Sterically congested ester formation from α-substituted malononitrile and alcohol by an oxidative method using molecular oxygen

Article abstract of DOI:10.1002/ejoc.201800984

A metal-free oxidative esterification or thio-esterifica-tion of readily available substituted malononitrile and alcohol or thiol has been developed by simply mixing α-substituted malononitrile and alcohol or thiol in the presence of base under a molecular oxygen atmosphere. Sterically hindered ester or thioester can be prepared efficiently.

Full text of DOI:10.1002/ejoc.201800984

DOI: 10.1002/ejoc.201800984
Communication
Oxidative Esterification
Sterically Congested Ester Formation from α-Substituted
Malononitrile and Alcohol by an Oxidative Method
Using Molecular Oxygen
Yujiro Hayashi,*[a] Jing Li,[a] Hirotaka Asano,[a] and Daisuke Sakamoto[a]
Abstract: A metal-free oxidative esterification or thio-esterifica- malononitrile and alcohol or thiol in the presence of base under
tion of readily available substituted malononitrile and alcohol a molecular oxygen atmosphere. Sterically hindered ester or
or thiol has been developed by simply mixing α-substituted thioester can be prepared efficiently.
Introduction
the presence of base under a molecular oxygen atmosphere.[10]
A mechanistic study proved that acyl cyanide is a key interme-
diate, which reacts with amine to generate sterically hindered
amide (Figure 1). It was anticipated that sterically hindered ester
would be formed when alcohol was employed as a nucleophile
instead of amine. In this communication, we disclose the suc-
cessful realization of this scenario.
Esters are one of the most important units in organic synthe-
sis.[1] Classical methods for ester synthesis are based on nucleo-
philic substitution of carboxylic acid derivatives such as carbox-
ylic acid halides, anhydrides, and activated esters with alco-
hols.[2] In spite of the many synthetic methods for the genera-
tion of esters, the ester formation of the sterically hindered
carboxylic acid is still a challenging transformation because of
its difficulty based on steric reason.
On the other hand, acyl cyanide is a reactive species and it
can be widely utilized in organic synthesis. In spite of its high
reactivity as an activated carboxylic acid equivalent, it is not
widely used in the synthesis of ester because of the limitation
of the generation of acyl cyanides.[3] Generally, acyl cyanides
can be prepared by the reactions of acid halides with a variety
of metal cyanides or trimethylsilyl cyanide.[4a] An alternative
method is the oxidation of cyanohydrins or phenyl cyanide with
strong oxidants or using transition metals.[4b,4c] The oxidation
of α-substituted malononitrile using strong oxidation reagents
such as MCPBA, H2O2, or Oxone is also widely used to generate
acyl cyanide, but there is a limitation in the substrate scope.[5]
In addition, while the protected hydroxyl malononitriles are
known as masked acyl cyanides, these methods still have a limi-
tation of the substrate scope for sterically hindered systems.[6]
An efficient and simple procedure to construct a sterically
hindered ester without a transition metal catalyst, elaborate re-
agent, and strong oxidants is still urgently required.
Figure 1. a) Known methods to generate acyl cyanide, b) the present method
to make ester or thioester using in situ generated acy cyanide.
We have already developed a series of novel transition
metal-free oxidative generations of ketones,[7] amides,[8] and es-
ters[9] from nitroalkane by the use of molecular oxygen. Re-
cently, we developed an efficient method to generate sterically
hindered amide from α-substituted malononitrile and amine in
We selected a readily prepared α-substituted malononitrile
1a and benzyl alcohol 2a as a model system for the optimiza-
tion of the formation of sterically hindered ester 3aa (Table 1).
Based on our previous procedures for sterically hindered amide
synthesis,[10] Cs2CO3 was selected as a base in CH3CN under O2
atmosphere at 50 °C as an initial study. To our delight, malono-
nitrile 1a was completely consumed and the desired ester 3aa
was generated in 82 % yield after 2 h (entry 1). In order to
further improve the chemical yield, other carbonate bases such
as Na2CO3 (entry 2) and K2CO3 (entry 3) were screened, but the
[a] Graduate School of Science, Tohoku University,
6-3 Aramaki-Aza, Aoba-ku, Sendai 980-8578, Japan
E-mail: yhayashi@m.tohoku.ac.jp
http://www.ykbsc.chem.tohoku.ac.jp
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800984.
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Communication
reaction was slow with a lower yield. The decrease of the reac- (3aa, 3ac). In the case of 2-chloro-1-ethanol, which might gen-
tion temperature to room temperature increased the yield of erate oxirane, the ester was obtained in good yield (3ab).
ester to 90 % with a longer reaction time (entry 4).
Phenol is also employed very well (3ad). Alcohols such as allyl
and propynyl alcohols displayed high reactivity to generate the
corresponding esters (3ae, 3af). In addition, an unprotected
1,3-diol with primary and secondary alcohol moieties afforded
the corresponding ester chemoselectively in primary alcohol
site in 95 % yield (3ag). The alcohol reacted selectively without
reaction of N-Boc-protected amine moiety (3ah). Even sterically
hindered iPrOH is a suitable alcohol (3ai). tert-Butylthiol, which
is easily oxidized, worked very well to afford the desired thio-
ester in 68 % yield (3aj).
The generality in the malononitrile moiety[11,12] was exam-
ined using benzyl alcohol 2a as a representative alcohol
(Table 3). α-Substituted malononitriles such as α-benzyl or α-
cyclohexyl were excellent substrates to provide esters in good
yield (3ba, 3ca). As for the substrates having aromatic groups
at the α-position of malononitrile, the reaction proceeded to
Table 1. Optimization of oxidative esterification of 1a and 2a.[a]
Entry
Base
Time [h]
Temp. [°C]
Yield [%]
1
2
Cs2CO3
Na2CO3
K2CO3
2
50
50
50
r.t.
82
21
71
90
66
57
11
3
4[b]
Cs2CO3
[a] Reactions were conducted with 1a (0.5 mmol), benzyl alcohol 2a
(0.5 mmol) under O2 (1 atm). [b] Cs2CO3 was dried under a flame.
Next, the scope of the esterification of alcohol moiety was
investigated with the optimized conditions using 2,2-dimethyl-
3-phenylpropane-1,1-dicarbonitrile (1a) as a representative mal-
ononitrile (Table 2). MeOH and BnOH are suitable nucleophiles
Table 3. Coupling reaction of sterically hindered malononitriles 1 with benzyl
alcohol 2a.[a]
Table 2. Coupling reaction of sterically hindered malononitrile 1a with various
alcohols.[a]
[a] Unless noted otherwise, all reactions were conducted with 1a (0.5 mmol),
alcohol 2 (0.5 mmol), Cs2CO3 (1.0 mmol) in CH3CN at rt under O2 (1 atm.).
[b] MeOH (1.0 mmol) was used. [c] Alcohol (0.55 mmol) was used at 60 °C.
[d] tBuSH (1.0 mmol) was used.
[a] Unless noted otherwise, all reactions were conducted with 1 (0.5 mmol),
benzyl alcohol 2a (0.5 mmol), Cs2CO3 (1.0 mmol) in CH3CN (0.1
M) at room
temperature under O2 (1 atm.). [b] Reaction was conducted in CH3CN at
100 °C. [c] Reaction was conducted at 70 °C.
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Communication
[3] Application of acyl cyanide intermediate in synthesis, see: a) S. Hünig, R.
Schaller, Angew. Chem. Int. Ed. Engl. 1982, 21, 36–49; Angew. Chem. 1982,
94, 1–15; b) S. Takuma, Y. Hamada, T. Shioiri, Chem. Pharm. Bull. 1982,
30, 3147–3135; c) S. Lundgren, E. Wingstrand, C. Moberg, Adv. Synth.
Catal. 2007, 349, 364–372; d) H. H. Choi, Y. H. Son, M. S. Jung, E. J. Kung,
Tetrahedron Lett. 2011, 52, 2312–2315.
[4] Transition metal mediated synthesis of benzoyl cyanides from benzyl
cyanide under aerobic conditions: a) S.-I. Murahashi, T. Naota, N. Naka-
jima, Tetrahedron Lett. 1985, 26, 925–928; b) X. Chen, T. Chen, Q. Li, Y.
Zhou, L.-B. Han, S.-F. Yin, Chem. Eur. J. 2014, 20, 12234–12238; c) Y. Sugi-
ura, Y. Tachikawa, Y. Nagasawa, N. Tada, A. Itoh, RSC Adv. 2015, 5, 70883–
70886.
afford the esters (3da, 3ea) with a longer reaction time. When
the α-position of malononitrile are sterically congested quater-
nary carbon, the reaction proceeded as well to provide the cor-
responding esters in good yield (3fa–3ka).
Based on our previous mechanistic studies of making
amides[10] from malononitriles, a possible reaction mechanism
is illustrated in Figure 2. The α-substituted malononitrile is
firstly deprotonated to generate an anion, which reacts with
molecular oxygen to form a peroxide adduct 4. Peroxide 4
would fragment into acylating species 5, which is intercepted
by the alcohol or thiol nucleophiles to afford ester 3 or thio-
ester.
[5] Oxidative methods to synthesize acyl cyanide intermediates from
malononitriles: a) M. Brünjes, M. J. Ford, H. Dietrich, K. Wilson, Synlett
2015, 26, 1365–1370; b) S. Fçrster, O. Tverskoy, G. Helmchen, Synlett
2008, 2803–2806.
[6] a) K. S. Yang, A. E. Nibbs, Y. E. Turkmen, V. H. Rawal, J. Am. Chem. Soc.
2013, 135, 16050–16053; b) K. S. Yang, V. H. Rawal, J. Am. Chem. Soc.
2014, 136, 16148–16151.
[7] For a metal free Nef reaction using O2 to make ketones and α,ꢀ-unsatu-
rated ketones from nitroalkanes and nitroalkenes: a) Y. Hayashi,
S. Umemiya, Angew. Chem. Int. Ed. 2013, 52, 3450–3452; Angew. Chem.
2013, 125, 3534–3536; b) S. Umemiya, K. Nishino, I. Sato, Y. Hayashi,
Chem. Eur. J. 2014, 20, 15753–15759.
[8] Oxidative amidation of primary nitroalkanes using O2: a) J. Li, M. J. Lear,
Y. Kawamoto, S. Umemiya, A. Wong, E. Kwon, I. Sato, Y. Hayashi, Angew.
Chem. Int. Ed. 2015, 54, 12986–12990; Angew. Chem. 2015, 127, 13178–
13182; b) J. Li, M. J. Lear, E. Kwon, Y. Hayashi, Chem. Eur. J. 2016, 22,
5538–5542.
[9] J. Li, M. J. Lear, Y. Hayashi, Chem. Commun. 2018, 54, 6360–6363.
[10] For challenging one-pot O2-mediated amidations of 1,1-dicyanoalkanes
via dioxiranes and acyl cyanides, see: J. Li, M. J. Lear, Y. Hayashi, Angew.
Chem. Int. Ed. 2016, 55, 9060–9064; Angew. Chem. 2016, 128, 9206–9210.
[11] Selected examples: Synthesis of hindered α-substituted malononitrles
from malononitriles: a) R. O. Hutchins, B. E. Maryanoff, Org. Synth. 1973,
53, 21–25; b) Synthesis of α,α,α-trisubstited malononitriles by conjugate
addition of organometallic compounds to disubstituted methylene-
malononitrile: c) Z. Florjańczyk, U. Iwaniak, J. Organomet. Chem. 1983,
252, 275–280; d) G. A. Russell, P. Chen, C.-F. Yao, B. H. Kim, J. Am. Chem.
Soc. 1995, 117, 5967–5972.
Figure 2. Proposed oxidative conversion of α-substituted malononitrile into
ester.
In summary, we have developed an efficient and practical
method for the synthesis of esters or thioesters from α-substi-
tuted malononitriles and alcohols or thiol under molecular oxy-
gen. Sterically congested ester, which is difficult to synthesize
using the conventional methods, can be prepared successfully
in good yield. The reaction is simple, and requires only mixing
malononitrile derivative, alcohol, or thiol and base under an O2
atmosphere without a transition metal catalyst, strong oxidant,
or elaborate reagent.
Acknowledgments
This work was funded by JSPS KAKENHI Grant Number JP
16K13942.
[12] Selected examples of asymmetric synthesis of α-substituted malono-
nitrile, see; a) T. Arai, T. Moribatake, H. Masu, Chem. Eur. J. 2015, 21,
10671–10675; b) M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N. Jacobsen,
J. Am. Chem. Soc. 2005, 127, 1313–1317; c) Y. Hoashi, T. Okino, Y. Take-
moto, Angew. Chem. Int. Ed. 2005, 44, 4032–4035; Angew. Chem. 2005,
117, 4100–4103.
Keywords: Esters · Malononitrile · Oxygen ·
Esterification · Steric hindrance
[1] a) K. Ishihara, Tetrahedron 2009, 65, 1085–1109; b) J. Otera, J. Nishikido,
Esterification: Methods, Reactions, and Applications; Wiley-VCH, Weinheim,
2003.
[2] J. Otera, J. Nishikido, Esterification: Methods Reactions, and Applications,
2nd ed.; Wiley-VCH, Weinheim, 2010.
Received: June 25, 2018
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Communication
Oxidative Esterification
Y. Hayashi,* J. Li, H. Asano,
D. Sakamoto ........................................ 1–4
Sterically Congested Ester Forma-
tion from α-Substituted Malono-
nitrile and Alcohol by an Oxidative
Method Using Molecular Oxygen
A metal-free oxidative esterification or mixing α-substituted malononitrile
thio-esterification of readily available and alcohol or thiol in the presence of
substituted malononitrile and alcohol base under a molecular oxygen atmos-
or thiol has been developed by simply phere.
DOI: 10.1002/ejoc.201800984
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim