A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

Article abstract of DOI:10.3762/bjoc.15.287

The acylation of the acetonitrile anion with lactones and esters in ethereal solvents was successfully exploited using inexpensive KOt-Bu to obtain a variety of β-ketonitriles and trifunctionalized building blocks, including useful O-unprotected diols. It was discovered that lactones react to produce the corresponding derivatized cyclic hemiketals. Furthermore, the addition of a catalytic amount of isopropanol, or 18-crown-6, was necessary to facilitate the reaction and to reduce side-product formation under ambient conditions.

Full text of DOI:10.3762/bjoc.15.287

A green, economical synthesis of β-ketonitriles and
trifunctionalized building blocks from esters and lactones
Daniel P. Pienaar*, Kamogelo R. Butsi, Amanda L. Rousseau and Dean Brady
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2930–2935.
Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, PO Wits 2050, Johannesburg, South Africa
doi:10.3762/bjoc.15.287
Received: 16 September 2019
Accepted: 22 November 2019
Published: 06 December 2019
Email:
Daniel P. Pienaar* - Daniel.Pienaar@wits.ac.za
* Corresponding author
This article is part of the thematic issue "Green chemistry II".
Guest Editor: L. Vaccaro
Keywords:
acylation; β-ketonitrile; enolizable; trifunctionalized; sustainable
© 2019 Pienaar et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The acylation of the acetonitrile anion with lactones and esters in ethereal solvents was successfully exploited using inexpensive
KOt-Bu to obtain a variety of β-ketonitriles and trifunctionalized building blocks, including useful O-unprotected diols. It was
discovered that lactones react to produce the corresponding derivatized cyclic hemiketals. Furthermore, the addition of a catalytic
amount of isopropanol, or 18-crown-6, was necessary to facilitate the reaction and to reduce side-product formation under ambient
conditions.
Introduction
β-Ketonitriles represent highly versatile intermediates for the of employing explosive sodium amide in synthesis are well
synthesis of heteroaromatic compounds and a wide variety of known [6] and amidine side-product formation was observed at
pharmaceuticals. A recent review by Kiyokawa et al. summa- times through reaction of the nucleophilic amide base with
rizes the applications of these valuable compounds and the nitrile. Furthermore, clearly two equivalents of base (and
abundant methods that have been developed over recent nitrile) were necessary to drive the reactions to completion as
decades to prepare them [1], most of which still involve envi- the acylated product is more acidic than the nitrile starting ma-
ronmentally unfriendly transition-metal-based reactions. Acyl- terial. More recently, ester or Weinreb amide reactions with
ations of in situ-generated nitrile anions with esters to produce acetonitrile using lithium bases at low temperature [7], or simi-
β-ketonitriles were first reported long ago, for example by using larly NaH at high temperatures [8], have been reported as
sodium methoxide [2], sodium ethoxide [3] or sodium amide feasible alternatives with varied success and usually a lack of
[4,5]. The reaction was found to proceed more efficiently when general applicability (e.g., enolizable esters and ketone prod-
using sodium amide as the base [5], although the inherent risks ucts may react undesirably under these highly basic reaction
2930

Beilstein J. Org. Chem. 2019, 15, 2930–2935.
conditions). Furthermore, these methods constitute either lowed by reaction with acetonitrile (CH3CN), a multistep ap-
expensive, less scalable procedures employing an excess of proach would be less economical in industry (Scheme 1).
reagents, hazardous, flammable, or toxic reagents and high tem-
peratures are required, which, in turn, may be detrimental to Results and Discussion
more highly functionalized starting materials. Nevertheless, this To date, the most economically appealing conditions from an
reaction under milder conditions is a valuable C–C bond- environmentally friendly perspective entail relatively mild base-
forming reaction for the preparation of β-substituted carboxylic promoted (potassium tert-pentoxide or potassium tert-butoxide)
acid derivatives, in general, from cheap commercially available acylation of substituted nitrile anions with esters under ambient
esters, and as such merited further investigation.
conditions, as published by Ji et al. (2006) [9] and Kim et al.
(2013) [10]. The large excess of ester and expensive base
We required a green, safe and scalable process for the facile (potassium tert-pentoxide) required in the former method, in
production of O-unprotected hydroxylated β-hydroxynitrile 1 our opinion rendered it less economical and practical as a scal-
via trifunctionalized β-ketonitrile 2 by a direct, atom-economi- able option. Furthermore, when we applied Kim’s (KOt-Bu)
cal ring opening of enolizable δ-valerolactone (3, Scheme 1). method to δ-valerolactone, we obtained a highly viscous oil
Although a two-step (or four-step, should hydroxy group made up of a mixture of inseparable compounds that were
O-protection prove to be necessary prior to acylation) protocol unidentifiable by crude 1H NMR spectroscopy (see Supporting
could, in theory, be envisaged to produce β-ketonitrile 2 from 3 Information File 1). Similarly, using dry THF, 1 equiv CH3CN
by ring-opening esterification to afford hydroxy ester 4 fol- and 1 equiv KOt-Bu at rt, we obtained within minutes a precipi-
tated amorphous gum which, upon work-up (partitioning be-
tween EtOAc and water) and removal of the solvents in vacuo,
afforded a complex mixture of undesirable products by
1H NMR spectroscopy. However, to our delight, upon the addi-
tion of 20 mol % isopropanol (IPA) to the THF reaction mix-
ture, we obtained a moderate amount of the desired product,
albeit not as the open-chain β-ketonitrile 2, but exclusively as
the corresponding, cyclized hemiketal 5 (Scheme 2).
Furthermore, when using the green, sustainably produced sol-
vent 2-methyltetrahydrofuran (2MeTHF) [11,12], in place of
THF, we obtained a significantly higher yield of 5. Remarkably,
Scheme 1: Proposed retrosynthesis of the free diol 1.
Scheme 2: Preparation of O-unprotected, trifunctionalized synthons from lactones.
2931

Beilstein J. Org. Chem. 2019, 15, 2930–2935.
a crude yield of 80% of the hemiketal was obtained from tech- The application of this method to produce the analogous
nical grade, solidified δ-valerolactone that had previously been hemiketal 6 from γ-butyrolactone was not as efficient. Al-
stored at rt (a compound which is known to polymerize though the desired product 6 could indeed be isolated in 15%
unavoidably upon storage, and the technical grade reagent yield from γ-butyrolactone when the same reaction conditions
contains up to 25% polymerized material). The crude product were applied in THF, the use of 2MeTHF as solvent resulted in
was shown to be almost pure by 1H NMR and TLC. It can be a complex mixture with only traces of the desired product, as
seen in Supporting Information File 1 that the crude product ob- revealed by crude product NMR spectroscopy. It is thought that
tained using 2MeTHF was significantly more enriched/purer in the semivolatility of product 6 may have also resulted in lower
hemiketal 5 than that obtained using THF as the solvent. Pure yields compared to 5.
product was readily obtained in 70% yield after purification by
column chromatography. We reasoned that the lower aqueous It is well known that cyclic compounds often react differently
miscibility of 2MeTHF, as compared to THF, resulted in a more dependent on their ring size, with 5-membered rings being gen-
efficient product extraction procedure, which further contribut- erally more constrained and therefore more likely to ring-open
ed to the increased yield of 5. Varying the amount of IPA than 6-membered rings. For example, in sugars, hemiacetal
resulted in lower yields and more complex product mixtures. pyranoses (due to reduced bond angle strain) are energetically
Substitution of IPA with tert-butanol or ethanol resulted in sig- much more favored in solution compared to the corresponding
nificantly lower product yields and a more complex product 5-membered furanoses [17]. Significantly, 1H (500 MHz) and
profile, as observed by crude product 1H NMR spectroscopy. 13C NMR (126 MHz) of the purified product 6 (pure by TLC)
indicated traces of what appears to be the uncyclized β-ketoni-
The mechanism by which IPA facilitates the reaction towards trile 7 (see Supporting Information File 1). This suggests
the formation of the cyclic hemiketal and indeed, the desired that, in solution, the keto–hemiketal equilibrium for the
β-ketonitrile scaffold, has not been conclusively determined in butyrolactone product does not favor completely hemiketal 6,
this work. It is well known that strong-base deprotonation of as was observed for the 6-membered cycle 5. The authors
acetonitrile leads to the formation of a nitrile-stabilized carb- therefore propose that formation of the 6-membered hemiketal
anion, in resonance with a ketene iminate anion. It has been ring is more energetically favored under these reaction condi-
calculated that the latter CN double-bonded species is relative- tions, compared to the analogous 5-membered system.
ly unstable compared to the CN triple-bonded carbanion This effectively shields both the enolizable ketone and the steri-
species, which has the negative charge localized on the α-car- cally unhindered primary hydroxy functional groups in the
bon atom [13]. This carbanion is therefore an excellent nucleo- valerolactone-derived product in situ, which reduces the
phile and is usually generated from nitriles using metal amides occurrence of side-reactions and side-products, e.g., aldol reac-
or other strong bases [14,15]. Under our reaction conditions at tions and polymerization, and results in a higher yield of the
rt, we propose that the presence of a catalytic amount of IPA in- desired product compared to that obtained from γ-butyrolac-
creases the dielectric constant of the solvent as a whole, thereby tone.
increasing the solubility of both the KOt-Bu base and the aceto-
nitrile derived KCH2CN salt. This effectively accelerates the With compounds 5 and 6 in hand, simple and mild reduction
generation of the latter and as such, its reaction with the lactone protocols at rt satisfyingly afforded the desired diols 1 and 8,
(or ester) carbonyl carbon. By increasing the solubility of the thereby indicating that the hemiketals are still fully reducible
conjugate base salt, the pKa of acetonitrile in the ethereal sol- under standard ketone reduction conditions. Purification of 6
vent is effectively lowered by adding a small amount of polar, afforded only a 10% overall yield of the diol 8, but the direct
protic IPA and this facilitates acetonitrile deprotonation. Alter- conversion of crude intermediate product 6 resulted in a
natively, the addition of a crown ether is also known to en- doubling of the overall yield of the diol from lactone to 20%
hance nucleophilic substitution reaction rates, but in this case (Scheme 2).
through the suppression of ion-pairing [16]. We also investigat-
ed this option for the first time in the synthesis of β-ketonitriles Due to the interest in the potential preparation of pyrimidines
from esters, as described later (see Table 1). Finally, it is prob- from β-ketonitriles and guanidine [18], we wanted to test the
able that the presence of protic IPA suppresses enolization as general applicability of this method for access to a variety of
the reaction progresses, by quenching KOt-Bu generated alkyl and aryl-substituted β-ketonitriles (as summarized in
enolates and similarly, reactive alkoxide anions. This reduces Table 1). When we applied this methodology to ethyl cyclo-
the occurrence of undesirable side-reactions, e.g., intermolecu- propane carboxylate in THF, we were delighted to obtain the
lar aldol reaction, lactone/ketonitrile product dimerization and desired (relatively volatile) product 9 in modest yield, because
ring-opening polymerization.
in our hands previous attempts to prepare 9 in sufficient
2932

Beilstein J. Org. Chem. 2019, 15, 2930–2935.
Table 1: Preparation of a variety of β-ketonitriles.
Entry
Product
R1
R2
CH3CN
(equiv)
KOt-Bu
(equiv)
Additive
(equiv)
Solvent
(time at rt)
Yield (%)
IPA
2MeTHF
(2 h)
1
2
9
Et
2
2
2
2
48a
47
(0.2)
IPA
(0.2)
2MeTHF
(2 h)
10
Me
IPA
2MeTHF
(1 h)
3
4
5
11
12
13
Me
Me
Me
2
2
2
2
2
2
53
76a
47
(0.2)
IPA
(0.2)
2MeTHF
(2 h)
IPA
(0.2)
2MeTHF
(2 h)
IPA
2MeTHF
(2 h)
6
7
14
15
Me
Me
2
2
2
2
43
68
(0.2)
IPA
(0.2)
2MeTHF
(2 h)
IPA
2MeTHF
(2 h)
8
9
16
17
18
Me
Et
2
2
29b
64
(0.2)
IPA
(0.2)
2MeTHF
(30 min)
1.5
1.2
1.1
1.2
IPA
(0.1)
MTBE
(2 h)
10
Me
38
18-crown-6
(0.1)
MTBE
11
12
18
18
Me
Me
1.2
1.2
1.2
1.2
58
67
(30 min)
18-crown-6
(0.1)
2MeTHF
(30 min)
aSemivolatile products of which yield losses may have occurred upon solvent removal in vacuo. bA significant amount of the corresponding carboxylic
acid was isolated as side-product. This suggests that base-catalyzed ester alcoholysis may be a competing side-reaction.
amounts by following a literature procedure using NaH (in Other methods were explored in an attempt to increase product
refluxing THF) [8] had failed. The reaction, again with yields. Although a putative radical mechanism that may be
20 mol % IPA added and under an inert N2 atmosphere, promoted in the presence of oxygen had previously been postu-
afforded a similar product yield using 2MeTHF as solvent. lated by Kim et al. [10], we did not obtain increased product
Increasing the reaction time to 24 h did not increase yields when carrying out the reaction in air. Furthermore,
the product yield, and residual starting material was heating the reaction mixtures above rt when using NaH as a
observed throughout the reaction course, by TLC base in refluxing THF was clearly detrimental to product yield
monitoring. Due to the persistent presence of unreacted according to our previous observations and was not attempted.
starting materials in all examples given, it was decided
to dose with second equivalents of base (KOt-Bu) and CH3CN Significantly, no side-products were observed in the organic
after 1 h of reaction, as seen in most examples in Table 1. extract after work-up, and a series of β-ketonitriles (some of
Disappointingly, we were unable to further significantly which are semivolatile compounds) was successfully prepared
increase product yields, for example for the phenyl-substituted and isolated under standard, ambient conditions in modest
fluoxetine (Prozac®) intermediate 10 [19], which remained at yields. The best yields were obtained for the 2-propyl 12 (76%)
ca. 50%.
and cyclohexyl 15 (68%) analogues. We were pleased to obtain
2933

Beilstein J. Org. Chem. 2019, 15, 2930–2935.
References
the highly versatile and synthetically useful cinnamoylacetoni-
trile 17 [20] from renewable ethyl cinnamate in 64% yield, as
this yield was comparable to more expensive and hazardous
lithiation protocols [7].
1. Kiyokawa, K.; Nagata, T.; Minakata, S. Synthesis 2018, 50, 485–498.
doi:10.1055/s-0036-1589128
2. Long, R. S. J. Am. Chem. Soc. 1947, 69, 990–995.
doi:10.1021/ja01197a004
3. Dorsch, J. B.; McElvain, S. M. J. Am. Chem. Soc. 1932, 54,
2960–2964. doi:10.1021/ja01346a047
4. Levine, R.; Hauser, C. R. J. Am. Chem. Soc. 1946, 68, 760–761.
doi:10.1021/ja01209a016
5. Eby, C. J.; Hauser, C. R. J. Am. Chem. Soc. 1957, 79, 723–725.
doi:10.1021/ja01560a060
6. Urben, P. G.; Pitt, M. J., Eds. Bretherick's Handbook of Reactive
Chemical Hazards, 7th ed.; Academic Press: Oxford, United Kingdom,
2007; pp 1686–1688.
7. Mamuye, A. D.; Castoldi, L.; Azzena, U.; Holzer, W.; Pace, V.
Org. Biomol. Chem. 2015, 13, 1969–1973. doi:10.1039/c4ob02398f
8. Miyamoto, Y.; Banno, Y.; Yamashita, T.; Fujimoto, T.; Oi, S.;
Moritoh, Y.; Asakawa, T.; Kataoka, O.; Yashiro, H.; Takeuchi, K.;
Suzuki, N.; Ikedo, K.; Kosaka, T.; Tsubotani, S.; Tani, A.; Sasaki, M.;
Funami, M.; Amano, M.; Yamamoto, Y.; Aertgeerts, K.; Yano, J.;
Maezaki, H. J. Med. Chem. 2011, 54, 831–850.
doi:10.1021/jm101236h
9. Ji, Y.; Trenkle, W. C.; Vowles, J. V. Org. Lett. 2006, 8, 1161–1163.
doi:10.1021/ol053164z
10.Kim, B. R.; Lee, H.-G.; Kang, S.-B.; Jung, K.-J.; Sung, G. H.; Kim, J.-J.;
Lee, S.-G.; Yoon, Y.-J. Tetrahedron 2013, 69, 10331–10336.
doi:10.1016/j.tet.2013.10.007
Finally, we attempted method optimization for the production
of a commercially important pharmaceutical intermediate, thio-
phene-substituted β-ketonitrile precursor 18 of the antidepres-
sant drug duloxetine (Cymbalta®) [21,22]. It was interesting to
note that, although 38% of the thiophene product could be ob-
tained using methyl tert-butyl ether (MTBE) with 0.1 equiv IPA
as co-solvent/additive, a significantly higher yield of 18 was ob-
tained when we used 10 mol % 18-crown-6 ether instead of IPA
in a similarly catalytic amount. The yield was further improved
to 67% using 2MeTHF as the solvent. It should be noted that
the use of the crown ether resulted in recovery complications
for some of the other compounds (e.g., when this methodology
was applied to δ-valerolactone and γ-butyrolactone) and may
therefore not be universally beneficial.
Conclusion
In conclusion, mild, environmentally friendly procedures were
developed for the preparation of trifunctionalized building
blocks (hydroxylated β-ketonitriles) and valuable β-ketonitriles
(including enolizable compounds) in modest to good yields
from lactones and esters. We are currently investigating novel
applications of diols 1 and 8, as well as the application of this
methodology for the synthesis of glycomimetic products from
sugar lactones, and for the synthesis of various pyrimidines.
11.Sheldon, R. A. Green Chem. 2017, 19, 18–43.
doi:10.1039/c6gc02157c
12.Clarke, C. J.; Tu, W.-C.; Levers, O.; Bröhl, A.; Hallett, J. P. Chem. Rev.
2018, 118, 747–800. doi:10.1021/acs.chemrev.7b00571
13.Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121,
715–726. doi:10.1021/ja982692l
14.Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005, 70,
2200–2205. doi:10.1021/jo047877r
15.Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1–23.
doi:10.1016/s0040-4020(01)01134-6
16.Cook, F. L.; Bowers, C. W.; Liotta, C. L. J. Org. Chem. 1974, 39,
3416–3418. doi:10.1021/jo00937a026
Supporting Information
Supporting Information File 1
17.Collins, P.; Ferrier, R. Monosaccharides – Their Chemistry and Their
Roles in Natural Products; John Wiley & Sons Ltd.: Chichester, UK,
1995; 11 and 43.
18.Liu, B.; Liu, M.; Xin, Z.; Zhao, H.; Serby, M. D.; Kosogof, C.;
Nelson, L. T. J.; Szczepankiewicz, B. G.; Kaszubska, W.;
Schaefer, V. G.; Falls, H. D.; Lin, C. W.; Collins, C. A.; Sham, H. L.;
Liu, G. Bioorg. Med. Chem. Lett. 2006, 16, 1864–1868.
doi:10.1016/j.bmcl.2006.01.012
Experimental procedures, compound characterization data
and NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-287-S1.pdf]
Acknowledgements
See for an example.
19.Hammond, R. J.; Poston, B. W.; Ghiviriga, I.; Feske, B. D.
Tetrahedron Lett. 2007, 48, 1217–1219.
KRB thanks the National Research Foundation (South Africa)
and the SABINA network for funding. DP and DB gratefully
acknowledge the Department of Science and Technology
Biocatalysis Initiative (Grant 0175/2013) and CHIETA (South
Africa) for funding. The authors wish to thank Thapelo Mbhele,
Tracy Lau and Vaughn Silversten for technical assistance.
doi:10.1016/j.tetlet.2006.12.057
20.Swellem, R. H.; Allam, Y. A.; Nawwar, G. A. M.
Z. Naturforsch., B: J. Chem. Sci. 1999, 54, 1197–1201.
doi:10.1515/znb-1999-0917
21.Rimoldi, I.; Facchetti, G.; Nava, D.; Contente, M. L.; Gandolfi, R.
Tetrahedron: Asymmetry 2016, 27, 389–396.
doi:10.1016/j.tetasy.2016.04.002
22.Wang, G.; Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005, 16,
1873–1879. doi:10.1016/j.tetasy.2005.04.002
ORCID® iDs
Daniel P. Pienaar - https://orcid.org/0000-0003-0609-1989
Kamogelo R. Butsi - https://orcid.org/0000-0003-4734-2465
Amanda L. Rousseau - https://orcid.org/0000-0002-9339-1797
2934

Beilstein J. Org. Chem. 2019, 15, 2930–2935.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.15.287
2935