Diversification of the Renewable Furanic Platform via 5-(Chloromethyl)furfural-Based Carbon Nucleophiles

Article abstract of DOI:10.1002/cssc.202001718

Biobased 5-(chloromethyl)furoate and 5-methylfuroate esters can be deprotonated to function as furylogous lithium enolates, and the former can also undergo zinc insertion to access Reformatsky-type chemistry. Carbon nucleophilicity represents hitherto lit

Full text of DOI:10.1002/cssc.202001718

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Diversification of the Renewable Furanic Platform via 5-
(Chloromethyl)furfural-Based Carbon Nucleophiles
Authors: Mark Mascal, Haoqian Miao, Nikolay Shevchenko, and
Andrew Otsuki
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To be cited as: ChemSusChem 10.1002/cssc.202001718
Link to VoR: https://doi.org/10.1002/cssc.202001718
01/2020

10.1002/cssc.202001718
ChemSusChem
Diversification of the Renewable Furanic Platform via 5-(Chloromethyl)furfural-Based Carbon
Nucleophiles
Haoqian Miao,† Nikolay Shevchenko,† Andrew L. Otsuki, and Mark Mascal*[a]
Department of Chemistry, University of California Davis, Davis, California 95616, United States
KEYWORDS: biobased products; 5-(chloromethyl)furfural; Darzens reaction; platform molecules;
Reformatsky reaction
Abstract
Biobased 5-(chloromethyl)furoate and 5-methylfuroate esters can be deprotonated to function as
furylogous lithium enolates, and the former can also undergo zinc insertion to access Reformatsky-type
chemistry. Carbon nucleophilicity represents hitherto little-explored reactivity in these key
carbohydrate-derived platform molecules, expanding their synthetic utility and potentially opening up
new sustainable product markets, e.g. in epoxy resins or biobased dyes.
Introduction
Much continues to be made of the potential of 5-(hydroxymethyl)furfural (HMF) 1 to serve as a
carbohydrate-derived platform molecule for the production of biobased chemicals, despite the fact that
it is only practically derivable from the food sugar fructose.[1] 5-(Chloromethyl)furfural (CMF) 2, on the
other hand, has attracted comparatively less attention, and yet can be made in high yield directly from
raw biomass.[2] Both HMF 1 and CMF 2 have been used in a variety of synthetic contexts,[3,4] which can
be summarized as shown in Figure 1.
Figure 1. Charge affinities present in HMF (left) and CMF (right). Blue = native; red = this work.
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10.1002/cssc.202001718
ChemSusChem
Since synthesis formally involves the generation of C–C bonds, the presence of a leaving group in
CMF has always been a significant advantage over HMF, allowing the introduction of carbon
nucleophiles by substitution,[5,6] as well as catalytic transition metal-mediated reactions.[7] In this work,
we demonstrate even greater versatility by rendering the methylene group C-nucleophilic via the
generation of either a furylogous enolate or an organometallic function.
Previous efforts to manipulate the chloromethyl group in CMF for synthetic purposes include
conversion to a phosphonium salt[8] or sulfone,[9] which enables the generation of stabilized anions.
Derivatives of this kind, however, have limited applications and show poor atom economy. Mikochik and
Cahana described attack at the carbonyl group of 2 with an N-heterocyclic carbene, which expels the
chlorine and formally imparts nucleophilic character to the methylene carbon, although in this case only
towards protonation.[10] Most recently, Dai and coworkers adapted this same reactivity to carbon
electrophiles, although the poor nucleophilicity restricted the scope to trifluoromethyl aryl ketones,
oxalates, and related systems.[11]
In principle, CMF and its derivatives should be able to form furylogous enolates as depicted in
Scheme 1, due to the relatively weak aromaticity of the furan ring. This effect should also help stabilize
organometallic centers, where charge is concentrated on carbon. Attempting this with CMF itself would
be challenging due to the reactivity of the aldehyde, and in fact the approach has been used to prepare
a CMF homopolymer.[12] The corresponding esters, however, should possess sufficient stability to allow
the kind of species represented in Scheme 1 to be realized. Recently, we showed how CMF could be
converted in a single step to 5-(chloromethyl)furan-2-carbonyl chloride (CMFCC) 3, which is readily
quenched by alcohols to give 5-(chloromethyl)furoic acid esters.[13] We describe here the generation of
carbon nucleophiles based around this system, thereby significantly enhancing the synthetic utility of
the biobased furanic platform.
Scheme 1. Concept of furylogous enolate generation from CMF derivatives (X = H, Cl; Y = H, OR).
Results and Discussion
The direct oxidation of CMF 2 to CMFCC 3 is remarkably facile. t-BuOCl is made by mixing household
bleach, t-butanol, and acetic acid, followed by phase separation. CMF is added and the resulting CMFCC
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10.1002/cssc.202001718
ChemSusChem
can be used directly without purification to make the 5-(chloromethyl)furoate esters like 4 and 5
(Scheme 2). Interestingly, although the chlorine in CMF 2 is quickly substituted by ethanol at room
temperature,[14] it is preserved during the synthesis of the ester 4, and can only be likewise displaced by
heating at >100 °C.[13]
Scheme 2. Reagents and conditions: a. t-BuOCl, RT, 24 h, 80%; b. 4: EtOH, 50 °C, 6h, 82%. 5: t-BuOH,
DMAP, 30 °C, 18 h, 70%.
Attempts to form an enolate directly from these esters using LDA in the presence of an aldehyde led
to a Darzens type reaction to give epoxides. Yields were highest using the t-butyl ester 5. Quenching
with furfural 6 gave a mixture of stereoisomeric products 7a and 7b (Scheme 3). The reaction also works
well with benzaldehyde (see SI).
Scheme 3. Reagents and conditions: a. 1.2 eq. LDA, THF, -78 °C to RT, 1 h, 63%, cis/trans ratio 60:40.
Success with the Darzens reaction led us to consider whether simple 5-methylfuroate esters would
similarly deprotonate. These can be prepared in a single step from CMF.[10] Alternatively, we can apply
the t-BuOCl + alcohol quench method to 5-methylfurfural (5-MF) 8 as shown in Scheme 4. We have
previously described the preparation of 5-MF by reduction of CMF in >90% yield.[15] Deprotonation of 9
with LDA and quenching with furfural installed a 2-(furan-2-yl)-2-hydroxyethyl group (10), while
homologation with methyl iodide gave 5-ethylfuroate ester 11.
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10.1002/cssc.202001718
ChemSusChem
Scheme 4. Reagents and conditions: a. t-BuOCl, RT, 24 h, then t-BuOH, DMAP, 30 °C, 18 h, 62%; b. 1.2
eq. LDA, furfural, THF, -78 °C to RT, 12 h, 65%; c. 1.2 eq. LDA, MeI, THF, -78 °C to RT, 12 h, 63%.
Although direct deprotonation was facile for ester 9, we also considered whether a CMF derivative
could serve as a furylogous Reformatsky nucleophile. Zinc enolates are known for their gentle reactivity
and functional group tolerance, such that the reaction could be attempted on the ethyl ester 4.
Interestingly, the literature already described the preparation of a zinc insertion product of 4.[16] The
authors reported attempts to use the resulting organozinc reagent for synthetic purposes, i.e. C-C bond
formation using copper- and nickel-catalyzed coupling reactions, with limited success. We treated 4 with
activated zinc in the presence of furfural 6 or 5-methylfurfural 8 to respectively produce 12, the ethyl
ester analogue of 10, and 13, in high yields (Scheme 5). The corresponding reaction with benzaldehyde
gave the addition product in 99% yield (see SI).
Finally, given our strong interest in the production of sustainable dyes,[17] the opportunity to create
extended conjugation was clearly present in 12 and 13. That said, we tested acid-catalyzed dehydration
on 12 and found it to be surprisingly sluggish. In terms of color performance, yellow product 14 was
comparable in wavelength (max 343 nm) and molar absorptivity (3.6 × 104 M-1cm-1) to the natural
pigment retinoic acid.[18] Other green dehydration methods for 12 and 13 are currently under
investigation. We also note the potential to exchange 2,5-diformylfuran[13] for 6/8 in the reaction in
Scheme 5, which would ultimately deliver the even stronger chromophore 15. Interestingly, the
dehydration reaction to produce 14 also gave a significant amount of dimeric self-alkylation product 16
(24%). Materials like this may also be of potential interest as extended chromophores, assuming the
unsaturation can be reintroduced to give 17, which is a furan-substituted version of 15. We have
modeled the electronic absorption spectra of 15 and 17, which are predicted to have maxima at 414 and
416 nm, respectively, centering their absorbance in the visible (violet) region of the spectrum (see SI).
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10.1002/cssc.202001718
ChemSusChem
Scheme 5. Reagents and conditions: a. a. Zn, cat. I2, THF, 40 °C, 18 h, 88% (12), 78% (13); b. Amberlyst
15, 3 Å molecular sieves, toluene, 60 °C, 7 h, 64%, cis/trans ratio 6:94.
Conclusion
Diversification of the synthetic utility of platform chemicals is the key to unlocking new markets for
sustainable products. Up to now, the methylene group of CMF (and HMF) has seen limited engagement
as a nucleophile. Here, we report the direct deprotonation of ester derivatives of CMF and 5-
methylfurfural to give furylogous enolates. In the case of the chloromethylfuroate ester, the Darzens
products represent a potentially new approach to preparing precursors to novel biobased epoxy resins.
The deprotonated 5-MF ester reacts like any other enolate, giving typical addition and substitution
products. Finally, chloromethylfuroates can also participate in Reformatsky-type reactivity, giving
carbonyl addition products in high yields, the dehydration of which has the potential to expand the
repertory of sustainable, biobased dyes.
†Equal contributors to this work
[a] H. Miao, Dr. N. Shevchenko, A. L. Otsuki, Prof. M. Mascal
Department of Chemistry, University of California Davis
1 Shields Avenue, Davis, California 95616 (USA)
E-mail: mjmascal@ucdavis.edu
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10.1002/cssc.202001718
ChemSusChem
Supporting Information available: General experimental information, synthetic procedures and data,
NMR spectra, UV-visible spectra, computational details
References
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Graphical abstract:
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