Solvolysis of 4-halogeno-4-alkyl-2,6-di-tert-butylcyclohexa-2,5-dienones induced by positive halogen donors as electrophiles

Article abstract of DOI:10.1071/CH13257

Positive halogen donors such as N-iodosuccinimide (NIS) induce solvolysis of dienones 1, as model 4-halogenocyclohexa-2,5-dienones, in different hydroxylic solvents (ROH), yielding the 4-RO-cyclohexa-2,5-dienones (2). The rate of the solvolysis with NIS is highly dependent on the structure of ROH. The problem of such dependency is overcome by running the reaction in ROH diluted with MeCN, a polar aprotic solvent, in place of pure ROH; the rate of the reaction in the ROH-MeCN solvent mixture is almost independent of the structure (or the polarity) of ROH, and the reaction is completed faster or markedly faster than in neat ROH. The results suggest that the solvolysis rate is controlled by the polarity of the solvent system, although the hydrogen-bond acceptability of MeCN for dilution also accelerates the reaction. A mechanism for the solvolysis is proposed, involving electrophilic attack of a positive halogen donor at the halogen atom of 1, generating the 4-oxocyclohexa-2,5-dienyl cation intermediates (8) via the rate-limiting polar transition states. CSIRO 2013.

Full text of DOI:10.1071/CH13257

CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 1386–1392
Full Paper
http://dx.doi.org/10.1071/CH13257
Solvolysis of 4-Halogeno-4-Alkyl-2,6-di-tert-
butylcyclohexa-2,5-dienones Induced by Positive
Halogen Donors as Electrophiles
Kanji Omura
College of Nutrition, Koshien University, Momijigaoka, Takarazuka, Hyogo 665-0006,
Japan. Current address: 2-10-26-204, Sakaemachi, Takarazuka, Hyogo 665-0845,
Japan. Email: omura.k@ion.ocn.ne.jp
Positive halogen donors such as N-iodosuccinimide (NIS) induce solvolysis of dienones 1, as model 4-halogenocyclohexa-
2,5-dienones, in different hydroxylic solvents (ROH), yielding the 4-RO-cyclohexa-2,5-dienones (2). The rate of the
solvolysis with NIS is highly dependent on the structure of ROH. The problem of such dependency is overcome by running
the reaction in ROH diluted with MeCN, a polar aprotic solvent, in place of pure ROH; the rate of the reaction in the ROH-
MeCN solvent mixture is almost independent of the structure (or the polarity) of ROH, and the reaction is completed faster
or markedly faster than in neat ROH. The results suggest that the solvolysis rate is controlled by the polarity of the solvent
system, although the hydrogen-bond acceptability of MeCN for dilution also accelerates the reaction. A mechanism for the
solvolysis is proposed, involving electrophilic attack of a positive halogen donor at the halogen atom of 1, generating the
4-oxocyclohexa-2,5-dienyl cation intermediates (8) via the rate-limiting polar transition states.
Manuscript received: 15 May 2013.
Manuscript accepted: 14 July 2013.
Published online: 21 August 2013.
But
But
O
But
O
Introduction
H
ꢀ
H
H
ꢁ
Previously, we studied the reaction of 2,6-di-tert-butylphenol
with I2 and H2O2 in MeOH, and proposed that it involves gen-
eration of the 4-iodocyclohexa-2,5-dienone, a short-lived inter-
mediate, and that the dienone is electrophilically deiodinated by
I2 generating the 4-oxocyclohexa-2,5-dienyl cation, to which
MeOH adds giving the 4-methoxycyclohexa-2,5-dienone,
another short-lived intermediate (Eqn 1).[1] We assumed that
4-halogenocyclohexa-2,5-dienonesingeneral are inthesameway
solvolysed by the assistance of positive halogen donors, sources
ofpositivehalogen. Toprove the assumption, a limited numberof
stable 4-halogenocyclohexa-2,5-dienones, the title dienones (1),
were chosen as model substrates, and solvolysis of 1 by different
hydroxylic solvents in the presence of a positive halogen donor
was closely investigated (Eqn 2). Such a study needed to be
carefullydone, because 4-halogenocyclohexa-2,5-dienones have
been shown to be solvolysed spontaneously by hydroxylic
solvents. Thus, 4-bromo-4-methyl-2,6-di-tert-butylcyclohexa-
2,5-dienone (1bj) is converted to 4-methoxy-4-methyl-2,6-di-
tert-butylcyclohexa-2,5-dienone (2bv) when dissolved in
MeOH.[2] Likewise, 4-bromo-2,4,6-tri-tert-butylcyclohexa-2,5-
O
ꢀ
I2 ꢀ I
MeOH
I I
I
OMe
But
But
But
ð1Þ
But
But
Rꢂ
Rꢂ
Positive halogen donor
ROH
O
O
OR
X
But
But
2
1
a: Rꢂ ꢃ t-Bu
b: Rꢂ ꢃ Me
j: X ꢃ Br
k: X ꢃ Cl
u: R ꢃ H
v: R ꢃ Me
w: R ꢃ Et
x: R ꢃ i-Pr
y: R ꢃ t-Bu
z: R ꢃ Ac
ð2Þ
dienone
(1aj),[3]
4-bromo-2,4,6-trimethylcyclohexa-2,5-
dienone,[3] and 4-chloro-4-methylcyclohexa-2,5-dienones
bearing a methyl or chloro substituent at the 2- and 6-positions[4]
are solvolysed by MeOH and/or H2O at room temperature,
although some of these solvolyses are too slow to be practical.
The spontaneous solvolysis with hydroxylic solvents other than
H2O and MeOH appears unknown. Thus, spontaneous solvo-
lysis of 1 was also investigated for comparison. This paper
reports the results of such a study.
Results and Discussion
To start with, we examined the effect of different positive hal-
ogen reagents on the methanolysis of 1aj (Table 1). The reaction
was carried out at 08C or 358C by adding 1aj in one portion to
MeOH containing or not containing 1 molar equivalent of a
positive halogen donor and stirring the resulting mixture.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

Halide Solvolysis Induced by Positive Halogen Donors
1387
Table 1. Spontaneous and positive halogen donor-assisted solvolysis of
1aj in MeOHA
Table 2. Spontaneous and NIS-assisted solvolysis of 1aj in ROHA
Run ROH
Donor Temp Time
Recovery
Product [%]B
Run Donor Temp [8C] Time [min] Recovery of 1aj [%]B Product [%]B
[8C]
[min] of 1aj [%]B
2a
3a
2av
3a
1C
2D
3
MeOH
MeOH
EtOH
35
0
15
15
30
30
30
15
30
20
30
30
30
30
30
15
59
0
2av (36)
2av (100)
2aw (0)
2aw (24)
2aw (6)
2aw (100)
2ax (0)
3
4
1
2
3
4
5
6
7
8
9
0
35
0
30
15
30
30
30
15
11
15
15
100
59
35
6
tr
36
NIS
3
35
55
0
100
72
94
0
Br2
65
4
EtOH
I2
0
71
21
5
EtOH
NIS
NIS
NBS
NBS
NIS
NIS
DIHC
0
100
0
tr
6
EtOH
35
55
82E
35
55
83E
35
75
35
35
0
100
88
7
i-PrOH
i-PrOH
100
3
tr
12
0
8
2ax (4)
93
0
100
100
9
i-PrOH NIS
i-PrOH NIS
t-BuOH NIS
AcOH
93
0
2ax (7)
0
0
10
11
12
13
14
2ax (97)
2ay (0)
3
100
100
72
0
ACarried out with 1aj (2 mmol) in MeOH (30 mL) containing or not con-
taining a positive halogen donor (2 mmol).
BDetermined by 1H NMR.
2az (0)
AcOH
2az (2)
17
AcOH
NIS
2az (100)
CUsing 1 mmol.
ACarried out with 1aj (2 mmol) in ROH (30 mL) containing or not con-
taining NIS (2 mmol).
BDetermined by 1H NMR.
Positive halogen donors employed were Br2, I2, N-bromo-
succinimide (NBS), N-iodosuccinimide (NIS), and 1,3-diiodo-
5,5-dimethylhydantoin (DIH), all of which are readily available
or easily accessible. The yields of the products were determined
CIdentical with run 2, Table 1.
DIdentical with run 8, Table 1.
EReflux temperature.
1
by H NMR spectroscopy. The reaction in MeOH without an
additive, which, as described above, has been already studied,[3]
at 08C for 30 min resulted in practically quantitative recovery of
1aj (run 1), while at 358C reaction was found to be reasonably
fast, giving 4-methoxy-2,4,6-tri-tert-butylcyclohexa-2,5-
dienone (2av) principally and a small amount of 2,4,6-tri-tert-
buylphenol (3a) (run 2). In the presence of Br2, I2, NIS, or DIH,
the reaction took place smoothly at 08C (runs 3, 4, 7 and 8, and
9). The yield of 2av was quantitative except that the reaction
with I2 afforded a significant amount of 3a as a by-product.
Employment of 0.5 molar equivalents of DIH sufficed to com-
plete the reaction. NBS was effective in promoting the methano-
lysis at 358C but not at 08C (runs 5 and 6). The positive halogen
donors thus can indeed assist the methanolysis of 1aj, and NIS
and DIH are most effective, with which the reaction is fast and
clean. The studies on solvolysis of 1 that followed were con-
ducted by using NIS as the positive halogen donor.
Solvolysis with or without NIS of 1aj in different kinds of
hydroxylic solvents (henceforth ROH; R ¼ H, Me, Et, i-Pr, t-Bu,
and Ac) at different temperatures was attempted, and the results
are shown in Table 2. Unlike the unassisted reaction of 1aj in
MeOH (run 1, identical with run 2, Table 1), that in EtOH did not
proceed at all at 358C (run 3). Even at 558C, the solvolysis was
reluctant and only a small amount of 4-ethoxy-2,4,6-tri-tert-
butylcyclohexa-2,5-dienone (2aw) was found to form (run 4). In
the presence of NIS, however, the ethanolysis was completed
quickly at 358C and gave 2aw quantitatively (run 6), although it
was quite slow at 08C (run 5). Spontaneous decomposition of 1aj
in i-PrOH proved even slower than that in EtOH; almost all of
1aj was recovered intact after the treatment with i-PrOH at 558C
for 30 min (run 7). In refluxing i-PrOH, 1aj decomposed
smoothly. However, the principal product was 3a and the
expected product, 4-isopropoxy-2,4,6-tri-tert-butylcyclohexa-
2,5-dienone (2ax), was obtained only as a minor product (run 8).
The sluggish and fast, spontaneous reductive debromination
of 1aj with i-PrOH at 258C[3] and at reflux temperature,[5]
respectively, has been previously reported. The mechanism of
the reduction of 1aj by i-PrOH has been explored.[3] The
NIS-assisted solvolysis of 1aj in i-PrOH was quite slow at
358C (run 9), but fast enough at 558C to be complete in 30 min
and gave 2ax nearly quantitatively together with a small amount
of 3a (run 10). Dienone 1aj was found unreactive in t-BuOH at
reflux temperature even in the presence of NIS (run 11). Finally,
the reaction of 1aj with AcOH was attempted. The reaction
without NIS did not occur at 358C (run 12). Even at 758C, it took
place slowly and gave a mixture of products including only a
small amount of 4-acetoxy-2,4,6-tri-tert-butylcyclohexa-2,5-
dienone (2az) (run 13). In contrast, the reaction with NIS
finished quickly at 358C and 2az was obtained cleanly (run
14). Thus, NIS can assist or induce solvolysis of 1aj not only
with MeOH but also with EtOH, i-PrOH, and AcOH.
We then studied the NIS-assisted solvolysis of 1aj in ROH
diluted with an aprotic solvent (Table 3). The reaction was
carried out by using a 1 : 9 (v/v) solvent mixture of ROH and an
aprotic solvent (henceforth ROH/aprotic-solvent). At 08C, the
solvolysis in MeOH/MeCN was found complete in a short time
1
(5 min) providing 2av quantitatively as estimated by H NMR
spectroscopy. The yield of 2av isolated by column chromato-
graphy was 97 % (run 6). This methanolysis was somewhat
faster than in neat MeOH (run 2, Table 2). No reaction of 1aj
took place in MeOH/MeCN if NIS was omitted (run 1). It did
occur at 358C, but was significantly slower than that in MeOH
(run 2, compare with run 1, Table 2). The following other
reactions of 1aj were all conducted at 08C. The assisted
methanolysis in MeOH/acetone (run 7) and MeOH/MeNO2
(run 8) was as fast as that in MeOH/MeCN. However, the
assisted methanolysis in MeOH/CHCl3 (run 3), MeOH/
1,2-dimethoxyethane (DME) (run 4), or MeOH/PhMe (run 5)
did not proceed to any appreciable extent even after 30 min
reaction. The assisted solvolysis of 1aj in EtOH/MeCN (run 9),
i-PrOH/MeCN (run 10), H2O/MeCN (run 12), and AcOH/
MeCN (run 13) turned out to be apparently equally fast as
that in MeOH/MeCN, giving 2aw, 2ax, 4-hydroxy-2,4,6-tri-
tert-butylcyclohexa-2,5-dienone (2au), and 2az, respectively,
quantitatively or nearly quantitatively. No phenol 3a was
obtained from run 10. The assisted reaction of 1aj in t-BuOH/
MeCN was also completed fast at the low temperature and gave

1388
K. Omura
Table 3. NIS-assisted solvolysis of 1aj in ROH/aprotic-solventA
Table 4. Spontaneous and NIS-assisted solvolysis of 1ak in ROH and
ROH/MeCNA
Run
ROH
Aprotic
solvent
Time
[min]
Recovery
of 1aj [%]B
Product [%]B
2a
Run Solvent
Donor
Time
Recovery
Product [%]B
[min] of 1ak [%]B
2a
1C
2C,D
3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
CHCl3
DME
30
15
30
30
30
5
100
92
2av (0)
2av (8)
1
MeOH
180
180
30
30
5
62
100
10
2av (36)
2av (tr)
100
100
100
0
2av (tr)
2
MeOH/MeCN
MeOH
4
2av (tr)
3
4C
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
2av (90)
2av (0)
5
PhMe
2av (tr)
MeOH/MeCN
MeOH/MeCN
EtOH
100
0
6
MeCN
Acetone
2av (100E)
2av (84)
2au (16)
2av (100)
2aw (100)
2ax (100)
2ay (66F)
2au (22F)
2au (100)
2az (96)
2au (4)
5
2av (100)
2aw (0)
7
5
0
6
30
5
100
0
7
EtOH/MeCN
i-PrOH
2aw (100)
2ax (0)
8
MeOH
EtOH
MeNO2
MeCN
MeCN
5
5
5
5
0
0
0
0
8
30
5
100
0
9
9
i-PrOH/MeCN
t-BuOH/
2ax (100)
2ay (16)
2au (19)
2au (100)
2az (84)
10
11
i-PrOH
10
5
40
t-BuOH MeCN
MeCN
11
12
H2O/MeCN
AcOH/MeCN
NIS
NIS
5
5
0
5
12
13
H2O
MeCN
MeCN
5
5
0
0
AcOH
ACarried out at 358C with 1ak (2 mmol) in ROH (30 mL) or a mixture of
ROH (3 mL) and MeCN (27 mL), containing or not containing NIS
ACarried out at 08C with 1aj (2 mmol) and NIS (2 mmol) in a mixture of
ROH (3 mL) and an aprotic solvent (27 mL).
BDetermined by 1H NMR.
(2 mmol).
BDetermined by 1H NMR.
CReaction at 08C.
CNIS was omitted.
DReaction carried out at 358C.
EYield after column chromatography was 97 %.
FYield after column chromatography.
Table 5. Spontaneous solvolysis of 1bj and 1bk in ROH and their
NIS-assisted solvolysis in ROH/MeCNA
Run 1b Solvent
Donor Time Recovery Product [%]B
4-tert-butoxy-2,4,6-tri-tert-butylcyclohexa-2,5-dienone (2ay)
in 66 % yield together with 2au (22 %), as isolated by column
chromatography (run 11). As is apparent from the results
shown in Tables 2 and 3, the NIS-assisted solvolysis of 1aj in
ROH/MeCN was faster or much faster than that in pure ROH.
The difference between the rates of the assisted solvolysis in
t-BuOH/MeCN and in pure t-BuOH (run 11, Table 2) was
most dramatic.
[min] of 1b [%]
2b
1C
2
3C
1bj MeOH
30
5
0
0
2bv (79)D
2bv (90)
2bw (35E)
2bw (89)
2bx (24E)
2bx (87)
2by (6)F
1bj MeOH/MeCN NIS
1bj EtOH
30
5
18E
4
1bj EtOH/MeCN
1bj i-PrOH
NIS
0
5C
6
120
5
41E
0
1bj i-PrOH/MeCN NIS
7
1bj t-BuOH/
MeCN
NIS
5
0
Spontaneous and NIS-assisted solvolysis of 4-chloro-2,4,6-
tri-tert-butylcyclohexa-2,5-dienone (1ak) was also investigated
at 358C, and the results are shown in Table 4. Unassisted reaction
of 1ak in MeOH took place to afford 2av but proceeded much
slower than that of 1aj (run 1, compare with run 1, Table 2), and
the reaction of 1ak in MeOH/MeCN hardly progressed (run 2).
The NIS-assisted solvolysis in MeOH proceeded significantly
faster than the unassisted process in the same solvent (run 3).
The assisted reaction in MeOH/MeCN was finished even faster,
taking only a short time (5 min) (run 5), although it did not occur
at 08C (run 4). The solvolysis in EtOH and in i-PrOH did not take
place even in the presence of NIS (runs 6 and 8), while the
assisted solvolysis in EtOH/MeCN and in i-PrOH/MeCN was
completed as rapidly as that in MeOH/MeCN and gave 2aw and
2ax, respectively (runs 7 and 9). The assisted hydrolysis in H2O/
MeCN was analogously rapid and gave 2au cleanly (run 11).
The assisted solvolysis in t-BuOH/MeCN and in AcOH/MeCN
was somewhat slower, and the yields of 2ay and 2az, respec-
tively, was unsatisfactory or not quantitative (runs 10 and 12).
The reaction in t-BuOH/MeCN was anomalous; even when the
reaction time was extended to 30 min, a significant amount of
1ak still remained intact and the amounts of unidentified
products increased. The effect of NIS on the solvolysis of 1ak
showed basically the same trend as was observed in the
solvolysis of 1aj, although the solvolysis of 1ak, assisted or
unassisted, was slower than that of 1aj.
8
1bj H2O/MeCN
1bk MeOH
NIS
13
30
5
0
24E
0
2bu (95)
2bv (57E,G
2bv (94)
2bw (90)
2bx (93)
2bu (96)
9C
10
11
12
13
)
1bk MeOH/MeCN NIS
1bk EtOH/MeCN NIS
1bk i-PrOH/MeCN NIS
1bk H2O/MeCN NIS
5
0
5
0
13
0
ACarried out at 08C with 1bj or 1bk (2 mmol) in ROH (30 mL) or in a mixture
of ROH (3 mL) and MeCN (27 mL), containing or not containing NIS
(2 mmol).
BYield after column chromatography.
CReaction at 258C.
DIn addition, 4 (12 %) was obtained.
EDetermined by 1H NMR.
FIn addition, 5 (43 %) and 6 (38 %) were obtained.
GIn addition, 4 (10 %) was obtained.
spontaneous solvolysis in ROH and the NIS-assisted reaction in
ROH/MeCN were attempted and the results were compared. For
the product analysis, column chromatography was employed in
most cases. According to the previous study, the yield of 2bv
from spontaneous solvolysis of 1bj in MeOH at room tempera-
ture is quantitative.[2] The reaction was reinvestigated in this
laboratory; addition of 1bj to MeOH and stirring the resulting
mixture for 30 min at 258C provided 2bv (79 %) and 4-hydroxy-
3,5-di-tert-butylbenzyl methyl ether (4) (12 %) (run 1).
A similar treatment of 1bj with EtOH in place of MeOH
Finally, solvolysis of 1bj and 4-chloro-4-methyl-2,6-di-tert-
butylcyclohexa-2,5-dienone (1bk) was studied (Table 5). The

Halide Solvolysis Induced by Positive Halogen Donors
1389
produced 4-ethoxy-4-methyl-2,6-di-tert-butylcyclohexa-2,5-
dienone (2bw) with selectivity of ,40 % together with some
amount of unreacted 1bj (run 3). Spontaneous reaction of 1bj
with i-PrOH was slow at 258C and gave 4-isopropoxy-4-methyl-
2,6-di-tert-butylcyclohexa-2,5-dienone (2bx) with relatively
low selectivity (run 5). Other products from runs 3 and 5 were
not examined. All the reactions of 1bj in the presence of NIS in
ROH/MeCN were conducted at 08C. The reactions in MeOH/
MeCN, EtOH/MeCN, and i-PrOH/MeCN were all finished in a
short time (5 min), and 2bv, 2bw, and 2bx, respectively, were
isolated in yields well over 80 % (runs 2, 4, and 6). From the
reaction in H2O/MeCN, 4-hydroxy-4-methyl-2,6-di-tert-butyl-
cyclohexa-2,5-dienone (2bu) was obtained also in a high yield,
but it took more time for completion (run 8). The somewhat slow
reaction in H2O/MeCN can probably be attributed to slow
dissolution of 1bj in the medium due to the relatively poor
solubility (see Experimental section). Interestingly, 4-hydroxy-
3,5-di-tert-butylbenzyl alcohol, isomeric with 2bu, is reported
to be obtained quantitatively by allowing a solution of 1bj in
acetone containing H2O to stand at room temperature.[2] The
reaction in t-BuOH/MeCN was also fast, but 4-tert-butoxy-4-
methyl-2,6-di-tert-butylcyclohexa-2,5-dienone (2by) was a
minor product, the major products being 4-hydroxy-3,5-di-
tert-butylbenzyl tert-butyl ether (5) and 4-hydroxy-3,5-di-tert-
butylbenzaldehyde (6) (run 7). Attempts to prepare 2ay and 2by
by chemical or electrochemical oxidation of 3a and 4-methyl-
2,6-di-tert-buylphenol (3b), respectively, in the presence of
t-BuOH, a sterically hindered alcohol, give unsatisfactory
results or fail.[6] Spontaneous methanolysis of 1bk in MeOH
took place slower than that of 1bj at 258C and gave 2bv
principally and 4 (run 9). The NIS-assisted reactions of 1bk,
also conducted at 08C in MeOH/MeCN, EtOH/MeCN, i-PrOH/
MeCN, and H2O/MeCN, were as fast as those of 1bj, and 2bv,
2bw, 2bx, and 2bu, respectively, and were isolated in 90 % yield
or higher (runs 10–13). Thus, the solvolysis of 1bj and 1bk in
ROH/MeCN with NIS not only is faster but also provides the
solvolysis products in higher selectivity than that in ROH
without NIS.
preparation of 2 from 1. It is noteworthy that the rate of the
assisted solvolysis is highly dependent on the solvent system. It
is discussed if such dependency is in line with our original
mechanistic assumption, on the basis of the results of the
reaction of 1aj (summarised in Tables 2 and 3), which was
studied most closely. According to the assumption, the iodine of
NIS electrophilically attacks the Br of 1aj, thus inducing
heterolytic cleavage of the C–Br bond to generate, via the
rate-limiting polar transition state, the 4-oxocyclohexa-2,5-
dienyl cation (7), to which ROH adds providing 2a, and IBr
(Scheme 1).[7] The transition state will be stabilised by a polar
solvent system and the reaction in it will be favoured. Table 2
shows that the rate of theassisted solvolysis of 1aj in neat alcohol
ROH increases in the order t-BuOH , i-PrOH , EtOH ,
MeOH, and the polarity of alcohol ROH increases in the same
order.[8] The preference of the reaction for a polar solvent can
also be seen in Table 3; the assisted methanolysis in MeOH/
aprotic-solvent, of which the aprotic solvent is the major
component, is rapid when the aprotic solvent is polar (MeCN,
acetone, and MeNO2) and slow when it is weakly polar (CHCl3,
DME, and PhMe). According to representative solvent polarity
scales (j*, Py, S 0, and SPP), MeCN is more polar than MeOH.[8]
Taking that to be the case, ROH/MeCN is more polar than any of
neat ROH (excepting H2O), and the solvent polarity of ROH/
MeCN will be largely controlled by that of MeCN. Therefore, it
is understandable to see that the assisted solvolysis of 1aj in
ROH/MeCN is fast as compared with that in ROH and is
seemingly equally rapid irrespective of whichever ROH is used.
However, it is questionable if polarity is the sole solvent
property which influences the rate of the solvolysis of 1aj. In
this regard, it is noted that the spontaneous methanolysis of 1aj
giving 2av is, contrary to the assisted one, slower in MeOH/
MeCN than in MeOH. This will not be an unexpected result,
because the weak hydrogen bond between MeOH and the Br in
1aj,[9] the driving force for heterolytic dissociation of the C–Br
bond in the pure SN1 reaction,[3,10] can be broken by MeCN as a
hydrogen-bond acceptor but not as a donor. In the assisted
reaction, on the contrary, the chance of formation of 2av will
be more in MeOH/MeCN than in MeOH because of more
chance of encounter of 1aj and NIS in their free forms leading
to the transition state, due to interruption by MeCN of hydrogen
bonding of MeOH with 1aj and NIS. The difference in the
assisted reaction between the rate of the formation of 2a in ROH
and that in ROH/MeCN, which is extremely large depending on
the structure of ROH, is thought to be ascribed not only to the
high polarity but also to the hydrogen-bond acceptability, of the
aprotic solvent. The generation of cation 7 from 1aj and NIS can
be discussed from a different aspect, based on additional
experiments. Treatment of 1aj with NIS in MeCN containing
equimolar MeOH and H2O (12.5 equiv each) for a short period at
08C gave 2av and 2au in a molar ratio of 1 : 0.47. MeOH is
usually accepted to be more nucleophilic than H2O towards
A summary of the results of the NIS-assisted solvolysis of 1
shown in Tables 2–5 is as follows: (1) The rate of the reaction of
1a in pure ROH is markedly dependent on the structure of ROH.
(2) The reaction of 1a in ROH/MeCN is faster or far faster than
that in ROH. (3) All of the reactions of 1a in ROH/MeCN are
finished quickly under the same or almost the same respective
reaction conditions. (4) All the reactions of 1b in ROH/MeCN
are also completed with the same or almost the same speed at the
low temperature. Thus, for preparing 2 from 1 by the aid of NIS,
it is in general much favourable to undergo the reaction in ROH/
MeCN rather than neat ROH.
The experimental results thus obtained will suffice to prove
the effect of positive halogen donors on the solvolysis of 1 and
the practical utility of the donor-assisted solvolysis for
But
But
O
O
But
O
But
O
ꢀ I Br ꢀ HN
But
But
Br
But
δꢀ
But
OR
O
ꢀ I
N
Brδꢁ
O
ꢀ
But
ROH
But
But
But
δꢀ O
O
O
I
δꢁ
1aj
NIS
7
2a
N
O
Scheme 1. Mechanism of the NIS-induced solvolysis of 1aj.

1390
K. Omura
carbocations.[11] A similar experiment with equimolar MeOH
and EtOH in MeCN gave 2av and 2aw in a molar ratio of
1 : 0.59. The nucleophilicity of EtOH towards 7 in MeCN,
therefore, appears to lie between those of MeOH and H2O.
The nucleophilicity towards benzhydryl cations[12] and vinyl
cations[13] in MeCN increases in the order H2O , EtOH ,
MeOH. Dienone 1aj and Agþ in protic media including MeOH
gives, via 7, the 4-oxy functionalised cyclohexa-2,5-dienones
including 2av.[14,15] Treatment of 1aj with AgClO4 in equimolar
MeOH and EtOH at 08C readily gave 2av and 2aw in a molar
ratio of 1 : 0.58 in a high total yield. The same treatment of 1aj
with NIS in place of AgClO4 slowly gave 2av and 2aw in a molar
ratio of 1 : 0.56, which can be taken to be identical within
experimental error to that obtained from the Agþ reaction.
Overall, the experimental observations are compatible with
the proposed mechanism.
whereas attempted preparation of 2bx by reaction of 3b in
i-PrOH with PhI(OAc)2, H5IO6, or Tl(NO3)3, which are among
the representative oxidants for conversion of phenols into qui-
nols and their derivatives, gives much less satisfactory
results.[6a] It is expected that, with the aid of a positive halogen
donor such as NIS, many other halogenocyclohexadienones are
in analogous ways solvolysed efficiently in various kinds of
hydroxylic solvents diluted with MeCN and that there are cases
where positive halogen donors, as another non-metallic oxidant,
are a better substitute for the previously employed oxidants
for inter- or intramolecular oxygenative dearomatisation of
phenols.[6,18] Such applications await further investigation.
Experimental
General
1H NMR (90 MHz) spectra were taken in CDCl3 on a Hitachi
R-1900 spectrometer. Column chromatography was conducted
on silica gel (SiO2) (Merck SiO2 60) using gradient elution
(100% petroleum ether to 50 %/50 % petroleum ether/benzene).
Thin-layer chromatography (TLC) was run on SiO2 (Merck
SiO2 60 F254 plates). NIS and anhydrous AgClO4 were pur-
chased from TCI and Aldrich, respectively, and used as
received. Phenol 3a was purchased from TCI, and column-
chromatographed with petroleum ether to eliminate a small
amount of coloured material as a contaminant. All other reagents
and solvents were obtained from WAKO and used without
further purification. Dienones 1 decomposed upon column
chromatography. Unless otherwise stated, solvolysis experi-
ments were carried out in a screw-capped bottle. Pulverised
Conclusion
Positive halogen donors induce solvolysis of 1 as model
4-halogenocyclohexa-2,5-dienones by hydroxylic solvents. NIS
is among the most effective donors. Solvolysis of 1 with NIS
by different kinds of hydroxylic solvents (ROH) give the
4-RO-cyclohexa-2,5-dienones (2) in most cases in high yields,
while the spontaneous solvolysis is of limited synthetic use.
Conducting the NIS-assisted solvolysis in ROH diluted with
MeCN, a polar aprotic solvent, is preferred or far preferred to
that in pure ROH. This is because the rate of the reaction is
controlled by the polarity of the solvent system, although the
hydrogen-bond acceptability of MeCN for dilution also is
involved in accelerating the reaction. The experimental findings
are in accord with the mechanistic proposal that a positive hal-
ogen donor attacks electrophilically at the halogen atom of 1
generating, via the rate-limiting polar transition states, the
4-oxocyclohexa-2,5-dienyl cations (8) (identical with 7 when
R0 ¼ t-Bu). In other words, positive halogen dehalogenates 1
electrophilically. Electrophilic dehalogenation of 1 with posi-
tive halogen (Halþ) is in contrast with nucleophilic dehalo-
genation of 1 with negative halogen (Halꢀ) in combination with
Hþ.[16] The reductive dehalogenation of 1 is the reverse reaction
1
crystals of 1 were used for reactions. H NMR spectroscopic
analysis of a crude reaction product was done in conjunction
with TLC analysis. Identification of an isolated product by
1
comparison with an authentic sample was carried out with H
NMR spectroscopy, melting point measurement, and TLC.
Spontaneous and Positive Halogen Donor-assisted
Solvolysis of 1aj in MeOH (Table 1)
To MeOH (30 mL) or to a solution of a positive halogen donor
(2 mmol) in MeOH (30 mL) was added 1aj[19] (682 mg, 2 mmol)
in one portion, and the mixture was stirred at the temperature for
the time indicated in Table 1. In run 9, 1 mmol (380 mg) of
DIH[20] was employed as the positive halogen donor. The
reaction mixture was poured into aqueous NaHSO3 (0.6 g), and
extractive workup with diethyl ether gave a residual crude
product, which was analysed by 1H NMR spectroscopy.
Compound 2av (from run 8): colourless crystals from MeOH,
identical with an authentic sample;[21] mp 55.5–56.58C (lit.[22]
mp 58–598C).
of halogenation of
3 with molecular halogen (Hal2)
(Scheme 2).[17] As the scheme suggests, one-pot synthesis of 2
directly from phenols 3 will be possible by using a positive
halogen donor(s). Indeed, we have lately shown that 2bx is
readily prepared by sequential addition of Br2 (generating 1bj
in situ) and NIS to a solution of 3b in an i-PrOH-MeCN mixture,
But
Rꢂ
O
Hal2
ꢀ
ꢀ
ꢀ
Hal
But
Spontaneous and NIS-assisted Solvolysis of 1aj in ROH
8
(Table 2)
1
ꢀ
ꢁ
To ROH (30 mL) or to a solution of NIS (450 mg, 2 mmol) in
ROH (30 mL) was added 1aj (2 mmol) in one portion, and the
mixture was stirred at the temperature for the time indicated in
Table 2. Runs 8 and 11 were carried out in a flask equipped with
a reflux condenser. Pouring the mixture into aqueous NaHSO3
and extractive workup gave a crude product, which was ana-
lysed by 1H NMR spectroscopy.
Compound 2aw (from run 6): pale yellow crystals from
hexane, identical with an authentic sample;[6a] mp 39–428C
(lit.[6b] mp 39–418C).
Hal
H
But
Hal2
HO
But
Rꢂ
ꢀ
3
a: Rꢂ ꢃ t-Bu
b: Rꢂ ꢃ Me
Scheme 2. Electrophilic dehalogenation of 1 by positive halogen.

Halide Solvolysis Induced by Positive Halogen Donors
1391
Compound 2az (from run 14): colourless crystals from
hexane; mp 75–788C (lit.[23] mp 76–77.58C).
Compound 2bx (from run 6): colourless crystals from
MeOH, identical with an authentic sample;[6a] mp 70–73.58C
(lit.[6a] mp 70–73.58C).
NIS-assisted Solvolysis of 1aj in ROH/Aprotic-solvent
(Table 3)
Compound 2by (from run 7): colourless crystals from EtOH,
identical with an authentic sample;[6a] mp 65–678C (lit.[6a]
mp 64.5–66.58C).
Compound 4 (from run 1): colourless crystals from hexane,
identical with an authentic sample;[31] mp 101–1038C
(lit.[32] mp 99.58C).
Compound 5 (from run 7): colourless crystals from hexane,
identical with an authentic sample;[6a] mp 67–698C (lit.[6a]
mp 68–69.58C).
Compound 6 (from run 7): colourless crystals from AcOEt,
identical with an authentic sample;[31] mp 188–1918C (lit.[2]
mp 1898C).
To a solution of NIS (2 mmol) in a solvent mixture of ROH
(3 mL) and an aprotic solvent (27 mL) was added 1aj (2 mmol)
in one portion, and the resulting mixture was stirred at 08C for
the time indicated in Table 3. In runs 1 and 2, NIS was omitted.
In run 2, the reaction was done at 358C. Pouring the mixture into
aqueous NaHSO3 and extractive workup gave a crude product,
1
1
which was analysed by H NMR spectroscopy. After the H
NMR analysis, the crude product from run 6 was chromato-
graphed to give 2av (566 mg, 97 %). The crude product from run
11 was chromatographed to give 2ay (441 mg, 66 %) and 2au
(122 mg, 22 %).
Competitive Reactions
Compound 2au (from run 12): colourless crystals from
hexane, identical with an authentic sample;[21] mp 86–1288C
(lit. mp 82–124,[21] 113–125,[23] 129–130,[24] and 80.9–
82.18C[25]).[26]
Compound 2ax (from run 10): nearly colourless oil, identical
with an authentic sample;[6a] (lit. oil[6a] and mp 308C[6b]).
Compound 2ay (from run 11): colourless crystals from
hexane, identical with an authentic sample;[6a] mp 48–49.58C
(lit.[27] 43–458C).
To a solution of NIS (2 mmol) in MeCN (27 mL) containing
MeOH (800 mg, 25 mmol) and H2O (450 mg, 25 mmol) was
added 1aj (2 mmol) in one portion, and the resulting mixture was
stirred at 08C for 5 min. Pouring the mixture into aqueous
NaHSO3 and extractive workup gave a crude product, which
was analysed by 1H NMR spectroscopy to consist of 2av (68 %)
and 2au (32 %). The reaction with EtOH (1150 mg, 25 mmol) in
place of the H2O gave 2av (63 %) and 2aw (37 %). The reaction
with 1aj (2 mmol) and NIS (2 mmol) in a solvent mixture
(30 mL) of equimolar MeOH and EtOH at 08C for 60 min gave
2av (64 %) and 2aw (36 %).
Spontaneous and NIS-assisted Solvolysis of 1ak in ROH
and ROH/MeCN (Table 4)
To a solution of AgClO4 (417 mg, 2 mmol) in a solvent
mixture (30 mL) of equimolar MeOH and EtOH was added 1aj
(2 mmol) in one portion, and the resulting mixture was stirred at
08C for 10 min. The mixture was filtered to give a grayish solid
(367 mg, 98 % as AgBr). Pouring the filtrate into water and
extractive workup gave a crude product, which contained 2av
(60 %) and 2aw (35 %) as estimated by 1H NMR spectroscopy.
The reactions of 1aj (2 mmol) with AgClO4 (2 mmol) in MeOH
(30 mL) and in EtOH (30 mL) in place of the MeOH-EtOH
mixture gave 2av and 2aw, respectively, in over 90 % yields.
In the above four competitive runs, no or little reaction of 1aj
took place if NIS or AgClO4 was omitted.
To a solution of NIS (2 mmol) in ROH (30 mL) or in a solvent
mixture of ROH (3 mL) and MeCN (27 mL) was added 1ak[28]
(593 mg, 2 mmol) in one portion, and the resulting mixture was
stirred at 358C for the time indicated in Table 4. In runs 1 and 2,
NIS was omitted. In run 4, the reaction was done at 08C. Pouring
the mixture into aqueous NaHSO3 and extractive workup gave a
crude product, which was analysed by 1H NMR spectroscopy.
Spontaneous Solvolysis of 1bj and 1bk in ROH and their
NIS-assisted Solvolysis in ROH/MeCN (Table 5)
To ROH (30 mL) or to a solution of NIS (2 mmol) in a solvent
mixture of ROH (3 mL) and MeCN (27 mL) was added 1bj[2]
(598 mg, 2 mmol) or 1bk[28] (510 mg, 2 mmol) in one portion,
and the resulting mixture was stirred at the temperature for the
time indicated in Table 5. In runs 8 and 13, the reacting mixtures
became homogeneous after ,11 min; in the other runs in the
table, the reacting mixtures became homogeneous within 5 min.
Pouring the mixture into aqueous NaHSO3 and extractive
workup gave a crude product, which was subjected to column
chromatography. For instance, the chromatography of the
product from run 1 gave 2bv (396 mg, 79 %) and 4 (60 mg,
12 %). The crude products from runs 3, 5, and 9 were analysed
by 1H NMR spectroscopy. For ready isolation of 2b except 2by
from the solvolyses with NIS, recrystallisation of the crystalline
crude reaction products was convenient.
Compound 2bu (from run 8): colourless crystals from hexane,
identical with an authentic sample;[29] mp 112–113.58C (lit.[30]
mp 111–1128C).
Compound 2bv (from run 1): colourless crystals from
MeOH, identical with an authentic sample;[21] mp 92–948C
(lit.[2] mp 948C).
Compound 2bw (from run 4): colourless crystals from
MeOH, identical with an authentic sample;[6a] mp 70–718C
(lit.[6a] mp 69.5–718C).
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