Hypervalent Iodine Chemistry: Mechanistic Investigation of the Novel Haloacetoxylation, Halogenation, and Acetoxylation Reactions of 1,4-Dimethoxynaphthalenes

Article abstract of DOI:10.1021/jo970525i

Treatment of 1,4-dimethoxynaphthalenes with iodosobenzene diacetate and trimethylsilyl chloride or bromide furnished the haloacetoxylated, acetoxylated, and halogenated 1,4-dimethoxynaphthalenes in excellent yield. The reaction pathway for each transformation was shown to be a function of reagent stoichiometry. A mechanistic hypothesis is presented that rationalizes the reaction pathways and explains the subtle differences in the halogenation reactions. The acetoxylation, for example, is thought to involve the formation of an iodonium ion that promotes the nucleophilic addition of acetate ion and subsequent 1,2-acetyl migration. Bromination occurs as a direct result of the oxidation of trimethylsilyl bromide to bromine, followed by electrophilic aromatic substitution. Chlorination is thought to proceed via a radical process and not the formation of molecular chlorine from the dissociation of iodosobenzene dichloride. The haloacetoxylation reaction also appears to be fairly specific for 1,4-dimethoxynaphthalenes, since the analogous reaction with a 1,4-dimethoxybenzene derivative was unsuccessful.

Full text of DOI:10.1021/jo970525i

J . Org. Chem. 1997, 62, 5321-5326
5321
Hyp er va len t Iod in e Ch em istr y: Mech a n istic In vestiga tion of th e
Novel Ha loa cetoxyla tion , Ha logen a tion , a n d Acetoxyla tion
Rea ction s of 1,4-Dim eth oxyn a p h th a len es
P. Andrew Evans* and Thomas A. Brandt
Brown Laboratory, Department of Chemistry and Biochemistry, University of Delaware,
Newark, Delaware 19716
Received March 21, 1997
Treatment of 1,4-dimethoxynaphthalenes with iodosobenzene diacetate and trimethylsilyl chloride
or bromide furnished the haloacetoxylated, acetoxylated, and halogenated 1,4-dimethoxynaphtha-
lenes in excellent yield. The reaction pathway for each transformation was shown to be a function
of reagent stoichiometry. A mechanistic hypothesis is presented that rationalizes the reaction
pathways and explains the subtle differences in the halogenation reactions. The acetoxylation, for
example, is thought to involve the formation of an iodonium ion that promotes the nucleophilic
addition of acetate ion and subsequent 1,2-acetyl migration. Bromination occurs as a direct result
of the oxidation of trimethylsilyl bromide to bromine, followed by electrophilic aromatic substitution.
Chlorination is thought to proceed via a radical process and not the formation of molecular chlorine
from the dissociation of iodosobenzene dichloride. The haloacetoxylation reaction also appears to
be fairly specific for 1,4-dimethoxynaphthalenes, since the analogous reaction with a 1,4-
dimethoxybenzene derivative was unsuccessful.
In tr od u ction
substitution.6 Herein, we provide a full account of our
work, in which we propose alternative mechanistic
hypotheses for the reactions of 1,4-dimethoxynaphtha-
lenes with iodosobenzene diacetate and trimethylsilyl
halides.
Hypervalent iodine reagents have become increasingly
popular for affecting a variety of synthetic transforma-
tions.1,2 This may be attributed to their ambiphilic
nature which is a direct result of the ability to vary both
the apical ligands on iodine and the electronic nature of
the aryl group. This, in turn, allows the reactivity of the
reagent to be varied to facilitate a particular transforma-
tion. In addition to these features, the iodoarene byprod-
uct is relatively innocuous, avoiding the high toxicity of
the more traditional lead- and selenium-based reagents.
Furthermore, the iodoarene may be recovered, oxidized,
and then resubmitted to the reaction, making the process
relatively environmentally benign.
In a preliminary study, we described a series of
complementary haloacetoxylation reactions with 1,4-
dimethoxynaphthalenes using the reagent combination
of iodosobenzene diacetate and trimethylsilyl bromide.3
This reaction was a serendipitous discovery during the
course of our synthetic studies aimed at the total syn-
thesis of fredericamycin A,4 in which the bromination of
the ethylene ketal 1 to afford 3 was required (eq 1). Prior
to these studies relatively few examples of the halogena-
tion of aromatic systems using hypervalent iodine chem-
istry had been reported.5 Kita and co-workers have,
however, described the nucleophilic functionalization of
electron rich aryl ethers with carbon, oxygen, nitrogen,
and sulfur nucleophiles. The reactions were proposed to
involve a radical cation species, formed between the
electron rich aromatic substrate and iodosobenzene bis-
(trifluoroacetate), that promoted nucleophilic aromatic
Resu lts a n d Discu ssion
In the course of our synthetic studies, the regiospecific
bromination of the ethylene ketal 1 was required. At-
tempted bromination with a standard electrophilic bro-
mide source (NBS) failed to afford the desired bromide
3, and thus we decided to examine alternative sources
of bromide ion. Magnus et al. demonstrated that the
combination of iodosobenzene and a trimethylsilyl halide
provides an electrophilic halogen source (PhIX2 where X
) Cl and Br), which readily undergoes electrophilic
reactions with silyl enol ethers.7 Treatment of 1 with
iodosobenzene diacetate and trimethylsilyl bromide fur-
nished 3-acetoxy-2-bromo-1,4-dimethoxynaphthalene (2)
in 57% yield, rather than the desired 2-bromo-3,3-
(ethylenedioxy)-1,4-dimethoxynaphthalene (3) (eq 1). This
novel transformation may be envisioned as the formal
addition of AcOBr to the benzyne derived from 1,4-
dimethoxynaphthalene. This reaction clearly deserved
further investigation.
(5) For related examples of halogenation of aromatic systems using
hypervalent iodine reagents, see: Neu, R. Ber. Dtsch. Chem. Ges. 1939,
72, 1505. Ogata, Y.; Aoki, K. J . Am. Chem. Soc. 1968, 90, 6187.
Angelini, G.; Sleiter, G. Gazz. Chim. Ital. 1975, 105, 961. Amey, R. L.;
Martin, J . C. J . Am. Chem. Soc. 1979, 101, 5294. Merkushev, E. B.;
Simakhina, N. D.; Koveshnikova, G. M. Synthesis 1980, 486. Gallos,
J .; Varvoglis, A. J . Chem. Res., Synop. 1982, 150. Robins, M. J .; Barr,
P. J .; Giziewicz, J . Can. J . Chem. 1982, 60, 554. Bovonsombat, P.;
Djuardi, E.; McNelis, E. Tetrahedron Lett. 1994, 35, 2841 and pertinent
references cited therein.
(6) (a) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanka, K.; Yakura, T.
Tetrahedron Lett. 1991, 32, 4321. (b) Kita, Y.; Tohma, H.; Hatanaka,
K.; Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J . Am. Chem.
Soc. 1994, 116, 3684. (c) Kita, Y.; Takada, T.; Mihara, S.; Tohma, H.
Synlett 1995, 211. (d) Kita, Y.; Takada, T.; Mihara, S.; Whelan, B. A.;
Tohma, H. J . Org. Chem. 1995, 60, 7144.
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine;
VCH: New York, 1992.
(2) (a) Varvoglis, A. Synthesis 1984, 709. (b) Merkushev, E. B. Rus.
Chem. Rev. 1987, 56, 826. (c) Moriarty, R. M.; Vaid, R. K.; Koser, G.
F. Synlett 1990, 365. (d) Moriarty, R. M.; Vaid, R. K. Synthesis 1990,
431. (e) Stang, P. J . Angew. Chem., Int. Ed. Engl. 1992, 31, 274. (f)
Stang, P. J .; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(3) Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37, 6443.
(4) Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37, 1367.
(7) Magnus, P.; Lacour, J .; Evans, P. A.; Roe, M. B.; Hulme, C. J .
Am. Chem. Soc. 1996, 118, 3406.
S0022-3263(97)00525-2 CCC: $14.00 © 1997 American Chemical Society

5322 J . Org. Chem., Vol. 62, No. 16, 1997
Evans and Brandt
Ta ble 1. Ha loa cetoxyla tion , Acetoxyla tion , a n d
Ha logen a tion of 1,4-Dim eth oxyn a p h th a len e Der iva tives
Table 1 summarizes the results from our detailed
investigation of this novel chemistry. It is clear that the
reagent stoichiometry governs the reaction pathway. This
study also explored the scope and limitations of the
haloacetoxylation, halogenation, and acetoxylation reac-
tions of 1,4-dimethoxynaphthalenes with iodosobenzene
diacetate and trimethylsilyl halides.
The optimum conditions for the one-pot haloacetoxyl-
ation of the ethylene ketal 1 and 1,4-dimethoxynaphtha-
lene (4) required the sequential addition of iodosobenzene
diacetate and trimethylsilyl bromide, followed by 2 equiv
of iodosobenzene diacetate, to furnish 3-acetoxy-2-bromo-
1,4-dimethoxynaphthalene (2) in good yield (entries 1 and
2). The 1,4-dimethoxynaphthalene (4), available from
1,4-naphthoquinone, provides a versatile intermediate for
synthetic applications and demonstrates that the ethyl-
ene ketal is not essential for this reaction. Interestingly,
the attempted chloroacetoxylation of 1 and 4 under
similar conditions with trimethylsilyl chloride failed to
afford 9. Selective bromination of 1 and 4 was achieved
by simply reducing the amount of iodosobenzene diac-
etate (entries 3 and 4), and chlorination of 4 was achieved
using trimethylsilyl chloride (entry 5). The bromide 5
and chloride 6 could also be further brominated (entries
6 and 7), and in fact the dibromide 7 could be prepared
directly from the parent 1,4-dimethoxynaphthalene (4)
in a one-pot process (entry 8). The dibromide 7 provides
a useful benzyne surrogate for target directed synthesis.8
Interestingly, neither the bromide 5 or the chloride 6
chlorinated smoothly (see eqs 6 and 7). The selective
acetoxylation of 5 and 6 was also examined, in which the
corresponding haloacetoxylated adducts 2 and 9 were
obtained in good yields (entries 9 and 10).
a
Reactions were all run using 1 mmol of the 1,4-dimethoxy-
b
naphthalene. Method A: (i) PhI(OAc)2, TMSBr, 0 °C, (ii) PhI(O-
Ac)2, 0 °C to rt. Method B: PhI(OAc)2, TMSBr, 0 °C. Method C:
PhI(OAc)2, TMSCl, 0 °C to rt. Method D: (i) PhI(OAc)2, TMSBr, 0
°C to rt, (ii) PhI(OAc)2, TMSBr 0 °C to rt. Method E: PhI(OAc)2,
cat. TMSBr, 0 °C to rt. c Isolated yields.
to clarify the nature of the mechanism operative herein
with iodosobenzene diacetate, a mechanistic study was
undertaken. Preliminary analysis using UV spectroscopy
did not provide any evidence to support the existence of
a charge transfer complex between iodosobenzene diac-
etate or the iodosobenzene dihalide species with 1,4-
dimethoxynaphthalene (4), as had been proposed for the
more reactive iodosobenzene bis(trifluoroacetate).6 Fur-
thermore, the halogenation reactions occur in relatively
nonpolar solvents (CH2Cl2), which is in sharp contrast
to the substitutions reported with iodosobenzene bis(tri-
fluoroacetate) which require polar protic solvents
(CF3CH2OH).
The attempted extension of this chemistry to electron
rich benzene derivatives did not proceed as expected.
Treatment of the ethylene ketal 10 under the standard
brominating reaction conditions gave the bromo aldehyde
11 in 38% yield rather than the expected ipso-substitu-
tion product 12 (eq 2).
An alternative mechanistic hypothesis put forward by
Magnus and co-workers for silyl enol ethers proposes the
formation of an iodosobenzene dihalide species as the
electrophilic halogen source.7 However, our results in-
dicate that the chlorination and bromination reactions
were distinct from one another, in terms of their relative
rates of reaction and their substrate selectivity. The
bromination of 1,4-dimethoxynaphthalene (4) is, for
example, approximately 70 times faster than the analo-
gous chlorination reaction. The two reactions also have
contrasting specificity, as exemplified by their reaction
with the ethylene ketal 1. Bromination of 1 proceeds via
an ipso-substitution9 pathway to furnish the bromide
Mech a n istic Hyp oth esis for Ha logen a tion a n d
Acetoxyla tion Rea ction s
(a ) Ha logen a tion . Kita and co-workers proposed that
electron rich aryl ethers react with iodosobenzene bis-
(trifluoroacetate) to generate radical cations, which then
promote nucleophilic substitution.6 Therefore, in order
(8) Giles, R. G. F.; Hughes, A. B.; Sargent, M. V. J . Chem Soc.,
Perkin Trans. 1 1991, 1581.

Hypervalent Iodine Chemistry
J . Org. Chem., Vol. 62, No. 16, 1997 5323
5, while the chlorination under analogous conditions
afforded a mixture of 13, 14, and 15 (eq 3). This evidence
clearly suggests that the two reactions do not proceed via
the same mechanistic pathway.
NMR and UV-vis experiments confirm that iodosoben-
zene diacetate and trimethylsilyl bromide produce bro-
mine. Figure 1 depicts a series of NMR spectra that show
the clean and rapid (ca. 5 min) reduction of iodosobenzene
diacetate to iodobenzene in the absence of the substrate,
(Figure 1, A and B), which upon addition of 4 results in
conversion to 5 in ca. 5 min (Figure 1, C). Figure 2
provides a UV-vis absorbance trace illustrating rate of
consumption of bromine upon addition of the 1,4-
dimethoxynaphthalene (4).10,11 Treatment of 4 or the
ethylene ketal 1 with bromine also furnished the bromide
5 in excellent yield, confirming this assumption. Hence,
iodosobenzene diacetate/trimethylsilyl bromide provides
a convenient source of molecular bromine.
In order to gain further insight into the chlorination
reactions, a similar series of NMR experiments were
carried out to determine the nature of the chlorinating
species, as illustrated in Figure 3. Treatment of io-
dosobenzene diacetate with trimethylsilyl chloride leads
to a mixture of iodosobenzene dichloride and what
F igu r e 1. A ) PhI(OAc)2; B ) PhI(OAc)2/TMSBr affords PhI
and Br2 after 5 min; C ) PhI(OAc)2/TMSBr and 4 furnishes
PhI and 5 after 5 min.
(9) The regioselectivity and substrate specificity were examined in
order to confirm our assumptions with respect to the ipso-substitution
of the ethylene acetal 1. Treatment of the deuterated ethylene ketal i
(93% D incorporation) under the standard brominating conditions gave
the bromide ii (91% D incorporation) in 95% yield, confirming the
regiochemistry.
F igu r e 2. Plot of the UV-vis absorbance of Br2 (from
PhI(OAc)2, TMSBr) as a function of time upon addition of 1,4-
dimethoxynaphthalene (4): 1 ) 10 s, 2 ) 60 s, 3 ) 290 s, 4 )
1200 s.
This reaction appears to be specific for the ethylene ketal, since the
attempted bromination of the aldehyde iii and the ester iv did not
afford the ipso-substitution product 5.
appears to be the mixed iodosobenzene chloroacetate
species (Figure 3, B, and eq 4). Addition of the 1,4-
dimethoxynaphthalene (4) gave the chloride 6 (Figure 3,
D). The reaction is considerably slower than the analo-
gous bromination reaction, and iodobenzene is formed as
the reaction proceeds over ca. 6 h compared to 5 min
(compare Figure 1, C, to Figure 3, C). Furthermore, there
is only a trace amount of iodobenzene present in the NMR
spectrum until the addition of the substrate. Iodosoben-
zene dichloride has been shown to dissociate to iodoben-
zene and chlorine (eq 4), and the dissociation constant is
considerably lower in nonpolar solvents.12 Therefore, it
was entirely possible that the chlorinations described
herein could be the result of a slow dissociation to form
chlorine.
On the basis of these observations, it appears that the acetal facilitates
the ipso-substitution through the formation of the an oxonium ion, as
outlined in the proposed mechanism depicted below.
(10) The reducing power of the halide ions increases in the order
I- > Br- > Cl- > F-; Gusarsky, E.; Treinin, A. J . Phys. Chem. 1965,
69, 3176. Trimethylsilyl iodide is readily oxidized to iodine with
iodosobenzene diacetate. Treatment of the 1,4-dimethoxynaphthalene
(4) with this reagent combination gave none of the desired iodide.
(11) The λmax for the UV-vis absorbance for molecular bromine in
dichloromethane was confirmed independently.

5324 J . Org. Chem., Vol. 62, No. 16, 1997
Evans and Brandt
Sch em e 1
•
•
•
•
prepared in situ, resulted in the clean and rapid conver-
sion of 4 to 6 (98%) in ca. 30 min. Alternatively,
photolysis of 4 with a sunlamp, with in situ formation of
the reagent, furnished 6 (88%) in ca. 3.5 h. However,
increasing the amount of TEMPO (10 equiv) retarded the
rate of reaction significantly, with the reaction only 75%
complete after ca. 48 h. Indeed, the catalytic role of the
TEMPO is clearly demonstrated in the chlorination of 4
(eq 6), in which the dichloride 16 was obtained in ca. 2
h. The analogous transformation in the absence of
TEMPO fails to go to completion even after ca. 48 h,
affording a mixture of mono- and dichlorinated products.
F igu r e 3. A ) PhI(OAc)2; B ) PhI(OAc)2/TMSCl leads to a
∼1:1 mixture of PhIOAcCl/PhICl2 after 1.5 h; C ) PhI(OAc)2/
TMSCl and 4 furnishes a mixture containing PhI and 6 after
5 min; D ) PhI(OAc)2/TMSCl and 4 affords PhI and 6 after 6
h.
In order to test this hypothesis, the ethylene ketal 1
and the 1,4-dimethoxynaphthalene (4) were indepen-
dently treated with molecular chlorine, which resulted
in the rapid formation of 2,3-dichloro-1,4-dimethoxy-
naphthalene, in ca. 2 min, in addition to polychlorinated
products (eq 5). The increased rate of reaction and poor
selectivity are in complete contrast to the reagent derived
from iodosobenzene diacetate and trimethylsilyl chloride.
Furthermore, the ipso-substitution pathway of ethylene
ketal 1 is not operative (see, eq 7) with the hypervalent
iodine derived reagent and thus provides clear evidence
for an alternative mechanistic pathway clearly demon-
strating that chlorine is not the reagent responsible for
the chlorination reactions.
The last piece of evidence to support the existence of a
radical chlorination process was obtained from the at-
tempted chlorination of the bromide 5, in which scram-
bling of the halogens was observed (eq 7).
It was also possible that iodosobenzene dichloride was
the reagent responsible for the chlorinations. To test this
hypothesis an authentic sample was prepared from
iodosobenzene and trimethylsilyl chloride.7 Treatment
of 4 with iodosobenzene dichloride nearly doubled the
rate of reaction (3.5 h) and furnished the chloride 6 in
92% yield. Further insight into the possible reactive
species was gained from the following experiments.
Addition of a catalytic amount of the stable free radical
TEMPO13 (10 mol %) to the reaction, with the reagent
Therefore, the chlorination presumably involves a
radical process rather than an electrophilic pathway
involving chlorine as outlined in Scheme 1. Homolysis
of iodosobenzene diacetate can presumably provide a
chlorine radical which then adds to the 1,4-dimethoxy-
naphthalene (4) to furnish 17. The radical intermediate
then undergoes a single electron transfer to afford 18,
iodobenzene, and chloride ion. The chloride ion then
facilitates rearomatization to afford the chlorinated 1,4-
dimethoxynaphthalene 6 and hydrogen chloride.
(12) (a) Keefer, R. M.; Andrews, L. J . J . Am. Chem. Soc. 1956, 78,
5350. (b) McCusker, P. A.; Makowski, H. S. J . Am. Chem. Soc. 1957,
79, 5185. (c) J effrey, E. A.; Andrews, L. J .; Keefer, R. M. J . Org. Chem.
1965, 30, 617. (d) Olah, G. A.; Piteau, M.; Laali, K.; Rao, C. B.; Farooq,
O. J . Org. Chem. 1990, 55, 46.
(13) For an example of TEMPO as a radical trap in hypervalent
iodine chemistry, see: Togo, H.; Aoki, M.; Kuramochi, T.; Yokoyama,
M. J . Chem. Soc., Perkin Trans. 1 1993, 2417.

Hypervalent Iodine Chemistry
Sch em e 2
J . Org. Chem., Vol. 62, No. 16, 1997 5325
would give an ene-oxonium ion species 21 which could
facilitate the acetyl migration. Rearomatization of the
carbocation intermediate 22 would then give the acetoxyl-
ated bromide 2.14 This is in complete contrast to the more
general reaction pathway in which 1,2- rather than 1,4-
addition predominates and also explains the observed
regiochemistry.15
•
In conclusion, we have developed a novel method for
the haloacetoxylation, acetoxylation, and halogenation,
of 1,4-dimethoxynaphthalenes using hypervalent iodine
chemistry. A mechanistic hypothesis is forwarded that
provides a plausible explanation for the difference in the
halogenation reactions, based on oxidation potentials of
the halide source, and the reason for the required
stoichiometry (PhI(OAc)2/TMSX) to effect both the halo-
genation and acetoxylation reactions. Interestingly, the
haloacetoxylation reaction may be envisioned as the
formal addition of AcOX to a benzyne, and it appears to
be specific for 1,4-dimethoxynaphthalene derivatives.
Although, the bromination reaction provides no real
advantage over molecular bromine, the ability to selec-
tively chlorinate with the hypervalent iodine reagent is
likely to have numerous synthetic applications in light
of our mechanistic findings.
•
•
Sch em e 3
Exp er im en ta l Section
Gen er a l. The chemical shifts of the 1H NMR and 13C NMR
spectra were all recorded relative to chloroform or benzene.
Multiplicity’s were determined with the aid of a APT sequence,
separating methylene and quaternary carbons ) e (even) from
methyl and methine ) o (odd). Melting points are uncorrected.
GLC analysis was carried out using an HP 6890 Series GLC
system using an HP-1 (cross-linked methylsiloxane) capillary
column (flow rate: 1 mL/min). UV experiments were per-
formed on a Hewlett-Packard HP8452A diode-array spectro-
photometer. All compounds were purified as specified and
gave spectroscopic data consistent with being g95% the
assigned structure. Analytical TLC was carried out on pre-
coated 0.2 mm thick Merck 60 F254 silica plates. Flash
chromatography was carried out using Merck silica gel 60
(230-400 mesh).
All reagents and starting materials were obtained from
commercial suppliers (Acros, Aldrich, Fluka, and Lancaster)
and were used without purification except where indicated.
Dichloromethane was dried over and freshly distilled from
calcium hydride. All reactions were carried out under an inert
atmosphere of dry nitrogen using oven-dried or flame-dried
glassware.
3-Acet oxy-2-b r om o-1,4-d im et h oxyn a p h t h a len e (2).
Meth od A. Iodosobenzene diacetate (0.361 g, 1.12 mmol) was
dissolved in anhydrous dichloromethane (6 mL) and cooled
with stirring to 0 °C. Neat trimethylsilyl bromide (300 µL,
2.25 mmol) was added, and the mixture stirred at 0 °C for 30
min, resulting in a clear orange solution. 1,4-Dimethoxynaph-
thalene-2-carboxaldehyde ethylene ketal (1) (0.263 g, 1.01
mmol) was dissolved in anhydrous dichloromethane (2 mL)
and added via a Teflon cannula. The reaction mixture was
stirred for 1 h at 0 °C, resulting in the complete conversion of
1 to 5 (TLC control; 1:4 ethyl acetate/hexane). Additional
iodosobenzene diacetate (0.652 g, 2.02 mmol) was then added
in one portion, and the reaction mixture was stirred for a
further hour at 0 °C. The reaction mixture was then warmed
The proposed catalytic role of TEMPO is outlined in
Scheme 2. TEMPO can accelerate the initial rate of
homolysis of iodosobenzene dichloride and the formation
of a chloride radical. The hypervalent iodine/TEMPO
adduct can then undergo further homolysis to regenerate
the TEMPO which recatalyzes the initial homolysis. The
hypervalent iodine radical that is formed is then likely
to undergo single electron transfer. Although the exact
mechanistic pathway is not known, this working hypoth-
esis is consistent with the experimental results.
(b) Acetoxyla tion . The nature of the acetoxylation
reaction was clarified from the following results. Pre-
liminary studies demonstrated that the acetoxylation
occurred with iodosobenzene diacetate and catalytic
trimethylsilyl bromide. This combination had been
demonstrated to furnish molecular bromine; hence it was
unlikely that the trimethylsilyl bromide was directly
responsible. The byproduct from the halogenation is
hydrogen bromide. Indeed, treatment of the bromide 5
with iodosobenzene diacetate and a catalytic amount of
hydrogen bromide furnished the acetoxylated bromide 2
in 74% yield (eq 8).
(14) For an example of a similar mechanism for the acetoxylation
of p-substituted acetanilides, see: Kokil, P. B.; Patil, S. D.; Ravin-
dranathan, T.; Madhavan Nair, P. Tetrahedron Lett. 1979, 989.
(15) (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton,
J . S. J . Org. Chem. 1992, 57, 2135. (b) Wipf, P.; Kim, Y.; Fritch, P. C.
J . Org. Chem. 1993, 58, 7195. (c) Mitchell, A. S.; Russell, R. A.
Tetrahedron Lett. 1993, 34, 545. (d) Pelter, A.; Elgendy, A. M. A. J .
Chem. Soc., Perkin Trans. 1 1993, 1891. (e) McKillop, A.; McLaren,
L.; Taylor, R. J . K. J . Chem. Soc., Perkin Trans. 1 1994, 2047. (f) Kita,
Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.; Fujita, S.; Tohma,
H. J . Org. Chem. 1996, 61, 223 and pertinent references cited therein.
Therefore, the proposed mechanism for acetoxylation
is outlined in Scheme 3. The formation of the iodonium
ion 19 facilitates the 1,2-addition of the acetate ion to
the oxonium ion. â-Elimination of the iodonium ion

5326 J . Org. Chem., Vol. 62, No. 16, 1997
Evans and Brandt
to room temperature and partitioned between saturated aque-
ous NaHCO3 solution and dichloromethane. The organic
layers were combined, dried (Na2SO4), and filtered, and the
solvent was removed in vacuo to afford the crude product.
Purification by flash chromatography on silica gel (eluting with
1:9 ethyl acetate/hexane) furnished the title compound 2 (0.248
g, 75%) as an off-white crystalline solid.
Meth od B. 2-Bromo-1,4-dimethoxynaphthalene (5) (0.27
g, 1.01 mmol) was dissolved in anhydrous dichloromethane (10
mL) and cooled with stirring to 0 °C. Iodosobenzene diacetate
(0.724 g, 2.25 mmol) was added to the solution followed by
addition of neat trimethylsilyl bromide (34 µl, 0.25 mmol). The
reaction mixture was stirred at 0 °C for an hour before being
allowed to warm to room temperature where it was stirred
for an additional hour. The reaction mixture was partitioned
between saturated aqueous Na2S2O4 solution and dichlo-
romethane. The organic layers were combined, dried (Na2SO4),
and filtered, and the solvent wars emoved in vacuo to afford
the crude product. Purification by flash chromatography on
silica gel (eluting with 1:9 ethyl acetate/hexane) furnished the
title compound 2 (0.250 g, 76%) as an off-white crystalline
solid.
Meth od C. Iodosobenzene diacetate (0.361 g, 1.11 mmol)
was dissolved in anhydrous dichloromethane (6 mL) and cooled
with stirring to 0 °C. Neat trimethylsilyl bromide (300 µL,
2.25 mmol) was added, and the mixture was stirred at 0 °C
for 30 min, resulting in a clear orange solution. 1,4-Dimeth-
oxynaphthalene (4) (0.191 g, 1.01 mmol) was dissolved in
anhydrous dichloromethane (2 mL) and added via Teflon
cannula. The reaction mixture was stirred for 40 min at 0
°C, resulting in the complete conversion of 4 to 5 by thin layer
chromatography (1:4 ethyl acetate/hexane). Additional io-
dosobenzene diacetate (0.722 g, 2.22 mmol) was then added
to the reaction in one portion. The reaction mixture was
stirred for 10 min at 0 °C and then partitioned between a
saturated aqueous Na2S2O4 solution and dichloromethane. The
organic layers were combined, dried (Na2SO4), and filtered,
and the solvent was removed in vacuo to afford the crude
product. Purification by flash chromatography on silica gel
(eluting with 1:9 ethyl acetate/hexane) furnished the title
compound 2 (0.266 g, 80%) as an off-white crystalline solid:
mp 130-131 °C; IR (CHCl3) 1776 (s), 1584 (m) cm-1; 1H NMR
(250 MHz, CDCl3) δ 8.06-8.13 (m, 2H), 7.50-7.59 (m, 2H),
3.98 (s, 3H), 3.94 (s, 3H), 2.44 (s, 3H); 13C NMR (62.5 MHz,
CDCl3, APT) δ 168.28 (e), 150.69 (e), 144.69 (e), 137.70 (e),
128.05 (e), 127.36 (e), 127.03 (o), 126.86 (o), 122.54 (o), 122.39
(o), 109.49 (e), 62.04 (o), 61.66 (o), 20.65 (o); HRMS (M+) calcd
for C14H13O280Br 323.9997, found 323.9993.
(e), 127.31 (o),125.60 (o), 125.30 (e), 122.50 (e), 122.42 (o),
121.61 (o), 105.50 (o), 61.26 (o), 55.76 (o); HRMS (M+) calcd
for C12H11O2Cl 222.0447, found 222.0458.
3-Acet oxy-2-ch lor o-1,4-d im et h oxyn a p h t h a len e (9).
2-Chloro-1,4-dimethoxynaphthalene (6) (0.226 g, 1.02 mmol)
was dissolved in anhydrous dichloromethane (10 mL) and
cooled with stirring to 0 °C. Iodosobenzene diacetate (0.654
g, 2.25 mmol) was added to the solution followed by addition
of neat trimethylsilyl bromide (34 µL, 0.25 mmol). The
reaction mixture was stirred at 0 °C for an hour before being
allowed to warm to room temperature where it was stirred
for an additional hour. The reaction mixture was partitioned
between a saturated aqueous NaHCO3 solution and dichlo-
romethane. The organic layers were combined, dried (Na2SO4),
and filtered, and the solvent was removed in vacuo to afford
the crude product. Purification by flash chromatography on
silica gel (eluting with 1:9 ethyl acetate/hexane) furnished the
title compound 9 (0.202 g, 71%) as an off-white crystalline
solid: mp 119-124 °C; IR (CHCl3) 1778 (s), 1589 (m) cm-1; 1H
NMR (250 MHz, CDCl3) δ 8.06-8.11 (m, 2H), 7.50-7.56 (m,
2H), 3.99 (s, 3H), 3.94 (s, 3H), 2.44 (s, 3H); 13C NMR (62.5
MHz, CDCl3, APT) δ 168.29 (e), 149.20 (e), 144.64 (e), 136.82
(e), 127.39 (e), 127.18 (e), 126.88 (o), 126.84 (o), 122.37 (o),
122.16 (o), 118.72 (e), 62.00 (o), 61.58 (o), 20.45 (o); HRMS (M+)
calcd for C14H13O4Cl 280.0502, found 280.0506.
2,3-Dich lor o-1,4-d im eth oxyn a p h th a len e (16). Trimeth-
ylsilyl chloride (195 µL, 2.21 mmol) was added to a solution of
iodosobenzene diacetate (0.363 g, 1.11 mmol) in anhydrous
dichloromethane (5 mL) at 0 °C and stirred for ca. 1 h. 1,4-
Dimethoxynaphthalene (4) (0.195 g, 1.04 mmol) and TEMPO
(0.016 g, 10 mol %) were dissolved in anhydrous dichlo-
romethane (2 mL) and then added via Teflon cannula to the
reaction mixture. The reaction mixture was stirred for 1 h at
0 °C (TLC control for 4 to 6; 1:4 ethyl acetate/hexanes).
Trimethylsilyl chloride (198 µL, 2.24 mmol) was then added
to a second portion of iodosobenzene diacetate (0.369 g, 1.12
mmol) in anhydrous dichloromethane (5 mL) at 0 °C and
stirred for ca. 1 h. The solution of 6 was then added via Teflon
cannula to this solution at 0 °C and the reaction warmed to
room temperature and stirred for ca. 1 h. The reaction mixture
was then concentrated in vacuo to afford a crude product which
was purified by flash chromatography on silica gel (eluting
with 1:39 then 1:19 ethyl acetate/hexane) to furnish the title
compound 1617 (0.226 g, 88%) as an off-white crystalline
solid: mp 105-107 °C; IR (CHCl3) 2937 (w), 1563 (m) cm-1
;
1H NMR (250 MHz, CDCl3) δ 8.04-8.12 (m, 2H),7.52-7.59 (m,
2H), 3.98 (s, 6H); 13C NMR (62.5 MHz, CDCl3, APT) δ 149.65
(e), 127.58 (e), 127.22 (o), 122.94 (e), 122.29 (o), 61.39 (o);
HRMS (M+) calcd for C12H10O2Cl2 256.0057, found 256.0074.
2-Ch lor o-1,4-d im eth oxyn a p h th a len e (6). Iodosobenzene
diacetate (0.395 g, 1.22 mmol) was dissolved in anhydrous
dichloromethane (6 mL) and the opaque solution cooled to 0
°C with stirring. Neat trimethylsilyl chloride (212 µL, 2.45
mmol, freshly distilled from CaH2) was added, and the mixture
was stirred at 0 °C for 1 h, resulting in a slightly yellow
solution. 1,4-Dimethoxynaphthalene (4) (0.209 g, 1.10 mmol)
was dissolved in dichloromethane (2 mL) and then added via
Teflon cannula, resulting in a more intense yellow color. The
reaction mixture was stirred for 1 h at 0 °C and then warmed
to room temperature and stirred for 5 h. The solvent was then
removed in vacuo to afford the crude product. Purification by
flash chromatography on silica gel (eluting with 1:49 and then
1:19 ethyl acetate/hexane) furnished the title compound 616
(0.205 g, 83%) as a white crystalline solid: mp 76-80 °C; IR
(CHCl3) 3013 (m), 2939 (m), 1622 (m), 1582 (s) cm-1; 1H NMR
(250 MHz, CDCl3) δ 8.18-8.22 (m, 1H), 8.04-8.08 (m, 1H),
Ack n ow led gm en t. We thank the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for generous financial support.
Professor Colin Thorpe is thanked for advice and
assistance with the UV experiments.
Su p p or tin g In for m a tion Ava ila ble: Experimental details
for the preparation and full characterization of 1, 4-5, 7-8,
16, and ii, in addition to 1H-NMR spectra for compounds 1-2,
4-9, 16, and ii (17 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
7.44-7.59 (m, 2H), 6.74 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H); 13
C
NMR (62.5 MHz, CDCl3, APT) δ 152.15 (e), 145.36 (e), 129.05
J O970525I
(16) Laatsch, H. Liebigs Ann. Chem. 1980, 140.
(17) Inoue, A.; Kuroki, N.; Konishi, K. Chem. Abstr. 1961, 55, 13853f.