0, 13.2 Hz, 1H), 2.95 (dd, J¼4.0, 12.0 Hz, 1H), 3.32 (s,
H), 3.38 (s, 3H), 3.48 (dd, J¼3.2, 10.4 Hz, 2H), 3.59 (s,
H), 3.64 (d, J¼11.2 Hz, 2H), 4.91 (d, J¼0.8 Hz, 1H), 6.26
p
p
p
3.1.16. (1S ,2R ,4R )-5-Bromo-8,8-dimethoxy-6-methyl-
7-oxobicyclo[2.2.2]oct-5-en-2-yl cyanide (4g). (The
selected H NMR data of 4g presented here was
taken from the spectra of isomeric mixture of 3g and
4g.)
1
1
3
(
2
dd, J¼0.8, 1.6 Hz, 1H); C NMR (100 MHz, CDCl ) d
3
1.68 (CH ), 22.88 (CH ), 27.11 (CH ), 30.17 (C), 31.05
3 3 2
(
CH), 37.28 (CH), 49.47 (CH ), 50.05 (CH ), 54.15 (CH ),
3 3 3
1
7
1
7
2
(
3
6
6.93 (CH ), 77.27 (CH ), 83.71 (C), 93.26 (C), 99.23 (CH),
2
Mp 83.5–84.88C; H NMR (400 MHz, CDCl ) d 1.86
3
2
18.62 (C), 122.31 (CH), 145.60 (C), 196.34 (C); MS (EI,
5 eV) m/z (relative intensity) 323 (92), 292 (25), 268 (58),
22 (85), 190 (63), 182 (100), 147 (43), 109 (26), 69 (71), 41
(s, 3H), 2.07–2.11 (apparent ddd, 1H), 2.41 (ddd, J¼3.2,
3.2, 13.2 Hz, 1H), 2.89 (ddd, J¼4.0, 4.0, 12.0 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ) d 19.28 (CH ), 24.62 (CH ),
3 3 3
þ
23.1733, found 323.1730. Anal. calcd for C H NO : C,
1.52; H, 7.17; N, 3.99. Found: C, 61.48; H, 7.21; N, 4.14.
35); HRMS (EI) calcd for C H NO (M 2CO)
1
26.85 (CH ), 48.65 (CH), 50.06 (CH ), 50.49 (CH),
2 3
56.56 (CH), 93.67 (C), 119.96 (C), 120.15 (C), 132.18
(C), 196.04 (C); MS (EI, 75 eV) m/z (relative intensity) 273
7
25
5
1
8
25
6
(
99), 256 (33), 242 (20), 192 (69), 132 (30), 90 (36), 59 (59),
p
.1.13. (1S ,2R ,4R )-5-Bromo-1-(5,5-dimethyl-1,3-
p
p
79
þ
BrNO (M 2CO)
14 2
81
3
dioxan-2-yl)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-en-
43 (19); HRMS (EI) calcd for C H
1
271.0207, found 273.0207, calcd for C H
1
BrNO2
14
1
1
2
2
3
-yl cyanide (4d). Mp 125.2–126.88C; IR (film) 2957,
273.0187, found 273.0187. Anal. calcd for C H BrNO :
12 14 3
C, 48.02; H, 4.70; N, 4.67. Found: C, 47.88; H, 4.89; N,
4.61.
241, 1749 cm2 ; H NMR (400 MHz, CDCl ) d 0.73 (s,
1
1
3
H), 1.17 (s, 3H), 2.12 (ddd, J¼3.2, 12.0, 15.2 Hz, 1H), 2.32
(
ddd, J¼2.8, 4.4, 13.2 Hz, 1H), 3.11 (dd, J¼4.4, 12.0 Hz,
p
p
p
1
3
H), 3.32 (dd, J¼3.2, 5.6 Hz, 1H), 3.35 (s, 3H), 3.37 (s, 3H),
.52–3.66 (m, 4H), 5.04 (s, 1H), 6.47 (d, J¼2.4 Hz, 1H);
C NMR (100 MHz, CDCl ) d 21.45 (CH ), 22.94 (CH ),
3.1.17. (1R ,2R ,4R )-5-Bromo-8,8-dimethoxy-1-methyl-
7-oxobicyclo[2.2.2]oct-5-en-2-yl cyanide (4h). Mp 118.3–
1
3
1
118.98C; IR (film) 2945, 2240, 1746, 1610; H NMR
(400 MHz, CDCl ) d 1.43 (s, 3H), 2.16 (ddd, J¼2.8, 12.0,
3
3
3
2
6.35 (CH ), 26.75 (CH), 30.06 (C), 48.29 (CH), 49.97
2
3
(
CH ), 50.58 (CH ), 59.30 (C), 76.52 (CH ), 76.83 (CH ),
3
14.8 Hz, 1H), 2.45 (ddd, J¼3.2, 3.2, 13.2 Hz, 1H), 2.73 (dd,
J¼4.0, 12.0 Hz, 1H), 3.33 (d, J¼4.0 Hz, 1H), 3.36 (s, 3H),
3
2
2
9
1
3.93 (C), 97.00 (CH), 118.30 (C), 124.65 (C), 125.78 (CH),
94.54 (C); MS (EI, 75 eV) m/z (relative intensity) 371
1
3
3.37 (s, 3H), 5.97 (d, J¼2.4 Hz, 1H); C NMR (100 MHz,
(
100), 285 (99), 256 (7), 206 (35), 178 (8), 115 (23), 69 (53),
9 (36), 29 (9); HRMS (EI) calcd for C H
CDCl ) d 15.90 (CH ), 27.57 (CH ), 31.70 (CH), 48.37
2
3
3
7
22
9
5 BrNO4
M 2CO) 371.0732, found 371.0732, calcd for
(CH), 50.15 (CH ), 50.76 (CH ), 53.18 (C), 93.56 (C),
3 3
1
6
þ
(
118.69 (C), 126.35 (C), 130.53 (CH), 197.86 (C); MS (EI,
75 eV) m/z (relative intensity) 271 (43), 195 (39), 192 (49),
132 (56), 117 (48), 91 (54), 59 (100); HRMS (EI) calcd for
8
1
C H BrNO4 373.0711, found 373.0712. Anal. calcd
6 22
for C H BrNO : C, 51.01; H, 5.54: N, 3.50. Found: C,
1
1
7
22
5
þ
5
1.22: H, 5.81: N, 3.36.
C H BrNO (M 2CO) 271.0207, found 271.0211. Anal.
2
1
14
3

4046
S. K. Chittimalla, C.-C. Liao / Tetrahedron 59 (2003) 4039–4046
calcd for C H BrNO : C, 48.02; H, 4.70; N, 5.01. Found:
1
C, 48.59: H, 4.62: N, 5.01.
Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5.
Chapter 4.1. (e) Craig, D. Chem. Soc. Rev. 1987, 187.
. Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
2
14
3
2
3
3
.1.18. Dimer 5a. For the spectral data see Ref. 3.
3. Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song,
L.-D.; Shiao, H.-C. J. Org. Chem. 1999, 64, 4102.
4. Lai, C.-H.; Shen, Y.-L.; Liao, C.-C. Synlett 1997, 1351.
5. Gao, S.-Y.; Ko, S.; Lin, Y.-L.; Peddinti, R. K.; Liao, C.-C.
Tetrahedron 2001, 57, 297.
p
.1.19. (1R ,2S ,4R )-1,7,7-trimethoxy-8-oxobicyclo-
p
p
[
2.2.2]oct-5-en-2-yl cyanide (6i). Mp 80.7–81.58C; IR
1
(
film) 2949, 2341, 2359, 1746; H NMR (400 MHz, CDCl )
3
d 1.90 (ddd, J¼3.6, 3.6, 13.6 Hz, 1H), 2.28 (dddd, J¼0.8,
6. Chen, C.-H.; Rao, P. D.; Liao, C.-C. J. Am. Chem. Soc. 1998,
120, 13254.
2
1
1
1
.8, 10.0, 12.8 Hz, 1H), 3.19 (dddd, J¼1.2, 2.0, 3.6, 5.6 Hz,
H), 3.42 (s, 3H), 3.45 (s, 3H), 3.61 (ddd, J¼0.8, 3.6,
0.0 Hz, 1H), 3.71 (s, 3H), 6.28 (ddd, J¼0.8, 6.4, 8.8 Hz,
7. Hsieh, M.-F.; Peddinti, R. K.; Liao, C.-C. Tetrahedron Lett.
2001, 42, 5481.
1
3
H), 6.56 (ddd, J¼0.8, 1.2, 8.8 Hz, 1H); C NMR
8. Lai, C.-H.; Ko, S.; Rao, P. D.; Liao, C.-C. Tetrahedron Lett.
2001, 42, 7851.
(
100 MHz, CDCl ) d 26.65 (CH ), 29.45 (CH), 45.83
3
2
(
9
CH), 51.63 (CH ), 52.86 (CH ), 54.51 (CH ), 83.24 (C),
3
5.13 (C), 120.79 (C), 125.84 (CH), 135.06 (CH), 197.62
C); MS (EI, 75 eV) m/z (relative intensity) 237 (24), 209
9. Rahman, S. M. A.; Ohno, H.; Murata, T.; Yoshino, H.; Satoh,
N.; Murakami, K.; Patra, D.; Iwata, C.; Maezaki, N.; Tanaka,
T. J. Org. Chem. 2001, 66, 4831.
3
3
(
(
(
46), 194 (98), 178 (100), 162 (96), 135 (28), 134 (39), 95
24), 76 (17), 73 (24), 59 (49); HRMS (EI) calcd for
10. Hayashi, Y.; Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org.
Chem. 2002, 67, 9443.
þ
C H NO (M ) 237.1001, found 237.1005. Anal. calcd
4
for C H NO : C, 60.75; H, 6.37: N, 5.90. Found: C, 61.16:
1
H, 6.48: N, 5.75.
11. Wu, J.-D.; Shia, K.-S.; Liu, H.-J. Tetrahedron Lett. 2001, 42,
4207, and references therein.
12. Jung, M. E. J. Org. Chem. 1992, 57, 3528.
1
2
15
2
15
4
1
3. (a) Yen, C.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2,
909. (b) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.;
Liao, C.-C. J. Org. Chem. 2002, 67, 6493.
2
Acknowledgements
1
15. CCDC deposition No. 186961.
4. CCDC deposition No. 186960.
Financial support from the National Science Council of
Republic of China is gratefully acknowledged. We sincerely
thank Dr R. K. Peddinti for helpful discussions.
16. Chu, C.-S.; Lee, T.-H.; Liao, C.-C. Synlett 1994, 635.
17. Garc ´ı a, J. I.; Mayoral, J. A.; Salvatella, L. Acc. Chem. Res.
2
8. Hsieh, M.-F.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1999,
000, 10, 658.
1
References
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1
1
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