Regioselective lithiation of resorcinol derivatives: Synthesis of mono O-MOM- and O-benzylresorcinols prenylated at C-2 or C-4 positions

Article abstract of DOI:10.1055/s-1999-3487

Resorcinol derivatives 3-benzyloxy-1-methoxymethoxybenzene (3b) and 4- benzyloxy-1-bromo-2-methoxymethoxybenzene (3c) were regioselectively lithiated. The resulting aryllithium intermediates or their cuprate derivatives were reacted with allyl bromide (4a

Full text of DOI:10.1055/s-1999-3487

PAPER
1017
Regioselective Lithiation of Resorcinol Derivatives: Synthesis of Mono
O-MOM- and O-Benzylresorcinols Prenylated at C-2 or C-4 Positions
Alessandro B. C. Simas,a,b Antonio L. Coelho,a Paulo R. R. Costaa
aLaboratório de Síntese Assimétrica (LASA), Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, CCS, Bl.
H, Ilha da Cidade Universitária, 21941-590, Rio de Janeiro, RJ, Brazil
bDepartamento de Química, ICE, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
Fax +55(21)2702683; E-mail abcsimas@nppn.ufrj.br; alcoelho@nppn.ufrj.br or prrcosta@nppn.ufrj.br
Received 3 August 1998; revised 3 December 1998
mediates, prenylated at the C-2 or C-4 position and differ-
Abstract: Resorcinol derivatives 3-benzyloxy-1-methoxymeth-
entially protected at the phenol groups, as in compounds
1 and 2, respectively (Figure 1), by using new resorcinol
derivatives 3b and 3c (Figure 2), easily prepared from 3-
oxybenzene (3b) and 4-benzyloxy-1-bromo-2-methoxymethoxy-
benzene (3c) were regioselectively lithiated. The resulting aryllith-
ium intermediates or their cuprate derivatives were reacted with
allyl bromide (4a), prenyl bromide (4b) and (E)-4-benzyl-1-bromo- benzyloxyphenol (3a).
3-methylbut-2-ene (4c), leading to C-2 and C-4 substituted resorci-
nols 6 and 7, respectively. The use of 2-methyl-2-vinyloxirane (5)
as electrophile was also studied as another means of introduction of
an oxygenated prenyl side chain on 3b or 3c. Prenylated compounds
6 and 7 could be transformed into the corresponding mono O-pro-
tected resorcinols 8, 9 and 10 by selective removal of either the ben-
zyl or MOM group.
3a, R1= R2= H
BnO
R2
OR1
3b, R1= MOM, R2= H
3c, R1= MOM, R2= Br
Figure 2. Benzylated resorcinol derivatives
Key words: resorcinol derivatives, prenylation, lithiation
The benzyl and MOM protecting groups were chosen be-
cause they can be selectively removed under different
conditions.6 In addition, the MOM group, a strong direct-
ing ortho-metallation group,7 would ensure the regioselec-
tivity of deprotonation at C-2 position of compound 3b.
The regioselectivity for the lithiation of 3c at C-4 position
would be secured by the presence of bromine atom (met-
al-halogen exchange).
The presence of prenylated resorcinol moieties such as 1
and 2 (Figure 1) in the structure of natural products isolat-
ed from plants and fungi is widespread. The prenyl unity
may also appear hydroxylated at the pro-E methyl group
or as part of an additional furan or pyran ring.1
R3
R2
R1O
O
The use of the benzyl protecting group in Directed ortho
Metallation (DoM) appears not to have been systematical-
ly studied.8 Therefore, we sought the optimal conditions
for the regioselective lithiation of 3b. We found that the
use of BuLi in a mixture of hexanes/cyclohexane at room
temperature gives complete and clean deprotonation at C-
2 position, proven by quench with D2O. The lithiation did
not require the employment of stronger bases (s-BuLi or
t-BuLi) or deaggregating agents such as TMEDA.4 The
possible deprotonation at the benzylic carbon or self-re-
protonation by the benzylic hydrogens was not observed.
However, when the deprotonation of 3b (BuLi) was run in
THF and the reaction was quenched with aqueous NH4Cl,
a more polar substance (TLC, silica gel) was obtained
along with 3b. This result points out the requirement of
hydrocarbon solvents in the deprotonation step for the
achievement of good yields.
R1O
R2
R3
1
2
R
2 = R3= CH3
R2 = CH3, R3= CH2OH
Figure 1. Prenylated resorcinol moieties
While the introduction of the prenyl group in resorcinol or
its derivatives under Friedel–Crafts conditions has been
reported as suffering from lack of regioselectivity,2 scat-
tered examples may be found on the regioselective intro-
duction of allylic electrophiles via resorcinol-derived
organometallics, leading to substitution at the C-2 posi-
tion.3,4 Selective substitution at the C-4 position has been
achieved through preliminary protection of the C-2 posi-
tion with a TMS group.5
The organolithium intermediate generated from 3b was
allowed to react with 4a (Scheme 1, Table 1, Entry 1) and
the best result was obtained when the ether and 4a were
added at 0oC and the resulting mixture was heated to re-
flux for 2 hours, leading to 6a. Under the same conditions,
the use of 4b and (E)-4-benzyloxy-1-bromo-3-methylbut-
2-ene (4c) as alkylating agents (Table 1, Entries 2 and 3,
Due to the potential of prenylated resorcinols as synthetic
precursors of natural products,3 we set out to investigate
the possibility of regioselective preparation of such inter-
Synthesis 1999, No. 6, 1017–1021 ISSN 0039-7881 © Thieme Stuttgart · New York

1018
A. B. C. Simas et al.
PAPER
Table 1 Reaction of 3b with Electrophiles
Condition 1) led to prenylated products 6b and 6c. We did
not observe the presence of regioisomers or products orig-
inated by a SN2’ type reaction. The prenylation of 3b could
be accomplished under softer conditions if the organolith-
ium intermediate was first transformed into the corre-
sponding cuprate (Table 1, Entry 2, Conditions 2 or 3)
followed by trapping with 4b (–78oC to r.t.). Condition 3
(use of CuCN•2 LiCl)9 is particularly convenient due to
the higher solubility of the generated cuprate, which
makes it more suitable to large-scale preparations. We
also attempted to incorporate an oxygenated prenyl chain
through the use of vinyl epoxide 5 as electrophile via the
aryllithium intermediate derived from 3b itself (Table 1,
Entry 4, Condition 1).10 Unfortunately, the starting mate-
rial was recovered. The cuprate obtained through use of
CuCN•2 LiCl as a copper source (Table 1, Entry 4, Con-
dition 3) reacted with epoxide 5 affording allylic alcohol
Entry
Electro-
phile
Condi-
tion
Product
Yield (%)
1
2
4a
4b
1a
1a
2b
3c
1a
1d
3c
6a
6b
6b
6b
6c
6d
6d
70
69
62
60
62
0
3
4
4c
5
46e
a 4 or 5 in Et2O, reflux, 2h.
b CuCN/THF, –78→30°C; then 4, –78°C→r.t.
c CuCN 2 LiCl/THF, –78→30°C; then 4 or 5, –78°C→r.t.
d THF, –78°C → r.t. (overnight) (instead of Et2O, reflux).
e 56% based on recovered starting material; E/Z = 3.6:1.0.
6d in moderate yield as an unseparable E/Z (3.6:1, respec- tions for the alkylation step. However, we found that the
tively) mixture of stereoisomers.11 We expected a stereo- reaction still required use of reflux to give 7a in good
selectivity as high as the ones described in the literature yield. The prenylated resorcinol 7b was obtained through
for reactions of 5 and cuprates prepared both from organ- the use of electrophile 4b (Table 2, Entry 2). As an attempt
olithium and Grignard reagents (E/Z ratio ranging from to improve the yield of 7b, a cuprate derivative of 3c was
11:1 to 32:1).12 The double bond geometry in the major prepared and reacted with 4b (Table 2, Entry 2, Condition
product was confirmed by O-benzylation of 6d and com- 3), but the result was disappointing. Besides low yield, the
1
parison with the H NMR spectrum of substance 6c (E- reaction gave substantial amounts of the reduction prod-
stereoisomer). The low stereoselectivity shown by the re- uct 3b and a small amount of the SN2' product. Further-
action of 5 makes the use of electrophile 4c (Table 1, En- more, the incorporation of an oxygenated prenyl chain on
try 3) important as it allows the introduction of an resorcinol 3c by employment of allylic epoxide 5 was
oxygenated prenyl moiety presenting an E-controlled ge- studied. Interestingly, the aryllithium species derived
ometry.
from 3c reacted quite cleanly with 5 (Table 2, Entry 3,
Condition 2), affording the SN2' product 7c with high E-
stereoselectivity (15:1). The double bond geometry was
determined by NOE-diff experiments. This stereoselec-
tivity is in contrast with previous reports on the reaction
of 5 with aryllithium species, where a Z-selectivity was re-
ported.10 Again, improvement of the yield of the last reac-
tion was attempted by employment of cuprates. The
organocopper species produced by using CuCN•2 LiCl as
copper source, did not react with epoxide 5, while the cu-
prate obtained by using CuI (Table 2, Entry 3, Condition
3) led to product 7c (2:1 E/Z mixture of stereoisomers, re-
spectively) in low yield, though. As it had occurred in the
R5
R4
i - BuLi / cyclohexane
oC → rt / 1h
ii - see Table 1
MOMO
OBn
MOMO
0
OBn
3b
6a, R4 = R5= H
6b, R4 = R5= CH3
6c, R4 = CH3, R5= CH2OBn
6d, R4 = CH3, R5= CH2OH
R4
R5
Br
O
4a, R4= R5= H
5
Table 2 Reaction of 3c with Electrophiles
4b, R4= R5= CH3
4c, R4= CH3, R5= CH2OBn
Entry
Electro-
phile
Condi-
tion
Product
Yield (%)
Scheme 1
1
2
4a
4b
1a
1a
2b
2b
3c
7a
7b
7b
7c
7c
60
58
<36d
29e
59f
In order to obtain compounds 7 (Scheme 2, Table 2), the
regioisomers of prenylated resorcinols 6, bromine-lithium
exchange on 3c was effected. The resulting aryllithium in-
termediate was reacted with MeI, leading to incorporation
of methyl group at the C-4 position in almost quantitative
yield. Afterwards, we turned to the alkylation with elec-
trophile 4a (Scheme 2, Table 2, Entry 1). Since the lithiat-
ed species here is less sterically crowded than the one
originated from substrate 3b, we expected milder condi-
3
5
a 4/eyclohexane, reflux 2h.
b CuI/THF, –78→ –30°C; then 4 or 5, –78°C→r.t.
c 5/–78°C→r.t.
d An inseparable side product was observed. Yield estimated by
1H NMR spectroscopy.
e E/Z = 2:1.
f E/Z = 15:1.
Synthesis 1999, No. 6, 1017–1021 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Mono O-MOM- and O-Benzylresorcinols Prenylated at C-2 or C-4-Positions
1019
formation of 7b via a cuprate, the reduction product 3b In summary, we have studied the lithiation of O-benzyl
was an important fraction of the crude product. These dis- protected resorcinol derivatives and their reactions with
appointing results in reactions involving cuprates pre- electrophiles 4b, 4c and 5, leading to resorcinols allylated
pared from 3c are somewhat surprising if one takes into and prenylated at C-2 or C-4 positions.15 A comparative
account literature reports of similar procedures.9
study of the reactivity of aryllithium intermediates and
their corresponding cuprates towards those electrophiles
was carried out. It was demonstrated that, in general, the
prenylation reactions do not require the intervention of cu-
prates, although the use of such intermediates allowed that
the prenyl side chain be introduced on resorcinol deriva-
tive 3b under softer conditions. Nevertheless, the employ-
ment of a cuprate derived from 3b was required for
successful reaction with allylic epoxide 5. The benzyl pro-
tecting group has been shown to be compatible with
MOM-directed lithiation of resorcinols under certain con-
ditions. The possibility of selective removal of both pro-
tecting groups in resorcinol derivatives 6 and 7 makes
these compounds interesting intermediates for the synthe-
sis of natural products.
i - BuLi / THF
-78 oC / 15min.
ii - see Table 2
MOMO
Br
OBn
MOMO
OBn
3c
R5
R4
Br
R5
O
7a, R4 = R5= H
R5
4a, R4= R5= H
4b, R4= R5=CH3
7b, R4 = R5= CH3
5
7c, R4 = CH3, R5= CH2OH
Scheme 2
The use of the described prenylation method in total syn-
thesis is currently under investigation in our laboratory.
We are also studying the compatibility of the benzyl pro-
tecting group with other strong DMGs.
Once the desired resorcinol derivatives 6 and 7 were ob-
tained, our next goal was the selective removal of the ben-
zyl or MOM (methoxymethyl) protecting group, in order
to obtain the corresponding mono protected compounds
(Scheme 3). Reaction of 6b with hydrogen using Pd/C led
not only to hydrogenolysis of the O-benzyl group but to a
simultaneous reduction of the prenyl moiety double bond.
Nevertheless, the selective cleavage of the benzyl group
of 6b was achieved through reduction with Na/NH3, lead-
ing to 8a.13 When 6c was submitted to the same reaction
conditions, both benzyl protecting groups were removed
and 8b was obtained. The MOM group of 6b and 6c was
selectively removed by reaction with PPTS (pyridinium
p-toluenesulfonate) in i-PrOH under reflux to give com-
pounds 9a and 9b.14 The selective removal of the benzyl
group of substance 7b was achieved by the same condi-
tions used on 6b affording phenol 10.
The electrophile (E)-4c was prepared by essentially the same proce-
dure which Hiroi and Hirasawa employed in the synthesis of (E)-4-
acetoxy-1-bromo-3-methylbut-2-ene.16 Epoxide 5 (purchased from
Aldrich) was dried over CaH2 and distilled. LiCl was heated at
120oC under a 0.5 Torr vacuum for 1.5 h before use. For general
methods, see Ref. 3c.
3-Benzyloxy-1-methoxymethoxybenzene (3b)
To a stirred suspension of NaH (0.576 g, 12 mmol) in THF (10 mL)
under N2 at 0oC was added dropwise a solution of 3a17 (1.93 g, 9.7
mmol) in THF (10 mL). The ice-bath was removed and the mixture
was stirred at r.t. for 10 min. Then, it was cooled to 0oC and DMF
(4.0 mL) followed by MOMCl (0.95 mL 12.5 mmol) was added.
After 10 min, the ice-bath was removed. After stirring at r.t. for 1 h,
H2O (30 mL) was added and the product was extracted with EtOAc
(100 mL). The organic layer was dried (Na2SO4) and concentrated.
Flash chromatography18 (EtOAc/hexanes, 3:97, 5:95) of the residue
afforded 3b as a colorless oil (2.15g, 91%).
R
i
R
R
1H NMR (CDCl3/TMS): d = 3.46 (s, 3 H), 5.02 (s, 2 H), 5.14 (s,
2 H), 6.59–6.71 (m, 3 H), 7.17 (dd, 1 H, J = 8.4, 8.4 Hz),
7.25–7.45 (m, 5 H).
MOMO
OH
MOMO
OBn
HO
OBn
ii
13C NMR: d = 55.7, 69.7, 94.2, 103.4, 108.0, 108.5, 127.3, 127.7,
9a, R= H , 88%
9b, R= OBn , 89%
8a, R= H , 89%
6b, R= H
128.3, 129.7, 136.7, 158.2, 159.7.
8b, R= OH , 90%
6c, R= OBn
HRMS: m/z calcd for C15H16O3 (M+): 244.1099 found: 244.1097.
4-Benzyloxy-1-bromo-2-methoxymethoxybenzene (3c)
MOMO
OH
MOMO
OBn
To a stirred solution of 3a (2 g, 10 mmol) in CH2Cl2 (30 mL) at –
30°C was added solid NBS (1.78 g, 10 mmol) under N2 atmosphere
via a solid addition funnel. The mixture was stirred at the same tem-
perature for 30 min. After removal of the cooling bath, the mixture
was kept at r.t. for 10 min. Then, more CH2Cl2 was added and the
mixture was successively washed with H2O (20mL), brine (20mL)
and H2O (20mL). The organic layer was dried (Na2SO4) and con-
centrated to give a light-green oil. This material was purified by
flash chromatography (hexanes/CH2Cl2, 30:70) affording 2-bromo-
5-benzyloxyphenol (1.37 g, 49% yield) as low melting solid. This
compound had the phenol group protected by MOMCl through the
i
80%
10
7b
Reagents and conditions: i) Na/NH3/Et2O, –78°C, 10 min; ii) PPTS/i-
PrOH, 3 h, reflux, 3 h
Scheme 3
Synthesis 1999, No. 6, 1017–1021 ISSN 0039-7881 © Thieme Stuttgart · New York

1020
A. B. C. Simas et al.
PAPER
same procedure described for preparation of resorcinol 3b. Thus, 3c
MS (EI): m/z (%) = 328 (M+, 1).
was obtained as a colorless thick oil (95% yield).
1H NMR (CDCl3/TMS): d = 3.51 (s, 3 H), 5.03 (s, 2 H), 5.19 (s, 2
H), 6.53 (dd, 1 H, J = 2.75, 8.3 Hz), 6.84 (d, 1 H, J = 2.75 Hz), 7.30–
7.45 (m, 6 H).
3-Benzyloxy-1-methoxymethoxy-4-(3-methylbut-2-enyl)ben-
zene (7b); General Procedure for Alkylation of 3c via Aryllithi-
um Species
To a solution of 3c (0.323 g, 1 mmol) in THF (5 mL) and cyclohex-
ane (5 mL) at –78°C was added BuLi in hexanes (1.13 mL, 1.5
mmol, 1.36 M). The reaction was kept at this temperature for 15
min. Afterwards, prenyl bromide (4b; 0.25 mL, 2.15 mmol) was
added, the mixture allowed to warm to r.t. and heated to reflux for
2 h. After cooling to r.t., H2O was added and the product was ex-
tracted with CH2Cl2. The organic layer was dried (Na2SO4) and con-
centrated. The crude product was purified by preparative TLC
(EtOAc/hexanes, 5:95) furnishing 2b (0.181 g, 58%).
1H NMR (CDCl3/TMS): d = 1.73 (br, 6 H), 3.26 (d, 2 H, J = 7.24),
3.48 (s, 3 H), 5.04 (s, 2 H), 5.17 (s, 2 H), 5.28 (m, 1 H), 5.56 (dd, 1
H, J = 8.3, 2.5 Hz), 6.76 (d, 1 H, J = 2.5 Hz), 7.03 (d, 1 H, J = 8.3
Hz), 7.28–7.46 (m, 5 H).
13C NMR: d = 56.23, 70.21, 95.05, 103.63, 104.16, 108.97, 127.40,
127.98, 128.48, 133.04, 136.36, 154.34, 159.01.
MS (EI): m/z (%) = 322 (M+, 2), 91 (100).
3-Benzyloxy-1-methoxymethoxy-2-(3-methylbut-2-enyl)ben-
zene (6b); Typical Procedure for Alkylation of 3b via Aryllithi-
um Species
A solution of BuLi in hexanes (1.13 mL, 1.5 mmol, 1.36 M) was
added dropwise to a stirred solution of3b (0.25 g, 1.02 mmol) in cy-
clohexane (2.0 mL) under N2 at 0°C. After 5 min, the ice bath was
removed and the mixture was allowed to warm to r.t. After stirring
for 1 h, the resulting brown suspension was cooled to 0°C and Et2O
(2.0 mL) was added followed by prenyl bromide (4b; 0.26 mL, 2.25
mmol). The mixture was heated at 60–70°C for 2 h. After cooling
to r.t., H2O (10 mL) was added and the product extracted with
EtOAc (50 mL). The organic layer was washed with H2O (30 mL),
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (EtOAc/hexanes, 1:99, 3:97) which afforded 6b
(0.221 g, 69%) as a yellow oil.
1H NMR (CDCl3/TMS) : d = 1.65 (s, 3 H), 1.70 (s, 3 H), 3.40–3.47
(d, 2 H), 3.47 (s, 3 H), 5.06 (s, 2 H), 5.19 (s, 2 H), 5.29–5.19 (m, 1
H), 6.61 (d, 1 H, J = 8.4 Hz), 6.73 (d, 1 H, J = 8.4 Hz), 7.07 (dd, 1
H, J = 8.4, 8.4 Hz), 7.45–7.29 (m, 5 H).
13C NMR (CDCl3/TMS): d = 17.6, 22.5, 25.6, 55.8, 70.1, 94.3,
105.8, 107.2, 119.6, 122.8, 126.6, 127.5, 128.3, 130.8, 137.3, 155.6,
157.2.
13C NMR (CDCl3/TMS): d = 17.61, 25.67, 27.92, 55.84, 70.04,
94.35, 102.21, 106.86, 122.86, 123.25, 127.42, 127.76, 128.41,
129.58, 131.88, 137.04, 155.50, 157.94.
MS (EI): m/z (%)= 312 (M+, 18).
3-Benzyloxy-6-[(E)-4-hydroxy-3-methylbut-2-enyl]-1-meth-
oxymethoxybenzene (7c)
A stirred solution of 3c (0.323 g, 1.0 mmol) in THF (3.0 mL) under
argon at –78°C was treated with BuLi in hexanes (0.96 mL, 1.3
mmol, 1.35 M). After 15 min, epoxide 5 (0.15 mL, 1.5 mmol) was
added and the mixture was allowed to warm to r.t. over 1.5 h. After
stirring overnight at r.t., an aq sat. solution of NH4Cl (15 mL) was
added and the product was extracted with EtOAc (50 mL). The or-
ganic layer was washed with H2O (20 mL), dried (Na2SO4) and con-
centrated. The crude product was purified by flash chromatography
(EtOAc/hexanes, 4:96, 20:80, and 30:70) affording 7c (0.193 g,
59%) as a yellow oil.
1H NMR (CDCl3/TMS): d = 1.78 (s, 3 H), 3.33 (d, 2 H, J = 7.2 Hz),
3.48 (s, 3 H), 4.03 (s, 2 H), 5.03 (s, 2 H), 5.18 (s, 2 H), 5.57 (tq, 1
H, J = 7.2, 1.4 Hz), 6.56 (dd, 1 H, J = 8.3, 2.5 Hz), 6.78 (d, 1H , J =
2.5 Hz), 7.30–7.48 (m, 5 H).
13C NMR (CDCl3/TMS): d = 13.5, 27.6, 55.8, 68.6, 69.9, 94.3,
102.2, 106.9, 122.3, 124.4, 127.3, 127.7, 128.3, 129.6, 134.9, 136.9,
155.5, 158.0.
MS (EI): m/z (%) = 328 (M+, 6).
IR (film): n = 3409 cm–1 (br).
HRMS: m/z calcd for: C20H24O3 (M+) 312.1725, found: 312.1720.
3-Benzyloxy-2-[(E)-4-hydroxy-3-methylbut-2-enyl]-1-meth-
oxymethoxybenzene (6d) (Major Stereoisomer); Typical Proce-
dure for Alkylation of 3b via Cuprates
A solution of BuLi in hexanes (1.57 mL, 2.13 mmol, 1.35 M) was
added dropwise to a stirred solution of 3b (0.40 g, 1.64 mmol) in cy-
clohexane (1.6 mL) under N2 at 0°C. After 5 min, the ice-bath was
removed and the reaction was allowed to proceed at r.t. for 1 h.
Then, THF (2.5 mL) was added to the resulting brown suspension
in order to homogenize it. This solution was transferred dropwise to
a stirred slurry of CuCN (0.19 g, 2.12 mmol) and LiCl (0.18 g, 4.25
mmol) (CuCN•2 LiCl) in THF (1.5 mL) under N2 at –78°C. At this
temperature, the obtained mixture was kept for 10 min and, then, the
–78°C bath was quickly replaced by a –30°C one. After 30 min, the
reaction was cooled to –78°C. The epoxide 5 (0.32 mL, 3.28 mmol)
was added and the temperature was allowed to rise till r.t. over 1.5
h. After stirring overnight at r.t., a sat. aq solution of NH4Cl (10 mL)
was added. The obtained heterogeneous mixture was subjected to
filtration under vacuum and the filtrate was washed thoroughly with
EtOAc (100 mL). The organic layer was washed with H2O (30 mL),
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (EtOAc/hexanes, 4:96, 30:70) to give recovered
3b (71 mg) and 6d (249 mg, 46, 56% based on recovery of 3b) as a
yellow oil.
3-Methoxymethoxy-2-(3-methylbut-2-enyl)phenol (8a); Gener-
al Procedure for the Cleavage of the Benzyl Group on 6 or 7
A solution of 6b (0.156 g, 0.5 mmol) in Et2O (3 mL) was added to
liquid ammonia (10 mL) in a dry ice-acetone bath. To the obtained
solution pieces of sodium (~ 0.043 g) were added until a character-
istic deep blue color persisted. After stirring for 10 min, the reaction
was quenched by addition of an aq sat. solution of NH4Cl. The dry
ice bath was removed to allow the ammonia to evaporate. After-
wards, CH2Cl2 was added to the residue and the mixture was
washed with brine. The organic layer was dried (Na2SO4) and evap-
orated to give the crude product, further purified by preparative
TLC to give pure 8a (0.099 g, 89%) as a yellow solid.
1H NMR (CDCl3/TMS): d = 1.77 (d, 3 H, J = 1.28 Hz), 1.82 (3 H, J
= 0.82 Hz), 3.44 (d, 2 H, J = 5.87 Hz), 3.48 (s, 3 H), 5.18 (s, 2 H),
5.24 (m, 1 H), 5.32 (br, 1 H), 6.50 (dd, 1 H, J = 1, 8.24 Hz), 6.66
(dd, 1 H, J = 1, 8.24 Hz), 7.02 (t, 1 H, J = 8.24 Hz).
13C NMR (CDCl3/TMS): d = 17.68, 22.40, 25.62, 55.89, 94.55,
109.58, 116.48, 106.59, 121.91, 126.98, 133.68, 155.18, 155.47.
1H NMR: d= 1.74 (s, 3 H), 3.46 (s, 3 H), 3.44–3.54 (d, 2 H), 3.93 (s,
2 H), 5.05 (s, 2 H), 5.18 (s, 2 H), 5.49 (tq, 1 H, J = 7.2, 1.4 Hz), 6.61
(d, 1 H, J = 8.2 Hz), 6.73 (d, 1 H, J = 8.2 Hz), 7.08 (dd, 1 H, J = 8.2,
8.2 Hz), 7.24–7.46 (m, 5 H).
13C NMR (CDCl3/TMS): d= 13.6, 22.1, 55.9, 69.0, 105.7, 118.7,
126.9, 127.1, 127.7, 128.3, 134.2, 137.2, 155.6, 157.2.
IR (film): n = 3403 cm–1 (br).
Synthesis 1999, No. 6, 1017–1021 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Mono O-MOM- and O-Benzylresorcinols Prenylated at C-2 or C-4-Positions
1021
HRMS: m/z calcd for: C13H18O3 (M+) 222.1256, found: 222.1257.
(4) a) Bradbury, B. J.; Sindelar, R. D. J. Heterocycl. Chem. 1989,
26, 1827.
b) Kaufman, T. S.; Srivastava, R. P.; Sindelar, R. D.; Scesney,
S. M.; Marsh, Jr., H. C. J. Med. Chem. 1995, 38, 1437.
c) Ueki, Y.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron
Lett. 1996, 37, 5719.
3-Benzyloxy-2-(3-methylbut-2-enyl)phenol (9a); General Pro-
cedure for the Cleavage of the MOM Group in 6 or 7
To a solution of 6b (0.156 g, 0.5 mmol) in i-PrOH ( 2 mL) under N2
was added PPTS (~ 25 mg) and the mixture was heated to reflux for
3 h. Then, it was cooled to r.t. and CH2Cl2 was added. The resulting
mixture was successively washed with brine (10 mL) and H2O (10
mL), dried (Na2SO4) and concentrated. The residue was purified by
preparative TLC to give 9a (0.118 g, 88%) as a yellow oil.
1H NMR (CDCl3/TMS): d = 1.72 (d, 3 H, J = 1.19 Hz), 1.78 (s, 3
H), 7.25–7.46 (m, 5 H), 3.47 (d, 2 H, J = 7.15 Hz), 5.06 (s, 2 H),
5.25 (t, 1 H, J = 7.15 Hz), 5.32 (s, 1 H), 6.48 (dd, 1 H, J = 1, 8.24
Hz), 6.54 (dd, 1 H, J = 0.92, 8.24 Hz), 7.03 (t, 1 H, J = 8.24 Hz).
(5) Ronald, R. C.; Wheeler, C. J. J. Org. Chem. 1984, 49, 1658.
(6) Greene, T.W.; Wuts, P.G.M., Protective Groups in Organic
Synthesis; 2nd ed, Wiley, New York, 1991.
(7) a) Snieckus, V. Chem. Rev. 1990, 90, 879.
b) Gschwend, H.W.; Rodriguez, H.R. Org. React. 1979, 26, 1.
c ) Winkle. M.R.; Ronald, R.C. J. Org. Chem. 1982, 47, 2101.
(8) While this work was under way, two papers related to lithiati-
on of O-benzyl protected aromatic compounds have appeared:
a) Smith, J.R.L.; O’Brien, P.; Reginato, G. Tetrahe-
dron:Asymm. 1997, 8, 3415.
13C NMR (CDCl3/TMS): d= 17.73, 22.39, 25.67, 70.36, 104.55,
109.03, 115.65, 121.95, 127.02, 127.13, 127.64, 128.35, 134.04,
137.25, 155.37, 157.03.
b) Barrero, A.F.; Alvarez-Manzaneda, E.J.; Chahboun, R. Te-
trahedron 1998, 54, 5635.
(9) Tucker, C.E.; Majid, T.N.; Knochel, P. J. Am. Chem. Soc.
1992, 114, 3983.
Acknowldgement
(10) Aithie, G.C.M.; Miller, J.A. Tetrahedron Lett. 1975, 4419.
(11) a) Sato, K.; Miyamoto, O.; Inoue, S.; Yamamoto, T; Hirasa-
wa, Y. J. Chem. Soc. Chem. Commun. 1982, 153.
b) Schmid, R.; Antoulas, S.; Ruttimann, A.; Schmid, M.; Vec-
chi, M.; Weiser, H. Helv. Chim. Acta 1990, 73, 1276.
c) Lipshutz, B.H.; Kozlowski, J.; Wilhelm, R.S. J. Am. Chem.
Soc. 1982, 104, 2305.
We thank UFRJ and FAPERJ for fellowships granted to Drs. Simas
and Coelho; CNPq, FUJB, FINEP-PADCT and FINEP-PRONEX
for financial support; Eduardo Miguez and Francisco Santos for 1H
NMR and 13C NMR spectra; Cristina Miguez for mass spectra
(NPPN-UFRJ); and Eli B. Siqueira (ICE-UFRRJ) for IR spectra.
(12) Marshall, J.A. Chem Rev. 1989, 89, 1503.
(13) Reist, E.J.; Bartuska, V.J.; Goodman; L. J.Org. Chem. 1964,
29, 3725.
(14) a) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
1977, 42, 3772.
References
(1) For recent reviews, see:
Donnely, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1995, 12,
321.
b) Sterzycki, R. Synthesis 1979, 724.
Tahara, S.; Ibrahim, R. K. Phytochemistry 1995, 38, 1073.
Harborne, J.B.; Williams, C.A. Nat. Prod. Rep. 1995, 12, 639.
(2) Vela, M. A.; Fischer, N. H. In Studies in Natural Products
Chemistry: Stereoselective Synthesis (Part C); Atta-ur-Rah-
man, Ed.; Elsevier: 1990; Vol. 4, p 367.
(15) Novel methodologies of incorporation of allylic substituents
on arenes via transition metal catalysis have appeared in the
literature. Nevertheless, those are not as straightforward as the
one presented here. Moreover, they usually produce SN2’ pro-
ducts as well. For an example, see:
Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron
1994, 50, 6017.
(16) Hiroi, K.; Hirasawa, K. Chem. Pharm. Bull. 1994, 42, 786.
(17) Fitton, A.O.; Ramage, G.R. J. Chem Soc. 1962, 4870.
(18) Still, W.C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(3) a) Boltze, K.-H; Dell, H.-D. Angew. Chem. 1966, 78, 389; An-
gew. Chem. Int. Ed. Engl. 1966, 5, 415.
b) Cotterill, P.J.; Owen, P.J.; Scheinmann, F. J. Chem. Soc.
Perkin. Trans. 1, 1974, 2423.
c) Coelho, A. L.; Vasconcellos, M. L. A. A.; Simas, A. B. C.;
Rabi, J. A.; Costa, P. R. R. Synthesis 1992, 914.
d) Shih, T.L.; Wyvratt, M.J.; Mrozik, H. J. Org. Chem. 1987,
52, 2029.
Article Identifier:
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Synthesis 1999, No. 6, 1017–1021 ISSN 0039-7881 © Thieme Stuttgart · New York