NaBH4 in N-methylpyrrolidone: a safe alternative for hydride displacement reaction.

Article abstract of DOI:10.1016/S0960-894X(01)00565-0

Enhanced reactivity of NaBH4 was observed as a solution in N-methylpyrrolidone (NMP). Thus, a simple protocol for debromination of alkyl bromide and sulfonate is devised with NMP as a key solvent. Also described is a new mixed borohydride system, NaBH4-LiOTf-NMP, which works as an alternative to NaBH3CN for the SN2 type displacement. No reports have ever revealed usefulness of NMP in borohydride reduction.

Full text of DOI:10.1016/S0960-894X(01)00565-0

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2787–2789
NaBH4 in N-Methylpyrrolidone: A Safe Alternative for Hydride
Displacement Reaction
Yasuhiro Torisawa,* Takao Nishi and Jun-ichi Minamikawa
Process Research Laboratory, Second Tokushima Factory, Otsuka Pharmaceutical Co. Ltd., Kawauchi-cho,
Tokushima 771-0182, Japan
Received 2 July 2001; accepted 11 August 2001
Abstract—Enhanced reactivity of NaBH4 was observed as a solution in N-methylpyrrolidone (NMP). Thus, a simple protocol for
debromination of alkyl bromide and sulfonate is devised with NMP as a key solvent. Also described is a new mixed borohydride
system, NaBH4–LiOTf–NMP, which works as an alternative to NaBH3CN for the SN2 type displacement. No reports have ever
revealed usefulness of NMP in borohydride reduction. # 2001 Elsevier Science Ltd. All rights reserved.
Current trends in synthesis have focused on the effi-
ciency and safety in the operational as well as ecological
sense for every conventional synthetic process. Particu-
larly a user-friendly system should be devised for such
basic organic transformations as classical aromatic sub-
stitution as well as functional group interconversions
including oxidation and reduction.1 We feltht atselec-
tive reduction by NaBH4 was the case to be re-investi-
gated, because of its low cost and moderate
chemoselectivity.2,3 Among the transformations by
NaBH4, we focused on the debromination of alkyl bro-
mides to alkanes, because a few useful methods are
available by the use of NaBH4, and actually an
improved method was required in our research for the
conversion of the bromide (1) into the alkane (2).4
such as DMSO, DMF, sulfolane and HMPA as sum-
marized in Scheme 1.3 Reaction in diglyme at high
temperature is also reported for the reduction of a vari-
ety of functional groups in the presence of inorganic
salts.2f The major problems with DMSO and DMF are
that NaBH4 can form BH3 in these solvents and have
explosive reaction with solvents. The unpleasant smell
associated with DMSO is due to the reduction of
DMSO to Me2S by BH3. We were thus drawn to the
possibility that the more stable solvent N-methylpyrro-
lidone (NMP, shown below) mightwork as an aletr-
native solvent for NaBH4. An explosive runaway
reaction of NaBH4 in DMF solution is noted in the
textbook,3a while no reports have revealed the utility of
its cyclic congener NMP in NaBH4 reduction.
To our gratitude, NaBH4 showed comparable or greater
solubility in NMP than in DMSO at room temperature.
A room temperature debromination of the model bro-
mide (3) or mesylate (4) did proceed in NMP in a
slightly exothermic way (75–80% isolated yields with a
trace amount of side products) within 3 h. Reaction
with the mesylate (4) was somewhatslower and small
amounts of the starting material (4) were recovered after
3 h, while reaction of the corresponding chloride was
Reduction of alkyl halides and sulfonates by NaBH4 or
NaBH3CN is best carried out in polar aprotic solvents
*Corresponding author. Tel.: +81-88-655-2126; fax: +81-88-637-
1144; e-mail: torisawa@fact.otsuka.co.jp
Scheme 1. Initial survey for debromination.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00565-0

2788
Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2787–2789
Table 1. Model study in NMP
is summarized in Scheme 2. In the radical reaction of 1
with two equivalents of Bu3SnH, the product (2) was
obtained in 45% yield along with recovered bromide
(1). Use of large excess of tin reagent was successful but
inconvenient on a large scale. Another protocol using
excess NaBH4 in DMSO was satisfactory to give 2 in
60% yield after chromatographic separation from the
polar by-products. Furthermore, unpleasant smell dur-
ing work up was an obvious nuisance. Another reliable
reaction was also attained by the use of excess
NaBH3CN in HMPA affording 2 in 70–80% yield after
chromatographic separation. We then substituted
HMPA with NMP. To our gratitude, the reaction of 1
with NaCNBH4 in NMP gave 2 in high yield after
heating at 120 ꢀC for 1 h (Scheme 2). This reaction
could be performed up to 60 g scales without difficulty
in the work up stage and no violent reaction was
observed.
Substrate
Reagentsa
Conditions 5 (yields)b (%)
1. 3 (1.0 g)
2. 3 (3.0 g)
3. 3 (3.0 g)c
4. 4 (3.0 g)
5. 3 (1.0 g)d
NaBH4/DMSO
NaBH4/NMP
NaBH4/NMP
rt, 1 h
rt, 3 h
rt, 3 h
70
78
75
70
80
NaBH4/NMP (4 equiv)
NaBH3CN/NMP
rt, 3 h
ꢁ80 ꢀC, 1 h
aReagent (2 equiv) was added portionwise to a solution of 3 or 4.
bIsolated yields after silica gel short path are shown.
c3 was added to a solution of NaBH4 in NMP.
Although numerous examples are known for the reac-
tion of NaBH4 and NaBH3CN in polar solvents such as
DMSO, diglyme and HMPA,2 no reports have revealed
the usefulness of NMP in debromination reactions.
d3 was added to a solution of NaBH3CN in NMP.
very slow at ambient temperature. Nearly the same
result was obtained with DMSO as a solvent, but we
observed side reaction with solvent DMSO, which
caused a foamy mixture with an unpleasant smell as
mentioned. As shown in the last example of Table 1, we
also found that NMP could supplant hazardous HMPA
in the reaction with NaBH3CN under heating. The
combination of NaBH3CN and NMP gave us the best
resultduring our search for debromination.
Optimized protocol in NMP
Encouraged by the initial finding, we further searched
for a reagent system that is equivalent (or supplant) to
NaBH3CN in NMP for the conversion of 1 to 2. Reac-
tion of 1 with NaBH4 in NMP at room temperature was
not satisfactory, affording 2 in less than 30% yield after
3 h stirring. Addition of excess LiCl was found to be
beneficial as mentioned in other reductions.3 Thus, the
reduction of 1 with NaBH4 in NMP in the presence of
LiCl was carried outot afford 2 nearly the same as the
case of NaBH3CN (run 5) after 10–30 h stirring at room
temperature. In a large-scale reaction with LiCl, how-
ever, itwas found ht atinsoluble saltformed a suspen-
sion and reaction needed heating at 60 ꢀC for 1 h. We
Debromination of 1
Next investigation moved to the debromination of 14
with the above-mentioned conditions as well as con-
ventional conditions. Survey by the reported protocols
Scheme 2. Debromination of 1.

Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2787–2789
2789
found that LiOTf was a convenient alternative choice.
Addition of LiOTf resulted in a more homogeneous
solution than LiCl and reaction was almost complete at
room temperature. In the reactions with 10–20 g of
bromide, it was convenient to warm the mixture (rt to
60 ꢀC) to complete within 1 h. We also observed that
further heating after the consumption of 1 slowly caused
a conversion of the initial product (2) into the polar
product, in which further demethylation of one meth-
oxy group took place. Further study is necessary to
clarify the role of LiOTf or other related salts in the
reduction in NMP.
100–125 ꢀC for 1 h. The mixture was cooled in ice bath
and worked up as above. Repeated extraction gave a
nearly pure solid product(ca. 23 g) after evaporation of
the dried extracts. By a simple crystallization, a nearly
pure material was obtained as a white solid (2, 89%).
Reduction by NaBH4–LiOTf in NMP
To a stirred solution of NaBH4 (3.0 g) and LiOTf (3.0 g)
in NMP (50 mL) was added at room temperature the
crystalline bromide (1, 10.0 g) and resulting mixture was
stirred at room temperature (exothermic reaction) and
further at 60 ꢀC for 1 h. The mixture was carefully
worked up as above. A solid product(ca.12 g) was
obtained after evaporation of the dried solvents, which
was further purified by column chromatography to give
nearly pure material as a white solid (2, 88%).
In summary, we have shown that the reaction of boro-
hydrides in NMP is a convenient alternative for debro-
mination. Increased solubility and reactivity of NaBH4
was attained in NMP as compared to DMSO. Although
some explosive reaction of NaBH4 in DMF was repor-
ted, we observed no such undesirable reaction in NMP,
which is also less harmful than DMF. In most cases,
reaction mixture formed a homogeneous solution, in
which NaBH4 was stable to effect the debromination at
room temperature without any runaway reaction. Sim-
ple work up gave nearly pure product as indicated in the
experimental procedures shown below. By a fine-tuning
with additional Li-salt, a chemoselective debromination
of some labile bromides can be attained. The mixed
Acknowledgements
We are grateful to both Professors Bakthan Singaram
(UCSC) and Kozo Shishido (University of Tokushima)
for their informative commentary on the NaBH4
reduction and encouragement.
agent(NaBH –LiOTf–NMP) worked as an alternative
4
to LiBH4 and NaCNBH3, both of which are obviously
hazardous in large-scale operations. Very little is known
about the behavior of NMP under reduction conditions.
We are now investigating the fate of NMP under forced
reduction conditions. Further application to other
functional groups such as carbonyl and nitro groups is
also in progress in this laboratory.5
References and Notes
1. For example, see: Bolm, C.; Beckmannn, O.; Dabard, A. G.
Angew. Chem., Int. Ed. Engl. 1999, 907.
2. (a) As recent efforts for various reduction, see: Gevorgyan,
V.; Rubin, M.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2001,
66, 1672 and references therein. (b) Narasimhan, S.; Balaku-
mar, R. Synth. Commun. 2000, 30, 4387 and references therein.
(c) Crich, D.; Neelamkavil, S.; Sartillo-Piscil, F. Org. Lett.
2000, 2, 4029. (d) Chary, K. P.; Ram, S. R.; Salahuddin, S.;
Iyengar, D. S. Synth. Commun. 2000, 30, 3559. (e) Desai,
D. G.; Swami, S.; Hapase, S. B. Synth. Commun. 1999, 29,
1033. (f) Yang, C.; Pittman, C. U., Jr. Synth. Commun. 1998,
28, 2027.
3. (a) For an overview, see: Banfi, L.; Narisano, E.; Riva, R.
In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley & Sons: New York, 1995; Vol. 7, p
4522. (b) Hutchins, R. O.; Hutchins, M. K. ibid, p 4539.
4. Torisawa, Y.; Nishi, T.; Minamikawa, J. Org. Proc. Res.
Dev. 2001, 84 and references cited therein.
5. In our preliminary survey, simple azides and aromatic nitro
group were able to reduce to amine derivative in moderate
yields on heating with NaBH4–NMP system. Both aldehydes
and esters were easily reduced to the corresponding alcohols,
while some N-aryl lactams were reduced into amines after long
time heating in the NaBH4–LiOTf–NMP system. From these
initial surveys we speculated that reaction with NaBH4–
LiOTf–NMP was almost equally as effective as the NaBH4–
ZrCl4 system. A comparative study for NaBH4 reduction in
NMP with some additives will be reported in due course.
6. The requisite bromide 3 was prepared from commercially
available 5-phenyl-1-pentanol (Aldrich) by the treatment of
CBr4 and PPh3 in CH2Cl2 under cooling.
Experimental Details for the Reduction in NMP
General procedure (Table 1, entry 3)
To a stirred solution of NaBH4 (1.0 g, 2 equiv) in NMP
(30 mL) was slowly added a solution of bromide (3,
3.0 g)6 in NMP (2 mL). Instantaneous reaction was
observed and the resulting mixture was stirred at room
temperature for 3 h. The mixture was first diluted with
solventand quenched carefully wiht H 2O in the cold.
After gas evolution subsided, the mixture was diluted
with aqueous solvent. Repeated extraction gave pro-
ducts after evaporation of the dried extracts (a trace of
products was present in aqueous layer). Through an
SiO2 short column, a nearly pure material was obtained
as colorless oil (5, 75%).
NaBH3CN reduction in NMP
To a stirred solution of NaBH3CN (10.0 g) in NMP
ꢀ
(100 mL) was added carefully at60 C the solid bromide
powder (1, 21.0 g)4 and resulting mixture was stirred at