Identification of a boron-containing intermediate in the boron tribromide mediated aryl propargyl ether cleavage reaction

Article abstract of DOI:10.1021/jo802207y

An alternate reaction mechanism for the boron tribromide mediated deprotection of aryl propargyl ethers based on the isolation of a key boron-containing byproduct is proposed. On the basis of the new mechanistic insight, we discovered that HBBr₂ · SMe₂ can also be used for cleaving aryl propargyl ethers.

Full text of DOI:10.1021/jo802207y

SCHEME 1. Proposed Reaction Mechanism
Identification of a Boron-Containing Intermediate
in the Boron Tribromide Mediated Aryl
Propargyl Ether Cleavage Reaction
Min-Liang Yao,† Marepally Srinivasa Reddy,†
Wenbin Zeng,‡ Kelly Hall,† Ingrid Walfish,§ and
George W. Kabalka*,†
Departments of Chemistry and Radiology, The UniVersity of
Tennessee, KnoxVille, 37996-1600, Department of Medicine,
Graduate School of Medicine, The UniVersity of Tennessee,
1924 Alcoa Highway, KnoxVille, 37920, and Department of
Chemistry, State UniVersity of New York at New Paltz, New
York, 12561
SCHEME 2. Currently Proposed Reaction Mechanism
kabalka@utk.edu
ReceiVed October 13, 2008
alkoxyboron monohalide intermediate.5 Further investigations
of these novel reactions led us to develop reactions in which
hydroxyl groups were substituted by stereodefined halovinyl,6
alkynyl,7 and allyl8 moieties using boron halides. In these
studies, we found that aryl methoxy groups were stable in the
presence of either preformed or in situ generated vinylboron
dibromides.5,6 In view of the fact that the syn addition of boron
tribromide to terminal alkynes is a fast process at -78 °C,9 we
felt that the aryl propargyl ether cleavage reaction might proceed
through a pathway that differed from the one proposed earlier
(Scheme 2): addition of boron tribromide to the terminal alkyne
would first generate the vinylboron dibromide intermediate 1
(consistent with the reported NMR study3); then C-O bond
cleavage would occur as a result of the presence of the
vinylboron dibromide (a Lewis acid) and afford intermediate
2; hydrolysis of intermediate 210 would then give the observed
products (phenol and bromovinylboronic acid 3). Notably, the
pathway we propose is also consistent with the observed failure
of boron tribromide to react with a propargyl ether containing
an internal alkyne because boron tribromide is known to react
only slowly with internal alkynes.9
An alternate reaction mechanism for the boron tribromide
mediated deprotection of aryl propargyl ethers based on the
isolation of a key boron-containing byproduct is proposed.
On the basis of the new mechanistic insight, we discovered
that HBBr2 · SMe2 can also be used for cleaving aryl
propargyl ethers.
Recently, a boron tribromide mediated aryl propargyl ether
deprotection reaction was reported (Scheme 1).1 The reaction
proceeds smoothly at room temperature, and a variety of
functional groups (-Br, -CO2Et, -NO2, -OMe) are tolerated by
the reaction conditions. The stability of aryl methoxy groups
under the reaction conditions is notable because boron tribro-
mide is known to be an effective reagent for cleaving aryl
ethers.2 A mechanism involving the delivery of bromine to the
propargyl terminus, to generate a bromoallene, was proposed
on the basis of a NMR study of the reaction (Scheme 1).3
In recent years, we have developed a number of novel
reactions involving boron halide derivatives. Examples include
a boron trihalide mediated alkyne-aldehyde coupling reaction
leading to stereodefined 1,4-pentadienes4 that proceeds through
an unprecedented C-O bond cleavage originating from an
(5) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu, Z.; Ju, Y.; Quick, T. J.
Org. Chem. 2008, 73, 2668.
(6) (a) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2004, 6, 3929. (b) Kabalka,
G. W.; Yao, M.-L.; Borella, S.; Wu, Z. Chem. Commun. 2005, 2492. (c) Kabalka,
G. W.; Yao, M.-L.; Borella, S.; Wu, Z. Org. Lett. 2005, 7, 2865.
(7) (a) Kabalka, G. W.; Yao, M.-L.; Borella, S. Org. Lett. 2006, 8, 879. (b)
Kabalka, G. W.; Borella, S.; Yao, M.-L. Synthesis 2008, 325.
(8) (a) Kabalka, G. W.; Yao, M.-L.; Borella, S. J. Am. Chem. Soc. 2006,
128, 11320. (b) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Goins, L. K.
Organometallics 2007, 26, 4112.
(9) Lappert, M. F.; Prokai, B. J. Organomet. Chem. 1964, 1, 384.
(10) The detection of phenol by TLC, before quenching of the reaction either
with water or with saturated aqueous NaHCO3 at 0 °C, indicates that the C-O
bond cleavage most likely occurred in the reaction process, as opposed to the
cleavage being induced by the HBr formed during the hydrolysis process.
† Departments of Chemistry and Radiology, The University of Tennessee.
‡ Graduate School of Medicine, The University of Tennessee.
§ State University of New York at New Paltz.
(1) Punna, S.; Meunier, S.; Finn, M. G. Org. Lett. 2004, 6, 2777.
(2) (a) Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.;
Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719. (b)
Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249. (c) Benton, F. L.; Dillon,
T. E. J. Am. Chem. Soc. 1942, 64, 1128.
(3) NMR monitoring of the reaction clearly demonstrated that the alkyne
unit participated in the propargyl ether bond cleavage (the absence of alkyne
resonances along with the appearance of several vinyl protons).
(4) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 1491.
10.1021/jo802207y CCC: $40.75
Published on Web 12/18/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1385–1387 1385

SCHEME 3. C-O Bond Cleavage Using Vinylboron
Dibromide
SCHEME 5. Evidence Supporting the New Mechanism:
Isolation of a Vinyl Trifluoroborate Product
SCHEME 6. Preparation of Authentic Sample
SCHEME 4. Transformations of Bromovinylboron
Dibromide
With the knowledge that bromovinylboronic acids could be
isolated as their stable trifluorobonate salts, we then investigated
the reaction of 4-nitrophenyl propargyl ether with boron
tribromide. (The goal being the validation of the newly proposed
reaction mechanism.) The reaction was carried out according
to the literature procedure1 and was quenched by transferring
the reaction mixture, under an argon atmosphere, to an aqueous
Et2O/NaHCO3 mixture at 0 °C. Three equivalents of KHF2 were
then added, and the mixture was stirred for 20 min. Removal
of the solvents under vacuum afforded a brown solid. After
washing the solid with dry diethyl ether to remove the coproduct,
4-nitrophenol, and a trace amount of propargyl ether, a white
solid was obtained. Extraction of the white solid three times
with hot acetone, followed by solvent removal, yielded orga-
notrifluoroborate 7 in 41% yield. The resonances observed at
6.26-6.28 ppm (m) and 4.28 ppm (s) in the 1H NMR spectrum
and at 44.5 ppm in the 13C NMR spectrum fit well with the
structural assignment for compound 7. The vinyl carbon was
not visible in the 13C NMR spectrum owing to the nearby
fluorine nucleus. In addition, the observed HRMS analysis
(266.8644 for [M - K]- peak) supports the structural assign-
ment.
For structural identification purposes, a standard organotrif-
luoroborate sample 7 was synthesized from fully characterized
boron pinacolate ester 8 (Scheme 6). The NMR data demon-
strated that the organotrifluoroborate obtained was identical to
the material obtained in the reaction outlined in Scheme 5.
On the basis of the newly proposed reaction mechanism, we
deduced that HBBr2 would also be suitable for cleaving
propargyl ethers bearing terminal alkynes. The facile addition
of HBBr2 to the terminal alkyne moiety in propargyl ether would
generate intermediate 9, which is similar in structure to the
earlier proposed intermediate 1. The experimental results
confirmed our hypothesis (Scheme 7).
To test the hypothesis that a vinylboron dibromide could
cleave a C-O ether bond,11 preformed vinylboron dibromide
was allowed to react with phenyl allyl ether (Scheme 3). The
cleavage reaction occurred rapidly at room temperature and the
phenyl allyl ether was consumed within 3 min. For phenyl allyl
ether (bearing a terminal alkene), the Claisen rearrangement
product is formed (61% yield) along with the anticipated phenol
(in 12% yield). For a phenyl allyl ether bearing an internal
alkene (structurally similar to intermediate 1), the reaction gives
the expected phenol in 67% yield along with some of the Claisen
product. Thus, vinylboron dibromide reagents readily cleave the
C-O bond in allyl ethers.
In further support of the proposed mechanism, we decided
to isolate bromovinylboronic acid 3 as the corresponding
trifluoroborate derivative. Interestingly, no literature report for
the conversion of halovinylboron dihalides to the corresponding
trifluoroborate derivatives could be found.12 Therefore, we
investigated the feasibility of this transformation using the
readily available 2-phenyl-2-bromovinylboron dibromide (Scheme
4). The bromovinylboron dibromide was first converted to
bromovinylboronic acid 4 by reaction with an aqueous mixture
of Et2O/NaHCO3 at 0 °C. Attempts to purify vinylboronic acid
4 via recrystallization in water induced dehaloboration (phenyl
acetylene formed).13 Therefore, crude 4 was used directly to
synthesize the corresponding boron pinacolate ester. Boron
pinacolate 5 was isolated in 67% yield (in three steps based on
phenyl acetylene) using silica gel column chromatography. The
preparation of organotrifluoroborate 6, either from the crude
vinylboronic acid 4 or the boron pinacolate ester 5, was
successful using reported procedures.14 Good yields were
obtained in both cases (Scheme 4).
(11) The C-O ether bond cleavage mediated by organoboron halides, such
as PhBCl2 and 9-Br-9-BBN is known,2b but C-O bond cleavage using
bromovinylboron dibromide had not been previously reported.
(12) (a) Hara, S.; Ishimura, S.; Suzuki, A. Synlett 1996, 993. (b) Petasis,
N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. (c) Batey, R. A.;
MacKay, D. B.; Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075.
(13) For other 2-halovinylboron compounds that undergo dehaloboration
reaction, see: (a) Suzuki, A.; Miyaura, N.; Abiko, S.; Itoh, M.; Brown, H. C.;
Sinclair, J. A.; Midland, M. M. J. Am. Chem. Soc. 1973, 95, 3080. (b) Eisch,
J. J.; Gonsior, L. J. J. Organomet. Chem. 1967, 8, 53.
In summary, an alternate reaction mechanism is proposed for
the boron tribromide mediated deprotection of aryl propargyl
ethers. A key boron-containing byproduct, which strongly
(14) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020. (b) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424.
1386 J. Org. Chem. Vol. 74, No. 3, 2009

SCHEME 7. Propargyl Ether Cleavage Using HBBr2 ·SMe2
Complex
13C NMR: δ 140.9, 140.1, 129.3, 128.3, 128.1, 127.5, 83.8, 24.8.
Anal. Calcd for C14H18BBrO2: C, 54.42; H, 5.87. Found: C, 54.48;
H, 5.63.
Isolation of Compound
7 from the BBr3-Mediated
Propargyl Deprotection Reaction. To a solution of the propargyl
ether, 1-nitro-4-prop-2-ynyloxybenzene (2.0 mmol, 354 mg), in dry
CH2Cl2 (6 mL) under argon atmosphere was added BBr3 (1.0 M in
CH2Cl2, 2.0 mmol, 2.0 mL) dropwise at room temperature. The
reaction mixture was stirred for 35 min at room temperature and
then transferred by a double-ended needle to a mixture of diethyl
ether (5 mL) and aqueous NaHCO3 (168 mg of NaHCO3 in 3 mL
of water) at 0 °C. The mixture was stirred at room temperature for
another 15 min. Subsequently, methanol (2 mL) and aqueous KHF2
(6.0 mmol, 468 mg in 3 mL of water) was added, and the mixture
was stirred for another 20 min. Removal of the solvents under
vacuum afforded a brown solid. After washing the solid with dry
diethyl ether to remove the coproduct 4-nitrophenol and a trace
amount of propargyl ether, a white solid was obtained. Extraction
of the white solid with hot acetone (3 × 10 mL), followed by
solvent removal, yielded organotrifluoroborate 7 in 41% yield. 1H
NMR (250 MHz, DMSO-d6): δ 6.26-6.28 (m, 1H), 4.28 (s, 2H).
13C NMR: δ 44.5. Calcd HRMS for C3H3BBr2F3K: 266.8627 ([M
- K]- peak). Found: 266.8644.
supports the newly proposed mechanism, was isolated by
converting it into organotrifluoroborate 7. Based on the proposed
reaction mechanism, we discovered that HBBr2 is also an
effective cleaving reagent for propargyl ethers bearing terminal
alkyne moieties.
Experimental Section
All glassware was dried in an oven heated to 120 °C for at least
12 h and then cooled prior to use. Dichloromethane was distilled
over CaH2 prior to use. Reactions were magnetically stirred and
monitored by TLC. Products were purified by flash chromatography,
using silica gel (230-400 mesh, 60 Å). Boron tribromide (1.0 M
in methylene chloride), dibromoborane dimethyl sulfide complex
solution (1.0 M in methylene chloride), phenylacetylene, and
propargyl bromide solution (80 wt % in toluene) were used as
received.
Synthesis of Compound 8. The procedure paralleled that
described for compound 5. The reaction was carried out on a 10
mmol scale, and compound 8 was purified by column chromatog-
raphy (silica-gel, EtOAc-hexanes, 1:5) as a colorless liquid (1.97
Synthesis of Compound 5. To a solution of phenylacetylene
(10 mmol, 1.02 g) in CH2Cl2 (20 mL) at 0 °C was added BBr3 (1.0
M in CH2Cl2, 10 mmol, 10 mL). The mixture was stirred at room
temperature for 15 min. The resulting red-purple reaction mixture
was transferred by a double-ended needle to a mixture of diethyl
ether (5 mL) and aqueous NaHCO3 (1.70 g of NaHCO3 in 15 mL
of water) at 0 °C. The mixture was stirred at room temperature for
15 min. The aqueous layer was separated and extracted with CH2Cl2
(2 × 15 mL), and the combined organic phase was washed with
cold water and then brine. The organic phase was subsequently
dried over anhydrous magnesium sulfate. Removal of solvents under
vacuum followed by washing with hexanes (15 mL) yielded crude
boronic acid 4 as a pale yellow solid. Crude 4 was then added to
a solution of pinacol (11.0 mmol, 1.30 g) in ethyl ether (40 mL).
Anhydrous magnesium sulfate (20.0 mmol, 2.40 g) was added, and
the mixture was stirred overnight at room temperature. After
filtration and removal of the solvent under vacuum crude compound
5 was obtained. The product (2.07 g) was isolated in 67% yield by
1
g, 61% for three steps). H NMR (250 MHz, CDCl3): δ 6.35 (s,
1H), 4.24 (s, 2H), 1.30 (s, 12H). 13C NMR: δ 136.0, 83.4, 39.4,
24.7. IR (film, νmax/cm-1): 2979, 2919, 1629, 1380, 1372, 1348,
1142, 967, 848, 764, 749. Anal. Calcd for C9H15BBr2O2: C, 33.18;
H, 4.64. Found: C, 33.47; H, 4.71.
Acknowledgment. Acknowledgement is made to the Donors
of the American Chemical Society Petroleum Research Fund
for partial support of this research. We also wish to thank the
U.S. Department of Energy and the Robert H. Cole Foundation.
I.W. is grateful for a University of Tennessee Summer Under-
graduate Research Fellowship.
Supporting Information Available: 1H and 13C NMR data
for all new compounds reported, preparation of starting material
propargyl ether. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
flash column chromatography. H NMR (250 MHz, CDCl3): δ
7.58-7.62 (m, 2H), 7.31-7.33 (m, 3H), 6.43 (s, 1H), 1.34 (s, 12H).
JO802207Y
J. Org. Chem. Vol. 74, No. 3, 2009 1387