Selectivity adjustment in the cleavage of allyl phenyl and methyl phenyl ethers with boron trifluoride-methyl sulfide complex

Article abstract of DOI:10.1055/s-2005-865304

Cleavage of model allyl phenyl and methyl phenyl ethers with boron trifluoride-methyl sulfide complex is described. The demonstrated strong dependence of the reaction rate on the substitution pattern of the phenyl ring and the reaction conditions make it potentially possible to selectively cleave a single methoxy (or allyloxy) group in poly methoxy (or allyloxy) compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865304

SHORT PAPER
1575
Selectivity Adjustment in the Cleavage of Allyl Phenyl and Methyl Phenyl
Ethers with Boron Trifluoride–Methyl Sulfide Complex
S
electivityinthe Cleav
a
age of
A
lly
r
l
P
henyl
e
andMethy
k
l
P
henyl
E
ther
s
T. Konieczny,* Grzegorz Maciejewski, Wojciech Konieczny
Department of Organic Chemistry, Medical University of Gdańsk, Gen. J. Hallera Str. 107, 80-416 Gdańsk, Poland
Fax +48(58)3493206; E-mail: markon@amg.gda.pl
Received 20 October 2004; revised 7 February 2005
concentration of the BF3 complex could increase the time
several times (entry 11). Similarly as for the methyl deriv-
atives, significantly longer reaction time (entries
14,15,17) and/or higher temperature (entry 15) were re-
Abstract: Cleavage of model allyl phenyl and methyl phenyl ethers
with boron trifluoride–methyl sulfide complex is described. The
demonstrated strong dependence of the reaction rate on the substi-
tution pattern of the phenyl ring and the reaction conditions make it
potentially possible to selectively cleave a single methoxy (or allyl- quired for allyl ethers bearing electron-attracting substitu-
oxy) group in polymethoxy (or allyloxy) compounds.
ents.
Key words: ethers, cleavage, regioselectivity, substituent effects,
boron trifluoride, methyl sulfide
Both allyloxy and methoxy derivatives containing ortho
hydroxy groups were cleaved very easily (entries 7,16),
apparently due to a strong neighboring group participa-
tion. Phenyl acetate (18) was not cleaved under the reac-
tion conditions used (entry 18).
Boron trifluoride–methyl sulfide complex is a known,
commercially available ether cleaving reagent.1 Unfortu-
nately, information on its use is scattered in the chemi-
cal literature and is not easily traceable. We found just a
few reports describing its application: three on benzyl
ethers,2–4 three on methyl ethers,3–5 and one on di-tert-bu-
tylsilylene ethers.6 To our knowledge, the reagent has not
yet been described as a cleaving agent for allyl ethers.
The observed, strong influence of molecular environment
and reaction conditions suggested that, eventually, a se-
lective cleavage of one of the few identical groups present
in the molecule can be achieved. Indeed, reaction of
dimethoxyacetophenone 9 at 0 °C gave products of mono-
demethylation 26 and didemethylation 27 in the ratio 16:1
(entry 9), while at room temperature exclusively dihy-
droxy derivative 27 was isolated. Similarly, dimethoxy
sulfone 10 gave at 0 °C monohydroxy derivatives 28 and
29, and dihydroxy compound 30 in the ratio 15:5:1, re-
spectively (entry 10), while at room temperature 30 was
isolated as the sole product.
In our on-going project we have noticed high selectivity in
the deprotection of various methoxyflavonoids with
BF3·SMe2. Consequently, we performed several model re-
actions of simple methyl protected phenols (Scheme 1),
and found strong influence of the phenyl ring substitution
pattern on the rate of deprotection. For comparison, a set
of allyl-protected phenols was also reacted with the
BF3·SMe2 complex. The results are presented in Table 1.
In summary, the results confirmed that boron trifluoride–
methyl sulfide complex is a convenient reagent to cleave
methyl phenyl ethers. The reaction strongly depends on
molecular environment of the cleaved group, and on the
reaction conditions. Especially, ortho-located hydroxy
group dramatically accelerates the deprotection, both for
the allyl and methyl derivatives. The above factors can be
applied to achieve a selective deprotection of one of two
identical groups.
OR
OH
BF3⋅SMe2
X
X
CH2Cl2
OR
OR (OH)
R = allyl or methyl
Scheme 1
As could be expected, the allyl ethers are more reactive
than methoxy groups. Similar to the methyl ethers, their
reactivity is strongly influenced by other substituents
present in the molecule. The cleavage of allyl ethers with
boron trifluoride-methyl sulfide complex has not been de-
scribed yet, and the procedure presented here adds to the
already known methods of deprotection of allyl ethers:
palladium p-allyl methodology,7,8 and the most recent
ones using LiCl/NaBH4,9 TMSCl/NaI,10 perfluoroalkyla-
tion/elimination,11 and NaBH4/I2.12
Most of the methyl ethers could be cleaved in few hours
under mild condition (entries 1–3). Deprotection of meth-
yl ethers bearing electron-withdrawing groups required
more time (entries 5,6), but could be accelerated by a large
excess of the reagent (entry 5). However, the methyl de-
rivative of salicylaldehyde (8) (entry 8) was more reac-
tive, surprisingly, even more reactive than its allyl analog
17 (entry 17). The allyl ethers were, generally, cleaved in
few minutes at 0 °C (entries 4, 11–13), but decrease in
SYNTHESIS 2005, No. 10, pp 1575–1577
x
x.
x
x
.
2
0
0
5
Advanced online publication: 07.04.2005
DOI: 10.1055/s-2005-865304; Art ID: P12904SS
© Georg Thieme Verlag Stuttgart · New York

1576
M. T. Konieczny et al.
SHORT PAPER
Table 1 Cleavage of Ethers with Boron Trifluoride-Methyl Sulfide Complex
Entry
Substrate
Reaction Conditions
Temp, Time
Productsa
(Yield %)
Results for Derivatives of Anisole (1):
1
2
3
1 X = H
0 °C, 3 h
0 °C, 3 h
1 (traces) + 19 (80)
2 (10) + 20 (62)
2 X = 4-Cl
3 X = 4-OH
0 °C, 2 h
r.t., 3 h
3 (33) + 21 (42)
21 (92)
4
5
4 X = 4-OCH2CH=CH2
5 X = 4-NO2
0 °C, 5 min
4 (3) + 3 (85) + 21 (5)
r.t., 6 h
22 (87)
22 (85)
r.t., 3 hb
6
7
8
9
6 X = 4-CHO
7 X = 2-OH
8 X = 2-CHO
r.t., 6 h
6 (64) + 23 (15)
24 (90)
0 °C, 5 min
r.t., 2 h
25 (88)
9 X = 2-COCH3,
4-OCH3
0 °C, 10 min
r.t., 1.5 h
26 (64) + 27 (4)
27 (74)
10
10 X = 2-SO2CH3, 4-OCH3 (Ref.3)
0 °C, 3 h
r.t., 4 h
28 (58) + 29 (19) + 30 (4)
30 (79)
Results for Derivatives of Allyloxybenzene (11):
11
11 X = H
0 °C, 10 min
0 °C, 40 minc
19 (85)
19 (80)
12
13
14
15
12 X = 4-Cl
0 °C, 10 min
0 °C, 5 min
0 °C, 1 h
20 (89)
21 (94)
22 (91)
13 X = 4-OH
14 X = 4-NO2
15 X = 4-CHO
0 °C, 3 h
r.t., 1.5 h
15 (22) + 23 (62)
23 (92)
16
17
18
16 X = 2-OH
0 °C, 5 min
r.t., 3 h
24 (95)
17 X = 2-CHO
phenyl acetate (18)
17 (1) + 25 (65)
no reaction
r.t., 5 h
a Products: phenol (19); 4-chlorophenol (20), hydroquinone (21); 4-nitrophenol (22); 4-hydroxybenzaldehyde (23); catechol (24); salicylalde-
hyde (25); 2¢-hydroxy-5¢-methoxyacetophenone (26); 2¢,5¢-dihydroxyacetophenone (27); 3-methanesulfonyl-4-methoxyphenol (28); 2-meth-
anesulfonyl-4-methoxyphenol (29); 2-methanesulfonyl-4-hydroxyphenol (30).
b 18-Times excess of BF3·SMe2 was used instead of the typical 6-times excess.
c 2-Times excess of BF3·SMe2 was used instead of the typical 6-times excess.
1H NMR (500 MHz, DMSO-d6): d = 7.22 (d, 1 H, J = 2.9 Hz, H-2),
7.13 (d, 1 H, J = 8.8 Hz, H-5), 7.05 (dd, 1 H, J = 8.8, 2.9 Hz, H-6),
3.85 (s, 3 H, OCH3), 3.21 (s, 3 H, SO2CH3); NOE effect between
OCH3 and H-5.
Cleavage of Allyl and Methyl Ethers; General Procedure
To a solution of allyl or methyl ether (1 mmol) in anhyd CH2Cl2 (1.5
mL) was added BF3·SMe2 complex (Aldrich) (6 mmol) and the re-
action mixture was stirred at the given temperature (Table 1). At the
given time, usually at the completion according to TLC analyses,
the reaction was quenched with MeOH, evaporated, and the residue
was separated on a silica gel column. All common products were
identified by comparison with original samples by TLC analysis
and IR spectroscopy.
2-Methanesulfonyl-4-methoxyphenol (29)
Mp 115–116 °C (Lit.13 mp 122–123 °C).
1H NMR (500 MHz, DMSO-d6): d = 7.20 (d, 1 H, J = 3.4 Hz, H-3),
7.13 (dd, 1 H, J = 8.8, 3.4 Hz, H-5), 6.99 (d, 1 H, J = 8.8 Hz, H-6),
3.73 (s, 3 H, OCH3), 3.24 (s, 3 H, SO2CH3).
3-Methanesulfonyl-4-methoxyphenol (28)
Mp 145–146 °C.
Synthesis 2005, No. 10, 1575–1577 © Thieme Stuttgart · New York

SHORT PAPER
References
Selectivity in the Cleavage of Allyl Phenyl and Methyl Phenyl Ethers
1577
(7) Guibé, F. Tetrahedron 1997, 53, 13509.
(8) Guibé, F. Tetrahedron 1998, 54, 2967.
(9) RajaRam, S.; Chary, K. P.; Salahuddin, S.; Iyengar, D. S.
Synth. Commun. 2002, 32, 133.
(10) Kamal, A.; Laxman, E.; Rao, N. V. Tetrahedron Lett. 1999,
40, 371.
(11) Yu, B.; Li, B.; Zhang, J.; Hui, Y. Tetrahedron Lett. 1998, 39,
4871.
(12) Thomas, R. M.; Mohan, H.; Iyengar, D. S. Tetrahedron Lett.
1997, 38, 4721.
(1) Fieser, M. Fieser & Fieser’s Reagents for Organic
Synthesis, Vol. 10; Wiley-Interscience: New York, 1982, 51.
(2) Fuji, K.; Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980,
28, 3662.
(3) Konieczny, M. T.; Horowska, B.; Kunikowski, A.; Konopa,
J.; Wierzba, K.; Yamada, Y.; Asao, T. Synthesis 2001, 1363.
(4) Konieczny, M. T.; Horowska, B.; Kunikowski, A.; Konopa,
J.; Wierzba, K.; Yamada, Y.; Asao, T. J. Org. Chem. 1999,
64, 359.
(13) Chapman, D. D.; Jones, E. T.; Wilgus, H. S. III; Nelander,
(5) Meyers, M. J.; Carlson, K. E.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. Lett. 1998, 8, 2589.
D. H.; Gates, J. W. Jr. J. Org. Chem. 1965, 30, 1520.
(6) Yu, M.; Pagenkopf, B. L. J. Org. Chem. 2002, 67, 4553.
Synthesis 2005, No. 10, 1575–1577 © Thieme Stuttgart · New York