N-methylpyrrolidine-zinc borohydride: As a new stable and efficient reducing agent in organic synthesis

Article abstract of DOI:10.1081/SCC-120015705

N-Methylpyrrolidine-zinc borohydride is readily prepared and used for reduction of a variety of organic compounds such as aldehydes, ketones, acid chlorides, and esters. Reactions are performed in THF at room temperature or under reflux condition and the yields are good to excellent. Complete regio-selectivity are observed in reduction of α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1081/SCC-120015705

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N -Methylpyrrolidine-zinc Borohydride: As a New Stable
and Efficient Reducing Agent in Organic Synthesis
M. Tajbakhsh a b , M. M. Lakouraj a b , F. Mohanazadeh a & A. Ahmadi-nejhad a
a Institute of Chemistry , Mazandran University , Babolsar, Iran
b Institute of Chemistry , Mazandran University , Babolsar 47415, Iran
Published online: 21 Aug 2006.
To cite this article: M. Tajbakhsh , M. M. Lakouraj , F. Mohanazadeh & A. Ahmadi-nejhad (2003) N -Methylpyrrolidine-zinc
Borohydride: As a New Stable and Efficient Reducing Agent in Organic Synthesis, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:2, 229-236, DOI: 10.1081/SCC-120015705
To link to this article: http://dx.doi.org/10.1081/SCC-120015705
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 2, pp. 229–236, 2003
N-Methylpyrrolidine-zinc Borohydride:
As a New Stable and Efficient Reducing Agent
in Organic Synthesis
*
*
M. Tajbakhsh, M. M. Lakouraj, F. Mohanazadeh,
and A. Ahmadi-nejhad
Institute ofChemistry, Mazandran University, Babolsar, Iran
ABSTRACT
N-Methylpyrrolidine-zinc borohydride is readily prepared and used
for reduction of a variety of organic compounds such as aldehydes,
ketones, acid chlorides, and esters. Reactions are performed in THF
at room temperature or under reflux condition and the yields are
good to excellent. Complete regio-selectivity are observed in reduc-
tion of a,b-unsaturated carbonyl compounds.
Key Words: N-Methylpyrrolidine; Zinc borohydride; Selective
reduction; a,b-unsaturated carbonyls.
*Correspondence: M. Tajbakhsh and M. M. Lakouraj, Institute ofChemistry,
Mazandran University, Babolsar 47415, Iran. E-mail: tajbaksh@umz.ac.ir and
mlakaraj@yahoo.com.
229
DOI: 10.1081/SCC-120015705
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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230
Tajbakhsh et al.
Although a large number oftransition metal borohydrides are
known,[1] there are few reports on the use of these reducing agents.
This is primarily because almost all ofthem are volatile unstable material
and unless modified cannot be used in organic synthesis. Among them,
zinc borohydride has been used frequently in a variety of reductive trans-
formation.[2] However, due to its instability it should be used as a fresh
ethereal solution, even when it is supported on silica gel it should be use
[3]
on the same day ofits preparation.
Stabilization ofthis worthy redu-
cing agent has also achieved by complexation with polymeric ligands.[4]
Recently, coordination polymer ofZn(BH 4)2 with bidentate ligands have
been reported.[5] But, the reducing ability ofthe reagent diminished
severely. Herein, we introduce N-methylpyrrolidine-zinc borohydride
[NMP-Zn(BH4)2], as a new stable reducing agent for efficient and selec-
tive reduction ofaldehydes, ketones, acid chlorides, and esters. NMP-
Zn(BH4)2 is a white powder which can be stored at room temperature. It
decompose at 250ꢀC and is completely insoluble in aprotic solvents.
Based on the data obtained by atomic absorption and borohydride
content in iodometric titration, together with elemental analysis showed
within experimental error that the reagent is in form of (I):
As shown in Table 1, a number ofaldehydes are easily reduced to the
corresponding alcohols with high yields in tetrahydrofurane at room
temperature (Sch. 1).
Aliphatic ketones underwent complete reduction, whereas the arom-
atic ketones remained intact under identical condition. Reduction of
aromatic ketones proceeds at longer periods in reflux condition (Table 2).
Therefore, chemoselective reduction of aldehydes vs. ketones are
achieved at room temperature, and the unreacted ketone is recovered
in each case (Sch. 2).
Regioselective reduction ofaldehydes and ketones is a clean reaction
for preparation of allylic alcohols.[6] In order to show the regioselectivity
ofthe reagent, reduction of a,b-unsaturated aldehydes or ketones are
studied. The results are summarized in Table 3. As seen, selective
1,2-reduction afforded the corresponding allylic alcohols in high yields.

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N-Methylpyrrolidine-zinc Borohydride
231
Table 1. Reduction ofaldehydes with NMP-Zn(BH ) in THF.a
4 2
Entry No.
R
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
15
10
15
10
10
15
240
15
10
10
30
3
92
98
97
100c
100c
100c
100c
89
92
90
98
96
2-NO2C6H4
4-ClC6H4
2-ClC6H4
2-HOC6H4
3-HOC6H4
4-HOC6H4
4-BrC6H4
4-MeC6H4
MeCH¼CH
PhCH¼CH
n-C3H7
n-C5H11
6
93
aReactions are performed at room temperature using 3:1 molar ratio
ofsubstrate to reducing agent.
bYields refer to isolated products.
cGC yields.
Scheme 1.
Direct conversion ofacid chlorides into the corresponding alcohols
is a useful reaction and some hydride reagents have been introduced for
this purpose.[7] As mentioned in Table 4, a series ofacid chlorides are
efficiently converted to their corresponding alcohols in good to excellent
yields.
Finally, a variety ofcarboxylic acid esters are reduced to correspond-
ing alcohols in moderate to good yields (Table 5). Selective reduction of
aliphatic esters vs. aromatic esters has an interest in organic synthesis,[2,8]
we have found that this reagent readily induces an excellent chemo-
selectivity in reduction ofaliphatic esters over aromatic one as well as
zinc borohydride, without any assist ofsonication (Sch. 3).
It is surprising to note that almost all ofthe modified zinc boro-
hydrides reagents are failed to do this transformation.

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232
Tajbakhsh et al.
Table 2. Reduction ofketones (RCOR) with NMD-Zn(BH ) .a
4 2
Entry
No.
Time
(min)
Yieldb
(%)
R
R
Condition
1
2
3
4
5
6
7
8
9
C6H5
5-MeOC6H4
C6H5
4-ClC6H4
Ph
2-ClC6H4
n-C4H9
CH3
CH3
CH3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t
r.t
r.t
r.t
r.t
90
120
60
40
40
30
15
5
100
100
95
100
93c
100
95
90
96
95
C6H5
C6H5
PhCO
C6H5
CH3
CH3
a-Ionone
4-Phenylcyclohexanone
90
60
5
10
11
12
Cyclohexanoned
100
100
Cyclopentanoned
r.t
25
aReactions were performed in THF using an equimolar ratio of reactants.
bYields refer to isolated products.
c1,2-Diphenyl ethylene glycol is obtained as sole product.
dGC yields.
Scheme 2.
EXPERIMENTAL
Chemicals were either prepared in our laboratory or were purchased
from Fluka, Merck, or BDH companies. All reaction products are known
compounds and were identified by comparison oftheir spectra and
physical data with those ofthe authentic samples. Reaction monitoring

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N-Methylpyrrolidine-zinc Borohydride
233
Table 3. Regioselective reduction of a,b-unsaturated aldehydes, ketones, and
esters with NMD-Zn(BH4)2 in THF.
Time
(min)
Yield
(%)a
Entry No.
Substrate
Product
1
2
3
4
MeCH¼CHCHO
PhCH¼CHCHO
PhCH¼CHCOMe
PhCH¼CHCOPh
MeCH¼CHCH2OH
PhCH¼CHCH2OH
10
30
55
70
90
98
98
97
PhCH¼CHCH(OH)Me
PhCH¼CHCH(OH)Ph
3
4
60
90
95b
96b
5
6
MeCH¼CHCO2Me
PhCH¼CHCO2Me
MeCH¼CHCH2OH
PhCH¼CHCH2OH
45
65
90
94
aYields refer to isolated.
bGC yields.
Table 4. Reduction ofacid chlorides (R-COCl) with NMP-Zn(BH ) .a
4 2
Entry No.
R
Time (min)
Yield (%)
1
2
3
4
5
6
7
C6H5
2-ClC6H4
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
120
70
40
35
70
60
70
100
82
98
100
100
85
CH3(CH2)3CH2
CH3(CH2)5CH2
89
aReactions are conducted in THF at room temperature using 1:1 ratio of
reducing agent to ester.
and purity determination ofthe products were accomplished by TLC.
The IR and NMR spectra were recorded on Pye-unicam SP 1100 spectro-
photometer and JEOL 60 MHz spectrometer, respectively. Elemental
analysis were performed on a LECO 250 instrument.

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234
Tajbakhsh et al.
Table 5. Chemoselective reduction ofesters with NMP-Zn(BH ) .a
4 2
Entry No.
Esters
PhCO2Me
PhCO2Me
PhCO2CH2Ph
PhCO2CH2Ph
n-C8H17CO2Et
CH3CO2Et
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
36
0.1
36
0.1
0.1
0.1
0.75
0.1
52
0
60
0
90
85c
92
88c
CH3CH¼CHCO2Et
CH3CH2CO2Me
aReactions are conducted in THF at room temperature using 1:1
ratio ofreducing agent to ester.
bYields refer to isolated.
cGC yields.
Scheme 3.
Preparation of N-Methylpyrrolidine Zinc Borohydride
[NMP-Zn(BH4)2]
To a freshly prepared ethereal solution of zinc borohydride
(0.03 mol, 200 mL), N-methylpyrrolidine (2.56 g, 0.03 mol) was added
in drop wise. Then, the mixture stirred at room temperature for 1.0 h
under nitrogen atmosphere. The precipitate filtered off and washed with
diethyl ether (10 mL). The white powder dried in vaccum desicator to
produce (4.3 g, 80% yield). Elemental analysis; found: C, 33.28; H,
19.06; N, 7.78; Zn, 36.42. Calculated: C, 33.35; H, 19.00; N, 7.76;
Zn, 36.32.

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N-Methylpyrrolidine-zinc Borohydride
235
General Procedure for Reduction of Aldehydes, Ketones, and
Esters with [NMP-Zn(BH4)2]
To a solution ofsubstrate (1.0 mmol) in tetrahydrofuran (10 mL), the
reagent (0.06 g, 0.33 mmol) was added. The reaction mixture stirred at
room temperature for specified time (Tables 1–5). Progress of the reac-
tion is monitored by TLC. After completion of the reaction, 5% HCl
(15 mL) was added and stirred for 10 min. On extraction with ether
(20 mL), the organic layer was dried over Mg(SO4)2. Evaporation of
the solvent under reduced pressure gave the desirable product.
General Procedure for the Reduction of Acylchlorides
with NMP-Zn(BH4)2
To a tetrahydrofuran solution (10 mL) of acyl chloride (1.0 mmol)
was added NMP-Zn(BH4)2 (0.18 g, 1.0 mmol). The mixture was then
stirred at room temperature until completion ofthe reaction; as moni-
tored by TLC. After addition of 5% HCL (10 mL), the mixture extracted
with diethyl ether (2 Â 20 mL). The combined organic layers were dried
on Mg(SO4) and evaporated to give the corresponding alcohol.
ACKNOWLEDGMENT
We are grateful to Mazandran University for financial support in
this work.
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Received in the Netherlands December 10, 2001