Borane - THF: New solutions with improved thermal properties and stability

Article abstract of DOI:10.1021/op060203t

A new generation of borane-THF solutions stabilized with 0.005 M of 1,2,2,6,6-pentamethylpiperidine or N-isopropyl-N-methyl-tert-butylamine have been developed. These BTHF solutions show superior stability and reactivity at ambient temperatures when compared to BTHF complex unstabilized or stabilized with 0.005 M NaBH₄.

Full text of DOI:10.1021/op060203t

Organic Process Research & Development 2007, 11, 210−214
Borane-THF: New Solutions with Improved Thermal Properties and Stability†
‡
,‡
⊥
§
‡
‡
Mark Potyen, Kanth V. B. Josyula,* Mike Schuck, Sean Lu, Peng Gao, and Chris Hewitt
Aldrich Chemical Company Inc., 6000 North Teutonia AVenue, Milwaukee, Wisconsin 53209, U.S.A.,
and Sigma-RBI, 3 Strathmore Road, Natick, Massachusetts 01760, U.S.A.
Abstract:
rium in borane-THF solutions, at normal pressures results
A new generation of borane-THF solutions stabilized with
in the formation of free diborane. The borane complexed to
THF can ring-open the THF to produce dibutoxyborane or
tributoxyborane (eq 1).
0.005 M of 1,2,2,6,6-pentamethylpiperidine or N-isopropyl-N-
methyl-tert-butylamine have been developed. These BTHF
solutions show superior stability and reactivity at ambient
temperatures when compared to BTHF complex unstabilized
or stabilized with 0.005 M NaBH
4
.
Diborane (B ) is a versatile reagent with a multitude
2 6
H
of applications in organic and inorganic syntheses. Being a
pyrophoric gas, diborane is routinely used as borane-Lewis
base complexes, as they are safer and more convenient to
handle. Numerous applications of these borane complexes
in the synthesis of pharmaceuticals and in other industrial
processes have been reported.1 Borane-tetrahydrofuran
complex (also referred to as “BTHF” or “BTHF complex”)
is one of the most widely used borane-Lewis base com-
plexes for synthetic applications, such as the hydroboration
of carbon-carbon double and triple bonds, and the reduction
This ring opening is minimal or absent below 5 °C.
However, it is facile at and above room temperature. This is
most likely due to the recomplexation of borane with THF,
which is exothermic and may result in localized heating.6
Previously, this problem was partially addressed by
stabilizing these BTHF solutions with a small amount of
7
NaBH
4
. While NaBH
4
-stabilized BTHF solutions lose very
little hydride activity when stored and used at 0 °C, these
BTHF solutions lose activity over time when kept at ambient
temperatures, creating both safety and stability concerns.7
Under the United States Department of Transportation (DOT)
regulations, shipment of a package (at ambient temperature)
containing a material which is likely to decompose with a
self-accelerated decomposition temperature (SADT) of less
than or equal to 50 °C, with an evolution of a dangerous
quantity of heat or gas when decomposing, is prohibited
unless the material is sufficiently stabilized or inhibited.9
BTHF solutions having concentrations in excess of about 1
mole per liter generally cannot meet the SADT mandated
,8,10
2
of various functional groups. While several other borane
reagents are available, BTHF continues to be the reagent of
choice for such applications.1
,3
Although effective in synthetic applications, BTHF suffers
a few disadvantages. As a weak Lewis base, THF can
complex with borane to form only up to 2.5 M BTHF
4
solution under normal pressures. At high diborane pressures,
4
b
solutions of 5 M BTHF in THF have been reported. Even
at low concentrations, such as 1.0 M, BTHF loses its hydride
5
10
activity over time when stored at room temperature. It is
by the DOT.
known that THF forms a weak complex with borane and is
subject to dissociation to reach a dynamic equilibrium
between borane and THF in BTHF solution. This equilib-
The stabilizer, NaBH
THF solution and forms complexes with borane to produce
4
, is sparingly soluble in borane-
4
(
6) (a) When borane gas is passed into anhydrous THF at room temperature, a
5
-10 °C temperature rise is generally observed. Accordingly, it is always
†
Dedicated to the late Prof. Herbert C. Brown, a great mentor and pioneer
a practice to cool the THF to 10 °C (ice water) to control the heat of reaction,
to avoid undesired side products. (b) During stability testing, when BTHF
solutions were heated without stirring, the decomposition was found to be
more rapid than with stirring. This may have been from hot spots that were
created where the immersion heating coil contacts the solution.
in boron chemistry.
*
Corresponding author. Fax: (414) 438-4225. E-mail: kjosyula@sial.com.
Aldrich Chemical Company.
Sigma-RBI.
‡
§
⊥
Current address: Sigma Group, 1300 Canal Street, Milwaukee, WI 53233.
(7) (a) Brown, H. C. U.S. Patent 3,634,277, 1972. (b) When 0.005% NaBH
stabilizer was used, all of the NaBH stayed in the THF solution. However,
when more than 0.01% NaBH stabilizer was used, some precipitation was
observed, and the B NMR indicated signals due to NaBH ‚BH (δ: -24
ppm) in addition to NaBH (δ: -40 ppm).
4
(
1) (a) Brown, H. C.; Zaidlewicz, M. Organic Synthesis Via Boranes; Aldrich
Chemical: Milwaukee, 2001; Vol. 2. Product Number Z40,095-5. (b) Pelter,
A.; Smith, K.; Brown, H. C. Borane Reagents; Academic Press: London,
4
4
1
1
4
3
1
988. (c) Yardley, J. P.; Fletcher, H., III;, Russell, P. B. Experientia 1978,
4
3
4, 1124. (d) Renn, O.; Meatres, C. F. Bioconjugate Chem. 1992, 3, 563.
(8) Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.; Corella, J. A. J.
Org. Chem. 2002, 67, 2970.
(e) Follet, M. Chem. Ind. 1986, 123.
(
(
(
2) Zaidlewicz, M.; Brown, H. C. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; J. Wiley: New York, 1995; Vol. 1, p 638.
3) For a review on amine-boranes, see: Kanth, J. V. B. Aldrichimica Acta
(9) For requirements and testing details, see: Code of Federal Regulations 49
CFR 173.21 (f), 10-1-03 edition, U.S. Government Printing Office, p 417.
A link to this reference can be found at: http://www.access.gpo.gov/nara/
cfr/waisidx_03/49cfr173_03.html. Some experimental details are given in
the Supporting Information.
2
002, 35, 57.
4) (a) Wirth, H. E.; Massoth, F. E.; Gilbert, D. X. J. Phys. Chem. 1958, 52,
70. (b) Elliott Roth, W. L.; Roedel, G. F.; Boldebuck, E. M. J. Am. Chem.
8
4
(10) (a) SADT testing of 1.0 M BTHF stabilized with 0.005 M NaBH , using
Soc. 1952, 74, 5211.
the procedure described in ref 9, resulted in a 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.
(
5) (a) Lane, C. F. Chem. ReV. 1976, 76, 773. (b) Brown, H. C.; Heim, P.;
Yoon, N. M. J. Am. Chem. Soc. 1970, 92, 1637. (c) Prasad, A. S. B.; Kanth,
J. V. B.; Periasamy, M. Tetrahedron 1992, 48, 4623.
2
10
•
Vol. 11, No. 2, 2007 / Organic Process Research & Development
10.1021/op060203t CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/08/2007

Table 1. Sealed NMR tube studies at 50 °C using 1.0 M
BTHF: percent of remaining BTHF complex by 11B NMR
stabilizer with
concentration
24 h
(%)
48 h
(%)
72 h
(%)
entry
1
2
3
4
5
6
7
8
9
unstabilized
82
83
83
81
83
89
90
91
83
85
88
87
92
89
92
59
57
58
55
59
64
66
69
65
65
73
74
78
79
77
39
37
39
36
43
43
45
47
48
49
59
61
64
67
72
2
0.005 M Me S
n
0.01 M BuNEt
2
n
0.005 M BuNEt
2
t
i
0.005 M BuN BuEt
0.005 M LiBH
0.005 M NaBH
0.01 M NaBH
4
4
4
i
0.005 M PhN PrEt
i
i
Figure 1. Heat generation for decomposition of 1.0 M BTHF
with selected stabilizers at 50 °C.
10
11
12
13
14
15
0.005 M Pr
0.005 M Et
2
N Bu
N Oct
t
2
0.0025 M NIMBA
0.005 M PMP
0.005 M NIMBA
0.01 M NIMBA
Table 2. Sealed NMR tube studies at 50 °C using 1.5 M
1
1
BTHF: percent of remaining BTHF complex by B NMR
2
4 h
48 h
(%)
72 h
(%)
entry
stabilizer with concentration
(%)
4 3 2 7
NaBH :BH or NaB H
species as observed by 11B NMR,
which may precipitate out on long standing, reducing the
stability of the solution.7b Consequently, the exact amount
1
2
3
unstabilized
0.01 M NIMBA
0.01 M PMP
71
87
85
38
68
63
19
49
45
of stabilizer in a given solution is not consistent, leading to
inconsistent performance during applications.8,11 As a major-
ity of BTHF applications, such as hydroboration, carboxylic
acid, aldehyde, and ketone reductions are carried out at or
below 25 °C,5 for high-temperature synthetic applications
such as reduction of nitriles the loss of hydride activity
directly results in the usage of more reagent.3
In order to develop a safer and more stable BTHF for
applications in organic syntheses, we have undertaken a study
to explore new stabilizers for BTHF that minimize or reduce
the above-mentioned problems. Such solutions would both
improve safety and stability, and hence could reduce the
requirement of using excess reagent.
is a marginal change by increasing the stabilizer concentra-
tion to 0.01 M (entry 15), or reducing it to 0.0025 M (entry
12). From these variations, we decided to keep the stabilizer
at 0.005 M in 1.0 M BTHF to achieve optimal results with
a minimum concentration of the stabilizer.
,12
,5
The two selected stabilizers were further studied at 0.01
M stabilizer in 1.5 M BTHF solutions. Results obtained from
1
1
the sealed B NMR studies in 1.5 M BTHF are presented
in Table 2. Here also, the additives stabilize the BTHF
1
3
solution to a considerable extent.
Using larger sample sizes in a sealed autoclave reactor,
11
the B NMR integration was directly correlated to the active
hydride content. The active hydride content was measured
by hydrolyzing the resulting solution and measuring the
Results and Discussion
1
4
A suitable borane scavenger must be freely miscible with
BTHF solution and should be able to complex weakly with
the free borane. Also, the stability effect must be achieved
with a minimum amount of this stabilizer, in order not to
contaminate products or complicate reaction workup. With
this in mind, several Lewis bases with varying steric and
electronic factors were screened as potential stabilizers.
hydrogen evolved.
Finally, these selected candidates were subjected to the
United Nations recommended testing protocol for shipment
9
,13
of dangerous goods. The test for 1.0 M BTHF stabilized
with 0.005 M NaBH showed that this material is capable
4
of undergoing self-accelerating decomposition from 42 °C
(SADT: 45 °C), which fails to meet the threshold for ambient
temperature shipping. On the other hand 1.0 M BTHF
stabilized with N-isopropyl-N-methyl-butylamine (NIMBA)
or 1,2,2,6,6-pentamethylpiperidine (PMP) showed higher
critical ambient temperatures resulting in higher SADT,
making it much safer to ship and handle at ambient
temperature. For example, 1 M BTHF stabilized with 0.005
M PMP, has a critical ambient temperature of >45 °C with
11
The initial screening was carried out by B NMR studies,
placing 0.8 mL of BTHF of a given concentration and the
stabilizer in a NMR tube and sealing the tube. The tube was
then heated in a uniform temperature-controlled bath. Using
11
B NMR, the progress of the decomposition was monitored.
The results obtained using 1.0 M BTHF solutions with
selected stabilizers, are described in Table 1.
From the data in Table 1, it is clearly evident that some
amines (entries 11, 13 and 14) show significant stabilization
of the BTHF solution when compared to unstabilized
13
SADT of 50 °C. Figure 1 depicts the heat generation pattern
of 1 M BTHF stabilized with NaBH , NIMBA or PMP, under
4
adiabatic conditions at 50 °C. The rate of heat generation is
4
borane-THF as well as NaBH -stabilized BTHF. Also, there
relatively slow for the amine-stabilized BTHF, when com-
(
11) (a) Fu, X;, McAllister, T. L.; Thiruvengadam, T. K.; Tann, C-H.; Su, D.
(13) For details, please see the Supporting Information
(14) (a) See Supporting Information section for details. (b) The hydride
estimations were carried out using the procedures described in: Brown, H.
C. Organic Syntheses Via Boranes; Aldrich Chemical Co., Inc.: Milwaukee,
WI, 1997; Vol. 1.
Tetrahedron Lett. 2003, 44, 801. (b) Xu, J.; Wei, T.; Zhang, Q. J. Org.
Chem. 2003, 68, 10146.
(12) Lobben, P. C.; Leung, S. S-W.; Tummala, S. Org. Process Res. DeV. 2004,
8
, 1072.
Vol. 11, No. 2, 2007 / Organic Process Research & Development
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211

Figure 2. Stability studies of 1.0 M BTHF at 22 °C.
Figure 3. Stability studies of 1.0 M BTHF at 50 °C.
pared to that for BTHF stabilized with NaBH
resulting in higher SADT.
4
, directly
with 0.005 M NIMBA indicated the presence of 58% active
BTHF as compared to 24% in unstabilized BTHF (Figure
3). Also, the B NMR study indicated the dissociation
pathway of BTHF stabilized with NIMBA, PMP is consider-
ably different from BTHF unstabilized or stabilized with
The stability of BTHF at 0 °C is well established.7a,8
However, when stored at room temperature, degradation is
rapid for unstabilized BTHF. Fortunately, our studies indi-
cated superior stability of 1.0 M BTHF stabilized with 0.005
M NIMBA. Figure 2 depicts the stability study results of 1
11
NaBH
some higher borane species were observed, whereas with
BTHF unstabilized or stabilized with NaBH , THF-cleaved
4
. In the case of amine-stabilized BTHF solutions,
11
M BTHF with and without stabilizer, observed in B NMR,
in a sealed NMR tube.
4
products are the major impurities. Further studies on
understanding this dissociation pathway are in progress and
will be the subject of further reports in this area. The higher
thermal stability of BTHF containing 0.005 M NIMBA
should not only make this more safe for shipping, but should
also make the reagent more desirable for application at
elevated temperatures.
In order to establish the utility of these new amine-
stabilized BTHF solutions, representative hydroboration and
reduction reactions were carried out with 1-decene and
acetophenone, respectively. For comparison, reactions were
also carried out with 1.0 M BTHF solution stabilized with
Encouraged by the improved stability of 1.0 M BTHF
containing 0.005 M NIMBA, we have also carried out similar
sealed NMR tube experiments at 50 °C. Since, borane-THF
dissociates rapidly at higher temperatures, it was always used
in excess or other borane-Lewis base complexes such as
BMS and amine-borane complexes were used for high-
temperature synthetic applications.3 Surprisingly, the 1.0
M BTHF stabilized with 0.005 M NIMBA showed superior
stability, even at 50 °C, when compared to unstabilized or
,5b
1
3
stabilized with 0.005 M NaBH
4
. For example, after 96 h
heating at 50 °C, the 11B NMR of 1.0 M BTHF stabilized
212
•
Vol. 11, No. 2, 2007 / Organic Process Research & Development

Table 3. Reduction of acetophenone
a calculated amount of the stabilizer was added. This solution
was diluted to the required concentration with additional
anhydrous THF, and 0.8 mL portions of the solution were
removed by nitrogen-flushed syringes to nitrogen-flushed,
oven-dried NMR tubes. The NMR tubes were sealed and
placed in a temperature-controlled bath, heated for a fixed
1
.0 M BTHF with
GC yield
(%)
isolated yield
(%)
stabilizer (0.005 M)
1
1
time, and then removed for evaluation by B NMR.
Typical Procedure for Autoclave Reactor Studies at
50 °C Using 1.0 M BTHF. Stabilized solutions were
prepared as above, and 25 mL portions of the solution were
removed by nitrogen-flushed syringes to oven-dried, nitrogen-
flushed glass vessels in a 1 L pressure reactor. The reactor
was sealed and heated with an oil bath. After the desired
reaction time the apparatus was cooled to room temperature.
NaBH
PMP
NIMBA
4
98
99
98
94
95
94
Table 4. Hydroboration-oxidation of 1-decene
1
1
Samples were removed for evaluation by B NMR and
hydrogen evolution.
1
.0 M BTHF with GC yield isolated yield regioselectivity
Typical Experimental Procedure for the Racemic
Reduction of Acetophenone. In an oven-dried round-bottom
flask, the stabilized borane solution (Aldrich 176192, 650412,
or 630390, ca. 1 M in THF, 13.3 mmol) was diluted with 2
volumes of anhydrous THF. The diluted solution was cooled
to 0 °C. Acetophenone (10 mmol) was added over 5 min.
The reaction mixture was stirred with a magnetic stirrer at
room temperature for 2 h. The reaction was quenched by
stabilizer (0.005 M)
(%)
(%)
(1:2)
NaBH
PMP
NIMBA
4
96
94
97
92
90
93
94:6
94:6
94:6
0
4
.005 M NaBH . In this comparative study, both amine-
stabilized BTHF solutions performed similarly to those
stabilized with NaBH (Tables 3 and 4).
In both the cases, usual workup provided essentially pure
alcohol product. Simple HCl wash removed the amine
stabilizer effectively providing analytically pure samples,
addition of H
mixture was washed with 3 M HCl (10 mL). The organic
phase was washed with H O (10 mL) and brine (10 mL),
2
O (10 mL). Ether (10 mL) was added. The
4
2
dried over magnesium sulfate, and filtered. The solvent was
removed to record the crude yield and for GC quantification.
The clear liquid was passed through a silica gel plug (2 cm
1
5
which were cross-compared to the literature reports.
In conclusion, we report new amine-stabilized borane-
×
4 cm i.d.) with ether (100 mL). After the solvent was
removed, the yield of isolated product was obtained by GC
and weighing.
THF solutions for applications in organic syntheses. Though
M BTHF stabilized with NaBH is still a viable option for
4
1
synthetic application if handled with caution, this new
generation of BTHF solutions is significantly more stable
than the previously available BTHF reagents, whilst retaining
the qualities of high reactivity and simple workup. In
addition, these new reagents enable safer shipping and use
in organic synthesis involving borane-THF at temperatures
(
i) Reduction of acetophenone using BTHF stabilized with
NaBH : yield (98% by GC; isolated 1.15 g (94%)). GC was
run on HP5890 and an RTx-50 column with retention time
.994 min (100 °C (1 min), then 100 °C to 180 °C @10
C/min; splitless, Inj. 200 °C, Det. 250 °C).
ii) Reduction of acetophenone using BTHF stabilized
4
3
°
(
4
higher than ambient. For both NaBH -stabilized as well as
with PMP: yield (99% by GC; isolated 1.16 g (95%)). GC
was run on HP5890 and an RTx-50 column with retention
time 4.012 min.
amine-stabilized BTHF reagents, keeping them in a temper-
ature-controlled environment (2-8 °C) for long-term storage
is necessary for optimal utility and safety.16 Further studies
on understanding the mechanism of this stability effect and
other synthetic applications are underway and will be the
subject of future reports.
(iii) Reduction of acetophenone using BTHF stabilized
with NIMBA: yield (98% by GC; isolated 1.15 g (95%)).
GC was run on HP5890 and an RTx-50 column with
retention time 3.998 min.
Typical Experimental Procedure for the Hydrobora-
tion-Oxidation of 1-Decene. In an oven-dried round-bottom
flask, the stabilized borane solution (Aldrich 176192, 650412,
or 630390, ca. 1 M in THF, 7.5 mmol) was diluted with 1.5
volumes of anhydrous THF. The diluted solution was cooled
to 0 °C. 1-Decene (D1807, 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
Experimental Section
Typical Procedure for Sealed NMR Tube Studies at
50 °C Using 1.0 M BTHF. Unstabilized BTHF solutions
were prepared by passing diborane gas into THF solution
as described in the literature. This stock solution was
transferred to a nitrogen-flushed, oven-dried vessel, and then
1
(
15) Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem.
000, 65, 4655.
°
C. NaOH solution (3 M, 9 mL) was then added. Hydrogen
peroxide (216763, 30 wt % in water, 3 mL) was added at
0 °C. The reaction mixture was stirred at 50 °C for 2 h and
then cooled to room temperature. Ether (20 mL) was added.
2
(
16) 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 .
1
Vol. 11, No. 2, 2007 / Organic Process Research & Development
•
213

The organic phase was washed with H
2
O (20 mL) and brine
GC was run on HP5890 and an RTx-50 column with
retention times 5.28 min (1-decanol) 4.21 (2-decanol);
isomeric ratio 1-decanol:2-decanol ) 94.1:5.9.
(20 mL), dried over magnesium sulfate, and filtered. Solvent
was removed to record the crude yield and for GC quanti-
fication of regioisomers 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 an isolated yield. GC was used
to quantify the ratios of the regioisomers in the isolated
product.
Acknowledgment
We thank Dr. Gordon Amery, Sigma-Aldrich, Gillingham,
U.K.; Dr. Bob Venugopal, Chilworth Technologies, New
Jersey; and Mr. Chad Jacobsen and Mr. Kevin Priebe, Sigma-
Aldrich, Sheboygan Falls, for their help with this project.
(
i) Hydroboration of 1-decene using BTHF stabilized with
NaBH : yield (96% by GC; isolated 2.18 g (92%)). GC was
run on HP5890 and an RTx-50 column with retention times
.34 min (1-decanol) 4.22 (2-decanol); isomeric ratio 1-de-
canol:2-decanol ) 93.9:6.1 (100 °C (1 min), then 100 °C to
50 °C @10 °C/min; Inj. 200 °C, Det. 250 °C).
ii) Hydroboration of 1-decene using BTHF stabilized
4
5
Supporting Information Available
Details of the compound stability data, accelerating
calorimetry, and adiabatic Dewar calorimetry data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2
(
with PMP: yield (94% by GC; isolated 2.13 g (90%)). GC
was run on HP5890 and an RTx-50 column with retention
times 5.54 min (1-decanol) 4.30 (2-decanol); isomeric ratio
1
-decanol:2-decanol ) 94.4:5.6.
iii) Hydroboration of 1-decene using BTHF stabilized
with NIMBA: yield (97% by GC; isolated 2.21 g (93%)).
Received for review October 3, 2006.
OP060203T
(
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