Sodium cyanoborohydride-mediated direct conversion of some heterocyclic aldehydes to esters

Article abstract of DOI:10.1080/00397911.2010.502988

An exceptional oxidizing behavior of sodium cyanoborohydride is observed where electron-withdrawing heterocyclic aldehydes are directly converted to their corresponding esters on treatment of sodium cyanoborohydride in methanol. The spectral analysis and

Full text of DOI:10.1080/00397911.2010.502988

Synthetic Communications1, 41: 2505–2510, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.502988
SODIUM CYANOBOROHYDRIDE–MEDIATED DIRECT
CONVERSION OF SOME HETEROCYCLIC ALDEHYDES
TO ESTERS
Shyamaprosad Goswami,1 Anita Hazra,1 Jia Hao Goh,2 and
Hoong-Kun Fun2
1Department of Chemistry, Bengal Engineering and Science University,
Shibpur, Howrah, West Bengal, India
2X-Ray Crystallography Unit, School of Physics, Universiti Sains Malaysia,
Penang, Malaysia
GRAPHICAL ABSTRACT
Abstract An exceptional oxidizing behavior of sodium cyanoborohydride is observed where
electron-withdrawing heterocyclic aldehydes are directly converted to their corresponding
esters on treatment of sodium cyanoborohydride in methanol. The spectral analysis and
single-crystal structure confirm the formation of esters.
Keywords Esterification; heterocyclic aldehydes; heterocyclic esters; sodium
cyanoborohydride
INTRODUCTION
Sodium cyanoborohydride is a popular reducing agent and is used to reduce a
wide range of organic functional groups selectively.[1–3] Previous applications of this
reagent have been reported, such as reductions of ketone, aldehyde, oxime, and
enamine.[4–6] To date, the conversion of heterocyclic aldehydes to esters by the use
of this reagent has not been reported.
Interestingly, we have observed that the reaction of sodium cyanoborohydride
with quinoxaline aldehyde or pterin aldehyde in the presence of dry alcohol cleanly
leads to the unexpected formation of esters from corresponding aldehydes instead of
the usual reduction of aldehydes to alcohol (Scheme 1).
Received January 28, 2010.
Address correspondence to Shyamaprosad Goswami, Department of Chemistry, Bengal
Engineering and Science University, Shibpur, Howrah 711103, West Bengal, India. E-mail:
spgoswamical@yahoo.com
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S. GOSWAMI ET AL.
Scheme 1. One-step synthesis of heterocyclic esters from the corresponding aldehydes.
Heterocyclic esters are important compounds considering their biological and
pharmaceutical aspects.[7] Only a few methods are available for the synthesis of
heterocyclic esters.[8] Here, we report esterification of some electron-withdrawing
heterocyclic aldehydes to esters by using sodium cyanoborohydride. The results
are summarized in Table 1.
As shown in Table 1, it has been observed that more electron-deficient hetero-
cyclic aldehydes only are converted to the corresponding esters with reasonably good
yields. The time required for these reactions is 30 min to 1 h. In the case of pterin
aldehyde, the reaction occurs at room temperature, whereas all the other reactions
are carried out at 40–50 ꢀC. The reaction is mild, clean, and rapid. The reactions
are also carried out at pH 3–4 (methanolic solution of HCl), where we also isolate
Table 1. Synthesis of heterocyclic esters from electron-deficient heterocyclic aldehydesa
Entry
Aldehyde
Product
Yield (%)
Mp (ꢀC)
156–158
a
72
b
c
68
80
79
65
142–144
110–112
62–64
d
e
155–156
aReactions were monitored by TLC analysis. Isolated yields were of chromatographically obtained pure
materials.

CONVERSION OF HETEROCYCLIC ALDEHYDES
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Table 2. Reactions of quinoxaline-2-aldehyde with different alcohols
Entry
a
Alcohol
Product
Yield (%)
Mp (ꢀC)
75–76
EtOH
72
b
c
65
60–62
No esterification
the corresponding esters. The products are characterized by infrared (IR), NMR,
and mass spectroscopy. Heterocyclic aldehydes such as pyridine aldehyde or
phenanthroline-2,9-dialdehyde are reduced to their corresponding alcohols accord-
ing to the usual reducing behavior of sodium cyanoborohydride.
On the reaction of quinoxaline-2-aldehyde, we have isolated the corresponding
ethyl or isopropyl esters by changing the solvent to ethanol or isopropanol, although
the yields gradually decrease by the use of primary to secondary alcohols (Table 2).
In the case of using tertiary butyl alcohol, no esterification occurs.
The final confirmation of the structure (i.e., formation of ester) is obtained by
x-ray crystallographic investigation.[9] Here the single-crystal structure of compound
2 (methyl-7-pivaloylamino-[1,8]naphthyridine-2-carboxylate) (Fig. 1) is also pre-
sented. The naphthyridine ring (C1=N1=C2–C8=N2) lies on a crystallographic mir-
ror plane and is planar. There are no classical hydrogen bonds. Intramolecular
C3—H3 ꢁ ꢁ ꢁ O2 and C7—H7 ꢁ ꢁ ꢁ O3 interactions stabilize the molecular structure.
Figure 1. Illustrations of the crystal structure of compound 2: (a) ORTEP diagram (50% probability);
(b) crystal packing viewed down crystallographic b axis.

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S. GOSWAMI ET AL.
Intermolecular C4–H4 ꢁ ꢁ ꢁ O1 interactions build up the crystal structure, which con-
sists of one-dimensional infinite chains along the crystallographic a axis. The crystal
˚
structure is further stabilized by p–p interactions [3.7466(3) A] involving the
centroids of C1=N1=C2–C5 and C1=C5–C8=N2 pyridine rings, respectively.
In conclusion, we report here that electron-withdrawing heterocyclic aldehydes
are selectively oxidized by sodium cyanoborohydride to their corresponding esters.
The reaction has been observed to work well with the previously mentioned hetero-
cyclic aldehydes. The exceptional oxidative property of sodium cyanoborohydride
instead of the usual reducing property has been demonstrated.
EXPERIMENTAL
General Procedure for the Direct Synthesis of Heterocyclic
Ester from the Corresponding Aldehyde
Quinoxaline-2-aldehyde (160 mg, 1.01 mmol) was dissolved in dry methanol
and stirred at room temperature. Sodium cyanoborohydride (purchased from
Aldrich Chemical Co.) (75.4 mg, 1.2 mmol) was added slowly without further purifi-
cation. The mixture was then warmed at 50–60 ꢀC for 1 h. Excess methanol was eva-
porated through vacuum distillation, and the reaction mixture was quenched with
saturated ammonium chloride solution. The mixture was extracted with chloroform,
and the organic layer was evaporated. The compound was then purified through
column chromatography by eluting with 15% ethyl acetate in petroleum ether to
afford a pure crystalline solid (3).
Selected Data
Methyl-2-pivaloylaminopteridine-7-carboxylate (1). Mp 156–158 ꢀC. IR
1
(KBr): 3163, 2982, 1732, 1682, 1542, 1224, 770 cmꢂ1. H NMR (CDCl3, 500 MHz)
(ppm): 12.56 (bs, 1H), 9.32 (s, 2H), 4.07 (s, 3H), 1.36 (s, 9H). MS (LCMS): m=z
(%): 306.2 [(M þ H)þ, 100]. Anal. calcd. for C13H15N5O4: C, 51.15; H, 4.95; N,
22.94; Found: C, 51.27; H, 4.81; N, 22.85.
Methyl-7-pivaloylamino-[1,8]naphthyridine-2-carboxylate (2). Mp 142–
1
144 ꢀC. IR (KBr): 3432, 2960, 1744, 1692, 1620, 1325, 860 cmꢂ1. H NMR (CDCl3,
500 MHz) (ppm): 8.67 (d, 1H, J ¼ 8.92 Hz), 8.53 (bs, 1H), 8.30 (d, 1H, J ¼ 8.24 Hz),
8.25 (d, 1H, J ¼ 8.92 Hz), 8.19 (d, 1H, J ¼ 8.23 Hz), 4.06 (s, 3H), 1.36 (s, 9H). MS
(LCMS): m=z (%): 288.2 [(M þ H)þ, 100], 289.2 [(M þ 2H)þ, 20], 204.1 (15).
Crystallographic data of compound 2. C15H17N3O3; Mr ¼ 287.32;
monoclinic, P21=m; block, colorless; Z ¼ 2; F(000) ¼ 304; D ¼ 1.385 g=cm3;
3
˚
˚
˚
˚
V ¼ 688.97(3)A ; Cu Ka radiation; k ¼ 1.54178 A; a ¼ 6.45930(10)ꢂA1; b ¼ 6.7201(2)A;
c ¼ 15.9665(3) A; a ¼ 90 ; b ¼ 96.2290(10) ; c ¼ 90 ; m ¼ 0.810 mm ; h ¼ 7.16–67.25ꢀ;
crystal size ¼ 0.13 ꢃ 0.18 ꢃ 0.41; T ¼ 100 K. Crystallographic data for the structural
analysis have been deposited with the Cambridge Crystallographic Data Center
(CCDC), No. 762718.
ꢀ
ꢀ
ꢀ
˚
Methyl quinoxaline-2-carboxylate (3). Mp 110–112 ꢀC. IR (KBr): 2998,
1
2950, 1715, 1496, 1435, 1320, 1101, 786 cmꢂ1. H NMR (CDCl3, 400 MHz) (ppm):

CONVERSION OF HETEROCYCLIC ALDEHYDES
2509
9.55 (s, 1H), 8.30 (d, 1H, J ¼ 8.00 Hz), 8.19 (d, 1H, J ¼ 8.80 Hz), 7.89 (m, 2H), 4.13
(s, 3H). MS (LCMS): m=z (%): 189.1 [(M þ H)þ, 100], 175.1 (15), 147.1 (75).
Methyl pyrido[2,3-b]pyrazine-3-carboxylate (5). Mp 155–156 ꢀC. IR
1
(KBr): 3063, 2965, 1714, 1574, 1337, 1122, 972 cmꢂ1. H NMR (CDCl3, 500 MHz)
(ppm): 9.65 (s, 1H), 9.31 (s, 1H), 8.55 (d, 1H, J ¼ 8.50 Hz), 7.84 (d, 1H, J ¼ 6.23 Hz),
5.30 (s, 3H). MS (LCMS): m=z (%): 190.1 [(M þ H)þ, 50]. Anal. calcd. for
C9H7N3O2: C, 57.14; H, 3.73; N, 22.21. Found: C, 57.02; H, 3.96; N, 22.13.
Isopropyl quinoxaline-2-carboxylate (7). Mp 60–62 ꢀC. IR: 3433, 2919,
1
1705, 1636, 1468, 1383, 1098, 776 cmꢂ1. H NMR (500 MHz, CDCl3) (ppm): 9.51
(s, 1H), 8.32 (d, 1H, J ¼ 8.50 Hz), 8.18 (d, 1H, J ¼ 8.50 Hz), 7.87 (m, 2H), 5.44 (t,
1H, J ¼ 12.50 Hz), 1.50 (d, 6H, J ¼ 6.50 Hz). MS (LCMS): m=z (%): 217.2 [(M þ H)þ,
25], 175.1 (100). Anal. calcd. for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.79; H, 5.46; N, 13.07.
ACKNOWLEDGMENTS
We thank the Council of Scientific and Industrial Research (CSIR) [No.
01(2292)=09=EMR-II], government of India, for financial support. A. H. thanks
the CSIR, government of India, for a research fellowship. The authors also thank
the Malaysian Government and Universiti Sains Malaysia (USM) for Research
University Golden Goose Grant No. 1001=PFIZIK=811012. J. H. G. thanks the
USM for a fellowship.
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