Diels-Alder Reactions of Furans with Itaconic Anhydride: Overcoming Unfavorable Thermodynamics

Article abstract of DOI:10.1021/acs.orglett.6b00929

Unfavorable thermodynamics often render furans reluctant to engage in high-yielding Diels-Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to

Full text of DOI:10.1021/acs.orglett.6b00929

Letter
pubs.acs.org/OrgLett
Diels−Alder Reactions of Furans with Itaconic Anhydride:
Overcoming Unfavorable Thermodynamics
Ashok D. Pehere, Shu Xu, Severin K. Thompson, Marc A. Hillmyer, and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: Unfavorable thermodynamics often render furans reluctant to engage in
high-yielding Diels−Alder (DA) cycloaddition reactions. Here, we report the highly
efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl
alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride
ring opening and crystal lattice energy of the product overcome the loss of aromaticity of
1
the furanoid diene. Detailed H NMR studies provided valuable insights about relevant
kinetic and thermodynamic features.
taconic acid1 and furfural2 are two chemicals abundantly
analysis that the spectral data be recorded soon after sample
preparation because the retro-Diels−Alder reaction was also
operative at room temperature, and dilution (here, from neat to
NMR sample concentration) shifts the equilibrium composition
of this bimolecular-to-unimolecular process toward the starting
pair of reactants (here, 1 + 3). Two diastereomeric products, 4-
endo and 4-exo, are produced (Figure 1a and Table 1, entry 1).
I
available from biomass. The first arises by the classical citric
acid (or tricarboxylic or Krebs3) cycle and the second by acid-
catalyzed dehydration of 5-carbon sugars prevalent in, for
example, corncobs (see Volume 1 of Organic Syntheses4). For a
century, it has been known that each itaconic anhydride (1, IA)
and furfuryl alcohol (2, FA) is readily available by simple
conversions (dehydration5 and reduction,6 respectively) of these
readily available precursors.
The ability of IA to function as a dienophile in Diels−Alder
(DA) cycloaddition reactions was described even in the first
publication by Diels and Alder.7 The use of furan as a diene was
reported 1 year later in their second paper on the subject of
“hydroaromatic synthesis”.8 Remarkably, we can find no reports
of IA (1) or itaconic acid (or its esters) ever having been reacted
with any furan derivative in the intervening >85 years. This is in
spite of the fact that DA adducts of furans with many other types
of dienophiles have been appropriated as strategically valuable
and enabling intermediates in numerous syntheses of complex
molecules.9
With an eye toward the preparation of novel reactive
monomers from furans for use in sustainable polymer syn-
thesis,10 we have studied the reactions of IA (1) with various
furans and report our findings here. A hallmark of furans as
participants in DA cycloadditions is the often unfavorable
enthalpic change upon product formation. This frequently
results in only low equilibrium conversion to the [4 + 2] adduct
because of loss of heteroaromaticity in the diene and ring strain in
the 7-oxanorbornene product.11 This is all the more true for 1,1-
disubstituted dienophiles analogous to 1 (e.g., methacrolein,12a
methacrylates,12a−c and methacrylonitrile12d), where the equili-
brium concentration of product ranges from 7 to 36% even in the
presence of 20-fold excess of furan, at low temperature, and/or
under high pressure.
Figure 1. (a) Rate and final equilibrium resting state for the DA reaction
between IA (1) and furan 3. (b) Conversion of 4-endo to 5 via 4-endo-
h2 and 3D structure of 5 from a single-crystal X-ray analysis.
[Cambridge Crystallographic Data Centre (CCDC) deposition
#1481187]. This is the half-time for reaching the final equilibrium
mixture (the ratio for 1/4-exo/4-endo was 73:13:14).
a
Even at early time points, they formed at nearly identical rates.
After 40 h, the system had essentially reached its equilibrium
state, which comprises a ratio of 73% of the initial IA (1) and 27%
of the sum of the two DA adducts. At equilibrium, there was a
very slight predominance of 4-endo over the amount of 4-exo.
These diastereomeric DA adducts were sufficiently stable to be
isolable by rapid chromatographic separation on silica gel, even
though some retro-DA reaction was occurring as the solutions
were being manipulated. Isolated solid-state samples of each
We first describe reactions between IA (1) and a variety of
simple furans, starting with furan 3. In one experiment, IA was
dissolved in 20 equiv of furan and held at ambient temperature.
Aliquots were periodically withdrawn and dissolved in CDCl3 to
monitor reaction progress. It was important in this kind of
Received: March 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
constitutional isomers. Again, we used an excess of the furan
component as the solvent in this ambient temperature
experiment and monitored the reaction progress over time. We
observed (i) that the proximal isomers are formed more quickly
than the distal, a reasonable event given the electronic
polarization imparted by the donor methyl group in 8; (ii) that
the distal isomers eventually predominated over the proximal,
again reasonable, now on the basis of minimization of steric
compression; and (iii) that the equilibrium amounts of the four
products (Table 1, entry 3) are in line with the observed
equilibrium ratios of DA adducts 4 and 7. Finally, the overall
extent of conversion was intermediate between that of furan and
the 2,5-dimethylated derivative 6.
Table 1. Reactions of Itaconic Anhydride (1) with Furans 3, 6,
8, and 10 (20 equiv) at Ambient Temperature
2-Acetoxymethylfuran (10) was another diene substrate that
proved informative (Table 1, entry 4). At equilibrium, the four IA
DA adducts 11 were formed, again to an extent intermediate
between that of 4 versus 7. This was observed to be the slowest of
all reactions we studied, consistent with the acetoxymethyl
substituent having a weakly electron-withdrawing character. As
was the case for 9, at equilibrium, the distal isomers
predominated. The assignments of structure to the distal versus
proximal substitution patterns among the isomers of 9 and 11
were based on the difference in coupling patterns of the
resonances for the bridgehead protons (at C4) in each (see SI).
HMQC and HMBC NMR analyses also were consistent with the
assignments.
We then turned to the reaction between the bioderived FA (2)
and IA (1). Initially, we monitored the behavior of an equimolar
mixture of this diene/dienophile pair in CDCl3 solution (∼1.5
M). After being held at 55 °C for 10 min, a few percent of total
conversion to a mixture of four DA adducts was seen, which is
well in line with the behavior (rate and ratio) observed for the
reaction between the acetate 10 and 1. By analogy then, we
presumed these four compounds to be a mixture of the four
isomeric anhydrides 12 (Figure 2a). When this reaction solution
was examined after 7 days, a new, fifth component was seen to
emerge at about 15% relative to the unconsumed IA (1). The
appearance of (i) a broad downfield resonance and (ii) a pair of
downfield doublets (δ 4.62 and 4.83, Jab = 10.8 Hz) in this new,
dominant compound suggested that a carboxylic acid lactone had
formed; it is reasonable to anticipate a conversion of one of 12-
prox-exo or 12-prox-endo to a ring-opened lactone acid by one
of the four pathways implied by arrows “a” or “b” in 12-prox-exo
or “a′” or “b′” in 12-prox-endo (Figure 2a). The favorable free
energy change associated with anhydride opening provides a
driving force for DA adduct formation.
The significant breakthrough was achieved when an equimolar
mixture of 1 and 2 was allowed to react in the bulk. A suspension
of solid 1 (95% grade) in liquid 2 (98% grade) at ambient
temperature changed over time in consistency. After about 3.5 h,
the initial heterogeneous slurry could no longer be magnetically
stirred; we could identify in the NMR spectrum of an aliquot the
presence of all four isomeric anhydrides 12 (Figure 3), albeit to
the total extent of only ca. 5%, along with a significant amount of
the same fifth component mentioned above. After 10 h, the
composition of the bulk mixture was that of a paste, and after 18
h, it had turned to a solid mass. This material now comprised
largely a single component, having the same spectral properties
as those of the new, fifth component that had appeared after 7
days in the homogeneous CDCl3 solution experiment described
above. The 13C NMR spectrum of this compound showed a
carbonyl resonance at δ 177.8 ppm, suggestive that it contained a
five-membered butyrolactone ring.13 X-ray diffraction showed
isomer were considerably more stable. Upon dissolution in
CDCl3 or C6D6, each isomer began to slowly revert to 1 and 3
(ca. 50% conversion after 6 h), consistent with the rate of their
formation and final equilibrium ratios.
Our assignment of the diastereomeric relationship within each
of the 4-exo and 4-endo was initially based on detailed analyses
of NMR data [see Supporting Information (SI)]. This was
subsequently confirmed by an X-ray structure of the diacid 5
(Figure 1b) obtained by catalytic hydrogenation of 4-endo to the
derivative 4-endo-h2, which was then hydrolyzed to the
crystalline diacid 5. Diagnostic features in the 1H NMR spectral
data of each diastereomer of 4 were then useful in assessing the
relative configuration of the DA adducts prepared from
additional furan derivatives (cf. 4, 7, 9, and 11 in Table 1);
details are provided in the SI.
2,5-Dimethylfuran (6) was the next diene studied, again in an
experiment where it was used as the reaction solvent and in ca.
20-fold excess over IA (1). The results are summarized in Table 1
(entry 2). The reaction of 6 with 1 was notably faster than that of
furan (t1/2 ∼ 15 min vs ∼8 h at 23 °C); apparently, the greater
electron density in diene 6 is a more important factor than the
increase in its steric bulk. However, the reaction proceeded to a
considerably lower equilibrium conversion (ca. 5%) of the sum of
DA adducts 7-endo and 7-exo, which reflects the greater steric
compression between the substituents on the spirocyclic carbon
and the adjacent (proximal) bridgehead methyl group present in
̀
adducts 7 vis-a-vis adducts 4. At an intermediate time point (10
min, ca. 3% conversion), formation of the major isomer had
outpaced that of the minor to the extent of ca. 2:1, a ratio that
remained essentially constant thereafter.
We next examined the reaction of IA with 2-methylfuran (8), a
desymmetrized diene that could give rise to four isomeric, NMR-
distinguishable DA adducts. These are a pair of endo and exo
diastereomers for each of a distal (9-dist-endo and 9-dist-exo)
versus a proximal (9-prox-endo and 9-prox-exo) pair of
B
DOI: 10.1021/acs.orglett.6b00929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. (a) Reaction manifold showing the equilibration among 1 + 2, four isomeric anhydrides 12, lactone acids 13 and 14, and monofurfuryl
itaconates 15. (b) DFT [M06-2X/6-31+G(d,p) (SMD/CHCl3); see SI for details] free energies (kcal·mol−1) of the four isomeric lactone esters from
ring opening of 12-prox-endo and 12-prox-exo and the (more stable) monofurfuryl itaconate esters 15a and 15b. (For X-ray structure details see
CCDC deposition #1481188).
Figure 3. 1H NMR spectrum in acetone-d6 of an aliquot of the bulk reaction mixture from 1:1 IA (1) and FA (2). (a) Resonances from the major product
14 are assigned. (b) Vertical scale increased 5×; the principal minor components are denoted; integration of all components indicates a 94% yield of 14
(see SI for full-page version of this graphic).
the structure to be that of the lactone acid 14, arising therefore
from 12-prox-exo, presumably by path “a”.
Crystal lattice energies have been exploited for additional
purposes in the arena of furan DA chemistry.14
A sample removed from the bulk mixture of 1 and 2 after just
30 min was immediately chromatographed on silica gel. The
structures of three constituents, each obtained in <1% yield,15
were deduced. In dilute CDCl3 solution, each of the anhydrides
12-dist-endo and 12-dist-exo, assigned as such by comparative
NMR analyses with some of the previous DA adducts, was
observed to revert to 1 and 2 at room temperature in a matter of
minutes. The third sample proved to be an acid lactone isomeric
The fact that the rapidly formed, steady-state mixture of the
four DA adducts 12 transformed to essentially the single-
component 14 indicates rapid reversibility of each of 12 back to
IA (1) and FA (2). The 1H NMR spectrum of an aliquot taken
from an equimolar mixture after 2 days is shown in Figure 3.
Integration of key resonances indicated that the chemical yield
for formation of 14 was 94%. The driving force for the conversion
of IA + FA to 14 comes both from (i) the opening of the
anhydride and (ii) the crystallization of the product from a
dynamic, interconverting mixture of multiple components.
1
with 14. It contained ∼20% of a second compound whose H
NMR resonances suggested it to be the anhydride 12-prox-endo.
Within a day in CDCl3, this anhydride had converted to the same
C
DOI: 10.1021/acs.orglett.6b00929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
new acid lactone. By a series of correlation experiments (see
below), we concluded the structure of this new lactone to be 13,
arising by the attack indicated by “b′” in structure 12-prox-endo
(Figure 2a).
support of the NIH Shared Instrumentation Grant program
(S10OD011952). Computations were performed with resources
made available by the University of Minnesota Supercomputing
Institute (MSI).
Monitoring the thermal behavior of a CDCl3 solution of the
lactone acid 14 was also informative. At 80 °C, a 1:4 mixture of
the two monofurfuryl itaconate esters 15a and 15b (structure
assignment discussed below) was formed. Isomer 15b cannot
arise from direct retro-DA reaction of 14. Instead, 14 apparently
reverts to 12-prox-exo and, in turn, 2 and 1, which then can
repopulate the mixture of 15a and 15b. All of these intermediates
were detectable (1H NMR; see SI). To probe whether 14 can
lead to 15a directly by a retro-DA reaction, we converted 14 to
the methyl ester 14Me. This compound was very stable at 80 °C in
CDCl3, and only upon heating to 140 °C in the melt did it finally
and solely revert to the ester 15aMe. An authentic sample of
15aMe was prepared by Mitsunobu esterification reaction
between FA (2) and the commercially available monomethyl
itaconate 16. The rate of the retro-DA reaction of 14Me suggests
that 14 does not proceed directly to 15a. A 1:1 mixture of IA and
benzyl alcohol, a DA-silent mimic of FA (2), at 80 °C produced a
mixture of monobenzyl itaconates in which the major isomer was
the analogue of 15b.16
We returned to the isomeric lactone acid 13 and converted it
to the methyl ester 13Me. Like its analogue 14Me, this ester also
showed clean retro-DA behavior when heated neat at 140 °C
(partial reversion after 1 min and complete after 5 min). Only the
mixed diester 15bMe was produced, verifying that 13 embodied a
valero- rather than butyrolactone subunit.
In summary, detailed NMR analyses of an array of related
Diels−Alder reactions between bioderivable IA (1) and furans
has provided an understanding of a number of the underlying
kinetic and thermodynamic issues. We have discovered that the
metastable lactone acid 14 can be produced in high yield (94%)
under trivial reaction conditions [1:1 mixture of IA (1) and FA
(2), neat, ambient temperature]. This opens the way for studying
its further conversion into derivatives amenable to polymer-
ization, a topic we are currently exploring.
REFERENCES
■
(1) Medway, A. M.; Sperry, J. Green Chem. 2014, 16, 2084−2101 and
refs therein.
(2) Cai, C. M.; Zhang, T.; Kumar, R.; Wyman, C. E. J. Chem. Technol.
Biotechnol. 2014, 89, 2−10 and refs therein.
(3) The discoveries of key elements of the citric acid cycle were
recognized by Nobel Prizes in Physiology or Medicine in 1937 (to
Albert Szent-Gyorgyi) and 1953 (to Hans Adolf Krebs): http://www.
̈
nobelprize.org/nobel_prizes/medicine/laureates/1937 and http://
www.nobelprize.org/nobel_prizes/medicine/laureates/1953 (each ac-
cessed Mar 16, 2016).
(4) Adams, R.; Voorhees, V. Org. Synth. 1921, 1, 49−51.
(5) Fittig, R.; Batt, L.; Bock, K.; Salomon, H.; Wernher, G. J. Liebigs
Ann. Chem. 1904, 331, 151−196.
(6) Kaufmann, W. E.; Adams, R. J. Am. Chem. Soc. 1923, 45, 3029−
3044 and earlier citations therein..
(7) Diels, O.; Alder, K. J. Liebigs Ann. der Chem. 1928, 460, 98−122.
(8) Diels, O.; Alder, K. Ber. Dtsch. Chem. Ges. B 1929, 62, 554−562.
(9) Raczko, J.; Jurczak, J. Furan in the Synthesis of Natural Products. In
Studies in Natural Products Chemistry; Atta ur Rahman, Ed.; Elsevier
Science: Amsterdam, 1995; Vol. 16, pp 639−685.
(10) (a) Shiramizu, M.; Toste, F. D. Chem. - Eur. J. 2011, 17, 12452−
12457. (b) Williams, C. L.; Chang, C.-C.; Do, P.; Nikbin, N.;
Caratzoulas, S.; Vlachos, D. G.; Lobo, R. F.; Fan, W.; Dauenhauer, P.
J. ACS Catal. 2012, 2, 935−939. (c) Pacheco, J. J.; Davis, M. E. Proc.
Natl. Acad. Sci. U. S. A. 2014, 111, 8363−8367. (d) Mahmoud, E.;
Watson, D. A.; Lobo, R. F. Green Chem. 2014, 16, 167−175.
(11) (a) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999,
55, 13521−13642. (b) Bur, S.; Padwa, A. [4 + 2] Cycloaddition
Chemistry of Substituted Furans. In Methods and Applications of
Cycloaddition Reactions in Organic Syntheses, 1st ed.; Nishiwaki, N., Ed.;
Wiley: New York, 2014; pp 355−406.
(12) (a) Dauben, W. G.; Krabbenhoft, H. O. J. Am. Chem. Soc. 1976,
98, 1992−1993. (b) Murai, A.; Takahashi, K.; Taketsuru, H.;
Masamune, T. J. Chem. Soc., Chem. Commun. 1981, 221−222.
(c) Hayashi, Y.; Nakamura, M.; Nakao, S.; Inoue, T.; Shoji, M. Angew.
Chem., Int. Ed. 2002, 41, 4079−4081. (d) Rimmelin, J.; Jenner, G.;
Rimmelin, P. Bull. Soc. Chim. Fr. 1978, II-461−II-464.
(13) Lambert, J. B.; Wharry, S. M.; Block, E.; Bazzi, A. A. J. Org. Chem.
1983, 48, 3982−3985.
(14) (a) Guidi, A.; Theurillat-Moritz, V.; Vogel, P. Tetrahedron:
Asymmetry 1996, 7, 3153−3162. (b) Sevin, A.; Vogel, P. J. Org. Chem.
1994, 59, 5920−5926. (c) Theurillat-Moritz, V.; Vogel, P. Tetrahedron:
Asymmetry 1996, 7, 3163−3168.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00929.
Experimental procedures and structural characterization
data for all new compounds and 1H and 13C NMR spectra
(PDF)
(15) This example serves as a reminder of the value of the notion that a
1% yield is infinitely greater than 0%. Importantly, the identification of
these trace products revealed significant features about the energetics of
several aspects of the reaction manifold.
(16) Cheng, X.; Li, L.; Uttamchandani, M.; Yao, S. Q. Org. Lett. 2014,
16, 1414−1417.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hoye@umn.edu.
Notes
The authors declare the following competing financial
interest(s): A.D.P. and T.R.H. are named as co-inventors on a
provisional patent application.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by the
Minnesota Corn Growers Association and the Center for
Sustainable Polymers at the University of Minnesota, an NSF-
supported Center for Chemical Innovation (CHE-1413862).
NMR data were recorded on an instrument purchased with
D
DOI: 10.1021/acs.orglett.6b00929
Org. Lett. XXXX, XXX, XXX−XXX