Systematic investigations on the reduction of 4-aryl-4-oxoesters to 1-aryl-1,4-butanediols with methanolic sodium borohydride

Article abstract of DOI:10.3762/bjoc.6.94

4-Aryl-4-oxoesters undergo facile reduction of both the keto and the ester groups with methanolic NaBH₄ at room temperature to yield the corresponding 1-aryl-1,4-butanediols whereas 4-alkyl-4-oxoesters furnish the corresponding 1,4-butanolides via selective reduction of the keto moiety. Results of a detailed and systematic investigation of the reaction are described.

Full text of DOI:10.3762/bjoc.6.94

Systematic investigations on the reduction of 4-aryl-
4-oxoesters to 1-aryl-1,4-butanediols with methanolic
sodium borohydride
Subrata Kumar Chaudhuri1, Manabendra Saha2, Amit Saha3
and Sanjay Bhar*3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 748–755.
1Khorop High School, Howrah, West Bengal, India, 2Department of
Chemistry, Surendranath College (Evening), Kolkata 700 009, India
and 3Department of Chemistry, Organic Chemistry Section, Jadavpur
University, Kolkata 700 032, India, Fax: +91-033-24146223
doi:10.3762/bjoc.6.94
Received: 16 June 2010
Accepted: 12 August 2010
Published: 02 September 2010
Email:
Sanjay Bhar* - sanjaybharin@yahoo.com
Associate Editor: D. Y. Gin
* Corresponding author
© 2010 Chaudhuri et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
diols; esters; lactones; reduction
Abstract
4-Aryl-4-oxoesters undergo facile reduction of both the keto and the ester groups with methanolic NaBH4 at room temperature to
yield the corresponding 1-aryl-1,4-butanediols whereas 4-alkyl-4-oxoesters furnish the corresponding 1,4-butanolides via selective
reduction of the keto moiety. Results of a detailed and systematic investigation of the reaction are described.
Introduction
Chemoselective reductions of aldehydes, ketones and imines are relative proportions of substrate and reagent. Despite the occur-
generally accomplished using NaBH4 in methanol where other rence of several recent reports of borohydride-mediated reduc-
reducible functional groups, e.g. esters, nitro, nitriles, etc., tion of the ester moiety in α-oxo- [18,19] and β-oxoesters [20],
remain unaffected [1-10]. Although it has been reported that sodium borohydride in various alcoholic solvents, often in the
some aliphatic and aromatic esters have been reduced with a presence of additives [21], has been judiciously utilized [22] for
large excess of sodium or other metal borohydrides [11,12], the chemoselective reduction of the oxo-group, occasionally
often in higher boiling solvents [13] and in combination with with subsequent transesterification and the formation of the
various additives [14,15] including at a cationic micellar surface alkoxy-modified β-hydroxyesters. γ-Oxoesters react chemose-
[16], selective reduction of the keto group in oxoesters has been lectively with sodium borohydride to produce the corres-
accomplished using potassium borohydride in refluxing ethanol ponding γ-hydroxyesters [1,2,17,23-27] (sometimes in the form
[17] where the product distribution critically depends on the of γ-lactone) [24]. Following the above noted literature prece-
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Beilstein J. Org. Chem. 2010, 6, 748–755.
Scheme 1: Facile reduction of γ-aryl-γ-ketoesters to the corresponding diols with methanolic NaBH4 at room temperature.
dences [1,2,17,22-27] on the utility of NaBH4, we attempted to affecting the oxidation state of the alkoxycarbonyl moiety
reduce 4-aryl-4-oxoesters with methanolic NaBH4 chemoselec- (Scheme 3).
tively. Surprisingly, we found that 4-aryl-4-oxoesters under-
went facile reduction of both the keto and the ester groups with
methanolic NaBH4 at room temperature to yield the corres-
ponding 1-aryl-1,4-butanediols whereas 4-alkyl-4-oxoesters
furnished the corresponding 1,4-butanolides via selective reduc-
tion of the keto moiety. These results, to the best of our knowl-
edge, have no literature precedence. We describe herein our
Scheme 3: Facile reduction of γ-alkyl-γ-ketoester to the corres-
ponding lactone with methanolic NaBH4 at room temperature.
systematic investigations to elucidate the different parameters
involved in these reactions and to establish their synthetic
usefulness.
From the results obtained so far, it is obvious that NaBH4 in
Results and Discussion
methanol can be efficiently used for the synthesis of 1-aryl-1,4-
When, the γ-aryl-γ-ketoesters (1a–1f) were treated with butanediols from the easily accessible 4-aryl-4-oxoesters (Ta-
methanolic NaBH4 (4 equiv) at room temperature (room ble 1) instead of employing the more costly and hazardous
temperature implies 30 °C throughout) both the oxo- and the LiAlH4 which also often gives rise to several non-identifiable
alkoxycarbonyl moieties were reduced to give the diols (2a–2f), by-products. Structurally varied 1-aryl-1,4-butanediols are of
as shown in Scheme 1.
great synthetic value with immense applications in cationic
polymerizations [34], as intermediates for the syntheses of
γ-Aryl-α,β-unsaturated-γ-ketoesters (1g and 1h), on similar important acyclic antiviral nucleosides [35] and cyclic ethers
treatment, furnished the saturated diols (2a and 2b) by the [36].
reduction of both the keto and the ester groups along with
complete hydrogenation of the double bond (Scheme 2).
Detailed results are shown in Table 1.
Substrate 5 also underwent similar transformation under more
drastic conditions to give a mixture of diol 6 [37] and lactone 7
[38], as shown in Scheme 4. In this instance no reaction took
place at room temperature even after 24 h which might be
At this point it is very interesting and important to note that ascribed to the lower electrophilicity of both the oxo- and
only the oxo function of 4-alkyl-4-oxoester 3 was selectively alkoxycarbonyl functionalities of 5 from both electronic and
reduced under the same conditions to yield lactone 4 without steric standpoints.
Scheme 2: Facile reduction of γ-aryl-α,β-unsaturated-γ-ketoesters to the diols with methanolic NaBH4 at room temperature.
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Beilstein J. Org. Chem. 2010, 6, 748–755.
Table 1: Reduction of 4-aryl-4-oxoesters (saturated and α,β-unsaturated) with NaBH4 in MeOH at room temperature (30 °C).
Entry
Substrate
Product
Yield (%)a
82 [28,29]
1
1a
1b
1c
2a
2b
2c
2
3
86 [30]
80 [31,32]
4
5
71
1d
2d
67 [33]
1e
1f
2e
2f
6
7
81
83 [28,29]
1g
2a
8
85 [30]
1h
2b
aYields refer to pure products, fully characterized spectroscopically (1H NMR, 300 MHz). References for known compounds are given in parenthesis
after the respective yields.
Scheme 4: Reduction of methyl o-benzoylbenzoate with methanolic NaBH4.
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Beilstein J. Org. Chem. 2010, 6, 748–755.
The des-keto ester 8, as expected, was totally unaffected
Table 3: Comparative studya on reduction of various oxo-groups.
(Scheme 5) and was recovered unchanged.
Entry
Substrate
Relative proportion (%)b of
Substrate
Reduced products
γ-Hydroxy
Lactone
ester
1
2
3
4
1a
–
62.5
32.1
37.5
67.9
Scheme 5: Reluctance of ester 8 towards reduction with methanolic
NaBH4 at room temperature.
3
–
Acetophenone
Butyrophenone
49.2
61.0
50.8
39.0
aNaBH4 (4 equiv) in Et2O, MeOH (2 equiv), 30 °C, 1 h. bDetermined by
300 MHz 1H NMR.
Therefore, it is clear that the presence of both the aryl moiety
and the oxo-function at the γ-carbon with respect to ester func-
tionality is essential to bring about reduction of ester group with
NaBH4. No reduction occurred when the reactions were carried
out in anhydrous ether in place of methanol, however, proportion of the lactone (compared to hydroxyester) was much
substrates 1a and 1b in the ethereal medium underwent trans- higher for 1a than for 3.
formations in the presence of various protic polar co-solvents
with different product distributions depending upon the nature The intermediacy of lactone 9 [24] was also established by an
of the co-solvent (Table 2).
independent route as outlined in Scheme 6.
Compounds 1a, 3, acetophenone and butyrophenone were indi- In order to prove the essentiality of the intermediacy of a
vidually subjected to reduction in ether (Table 3) in the pres- lactone, compound 1g (with the keto and ester moieties kept far
ence of MeOH (2 equiv) for a limited period of time (1 h). It apart for lactonization due to trans-geometry of the olefinic
was observed that the reduction of the keto group in the linkage) was treated with NaBH4 (4 equiv) in methanol.
γ-oxoesters 1a and 3 (entries 1 and 2 in Table 3) with the for- However, this reaction unexpectedly led to the exclusive forma-
mation of the lactones 9 and 4 as one of the products was much tion of 2a. With a smaller amount (2 equiv) of NaBH4 in
faster than the reduction of aryl alkyl ketones (entries 3 and 4 in methanol, compound 1g gave 9 and 2a in a ratio of
Table 3). Therefore, formation of lactone as the intermediate 69:31(Scheme 7).
might be crucial for more facile reduction of the keto moiety in
case of γ-oxoesters (entries 1 and 2 in Table 3), which is not It was presumed that the formation of 2a from 1g might occur
possible in the case of normal aryl alkyl ketones (entries 3 and 4 through the initial reduction of the keto group with the forma-
in Table 3). It is also interesting to note that although in both 1a tion of the γ-hydroxy-γ-aryl-α,β-unsaturated ester 10 [25]. In
and 3 the keto group was completely reduced, the relative this connection it should be noted that when a limited amount of
Table 2: Reactionsa of 1a and 1b with NaBH4 in anhydrous ether in the presence of protic polar co-solvents.
Entry
SM
Co-solvent
Relative product distribution (%)b
Substrate
Lactone
Diol
Hydroxyester
1
2
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
MeOH
EtOH
t-BuOH
H2O
–
37.1
40.6
94.2
2.1
62.9
59.4
–
–
–
–
3
5.8
86.1
87.3
–
–
4
11.8
9.6
99.0
51.8
–
–
5
AcOH
MeOH
EtOH
t-BuOH
H2O
3.1
–
6
Trace
48.2
18.1
15.4
51.4
–
7
–
–
8
60.4
48.7
21.9
21.5
35.9
26.6
9
–
10
AcOH
–
aNaBH4 (4 equiv) in Et2O, co-solvent (2 equiv), 30 °C, 4 h. bDetermined by 300 MHz 1H NMR.
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Beilstein J. Org. Chem. 2010, 6, 748–755.
Scheme 6: Intermediacy of a lactone in the formation of diol.
Scheme 7: Diol formation from γ-aryl-α,β-unsaturated-γ-ketoester through the intermediacy of a saturated lactone during the reduction with
methanolic NaBH4.
borohydride (1.2 equiv) was employed, we obtained the corres- gate reduction of olefinic linkage by intramolecular hydride
ponding γ-hydroxy-trans-α,β-enoic ester 10 from 1g. attack to produce saturated 4-hydroxyester, which subsequently
γ-Hydroxy-α,β-acetylenic esters have been reported [26] to cyclizes to yield 9 and then further reduced to the diol 2a.
undergo conjugate reduction of the triple bond with NaBH4 at
low temperature (−34 °C) to give the corresponding γ-hydroxy-
α,β-alkenoic esters, where the conjugate reduction does not
proceed beyond the double bond. However, we have observed
conjugate reduction of γ-hydroxy-α,β-alkenoic esters with
methanolic NaBH4 (4 equiv) at 30 °C during the transforma-
tion of 10 to 2a. Conjugate reduction here might be explained
by the following plausible mechanistic scheme (Figure 1) where
a mixed alkenyloxy alkoxy borohydride is initially formed by
the reaction of 10 with sodium borohydride followed by conju-
This postulate is supported by the observation that the proposed
intermediate 10 (independently synthesized from 11) is reduced
to 2a by the present method (Scheme 8, dotted arrows denote
the route proposed in Figure 1).
The fact that the reduction of the keto group occurs before the
conjugate reduction of the olefinic linkage has also been estab-
lished in this study. In the basic reaction medium produced by
NaBH4, the –COOH group is converted to –COO−, and as a
Figure 1: Mechanistic rationale for diol formation during the reduction of a γ-aryl-α,β-unsaturated-γ-ketoester with methanolic NaBH4.
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Beilstein J. Org. Chem. 2010, 6, 748–755.
Scheme 8: Intermediacy of γ-aryl-α,β-unsaturated-γ-hydroxyester during the reduction of γ-aryl-α,β-unsaturated-γ-ketoesters with methanolic NaBH4.
result the double bond is no longer electron-deficient. The Possibly, compound 13 was first reduced at the carbonyl func-
conjugate reduction by the intramolecular nucleophilic attack of tion followed by concomitant dehydrobromination (under the
the hydride is therefore not feasible. As a consequence, the –OH basic reaction conditions), conjugate reduction at olefinic
and –COO− are too far apart to interact with each other. There- linkage, further dehydrobromination to 10 and subsequent
fore a single bond between the carbinol carbon and carboxylic conjugate reduction of 10 with the formation of 9 (as per the
acid moiety is impossible and hence no possibility of rotation, previous mechanistic scheme shown in Figure 1) and reduction
lactonization and subsequent reduction to diol 2a. For this of 9 to 2a. The formation of 10 from 13 has been confirmed by
reason the γ-keto-α,β-enoic acid 11 on treatment with 4 equiv of the isolation of 10 (as the major product) as the outcome of the
NaBH4 in methanol smoothly furnished 12 as the preponderant reaction of 13 with a limited amount of NaBH4 (1.5 equiv), as
product without conjugate reduction and subsequent reductive shown in Scheme 10.
functional group transformation.
The crucial role of the lactone formation during the borohy-
When substrate 13 [39] (with vicinal anti-dibromo substituents dride-mediated reduction of 4-aryl-4-oxoester to 1,4-diols was
to increase the rotational barrier of the single bond) was reacted finally established (Scheme 11) when substrate 14 [40] (inca-
with methanolic NaBH4 (4 equiv) at room temperature, a mix- pable of lactonization due to distal spatial disposition of the
ture of 9, 10 and 2a was obtained in a ratio of 44:15:41 (as oxo- and methoxycarbonyl moieties imposed by the rigidity of
determined by 300 MHz 1H NMR), as shown in Scheme 9.
the cyclopropane ring system) underwent selective reduction of
Scheme 9: Reduction of γ-aryl-α,β-anti-dibromo-γ-ketoester with methanolic NaBH4.
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Beilstein J. Org. Chem. 2010, 6, 748–755.
Scheme 10: Intermediacy of γ-aryl-α,β-unsaturated-γ-hydroxyester during the reduction of γ-aryl-α,β-anti-dibromo-γ-ketoester with methanolic
NaBH4.
Scheme 11: Chemoselective reduction of keto group in the presence of ester moiety where structural rigidity prevents the formation of a lactone inter-
mediate during the reduction of γ-aryl-γ-ketoester with methanolic NaBH4.
the oxo-functionality only under refluxing conditions to yield Acknowledgements
15. No significant reaction was observed at room temperature The authors express sincere gratitude to Mr. N. Dutta of Indian
(monitored by TLC) even after 12 h.
Association for the Cultivation of Science, Kolkata, India for
necessary assistance. Financial and infrastructural support from
From the investigations carried out so far, the intermediacy of a UGC-CAS programme in Chemistry, Jadavpur University,
lactone during the NaBH4-mediated facile reduction of satu- DST-PURSE programme and DST-FIST programme are also
rated and α,β-unsaturated-γ-aryl-γ-oxoesters to the corres- gratefully acknowledged.
ponding saturated 1,4-butanediols has been firmly established.
References
1. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.;
However, the reason for more facile reduction of the γ-aryl-
lactones to diols and the relative reluctance of the γ-alkyl
Part A and Part B; Plenum Press: New York, 1990.
analogues is not yet clear.
2. House, H. O. Modern Synthetic Reactions; Benjamin/Cummings
Publishing Company: MA, 1972.
Conclusion
From the above study, a novel method utilizing NaBH4 in
3. Kim, J.; Bruning, J.; Park, K. E.; Lee, D. J.; Singaram, B. Org. Lett.
2009, 11, 4358–4361. doi:10.1021/ol901677b
methanol that can provide clean, cost-effective and facile access
to differently substituted 1-aryl-1,4-butanediols in good yield
and high purity from the easily accessible precursors has been
developed. The results also indicate that caution should be exer-
cised when methanolic sodium borohydride is used as a reagent
[1,2,17,22-27] for the chemoselective reduction of the keto
group of all types of γ-oxoesters.
4. Alinezhad, H.; Tajbakhsh, M.; Zare, M. Synth. Commun. 2009, 39,
2907–2916. doi:10.1080/00397910802691882
5. Sawada, T.; Ishii, H.; Ueda, T.; Aoki, J. Synth. Commun. 2009, 39,
3912–3923. doi:10.1080/00397910902883546
6. Alinezhad, H.; Tajbakhsh, M.; Mahdavi, N. Synth. Commun. 2010, 40,
951–956. doi:10.1080/00397910903026731
7. Cook, C.; Guinchard, X.; Liron, F.; Roulland, E. Org. Lett. 2010, 12,
744–747. doi:10.1021/ol902829e
8. Watanabe, T.; Imaizumi, T.; Chinen, T.; Nagumo, Y.; Shibuya, M.;
Usui, T.; Kanoh, N.; Iwabuchi, Y. Org. Lett. 2010, 12, 1040–1043.
doi:10.1021/ol1000389
Supporting Information
9. McIver, A. L.; Deiters, A. Org. Lett. 2010, 12, 1288–1291.
doi:10.1021/ol100177u
General experimental procedure for the NaBH4 reduction
and the spectral data of the products are presented as
supplementary data.
10.Collins, J.; Rinner, U.; Moser, M.; Hudlicky, T.; Ghiviriga, I.;
Romero, A. E.; Kornienko, A.; Ma, D.; Griffin, C.; Pandey, S.
J. Org. Chem. 2010, 75, 3069–3084. doi:10.1021/jo1003136
11.Brown, H. C.; Mead, E. J.; Subba Rao, B. C. J. Am. Chem. Soc. 1955,
77, 6209–6213. doi:10.1021/ja01628a044
Supporting Information File 1
Experimental.
12.Brown, M. S.; Rapoport, H. J. Org. Chem. 1963, 28, 3261–3263.
doi:10.1021/jo01046a538
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-94-S1.pdf]
13.Soai, K.; Oyamada, H.; Ookawa, A. Synth. Commun. 1982, 12,
463–467. doi:10.1080/00397918208065953
754

Beilstein J. Org. Chem. 2010, 6, 748–755.
14.Yamakawa, T.; Masaki, M.; Nohira, H. Bull. Chem. Soc. Jpn. 1991, 64,
2730–2734. doi:10.1246/bcsj.64.2730
License and Terms
15.Bhanu Prasad, A. S.; Bhaskar Kanth, J. V.; Periasamy, M. Tetrahedron
1992, 48, 4623–4628. doi:10.1016/S0040-4020(01)81236-9
16.Das, D.; Roy, S.; Das, P. K. Org. Lett. 2004, 6, 4133–4136.
doi:10.1021/ol0481176
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
17.Barnett, J. E. G.; Kent, P. W. J. Chem. Soc. 1963, 2743–2747.
doi:10.1039/JR9630002743
18.Dalla, V.; Cotelle, P.; Catteau, J. P. Tetrahedron Lett. 1997, 38,
1577–1580. doi:10.1016/S0040-4039(97)00154-8
19.Dalla, V.; Catteau, J. P.; Pale, P. Tetrahedron Lett. 1999, 40,
5193–5196. doi:10.1016/S0040-4039(99)01006-0
20.Soai, K.; Oyamada, H. Synthesis 1984, 605–607.
doi:10.1055/s-1984-30911
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
21.Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron 1993, 49,
11169–11182. doi:10.1016/S0040-4020(01)81804-4
22.Padhi, S. K.; Chadha, A. Synlett 2003, 639–642.
doi:10.1055/s-2003-38366
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.6.94
23.Nozaki, H.; Kondô, K.; Nakanisi, O.; Sisido, K. Tetrahedron 1963, 19,
1617–1623. doi:10.1016/S0040-4020(01)99236-1
24.Karnik, A. V.; Patil, S. T.; Patnekar, S. S.; Semwal, A. New J. Chem.
2004, 28, 1420–1422. doi:10.1039/b409061f
25.Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443–445.
doi:10.1016/S0040-4039(02)02602-3
26.Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785–1787.
doi:10.1021/ol0495366
27.Ward, R. S. Selectivity in Organic Synthesis; John Wiley and Sons:
West Sussex, England, 1999; pp 4 ff.
28.Mori, N.; Ōmura, S.; Tsuzuki, Y. Bull. Chem. Soc. Jpn. 1965, 38,
1631–1634. doi:10.1246/bcsj.38.1631
29.Tanner, D.; Groth, T. Tetrahedron 1997, 53, 16139–16146.
doi:10.1016/S0040-4020(97)10053-9
30.Bhat, K. S.; Rao, A. S. Indian J. Chem. 1981, 20B, 355–358.
31.Mudryk, B.; Cohen, T. J. Org. Chem. 1989, 54, 5657–5659.
doi:10.1021/jo00285a008
32.Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahedron: Asymmetry 2003,
14, 1575–1580. doi:10.1016/S0957-4166(03)00281-7
33.Gurudutt, K. N.; Pasha, M. A.; Ravindranath, B.; Srinivas, P.
Tetrahedron 1984, 40, 1629–1632.
doi:10.1016/S0040-4020(01)91816-2
34.Azuma, N.; Sanda, F.; Takata, T.; Endo, T. Macromolecules 1998, 31,
1710–1715. doi:10.1021/ma971082n
35.Mullah, K. B.; Bentrude, W. G. J. Org. Chem. 1991, 56, 7218–7224.
doi:10.1021/jo00026a008
36.Shibata, T.; Fujiwara, R.; Ueno, Y. Synlett 2005, 152–154.
doi:10.1055/s-2004-835664
37.Kirmse, W.; Kund, K. J. Org. Chem. 1990, 55, 2325–2332.
doi:10.1021/jo00295a018
38.Newman, M. S. J. Org. Chem. 1961, 26, 2630–2633.
doi:10.1021/jo01066a004
39.Chaudhuri, S. K.; Roy, S.; Saha, M.; Bhar, S. Synth. Commun. 2007,
37, 271–274. doi:10.1080/00397910601033617
40.Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J.
Angew. Chem., Int. Ed. Engl. 2003, 42, 828–831.
doi:10.1002/anie.200390222
755