Preparation and Reactivity of Biomass-Derived Dihydro-Dioxins

Article abstract of DOI:10.1002/cssc.201802109

The depolymerization of the biopolymer lignin can give pure aromatic monomers but selective catalytic approaches remain scarce. Here, an approach was rerouted to deliver an unusual phenolic monomer. This monomer's instability proved challenging, but a degradation study identified strategies to overcome this. Heterocycles and a useful synthetic intermediate were prepared. The range of aromatics available from the β-O-4 unit in lignin was extended.

Full text of DOI:10.1002/cssc.201802109

Accepted Article
Title: Preparation and Reactivity of Biomass-derived dihydro-Dioxins
Authors: Nicholas James Westwood, James Montgomery, Karl Kempf,
Daniel Miles-Barrett, Oxana Kempf, and Tomas Lebl
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201802109
Link to VoR: http://dx.doi.org/10.1002/cssc.201802109
A Journal of
www.chemsuschem.org

10.1002/cssc.201802109
ChemSusChem
COMMUNICATION
Preparation and Reactivity of Biomass-derived dihydro-Dioxins
James R. D. Montgomery,[a] Karl Kempf,[a] Daniel M. Miles-Barrett,[a] Oxana Kempf,[a] Tomas Lebl and
Nicholas J. Westwood*[a]
Abstract: The depolymerisation of the biopolymer lignin can give pure
aromatic monomers but selective catalytic approaches remain scarce.
Here, an approach was re-routed to deliver an unusual phenolic
monomer. This monomer’s instability proved challenging but a
degradation study identified strategies to overcome this. Heterocycles
and a useful synthetic intermediate were prepared. The range of
aromatics available from the -O-4 unit in lignin was extended.
metal triflates or triflic acid with ethylene glycol (EG) to target the
β-O-4 linkage 1 (Figure 1).[7] This approach generates C2
products[7] including 2 with trace amounts of C3 products (e.g.
3).[7b] Recently, the reaction of a dioxasolv pinewood lignin with
Fe(OTf)3 and EG gave 2 in 16 wt% yield.[7b]
The C2:C3 ratio is determined by the fate of intermediate 4.
Deformylation of 4 gives the C2 acetal 2 whereas a range of
mechanisms can be considered for formation of the C3 product 3
from 4 (Scheme S1). Here we describe the re-routing of this
reaction to favour the C3 pathway, delivering an additional
aromatic monomer from the -O-4 unit in lignin. Our strategy is
based on acylation of the -alcohol (and coincidentally the -
alcohol) in the -O-4 unit. This substrate modification blocks the
C2 pathway by stopping deformylation of 4. Initial studies were
focused on the reaction of lignin models 5a and 5b (Scheme 1,
Tables 1 and S1). Overall the results demonstrated that an almost
complete selectivity switch could be achieved both in the models
and with lignin.
As the second most abundant natural polymer, lignin will
contribute to a sustainable future.[1] Whilst lignin has a complex
structure, its construction from arylpropene units[2] means it can
deliver aromatics.[3] Pure aromatic monomers can be prepared
from lignin[4], but alternative monomers continue to be targeted.
This is because a focus on just a few compounds, such as
vanillin[5], limits opportunities and creates a strong dependence on
the market price of a few monomers.[6] Diverse processing of
lignin remains a major challenge.
OH
MeO

R
O
O
R
O
O

O
O
O

M(OTf)n
or TfOH
HO
HO
OMe
4
RO
O
C2 Pathway
(major pathway in
previous work)
O
OMe
minor
products
+
+
C3 Pathway
(major pathway
in this work)
OR
EG
Dioxane
1 example of a -O-4
unit in lignin (R = H or OMe)
140°C
15 mins
OMe
OMe
OMe
O
O
OMe
OMe
OMe
(C3)
R
O
R
5a
6 (C2)
R = H
5b R = Ac
5c-h see Table 2
7
O
HO
HO
OMe
OH
OMe
O
C2 Acetal (Major)
C3 dihydro-dioxin (Minor)
MeO
MeO
2
R = H
3 R = H
O
OMe
AcO
in this
work:
C2:C3 ratios reversed so that C3 product dominates
8 (mixture of
diastereomers)
Figure 1. Processing the β-O-4 linkage in lignin to generate phenolic monomers
using metal triflates/TfOH and ethylene glycol. The literature[7] reports C2-
products. Here the C2:C3 ratio is reversed to give C3-products.
Scheme 1. Overview of study on lignin models 5a-5h.
Reaction of 5a and its acetylated derivative 5b with EG and
Fe(OTf)3 at 140 °C for 15 minutes led to a significant difference in
the C3:C2 product ratios (Table 1, entries 1 and 2). In line with the
literature,[7a, 7c] 5a was fully converted to the C2 acetal 6 (entry 1,
Figure S1) with trace amounts of C3 dioxene 7 also formed. In
contrast, 5b was fully converted to 6 and 7 in a C3 7:C2 6 ratio of
1:1 (entry 2). The reaction of 5a and 5b with alternative metal
triflates was carried out. For 5b with Bi(OTf)3, Al(OTf)3, Hf(OTf)4
or Cu(OTf)2, the same reversal of selectivity was seen as with
Fe(OTf)3 with 7 being the dominant product (entries 3-6). When
Cu(OTf)2 was used, a third product was identified (diastereomeric
mixture 8, entry 6, Figure S2).[8] In all the reactions and especially
when triflic acid or Fe(OTf)3 were used (entries 7 and 2), the C2
For lignin to function as a source of aromatics, selective
depolymerisation strategies are needed. Barta et al. have used
[a]
J. R. D. Montgomery, Dr K. Kempf, D. M. Miles-Barrett, O. Kempf,
Dr T. Lebl, Prof. N. J. Westwood
School of Chemistry and Biomedical Sciences Research Complex
University of St Andrews and EaStCHEM
St Andrews, Fife, KY16 9ST, UK
E-mail: njw3@st-andrews.ac.uk
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201802109
ChemSusChem
COMMUNICATION
acetal 6 was still formed from 5b. One possible explanation was
that hydrolysis or transesterification with EG of the -ester in 5b
had occurred re-opening the C2 pathway. When the reaction of 5b
with TfOH was repeated at a two-fold dilution (c.f. entries 7 and
8), full conversion of 5b was still observed but the C3 7:C2 6 ratio
increased to 1.7 (Figure S3), potentially consistent with a
decreased conversion of 5b to 5a.
explanation may be an inability to detect incomplete benzoylation
of the -O-4 -alcohols in lignin using 2D HSQC analysis. Whilst
this approach enabled the isolation of the C3-product 3 from lignin
for the first time, concerns about product stability were raised.
Table 2. TfOH-catalysed reaction of β-O-4 derivatives. Yields and ratios of
C2 6 and C3 7 determined by 1H NMR. Reactions run in triplicate (Table S2).
Entry
lignin
model
R
Average NMR
Yield of 6, 7
C3:C2 ratio
(yield)
Table 1. Metal triflate screen: ratio of products 6-8 (Scheme 1), determined
by 1H NMR expressed in form that gives a total of 100 molecules.
1
2
3
4
5
6
7
5b
5c
5d
5e
5f
MeCO
EtCO
24 ± 0.36, 40 ± 2.9
14 ± 0.32, 40 ± 2.7
7 ± 0.36, 44 ± 2.0
1 ± 0.04, 47 ± 0.7
0, 41 ± 3.7
1.7 (64)
2.9 (54)
Entry
Substrate
Catalyst
Products 6-8 (rel.
C3:C2 for
5b (for 5a)
amounts) [c]
1
2
3
4
5
6
7
8
5a
5b
5b
5b
5b
5b
5b
5b
Fe(OTf)3
Fe(OTf)3
Bi(OTf)3
Al(OTf)3
Hf(OTf)4
Cu(OTf)2
TfOH
6 (96), 7 (4)
6 (50); 7 (50)
(<0.1) [a]
1 [b] (<0.1)
2.6 (< 0.1)
1.4 (< 0.1)
2.0 (<0.1)
4.0 (<0.1)
0.7 (<0.1)
1.7
iso-propylCO
tert-butylCO
PhCO
6.3 (51)
47 (48)
6 (28); 7 (72)
only C3 (41)
only C3 (45)
only C3 (49)
6 (42); 7 (58))
6 (33); 7 (67)
5g
5h
p-F-PhCO
p-MeO-PhCO
0, 45 ± 1.9
0, 49 ± 4.8
6 (18), 7 (72), 8 (10)
6 (59); 7 (41)
A detailed study of the stability of 3 was carried out (Scheme S2).
Previous literature reports on related but not identical
compounds[10] suggested that formation of either diester 9 or
diketone 10 was likely. 3 was found to degrade on storage in
CDCl3 (in air) to a mixture of compounds including the predicted
9 and 10 (c.f. Figures 2Ai-2Aiii). The reaction of 3 with mCPBA
was interesting and the outcome variable. For example, an
authentic sample of 9 was prepared for comparison by reaction of
3 with two equivalents of mCPBA via a Grob-fragmentation
(Figures 2Aiv and 2B).[11] When 3 was reacted with one equivalent
of mCPBA, an authentic sample of diketone 10 was obtained.
TfOH [d]
6 (37); 7 (63)
[a] reaction conditions based on ref.[7a] Fe(OTf)3 (3 mol%), EG (2.7 eq),
140°C, 1,4-dioxane, 15 mins.; [b] repeated and products isolated to give a
C3 7:C2 6 ratio of 1.4; [c] In all cases in Tables 1 and 2, only trace quantites
of degradation products of 7 were observed (Figure S4); [d] Reaction diluted.
C2:C3 NMR yield increased to 64% c.f. original concentration (entry 7, 28%).
It was decided to vary the structure of the -ester in 5b. Increasing
the size of the ester substituent from Me (5b, Table 2 entry 1 and
Table S2) to Et in 5c and iso-propyl in 5d led to C3 7:C2 6 ratios of
2.9 and 6.3 respectively (entries 2 and 3 and Figure S4). Although
the C3:C2 ratio had increased, trace amounts of 6 were observed
even when 5e was used (entry 4). Next, benzoylated derivatives
5f-h were prepared and, under analogous conditions, gave
exclusively the C3 product 7 with full conversion (entries 5-7).
These conditions achieved both the desired switch in reaction
outcome and yields that were in line with literature reports.[7c]
Studies continued with a benzoylated lignin.
A softwood Douglas fir lignin (DFL) was prepared[9] and
converted to benzoylated lignin (Bz-DFL) using N-methyl-
imidazole and benzoic anhydride. 2D HSQC NMR analysis was
consistent with full conversion of all the β-O-4 units (Figures S5-
S8). Reaction of Bz-DFL with TfOH and EG using an extended
reaction time of 1 hour proved successful with C3 product 3
(Figure 1) being isolated after chromatographic purification (Table
S3 and Figure S9). It also proved possible to recover significant
quanties of benzoic acid from this reaction when it was run on a
larger scale (Figure S10). Analysis of the remaining lignin
indicated that full conversion of the benzoylated -O-4 units had
occured (Figure S10C). Interestingly, a small quantity of the C2
product 2 was also generated from this Bz-DFL. One possible
Figure 2. A. Selected region of the 1H NMR analysis of: (i) purified 3; 3 stored
in CDCl3 for (ii) 7 and (iii) 29 days; (iv) 10; (v) 9; (vi) 11; B. Reaction conditions
used for selective conversion of 3 to 9 or 10; C. Structures of novel compounds
11 and 12. * signals corresponding to additional unidentified degradation
products. + signal assigned to methyl group adjacent to carbonyl in 12.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201802109
ChemSusChem
COMMUNICATION
Addition of one equivalent of water and a catalytic amount of TfOH
in addition to the mCPBA lead to the formation of 10 as the
exclusive product (Figures 2Av and 2B, Figure S10). More
detailed inspection of the degradation of 3 in CDCl3, showed the
presence of two additional products which contained a methyl
signal at either 1.70 or 2.17 ppm respectively (Figures 2Aii-iii).
The structures of these novel compounds 11 and 12 were
assigned as isomeric mono-acetals of diketone 10 (Figures 2Avi,
2B and Figure S11). One possible mechanism for formation of 11
and 12 from 3 involves acid-catalysed opening of an initially
formed epoxide followed by subsequent ether-oxygen
migration.[12]
With a more detailed understanding of the degradation of 3 in
hand, a reanalysis of the reactions reported in Tables 1 and 2 was
carried out. It was confirmed that no significant degradation of 7
had occurred under the 15 minute TfOH reaction conditions (e.g.
Figure S12). However, the reactions of the lignin models 5b-h did
not involve extended heating times or purification of 7 by column
chromatography, as was required to generate 3 from lignin (Bz-
DFL). Given (i) the relative instability of 3, (ii) the observation of
degradation products of 3 in the mixture of lignin-derived
monomers (Figure S14) and (iii) the number of reactive groups
(e.g. alcohols) present in lignin that 3 or degradation products of
and the diesters 9 and 14 are potentially very useful building
blocks. For example, conversion of diketone 13 to the
corresponding imidazole 15 was readily achieved. Imidazole 15
was prepared using two biomass-derived aromatic monomers
and related imidazoles are known to possess interesting
biological activity.[13] In parallel, diketone 10 was converted to
pyrazine 16. The degradation of 3 to the corresponding diester 9
is, in some ways, disappointing as the hard-earned C3 tail in 3
would lose two of the three carbons if hydrolysis or reduction of
the esters was carried out. In an attempt to retain the two carbon
atoms, it was decided to submit 14 to an intramolecular Claisen-
type ester condensation reaction. Gratifyingly, this resulted in the
formation of -ketoester 17 after transesterification using NaOMe.
To the best of our knowledge this is the first time that a
synthetically useful structure of this type has been prepared from
lignin.
In conclusion, we have described the controlled depolymerisation
of the -O-4 unit in the biopolymer lignin to deliver a phenolic
dioxene monomer 3. This was achieved via a strategic re-routing
of
a metal triflate/TfOH-catalysed depolymerisation protocol
through an accessible modification (benzolyation) of the substrate.
Interestingly, a number of natural lignins contain significant
amounts of -acylation/acetylation (e.g. grasses) so the C3-
pathway described here could well be relevant if these are used
as the source of lignin. Despite the fact that a significant amount
of benzoic anhydride was used to protect the α- and γ-alcohols of
the β-O-4 linkage in lignin, benzoic acid was easily recovered at
the end of the depolymerisation reaction. This could in theory be
recycled back into benzoic anhydride and used in the next round
of a process (see Figure S10 for more details). A detailed study
of the stability of 3 guided alternative strategies for generating
useful heterocycles and synthetic intermediates from lignin.
Continued efforts to deliver a wider range of aromatics from lignin
may well prove important as the biorefinery concept continues to
develop.
3
could react with, it seems reasonable to assume that
degradation of 3 has an impact on the observed yields from lignin.
Rather than fight against instability of 3, it was decided to embrace
its reactivity as a means of preparing more stable products.[7a-c]
O
X
attempted purification
led to partial degradation
O
mixtures of O-protected 3 and
O-protected degradation products
X
HO
O-protection
3
OMe
O
O
O
1. oxidation
1. degradation
2. purification
3. protection
2. chromatography
3. PivCl, Et3
O
N
+
R
R
O
O
OMe
OMe
O
O
O
OPiv
ArCHO, NH4OAc
AcOH, 77oC
10 R = H
R = Piv
9 R = H
14
R = Piv
MeO
13
1. LiHMDS, THF,
-78oC to r.t.
Experimental Section
1,2-phenylendiamine
NH4Cl, DCM, r.t.
2. NaOMe, MeOH
N
O
Triflic acid cleavage of protected G-G β-O-4 models 5b-h.Reactions were
performed in triplicate. Stock solutions of 5b-h in 1,4-dioxane (33.3 mg
mL-1) and triflic acid in 1,4-dioxane (1.73 mg mL-1) were prepared.
Reaction solutions were prepared by mixing the two stock solutions (1.5
mL of each) and ethylene glycol (25 mg) in a sealed tube. The reaction
mixture was then heated to 140 °C for 15 mins in a preheated oil bath and
allowed to cool to room temperature in a water bath. The solution was
diluted with ethyl acetate (20 mL) and washed with water (20 mL) and brine
(20 mL). The organic phase was dried over MgSO4 and concentrated in
vacuo. Once dry and as quickly as possible, the crude product mixture was
dissolved in CDCl3 (0.7 mL) and analysed by quantitative 1H NMR methods.
HN
OMe
N
HO
HO
N
OMe
17
MeO
OPiv
MeO
16
15
Scheme 2. Summary of studies carried out on 3 culminating in preferred
approach to processing of 3 en route to exemplar heterocycles and the
synthetically useful -ketoester 17. The three carbon units present in the tail of
3 and 9/10 are highlighted to show how they are separated and then rejoined
via the intramolecular Claisen reaction. 15 prepared from 13 and 16 from 10.
Use of protection step to give 13 and 14 was optional.
Acknowledgements
It was decided to force the conversion of 3 under oxidative
conditions (using mCPBA), purify the degradation products 9 and
10 and then, in an optional step, protect the phenolic oxygen with
a pivaloyl protecting group. This process proved reproducible and
delivered pure samples of diketones 10 and 13 as well as diesters
9 and 14 (Scheme 2). It is clear that both the diketones 10 and 13
This work was supported by EPSRC PhD studentships
EP/1654168 (JRDM) and EP/1518175 (DMMB) and the Industrial
Biotechnology Innovation Centre (DMMB). We also acknowledge
the EPSRC UK Mass Spectrometry Facility at Swansea University
This article is protected by copyright. All rights reserved.

10.1002/cssc.201802109
ChemSusChem
COMMUNICATION
P. J. Deuss, C. S. Lancefield, A. Narani, J. G. de Vries, N. J. Westwood,
K. Barta, Green Chem. 2017, 19, 2774-2782; c) P. J. Deuss, M. Scott, F.
Tran, N. J. Westwood, J. G. de Vries, K. Barta, J. Am. Chem. Soc. 2015,
137, 7456-7467; d) C. W. Lahive, P. J. Deuss, C. S. Lancefield, Z. Sun,
D. B. Cordes, C. M. Young, F. Tran, A. M. Slawin, J. G. de Vries, P. C.
Kamer, N. J. Westwood, K. Barta, J. Am. Chem. Soc. 2016, 138, 8900-
8911; e) A. Kaiho, M. Kogo, R. Sakai, K. Saito, T. Watanabe, Green
Chemistry 2015, 17(5), 2780-2783.
and Dr Carolyn Horsburgh at the University of St Andrews for
mass spectrometry analysis.
Keywords: dihydro-dioxin • hetereocycles • renewable
monomers • depolymerisation • lignin
[8] J. M. Fraile, J. I. García, Z. Hormigón, J. A. Mayoral, C. J. Saavedra, L.
Salvatella, ACS Sustainable Chem. Eng. 2017, 6, 1837-1847.
[9] C. S. Lancefield, O. S. Ojo, F. Tran, N. J. Westwood, Angew. Chem. Int.
Ed. 2015, 54, 258-262.
[10] a) K. G. Bendinskas, A. Harsch, R. M. Wilson, W. R. Midden,
Bioconjugate Chem. 1998, 9, 555-563; b) E. T. Mack, A. B. Carle, J. T.
M. Liang, W. Coyle, R. M. Wilson, J. Am. Chem. Soc. 2004, 126, 15324-
15325.
[1] a) A. Naseem, S. Tabasum, K. M. Zia, M. Zuber, M. Ali, A. Noreen, Int.
J. Biol. Macromol. 2016, 93, 296-313; b) R. Rinaldi, R. Jastrzebski, M. T.
Clough, J. Ralph, M. Kennema, P. C. Bruijnincx, B. M. Weckhuysen,
Angew. Chem. Int. Ed. 2016, 55, 8164-8215; c) C. Xu, R. A. Arancon, J.
Labidi, R. Luque, Chem. Soc. Rev. 2014, 43, 7485-7500.
[2] F. S. Chakar, A. J. Ragauskas, Industrial Crops & Products 2004, 20,
131-141.
[3] J. Zakzeski, P. C. A. Bruijnincx, A. L. Jongerius, B. M. Weckhuysen,
Chem. Rev. 2010, 110, 3552-3599.
[11] R. Curci, L. Lopez, L. Troisi, S. M. K. Rashid, A. P. Schaap, Tetrahedron
Lett. 1988, 29, 3145-3148.
[4] Z. Sun, B. Fridrich, A. de Santi, S. Elangovan, K. Barta, Chem Rev 2018,
[12] I. Hanna, Tetrahedron Lett. 1995, 36, 889-892.
118, 614-678.
[13] I. Mejdrova, D. Chalupska, M. Kogler, M. Sala, P. Plackova, A.
Baumlova, H. Hrebabecky, E. Prochazkova, M. Dejmek, R. Guillon, D.
Strunin, J. Weber, G. Lee, G. Birkus, H. Mertlikova-Kaiserova, E. Boura,
R. Nencka, J. Med. Chem. 2015, 58, 3767-3793.
[5] M. Fache, B. Boutevin, S. Caillol, ACS Sustainable Chem. Eng. 2016, 4,
35-46.
[6] Z. Strassberger, S. Tanase, G. Rothenberg, RSC Adv. 2014, 4, 25310-
25318.
[7] a) P. J. Deuss, C. W. Lahive, C. S. Lancefield, N. J. Westwood, P. C.
Kamer, K. Barta, J. G. de Vries, ChemSusChem 2016, 9, 2974-2981; b)
This article is protected by copyright. All rights reserved.

10.1002/cssc.201802109
ChemSusChem
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.