Diels-Alder reactions of five-membered heterocycles containing one heteroatom

Article abstract of DOI:10.1016/j.tetlet.2014.10.114

Diels-Alder reactions of five-membered heterocycles containing one heteroatom with an N-arylmaleimide were studied. Cycloaddition of 2,5-dimethylfuran (4) with 2-(4-methylphenyl)maleimide (3) in toluene at 60 °C gave bicyclic adduct 5. Cycloadditions of 3 with 2,5-dimethylthiophene (11) and 1,2,5-trimethylpyrrole (14) were also studied. Interestingly, the bicyclic compound 5 cleanly rearranged, with loss of water, when treated with p-toluenesulfonic acid in toluene at 80 °C to give 4,7-dimethyl-2-p-tolylisoindoline-1,3-dione (6).

Full text of DOI:10.1016/j.tetlet.2014.10.114

Tetrahedron Letters 55 (2014) 7002–7006
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diels–Alder reactions of five-membered heterocycles containing one
heteroatom
⇑
Xiaoyuan Ding, Son T. Nguyen, John D. Williams, Norton P. Peet
Department of Chemistry, Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Diels–Alder reactions of five-membered heterocycles containing one heteroatom with an N-arylmaleimide
were studied. Cycloaddition of 2,5-dimethylfuran (4) with 2-(4-methylphenyl)maleimide (3) in toluene at
Received 21 August 2014
Revised 14 October 2014
Accepted 21 October 2014
Available online 31 October 2014
60 °C gave bicyclic adduct 5. Cycloadditions of 3 with 2,5-dimethylthiophene (11) and 1,2,5-trimethylpyr-
role (14) were also studied. Interestingly, the bicyclic compound 5 cleanly rearranged, with loss of water,
when treated with p-toluenesulfonic acid in toluene at 80 °C to give 4,7-dimethyl-2-p-tolylisoindoline-1,
3-dione (6).
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Diels–Alder reactions
Dienes
Dienophiles
Acid-catalyzed reactions
We recently reported a screening campaign for type three
secretion system (T3SS) inhibitors that identified differentiated
hit compounds, which we grouped into three scaffolds.1 One of
these scaffolds was represented by the bicyclic compound 5, and
Interestingly, we were able to effect a very efficient, very clean
conversion of bicyclic compound 5 to 4,7-dimethyl-2-(4-methyl-
phenyl)phthalimide (6) in quantitative yield. This acid-catalyzed
rearrangement proceeded in toluene at reflux in the presence of
a catalytic amount of p-toluenesulfonic acid. Although we could
not find other examples of this exact conversion, we did find a
1
close analogs with different substituents in the phenyl ring. Our
first task was to prepare an authentic sample of compound 5 to
confirm activity. We also wished to explore rearrangement chem-
istry that the bicyclic compound 5 might undergo, as we predicted
may happen, upon treatment with acid. In addition, we explored
the biological activity of similar compounds and synthesized
compounds related to 5 with varied heteroatoms in the oxygen-
containing bridge. The findings from these synthetic investigations
are presented in this Letter.
somewhat related dehydrative rearrangement of
a tricyclic
dihydrofuran compound that produced a 2,3,6,7-tetrahydro-as-
1
0
indacene-1,8-dione. Also, there are reports of the preparation of
phthalimides directly from 2,5-dimethylfuran (4) and maleimides,
wherein the intermediate Diels–Alder adducts are not isolated but
are presumably intermediates that rearrange in situ.1
1,12
The
mechanism that we propose for the conversion of 5–6 is shown
in Scheme 2.
The synthesis of hit compound 5 is presented in Scheme 1.
Solutions of p-toluidine (1) and maleic anhydride (2) in tetrahydro-
furan were combined, and after 15 minutes, the solvent was dec-
anted and the remaining solid was treated with acetic anhydride
and sodium acetate at 120 °C with microwave irradiation to
We prepared an authentic sample of phthalimide 6, using a
4
recently reported procedure, to verify the structure. Treatment
of commercially available 4,7-dimethylphthalimide (7) with
p-toluidine (1) in dimethylformamide using microwave conditions
(Scheme 1) produced an authentic sample of 6, which was identical
in every respect to the material produced from the very efficient,
acid-catalyzed dehydrative rearrangement of exo adduct 5.
Moreover, we were able to also produce the endo adduct from
the Diels–Alder reaction of imide 3 with 2,5-dimethylfuran (4),
when we used diethyl ether as the solvent at room temperature,
as shown in Scheme 3. The distinguishing characteristic between
the exo and endo regiochemistries in these adducts is the position
of the bridgehead protons alpha to the carbonyl groups. These
2
–4
produce 1-p-tolyl-1H-pyrrole-2,5-dione (3) in 62% yield.
Subsequent treatment of maleimide 3 with 2,5-dimethylfuran (4)
in toluene at 80 °C gave the exo Diels–Alder adduct 5 in 50% yield.
It is well-known that both furan5 and 2,5-dimethylfuran
,6
7–9
produce exo Diels–Alder adducts with maleimides under elevated
temperature conditions, and that an endo product can be produced
if the Diels–Alder reaction is done at room temperature and kept in
the dark.
protons appear as a singlet at d 2.97 (CDCl
3
) for the exo adduct 5,
⇑
Corresponding author. Tel.: +1 616 298 8483; fax: +1 616 298 7337.
E-mail address: nppeet@gmail.com (N.P. Peet).
and at d 3.37 (CDCl ) for the endo adduct 10. These assignments
3
http://dx.doi.org/10.1016/j.tetlet.2014.10.114
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

X. Ding et al. / Tetrahedron Letters 55 (2014) 7002–7006
7003
H C
3
O
CH3
O
(
1) THF, rt, 15 min
4
NH2
O
O
N
O
toluene,
60°C, 3h
50%
(
2) Ac O, AcONa, µW,
2
O
H C
120 °C, 30 min,
62%
3
H3C
2
3
1
CH3
CH3
CH3
O
O
O CH3
O
N
1
, DMF, µW
p-TsOH
CH3
O
N
CH3
1
h
toluene,
H O
20%
80 °C, 16 h
H C
3
O
O
H
CH3
100 %
5
7
6
exo adduct
Scheme 1. Synthesis of bicyclic Diels–Alder adduct 5 and its conversion to phthalimide 6.
CH3
p-TsOH
O
O CH3
O
N
toluene
CH3
N
CH3
8
0 °C, 16 h
H O
H3C
H
O
CH3
5
6
+
H
-H2O
H
O CH3
CH3
CH3
H O
HO
O
N
-H
CH3
N
CH3
H O
O
9
H3C
H
8
Scheme 2. Proposed mechanism for the acid-catalyzed rearrangement of Diels–Alder adduct 5 to phthalimide 6.
CH3
O
H3C
O
H
H
CH3
O
O
O CH3 O
4
N
CH3
+
H C
N
N
3
Et2O,
r.t., 3 days
O
H O
O
H3C
H
H C
3
3
5
10
CH3
exo adduct
m.p. 128 °C
endo adduct
m.p. 150 °C
5 : 10 = 1 : 4
Scheme 3. Preparation of endo Diels–Alder adduct 10 from maleimide 3 and furan 4.
for exo and endo isomers for maleimide adducts with 2,5-dimeth-
ylfuran (4), where the exo bridgehead protons are consistently ca.
d 0.40 ppm upfield with respect to the endo isomer, are well-
documented in the literature.9
We next explored the reactivity of imide 3 with 2,5-dimethyl-
thiophene (11) as shown in Scheme 4. Although diene 11 was not
reactive enough to undergo [2+4] cycloaddition with 3 in toluene
at 60 °C, we were able to produce a cycloadduct in the presence
of m-chloroperoxybenzoic acid, which converted thiophene 11 to
its corresponding sulfoxide in situ to provide a more reactive diene.
The structure of this adduct is the endo adduct 13, which is
p-toluenesulfonic acid in toluene, albeit at a significantly slower
rate than 6 was produced from 5, to give phthalimide 6.
We also attempted to prepare a Diels–Alder adduct between
1,2,5-trimethylpyrrole (14) and maleimide 3. It is reported that
cycloaddition reactions of pyrroles with alkenes are limited by
the inherent thermodynamic instability of the cycloadducts
wherein cycloreversion or retro-Mannich reactions (followed by
,10
1
5–17
rearomatization) are predominant.
When we treated pyrrole
14 with maleimide 3, in toluene at 60 °C as shown in Scheme 5,
we observed no cycloadducts from these reactants. However, we
did obtain a small amount of adduct that arose from maleimide
3 and a furan-containing contaminant that was present in our
commercial sample of 14, which we determined to have an
completely analogous to another reported cycloadduct whose
structure was confirmed by X-ray diffraction.1
3,14
Interestingly,
adduct 13 also underwent acid-catalyzed rearrangement with
3
empirical formula of C19H19NO from mass spectral analysis. We

7
004
X. Ding et al. / Tetrahedron Letters 55 (2014) 7002–7006
O
S
CH3
)
H
H
1
) BF •Et O
3
2
2
CH3
S
O
CH Cl
O
2
−
20 °C
p-TsOH
N
+
N
CH3
H3C
O
toluene
(
2) mCPBA
8
0 °C, 3 d
CH3
O
33%
1
3
11
3
CH3
toluene, 60 °C
CH3
O
S
CH3
O
N
CH3
N
CH3
O
CH3
H O
H C
6
3
H
12
7%
(
66% recoverd starting
material 13)
Scheme 4. Preparation of thiophene sulfoxide Diels–Alder adduct 13 and its rearrangement to phthalimide 6.
H3C
CH3
N
O
N
CH3
O
toluene
CH3 +
N
CH3
N
CH3
6
0 °C
H O
CH3
4
O
3
H C
3
H
1
15
O CH3
O
N
O
O
N
H C
3
O CH3 O
H C
3
CH3
H3CO
CH3
H3CO
N
CH3
H O
H3CO
H O
O
H C
3
H
O
3
H C
H
H O
O
H
1
6
17
18
Scheme 5. Attempted preparation of a Diels–Alder adduct between 1,2,5-trimethylpyrrole (14) and maleimide 3, and potential structures of the unknown product.
proposed, from NMR analysis, that this compound should have one
of the structures shown at the bottom of Scheme 5, (i.e., structures
felt was upfield from where a vinyl carbon signal should appear.
These data suggested that compounds 17 or 18 would better fit
the data, as these compounds would have allylic protons in the d
5 ppm range and would have an allylic bridgehead carbon signal
downfield from d 84.34 ppm. Thus, we next set out to prepare an
authentic sample of compound 17.
1
6–18). We realized that three additional structures were theoret-
ically possible, wherein the carbomethoxy group would reside at
the bridgehead position next to the ether oxygen. However, we
considered these structures less likely, since they would be
1
8
products arising from a less reactive, more electron poor diene.
The synthesis of compound 17 is shown in Scheme 7. Propargyl
alcohol (22) was acylated with methyl chloroformate (23) to give
We first prepared an authentic sample of compound 16, to
determine whether this might be the material formed from
maleimide 3 and a substituted furan impurity that was present
in our commercial sample of 14. As shown in Scheme 6, we treated
methyl 3-oxovalerate (19) with propargyl bromide (20), in the
presence of cuprous iodide and DBU in toluene at 90 °C for
2
0
methyl prop-2-ynyl carbonate (24). Treatment of carbonate 24
with methyl acetoacetate under palladium-catalyzed conditions,
followed by treatment with 2 M aqueous hydrochloric acid gave
a modest yield of 2,4-dimethylfuran-3-carboxylic acid methyl
ester (25). Furan 25 underwent very clean and efficient cycloaddi-
tion with maleimide 3 in toluene at 60 °C to provide compound 17,
which was identical in every respect with the unknown cycload-
duct that was isolated from the treatment of 1,2,5-trimethylpyr-
role (14) with maleimide 3.
1
9
2
6 h to provide 2,5-dimethylfurancarboxylic acid methyl ester
(21). Furan 21 underwent cycloaddition with maleimide 3 in mod-
est yield to give the expected cycloadduct 16. Although the spectral
data for compound 16 were very similar to the spectral data gath-
ered for the unknown compound, the two materials were distinct.
For instance, the bridgehead protons for compound 16 appeared at
The regiochemistry of exo adduct 17 is clearly demonstrated by
1
examining the H NMR spectrum, which displays coupling between
d 3.12 and d 3.02 (coupling constant 6.3 Hz, CHCl
bridgehead protons appeared at d 3.12 and d 3.06 (coupling
constant 6.6 Hz, CHCl ) for the unknown compound. The biggest
3
), whereas these
the maleimide bridgehead protons (as previously described) and no
observed coupling between the furan bridgehead proton and the
adjacent maleimide bridgehead proton. Inspection of a structural
model for this compound reveals that the dihedral angle defined
by these two bridgehead protons and the carbons to which they
are attached is close to 90°. Lack of observed coupling between pro-
3
1
difference in the H NMR spectra of these compounds was that
the vinyl proton in compound 16 appeared as a singlet at d 7.06,
and this signal was not present in the unknown compound, but
its counterpart signal was a singlet that appeared at d 5.10.
tons configured with a dihedral angle of 90° is consistent with the
1
3
21,22
The C position for the carbon atom bearing this proton in the
unknown compound appeared at d 84.34 ppm (CHCl ), which we
prediction from the Karplus equation.
An endo regiochemistry,
3
where the dihedral angle is ca. 60°, would clearly display coupling

X. Ding et al. / Tetrahedron Letters 55 (2014) 7002–7006
7005
O
N
CH3
H C
3
O
O
O
O
DBU, CuI,
3
CH3
H C
CH3
+
Br
3
O
toluene, 60°C, 27 h
toluene, 90°C,
26 h
O
O
CH3
21
19
20
8%
O
CH3
O
N
CH3
H CO C
3
2
H
H
O
H C
3
16
16%
Scheme 6. Synthesis of an authentic sample of compound 16.
pyridine,
O
O
Et O
O
2
O
CH3
0
-20 °C, 23 h
CH3
Cl
O
CH3 H3C
O
HO
+
CH3
O
O
52%
(1) Pd (dba) •CHCl ,
2 3 3
H C
O
O
3
24
dppe, THF, r.t., 4 h
2) 2N HCl, r.t., 20 h
CH3
O
O
2
2
(
23
1
5%
25
O
N
O
O
H C
3
toluene,
0 °C, 25 h
100%
N
CH3
CH3
H CO
3
6
3
H O
O
H C
3
H
1
7
Scheme 7. Synthesis of an authentic sample of compound 17.
between the furan bridgehead proton and the adjacent maleimide
bridgehead proton of ca. 4.5 Hz.
character of pyrroles, as compared with furans or thiophenes,
limits their reactivity toward cycloaddition reactions.15
It is not clear why our commercial sample of pyrrole 14 was
contaminated with furan 25.23 The classic synthesis of 2,5-dimeth-
ylpyrrole involves the condensation of acetonylacetone with
Recent reports have described the preparation of phosphole-
N-phenylmaleimide [4+2] cycloadducts as precursors to the
3
1
preparation of nucleophilic phosphinidines,
secondary
24
32
33
ammonium carbonate, and this process produces pyrrole 14 if
phosphine–borane complexes,
and dibromophosphines.
2
5
26
methylamine or N-methylformamide is substituted for ammo-
Interestingly, these cycloadducts are endo adducts, as shown by
3
2
nium carbonate. It is difficult to imagine the coproduction of furan
X-ray crystallography. Thus, it is possible to perform [4+2]
cycloadditions of N-phenylmaleimides with five-membered ring
heterocycles containing one heteroatom, when that single
heteroatom is oxygen, sulfur, nitrogen, or phosphorous.
2
5 using these synthetic routes. Pyrroles are also commonly pre-
27–30
pared using the Knorr pyrrole synthesis,
and it is conceivable
that furan 25 might have been produced as a coproduct using this
procedure. We felt it was important to spend the considerable
effort that we did to establish the structure of cycloadduct 17 with
the reactive maleimide 3, since pyrrole 14 was completely unreac-
tive with 3, but 3 was very reactive with the minor component,
furan 25. Thus, this structural information is now available to
others who might encounter similar difficulties in treating pyrrole
In summary, we have investigated the cycloaddition reactions
of N-arylmaleimide 3 with furans and thiophenes, and shown that
the cycloadducts with 2,5-dimethylfuran (4) and 2,5-dimethylthio-
phene S-oxide undergo acid-catalyzed rearrangements to produce
phthalimide 6. Although 1,2,5-trimethylpyrrole (14) did not
undergo cycloaddition with 3 under the conditions we employed,
we isolated and characterized the interesting cycloadduct 17 that
was produced from furan 25, which was present as an impurity
in the sample of 14 that we used.
1
4 with additional dienophiles.
We did consider further studies with other pyrroles to effect
cycloaddition products with maleimide 3. However, as previously
mentioned, cycloadducts of pyrroles with dienophiles are inher-
ently thermodynamically unstable.1
5–17
Osmium complexation of
Acknowledgements
pyrroles has allowed the production of cycloadducts with malei-
mides and other dienophiles; however, decomplexation is not
straightforward and stable cycloadducts can only be isolated after
reduction of the resulting dihydropyrrole.15 The greater aromatic
This work was supported in part by DHHS/NIH Grant R43
AI-068185 from the National Institute of Allergy and Infectious
Diseases (NIAID) NIH – United States.

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X. Ding et al. / Tetrahedron Letters 55 (2014) 7002–7006
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Supplementary data
Supplementary data associated with this article can be found, in
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