ROMPgel-supported biphenyl and naphthalene: Reagents for lithiation reactions with minimal purification

Article abstract of DOI:10.1016/S0040-4039(01)02317-6

The synthesis of ring opening metathesis, polymer (ROMPgel) supported naphthalene and biphenyl reagents was carried out. These reagents were utilized for catalytic lithiation reactions of aryl and alkyl chlorides and for the reductive deprotection of benzyl and allyl ethers.

Full text of DOI:10.1016/S0040-4039(01)02317-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1081–1083
ROMPgel-supported biphenyl and naphthalene: reagents for
lithiation reactions with minimal purification
Thomas Arnauld, Anthony G. M. Barrett* and Brian T. Hopkins
Department of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AY, UK
Received 27 November 2001; accepted 5 December 2001
Abstract—The synthesis of ring opening metathesis, polymer (ROMPgel) supported naphthalene and biphenyl reagents was
carried out. These reagents were utilized for catalytic lithiation reactions of aryl and alkyl chlorides and for the reductive
deprotection of benzyl and allyl ethers. © 2002 Elsevier Science Ltd. All rights reserved.
Polymer-supported reagents are convenient for parallel
solution phase synthesis with the removal of undesired
by-products through simple phase separation.1 For
example, polystyrene supported toluene-4-sulfonyl
azide has been used as a diazo transfer reagent to
generate diethyl diazomalonate which was then purified
by simple separation.2 With the emergence of combina-
torial chemistry in the pharmaceutical industry, poly-
mer-supported reagents have been re-established as one
of the most effective methodologies for the amalgama-
tion of traditional solution phase chemistry with
automation through the use of robotics.
of unstable organolithium compounds in organic syn-
thesis.8 Halogen–lithium exchange can be achieved
through reaction of an alkyl or aryl halide with an
alkyllithium base or reduction of the halide species with
lithium metal.9 In the latter method, it is first necessary
to activate the metal when performing the reaction at
low temperature, which is achieved by using an arene
electron carrier such as naphthalene and biphenyl.10
Arene catalyzed lithiation has been utilized for diverse
transformations, including reductive carbon–oxygen11
and carbon–sulfur cleavages,12 lithiation of functional-
ized alkyl and aryl chlorides,13 reductive opening of
saturated heterocycles,14 and deprotection of a number
of protecting groups.15
The Barrett group has devised a novel approach to the
synthesis of polymer supported reagents utilizing ring
opening metathesis polymerization (ROMP) to support
diverse reagents. This methodology has been successful
in the synthesis of unsaturated esters and nitriles
through Horner–Emmons reactions,3 the synthesis of
amides including Mosher amides utilizing ROMPgel4
supported N-hydroxysuccinimide ester and for the syn-
thesis of oxadiazoles5 and oxazoles.6 ROMPgel anhy-
dride scavengers7 have also been found to be effective
for the removal of excess amine and hydrazine from
solution phase reactions.
Ph
b
Br
a
n
Ph
3
1
2
Scheme 1. Reagents and conditions: (a) Pd(PPh3)2(OAc)2, nor-
bornadiene, DMF, piperidine, HCO2H, 60°C, 4 h, 75%; (b) i.
4 (1.5 mol%), CH2Cl2, 25°C, 12 h, 100%; ii. 5 (10 mol%),
PhH, H2, 150 psi, 120 h, 84%.
We now wish to report the application of ROMPgel
supports to immobilize biphenyl and naphthalene to
facilitate arene catalyzed lithiation reactions. ROMPgel
supported arenes would allow for the facile purification
of multifunctionalised compounds after an arene medi-
ated lithiation through simple filtration. Arene cata-
lyzed lithiation is a powerful method for the generation
Synthesis of the ROMPgel supported biphenyl
(ROMPgel biphenyl) was achieved via
a Heck
coupling16 of 4-bromobiphenyl 1 to norbornadiene to
afford 2 in 75% yield. Subsequent polymerization of
norbornadiene 2 was then carried out with Grubbs’
catalyst 4 (1.5 mol%) affording the insoluble ROMPgel
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02317-6

1082
T. Arnauld et al. / Tetrahedron Letters 43 (2002) 1081–1083
without using any cross-linker. The resulting polymer
was suspended in benzene and hydrogenated in the
presence of a homogenous catalyst 5 (10 mol%) to
afford the reduced ROMPgel 3 in 84% yield17 (Scheme
1). A similar strategy was utilized for the synthesis of
the ROMPgel supported naphthalene 6 (ROMPgel
naphthalene) in 66% yield. Arene lithiations of chlori-
nated compounds are traditionally conducted using a
stoichiometric amount of naphthalene or biphenyl,
either by the formation of the lithium species and
subsequent addition of an electrophile or by the prepa-
ration of the lithium species in the presence of the
electrophile.
After hydrolysis, the polymer was simply removed by
filtration through a short pad of silica (one fraction)
and the solvent evaporated to afford the desired
product in good yield and purity (Table 1). ROMPgel
arenes 3 and 6 are easily prepared and inexpensive
reagents which are convenient alternatives to the
polystyrene arene resins utilized by Yus and co-
workers.18
It is clear from Table 1 that ROMPgels 3 and 6 are
useful for catalyzed lithiation reactions with minimal
purification. Both chlorides 7 and 8 were smoothly
converted into the corresponding alkyl and benzyl
lithium reagents and trapped with several elec-
trophiles.19 Lithiation of the aryl chloride 9 and reac-
tion with acetophenone and benzaldehyde gave adducts
of lower purity. Finally, we examined the use of the
ROMPgel arenes 3 and 6 for reductive cleavage of
benzyl and allyl ether protecting groups, which are
traditionally removed either by hydrogenation or using
Lewis acids and oxidants.20 We chose 1-naphthol and
critronellol as the substrates, which were protected as
benzyl, allyl and silyl ethers using traditional
protocols.21
Ph
PCy3
Cl
n
Ru
(Ph3P)3RhCl
Cl
Ph
PCy3
6
4
5
Recently, Yus and co-workers15 have reported the
preparation of organolithium species using only a cata-
lytic amount of the arene (ca. 10 mol%), both in
solution and using a polystyrene supported naphthalene
and biphenyl.
The results, which are summarized in Scheme 3 and
Table 2 show that deprotection of allyl and benzyl
ethers is possible using reduction in the presence
ROMPgel 3 and 6.
To determine the utility of ROMP 3 and 6, we exam-
ined a series of reductive lithiation reactions. Thus, a
series of chlorinated compounds were allowed to react
with an excess of lithium metal and the ROMPgel arene
3 or 6 (ca. 10 or 20 mol%) in THF at −78°C. Subse-
quent addition of an electrophile and hydrolysis gave
rise to the expected products (Scheme 2 and Table 1).
To conclude, we have successfully demonstrated the
applicability of ROMPgel naphthalene 6 and biphenyl
3 for a series of arene catalyzed lithiation reactions. The
two ROMPgel supported reagents are worthwhile alter-
natives to the use of naphthalene and biphenyl in
a
a
R E
R Cl
R1 O H
R1 O R2
Me Me
O
O
10
11
O
O
RCl =
Cl
Cl
OH
Cl
R1OH =
or
OH
7
9
8
11a
11b
Scheme 2. Reagents and conditions: (a) Li, ROMPgel arene
support 3 or 6 (10 mol% or 20 mol%), E+=PhAc, or PhCHO,
or R3SiCl, THF, −78 to 25°C, MeOH.
Scheme 3. Reagents and conditions: (a) Li, ROMPgel arene
supports 3 and 6 (10 mol%), THF, −78°C, MeOH.
Table 1.
Chloride
Polymer
Electrophile
Time (h)
Yielda (%)
Purityb (%)
7
7
7
8
8
8
9
9
3
3
6
3
3
6
3
6
PhAc
20
20
20
20
20
20
30
30
87
88
81
85
78
77
71
65
91
96
92
91
93
90
81
80
PhCHO
tBuPh2SiCl
PhAc
PhCHO
tBuMe2SiCl
PhAc
PhCHO
a Isolated yields.
b Purity as determined by GC–MS and 1H NMR.

T. Arnauld et al. / Tetrahedron Letters 43 (2002) 1081–1083
1083
Table 2.
R1
R2
Polymer
Time (h)
Yield (%)
71
Purity (%)
11a
11a
11a
11b
11b
11b
PhCH2
3
3
6
6
6
3
40
40
40
40
40
40
80
83
–
96
92
–
Allyl
73
tBuMe2SiCl
PhCH2
a
89
Allyl
86
tBuMe2SiCl
a
a No reduction observed.
solution phase chemistry and eliminate the need for
laborious chromatography or vacuum sublimation to
remove the naphthalene or biphenyl.
14. (a) Bartmann, E. Angew. Chem., Int. Ed. Engl. 1986, 25,
653; (b) Yus, M.; Soler, T.; Foubelo, F. Tetrahedron
2001, 12, 801.
15. Alonso, E.; Ramo´n, D. J.; Yus, M. Tetrahedron 1997, 53,
14355.
16. Arcadi, A.; Marinelli, F.; Bernocchi, E.; Cacchi, S.;
Ortar, G. J. Organomet. Chem. 1989, 368, 249.
17. Typical procedure for the preparation of ROMPgel: Ben-
Acknowledgements
zylidene
bis(tricyclohexylphosphine)dichlororuthenium
We thank Merck KGaA for generous support of this
research. Additionally we thank GlaxoSmithKline for
the valuable endowment (to A.G.M.B.), the EPSRC
and the Wolfson Foundation for establishing the Wolf-
son Centre for Organic Chemistry in Medical Science at
Imperial College.
(12 mg, 10 mmol) in CH2Cl2 (2 mL) was slowly added to
a stirred solution of 5-(4-phenylphenyl)bicyclo[2.2.1]hept-
2-ene (250 mg, 1.00 mmol) in CH2Cl2 (1.5 mL). The
solution was stirred at room temperature for 12 h. Ethyl
vinyl ether (3 mL) was added, followed by the addition of
CH2Cl2 (5 mL). The solution was filtered to afford a
brown solid which was washed with MeOH (30 mL),
CH2Cl2 (30 mL), Et2O (30 mL) and dried in vacuo to
afford the corresponding ROMP (250 mg, 100%) as a
white solid. The solid was suspended in benzene and to
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