Boron Trichloride/Tetra-n-Butylammonium Iodide: A Mild, Selective Combination Reagent for the Cleavage of Primary Alkyl Aryl Ethers

Full text of DOI:10.1021/jo9910740

J . Org. Chem. 1999, 64, 9719-9721
9719
more, the combination reagent provides selective dealky-
lation in certain cases.
Bor on Tr ich lor id e/Tetr a -n -Bu tyla m m on iu m
Iod id e: A Mild , Selective Com bin a tion
Rea gen t for th e Clea va ge of P r im a r y Alk yl
Ar yl Eth er s
A comparative example highlights the reactivity of the
BCl3/n-Bu4NI reagent system. In procedures described
by Sun et al.,14 variously substituted dimethoxyfluo-
robenzenes (e.g., 1) were cleaved with BBr3 (3 equiv/
CH2Cl2). The reaction typically requires 24-48 h at
ambient temperatures, and additional BBr3 is often
required (0.5 equiv) to completely drive the conversion
of 1 to 2.
Paige R. Brooks, Michael C. Wirtz, Michael G. Vetelino,
Diane M. Rescek, Graeme F. Woodworth,
Bradley P. Morgan, and J otham W. Coe*
Central Research Division, Pfizer, Inc.,
Groton, Connecticut 06340
Received J uly 6, 1999
A number of reagents are routinely used to cleave
primary alkyl aryl ethers1 such as BBr3,2 EtSNa/DMF,3
TMSI,4 py-HCl,5 and HBr/AcOH.6,7 Boron-based reagents
are particularly versatile for this transformation, as the
Lewis acidity of the boron center and the nucleophilic
nature of the ligands can be effectively manipulated (e.g.,
2-bromo-1,3,2-benzodioxaborole,8 9-Br-BBN,9and Me2-
BBr10). We report herein that a mixture of BCl3 and
anhydrous n-Bu4NI is a powerful reagent combination
for the facile cleavage of primary alkyl aryl ethers at low
to ambient temperatures.11 Boron trichloride alone does
not remove isolated aryl methyl groups at low temper-
atures,12 although it is extremely effective when chelation
is possible.13 With n-Bu4NI present (1.1 equiv), however,
BCl3 reactivity toward primary alkyl aryl ethers is
greatly enhanced. The resulting combination reagent
system is mild, generally applicable, and operationally
simple, and it can provide results superior to those of
BBr3 for the cleavage of numerous substrates. Further-
Using our modified BCl3/n-Bu4NI procedure, n-Bu4NI
(2.5 equiv) and 3,5-dimethoxyfluorobenzene (1) in
CH2Cl2 (0.2 M) are treated with BCl3 (2.5 equiv, 1 M
CH2Cl2) at -78 °C and then warmed to 0 °C. Complete
conversion to 5-fluororesorcinol (2) occurs in 2 h (77%
isolated yield).
To determine the generality of the method, we have
studied the dealkylation of a variety of substrates. In a
typical experiment, a 0.2-0.5 M solution of substrate and
n-Bu4NI15 (1.1 equiv) in anhydrous CH2Cl2 is treated with
BCl3 at -78 °C (1 M in CH2Cl2). The reaction solution is
monitored and then treated as indicated (see Table 1 and
the Experimental Section for equivalents, temperature,
and time). Aqueous workup and chromatography provide
the target phenols.
Methyl-, ethyl-, and benzylnaphthyl ethers are readily
cleaved (3, 4, 6, 7); however, isopropyl naphthyl ether is
stable under these conditions (5).13f Severe steric con-
straints also retard the reaction (8 vs 9). Selective
cleavage of benzyl ethers in the presence of methyl ethers
is achieved (10), and methylenedioxy groups are readily
cleaved at -78 °C (11).13d
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991; Chapter 3.
(b) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249. (c) Ranu, B. C.;
Bhar, S. Org. Prep. Proced. Int. 1996, 28, 371-409.
(2) (a) Benton, F. L.; Dillon, T. E. J . Am. Chem. Soc. 1942, 64, 1128.
(b) McCombie, J . F. W.; Watts, M. L. Chem. Ind. (London) 1963, 1658.
(c) McCombie, J . F. W.; Watts, M. L.; West, D. E. Tetrahedron 1968,
24, 2289. (d) J effery, B. Synth. Commun. 1979, 9, 407.
(3) (a) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.
(b) Feutrill, G. I.; Mirrington, R. N. Aust. J . Chem. 1972, 25, 1719. (c)
Kende, A. S.; Rizzi, J . P. Tetrahedron Lett. 1981, 22, 1779.
(4) J ung, M. E.; Lyster, M. A. J . Org. Chem. 1977, 42, 3761.
(5) Gates, M.; Tschudi, G. J . Am. Chem. Soc. 1956, 78, 1380.
(6) Kawasaki, I.; Matsuda, K.; Kaneko, T. Bull. Chem. Soc. J pn.
1971, 44, 1986.
(7) New methods continue to be developed. For isopropyl ethers,
see: (a) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J . Org. Chem.
1998, 63, 9139. (b) Horie, T.; Shibata, K.; Yamashita, K.; Kawamura,
Y.; Tsukayama, M. Chem. Pharm. Bull. 1997, 45, 446. For allyl ethers,
see: (c) Kamal, A.; Laxman, E.; Rao, N. V. Tetrahedron Lett. 1999,
40, 371. (d) Taniguchi, T.; Ogasawara, K. Angew. Chem., Int. Ed. 1998,
37, 1136. For an effective alternative acidic methoxyl cleavage, see:
(e) Fujii, N.; Irie, H.; Yajima, H. J . Chem. Soc., Perkin Trans. 1 1977,
2288.
Other functionalities are well tolerated16 but may alter
the required BCl3/substrate stoichiometry. For instance,
(13) (a) Dean, F. M.; Goodchild, J .; Houghton, L. E.; Martin, J . A.;
Morton, R. B.; Parton, B.; Price, A. W.; Somvichien, N. Tetrahedon
Lett. 1966, 4153. (b) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y.
Tetrahedron Lett. 1981, 22, 899. (c) Dolson, M. G.; Chenard, B. L.;
Swenton, J . S. J . Am. Chem. Soc. 1981, 103, 5263. (d) Swenton, J . S.;
Anderson, D. K.; J ackson, D. K.; Narasimhan, L. J . Org. Chem. 1981,
46, 4825. (e) Teital, S.; O’Brien, J .; Brossi, A. J . Org. Chem. 1972, 37,
3368. For the cleavage of isopropyl ethers flanked by ethers, see: (f)
Sala, T.; Sargent, M. V. J . Chem. Soc., Perkin Trans. 1 1979, 2593.
(14) Sun, W.-C.; Gee, K. R.; Klaubert, D. H.; Haugland, R. P. J . Org.
Chem. 1997, 62, 6469.
(8) (a) Boeckman, R. K., J r.; Potenza, J . C. Tetrahedron Lett. 1985,
26, 1411. (b) King, P. F.; Stroud, S. G. Tetrahedron Lett. 1985, 26, 1415.
(9) Bhatt, M. V. J . Organomet. Chem. 1978, 156, 221.
(10) (a) Guindon, Y.; Yoakim, C.; Morton, H. E. Tetrahedron Lett.
1983, 24, 2969. (b) Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron
Lett. 1983, 24, 3969.
(11) Previously, this approach has been exploited by combining
crown ethers and alkali-metal iodides with BBr3. For aliphatic ethers,
see: (a) Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981, 22,
4239. For a similar combination method employed in the selective
dealkylation of alkyl ethers, see: (b) Node, M.; Kamimoto, T.; Nishide,
K.; Fujita, E.; Fuji, K. Bull. Inst. Chem. Res. 1992, 70, 308.
(12) (a) Ramser, H.; Wiberg, E. Chem. Ber. 1930, 63, 1136. (b)
Gerrard, W.; Lappert, M. F. J . Chem. Soc. 1952, 1486 and reference
cited in ref 1b.
(15) Fresh commercial anhydrous n-Bu4NI is acceptable in most
instances and should be handled under an inert atmosphere. The
reagent performance diminishes with improper handling and storage.
Sensitive substrates may require the recrystallization of n-Bu4NI from
hot toluene to provide strictly anhydrous material. See: (a) Perrin, D.
D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.;
Permagon Press Ltd.: Oxford, 1988; p 280, (b) Blau, R. J .; Espenson,
J . H. J . Am. Chem. Soc. 1986, 108, 1962.
(16) Unsatisfactory performance of this reagent combination is
observed with 1-NH-indoles, nitro aromatics (partial nitro reduction),
and some conjugated derivatives, such as 6-methoxytetralone (20,
methyl stable to conditions, see text). Peculiar results have been
observed with 2-bromo-1,3,5-trimethoxybenzene; debromination occurs,
instead of ether cleavage and, after workup, provides the parent 1,3,5-
trimethoxybenzene.
10.1021/jo9910740 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/25/1999

9720 J . Org. Chem., Vol. 64, No. 26, 1999
Ta ble 1. BCl3/n -Bu 4NI Med ia ted P r im a r y Alk yl Ar yl Eth er Clea va ge
Notes
a
b
N.R. (no reaction). With 1.3 equiv of n-Bu4NI (see the Experimental Section).
although 7-ethoxymethoxychromen-2-one (12) cleaves
readily at -78 °C, the corresponding 7-allyloxychromen-
2-one (13) requires additional BCl3 and warming to
complete the conversion (2.5 equiv total, 20 °C, 2 h).7c
For substrates possessing multiple Lewis base sites,
additional BCl3 will be required to chelate the more basic
spectator groups (13-19). Additionally, the rate of ether
cleavage is demonstrably reduced with resonance delo-
calization by electron-withdrawing groups. Thus, meta-
positioned target ethers are more rapidly cleaved than
ortho- or para-resonance delocalized ethers. This is
successfully exploited in the selective cleavage of the
5-methyl ether of 2,5-dimethoxybenzonitrile (18).
In our view, the BCl3/n-Bu4NI reagent combination
reactivity is between that of BBr3 and BI3.19 These
vigorous reagents presumably dissociate more readily to
provide oxonium ion activation (ArOR′BX2)+ and free
nucleophilic halide ion (X-). With the BCl3/n-Bu4NI
reagent combination, iodide may act as both a stabilizing
ligand on boron, favoring formation of a reactive oxonium
ion species (ArOR’BIX)+, and a source of potent nucleo-
philic iodide.20-22 We have found that the reaction does
not proceed in the absence of iodide: 3-methoxybenzoni-
(18) An orange complex forms with 20 and n-Bu4NI upon addition
of BCl3 that is stable at 20 °C for >6 h. 11B NMR experiments reveal
that a 1/1 mixture of BCl3 and 20 exhibits one predominant signal at
-50.5 ppm (CD2Cl2). A 2/1 mixture of BCl3 and 6-methoxy-1-tetralone
20 exhibits two signals at -50.5 and -12.6 ppm: one is substrate
complexed BCl3 and one is free, uncomplexed BCl3. In contrast,
isomeric tetralone 19 exhibits multiple complexed 11B NMR signals
with both 1 and 2 equiv of BCl3; however, no signal for free BCl3 is
observed at -12.6 ppm. These results suggest that direct boron-oxygen
complex formation is a requirement for ether cleavage.
(19) (a) Povlock, T. P. Tetrahedron Lett. 1967, 4131. (b) Lansinger,
J . M.; Ronald, R. C. Synth. Commun. 1979, 9, 341. (c) Narayana, C.;
Padmanabhan, S.; Kabalka, G. W. Tetrahedron Lett. 1990, 31, 6977.
(20) For a discussion of the role of the facile dissociation of I- from
a L2MgI2 species, see: Corey, E. J .; Li, W.; Reichard, G. A. J . Am.
Chem. Soc. 1998, 120, 2330.
As a general rule, 1.5 equiv of BCl3 is sufficient to effect
dealkylation, provided that 1.0 equiv of additional BCl3
is introduced for each additional basic group.
6-Methoxy-1-tetralone (20) is an exception and is not
cleaved under these reaction conditions.17 In this case,
resonance interactions sufficiently reduce the basicity of
the target ether, rendering complexation with boron
impossible.18
(17) For cleavage of 6-methoxy-1-tetralone with 47% aq HBr, see:
Bayer, H.; Batzl, C.; Hartmann, R. W.; Mannschreck, A. J . Med. Chem.
1991, 34, 2685.
(21) Eis, M. J .; Wrobel, J . E.; Ganem, B. J . Am. Chem. Soc. 1984,
106, 3693. For a discussion of ligand disproportionation and redistribu-
tion, see refs 7-9 cited therein.

Notes
J . Org. Chem., Vol. 64, No. 26, 1999 9721
trated, and purified by chromatography on silica gel to provide
a white crystalline solid (370 mg, 77%): mp 134-136 °C; Rf 0.31
(1:3 EtOAc:hexanes); 1H NMR (CD3OD, δ) 6.05 (m, 1 H), 5.99
(dd, J ) 10.6, 2.1 Hz, 1 H); GC-MS m/z 128 (M+).
trile is stable to 2.5 equiv of BCl3/1.1 equiv of BnEt3NCl
at 20 °C for 24 h and at 40 °C for 5 h in CH2Cl2. With
the BCl3/n-Bu4NI reagent combination, this conversion
is complete between 0 and 10 °C (<2 h).23,24
The BCl3/n-Bu4NI reagent combination adds a powerful
option to the methods available for the cleavage of
primary alkyl aryl ethers by providing mild, selective
ether cleavage at low temperature in short reaction
times.25
1-Na p h th ol (Clea va ge of 6). 1-Ethoxynaphthalene (6, 861
mg, 5.0 mmol) and n-Bu4NI (2.03 g, 5.50 mmol) were stirred in
dry CH2Cl2 (25 mL) at -78 °C under N2. A solution of BCl3 (7.5
mL, 1 M in CH2Cl2, 7.50 mmol) was added over 2 min. After 5
min, the solution was allowed to warm to 0 °C and was stirred
for 1 h. The reaction solution was quenched with ice and H2O,
stirred for 30 min, diluted with saturated aqueous NaHCO3
solution, and extracted with CH2Cl2. The combined organic layer
was dried by filtration through a cotton plug, concentrated, and
purified by chromatography on silica gel to provide 1-naphthol
Exp er im en ta l Section
1
(709 mg, 98%): mp 89-90 °C; Rf 0.73 (1:3 EtOAc:hexanes); H
Unless otherwise noted, all materials were purchased from
commercial sources. Anhydrous CH2Cl2 (99.8%), 1 M BCl3 in
CH2Cl2 (in Sure/Seal bottles), and n-Bu4NI were handled under
a dry nitrogen atmosphere. Thin-layer chromatography was
performed with EM separation technology silica gel F254. Silica
gel chromatography was carried out with J . T. Baker 40 µm silica
gel according to Still’s procedure.26 All glassware was flame dried
NMR (CDCl3, δ) 8.21 (m, 1 H), 7.83 (m, 1 H), 7.49-7.28 (4 H),
6.80 (d, J ) 7.5 Hz, 1 H), 5.29 (br s, OH); GC-MS m/z 144 (M+).
2-(4-Hyd r oxyp h en yl)a ceta te (Clea va ge of 13). Methyl
2-(4-hydroxyphenyl)acetate (13, 538 mg, 3.00 mmol) and n-Bu4-
NI (1.43 g, 3.88 mmol) were stirred in dry CH2Cl2 (15 mL) at
-78 °C under N2. A solution of BCl3 (7.5 mL, 1 M in CH2Cl2,
7.50 mmol) was added over 2 min. After 5 min, the reaction
solution was allowed to warm to 20 °C and was stirred for 1 h.
The reaction solution was quenched with ice and H2O, stirred
30 min, diluted with saturated aqueous NaHCO3 solution, and
extracted with CH2Cl2. The combined organic layer was dried
by filtration through a cotton plug, concentrated, and purified
by chromatography on silica gel (1/9 EtOAc/hexanes) to provide
methyl 2-(4-hydroxyphenyl)acetate (382 mg, 84%): mp 53-54
1
under a dry nitrogen purge, prior to use. H NMR spectra were
collected at 400 MHz with residual CHCl3 as standard (7.26
ppm). 11B NMR spectra (160 MHz) were obtained on a Bruker
DMX500 Avance spectrometer using direct detection with a 10
mm broad-band probe. The spectra were acquired at ambient
temperatures using 90° pulses, 1.0 s relaxation delay, a sweep
width of 500 ppm with 32K points, and 32 scans. The data were
collected using either a 1 H decoupling pulse sequence or spin-
echo with 20 ms echo time to reduce the broad signal from the
NMR tube. A 1 Hz line broadening was used to process the
spectra. Chemical shifts were measured in ppm using BCl3 in
CD2Cl2, set to -12 ppm as the external reference. Melting points
are uncorrected. All spectroscopic data for known compounds
were in complete accord with literature values.
Registry numbers. Substrates: 1, 52189-63-6; 3, 93-04-9; 4,
93-18-5; 5, 15052-09-2; 6, 5328-01-8; 7, 607-58-9; 8, 1004-66-6;
9, 1516-95-6; 10, 21144-16-1; 11, 94-59-7; 13, 31005-03-5; 14,
15799-79-8; 15, 23786-14-3; 16, 1527-89-5; 17, 874-90-8; 18,
5312-97-0; 19, 1078-19-9; 20, 2472-22-2. Products: 2, 75996-29-
1; 3 and 4, 135-19-3; 6 and 7, 90-15-3; 8, 576-26-1; 10, 150-19-6;
11, 1126-61-0; 12 and 13 93-35-6; 14, 99-07-0; 15, 14199-15-6;
16, 873-62-1; 17, 767-00-0; 18, 180526-90-3; 19, 52727-28-3.
3,5-Dih yd r oxyflu or oben zen e (2). 3,5-Dimethoxyfluoroben-
zene (1, 585 mg, 3.75 mmol) and n-Bu4NI (3.46 g, 9.39 mmol)
were stirred in dry CH2Cl2 (18 mL) at -78 °C under N2. A
solution of BCl3 (9.38 mL, 1 M in CH2Cl2, 9.38 mmol) was added
over 2 min. After 5 min, the solution was warmed to 0 °C and
was stirred for 2 h. The reaction solution was quenched with
ice and H2O, stirred for 30 min, and partially concentrated to
remove CH2Cl2. After H2O was added, the mixture was extracted
with Et2O. The combined organic layer was washed with
saturated aqueous NaCl solution, dried over Na2SO4, concen-
1
°C; Rf 0.37 (1:3 EtOAc:hexanes); H NMR (CDCl3, δ) 7.09 (d, J
) 8.2 Hz, 1 H), 6.73 (d, J ) 8.2 Hz, 1 H), 5.78 (br s, OH), 3.69
(s, 3 H), 3.55 (s, 2 H); GC-MS m/z 166 (M+).
5-Hyd r oxy-2-m eth oxyben zon itr ile (Clea va ge of 18). 2,5-
Dimethoxybenzonitrile (18, 816 mg, 5.00 mmol) and n-Bu4NI
(2.03 g, 5.50 mmol) were stirred in dry CH2Cl2 (25 mL) at -78
°C under N2. A solution of BCl3 (17.5 mL, 1M in CH2Cl2, 17.50
mmol) was added over 2 min. After 5 min, the solution was
allowed to warm to 20 °C and was stirred for 40 min (translucent
brown solution). The reaction mixture was quenched with ice,
stirred for 30 min, diluted with saturated aqueous NaHCO3
solution, and extracted with CH2Cl2. The combined organic layer
was dried through a cotton plug, concentrated, and purified by
chromatography on silica gel to provide a crystalline solid (650
mg, 87%): mp 114-116 °C; Rf 0.28 (2:3 EtOAc:hexanes); 1H
NMR (CDCl3, δ) 7.04 (m, 2 H), 6.84 (d, J ) 10.0 Hz, 1 H), 5.47
(OH), 3.86 (s, 3 H); NOE difference data, irradiation of δ 3.86
(methyl) causes enhancement of δ 6.84 doublet; GC-MS m/z 149
(M+). Anal. Calcd for C8H7NO2: C, 64.4; H, 4.7; N, 9.4. Found:
C, 64.5; H, 4.7; N, 9.4.
7-Eth oxym eth oxych r om en -2-on e (12). 7-Hydroxychromen-
2-one (2.0 g, 12.34 mmol), n-BuNI (50 mg), and DMF (50 mg)
were stirred in THF (50 mL) under N2 and treated with t-BuOK
(1.57 g, 14.00 mmol). After being stirred for 5 min, the yellow
dispersion was treated with chloromethylethyl ether (1.28 g,
13.57 mmol). After 18 h at room temperature, the reaction
mixture was treated with Et2O (50 mL) and 1 N NaOH (50 mL).
The organic layer was separated, washed with water and brine,
and dried over Na2SO4. Evaporation afforded a crude oil which
was purified by chromatography on silica gel to provide a white
crystalline solid (1.65 g, 61%): mp 79-81 °C; Rf 0.51 (1:3
(22) 11B NMR studies of equimolar quantities of BCl3 and n-Bu4NI
in CD2Cl2 at 20 °C (∼2 h) indicate a ratio of peak heights of 23/1/9/3
at -51.6, -71.8, -101.7, and -140.3 ppm, respectively. For 11B NMR
results with coordinated BX3 complexes, see: Anton, K.; No¨th, H.;
Pommerening, H. Chem. Ber. 1984, 117, 2479.
(23) The order of addition that we have found to be the most
experimentally convenient is to add BCl3 to a combination of n-Bu4NI
and substrate. We have observed no qualitative or quantitative
differences in ether cleavage performance by adding BCl3 to substrate
followed by n-Bu4NI in CH2Cl2.
(24) Benzyl iodide and 3-methoxyphenol were isolated from the
cleavage of 10. No benzyl chloride was detected (GC-MS).
(25) Attempts to use catalytic n-Bu4NI with stoichiometric alkali
metal halides have not met with success. Also see ref 11.
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
1
EtOAc:hexanes); H NMR (CDCl3, δ) 7.62 (d, J ) 9.5 Hz, 1 H),
7.36 (d, J ) 8.5 Hz, 1 H), 7.00 (d, J ) 2.5 Hz, 1 H), 6.94 (dd, J
) 8.5, 2.5 Hz, 1 H), 6.25 (d, J ) 9.5 Hz, 1 H), 5.26 (s, 2 H), 3.71
(q, J ) 7.0 Hz, 2 H), 1.20 (t, J ) 7.0 Hz, 3 H); AP-CI MS m/z
221.1 ((M + 1)+). Anal. Calcd for C8H7NO2: C, 65.5; H, 5.5.
Found: C, 65.5; H, 5.7.
J O9910740