Triphenylphosphine-Induced Ring Contraction of 1,2-Dioxines

Article abstract of DOI:10.1021/jo030330c

Triphenylphosphine inserts into the peroxide bond of 1,2-dioxines, initiating ring contraction with loss of triphenylphosphine oxide. This process yields dihydrofuran oxides in 54-97% yield from oxirenyl[2,3-c] [1,2]dioxines and dihydrofurans from 3,6-dih

Full text of DOI:10.1021/jo030330c

SCHEME 1
Tr ip h en ylp h osp h in e-In d u ced Rin g
Con tr a ction of 1,2-Dioxin es
Ben W. Greatrex and Dennis K. Taylor*
Department of Chemistry, University of Adelaide,
South Australia 5005, Australia
dennis.taylor@adelaide.edu.au
Received October 28, 2003
Abstr a ct: Triphenylphosphine inserts into the peroxide
bond of 1,2-dioxines, initiating ring contraction with loss of
triphenylphosphine oxide. This process yields dihydrofuran
oxides in 54-97% yield from oxirenyl[2,3-c][1,2]dioxines and
dihydrofurans from 3,6-dihydro-1,2-dioxines with inversion
of stereochemistry at either the 2 or 5 position in the furan
product.
with phosphines or dialkylsulfides.15-17 We have recently
reported the synthesis of a range of monocyclic 1,2-
dioxines 8 where the double bond has been epoxidized
and we hypothesized that these substrates would be ideal
candidates for ring contraction due to the freedom of
rotation that would result in the intermediate ions.18
Furthermore, the product epoxytetrahydrofuran ring
structure 9 finds extensive use in organic synthesis and
is found in natural products and is therefore an impor-
tant target.19-22
Both trialkylphosphines and trialkyl phosphites are
effective reducing agents for peroxide bonds and so both
were used in the reactions of 1,2-dioxines 8. The results
from the reactions of 1,2-dioxines 8a -g with trivalent
phosphorus reagents are summarized in Table 1 and
Scheme 2.
1,2-Dioxines (endoperoxides) 1 are an important class
of compounds as they are easily prepared from 1,3-dienes
and synthetically useful for the introduction of 1,4-oxygen
functionality into organic molecules.1-3 The weakness of
the endocyclic peroxide bond means that a large array
of reagents may be used to transform 1,2-dioxines into
interesting molecules. One of these, trivalent phosphorus
inserts into the peroxide bond yielding reactive phospho-
rane intermediates which undergo nucleophilic substitu-
tion or elimination reactions, Scheme 1.4-7
Bicyclic endoperoxides containing a double bond such
as 2 are reduced by trivalent phosphorus compounds to
allylic epoxides 3 with concomitant phosphorus oxide
formation.8-10 Fully saturated bicyclic endoperoxides 4
yield trans 1,4-diols 5 by hydrolysis of the phosphorus-
containing intermediates.6 Both of these processes occur
because of the inability of the intermediate ionic species
to undergo intramolecular nucleophilic displacement at
the C-O-P+R3 center because of the barriers to rotation
in the cyclic system.
When 8a was allowed to react with triphenylphosphine
at 25 °C a mixture of products both from ring contraction
(9a , 12%) and hydrolysis (10, 54%) were isolated. The
meso stereochemistry of 10 indicated that hydrolysis of
the intermediates occurred at the phosphorus center
rather than the carbon center. Monitoring the reaction
When monocyclic peroxy lactones 6 are treated with
triphenylphosphine, ring-contraction to give 7 results
from nucleophilic attack at the C-O-P+R3 center, indi-
cating that when rotation is possible, ring contraction is
a favorable process, Scheme 1.11-14 Ring-contraction is
also seen in 1,2-dioxetanes yielding epoxides when treated
1
by H and 31P NMR showed no phosphorus-containing
intermediates. When the mixture of 8a and triphen-
ylphosphine was heated to reflux in CDCl3, the ring-
contracted product 9a was isolated in 81% yield. In
contrast, no reaction was seen between dioxine 8a and
triethyl phosphite at room temperature. When the mix-
ture was heated to reflux for 7 days, full conversion to
the ring contracted furan 9a occurred resulting in an 84%
isolated yield, entry 3. The reaction of dicyclohexyl
dioxine 8b and triphenylphosphine only gave a moderate
yield of ring-contracted dihydrofuran oxide when heated
* Corresponding author.
(1) Takahashi, Y.; Wakamatsu, K.; Morishimu, S.; Miyashi, T. J .
Chem. Soc., Perkin Trans. 2 1993, 243.
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1985, 41, 2147.
(3) Hewton, C. E.; Kimber, M. C.; Taylor, D. K. Tetrahedron Lett.
2002, 43, 3199.
(4) Balci, M. Chem. Rev. 1981, 81, 91.
(5) Baumstark, A. L.; Barrett, M.; Kral, K. M. J . Heterocycl. Chem.
1982, 19, 201-203.
(6) Clennan, E. L.; Heah, P. C. J . Org. Chem. 1981, 46, 4105-4107.
(7) Clennan, E. L.; Heah, P. C. J . Org. Chem. 1984, 49, 2284-2286.
(8) Pierson, G. O.; Runquist, O. A. J . Org. Chem. 1969, 34, 3654.
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Am. Chem. Soc. 1975, 97, 3850-3851.
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Tetrahedron Lett. 1993, 34, 5247-5250.
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(18) Greatrex, B. W.; J enkins, N. F.; Taylor, D. K.; Tiekink, E. R.
T. J . Org. Chem. 2003, 68, 5205.
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10.1021/jo030330c CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/28/2004
J . Org. Chem. 2004, 69, 2577-2579
2577

SCHEME 2
SCHEME 3
TABLE 2. Rin g Con tr a ction of 3,6-Dih yd r o-1,2-d ioxin es
1 w ith P P h 3
entrya
1,2-dioxine
yieldb (%) of 12
1
2
3
1a
1b
1c
63
60
35
TABLE 1. Rin g Con tr a ction of Ep oxy-1,2-d ioxin es 8
a
Reaction performed on 100-300 mg of 1 with 1.5 equiv of PPh3
in CHCl3 at 60 °C for 3 h. b Isolated yield by flash chromatography.
entrya 1,2-dioxine
PR3
T, °C (time, h) yieldb (%) of 9
1
2
3
4
5
6
7
8
9d
8a
8a
8a
8b
8c
8d
8e
8f
PPh3
PPh3
P(OEt)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
25 (72)
60 (16)
60 (168)
60 (72)
60 (5)
60 (5)
60 (5)
60 (16)
60 (3)
12
81
84
54
83
91
97
67
85
Once the dihydrofurans 12b,c had been prepared, it
was possible to convert them to the dihydrofuran oxides
9d ,e to confirm the structural identity of both com-
pounds. Thus, epoxidation of 12a ,b with m-CPBA gave
the dihydrofuran oxides 9d ,e in quantitative yield by 1H
NMR supporting the assigned structures for both com-
pounds. It appears that increased temperature is neces-
sary to ensure that ring-contraction is the dominant mode
of reaction between 1,2-dioxines and triphenylphosphine.
The elevated temperature promoted the intramolecular
reaction at the expense of the intermolecular hydrolysis
giving cleaner reactions.
8g
a
Reactions were performed on a scale of 10-300 mg in CHCl3
or CDCl3. Isolated yield by column chromatography. c Florisil
b
d
used as chromatographic stationary phase. Reaction yielded 11
not 9g.
to 60 °C, entry 4. The dihydrofuran oxide was the sole
product from the reaction by H NMR but appeared to
Due to the ready accessibility of the parent 1,2-dioxines
1 and the near quantitative yield for the epoxidation of
the 1,2-dioxines, this procedure represents an efficient
synthesis of 3-substituted dihydrofuran oxides. Further-
more, the reaction of phosphines with monocyclic 3,6-
dihydro-1,2-dioxines is a useful method for the synthesis
of substituted 2,5-dihydrofurans. An examination of the
full scope of the ring contraction of monocyclic endoper-
oxides is underway and may facilitate the use of the ring
contraction in targeted structure synthesis.
1
decompose during isolation. Application of the ring-
contraction methodology to 4-substituted 1,2-dioxines
8c-e gave solely ring contraction products in excellent
yield, entries 5-7. Comparison of the 13C spectra of these
epoxides with that reported for similar analogues con-
firmed the identity of the epoxides.23 Methyl substituted
1,2-dioxine 8g gave a ring-contracted product with in-
verted stereochemistry at the phenyl center. Definitive
assignment of the known product 11 using 2D ROESY
NMR was not possible and so 11 was assigned on the
basis of the previously reported stereochemistry.
Exp er im en ta l Section
In a recent report by Montaudon et al., a low yield
(15%) of dihydrofuran was found in the triphenylphos-
phine mediated reduction of a 3,6-dihydro-1,2-dioxine.24
The success we had seen in the ring contractions for the
epoxides 8 caused us to examine the ring-contraction of
monocyclic 3,6-dihydro-1,2-dioxines that still contained
a double bond. The 3,6-dihdro-1,2-dioxines 1 can undergo
competing elimination reactions and so could have po-
tentially yielded a mixture of allylic epoxide and ring-
contracted compounds. We found that when treated with
1.5 equiv of triphenylphosphine at 60 °C in CHCl3, 1a -c
afforded the oxygen sensitive ring-contracted dihydro-
furans 12a -c as the major products, Table 2 and Scheme
3. Both 3- and 2-substituted dihydrofurans were prepared
by this method in moderate yield.
Gen er a l P r oced u r e for th e Rin g-Con tr a ction of Ep oxy-
1,2-d ioxin es 8a -g. To a stirred solution of 1,2-dioxine (1 mmol)
in chloroform (5 mL) was added triphenylphosphine (393 mg,
1.5 mmol) and the mixture heated to reflux until complete by
1H NMR or TLC. The mixture was then concentrated in vacuo,
and the products were purified by flash chromatography.
(()-(1a R,2R,4R,4a S)-2,4-Dip h en yltetr a h yd r ooxir en o[2,3-
c]fu r a n 9a : colorless oil purified by column chromatography
(Florisil); Rf 0.82 (CH2Cl2); IR (neat) 3031, 2863, 1494, 1451,
1056, 739, 698 cm-1 1H NMR (CDCl3, 300) δ 3.92 (d, J ) 2.6
;
Hz, 1H), 3.94 (dd, J ) 2.6, 0.6 Hz, 1H), 5.16 (s, 1H), 5.40 (s,
1H), 7.33-7.55 (m, 10H); 13C NMR (CDCl3, 50) δ 59.7, 60.1, 78.7,
79.8, 125.9, 127.3, 128.1, 128.3, 128.4, 128.8, 136.8, 138.4; EIMS
m/z 238 (M+, 20), 211 (30), 105 (100); HRMS calcd for (M + Na,
ESI) C16H14O2Na 261.0891, found 261.0886.
(()-(1aR,2R,4R,4aS)-2,4-Dicycloh exyltetr a h yd r ooxir en o-
[2,3-c]fu r a n 9b: colorless oil; Rf 0.58 (90:10 hexane/ethyl
acetate); IR (neat) 2924, 1449, 1062, 868, 732 cm-1 1H NMR
;
(23) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Org. Lett. 2001,
3, 3401-3403.
(24) Campagnole, M.; Bourgeois, M.-J .; Montaudon, E. Tetrahedron
2002, 58, 1165-1171.
(CDCl3, 300) δ 0.94-1.74 (m, 21H), 1.80-2.0 (m, 1H), 3.48 (d, J
) 5.8 Hz, 1H), 3.57 (d, J ) 2.0 Hz, 1H), 3.64 (dd, J ) 2.0, 0.6
Hz, 1H), 3.75 (d, J ) 5.6 Hz, 1H); 13C NMR (CDCl3, 75) δ 25.7,
2578 J . Org. Chem., Vol. 69, No. 7, 2004

25.8, 25.9, 25.9, 26.3, 26.4, 28.8, 29.1, 29.3, 30.6, 39.2, 40.0, 56.8,
57.7, 81.7, 82.0; EIMS m/z 251 (MH+, 100), 233 (85), 95 (50);
HRMS calcd for (M + Na, ESI) C16H26O2Na 273.1830, found
273.1827.
(()-(1a R,2R,5a )-1a -Met h yl-2-p h en ylp er h yd r ooxir en o-
[2,3-c]fu r a n 11:25 colorless oil; Rf 0.48 (70:30 hexane/ethyl
acetate); IR (neat) 3031, 2931, 2866, 1493, 1455, 1063, 832, 699
cm-1; 1H NMR (CDCl3, 300) δ 1.29 (s, 3H), 3.78 (s, 1H), 4.16 (d,
J ) 10.8 Hz, 1H), 4.19 (d, J ) 10.8 Hz, 1H), 4.89 (s, 1H), 7.22-
7.42 (m, 5H); 13C NMR (CDCl3, 75) δ 14.4, 63.1, 67.1, 68.4, 82.8,
126.6, 128.1, 128.6, 140.0; EIMS m/z 176 (M+, 5), 133 (10), 105
(100).
1a -Hexyltetr a h yd r ooxir en o[2,3-c]fu r a n 9c: colorless oil;
Rf 0.15 (CH2Cl2); IR (neat) 2930, 2857, 1466, 1078, 908, 758 cm-1
;
1H NMR (CDCl3, 300) δ 0.88 (t, J ) 6.9 Hz, 3H), 1.23-1.46 (m,
8H), 1.74-2.04 (m, 2H), 3.55 (s, 1H), 3.61 (d, J ) 10.2 Hz, 1H),
3.67 (dd, J ) 10.5, 0.6 Hz, 1H), 3.89 (d, J ) 10.2 Hz, 1H), 3.67
(d, J ) 10.5 Hz, 1H); 13C NMR (CDCl3, 75) δ 13.9, 22.4, 25.4,
27.9, 29.2, 31.5, 60.5, 67.0, 67.6, 69.0; EIMS m/z 170 (M+, 4),
152 (4), 55 (95), 43 (100); HRMS calcd for (M + Na, ESI)
C10H18O2Na 193.1204, found 193.1212.
2-Cycloh exyl-2,5-d ih yd r ofu r a n 12a : unstable colorless oil;
Rf 0.40 (90:10 hexane/ethyl acetate); 1H NMR (CDCl3, 300) δ
0.97-1.72 (m, 11H), 4.60-4.61 (m, 3H), 5.79 (ddd, J ) 6.3, 2.4,
1.2 Hz, 1H), 5.86 (br d, J ) 6.3 Hz, 1H); 13C NMR (CDCl3, 75) δ
26.1, 26.1, 26.5, 28.4, 28.6, 43.4, 75.2, 90.6, 126.7, 128.1; EIMS
m/z 168 (M + O), 152 (M+, 10), 151 (70), 135 (100).
1a -(1-Ad a m a n tyl)tetr a h yd r ooxir en o[2,3-c]fu r a n 9d : col-
3-(1-Adam an tyl)-2,5-dih ydr ofu r an 12b: colorless solid which
decomposed over several days; Rf 0.50 (30:70 hexane/CH2Cl2);
orless oil; Rf 0.16 (CH2Cl2); IR (neat) 2904, 1453, 1080, 860 cm-1
;
1H NMR (CDCl3, 300) δ 1.65-1.80 (m, 12H), 2.01 (br s, 3H), 3.61
(br d, 10.5 Hz, 1H), 3.62 (br s, 1H), 3.83 (dd, J ) 9.9, 0.9 Hz,
1H), 3.88 (d, J ) 9.9 Hz, 1H), 3.97 (d, J ) 10.5 Hz, 1H); 13C
NMR (CDCl3, 75) δ 27.8, 31.9, 36.5, 38.8, 57.7, 65.6, 67.5, 73.0;
EIMS m/z 220 (M+, 20), 191 (30), 135 (100). Anal. Calcd for
C14H20O2: C, 76.33; H, 9.15. Found: C, 75.73; H, 9.10.
IR (Nujol) 1651, 1102, 1082, 906, 784 cm-1 1H NMR (CDCl3,
;
300) δ 1.65-1.76 (m, 12H), 1.99 (br s, 3H), 4.63-4.64 (m, 4H),
5.38 (m, 1H); 13C NMR (CDCl3, 75) δ 28.3, 33.8, 36.8, 41.7, 73.7,
76.0, 116.0, 150.1; EIMS m/z 204 (M+, 20), 176 (20), 135 (100);
HRMS calcd for (MH+, ESI) C10H21O1 205.1592, found 205.1597.
3-Cycloh exyl-2,5-d ih yd r ofu r a n 12c: unstable colorless oil;
Rf 0.28 (90:10 hexane/ethyl acetate); IR (neat) 2925, 2852, 1448,
1a -Cycloh exyltetr a h yd r ooxir en o[2,3-c]fu r a n 9e: color-
less oil; Rf 0.11 (CH2Cl2); IR (neat) 2927, 2852, 1449, 1081, 909,
1071 cm-1 1H NMR (CDCl3, 300) δ 1.16-1.28 (m, 5H), 1.66-
;
1.78 (m, 5H), 1.83 (br s, 1H), 4.55-4.59 (m, 2H), 4.61-4.65 (m,
2H), 5.40-5.42 (m, 1H); 13C NMR (CDCl3, 75) δ 26.1, 26.2, 31.9,
36.6, 75.7, 75.9, 116.9, 145.7; EIMS m/z 152 (M+, 40), 123 (40),
69 (100).
863 cm-1 1H NMR (CDCl3, 300) δ 1.09-1.29 (m, 5H), 1.66-
;
1.77 (m, 6H), 3.59 (s, 1H), 3.65 (dd, J ) 10.5, 0.6 Hz, 1H), 3.66
(d, J ) 10.2 Hz, 1H), 3.89 (d, J ) 10.2 Hz, 1H), 3.97 (d, J ) 10.5
Hz, 1H); 13C NMR (CDCl3, 75) δ 25.8, 25.9, 26.0, 28.8, 29.4, 36.5,
59.4, 67.6, 67.7, 70.4; EIMS m/z 150 (M+ - H2O, 35), 111 (70),
95 (90), 67 (100). Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: C, 71.10; H, 9.65.
Ack n ow led gm en t. We thank Dr Thomas Avery and
Tony Robinson for the synthesis of 1,2-dioxines 8c-e.
We thank the Australian Research Council for funding.
2,2-Dip h en yltetr a h yd r ooxir en o[2,3-c]fu r a n 9f: colorless
solid; mp 115-117 °C; Rf 0.50 (80:20 hexane/ethyl acetate); IR
(Nujol) 1048, 867, 700 cm-1; 1H NMR (CDCl3, 300) δ 3.86 (dd, J
) 3.0, 0.6 Hz, 1H), 3.91 (dd, J ) 10.8, 0.6 Hz, 1H), 4.29 (d, J )
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for 8c-e,g and 10. 1H or 13C NMR spectra for 1c,
8c,e, 9a -c,f, 10, and 12a -c. This material is available free
of charge via the Internet at http://pubs.acs.org.
3.0 Hz, 1H), 4.31 (d, J ) 10.8 Hz, 1H), 7.25-7.48 (m, 10H); 13
C
NMR (CDCl3, 75) δ 56.3, 61.0, 67.2, 85.9, 126.0, 127.1, 127.6,
128.2, 128.6, 141.3, (2 masked aromatics); EIMS m/z 238 (30),
182 (20), 105 (100); HRMS (ESI) calcd for (M + Na) C16H14O2-
Na 261.0891, found 261.0887.
J O030330C
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2555-2557.
J . Org. Chem, Vol. 69, No. 7, 2004 2579