Reductions of carboxylic acids and esters with NaBH4 in diglyme at 162°C

Article abstract of DOI:10.1081/SCC-120018935

Aromatic esters, including the extremely sterically hindered ester: tamyl 2-chlorobenzoate, are readily reduced to the corresponding benzyl alcohols in high yield with NaBH₄ in refluxing diglyme (162°C). In sharp contrast, aliphatic esters usually gave only low yields of alcohols. Instead, diglyme fragmentation products are formed which undergo transesterification reactions, producing complex product mixtures including products such as RCOOCH₂CH₂OCH₃. The mechanism of this process involves sodium borohydride-induced S_N2 cleavage of diglyme (hydride attack) at high temperatures. However, when the extremely electron rich, 3,4,5-trimethoxybenzoic acid is treated with NaBH₄/diglyme at 162°C (with or without an equivalent of LiCl), no 3,4,5-trimethyoxybenzyl alcohol is formed. The electron rich and hindered ester, t-amyl-3,4,5-trimethoxybenzoate, also does not reduce under these conditions (with or without LiCl). However, both methyl and isopropyl 3,4,5-trimethoxybenzoate esters were converted into 3,4,5-trimethyoxybenzyl alcohol in good yields in NaBH₄/diglyme/LiCl at 162°C. These reductions did not occur unless LiCl was present, illustrating the electron releasing effect of the three methoxy functions which reduce the carbonyl group's reactivity.

Full text of DOI:10.1081/SCC-120018935

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Reductions of Carboxylic Acids and Esters with NaBH4
in Diglyme at 162°C
a
a
Hua-Jie Zhu & Charles U. Pittman Jr.
a
University/Industry Chemical Research Center, Department of Chemistry, Mississippi State
University, Mississippi State, Mississippi, USA
Version of record first published: 17 Aug 2006
To cite this article: Hua-Jie Zhu & Charles U. Pittman Jr. (2003): Reductions of Carboxylic Acids and Esters with NaBH4
in Diglyme at 162°C, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:10, 1733-1750
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 10, pp. 1733–1750, 2003
Reductions of Carboxylic Acids and Esters
with NaBH in Diglyme at 1628C
4
Hua-Jie Zhu and Charles U. Pittman Jr.*
University/Industry Chemical Research Center,
Department of Chemistry, Mississippi State University,
Mississippi State, Mississippi, USA
ABSTRACT
Aromatic esters, including the extremely sterically hindered ester: t-
amyl 2-chlorobenzoate, are readily reduced to the corresponding
benzyl alcoholsin high yield with NaBH
ꢀ
4
in refluxing diglyme
(
162 C). In sharp contrast, aliphatic esters usually gave only low yields
of alcohols. Instead, diglyme fragmentation products are formed
which undergo transesterification reactions, producing complex pro-
duct mixturesincluding products su ch asRCOOCH
2 2 3
CH OCH . The
mechanism of this process involves sodium borohydride-induced SN2
cleavage of diglyme (hydride attack) at high temperatures. However,
when the extremely electron rich, 3,4,5-trimethoxybenzoic acid is
*
Correspondence: Charles U. Pittman Jr., University/Industry Chemical
Research Center, Department of Chemistry, Box 9573 Mississippi State
University, Mississippi State, MS 39762, USA; Fax: (662) 328-7611; E-mail:
cpittman@ra.msstate.edu.
1
733
DOI: 10.1081/SCC-120018935
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1
734
Zhu and Pittman
ꢀ
treated with NaBH /diglyme at 162 C (with or without an equivalent
4
of LiCl), no 3,4,5-trimethyoxybenzyl alcohol isformed. The electron
rich and hindered ester, t-amyl-3,4,5-trimethoxybenzoate, also does
not reduce under these conditions (with or without LiCl). However,
both methyl and isopropyl 3,4,5-trimethoxybenzoate esters were con-
verted into 3,4,5-trimethyoxybenzyl alcohol in good yieldsin
ꢀ
NaBH /diglyme/LiCl at 162 C. These reductions did not occur
4
unless LiCl was present, illustrating the electron releasing effect of
the three methoxy functionswhich reduce the carbonyl group’s
reactivity.
Key Words: Sodium
borohydride;
Transesterification; Carboxylic acids; Esters.
Reductions;
Diglyme;
INTRODUCTION
The reduction of aliphatic esters with sodium borohydride in protic
solvents is extremely slow and therefore not practiced for industrial
processes. In aprotic solvents, such as dichloromethane, the reduction
of ethyl laurate with tetrabutylammonium borohydride isonly 25% com-
ꢀ
[1]
plete after four daysat 25 C. However, if an electron withdrawing atom
or functional group isadjacent to the carbonyl group, the reduction can
be carried out. Thishasbeen demon st rated when the electron withdraw-
[
2]
[3,4]
[5]
ing group isan epoxy, chloro,
acidsand e ts erscan be reduced to alcoholsby combining NaBH
or cyano function. Some saturated
and
Unsaturated acids or esters formed com-
4
[
6,7]
AlCl at room temperature.
3
[
6,7]
plex compounds under these conditions.
NaBH when catalyzed by LiCl (or LiI) in THF.
Esters have been reduced by
[
8–10]
Other metallic ions,
were used to enhance the reduction
efficiency of NaBH in variousreduction s. Reductionsof aromatic car-
4
[11]
[12–14]
such as TiCl4
and CaCl2
4
ꢀ
boxylic acidsand aromatic e st erswith NaBH
been actively investigated in our laboratory under a variety of conditions,
both with and without LiCl present.
reduced to benzyl alcohol at high temperature in diglyme. Aromatic
amides and nitriles were also reduced under these conditions.
temperature borohydride reductionsa ol s can dechlorinate aromatic
chloro compounds us ch as4-chlorobiphenol and PCB.s
in diglyme at 162 C have
4
[
15]
Ethyl benzoate wasreadily
[
15,16]
High
[
17]
Aliphatic
esters and carboxylic acids have not been studied under comparable
conditions.

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Reductions of Carboxylic Acids and Esters
1735
Aspart of a general effort to extend the utility of NaBH , we have
4
examined itsu se at high temperature in order to determine if NaBH 4 will
be able to effect reductionswhich currently require LiAlH , LiEt BH,
and other more expensive and more difficult to handle hydride reducing
4
3
reagents. NaBH is thermally stable. Nevertheless, very few studies of its
4
reductions at high temperature have appeared. It has usually been used in
ꢁ
hydroxylic solvents. When heated in water or alcohols, BH4 reactsto
produce hydrogen, limiting itsapplication temperature. NaBH 4 haslow
solubility in most solvents which has limited its application.
Herein, we report the NaBH4 reductionsof both aromatic and
ꢀ
aliphatic carboxylic acidsin diglyme at 162 C. Furthermore, representa-
tive alkyl esters of both aromatic and aliphatic carboxylic acids were
ꢀ
treated with NaBH at 162 C. Cinnamic acidsand aliphatic e ts ersof
4
cinnamic acids also reacted under these conditions but gave poor yields
of cinnamyl alcohol.
EXPERIMENTAL
General
All chemicalswere purcha es d from Aldrich Company except for
1
diglyme which wasa gift from Ferro Corporation. H NMR spectra
were obtained on a General Electric QE-300 instrument. A Varian
3300 GC wasu es d (DB-5, 30 m). GC/MS were obtained on a Varian
Saturn 2000 instrument. Melting points were uncorrected. Many of the
1
esters were synthesized. H NMR spectra and/or mass spectrometry data
are summarized together after the example syntheses.
Typical Procedure for the Syntheses of Esters
Methyl 2-chlorobenzoate (3): NEt (450 mL, 3.2 mmol) wasadded to a
3
methanol solution of 2-chlorobenzoyl chloride (525 mg, 3.0 mmol) at room
temperature. After 10 h most of the methanol was evaporated under
reduced pressure (30–40 mmHg). The residue was washed with water
and then extracted with ethyl acetate. The ethyl acetate extract was
dried over sodium sulfate, filtered, and ethyl acetate was removed
(
30–40 mmHg). The crude ester was purified by chromatography over
silica gel using mixture of hexane and ethyl acetate as the eluent. Methyl
-chlorobenzoate, 3 (483 mg, 95% yield), wasobtained asa colorle ss oil by
2

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736
Zhu and Pittman
removing the solvents in vacuo. Only one peak was found in the GC,
1
confirming itspurity was>98%. H NMR confirmed the structure.
Isopropyl 2-chlorobenzoate (4): NEt (450 mL, 3.2 mmol) wasadded to
3
a CH Cl solution of 2-chlorobenzoyl chloride (525 mg, 3.0 mmol) and
2
2
iso-propanol (250 mL, 198 mg, 3.3 mmol) at room temperature and kept
overnight. The reaction solution was washed with water three times and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure (30–40 mmHg). The residue was purified by chromatography
over silica gel using a mixture of hexane and ethyl acetate as the
eluent. A colorless oil, isopropyl 2-chlorobenzoate, 4, (543 mg, 91%
yield), was obtained by removing the solvents in vacuo. GC anaysis
1
gave only a single peak confirming the purity of 4 was97%. H NMR
confirmed the structure.
t-Amyl 2-chlorobenzoate (5): n-BuLi (2.7 M, 1.1 mL, 3.0 mmol) was
added to the THF solution of t-amyl alcohol (440 mL, 352 mg,
ꢀ
ꢀ
4
.0 mmol) at ꢁ20 C. Then 2-chlorobenzoyl chloride (525 mg, 3.0 mmol)
wasadded at ꢁ20 C. The following day the solvent was removed to give a
solid that was dispersed into 3.0 mL water followed by extraction with
ethyl acetate. After drying over sodium sulfate, the solvent was removed at
3
0–40 mmHg. The residue was chromatographed over silica gel using
hexane/ethyl acetate mixturesasthe eluent. A colorlesliquid, t-amyl
-chlorobenzoate, 5 (608 mg, 90% yield), wasobtained by removing the
2
1
solvents. The GC purity was >97%. H NMR confirmed the structure.
The other esters (methyl octanoate, 9, isopropyl octanoate, 10, t-amyl
octanoate, 11, methyl cinnamate, 16, isopropyl cinnamate, 17, t-amyl
cinnamate, 18, methyl 3,4,5-trimethoxybenzoate, 21, isopropyl 3,4,5-
trimethoxybenzoate, 22, t-amyl 3,4,5-trimethoxybenzoate, 23) were
synthesized using similar procedures. In every case their GC-determined
1
puritiesexceeded 96–97%. H NMR confirmed their structures.
Typical Procedure for the Reduction of Carboxylic Acids and
Carboxylic Esters in NaBH /Diglyme at 1628C
4
Reduction of benzoic acid in NaBH /diglyme at 1628C: Sodium
4
borohydride (75 mg, 2.0 mmol) wasadded to a refluxing diglyme (10 mL)
ꢀ
solution of benzoic acid, 1, (244 mg, 2.0 mmol) at 162 C. After 1 h, an
aliquot waswithdrawn, quenched with 15% (w/w) H SO and analyzed
2
4
by GC. The starting material was consumed completely. Quenching the
reaction mixture with 15% H SO gave a very low total isolated yield,
because the diglyme can dissolve in water, making workup very difficult.
2
4

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Reductions of Carboxylic Acids and Esters
1737
After several attempts, an effective method was found for product
isolation.
After the reaction was finished, most of the diglyme was evaporated
under reduced pressure (10–15 mmHg) and collected for recycle
(
The residue was dissolved in a little water and 15% H SO wasu se d to
to evaluate the feasiblity of reusing diglyme in large scale reactions).
2
4
bring the pH value to about 7. This os lution wasextracted with ethyl
acetate. The ethyl acetate solution was dried over sodium sulfate and the
ethyl acetate wasremoved at 30–40 mmHg. The re si due waschromatog-
raphed column over silica gel (to remove any impurities) using hexane/
ethyl acetate asthe elutant. Benzyl alcohol, 6 (178 mg, 82% yield) was
obtained as a colorless liquid (single GC peak) by removing the solvents
1
in vacuo. H NMR confirmed its st ructure.
Reductions of 3,4,5-trimethoxybenzoic acid (20) and t-amyl 3,4,5-tri-
methyoxybenzoates (23): A diglyme (5.0 mL) solution of 3,4,5-trimethoxy-
ꢀ
benzoic acid (424 mg, 2.0 mmol) washeated to 162 C, and then sodium
borohydride (74 mg, 1.0 mmol) wasadded after the temperature reached
ꢀ
to 162 C. After one hour, an aliquot waswithdrawn and quenched with
15% (w/w) H SO , and the solution was analyzed with GC. Only the
starting acid was found. No 3,4,5-trimethyoxybenzyl alcohol, 24, had
2 4
formed. After 8 h, no alcohol wasgenerated.
3,4,5-Trimethyoxybenzyl alcohol wasproduced in 85% yield after 5 h
Table 5) when one equivalent of LiCl wasadded (per equivalent of
(
substrate) to an otherwise identical reaction before heating the solution
ꢀ
to 162 C. The other conditions were the same as the described above in
the reduction carried out in the absence of LiCl.
The reduction of t-amyl 3,4,5-trimethoxybenzoate did not take
place without added LiCl in the presence of one equivalent of NaBH
4
ꢀ
ꢀ
at 162 C.The t-amyl ester remained unchanged after 5 h at 162 C. If one
equivalent of LiCl wasadded, 3,4,5-trimethyoxy benzyl alcohol was
produced in 81% yield in 5 h.
2-Chlorobenzoic acid, 2, octanoic acid, 8, cinnamic acid, 15, and esters
–5, 9–11, 16–18, and 21 and 22 were subjected to NaBH reduction in a
3
similar manner.
4
Spectra Data
All compoundsli ts ed below were obtained in us fficient purity to
give a single GC peak and no impurity peaks were observed in
the NMR except for 8, 12–14 which were obtained asa si ngle product
mixture and identified by GC–MS and compared to standards.

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Zhu and Pittman
1
Methyl 2-chlorobenzoate (3): Colorless liquid, H NMR (300 MHz),
ꢀH(CDCl ): 7.81 (1H, m), 7.42 (2H, m), 7.29 (1H, m), 3.91 (3H, s).
3
1
Isopropyl 2-chlorobenzoate (4): Colorless liquid, H NMR (300MHz),
ꢀH(CDCl ): 7.75 (1H, m), 7.41 (2H, m), 7.29 (1H), 5.29 (1H, m,
3
J ¼ 6.26 Hz), 1.37 (6H, d, J ¼ 6.27Hz).
1
t-Amyl 2-chlorobenzoate (5): Colorless liquid, H NMR (300 MHz),
ꢀH (CDCl ): 7.73 (1H, m), 7.40 (2H, m), 7.28 (1H, m), 1.93 (2H, q,
3
J ¼ 7.53 Hz), 1.57 (6H, s), 0.97 (3H, t, J ¼ 7.52 Hz).
1
Benzyl alcohol (6): Colorless liquid, H NMR (300 MHz), ꢀH
(
CDCl ): 7.38–7.30 (5H, m), 4.68 (2H, s).
3
ꢀ
1
-Chlorobenzyl alcohol (7): M.p. 68.5–70.0 C, H NMR (300 MHz),
2
ꢀH(CDCl ), 7.46 (1H, m), 7.35 (1H, m), 7.23 (2H, m), 4.77 (2H, s), 2.15
3
(
1H, br. s).
Octanoic acid (8): GC/MS (EI): m/z 145 (Mþ1, 12%), 101
MꢁCO H, 43%), 73 (70%), 60 (100%).
(
2
1
Methyl octanoate (9): Colorless liquid, H NMR (300 MHz),
ꢀH(CDCl ): 3.64 (3H, s), 2.28 (2H, t, J ¼ 7.45 Hz), 1.60 (2H, m,
3
J ¼ 7.30 Hz), 1.27 (8H, m), 0.87 (3H, t, J ¼ 6.97 Hz). GC/MS (EI): m/z
1
59 (Mþ1, 18%), 127 (13%), 87 (60%), 74 (100%).
1
Isopropyl octanoate (10): Colorless liquid, H NMR (300MHz),
ꢀH(CDCl ): 4.98 (1H, m, J ¼ 6.26Hz), 2.24 (2H, t, J ¼ 7.38Hz), 1.59 (2H, m,
3
J ¼ 7.34Hz),1.26(8H,m),1.20(6H,d,J ¼ 6.27Hz),0.86(3H,t,J ¼ 6.95Hz).
1
t-Amyl octanoate (11): Colorless liquid, H NMR (300 MHz),
ꢀH(CDCl ): 2.20 (2H, t, J ¼ 7.37 Hz), 1.77 (2H, q, J ¼ 7.52 Hz), 1.56
3
(
2H, m, J ¼ 7.32 Hz), 1.40 (6H, s), 1.27 (8H, m), 0.86 (3H, t, J ¼ 7.57 Hz).
þ
Octanol 12: GC/MS (EI): m/z 130 (M , 1%), 112 (M ꢁ H O, 3%), 73
2
(
50%), 69 (86%), 55 (100%).
2
-Methoxyethyl octanoate (13): GC/MS (EI), m/z 203 (Mþ1, 25%),
1
71 (M ꢁ OCH , 12%), 127 (M ꢁ C H CO, 60%), 58 (100%).
3
7
15
2-(2-Methoxyethoxy)ethyl octanoate (14): GC/MS (EI): m/z 145
(
M ꢁ CH OC H OC H , 100%), 127 (M ꢁ C H CO, 32%), 103 (8%),
3
2
4
2
4
7
15
8
3 (35%), 69 (30%), 55 (61%).
Methyl cinnamate (16): M.p. 33.5–35 C, H NMR (300 MHz),
ꢀH(CDCl ): 7.70 (1H, d, J ¼ 16.04 Hz), 7.52 (2H, m), 7.38 (3H, m), 6.44
ꢀ
1
3
(
1H, d, J ¼ 16.03 Hz), 3.81 (3H, s).
Isopropyl cinnamate (17): Colorless liquid, H NMR (300 MHz),
1
ꢀH(CDCl ): 7.67 (1H, J ¼ 16.05 Hz), 7.53 (2H, m), 7.39 (3H, m), 6.42
3
(
1H, d, J ¼ 15.99 Hz), 5.15 (1H, m, J ¼ 6.20 Hz), 1.32 (6H, d, J ¼ 6.27 Hz).
1
t-Amyl cinnamate (18): Colorless liquid, H NMR (300 MHz),
ꢀH(CDCl ): 7.58 (1H, d, J ¼ 15.98 Hz), 7.51 (2H, m), 7.38 (3H, m), 6.38
3
(
1H, d, J ¼ 16.01 Hz), 1.86 (1H, q, J ¼ 7.50 Hz), 1.50 (6H, s), 0.93 (3H, t,
J ¼ 7.47 Hz).

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Reductions of Carboxylic Acids and Esters
1739
ꢀ
1
Methyl 3,4,5-trimethoxybenzoate (21): M.p. 80–82 C, H NMR
300 MHz), ꢀ (CDCl ): 7.29 (2H, s), 3.90 (12H, s).
(
H
3
ꢀ
1
Isopropyl 3,4,5-trimethoxybenzoate (22): M.p. 39–41 C, H NMR
300 MHz), ꢀ (CDCl ): 7.28 (2H, s), 5.30 (1H, m, J ¼ 6.26 Hz), 3.91
(
(
H
3
6H, s), 3.89 (3H, s), 1.36 (6H, J ¼ 6.26 Hz).
1
t-Amyl 3,4,5-trimethoxybenzoate (23): Colorless oil, H NMR
300 MHz), ꢀ (CDCl ): 7.25 (2H, s), 3.89 (6H, s), 3.88 (3H, s), 1.90
(
(
H
3
2H, m, J ¼ 7.51 Hz), 1.56 (6H, s), 0.97 (3H, t, J ¼ 7.46 Hz).
1
,4,5-Trimethoxybenzyl alcohol (24): (300MHz), H NMR ꢀ (CDCl ):
3
H 3
6.56 (2H, s), 4.59 (2H, s), 3.83 (6H, d, J ¼ 0.69Hz), 3.80 (3H, d, J ¼ 0.57Hz).
RESULTS AND DISCUSSION
Reduction of Aromatic Acids (1–2) and Esters (3–5)
in NaBH /Diglyme at 1628C
4
The reductionsof benzoic acid ( 1), 2-chlorobenzoic acids( 2), and
ꢀ
several alkyl 2-chlorobenzoates (3–5) with NaBH in diglyme at 162 C
4
gave good to excellent yieldsof benzyl alcohol or 2-chlorobenzyl alcohol,
respectively (see Sch. 1). A good workup method for product isolation
and solvent recycle was found. Representative reductions are shown in
ꢀ
Table 1. Thus, raising the temperature to 162 C enablesNaBH to reduce
4
these aromatic carboxylic acids to alcohols. Carboxylic acids are typically
considered inert to NaBH because the carboxylate anion is formed
making hydride attack at the carbonyl carbon very difficult.
4
Scheme 1.

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Reductions of Carboxylic Acids and Esters
Table 2. Reductionsof octanoic acid by NaBH 4 in diglyme at 162 C.
1741
ꢀ
a
NaBH /substrate
(mole ratio)
4
Time
(h)
Unreacted
octanoic acid (%)
1-Octanol
(%)
Entry
1
2
3
4
0.9
1.0
1.2
2.0
2.5
1.0
3.0
7.0
79
71
65
52
20
29
33
46
a
No esters were observed which could have resulted from esterification of octa-
noic acid by alkoxide fragment from diglyme. The yieldsin columns4 and 5 are
from GC measurements.
Reduction of Octanoic Acid (8) and Alkyl Octanoates (9–11)
in NaBH /Diglyme at 1628C
4
The reduction of octanoic acid to 1-octanol, 12, by NaBH in diglyme
4
ꢀ
at 162 C doesnot occur ea si ly. When the mole ratio of NaBH to octanoic
4
acid wasincrea se d from 0.9, 1.0, 1.2, and 2.0, the octanoic acid wasnever
ꢀ
consumed completely. Even after 7.0 h at 162 C using a 2 mol excess of
NaBH , 52% of the octanoic acid remained and only a 46% yield of
4
octanol, 12, wasproduced. When 1 equiv. of NaBH 4 wasu se d, a 29%
yield (GC) of octanol was obtained in 1 h (see Table 2) and using 0.9 equiv.
ꢁ
ꢀ
of BH4 at 162 C for 2.5 h only produced 20% otanol. Using larger
amountsof NaBH 4 and longer times usually gave higher alcohol yields.
However, thisdid not alwaysoccur. The reaction mixturesare heteroge-
neous since the solubility of NaBH4 in refluxing diglyme isonly
0.43 g/100 g diglyme. Thus, the reaction may take place at NaBH surfaces.
4
Certainly, all the octanoic acid is present in solution as the carboxylate
anion. Hydride attack on thiscarboxylate anion isvery difficult si nce a
dianion must result and this leads to a high activation energy in solution.
Reductionson the su rface may be favored by coordination of the dianion’s
þ
oxygenswith Na ions of the solid. In all of these reactions, NaBH was
4
ꢀ
added to the substrate/diglyme solutions at 162 C.
In certain reactions, the NaBH wasadded at temperaturesbetween
4
ꢀ
1
00–130 C where the solubility of NaBH isgreater. However, improved
4
yieldswere not obtained. Moreover, the addition of LiCl did not give
improved alcohol yields.
Since reduction of octanoic acid, 8, is sl ow, hydride attack on diglyme
ꢀ
ꢁ
may compete at 162 C, giving alkoxide ion us sc h asCH
ꢁ
O ,
CH OCH CH O etc. However, no esterification of octanoic acid was
3
3
2
2
observed. The products were octanol, 12, and unreduced octanoic acid, 8.

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742Zhu and Pittman
Scheme 2.
NaBH reductionsof methyl, i os propyl, and t-amyl octanoate are
4
shown in Sch. 2. Samples were summarized in Table 3. Surprisingly,
ꢀ
the reduction of all three esters as very slow at 162 C. In reductionsof
9
at a NaBH /methyl octanoate ratio of 0.65, no octanol wasobtained
4
after 5 h (Entries 1 and 2). Substantial amounts of this ester substrate
remained in these reactions even when LiCl was added as a promoter.
Since thisreduction is lso w, hydride attack on diglyme can compete
ꢁ
ꢁ
to produce three alkoxide ions: CH O , CH OCH CH O , and
3
3
2
2
ꢁ
CH OCH CH OCH CH O . These alkoxides react with the substrate
3
2
2
2
2
to produce transesterification products 9, 13, and 14 (see Sch. 2) in
addition to octanol. Methyl octanoate, 9, undergoestran es ts erification
ꢁ
with CH O so the remaining 9 in the reaction mixture cannot be
3
distinguished from 9 formed by transesterification. However, formation
of 9 during reactionsof i so propyl and t-amyl octanoates, 10 and 11, show
that thistran se st erification proceeds(Entries5–7, Table 3).
The complex product mixtures demonstrate that these NaBH high
4
temperature reductions are not suitable for reducing alkyl aliphatic esters
to the corresponding alcohols. Aliphatic ester reductions were slower than
those of benzoate esters. This result is the opposite of what is expected.
Resonance delocalization between the phenyl ring and carbonyl group
should slow the rate of hydride attack at carbonyl carbon of aromatic
esters relative to that in aliphatic esters. The low rate of aliphatic ester
reduction permitsS 2 attack by hydride on diglyme to compete (Sch. 3),
N
producing alkoxide ionsby cleavage of the os lvent. The alkoxide ions
produced then transesterify the original ester producing esters 9, 13, and
14. LiCl addition (Entries3 and 4, Table 3) would be expected to sp eed
ester reduction by the coordination of Li to the carbonyl oxygen,
þ
þ
thereby enhancing the rate of hydride attack. However, Li also enhances
ꢁ
the rate of diglyme cleavage by BH at these high temperatures.
4
The presence of octanoic acid, 8, observed in Entries 1–7 (Table 3)
indicatesthat S 1 or S 2 substitution or E-2 elimination occurs,
N
N
generating the carboxylate anion from the ester (Sch. 4). Upon workup,
protonation givesoctanoic acid. S N1 and E-2 processes can’t occur on
methyl octanoate so S 2 attack by hydride isinvolved. However, the
N
observed 8% and 20% yields of octanoic acid, 8, from t-amyl octanoate

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Reductions of Carboxylic Acids and Esters
1743

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Zhu and Pittman
Scheme 3.
Scheme 4.
11 (Entries6 and 7, Table 3) ismore likely to re su lt by an S N1 or E-2
pathway. t-Amyl octanoate, 11, isexpected to reduce more sl owly than its
methyl or isopropyl analogs because of the t-amyl group’s substantial
steric effect. The t-amyl group should hinder nucleophilic attack at the
carbonyl carbon. No octanol wasob es rved in NaBH
consistant with this view. Slower reduction allows time for both trans-
reduction of 11,
4
esterification to occur and octanoic acid to form. S 2 substitution on 11
N
seems unlikely.
The transesterification products were identified by GC–MS. The
amount of transesterification products increased with time from 2 h to
7
h. No esterification of octanoic acid with diglyme fragments took place
during the octanoic acid reductions. When isopropyl octanoate is dissolved
ꢀ
into the diglyme in the absence of NaBH and then warmed to 162 C for
4
10 h, no other reaction productswere ob es rved (GC), confirming that
sodium borohydride is necessary in the transesterification reactions.
ꢀ
Diglyme washeated with os dium borohydride at 162 C to study
its st ability at high temperature. Methanol isone of the productsformed.
These high temperature NaBH reductionsof methyl octanoate also
4
1
generated both methyl formate and methanol (identified by H NMR).
Methyl formate doesnot appear in reactionsof diglyme with NaBH 4.
The esters must be present. Methyl formate is postulated to arise from
hydride attack on dimethyl carbonate (Sch. 5). Dimethyl carbonate could
be envisioned to form by high temperature methoxide attack on methyl
ꢁ
octanoate followed by occassional loss of C H (Sch. 5).
7 15

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Reductions of Carboxylic Acids and Esters
1745
Scheme 5.
Scheme 6.
Reductions of Cinnamic Acid (15) and Alkyl Cinnamates
(
16–18) with NaBH in Diglyme at 1628C
4
The reductionsof cinnamic acid and itsmethyl, 16, isopropyl,
7, and t-amyl, 18, esters with NaBH were investigated in diglyme
1
at 162 C (Sch. 6). Cinnamic acid wasconverted to cinnamyl alcohol, 19,
4
ꢀ
in 67% yield (GC) after 7.0 h in the presence of 1 equiv. of NaBH (Table
4
4
, Entry 2). Only 3% of the cinnamic acid were remained and 30% of the
material balance were unknown products. No reaction was observed in
h (Entry 1) but 97% of the acid wascon su med in 7 h (Entry 2). Thisis
2
reminiscent of methyl octanoate reduction (Entries 1 and 2) in Table 3.
Again, such irregularities may signal that a heterogeneous reaction is
occurring. Overall, exact rateswere difficult to reproduce but the trends
were consistent. Cinnamic acid was more readily reduced to alcohol than
octanoic acid but more slowly reduced than benzoic and 2-chlorobenzoic
acids.
Methyl cinnamate, 16, can be reduced to cinnamyl alcohol, 19, with
ꢀ
NaBH in diglyme at 162 C in about 65% yield (GC) after 3 h. Other
4
products were also formed, but they were not studied. Only 2% of the

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Reductions of Carboxylic Acids and Esters
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Zhu and Pittman
Scheme 7.
starting material remained (GC). In contrast, reduction of isopropyl
cinnamate with NaBH gave only a 2% yield of cinnamyl alcohol at
4
96% ester conversion (Entry 4, Table 4). By-products represented 94%
of the GC area. No cinnamyl alcohol wasproduced in 3 h from t-amyl
cinnamate, 18, using a NaBH /ester feed ratio of 0.7 although the ester
4
was100% con us med. Only unknown productswere produced which
were not studied (Entries 5, Table 4).
Reduction of 3,4,5-Trimethoxybenzoic Acid (20) and
Alkyl 3,4,5-Trimethoxybenzoates (21–23)
Attemptsto reduce reduced 3,4,5-trimethoxybenzoic acid, 20, with
NaBH4 in diglyme produced no 3,4,5-trimethoxybenzyl alcohol, 24
(
Table 5, Entries1 and 2). Acid, 20, wasrecovered unchanged after 8 h
both in the presence or absence of 1 equiv. of LiCl. Apparently the three
electron donating methoxy groupsdeactivate the 3,4,5-trimethyoxybenzo-
ate anion to hydride attack at the carbonyl carbon relative to hydride attack
on the carboxylate anionsof benzoic and 2-chlorobenzoic acids(Sch. 7).
Methyl and isopropyl trimethoxybenzonates, 21 and 22, also
remained unreacted after treating with NaBH for long periodsin reflux-
4
ing diglyme (Table 5, Entries3 and 5). Furthermore, no tran se st erifica-
tion productsformed from diglyme cleavage. However, both 21 and 22
were reduced in good yieldsto 3,4,5-trimethoxybenzyl alcohol, 24 (85 and
83% yieldsre sp ectively) in identical reactions(5 h) where an equivalent of
LiCl wasadded (Entries4 and 6). Thisillu st ratesthe activating effect of
þ
the Li cation. Finally, t-amyl 3,4,5-trimethoxybenzoate, 23, did not
react under these conditions even with LiCl present (Table 5, Entries 7
and 8). The larger steric bulk of the t-amyl group apparently retardsthe
ꢁ
approach of BH to the carbonyl carbon. This, coupled with the electron
4

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Reductions of Carboxylic Acids and Esters
1749
rich nature of the system, slows reduction. No 3,4,5-trimethoxybenzoic
acid wasformed. Thu s, S N1, S 2, or E-2 reactionsof the t-amyl ester do
not occur, in contrast to the behavior of t-amyl octanoate.
N
SUMMARY
Diglyme isa good os lvent for the reduction of aromatic acids
ꢀ
and esters with NaBH4 at 162 C to give corresponding alcohols.
High temperaturesincre ae s the range of functional groupswhich
NaBH can reduce. Diglyme isnot asgood a so lvent for the reduction
4
of aliphatic esters due to the formation of transesterification products.
Aliphatic acids and esters form alcohols, but diglyme cleavage competes.
This leads to the formation of transesterification products. Aliphatic
esters, surprisingly, reduce more slowly than aromatic esters.
The very electron rich 3,4,5-trimethoxybenzoate esters and the parent
ꢀ
acid cannot be reduced by NaBH at 162 C. The methyl and isopropyl
4
3,4,5-trimethoxybenzoatesare reduced when LiCl isadded.
ACKNOWLEDGMENTS
The work was supported, in part, by the Morton Division of Rohm
and Haasand the Grant Divi si on of Ferro Corp.
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Received in the USA February 22, 2002