Furanodendralenes

Article abstract of DOI:10.1021/jo500458y

An examination of Diels-Alder reactions of furan-containing analogues of dendralenes has revealed complex and fascinating reaction sequences, which chart the inherent site and stereoselectivity of these processes and give rapid access to structures of hig

Full text of DOI:10.1021/jo500458y

Article
pubs.acs.org/joc
Furanodendralenes
Thomas Fallon,† Anthony C. Willis,† Michael N. Paddon-Row,*,‡ and Michael S. Sherburn*,†
†Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory 0200, Australia
‡School of Chemistry, The University of New South Wales, Sydney, New South Wales 2052, Australia
S
* Supporting Information
ABSTRACT: An examination of Diels−Alder reactions of furan-containing
analogues of dendralenes has revealed complex and fascinating reaction
sequences, which chart the inherent site and stereoselectivity of these
processes and give rapid access to structures of high molecular complexity.
laboratory, it is not an ideal precursor since it readily dimerizes
under normal laboratory conditions.
INTRODUCTION
■
Growing interest in the dendralene family of branched
unsaturated hydrocarbons1 can be traced, in large part, to
their significant synthetic potential. These compounds behave
as multidienes, participating in diene-transmissive Diels−Alder1,2
(DTDA) sequences that allow a rapid increase in structural
complexity.3 DTDA sequences of the simplest members,
[3]dendralenes, have been studied the most intensively. The
parent [3]dendralene (1), for example, has been shown to react
as a diene in a selective single cycloaddition reaction with a
range of electron-poor dienophiles4 (Scheme 1). The resulting
monocycloadduct carries a “transmitted” semicyclic diene that
readily undergoes a second cycloaddition. Four new C−C
bonds and a new decalin system are generated in this powerful
double cycloaddition sequence, and moreover, the ability to
employ two different dienophiles is of obvious value.
Nevertheless, while [3]dendralene is manageable in the
[4]Dendralene (2) is, in contrast, a bench stable compound,
showing no sign of decomposition when stored neat in the
laboratory. This compound undergoes DTDA sequences
involving up to three cycloadditions (Scheme 2).5 While
significant progress is being made, there remains issues of
selectivity in DTDA sequences involving [4]dendralene. First,
uncatalyzed reactions generally give mixtures of products
resulting from additions to the two different (terminal and
internal) diene sites. Second, an initial addition to a terminal site
produces a compound that is more reactive as a diene than the
starting [4]dendralene, thereby leading to double DA adducts
and precluding the possibility of two different dienophiles being
employed in these two discrete cycloadditions.
In addition to these reactivity problems, DTDA sequences
involving the parent [3]dendralene and [4]dendralene produce
compounds that lack the functionality to allow rapid
elaboration into potential natural product targets. This study
introduces a solution to the stability issue of [3]dendralene and
generates more functionalized DTDA products. It also extends
DTDA chemistry into the realm of thermodynamically
controlled processes, thereby offering a potential solution to
processes plagued by low levels of kinetic selectivity.
Scheme 1. DTDA Sequence Between [3]Dendralene (1) and
the Representative Dienophile N-Methylmaleimide (NMM)
Furans are well-known as versatile dienes that permit the
formation of oxygenated cyclohexene systems, through cyclo-
additions that are often found to be reversible on mild heating.6
The purpose of this study was to unite the DTDA chemistry of
dendralenes and the synthetic accessibility and versatility of
furans. Depicted in Figure 1, are the four simplest
furanodendralenes, structures 3,7 4, 5,8,9 and 6, which are
obtained by formal replacement of a pair of diene inside
hydrogens of a dendralene with an oxygen.10 In this study we
report the Diels−Alder (DA) chemistry of furano[3]dendralene
structure 3 and the three furano[4]dendralenes 4, 5, and 6 with
maleimide dienophiles. We demonstrate that the incorporation
Received: February 25, 2014
Published: February 28, 2014
© 2014 American Chemical Society
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Scheme 2. DTDA Sequences Between [4]Dendralene (2) and N-Methylmaleimide (NMM)
RESULTS AND DISCUSSION
■
3-Vinylfuran 3 has been prepared several times, invariably by
Peterson olefination of commercially available 3-furaldehyde.7
We find that the volatility of 3-vinylfuran 3 (bp ca. 85 °C)
renders these procedures challenging, at least to obtain the
compound in pure, solvent-free form. We therefore developed a
new approach employing the DBU elimination of 3-(2′-
bromoethyl)furan (Scheme 4), with the product isolated in
pure form by bulb-to-trap distillation from the reaction mixture.
2-(3-Furyl)-1,3-butadiene 4 was prepared via a Ni(0)-catalyzed
Negishi cross-coupling reaction between chloroprene and the
organozinc reagent derived from 3-bromofuran. We recently
reported a synthesis of 3,3′-bifuran 5,8 using a modified version
of previously reported protocols.9 3,4-Divinylfuran 6 was
prepared through a double Kumada−Tamao−Corriu cross-
coupling reaction between 3,4-dibromofuran and vinyl
magnesium bromide.
Figure 1. Dendralenes and furanodendralenes.
of furan rings into dendralene systems dramatically changes the
reactivity and selectivity of DTDA sequences, and leads rapidly
to oxygenated multicyclic structures, which should find
application in efficient target synthesis.
3-Vinylfuran 37 underwent a DA reaction with 1 mol equiv of
N-methylmaleimide (NMM) in CDCl3 at 50 °C to give
predominantly a 1:1 mixture of exo and endo furan adducts 7
and 8 in 61% yield (Scheme 5). A small amount (4%) of the
semicyclic diene addition product 9 was also isolated.14 This
distribution of products is significantly different from all
previous reports of cycloadditions involving more highly
substituted 3-alkenylfurans.12,13 It is also different to the
computationally predicted selectivities of the reaction of 3-
vinylfuran with maleic anhydride by Sastry.15 This result is,
however, consistent with our M06-2X/6-311+G(2df,p)//
B3LYP/6-31G(d) calculations, which predict a 1:1 ratio of
endo:exo products and an 85:15 ratio of furan diene:semicyclic
diene addition.
DTDA reaction sequences involving a furofuran11 and 3-
alkenylfurans12 have been reported, as have single additions of
dienophiles to the semicyclic diene site of 3-alkenylfurans.13 All
prior work in this area involves furano[3]dendralenes, with two
reports of DTDA reaction sequences previously published.
Thus, Eberbach and co-workers reported a single example of a
DTDA sequence involving a furofuran (Scheme 3a)11 and
́
Benıtez and co-workers examined the DTDA reactivity of
substituted 3-alkenyl furans (Scheme 3b).12 Two separate
reports of single cycloadditions of dienophiles to the semicyclic
diene site of 3-alkenyl furans have also appeared, in reactions
that represent key steps in total syntheses of natural products
(Scheme 3c,d).13 The goal of the present study was to develop
a better understanding of the reactivity of these systems by
preparing and studying a significantly broader range of
substrates, and ones that lack extraneous substituents that
might bias the outcomes of cycloaddition reactions.
Upon exposure of 3-vinylfuran 3 to an excess of dienophile,
no less than six products were obtained, in a high overall yield
(Scheme 5). The four stereoisomeric DTDA products 10, 11,
12, and 13 represented 90% of the mass balance from the
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Scheme 3. Published Examples of DA Reactions Involving 3-Alkenylfurans
Scheme 4. Synthesis of Furanodendralenes
the oxa-bridge introduces a steric penalty toward endo
approach, allowing the exo pathway to compete. In addition
to these bis-adducts, small amounts of semicyclic monoadduct
9 and its isomer 14 were also isolated. Furan 14 is the product
of aromatization of 9, presumably through a stepwise
mechanism.
The reactions of the three furano[4]dendralenes with
maleimide dienophiles are summarized in Scheme 6. 2-(3-
Furyl)-1,3-butadiene 410 is an interesting substrate since it
carries three distinct diene sites, namely the furan diene, an
acyclic 1,3-butadiene, and a semicyclic diene. When treated
with 1 mol equiv of NMM, the rapid and clean formation of
monoadduct 15 is observed (Scheme 6a). This outcome
reflects the higher reactivity of the acyclic 1,3-butadiene unit.
Reaction at either of the other two sites would require a break
in aromaticity, which is too high an energetic penalty. Our
M06-2X/6-311+G(2df,p)//B3LYP/6-31G(d) calculations con-
firm that endo and exo-mode additions of NMM with 1,3-
butadiene have significantly lower activation enthalpies and free
energies than those between NMM and furan.
In stark contrast to this highly selective monoaddition, when
furano[4]dendralene 4 was treated with an excess of NMM, a
complex mixture of products was obtained. Upon the basis of
the results with 3-vinylfuran 3, we suspect a preference for the
furan diene in the reaction between monoadduct 15 and NMM.
This reaction would give four stereoisomeric double DA
adducts, each of which would give at least two triple DA
adducts.
reaction. These structures were secured through single crystal
X-ray analyses.16 Double DA adducts 10 and 11 are derived
from exo-monoadduct 7, with double DA adducts 12 and 13
originating from endo-monoadduct 8. It is evident that
semicyclic dienes 7 and 8 undergo kinetically controlled
cycloadditions with NMM with high π-diastereofacial selectiv-
ity, inasmuch as all four double cycloadducts are the result of
addition syn- to the oxa bridge of the oxa-norbornene (as
depicted in red in Scheme 5). Approach to the opposite face of
vinyl-oxa-norbornenes 7 and 8 is evidently much more
sterically challenging. Interestingly, the endo:exo ratio for each
of the two cycloadditions is ca. 2:1. Presumably the presence of
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Scheme 5. Reaction of 3-Vinylfuran 3 with N-Methyl
Maleimide (NMM)
Scheme 6. Reaction of Furano[4]dendralenes 4, 5, and 6
with Maleimide Dienophiles
a
a
Products from the 1 mol equiv of NMM reaction are depicted in the
shaded box, products from the 4 mol equiv of NMM reaction are
unshaded.
The reaction of 3,3′-bifuran 58 with 1 mol equiv of NMM is
highly site selective for one of the two equivalent furan dienes,
giving a 1:1 mixture of exo and endo monoadducts 16 and 17 in
82% yield (Scheme 6b). The chemoselectivity of this reaction is
interesting: the high yielding formation of monoadducts 16 and
17 demonstrates that these 3-alkenylfurans are significantly less
reactive toward NMM than is the starting bifuran 5.
Presumably, the furan diene units of the monoadducts are
both sterically more shielded and electronically less activated
than in the bifuran precursor. The apparently exclusive site
selection witnessed in this reaction, specifically for the furan
diene rather than the internal diene, is predicted by our M06-
2X/6-311+G(2df,p)//B3LYP/6-31G(d) calculations and is
also consistent with simple aromaticity arguments: addition at
a furan diene breaks the aromaticity of only one ring, whereas
addition at the internal diene site of bifuran would break the
aromaticity of two furan rings.
lack of selectivity is offset by a noteworthy boost in molecular
complexity, with 6 new C−C bonds and 12 contiguous
stereogenic centers generated in one simple synthetic
operation. We remain cautious on the matter of the pathway
to this product and its implications; the characterization of
stereoisomer 18 is probably related to its ease of isolation
rather than its ease of formation.
When 3,4-divinylfuran 6 was treated with N-phenyl-
maleimide (NPM; this compound was used in place of
NMM in this series to produce more highly crystalline products
to facilitate structure elucidation through single crystal X-ray
analysis)16 at 50 °C, a ca. 2:3 mixture of endo and exo adducts
19 and 20 was produced (Scheme 6c). The observation of
addition to the furan diene instead of the semicyclic diene, and
the formation of both endo and exo isomers in roughly the same
amounts, is consistent with the DA reactions of the other
furanodendralenes reported in this study.
Treatment of 3,3′-bifuran 5 with an excess of NMM gave a
complex mixture of products from which triple DA adduct 18
could be isolated after HPLC purification (Scheme 6b). The
structure of this multicyclic system was unambiguously
established using single crystal X-ray analysis.16 This reaction’s
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Scheme 7. Domino Pericyclic Reactions Involving 3,4-Divinylfuran 6 and N-Phenyl Maleimide
When 3,4-divinylfuran 6 was treated with an excess of NPM
at 120 °C, double DA adduct 21 was the major product. Under
these conditions, isomeric double DA product 22 and triple DA
adduct 23 were also isolated. Tris-adduct 23 was isolated as a
single stereoisomer and is the result of an initial DA reaction by
NPM at the semicyclic diene site of divinylfuran 6, followed by
a second addition to the other semicyclic diene site and finally
an addition to the resulting transmitted diene. Evidently,
following the first addition, the subsequent two additions are
highly selective. If a method can be developed to steer the
initial site selectivity to the semicyclic diene, a high yield of a
single diastereomeric product can be anticipated.
A final set of experiments were conducted to identify the
origins of double DA adducts 21 and 22 (Scheme 7). Heating
the exo adduct 20 in refluxing toluene induced 6π-electro-
cyclization and the formation of 1,3-cyclohexadiene 25 in 90%
yield. When endo adduct 19 was exposed to the same
conditions, a mixture of 6π-electrocyclization products 24 and
25 was obtained. The formation of exo electrocyclization
product 25 from endo Z-triene precursor 19 can be explained
by a heat-promoted retro-DA reaction to give 6 and NPM,
followed by an exo DA reaction to give 20 and, finally, a 6π-
electrocyclization to give 25.
adduct 19, is reunited with the major exo adduct 20 at the end
of the sequence, specifically hexacycle 21.
CONCLUSION
■
To summarize, this exploratory study has demonstrated that
the readily accessible furanodendralenes represent a fascinating
platform for cascade pericyclic processes that contain multiple
reversible and irreversible events. The DA reactions of the three
furano[4]dendralene systems investigated here, namely, 4, 5,
and 6, have significantly expanded upon previous efforts in this
field. Our work has revealed a rich and diverse chemistry and
the rapid formation of complex multicyclic systems. Impor-
tantly, the outcomes of DA reactions of the furanodendralenes
can now be rationalized through computational studies and an
appreciation of the behaviors of different classes of diene
systems. Evidently, challenges remain. In particular, methods to
control the outcome of these domino sequences must be
developed. The investigation described herein paves the way for
such studies, which will ultimately set the scene for applications
in target synthesis.
EXPERIMENTAL SECTION
■
1
General Methods. H NMR spectra were recorded at 800, 600,
DA reactions of 6π-electrocyclization products 24 and 25
were examined under both thermal and high pressure
conditions. exo-1,3-Cyclohexadiene 25 reacted with NPM to
give exo-syn-endo17 compound 21 as the only isolable product.
Isomer 22 (Scheme 6c) must arise through a 1,5-hydrogen shift
of intermediate 25 followed by DA addition to the rearranged
1,3-cyclohexadiene intermediate.
400, and 300 MHz. Residual chloroform (δ 7.26 ppm) was used as the
internal reference for 1H NMR spectra recorded in this solvent.
Coupling constants (J) are quoted to the nearest 0.1 Hz. 13C NMR
spectra were recorded at 200, 150, 100, or 75 MHz. The central line of
the deuterochloroform signal (δ 77.1 ppm) was used as an internal
reference for 13C NMR spectra recorded in this solvent. Assignment of
carbon signals was assisted by DEPT or HSQC experiments. IR
spectra were recorded as thin films on sodium chloride plates for oils
or as potassium bromide discs for solid products. Mass spectra were
recorded using electron impact (EI+) ionization mode at 70 eV for
low-resolution mass spectra. High-resolution mass spectra were
recorded employing a magnetic sector analyzer at 70 eV. Melting
points are uncorrected. Analytical thin layer chromatography was
performed using silica gel plates, precoated with silica gel 60 F243 (0.2
mm). Flash chromatography employed 230−400 mesh silica gel.
Reactions were conducted under a positive pressure of dry argon or
nitrogen in oven-dried glassware. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were dried over sodium wire and distilled
from sodium benzophenone ketyl. Petrol refers to 40−60 °C
petroleum spirits unless otherwise stated. Commercially available
chemicals were purified by standard procedures or used as purchased.
When endo-1,3-cyclohexadiene 24 was treated with NPM at
19 kbar pressure, the corresponding double DA adduct 26 was
1
isolated in 29% yield (the yield was estimated at 75% by H
NMR analysis of the crude product mixture).18 When treated
with excess NPM at 150 °C, however, endo-1,3-cyclohexadiene
24 gave rise to exo-syn-endo adduct 21 as the only observed
product in 19% yield (this reaction was accompanied by
significant decomposition). The formation of 21 in this reaction
is notable and must arise first by initial DA reaction to give 26
followed by retro DA reaction to furan intermediate 27 then
exo DA reaction to 21. In effect, the minor product from the
initial cycloaddition to the furano[4]dendralene 6, namely, endo
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3-Vinylfuran (3). 3-(2-Bromoethyl)furan19 (2.0 g, 11.4 mmol) was
dissolved in DMSO (10 mL) in a 100 mL three-neck round-bottomed
flask equipped with a short vigreux column connected to a liquid
nitrogen cooled trap. The solution was stirred at rt, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (3.42 mL, 22.85 mmol, 2.0 mol equiv)
was added dropwise. The solution was stirred at rt for two hours, and
then the system was carefully evacuated (double manifold) keeping the
pressure above 10 mbar. The solution was then slowly heated to 75 °C
and stirred for 30 min, after which time the distillation was deemed
complete. 3-Vinylfuran (3) was collected in the trap in pure form as a
= 17.7 Hz), 5.40 (1H, s), 5.31 (1H, d, J = 10.8 Hz), 5.27 (1H, s), 2.98
(3H, s), 2.96 (1H, d, J = 6.5 Hz), 2.86 (1H, d, J = 6.5 Hz); 13C NMR
(200 MHz; CDCl3) δ/ppm 176.4 (C), 176.1 (C), 148.9 (C), 131.6
(CH), 127.7 (CH), 118.1 (CH2), 82.1 (CH), 80.4 (CH), 49.9 (CH),
47.5 (CH), 25.1 (CH3); νmax (film)/cm−1 3006, 2950, 1772, 1698,
1573, and 1436; EIMS (70 eV) m/z (%) 205.1 (13, [M]+), 149.0 (11),
120.0 (28), 94.0 (100); HREIMS calcd for C11H11NO3 [M]+
205.0739, found 205.0744.
1
8: Rf 0.20 (1:1 ether:pentane); H NMR (800 MHz; CDCl3) δ/
ppm 6.34 (1H, dd, J = 17.6 and 10.8 Hz), 5.47 (1H, d, J = 5.44 Hz),
5.48 (1H, d, 17.6 Hz), 5.32−5.30 (2H, m), 3.63 (1H, dd, J = 7.5 and
5.8 Hz), 3.58 (1H, dd, J = 7.2 and 5.5 Hz), 2.78 (3H, s); 13C NMR
(200 MHz; CDCl3) δ/ppm 175.1 (C), 173.9 (C), 147.0 (C), 129.2
(CH), 127.7 (CH), 120.0 (CH2), 80.4 (CH), 79.6 (C), 48.5 (CH),
46.4 (CH), 24.6 (CH3); νmax (film)/cm−1 2955, 2924, 1776, 1699,
1571 and 1433; EIMS (70 eV) m/z (%) 205.1 (14, [M]+), 149.0 (15),
120.0 (23), 94.0 (100); HREIMS calcd for C11H11NO3 [M]+
205.0739, found 205.0740.
9: Rf 0.08 (1:1 ether:pentane), mp 240−243 °C (CH2Cl2/hexane);
1H NMR (800 MHz; CDCl3) δ/ppm 6.91 (1H, s), 5.64 (1H, d, J = 2.3
Hz), 5.42 (1H, dd, J = 7.4 and 3.7 Hz), 4.93 (1H, dt, J = 8.2 and 3.3
Hz), 3.68 (1H, dd, J = 8.4 and 8.4 Hz), 3.05 (1H, t, J = 7.0 Hz), 2.97−
2.94 (1H, m), 2.90 (3H, s), 2.02−1.99 (1H, m); 13C NMR (200 MHz;
CDCl3) δ/ppm 179.0 (C), 174.3 (C), 155.5 (H), 142.9 (C), 106.7
(CH), 103.9 (CH), 79.1 (CH), 42.5 (CH), 38.5 (CH), 25.4 (CH2),
25.1 (CH3); νmax (KBr)/cm−1 2952, 2923, 1775, 1697, 1566, and
1435; EIMS (70 eV) m/z (%) 205.1 (100, [M]+), 120.0 (97), 94.0
(66), 91 (64); HREIMS calcd for C11H11NO3 [M]+ 205.0739, found
205.0734.
1
colorless, volatile oil (396 mg, 37%). H NMR and 13C NMR spectra
were consistent with those reported in the literature.20
3-(Buta-1,3-dien-2-yl)furan (4). 3-Bromofuran (1.35 mL, 15.0
mmol) was dissolved in THF (30 mL), and the solution was cooled to
−70 °C. n-BuLi in hexanes (1.6 M, 9.4 mL, 15.0 mmol, 1.0 mol equiv)
was slowly added over 15 min, and the solution was stirred for 30 min.
A solution of ZnBr2 (3.72 g, 16.5 mmol, 1.1 mol equiv) in THF (12
mL) was slowly added over 15 min. The solution was allowed to warm
to 0 °C, after which Ni(dppp)Cl2 (490 mg, 0.9 mmol, 6 mol %) was
added followed by chloroprene (1.40 g, 15.8 mmol, 1.05 equiv). The
solution was allowed to warm to rt and stirred for 2 h. The solution
was then poured onto a mixture of pentane (150 mL) and water (150
mL). The organic phase was washed with water (8 × 100 mL) and
then brine (100 mL). The organic phase was dried over MgSO4, and
the solvent was carefully removed under reduced pressure (100 mbar/
0 °C) to give the title compound 4 as a colorless, volatile oil (1.38 g,
77%): 1H NMR (300 MHz; CDCl3) δ/ppm 7.48 (1H, br. s) 7.41 (1H,
dd, J = 2.1 and 1.8 Hz) 6.54 (1H, ddd, J = 17.4, 10.5, and 0.6 Hz) 6.49
(1H, ddd, J = 1.5, 0.6, and 0.3 Hz) 5.45 (1H, dd, J = 17.4, and 1.5 Hz)
5.22 (3H, m); 13C NMR (75 MHz; CDCl3) δ/ppm 142.8 (CH), 139.8
(CH), 138.5 (CH), 137.2 (C), 124.2 (C), 116.4 (CH2), 115.0 (CH2),
101.0 (CH); νmax (film)/cm−1 2977, 1840, 1796, 1632, 1599, 1575,
1556 and 1507; GCMS (75 eV) m/z 120 (58, [M]+), 91 (100);
HREIMS calcd for C8H8O [M]+ 120.0575, found 120.0576.
Compounds 10, 11, 12, 13, 9, and 14. Durene (19 mg, 0.142
mmol) was weighed into a valve-appended NMR tube and dissolved in
benzene-d6 (0.5 mL). 3-Vinylfuran 3 (0.285 mmol, as determined by
1
quantitative H NMR analysis against durene) was added followed by
N-methylmaleimide (126 mg, 1.138 mmol, 4.0 mol equiv), and an
additional aliquot of benzene-d6 (0.7 mL) was added. The tube was
sealed and heated at 80 °C for 1 h. The solution was cooled, and the
solvent was removed in vacuo. The residue was subjected to flash
chromatography on silica gel using gradient elution with diethyl ether
to ethyl acetate:diethyl ether 2:1 to give the title compounds as white
solids (compound 9 and 14; 5 mg, 8% as a 16:84 9:14 mixture,
compounds 11, 12, and 13; 58 mg, 64% as a 50:27:23 mixture
11:12:13 and compound 10; 23 mg, 26%). Analytical samples of
compounds 11, 12, and 13 were obtained by preparative HPLC
(SunFire preparative column, ethyl acetate:hexane 1:1, 8.5 mL/min;
13, tR 27 min; 11, tR 32 min; 12, tR 35 min). Recrystallization of
compound 10 from chloroform/hexane gave crystals suitable for single
crystal X-ray analysis. Recrystallization of compound 11 from
dichloromethane/heptane gave crystals suitable for single crystal X-
ray analysis. Recrystallization of compounds 12 and 13 from
dichloromethane/hexane gave crystals suitable for single crystal X-
ray analysis.
3,4-Divinylfuran (6). 3,4-Dibromofuran21 (12.07 g, 53.4 mmol)
was dissolved in THF (25 mL), and Ni(dppp)Cl2 (1.16 g, 2.14 mmol,
4 mol %) was added. The solution was stirred, and a solution of vinyl
magnesium bromide in hexanes (1.0 M, 134 mL, 133.6 mmol) was
slowly added such that the temperature did not exceed 60 °C. The
solution was then heated at 60 °C for 2 h and cooled to rt, and 1 M
HCl (200 mL) was added. The mixture was extracted with pentane
(300 mL), and the organic phase washed with water (6 × 200 mL)
and then brine. The organic phase was then dried over MgSO4, and
the solvent carefully removed under reduced pressure (40 mbar/0 °C).
The residue was subjected to flash chromatography on silica gel eluting
with pentane to give, after careful evaporation of the solvent (40
mbar/0 °C), the title compound 6 as a colorless oil (3.10g, 48%): Rf
1
0.47 (pentane); H NMR (300 MHz; CDCl3) δ/ppm 7.44 (2H, s),
6.57 (2H, dd, J = 17.7 and 11.1 Hz), 5.49 (2H, dd, J = 17.7 and 1.5
Hz), 5.21 (2H, dd, J = 11.1 and 1.5 Hz); 13C NMR (75 MHz; CDCl3)
δ/ppm 140.5 (CH), 126.5 (CH), 123.4 (C), 155.5 (CH2); νmax
(film)/cm−1 2926, 1640, and 1528; EIMS (75 eV) m/z 120.1 (35,
[M]+), 91.1 (100, [M − CO]+); HREIMS calcd for C8H8O [M]+
120.0575, found 120.0575.
1
14: Rf 0.30 (ether), mp 122−123 °C (CH2Cl2/hexane); H NMR
(400 MHz; CDCl3) δ/ppm 7.38 (1H, d, J = 2.0 Hz), 6.23 (1H, d, J =
2.0 Hz), 4.08 (1H, d, J = 8.4 Hz), 3.36 (1H, ddd, J = 8.4, 4.4, and 4.0
Hz), 2.97 (3H, s), 2.56−2.47 (1H, m), 2.44−2.35 (2H, m), 1.91−1.82
(1H, m); 13C NMR (100 MHz; CDCl3) δ/ppm 178.4 (C), 174.7 (C),
143.2 (CH), 142.7 (C), 119.6 (C), 110.4 (CH), 41.1 (CH), 40.3
(CH), 25.1 (CH3), 22.0 (CH2), 19.2 (CH2); νmax (KBr)/cm−1 2935,
2853, 1771, 1700, 1500 and 1439; EIMS (70 eV) m/z (%) 205.1 (55,
[M]+), 120.1 (100), 91.0 (49); HREIMS calcd for C11H11NO3 [M]+
205.0739, found 205.0744.
Compounds 7, 8, and 9. Durene (16.5 mg, 0.123 mmol) was
weighed into a valve-appended NMR tube and dissolved in CDCl3
(0.5 mL). To this was added 3-vinylfuran 3 (0.35 mmol, as determined
by subsequent quantitative 1H NMR analysis against durene), N-
methylmaleimide (39 mg, 0.35 mmol, 1.0 mol equiv) and then CDCl3
(0.3 mL). The tube was sealed and heated at 50 °C for 2.5 h. The
solvent was removed in vacuo, and the residue was subjected to flash
chromatography on silica gel using gradient elution with 1:1 diethyl
ether:pentane to 100% diethyl ether to give the title compounds 7 and
8 as a 1:1 mixture (44 mg, 61%) and compound 9 as a white powder
(3 mg, 4%). Analytical samples of 7 and 8 were obtained by
preparative HPLC (Waters SunFire column, 1:1 EtOAc:hexane, 8.5
mL/min; 7, tR 9.0 min; 8, tR 10.5 min). Compounds 7 and 8 were
obtained as colorless oils.
10: Rf 0.19 (ethyl acetate:diethyl ether 2:1); mp 247−255 °C
1
(CHCl3/hexane); H NMR (800 MHz; CDCl3) δ/ppm 5.92−5.92
(1H, m), 5.49 (1H, s), 4.92 (1H, s), 3.36 (1H, dd, J = 8.7 and 8.7 Hz),
3.10 (1H, t, J = 7.0 Hz), 3.05 (1H, d, J = 6.9 Hz), 2.96 (1H, d, J = 6.8
Hz), 2.92 (3H, s), 2.86 (3H, s), 2.85 (1H, dd, J = 14.1 and 7.4 Hz),
2.27 (1H, d, J = 8.7 Hz), 2.04 (1H, d, J = 15.2 Hz); 13C NMR (200
MHz; CDCl3) δ/ppm 178.8 (C), 176.4 (C), 176.2 (C), 176.0 (C),
141.8 (C), 118.1 (CH), 79.6 (CH), 79.5 (CH), 49.6 (CH), 48.9
(CH), 42.3 (CH), 40.2 (CH), 39.2 (CH), 25.2 (CH3), 25.1 (CH3),
1
7: Rf 0.20 (1:1 ether:pentane); H NMR (800 MHz; CDCl3) δ/
ppm 6.40 (1H, dd, J = 17.7 and 10.8 Hz), 6.25 (1H, s) 5.44, (1H, d, J
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23.5 (CH2); νmax (KBr)/cm−1 2961, 2933, 1767, 1692, and 1435;
EIMS (70 eV) m/z (%) 316.1 (100, [M]+), 120.1 (77), 91.1 (93);
HREIMS calcd for C16H16N2O5 [M]+ 316.1059, found 316.1063.
11: Rf 0.36 (ethyl acetate:diethyl ether 2:1); tR 35 min (ethyl
acetate:hexane 1:1, 8.5 mL/min, SunFire prep column); mp 220−222
flash chromatography on silica gel eluting with CH2Cl2:MeOH
99.5:0.5 to give both compounds as white solids. A sample of exo-
adduct 17 was recrystallized from CH2Cl2/heptane to give crystals
suitable for single crystal X-ray analysis.
16: Rf 0.19 (7:3 diethyl ether:hexane), 0.08 (CH2Cl2:MeOH
1
1
°C (CH2Cl2/hexane); H NMR (800 MHz; CDCl3) δ/ppm 5.94−
99.5:0.5); mp 48−51 °C (CH2Cl2); H NMR (400 MHz; CDCl3) δ/
5.93 (1H, m), 5.51 (1H, d, J = 6.4 HZ), 4.96 (1H, d, J = 6.1 Hz), 3.63
(1H, dd, J = 9.3 and 6.5 Hz), 3.56 (1H, dd, J = 9.3 and 6.2 Hz), 3.32
(1H, t, J = 8.6 Hz), 3.08 (1H, t, J = 6.8 Hz), 2.91 (1H, s), 2.89 (1H, s)
2.86 (1H, ddd, J = 15.4, 7.4, and 1.7 Hz), 2.14 (1H, d, J = 8.6 Hz), 1.96
(1H, d, J = 15.3 Hz); 13C NMR (200 MHz; CDCl3) δ/ppm 78.7 (C),
176.3 (C), 175.2 (C), 174.2 (C), 139.9 (C), 120.3 (CH), 78.6 (CH),
78.3 (CH), 51.2 (CH), 50.6 (CH), 40.2 (CH), 39.8 (CH), 39.0 (CH),
25.1 (CH3), 24.7 (CH3), 23.5 (CH2); νmax (KBr)/cm−1 2961, 2933,
1767, 1692 and 1435; EIMS (70 eV) m/z (%) 316.1 (100, [M]+),
120.1 (97), 91.1 (98); HREIMS calcd for C16H16N2O5 [M]+ 316.1059,
found 316.1050.
ppm 7.49 (1H, br. s), 7.36 (1H, dd, J = 1.8 and 1.5 Hz,) 6.35 (1H, dd,
J = 2.1 and 0.9 Hz), 6.26 (1H, d, J = 1.8 Hz), 5.41 (1H, d, J = 4.2 Hz),
5.37 (1H, d, J = 5.3 Hz), 3.67−3.57 (2H, m), 2.66 (3H, s); 13C NMR
(100 MHz; CDCl3) δ/ppm 175.2 (C), 174.0 (C), 144.0 (CH), 141.1
(CH), 139.4 (C), 124.9 (CH), 117.8 (C), 108.1 (CH), 81.1 (CH),
80.4 (CH), 48.4 (CH), 46.5 (CH), 24.5 (CH3); νmax (film)/cm−1
2919, 1775, 1698, and 1434; EIMS (70 eV) m/z (%) 245.1 (60,
[M]+), 160.1 (28) 134.0 (100); HREIMS calcd for C13H11NO4 [M]+
245.0688, found 245.0689.
17: Rf 0.19 (7:3 diethyl ether:hexane), 0.13 (CH2Cl2:MeOH
1
99.5:0.5); mp 157−158 °C (CH2Cl2/heptane); H NMR (400 MHz;
12: Rf 0.36 (ethyl acetate:diethyl ether 2:1); tR 32 min (ethyl
CDCl3) δ/ppm 7.62 (1H, br. s), 7.45 (1H, dd, J = 2.1 and 1.5 Hz),
6.46 (1H, dd, J = 1.8 and 0.9 Hz), 6.38 (1H, d, J = 2.1 Hz), 5.35 (1H,
s), 5.33 (1H, d, J = 1.5 Hz), 3.00 (1H, d, J = 6.6 Hz), 2.99 (3H, s),
2.89 (1H, d, J = 6.6 Hz); 13C NMR (100 MHz; CDCl3) δ/ppm 176.3
(C), 176.1 (C), 144.4 (CH), 141.3 (C), 140.0 (CH), 127.0 (CH),
117.5 (C), 108.4 (CH), 82.0 (CH), 77.3 (CH), 49.9 (CH), 47.6
(CH), 25.1 (CH3); νmax (film)/cm−1 2928, 1772, 1698, and 1435;
EIMS (70 eV) m/z (%) 245.1 (32, [M]+), 134.1 (100); HREIMS
calcd for C13H11NO4 [M]+ 245.0688, found 245.0689.
acetate:hexane 1:1, 8.5 mL/min, SunFire prep column); mp 267−268
1
°C (CH2Cl2/heptane); H NMR (800 MHz; CDCl3) δ/ppm 6.04−
6.03 (1H, m), 5.25 (1H, m) 5111 (1H, m), 3.06 (1H, m, J = 7.0 Hz),
3.03 (1H, d, J = 8.4 Hz), 3.01 (3H, s), 2.99 (3H, S), 2.85−2.80 (2H,
m), 2.64 (1H, t, J = 10.0 Hz) 1.95 (1H, d, J = 10.4 Hz), 1.92−1.91
(1H, m); 13C NMR (200 MHz; CDCl3) δ/ppm 178.5 (C), 178.0 (C),
176.1 (C), 175.9 (C), 143.1 (C), 118.7 (CH), 81.3 (CH), 80.8 (CH),
49.5 (CH), 48.7 (CH), 44.4 (CH), 43.0 (CH), 39.0 (CH), 25.4
(CH3), 24.8 (CH3), 24.3 (CH2); νmax (KBr)/cm−1 2922, 1770, 1693,
1435 and 1388; EIMS (70 eV) m/z (%) 316.1 (100, [M]+), 120.1
(60), 91.1 (56); HREIMS calcd for C16H16N2O5 [M]+ 316.1059,
found 316.1063.
Tris-Adduct 18. 3,3′-Bifuran 5 (72 mg, 0.537 mmol) and N-
methylmaleimide (239 mg, 2.15 mmol, 4.0 mol equiv) were dissolved
in benzene (1 mL), and the resulting mixture was heated in a
microwave reactor at 80 °C for 2 h. The solvent was evaporated, and
the residue was subjected to flash chromatography on silica gel eluting
with ethyl acetate to give a mixture that was further purified using
preparative HPLC (Altech SemiPrep column eluting with ethyl acetate
at 4.5 mL/min, tR 7.4 min) to give the title compound 18 as a white
crystalline solid (34 mg, 7% yield). A sample was recrystallized from
acetone/water and gave crystals suitable for single crystal X-ray
13: Rf 0.36 (ethyl acetate:diethyl ether 2:1); tR 27 min (ethyl
acetate:hexane 1:1, 8.5 mL/min, SunFire prep column); mp 245 °C
1
(CH2Cl2/hexane); H NMR (800 MHz; CDCl3) δ/ppm 6.05−6.05
(1H, m), 5.28 (1H, d, J = 6.2 Hz), 5.15 (1H, d, J = 6.1 Hz), 3.67 (1H,
dd, J = 9.3 and 6.3 Hz), 3.61 (1H, dd, J = 9.3 and 6.2 Hz), 3.00 (3H,
s), 2.87 (3H, s), 2.81−2.78 (28, m), 2.62 (1H, t, J = 9.8 Hz), 1.82−
1.80 (2H, m); 13C NMR (200 MHz; CDCl3) δ/ppm 178.4 (C), 177.5
(C), 174.7 (C), 174.1 (C), 141.5 (C), 121.2 (CH), 80.1 (CH), 79.9
(CH), 51.1 (CH), 50.7 (CH), 43.2 (CH), 42.3 (CH), 38.9 (CH), 24.9
(CH3), 24.9 (CH3), 24.4 (CH2); νmax (KBr)/cm−1 2953, 2892, 1782,
1766, 1698 and 1436; EIMS (70 eV) m/z (%) 316.1 (15, [M]+), 120.1
(10), 91.1 (11), 85.0 (65) 83.0 (100); HREIMS calcd for C16H16N2O5
[M]+ 316.1059, found 316.1059.
1
analysis: Rf 0.54 (ethyl acetate), mp >300 °C (acetone/water); H
NMR (600 MHz; CDCl3) δ/ppm 5.28−5.27 (1H, m), 5.21 (1H, s),
5.19 (1H, s), 3.73−3.69 (2H, m), 3.03 (1H, d, J = 7.1 Hz), 2.98 (1H,
d, J = 7.1 Hz), 2.98 (3H, s), 2.98 (3H, s), 2.83 (3H, s), 2.61−2.57 (2H,
m), 2.00−1.96 (1H, m), 1.89−1.85 (1H, m); 13C NMR (150 MHz;
CDCl3) δ/ppm 177.2 (C), 176.7 (C), 175.6 (C), 175.3 (C), 174.2
(C), 174.1 (C), 134.5 (C), 131.1 (C), 81.4 (CH), 79.8 (CH), 78.8
(CH), 78.2 (CH), 51.0 (CH) 50.6 (CH), 49.1 (CH), 48.4 (CH), 44.8
(CH), 42.7 (CH), 42.3 (CH), 42.0 (CH), 25.4 (CH3) two coincident
signals, 25.0 (CH3); νmax (film)/cm−1 2952, 1777, 1701, 1436 and
1382; EIMS (70 eV) m/z (%) 467.1 (100, [M]+), 113.2 (72);
HREIMS calcd for C23H21N3O8 [M]+ 467.1329, found 467.1322.
Compounds 19 and 20. 3,4-Divinylfuran 6 (601 mg, 5.0 mmol)
was dissolved in PhMe (20 mL), and N-phenylmaleimide (866 mg, 5.0
mmol, 1.0 mol equiv) was added. The solution was stirred at 50 °C for
1 h. The solvent was removed in vacuo, and the residue was subjected
to flash chromatography on silica gel eluting with 2:3 diethyl
ether:hexane to give the title compounds 19 and 20 as white solids
(endo-adduct 19; 474 mg, 32%, exo-adduct 20; 804 mg, 55%).
19: Rf 0.08 (2:3 diethyl ether:hexane); mp >200 °C (diethyl
Compound 15. 2-(3-Furyl)-1,3-butadiene 4 (70 mg, 0.582 mmol)
was dissolved in chloroform (1.2 mL), and N-methylmaleimide (65
mg, 0.582 mmol, 1.0 equiv) was added. The solution was allowed to
stand at rt for 2 h. The solvent was removed in vacuo, and the residue
was subjected to flash chromatography on silica gel eluting with 2:3
diethyl ether:petroleum spirits to give the title compound 15 as a
white solid (132 mg, 92%). A sample was recrystallized from
dichloromethane to give crystals suitable for single crystal X-ray
analysis: Rf 0.07 (2:3 diethyl ether:petroleum spirits); mp 83−84 °C
(CH2Cl2); 1H NMR (400 MHz; CDCl3) δ/ppm 7.42 (1H, br. s), 7.32
(1H, dd, J = 1.8 and 1.5 Hz), 6.42 (1H, dd, J = 1.8 and 0.9 Hz), 6.00
(1H, ddd, J = 6.6, 3.6, 2.7 Hz), 3.20−3.08 (2H, m), 2.89 (3H, s), 2.84
(1H, dd, J = 12.3 and 2.7 Hz), 2.71 (1H, ddd, J = 15.6, 9.6, and 2.7
Hz), 2.50−2.42 (1H, m), 2.39−2.31 (1H, m); 13C NMR (100 MHz;
CDCl3) δ/ppm 180.1 (C), 197.7 (C), 143.7 (CH), 138.5 (CH), 130.6
(C), 126.2 (C), 120.4 (CH), 107.3 (CH), 39.4 (CH), 39.2 (CH), 26.3
(CH2), 25.1 (CH3), 24.2 (CH2); νmax (film)/cm−1 2951, 2902, 2849,
1774 and 1694; EIMS (70 eV) m/z (%) 232.1 (56, [M + H]+), 231.1
(87, [M]+), 216.1 (9, [M − CH3]+) 146.1 (100, [M − C3H3NO2]+);
HREIMS calcd for C13H13NO3 [M]+ 231.0895, found 231.0896.
Compounds 16 and 17. 3,3′-Bifuran 5 (134 mg 1.0 mmol) was
dissolved in chloroform (2 mL), and N-methylmaleimide (111 mg, 1.0
mmol, 1.0 mol equiv) was added. The solution was stirred at 50 °C for
2.5 h. The solvent was removed in vacuo, and the residue was
subjected to flash chromatography on silica gel eluting with 7:3 diethyl
ether:hexane to give the title compounds 16 and 17 as a 1:1 mixture
(202 mg, 82%). Analytical samples of both isomers were obtained by
1
ether:hexane); H NMR (800 MHz; CDCl3) δ/ppm 7.39 (2H, t, J =
7.7 Hz), 7.34 (1H, t, J = 7.4 Hz), 7.02 (2H, d, J = 7.7 Hz), 6.62 (2H,
dd, J = 17.5 and 11.0 Hz), 5.64 (2H, s), 5.46 (2H, d, J = 17.7 Hz), 5.39
(2H, d, J = 11.0 Hz), 3.84 (2H, d, J = 1.4 Hz); 13C NMR (200 MHz;
CDCl3) δ/ppm 172.6 (C), 140.1 (C), 131.5 (C), 129.2 (CH), 128.8
(CH), 126.6 (CH), 125.2 (CH), 120.2 (CH2), 81.3 (CH), 48.3 (CH),
νmax (KBr)/cm−1 2986, 2959, 1777, 1709, 1312, 1598 and 1495; EIMS
(70 eV) m/z (%) 293.1 (45, [M]+), 173.0 (42), 146.1 (30),119.0 (42),
91.0 (100); HREIMS calcd for C18H15NO3 [M]+ 293.1052, found
293.1055.
20: Rf 0.15 (2:3 diethyl ether:hexane); mp 191−193 °C (diethyl
1
ether:hexane); H NMR (800 MHz; CDCl3) δ/ppm 7.48 (2H, t, J =
7.7 Hz), 7.40 (1H, t, J = 7.4 Hz), 7.29 (2H, d, J = 7.4 Hz), 6.58 (2H,
dd, J = 17.5 and 10.9 Hz) 5.58 (2H, s) 5.50 (2H, d, J = 17.6 Hz), 5.38
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(28, d, J = 10.9 Hz), 3.09 (2H, s); 13C NMR (200 MHz; CDCl3) δ/
ppm 175.2 (C), 141.9 (C), 131.9 (C), 129.3 (CH), 128.9 (CH), 126.7
(CH), 125.3 (CH), 118.1 (CH2), 82.4 (CH), 49.4 (CH); νmax (KBr)/
cm−1 3011, 1776, 1713, 1611, 1598 and 1497; EIMS (70 eV) m/z (%)
293.1 (100, [M]+), 175.0 (61), 173.0 (63), 118.0 (92), 91.0 (59);
HREIMS calcd for C18H15NO3 [M]+ 293.1052, found 293.1050.
Compounds 21, 22, and 23. 3,4-Divinylfuran 6 (120 mg, 1.0
mmol) and N-phenylmaleimide (1.04 g, 6.0 mmol, 6.0 mol equiv)
were combined in a microwave tube and heated at 120 °C for 1 h. The
gummy residue was subjected to flash chromatography on silica gel
eluting with 3:1 ethyl acetate:hexane to give a mixture of compounds
21, 22, and 23 in a 62:12:26 ratio (244 mg 52%, ratio determined by
quantitative 1H NMR). Analytical samples were obtained by
preparative HPLC (SunFire prep column, ethyl acetate:hexane
70:30, 8.5 mL/min; 23, tR 4.0 min; 27, tR 6.5 min; 21, tR 16.0 min).
Samples of compounds 21 and 23 were recrystallized from
chloroform/hexane, respectively, to give crystals suitable for single
crystal X-ray analysis.
The solution was then passed through a short pad of silica eluting with
diethyl ether:hexane 1:1. The solvent was removed in vacuo to give the
title compound 25 as a white solid (72 mg, 90%): Rf 0.17 (2:3 diethyl
ether/hexane); mp 154−156 °C (diethyl ether/hexane): 1H NMR
(800 MHz; CDCl3) δ/ppm 7.44 (2H, dd, J = 6.9, 6.9 Hz), 7.37 (1H,
dd, J = 7.0, 7.0 Hz), 7.25 (2H, dd, J = 7.3, 7.3 Hz), 5.67 (2H, s) 5.23
(2H, s) 3.16 (2H, s), 2.26 (4H, s); 13C NMR (200 MHz; CDCl3) δ/
ppm 175.7 (C), 136.7 (C), 131.9 (C), 129.3 (CH), 128.9 (CH), 126.6
(CH), 114.8 (CH), 81.2 (CH), 50.2 (CH), 22.1 (CH2); νmax (KBr)/
cm−1 2961, 2915, 1778, 1708, 1595, 1501 and 1494; EIMS (70 eV) m/
z (%) 293.1 (70, [M]+), 146.1 (39), 120.1 (100), 91.1 (46), HREIMS
calcd for C18H15NO3 [M]+ 293.1052, found 293.1055.
Compounds 24 and 25. Compound 19 (105 mg, 0.358 mmol)
was dissolved in toluene (2.5 mL), and the solution was stirred at
reflux to 12 h. The solvent was removed in vacuo, and the residue was
subjected to flash chromatography on silica gel using a gradient elution
from 2:3 diethyl ether:hexane to 3:2 diethyl ether:hexane to give the
title compounds 24 and 25 as white solids (endo-adduct 24; 58 mg,
55%, exo-adduct 25; 38 mg, 36%).
1
21: Rf 0.38 (ethyl acetate); mp 184−185 °C (CHCl3/hexane); H
NMR (800 MHz; CDCl3) δ/ppm 7.39 (2H, dd, J = 7.6 and 7.6 Hz),
7.35 (2H, dd, J = 7.6 and 7.6 Hz), 7.33−7.29 (2H, m), 7.19 (2H, d, J =
6.6 Hz), 7.04 (2H, d, J = 7.4 Hz), 5.32 (2H, s), 3.65 (2H, s), 3.04 (2H,
s), 2.87 (2H, s), 1.73 (2H, d, J = 8.4 Hz), 1.09 (2H, d, J = 8.6 Hz); 13C
NMR (200 MHz; CDCl3) δ/ppm 176.9 (C), 174.7 (C), 148.3 (C),
131.8 (C), 131.6 (C), 129.3 (CH), 129.3 (CH), 129.0 (CH), 128.9
(CH), 126.9 (CH), 126.6 (CH), 82.6 (CH), 48.7 (CH), 44.2 (CH),
33.2 (CH), 24.8 (CH2); νmax (KBr)/cm−1 2954, 2873, 1776, 1710,
1597 and 1499; EIMS (70 eV) m/z (%) 466.1 (1, [M]+), 293.1 (100),
173.0 (90), 118.0 (82), 91.0 (57); HREIMS calcd for C28H22N2O5
[M]+ 466.1529, found 466.1528.
24: Rf 0.06 (diethyl ether/hexane 2:3); mp 150−151 °C (diethyl
ether/hexane); 1H NMR (800 MHz; CDCl3) δ/ppm 7.44 (2H, dd, J =
7.6 and 7.6 Hz), 7.36 (1H, dd, J = 6.7 and 6.7 Hz), 7.19 (2H, d, J = 8.4
Hz), 5.68 (2H, s), 5.26 (2H, dd, J = 3.8 and 2.2 Hz), 3.73 (2H, dd, J =
4.0 and 2.4 Hz), 2.27−2.20 (4H, m); 13C NMR (200 MHz; CDCl3)
δ/ppm 173.6 (C), 134.9 (C), 131.6 (C), 129.2 (CH), 128.7 (CH),
126.1 (CH), 116.5 (CH), 79.9 (CH), 51.2 (CH), 22.2 (CH2); νmax
(KBr)/cm−1 2928, 2828, 1776, 1713, 1598 and 1499; EIMS (70 eV)
m/z (%) 293.1 (25, [M]+), 175.1 (69), 146.1 (42), 120.1 (100), 91.1
(78); HREIMS calcd for C18H15NO3 [M]+ 293.1052, found 293.1055.
Compound 21. Thermal Conditions. Compound 25 (147 mg, 0.5
mmol), N-methylmaleimide (346 mg, 1.59, 3.0 mol equiv), and BHT
(10 mg) were combined and heated in a microwave reactor at 120 °C
for 1 h. The residue was subjected to flash chromatography on silica
gel using a gradient elution from 3:1 ethyl acetate:hexane to ethyl
acetate to give the title compound 21 as a light yellow solid (130 mg,
56%).
High Pressure Conditions. Compound 25 (131 mg, 0.447 mmol)
and N-phenylmaleimide (155 mg, 0.895 mmol, 2.0 equiv) were
dissolved in dichloromethane (6 mL), and the solution was placed into
a high pressure Teflon vessel. The vessel was placed into a hydraulic
press and compressed at 19 kbar overnight. The solvent was removed
in vacuo, and the residue was subjected to flash chromatography on
silica gel eluting with ethyl acetate to give the title compound 21 as a
light yellow solid (145 mg, 70%).
Compound 26. Compound 24 (27.7 mg, 0.0944 mmol) and N-
phenylmaleimide (32.7 mg, 0.189 mmol, 2.0 mol equiv) were
dissolved in dichloromethane (0.5 mL) in a Teflon high pressure
vessel. The vessel was placed into a hydraulic press and compressed at
19 kbar overnight. The solution was then passed through a short pad
of silica eluting with chloroform after which the solvent was removed
in vacuo. The residue was then subjected to preparative HPLC
(SunFire prep column eluting with ethyl acetate:hexane 1:1, 8.5 mL/
min, tR 12.0 min) to give the title compound 26 as a white solid (12
mg, 29%,). The poor isolated yield reflects difficulties in isolation. In a
separate run the crude material was analyzed by 1H NMR
spectroscopy against an internal standard, which revealed a clean
conversion to the product in 75% yield.
1
22: mp 166−167 °C (benzene); H NMR (800 MHz; CDCl3) δ/
ppm 7.47 (2H, dd, J = 7.7 and 7.7 Hz), 7.42 (2H, dd, J = 7.7 and 7.7
Hz), 7.40 (1H, dd, J = 7.5 and 7.5 Hz), 7.35 (1H, dd, J = 7.4 and 7.4
Hz), 7.29 (2H, d, J = 7.5 Hz), 7.18 (2H, d, J = 7.4 Hz), 6.21 (1H, d, J
= 6.2 Hz), 5.55 (1H, s), 5.20 (1H, s), 3.47 (1H, d, J = 7.0 Hz), 3.40
(1H, s), 3.22 (1H, dd, J = 8.2 and 4.0 Hz), 3.20 (1H, d, J = 7.0 Hz),
3.04 (1H, d, J = 8.2 Hz), 1.87−1.82 (2H, m), 1.79−1.77 (1H, m), 2.23
(1H, dd, J = 12.1, 12.1, and 4.8 Hz); 13C NMR (200 MHz; CDCl3) δ/
ppm 176.3 (C), 176.0 (C), 175.7 (C), 175.0 (C), 145.4 (C), 131.8 (C,
two coincident signals), 129.3 (CH), 129.2 (CH), 129.0 (CH), 128.7
(CH), 126.6 (CH), 126.3 (CH), 120.8 (CH), 83.1 (CH), 79.1 (CH),
50.2 (C), 49.9 (CH), 46.2 (CH), 45.0 (CH), 45.0 (CH), 31.5 (CH),
28.6 (CH2), 26.7 (CH2); νmax (KBr)/cm−1 2960, 2923, 2851, 1776,
1713, 1631, 1598 and 1498; EIMS (70 eV) m/z (%) 466.2 (33, [M]+),
173.1 (32), 85.1 (50), 71 (70), 56 (100); HREIMS calcd for
C28H22N2O5 [M]+ 466.1529, found 466.1527.
The structure and stereochemistry of compound 22 was established
1
by two-dimensional NMR analysis. From the H, 13C, COSY, and
HSQC NMR spectra, the atom connectivity of the structure was
established. The stereochemistry was assigned on the basis of the NOE
enhancements, as shown in the Supporting Information.
23: mp 190−193 °C (CHCl3/hexane); 1H NMR (800 MHz;
CDCl3) δ/ppm 7.49 (2H, dd, J = 7.6 and 7.6 Hz), 7.45−7.42 (5H, m),
7.38 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.24 (2H, d, J = 7.8
Hz), 7.21 (2H, d, J = 7.8 Hz), 7.20 (2H, d, J = 7.8 Hz), 3.77−3.73
(2H, m), 3.49 (1H, dd, J = 9.2 and 5.3 Hz), 3.46−3.45 (1H, m), 3.31−
3.29 (1H, m), 2.95 (1H, d, J = 11.2 Hz), 2.74−2.70 (2H, m), 2.43−
2.39 (1H, m), 2.15 (1H, s), 1.89 (1H, ddd, J = 13.6, 5.1, and 5.1 Hz);
13C NMR (200 MHz; CDCl3) δ/ppm 178.0 (C), 177.0 (C), 176.9
(C), 174.8 (C), 173.6 (C), 173.2 (C), 134.5 (C), 134.4 (C), 131.6
(C), 131.5 (C), 131.3 (C), 129.5 (CH), 129.1 (CH), 129.1 (CH),
128.9 (CH), 128.7 (CH), 128.7 (CH), 126.4 (CH), 126.1 (CH),
125.7 (CH), 82.9 (CH), 80.9 (CH), 47.4 (CH), 46.4 (CH), 44.7
(CH), 42.1 (CH), 41.2 (CH), 41.0 (CH), 31.8 (CH), 30.3 (CH), 27.0
(CH2), 26.3 (CH2); νmax (KBr)/cm−1 2962, 2926, 2854, 1778, 1710,
1586 and 1498; EIMS (70 eV) m/z (%) 639.2 (100, [M]+), 491.1
(12), 318.1 (15), 175.1 (60); HREIMS calcd for C38H29N3O7 [M]+
639.2006, found 639.2004.
26: mp 181−182 °C (CHCl3/hexane); 1H NMR (800 MHz;
CDCl3) δ/ppm 7.39 (2H, t, J = 7.7 Hz), 7.35 (2H, t, J = 7.6 Hz),
7.33−7.29 (2H, m), 7.19 (2H, d, J = 6.6 Hz), 7.04 (2H, d, J = 7.4 Hz),
5.32 (2H, s), 3.65 (2H, s), 3.04 (2H, s), 2.87 (2H, s), 1.73 (2H, d, J =
8.4 Hz), 1.09 (2H, d, J = 8.6 Hz); 13C NMR (200 MHz; CDCl3) δ/
ppm 176.9 (C), 174.7 (C), 148.3 (C), 131.8 (C), 131.6 (C), 129.3
(CH), 129.3 (CH), 129.0 (CH), 128.9 (CH), 126.9 (CH), 126.6
(CH), 82.6 (CH), 48.7 (CH), 44.2 (CH), 32.2 (CH), 24.8 (CH2);
νmax (KBr)/cm−1 2955, 2872, 1778, 1703, 1595 and 1494; EIMS (70
eV) m/z (%) 466.1 (2, [M]+), 293.1 (100), 173.0 (83), 118.0 (80),
91.0 (55); HREIMS calcd for C28H22N2O5 [M]+ 466.1529, found
466.1529.
Compound 25. Compound 20 (80 mg, 0.273 mmol) was
dissolved in toluene, and the solution was stirred at reflux for 12 h.
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dx.doi.org/10.1021/jo500458y | J. Org. Chem. 2014, 79, 3185−3193

The Journal of Organic Chemistry
Article
Compound 21. Compound 24 (37.1 mg, 0.126 mmol) and N-
phenylmaleimide (131 mg, 0.759 mmol, 6.0 mol equiv) were dissolved
in toluene (0.5 mL), and the resulting solution was heated in
microwave reactor at 150 °C for 38 h. The solvent was removed in
vacuo, and the residue was subjected to flash chromatography on silica
gel eluting with ethyl acetate to give the title compound 21 (11 mg,
19%).
Isomerization of 26 to 21. A solution of compound 26 (3.4 mg,
0.00729 mmol) and N-phenylmaleimide (25 mg, 0.146 mmol, 20 mol
equiv) in toluene (0.2 mL) was heated at reflux for 6 h. The solvent
was evaporated under reduced pressure, and the residue was dissolved
in CDCl3 containing tetrachloroethylene (10 μL). Analysis of the
sample by 1H NMR spectroscopy revealed clean conversion to the exo-
adduct 21 in 73% yield.
(10) See ref 8 for a multigram scale synthesis of compound 5.
(11) Eberbach, W.; Fritz, H.; Laber, N. Angew. Chem., Int. Ed. Engl.
1988, 27, 568.
(12) Benítez, A.; Herrera, F. R.; Romero, M.; Talamas
́
, F. X.;
Muchowski, J. M. J. Org. Chem. 1996, 61, 1487.
(13) (a) Fang, L.-Z.; Liu, J.-K. Heterocycles 2009, 78, 2107.
(b) McNamara, J. M.; Kishi, Y. Tetrahedron 1984, 40, 4685.
(14) The mass balance for this reaction was unreacted 3 and a
mixture of the double DA products 10, 11, 12, and 13. Interestingly,
the 1:1 ratio of exo and endo furan diene adducts 7 and 8 remained
constant throughout this reaction, while the amount of precursor
declined and that of the double DA adducts increased. The
implications of these observations on the reversibility of DA reactions
involving 3 and related observations with 4, 5, and 6 are discussed in
the Supporting Information.
(15) Gayatri, G.; Sastry, G. N. J. Phys. Chem. A 2009, 113, 12013.
(16) See the Supporting Information for details.
(17) This product is the result of NPM docking in an endo-manner to
the 1,3-cyclohexadiene group of exo-adduct 21 with a syn-disposition
relative to the oxa-bridge.
ASSOCIATED CONTENT
* Supporting Information
■
S
Selected NOE enhancements of compound 22; a discussion of
the potential for thermodynamic control in the Diels−Alder
reaction between NMM and 3, and implications for other
members of the series; CIFs and anisotropic displacement
ellipsoid plots for compounds 10−13, 15, 17, 18, 21, 23, and
26 (CCDC Nos. 966665−966674, respectively); computational
(18) The low yield in this case likely reflects losses encountered
during purification on HPLC.
(19) (a) Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R. M.;
Wright, D. L. J. Org. Chem. 2004, 69, 3726. (b) Tanis, S. P.; Herrinton,
P. M. J. Org. Chem. 1985, 50, 3988.
1
details; H and 13C NMR spectra of all new compounds. This
(20) Hersel, U.; Steck, M.; Seifert, K. Eur. J. Org. Chem. 2000, 1609.
(21) Prepared according to the procedure: Mee, S. P. H.; Lee, V.;
Baldwin, J. E.; Cowley, A. Tetrahedron 2004, 60, 3695.
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: michael.sherburn@anu.edu.au (synthetic).
*E-mail: m.paddonrow@unsw.edu.au (computational).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Australian Research Council.
MNP-R acknowledges that the computational component of
this research was undertaken with the assistance of resources
provided at the NCI National Facility through the National
Computational Merit Allocation Scheme supported by the
Australian Government. We thank Dr. Ian Cade (ANU) for a
preliminary X-ray analysis of compound 23.
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■
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