Halonium ion-mediated reaction of unsaturated hydroperoxy acetals. Competition between the formation of cyclic peroxides and the migration of the methoxy (or hydroxy) group

Article abstract of DOI:10.1021/jo991499m

Monoozonolyses of dienes 2 in methanol gave in each case the corresponding unsaturated α-methoxy hydroperoxides 3. Capture of 2-alkyl- substituted cyclohexanone oxides by methanol was highly diastereoselective, thereby providing exclusively the hydroperoxides derived from attack by methanol from the less hindered face of the carbonyl oxide intermediates. Halonium ion-mediated reactions of the hydroperoxides 3 gave the novel methoxy- or hydroxy-migrated products, together with the expected halogen- substituted 1,2-dioxanes and/or 1,2-dioxepanes, the composition of the product mixture being a function of the halogenating agent utilized and the structure of 3.

Full text of DOI:10.1021/jo991499m

J . Org. Chem. 2000, 65, 1069-1075
1069
Ha lon iu m Ion -Med ia ted Rea ction of Un sa tu r a ted Hyd r op er oxy
Aceta ls. Com p etition betw een th e F or m a tion of Cyclic P er oxid es
a n d th e Migr a tion of th e Meth oxy (or Hyd r oxy) Gr ou p
Takahiro Tokuyasu,† Araki Masuyama,† Masatomo Nojima,*,†,‡ and Kevin J . McCullough*,§
Department of Materials Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565, J apan,
and Department of Chemistry, Heriot-Watt University, Edinburgh EH14 4AS, Scotland
Received September 23, 1999
Monoozonolyses of dienes 2 in methanol gave in each case the corresponding unsaturated R-methoxy
hydroperoxides 3. Capture of 2-alkyl-substituted cyclohexanone oxides by methanol was highly
diastereoselective, thereby providing exclusively the hydroperoxides derived from attack by methanol
from the less hindered face of the carbonyl oxide intermediates. Halonium ion-mediated reactions
of the hydroperoxides 3 gave the novel methoxy- or hydroxy-migrated products, together with the
expected halogen-substituted 1,2-dioxanes and/or 1,2-dioxepanes, the composition of the product
mixture being a function of the halogenating agent utilized and the structure of 3.
The discovery of antimalarial activity of artemisinin
and various other 1,2,4-trioxane derivatives has stimu-
lated recent interest in the development of new methods
for synthesis of analogous cyclic peroxide systems.1 In
this respect, we2 and Dussault3 reported independently
that halonium ion-mediated cyclization of unsaturated
hydroperoxy acetals provided a convenient synthetic
route to 1,2,4-trioxanes and related 1,2,4-trioxepanes.
Since 1,2-dioxanes, for example, arteflene and yingzhaosu
C, and 1,2-dioxepanes also exhibit significant antima-
larial activity,4-6 we describe herein the results of some
recent investigations into the synthesis of new 1,2-
dioxane and 1,2-dioxepane derivatives via halonium ion-
mediated cyclization of the unsaturated hydroperoxy
acetals 3 derived from the trapping of unsaturated
carbonyl oxides by methanol.
Resu lts a n d Discu ssion
P r ep a r a tion of Un sa tu r a ted Hyd r op er oxy Acet-
a ls. The required unsaturated hydroperoxy acetals 3
were synthesized by monoozonolysis of the appropriate
diene 2 in MeOH-CH2Cl2. With the exception of 2c, the
diene substrates 2 were enol ether derivatives, obtained
from the corresponding unsaturated ketones as outlined
in Scheme 1. Taking advantage of the known chemose-
lectivity of ozone toward electron-rich enol ethers, the
reaction of diene 2a with 1 equiv of ozone in MeOH-
CH2Cl2 at -70 °C, followed by column chromatography
on silica gel, gave exclusively 1-methoxy-2-(2-methyl-2-
propenyl)cyclohexyl hydroperoxide (3a ). Ozonolyses of
dienes 2b-f under similar conditions afforded the cor-
responding R-methoxyalkyl hydroperoxides 3b-f in mod-
erate to good yield (Scheme 1). Although they were
spectroscopically pure on isolation, the hydroperoxides
3a -c, obtained as oils, were found to be too thermally
labile to provide satisfactory elemental analysis data.
It is interesting to note that the hydroperoxides 3a ,d ,f
were isolated as single isomers, which implies that
capture of corresponding 2-alkyl-substituted cyclohex-
anone O-oxide by methanol must show a high degree of
† Osaka University.
‡ Phone and fax: +81-6-6879-7928. E-mail: nojima@ap.chem.eng.
osaka-u.ac.jp.
§ Heriot-Watt University.
(1) (a) J efford, C. W. In Comprehensive Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsvier: Oxford,
1996; Vol. 6, Chapter 20. (b) Zhou, W.-S.; Xu, X.-X. Acc. Chem. Res.
1994, 27, 211. (c) Haynes R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997,
30, 73. (d) Robert A.; Meunier, B. Chem. Soc. Rev. 1998, 27, 273. (e)
Cumming, J . N.; Ploypradith, P.; Posner, G. H. Adv. Pharmocol. 1997,
37, 253-297. (f) Haynes, R. K.; Pai, H. H.-O.; Voerste, A. Tetrahedron
Lett. 1999, 40, 4715. (g) Posner, G. H.; O’Dowd, H.; Caferro, T.;
Cumming, J . N.; Ploypradith, P.; Xie, S.; Shapiro, T. A. Tetrahedron
Lett. 1998, 39, 2273. (h) Vroman, J . A.; Khan, I. A.; Avery, M. A.
Tetrahedron Lett. 1997, 38, 6173.
1
diastereofacial selectivity. Since in the H NMR spectra
of these hydroperoxides 3a ,d ,f the signal of the methine
hydrogen at C-2 overlapped with methylene signals, the
stereochemistry of these compounds could not be readily
determined. On the other hand, NOE measurements
obtained from a related compound, 3g, isolated in 95%
yield as a single isomer from the ozonolysis of 1-meth-
oxymethylene-2-phenylcyclohexane (2g) in methanol,
indicated that the phenyl group and the hydroperoxy
(2) Ushigoe, Y.: Kano, Y.; Nojima, M. J . Chem. Soc., Perkin Trans
1 1997, 5.
(3) Dussault, P. H.; Davies, D. R. Tetrahedron Lett. 1996, 37, 463.
(4) (a) Meshnick, S. R.; J efford, C. W.; Posner, G. H.; Avery, M. A.;
Peters, W. Parasitol. Today 1996, 12, 79. (b) Boukouvalas, J .; Pouliot,
R.; Fre´chette, Y. Tetrahedron Lett. 1995, 36, 4167. (c) O’Neill, P. M.;
Searle, N. L.; Raynes, K. J .; Maggs, J . L.; Ward, S. A.; Storr, R. C.;
Park, B. K.; Posner, G. H. Tetrahedron Lett. 1998, 39, 6065. (d) Dong,
Y.; Matile, H.; Chollet, J .; Kaminsky, R.; Wood, J . K.; Vennerstrom, J .
L. J . Med. Chem. 1999, 42, 1477.
(5) Synthesis of 1,2-dioxanes: (a) Dussault, P. H.; Woller, K. R. J .
Am. Chem. Soc. 1997, 119, 3824. (b) Nguyen, V,-H.; Nishino, H.;
Kurosawa, K. Tetrahedron Lett. 1997, 38, 1773. (c) Fielder, S.; Rowan,
D. D.; Sherburn, M. S. Tetrahedron 1998, 54, 12907. (d) Bachi, M. D.;
Korshin, E. E. Synlett 1998, 122. (e) J efford, C. W.; Eschenhof, H.;
Bernardinelli, G. Heterocycles 1998, 47, 283. (f) Clennan, E. L.; Foote,
C. S. In Organic Peroxides; Ando, W., Ed.; Wiley: New York, 1992;
Chapter 6.
(6) Naturally occurring 1,2-dioxepane: Kamchonwongpaisan, S.;
Nilanonta, C.; Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth,
Y.; Yuthavong, Y.; Kongsaree P.; Clardy, J . Tetrahedron Lett. 1995,
36, 1821. Synthesis of 1,2-dioxepanes: (a) Ninomiya, I.; Naito, T.;
Miyata, O. In Comprehesive Heterocyclic Chemistry II; Newkome, G.
R., Ed.; Elsevier: Oxford, 1996; Vol. 9, pp 233-238 and 1039-1146.
(b) Kajikawa, S.; Noiri, Y.; Shudo, H.; Nishino, H.; Kurosawa, K.
Synthesis 1998, 1457. (c) Dussault, P. H.; Lee, H.-J .; Niu, Q. J . J . Org.
Chem. 1995, 60, 784. (d) Haraldson, C. A.; Karle, J . M.; Freeman, S.
G.; Duvadie, R. K.; Avery, M. A. Bioorg. Med. Chem. Lett. 1997, 7,
2357.
10.1021/jo991499m CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/27/2000

1070 J . Org. Chem., Vol. 65, No. 4, 2000
Tokuyasu et al.
Sch em e 1
Sch em e 2
Ha lon iu m Ion -Med ia ted Cycliza tion of Un sa tu r -
a ted Hyd r op er oxy Aceta ls. With the starting materi-
als 3 in hand, a series of iodonium ion-mediated cycliza-
tions were conducted using three different reagents:
N-iodosuccinimide (NIS)-NaHCO3,2 I2-KOBut,3 and bis-
(sym-collidine)iodine(I) hexafluorophosphate (BCIH).9a
Although NIS-NaHCO3 and I2-KOBut have been used
previously in the preparation of cyclic peroxides,2,3 the
effectiveness of BCIH for the synthesis of 1,2-dioxanes
and 1,2-dioxepanes from the corresponding unsaturated
hydroperoxides was of particular interest because this
reagent is known to promote cyclization reactions leading
to the entropically less favored medium-sized cyclic
ethers and lactones.9a
Treatment of the methoxy hydroperoxide 3a with NIS
afforded the corresponding 1,2-dioxane 5a (14% yield; a
single stereoisomer) and the iodo ketone 6a (25% yield),
arising from the unexpected migration of the methoxy
group.10 The NOE measurement of the isolated dioxane
5a suggested that the methoxy and iodomethyl groups
were cis (Scheme 2 and the Experimental Section). The
reaction of 3a with I2-KOBut gave similar results. Under
the reaction conditions described above for 3a , the
hydroperoxide 3b also provided similar mixtures of the
corresponding 1,2-dioxane 5b and ketone 6b. When the
hydroperoxide 3c was treated with NIS, however, only a
ketone, 6c, was isolated in 31% yield, whereas a mixture
of the 1,2-dioxane 5c and ketone 6c was obtained from
the reaction with I2-KOBut (Scheme 3).
were cis (Experimental Section), suggesting that metha-
nol attacked the carbonyl oxide moiety from the less
hindered face anti to the phenyl substituent. By analogy,
similar configurations have been tentatively assigned for
compounds 3a ,d ,f (Scheme 1).7 Dussault and Zope8 have
reported that addition of tert-butyl alcohol to an acyclic
carbonyl oxide was highly diastereoselective although the
addition of the sterically less hindered methanol and
2-propanol exhibited only moderate diastereoselectivity.
The structure of the crystalline 1,2-dioxane 5c was
determined by X-ray crystallographic analysis (Figure
1).11 The central 1,2-dioxane ring adopts a slightly
distorted chair conformation with the sterically more
(7) The related singlet oxygenation of 1-methoxymethylene-2-(2-
cycanoethyl)cyclohexane also shows the same diastereoselectivity: (a)
Hamzaoui, M.; Provot, O.; Camuzat-Dedenis, B.; Moskowitz, H.;
Mayrargue, J .; Ciceron, L.; Gay, F. Tetrahedron Lett. 1998, 39, 4029.
(b) Cumming, J . N.; Wang, D.; Park, S. B.; Shapiro, T. A.; Posner, G.
H. J . Med. Chem. 1998, 41, 952.
(9) For a general discussion for the halonium ion-mediated cylization
see: (a) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453. (b)
Kitagawa, O.; Taguchi, T. J . Synth. Org. Chem. J pn. 1998, 56, 661.
(10) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Syn-
thesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter
1.9.
(8) Dussault, P. H.; Zope, U. R. J . Org. Chem. 1995, 60, 8218.

Halonium Ion-Mediated Reaction of Hydroperoxy Acetals
J . Org. Chem., Vol. 65, No. 4, 2000 1071
Sch em e 4
F igu r e 1. Molecular structure of 1,2-dioxane derivative 5c
(ORTEP9).
Sch em e 3
demanding phenyl groups equatorial and the methoxy
and iodomethyl groups axial.
product 6a (20%). The dioxane 5a was obtained as a 3:2
mixture of cis and trans stereoisomers, in marked
contrast to the fact that 5a was isolated as a single
isomer from the reaction with NIS or I2-KOBut (the
ratios of products, if formed as mixtures of isomers, are
shown in the schemes). On the basis of the structure of
the starting material 3a , the relation of the methoxy and
iodomethyl groups in the minor isomer is considered to
be trans.
Consistent with its reported ability to promote the
formation of the entropically disfavored seven- and eight-
membered cyclic ethers from unsaturated alcohols,9a
BCIH has proved to be the most effective reagent for the
production of the cyclic peroxides from the unsaturated
hydroperoxy acetals 3 (Schemes 2 and 4). For example,
the reaction of 3a with BCIH gave the corresponding
dioxane 5a in 29% yield together with the rearrangement
Thus, in the iodonium ion-mediated reactions of 3a -
c, two alternative processes (paths a and b, Scheme 2)
can compete, with the relative contributions of each being
a marked function of the structure of 3 and the nature
of the iodonium ion reagents. Attack of the hydroperoxy
group on the electron-deficient carbon of the iodonium
ion intermediate 4a yields the 1,2-dioxane 5a after
deprotonation (path a). Alternatively, the formation of
ketone 6a requires an intramolecular migration of the
methoxy group,10 followed by heterolytic O-O bond
fission (path b). Consistent with the proposed intramo-
lecular process, reaction of 3a with NIS in the presence
of 1.2 equiv of CD3OD gave the product 6a , which did
(11) Crystal data for 5c: C18H19IO3, M ) 410.23, colorless needles,
triclinic, space group P1h (no. 2), a ) 8.7230(10) Å, b ) 10.006(2) Å, c
) 10.780(2) Å, R ) 64.410(10)°, â ) 82.83(2)°, γ ) 77.24(2)°, V ) 827.2-
(2) Å3, Z ) 2, Dc ) 1.647 g cm-3, F(000) ) 408, µ(Mo KR) ) 1.945 mm-1
,
final discrepancy factors R ) 0.025 and Rw ) 0.067. Crystal data for
8d : C12H21BrO3, M ) 293.20, colorless needles, monoclinic, space group
P21/c (no. 14), a ) 12.399(4) Å, b ) 9.849(4) Å, c ) 10.699(3) Å, â )
100.18(2)°, V ) 1286.0(7) Å3, Z ) 4, Dc ) 1.514 g cm-3, F(000) ) 608,
µ(Mo KR) ) 3.188 mm-1, final discrepancy factors R ) 0.036 and Rw
) 0.084. The X-ray diffraction data were collected on a Siemens P4
diffractometer using graphite-monochromated Mo KR (λ ) 0.710 73
Å) at T ) 160 K and corrected for absorption, and the structure was
solved by direct methods. All crystallographic calculations were carried
out using SHELXTL (version 5.1) (Sheldrick, G. M., Brucker AXS Inc.,
Madison, WI).

1072 J . Org. Chem., Vol. 65, No. 4, 2000
Tokuyasu et al.
Sch em e 5
F igu r e 2. Molecular structure of 1,2-dioxepane derivative 8d
(ORTEP9).
not contain any deuterium (Scheme 2). Assuming that
the methoxy group and the side chain were 1,2-diequa-
torial in 3a , then path b (5-exo attack) would be entropi-
cally favorable. Molecular models suggest that in 4a the
electron-deficient carbon could be placed in close proxim-
ity to the methoxy group. Moreover, CdO bond formation
in the final step could provide an additional driving force.
Treatment of the methoxy hydroperoxide 3d with
BCIH gave the desired 1,2-dioxepane 5d in 64% yield as
the sole isolable product. The analogous reaction between
3d and NIS, however, produced a mixture of the 1,2-
dioxepane 5d (25% yield) and the unexpected furan
derivative 10d (35% yield) (Scheme 4). The furan 10d
was found to be the kinetically controlled product, since
treatment of 5d with NIS resulted in the quantitative
recovery of 5d . The analogous reaction of 3f with NIS
afforded the corresponding furan derivative 10f in 30%
yield but apparently none of the 1,2-dioxepane 5f,
whereas 5f was isolated in 43% yield on reaction of 3f
with BCIH (Scheme 4). The reaction of hydroperoxides
3d ,f with I2-KOBut resulted in the formation of a
complex mixture of unidentified products.
Although the hydroperoxides 3a and 3d form the
corresponding cyclic peroxides 5a and 5d , respectively,
when treated with NIS, the disparate structures of the
nonperoxidic products 6a and 10d indicate that they have
been formed by distinctly different pathways, the former
by methoxy group migration (vide supra) and the latter
by cleavage of the O-O bond of the cyclic intermediate
9d . Thus, reaction of 11a , the tert-butyldimethylsilyl-
protected derivative of 3a , with NIS gave the methoxy-
migration product 6a in enhanced yield consistent with
total suppression of the cyclization process involving the
peroxide group (Scheme 5). Under similar conditions, the
reaction of the TBDMS compound 11d with NIS produced
only a complex mixture of unidentified products. This is
in reasonable agreement with the notion that dioxepane
5d and furan 10d are both derived from the cyclic
intermediate 9d arising from attack of the terminal
oxygen of the hydroperoxy group on the carbocation
center of the iodonium ion 4d (Scheme 4).
cally favorable in the case of the halonium ion 4d ,
molecular models suggest that, as a consequence of the
longer side chain in 4d , approach of the electron-deficient
carbon to the methoxy group directly attached to the
cyclohexane ring suffers significant steric congestion. The
alternative attack by the hydroperoxy group with a lesser
steric demand (7-endo attack) predominantly occurs to
give the cyclic intermediate 9d . Subsequent deprotona-
tion, which would be assisted by collidine in the case of
BCIH, results in the formation of the 1,2-dioxepane 5d
(path a in Scheme 4). In the case of NIS, the succinimide
anion, which is probably strongly coordinated to the
iodonium ion, does not seem to work as an efficient base,
and as a result, the alternative bond reorganization
involving O-O bond scission12 (path b in Scheme 4) can
compete, thereby providing the furan derivative 10d . In
the case of 3a having a shorter side chain, a process
similar to path b in Scheme 4 does not seem to be
important, since the expected product would be the ring-
strained oxetane derivative.
The reaction of hydroperoxide 3a with N-bromosuc-
cinimide (NBS) in the presence of NaHCO3 afforded the
methoxy-migrated ketone 7a in 48% yield rather than
the expected 1,2-dioxane (Scheme 2). Similar trends were
observed for 3b,c (Scheme 3). In contrast, the analogous
reactions of hydroperoxides 3d -f with NBS did provide
the expected dioxepanes 8d -f together with the ketones
7d -f, demonstrating again that the substrate with a
longer side chain favors the formation of the cyclic
peroxide, reflecting the ease in approach of the hydro-
peroxide group to the electron-deficient carbon of the
halonium ion intermediate (Schemes 3 and 4).
The structure of the major isomer of compound 8d , as
determined by X-ray crystallographic analysis, consists
of a chairlike cyclohexane ring cis-fused to a 1,2-dioxe-
pane ring which adopts a twist-chair conformation (Fig-
ure 2).11 Moreover, the structural features of this isomer
of 8d are entirely consistent with (a) the syn relationship
established between the hydroperoxy and the 3-methyl-
2-butenyl groups in the substrate 3d as discussed above
(Scheme 1) and (b) the ring closure mechanism proposed
in Scheme 4, which should result in the terminal peroxide
oxygen and the bromine in 8d being antiperiplanar
Thus, (1) the reaction of 3d seems to proceed exclu-
sively via the cyclic intermediate 9d , while the methoxy
migration is important in the case of 3a , and (2) the
reaction of 3d with BCIH gives predominantly the
dioxepane 5d , while the formation of the furan 10d is
important in the reaction with NIS. Although methoxy
group migration (6-endo attack) should also be entropi-
(12) A similar C-O bond formation with the concomitant O-O bond
fission has been proposed for the formation of 2-bromo-9-oxabicyclo-
[4.2.1]nonane from the reaction of 5-hydroperoxycyclooctene with
NBS: Bloodworth, A. J .; Curtis, R. J .; Spencer, M. D.; Tallant, N. A.
Tetrahedron 1993, 49, 2729.

Halonium Ion-Mediated Reaction of Hydroperoxy Acetals
J . Org. Chem., Vol. 65, No. 4, 2000 1073
2-Meth oxy-5-m eth yl-5-h exen -2-yl h yd r op er oxid e (3b):
(observed torsion angle: O(1)-C(1)-C(2)-Br(1) 174.1-
(2)°).
1
oil; Η NMR δ 1.36 (s, 3 H), 1.75 (s, 3 H), 1.8-1.9 (m, 2 H),
2.0-2.1 (m, 2 H), 3.33 (s, 3 H), 4.71 (s, 2 H), 8.36 (s, 1 H); 13C
NMR δ 19.10, 22.66, 32.06, 33.14, 48.98, 107.02, 109.88,
145.32.
It is remarkable that the reaction of 3f with NIS gives
exclusively the furan derivative 10f, while the reaction
of the same substrate with NBS results in the formation
of the ketone 7f together with a small amount of the
dioxepane 8f. Thus, a difference in nature (e.g., elec-
tronegativity and polarizability) between the halonium
ions, 4f (X ) I) and 4f (X ) Br), seems to play an
important role in determining the course of the reaction.
Thus, the harder, more electrophilic Br+ may promote
the methoxy migration via the kinetically favored 1,4-
shift. In this respect, NBS is well-known to be the reagent
of choice for the cyclofunctionalization reactions of un-
saturated acetals.10
1-Meth oxy-2-p h en ylcycloh exyl h yd r op er oxid e (3g): mp
88-90 °C (from ethyl acetate-hexane); 1H NMR δ 1.3-1.5 (m,
1 H), 1.5-1.6 (m, 1 H), 1.6-1.9 (m, 4 H), 1.9-2.1 (m, 1 H),
2.38 (dt, J ) 13.2 and 4.0 Hz, 1 H), 2.98 (dd, J ) 11.4 and 3.7
Hz, 1 H), 3.22 (s, 3 H), 7.2-7.4 (m, 5 H), 7.58 (s, 1 H); 13C
NMR δ 22.84, 25.12, 30.19, 31.02, 51.00, 51.12, 106.58, 126.51,
127.89, 129.54, 141.15. Anal. Calcd for C13H1803: C, 70.25; H,
8.16. Found: C, 70.07; H, 8.12. In the NOE measurement,
irradiation of the signal due to the methoxy group resulted in
the enhancement of the hydrogen at C-2 (δ 2.9-3.0, m) (2%)
and two hydrogens at C-6 (δ 1.5-1.6 (m) and 2.38 (dt)) (4.5%
to each). By the irradiation of the signal of the hydrogen at
C-2, an enhancement of the signal due to one of the hydrogens
at C-6 (δ 1.5-1.6 (m)) (4.0%) was induced. No NOE was
observed between the hydroperoxy group and the hydrogen
at C-2.
Con clu sion
By the appropriate choice of halogenating agent and
unsaturated hydroperoxide substrate 3, several new 1,2-
dioxanes or 1,2-dioxepanes could be synthesized. BCIH
seems to be the best reagent for the synthesis of these
peroxides, particularly 1,2-dioxepane because of the
absence of a reactive counteranion9a and the expected role
of collidine as a nonnucleophilic base. In the halocycliza-
tion reactions the unexpected migration of either a
methoxy or a hydroxy group was also found to compete
strongly, thereby providing the corresponding ketone or
furan derivatives. The variation in reaction outcome can
be rationalized from the results in terms of the difference
in (a) the structure of unsaturated hydroperoxide sub-
strates 3 and (b) the intrinsic nature of the halogenating
agents.
Rea ction of Hyd r op er oxid es 3b,e w ith N-Iod osu ccin -
im id e. Reaction of a hydroperoxide, 3b, with NIS is repre-
sentative. To a CH2Cl2 solution (25 mL) of 3b (110 mg, 0.69
mmol) were added NIS (320 mg, 1.4 mmol) and then NaHCO3
(56 mg, 0.67 mmol). The mixture was stirred at room temper-
ature for 15 h (the flask was covered by aluminum foil) and
then diluted with hexanes-ether (30 mL; 8:2). The precipitated
succinimide was removed by filtration and washed with
hexane (3 × 5 mL), and the combined filtrate and washings
were washed with aqueous Na2S2O3 and saturated brine and
dried (MgSO4). The organic layer was concentrated by a
rotatory evaporator to leave the oily residue, which was
subjected to column chromatography on silica gel. Elution with
ether-hexane (5:95) gave a dioxane, 5b (54 mg, 28%). Sub-
sequent elution with ether-hexane (15:85) gave a ketone, 6b
(64 mg, 34%).
3-Iodom eth yl-6-m eth oxy-3,6-dim eth yl-1,2-dioxan e (5b):
1
oil; H NMR δ 1.27 (s, 3 H), 1.28 (s, 3 H), 1.7-1.8 (m, 3 H),
Exp er im en ta l Section
1.9-2.1 (m, 1 H), 3.32 (s, 3 H), 3.50 (s, 2 H); 13C NMR δ 12.54,
19.73, 24.40, 27.60, 30.51, 49.06, 78.08, 101.87. Anal. Calcd
for C8H15IO3: C, 33.58; H, 5.28. Found: C, 33.69; H, 5.25.
6-Iodo-5-m eth oxy-5-m eth yl-2-h exan on e (6b): oil; 1H NMR
δ 1.27 (s, 3 H), 1.8-2.1 (m, 2 H), 2.18 (s, 3 H), 2.50 (t, J ) 7.9
Hz, 2 H), 3.17 (s, 3 H), 3.23 (d, J ) 10.9 Hz, 1 H), 3.30 (d, J )
10.9 Hz, 1 H); 13C NMR δ 15.06, 22.50, 30.01, 30.08, 37.89,
49.54, 73.82, 208.05. Anal. Calcd for C8H15IO2: C, 35.57; H,
5.60. Found: C, 35.58; H, 5.59.
Gen er a l P r oced u r es. 1H (270 MHz; 400 MHz for NOE
studies) and 13C (67.5 MHz) NMR spectra were obtained in
CDCl3 solution with SiMe4 as the standard. Unsaturated
ketones 1a ,b,d -f 13 and the derived dienes 2a ,b,d -f 14 were
prepared by the reported methods. The vinyl ether 2g was
prepared from 2-phenylcyclohexanone in a similar way. 2,5-
Diphenyl-1,5-hexadiene (1c) was synthesized from 1,2-diben-
zoylethane by the conventional Wittig reaction.15 BCIH was
prepared by the method of Simonot and Rousseau.16
Rea ction of Hyd r op er oxid es 3d ,f w ith N-Iod osu ccin -
im id e. Reaction of a hydroperoxide, 3d , with NIS is repre-
sentative. To a CH2Cl2 solution (25 mL) of 3d (310 mg, 1.5
mmol) were added NIS (633 mg, 2.9 mmol) and then NaHCO3
(122 mg, 1.5 mmol). The mixture was stirred at room temper-
ature for 15 h (the flask was covered by aluminum foil). After
workup as described above, the oily residue was subjected to
column chromatography on silica gel. Elution with ether-
hexane (5:95) gave a dioxepane, 5d (84 mg, 25%, a 7:3 mixture
of two isomers). Subsequent elution with diethyl ether-hexane
(10:90) gave a tetrahydrofuran derivative, 10d (132 mg, 35%,
a 9:2 mixture of two isomers). Treatment of 10d (100 mg) with
NIS (128 mg) for 15 h, followed by column chromatography
on silica gel, resulted in the recovery of 10d (95 mg).
5-Iod o-1-m eth oxy-4,4-d im eth yl-2,3-d ioxa bicyclo[5.4.0]-
u n d eca n e (5d ) (m a jor isom er ): mp 82-83 °C; 1H NMR δ
1.1-2.7 (m, 11 H), 1.28 (s, 3 H), 1.43 (s, 3 H), 3.17 (s, 3 H),
4.54 (dd, J ) 8.6 and 4.6 Hz, 1 H); 13C NMR δ 20.54 (CH2),
22.05 (CH3), 22.18 (CH2), 25.12 (CH3), 25.59 (CH2), 28.74 (CH2),
38.56 (CH2), 39.82 (CH), 44.31 (CH), 48.23 (CH3), 84.67 (C),
107.55 (C). Anal. Calcd for C12H21IO3: C, 42.37; H, 6.22; I,
37.30. Found: C, 42.69; H, 5.94; I, 37.34. The minor isomer
was obtained as an admixture with 70% of the major one (oil).
The following additional signals were assigned to this isomer:
1H NMR δ 1.50 (s, 3 H), 1.52 (s, 3 H), 3.23 (s, 3 H), 4.03 (dd,
J ) 12.1 and 6.3 Hz, 1 H); 13C NMR δ 21.31 (CH2), 22.30 (CH2),
Caution: Since organic peroxides are potentially hazardous
compounds, they must be handled with due care; avoid
exposure to strong heat or light, mechanical shock, oxidizable
organic materials, or transition metal ions. No particular
difficulties were experienced in handling any of the new
peroxides synthesized in this work using the reaction scales
and procedures described below together with the safeguard
mentioned above.
Mon oozon olysis of Dien es in MeOH-CH2Cl2. Ozonoly-
sis of a vinyl ether, 2b, is representative. Into a solution of 2b
(445 mg, 3.2 mmol) in CH2Cl2 (25 mL) and methanol (5 mL)
was passed a slow stream of ozone (1 equiv) at -70 °C. After
extraction with ether (70 mL), the organic layer was washed
with ice-cold sodium bicarbonate and saturated brine and dried
over anhydrous MgSO4. After evaporation of the solvent under
reduced pressure, the products were isolated by column chro-
matography on silica gel. Elution with diethyl ether-hexane
(1:9) gave the unsaturated hydroperoxide 3b (350 mg, 69%).
(13) Corey, E. J .; Enders, D. Chem. Ber. 1978, 111, 1337.
(14) Fukagawa, R.; Nojima, M. J . Chem. Soc., Perkin Trans. 1 1994,
2449.
(15) (a) Lutz, R. E. Love, L. J r.; Palmer, F. S. J . Am. Chem. Soc.
1935, 57, 1953. (b) Marvel, C. S.; Gall, E. J . J . Org. Chem. 1960, 25,
1784.
(16) Simonot, B.; Rousseau, G. J . Org. Chem. 1994, 59, 5912.

1074 J . Org. Chem., Vol. 65, No. 4, 2000
Tokuyasu et al.
24.93 (CH2), 26.65 (CH3), 27.48 (CH3), 30.55 (CH2), 40.58 (CH),
41.49 (CH2), 41.60 (CH), 48.38 (CH3), 84.96 (C), 107.01 (C).
Meth yl 5-[2-(4-iod o-5,5-d im eth yltetr a h yd r ofu r a n yl)]-
10.9 Hz, 1 H), 3.75 (d, J ) 10.9 Hz, 1 H), 7.2-7.8 (m, 8 H),
7.85 (m, 2 H); 13C NMR δ 14.88, 30.39, 33.25, 50.08, 78.53,
126.22, 127.98, 128.34, 128.50, 133.06, 141.26, 199.25; MS m/z
(rel intens) 261 (M+ - CH2CH2COPh) (100), 253 (M+ - CH2I)
(87), 105 [M+ - CH2CH2C(CH2I)(OMe)Ph] (74). Anal. Calcd
for C18H19IO2: C, 54.84; H, 4.86. Found: C, 54.65; H, 4.64.
Rea ction of th e Hyd r op er oxid e 3a ,d ,f w ith BCIH. The
reaction of 3f is representative. To a CH2Cl2 solution (25 mL)
of the hydroperoxide 3f (310 mg, 1.4 mmol) were added BCIH
(1.5 g, 2.9 mmol) and NaHCO3 (130 mg, 1.5 mmol), and then
the mixture was stirred at room temperature for 15 h (the flask
was covered by aluminum foil). After the workup as described
above, the components of the crude product mixture were
separated by column chromatography on silica gel. Elution
with diethyl ether-hexane (4:96) gave a dioxepane, 5f (210
mg, 43%, a 3:2 mixture of two isomers).
4-Iod om et h yl-1-m et h oxy-4-m et h yl-2,3-d ioxa b icylco-
[5.4.0]u n d eca n e (5f): oil; 1H NMR δ 1.1-2.3 (m, 13 H), 1.28
(s, major) + 1.43 (s) (3 H), 3.17 (s, major) + 3.18 (s, major) +
3.43 (d, J ) 10.2 Hz) + 3.59 (d, J ) 10.2 Hz) (2 H), 3.29 (s) +
3.30 (s, major) (3 H); 13C NMR δ 13.50 (CH2), 13.80 (CH2), 21.03
(CH2), 22.28 (CH2), 22.41 (CH2), 22.59 (CH3), 24.89 (CH2), 24.93
(CH2), 26.15 (CH3), 26.60 (CH2), 26.90 (CH2), 30.12 (CH2), 30.53
(CH2), 36.95 (CH2), 38.82 (CH2), 41.69 (CH), 48.20 (CH3), 48.47
(CH3), 81.80 (C), 82.66 (C), 107.55 (C), 108.00 (C). Anal. Calcd
for C12H21IO3: C, 42.37; H, 6.22. Found: C, 42.00; H, 6.31.
P r otection of th e Hyd r op er oxid es 3 by ter t-Bu tyld i-
m eth ylsilyl Gr ou p . The synthesis of 11a is representative.17
To a CH2Cl2 solution (35 mL) of TBDMSCl (460 mg, 3.0 mmol)
and the hydroperoxide 3a (300 mg, 1.5 mmol) was added a
CH2Cl2 solution (15 mL) of imidazole (210 mg, 3.1 mmol) at 0
°C, and the mixture was stirred at room temperature for 15
h. After removal of the precipitate by filtration, the organic
layer was washed with aqueous NH4Cl followed by saturated
brine and dried over anhydrous MgSO4. After evaporation of
the solvent, the residue was subjected to column chromatog-
raphy on silica gel. Elution with ether-hexane (2:98) gave the
peroxide 11a (300 mg, 64%).
1
va ler a te (10d ): oil (a 9:2 mixture of two isomers); H NMR
(major isomer) δ 1.3-1.8 (m, 6 H), 1.32 (s, 3 H), 1.39 (s, 3 H),
2.0-2.2 (m, 1 H), 2.32 (t, J ) 7.4 Hz, 2 H), 2.58 (dt, J ) 12.6
and 6.3 Hz, 1 H), 3.67 (s, 3 H), 3.8-3.9 (m, 1 H), 4.01 (dd, J )
11.2 and 6.6 Hz, 1 H); 13C NMR (major isomer) δ 24.78 (CH2),
25.43 (CH2), 25.72 (CH3), 29.17 (CH3), 30.50 (CH), 33.84 (CH2),
36.61 (CH2), 43.74 (CH2), 51.43 (CH3), 77.72 (CH), 81.80 (C),
1
173.96 (C); H NMR (minor isomer) δ 1.33 (s, 3 H), 1.36 (s, 3
H), 2.32 (t, J ) 7.4 Hz, 2 H), 3.67 (s, 3 H); 13C NMR (minor
isomer) (only the characteristic signals are shown) δ 24.15
(CH2), 25.05 (CH2), 25.88 (CH3), 25.99 (CH3), 31.11 (CH), 36.07
(CH2), 42.91 (CH2), 51.45 (CH3), 74.74 (CH), 82.52 (C); MS (EI)
m/z (rel intens) 225 [M+ - (CH2)4CO2Me] (89), 213 (M+ - I)
(83), 74 (25); HRMS [(M + H)+] m/z calcd for C12H22IO3
314.0614, found 314.0615.
Rea ction of Hyd r op er oxid es 3a w ith N-Iod osu ccin -
im id e in th e P r esen ce of CD3OD. To a CH2Cl2 solution (25
mL) of 3a (250 mg, 1.2 mmol) and CD3OD (70 µL) were added
NIS (566 mg, 2.5 mmol) and then NaHCO3 (110 mg, 1.3 mmol).
The mixture was stirred at room temperature for 15 h. After
the workup as described above, the residue was separated by
column chromatography on silica gel. Elution with ether-
hexane (5:95) gave a dioxane, 5a (32 mg, 8%). Further elution
with ether-hexane (10:90) gave a ketone, 6a (80 mg, 20%).
4-Iod om eth yl-1-m eth oxy-4-h yd r oxy-1,2-d ioxa bicyclo-
[4.4.0]d eca n e (5a ): oil; 1H NMR δ 1.2-2.1 (m, 10 H), 2.1-
2.2 (m, 1 H), 1.31 (s, 3 H), 3.32 (s, 3 H), 3.41 (d, J ) 9.7 Hz, 1
H), 3.44 (d, J ) 9.7 Hz, 1 H); 13C NMR δ 15.46, 21.37, 21.66,
22.07, 25.20, 27.03, 34.54, 36.07, 48.90, 81.21, 106.07. Anal.
Calcd for C11H19IO3: C, 40.51; H, 5.87. Found: C, 40.88; H,
5.79. Irradiation of the methoxy group (δ 3.32) resulted in the
enhancement of the signals due to the iodomethyl group (δ
3.44) (the exact extent of the enhancement was not deter-
mined, because two signals resonated at very near positions)
and the bridgehead hydrogen at C-6 (δ 2.1-2.2) (1.0%). No
enhancement of the methyl signal (δ 1.31) was observed. Also,
a small enhancement of the signal of H-6 was observed by the
irradiation of the iodomethyl hydrogen at δ 3.44 (1%). In the
reaction with BCIP, 5a was obtained as a 3:2 mixture of two
isomers. The following additional signals were assigned to the
minor isomer: 1H NMR δ 1.41 (s, 3 H), 3.34 (s, 3 H); 13C NMR
δ 11.61, 20.38, 22.18, 24.87, 25.84, 26.96, 33.93, 34.77, 49.22,
79.44, 105.19.
1-Meth oxy-2-(2-m eth yl-2-p r op en yl)cycloh exyl ter t-bu -
1
tyld im eth ylsilyl p er oxid e (11a ): oil; H NMR δ 0.18 (s, 6
H), 0.96 (s, 9 H), 1.2-1.7 (m, 8 H), 1.69 (s, 3 H), 2.0-2.4 (m,
3 H), 3.31 (s, 3 H), 4.67 (s, 1 H), 4.74 (s, 1 H); 13C NMR δ -5.75,
-5.68, 18.31, 20.42, 21.75, 22.43, 24.60, 26.00, 26.18 (3C),
35.40, 37.50, 48.45, 106.65, 111.64, 144.58. Anal. Calcd for
C
17H34O3Si: C, 64.92; H, 10.90. Found: C, 65.20; H, 10.72.
Rea ction of th e P er oxid e 11a w ith NIS. To a CH2Cl2
2-(3-Iod o-2-m et h oxy-2-m et h ylp r op yl)cycloh exa n on e
(6a ): oil; 1H NMR δ 1.2-2.6 (m, 11 H), 1.25 (s, 3 H), 3.11 (s, 3
H), 3.20 (s, 1 H), 3.21 (s, 1 H); 13C NMR δ 16.66, 23.74, 25.02,
28.23, 34.54, 36.48, 41.89, 46.44, 49.62, 74.29, 212.25. Anal.
Calcd for C11H19IO2: C, 42.60; H, 6.17. Found: C, 42.71; H,
5.95.
solution (25 mL) of 12a (290 mg, 0.91 mmol) were added NIS
(420 mg, 1.9 mmol) and then NaHCO3 (80 mg, 0.95 mmol).
The mixture was stirred at room temperature for 15 h (the
flask was covered by aluminum foil) and then diluted with
hexane (30 mL). After the conventional workup, the residue
was subjected to column chromatography on silica gel. Elution
with ether-hexane (10:90) gave a ketone, 6a (180 mg, 64%, a
3:1 mixture of two isomers).
Rea ction of Hyd r op er oxid es 3a -f w ith N-Br om osu c-
cin im id e. Reaction of a hydroperoxide, 3d , is representative.
To a CH2Cl2 solution (25 mL) of 3d (310 mg, 1.4 mmol) were
added NBS (510 mg, 2.9 mmol) and then NaHCO3 (130 mg,
1.5 mmol). The mixture was stirred at room temperature for
15 h (the flask was covered by aluminum foil). After conven-
tional workup, the oily residue was subjected to column
chromatography on silica gel. Elution with ether-hexane (3:
97) gave a dioxepane, 8d (95 mg, 23%, a 3:1 mixture of two
isomers), which on recrystallization from ethyl acetate-hexane
afforded the major isomer. Subsequent elution with ether-
hexane (8:92) gave a ketone, 7d (66 mg, 17%), which was
contaminated by inseparable impurities (ca. 10%).
Rea ction of th e Hyd r op er oxid e 3c w ith I2-KOBu t. To
a THF solution (25 mL) of the hydroperoxide 3c (230 mg, 0.80
mmol) and KOBut (92 mg, 0.82 mmol) was added I2 (610 mg,
2.4 mmol) over 5 min at 0 °C, and then the mixture was stirred
at room temperature for 13 h (the flask was covered by
aluminum foil). Ether (70 mL) was added, and the organic
layer was separated, washed with aqueous Na2S2O3 followed
by saturated brine, and dried over anhydrous MgSO4. After
evaporation of the solvent under reduced pressure, the residue
was subjected to column chromatography on silica gel. Elution
with diethyl ether-hexane (3:97) gave a dioxane, 5c (101 mg,
30%). Subsequent elution with diethyl ether-hexane (5:95)
gave a ketone, 6c (87 mg, 27%).
3-Iod om eth yl-6-m eth oxy-3,6-d ip h en yl-1,2-d ioxa n e (5c):
mp 141-142 °C (from ether-hexane); 1H NMR δ 1.9-2.2 (m,
2 H), 2.2-2.4 (m, 1 H), 2.4-2.6 (m, 1H), 3.22 (s, 3 H), 3.96 (s,
2 H), 7.3-7.5 (m, 10 H); 13C NMR δ 12.10, 27.44, 32.13, 50.53,
81.06, 102.95, 125.36, 125.59, 128.32, 128.50, 128.61, 139.26,
141.06. Anal. Calcd for C18H19IO3: C, 52.70; H, 4.67; I, 30.93.
Found: C, 52.66; H, 4.56; I, 30.69.
5-Br om o-1-m eth oxy-4,4-dim eth yl-2,3-dioxabicyclo[5.4.0]-
u n d eca n e (8d ) (m a jor isom er ): mp 96-97 °C (from hex-
1
anes-ethyl acetate); H NMR δ 1.2-2.5 (m, 11 H), 1.34 (s, 3
H), 1.51 (s, 3 H), 3.28 (s, 3 H), 3.95 (dd, J ) 12.0 and 3.5 Hz,
5-Iod o-4-m eth oxy-1,4-d ip h en yl-1-p en ta n on e (6c): mp
1
82-83 °C (from ether-hexane); H NMR δ 2.2-2.4 (m, 1 H),
(17) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
2.4-2.8 (m, 2 H), 2.8-3.0 (m, 1 H), 3.25 (s, 3 H), 3.60 (d, J )

Halonium Ion-Mediated Reaction of Hydroperoxy Acetals
J . Org. Chem., Vol. 65, No. 4, 2000 1075
1 H); 13C NMR δ 19.86 (CH3), 21.31 (CH2), 22.25 (CH2), 24.89
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research on Priority
Areas (11147216 and 11140244) from the Ministry of
Education, Science, Culture and Sports of J apan. We
thank the British Council (Tokyo) for the award of a
travel grant to A.M., M.N., and K.J .M.
(CH2), 25.10 (CH3), 30.71 (CH2), 38.96 (CH2), 42.17 (CH), 48.39
(CH3), 59.77 (CH), 84.89 (C), 106.95 (C). Anal. Calcd for C12H21
-
BrO3: C, 49.16; H, 7.22. Found: C, 48.98; H, 7.17. The minor
isomer was obtained in an admixture with 67% of the major
one (oil). The following additional signals were assigned to this
isomer: 1H NMR 1.32 (s, 3 H), 1.50 (s, 3 H), 3.39 (s, 3 H), 4.41
(dd, J ) 7.3 and 4.0 Hz, 1 H); 13C NMR δ 20.77 (CH2), 25.03
(CH3), 25.10 (CH3), 25.34 (CH2), 26.00 (CH3), 29.34 (CH2), 36.37
(CH2), 37.45 (CH), 38.60 (CH2), 48.32 (CH3), 60.66 (CH), 84.69
(C), 107.62 (C).
2-(2-Br om o-3-m eth oxy-3-m eth ylbu tyl)cycloh exa n on e
(7d ): oil (ca. 90% purity); 1H NMR δ 1.2-2.2 (m, 7 H), 1.34 (s,
6 H), 2.2-2.4 (m, 3 H), 2.7-2.8 (m, 1 H), 3.29 (s, 3 H), 4.32
(dd, J ) 11.9 and 1.7 Hz, 1 H); 13C NMR δ 22.50 (CH3), 23.36
(CH3), 25.44 (CH2), 28.37 (CH2), 34.39 (CH2), 35.72 (CH2), 42.57
(CH2), 49.18 (CH), 49.52 (CH3), 63.27 (CH), 76.66 (C), 213.15
(C).
Su p p or tin g In for m a tion Ava ila ble: Preparation meth-
ods and the physical properties of dienes 2a -f, hydroperoxides
3a ,c-f, products 5e, 6e, 7a -c,e,f, and 8a -c,e,f, and a
TBDMS-protected peroxide, 12d , and crystal data, atomic
coordinates, bond lengths and angles, and displacement
parameters for 5c and 8d . This material is available free of
charge via the Internet at http//pubs.acs.org.
J O991499M