Intramolecular cycloaddition in cyclohexa-2,4-dienone and photochemical reactions: An efficient route to azatriquinane and azasterpurane frameworks

Article abstract of DOI:10.1055/s-2008-1072588

A novel, efficient and stereoselective entry to azatriquinane and azasterpurane frameworks from simple aromatic precursor, is described. The methodology involves in situ generation of cyclohexa-2,4-dienones containing a tether and intramolecular π4s+π2s cycloaddition that leads to a bicyclo[2.2.2]octenone-annulated five-membered ring that contains nitrogen. Further manipulation of the resulting adduct followed by photochemical sigmatropic shifts readily furnished the azatriquinane and azasterpurane frameworks. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072588

1222
LETTER
Intramolecular Cycloaddition in Cyclohexa-2,4-dienone and Photochemical
Reactions: An Efficient Route to Azatriquinane and Azasterpurane Frame-
works
E
fficient
Route to
i
Azatriq
s
uinane an
h
dAzasterpur
w
ane Frameworks akarma Singh,*a Bharat C. Sahu,a Shaikh M. Mobinb
a
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
National Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Mumbai 400076, India
Fax +91(22)25723480; E-mail: vks@chem.iitb.ac.in
b
Received 13 February 2008
OMe
O
OMe
O
H
H
Me
Me
Abstract: A novel, efficient and stereoselective entry to aza-
triquinane and azasterpurane frameworks from simple aromatic pre-
cursor, is described. The methodology involves in situ generation of
cyclohexa-2,4-dienones containing a tether and intramolecular
p4s+p2s cycloaddition that leads to a bicyclo[2.2.2]octenone-annu-
lated five-membered ring that contains nitrogen. Further manipula-
tion of the resulting adduct followed by photochemical sigmatropic
shifts readily furnished the azatriquinane and azasterpurane frame-
works.
O
O
H
H
1
2
R3
R3
H
H
H
H
R2
R2
N
Ts
N
O
Ts
O
R1
R1
4
3
Key words: cyclohexa-2,4-dienone, cycloaddition, oxa-di-p-meth-
ane rearrangement, 1,3-acyl shift photochemistry
Figure 1
R2
R3
OH
The efficient creation of molecular complexity from simple
precursors, atom economy and stereoselectivity are some of
the important criteria in the design and development of new
synthetic methods.1–3 Cascades of reactions2d,f or reactions
in tandem2c,e,3 and multicomponent reactions4 are often em-
ployed to achieve this objective. Triquinanes have stimulat-
ed intense interest on account of their molecular structure
and biological activity.5–7 Recently, heteroanalogues of
polyquinanes, especially the tricyclic compounds of type 1
and 2 (Figure 1) and their congeners having oxatriquinane
framework were found to exhibit potent in vitro cytotoxic
activity against murine lymphoma L1210 cells and human
epidermoid carcinoma KB cells.8a,b While there are a num-
ber of methods for the synthesis of carbocyclic triquinanes
only a few methods exists for oxatriquinanes8 and aza-
polyquinanes.9
OH
O
R
R1
N
3
hν, 3
T
R1
N
8
5
R
O
R = Ts
hν, 1
S
O
O
O
4
R
R1
N
R1
N
7
6
R
Scheme 1
dienones of type 7, derived from the aromatic precursor 8
In view of the biological significance of het-
eropolyquinanes and our continuing interest in this area,
we considered developing a route to azapolyquinanes of
the type 3 and compounds of type 4 which are aza-ana-
logues of sterpuranes, a unique class of sesquiterpenes.10
We envisaged that a 1,2-acyl shift in the tricyclic system
of the type 5 would furnish the azatriquinane 3 whereas a
photochemical 1,3-acyl shift in 5 would provide an entry
into azasterpuranes 4 (Scheme 1). Further, it was thought
that the chromophoric systems of type 5 could be derived
from the ketoepoxide 6 which in turn may be obtained by
the intramolecular Diels–Alder reaction in cyclohexa-2,4-
(Scheme 1).
Towards our objective, the benzylic alcohol 9a, readily
available from p-cresol, was treated with triphenylphos-
phine and bromine11 to give the bromide 9b in a good
yield. Reaction of 9b with N-allyl tosylamine in the pres-
ence of K2CO3 gave the N-alkylated product 10 in quanti-
tative yield which on acid-catalyzed hydrolysis furnished
the desired aromatic precursor 11 with excellent yield. A
solution of 11 in acetonitrile was oxidized with aqueous
sodium metaperiodate12a,b at 0–5 °C, according to a proce-
dure developed in our laboratory.12c Chromatography of
the product gave the adduct 13 in a good yield (72%;
Scheme 2). The structure of the adduct 13 was deduced
from 1H NMR and COSY spectroscopic analysis and con-
firmed by further transformations (vide infra).13
SYNLETT 2008, No. 8, pp 1222–1224
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072588; Art ID: G03308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Route to Azatriquinane and Azasterpurane Frameworks
1223
Me
O
H
Me
O
H
Me
O
Me
HO
OH
hν
Ts
OH
O
15
N
Ts
N
O
Ts
acetone
45 min
N
K2CO3
N-allyl-
Me
HCl
THF
18 (62%)
Me
tosylamine
Me
H
H
11 (85%)
Me
10 (quant.)
9a, R = OH
hν
N
Ts
aq NaIO4
MeCN
PPh3Br2
9b, R = Br (60%)
benzene
30 min
O
Me
19 (52%)
O
O
O
Me
Me H
H
H
H
Ts
N
Me
Me
Me
O
N
Ts
N
O
Ts
O
Me
21 (55%)
Me
N
Me
Ts
12
20 (25%)
13 (72%)
Scheme 4
Scheme 2
OH
H
excitation, whereas a 1,3-acyl shift is observed upon sin-
glet excitation. Though, these reactions are general and
quite characteristic of their excited states, small structural
changes and functional groups often control the reaction
in a subtle fashion. Keeping this in mind, a solution of 15
in acetone (both sensitizer and solvent) was irradiated
with a 125-W mercury vapor lamp in a Pyrex immersion
well for one hour and the tetracyclic ketone 18 was ob-
tained in a good yield as a result of 1,2-acyl shift
(Scheme 4).17 Similarly, irradiation of 15 in anhydrous
benzene in a Pyrex immersion well for about half an hour
led to a clean reaction and gave the tricyclic compound 19
as a result of 1,3-acyl shift in a good yield (52%).18 Simi-
lar irradiation of 17 also gave the compounds 20 and 21
after sensitized and direct irradiation, respectively.
O
O
O
O
Me
Me
Me
1. Jones
Zn, NH4Cl
aq MeOH
2. aq THF
∆
N
N
N
Ts
Ts
13
Ts
14 (73%)
15 (52%)
Zn, NH4Cl
dioxane, ∆
Me
Me
Me
H
O
O
Me
Me
NaH, THF
MeI
N
N
Ts
Ts
17 (72%)
16 (62%)
Scheme 3
In summary, a novel stereoselective route to azatriquinane
and azasterpurane frameworks is described. Intramolecu-
lar cycloaddition of the in situ generated cyclohexa-2,4-
dienone and photochemical reactions in the triplet and sin-
glet excited states are the key features of methodology.
The presence of ketoepoxide functionality in the adduct
13 provided opportunity for further manipulation. Thus,
the adduct 13 was treated with Zn in aqueous methanol
containing ammonium chloride at ambient temperature to
give the b-keto alcohol 14 (syn/anti mixture, 73% yield)
as the major product. Oxidation of 14 with Jones reagent
and subsequent decarboxylation furnished the azatricyclic
compound 15 (Scheme 3).14 Alternatively, the reduction
of adduct 13 with Zn–NH4Cl in refluxing anhydrous diox-
ane gave 16 as a result of deoxygenation of the oxirane
ring. Alkylation of 16 with methyl iodide in the presence
of NaH–THF gave the compound 17 in good yield
(Scheme 3). The structures of all the compounds were
supported by spectral data. The stereostructure of com-
pound 15 was further confirmed by a single-crystal X-ray
structure determination14 and hence it also established the
structure of the adduct 13 and other related compounds.
Acknowledgment
We thank CSIR, New Delhi for continuing financial support. We
also thank DST, New Delhi for creating the National Single Crystal
Diffraction Facility.
References and Notes
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Synlett 2008, No. 8, 1222–1224 © Thieme Stuttgart · New York

1224
V. Singh et al.
LETTER
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d = 200.9 (CO), 146.4, 143.8, 133.9, 129.8, 127.3, 121.6,
58.8, 56.6, 52.0, 51.8, 49.2, 44.6, 41.5, 24.8, 21.5, 20.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H22SNO4:
360.1270; found: 360.1274.
(14) Data of the compound 15: mp 164–166 °C. IR: 1723 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.73 (d, J = 8.0 Hz, 2 H),
7.34 (d, J = 8.0 Hz, 2 H), 5.00 (br m, 1 H, b-H of b,g-enone
moiety), 3.60–3.64 (m, 2 H), 3.44 (d, J = 10.3 Hz, 1 H),
2.71–2.79 (m, 2 H), 2.44 (s, 3 H), 1.83–2.18 (m, 4 H), 1.79
(d, J = 1.8 Hz, 3 H), 1.16–1.21 (m of dd, J1 = 12.5 Hz, J2 =
5.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 207.6 (CO),
148.7, 143.6, 134.3, 129.9, 127.5, 120.2, 59.3, 52.4, 49.6,
40.6, 38.9, 37.9, 28.0, 21.7, 19.8. HRMS (ESI): m/z [M + H]+
calcd for C18H21SNO3: 332.1320; found: 332.1306. Crystal
data: C18H21NO3S, M = 331.42, crystal size = 0.23 × 0.18 ×
0.15 mm, monoclinic, P21/n, Z = 4, a = 11.4521(8), b =
10.5769(7), c = 13.7991(9) Å, l = 0.71073 Å, a = 90.000
b = 103.366(6)°, V = 1626.18(19) Å3, Dcalcd = 1.354 mg/m3,
T = 150 (2) K, F(000) = 704. Reflections collected/unique =
9895/1761, [R(int) = 0.0581], final R indices [I > 2s(I)],
R1 = 0.0581, wR2 = 0.1019, R indices (all data), R1 = 0.1126,
wR2 = 0.1161. The complete crystal data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif quoting
the CCDC number 677807.
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(13) All the compounds gave satisfactory spectral and analytical
data. Data for adduct 13: mp 159–161 °C. IR: 1733 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.70–7.74 (m, 2 H), 7.31–7.37
(m, 2 H), 5.20–5.24 (br m, 1 H, b-H of b,g-enone moiety),
3.60–3.68 (m merged with part of an AB system, JAB = 10.6
Hz, 2 H), 3.52 (part of an AB system, JAB = 10.6 Hz, 1 H),
3.14 (part of an AB system, JAB = 6.0 Hz, 1 H), 2.85–2.92 (m
merged with another signal, 1 H), 2.84 (part of an AB
system, JAB = 6.0 Hz, 1 H), 2.45 (s, 3 H, Me), 2.12–2.34 (m,
3 H), 1.87 (d, J = 1.5 Hz, 3 H, Me), 1.26 (ddd, J1 = 12.1 Hz,
J2 = 5.1 Hz, J3 = 1.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
(b) Singh, V. In CRC Handbook Organic Photochemistry
and Photobiology; Horspool, W. M.; Lenci, F., Eds.; CRC
Press: Boca Raton, 2004, Chap. 78. (c) Singh, V. In CRC
Handbook Organic Photochemistry and Photobiology;
Horspool, W. M.; Lenci, F., Eds.; CRC Press: Boca Raton,
2004, Chap. 79.
(17) Data for compound 18: IR: 1726 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.61 (d, J = 8.0 Hz, 2 H, ArH), 7.29 (d, J = 8.0
Hz, 2 H), 3.22–3.27 (m, 2 H), 2.94 (superimposed dd, J1 =
9.0 Hz, 1 H), 2.78 (d, J = 9.7 Hz, 1 H), 2.64 (dd, J1 = 9.7 Hz,
J2 = 5.2 Hz, 1 H), 2.50 (dd, J1 = 18.3 Hz, J2 = 10.0 Hz, 1 H),
2.27–2.46 (s merged with a m, 4 H), 1.86–1.89 (m, 1 H),
1.69–1.80 (m, 2 H), 1.34 (s, 3 H), 1.18–1.21 (br m, 1 H). 13
NMR (100 MHz, CDCl3): d = 213.9, 144.2, 131.5, 129.9,
128.2, 53.1, 48.7, 48.6, 46.7, 46.0, 45.5, 45.4, 45.2, 41.8,
21.7, 13.5. HRMS (ESI): m/z [M + H]+ calcd for
C18H21SNO3: 332.1320; found: 332.1309.
C
(18) Data for compound 19: mp 132–134 °C. IR: 1772 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.72 (d, J = 8.0 Hz, 2 H), 7.34
(d, J = 8.0 Hz, 2 H), 5.29 (br s, 1 H), 4.06 (m of d, J = 14.3
Hz, 1 H), 3.89 (superimposed dd, J1 = J2 = 8.0 Hz, 1 H), 3.74
(m of d, J = 14.3 Hz, 1 H), 2.95 (dd, J1 = 17.7 Hz, J2 = 9.1
Hz, 1 H), 2.67–2.74 (m, 2 H), 2.50–2.58 (m, 1 H), 2.44 (s, 3
H, Me), 2.34–2.42 (m, 1 H), 2.00 (ddd, J1 = 12.3 Hz, J2 = 6.1
Hz, J3 = 2.4 Hz, 1 H), 1.22 (s, 3 H), 1.00–1.07 (m, 1 H). 13
NMR (100 MHz, CDCl3): d = 208.8, 143.8, 139.8, 133.4,
129.9, 127.8, 118.7, 63.1, 53.7, 51.4, 46.1, 33.9, 30.8, 23.8,
21.7, 20.3. HRMS (ESI): m/z [M + Na]+ calcd for
C18H21SNO3Na: 354.1140; found: 354.1143.
C
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