A safe and scalable procedure for preparation of α-picoline-borane from sodium mono-acyloxyborohydrides and α-picoline

Article abstract of DOI:10.1021/op2003858

Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF in situ, is treated with α-picoline in THF under mild conditions to give α-picoline-borane in an excellent yield. This method can be a practical preparation for α-picoline-borane.

Full text of DOI:10.1021/op2003858

Article
pubs.acs.org/OPRD
A Safe and Scalable Procedure for Preparation of α-Picoline−Borane
from Sodium Mono-acyloxyborohydrides and α-Picoline
†
†
†
∥
‡
‡
Yasushi Kawase, Takehiro Yamagishi, Teruo Kutsuma, Huo Zhibao, Yoshinori Yamamoto,
§
§
,†
Tomohiro Kimura, Tadashi Nakata, Tadashi Kataoka, and Tsutomu Yokomatsu*
†
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Department of Chemistry, Graduate School of Chemistry, Tohoku University, Aramaki 6-3, Aoba-ku, Sendai, Miyagi 980-8578,
‡
Japan
§
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
∥Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
*
S Supporting Information
ABSTRACT: Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF
in situ, is treated with α-picoline in THF under mild conditions to give α-picoline−borane in an excellent yield. This method can
be a practical preparation for α-picoline−borane.
mine−boranes are widely used as reducing agents for
RESULTS AND DISCUSSION
There are three known types of reactions for the preparation of
■
A
electroless plating. In the area of organic synthesis, some
of them are effective reducing reagents for reductive amination
amine−boranes: (1) Reaction of amines with gaseous diborane
1
or borane−ligand complexes (BH −L), such as BH −THF and
as well. In particular, aromatic amine−boranes have some
3
3
1
1,12
BH −dimethylsulfide, prepared in situ.
(2) Reaction of
(3) Reaction of NaBH
4
15
advantages for this purpose because the reaction can be
achieved without preformation of imines and shows suitable
reducibility. Among aromatic amine−boranes, pyridine−borane
3
1
3,14
amine hydrochlorides and NaBH .
4
with amines in the presence of cation-exchange resins. Each
reaction described above, however, has some problems from an
industrial production viewpoint. (1) Hazardous diborane or
borane complexes should be handled at special facilities. (2)
Since both NaBH4 and amine hydrochlorides have less
solubility in general organic solvents, a large amount of
solvents is required. (3) Cation-exchange resins are expensive.
In general, nonhazardous processes achieved under mild
conditions using inexpensive raw materials are ideal for process
chemistry. Therefore, if α-Pic-BH3 can be prepared from
NaBH4 and α-picoline without using diborane or borane
complexes around room temperature in a limited amount of
organic solvent, it can be quite a promising process for this
reagent. In this paper, we report on a safe, inexpensive, and
mild procedure for the synthesis of α-Pic-BH3.
(
Pyr-BH ) is one of the most useful reagents for reductive
3
2
amination. The application of Pyr-BH3 to the process
chemistry, however, is limited due to its thermal instability
3
and explosive nature. As convenient alternatives, picoline−
4
5
boranes (Pic-BH3) and 5-ethyl-2-methylpyridine−borane
have been developed, and some reports on reductive amination
with these reagents were presented. For example, we have
recently reported on the one-pot synthesis of alkoxyamine
derivatives from carbonyl compounds via oxime ethers with α-
picoline−borane (α-Pic-BH ). We have also reported that N-
3
benzyl-protected amino acid derivatives were readily prepared
by α-Pic-BH -mediated reductive alkylation of α-amino acid
3
6
,7
esters. α-Pic-BH is regarded as a safer reducing regent than
Yamada et al. reported on the asymmetric reduction of cyclic
imines through imine−borane complexes with chiral sodium
3
Pyr-BH for the following reasons: (1) Differential scanning
3
16
calorimetric data reveals that α-Pic-BH has a higher onset
triacyloxyborohydrides. During their mechanistic study on the
asymmetric reduction, the authors found sodium mono-
3
8
temperature than Pyr-BH . (2) The flash point of α-Pic-BH is
3
3
(
trifluoroacetoxy)borohydride (NaBH (OCOCF )), prepared
3 3
known to be higher than that of Pyr-BH by closed-cup
3
9
in situ from NaBH and trifluoroacetic acid, reacted it with γ-
4
evaluation. (3) Furthermore, we confirmed that crystalline α-
picoline in THF to give γ-picoline−borane in moderate yield. It
is unlikely that this reaction is mediated via diborane since
sodium acyloxyborohydrides (NaBH (OCOR)) 2 have some-
Pic-BH could be recovered completely after heating to 140 °C
3
without hazardous degradation and was not decomposed under
ambient conditions for over 2 years, judging from the HPLC
3
17
what different reactivities from diborane. Although this
reaction suggests that NaBH (OCOCF ) may also be a useful
analysis. Thus, production processes using α-Pic-BH could be
3
3
3
thought to be quite promising; however, its aggressive
application to process chemistry has not been made. One of
the primary reasons must be that the reagent is expensive owing
reagent for the preparation of the target α-Pic-BH , the use of
3
Received: December 27, 2011
Published: February 21, 2012
10
to the lack of cost-effective preparations.
©
2012 American Chemical Society
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Organic Process Research & Development
Article
expensive trifluoroacetic acid as a reagent is unfavorable for the
practical procedure in process chemistry. Therefore, to avoid
the use of trifluoroacetic acid, several kinds of 2 were prepared
Pic-BH was difficult to be separated from the remaining α-
picoline by column chromatography.
3
Although we did not make the mechanistic study on these
reactions in detail, we believed on the basis of the previous
from inexpensive carboxylic acids 1 and NaBH , and treated
4
17c
with α-picoline in one-pot to give α-Pic-BH (Scheme 1).
study reported by Umino and co-workers that the reaction
pathway through free diborane can be eliminated from the
possible mechanism. The authors reported the reduction of
3
Scheme 1. Practical preparation of α-Pic-BH3
amides to amines with NaBH (OCOR) and proved the reactive
3
species in this reduction are not free diborane by some
investigations of externally generated gases from NaB-
H (OCOR) and the reducibility of this reaction system.
3
With the above results in mind, we next investigated in detail
the reaction of NaBH OBz with α-picoline. We focused on
3
surveying the proper reaction temperature and isolation
procedure that shows a high yield without recovering starting
materials. (Scheme 3). The results are summarized in Table 2.
First, we explored the appropriate carboxylic acid for the one-
pot synthesis of α-Pic-BH as illustrated in Scheme 2. In these
3
Scheme 2. One-pot synthesis of α-Pic-BH from carboxylic
acids
3
Scheme 3. One-pot synthesis of α-Pic-BH
from NaBH
OBz
3
3
experiments, NaBH was treated with 1 equiv of carboxylic
Table 2. Effects of temperature on the reaction of
a
4
NaBH OBz with α-picoline
acids in THF at 0 °C for 1 h, and the resulting NaBH (OCOR)
3
3
was reacted with α-picoline at room temperature for 24 h. The
results are summarized in Table 1.
b
run
T (°C)
time (h)
α-Pic-BH (%)
3
1
2
rt
40
40
24
12
5
68
81
93
Table 1. Reaction of sodium acyloxyborohydrides 2 with α-
c
3
a
picoline
a
All reactions were carried out in the presence of NaBH (10 mmol),
benzoic acid (10 mmol), and α-picoline (10 mmol) in THF (10 mL)
except run 3. Isolated yields. Carried out the reaction in the presence
of NaBH (10 mmol), benzoic acid (10 mmol), and α-picoline (10
4
b,c
run
acid
R
α-Pic-BH (%)
3
b c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
45
43
59
59
68
58
61
47
4
ClCH2
mmol) in THF (15 mL).
Cl CH
2
2
Cl C
3
In all runs, except run 3, NaBH OBz was prepared at 0 °C in
THF from NaBH and benzoic acid, and then reacted with α-
3
Ph
4
2-chlorophenyl
4-nitrophenyl
3-nitrophenyl
picoline at varying temperatures. To find mild conditions for
the completion of the reaction within 24 h, the reactions
around room temperature were examined. Although the
unreacted α-picoline was recovered from the reaction
conducted at room temperature (run 1), elevating the
1g
1h
a
All reactions were carried out in the presence of NaBH (10 mmol),
4
carboxylic acid (10 mmol), and α-picoline (10 mmol) in THF (10
b
c
mL). Isolated yields. Unreacted α-picoline was recovered.
temperature to 40 °C gave α-Pic-BH in 81% yield within 12
3
h accompanied by a trace amount of α-picoline (run 2). This
reaction was carried out heterogeneously due to the low
When sodium monoacetoxyborohydride (NaBH OAc),
3
derived from NaBH4 and acetic acid, one of the most
inexpensive carboxylic acids, was treated with α-picoline, the
desired α-Pic-BH3 was obtained in 49% yield along with
recovered α-picoline (run 1). In order to enhance the leaving
ability of the acyloxy groups from the boron atom, the reactions
of the sodium chloroacetoxyborohydrides derived from the
chloroacetic acids were examined. However, the expected
effects were hardly observed (run 2−4). On the other hand, we
solubility of NaBH OBz in THF. Therefore, we expected that
3
the reaction would be accelerated with the complete dissolution
of NaBH OBz during the reaction. When NaBH was reacted
3
4
with benzoic acid in THF at 40 °C under a slightly diluted
concentration, a clear solution of NaBH OBz in THF was
3
obtained. This reagent reacted with α-picoline rapidly and
completely within 5 h to give α-Pic-BH in an excellent yield
3
(
run 3).
found that sodium monobenzoxyborohydride (NaBH OBz),
3
The soundness of this process was demonstrated by its being
scalable in large quantities up to a 10 g synthesis of α-Pic-BH3
without purification by column chromatography as illustrated in
prepared from benzoic acid and NaBH in a similar manner,
4
reacted smoothly with α-picoline to give α-Pic-BH in 68%
3
yield (run 5). The utilization of sodium monoaryloxyborohy-
drides bearing electron-withdrawing substituents on the
aromatic rings, which are expected to enhance the leaving
ability of aryloxy groups, unfortunately lowered the yields (run
Scheme 4. The reaction of NaBH OBz, prepared from 3.8 g of
3
NaBH and 12.2 g of benzoic acid at 40 °C in situ, with 9.3 g of
4
α-picoline at 40 °C for 4.5 h, was followed by the removal of
the resulting sodium benzoate by washing with water to give
5
−8). In all runs, unreacted α-picoline remained. We found
crude α-Pic-BH . The crude product was recrystallized from
toluene-n-heptane (1:1) to give 9.5 g (89%) of α-Pic-BH3.
3
that some of α-Pic-BH was lost during the purification since α-
3
4
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Organic Process Research & Development
Article
Scheme 4. Ten-gram-scale synthesis of α-Pic-BH from
benzoic acid, α-picoline, and NaBH4
reaction mixture was stirred for 1 h at 0 °C and allowed to
warm to room temperature. α-Picoline (0.94 mL, 10 mmol)
was added to the mixture in one portion, and then the mixture
was heated to 40 °C and stirred for 12 h at 40 °C. After being
stirred at room temperature, the mixture was cooled to 0 °C
and treated with water for 10 min at 0 °C. The mixture was
extracted with AcOEt three times, the combined extract was
3
washed with 1 M HCl, sat. aq NaHCO and sat. aq NaCl and
3
During the reaction of NaBH OBz and α-picoline, the
thermal change of the reaction was hardly observed.
Furthermore, we measured differential scanning calorimetry
3
dried over Na SO . After removal of Na SO by filtration, the
2
4
2
4
filtrate was concentrated in vacuo. The residue was purified by
silica-gel column chromatography (n-hexane-AcOEt 10:1−2:1)
(
DSC) of resulting α-Pic-BH in order to evaluate the safety of
3
to give α-Pic-BH (820 mg) as colorless crystals in 81% yield.
3
this reaction around the reaction temperature (Figure 1). As
shown in Figure 1, the hazardous exothermal reaction is not
observed around 40 °C. Therefore, we believe that this
procedure is not only the safe process but also the scalable
process to α-Pic-BH3.
Optimized Procedure for Preparation of α-Pic-BH3
from NaBH , Benzoic Acid, and α-Picoline in a Small
4
Scale. A solution of benzoic acid (1.220 g, 10 mmol) in THF
(
7.5 mL) was added dropwise to a suspension of NaBH (380
4
mg, 10 mmol) in THF (7.5 mL) by syringe with stirring at 0 °C
under an Ar atmosphere. The reaction mixture was stirred for 1
h at 0 °C and allowed to warm to 40 °C. α-Picoline (930 mg,
10 mmol) was added to the mixture in one portion. After being
stirred for 5 h at 40 °C, the mixture was poured on cold water
CONCLUSION
■
In conclusion, we present the practical synthesis of α-Pic-BH3
from NaBH OBz, easily prepared from NaBH and benzoic
3
4
acid in situ, and α-picoline in THF under mild conditions.
Because of this safe and inexpensive process, we believe that
this study will contribute to the aggressive utilization of α-Pic-
(
5 mL). The volatile component (THF) of the mixture was
removed in vacuo, and the resulting mixture was extracted with
AcOEt (7.5 mL × 2); the combined extracts were washed with
0.5 M aqueous citric acid (2 mL × 2) and 10% aqueous NaCl
BH in process chemistry.
3
(
2 mL × 2), and dried over Na SO (1 g). After removal of
2 4
2 4
EXPERIMENTAL SECTION
Characterization of α-Pic-BH . All α-Pic-BH obtained in
■
Na SO by filtration, the filtrate was concentrated in vacuo to
3
3
give α-Pic-BH (1.000 g) as colorless needles in 94% yield.
3
1
this study was characterized by high-resolution H NMR (400
Further purification of the material was achieved by silica gel
1
3
or 300 MHz, CDCl ) and C NMR (100 or 75 MHz, CDCl ).
column chromatography (SiO : 30 g, AcOEt) to give α-Pic-
3
3
2
1
13
H and C NMR data are consistent with those of an authentic
specimen.
General Procedure for Reaction of Acyloxyborohy-
BH (997 mg) as colorless needles in 93% yield.
3
A 10-g-Scale Synthesis of α-pic-BH3 from NaBH4,
Benzoic Acid, and α-Picoline without Purification by
Column Chromatography. A solution of benzoic acid (12.20
g, 0.1 mol) in 75 mL of THF was added dropwise to a
drides with α-Picoline for Tables 1 and 2. A typical
procedure is described for preparation of α-Pic-BH3 via
NaBH OBz (run 2, Table 2). A solution of benzoic acid
suspension of NaBH (3.8 g, 0.1 mol) in 75 mL of THF with
3
4
(
1.220 g, 10 mmol) in THF (5 mL) was added dropwise to a
stirring at 0 °C under a N atomosphere. The reaction mixture
2
suspension of NaBH (380 mg, 10 mmol) in THF (5 mL) by
syringe with stirring at 0 °C under an Ar atmosphere. The
was stirred for 1 h at 0 °C, and the resulting NaBH OBz was
4
3
dissolved by warming the mixture to 40 °C. A solution of α-
Figure 1. DSC data for α-Pic-BH3.
4
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Organic Process Research & Development
Article
picoline (9.30 g, 0.1 mol) in THF (93 mL) was added to the
reaction mixture and stirred for 4.5 h at 40 °C. Water (50 mL)
was added to the reaction mixture, and the volatile component
(16) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin
Trans. I 1983, 265.
(17) (a) Iwakuma, T.; Umino, N.; Itoh, N. J. Synth. Org. Chem. Jpn.
1977, 35, 300. (b) Umino, N; Iwakuma, T.; Itoh, N. Tetrahedron Lett.
1976, 2875. (c) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett.
1976, 763.
(
THF) of the mixture was evaporated in vacuo. The residue
was extracted with AcOEt (75 mL × 3), and the combined
extract was washed with 0.5 M aqueous citric acid (15 mL × 2)
and 10% aq NaCl (15 mL × 2) and then dried over MgSO (10
4
g). After removal of MgSO by filtration, the solvent was
4
evaporated in vacuo. The residual solid was recrystallized from
toluene−n-heptane (5 mL/25 mL) to give α-Pic-BH (9.50 g)
3
as colorless needles in 89% yield.
ASSOCIATED CONTENT
■
*
S
Supporting Information
NMR charts for α-Pic-BH . This material is available free of
3
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
yokomatu@toyaku.ac.jp
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
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(
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(
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9) Both flash points are available from material safety data sheets
(
(
(
2
(
5
(
(
(
2
(
issued by Sigma-Aldrich Co.. See the web site as follows; http://www.
sigmaaldrich.com/.
(
10) α-Pic-BH is commercially available from Sigma-Aldrich Co.,
3
Junsei Chemical Co., Ltd., and so on.
11) Brown, H. C.; Schlesinger, H. I.; Cardon, S. Z. J. Am. Chem. Soc.
942, 64, 325.
12) α-Pic-BH is generally prepared by bubbling diborane through a
(
1
(
3
solution of α-picoline in n-heptane, see; Mooney, E. F.; Qaseem, M. A.
J. Inorg. Nucl. Chem 1968, 30, 1439.
(
7
(
13) Taylor, M. D.; Grant, L. R.; Sands, C. A. J. Am. Chem. Soc. 1955,
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addition of NaBH to the mixture of amines and strong acids in
4
aqueous organic solvents. This method afforded α-Pic-BH around
3
6
0% yield. See; Kikugawa, Y. Jpn. Kokai Tokkyo Koho. JP 200819231
A1 20080131, 2008.
15) Kikugawa, Y. Jpn. Kokai Tokkyo Koho. JP 200086594 A1
0000328, 2000..
(
2
4
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dx.doi.org/10.1021/op2003858 | Org. Process Res. Dev. 2012, 16, 495−498