New amine-stabilized deuterated borane-tetrahydrofuran complex (BD3-THF): convenient reagent for deuterium incorporations

Article abstract of DOI:10.1016/j.tetlet.2007.01.134

Convenient methods for the preparation of BD₃-THF complex were developed. Certain amines stabilize the BD₃-THF for long-term storage. Regioselectivity studies were carried out with the new amine-stabilized BD₃-THF with rep

Full text of DOI:10.1016/j.tetlet.2007.01.134

Tetrahedron Letters 48 (2007) 2335–2337
New amine-stabilized deuterated borane–tetrahydrofuran
complex (BD3–THF): convenient reagent for
deuterium incorporations
Robert C. Todd,a,b M. Mahmun Hossain,b,* Kanth V. Josyula,a
Peng Gao,a,* John Kuoc and C. T. Tanc
aAldrich Chemical Company, 6000 N. Teutonia Avenue, Milwaukee, WI 53209, United States
bUniversity of Wisconsin Milwaukee, Department of Chemistry and Biochemistry, 3210 N. Cramer,
Milwaukee, WI 53211, United States
cSigma–Aldrich, Isotec, 3858 Benner Road, Miamisburg, OH 45342, United States
Received 19 December 2006; revised 18 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—Convenient methods for the preparation of BD3–THF complex were developed. Certain amines stabilize the BD3–THF
for long-term storage. Regioselectivity studies were carried out with the new amine-stabilized BD3–THF with representative olefins.
Hydroboration of olefins provides a convenient tool for making corresponding deuterated alcohols after oxidation.
ꢀ 2007 Elsevier Ltd. All rights reserved.
BH3–THF (BTHF) is a reagent of choice for several syn-
thetic transformations, such as reduction and hydrobo-
ration.1 We recently sought a convenient synthesis of a
borane-labeling reagent for introducing a deuterium la-
bel in a highly efficient and selective fashion. Though a
few deuterium labeled reagents, such as NaBD4, LiAlD4
and Li(sec-butyl)3BD are known, BD3–THF is known
to provide selective deuterium insertions, otherwise not
possible.2 The ideal reagent was to be highly stable
and relatively easy to use, preferably as a solution. As
borane–Lewis base complexes are finding an ever-
increasing role in organic transformations, in particular
borane tetrahydrofuran, we began looking into the syn-
thesis, stability and synthetic utility of BD3–THF. Here-
in we wish to report an improved synthesis of BD3–
THF, stability studies and applications in the hydro-
boration of representative olefins.
purity and low volatility to other glyme type solvents,
triglyme was chosen as the solvent of choice. Substitut-
ing NaBD4 for NaBH4, direct application of Brown’s lit-
erature conditions for generating diborane succeeded in
yielding a 1 M solution of borane-d3 complex in THF
quantitatively. THF complex 2 was generated by intro-
ducing the labeled diborane (B2D6) gas stream 1 from
the reactor into a separate reactor containing THF,
which was re-distilled over lithium aluminum deuteride
prior to use (Scheme 1). The reaction proved amenable
to scale up, with the same yield obtained whether on a
0.5 mol or 1.0 mol scale.4
Similar to BH3–THF, BD3–THF is also not stable at
room temperature for extended periods of time.5 Com-
mercial BH3–THF is stabilized with NaBH4, NaBD4
was used to stabilize BD3–THF.6 The presence of
The method chosen for generating B2D6 (1) was mod-
eled off the procedure reported by Brown and co-work-
ers for generating diborane gas using boron trifluoride
as the Lewis acid in glyme solvents.3 Owing to its high
D
D
D
D
D
triglyme
0 °C
+ 3 NaBF4
3 NaBD4 + 4 BF3:Et2O
2
B
B
D
1
D
D
D
D
D
D
THF
0-5 °C
Keywords: BD3–THF complex; Stability; Hydroboration; Olefins;
Regioselectivity.
2 BTHF-d3
B
B
2
*
Corresponding authors. E-mail addresses: mahmun@uwm.edu;
pgao@sial.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.134

2336
R. C. Todd et al. / Tetrahedron Letters 48 (2007) 2335–2337
Table 1. Regioselectivity of hydroboration–oxidation of representative
olefins using BD3–THF and BH3–THF in THF at room temperature
sodium borohydride as a stabilizer is known to create
safety issues as well as some adverse affects in applica-
tions.7,8 Recently, we have undertaken a detailed study
to find more effective stabilizers for BH3–THF and
found that certain hindered amines are superior stabiliz-
ers of BH3–THF compared to NaBH4. Solutions of 1 M
BTHF containing 0.005 M% N-isopropyl-N-methyl-t-
butylamine (NIMBA) showed superior thermal proper-
ties, directly resulting in improved stability.9 Similar
stability effect was observed for BD3–THF, when stabi-
lized with 0.005 M% N-isopropyl-N-methyl-t-butyl-
amine (NIMBA). These solutions did not show any
noticeable degradation in hydride content by 11B
NMR, when stored at 4–8 ꢁC for at least six months.
Olefin
BD3–THFa
BH3–THF
(Terminal:internal)
(Terminal:internal)
1-Octene
96:4
96:4
Styrene
87:13
85:15
Allyl chloride
2-Methyl-2-butene
Norbornene
78:22
94:6
94:6 (exo:endo)
72:28
98:2
97:3 (exo:endo)
a Reactions were carried out using borane 2 (5 mmol) and an olefin
(15 mmol) in a total volume of 10 mL solution in THF.
decomposition being directly proportional to the con-
centration of BTHF.
As a result, we also extended the stability studies at ele-
vated temperatures for BD3–THF. The adduct thus
obtained (1 M solution in THF), maintained under
nitrogen, was subjected to elevated temperature studies
(50 ꢁC) in sealed NMR tubes over a period of 96 h.
When stabilized with 0.005 M N-isopropylmethyl-t-
butylamine (NIMBA), the 11B NMR showed approxi-
mately 90% BD3–THF remained after 80 h of heating
at 50 ꢁC (Fig. 1).10 Collecting concentration of BTHF
versus time data for at least 3 half lives shows curvature
indicating decomposition to be first order in BTHF.
Decomposition furthermore appears to be an intermo-
lecular event over intramolecular based on the rate of
Regioselectivity of hydroboration. 1-Octene, styrene, 4-
bromostyrene, norbornene, 2-methyl-2-butene, 2,3-di-
methyl-2-butene and allyl chloride were hydroborated
using 2 at room temperature in THF, then subsequently
oxidized to the corresponding alcohol.11 1-Ocetene and
styrene were hydroborated in a 3:1 ratio (Scheme 2),
whereas allyl chloride was hydroborated in a 1:1 molar
ratio as reported for BH3–THF.1d,12 Intermediate
organoboranes were oxidized with H2O2–NaOH, and
1
the product alcohols analyzed by GC–MS, H NMR
and deuterium NMR. The results are tabulated in Table
1.
Although, the regioselectivity trends observed during
hydroboration/oxidation of olefins with BD3–THF is
similar to that reported for BH3–THF,1a,d minor differ-
ences obtained may possibly be due to a combination of
steric and isotopic effects.
100.0%
80.0%
60.0%
In conclusion, we report a new, convenient procedure
for the preparation of deuterated borane–THF. The
BD3–THF thus prepared can be stabilized with
0.005 M N-isopropyl-N-methyl-t-butylamine (NIMBA)
to provide thermally stable BD3–THF. Regioselecivity
studies with BD3–THF showed similar results to that re-
ported for BH3–THF. Further works on the synthetic
utility of this amine-stabilized BD3–THF solutions are
in progress and will be the subject of future publications.
BD -THF (NIMBA)
3
BH -THF (NIMBA)
3
BH -THF (unstabilized)
40.0%
3
BD -THF (unstabilized)
3
20.0%
0.0
20.0
40.0
60.0
80.0
Hours
Figure 1.
1. BD3-THF
2. H2O2, NaOH
D
OH
OH
D
+
THF
1. BD3-THF
2. H2O2, NaOH
OH
D
Cl
Cl
Cl
+
THF
D
OH
1. BD3-THF
2. H2O2, NaOH
OH
D
+
OH
THF
D
Scheme 2.

R. C. Todd et al. / Tetrahedron Letters 48 (2007) 2335–2337
2337
D. Tetrahedron Lett. 2003, 44, 801; (c) Xu, J.; Wei, T.;
Zhang, Q. J. Org. Chem. 2003, 68, 10146.
Acknowledgement
9. (a) Potyen, M.; Josyula, K. V. B.; Schuck, M.; Lu, S.;
Gao, P.; Hewitt, C. Org. Process. Res. Dev., in press;
(b) For further details about the safe handling of new
amine-stabilized BTHF solutions, please see Aldrich
Technical Bulletin 218, which can be requested by e-mail:
(aldrich@sial.com) or can be accessed on the web: http://
www.sigmaaldrich.com/aldrich/bulletin/al_techbull_al218.
pdf.
The authors thank Dr. Chris Hewitt for his encourage-
ment and support.
References and notes
10. Typical procedure for sealed NMR tube studies at 50 ꢁC
using 1.0 M BD3–THF. Freshly prepared unstabilized
BD3–THF solution was transferred to a nitrogen flushed
oven-dried vessel and a calculated amount of the stabilizer
was added. This solution was diluted to the required
concentration by additional anhydrous THF. Solution
(0.8 mL) was removed by nitrogen flushed syringe to a
nitrogen flushed oven-dried NMR tube. The NMR tube
was sealed and was placed in a temperature-controlled
bath and heated for a fixed time then removed for
evaluation by 11B NMR.
1. (a) Brown, H. C.; Zaidlewicz, M. In Organic Synthesis via
Boranes; Aldrich Chemical: Milwaukee, 2001; Vol. 2,
Product No. Z40,095-5; (b) Pelter, A.; Smith, K.; Brown,
H. C. Borane Reagents; Academic Press: London, 1988; (c)
Follet, M. Chem. Ind. 1986, 123; (d) Zaidlewicz, M.;
Brown, H. C. In Encyclopedia or Reagents for Organic
Synthesis; Paquette, L. A., Ed.; J. Wiley: New York, 1995;
Vol. 1, p 638.
2. (a) Gartner, P.; Novak, C.; Knollmuller, M.; Gmeiner, G.
ARKIVOC 2001, 9; (b) O’Connor, E. J.; Kobayashi, M.;
Floss, H. G.; Gladysz, J. A. J. Am. Chem. Soc. 1987, 109,
4837.
11. Hydroboration of representative olefins, such as 1-octene,
styrene, allyl chloride, 2-methyl-2-butene and norbornene,
with NIMBA stabilized BTHF solution was carried out in
THF. The procedure followed for all the olefins is the
same. The procedure followed for 1-decene in THF using
BD3–THF is representative. In an oven-dried round-
bottomed flask, the NIMBA stabilized BD3–THF (1 M in
THF, 7.5 mmol, commercially available from Aldrich, cat
# 66,771-4) was diluted with 1.5 volumes of anhydrous
THF. The diluted solution was cooled to 0 ꢁC. 1-Decene
(15 mmol) was added over 5 min. The reaction mixture
was stirred with a magnetic stirrer at room temperature
for 2 h. The reaction was cooled to 10 ꢁC. A NaOH
solution (3 M, 9 mL) was then added. Hydrogen peroxide
(30 wt % in water, 3 mL) was then charged at 10 ꢁC. The
reaction mixture was stirred at 50 ꢁC for 2 h and then
cooled to room temperature. Ether (20 mL) was added.
The organic phase was washed with H2O (20 mL) and
brine (20 mL), dried over magnesium sulfate and filtered.
Solvent was removed to record the crude yield and for GC
quantification of regio-isomers 1- and 2-decanol. The clear
liquid was passed through a silica gel plug (3 cm · 5 cm
i.d.) with ether (150 mL) to give a quantitative yield. GC
was used to quantify the ratios of the regio-isomers in the
isolated product. Yield (97%) by GC; isolated 2.21 g
(93%), GC was ran on HP5890 and an RTx-50 column
with retention times 5.28 min (1-decanol) 4.21 (2-decanol);
isomeric ratio 1-:2-decanol; 96:4 (100 ꢁC (1 min), then
100–250 ꢁC @ 10 ꢁC/min; Inj. 200 ꢁC, Det. 250 ꢁC). (98%
deuterium content by mass spectroscopy).
3. Kanth, J. V. B.; Brown, H. C. Inorg. Chem. 2000, 39, 1795.
4. Generation of diborane using borohydride in tetraglyme and
BF3–Et2O. The procedure followed for generating a 1 M
BD3–THF solution in THF is the same as that for BH3–
THF. In an oven-dried round-bottomed flask, NaBD4
(26 g, 621 mmol) was charged along with anhydrous
tetraglyme (175 mL, 968 mmol). The resulting turbid
solution was then cooled to 0 ꢁC. BF3–Et2O (105 mL,
0.826 mmol) was then charged to the reaction mixture
over a period of 50 min at 0 ꢁC. After ca. 50% of the
etherate was added, diborane gas was then generated and
allowed to pass through a À78 ꢁC cold trap before being
allowed to sparge into agitated anhydrous THF (600 g,
9 mol) at 0 ꢁC. Diborane generation ceased 40 min upon
completing the BF3–Et2O addition. 11B NMR: À0.8
(quartet). Hydride analysis using a (1:1) glycerol:water
solution: 1.05 M.
5. Brown, H. C. U.S. Patent 3,634,277, 1972.
6. See product details of BD3–THF from Cambridge Isotope
laboratories, Inc, cat # DLM-1315-0.25, this can be
accessed via web at: http://www.isotope.com/cil/products/
displayproduct.cfm?prod_id=5439.
7. (a) SADT testing of 1.0 M BTHF stabilized with 0.005 M
NaBH4, using the procedure described in Ref. 9, resulted
in self-accelerating temperature of 42 ꢁC; (b) For an
industrial incident involving 2 M THF in a 400 L cylinder,
please see: Chem. Eng. News, July 1, 2002 and safety
highlights in Org. Process. Res. Dev., 2003, 7, 1029.
8. (a) Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D.
R.; Corella, J. A. J. Org. Chem. 2002, 67, 2970; (b) Fu, X.;
McAllister, T. L.; Thiruvengadam, T. K.; Tann, C.-H.; Su,
12. Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz,
M. J. Org. Chem. 2000, 65, 4655.