Transformation of hydroxycycloalkanones to oxabicycloalkenes

Article abstract of DOI:10.3987/COM-09-11728

Oxabicycloalkenes, which represent anti-Bredt enol ethers, can be generated by catalytic dehydration of the hemiacetals of hydroxycycloalkanones (Method I). Another option is provided by the transformation of hydroxycycloalkanones to the corresponding 1,2,3-selenadiazoles and their thermal fragmentation on Cu powder (Method II). The intermediate hydroxycycloalkynes show a transannular addition of the OH group to the triple bond. Altogether seven new oxabicycloalk-1-enes were obtained by this methods.

Full text of DOI:10.3987/COM-09-11728

HETEROCYCLES, Vol. 78, No. 9, 2009
2201
HETEROCYCLES, Vol. 78, No. 9, 2009, pp. 2201 - 2208. © The Japan Institute of Heterocyclic Chemistry
Received, 8th April, 2009, Accepted, 21st May, 2009, Published online, 21st May, 2009.
DOI: 10.3987/COM-09-11728
TRANSFORMATION
OF
HYDROXYCYCLOALKANONES
TO
OXABICYCLOALKENES
Guido Krämer, Heiner Detert, and Herbert Meier*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-
55099 Mainz, Germany
e-mail: hmeier@mail.uni-mainz.de
Abstract  Oxabicycloalkenes, which represent anti-Bredt enol ethers, can be
generated by catalytic dehydration of the hemiacetals of hydroxycycloalkanones
(Method I). Another option is provided by the transformation of
hydroxycycloalkanones to the corresponding 1,2,3-selenadiazoles and their
thermal fragmentation on Cu powder (Method II). The intermediate
hydroxycycloalkynes show a transannular addition of the OH group to the triple
bond. Altogether seven new oxabicycloalk-1-enes were obtained by this methods.
In recent years an increasing number of natural products and closely related synthetic analogues, which
have the structures of oxabicycloalk-1-enes with an anti-Bredt enol ether functionality, have been
studied.1 The majority of them has the scaffold of 10-oxabicyclo [4.3.1]dec-1(9)-enes1a,e,f,i,j,k,p or 11-
oxabicyclo[6.2.1]undec-1(10)-enes.1c,d,l,m,n,r,t,u,v,w Another interesting realization of such enol ether
structures was achieved in the series of fullerenes.2 The preparation of these compounds requires multi-
step syntheses in which the formation of a strained enol ether double bond is a special challenge.
Bridgehead olefins with this substructure can have pyramidalized and/or twisted double bonds.
Hydroxycycloalkanones 1 provide an easy access to anti-Bredt enol ethers. Scheme 1 summarizes the
possible reaction routes. The cyclic hemiacetals 8, tautomers of 1, can be catalytically dehydrated to 11
and/or 12 (route I). Alternatively, 1 can be transformed to the stereoisomeric semicarbazones 2/3, for
which cyclic tautomers 4 exist as well. The subsequent ring closure reaction with SeO2 yields the 1,2,3-
selenadiazoles 5/6. The regioselectivity of the ring closure does not depend on the preferred isomer 2, 3 or
4. Thermal cleavage of 5/6 on cupper powder gives the hydroxycycloalkynes 7/9, which perform
transannular addition reactions: 7  10, 11 and 9  12, 13 (route II). Symmetric ketones 1 (m = n) yield
only one enol ether 1112 and only one semicarbazone 23, selenadiazole 56 and hydroxycycloalkyne

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HETEROCYCLES, Vol. 78, No. 9, 2009
79, but then two transannular addition products 1013 and 1112 can be formed. Two enol ethers can
result in the case n = m-1 (7  1011) and (9  1213). In all other cases (m-n > 1), the ketones 1 can
serve for the generation of four isomeric oxabicycloalkenes 1013. Of course, steric and/or electronic
effects can influence the regioselectivity in all unsymmetrical cases, and can lead to uniform products.
CONH2
NH
CONH2
HN
H2NCO
NH
NH
N
C
O
C
N
C
C
O
C
a
a
(CH2)n
(CH2)n
(CH2)m
(CH2)m
(CH2)n
(CH2)m
(CH2)n
(CH2)m
C
C
C
H
OH
N
H
OH
H
OH
Se
H
4
2
b
3
1
(m, n = 1, 2, ...)
m
b
n

N
N
Se
N
(CH2)m
(CH2)n
(CH2)m
(CH2)n-1
-1
C
C
H
OH
H
OH
5
6
OH
c
c
C
O
C
(CH2)n
(CH2)n
(CH2)m
(CH2)n-1
(CH2)m-1
(CH2)m
C
C
H
8
H
OH
H
OH
7
9
O
H
O
H
O
O
H
d
H
d
e
e
d
11
d
H
H
H
(CH2)n
(CH2)n-1
(CH2)n-1
(CH2)m-1
(CH2)m
(CH2)m
(CH2)n
(CH2)m-1
H
11
12
13
10
Scheme 1. Generation of oxabicycloalkenes 10-13 from hydroxycycloalkanones 1 by route I: 1
8 
11, 12 or route II: 1
8  2/3
4  5/6  7/9  10-13: (a) H2N-NH-CONH2, H+; (b) SeO2; (c)
160-180 oC; (d) 180-200 oC; (e) 90-120 oC, cat.
The -elimination of H2O can be performed by heating 1a-d
8a-d4-9 in the presence of catalytic
amounts of p-toluenesulfonic acid to 90-120 oC at 1 kPa (Scheme 2). In a typical procedure, 5-6 mmol of
starting compound was treated with 10 mg (0.05 mmol) p-toluenesulfonic acid monohydrate. The
generated water was removed under reduced pressure, so that the reverse reaction, the addition of water to
the reactive double bond of the anti-Bredt enol ether, can not take place. The anti-Bredt enol ethers were
then condensed in a cold trap. The residue contains bimolecular condensation products, derived from two
molecules 1 or from 1 and 8.3 These competing reactions decrease the yields - in particular for the smaller
and therefore more strained enol ethers. Due to symmetry reasons, the reactions of 8a and 8d are leading
to single enol ethers, whereas 8b and 8c generate the mixtures 11b/12b and 11c/12c, respectively.

HETEROCYCLES, Vol. 78, No. 9, 2009
2203
However, the dehydration of 8b is highly regioselective in favor of 8b  12b. Such a strong selectivity
can not be found in the case 8c  11c, 12c.
O
4
O
11b
24%
O
19%
OH
OH
(m = 3, n = 3)
96
11a
12a
8a
(m = 4, n = 3)
8b
12b
O
45
O
11c
63%
53%
O
OH
(m = 5, n = 3)
OH
55
8c
8d (m = 4, n = 4)
11d
12d
12c
Scheme 2. Monomolecular elimination (method I) of H2O from the
hemiacetals 8, which are in equilibrium with the corresponding
hydroxycycloalkanones 1 : 8a
1d8 (Method A: 90-120 oC, 1-3 kPa, 0.01 equivalent of p-toluene-
sulfonic acid
1a4, 8b
1b5, 8c
1c6,7, 8d
Method II in Scheme 1 makes use of the transannular addition of hydroxy groups to triple bonds in
cycloalkynols.10 Scheme 3 summarizes the generation of 10b, 10d, 10e, 11d, 11e, 12b and 13b. The
corresponding hydroxycycloalkanones 1 are transformed via the (Z/E)-semicarbazones 2/3 and their
bicyclic isomers 4 to the 1,2,3-selenediazoles 5 and/or 6. Thermal cleavage of 5 and/or 6 on Cu powder
o
o
yields at 160-180 C the hydroxycycloalkynes 7 and/or 9. At 180-200 C, the resulting anti-Bredt enol
ethers are formed in situ by the quantitative isomerization 7/9  1013. It is not necessary to isolate the
hydroxycycloalkynes. The cupper powder enhances the yields of the alkynes. It has no influence on the
transannular cyclization.
1,2,3-Selenediazole 5e11 was obtained in a yield of 90% by reaction of the corresponding oxo-
compound12 and H3CMgCl. 5-Hydroxycyclononanone 1b yielded via its semicarbazone 2b/3b/4b
44% of a 80:20 mixture of the 1,2,3-selenediazoles 5b and 6b.13 Accordingly, 6-hydroxycyclodecanone
1d furnishes 47% of 1,2,3-selenediazole 5d.14

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HETEROCYCLES, Vol. 78, No. 9, 2009
The hydroxycycloalkynes (7b,d,e; 9b) and the oxabicycloalkenes (10b,d,e; 11a,c,d,e; 12b,c; 13b) are
colorless oils. To our best knowledge, 7b, 7e, 9b, and 10b, 10e, 11c, 11e, 12b, 12c and 13b are new
compounds. The separation of enol ether mixtures by GC or HPLC seems to be feasible. We succeeded in
the separation of 11c and 12c by column chromatography on SiO2. However, a contact of pure 11c or 12c
with SiO2 in CDCl3 over several days led again to a catalytic equilibration (11c : 12c = 45 : 55).
O
CH3
HO
HO
A: 61%
B: 38%
N
N
10e (27%)
H3C
H3C
O
CH3
Se
5e
7e
11e (73%)
O
A: 93%
B: 49%
N
N
HO
HO
Se
10b
11b
7b
9b
5b
6b
12b (81%)
O
A: 93%
B: 69%
N
N
Se
HO
HO
13b (19%)
O
A: 96%
B: 53%
N
N
10d
11d
13d (34%)
12d (66%)
Se
HO
HO
7d
5d
6d
9d
Scheme 3. Thermal fragmentation of the 1,2,3-selenediazoles on Cu powder. Method A (160-180 oC, 10-2
o
-10-1 kPa) leads to the hydroxycycloalkynes. Method B (180-200 C, 10-2-10-1 kPa) leads directly to the
oxabicycloalkenes
Table 1 summarizes the characteristic NMR data of the hydroxycycloalkynes and the oxabicycloalkenes.
The (13C) values of the olefinic double bonds in the anti-Bredt compounds show a significant variation.
High  values for both olefinic carbon atoms were found for the systems 11a and 11e,

HETEROCYCLES, Vol. 78, No. 9, 2009
2205
which have the highest strain. The double bond has therein trans configuration related to the 8-membered
ring and cis configuration related to the 6-membered ring. The column RS in Table 1 contains the size of
the rings in which the double bonds have trans configuration. Compared to normal enol ethers, such as
(Z)-2-methoxy-2-butene15, ꢀ-C has in 11a,e a ꢀ value of 120.0 ± 0.3 ppm, which is about 17 ppm down-
field shifted. We attribute this effect to a low interaction of the p(ꢁ) orbital with the olefinic ꢂ bond, that
means to a low electron density on ꢀ-C. A complete correlation of the 1H and 13C chemical shifts is given
for 12b in Figure 1.
Table 1. Characteristic 1H and 13C NMR data of the hydroxycycloalkynes 7, 9
and the oxabicycloalkenes 10-13 (ꢀ values in CDCl3, TMS as internal standard)
__________________________________________________________
Compd. RS CꢃC
CHO
Compd. RS =CH =CO CHO
___________________________________________________________
11a
8
5.70
4.65
120.3 159.0 79.5
7e
8
ꢄ
10e
8
4.84
ꢄ
95.5, 96.3 73.4
111.8 157.0 74.9
11e 5.65
119.8 160.6 84.9
7b
88.8, 88.8 74.7
9b
87.6, 88.0 71.8
13b 4.48
109.3 154.9 75.6
11c 10 5.02
111.9 151.9 80.4
12c 10 4.72
8
ꢄ
9
4.11
3.94
10b
9
4.98
4.07
4.14
111.3 154.0 76.1
9
12b 5.17
109.7 155.3 72.6
9
9
4.10
4.12
4.02
102.2 151.7 72.7
7d 10
84.4, 84.9 69.6
4.25
4.00
10d 10
111.9 151.9 80.4
5.02
4.12
11d 10
113.2 156.3 74.5
__________________________________________________________
5.10

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HETEROCYCLES, Vol. 78, No. 9, 2009
1.46/1.75
35.6(124)
4.14
72.6(149)
H
H
1.31/2.20
29.3(127)
H
1.56/1.59
23.1(125)
H
O
H
H
H
H
H
1.94/2.04
17.9(130)
H
1.33/1.77
29.5(126)
H
155.3
H
H H
5.17
109.7(161)
2.06/2.12
32.2(131)
Figure 1. 1H and 13C NMR data of 10-oxabicyclo[4.3.1]dec-1(9)ene (12b); (1H)/(13C) values in
CDCl3,TMS as internal standard. The numbers in parentheses indicate the 1J (C,H) coupling constants in
Hz. The assignment of the signals is based on homo- and heteronuclear shift correlations and on NOE
measurements
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1
11. 5e: Viscous oil; H NMR (CDCl3):  = 3.55-3.00, m, 4H/2.20-1.85, m, 3H/1.85-1.28, m, 5H (CH2),
13
1.27 (s, 3H, CH3). C NMR (CDCl3):  = 160.6, 157.0 (heteroaromat. C), 73.0 (CqO), 40.9, 35.4,
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13
(br. s, 1H, OH), 2.00-1.30 (m, 8H, 4CH2). C NMR (CDCl3):  = 161.2, 160.2 (heteroaromat. C),
70.7 (CHO), 33.7, 32.1, 27.8, 26.4, 24.4, 22.5 (CH2). MS (EI): m/z (%) = 246 (2, M+, Se pattern), 137

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HETEROCYCLES, Vol. 78, No. 9, 2009
(44), 116 (100); 6b: viscous oil; 1H NMR (CDCl3):  = 3.74 (m, 1H, CH), 3.17 (m, 2H, CH2), 3.05 (m,
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o
1
14. 5d: mp 101-103 C. H NMR (CDCl3):  = 3.91 (m, 1H, CH), 3.20 (m, 3H), 3.05 (m,
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13
(m,1H), 1.02 (m, 1H) [7CH2]. C NMR (CDCl3):  = 160.1, 159.5 (heteroaromat. C), 69.8 (CHO),
77
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