Synthesis of 4-aza tricyclo [6.2.2.01,6]dodecenone and photoreactions: A stereoselective, entry to aza-polycyclic systems related to magellanine and congeners

Article abstract of DOI:10.1016/j.tet.2011.10.061

A stereoselective, route to aza-polycyclic systems related to magellanine, and congeners from simple aromatic precursor is described. Oxidative dearomatization leading to a highly reactive spiroepoxycyclohexa-2,4-dienone, intramolecular inverse demand π

Full text of DOI:10.1016/j.tet.2011.10.061

Tetrahedron 68 (2012) 238e243
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Synthesis of 4-aza tricyclo [6.2.2.01,6]dodecenone and photoreactions:
a stereoselective, entry to aza-polycyclic systems related to magellanine
and congeners
,
a
b
Vishwakarma Singh a , Pravin Bhalerao , Shaikh M. Mobin
*
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076 India
b National Centre for Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Mumbai 400 076 India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective, route to aza-polycyclic systems related to magellanine, and congeners from simple
aromatic precursor is described. Oxidative dearomatization leading to a highly reactive spiroepox-
Received 19 September 2011
Received in revised form 13 October 2011
Accepted 16 October 2011
ycyclohexa-2,4-dienone, intramolecular inverse demand
actions are key features of our approach.
p
4sþ
p
2s cycloaddition and photochemical re-
Available online 21 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Spiroepoxycyclohexa-2,4-dienone
DielseAlder reaction
Intramolecular cycloaddition
Tandem reaction
Oxidative dearomatization
1. Introduction
number of methods for the synthesis of polyquinanes,10 only a few
methods exist for the synthesis of heteropolyquinanes.
Rapid generation of molecular complexity from simple pre-
cursors is one of the important features of synthesis design and
development of methodology.1 Tandem reactions and multicom-
ponent reactions are often employed to achieve these objectives.2
Recently, the reactive species generated by oxidative dearomati-
zation of arenols such as cyclohexa-2,4-dienone ketals and conge-
ners have proved to be an important tool and provided an efficient
method for the synthesis of a diverse array of molecular structures
and natural products.3e5 Hetero-polyquinanes have generated
considerable interest.6 This is presumably due to interest in creat-
ing novel structures and also because some of the hetero-analogues
of polyquinanes exhibit interesting biological properties.6a,b In-
terestingly, the molecular structure of lycopodium alkaloids such as
magellanine 1, magellaninone 27a,b and paniculatine 37c (Fig. 1) also
contain a diquinane moiety annulated with a six-membered aza-
ring system. There are several approaches towards synthesis of
magellanine and related alkaloids.8,9 However, a majority of the
methods introduce the heteroatom at later stages by manipulating
a carbocyclic ring. It may be mentioned that while there are a large
In view of the above and our continuing interest in synthesis of
diverse molecular structures from simple aromatics, we considered
developing a methodology for the synthesis of aza-polyquinane
system of type 4, and aza tricyclic compound 5 from a simple ar-
omatic precursor 6 and wish to report our results herein.
Our plan is outlined in Scheme 1. Oxidative dearomatization,
intramolecular inverse demand cycloaddition and photochemical
Me
H
Me
H
OH
O
H
H
NMe
Me
N
H
H
H
H
O
X
X = OH, Magellanine (1)
X = O, Magellaninone (2)
Paniculatine (3)
OH OH
H
H
H
H
Ts
N
Ts
N
N
O
O
Ts
H
H
5
6
4
* Corresponding author. Tel.: þ91 22 2576 7168; fax: þ91 22 2576 7152; e-mail
address: vks@chem.iitb.ac.in (V. Singh).
Fig. 1. Lycopodium alkaloids, aza-polycyclic systems and aromatic precursor.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.061

V. Singh et al. / Tetrahedron 68 (2012) 238e243
239
H
H
H
H
O
H
Ts
hν
N
hν
O
N
Ts
1,3-acyl
shift
1,2-acyl
shift
O
5
4
N
9
Ts
O
OH
O
OH
O
π4s+π2s
O
oxidative
N
N
cycloaddition
dearomatization
Ts
Ts
6
N
8
7
Ts
Scheme 1. Retro-synthetic strategy for aza-polycyclic systems 4 and 5.
reactivity modulation are the key features of our strategy. It was
envisaged that triplet sensitized 1,2-acyl shift or oxa-di- -methane
rearrangement in tricyclic compound 9 having annulated aza-six
membered ring would provide the compound 4 in a stereo-
selective manner and that singlet excitation in 9 would lead to
compound 5 as a consequence of a 1,3 acyl shift. The tricyclic sys-
Towards synthesis of the keto-epoxide 8, a solution of com-
pound 6 in acetonitrile was subjected to oxidation with aq NaIO4
following a methodology developed in our group.12 Usual work-up
and chromatography furnished the desired endo-adduct 8 in good
yield (58%) along with the dimer 16 (25%) and a very small amount
of the aldehyde 15 formed by oxidation of hydroxymethyl group.
The adduct 8 arising through in situ generation of spiroepoxy
cyclohexa-2,4-dienone 7 and subsequent interception of cyclo-
p
tem 9 having a b,g-enone chromophore was thought to be derived
from the keto-epoxide 8, which in turn, was thought to be acces-
sible from the aromatic precursor 6 via a tandem oxidative dear-
hexadienone moiety by the
p
-bond of the aza-tether in an intra-
omatization to
cycloaddition.
7
and subsequent intramolecular
p
4sþ
p
2s
molecular
p
4sþ
p
2s cycloaddition fashion, whereas the dimer 16 is
formed as a consequence of intermolecular cycloaddition between
2 mol of 7 (Scheme 3).
There are several interesting features of the above strategy. The
aza-polycyclic frameworks 4 and 5 are present in the adduct 8 and
chromophoric system 9 in latent fashion. The adduct 8 is assembled
in a single stereoselective step from the aromatic precursor 6 thus
generating structural and stereochemical complexity in the be-
ginning of the synthetic route.
Though, the formation of adduct 8 in the aforementioned oxi-
dative dearomatizationecycloaddition is reasonably good, in-
termolecular cycloaddition between 2 mol of 7 competes to
a significant extent so as to give the dimer 16 at ambient temper-
ature. Therefore, it was thought that generation of spiroepox-
ycyclohexa-2,4-dienone 7 by pyrolysis of 16 may lead to efficient
formation of adduct 8 as a consequence of thermal activation. In-
deed, heating the dimer 16 at 140 ꢀC in o-dichlorobenzene fur-
nished the adduct 8 in excellent yield (85%) as a result of a retro-
DielseAlder-intramolecular DielseAlder cascade (Scheme 4).
The structure of adduct 8 was deduced from its spectral features.
2. Results and discussion
In principle, the desired tricyclic chromophoric system 9 may be
directly prepared by intramolecular cycloaddition in cyclohexa-2,4-
dienone of type 10 (Fig. 2). However, such cyclohexa-2,4-dienone is
not readily accessible, and in fact, it is the ketotautomer of the
corresponding phenol. Hence, we considered developing an in-
direct route to compound 9 via intramolecular cycloaddition in
spiroepoxycyclohexadienone such as 7 and manipulation of the
adduct.
Thus, 1H NMR (300 MHz, CDCl3) spectrum displayed signals at
(d, J¼8 Hz, 2H), 7.30 (d, J¼8 Hz, 2H) for aromatic protons of tosyl
group. Further, characteristic signals were shown at 6.55 (super-
imposed, dd, J¼7.6 Hz, 1H) and 5.76 (d, J¼7.6 Hz, 1H), for - and
proton of -enone moiety. The downfield signal of and up-field
signal due to proton of -enone group is a manifestation of
homoconjugation between -bond of bicyclo[2.2.2]octane moiety
and -bond of the carbonyl group. This clearly suggested that
d 7.60
d
g
b-
b,g
g
b
b,g
p
O
O
p
intramolecular cycloaddition had occurred to give adduct. Moreover,
the protons of the oxirane ring showed highly characteristic signals
O
N
N
Ts
as part of AB system at
2.82 (part of an AB system, JAB¼5.6 Hz, 1H). It further showed signal
at
d
3.14 (part of an AB system, JAB¼5.6 Hz, 1H),
Ts
7
10
d
3.92e3.86 (m of d J¼13.1 Hz, 1H), 3.70e3.64 (m, J¼13.1 Hz, 1H),
Fig. 2. Potential precursors for cycloaddition.
2.56e2.52 (m, 1H), 2.48e2.32 (m overlapped with a s, total 4H),
2.26e1.98 (cluster of m, 4H),1.85 (m of d, J¼13.5 Hz,1H),1.01 (m of d,
J¼w13.5 Hz, 1H) for other protons. 13C NMR (100 MHz, CDCl3)
Towards our objective, the aromatic precursor 6 was prepared
from alcohol 11 as shown in Scheme 2. Thus, compound 11, readily
available from 6-allyl salicyl alcohol,11 was treated with bromine,
triphenylphosphine and imidazole to give the bromide 12 in high
yield. The reaction of bromide 12 with allyltosyl amine in the
presence of K2CO3 and benzyltriethylamminuim chloride furnished
the desired compound 14 as a major product along with 13 arising
as a result of dehydrohalogenation. Hydrolysis of the acetal group
in 14 readily furnished the required aromatic precursor 6 in ex-
cellent yield.
spectrum also exhibited characteristic signal at d 204.4 for carbonyl
group in addition to signals at d 143.8,135.8,133.8,129.9,129.5,127.6,
57.6, 53.2, 51.1, 48.4, 42.6, 37.9, 36.2, 26.8, 26.1, 21.7.
The above spectral features clearly suggested the gross structure
of adduct. However, it was difficult to ascertain the endo-stereo-
chemistry of cycloaddition and orientation of the oxirane ring from
the spectral data alone. Hence, a single crystal X-ray structure de-
termination was undertaken, which confirmed the structure 8
(Fig. 3).

240
V. Singh et al. / Tetrahedron 68 (2012) 238e243
Me
O
Me
O
Me
O
Me
O
Me
O
Me
O
Br2, PPh3
N-allyltosylamine
imidazole,
CH2Cl2,
0 οC-rt
K2CO3,
C6H5CH2Et3N+ Cl−,
CH3CN, reflux, 24 h
Br
OH
12 (81%)
13 (30%)
11
+
Me
O
Me
O
OH
OH
aq. HCl
N
THF, rt, 12 h
Ts
N
Ts
6 (94%)
14 (49%)
Scheme 2. Preparation of aromatic precursor 6.
O
OH
OH
It may be interesting to note the efficient generation of molec-
ular complexity and stereoselectivity in the aforementioned cy-
cloaddition. The adduct 8 is endowed with appropriately disposed
functionalities that is necessary for further transformations in-
cluding the photochemical reactions.
O
aq. NaIO4
N
CH3CN, 0 οC-rt,
18 h
Ts
N
Ts
7
6
Towards synthesis of the chromophoric system 9, the keto-
epoxide 8 was treated with ZneNH4Cl in aq methanol at ambient
O
temperature to give the
syn/anti isomers. Oxidation of 17 with Jones’ reagent followed by
decarboxylation of the resulting -keto-acid furnished the desired
b-hydroxymethyl ketone 17 as a mixture of
O
O
OH
O
O
b
CHO
+
+
compound 9 in good yield (Scheme 5).
O
N
Ts
OH
N
N
H
O
O
Ts
N
15 (5%)
O
O
Ts
Ts
8 (58%)
16 (25%)
Zn-NH4Cl
1. Jones' reagent
aq. MeOH
rt, 12 h
2. aq. THF, Δ,
Scheme 3. Oxidative dearomatization and synthesis of keto-epoxide 8.
N
16 h
N
N
Ts
9 (78%)
Ts
17 (81%)
O
Ts
8
O
o-Dichlorobenzene
8
Scheme 5. Synthesis of chromophoric system 9 from keto-epoxide 8.
N
16
140 οC, 4 h
Ts
85%
7
Photochemical reactions of
b,g-enones have stimulated in-
terest for long time,13 which has enhanced recently because of
Scheme 4. Preparation of keto-epoxide 8 by retro-DielseAlder/DielseAlder cascade.
their synthetic potential.14,15 In general, rigid compounds having
a
b,g-enone chromophore undergo a 1,2-acyl shift or oxa-di-p-
methane rearrangement upon triplet sensitized irradiation
whereas a 1,3-acyl shift is observed on direct (1S) irradiation. The
mechanism and stereochemistry of oxa-di-p-methane rear-
rangement and 1,3-acyl shift have been studied in detail and
a correlation between excited state and reactivity has been
established.13,15 These reactions have proved to be important
synthetic methods since it permits transformation bridged
structures into ring fused system in a highly stereoselective
manner.14,15 Though these reactions are fairly general, the struc-
ture of chromophoric system and the functional groups control
the outcome in a subtle fashion.
In view of the above, a solution of compound 9 in acetone (both
solvent as well as sensitizer) was irradiated with a mercury vapour
lamp (APP, 125 W) for 50 min in a Pyrex immersion well under
nitrogen. Removal of solvent followed by chromatography gave the
aza compound 4 in good yield (Scheme 6) as a result of oxa-di-p-
methane rearrangement, in addition to some unreacted starting
material. Similarly, the direct irradiation of 9 in benzene for 1.5 h
gave the tricyclic compound 5 (Scheme 6) as a consequence of
Fig. 3. Crystal structure of adduct 8.

V. Singh et al. / Tetrahedron 68 (2012) 238e243
241
H
H
H
4.3. 8-[3-Aza(N-tosyl)hex-5-enyl]-2,2-dimethyl-1,3-
benzodioxin 14 and 8-vinyl-2,2-dimethyl-1,3-benzodioxin 13
H
O
H
Ts
hν
hν
N
O
benzene
1.5 h
Pyrex
acetone
50 min.
Pyrex
N
Ts
O
To a stirred solution of bromide 12 (1.0 g, 3.7 mmol) in dry
acetonitrile (100 mL) was added N-allyl tosylamine (1.5 g,
7.1 mmol), benzyl triethylamonium chloride (0.421 g, 1.8 mmol),
K2CO3 (1.0 g, 7.2 mmol) and the reaction mixture was refluxed for
24 h. Acetonitrile was removed under vacuum, water (10 mL) was
added to reaction mixture and aqueous layer was extracted with
diethyl ether (4ꢁ30 mL). Organic extract was combined and dried
over Na2SO4. Solvent was removed under reduced pressure and
product was purified by column chromatography on silica gel
(100e200). Elution with petroleum ether/ethyl acetate (95:5) gave
compound 13 (0.215 g, 30%) as clear liquid. Rf (10% EtOAc/petro-
4 (60%)
5 (58%)
N
9
Ts
Scheme 6. Photoreaction of 9 upon sensitized and direct irradiation.
1,3-acyl shift in excited singlet (1S) state. The structure of both
products was clearly revealed from their spectral data.
3. Conclusion
.
leum ether) 0.7; IR nmax (film): 1638 cmꢂ1 1H NMR (400 MHz,
In summary, we have described synthesis of 4-aza tricyclo
[6.2.2.01,6]dodecenones and aza-polycyclic systems from a simple
aromatic precursor. The methodology involves oxidative dear-
omatization of appropriately appended o-hydroxymethyl phenol 6
to spiroepoxycyclohexa-2,4-dienone in situ and intramolecular
CDCl3):
d
7.37 (t, J¼5.3 Hz, 1H), 6.95 (dd, J1¼17.4 Hz, J2¼11.2 Hz, 1H),
6.88e6.86 (m, 2H), 5.77 (dd, J1¼17.4 Hz, J2¼1.6 Hz, 1H), 5.27 (dd,
J1¼11.2 Hz, J2¼1.6 Hz, 1H), 4.8 (s, 2H), 1.56 (s, 6H). 13C NMR
(100 MHz, CDCl3):
d 148.7, 131.1, 126.3, 125.1, 124.1, 120.1, 119.7,
p
4sþ
p
2s cycloaddition which gives tricyclic keto-epoxide 8 in
114.7, 99.8, 61.1, 25.0.
a single stereoselective step. Manipulation of the oxirane ring led to
the chromophoric system 9 that upon photochemical reaction upon
triplet and singlet excitation led to aza-polycyclic systems 4 and 5,
respectively, in a stereoselective fashion.
Further elution with petroleum ether/ethyl acetate (90:10) gave
the desired compound 14 (0.720 g, 49%) as a colourless liquid. Rf
(10% EtOAc/petroleum ether) 0.5; IR nmax (film): 3365, 2927, 1597,
1467 cmꢂ1 1H NMR (300 MHz, CDCl3):
. d 7.70 (d with structure,
J¼8.5 Hz, 2H), 7.26 (d, J¼8.5 Hz, 2H), 6.96 (m, 1H), 6.88e6.78 (m,
2H), 5.70e5.60 (m, 1H), 5.25e5.10 (m, 2H), 4.8 (s, 2H), 3.57 (d,
J¼6.2 Hz, 2H), 3.35e3.25 (m, 2H), 2.85e2.45 (m, 2H), 2.4 (s, 3H),
4. Experimental section
4.1. General
1.50 (s, 6H). 13C NMR (100 MHz) CDCl3:
d 149.3, 143.2, 137.4, 133.3,
129.7, 129.2, 127.3, 126.5, 123.2, 120.1, 119.2, 118.8, 99.6, 61.0, 50.7,
46.9, 29.5, 24.9, 21.6. HRMS (ESI) (m/z): found 402.1754 [MþH]þ.
C22H28NO4S requires 402.1739.
IR spectra were recorded on Nicolet Impact 400 FT-IR in-
strument. 1H NMR and 13C NMR spectra were recorded on Mercury
Varian 400 MHz NMR and Varian VXR 300 instruments. The sam-
ples were dissolved in CDCl3 containing TMS as internal standard.
High resolution mass spectra were recorded on Q-T micro (YA 105)
mass spectrometer. Melting points were determined on a Veego
apparatus of Buchi type and are uncorrected. Reactions were
monitored by thin layer chromatography (TLC) using silica gel and
silica gel GF254 and spots were visualized with iodine vapour. The
organic extracts were dried on anhydrous sodium sulfate. Column
chromatography was performed on silica gel (60e120 or 100e200
mesh). The fractions eluted from column were concentrated at
reduced pressure on a Buchi rotavapor.
4.4. 2-[3-Aza(N-tosyl)hex-5-enyl]-6-hydroxymethylphenol 6
To a solution of 14 (2.00 g, 4.9 mmol) in THF (50 mL) was added
dil HCl (1 N, 50 mL) drop wise at 0 ꢀC and reaction mixture was
stirred at room temperature for 12 h. After that reaction mixture
was cooled to 0 ꢀC and NaHCO3 was added pinch by pinch. THF was
removed under vacuum and aqueous layer was extracted with
diethyl ether (3ꢁ20 mL). Organic extract was combined and dried.
Solvent was removed under vacuum and product was chromato-
graphed on silica gel. Elution with petroleum ether/ethyl acetate
(75:25) gave compound 6 (1.7 g, 94%) as a clear liquid. Rf (25%
EtOAc/petroleum ether) 0.5; IR nmax (film): 3383, 3054, 1597, 1467,
4.2. 8-(2-Bromoethyl)-2,2-dimethyl-1,3-benzodioxin 12
1340 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
7.62 (d, J¼8.4 Hz, 2H), 7.20
To a stirred solution of imidazole (1.9 g, 27.9 mmol) and tri-
phenylphosphine (5.0 g, 19.0 mmol) in dichloromethane (25 mL) at
0 ꢀC, was added a solution of bromine (0.5 ml, 1.53 g, 9.5 mmol) in
dichloromethane (2 mL) that led to formation of an orange pre-
cipitate. Reaction mixture was stirred at 0 ꢀC for 10 min. A solution
of the alcohol 11 (2.0 g, 9.7 mmol) in dry dichloromethane (20 mL)
was added in one portion to the reaction mixture. Reaction mixture
was further stirred at ambient temperature for 3 h. After that water
(10 mL) was added to the reaction mixture, organic layer was
separated and aqueous layer was extracted with dichloromethane
(3ꢁ20 ml). Combined organic extract was dried on sodium sulfate
and solvent was removed under vacuum and product was chro-
matographed on silica gel. Elution with petroleum ether/ethyl ac-
etate (95:5) gave bromide 12 (2.1 g, 81%) as clear liquid. Rf (7%
EtOAc/petroleum ether) 0.06; IR nmax (film): 2925, 2627, 2455,
(d, J¼8.4 Hz, 2H), 6.96 (d with str., J¼7.3 Hz, 1H), 6.84 (d with str.,
J¼7.3 Hz, 1H), 6.72e6.66 (m, 1H), 5.62e5.48 (m, 1H), 5.16e5.04 (m,
2H), 4.76 (s, 2H), 3.76 (d, J¼6.6 Hz, 2H), 3.30e3.24 (m, 2H),
2.86e2.78 (m, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 154.6,
143.3, 137.1, 133.2, 130.8, 129.8, 127.3, 126.5, 125.7, 124.7, 119.9, 119.1,
64.9, 51.0, 47.1, 30.1, 21.6. HRMS (ESI) (m/z): found 384.1241
[MþNa]þ. C19H23N O4SNa requires 384.1245.
4.5. 4-Aza-(N-tosyl)-9-spiroepoxy-endo-tricyclo[6.2.2.01,6
]
dodec-11-en-10-one 8, aldehyde 15 and dimer 16
To a stirred solution of compound 6 (1.00 g, 2.7 mmol) in ace-
tonitrile (50 mL) at 0 ꢀC, was added a saturated solution of sodium
metaperiodate (2.9 g, 13.5 mmol in 20 mL water) drop wise over
a period of 1 h and the reaction mixture was stirred for 5 h at 0 ꢀC.
Reaction mixture was further stirred for overnight at ambient
temperature. The reaction mixture was filtered through a Celite
pad. Brine was added to the filtrate, the organic layer was separated
and aqueous layer was extracted with ethyl acetate (3ꢁ30 mL).
Organic layer was combined and dried over Na2SO4. The solvent
was removed under reduced pressure and the product was
1414 cmꢂ1
.
1H NMR (300 MHz, CDCl3):
d
7.30 (dd, J1¼6.7 Hz,
J2¼1.6 Hz, 1H), 6.81e6.89 (m, 2H), 4.80 (s, 2H), 3.5 (t, J¼7.6 Hz, 2H),
3.10 (t, J¼7.6 Hz, 2H), 1.50 (s, 6H). 13C NMR (100 MHz, CDCl3):
d
149.3, 129.2, 126.8, 123.6, 120.0, 119.4, 99.7, 61.0, 34.0, 32.0, 24.9.
HRMS (ESI) (m/z): found 293.0160 [MþNa]þ. C12H15BrO2Na re-
quires 293.0147.

242
V. Singh et al. / Tetrahedron 68 (2012) 238e243
chromatographed on silica gel. Elution with petroleum ether/ethyl
acetate (90:10) first gave the aldehyde 15 as minor component
(0.050 g, 5%) as a liquid. Further elution with petroleum ether/ethyl
acetate (75:25) gave cycloadduct 8 (0.580 g, 58%) as a colourless
solid.
4.7. 4-Aza-(N-tosyl)-9-hydroxymethyl-endo-tricyclo[6.2.2.01,6
]
dodec-11-en-10-one 17
To a solution of adduct 8 (1.00 g, 2.7 mmol) in MeOH/H2O (6:1,
35 mL) was added zinc (activated, 1.5 g, excess) and NH4Cl (0.738 g,
13.9 mmol). The reaction mixture was stirred at ambient temper-
ature (30 ꢀC) for 12 h. It was filtered on a Celite bed and washed
with ethyl acetate. The filtrate was concentrated under vacuum,
and the residue was diluted with water (15 mL) and extracted with
ethyl acetate (4ꢁ25 mL). The combined extract was washed with
brine and dried. The solvent was removed under reduced pressure,
and the product was purified by column chromatography. Elution
with petroleum ether/ethyl acetate (65:35) gave the alcohol 17
(0.810 g, 81%, mixture of syn/anti isomers) as a colourless solid, mp
56e57 ꢀC. Rf (30% EtOAc/petroleum ether) 0.5; IR (KBr) nmax: 3459,
Continued elution with petroleum ether/ethyl acetate (75:25)
furnished the dimer 16 (0.250 g, 25%) as a thick liquid.
4.5.1. Data for the aldehyde 15. Rf (25% EtOAc/petroleum ether) 0.7;
IR (film) nmax: 1651 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d 11.20 (s, 1H),
9.80 (s, 1H), 7.68 (d, J¼8.0 Hz, 2H), 7.45e7.40 (m, 2H), 7.26 (d,
J¼8.0 Hz, 2H), 6.97e6.94 (m, 1H), 5.67e5.56 (m, 1H), 5.19e5.10 (m,
2H), 3.80 (d, J¼6.5 Hz, 2H), 3.38e3.36 (m, 2H), 2.93e2.89 (m, 2H),
2.4 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 196.8, 160.0, 143.3, 138.3,
137.1, 133.0, 132.5, 129.8, 127.3, 127.2, 120.4, 119.8, 119.2, 51.1, 46.5,
29.3, 21.6. HRMS (ESI) (m/z): found 360.1261 [MþH]þ. C19H22NO4S
requires 360.1270.
1715 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
7.60 (d, J¼8.1 Hz, 2H), 7.32
(d, J¼8.1 Hz, 2H), 6.62 (superimposed dd, J1¼J2¼7.3 Hz, 1H), 5.66 (d,
J¼7.3 Hz, 1H), 3.90e3.77 (m, 2H), 3.67e3.55 (m, 2H), 2.95 (br d,
J¼2.5 Hz, 1H), 2.44 (s, 3H), 2.42e1.80 (cluster of m, 8H), 0.88e0.76
4.5.2. Data for adduct 8. Rf (25% EtOAc/petroleum ether) 0.5, mp
160e162 ꢀC; IR (KBr) nmax: 1719 cmꢂ1. 1H NMR (300 MHz, CDCl3):
(m, 1H). 13C NMR (100 MHz, CDCl3):
d 212.8, 143.7, 139.0, 133.7,
d
7.60 (d, J¼8.0 Hz, 2H), 7.30 (d, J¼8.0 Hz, 2H), 6.55 (superimposed,
129.8, 128.2, 127.6, 62.5, 51.2, 49.2, 48.7, 42.9, 36.0, 33.9, 26.3, 25.6,
21.6. HRMS (ESI) (m/z): found 362.1434 [MþH]þ. C19H24NO4S re-
quires 362.1426.
dd, J¼7.6 Hz, 1H), 5.76 (d, J¼7.6 Hz, 1H), 3.92e3.86 (m of
d J¼13.1 Hz, 1H), 3.70e3.64 (m, J¼13.1 Hz, 1H), 3.14 (part of an AB
system, JAB¼5.6 Hz, 1H), 2.82 (part of an AB system, JAB¼5.6 Hz, 1H),
2.56e2.52 (m, 1H), 2.48e2.32 (m overlapped with a s, total 4H),
2.26e1.98 (cluster of m, 4H), 1.85 (m of d, J¼13.5 Hz, 1H), 1.01 (m of
4.8. 4-Aza-(N-tosyl)-endo-tricyclo[6.2.2.01,6]dodec-11-en-10-
one 9
d, J¼w13.5 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 204.4, 143.8,
135.8, 133.8, 129.9, 129.5, 127.6, 57.6, 53.2, 51.1, 48.4, 42.6, 37.9, 36.2,
26.8, 26.1, 21.7. HRMS (ESI) (m/z): found 382.1089 [MþNa]þ.
C19H21NO4SNa requires 382.1089.
To solution of alcohol 17 (0.180 g, 0.5 mmol) in acetone (20 mL)
was added freshly prepared Jones’ reagent drop wise at 0 ꢀC and the
reaction mixture was stirred for 30 min. After that isopropanol was
added to reaction mixture to quench excess Jones’ reagent. Solvent
was removed under reduced pressure and the residue was diluted
with water (10 mL) and aqueous layer was extracted with ethyl
acetate (5ꢁ30 mL). Organic extract was combined and dried over
Na2SO4. Removal of solvent gave a keto-acid that was directly
subjected for decarboxylation as described below.
The carboxylic acid thus obtained was dissolved in THF/H2O
(1:1, 30 mL) and reaction mixture was refluxed for 18 h. After that it
was saturated with NaCl, organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3ꢁ20 ml). Organic
extract was combined and dried on Na2SO4. Removal of solvent and
chromatography [petroleum ether/ethyl acetate (80:20)] gave
compound 9 (0.130 g, 78%) as a colourless solid, mp 55e56 ꢀC. Rf
(20% EtOAc/petroleum ether) 0.6; IR (KBr) nmax: 1719 cmꢂ1. 1H NMR
4.5.3. Crystal data of adduct 8. MF C19H21NO4S, mol. wt 359.43.
Crystal size¼0.23ꢁ0.17ꢁ0.14 mm. Space group: triclinic P1, Z¼2,
a¼6.9615 (4), b¼7.2855 (5), c¼17.7313 (9) A,
a
¼83.949(5)ꢀ,
ꢀ
b
¼83.392(4)ꢀ,
g
ꢀ
¼81.139(5)ꢀ. Dc: 1.358 Mg/m3. Crystal vol-
3
ꢀ
ume¼879.13(9) A , T¼150(2) K,
g
¼0.71073 A, F(000)¼380. Re-
flections collected/unique 6585/3084, [R(int)¼0.0262], final
R
indices [I>2 indices all data
s(I)], R1¼0.0356, wR2¼0.0762.
R
R1¼0.0707, wR2¼0.0818. Crystallographic data has been deposited
with Cambridge Crystallographic Data Center, CCDC no. 837557.
Copy of the data can be obtained, free of charge, on application to
CCDC. E-mail. deposit@ccdc.cam.ac.uk.
4.5.4. Data for the dimer 16. Rf (25% EtOAc/petroleum ether) 0.4; IR
(film) nmax: 1735 cmꢂ1
.
1H NMR (400 MHz, CDCl3):
d
7.75 (d,
(300 MHz, CDCl3):
d
7.60 (d, J¼9.2 Hz, 2H), 7.3 (J¼9.2 Hz, 2H), 6.50
J¼8.2 Hz, 2H), 7.65 (d, J¼8.2 Hz, 2H), 7.35 (d, J¼8.2 Hz, 2H), 7.28 (d,
J¼8.2 Hz, 2H), 6.80 (d, J¼4 Hz, 1H), 6.62 (dd, J1¼8.2 Hz, J2¼4 Hz, 1H),
5.88 (d, J¼8.2 Hz, 1H), 5.80e5.66 (m, 1H), 5.52e5.40 (m, 1H),
5.32e5.10 (cluster of m, 4H), 3.90e3.76 (m, 4H), 3.45e3.20 (m, 4H),
3.15e3.05 (m, 2H), 3.02 (d, J¼6 Hz, 1H), 2.90e2.85 (m, 3H),
2.80e2.60 (cluster of m, 2H), 2.40e2.15 (two singlets merged with
(superimposed dd, J1¼J2¼8 Hz, 1H), 5.63 (d, J¼8 Hz, 1H), 3.84 (m of
d, J¼11.6 Hz, 1H), 3.61 (m of d, J¼8 Hz, 1H), 2.95e2.90 (m, 1H), 2.43
(s, 3H), 2.41e2.31 (m, 1H), 2.11e1.80 (m, 7H), 0.98e0.90 (m, 1H). 13C
NMR (100 MHz, CDCl3):
d 210.6, 143.7, 138.2, 133.7, 129.8, 128.0,
127.7, 50.9, 48.9, 43.1, 39.5, 35.2, 31.6, 30.2, 26.5, 21.7. HRMS (ESI)
(m/z): found 354.1136 [MþNa]þ. C18H21NO3SNa requires 354.1140.
m, total 9H). 13C NMR (100 MHz, CDCl3):
d 205.2, 193.0, 143.6, 143.4,
141.9, 140.5, 137.2, 136.7, 133.97, 133.91, 133.0, 132.4, 130.0, 129.9,
127.3, 127.2, 119.99, 119.90, 59.7, 58.7, 57.2, 54.0, 51.9, 50.5, 45.7,
43.4, 41.1, 39.89, 39.83, 30.0, 29.2, 21.7, 21.6. HRMS (ESI) (m/z):
found 719.2471 [MþH]þ. C38H43N2O8S2 requires 719.2461.
4.9. 10-Aza-(N-tosyl)-tetracyclo[6.4.0.0.1,302,6]dodec-4-one 4
A solution of 9 (0.100 g, 0.3 mmol) in acetone (100 mL) (both as
solvent and sensitizer) was irradiated by mercury vapour lamp
(125 W) in a Pyrex immersion well under nitrogen for 50 min.
Solvent was removed and the product was chromatographed.
Elution with petroleum ether/ethyl acetate (75:25) first gave the
starting material (0.015 g, 15%). Further elution with petroleum
ether/ethyl acetate (70:30) gave the desired compound 4 (0.060 g,
60%) as a colourless solid, mp 122e124 ꢀC. Rf (25% EtOAc/petroleum
4.6. Preparation of adduct 8 from the dimer 16
A solution of dimer 16 (0.130 g) in o-dichlorobenzene (10 mL)
was heated at 140 ꢀC for 5 h. The reaction mixture was chromato-
graphed on silica gel. Elution with petroleum ether removed o-di-
chlorobenzene. Further elution with petroleum ether/ethyl acetate
(75:25) furnished the adduct 8 (0.110 g, 85%), which was identical
to the sample obtained in previous experiment.
ether) 0.5; IR (KBr) nmax: 1712 cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d
7.66 (d, J¼8 Hz, 2H), 7.32 (d, J¼8 Hz, 2H), 3.40e3.10 (m, 3H),
2.96e2.86 (m, 1H), 2.67 (t, J¼5.2 Hz, 1H), 2.56e2.40 (s, merged with
m, 4H), 2.36e2.26 (m, 1H), 2.22e2.10 (m, 2H), 1.82e1.75 (m, 2H),

V. Singh et al. / Tetrahedron 68 (2012) 238e243
243
L.; Deffieux, D. Synlett 2008, 467; (d) Pouysegu, L.; Deffieux, D.; Quideau, S.
Tetrahedron 2010, 66, 2235 and references therein.
1.66e1.60 (m, merged with signal due to H2O in CDCl3, 1H),
1.30e1.20 (m, 2H). 13C NMR (100 MHz, CDCl3):
214.7, 143.6, 134.5,
129.9, 127.4, 48.3, 46.2, 43.7, 43.6, 41.2, 41.0, 38.2, 36.9, 27.6, 21.6.
HRMS (ESI) (m/z): found 354.1131 [MþNa]þ. C18H21NO3SNa re-
quires 354.1140.
d
4. (a) Berube, A.; Drutu, I.; Wood, J. L. Org. Lett. 2006, 8, 5421; (b) Luo, S.-Y.; Jang,
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4.10. 10-Aza-(N-tosyl)-tricyclo[6.4.0.03,6]dodec-1-en-4-one 5
A solution of 9 (0.100 g, 0.3 mmol) in benzene (100 mL) was
irradiated by mercury lamp (125 W) in a Pyrex immersion well
under nitrogen for 1.5 h. Removal of solvent followed by column
chromatography [petroleum ether/ethyl acetate (80:20) as eluent]
gave 1,3-acyl shift product 5 (0.058 g, 58%) as a colourless solid, mp
6. (a) Toyota, M.; Nishikawa, Y.; Motoki, K.; Yoshida, N.; Fukumoto, K. Tetrahe-
dron 1993, 49, 11189; (b) Fukumoto, K.; Toyoda, S. Jpn. Patent 95179449, 1995;
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MacLean, D. B. Can. J. Chem. 1976, 54, 2893; (b) Loyola, L. A.; Morales, G.; Cas-
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150e151 ꢀC. Rf (25% EtOAc/petroleum ether) 0.6; IR (KBr) nmax
:
1780 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d
7.65 (d, J¼8.0 Hz, 2H), 7.34
(d, J¼8 Hz, 2H), 5.38e5.34 (m, 1H), 3.93e3.80 (complex m, 2H),
3.66e3.58 (m, 1H), 3.02e2.86 (m, 2H), 2.78e2.64 (m, 1H),
2.58e2.40 (m merged with s, total 5H), 2.32e2.18 (m, 2H),
1.96e1.84 (m, 2H), 1.24e1.15 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
205.2, 143.7, 137.1, 133.3, 129.8, 127.7, 115.6, 59.5, 51.5, 48.3, 46.8,
33.5, 31.0, 25.9, 22.1, 21.6. HRMS (ESI) (m/z): found 332.1312
[MþH]þ. C18H22NO3S requires 332.1320.
9. (a) Paquette, L. A.; Friedrich, D.; Pinard, E.; William, J. P.; Laurent, D. S.; Roden,
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Acknowledgements
We are grateful to the Department of Science and Technology
(DST), New Delhi for continued financial support and J.C. Bose fel-
lowship (V.S.). One of us (P.B.) is thankful to CSIR New Delhi for
a fellowship. Thanks are due to SAIF, IIT Bombay for spectral facil-
ities. We also thank DST for the creation of a National Centre for
Single Crystal X-ray diffraction facility.
References and notes
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