Selective metalation of 4,6-dibromoresorcinol dimethyl ether with LiTMP

Article abstract of DOI:10.1055/s-0030-1258135

4,6-Dibromoresorcinol dimethyl ether was selectively metalated at C-5 with lithium tetramethylpiperidide (LiTMP). A rationale for the selective metalation is proposed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258135

LETTER
1955
Selective Metalation of 4,6-Dibromoresorcinol Dimethyl Ether with LiTMP
M
etalation of 4, 6-D
e
ibromores
o
orcinol
D
im
r
g
e
r
e A. Kraus,* Insik Jeon, John Mengwasser, Aaron C. West, Theresa L. Windus
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +1(515)2940105; E-mail: gakraus@iastate.edu
Received 19 April 2010
of 2,6-dimethoxytoluene was found to generate a proton
NMR spectrum that differed from that of compound 2.
Abstract: 4,6-Dibromoresorcinol dimethyl ether was selectively
metalated at C-5 with lithium tetramethylpiperidide (LiTMP). A ra-
tionale for the selective metalation is proposed.
The reason for the high selectivity of deprotonation ortho
to the two bromines is not clear. In their key paper on the
metalation of 2,5- and 3,5-dibromoanisole with lithium
diisopropylamide at –85 °C, Serwatowski and co-workers
showed that a mixture of metalation products was pro-
duced and that the ratio of the products formed was time
dependent.7 They observed benzyne formation at temper-
atures above –70 °C. Hickey and co-workers studied the
metalation of 3-bromochlorobenzene on an industrial
scale and also found that benzyne formation could be min-
imized by careful control of reaction temperature.8
Key words: lithium tetramethylpiperidide, metalation, regioselec-
tivity, theory, alkylation
As part of a synthetic approach to substituted quinones
such as elisabethadione,1 we planned a synthetic route
from 4,6-dibromoresorcinol dimethyl ether (1), which is
readily generated from commercially available 1,3-
dimethoxybenzene (Scheme 1). Our plan was to introduce
the methyl group and an eight-carbon alcohol through se-
quential metalation of 1, and then use a palladium-medi-
ated cyclization to generate the tetralin framework.2
Although the product was not what we had expected, the
metalation was regioselective. We next examined the re-
action of the anion of 1 with representative electrophiles.
This work is described in Table 1.
Me
Br
O
O
OH
Me
OMe
Table 1 Reaction of Electrophiles with the Anion of 1
5
MeO
OMe
MeO
OMe
2
Br
H
LiTMP
E+
O
OMe
Me
Me
Me
Br
Br
Br
Br
Me
E
1
elisabethadione
Electrophile
methyl iodide
allyl bromide
Yield (%)
Compound
Scheme 1
96
98
0
2
3
–
–
4
5
6
7
Previous studies had shown the facile metalation of 1,3-
dimethoxybenzene using n-butyllithium.3,4 In contrast,
there have been only a few reports of the metalation of
1,3-dibromobenzenes.5,6 Surprisingly, treatment of 1 with
lithium tetramethylpiperidide (LiTMP) in tetrahydrofuran
(THF) at –78 °C followed by methyl iodide, afforded the
methylated derivative 2 in 96% yield as the sole product
(Scheme 2). The structure of 2 was supported by a strong
NOE correlation between the aromatic ring hydrogen and
the O-methyl groups. As additional support for the as-
signed structure, the product obtained from dibromination
6-methyl-5-hepten-2-one
ethyl bromoacetate
benzaldehyde
0
72
55
53
75
2-bromobenzaldehyde
butanal
iodine
MeO
OMe
As the results from Table 1 illustrate, a number of com-
pounds bearing acidic hydrogens, such as 6-methyl-5-
hepten-2-one and ethyl bromoacetate, did not afford the
desired products, presumably due to anion exchange. It is
likely that this exchange takes place because of the steric
hindrance that occurs between the electrophile and the
bromine atoms of the anion of 1. Fortunately, the anion of
1 reacts effectively with iodine, alkyl halides, and both al-
iphatic and aromatic aldehydes.
MeO
OMe
LiTMP
MeI
Br
Br
Br
Br
Me
2
Scheme 2
SYNLETT 2010, No. 13, pp 1955–1958
Advanced online publication: 09.07.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258135; Art ID: S02110ST
© Georg Thieme Verlag Stuttgart · New York

1956
G. A. Kraus et al.
LETTER
It had been shown by Trost and Saulnier that steric hin- absolute and relative energetics, are included in the Sup-
drance on the TBS protecting group can be used to direct porting Information.
metalation away from the positions ortho to the OTBS
In the computational work, the B3LYP calculations pro-
group.9 A more subtle effect termed ‘steric buttressing’
duced intermediates that were complexes of LiTMP with
has been invoked by Schlosser and co-workers to rational-
the various substituted benzenes species. The two bro-
mine atoms ortho to the hydrogen being abstracted would
have strong non-bonded interactions with any base. Dis-
ize the novel metalation reaction shown in Scheme 3.10 In
the absence of the triethylsilyl group, metalation occurs
ortho to the trifluoromethyl group.
sociation of the TMP dimer into the monomer may pre-
cede deprotonation.17 Optimizations of any separated
SiEt3
SiEt3
species at less than ~10 Å led to these complexes. For the
1,3-dibromo-4,6-dimethoxybenzene reactions, the initial
barrier of path 2 is 4.6 (5.7) kcal/mol lower than the initial
barrier of path 1 at the DFT (COSGMS) level without
ZPE (Scheme 5). With ZPE, the initial barrier of path 2 is
5.3 kcal/mol lower than the initial barrier of path 1. Fur-
thermore, both path 1 and path 2 are exothermic; however,
path 2 is exothermic by –13.4 kcal/mol whereas path 1 is
exothermic by –3.8 at the DFT level with ZPE. The COS-
GMS calculations also produced similar results for the
exothermicity (e.g., –15.5 and –3.8 kcal/mol).
CF3
CF3
BuLi, t-BuOK
Li
Scheme 3
Since we found no reports of the reaction of 1,3-
dimethoxybenzene with LiTMP, a possible explanation
for the observed result is that LiTMP does not readily
deprotonate 1,3-dimethoxybenzene at low temperatures.
Treatment of 1,3-dimethoxybenzene with LiTMP under
the conditions used to deprotonate 1, followed by addition
of benzaldehyde, afforded a 40% yield of the benzhydrol.
Significantly, a competition experiment using one equiv-
alent of 1,3-dimethoxybenzene and one equivalent of 1,3-
dibromobenzene with one equivalent of LiTMP, using
conditions employed to deprotonate 1 followed by
quenching with benzaldehyde, produced only the adduct
with 1,3-dibromobenzene (Scheme 4). In view of this ex-
periment, it is unlikely that steric buttressing plays a large
role in the observed selectivity with 1.
TMP
Li
H
LiTMP
MeO
OMe
OMe
Br
MeO
Br
Br
Br
Path 1
Path 2
MeO
MeO
Br
OMe
Br
OMe
Br
Br
Li
LiTMP
TMP
H
MeO
OMe
Br
Br
Scheme 5
LiTMP
+
PhCHO
Br
Br
For the 1,3-dibromobenzene and 1,3-dimethoxybenzene
reactions, calculations identified similar trends. Compari-
son of the initial barriers in both reactions favored depro-
tonation between the substituents (as opposed to the
hydrogens meta to the substituents) by ~6–10 kcal/mol.
Comparisons of the overall complex energetics in both re-
actions favored deprotonation between substituents by
~3–6 kcal/mol. In the 1,3-dimethoxybenzene reactions,
both DFT and COSGMS calculations identified endother-
mic reactions for both meta and ortho deprotonation. In
the 1,3-dibromobenzene reactions, COSGMS showed a
further increase in the exothermicity already present at the
DFT level for both deprotonations. These results support
those obtained in the competition experiment.
Ph
OH
Scheme 4
Theoretical analysis was used to further understand how
deprotonation competition occurs with respect to the reac-
tions of LiTMP with 1,3-dibromobenzene, 1,3-dimeth-
oxybenzene, and 1,3-dibromo-4,6-dimethoxy benzene
prior to electrophilic substitution. All stationary structures
(including transition states), energies, and frequencies
were calculated using the 6-311G(d,p) basis set for H, C,
N, Li and O and the Hay–Wadt LANL2DZdp ECP for the
Br at the HF and B3LYP levels of theory.11 The zero point
energies (ZPE) were calculated at –78 °C. B3LYP calcu-
lations using NWChem were performed to obtain struc-
tures including correlation and to improve the energetics
and frequencies.12 Finally, in order to incorporate some of
the solvent effects, single point energies were performed
with the B3LYP-COSGMS method as implemented in
GAMESS.13–15 For the COSGMS runs, an extrapolation
based on experimental data was used to obtain a dielectric
constant for the THF solvent at –78 °C of 12.02 Debyes.16
Geometries for all minima and transition states, as well as
The metalation of 1 is remarkably regioselective. The an-
ion is sufficiently stable at –78 °C to react with a variety
of electrophiles. Regardless of the origin of the regiose-
lectivity, this selective deprotonation will likely find a
number of applications in the synthesis of resorcinol-
based natural products.19
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 13, 1955–1958 © Thieme Stuttgart · New York

LETTER
Metalation of 4,6-Dibromoresorcinol Dimethyl Ether
1957
(16) CRC Handbook of Chemistry and Physics, 83rd ed.; Lide,
D. R., Ed.; CRC Press: Boca Raton, 2002.
(17) Pratt, L. M. THEOCHEM 2007, 811, 191.
(18) Chandrasekharan, V.; Unnikrishnan, P.; Sha, G. D.;
Bhattacharyya, S. C. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1980, 19, 1052.
Acknowledgment
G.K., I.J. and J.M. thank the National Institute of Health (Grant P01
ES12020) and the Office of Dietary Supplements for financial sup-
port through the Center for Research on Botanical Dietary Supple-
ments at Iowa State University. A.C.W. and T.L.W. thank the
National Science Foundation (Grant OISE-0730114) for financial
support.
(19) Representative experimental procedure. To a solution of
tetramethylpiperidine (326 mg, 0.392 mL, 2.3 mmol) in THF
(5 mL) at 0 °C was added n-BuLi (2.5 M in hexane, 0.843
mL, 2.1 mmol). After stirring for 20 min, the flask was
cooled to –78 °C and opened quickly, solid 4,6-dibromo-
resorcinol dimethyl ether (1; 297 mg, 1.0 mmol) was added
all at once, and the flask was immediately sealed. Compound
1 dissolved to give a homogeneous mixture, which became
a white slurry about 30 min after the addition. After stirring
at –78 °C for a total time of 3 h, a solution of allyl bromide
(607 mg, 0.424 mL, 5.0 mmol) in THF (1 mL) was added
over 1 min. The resulting mixture was stirred at –78 °C for
30 min, and then the ice bath was removed. After warming
to r.t., the reaction mixture was poured into saturated NH4Cl
solution and the aqueous layer was extracted twice with
diethyl ether. The combined organic layers were washed
with brine, dried over MgSO4 and filtered. The filtrate was
concentrated in vacuo and the residue was purified by silica
gel column chromatography (EtOAc–hexane, 1:99) to give 3
(329 mg, 98%) as a white solid.
References and Notes
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(5) (a) Leroux, F.; Schlosser, M. Angew. Chem. Int. Ed. 2002,
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(11) (a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A.
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M. P.; Blandeau, J.-P.; Davis, N. E.; Binning, R. C. Jr.;
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1,3-Dibromo-2-methyl-4,6-dimethoxybenzene (2):
Purification by column chromatography on silica gel
(EtOAc–hexane, 1:20) gave the title compound 2 in 96%
yield, which crystallized from benzene–hexane (3:1) as
white needles; mp 168–169 °C (Lit.18 168–169 °C). 1H
NMR (400 MHz, CDCl3): d = 6.42 (s, 1 H), 3.91 (s, 6 H),
2.62 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 155.7, 139.2,
105.7, 94.8, 56.5, 24.2. HRMS (EI): m/z calcd for
C9H10Br2O2: 309.9027; found: 309.9032. Anal. Calcd for
C9H10Br2O2: C, 34.87; H, 3.25. Found: C, 34.85; H, 3.20.
2-Allyl-1,3-dibromo-4,6-dimethoxybenzene (3):
Purification by column chromatography on silica gel
(EtOAc–hexane, 1:99) gave the title compound 3 in 98%
yield, which crystallized from hexane as white plates; mp
67–68 °C. 1H NMR (400 MHz, CDCl3): d = 6.45 (s, 1 H),
5.96–5.86 (m, 1 H), 5.12–5.07 (m, 2 H), 3.92 (s, 6 H), 3.87
(d, J = 8.00 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d =
155.9, 140.2, 133.1, 116.5, 105.8, 95.3, 56.5, 40.9. HRMS
(EI): m/z calcd for C11H12Br2O2: 335.9184; found: 335.9189.
(2,6-Dibromo-3,5-dimethoxyphenyl)(phenyl)methanol
(4): Purification by column chromatography on silica gel
(EtOAc–hexane, 1:9) gave the title compound 4 in 72%
yield, which crystallized from benzene–hexane (1:3) as
white prisms; mp 147–148 °C. 1H NMR (400 MHz, CDCl3):
d = 7.38–7.25 (m, 5 H), 6.80 (d, J = 11.2 Hz, 1 H), 6.55 (s,
1 H), 3.94 (s, 6 H), 3.87 (d, J = 11.2 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 156.2, 141.5, 141.4, 128.1, 126.9, 125.4,
96.3, 96.3, 76.5, 56.6. HRMS (EI): m/z calcd C15H14Br2O3:
401.9289; found: 401.9294.
(2-Bromophenyl)(2,6-dibromo-3,5-dimethoxy-
phenyl)methanol (5): Purification by column
chromatography on silica gel (EtOAc–hexane, 1:9) gave the
title compound 5 in 55% yield, which crystallized from
benzene–hexanes (3:1) as a white powder; mp 190–191 °C.
1H NMR (400 MHz, CDCl3): d = 7.58 (d, J = 8.0 Hz, 1 H),
7.37 (d, J = 8.0 Hz, 1 H), 7.22 (t, J = 8.0 Hz, 1 H), 7.14 (t,
J = 8.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.54 (s, 1 H),
3.93 (s, 6 H), 3.50 (d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 156.2, 139.8, 139.2, 133.4, 129.8, 129.3, 126.8,
123.7, 105.8, 96.5, 77.2, 56.7. HRMS (EI): m/z calcd for
C15H13Br3O3: 367.9446; found: 367.9450.
Synlett 2010, No. 13, 1955–1958 © Thieme Stuttgart · New York

1958
G. A. Kraus et al.
LETTER
2,6-Dibromo-1-iodo-3,5-dimethoxybenzene (7):
Purification by column chromatography on silica gel
(EtOAc–hexane, 1:9) gave the title compound 7 in 75%
yield, which crystallized from hexanes as white needles; mp
181–182 °C. 1H NMR (400 MHz, CDCl3): d = 6.57 (s, 1 H),
3.91 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 156.3, 112.2,
111.5, 96.9, 56.9. HRMS (EI): m/z calcd for C8H7Br2IO2:
421.7837; found: 421.7845.
1-(2,6-Dibromo-3,5-dimethoxyphenyl)butan-1-ol (6):
Purification by column chromatography on silica gel
(EtOAc–hexane, 1:9) gave the title compound 6 in 53%
yield as a pale-yellow viscous liquid which solidified upon
drying in vacuo; mp 73–74 °C. 1H NMR (400 MHz, CDCl3):
d = 6.44 (s, 1 H), 5.54–5.48 (m, 1 H), 3.89 (s, 6 H), 3.27 (d,
J = 8.0 Hz, 1 H), 2.12–2.03 (m, 1 H), 1.87–1.78 (m, 1 H),
1.65–1.53 (m, 1 H), 1.41–1.28 (m, 1 H). 13C NMR (100
MHz, CDCl3): d = 155.9, 141.9, 95.7, 75.9, 56.6, 37.2, 19.2,
13.9. HRMS (EI): m/z calcd for C12H16Br2O3: 367.9446;
found: 367.9450.
Synlett 2010, No. 13, 1955–1958 © Thieme Stuttgart · New York

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