The mechanism of unexpected reduction of dimethyl pyridine-2,3- dicarboxylate to 1,2,3,4-tetrahydrofuro[3,4-b]pyridin-5(7H)-one with sodium borohydride

Article abstract of DOI:10.1016/j.cclet.2012.07.013

An unexpected reduction of dimethyl pyridine-2,3-dicarboxylate to 1,2,3,4-tetrahydrofuro[3,4-b]pyridin-5(7H)-one with sodium borohydride in ethanol and tetrahydrofuran, respectively, is described, a hypothetic mechanism for the unusual reductive product is proposed.

Full text of DOI:10.1016/j.cclet.2012.07.013

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1122–1124
www.elsevier.com/locate/cclet
The mechanism of unexpected reduction of dimethyl
pyridine-2,3-dicarboxylate to 1,2,3,4-tetrahydrofuro[3,4-b]
pyridin-5(7H)-one with sodium borohydride
*
Yan Bo Tang, Qing Jian Zhang, De Quan Yu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy
of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Received 23 May 2012
Available online 23 September 2012
Abstract
An unexpected reduction of dimethyl pyridine-2,3-dicarboxylate to 1,2,3,4-tetrahydrofuro[3,4-b]pyridin-5(7H)-one with
sodium borohydride in ethanol and tetrahydrofuran, respectively, is described, a hypothetic mechanism for the unusual reductive
product is proposed.
# 2012 De Quan Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Reduction; Sodium borohydride; Dimethyl pyridine-2,3-dicarboxylate; 1,2,3,4-Tetrahydrofuro[3,4-b]pyridin-5(7H)-one; Reaction
mechanism
As a mild and efficient reducing agent, sodium borohydride (NaBH4) has been applied to a wide range of reduction
processes, such as aldehydes and ketones to alcohols, imines to amines [1]. In some cases, it can also reduce carboxylic
esters to alcohols in the presence of certain additives, such as iodine [2], zinc chloride [3], and so on, which can
enhance the reactivity of NaBH4. Boechat and coworkers found that aromatic esters [4] and heteroaromatic esters [5]
could be transformed into the corresponding alcohols by the addition of methanol to NaBH4 in tetrahydrofuran (THF).
Another example for the reduction of heteroaromatic ester with NaBH4 reported by Yoshiizumi et al. [6], who claimed
the reaction between dimethyl pyridine-2,3-dicarboxylate and NaBH4 in ethanol resulted in corresponding diol 2 in
85% yield (Scheme 1).
The aforementioned reaction was employed in our lab most recently under the same conditions as reported previously
[6]. Surprisingly, besides compound 2, a minor amount of unexpected tetrahydropyridine derivative 3 was also observed
(Scheme 1). Moreover, when we conducted the reaction in THF instead of ethanol, compound 3 was obtained as the only
product. Because the reduction of pyridyl ring with NaBH4 is so unusual, the formation of compound 3 from 1 is much
interesting. Here we will discuss the probable mechanism of the very unexpected reduction.
Similar to the NaBH4–MeOH system reported by Boechat et al. [4,5], the reductive potency of NaBH4 towards
esters could be enhanced in the presence of ethanol, therefore treatment of compound 1 with NaBH4 in ethanol
* Corresponding author.
E-mail address: dqyu@imm.ac.cn (D.Q. Yu).
1001-8417/$ – see front matter # 2012 De Quan Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.07.013

Y.B. Tang et al. / Chinese Chemical Letters 23 (2012) 1122–1124
1123
O
NaBH4
EtOH
OH
OH
+
O
N
N
H
O
O
2
3
O
O
O
N
NaBH4
THF
1
O
N
H
3
Scheme 1.
O
O
O
O
O
NaBH4
O
O
NaBH4
EtOH
O
OH
O
O
N
N
H
N
N
1
4
5
3
Scheme 2.
afforded diol 2 as major product. We initially considered minor product 3 was probably achieved through the pathway
as shown in Scheme 2. That was, reduction of 2-ester group (more electron-deficient and therefore to be reduced much
easier than 3-ester group due to nitrogen’s inductive effect) followed by intramolecular transesterification to convert
compound 1 into lactone 5, which was then reduced to 3. To investigate this putative pathway, reaction between
compound 5 and NaBH4 was carried out in ethanol. However, there was no compound 3 observed and compound 2 was
obtained as the only product (Scheme 3). The results above suggested that 3 should be achieved through other reaction
mechanism.
Despite the rarity of reducing pyridines into tetrahydropyridines with NaBH4, there were also some reports on
tetrahydropyridines reduced from pyridinium salts [7–11], which usually produced from pyridines. It is well known
that pyridinium salts are much easier to be reduced with NaBH4 because of its pyridyl ring’s lower electron cloud
density than pyridines’. Additionally, Brossi and coworkers had reported amine-borane complexes were achieved by
the reaction between pyridinium salts and NaBH4 [12]. From above it could be assumed that the unusual reduction in
this research was probably performed through nitrogen–boron complex intermediate pathway. Scheme 4 described the
possible mechanism for the formation of 3 in ethanol briefly. 2-Ester group of compound 1 was reduced firstly and
intermediate 6 was given, thereafter nitrogen coordinated with boron to form nitrogen–boron complex 7, whose
O
O
O
N
H
NaBH4
EtOH
3
O
N
OH
OH
5
N
2
Scheme 3.
O
O
O
O
O
O
O
O
O
O
O
O
- CH3OH
O
O
NaBH4
EtOH
NaBH4
O
OH
O
N
N
H
N
N
H
N
H
N
H
O
B
B
B
3
H
H
H
H
OEt
H
1
6
7
Scheme 4.

1124
Y.B. Tang et al. / Chinese Chemical Letters 23 (2012) 1122–1124
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
NaBH4
THF
NaBH4
O
O
O
N
B
H
N
H
N
B
H
N
H
N
H
H
H
N
H
O
O
H
H
B
H
3
H
1
8
Scheme 5.
pyridyl ring (with lower electron cloud density than compound 1) was reduced and intramolecular transesterification
was proceeded subsequently to yield compound 3.
When THF instead of ethanol was used as solvent, the reductive activity of NaBH4 towards ester would be
decreased, so it is difficult to reduce 2,3-biester moiety of compound 1 immediately. Instead, the pyridine-borane
complex 8 was formed first as shown in Scheme 5. Due to the presence of two electron-withdrawing ester groups and
the pyridine-borane complex, the electron cloud density of the pyridyl ring was low enough to allow its direct
reduction to the tetrahydropyridine ring. Subsequent reduction of 2-ester group and intramolecular transesterification
provided compound 3 finally. Notably, the reaction needed to be performed at high temperature (heating to vigorous
reflux and even over 75 8C) [13], otherwise neither pyridyl ring nor ester moiety of compound 1 could be reduced.
To summarize, it is so unusual to reduce pyridines with NaBH4 and the unexpected and interesting results in this
study add some valuable information on the reduction of this kind of compounds under mild reaction conditions.
Further studies on the reduction of pyridines with diverse substituents as well as other nitrogen-containing
heteroaromatic compounds with NaBH4 are in process.
References
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[4] N. Boechat, J.C.S. da Costa, J. de Souza Mendonca, et al. Tetrahedron Lett. 45 (2004) 6021.
[5] N. Boechat, J.C.S. da Costa, J. de Souza Mendonca, et al. Synth. Commun. 35 (2005) 3187.
[6] K. Yoshiizumi, M. Yamamoto, T. Miyasaka, et al. Bioorg. Med. Chem. 11 (2003) 433.
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[8] H. Sakagami, T. Kamikubo, K. Ogasawara, Chem. Commun. (1996) 1433.
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[11] S. Raucher, R.F. Lawrence, Tetrahedron Lett. 24 (1983) 2927.
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[13] Reduction of dimethyl pyridine-2,3-dicarboxylate with NaBH4. Entry 1: To a solution of dimethyl pyridine-2,3-dicarboxylate (195 mg,
1 mmol) in 5 mL ethanol was added NaBH4 (190 mg, 5 mmol) at 0 8C. The reaction mixture was refluxed for 20 h and then filtered while the
solution is hot. The filter cake was washed with hot ethanol and the combined filtrate was then concentrated. The residue was purified by silica
gel column chromatography (CH2Cl2:CH3OH:Et3N = 15:5:1) to give 83 mg compound 2 (yield 60%) and 15 mg compound 3 (yield 11%).
Entry 2: Dimethyl pyridine-2,3-dicarboxylate (195 mg, 1 mmol) was resolved in 5 mL THF, to the mixture was added NaBH4 (190 mg,
5 mmol) at 0 8C. The reaction mixture was heated to vigorous reflux for 4 h and then cooled to rt. 2 mL H2O was added to the mixture, which
allowed stirring for another 10 min. To the mixture was then added 5 mL CHCl3 and the organic phase was separated. After extracting the water
phase with CHCl3 (5 mL Â2), the combined organic phase were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (CH2Cl2:CH3OH:Et3N = 15:5:1) to give 103 mg compound 3 (yield 74%). 3: slight yellow
solid, mp 129–131 8C; 1H NMR (300 MHz, acetone-d6): d 6.42 (br, 1H), 4.54 (s, 2H), 3.31 (m, 2H), 2.13 (t, 2H, J = 6.0 Hz), 1.78 (m, 2H); 13
C
NMR (75 MHz, acetone-d6): d 173.9, 164.5, 90.8, 66.2, 41.8, 21.7, 18.3; HR-FAB-MS: m/z 140.0705 [M+H]+ (calcd. for C10H15O5: 140.0712).