NBS-Promoted Reactions of Symmetrically Hindered Methylphenols via p-Benzoquinone Methide

Article abstract of DOI:10.1021/jo9911185

Symmetrically hindered methylphenols 1 react smoothly with NBS to form transient intermediates, p-benzoquinone methides (BM), which can be further processed to give hydroxybenzaldehydes in the presence of DMSO. This reaction is initiated by the formation of the phenoxy radical, followed by disproportionation to afford BM. None of the side-chain-brominated product is observed. The existence of BM is supported by the following observations: the formation of BM in solution can be monitored by GC and GC-MS; the electrophilic methine part participates in electrophilic aromatic substitution with anisoles to give hydroxybenzylated products 15; and the double bond character of the exocyclic methine plays a role in [4 + 2] cycloaddition with diene to afford Diels-Alder adducts. In contrast, unsymmetrically hindered or simple methylphenol (p-cresol) with NBS gives the nuclear brominated products, as usual. The energies of symmetrically hindered BMs, unsymmetrically hindered BM, and simple BM were calculated using density functional theories. Relative stabilization energies calculated at the B3LYP/6-31G*//B3LYP/6-31G* level by an isodesmic equation are enhanced 3-6 kcal/mol for symmetrically hindered BMs.

Full text of DOI:10.1021/jo9911185

108
J . Org. Chem. 2000, 65, 108-115
NBS-P r om oted Rea ction s of Sym m etr ica lly Hin d er ed
Meth ylp h en ols via p-Ben zoqu in on e Meth id e
Woonphil Baik,* Hyun J oo Lee, J ung Min J ang, Sangho Koo, and Byeong Hyo Kim†
Department of Chemistry, Myong J i University, Yong In, Kyung Ki Do 449-728, Korea, and
Department of Chemistry, Kwangwoon University, Seoul, Korea
Received J uly 13, 1999
Symmetrically hindered methylphenols 1 react smoothly with NBS to form transient intermediates,
p-benzoquinone methides (BM), which can be further processed to give hydroxybenzaldehydes in
the presence of DMSO. This reaction is initiated by the formation of the phenoxy radical, followed
by disproportionation to afford BM. None of the side-chain-brominated product is observed. The
existence of BM is supported by the following observations: the formation of BM in solution can
be monitored by GC and GC-MS; the electrophilic methine part participates in electrophilic
aromatic substitution with anisoles to give hydroxybenzylated products 15; and the double bond
character of the exocyclic methine plays a role in [4 + 2] cycloaddition with diene to afford Diels-
Alder adducts. In contrast, unsymmetrically hindered or simple methylphenol (p-cresol) with NBS
gives the nuclear brominated products, as usual. The energies of symmetrically hindered BMs,
unsymmetrically hindered BM, and simple BM were calculated using density functional theories.
Relative stabilization energies calculated at the B3LYP/6-31G*//B3LYP/6-31G* level by an isodesmic
equation are enhanced 3-6 kcal/mol for symmetrically hindered BMs.
In tr od u ction
siently in dilute solution. Therefore, they usually cannot
be isolated, although they may be detectable by spec-
troscopy.5 The application of these highly reactive inter-
mediates in reactions with a wide variety of nucleophiles
is limited by their stability and the methods used for their
generation.6 Even though the same p-benzoquinone
methide can be generated by different methods, the same
reactions may not take place with a nucleophile because
of the difference in chemical environments. These un-
usual results with benzoquinone methides have been
described elsewhere.7 However, p-benzoquinone methides
with substituents on the terminal methylene (structure
C) can be isolated, and intramolecular electrophilic
substitution reactions have been well studied by Angle
and co-workers.8
Reactive benzoquinone methides have received con-
siderable attention since these intermediates were shown
to be involved in the oxidation of phenols1 and in the
biosynthesis of neolignans.2 The p-benzoquinone methide
A without a substituent on the methide part is highly
reactive, which can be explained by another resonance
structure B with a dipolar character that shows an
electrophilic property on its methine terminus. Thus, the
double bond and electrophilic characters of the exocyclic
alkylidene carbon have been exploited both in typical
Diels-Alder reactions with dienes3 and in 1,6-additions
with nucleophiles,4 such as phosphites,4a phosphines,4b
amines,4c or phenoxides,4d as a result of the additional
driving force of aromatization after conjugated addition.
However, the p-benzoquinone methides only exist tran-
(5) This transient intermediate A has been characterized by 1H NMR
spectroscopy in a dilute solution by Winstein. (a) Dyall, L. K.; Winstein,
S. J . Am. Chem. Soc. 1972, 94, 2196. (b) Winstein, S.; Filar, L. J .
Tetrahedron Lett. 1960, 25, 9.
(6) A few methodologies have so far been developed to generate 2,6-
di-tert-butylquinone methide in situ: (a) oxidation of 2,6-di-tert-butyl-
p-cresol with Ag2O5,7a or PbO2, also see Bolon, D. A. J . Org. Chem.
1970, 35, 715. Orlando, C. M. J . Org. Chem. 1970, 35, 3714. Hill, J .
H. L. J . Org. Chem. 1967, 32, 3214. Becker, H. D.; Gustafson, K. J .
Org. Chem. 1976, 41, 214; (b) treatment of 2,6-di-tert-butyl-4-hydroxy-
benzyl bromide with triethylamine;5,15b (c) thermal decomposition of
(4-hydroxy-3,5-di-tert-butylbenzyl)trimethylammonium iodide gener-
ated from Mannich base and CH3I;3c,4e,f and (d) treatment of 4-(ben-
zotriazol-1-ylmethyl)-2,6-di-tert-butylphenol with base.4f
(7) 2,6-Di-tert-butylbenzoquinone methide 3a generated from 3,5-
di-tert-butyl-4-hydroxybenzyl chroride with triethylamine reacts with
triethyl phosphite to afford bisphenol as a major product along with
2-5% of phosphonate. However, 3a prepared by the thermal decom-
position of Mannich base and CH3I, reacts with triethyl phosphite to
give phosphonate in 95% yield. See ref 4a and Dubs, P.; Stegmann,
W.; Luisoli, R.; Martin, R. EP 434606 A1 910626; Chem. Abstr. 115,
136390.
(8) (a) Angle, S. R.; Arnaiz, D. O.; Boyce, J . P.; Frutos, R. P.; Louie,
M. S.; Mattson-Arnais, H. L.; Raineer, J . D.; Turnbull K. D.; Yang, W.
J . Org. Chem. 1994, 59, 6322. (b) Angle, S. R.; Turnbull, K. D. J . Am.
Chem. Soc. 1989, 111, 1136. (c) Angle, S. R.; Louie, M. S.; Mattson, H.
L.; Yang, W. Tetrahedron Lett. 1989, 30, 1193. (d) Angle, S. R.; Rainier,
J . D. J . Org. Chem. 1992, 57, 6883.
† Kwangwoon University.
(1) (a) Harkin, J . M.; Taylor, W. I.; Battersby, A. R. Oxidative
Coupling of Phenols; Marcel Dekker Inc.: New York, 1967; pp 263-
300. (b) Omura, K. J . Org. Chem. 1992, 57, 306. (c) Diao, L.; Yang, C.;
Wan, P. J . Am. Chem. Soc. 1995, 117, 5369. (d) Omura, K. J . Org.
Chem. 1997, 62, 8790. (e) Omura, K. J . Org. Chem. 1984, 49, 3046. (f)
Sheppard, W. A. J . Org. Chem. 1992, 57, 6883. (g) For a review on
quinone methides, see: Wagner, H. U.; Gompper, R. The Chemistry of
Quinonoid Compounds; Patai, S., Ed.; J ohn Wiley and Sons: New
York, 1974; part 2, pp 1145-1178.
(2) (a) Omura, S.; Tanaka, H.; Okada, Y.; Marumo, H. J . Chem. Soc.,
Chem. Commun. 1976, 320. (b) St. Pyrek, J .; Achmatowicz, O.;
Zamojski, A. Tetrahedron 1977, 33, 673. (c) Scott, A. I. Quarterly Rev.
1965, 1. (d) Angle, S. R.; Turnbell, K. D. J . Am. Chem. Soc. 1990, 112,
3698.
(3) (a) Roper, J . M.; Everly, C. R. J . Org. Chem. 1988, 53, 2639. (b)
McClure, J . D. J . Org. Chem. 1962, 27, 2365. (c) Roper, J . M., U.S.
Patent 4,480,133, 1984. (d) Hatchard, W. R. J . Am. Chem. Soc. 1958,
80, 3640.
(4) (a) Starnes, W. H.; Myers, J . A.; Lauff, J . J . J . Org. Chem. 1969,
34, 3404. (b) Starnes, W. H.; Lauff, J . J . J . Org. Chem. 1970, 35, 1978.
(c) Becker, H.; Gustafsson, K. J . Org. Chem. 1976, 41, 214. (d)
Katritzky, A. R.; Zhang, Z.; Lang, H.; Lan, X. J . Org. Chem. 1994, 59,
7209. For examples of calixarene p-quinone methide, see: (e) Gutsche,
C. D.; Nam, K. C. J . Am. Chem. Soc. 1988, 110, 6153. (f) Alan, I.;
Sharma, S. K.; Gutsche, C. D. J . Org. Chem. 1994, 59, 3716.
10.1021/jo9911185 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/18/1999

NBS-Promoted Reactions of Methylphenols
J . Org. Chem., Vol. 65, No. 1, 2000 109
Ta ble 1. Oxid a tion of 2,6-Di-ter t-bu tyl-4-m eth ylp h en ol
u n d er va r iou s con d ition sa
entry promoter solvent
conditions
additive yields (%)b
1
2
NBS
NBS
(0.2 equiv)
I2
DMSO 120 °C, 10 min none
2a (95)
2a (89)
DMSO 120 °C, 3 h
DMSO 120 °C, 24 h
DMSO 120 °C, 24 h
none
none
none
none
3
4
5
2a (10)
1a (29)
2a (tr)
1a (29)
3a (69)
1a (29)
3a (95)
2a (78)
3a (11)
2a (91)
COCl2
NBS
Recently, we developed new methods for intermolecu-
lar electrophilic aromatic substitution with a transient
2,6-di-tert-butylbenzoquinone methide generated in situ
from the thermal decomposition of Mannich base-
(MeO)2SO2 and for the easy detection of the formation of
transient benzoquinone methide with GC-MS.9 Our
interest in the reactions of p-benzoquinone methides A
has prompted us to examine various reactions for in situ
preparation and electrophilic addition. In particular, we
have been interested in trapping the conjugated methine
part of A by an oxygen nucleophile. Dimethyl sulfoxide
(DMSO) as the nucleophilic oxygen donor has been used
in the oxidation of several different functional groups:
(i) in bromohydrin formation with olefins via the incor-
poration of oxygen to bromocarbonium ion,10 (ii) in benzil
formation with diphenylacetylene via the oxidation of a
vinyl cation,11 (iii) in the conversion of benzyl bromides
to benzaldehydes,12 (vi) in Pfitzner-Moffatt oxidation,13
etc. The nucleophilic oxygen of DMSO may be associated
with the exocyclic alkylidene carbon of A. A similar be-
havior is observed for a vinyl cation in the oxidation of
acetylenes by DMSO to give oxysulfonium cation (eq 1).11
CCl4
reflux, 4h
6
7
NBS
NBS
CCl4
CCl4
reflux, 24h
reflux, 24h
BPc
DMSO
8
NBS
CCl4 + 120 °C, 3 h
DMSO
none
a
Reactions were performed using 1a (1.0 mmol) and 1.2 equiv
b
of promoter in 10 mL of DMSO. The product distributions in all
cases were determined by GLC with an internal standard. c 0.1
equiv of benzoyl peroxide was added.
would help to increase the yield of hydroxybenzaldehydes.
Thus, we chose NBS as an effective oxidant for driving
the reaction because of the chance of H abstraction in
phenols by a succinimidyl radical.14 After the phenoxy
radical is generated, it is rapidly disproportionated to
p-benzoquinone methide and phenol, as shown in eq 2.15
We report here the successful formation of symmetrically
hindered p-benzoquinone methides and ab initio calcula-
tions for their stabilization energies.
Resu lts a n d Discu ssion
In adapting the DMSO reagent to this new use, we
systematically examined several known methods6 for
preparing transient intermediates to lead to oxidation.
Our initial investigations focused on the direct oxidation
of methyl substituents to formyl groups in sterically
hindered phenols. As expected, the oxidation of 2,6-di-
tert-butylbenzoquinone methide 3a generated in situ by
a well-known method, i.e., oxidation of 2,6-di-tert-butyl-
4-methylphenol 1a by Ag2O,6a took place when we added
DMSO to produce 3,5-di-tert-butyl-4-hydroxybenzalde-
hyde 2a . Unfortunately, the best yield we obtained was
26%, and dimerization of p-benzoquinone methide was
the major reaction pathway. In fact, these results
prompted a continuing study of the effects of p-benzo-
quinone methides on the performance of DMSO as an
oxygen donor. We did not think that the use of Ag2O
(1) Oxid a tion of p-Ben zoqu in on e Meth id es. 2,6-
Di-tert-butyl-4-methylphenol 1a (1 mmol) with NBS (1.2
mmol) in DMSO solution at 120 °C afforded 3,5-di-tert-
butyl-4-hydroxybenzaldehyde 2a in a quantitative yield
(eq 3, Table 1). The oxidation of 1a was completed within
10 min, and neither further oxidation to carboxylic acid
nor hydroxybenzyl bromide formation was observed. This
procedure offers significant advantages over the Duff
reaction and the Reimer-Tiemann formylation of phe-
nols, each of which gives low yields under harsh condi-
tions and sometimes requires the use of toxic reagents.16
Furthermore, the direct oxidation of p-alkylphenols for
the synthesis of p-carbonylphenols with common oxidants
was reported to be unsuccessful.17
(9) Baik, W.; Lee, H. J .; Yoo, C. H.; J ung, J . W.; Kim, B. H. J . Chem.
Soc., Perkin Trans. 1 1997, 587. We reported that the formation of
2,6-di-tert-butylbenzoquinone methide could be monitored by GLC
(equipped with an HP-1 capillary column), and the GC-MS (EI)
analysis of this transient intermediate showed a molecular ion peak
(m/z 218) of C15H22O.
(10) Dalton, R. D.; Dutta, V. P.; J ones, D. C. J . Am. Chem. Soc. 1968,
90, 5498.
(11) Wolfe, S.; Pilgrim, W. R.; Garrard, T. F.; Chamberlain, P. Can.
J . Chem. 1971, 49, 1099.
(12) (a) Kornblum, N.; J ones, W. J .; Anderson, G. J . J . Am. Chem.
Soc. 1959, 81, 4113. (b) Nace, H. R.; Monagle, J . J . J . Org. Chem. 1959,
24, 1792.
(13) (a) Pfitzer, K. E.; Moffatt, J . G. J . Am. Chem. Soc. 1965, 87,
5661. (b) Smith, W. E. J . Org. Chem. 1972, 37, 3972. (c) Nishinaga,
A.; Shimizu, T.; Matsuura, T. Tetrahedron Lett. 1981, 22, 5293. (d)
Torssell, K. Tetrahedron Lett., 1966, 7, 4445.
(14) The suggestion that the hydrogen-abstracting species by a
succinimidyl radical might be involved in NBS allylic bromination has
been presented. Skell, P. S.; Lindstrom, M. J .; Day, J . C. J . Am. Chem.
Soc. 1974, 96, 5616.
(15) (a) Omura, K. J . Org. Chem. 1991, 56, 921. (b) Neureiter, N. P.
J . Org. Chem. 1963, 28, 3486.

110 J . Org. Chem., Vol. 65, No. 1, 2000
Baik et al.
heated to form iodomethylpyridine, which was then
reacted with DMSO to give pyridine aldehyde via oxy-
dimethyl sulfonium iodide. However, in the case of I2 or
COCl2, 1a was oxidized in only trace amounts to form
2a , and most of the starting material was recovered
(entries 3 and 4). None of the halogenated products was
observed during the reactions.
To reinvestigate the halogenation of alkylphenols more
thoroughly, we examined the bromination of 1a with NBS
in CCl4 in either the absence or the presence of benzoyl
peroxide (entries 5 and 6). Surprisingly, neither 3,5-di-
tert-butyl-4-hydroxybenzyl bromide 5a nor the oxidized
product 2a was observed. Instead, we observed the
formation of p-benzoquinone methide 3a . After the
formation of 3a was complete, DMSO was added, and the
reaction mixture was heated for an additional 24 h (entry
7, eq 4). The oxidized product 2a was formed in 78% yield.
F igu r e 1. Time/course profile for the reaction of 1a and
NBS in DMSO (initial concentrations 0.1 and 0.02 M, respec-
tively).
The reaction proceeded by consuming either stoichio-
metric or catalytic amounts of NBS. For example, oxida-
tion of 1a with 0.2 equiv of NBS led to product 2a in 89%
yield and recovered 1a in 6% yield (entry 2) as well as
the stoichiometric reaction (entry 1). The catalytic reac-
tion proceeded slowly but was completed in 3 h. Surpris-
ingly, in this case, we observed the formation of a
transient intermediate, 2,6-di-tert-butylbenzoquinone
methide 3a , during the transformation of 1a to 2a , and
we did not observe any traces of a halogenated phenol.
Evidence for the formation of 3a in the reaction of 1a
with NBS is presented in Figure 1. Monitoring of this
reaction by GC showed that the decrease in 1a was
counterbalanced by a favorable trend in the sum of 3a
and 2a , which increased steadily until a certain point.
After ∼50% of 3a was generated in situ in solution, the
transient intermediate p-benzoquinone methide gradu-
ally disappeared from the reaction mixture, and eventu-
ally the sole product 2a was isolated in 89% yield.
However, the oxidation of 1a to 2a with a stoichiometric
amount of NBS occurs so fast that the p-benzoquinone
methide 3a is not detected. We were led to the use of I2
instead of NBS by a related report on the conversion of
methylpyridines to pyridine aldehydes with I2/DMSO.18
According to that report, methylpyridine-I2 complex was
Furthermore, the oxidation reaction of 1a with NBS
proceeded to produce 2a in a solution of CCl4-DMSO
(entry 8). The formation of 2a from 3a in entries 7 and 8
suggests that the oxidation proceeds via a p-benzo-
quinone methide in DMSO.
In an attempt to prove that the brominated meth-
ylphenol intermediate is not involved in the oxidation of
2,6-di-tert-butyl-4-methylphenol 1a with NBS, we tried
to oxidize isolated 3,5-di-tert-butyl-4-hydroxybenzyl bro-
mide3b 5a in DMSO solution without NBS at 120 °C (eq
4). However, the DMSO oxidation of 3,5-di-tert-butyl-4-
hydroxybenzyl bromide 5a did not occur even under these
vigorous conditions. Furthermore, simple hydroxybenzyl
bromides, such as p-hydroxybenzyl bromide, were not
oxidized at all, although the benzyl halide can be oxidized
to the benzaldehyde by DMSO.12 An important feature
of the reaction pathways is that 3,5-di-tert-butyl-4-
hydroxybenzyl bromide 5a is not involved as an inter-
mediate in the NBS-DMSO oxidation of 2,6-di-tert-butyl-
4-methylphenol.
The mechanism of the conversion of 2,6-di-tert-butyl-
4-methylphenol 1a to 3,5-di-tert-butyl-4-hydroxybenzal-
dehyde 2a could involve both radical initiation by NBS
and oxidation by DMSO (Schemes1 and 2). 2,6-Di-tert-
butyl-4-methylphenoxy radicals 6 are readily generated
by the oxidation of one electron of its phenol, and the
resulting phenoxy radicals 6 disproportionate rapidly to
yield the parent phenol 1a and p-benzoquinone methide
3a .15 Alternatively, a positive bromine attacks phenol to
form a hypobromite 7, which readily forms p-benzo-
quinone methide 3a , and hydrogen bromide may be
liberated by spontaneous dehydrobromination. Mean-
while, bromodimethylsulfonium bromide 8 would be
readily generated in situ from HBr in DMSO (eq 5).19
(16) To achieve formylation of phenols, HCN-AlCl3, aqueous NaOH,
or C6H12N4 is referred to as the reagent of choice. However, yields are
poor to fair, and low regioselectivities have been observed. For example,
the Duff reaction of 2,6-dimethoxyphenol gives 2b in 31% yield. For a
representative example, see: Larrow, J . F.; J acobsen, E. N.; Gao, Y.;
Hong, Y.; Nie, X. J . Org. Chem. 1994, 59, 1939.
(17) Most commonly used oxidants for the oxidationof methyl groups
on aromatic rings are cerium(IV), tert-butyl hydroperoxide with
catalysts, acetone cyanohydrin-AlCl3, chromium(VI), and O2 with
enzymes. Even though a number of methods are currently available,
attempts to achieve the direct oxidation of hindered methylphenols to
hydroxybenzaldehydes are met with difficulties. For example, methyl-
substituted aromatic systems can be oxidized cleanly to a single
aldehyde with ceric ammonium nitrate (CAN); however, toluenes with
strongly electron-donating substituents such as hydroxy, alkoxy, or
amino polymerize during the oxidation reaction. See: Trahanovsky,
W. S.; Young, L. B. J . Org. Chem. 1966, 31, 2033. Even with the O2-
enzyme lactase method, phenolic and benzylic hydroxyl groups re-
quire protection before oxidation of aromatic methyl groups. See:
Potthast, A.; Rosenau, T.; Chen, C.-L.; Gratzl, J . S. J . Org. Chem. 1995,
60, 4320. For reviews on the oxidation of methylarenes to their
aldehydes, see: (a) Wilberg, K. B. Oxidation in Organic Chemistry;
Wilberg, K. B., Ed.; Academic: New York, 1965; pp 101-105. (b)
Larock, R. C. Comprehensive Organic Transformation; VCH: New
York; 1989; pp 591-592.
(18) Markovac, A.; Stevens, C. L.; Ash, A. B.; Hackley, B. E. J . Org.
Chem. 1970, 35, 841.

NBS-Promoted Reactions of Methylphenols
J . Org. Chem., Vol. 65, No. 1, 2000 111
Ta ble 2. Oxid a tion of Ster ica lly Hin d er ed
Sch em e 1
p-Meth ylp h en ols by NBS in DMSO
methylphenols
molar ratio
entry
1
R1
R2
(1:NBS)
min
yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
t-Bu
OMe
Ph
i-Pr
Me
Me
OMe
H
t-Bu
OMe
Ph
i-Pr
Me
H
1:1.2
1:1.1
1:1.4
1:1.4
1:1.4
1:1.3
1:1.4
1:1.2
10
60
120
240
240
60
2a (95)
2b (95)
2c (93)
2d (86)
2e (83)
11fb (77)
11gb (56)
11h b (51)
1g
1h
H
H
60
60
a
The product yield was determined by GLC with an internal
b
standard. Compounds 11 are o-brominated methylphenols.
donating groups, such as methoxy, tert-butyl, or phenyl
groups. Furthermore, we observed a highly regioselective
mono-oxidation of 2,4,6-trimethylphenol to give a single
product, 3,5-dimethyl-4-hydroxybenzaldehyde, in 83%
yield (entry 5). The oxidation reaction takes place at the
para methyl substituent to lead to the predominant
formation of p-benzoquinone methide.
Sch em e 2
With a blocking group at the para position, ortho
regioselective oxidation of o-methylphenols was observed.
In the case of 4,6-di-tert-butyl-2-methylphenol 12, which
has a blocking group at the para position, oxidation gave
3,5-di-tert-butyl-2-hydroxybenzaldehyde 13 in 54% yield.
A trace amount of 3,5-di-tert-butyl-2-hydroxybenzyl bro-
mide 14 was also observed by GC-MS analysis (eq 6).
p-Benzoquinone methide 3a would then rapidly react
However, unsymmetrically substituted and simple p-
methylphenols underwent nuclear bromination at the
ortho position of p-methylphenols (Table 2, entries 6-8,
compounds 11). Only trace amounts of hydroxybenzal-
dehyde were observed. For example, in the case of
p-cresol 1h , oxidation to p-hydroxybenzaldehyde did not
occur with NBS in DMSO; instead, 2-bromo-4-meth-
ylphenol 11h and a trace of 2,6-dibromo-4-methylphenol
were obtained (entry 8). Recently, Majetich and co-
workers19 observed the electrophilic aromatic bromina-
tion of strongly activated benzenes with bromodimeth-
ylsulfonium bromide 8, generated in situ by treating
DMSO with aqueous HBr. Our results using NBS were
very similar to Majetich’s. These results support the
notion that unsymmetrically hindered or simple meth-
ylphenols react with NBS by an ionic process that
involves heterolytic dissociation of the N-Br bond.
However, symmetrically hindered methylphenols might
be subject to the formation of a stable transient inter-
mediate, p-benzoquinone methide, via a radical process.
The poor results with unsymmetrically substituted p-
methylphenols using NBS-DMSO promopted us to ex-
amine the competition between oxidation and nuclear
bromination. An equimolar mixture of 1a and 1h with
NBS (1 equiv) in DMSO under the same reaction condi-
tions gave 2a (39%), 11h (43%), and 15 (5%) (eq 7).
The hydroxybenzylated adduct 15 is produced by way
of the intermolecular electrophilic substitution of p-cresol
with 2,6-di-tert-butylbenzoquinone methide. As previ-
with 8, followed by the incorporation of DMSO to form
oxydimethyl sulfonium intermediate 10. The methine
part of 3a would be more electrophilic with the addition
of bromodimethylsulfonium to the oxygen of the carbonyl
of intermediate 9. When p-benzoquinone methide was
generated by a Ag2O method in the absence of NBS
(without the formation of 8), the oxidation with DMSO
alone occurred slowly and gave a very low yield. This may
suggest that a strong activation effect by the addition of
bromodimethylsulfonium bromide 8 to 3a is important
for the oxidation to occur readily. The subsequent oxida-
tion to 3,5-di-tert-butyl-4-hydroxybenzaldehyde 2a is
undoubtedly similar to the Pfitzner-Moffatt mecha-
nism.13
The application of NBS-DMSO oxidation to other
symmetrically hindered p-methylphenols provided their
p-formylphenols in over 83% yields (Table 2). The reac-
tion proceeded smoothly to completion within 4 h.
Slightly increased product yields were obtained when the
p-methylphenols were substituted with strong electron-
(19) Majetich, G.; Hicks, R.; Reister, S. J . Org. Chem. 1997, 62, 4321.
The mechanism accounts for the formation of bromomethylsulfonium
bromide 8 from DMSO and HBr, see: Mislow, K.; S. Mmons, T.; Melillo,
J .; Ternay, A. J . Am. Chem. Soc. 1964, 86, 1452.

112 J . Org. Chem., Vol. 65, No. 1, 2000
Baik et al.
Ta ble 3. In ter m olecu la r Electr op h ilic Su bstitu tion
Rea ction of Ar en es w ith p-Ben zoqu in on e Meth id e
Gen er a ted in Situ fr om 2,6-Di-ter t-bu tyl-4-m eth ylp h en ola
Lewis acid
(equiv)
entry
arene
anisole
anisole
anisole
anisole
phenol
p-cresol
solvent
CCl4
15a %b 16, %c
1
2
3
4
5
6
7
8
ZnCl2 (1.5) 83
8
14
65
35
75
43
93
48
DMSO ZnCl2 (3.0) 45 (35)d
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
none
11
ously mentioned, the electrophilic character of the exo-
cyclic alkylidene carbon in the transient p-benzoquinone
methide has been considered as a potential candidate for
the intermolecular substitution of arenes. From our
previous results,9 the intermolecular electrophilic aro-
matic substitution reaction of anisoles with p-benzo-
quinone methide generated from the Mannich base and
(CH3O)2SO2 affords the hydroxybenzylated products 15
in up to 94% yield in the presence of ZnCl2 (eq 8). The
AlCl3 (1.5) 31
ZnCl2 (1.5)
ZnCl2 (3.0)
ZnCl2 (1.0)
ZnCl2 (3.0)
8 (43)e
8 (55)e
o-anisidine
N,N-dimethyl-
aniline
0
8
9
N,N-dimethyl-
toluidine
4-bromoanisole CCl4
4-nitroanisole
p-xylene
CCl4
ZnCl2 (3.0) 45
40
10
11
12
ZnCl2 (1.0) 15
ZnCl2 (1.0) 19
56
29
33
CCl4
CCl4
ZnCl2 (1.0)
0 (47)e
a
Reactions were performed using 1a (1.0 mmol) and 5 equiv of
b
arene in 7 mL of solvent. The product distributions in all cases
were determined by GLC with an internal standard. c Overall yield
d
of mono- and dibrominated arene. 3,5-Di-tert-butyl-4-hydroxy
benzaldehyde. e 2,6-Di-tert-butyl-4-methylphenol was recovered.
effective Lewis acid for the electrophilic substitution
reaction of p-benzoquinone methide. A limitation of this
reaction was found with very strongly activated arenes,
indicating that NBS acted as a brominating reagent
rather than as an oxidant, and the phenolic compounds
are more susceptible to bromination than other examples.
Thus, the reaction of phenol with NBS in CCl4, carried
out under the same conditions, gives the nuclear bromi-
nated product contaminated with a small amount of
dibrominated phenols. In addition to the nuclear bromi-
nation by NBS, the free-radical side-chain brominations
of arenes could be a possible route in the presence of NBS.
However, the side-chain bromination of p-cresol does not
occur. Several groups have recognized that nuclear
bromination of phenols and anisoles with NBS is greatly
favored over side-chain bromination in propylene car-
bonate,20a CH3CN,20b-d CS2,20c DMF,20f or CCl4.20g,h De-
spite the apparent utility of NBS, it has not been widely
used for the halogenation of arenes in DMSO.21
It is also known that reactions with NBS are strongly
affected by changing the substituents on the arene and
the solvent. Contrary to the strongly activated arenes,
the electrophilic substitution reactions of arenes with
moderately activating substituents, such as N,N-di-
methyltoluidine, proceed to react with p-benzoquinone
methide to give the hydroxybenzylated products (entry
9). Meanwhile, hydroxybenzylation was very sluggish
with electron-withdrawing-group-substituted anisoles.
Inactivated arenes, such as toluene, xylene, or methyl-
coordination of Lewis acid to an oxygen of p-benzoquinone
methide generates the activated carbocation, which
participates in the aromatic substitution reaction of
arenes. Most arenes with activating substituents gave
the hydroxybenzylated products 15 in reasonable to high
yields. Therefore, we examined the arylation reaction of
benzoquinone methide generated from NBS in CCl4,
expecting formation of an activated p-benzoquinone
methide by ZnCl2, which would lead to arenes by elec-
trophilic substitution. In fact, the p-benzoquinone
methide of 1a with NBS was clearly formed in CCl4
(Table 1, entry 5), and the activation effect by bromodi-
methylsulfonium bromide 8 can be eliminated because
we did not use DMSO.
(2) Ar yla tion of p-Ben zoqu in on e Meth id es. A
mixture of 1a (5 mmol, a limiting reagent), anisole (25
mmol), and NBS (7.5 mmol) in the presence of ZnCl2 (5
mmol) was heated at 120 °C in CCl4 (30 mL) to give the
hydroxybenzylated anisole 15a in 83% yield with 86:14
para/ ortho regioselectivity (eq 9). The brominated ani-
soles 16 were also produced in overall 8% yield, along
with a trace amount of hydroxybenzaldehyde 2a .
(20) The nuclear bromination of activated aromatic compounds
(phenols, anisoles) with NBS is clearly favored by polar solvents such
as propylene carbonate: (a) Ross, S. D.; Finkelstein, M.; Petersen, R.
C. J . Am. Chem. Soc. 1958, 80, 4327. Nuclear bromination in CH3CN:
(b) Oberhauser, T. J . Org. Chem. 1997, 62, 4505. (c) Carreno, M. C.;
Ruano, J . L.; Sanz, G.; Toledo, M. A.; Urbano, A. Synlett. 1997, 1241.
(d) Carreno, M. C.; Ruano, J . L.; Sanz, G.; Toledo, M. A.; Urbano, A. J .
Org. Chem. 1995, 60, 5328. Nuclear bromination in DMF: (e) Michell,
R. H.; Lai, Y.; Williams, R. V. J . Org. Chem. 1979, 44, 4733. The
nuclear versus side-chain bromination of anisoles with NBS in CCl4
is also well documented, see: (f) Gruter, G. M.; Akkerman, O. S.;
Bickelhaupt, F. J . Org. Chem. 1994, 59, 4473. (g) Goldberg, Y.;
Bensimon, C.; Alper, H. J . Org. Chem. 1992, 57, 6374.
To investigate the substituent effect of arenes in the
electrophilic substitution reaction with p-benzoquinone
methide, we carried out more preliminary studies (Table
3). By changing the solvent from CCl4 to DMSO in the
presence of ZnCl2, both the oxidation of 1a and the
nuclear bromination of anisole occurred, as well as
hydroxybenzylation (entry 2). In the absence of ZnCl2,
the rate and yield of 15a were decreased, and the yield
of brominated anisoles was significantly increased in
CCl4. Attempts to increase the yield of hydroxybenzylated
product by changing the solvent and Lewis acid were
unsuccessful. Using CCl4 as a solvent, ZnCl2 was the most
(21) The site-selective bromination of arenes with aqueous HBr in
DMSO has recently been reported. However, this report lacks of the
varsity of arenes, and no example with NBS is appeared. See:
Srivastava, S. K.; Chauhan, P. M. S.; Bhaduri, A. P. J . Chem. Soc.,
Chem. Commun. 1996, 2679.

NBS-Promoted Reactions of Methylphenols
Ta ble 4. Electr op h ilic Su bstitu tion Rea ction of An isoles w ith 2,6-d ia lk yl-4-m eth ylp h en olsa
products, %b
J . Org. Chem., Vol. 65, No. 1, 2000 113
entry
1
anisoles
NBS (equiv)
ZnCl2 (equiv)
time (h)
15 (o/ p)
2
16c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
anisole
p-methylanisole
anisole
p-methylanisole
2,6-dimethylanisole
anisole
p-methylanisole
2,6-dimethylanisole
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
3.0
3.0
1.0
1.0
1.0
1.0
10
3
4
3
7
10
3
5
83 (86/14)
76
81 (85/15)
71
0
4
4
3
0
0
0
0
6
3
11
6
5
3
61
73 (84/16)
74
65
0
1
a
b
Reactions were performed using 1 (5.0 mmol) and 5 equiv of anisole in 30 mL of CCl4. The product distributions in all cases were
determined by GLC with an internal standard. c Overall yield of mono- and dibrominated arene.
Ta ble 5. [4 + 2] Cycloa d d ition Rea ction of
naphthalenes, did not react with p-benzoquinone meth-
2,6-Di-ter t-bu tylben zoqu in on e Meth id es 3a Dir ectly
ide; hence, 2,6-di-tert-butylbenzoquinone methide was
Gen er a ted in Situ fr om 1a a n d NBS-DMSO
dimerized very slowly. However, nuclear brominated
NBS
Et2AlCl time product
products on arenes were eventually formed as well.
Anisoles with moderately to non-activated substituents
were readily hydroxybenzylated with p-benzoquinone
methide.
entry
diene
(mmol) (mmol) (h)
(%)
1
2
3
2,3-dimethylbutadiene
isoprene
butadiene
1.5
1.5
2.5
1.5
1.5
2.5
5
15
7
64
60
67
We extended the intermolecular electrophilic substitu-
tion of anisoles with other symmetrical p-benzoquinone
methides (Table 4). In all cases, p-hydroxybenzylated
products 15 were obtained in reasonable yields. In
general, the reaction was highly regioselective (>84%)
to give the para-substituted products with anisole, and
the regioselectivity was independent of the substituent
on p-benzoquinone methide.
(3) Diels-Ald er R ea ct ion of p -Ben zoq u in on e
Meth id es. In a further effort to prove the formation of
transient intermediate 3a in the reaction of 2,6-di-tert-
butyl-4-methylphenol with NBS in either DMSO or CCl4,
we trapped 3a with 2,3-dimethylbutadiene to form
spiroketone 17 (eq 10).3 Spiroketones were first synthe-
of Et2AlCl. In all cases, hydroxybenzaldehyde was ob-
tained in 5-15% yield.
(4) Electr on ic Con sid er a tion s of p-Ben zoqu in on e
Meth id es. The in situ formation of benzoquinone meth-
ide by NBS was very sensitive to the electronic effect of
the corresponding phenols. Thus, the stabilities of p-
benzoquinone methides, 3a (R1, R2 ) t-Bu), 3e (R1, R2 )
Me), 3f (R1 ) t-Bu, R2 ) H), and 3h (R1, R2 ) H) were
calculated using density functional (DFT) geometry
optimizations at the Becke 3-Lee-Yang-Parr (B3LYP)
DFT level.22 Density functional methods, and B3LYP in
particular, can provide more reliable relative stabilization
energies of intermediates than the Hartree-Fock calcu-
lation.23 We compared the relative stabilities at the
B3LYP/6-31G* level by means of isodesmic equations
such as that illustrated in eq 11.
sized by treating 1a with lead dioxide in the presence of
diene, and this reaction proceeded via entrapment of a
benzoquinone methide intermediate to give a [4 + 2]
cycloadduct. Initially, we prepared spiroketone by treat-
ing 2,3-dimethylbutadiene with p-benzoquinone methide,
which was completely formed in the mixture of 1a and
NBS in CCl4, and obtained yields as high as 43%. Product
identification by NMR was straightforward. Because the
p-benzoquinone methide dienophile could be trapped, it
followed that in situ formation of p-benzoquinone methide
in the reaction of 1a with NBS-DMSO in the presence
of 2,3-dimethylbutadiene should give a direct synthesis
of spiroketone. A mixture of 1a , NBS, and 2,3-dimeth-
ylbutadiene in DMSO heated to 80 °C afforded spiroke-
tone 17 in 53% yield. Our Diels-Alder cycloaddition
reactions are promoted by Lewis acids. Thus, we next
turned our attention to a variation of this reaction using
Lewis acids, which proceeds with p-benzoquinone meth-
ide to provide the product in a higher yield. Among the
Lewis acids tried, we found that the reaction using Et2-
AlCl gave the best result. Table 5 shows the results of
the direct [4 + 2] cycloaddition reaction of 2,6-di-tert-
butyl-4-methylphenols with NBS-DMSO in the presence
The stabilization energies for 3a , 3e, 3f, and 3h are
+10.18, +7.65, +4.87, and +4.09 kcal/mol, respectively
(Table 6). Even though one tert-butyl group in 3f has a
conjugation effect, the energy of 3f is ∼3 kcal/mol lower
than that of dimethylbenzoquinone methide 3e. The
higher stabilization energies for symmetrically hindered
(22) The density functional theory calculations employed Becke’s
three parameter hybrid method (Becke, A. D. J . Chem. Phys. 1993,
98, 5648-5652) and the correlation functional of Lee (Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 785-789) within the Gaussian 94
program: Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, w.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. GAUSSIAN
94, Revision B.2; Gaussian, Inc.: Pittsburgh, PA, 1995.
(23) (a) Freeman, P. K. J . Am. Chem. Soc. 1998, 120, 1619. (b)
Patterson, E. V.; McMahon, R. J . J . Org. Chem. 1997, 62, 4398. (c)
Ammann, J . R.; Subramanian, R.; Sheridan, R. S. J . Am. Chem. Soc.
1992, 114, 7592. (d) Liu, J .; Niwayama, S.; You, Y.; Houk, K. N. J .
Org. Chem. 1998, 63, 1064. (e) Halton, B.; Cooney, M. J .; Boese, R.;
Maulitz, A. H. J . Org. Chem. 1998, 63, 1583.

114 J . Org. Chem., Vol. 65, No. 1, 2000
Baik et al.
Ta ble 6. Sta biliza tion En er gies of p-Ben zoqu in on e Meth id es Ca lcu la ted a t th e B3LYP /6-31G*//B3LYP /6-31G* Levela
3 (R1, R2)
BM
ethane
phenol
ethene
SEb (kcal/mol)
3a , (t-Bu, t-Bu)
3e, (Me, Me)
3f, (t-Bu, H)
3h , (H, H)
-660.052585
-424.020497
-502.796942
-345.432362
-79.830417
-79.830417
-79.830417
-79.830417
-661.279322
-425.413180
-504.032136
-346.776027
-78.587456
-78.587456
-78.587456
-78.587456
+10.18
+7.65
+4.87
+4.09
a
b
Energies in hartrees were uncorrected for zero-point energy. The stabilization energy SE ) Ephenol + Eethene - EBM - Eethane in
kcal/mol.
3,5-Di-ter t-bu tyl-4-h yd r oxyben za ld eh yd e (2a ): mp 179-
benzoquinone methides 3a and 3e, compared to 3f and
3h , can explain the conjugation effects. In particular, di-
tert-butylbenzoquinone methide 3a displays a symmetri-
cally bisected geometry without distortion, and thus it
gives an unusually higher stabilization energy. The
relatively high stabilization energies for 3a and 3e are
consistent with the experimental results that the forma-
tion of p-benzoquinone methide with NBS is predomi-
nant.
1
181 °C (lit.24a 178-181 °C); H NMR (CDCl3) δ 1.41 (s, 18H),
5.77 (s, 1H), 7.66 (s, 2H), 9.79 (s, 1H); LRMS (EI) m/z 234 (M+).
3,5-Dim eth oxy-4-h yd r oxyben za ld eh yd e (Syr in ga ld e-
h yd e) (2b): mp 110-111 °C (lit.24b 111-112 °C); 1H NMR
(CDCl3) δ 3.89 (s, 6H), 6.16 (s, 1H), 7.19 (s, 2H), 10.18 (s, 1H);
LRMS (EI) m/z 182 (M+).
3,5-Dip h en yl-4-h yd r oxyben za ld eh yd e (2c): mp 167-168
°C (lit.24c 168-170 °C); 1H NMR (CDCl3) δ 5.96 (s, 1H), 7.40-
7.55 (m, 10H), 7.81 (s, 2H), 9.94 (s, 1H); 13C NMR (CDCl3) δ
128.4, 129.1, 129.2, 129.5, 129.9, 131.8, 136.1, 154.8, 190.9;
LRMS (EI) m/z 274 (M+).
Su m m a r y
3,5-Diisop r op yl-4-h yd r oxyben za ld eh yd e (2d ): mp 103-
1
105 °C (lit.24d 106-108 °C); H NMR (CDCl3) δ 1.30 (d, J )
We examined the NBS oxidation of symmetrically
hindered alkylphenols to afford a p-benzoquinone meth-
ide 3 under mild conditions. Trapping of the electrophilic
exocyclic alkylidene in 3 by DMSO provides an efficient
route to formylphenols. This oxidation reaction is strongly
activated by the generation of more electrophilic methine
by the addition of bromodimethylsulfonium bromide to
3. Strikingly, the side-chain halogenation reaction of
symmetrically hindered alkylphenols does not occur with
NBS under free-radical conditions. However, when un-
symmetrically hindered methylphenols or p-cresol were
allowed to react with NBS in DMSO, the nuclear bromi-
nation process was predominant. Some attempts were
made to take advantage of the electrophilic and double
bond characters of benzoquinone methide that would
indicate its intermediacy in the NBS-promoted reaction.
First, the electrophilic substitution reaction of moderately
activated anisoles provided p-hydroxybenzylated ani-
soles in good yields. Second, the [4 + 2] cycloaddition
reaction with diene also proceeded to give reasonable
yields. In addition, the ab initio calculations show that
the relative stabilization energies of the symmetrically
hindered benzoquinone methides account for their
stability.
6.7 Hz, 12 H), 3.23 (m, 2H), 6.14 (s, 1H), 7.64 (s, 2H), 9.85 (s,
1H); 13C NMR (CDCl3) δ 22.50, 26.96, 126.26, 129.46, 134.56,
156.26, 192. 01; LRMS (EI) m/z 206 (M+).
3,5-Dim eth yl-4-h yd r oxyben za ld eh yd e (2e): mp 111-113
1
°C (lit.24e 111-112 °C); H NMR (CDCl3) δ 2.24 (s, 6H), 5.68
(s, 1H), 7.47 (s, 2H), 9.73 (s, 1H); LRMS (EI) m/z 150 (M+).
3,5-Di-ter t-bu tyl-2-h yd r oxyben za ld eh yd e (13): mp 54-
1
57 °C (lit.16 53-56 °C); H NMR (CDCl3) δ 1.25 (s, 9H), 1.34
(s, 9H), 7.27 (s, 1H), 7.51 (s, 1H), 9.79 (s, 1H), 11.66 (s, 1H);
LRMS (EI) m/z 234 (M + 1).
Gen er a l P r oced u r e for th e Ar yla tion w ith 2,6-Di-ter t-
bu tyl-4-m eth ylp h en ol. NBS (1.331 g, 7.5 mmol) was added
to a mixture of 2,6-di-tert-butyl-4-methylphenol (1.101 g, 5
mmol), anisole (2.717 mL, 25 mmol), and ZnCl2 (0.681 g, 5
mmol) in CCl4 (30 mL). The reaction mixture was heated at
120 °C for the time given in Table 4. After the reaction was
completed, brine solution and methylene chloride were poured
into the flask. The separated organic layer was washed with
water and dried over magnesium sulfate. The solvent was
removed in vacuo, and the residue was chromatographed with
hexanes-ethyl acetate (9:1) to give the product 15.
2,6-Di-t er t -b u t yl-4-[(4′-m e t h oxyp h e n yl)m e t h yl]p h e -
n ol (pa r a p r od u ct):9 mp 136-137 °C; 1H NMR (CDCl3) δ 1.33
(s, 18H), 3.70 (s, 3H), 3.73 (s, 2H), 4.97 (s, 1H), 6.75 (d, J )
8.5 Hz, 2H), 6.90 (s, 2H), 7.04 (d, J ) 8.5 Hz, 2H); 13C NMR
(CDCl3) δ 30.6, 34.6, 41.2, 55.5, 114.0, 125.6, 130.0, 132.3,
134.2, 136.1, 152.2, 158.1 ppm; LRMS (EI) m/z 326 (M+);
HRMS calcd for C22H30O2 326.2246, found 326.2237.
2,6-Di-ter t-bu tyl-4-[(2′-m eth oxy-5′m eth ylp h en yl)m eth -
yl]p h en ol:9 oil; 1H NMR (CDCl3) δ 1.32 (s, 18H), 3.80 (s, 2H),
4.59 (s, 1H), 5.02 (s, 1H), 6.65 (m, 1H), 6.85 (m, 2H), 6.98 (s,
2H); 13C NMR (CDCl3) δ 19.5, 29.3, 33.3, 35.5, 114.6, 124.1,
126.0, 127.0, 128.9, 130.4, 135.2, 150.7, 151.4; MS (EI) 326
(M+); HRMS calcd for C22H30O2 326.2246, found 326.2246.
2,6-Di-ter t-Bu tyl-4-[(4′-m eth oxy-3′,5′-d im eth ylp h en yl)-
m eth yl]p h en ol: mp 92-94 °C; 1H NMR (CDCl3) δ 1.33 (s,
18H), 2.16 (s, 6H), 3.60 (s, 3H), 3.69 (s, 2H), 4.97 (s, 1H), 6.76
(s, 2H), 6.91 (s, 2H); 13C NMR (CDCl3) δ 16.1, 30.3, 34.3, 41.2,
59.6, 125.3, 129.1, 130.5, 131.8, 135.7, 137.0, 152.0, 155.1;
LRMS (EI) m/z 354 (M+); HRMS calcd for C24H34O2 354.2558,
found 354.2550.
Exp er im en ta l Section
1H NMR spectra were recorded on a 300 MHz spectrometer
in CDCl3 solution. Mass spectra were obtained at a 70 eV via
GC-MS coupling. GC analyses were performed using a
capillary column (25 m × 0.2 mm i.d.). Melting points were
determined on a Mel-Temp II apparatus and were uncorrected.
3,5-Di-tert-butyl-4-hydroxybenzyl bromide3b was prepared from
3,5-di-tert-butyl-4-hydroxybenzyl alcohol and HBr gas accord-
ing to the published procedure. The known products (2a -e,
11, a n d 16) were identical in all respects (mp, IR, MS, and
NMR) with those previously reported.
Gen er a l P r oced u r e for th e Oxid a tion of 2,6-Di-ter t-
bu tyl-4-m eth ylp h en ol. NBS (0.213 g, 1.2 mmol) was added
to a solution of 2,6-di-tert-butyl-4-methylphenol (0.220 g, 1.0
mmol) in DMSO (10 mL). The reaction mixture was heated at
120 °C for the time given in Table 2. After the reaction was
completed, brine solution and methylene chloride were poured
into the flask. The separated organic layer was washed with
water and dried over magnesium sulfate. The solvent was
removed in vacuo, and the residue was chromatographed with
hexanes-ethyl acetate (9:1) to give the product.
2,6-Diisop r op yl-4-[(4′-m eth oxyp h en yl)m eth yl]p h en ol
(pa r a p r od u ct): oil; 1H NMR (CDCl3) δ 1.25 (d, J ) 6.96 Hz,
(24) (a) Cohen, L. J . Org. Chem. 1957, 22, 1333. (b) Allen, C. F. H.;
Leubner, G. W. Org. Syntheses Coll. Vol. 4, 866. (c). Unangst, P. C.;
Conner, D. T.; Centenco, W. A.; Sorenson, R. J .; Kostlan, C. R.; Sircar,
J . C.; Wright, C. D.; Schrier. D. J .; Dyer, R. D. J . Med. Chem. 1994,
37, 322. (d) Matsuura, T.; Nagamachi, T.; Matsuo, K.; Nishinaga, A.
J . Med. Chem. 1968, 11, 322. (e) Smith, W. E. J . Org. Chem. 1972, 37,
3972.

NBS-Promoted Reactions of Methylphenols
J . Org. Chem., Vol. 65, No. 1, 2000 115
12H), 3.14 (m, 2H), 3.80 (s, 3H), 3.85 (s, 2H), 4.71 (s, 1H), 6.84-
6.88 (m, 4H), 7.18 (d, J ) 8.43 Hz, 2H); 13C NMR (CDCl3) δ
22.71, 27.19, 40.67, 55.20, 113.70, 123.85, 129.61, 133.17,
133.54, 133.94, 148.14, 157.70; LRMS (EI) m/z 298 (M+);
HRMS calcd for C20H26O2 298.1933, found 298.1922.
2,6-Diisop r op yl-4-[(2′-m eth oxy-5′m eth ylp h en yl)m eth -
yl]p h en ol: oil; 1H NMR (CDCl3) δ 1.27 (d, J ) 6.75 Hz, 12H),
2.25 (s, 3H), 3.15 (m, 2H), 3.83 (s, 3H), 3.89 (s, 2H), 4.67 (s,
1H), 6.78 (d, J ) 8.04 Hz, 2H), 6.89 (s, 1H), 6.97 (s, 3H); 13C
NMR (CDCl3) δ 20.56, 22.80, 27.24, 35.58, 55.46, 110.28,
124.15, 127.30, 129.59, 130.20, 130.81, 132.71, 133.34, 148.04,
155.23; LRMS (EI) m/z 312 (M+); HRMS calcd for C21H28O2
312.2089, found 312.2072.
128.88, 128.97, 130.51, 132.94, 137.04, 150.40, 155.00; LRMS
(EI) m/z 281 (M - 1+); HRMS calcd for C18H22O2 270.1631,
found 270.1619.
Diels-Alder Reaction of 2,6-Di-ter t-bu tyl-4-m eth ylph e-
n ol w ith Dien es. To a mixture of 2,6-di-tert-butyl-4-meth-
ylphenol (0.220 g, 1.0 mmol) and ZnCl2 (0.408 g, 3 mmol) in
DMSO (10 mL) equipped with an ice-cooled condenser was
added NBS (0.266 g, 1.5 mmol). Diene (1 mL) was introduced;
the resulting mixture was refluxed for 3 h. After the mixture
cooled, water and methylene chloride were added. The organic
layer was washed with water and dried over MgSO4. The
solvent was removed in vacuo, and the residue was chromato-
graphed to give the product 17.
2,6-Diisop r op yl-4-[(4′-m eth oxy-3′,5′-d im eth ylp h en yl)-
m eth yl]p h en ol: mp 100-102 °C; 1H NMR (CDCl3) δ 1.23 (d,
J ) 6.96 Hz, 12H), 2.23 (s, 6H), 3.12 (m, 2H), 3.68 (s, 3H),
3.78 (s, 2H), 4.70 (s, 1H), 6.82 (s, 2H), 6.87 (s, 2H); 13C NMR
(CDCl3) δ 16.1, 22.7, 27.2, 41.0, 59.7, 123.9, 129.0, 130.5, 133.0,
133.6, 137.1, 148.2, 155.0; LRMS (EI) m/z 326 (M+); HRMS
calcd for C22H28O2 324.2089, found 324.2089.
2,4-Di-ter t-bu tyl-8-m eth yl-sp ir o[5.5]u n d eca -1,4,7-tr ien -
3-on e: mp 73-75 °C (lit.3b 73-74 °C); 1H NMR (CDCl3) δ 1.23
(s, 18H), 1.60 (t, J ) 6.4 Hz, 2H), 1.75 (s, 3H), 2.00-2.14 (m,
4H), 5.43 (t, J ) 1.6 Hz, 1H), 6.60 (s, 2H); 13C NMR (CDCl3) δ
23.3, 27.8, 29.5, 33.7, 34.6, 35.1, 37.1, 118.3, 133.2, 145.7, 185.7,
186.7; LRMS (EI) m/z 286 (M+).
2,4-Di-ter t-b u t yl-7,8-d im et h yl-sp ir o[5.5]u n d eca -1,4,7-
tr ien -3-on e: 1H NMR (CDCl3) δ 1.19 (s, 18H), 1.48 (t, J ) 6.5
Hz, 2H), 1.57 (d, J ) 1.6 Hz, 3H), 1.63 (d, J ) 0.6 Hz, 3H),
1.87 (s, 2H), 2.00 (brs, 2H), 6.53 (s, 2H); 13C NMR (CDCl3) δ
17.8, 18.1, 28.3, 28.5, 32.8, 33.6, 37.2, 40.1, 121.8, 123.7, 144.9,-
185.0, 185.7; LRMS (EI) m/z 300 (M+).
2,6-Dim eth yl-4-[(4′-m eth oxyph en yl)m eth yl]ph en ol (pa r a
1
p r od u ct): oil; H NMR (CDCl3) δ 2.17 (s, 6H), 3.75 (s, 3H),
3.80 (s, 2H), 4.53 (s, 1H), 6.76∼6.82 (m, 4H), 7.14 (d, J ) 29.28
Hz, 2H); 13C NMR (CDCl3) δ 15.85, 40.13, 55.18, 113.77,
122.94, 128.85, 129.63, 133.12, 133.93, 150.36, 157.76; LRMS
(EI) m/z 242 (M+); HRMS calcd for C16H18O2 242.1307 found
242.1303.
2,4-Di-ter t-bu tylsp ir o[5.5]u n d eca -1,4,7-tr ien -3-on e: 1H
NMR (CDCl3) δ 1.23 (s, 18H), 1.60 (t, J ) 3.2 Hz, 2H), 2.02-
2.19 (brm, 4H), 5.71-5.87 (brm, 2H), 6.63 (s, 2H); 13C NMR
(CDCl3) δ 23.3, 29.9, 33.4, 35.0, 35.2, 37.5, 124.6, 126.7; LRMS
(EI) m/z 272 (M+).
2,6-Dim eth yl-4-[(2′-m eth oxy-5′-m eth ylp h en yl)m eth yl]-
1
p h en ol: mp 50∼52 °C; H NMR (CDCl3) δ 2.04 (s, 6H), 2.20
(s, 3H), 3.74 (s, 3H), 3.78 (s, 2H), 4.52 (s, 1H), 6.69∼6.94 (m,
5H);13C NMR (CDCl3) δ 15.79, 20.40, 34.69, 55.43, 110.41,
122.78, 127.33, 128.92, 129.49, 129.92, 130.88, 132.57, 150.15,
155.10; MS (from GC-MS) 256 (M+); HRMS calcd for C17H20O2
256.1463, found 256.1453.
Ack n ow led gm en t. This work was supported by
Non-Directed Research Fund, Korea Research Founda-
tion, 1996. NMR and MS analyses were performed by
the Instrumental Laboratory supported by the Regional
Research Center.
2,6-Dim e t h yl-4-[(4′-m e t h oxy-3′,5′-d im e t h ylp h e n yl)-
m eth yl]p h en ol: mp 82-83 °C; 1H NMR (CDCl3) δ 2.18 (s,
6H), 2.22 (s, 6H), 3.74 (s, 3H), 3.69 (s, 3H), 6.78-6.80 (d, J )
5.07 Hz, 2H);13C NMR (CDCl3) δ 15.86, 40.44, 59.59, 122.98,
J O9911185