Evaluation of exo-endo ratios in the halolactonization of ω-unsaturated acids

Article abstract of DOI:10.1021/jo0017234

The reaction of 2-(ω-alkenyl)benzoic acids with bis(collidine)iodine and bis(collidine)bromine hexafluorophosphate was examined. Except with 2-but-3-enylbenzoic acid, for which only the exo lactone was obtained, for the other acids a mixture of exo-endo lactones was always obtained. The proportion of endo lactone was important for the acid chain length of 11 carbons (formation of a 12-membered ring endo lactone) and for the acid chain lengths higher than 14 carbons. The formation of the endo lactones was explained, on the base of molecular calculations, by competition between electronic and steric effects. These latter were developed by transannular interactions (for the acid chain lengths 8-11) and/or the conformations adopted by the chains (for the acid chain lengths ≥ 14,) which disfavored the formation of the exo lactones. The larger proportion of endo lactones observed with the bromo reagent compared to the iodo reagent seemed due to electronic factors.

Full text of DOI:10.1021/jo0017234

4304
J . Org. Chem. 2001, 66, 4304-4310
Eva lu a tion of exo-en d o Ra tios in th e Ha lola cton iza tion of
ω-Un sa tu r a ted Acid s
Marie-Claude Roux, Rene´e Paugam, and Ge´rard Rousseau*
Laboratoire des Carbocycles (Associe´ au CNRS), Institut de Chimie Mole´culaire d’Orsay, Baˆt. 420,
Universite´ de Paris-Sud, 91405 Orsay, France
grousseau@icmo.u-psud.fr
Received December 11, 2000
The reaction of 2-(ω-alkenyl)benzoic acids with bis(collidine)iodine and bis(collidine)bromine hexa-
fluorophosphate was examined. Except with 2-but-3-enylbenzoic acid, for which only the exo lactone
was obtained, for the other acids a mixture of exo-endo lactones was always obtained. The proportion
of endo lactone was important for the acid chain length of 11 carbons (formation of a 12-membered
ring endo lactone) and for the acid chain lengths higher than 14 carbons. The formation of the
endo lactones was explained, on the base of molecular calculations, by competition between electronic
and steric effects. These latter were developed by transannular interactions (for the acid chain
lengths 8-11) and/or the conformations adopted by the chains (for the acid chain lengths g 14,)
which disfavored the formation of the exo lactones. The larger proportion of endo lactones observed
with the bromo reagent compared to the iodo reagent seemed due to electronic factors.
Sch em e 1
In tr od u ction
We have previously reported that bis(collidine)iodine(I)
hexafluorophosphate was an excellent electrophile for the
preparation of medium ring lactones.1 We found that
structural modifications of the carbon chain were neces-
sary in order to form these lactones in acceptable yields.
The influence of an oxygen atom,1a gem-dialkyl,1b and
conformational constraints upon the lactonization reac-
tion were previously studied.1c In general, we observed
a competition between the exo mode and the endo mode
of cyclization for the formation of medium sized lactone
rings. This event occurred even in the absence of sub-
stituents on the terminal carbon of the double bond
(Scheme 1). Similar observations were reported in the
case of selenium reagents.2
Sch em e 2a
Electrophilic cyclization of acids leading to four- to six-
membered lactone rings, where the terminal carbon of
the double bond is unsubstituted, was observed to
proceed exclusively by an exo process.3 These results are
in agreement with Baldwin’s rules,4 which state that 3-7
exo-trig cyclizations are favored. Our previous results1
indicate that longer acid carbon chains favor the forma-
tion of lactones by the endo cyclization mode. We won-
dered if the observed trend would hold true for the
formation of macrolactones. We therefore investigated the
halolactonization of ω-unsaturated acids. The results
obtained for the macrolactone formation are compared
those we previously obtained as there are very few
similar literature examples.
a
(a) HC(OMe)3MeOH, cat. TsOH; (b) O3, CH2Cl2; (c) Ph3PdCH2;
(d) OH-, then H3O+; ( e) 2 LDA, THF/heptane; (f) Br(CH2)nCHdCH2.
Resu lts
For this study, 2-substituted benzoic acids were used
as they were expected to give good lactone yields for all
ring sizes investigated. The formation of 7- to 20-
membered lactone rings were consequently synthesized,
using bis(collidine)iodine and bis(collidine)bromine hexaflu-
orophosphate as reagents. 2-(But-3-enyl)benzoic acid 1a 5
was obtained from 1-tetralone. The alkenylbenzoic acids
1b-k were prepared by alkylation of the dianion of
2-methylbenzoic acid with unsaturated bromides (Scheme
2).
* Fax: (33) 1.69.15.62.78.
(1) (a) Simonot, B.; Rousseau G. J . Org. Chem. 1994, 59, 5912. (b)
Simonot, b.; Rousseau G. Tetrahedron Lett. 1993, 34, 4527. (c) Homsi,
F.; Rousseau, G. J . Org. Chem. 1998, 63, 5255. (d) For a review see:
Homsi, F.; Rousseau, G. Chem. Soc. Rev. 1997, 26, 453.
(2) (a) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S.
P. J . Am. Chem. Soc. 1979, 101, 3704. (b) Miyachi, N.; Satoh, H.;
Shibasaki, M. J . Chem. Soc., Perkin Trans. 1 1991, 2049.
(3) (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 171. (b)
Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: New York, 1991; Vol. 4, p 363.
(4) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
These alkylations were efficient when the dianion was
prepared by reaction of lithium diisopropylamide in
tetrahydrofuran at -30 °C in the presence of 20%
(5) Scholz, D. Liebigs Ann. Chem. 1984, 264-272.
10.1021/jo0017234 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

Halolactonization of ω-Unsaturated Acids
J . Org. Chem., Vol. 66, No. 12, 2001 4305
Sch em e 3
Ta ble 1. Ha lola cton iza tion of Acid s 1a -k
ring
iodo lactones
bromo lactones
overall yield exo:endo
(%) ratio
2a Br :2′a Br (95) 100:0
size of
exo-endo overall yield exo:endo
acid lactones (%) ratio
1a
1b
1c
1d
1e
1f
1g
1h
1i
7:8
8:9
2a I:2′a I (93) 100:0
2bI:2′bI (80) 98:2
2bBr :2′bBr (78)
80:20
66:34
52:48
47:53
64:36
72:28
75:25
70:30
66:34
50:50
9:10 2cI:2′cI (84)
10:11 2d I:2′d I (52)
11:12 2eI:2′eI (46)
12:13 2fI:2′fI (48)
13:14 2gI:2′gI (55)
14:15 2h I:2′h I (62)
15:16 2iI:2′iI (55)
16:17 2jI:2′jI (46)
19:20 2k I:2′k I (53)
69:31 2cBr :2′cBr (50)
60:40 2d Br :2′d Br (40)
53:47 2eBr :2′eBr (35)
82:18 2fBr :2′fBr (35)
84:16 2gBr :2′gBr (40)
85:15 2h Br :2′h Br (40)
81:19 2iBr :2′iBr (45)
76:24 2jBr :2′jBr (30)
67:33 2k Br :2′k Br (35)
1j
1k
F igu r e 1. Endo lactone 2′X ratio as a function of the number
of acid carbons.
heptane.6 In the absence of this cosolvent, lower yields
were observed. The subsequent halolactonizations were
carried out by slow addition (12 h) of the acids 1a -k to
a methylene chloride solution of bis(collidine)iodine or
bis(collidine)bromine hexafluorophosphate. The products
were separated by column chromatography on silica gel
after the reactions were judged completed. The structures
of the exo lactones 2a -k X and endo lactones 2′b-k X
Sch em e 4. Resu lts fr om MNDO Ca lcu la tion s of
Ha lon iu m In ter m ed ia tes F or m ed fr om 1-Bu ten e
1
(Scheme 3) were determined by H NMR and 13C NMR,
with the results reported in Table 1.
The halolactonizations of acid 1a led only to exo
lactones 2a X. Similar results have been previously
reported with 6-heptenoic acids.1a This is also the case
for the iodolactonization of 2-allyl and 2-vinylbenzoic
acids, which were found to lead to six- and five-membered
ring lactones, respectively.7 When the length of the acid’s
unsaturated chain of 1 was increased, we observed a
mixture of exo lactones 2 and endo lactones 2′ formed.
The maximum ratio of endo to exo lactonization was
observed with acid 1e and then decreased to a minimum
for acid 1h . With further chain elongation, the ratio was
observed to increased once again. The evolution of endo
lactones as a function of acid chain length 1 is reported
in Figure 1.
bridges formed as intermediates with 1-butene support
this assumption. These calculations were done with
MNDO semiempirical method on the proposed naked
halonium intermediate and the halonium intermediate
on which one molecule of collidine was fixed. The forma-
tion of the collidine-halonium intermediate has been
recently established8 when this kind of reagent is used
in halocyclizations. The results obtained from the semiem-
pirical calculations are reported in Scheme 4.
These calculations illustrate the influence of collidine
on the intermediate formed during the lactonization
reaction. Scheme 4 shows quite clearly that the partici-
pation of collidine led to less asymmetric halonium
intermediates. In all cases, carbon 2 bears a greater
positive charge relative to carbon 1. The results obtained
from the calculations are in agreement with those previ-
ously reported for haloniums formed from propene.9 They
Discu ssion
Considering only electronic factors, the regio addition
of an electrophile on a unsymmetrically substituted
carbon-carbon double bond should always give the
Markovnikov product. For halolactonizations, the exclu-
sive formation of exo-mode cyclization lactones should be
observed and is the case for butyro- and valerolactones
halolactonization.3 Endo-mode cyclization products are
obtained only if the carbon-carbon double bond is
terminally substituted by a carbocation stabilizing group,
i.e., an aryl group.3 Calculations of charge distributions
on the two carbons in the bromonium and the iodonium
(6) Creger, P. L. J . Am. Chem. Soc. 1970, 72, 1396-1397.
(7) (a) Reich, S. H.; Melnick, M.; Pino, M. J .; Fuhry, M. A. M.; Trippe,
A. J .; Appelt, K.; Davies, J . F., II; Wu, B.-V.; Musick, L. J . Med. Chem.
1996, 39, 2781. (b) Grunewald, G. L.; Dahanukar, V. H. J . Heterocycl.
Chem. 1994, 31, 1609.
(8) Cui, X.-L.; Brown, R. S. J . Org. Chem. 2000, 65, 5653
(9) (a) Galland, B.; Evleth, E. M.; Ruasse, M.-F. J . Chem. Soc., Chem.
Commun. 1990, 898. (b) Brown, R. S.; Nagorski, R. W.; Bennett, A. J .;
McClung, R. E. D.; Aarts, G. H. M.; Klobukowski, M.; McDonald, R.;
Santarsierso, B. D. J . Am. Chem. Soc. 1994, 116, 2448.

4306 J . Org. Chem., Vol. 66, No. 12, 2001
Roux et al.
Ta ble 2. Ca lcu la ted Rela tive En er gies of exo a n d en d o Tr a n sition Sta tes a n d La cton es
relative transition state stabilitya
entry acid
naked bromonium
collidinobromonium
relative lactone stabilitya
lactone ring size exptl exo:endo ratio
a
b
c
d
e
f
1a
1a
1e
1e
1h
1h
1k
1k
exo
endo
exo
endo
exo
endo
exo
0
10.7
0
0.9
0
1.5
0
0.1
0
5.4
0
0.7
0
1.7
0
0
7
8
100
0
7.2
3.4
0
3.0
0
11
12
14
15
19
20
47
53
75
25
50
50
g
h
5.8
0
endo
0
a
∆(∆ Hf) in kcal mol-1
.
Sch em e 5
dihedral angle O1C6+nC7+nBr (or O1C7+nC6+nBr) at 180°.
This value takes into account the antiperiplanar position
of the carboxylate function and the bromine atom en-
countered in the transition state. The second constraint
concerned the O1‚‚‚C6+n (or O1‚‚‚C7+n) distance. A distance
of 2.2 Å was selected as it represents the transition state
distance. To confirm our model, Hessian calculations (in
the case of 1a ) were carried out after fully location of the
transition structures by MNDO method for the exo and
endo approaches. Although this type of calculations is
assumed to have better correlation for ground-state
structures than for transition states, the results showed
that our model corresponded well to a transition struc-
ture, i.e., a first-order saddle point with the Hessian
having only one negative eigenvalue. All the transition
states were subsequently minimized with the MNDO
method using only the second constraint. The relative
stabilities of the exo and endo lactones 2 and 2′ were also
examined by molecular dynamic simulations with mo-
lecular mechanic calculations (MM2 force field type) and
minimization by MNDO method. Our results are reported
in Table 2. Calculations of the relative transition state
stabilities did not agree with our experimental results
when the acid functions, instead of the carboxylates, were
investigated. This suggest that the reaction process can
involve a deprotonated intermediate.
An energy difference of 7.2 Kcal mol-1 between the exo
and endo lactones from 1a (Table 2, entries a and b)
would exclusively form the exo lactone, which also agrees
well with our experimental data. However, this does not
hold true for the other acids. The endo lactones appear
to be more stable. If cyclization occurred under thermo-
dynamic control, endo products should exclusively be
formed. However, this is not the case. In fact, we have
previously reported that halolactonizations occur under
kinetic control with bis(collidine)iodine hexafluorophos-
phate.1 So, the relative stability of the endo and exo
lactones cannot be used as criteria for predicting the endo
and exo product ratios. The calculations provide evidence
that the halolactonizations occur under kinetic control.
The relative stability of the calculated exo and endo
transition states correlates well with our experimental
results. The results are consistent regardless of the
intermediate used in calculating the transition state. This
is due in fact to the large distance (3.70-4.10 Å) between
the halogen and the collidine nitrogen atom in the
complexed transition states. With acid 1e (Table 2,
entries c and d) and acid 1k (entries g and h) a small
difference between the energy of the two transition states
was found and are in agreement with our experimental
data. A larger difference was observed in the case of acid
1h (entries e and f). For acid 1k , the steric constraints
developed in the exo approach are due to “curling” of the
also imply endo-mode lactone cyclization should a priori
be disfavored. However, since this is not the case ob-
served with increasing acid chain length, a steric factor
must be present and therefore considered. For intermedi-
ate sized rings, transannular interactions (H/H repul-
sions for CH2 groups across the ring) exist and are
minimized principally at the expense of distorting rota-
tional angles. The observed increase in endo lactone ratio
with chain length ring sizes 8-11 implies steric hin-
drance induced by an endo approach is lower than those
in an exo approach. Therefore, these transannular inter-
actions supersede the electronic factor. However, for
larger rings the transannular interactions are assumed
to decrease to the point where they eventually become
insignificant relative to other effects.10 The decrease in
the endo lactone ratio for chain length 12-14 (Figure 1)
can be justified by this decrease. The increase of endo
lactone ratio observed for chain lengths greater than 14
is more surprising and seems to be due to the formation
of other steric interactions. These interactions disfavor
again the exo approaches in the halonium stabilized
intermediates.
Further computational studies were undertaken to
validate our hypothesis for the different endo and exo
ratios observed. Calculations were carried out on the
bromine compounds. The relative stabilities of the exo
versus the endo transition states were first examined
(Scheme 5). We hypothesize that the carboxylates and
not the acid functions participate in the transition state.
The appropriate chain conformations were determined
by molecular dynamic simulations with molecular me-
chanic calculations (MM2 force field type) including two
constraints. One involved locking the exo (or endo)
(10) (a) Winnick, M. A. Chem. Rev. 1981, 81, 491. (b) Illuminati,
G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.

Halolactonization of ω-Unsaturated Acids
J . Org. Chem., Vol. 66, No. 12, 2001 4307
sodium, and dichloromethane from calcium hydride. Reactions
were generally carry out under argon and in the dark for the
iodolactonizations. 4-Bromo-but-1-ene, 5-bromo-pent-1-ene,
6-bromo-hex-1-ene and 7-bromo-hept-1-ene were prepared
according to ref 12.
Sch em e 6. Con for m a tion of th e Br om on iu m s
Der iva ted fr om Acid 1k in th e exo a n d en d o
Tr a n sition Sta tes
Com p u ta tion a l An a lysis. Molecular dynamic simulations
using molecular mechanic calculations and structure minimi-
zation using MNDO method were carried out with Hyperchem
5.1 system.
8-Br om ooct-1-en e.13 1,8-Dibromooctane (0.1 mol, 27.2 g)
was added dropwise (4 h) to a solution of KOtBu (0.13 mol,
14.56 g) in THF at reflux. After cooling the solvent was
removed under vacuum, and water (50 mL) was added to the
residue. The aqueous phase was extracted with ether (3 × 50
mL). The organic phase was dried and concentrated under
vacuum. The crude bromide was purified by distillation under
vacuum: yield 9.6 g (50%); bp 92 °C/24 mmHg. 9-Bromonon-
1-ene14 and 12-bromododec-1-ene15 were prepared following the
same procedure (55% yields).
10-Br om od ec-1-en e.16 This compound was obtained in two
steps from commercially available 9-decen-1-ol by reaction of
its mesylate with LiBr in N-methylpyrrolidinone17 (overall
yield: 56%). 11-Bromo-undec-1-ene18 was obtained in the same
way (75%) from 10-undecen-1-ol. 15-Bromo-pentadec-1-ene19
was prepared in three steps from tert-butyl 14-pentadecenoate
by LiAlH4 reduction in THF (99% yield) followed by
transformation of the alcohol in bromide using the above
procedure (80%).
2-Bu t-3-en ylben zoic a cid 1a .5 This acid was obtained in
two steps from methyl 2-(3-oxopropyl)benzoate21 by Wittig
reaction (methyltriphenylphosphonium bromide, nBuLi in
ether (46%)) followed by saponification of the ester function
(KOH/MeOH, 90%).
cycle, which offsets the Markovnikov electronic effect
(Scheme 6). Such an effect was not observed in other
cases. These new steric interactions occur with large
rings as the Z conformation of the lactone function is
more stable than the E conformation.11 Consequently,
this imposes a less favorable conformation on the carbon
chain in the exo approach.
During these cyclizations, the proportion of endo lac-
tone was always higher with the bromo reagent than with
the iodo reagent (Figure 1). The electronic factor explains
these results (Scheme 4) where the difference in charges
calculated on carbons 1 and 2 are greater in the case of
the iodonium than in the case of the bromonium.
20
Gen er a l P r oced u r e for th e P r ep a r a tion of Acid s 1b-
1k . A dry three-necked flask equipped with a magnetical
stirrer, a thermometer and a rubber septum was charged with
dry THF (42 mL). The flask was cooled to -50 °C and 1.6 M
n-butyllithium in hexane (42 mL, 0.052 mol) was added,
followed by diisopropylamine (7.3 mL, 0.052 mol). After 30 min
at -50 °C, the mixture was warmed to -30 °C and a solution
containing o-toluic acid (2.79 g, 0.0205 mol), THF (20 mL) and
dry heptane (20 mL) was added in 2 h. To the deep red reaction
mixture was added the bromoalkene (0.029 mol) diluted in
THF (15 mL). After 2 h at -30 °C, water was added (100 mL),
and the organic phase was extracted twice with water (50 mL).
The aqueous phase was acidified (pH 2) with 2 N HCl and
then extracted with ether (3 × 150 mL). The combinated
Con clu sion
We report that the endo:exo ratio observed during the
electrophilic cyclization of ω-unsaturated acids depends
of the size of the lactones formed. For the first time, we
report the different factors responsible for control of the
cyclization of unsaturated acids leading to medium and
large lactone rings. A maximum of endo lactone was
observed for ring sizes comprising 10 and 11 members.
The proportion of endo lactone appears also to depend of
the nature of the electrophile used for the cyclization. The
unique formation of exo lactones in small rings (e7) is
mainly controlled by electronic factors (Markovnikov
effect) and the fact that steric hindrance disfavors endo
approaches. The formation of endo lactones for ring sizes
8-13 seems to involve transannular interactions, and
these are more important in the exo than in the endo
approaches. Exo lactone formation appears again disfa-
vored for large ring sizes (g14). Steric interactions that
disfavor the exo approaches are a result of conformations
adopted by the carbon chains. At least, we can notice a
reasonably good description of these halolactonizations
was obtained using an unsophisticated computional
model.
organic phases were dried (MgSO
4) and concentrated under
vacuum. The different acids were used for the halolactoniza-
tions without further purification.
2-P en t-4-en ylben zoic Acid 1b.1c 48%; 1H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 6.6 Hz, 1H), 7.10-7.40 (m, 1H),
7.40-7.20 (m, 2H), 6.00-5.80 (m, 1H), 5.10-4.90 (m, 2H), 3.05
(t, J ) 8.3 Hz, 2H), 2.20-2.10 (m, 2H), 1.80-1.60 (m, 2H).
Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.85;
H, 7.50.
2-Hex-5-en ylben zoic Acid 1c.1c 80%; 1H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.60-7.40 (m, 1H),
7.40-7.20 (m, 2H), 6.00-5.70 (m, 1H), 5.20-4.80 (m, 2H), 3.05
(12) Kraus, G. A.; Landgrebe, K. Synthesis 1984, 885.
(13) Rich, D. H.; Gardner, J . H. Tetrahedron Lett. 1983, 24, 5305.
(14) Gaubert, P.; Linstead, R. P.; Rydon, H. N. J . Chem. Soc. 1937,
1974.
(15) Cort, A. D.; Mandolini, L.; Masci, B. J . Org. Chem. 1983, 48,
3979.
(16) Hunnicutt, M. L.; Harris, J . M.; Lochmu¨ller, C. H. J . Phys.
Chem. 1985, 89, 5246.
(17) Ollivier, J .; Dorizon, P.; Piras, P.; De Meijere, A.; Salau¨n, J .
Inorg. Chim. Acta 1994, 222, 37.
(18) Tomecko, C. G.; Adams, R. J . Am. Chem. Soc. 1927, 49, 522.
(19) Christoffers, J .; Oertling, H. Tetrahedron 2000, 56, 1339.
(20) Hostetler, E. D.; Fallis, S.; McCarthy, T. J .; Welch, M. J .;
Katzenellenbogen, J . A. J . Org. Chem. 1998, 63, 1348.
(21) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1992, 57, 1429.
Exp er im en ta l Section
Gen er a l. Proton and 13C NMR spectra were recorded on a
250 MHz apparatus. Solvents were dried and purified prior
to use. Tetrahydrofuran was distilled from benzophenone/
(11) (a) Wiberg, K. B.; Waldron, R. F.; Schulte, G.; Saunders: M. J .
Am. Chem. Soc. 1991, 113, 971. (b) Huisgen, R.; Ott, H. Tetrahedron
1959, 6, 253.

4308 J . Org. Chem., Vol. 66, No. 12, 2001
Roux et al.
(t, J ) 8.3 Hz, 2H), 2.20-2.00 (m, 2H), 1.80-1.50 (m, 4H).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.55;
H, 8.20.
pentane/ether 95:5 to 99:1 in function of the product polarity).
The same procedure was used with bis(collidine)iodine(I)
hexafluorophosphate, except the reaction was conducted in
absence of light. The subsequent chromatography was con-
ducted without special case. The yields in lactones 2 and 2′
are reported in Table 1.
1
2-Hep t-6-en ylben zoic Acid 1d .1c 70%; H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.55-7.40 (m, 1H),
7.40-7.20 (m, 2H), 5.90-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05
(t, J ) 8.3 Hz, 2H), 2.15-1.90 (m, 2H), 1.75-1.55 (m, 4H).
Anal. Calcd for C14H18O2: C, 77.02; H, 8.31. Found: C, 77.15;
H, 8.40.
2-Oct-7-en ylben zoic Acid 1e. 65%; 1H NMR (CDCl3) 12.00
(bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.30-
7.20 (m, 2H), 5.90-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05 (t, J
) 8.5 Hz, 2H), 2.10-2.00 (m, 2H), 1.70-1.50 (m, 2H), 1.50-
1.35 (m, 6H); 13C NMR (CDCl3) 173.6, 145.9, 139.1, 132.7,
131.6, 131.1, 128.0, 125.7, 114.1, 34.5, 33.7, 31.6, 29.5, 28.9,
28.8. Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C,
77.45; H, 8.61.
2-Non -8-en ylben zoic Acid 1f. 60%; 1H NMR (CDCl3) 12.00
(bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.30-
7.20 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05 (t, J
) 8.5 Hz, 2H), 2.20-1.95 (m, 2H), 1.75-1.50 (m, 2H), 1.50-
1.20 (m, 8H); 13C NMR (CDCl3173.7, 145.9, 139.2, 133.3, 131.7,
131.2, 128.0, 125.7, 114, 34.5, 33.7, 31.7, 29.6, 29.2, 29.1, 29.0.
Anal. Calcd: C, 77.55; H, 8.68. Found: C, 77.45; H, 8.61. Anal.
Calcd for C16H22O2: C, 78.01; H, 9.00. Found: C, 78.25; H,
9.11.
2-Dec-9-en ylben zoic Acid 1g. 85%; 1H NMR (CDCl3) 12.00
(bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.60-7.40 (m, 1H), 7.35-
7.20 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05 (t, J
) 8.5 Hz, 2H), 2.20-1.95 (m, 2H), 1.70-1.50 (m, 2H), 1.50-
1.20 (m, 10H); 13C NMR (CDCl3) 173.8, 146.0, 139.2, 132.8,
131.6, 131.18, 128.0, 125.7, 114, 34.5, 33.8, 31.7, 29.6, 29.4,
29.3, 29.1, 28.9. Anal. Calcd for C17H24O2: C, 78.46; H, 9.23.
Found: C, 78.42; H, 9.22.
4,5-Dih yd r o-3-iod oom e t h yl-(3H )-b e n zo[c]oxe p in -1-
1
on e 2a I. Oil; H NMR (CDCl3) 7.70 (d, J ) 7 Hz, 1H), 7.60-
7.45 (m, 1H), 7.45-7.30 (m, 1H), 7.20 (d, J ) 7 Hz, 1H), 4.20-
4.00 (m, 1H), 3.50-3.15 (m, 2H), 3.10-2.90 (m, 1H), 2.90-
2.70 (m, 1H), 2.40-2.00 (m, 2H); 13C NMR (CDCl3) 169.9,
137.4, 132.7, 130.9, 130.0, 128.6, 127.3, 77.0, 33.7, 29.3, 5.5.
Anal. Calcd for C11H11IO2: C, 43.70; H, 3.64.Found: C, 43.79;
H, 3.68.
3-Br om om et h yl-4,5-d ih yd r o-(3H )-b en zo[c]oxep in -1-
on e 2a Br . Oil; 1H NMR (CDCl3) 7.75 (d, J ) 7 Hz, 1H), 7.60-
7.40 (m, 1H), 7.40-7.30 (m, 1H), 7.37-7.15 (m, 1H), 4.45-
4.15 (m, 1H), 3.70-3.40 (m, 2H), 3.10-2.25 (m, 2H), 2.20-
2.05 (m, 2H); 13C NMR (CDCl3) 170.1, 137.4, 132.7, 130.9,
130.0, 128.6, 127.4, 77.5, 32.7, 32.3, 29.2. Anal. Calcd for
C
11H11BrO2: C, 51.76; H, 4.35. Found: C, 51.58; H, 4.35.
7-Iodom eth yl-6-oxa-7,8,9,10-tetr ah ydr oben zocycloocten -
5-on e 2bI. Already described.1c
8-Iodo-6-oxa-8,9,10,11-tetr ah ydr o(7H)ben zocyclon on en -
1
5-on e 2b′I. Oil; H NMR (CDCl3) 7.85 (dd, J ) 6 and 1 Hz,
1H), 7.50-7.10 (m, 3H), 5.00 (dd, J ) 10 and 3 Hz, 1H), 4.45
(t, J ) 10 Hz, 1H), 4.40-4.10 (m, 1H), 3.10 (dd, J ) 11 and 4
Hz, 1H), 2.65-2.40 (m, 1H), 2.20-1.20 (m, 4H). Anal. Calcd
for C12H13IO2: C, 45.59; H, 4.14. Found: C, 45.68; H, 4.31.
7-Br om om e t h yl-6-oxa -7,8,9,10-t e t r a h yd r ob e n zocy-
cloocten -5-on e 2bBr . Oil; 1H NMR (CDCl3) 7.60-7.40 (m,
2H), 7.40-7.30 (m, 1H), 4.50-4.30 (m, 1H), 3.50 (dd, J ) 11
and 8 Hz, 1H), 3.35 (dd, J ) 11 and 8 Hz, 1H), 3.00-2.70 (m,
2H), 2.20-1.80 (m, 3H), 1.70-1.50 (m, 2H); 13C NMR (CDCl3)
170.7, 140.0, 131.9, 130.7, 129.8, 128.5, 79.4, 35.1, 33.0, 32.4,
26.1, 19.1. Anal. Calcd for C12H13BrO2: C, 53.55; H,0.4.87.
Found: C, 53.76; H, 4.76.
2-Un d ec-10-en ylben zoic Acid 1h . 70%; 1H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.60-7.40 (m, 1H),
7.40-7.25 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05
(t, J ) 8.5 Hz, 2H), 2.15-1.90 (m, 2H), 1.80-1.50 (m, 2H),
1.50-1.20 (m, 12H); 13C NMR (CDCl3) 173.7, 146.0, 139.1,
132.7, 131.6, 131.2, 130.5, 128.1, 125.7, 114.0, 34.5, 33.7, 31.7,
29.8, 29.6, 29.5, 29.1, 28.9. Anal. Calcd for C18H26O2: C, 78.79;
H, 9.55. Found: C, 78.67; H, 9.32.
8 -B r o m o -6 -o x a -8 ,9 ,1 0 ,1 1 -t e t r a h y d r o (7 H )b e n z o -
1
cyclon on en -5-on e 2b′Br . Oil; H NMR (CDCl3) 7.85 (dd, J
) 6 and 1 Hz, 1H), 7.50-7.40 (m, 1H), 7.35 (t, J ) 8 Hz, 1H),
7.20 (t, J ) 6 Hz, 1H), 5.00 (dd, J ) 12 and 2 Hz, 1H), 4.40 (t,
J ) 8 Hz, 1H), 4.35-4.20 (m, 1H), 3.20-2.90 (m, 2H), 2.50-
2.30 (m, 1H), 2.30-1.90 (m, 3H); 13C NMR (CDCl3) 169.0,
144.8, 132.3, 130.9, 130.7, 130.0, 126.6, 69.1, 47.00, 38.8, 35.9,
30.6. Anal. Calcd for C12H13BrO2: C, 53.55; H,0.4.87. Found:
C, 53.81; H, 4.62.
1
2-Dod ec-11-en ylben zoic Acid 1i. 90%; H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.55-7.40 (m, 1H),
7.30-7.10 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05
(t, J ) 8.5 Hz, 2H), 2.20-2.00 (m, 2H), 1.70-1.55 (m, 2H),
1.70-1.20 (m, 14H); 13C NMR (CDCl3) 28.9, 29.1, 29.4, 29.5,
29.6, 29.7, 29.8, 31.7, 33.8, 34.6, 114.0, 125.7, 127.1, 128.1, 130,
131.6, 139.1, 146.0, 173.7. Anal. Calcd for C19H28O2: C, 79.16;
H, 9.72. Found: C, 79.18; H, 9.77.
2-Tr id ec-12-en ylben zoic Acid 1j. 80%; 1H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.6-7.4 (m, 1H), 7.3-
7.15 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05 (t, J
) 8.5 Hz, 2H), 2.20-1.90 (m, 2H), 1.8-1.55 (m, 2H), 1.5-1.15
(m, 16H). Anal. Calcd for C20H30O2: C, 79.42; H, 10.00.
Found: C, 79.62; H, 9.82.
2-Hexadec-15-en ylben zoic Acid 1k. 80%; 1H NMR (CDCl3)
12.00 (bs, 1H), 8.05 (d, J ) 7.5 Hz, 1H), 7.6-7.4 (m, 1H), 7.4-
7.2 (m, 2H), 6.00-5.70 (m, 1H), 5.10-4.90 (m, 2H), 3.05 (t, J
) 8.5 Hz, 2H), 2.10-2.20 (m, 2H), 1.70-1.5 (m, 2H), 1.5-1.1
(m, 22H); 13C NMR (CDCl3) 28.1, 28.7, 28.9, 29.1, 29.4, 29.5,
29.6, 31.7, 32.8, 33.8, 33.9, 34.5, 114.0, 125.7, 125.8, 128.0,
131.1, 131.6, 131.8, 132.8, 139.1, 146, 173.7.
Ha lola cton iza tion : Rep r esen ta tive P r oced u r e. To a
methylene chloride solution (35 mL) of bis(collidine)bromine(I)
hexafluorophosphate22 (2.6 mmol, 1.21 g) was added in 10 h
at room temperature using a push-syringe, the 2-alkenylben-
zoic acid (2 mmol) in solution in methylene chloride (10 mL).
At the end of the addition silica gel was added (2 g), and the
solvent was removed under vacuum. The resulting powder was
placed on the top of a silica gel column, and the products were
isolated by liquid chromatography over silica gel (elution
7-Iod om e t h yl-6-oxa -8,9,10,11-t e t r a h yd r o(7H )b e n zo-
cyclon on en -5-on e 2cI. Already described.1c
7,8,9,10,11,12-Hexah ydr o-8-iodo-6-oxaben zocyclodecen -
5-on e 2′cI. Already described.1c
7-Br om om eth yl-6-oxa -8,9,10,11-tetr a h yd r o(7H)ben zo-
cyclon on en -5-on e 2cBr . Oil; 1H NMR (CDCl3) 7.90 (d, J ) 7
Hz, 1H), 7.50-7.35 (m, 1H), 7.35-7.20 (m, 2H), 5.35-5.15 (m,
1H), 3.75-3.40 (m, 3H), 2.75-2.55 (m, 1H), 2.20-1.40 (6H);
13C NMR (CDCl3) 170.1, 144.8, 132.3, 131.3, 130.8, 130.4,
126.3, 76.3, 34.8, 34.0, 31.1, 30.4, 23.1; HRMS calcd for
C
13H1579BrO2 (M+) 282.0256, found 282.0256.
8-Br om o-7,8,9,10,11,12-h exa h yd r o-6-oxa ben zocyclod e-
cen -5-on e 2′cBr . Oil; 1H NMR (CDCl3) 7.85 (d, J ) 7 Hz, 1H),
7.50-7.35 (m, 1H), 7.35-7.20 (m, 2H), 5.05 (dd, J ) 12 and 1
Hz, 1H), 4.30-4.00 (m, 2H), 3.38-3.20 (m, 1H), 2.70-2.50 (m,
1H), 2.50-2.30 (m, 2H), 2.00-1.30 (m, 4H); 13C NMR (CDCl3)
167.9, 143.4, 132.3, 131.4, 130.5 (2C), 126.2, 68.3, 46.0, 34.9,
32.1, 29.4, 26.5; HRMS calcd for C13H1579BrO2 (M+) 282.0256,
found 282.0256.
7,8,9,10,11,12-Hexa h yd r o-7-iod om eth yl-6-oxa ben zocy-
clod ecen -5-on e 2d I. Already described.1c
8,9,10,11,12,13-H e xa h yd r o-8-iod o-6-oxa (7H )b e n zo-
cyclou n d ecen -5-on e 2′d I. Already described.1c
7-Br om om eth yl-7,8,9,10,11,12-h exa h yd r o-6-oxa ben zo-
cyclod ecen -5-on e 2d Br . Oil; 1H NMR (CDCl3) 7.75 (dd, J )
7 and 1 Hz, 1H), 7.45-7.30 (m, 1H), 7.30-7.10 (m, 2H), 5.40-
5.20 (m, 1H), 3.70-3.40 (m, 2H), 3.15-3.00 (m, 1H), 2.60-
2.40 (m, 1H), 2.05-1.40 (m, 8H); 13C NMR (CDCl3) 168.6,
143.2, 131.6, 130.8, 130.7, 129.9, 126.0, 74.7, 33.3, 32.7, 29.6,
(22) Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 2000, 77, 206.

Halolactonization of ω-Unsaturated Acids
J . Org. Chem., Vol. 66, No. 12, 2001 4309
28.8, 27.4, 20.0; HRMS calcd for C14H1779BrO2 (M+) 296.0412,
found 296.0412.
7,8,9,10,11,12,13,14,15,16-Deca h yd r o-8-iod o-6-oxa ben -
zocyclotetr a d ecen -5-on e 2′gI. Oil; 1H NMR (CDCl3) 7.70 (dd,
J ) 2 and 7 Hz, 1H), 7.47-7.35 (m, 1H), 7.35-7.18 (m, 2H),
4.87 (q, J ) 7 Hz, 1H), 4.50 (m, 2H), 3.15-3.00 (m, 1H), 2.90-
2.75 (m, 1H), 2.75-1.15 (m, 14H); 13C NMR (CDCl3) 168.1,
143.2, 131.9, 131.5, 130.4; 129.7, 125.6, 68.7, 32.9, 32.0, 31.4,
29.2, 26.9, 25.9, 25.8, 24.7, 24.3. Anal. Calcd for C17H23IO2:
C, 52.86; H, 6.00. Found: C, 53.11; H, 6.21.
8-Br om o-8,9,10,11,12,13-h exa h yd r o-6-oxa (7H )b en zo-
1
cyclou n d ecen -5-on e 2′d Br . Oil; H NMR (CDCl3) 7.85 (dd,
J ) 7 and 1 Hz, 1H), 7.55-7.40 (m, 1H), 7.40-7.20 (m, 2H),
5.10-4.90 (m, 1H), 4.50-4.30 (m, 2H), 3.20-3.00 (m, 1H),
2.75-2.55 (m, 1H), 2.30-2.00 (m, 2H), 2.00-1.50 (m, 6H); 13
C
NMR (CDCl3) 168.3, 143.2, 132.0, 131.3, 130.8, 130.2, 126.0,
67.9, 47.0, 35.7, 31.5, 29.8, 25.9, 24.8; HRMS calcd for
7-Br om om eth yl-8,9,10,11,12,13,14,15-octa h yd r o-(7H)-6-
14H1779BrO2 (M+) 296.0412, found 296.0412.
1
C
oxa ben zocyclotr id ecen -5-on e 2gBr . Oil; H NMR (CDCl3)
8,9,10,11,12,13-H e xa h yd r o-7-iod om e t h yl-6-oxa (7H )-
7.70 (d, J ) 7 Hz, 1H), 7.48-7.35 (m, 1H), 7.35-7.18 (m, 2H),
5.57-5.38 (m, 1H), 3.58 (d, J ) 6 Hz, 2H), 3.20 (dt, J ) 6 and
12 Hz, 1H), 2.80-2.65 (m, 1H), 1.96-1.18 (m, 14H); 13C NMR
(CDCl3) 168.8, 142.7, 131.2, 130.5 (2C), 129.2, 125.5, 73.5, 34.3,
31.4 (2C), 30.6, 26.4, 26.3, 25.4, 25.2, 23.4. Anal. Calcd for
ben zocyclou n d ecen -5-on e 2eI. Already described.1c
8-Iod o-7,8,9,10,11,12,13,14-oct a h yd r o-6-oxa b en zocy-
clod od ecen -5-on e 2′eI. Already described.1c
7-Br om om et h yl-8,9,10,11,12,13-h exa h yd r o-6-oxa (7H )-
ben zocyclou n d ecen -5-on e 2eBr . Oil; 1H NMR (CDCl3) 7.70
(dd, J ) 8 and 1 Hz, 1H), 7.55-7.35 (m, 1H), 7.35-7.15 (m,
2H), 5.50-5.30 (m, 1H), 3.59 (d, J ) 8 Hz, 2H), 3.20-3.00 (m,
1H), 2.75-2.55 (m, 1H), 2.10-1.10 (m, 10H); 13C NMR (CDCl3)
168.9, 142.2, 131.3, 131.0, 129.9, 129.2, 125.8, 73.8, 34.8, 32.1,
30.4, 30.0, 24.8, 24.3, 22.8. Anal. Calcd for C15H19BrO2: C,
57.89; H, 6.15. Found: C, 57.98; H, 6.22.
C
17H23BrO2: C, 60.18; H, 6.83. Found: C, 60.33; H, 6.98.
8-Br om o-7,8,9,10,11,12,13,14,15,16-decah ydr o-6-oxaben -
zocyclotr id ecen -5-on e 2′gBr . Oil; 1H NMR (CDCl3) 7.70 (dd,
J ) 1 and 7 Hz, 1H), 7.50-7.38 (m, 1H), 7.35-7.20 (m, 2H),
4.75 (q, J ) 8 Hz, 1H), 4.50-4.35 (m, 1H), 3.25-3.00 (m, 1H),
2.88-2.68 (m, 1H), 2.10-1.15 (m, 15H); 13C NMR (CDCl3)
166.6, 143.3, 132.0, 131.6, 130.5, 129.8, 125.6, 66.8, 49.3, 32.0,
8-Br om o-7,8,9,10,11,12,13,14-octa h yd r o-6-oxa ben zocy-
clod od ecen -5-on e 2e′Br . Oil; 1H NMR (CDCl3) 7.78 (dd, J )
8 and 2 Hz, 1H), 7.55-7.35 (m, 1H), 7.35-7.20 (m, 2H), 4.90
(dd, J ) 3 and 10 Hz, 1H), 4.65-4.45 (m, 1H), 4.30 (t, J ) 11
Hz, 1H), 3.60-3.35 (m, 1H), 3.23 (dt, J ) 6 and 13 Hz, 1H),
31.9, 31.2, 26.9, 25.9, 24.5 (2C), 23.2. Anal. Calcd for C17H23
BrO2: C, 60.18; H, 6.83. Found: C, 60.55; H, 7.23.
-
7,8,9,10,11,12,13,14,15,16-Deca h yd r o-7-iod om et h yl-6-
oxa ben zocyclotetr a d ecen -5-on e 2h I. Oil; 1H NMR (CDCl3)
7.85 (d, J ) 7 Hz, 1H), 7.50-7.35 (m, 1H), 7.45-7.20 (m, 2H),
5.25-5.10 (m, 1H), 3.55-3.30 (m, 2H), 2.75-2.60 (m, 1H),
2.05-1.00 (m, 17H); 13C NMR (CDCl3) 167.9, 143.6, 131.4,
130.8, 130.4, 129.8, 125.5, 71.3, 33.3, 31.3, 31.2, 26.9, 25.8, 25.5,
25.4, 24.8, 21.8, 8.7; HRMS calcd for C18H25IO2 (M+) 400.0901,
found 400.0902.
8,9,10,11,12,13,14,15,16,17-Decah ydr o-8-iodo-(7H)-6-oxa-
b en zocyclop en t a d ecen -5-on e 2′h I. Oil; 1H NMR (CDCl3)
7.75 (d, J ) 7 Hz, 1H), 7.50-7.35 (m, 1H), 7.35-7.15 (m, 2H),
4.80 (dd, J ) 11 and 4 Hz, 1H), 4.50 (t, J ) 8 Hz, 1H), 4.40-
4.25 (m, 1H), 3.20-3.05 (m, 1H), 3.05-2.85 (m, 1H), 2.10-
1.00 (m, 16H); 13C NMR (CDCl3) 167.5, 143.9, 131.8, 131.2,
130.8, 129.5, 125.7, 68.9, 34.0, 33.7, 30.1, 30.0, 26.5, 25.8, 25.6,
25.5, 25.0, 24.2; HRMS calcd for C18H25IO2 (M+) 400.0901,
found 400.0899.
2.40-2.50 (m, 1H), 2.20-2.05 (m, 2H), 1.75-1.20 (m, 7H); 13
C
NMR (CDCl3) 168.4, 142.7, 131.7, 130.9, 130.8, 130.0, 125.7,
68.2, 46.6, 35.4, 30.8, 30.3, 25.1, 24.2, 23.2. Anal. Calcd for
C
15H19BrO2: C, 57.89; H, 6.15. Found: C, 57.78; H, 6.25.
7-Iod om eth yl-7,8,9,10,11,12,13,14-octa h yd r o-6-oxa ben -
zocyclod od ecen -5-on e 2fI. Oil; 1H NMR (CDCl3) 7.75 (dd, J
) 8 and 2 Hz, 1H), 7.50-7.32 (m, 1H), 7.32-7.20 (m, 2H), 5.25
(m, 1H), 3.50-3.30 (m, 2H), 3.15-3.00 (m, 1H), 2.90-2.70 (m,
1H), 2.10-1.90 (m, 2H), 1.70-1.20 (m, 10H); 13C NMR (CDCl3)
168.7, 142.5, 131.6, 131.3, 130.7, 129.8, 125.6, 74.6, 30.7, 30.4,
29.3, 25.3 (2C), 22.6, 21.5, 7.0. Anal. Calcd for C16H21IO2: C,
59.09; H, 6.51. Found: C, 59.20; H, 6.62.
8-Iod o-8,9,10,11,12,13,14,15-octa h yd r o-(7H)-6-oxa ben -
1
zocyclotr id ecen -5-on e 2′fI. Oil; H NMR (CDCl3) 7.70 (dd,
J ) 8 and 2 Hz, 1H), 7.50-7.32 (m, 1H), 7.32-7.20 (m, 2H),
4.82 (dd, J ) 11 and 2 Hz, 1H), 4.48 (t, J ) 10 Hz, 1H), 4.40-
4.25 (m, 1H), 3.15-3.00 (m, 1H), 2.85-2.60 (m, 1H), 2.25-
1.95 (m, 2H), 1.70-1.20 (m, 10H); 13C NMR (CDCl3) 168.5,
142.7, 131.7, 131.4, 130.7, 130.3, 125.8, 69.6, 36.0, 33.4, 30.0,
27.4, 25.3, 25.2, 24.0, 21.6. Anal. Calcd for C16H21IO2: C, 59.09;
H, 6.51. Found: C, 59.38; H, 6.81.
8-Br om o-8,9,10,11,12,13,14,15-octah ydr o-(7H)-6-oxaben -
zocyclotr id ecen -5-on e 2′fBr . 1H NMR (CDCl3) 7.75 (dd, J
) 9 and 2 Hz, 1H), 7.50-7.35 (m, 1H), 7.35-7.20 (m, 2H), 4.75
(dd, J ) 11 and 3 Hz, 1H), 4.45 (t, J ) 10 Hz, 1H), 4.35-4.20
(m, 1H), 3.20-3.00 (m, 1H), 2.80-2.60 (m, 1H), 2.30-2.15 (m,
1H), 2.15-1.95 (m, 1H), 1.70-1.20 (m, 10H); 13C NMR (CDCl3)
168.9, 142.8, 131.7, 130.7, 130.4, 129.9, 125.8, 67.6, 48.3, 34.6,
33.4, 30.0, 27.4, 24.9, 24.1, 23.9; HRMS calcd for C16H2179BrO2
(M+) 324.0725, found 324.0725.
7-Br om om et h yl-7,8,9,10,11,12,13,14-oct a h yd r o-6-oxa -
ben zocyclod od ecen -5-on e 2fBr . Oil; 1H NMR (CDCl3) 7.70
(dd, J ) 9 and 2 Hz, 1H), 7.50-7.35 (m, 1H), 7.35-7.20 (m,
2H), 5.35-5.20 (m, 1H), 3.65-3.45 (m, 2H), 3.15-3.00 (m, 1H),
2.90-2.65 (m, 1H), 2.10-1.90 (m, 2H), 1.70-1.20 (m, 10H);
13C NMR (CDCl3) 168.9, 142.6, 131.7, 131.4, 130.7, 129.9,
125.6, 74.8, 33.4, 30.7, 30.5, 28.2, 25.3, 25.2, 22.6, 21.9; HRMS
calcd for C16H2179BrO2 (M+) 324.0725, found 324.0724.
7-Iod om et h yl-8,9,10,11,12,13,14,15-oct a h yd r o-(7H )-6-
oxa ben zocyclotr id ecen -5-on e 2gI. Oil; 1H NMR (CDCl3)
7.75 (dd, J ) 2 and 7 Hz, 1H), 7.42 (t, J ) 7 Hz, 1H), 7.35-
7.20 (m, 2H), 5.35-5.22 (m, 1H), 3.43 (d, J ) 7 Hz, 2H), 3.15
(dt, J ) 7 and 12 Hz, 1H), 2.75 (dt, J ) 7 and 12 Hz, 1H),
2.00-1.85 (m, 1H), 1.85-1.74 (m, 1H), 1.74-1.10 (m, 12H);
13C NMR (CDCl3) 168.5, 142.7, 131.1, 130.4, 130.4, 129.2,
125.4, 73.5, 32.7, 31.4, 30.6, 26.3, 26.2, 25.4, 25.2, 23.3, 7.7.
Anal. Calcd for C17H23IO2: C, 52.86; H, 6.00. Found: C, 52.95;
H, 6.05.
7-Br om om eth yl-7,8,9,10,11,12,13,14,15,16-d eca h yd r o-6-
oxaben zocyclotetr adecen -5-on e 2h Br . Oil; 1H NMR (CDCl3)
7.80 (dd, J ) 9 and 2 Hz, 1H), 7.50-7.45 (m, 1H), 7.45-7.20
(m, 2H), 5.55-5.40 (m, 1H), 3.70-3.52 (m, 2H), 3.50-3.30 (m,
1H), 2.80-2.60 (m, 1H), 1.95-1.00 (m, 16H); 13C NMR (CDCl3)
168.0, 143.7, 131.5, 130.8, 130.5, 129.8, 125.5, 71.4, 34.9, 31.8,
31.3, 31.2, 26.9, 25.8, 25.5, 25.3, 24.8, 21.8; HRMS calcd for
C
18H2579BrO2 (M+) 352.1038, found 352.1038.
8-Br om o-8,9,10,11,12,13,14,15,16,17-d eca h yd r o-(7H)-6-
oxa b en zocyclop en t a d ecen -5-on e 2′h Br . Oil; 1H NMR
(CDCl3) 7.75 (d, J ) 9 and 2 Hz, 1H), 7.50-7.48 (m, 1H), 7.48-
7.15 (m, 2H), 4.75 (dd, J ) 11 and 4 Hz, 1H), 4.50 (t, J ) 9
Hz, 1H), 4.32-4.15 (m, 1H), 3.20-2.80 (m, 2H), 2.22-2.00 (m,
1H), 1.80-1.00 (m, 15H); 13C NMR (CDCl3) 167.8, 144.0, 131.9,
131.2, 130.4, 129.6, 125.8, 67.1, 50.3, 34.1, 32.8, 30.3, 26.8, 26.7,
25.9, 24.9, 24.2, 23.6; HRMS calcd for C18H2579BrO2 (M+)
352.1038, found 352.1027.
8,9,10,11,12,13,14,15,16,17-Decah ydr o-7-iodom eth yl-(7H)-
6-oxaben zocyclopen tadecen -5-on e 2iI. Oil; 1H NMR (CDCl3)
7.90 (dd, J ) 7 and 1 Hz, 1H), 7.55-7.35 (m, 1H), 7.35-7.15
(m, 2H), 5.30-5.15 (m, 1H), 3.70-3.50 (m, 1H), 3.50-3.30 (m,
2H), 2.60-2.40 (m, 1H), 2.00-1.65 (m, 2H), 1.65-1.10 (m,
16H); 13C NMR (CDCl3) 167.7, 144.2, 131.6, 130.8, 130.2, 130.1,
125.6, 72.2, 34.9, 33.7, 30.9, 26.9, 26.7 (2C), 25.9, 24.4, 24.2,
23.4, 8.6; HRMS calcd for C19H27IO2 (M+) 414.1057, found
414.1055.
7,8,9,10,11,12,13,14,15,16,17,18-Dod eca h yd r o-8-iod o-6-
oxa ben zocycloh exa d ecen -5-on e 2′iI. Oil; 1H NMR (CDCl3)
7.90 (dd, J ) 7 and 1 Hz, 1H), 7.55-7.35 (m, 1H), 7.35-7.15
(m, 2H), 4.70 (dd, J ) 11 and 4 Hz, 1H), 4.55 (dd, J ) 10 and
5 Hz, 1H), 4.50-4.30 (m, 1H), 3.70-3.40 (m, 2H), 3.10-2.95
(m, 2H), 2.10-1.10 (m, 16H); 13C NMR (CDCl3) 167.0, 144.6,
131.9, 131.4, 130.5, 130.1, 125.6, 68.0, 35.4, 33.5, 31.0, 29.7,

4310 J . Org. Chem., Vol. 66, No. 12, 2001
Roux et al.
29.3, 27.2, 26.5, 26.4, 25.7, 25.6, 24.6; HRMS calcd for C19H27
IO2 (M+) 414.1057, found 414.1055.
-
7.40-7.20 (m, 2H), 4.75 (dd, J ) 10 and 3 Hz, 1H), 4.55 (dd,
J ) 14 and 3 Hz, 1H), 4.40-4.25 (m, 1H), 3.15-2.95 (m, 2H),
2.10-1.80 (m, 2H), 1.70-1.00 (m, 18H); 13C NMR (CDCl3)
167.2, 144.8, 132.1, 131.0, 130.9, 129.0, 125.7, 67.6, 51.0, 34.2,
34.1, 30.8, 28.1, 27.5, 26.7, 26.5, 26.4, 26.3, 25.9, 25.4; HRMS
calcd for C20H2979BrO2 (M+) 380.1351, found 380.1347.
7-Iod om et h yl-6-oxa -8,9,10,11,12,13,14,15,16,17,18,19,-
20,21-t et r a d eca h yd r o-(7H )b en zocyclon on a d ecen -5-on e
7-Br om om eth yl-8,9,10,11,12,13,14,15,16,17-d eca h yd r o-
(7H)-6-oxa ben zocyclop en ta d ecen -5-on e 2iBr . Oil; 1H NMR
(CDCl3) 7.85 (dd, J ) 7 and 1 Hz, 1H), 7.55-7.35 (m, 1H),
7.35-7.15 (m, 2H), 5.55-5.35 (m, 1H), 3.70-3.45 (m, 3H),
2.60-2.40 (m, 1H), 1.90-1.65 (m, 3H), 1.65-1.10 (m, 15H);
13C NMR (CDCl3) 167.8, 144.1, 131.6, 130.5, 130.0, 129.1,
125.6, 72.2, 35.0, 33.7, 33.4, 30.9, 26.9, 26.7, 26.4, 25.7, 24.1,
24.0, 23.4. Anal. Calcd for C19H27BrO2: C, 62.13; H, 7.41.
Found: C, 62.55; H, 7.28.
8-Br om o-7,8,9,10,11,12,13,14,15,16,17,18-d od eca h yd r o-
6-oxa b en zocycloh exa d ecen -5-on e 2′iBr . Oil; 1H NMR
(CDCl3) 7.90 (dd, J ) 7 and 1 Hz, 1H), 7.55-7.35 (m, 1H),
7.35-7.15 (m, 2H), 4.75 (dd, J ) 11 and 6 Hz, 1H), 4.55 (dd,
J ) 11 and 6 Hz, 1H), 4.40-4.35 (m, 1H), 3.15-2.95 (m, 2H),
2.10-1.80 (m, 2H), 1.60-1.10 (m, 16H); 13C NMR (CDCl3)
167.4, 144.8, 132.0, 130.8 (2C), 130.6, 125.7, 66.5, 50.6, 34.2,
33.6, 31.2, 27.3, 27.0, 26.4, 26.0, 25.7, 24.9, 24.1. Anal. Calcd
for C19H27BrO2: C, 62.13; H, 7.41. Found: C, 62.41; H, 7.38.
7,8,9,10,11,12,13,14,15,16,17,18-Dod eca h yd r o-7-iod o-
m eth yl-6-oxaben zocycloh exadecen -5-on e 2jI. Oil; 1H NMR
(CDCl3) 8.00 (dd, J ) 8 and 1 Hz, 1H), 7.50-7.40 (m, 1H),
7.35-7.15 (m, 2H), 5.75-5.05 (m, 1H), 3.70-3.55 (m,1H), 3.48
(dd, J ) 11 and 5 Hz, 1H), 3.38 (dd, J ) 11 and 5 Hz, 1H),
2.70-2.40 (m, 1H), 2.05-1.85 (m, 2H), 1.85-1.00 (m, 18H);
13C NMR (CDCl3) 166.9, 145.2, 131.8, 130.8 (2C), 129.1, 125.6,
71.2, 34.1, 33.2, 30.6, 27.2, 27.1, 26.8 (2C), 26.5, 25.8, 25.0,
24.4, 9.1; HRMS calcd for C20H29IO2 (M+) 428.1214, found
428.1210.
8,9,10,11,12,13,14,15,16,17,18,19-d od eca h yd r o-8-iod o-6-
oxa (7H)ben zocycloh ep ta d ecen -5-on e 2′jI. Oil; 1H NMR
(CDCl3) 7.90 (dd, J ) 8 and 1 Hz, 1H), 7.50-7.40 (m, 1H),
7.35-7.15 (m, 2H), 5.10-4.90 (m, 1H), 4.70-4.50 (m, 1H),
4.45-4.30 (m, 1H), 3.20-2.90 (m, 2H), 1.70-1.00 (m, 20H);
13C NMR (CDCl3) 167.1, 144.8, 139.0, 132.0, 130.9, 128.9,
125.6, 69.0, 34.4, 33.7, 30.4, 29.8, 29.4, 29.0, 28.8, 28.6, 27.5,
27.4, 27.3, 26.2; HRMS calcd for C20H29IO2 (M+) 428.1214,
found 428.1210.
7-Br om om eth yl-7,8,9,10,11,12,13,14,15,16,17,18-d od eca -
h ydr o-6-oxaben zocycloh exadecen -5-on e 2jBr . Oil; 1H NMR
(CDCl3) 7.85 (d, J ) 7 Hz, 1H), 7.50-7.35 (m, 1H), 7.35-7.15
(m, 2H), 5.55-5.35 (m, 1H), 3.70-3.40 (m, 3H), 2.60-2.40 (m,
1H), 1.90-1.00 (m, 20H); 13C NMR (CDCl3) 167.0, 145.3, 131.9,
130.9, 130.7, 129.2, 125.7, 71.3, 35.2, 33.8, 32.8, 31.1, 27.2, 27.1,
26.8 (2C), 26.5, 25.4, 25.1, 24.4; HRMS calcd for C20H2979BrO2
(M+) 380.1351, found 380.1345.
1
2k I. Oil; H NMR (CDCl3) 8.05-7.90 (m, 1H), 7.55-7.35 (m,
1H), 7.35-7.15 (m, 2H), 5.10-4.90 (m, 1H), 3.60-3.35 (m, 3H),
3.35-3.15 (m, 1H), 2.85-2.15 (m, 1H), 2.00-1.00 (m, 25H);
13C NMR (CDCl3) 167.0, 144.7, 131.9, 130.9, 130.8, 129.5,
125.7, 72.5, 34.6, 34.2, 31.8, 29.4, 28.5, 28.2, 27.5 (2C), 27.4,
27.2, 27.0, 26.5, 26.1, 24.7, 8.7; HRMS calcd for C23H35IO2 (M+)
470.1683, found 470.1679.
7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22-Hexa d eca h y-
d r o-8-iod o-6-oxa ben zocycloeicosen -5-on e 2′k I. Oil; 1H
NMR (CDCl3) 8.05-7.90 (m, 1H), 7.55-7.35 (m, 1H), 7.35-
7.15 (m, 2H), 4.55 (d, J ) 9 Hz, 2H), 4.50-4.30 (m, 1H), 3.60-
3.42 (m, 1H), 3.10-2.90 (m, 2H), 2.00-1.00 (m, 25H); 13C NMR
(CDCl3) 167.1, 144.8, 131.9, 130.9, 130.8, 129.2, 125.7, 69.5,
34.3, 34.0, 32.8, 30.7, 29.7, 29.1, 28.7, 28.6 (2C), 27.7, 27.6,
27.1, 26.8, 26.6, 22.7; HRMS calcd for C23H35IO2 (M+) 470.1683,
found 470.1679.
7-Br om om eth yl-6-oxa -8,9,10,11,12,13,14,15,16,17,18,19,-
20,21-t e t r a d e ca h yd r o-(7H )-b e n zocyclon on a d e ce n -5-
on e. Oil; 1H NMR (CDCl3) 7.95 (dd, J ) 7 and 1 Hz, 1H), 7.55-
7.35 (m, 1H), 7.35-7.15 (m, 2H), 5.40-5.25 (m, 1H), 3.70-
3.55 (m, 2H), 3.50-3.40 (m, 2H), 3.30-3.10 (m, 1H), 2.85-
2.60 (m, 1H), 2.10-1.20 (m, 24H); 13C NMR (CDCl3) 167.1,
144.7, 131.9, 130.8, 130.7, 129.5, 125.7, 72.7, 34.7, 34.0, 32.8,
32.5, 31.8, 29.6, 29.4, 28.7, 28.5, 28.1, 27.6, 27.3, 26.4, 26.1,
24.7; HRMS calcd for C23H3579BrO2 (M+) 422.1820, found
422.1820.
8-Br om o-7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22-h exa-
1
d eca h yd r o-6-oxa ben zocycloeicosen -5-on e 2′k Br . Oil; H
NMR (CDCl3) 7.95 (dd, J ) 7 and 1 Hz, 1H), 7.55-7.35 (m,
1H); 7.35-7.15 (m, 2H), 4.65-4.45 (m, 2H), 4.45-4.25 (m, 1H),
3.60-3.45 (m, 1H), 3.10-2.85 (m, 2H), 2.10-1.10 (m, 25H);
13C NMR (CDCl3) 167.4, 144.6, 132.0, 130.9, 130.7, 129.2,
125.7, 68.1, 51.3, 34.5, 34.4, 31.9, 29.5, 29.2, 28.6, 27.8, 27.6,
27.4, 27.3, 27.0, 26.8, 26.6, 26.4; HRMS calcd for C23H3579BrO2
(M+) 422.1820, found 422.1820.
Ack n ow led gm en t. The authors thank Dr. Will
Skene for his assistance in the redaction of this
manuscript.
8-Br om o-8,9,10,11,12,13,14,15,16,17,18,19-d od eca h yd r o-
(7H)-6-oxaben zocycloh eptadecen -5-on e 2′jBr . Oil; 1H NMR
(CDCl3) 7.95 (dd, J ) 8 and 2 Hz, 1H), 7.55-7.40 (m, 1H),
J O0017234