Stereoselective synthesis of 6-oxabicyclo[3.2.1]octene via (3,5)-oxonium-ene reaction

Article abstract of DOI:10.1016/j.tet.2012.01.064

Oxabicyclo[3.2.1]octene can efficiently be synthesized by the reaction of (-)-terpinen-4-ol and aldehyde or epoxide catalyzed by indium triflate (In(OTf)₃) in good yields. The reaction is stereoselective and proceeds via (3,5)-oxonium-ene-type

Full text of DOI:10.1016/j.tet.2012.01.064

Tetrahedron 68 (2012) 2261e2266
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Stereoselective synthesis of 6-oxabicyclo[3.2.1]octene via (3,5)-oxonium-ene
reaction
*
Pipas Saha, Anil K. Saikia
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxabicyclo[3.2.1]octene can efficiently be synthesized by the reaction of (ꢀ)-terpinen-4-ol and aldehyde
or epoxide catalyzed by indium triflate (In(OTf)3) in good yields. The reaction is stereoselective and
proceeds via (3,5)-oxonium-ene-type reaction.
Received 17 November 2011
Received in revised form 20 January 2012
Accepted 23 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective
Oxabicyclic compound
Oxonium-ene reaction
Catalytic reaction
Indium (III) triflate
1. Introduction
for the synthesis of 6-oxabicyclo[3.2.1]octane and -octene have
been reported in the literature.6 Recently, Xu and co-workers have
Oxonium-ene reactions are important in organic synthesis due
to its ability to construct various cyclic ethers.1 Recently, several
cyclic ethers, such as tetrahydrofurans, tetrahydropyrans and oxa-
bicyclic compounds have been synthesized using this protocol.2
Several oxabicyclic compounds exhibit biological activity. Oxabi-
cyclo[3.3.1]nonene and its derivatives are known to behave as
oestrogen receptor ligands.3 We have synthesized oxabicyclo[3.3.1]
nonanone and -nonene using (3,5)-oxonium-ene cyclization re-
action starting from readily available naturally occurring terpe-
noids trans-p-menth-6-ene-2,8-diol and geraniol, respectively.2d,e
The chemistry of 8-oxabicyclo[3.2.1]octane and -octene (Fig. 1, A)
is extensively studied4 and are found to be a basic unit of many
natural products.5 But the chemistry of 6-oxabicyclo[3.2.1]octane
and -octene (Fig. 1, B) is still in its initial stage. A few methodologies
reported the presence of 6-oxabicyclo[3.2.1]octane moiety in nat-
ural products.7 Naturally occurring terpenoids are precursors of
biologically active compounds8 and intermediates in asymmetric
synthesis.9 The (ꢀ)-terpinen-4-ol is found to be a main constituent
of Melaleuca alternifolia (Tea Tree) oil, which possess antimicrobial
and other medicinal properties.10 This is also used for the synthesis
of some stereoisomers of p-menthane-1,2,4-triol.11 Herein, we wish
to disclose a methodology for the synthesis of 6-oxabicyclo[3.2.1]
octene via (3,5)-oxonium-ene reaction from the reaction of alde-
hydes or epoxides with commercially available (ꢀ)-terpinen-4-ol
catalyzed by indium triflate.
2. Results and discussion
Initially (ꢀ)-terpinen-4-ol (1 equiv), 1 was reacted with benz-
aldehyde (1 equiv), 2a in dry toluene under boron trifluoride
etherate (1 equiv) at 0 ꢁC and the desired cyclization product 3a was
obtained in 32% yield along with some decomposed products.
Further lowering the temperature to ꢀ30 ꢁC resulted in the same
yield. The reaction was also performed in the presence of other
Lewis acids and the results are summarised in Table 1. These results
showed that indium triflate (In(OTf)3) was the efficient Lewis acid,
which acted as a catalyst for this transformation. No reaction was
observed when scandium triflate or indium trichloride was used.
Among the solvents studied, dichloromethane was found to be the
best solvent, whereas acetonitrile was found to be ineffective.
O
O
B
A
Fig. 1. Different types of oxabicyclo[3.2.1]octane/octene.
* Corresponding author. Tel.: þ91 361 258 2316; fax: þ91 361 2690762; e-mail
address: asaikia@iitg.ernet.in (A.K. Saikia).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.064

2262
P. Saha, A.K. Saikia / Tetrahedron 68 (2012) 2261e2266
Table 1
LA
O
Reaction with different Lewis acids and solvents
H
OLA
R
H
R
H
H
Ph
PhCHO 2a
2
O
O
R
5
Lewis acid / Solvent
OH
O
4
HO
0
oC to rt
(3,5)-oxonium-ene
reaction
1
3a
1
Entry
Lewis acid (equiv)
Time/h
0.5
24
24
6
24
24
24
24
24
24
Solvent
Yielda (%)
H
H
H
H
1
2
3
4
5
6
7
8
9
BF3$Et2O (1)
Sc (OTf)3 (0.1)
In (OTf)3 (0.1)
In (OTf)3 (0.1)
In (OTf)3 (0.1)
In (OTf)3 (0.05)
Bi (OTf)3 (0.1)
Bi (OTf)3 (0.1)
InCl3 (0.1)
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
32
0
45
75
0
40
52
38
0
R
O
R
O
3
Scheme 1. Mechanism of the reaction.
10
InCl3 (0.2)
0
structure and stereochemistry of the compound was determined by
NOE experiment and X-ray crystallographic analysis (Fig. 2).12
There is a strong NOE between H1 and H7 protons of 3l, which
confirms that they are cis to each other (3l, Fig. 3). This structure is
further confirmed by the fact that the olefinic methyl protons at C-2
position are resonating at higher field in the case of endo aromatic
substituents at C-7 position than the corresponding aliphatic sub-
stituents. This indicates that the methyl protons are in the shielding
region of the aromatic ring.
a
Yields refer to isolated yield. The compound is characterized by IR, 1H, 13C NMR
and Mass spectroscopy.
Therefore, In(OTf)3 in dry CH2Cl2 was considered as the best com-
bination for this reaction and the scope of the reaction was in-
vestigated using various aldehydes (Table 2). In all of the cases
studied, 6-oxabicyclo[3.2.1]octenes 3aep could be obtained in high
purity without any side products as determined from 1H to 13C
NMR spectrum of the crude product. Both aliphatic and aromatic
aldehydes gave the corresponding products in good yields. The
substituents on the aromatic ring have a promising effect on this
reaction. The aromatic aldehydes having electron-donating groups
on the aromatic ring gave higher yields compared to the electron-
withdrawing groups on the ring. On the other hand, aliphatic al-
dehydes are better substrates than the aromatic aldehydes. This
might be due to the better stability imparted to the oxocarbenium
ion 5 (Scheme 1) by the aliphatic, and aromatic aldehydes having
electron-donating groups on the aromatic ring, which in turn is
attacked by the double bond efficiently. On the other hand, aro-
matic aldehydes having electron-withdrawing groups on the ring
destabilize the oxocarbenium ion 5. The reaction is stereoselective,
and in all the cases the fusion between two rings is cis-fusion. The
Fig. 2. ORTEP diagram of (1R,5R,7R)-7-(4-chlorophenyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3d).
NOE
Table 2
Synthesis of 6-oxabicyclo[3.2.1]octene
2
H
3
H
H
1
RCHO 2
H
8
4
7
R
In (OTf)3 / CH2Cl2
O
O
5
OH
0
oC to rt
3
1
Fig. 3. NOE diagram of compound 3l.
Entry
RCHO 2
Time (h)
Product 3
Yielda (%)
1
2
3
4
5
6
7
8
C6H5CHO 2a
6
5
6
7
7
8
6
7
7
7
5
5
4
5
7
7
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
75
82
80
68
65
64
66
60
62
64
94
92
88
85
84
82
The mechanism of the reaction can be explained as follows.
Lewis acid activates the aldehyde 2 for the nucleophilic attack by
alcohol 1 to give acetal 4, which after decomposition forms oxo-
carbenium ion 5. The oxocarbenium ion 5 undergoes (3,5)-oxo-
nium-ene cyclization reaction to give final product 3 (Scheme 1).
The reaction can also be extended to epoxides (Table 3). The
epoxides under Lewis acid conditions rearrange to aldehyde
equivalent.13 The results in Table 3 showed that monosubstituted
terminal epoxides (entry 1) are unreactive, whereas the 2,2-
disubstituted and styrene oxides give the corresponding products
in good to moderate yields. This is attributed to the lower stability
of the carbocation 7, formed from monosubstituted epoxides,
compared to 2,2-disubstituted epoxides and styrene oxides, where
carbocation 7 is better stabilized due to the tertiary and benzylic
centres, respectively.
p-MeeC6H4CHO 2b
p-MeOeC6H4CHO 2c
p-CleC6H4CHO 2d
p-BreC6H4CHO 2e
m-BreC6H4CHO 2f
p-FeC6H4CHO 2g
p-MeO2CeC6H4CHO 2h
p-NO2eC6H4CHO 2i
o-NO2eC6H4CHO 2j
CH3CH2CHO 2k
CH3(CH2)2CHO 2l
(CH3)2CHCH2 CHO 2m
CH3(CH2)5CHO 2n
cyclo-C6H11CHO 2o
C6H5CH2CHO 2p
9
10
11
12
13
14
15
16
a
Yields refer to isolated yield. The compounds are characterized by IR, 1H, 13C, 19
F
NMR and Mass spectroscopy.

P. Saha, A.K. Saikia / Tetrahedron 68 (2012) 2261e2266
2263
Table 3
3. Conclusions
Synthesis of 6-oxabicyclo[3.2.1]octene from epoxide
In summary, we have developed an efficient methodology for
the synthesis of 6-oxabicyclo[3.2.1]octene catalyzed by indium
triflate in good to high yields. To the best of our knowledge, this is
the first report for the synthesis of 6-oxabicyclo[3.2.1]octene
starting from a readily available naturally occurring terpenoid.
H
O
R'
6
In(OTf)3 / CH2Cl2
0 oC to rt
H
+
R
R
O
OH
R'
3
1
Yielda (%)
0
4. Experimental
Entry
1
Epoxide 6
Time/h
24
Product 3
H
H
4.1. General procedure for the synthesis of oxabicyclic
compounds from aldehydes. Typical procedure for the
synthesis of (1R,5R,7R)-5-isopropyl-2-methyl-7-phenyl-6-
oxabicyclo[3.2.1]oct-2-ene (3a, Table 2)
O
O
3q
H
H
To a suspension of In(OTf)3 (56.2 mg, 0.1 mmol) in dry CH2Cl2
(2 ml) at 0 ꢁC was added benzaldehyde (106.1 mg, 1 mmol). To this
solution (ꢀ)-terpinen-4-ol (154.3 mg, 1 mmol) in dry CH2Cl2 (2 ml)
was added dropwise over 5 min. The temperature was slowly
brought to room temperature. The reaction mixture was stirred at
room temperature for 6 h. The progress of the reaction was moni-
tored by TLC with hexane as eluent. After completion of the re-
action, it was quenched with saturated solution of NaHCO3. The
product was extracted with CH2Cl2 and then washed with brine and
water. The organic layer was dried (Na2SO4) and evaporated to give
the crude product, which was purified by short column chroma-
tography over silica gel (100% hexane) to give 3a (181.7 mg, 75%) as
O
2
3
6
7
68
62
O
3r
H
O
H
O
3p
H
H
O
O
a colourless oil; Rf (100% hexane) 0.50; ½a D25
þ129.91 (c 1.07, CHCl3);
ꢂ
4
5
8
8
55
58
O
Cl
Br
nmax (Neat) 2962, 2934, 1602, 1449, 1380, 1286, 1053, 1017, 751,
3s
702 cmꢀ1
;
dH (400 MHz, CDCl3), 1.00 (d, J¼6.8 Hz, 3H, eCHMe), 1.01
Cl
Br
H
(s, 3H, eC]CMe), 1.03 (d, J¼6.8 Hz, 3H, eCHMe), 1.83e1.88 (m, 1H,
eCHe), 1.95 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.07 (dd, J¼10.4 and
4.0 Hz, 1H, eCHe), 2.13e2.21 (m, 1H, eCHe), 2.32e2.40 (m, 1H,
eCHe), 2.55 (t, J¼3.6 Hz, 1H, eCHe), 5.22 (d, J¼3.2 Hz, 1H, eOCHe),
5.27 (br s, 1H, eC]CHe), 7.17e7.21 (m, 1H, eArH), 7.23e7.28 (m,
3H, eArH), 7.29e7.33 (m, 1H, eArH); dC (100 MHz, CDCl3) 17.8, 18.0,
23.1, 36.0, 36.7, 38.5, 48.4, 85.8, 87.4, 120.0, 126.1, 126.9, 127.7, 136.6,
140.5; HRMS (APCI): MHþ, found 243.1747. C17H22O requires
243.1749.
H
O
3t
H
H
O
6
7
60
O
4.2. Product characterization
3o
a
Yields refer to isolated yield. The compounds are characterized by IR, 1H, 13C
4.2.1. (1R,5R,7R)-5-Isopropyl-2-methyl-7-p-tolyl-6-oxabicyclo [3.2.1]
oct-2-ene (3b). Colourless solid; mp 58e60 ꢁC (210.2 mg, 82%); Rf
NMR and Mass spectroscopy.
(1% EtOAc/hexane) 0.54; ½a D25
ꢂ
þ133.34 (c 0.24, CHCl3); nmax (KBr)
2960, 2928, 1639, 1447, 1380, 1055, 1020, 800, 779 cmꢀ1
;
dH
The mechanism of the reactionwith epoxides is shown in Scheme
2. The epoxide 6 in the presence of Lewis acid rearranges to aldehyde
equivalent 8, which after nucleophilic attack by alcohol 1 gives acetal
9. The acetal 9 decomposes to give oxocarbenium ion 10, which after
(3,5)-oxonium-ene cyclization reaction gives final product 3.
(400 MHz, CDCl3) 0.99 (d, J¼7.2 Hz, 3H, eCHMe), 1.01 (d, J¼6.8 Hz,
3H, eCHMe), 1.02 (s, 3H, eC]CMe), 1.81e1.86 (m, 1H, eCHe), 1.94
(septet, J¼7.2 Hz, 1H, eCH(Me)2), 2.05 (dd, J¼10.4 and 3.6 Hz, 1H,
eCHe), 2.12e2.18 (m, 1H, eCHe), 2.30 (s, 3H, eArMe), 2.32e2.41
(m, 1H, eCHe), 2.51 (t, J¼3.6 Hz, 1H, eCHe), 5.17 (d, J¼3.2 Hz, 1H,
eOCHe), 5.25 (br s,1H, eC]CHe), 7.05 (d, J¼7.6 Hz, 2H, eArH), 7.17
(d, J¼7.6 Hz, 2H, eArH); dC (100 MHz, CDCl3) 17.8, 18.0, 21.3, 23.3,
36.0, 36.8, 38.4, 48.4, 85.7, 87.4, 119.9, 126.1, 128.4, 136.3, 136.7,
LA
R
LA
O
R
LA
O
R
O
R'
LA
R'
R'
137.5; HRMS (APCI): Mþ, found 256.1822. C18H24
256.1827.
O
requires
H
6
8
7
HO
4.2.2. (1R,5R,7R)-5-Isopropyl-7-(4-methoxyphenyl)-2-methyl-6-
1
oxabicyclo[3.2.1]oct-2-ene (3c). Colourless oil (217.9 mg, 80%); Rf
(3% EtOAc/hexane) 0.60; ½a D25
þ100.0 (c 0.32, CHCl3); nmax (Neat)
ꢂ
(3,5)-oxonium-ene
reaction
H
H
2960, 2928, 1613, 1511, 1463, 1363, 1246, 1055, 1037, 845, 803 cmꢀ1
;
H
OLA
R'
R
dH (400 MHz, CDCl3) 0.99 (d, J¼7.2 Hz, 3H, eCHMe), 1.01 (d,
J¼6.8 Hz, 3H, eCHMe), 1.04 (t, J¼1.2 Hz, 3H, eC]CMe), 1.81e1.86
(m, 1H, eCHe), 1.93 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.04 (dd,
J¼10.4 and 3.6 Hz, 1H, eCHe), 2.12e2.19 (m, 1H, eCHe), 2.32e2.39
(m, 1H, eCHe), 2.48 (t, J¼4.0 Hz, 1H, eCHe), 3.78 (s, 3H, eOMe),
R
R
O
O
O
R'
R'
9
10
3
Scheme 2. Mechanism of the reaction with epoxides.

2264
P. Saha, A.K. Saikia / Tetrahedron 68 (2012) 2261e2266
5.16 (d, J¼3.2 Hz, 1H, eOCHe), 5.27 (br s, 1H, eC]CHe), 6.80 (d,
J¼8.8 Hz, 2H, eArH), 7.21 (d, J¼8.4 Hz, 2H, eArH); dC (100 MHz,
CDCl3) 17.8, 18.0, 23.2, 36.0, 36.8, 38.4, 48.4, 55.4, 85.7, 87.1, 113.2,
119.9, 127.2, 132.6, 136.8, 158.7; HRMS (APCI): MHþ, found 273.1841.
C18H24O2 requires 273.1854.
4.2.7. Methyl 4-((1R,5R,7R)-5-isopropyl-2-methyl-6-oxabicyclo
[3.2.1]oct-2-en-7-yl)benzoate (3h). Colourless oil (180.2 mg, 60%);
Rf (4% EtOAc/hexane) 0.40; ½a D25
ꢂ
þ116.38 (c 1.77, CHCl3); nmax (Neat)
2961, 1722, 1611, 1435, 1277, 1111, 1056, 1017, 764, 713 cmꢀ1
;
dH
(400 MHz, CDCl3) 0.97 (t, J¼1.6 Hz, 3H, eC]CMe), 1.00 (d, J¼6.8 Hz,
3H, eCHMe), 1.03 (d, J¼6.8 Hz, 3H, eCHMe) 1.86e1.90 (m, 1H,
eCHe), 1.95 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.08 (dd, J¼10.4 and
3.6 Hz, 1H, eCHe), 2.15e2.22 (m, 1H, eCHe), 2.33e2.43 (m, 1H,
eCHe), 2.59 (t, J¼3.2 Hz, 1H, eCHe), 3.90 (s, 3H, eOMe), 5.24e5.27
(m, 2H, eOCHe, eC]CHe), 7.36 (d, J¼8.4 Hz, 2H, eArH), 7.94 (d,
J¼8.4 Hz, 2H, eArH); dC (100 MHz, CDCl3) 17.7, 17.9, 23.1, 35.9, 36.6,
38.5, 48.4, 52.0, 86.2, 87.0, 120.2, 126.1, 128.7, 129.1, 136.1, 146.2,
167.3; HRMS (APCI): MHþ, found 301.1795. C19H24O3 requires
301.1803.
4.2.3. (1R,5R,7R)-7-(4-Chlorophenyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3d). Colourless solid; mp 78e80 ꢁC
(188.2 mg, 68%); Rf (1% EtOAC/hexane) 0.48; ½a D25
þ109.09 (c 0.55,
ꢂ
CHCl3); nmax (KBr) 2965, 2928, 1594, 1465, 1369, 1289, 1102, 1091,
849, 760 cmꢀ1
;
dH (400 MHz, CDCl3) 0.98 (d, J¼6.8 Hz, 3H, eCHMe),
1.01 (d, J¼7.2 Hz, 3H, eCHMe), 1.03 (s, 3H, eC]CMe), 1.84e1.89 (m,
1H, eCHe), 1.93 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.06 (dd, J¼10.4
and 3.6 Hz, 1H, eCHe), 2.11e2.18 (m, 1H, eCHe), 2.31e2.39 (m, 1H,
eCHe), 2.52 (t, J¼3.6 Hz, 1H, eCHe), 5.17 (d, J¼3.6 Hz, 1H, eOCHe),
5.27 (br s, 1H, eC]CHe), 7.18e7.28 (m, 4H, eArH); dC (100 MHz,
CDCl3) 17.8, 17.9, 23.2, 36.0, 36.7, 38.5, 48.4, 86.1, 86.7, 120.2, 127.6,
127.9, 132.5, 136.3, 139.2; HRMS (APCI): MHþ, found 277.1348.
C17H21ClO requires 277.1359.
4.2.8. (1R,5R,7R)-5-Isopropyl-2-methyl-7-(4-nitrophenyl)-6-
oxabicyclo[3.2.1]oct-2-ene (3i). Colourless oil (178.2 mg, 62%); Rf
(5% EtOAc/hexane) 0.50; ½a D25
þ113.33 (c 0.30, CHCl3); nmax (Neat)
ꢂ
2966, 2928, 1606, 1525, 1348, 1288, 1104, 1051, 1011, 853, 720 cmꢀ1
;
dH (400 MHz, CDCl3) 0.99 (s, 3H, eC]CMe), 1.00 (d, J¼6.8 Hz, 3H,
eCHMe), 1.03 (d, J¼6.8 Hz, 3H, eCHMe), 1.87e1.92 (m, 1H, eCHe),
1.96 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.10 (dd, J¼10.8 and 4.0 Hz,
1H, eCHe), 2.16e2.23 (m, 1H, eCHe), 2.33e2.43 (m, 1H, eCHe),
2.64 (t, J¼3.6 Hz,1H, eCHe), 5.27e5.30 (m, 2H, eOCHe, eC]CHe),
7.46 (d, J¼8.4 Hz, 2H, eArH), 8.14 (d, J¼8.8 Hz, 2H, eArH); dC
(100 MHz, CDCl3) 17.7, 17.8, 23.1, 35.9, 36.5, 38.7, 48.4, 86.5, 86.7,
120.6, 123.0, 127.0, 135.7, 147.1, 148.7; HRMS (APCI): MHþ, found
288.1587. C17H21NO3 requires 288.1599.
4.2.4. (1R,5R,7R)-7-(4-Bromophenyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3e). Colourless solid; mp 68e70 ꢁC
(208.8 mg, 65%); Rf (1% EtOAc/hexane) 0.48; ½a D25
þ103.26 (c 1.84,
ꢂ
CHCl3); nmax (KBr) 2959, 2929, 1595, 1465, 1375, 1281, 1055, 1010,
847, 802 cmꢀ1
;
dH (400 MHz, CDCl3) 0.98 (d, J¼6.8 Hz, 3H, eCHMe),
1.01 (d, J¼6.8 Hz, 3H, eCHMe), 1.03 (t, J¼2.0 Hz, 3H, eC]CMe),
1.83e1.88 (m, 1H, eCHe), 1.93 (septet, J¼6.8 Hz, 1H, eCH(Me)2),
2.05 (dd, J¼10.8 and 4.0 Hz, 1H, eCHe), 2.12e2.18 (m, 1H, eCHe),
2.31e2.39 (m, 1H, eCHe), 2.53 (t, J¼3.6 Hz, 1H, eCHe), 5.15 (d,
J¼3.2 Hz, 1H, eOCHe), 5.26 (br s, 1H, eC]CHe), 7.17 (d, J¼8.4 Hz,
2H, eArH), 7.38 (d, J¼8.4 Hz, 2H, eArH); dC (100 MHz, CDCl3) 17.7,
17.9, 23.2, 35.9, 36.6, 38.5, 48.2, 86.0, 86.6, 120.1, 120.6, 127.9, 130.7,
136.2, 139.7; HRMS (APCI): Mþ, found 320.0771 (79Br), 322.0695
4.2.9. (1R,5R,7R)-5-Isopropyl-2-methyl-7-(2-nitrophenyl)-6-
oxabicyclo[3.2.1]oct-2-ene (3j). Semisolid (183.9 mg, 64%); Rf (3%
EtOAc/hexane) 0.40; ½a D25
ꢂ
þ75.80 (c 0.62, CHCl3); nmax (Neat) 2967,
2934, 1638, 1524, 1346, 1281, 1054, 1015, 748, 710 cmꢀ1
;
dH
(
81Br). C17H21BrO requires 320.0776 (79Br), 322.0755 (81Br).
(400 MHz, CDCl3) 0.99 (d, J¼7.2 Hz, 3H, eCHMe), 1.01 (t, J¼1.8 Hz,
3H, eC]CMe), 1.02 (d, J¼6.8 Hz, 3H, eCHMe), 1.88e1.98 (m, 2H,
eCHe, eCH(Me)2), 2.12e2.23 (m, 2H, 2ꢃ eCHe), 2.35e2.43 (m, 1H,
eCHe), 3.04 (t, J¼3.6 Hz, 1H, eCHe), 5.30 (br s, 1H, eC]CHe), 5.62
(d, J¼3.2 Hz, 1H, eOCHe), 7.37 (t, J¼7.2 Hz, 1H, eArH), 7.57 (t,
J¼7.2 Hz, 1H, eArH), 7.78 (d, J¼7.6 Hz, 1H, eArH), 7.93 (d, J¼8.4 Hz,
1H, eArH); dC (100 MHz, CDCl3) 17.8, 17.9, 22.9, 35.9, 36.5, 38.7, 46.7,
83.4, 86.2, 120.4, 123.9, 127.7, 129.5, 133.0, 136.4, 136.6, 148.1; HRMS
(APCI): Mþ, found 287.1512. C17H21NO3 requires 287.1521.
4.2.5. (1R,5R,7R)-7-(3-Bromophenyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3f). Colourless oil (205.6 mg, 64%); Rf
(1% EtOAc/hexane) 0.49; ½a D25
þ104.76 (c 0.63, CHCl3); nmax (Neat)
ꢂ
2965, 2934, 1593, 1467, 1421, 1369, 1294, 1260, 1050, 781, 747 cmꢀ1
;
dH (400 MHz, CDCl3) 0.99 (d, J¼6.8 Hz, 3H, eCHMe), 1.02 (d,
J¼6.8 Hz, 3H, eCHMe), 1.04 (dd, J¼2.0 and 1.6 Hz, 3H, eC]CMe),
1.84e1.88 (m, 1H, eCHe), 1.93 (septet, J¼6.8 Hz, 1H, eCH(Me)2),
2.05 (dd, J¼10.8 and 4.0 Hz, 1H, eCHe), 2.12e2.20 (m, 1H, eCHe),
2.31e2.40 (m, 1H, eCHe), 2.55 (t, J¼3.6 Hz, 1H, eCHe), 5.15 (d,
J¼3.2 Hz, 1H, eOCHe), 5.29 (br s, 1H, eC]CHe), 7.12 (t, J¼7.6 Hz,
1H, eArH), 7.18e7.22 (m, 1H, eArH), 7.31e7.34 (m, 1H, eArH), 7.43
(s, 1H, eArH); dC (100 MHz, CDCl3) 17.8, 17.9, 23.2, 35.9, 36.7, 38.5,
48.3, 86.2, 86.6, 120.2, 122.1, 124.9, 129.2, 129.3, 130.0, 136.1, 143.2;
4.2.10. (1R,5R,7S)-7-Ethyl-5-isopropyl-2-methyl-6-oxabicyclo[3.2.1]
oct-2-ene (3k). Colourless oil (182.7 mg, 94%); Rf (100% hexane)
0.65; ½a 2D5
ꢂ
þ47.37 (c 0.38, CHCl3); nmax (Neat) 2960, 2933, 1637,
1464, 1383, 1276, 1057, 1042, 860 cmꢀ1
;
dH (400 MHz, CDCl3) 0.92
(d, J¼7.2 Hz, 3H, eCHMe), 0.93 (t, J¼7.6 Hz, 3H, eCH2Me), 0.94 (d,
J¼6.8 Hz, 3H, eCHMe), 1.39e1.50 (m, 1H, eCHe), 1.54e1.64 (m, 1H,
eCHe), 1.66e1.70 (m, 1H, eCHe), 1.71e1.74 (m, 3H, eC]CMe),
1.78e1.86 (m, 2H, eCHe, eCH(Me)2), 1.87e1.94 (m, 1H, eCHe),
2.18e2.25 (m, 1H, eCHe), 2.33 (t, J¼3.2 Hz, 1H, eCHe), 3.89 (ddd,
J¼10.0, 6.8 and 3.2 Hz, 1H, eOCHe), 5.31 (br s, 1H, eC]CHe); dC
(100 MHz, CDCl3) 11.3, 17.8, 18.0, 24.0, 25.0, 36.0, 36.8, 38.0, 44.2,
84.4, 88.5, 120.2, 136.7; HRMS (APCI): MHþ, found 195.1745.
C13H22O requires 195.1749.
HRMS (APCI): Mþ, found 320.0768
( (
79Br), 322.0730 81Br).
C17H21BrO requires 320.0776 (79Br), 322.0755 (81Br).
4.2.6. (1R,5R,7R)-7-(4-Fluorophenyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3g). Colourless oil (171.8 mg, 66%); Rf
(1% EtOAc/hexane) 0.50; ½a D25
þ130.77 (c 0.26, CHCl3); nmax (Neat)
ꢂ
2961, 2933, 1606, 1508, 1465, 1380, 1221, 1056, 1020, 825, 803 cmꢀ1
;
dH (400 MHz, CDCl3) 0.99 (d, J¼6.8 Hz, 3H, eCHMe), 1.01 (d,
J¼6.8 Hz, 3H, eCHMe), 1.02 (s, 3H, eC]CMe), 1.82e1.88 (m, 1H,
eCHe), 1.94 (septet, J¼6.8 Hz, 1H, eCH(Me)2), 2.05 (dd, J¼10.8 and
4.0 Hz, 1H, eCHe), 2.12e2.19 (m, 1H, eCHe), 2.32e2.40 (m, 1H,
eCHe), 2.51 (t, J¼3.6 Hz, 1H, eCHe), 5.18 (d, J¼3.6 Hz, 1H, eOCHe),
5.27 (br s,1H, eC]CHe), 6.95 (t, J¼8.8 Hz, 2H, eArH), 7.22e7.28 (m,
2H, eArH); dC (100 MHz, CDCl3) 17.8, 18.0, 23.2, 36.0, 36.8, 38.5,
48.5, 86.0, 86.8, 114.6 (d, J¼21.3 Hz), 120.1 (d, J¼6.9 Hz), 127.7 (d,
J¼7.6 Hz), 136.2, 136.4, 162.1 (d, J¼243.3 Hz); dF (376 MHz, CDCl3/
C6F6) ꢀ220.51e(ꢀ220.43) (m, 1F); HRMS (APCI): Mþ, found
260.1568. C17H21FO requires 260.1576.
4.2.11. (1R,5R,7S)-5-Isopropyl-2-methyl-7-propyl-6-oxabicyclo[3.2.1]
oct-2-ene (3l). Colourless oil (191.7 mg, 92%); Rf (100% hexane)
0.60; ½a 2D5
ꢂ
þ44.64 (c 0.56, CHCl3); nmax (Neat) 2959, 2933, 2875,
1638, 1465, 1383, 1072, 1054, 968 cmꢀ1
;
dH (400 MHz, CDCl3) 0.92
(d, J¼6.8 Hz, 3H, eCHMe), 0.93 (t, J¼6.8 Hz, 3H, eCH2Me), 0.94 (d,
J¼6.8 Hz, 3H, eCHMe), 1.30e1.35 (m, 1H, eCHe), 1.36e1.46 (m, 2H,
2ꢃ eCHe), 1.51e1.58 (m, 1H, eCHe), 1.65e1.69 (m, 1H, eCHe),
1.70e1.73 (m, 3H, eC]CMe), 1.77e1.85 (m, 2H, eCHe, eCH(Me)2),
1.86e1.94 (m, 1H, eCHe), 2.17e2.25 (m, 1H, eCHe), 2.29 (t,

P. Saha, A.K. Saikia / Tetrahedron 68 (2012) 2261e2266
2265
J¼3.2 Hz, 1H, eCHe), 3.97 (ddd, J¼9.2, 6.0 and 3.2 Hz, 1H, eOCHe),
4.3. General procedure for the synthesis of oxabicyclic
compounds from epoxides. Typical procedure for the
synthesis of (1R,5R,7S)-5,7-diisopropyl-2-methyl-6-oxabicyclo
5.31 (br s, 1H, eC]CHe); dC (100 MHz, CDCl3) 14.5, 17.8, 17.9, 20.2,
24.0, 34.4, 36.0, 36.8, 37.9, 44.5, 84.3, 86.6, 120.2, 136.7; HRMS
(APCI): MHþ, found 209.1896. C14H24O requires 209.1905.
[3.2.1]oct-2-ene (3r)
4.2.12. (1R,5R,7S)-7-Isobutyl-5-isopropyl-2-methyl-6-oxabicyclo
To a suspension of In(OTf)3 (56.2 mg, 0.1 mmol) in dry CH2Cl2
(2 ml) at 0 ꢁC was added 1,2-epoxy-2-methyl propane (108.2 mg,
1.5 mmol). To this solution (ꢀ)-terpinen-4-ol (154.3 mg, 1 mmol)
in dry CH2Cl2 (2 ml) was added dropwise over 5 min. The tem-
perature was slowly brought to room temperature. The reaction
mixture was stirred at room temperature for 6 h. The progress of
the reaction was monitored by TLC with hexane as eluent. After
completion of the reaction, it was quenched with saturated solu-
tion of NaHCO3. The product was extracted with CH2Cl2 and then
washed with brine and water. The organic layer was dried
(Na2SO4) and evaporated to give the crude product, which was
purified by short column chromatography over silica gel (100%
hexane) to give 3r (141.7 mg, 68%) as a colourless oil; Rf (100%
[3.2.1]oct-2-ene (3m). Colourless oil (195.7 mg, 88%); Rf (100%
hexane) 0.60; ½a D25
ꢂ
þ40.98 (c 0.61, CHCl3); nmax (Neat) 2957,
2931, 2873, 1638, 1466, 1382, 1077, 1048, 979 cmꢀ1
;
dH
(400 MHz, CDCl3) 0.90 (d, J¼6.8 Hz, 3H, eCHMe), 0.91 (d,
J¼7.2 Hz, 3H, eCHMe), 0.92 (d, J¼6.4 Hz, 3H, eCHMe), 0.94 (d,
J¼7.2 Hz, 3H, eCHMe), 1.29 (septet, J¼7.2 Hz, 1H, eCHe), 1.42
(septet, J¼6.8 Hz, 1H, eCHe), 1.61e1.69 (m, 2H, 2ꢃ eCHe),
1.70e1.73 (m, 3H, eC]CMe), 1.77e1.85 (m, 2H, eCHe,
eCH(Me)2), 1.86e1.93 (m, 1H, eCHe), 2.17e2.24 (m, 1H, eCHe),
2.26 (t, J¼4.0 Hz, 1H, eCHe), 4.07 (ddd, J¼10.0, 6.4 and 3.2 Hz,
1H, eOCHe), 5.30 (br s, 1H, eC]CHe); dC (100 MHz, CDCl3) 17.7,
18.0, 23.2, 23.3, 24.1, 25.9, 36.0, 37.0, 37.9, 41.1, 44.8, 84.3, 84.8,
120.2, 136.7; HRMS (APCI): MHþ, found 223.1968. C15H26O re-
quires 223.1972.
hexane) 0.60; ½a D25
ꢂ
þ30.0 (c 0.20, CHCl3); nmax (Neat) 2958, 2928,
1640, 1467, 1386, 1278, 1056, 1020, 858 cmꢀ1
;
dH (400 MHz, CDCl3)
0.86 (d, J¼6.4 Hz, 3H, eCHMe), 0.90 (d, J¼6.8 Hz, 3H, eCHMe),
0.93 (d, J¼6.8 Hz, 3H, eCHMe), 0.98 (d, J¼6.4 Hz, 3H, eCHMe),
1.56e1.64 (m, 1H, eCHe), 1.65e1.69 (m, 1H, eCHe), 1.74e1.78 (m,
3H, eC]CMe), 1.79e1.84 (m, 2H, eCHe, eCH(Me)2), 1.85e1.93 (m,
1H, eCHe), 2.15e2.22 (m, 1H, eCHe), 2.40 (t, J¼2.8 Hz, 1H,
eCHe), 3.50 (dd, J¼10.0 and 2.8 Hz, 1H, eOCHe), 5.30 (br s, 1H,
eC]CHe); dC (100 MHz, CDCl3) 17.8, 17.9, 20.1, 20.7, 24.2, 30.2,
36.2, 36.7, 38.5, 43.7, 84.1, 93.2, 120.6, 136.9; HRMS (APCI): MHþ,
found 209.1898. C14H24O requires 209.1905.
4.2.13. (1R,5R,7S)-7-Hexyl-5-isopropyl-2-methyl-6-oxabicyclo[3.2.1]
oct-2-ene (3n). Colourless oil (212.9 mg, 85%); Rf (100% hexane)
0.58; ½a 2D5
ꢂ
þ45.83 (c 0.48, CHCl3); nmax (Neat) 2958, 2930, 2873,
1639,1466,1383,1075,1054, 875 cmꢀ1
;
dH (400 MHz, CDCl3) 0.87 (t,
J¼6.8 Hz, 3H, eCH2Me), 0.92 (d, J¼6.8 Hz, 3H, eCHMe), 0.94 (d,
J¼7.2 Hz, 3H, eCHMe), 1.20e1.35 (m, 8H, 4ꢃ eCH2e), 1.38e1.45 (m,
1H, eCHe), 1.53e1.61 (m, 1H, eCHe), 1.65e1.70 (m, 1H, eCHe),
1.71e1.73 (m, 3H, eC]CMe), 1.77e1.85 (m, 2H, eCHe, eCH(Me)2),
1.86e1.94 (m, 1H, eCHe), 2.17e2.25 (m, 1H, eCHe), 2.30 (t,
J¼3.6 Hz,1H, eCHe), 3.96 (ddd, J¼10.0, 6.8 and 3.2 Hz,1H, eOCHe),
5.31 (br s, 1H, eC]CHe); dC (100 MHz, CDCl3) 14.2, 17.8, 18.0, 22.8,
24.0, 27.0, 29.8, 32.0, 32.2, 36.0, 36.8, 38.0, 44.5, 84.4, 87.0, 120.2,
136.7; HRMS (APCI): MHþ, found 251.2368. C17H30O requires
251.2375.
4.3.1. (1R,5R,7S)-7-(4-Chlorobenzyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3s). Colourless oil (160.0 mg, 55%); Rf
(100% hexane) 0.65; ½a D25
ꢂ
þ20.45 (c 0.44, CHCl3); nmax (Neat) 2961,
2928,1637,1467,1380,1078,1055, 877, 831, 805 cmꢀ1
;
dH (400 MHz,
CDCl3) 0.91 (d, J¼6.8 Hz, 3H, eCHMe), 0.94 (d, J¼6.8 Hz, 3H,
eCHMe), 1.69e1.76 (m, 4H, eCHe, eC]CMe), 1.77e1.85 (m, 2H,
eCHe, eCH(Me)2), 1.94e2.03 (m, 1H, eCHe), 2.20e2.28 (m, 1H,
eCHe), 2.32 (t, J¼3.6 Hz, 1H, eCHe), 2.68 (dd, J¼14.4 and 5.2 Hz,
1H, eCHe), 2.87 (dd, J¼14.4 and 8.0 Hz, 1H, eCHe), 4.25 (ddd,
J¼10.4, 6.0 and 3.2 Hz, 1H, eOCHe), 5.39 (br s, 1H, eC]CHe),
7.17e7.26 (m, 4H, eArH); dC (100 MHz, CDCl3) 17.9(2C), 24.0, 36.1,
36.7, 38.0, 38.2, 45.0, 85.0, 86.2, 120.8, 128.4, 130.6, 131.8, 136.5,
138.8; HRMS (APCI): MHþ, found 291.1504. C18H23ClO requires
291.1515.
4.2.14. (1R,5R,7S)-7-Cyclohexyl-5-isopropyl-2-methyl-6-oxabicyclo
[3.2.1]oct-2-ene (3o). Colourless oil (208.7 mg, 84%); Rf (100%
hexane) 0.68; ½a D25
ꢂ
þ42.11 (c 0.57, CHCl3); nmax (Neat) 2950, 2924,
2851, 1641, 1448, 1380, 1083, 1055, 861 cmꢀ1
;
dH (400 MHz, CDCl3)
0.80e0.91 (m, 4H, 4ꢃ eCHe), 0.94 (d, J¼7.2 Hz, 3H, eCHMe), 0.96
(d, J¼7.2 Hz, 3H, eCHMe), 1.07e1.11 (m, 1H, eCHe), 1.12e1.17 (m,
2H, 2ꢃ eCHe), 1.18e1.24 (m, 2H, 2ꢃ eCHe), 1.25e1.29 (m, 1H,
eCHe), 1.54e1.58 (m, 1H, eCHe), 1.60e1.66 (m, 1H, eCHe), 1.69
(dd, J¼2.0 and 1.6 Hz, 3H, eC]CMe), 1.71e1.76 (m, 1H, eCHe), 1.81
(septet, J¼6.8 Hz, 1H, eCH(Me)2), 1.97e2.05 (m, 1H, eCHe), 2.20 (t,
J¼2.6 Hz, 1H, eCHe), 2.25e2.29 (m, 1H, eCHe), 3.51 (d, J¼9.6 Hz,
1H, eOCHe), 5.18 (br s, 1H, eC]CHe); dC (100 MHz, CDCl3) 18.1,
18.2, 22.1, 26.1(2C), 26.7, 29.7, 30.0, 34.4, 35.8, 36.2, 43.0, 43.1, 84.8,
4.3.2. (1R,5R,7S)-7-(4-Bromobenzyl)-5-isopropyl-2-methyl-6-
oxabicyclo[3.2.1]oct-2-ene (3t). Colourless oil (194.5 mg, 58%); Rf
(100% hexane) 0.65; ½a D25
ꢂ
þ32.50 (c 0.40, CHCl3); nmax (Neat) 2960,
2928, 1641, 1467, 1382, 1071, 1053, 878, 834, 802 cmꢀ1
;
dH
92.7, 118.4, 140.9; HRMS (APCI): MHþ, found 249.2212. C17H28
requires 249.2218.
O
(400 MHz, CDCl3) 0.90 (d, J¼7.2 Hz, 3H, eCHMe), 0.94 (d, J¼6.8 Hz,
3H, eCHMe), 1.69e1.76 (m, 4H, eCHe, eC]CMe), 1.78e1.85 (m,
2H, eCHe, eCH(Me)2), 1.94e2.02 (m, 1H, eCHe), 2.19e2.27 (m, 1H,
eCHe), 2.32 (t, J¼3.6 Hz, 1H, eCHe), 2.66 (dd, J¼14.4 and 5.2 Hz,
1H, eCHe), 2.84 (dd, J¼14.8 and 8.0 Hz, 1H, eCHe), 4.24 (ddd,
J¼10.4, 6.4 and 3.6 Hz, 1H, eOCHe), 5.39 (br s, 1H, eC]CHe), 7.13
(d, J¼8.0 Hz, 2H, eArH), 7.37 (d, J¼8.4 Hz, 2H, eArH); dC (100 MHz,
CDCl3) 17.9(2C), 24.1, 36.1, 36.7, 38.0, 38.2, 45.0, 85.0, 86.2, 119.8,
120.8, 131.0, 131.3, 136.5, 139.3; HRMS (APCI): MHþ, found 335.1019
4.2.15. (1R,5R,7S)-7-Benzyl-5-isopropyl-2-methyl-6-oxabicyclo
[3.2.1]oct-2-ene (3p). Colourless oil (210.2 mg, 82%); Rf (100%
hexane) 0.70; ½a D25
ꢂ
þ20.0 (c 0.30, CHCl3); nmax (Neat) 2960, 2928,
1638, 1453, 1382, 1064, 1055, 751, 700 cmꢀ1
;
dH (400 MHz, CDCl3)
0.92 (d, J¼6.8 Hz, 3H, eCHMe), 0.95 (d, J¼6.8 Hz, 3H, eCHMe),
1.68e1.76 (m, 4H, eCHe, eC]CMe), 1.79e1.87 (m, 2H, eCHe,
eCH(Me)2), 1.97e2.04 (m, 1H, eCHe), 2.21e2.28 (m, 1H, eCHe),
2.34 (t, J¼3.6 Hz, 1H, eCHe), 2.72 (dd, J¼14.4 and 6.4 Hz, 1H,
eCHe), 2.95 (dd, J¼14.4 and 7.2 Hz, 1H, eCHe), 4.33 (ddd,
J¼10.0, 6.4 and 3.2 Hz, 1H, eOCHe), 5.39 (br s, 1H, eC]CHe),
7.16e7.30 (m, 5H, eArH); dC (100 MHz, CDCl3) 17.9(2C), 24.1, 36.1,
36.8, 38.2, 38.4, 44.8, 84.8, 86.6, 120.7, 126.0, 128.3, 129.2, 136.6,
140.1; HRMS (APCI): MHþ, found 257.1894. C18H24O requires
257.1905.
(
79Br), 337.0971
337.0990 (81Br).
( (
81Br). C18H23BrO requires 335.1010 79Br),
Acknowledgements
Authors are grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial support (Grant No.

2266
P. Saha, A.K. Saikia / Tetrahedron 68 (2012) 2261e2266
Mrksich, M.; Greene, G. L. J. Biol. Chem. 2006, 281, 17909e17919; (d) Nakamura,
M.; Niiyama, K.; Yamakawa, T. Tetrahedron Lett. 2009, 50, 6462e6465.
4. (a) White, J. D.; Fukuyama, Y. J. Am. Chem. Soc. 1979, 101, 226e228; (b) Lautens,
M.; Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem. Soc. 1995, 117, 532e533; (c) Davies, H.
M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc. 1996, 118, 10774e10782; (d)
Lautens, M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 11090e11091; (e) Yin, J.; Lie-
beskind, L. S. J. Am. Chem. Soc. 1999, 121, 5811e5812; (f) Fan, J.-F.; Wu, Y.; Wu, Y.-
L. J. Chem. Soc., Perkin Trans. 1 1999, 1189e1191; (g) Lautens, M.; Frutos, O.;
Stammers, T. A. Tetrahedron Lett. 1999, 40, 8317e8321; (h) Lautens, M.; Renaud,
J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804e1805; (i) Millward, D. B.;
Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902e3909; (j) Hunt, K.
W.; Grieco, P. A. Org. Lett. 2001, 3, 481e484; (k) Hunt, K. W.; Grieco, P. A. Org.
Lett. 2002, 4, 245e248; (l) Leung, S.-K.; Chiu, P. Tetrahedron Lett. 2005, 46,
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7449e7458.
01(2332)/09/EMR-II). Authors gratefully acknowledge the X-ray
facility provided by DST, under Fist programme.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.064.
References and notes
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ꢀ
ꢁ
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