Regiocontrolled opening of 2-methyltetrahydrofuran with various boron reagents

Article abstract of DOI:10.1071/CH06272

Regiocontrolled halogenative cleavage of 2-methyltetrahydrofuran with various B-bromoboranes, by a predominantly S_N2-type mechanism favouring the formation of primary bromide, is described. A comparative study of the relative reactivities of BH₂Br?SMe₂, BHBr ₂?SMe₂, BBr₃, (MeO)₂BBr, and MeOBBr₂ revealed that the newly synthesized (MeO)₂BBr is a highly promising regioselective reagent, especially at lower temperatures. CSIRO 2006.

Full text of DOI:10.1071/CH06272

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 657–659
Regiocontrolled Opening of 2-Methyltetrahydrofuran
with Various Boron Reagents∗
Chandra D. RoyA,B
A Department of Chemistry, Herbert C. Brown Center for Borane Research, Purdue University,
West Lafayette, IN 47907, USA. Email: chandra0919@gmail.com
B Present address: EMD Biosciences, Inc., San Diego, CA, USA.
Regiocontrolled halogenative cleavage of 2-methyltetrahydrofuran with various B-bromoboranes, by a predomi-
nantly SN2-type mechanism favouring the formation of primary bromide, is described. A comparative study of
the relative reactivities of BH2Br·SMe2, BHBr2·SMe2, BBr3, (MeO)2BBr, and MeOBBr2 revealed that the newly
synthesized (MeO)2BBr is a highly promising regioselective reagent, especially at lower temperatures.
Manuscript received: 30 July 2006.
Final version: 20 August 2006.
Regioselective cleavage of unsymmetrical ethers is a highly
promising transformation in organic synthesis. 1-Bromo-
4-pentanol appears to be a very useful synthetic interme-
diate in natural product syntheses.[1] It can be achieved
directly by the regiocontrolled brominative cleavage of
2-methyltetrahydrofuran by taking advantage of the different
steric environments of the two ethereal C–O bonds. Several
reagents including MgBr2/Ac2O,[2] RCOX/PdII/R3SnX,[3]
RCOX/PtII,[4] MeCOCl/NaI,[5] ROCl/ZnCl2,[6] PhCOCl/Hg/
Al,[7] and ROCl/BiCl3,[8] are available for the selective
O-acylative ring opening of 2-methyltetrahydrofuran and
subsequent trapping of carbo-cations with halides, leading
to the formation of predominantly secondary alkyl halides.
Primary halides have also been obtained by the regioselective
cleavage of 2-methyltetrahydrofuran using (n-C4H9)4N+Br−
or I−/BF3 etherate,[9] AlCl3/NaI,[10] Me3SiCl/NaI,[11] and
tert-BuCOCl/NaI.[5] Boron halides and B-Br-9-BBN are
well recognized as ether-cleaving reagents.[12] The BBr3-
assisted halogenative cleavage of 2-methyltetrahydrofuran
yielded bromohydrins in a non-regioselective fashion. Guin-
don et al.[13] achieved the regiocontrolled ring opening of
2-methyltetrahydrofuran in a 3.5 : 1 regioisomeric ratio of
1-bromopentan-4-ol and 4-bromopentan-1-ol with dimethyl-
boron bromide (Me2BBr) at 0◦C. Our longstanding interests
in developing new boron-based reagents for organic syn-
thesis persuaded us to synthesize the structurally modified
B-bromoboranes (MeO)2BBr 4 and MeOBBr2 5. Consider-
ing the synthetic importance of 1-bromo-4-pentanol and its
ester derivatives, we undertook a comparative study of the
regioselective brominative cleavage of 1-methyltetrahydro-
furan with various B-bromoboranes. The preliminary results
of this study with newly synthesized reagents (MeO)2BBr
and MeOBBr2, along with the commercially available
BH2Br·SMe2, BHBr2·SMe2, and BBr3, are described in this
Communication.
Dimethoxyboronbromide,(MeO)2BBr 4,[14]andmethoxy-
boron dibromide, MeOBBr2 5, were prepared by treating
trimethylborate, (MeO)3B, with boron tribromide, BBr3 3,
in appropriate ratios in either CH2Cl2 or n-pentane at −78
or 0◦C (Scheme 1). The 11B NMR spectrum showed a sharp
peak at δB 22.6 (>95% chemical purity) for (MeO)2BBr in
CH2Cl2 solvent, with the complete disappearance of BBr3
(δB 41.0) and (MeO)3B (δB 18.0). A sharp 11B NMR signal
was seen at δB 26.0 for MeOBBr2.
First, the regioselective cleavage of 2-Me-THF 6 was stud-
ied with the commercially available reagent BH2Br·SMe2 1.
The cleavage of 6 with 1 provided a mixture of regioiso-
meric bromohydrins (yield 80%), 1-bromopentan-4-ol 7, and
4-bromopentan-1-ol 8 (3:1) in CH2Cl2 at room temperature
in 24 h (Scheme 1, Table 1). No significant cleavage (<5%)
occurred at −35◦C for 24 h. The replacement of a hydrogen
atom with an electronegative bromine atom (BHBr2·SMe2
2) resulted in an enhanced reactivity of the reagent, but
slightly lower regioselectivity (7:3). Boron tribromide, which
is highly reactive, afforded a mixture of 7 and 8 (3:2)
under identical reaction conditions (as for BH2Br·SMe2 and
BHBr2·SMe2). The 11B NMR study revealed that the cleav-
age of 2-Me-THF 6 with BBr3 was complete in 0.5 h in
CH2Cl2 at room temperature.
Next, we proceeded to test the effectiveness of these
two newly synthesized B-bromoboranes, (MeO)2BBr 4 and
MeOBBr2 5, in the regioselective cleavage of cyclic ether 6.
During our study on regio- and chemoselective ring open-
ing of epoxides,[14,15] (MeO)2BBr displayed relatively
∗ This paper is dedicated to the memory of my mentor, the late Professor Herbert C. Brown (1912–2004). The work described herein was carried out at Purdue
University during my stay as a post-doctoral research associate (1995–2001).
© CSIRO 2006
10.1071/CH06272
0004-9425/06/090657

658
C. D. Roy
Ϫ78 or 0°C
2 B(OCH3)3
ϩ
BBr3
3 (CH3O)2BBr
CH2Cl2, 15 min
11B NMR: δ 22.6 ppm
Ϫ78 or 0°C
B(OCH3)3 ϩ 2 BBr3
3 CH3OBBr2
CH2Cl2, 15 min
11B NMR: δ 26.0 ppm
.
.
BH2Br SMe2
BHBr2 SMe2 BBr3 (CH3O)2BBr CH3OBBr2
1
2
3
4
5
OCH3
Br
H3CO
H3C
OB(OCH3)2
Br
Br
O
B
H3C
(CH3O)2BBr
CH2Cl2
Br
Br
ϩ
ϩ
OB(OCH3)2
O
H3C
H3C
6
H2O
OH
OH
H3C
H3C
7
8
Scheme 1. Regiocontrolled brominative cleavage of 2-methyltetrahydrofuran with (MeO)2BBr.
Table 1. Regiocontrolled cleavage of 2-methyltetrahydrofuran with various bromoboranes
Br
OH
Entry
Reagent
Reaction conditionsA
Yield [%]B
OH
Br
7
8
1
2
3
4
5
6
7
8
BH2Br·SMe2
BH2Br·SMe2
BH2Br·SMe2
BHBr2·SMe2
BHBr2·SMe2
BHBr2·SMe2
BBr3
0◦C → RT, 24 h
−78◦C → RT, 18 h
−35◦C, 24 h
76
76
–
24
24
–
80
55
<5
88
88
80
95
93
85
91
83
20
90
90
0◦C → RT, 24 h
−78◦C → RT, 16 h
0◦C, 21 h
69
72
71
55
62
71
80
76
88
85
67
31
28
29
45
38
29
20
24
12
15
33
RT, 1.75 h
BBr3
−78◦C → RT, 18 h
9
(MeO)2BBr
(MeO)2BBr
(MeO)2BBr
(MeO)2BBr
(MeO)2BBr
MeOBBr2
RT, 0.25 h
10
11
12
13
14
−78◦C → RT, 16 h
−25◦C, 21 h
−78◦C, 5 h
−43◦C, 20 h
−78◦C → RT, 16 h
A 1.20 equiv. of reagent used.
B Regioselectivity and chemical yields were determined by 1H NMR spectroscopy using biphenyl as an
internal standard.
higher reactivity by cleaving 7-oxanorbornane into trans-
4-bromocyclohexan-1-ol in 1 h at −78◦C, but Me2BBr took
4 h at 0◦C. (BH2Br·SMe2 1 failed even after 4 h at −78◦C;
it could only cleave at room temperature in 16–24 h.) As
expected, this new reagent 4 very efficiently cleaved cyclic
ether 6 in less than 15 min at room temperature.The observed
lower regioselectivity (2.4:1) can be attributed to such higher
reactivity of this reagent. An optimal chemical yield (90%)
with regioselectivity (5.65:1) was achieved when the reac-
tion was conducted at −43◦C for 20 h. The cleavage was
slow at −78◦C (only 18–20% conversion after 5 h). Finally,
the cleavage of 2-Me-THF 6 was studied with the new
reagent 5 under identical conditions (at −78◦C, 12 h, then
slow warming, 12 h), which provided a regioisomeric mix-
ture of 7 and 8 (2:1) in comparison with (MeO)2BBr 4
(3.7:1).
In conclusion, B-bromoboranes react with unsymmetri-
cal cyclic ether 2-methyltetrahydrofuran in a regiocontrolled
fashion by a predominantly SN2-type reaction pathway,
affording primary bromide. The temperature of the reac-
tion has a strong effect on the regioselectivity, especially
with dimethoxyboron bromide 4. Dimethoxyboron bromide
appears to be the reagent of choice. The simple and conve-
nientmethodofpreparationofthesereagents, shorterreaction
times, highreactivities, andsimpleworkupproceduresshould
make these reagents highly practical in synthetic organic

Regiocontrolled Opening of 2-Methyltetrahydrofuran
659
chemistry. Further studies into the use of these new and other
structurally modified reagents will be reported.
References
[1] (a) D. P. Curran, D. Scholz, Monatsh. Chem. 1977, 108, 1401.
doi:10.1007/BF01046455
(b) H. Gerlach, P. Kuenzler, Helv. Chim. Acta 1980, 63, 2312.
doi:10.1002/HLCA.19800630821
[2] D. J. Goldsmith, E. Kennedy, R. G. Campbell, J. Org. Chem.
1975, 40, 3571. doi:10.1021/JO00912A022
[3] I. Pri-Bar, J. K. Stille, J. Org. Chem. 1982, 47, 1215.
doi:10.1021/JO00346A015
[4] J. W. Fitch, W. G. Payne, D. Westmoreland, J. Org. Chem. 1983,
48, 751. doi:10.1021/JO00153A031
[5] A. Oku, T. Harada, K. Kita, Tetrahedron Lett. 1982, 23, 681.
doi:10.1016/S0040-4039(00)86921-X
[6] P. Mimero, C. Saluzzo, R. Amouroux, Tetrahedron Lett.
1994, 35, 1553, and references therein. doi:10.1016/S0040-
4039(00)76756-6
Experimental
Manipulations and reactions with air-sensitive compounds were carried
out under nitrogen. Glassware was oven-dried, assembled while hot, and
cooled in a stream of dry nitrogen gas. 1H, 13C, and 11B NMR spec-
tra were recorded on a Varian–Gemini 300 MHz multinuclear NMR
spectrometer. The 11B NMR chemical shifts are reported as δ rela-
tive to BF3·OEt2. The starting substrate, 2-methyltetrahydrofuran 6,
BH2Br·SMe2 1, BHBr2·SMe2 2, BBr3 3, andB(OCH3)3 werepurchased
from Aldrich. Dichloromethane (CH2Cl2) was distilled over P2O5 and
stored under nitrogen.
Preparation of Methoxyboron Dibromide 5
[7] F. A. Luzzio, R. A. Bobb, Tetrahedron 1999, 55, 1851, and
references therein. doi:10.1016/S0040-4020(98)01226-5
[8] S. J. Coles, J. F. Costello, W. N. Draffin, M. B. Hursthouse,
S. P. Paver, Tetrahedron 2005, 61, 4447, and references therein.
doi:10.1016/J.TET.2005.02.080
The new reagent, methoxyboron dibromide 5, was prepared by mix-
ing trimethyl borate (1.0 equiv.) with boron tribromide (2.0 equiv.) in
either dichloromethane or n-pentane at −78 or 0◦C under nitrogen. The
11B NMR spectrum showed a sharp peak at δB 26.0 (>95% chemical
purity) for MeOBBr2 in CH2Cl2 with the complete disappearance of
BBr3 (δB 41.0) and (MeO)3B (δB 18.0).
[9] V. K. Yadav, A. G. Fallis, J. Org. Chem. 1986, 51, 3372.
doi:10.1021/JO00367A025
[10] M. Node, T. Kajimoto, K. Nishide, E. Fujita, K. Fuji, Tetrahedron
Lett. 1984, 25, 219. doi:10.1016/S0040-4039(00)99844-7
[11] M. Jatczak, R. Amouroux, M. Chastrette, Tetrahedron Lett. 1985,
26, 2315. doi:10.1016/S0040-4039(00)95084-6
[12] (a) S. U. Kulkarni, V. D. Patil, Heterocycles 1982, 18, 163.
(b) M. V. Bhatt, S. U. Kulkarni, Synthesis 1983, 249. doi:10.1055/
S-1983-30301
(c) M. V. Bhatt, J. Organomet. Chem. 1978, 156, 221.
doi:10.1016/S0022-328X(00)84879-2
[13] (a)Y. Guindon, C.Yoakim, H. E. Morton, Tetrahedron Lett. 1983,
24, 2969. doi:10.1016/S0040-4039(00)88071-5
Regioselective Cleavage of 2-Methyltetrahydrofuran 6
with (MeO)2BBr 4
To a cooled stirred solution of (MeO)2BBr 4 (6.0 mmol) in anhydrous
CH2Cl2 (20 mL) at −43◦C under nitrogen atmosphere, was slowly
added neat 2-methyltetrahydrofuran 6 by syringe. The resulting reac-
tion mixture was stirred at −43◦C for 20 h, and then treated with water
(10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 20 mL),
organic extracts were combined, dried (Na2SO4), filtered, and evapo-
rated under vacuum. The regioselectivity (7:8 5.65:1) was determined
on the basis of 1H NMR spectroscopic data by integrating and com-
paring the protons attached to either –OH or –Br present in both
regioisomers. The chemical yield (90%) was determined by 1H NMR
spectroscopy using biphenyl as an internal standard. 7 and 8: δH (CDCl3)
4.15 (m, CHOH), 3.85 (m, CHBr), 3.65 (t, CH2OH), 3.45 (t, CH2Br),
2.10–1.80 (m, CH2CH2CH2), 1.73 (d, CH(OH)CH3), 1.70–1.50 (m,
CH2CH2CH2), 1.21 (d, CH(Br)CH3).
(b) Y. Guindon, M. Therien, Y. Girard, C. Yoakim, J. Org.
Chem. 1987, 52, 1680, and references therein. doi:10.1021/JO
00385A007
[14] C. D. Roy, H. C. Brown, J. Chem. Res. 2006, 639.
[15] H. C. Brown, C. D. Roy, Mol. Online 1998, 2, 114.
doi:10.1007/S007830050066
Acknowledgment
Financial support from the Purdue Borane Research Fund is
greatly appreciated.