Unusual regio- and stereo-selectivity in Diels-Alder reactions between bulky N-phenylmaleimides and anthracene derivatives

Article abstract of DOI:10.1039/c4ob01052c

Unusual regio- and stereo-selectivity in Diels-Alder (D-A) reactions were achieved between bulky N-phenylmaleimides and anthracene derivatives. Using multiple substituents with steric hindrance on both diene and dienophile, a noticeable shift toward 1,4-addition was successfully obtained. The substrate scope in this reaction was broad and the highest yield of anti-1,4-adducts was over 90%. Novel structures of anti-1,4-adducts were confirmed by single crystal X-ray diffraction analysis. This study not only provides the first reported method of synthesizing anti-1,4-adducts and achieving otherwise unattainable regio- and stereo-selectivity, but also elucidates the importance of combining the steric effects of two reactants to shift products toward 1,4-adducts. Moreover, the resulting 1,4-adducts could be further functionalized through their halogen groups via carbon-carbon coupling reactions.

Full text of DOI:10.1039/c4ob01052c

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Unusual regio- and stereo-selectivity in
Diels–Alder reactions between bulky N-phenyl-
maleimides and anthracene derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 5102
Received 21st May 2014,
Accepted 3rd June 2014
Hao Chen, Erdong Yao, Chi Xu, Xiao Meng and Yuguo Ma*
DOI: 10.1039/c4ob01052c
www.rsc.org/obc
Unusual regio- and stereo-selectivity in Diels–Alder (D–A) reac-
Maleimide derivatives were typical dienophiles and have
tions were achieved between bulky N-phenylmaleimides and been applied successfully in many different areas, such as
anthracene derivatives. Using multiple substituents with steric hin- sensing the mercapto group,5 copolymers synthesis6 and self-
drance on both diene and dienophile, a noticeable shift toward healing materials.7 There is a rotational barrier around the
1,4-addition was successfully obtained. The substrate scope in this
C
phenyl–Nimide single bond in N-phenylmaleimides.8–10 Due to
reaction was broad and the highest yield of anti-1,4-adducts was the steric repulsion between imide carbonyl groups and bulky
over 90%. Novel structures of anti-1,4-adducts were confirmed by ortho substituents of the phenyl ring, the rotational barrier
single crystal X-ray diffraction analysis. This study not only pro- could be adjusted and utilized as a tuning factor for molecular
vides the first reported method of synthesizing anti-1,4-adducts rotors11 and non-covalent interaction measurement.12 Anthra-
and achieving otherwise unattainable regio- and stereo-selectivity, cene derivatives were well studied as inner-ring dienes and
but also elucidates the importance of combining the steric effects generally yielded adducts bridging the centre ring of the
of two reactants to shift products toward 1,4-adducts. Moreover, anthracene framework as a consequence of the high π-electron
the resulting 1,4-adducts could be further functionalized through density at 9,10-position.13–18 Achieving D–A cycloaddition at a
their halogen groups via carbon–carbon coupling reactions.
terminal ring (1,4-position) of the anthracene framework is
particularly challenging and elusive; until now there have been
only three reported examples of 1,4-adducts of anthracene
derivatives. In 1965, Klanderman’s group reported the first
example of benzyne addition on 1,4-position of 9,10-diaryl-
anthracenes in very low yields.19 In 2006, Fujita’s group took
advantage of pre-organization by incorporating one anthracene
derivative and one maleimide into a synthetic cage and
achieved unusual syn-1,4-adducts in high yields.20 Very
recently, McGlinchey’s group reported D–A reactions of several
dienophiles with 9-ferrocenyl-/9,10-diferrocenylanthracene and
the yield of 1,4-adducts could reach 38%.21
Herein, we described a new strategy to achieve unusual
regio- and stereo-selectivity in D–A reactions between N-phenyl-
maleimides with bulky ortho substituents and bulky anthra-
cene derivatives. We proposed that substantial steric
interactions between two bulky reactants would suppress 9,10-
cycloaddition and syn-1,4-cycloaddition, while the pathway
towards anti-1,4-cycloaddition products was relatively less hin-
dered (Scheme 1). Using multiple substituents with steric
hindrance on both diene and dienophile, a noticeable shift
toward 1,4-addition was successfully achieved. The substrate
scope in this report was broad and the highest yield of 1,4-
adducts was over 90%. Novel structures of anti-1,4-adducts
were confirmed by single crystal X-ray diffraction analysis.
Introduction
The Diels–Alder (D–A) reaction is one of the most important
reactions in modern organic chemistry and is widely used to
construct a six-membered ring with up to four stereogenic
centers in regio- and stereo-controlled ways.1 With the poten-
tial of forming carbon–carbon, carbon–heteroatom and hetero-
atom–heteroatom bonds, the reaction is a versatile tool for the
synthesis of functional materials,2 biologically active mole-
cules and natural products.3 For stereoselectivity of D–A cyclo-
addition, the endo adduct is stabilized by secondary orbital
interactions in the transition state (TS), while the regioselecti-
vity is controlled by both steric and electronic effects.4
Beijing National Laboratory for Molecular Sciences (BNLMS), Center for Soft Matter
Science and Engineering, Key Lab of Polymer Chemistry & Physics of Ministry of
Education, College of Chemistry, Peking University, Beijing, 100871, China.
E-mail: ygma@pku.edu.cn; Fax: (+86) 10-6275-1708; Tel: (+86) 10-6275-6660
†Electronic supplementary information (ESI) available: Experimental details of
1H NMR, 13C NMR and 19F NMR spectra, molecular modelling studies, single
crystal data and structure refinement. CCDC 940166, 940168 and 940171. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob01052c
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Table 1 D–A reaction results between 1 and 2a–k
Entry
Dienophile
Time/d
Conv.a
Ratio of 3/4a
1
2
1
1
92
88
2/98, 3a/4a
2/98, 3b/4b
3
4
1
1
72
43
3/97, 3c/4c
22/78, 3d/4d
Scheme 1 D–A cycloaddition between N-phenylmaleimides and
anthracene derivatives.
5b
6
3
5
5
5
5
5
8
94
28
56
90
21
35
0
14/86, 3e/4e
40/60, 3f/4f
45/55, 3g/4g
59/41, 3h/4h
26/74, 3i/4i
28/72, 3j/4j
—/—
To the best of our knowledge, this is the first report about
synthesizing anti-1,4-adducts of anthracene derivatives.
7
Results and discussion
8c
9
To obtain bulky N-phenylmaleimides, fluorine atoms were
chosen and introduced at the ortho-position of phenyl malei-
mide (2c–2e) to test whether the steric effect could shift the
regio- and stereo-selectivity. Meanwhile, fluorine atoms at the
para- and meta-positions of phenyl maleimide (2b) and 2a
were also synthesised as control molecules. Moreover, fluorine
atoms provided a nice spectroscopic handle to easily deter-
mine product distribution and characterize the structures of
adducts via 19F NMR. In entries 1 to 3 of Table 1, the ratios of
1,4-adducts to 9,10-adducts were 2 : 98, 2 : 98 and 3 : 97,
respectively, which coincided with the literature reports that
9,10-cycloaddition was normally observed between N-phenyl-
maleimide and anthracene derivatives.13–18 Meanwhile, the
nearly same ratios of 1,4-adducts to 9,10-adducts in entries 1
to 3 indicated that the electron-withdrawing effect of fluorine
insignificantly influenced the regio- and stereo-selectivity by
changing the reactivity of carbon–carbon double bonds of
10b
11b
Reactions were carried out in NMR tubes at 110 °C and the solvent was
0.6 mL TCE-d2 (1,1,2,2-tetrachloroethane-d2). a Determined by H NMR
1
integration. b Solvent was 0.2 mL TCE-d2. c The concentrations of 1h
and 2h were both 1.2 mM.
that the conformation of 2d and 2e changed to more twisted
N-phenylmaleimides. In entries 4 and 5, the ratios of 1,4- rather than 2a–2c, which was induced by significantly increas-
ing the repulsion when a hydrogen atom was replaced by a
adducts to 9,10-adducts increased to 22 : 78 and 14 : 86,
fluorine atom. These twisted 2d/2e would increase substantially
respectively. The isolated yields of anti-1,4-adducts 3d and 3e
were 13% and 10%, respectively. The anti-configuration of 3d steric interactions in the D–A reactions, suppress both 9,10-/
syn-1,4-cycloadditions and change the regioselectivity. Mean-
while, the 19F and 1H NMR spectra of 3d and 3e suggested that
and 3e was confirmed by 2D NMR spectroscopic experiments
(see ESI†) and single crystal X-ray diffraction analysis (Fig. 1).
Due to the desymmetrization from the methyloxy carbonyl the rotation of the Cphenyl–Nimide single bond was highly
restricted even at 100 °C on the NMR time scale, which was
also the consequence of the steric effect of imide carbonyl
groups and bulky ortho fluorine atoms. The different ratios of
adducts 3/4 in entries 4 and 5 were probably caused by the
extra three fluorine atoms of 2e, which decreased the elec-
tronic density of ortho fluorine atoms and the steric hindrance
group, a pair of enantiomers of 3d was observed in unit cells
of crystals.22
Comparing entries 1 through 5, a noticeable shift toward
1,4-addition was achieved by introducing difluoro-substituents
at ortho-positions of N-phenylmaleimides as expected. In
Table S4,† calculations and single X-ray data of 2a–2e indicated
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Table 2 D–A reaction results between 2d and 1a–n
Entry
1b
2
Diene
1a
1b
1c
Time/d
Conv.a
90
Ratio of 5/6a
2/98, 5a/6a
6/94, 5b/6b
22/78, 5c/6c
0/100, 5d/6d
0/100, 5e/6e
6/94, 5f/6f
R1 = H
1
3
3
1
1
3
3
5
5
5
5
5
5
5
R2 = H
R1 = Br
96
R2 = H
3
R1 = Ph
R2 = H
88
4b
5b
6
1d
1e
R1 = Me
R2 = H
99
Fig. 1 (a, b) Crystal structures of racemic 3d. (c, d) Crystal structures of
racemic 4e.
R1 = CH2OH
R2 = H
99
1f
R1 = CHO
R2 = H
93
7
1g
1h
1i
R1 = COOH
R2 = H
94
12/88, 5g/6g
22/78, 3d/4d
29/71, 5i/6i
28/72, 5j/6j
55/45, 5k/6k
95/5, 5l/6l
in the reaction.23 Although the A-value of the fluorine atom
was only 0.15 and slightly bigger than hydrogen (0.00),24 the
change from hydrogen to fluorine was enough to influence
regioselectivity here. The D–A reaction between 1h and 2d was
also carried out in four different solvents (octane, toluene,
TCE and DMSO) to study the influence of solvents, and results
showed that the polar solvent gave larger ratios of 1,4-adducts/
9,10-adducts than the non-polar ones, which could be
explained, as the polar group of 1h and 2d would be more
strongly solvated in polar solvents, leading to larger steric
effect.25
8b
9b
10
11
12
13
14c
R1 = COOMe
R2 = H
84
R1 = CN
R2 = H
34
1j
R1 = Br
64
R2 = Br
1k
1l
R1 = I
60
R2 = I
R1 = COOMe
R2 = COOMe
R1 = Ph
R2 = Br
63
1m
1n
77
88/12, 5m/6m
100/0, 5n/6n
R1 = Ph
R2 = Ph
95
Based on these results, we proposed that bulkier substitu-
ents could further improve the regioselectivity of D–A reactions
and generate more anti-1,4-adducts. Thus, various bulky sub-
stituents (CF3, Cl, Br, Me, Et and t-Bu) were introduced onto
the ortho-position of the phenyl ring. In entries 4, 6, 7 and 8 of
Table 1, the ratio of anti-1,4-adducts to 9,10-adducts gradually
increased. Especially in entry 8, the 1,4-adduct became the
major product and the isolated yield was up to 51%. Due to
the steric effect of these bulky substituents, the product distri-
bution was further adjusted and the increasing ratios bolstered
our design. Bulky substituents (CF3, Cl and Br) also changed
the conformation of 2f–2h from canted to perpendicular
according to single X-ray data.26 However, with changing the
substituents from methyl to ethyl, the ratio of two adducts just
slightly increased from 26 : 74 to 28 : 72. In entry 11, there was
no reaction to occur due to the bulkiest t-butyl group of N-phenyl-
maleimide. This could be explained by the steric effect
using A-value.24 Actually, methyl (A-value = 1.70) and ethyl
(A-value = 1.75) had similar steric effects, but the bulk
increases sharply for t-butyl (A-value = 4.5), which inhibited
the D–A reaction in entry 11. On the other hand, the electronic
effect of these substitutes insignificantly influenced the reac-
tivity of carbon–carbon double bonds of N-phenylmaleimides,
indicated by the slightly different chemical shifts in the corres-
ponding 1H NMR.
Reactions were carried out in NMR tubes at 110 °C and the solvent was
0.2 mL TCE-d2. a Determined by 1H NMR integration. b Solvent was
0.6 mL TCE-d2. c The temperature was 140 °C.
on anthracene was also studied. In entries 1 to 3 of Table 2,
with increasing steric bulk of 9-substitutes from the hydrogen
atom to the phenyl group, the ratio of anti-1,4-adducts/9,10-
adducts gradually increased from 2 : 98 to 22 : 78. In entries 4
to 9, the electronic effect also significantly influenced the ratio
of two adducts. Due to the electron-donating groups (Me and
CH2OH), the centre rings of anthracene were highly reactive
and yielded only 9,10-adducts. With increasing the electron-
withdrawing effect of 9-substitutes from CHO to CN, the ratio
of anti-1,4-adducts/9,10-adducts gradually increased from
6 : 94 to 29 : 71. So both steric and electronic effects played
important roles in shifting the regioselectivity. To further
increase the yields of 1,4-adducts, bulky groups (Br, I and Ph)
and electron-withdrawing groups (COOMe) were incorporated
at both the 9- and 10-positions of anthracene. As expected, the
ratio significantly increased in entries 10 to 14, compared to
entries 2, 3, and 8. In entries 12 to 14, the ratio increased to
95 : 5, 88 : 12 and 100 : 0, respectively. The isolated yield of
anti-1,4-adducts in entry 14 was up to 92%.
Due to the unique aromatic naphthyl structures of 5j and
5k with bromo and iodo substitutions, we used classical palla-
dium-catalyzed Suzuki and Sonogashira coupling reactions to
At the same time, the regioselectivity in D–A cycloadditions
influenced by the electronic and steric effects of substituents
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Table 3 D–A reaction results between different steric N-phenylmalei-
mides and anthracene derivatives
0 : 100
0 : 100
2 : 98
6 : 94
13 : 87
26 : 74
1 : 99
2 : 98
23 : 77
28 : 72
59 : 41
67 : 23
Fig. 2 Synthesis of 7a and 7b.
43 : 57
93 : 7
88 : 12
100 : 0
100 : 0
100 : 0
synthesize conjugated molecules 7a and 7b in high yields
(86% and 88%, respectively, Fig. 2). There was also great poten-
tial to use 5j and 5k to synthesize the conjugated polymers
containing these rigid scaffolds.
Although both N-phenylmaleimides and anthracene deriva-
tives have been used as reactants in D–A reactions for many
years, 1,4-cycloaddition was seldom found. In this study, we
thought that combining the steric effects of two reactants was
crucial for a noticeable shift toward 1,4-addition. Then, we
took three N-phenylmaleimides (2a, 2d and 2h) and six anthra-
cene derivatives (1a, 1b, 1h, 1j, 1m and 1n) with different
steric hindrance to fully understand the relationship between
combining the steric effect of two reactants and shifting the
product toward the 1,4-adduct. In Table 3, due to the limited
steric effect of 1a and 1b, the increasing steric effect of N-phenyl-
maleimides from 2a to 2h could only achieve the 1,4-adduct
in max. 26% yield. While reaction with 1h and 1j had a moder-
ate steric effect, the steric effect of N-phenylmaleimides (2a, 2d
and 2h) significantly changed the distribution of products and
1,4-adducts became the major products. When bulkier 1m and
1n reacted with N-phenylmaleimides, the presence of steric
groups of 1m and 1n could effectively hinder the 9,10-cyclo-
addition process and the demand of the steric effect of N-phenyl-
maleimides significantly decreased. Especially for 1n, there
was insignificant fluctuation of adduct ratios when N-phenyl-
maleimides changed from 2a to 2h. Except for the reaction
between 1m and 2a, 1,4-adducts were major products in all the
other reactions of 1m–1n with 2a–2h. On the other hand, the
reactivity diminished due to the bulky substituents, as indi-
cated by harsher reaction conditions with longer reaction
time.
Reactions were carried out in NMR tubes at 110 °C and the solvent was
0.2 mL TCE-d2. The ratio of 1,4-/9,10-adducts was determined by
1H NMR integration. The teaction time was 3–5 days and the
temperature was 110–140 °C.
were calculated by DFT at both M06-2X/6-31G(d) and B3LYP/
6-31G(d) levels of theory.27,28 From a careful comparison of
transition state structures (Table S5†), bulky 2d had significant
steric interactions with anthracene framework 1h in the case
of 9,10-/syn-1,4-cycloaddition, but anti-1,4-cycloaddition
remained unhindered. Meanwhile, at the M06-2X/6-31G(d)
level of theory, the difference of activation free energies ΔΔG≠
between 3d-TS (anti-1,4-adduct) and 4d-TS (9,10-adduct) was
3.0 kcal mol−1, while the difference between 3a-TS (anti-
1,4-adduct) and 4a-TS (9,10-adduct) ΔΔG≠ was 5.6 kcal mol−1
(see ESI† for a full comparison of energetics computed with
different methods). The significantly decrease of ΔΔG≠
between anti-1,4-cycloaddition and 9,10-cycloaddition induced
by 2d supported the regio- and stereo-selectivity observed in
the experiments.29
Conclusion
In this report, we described a new strategy to achieve unusual
regio- and stereo-selectivity in D–A reactions between N-phenyl-
maleimides with bulky ortho substituents and bulky anthra-
cene derivatives. A noticeable shift toward 1,4-addition was
successfully achieved using multiple substituents with steric
hindrance on both diene and dienophile. The substrate scope
in this report was broad, and the highest yield of the 1,4-
adduct was over 90%. Novel structures of anti-1,4-adducts were
successfully synthesized and fully characterized by 1H, 19F,
In this study, the adduct distribution was under kinetic
control at 110–140 °C, rather than thermodynamic control. To
prove this, component–exchange reactions of 3d/4d with 1a
were investigated and monitored by NMR in situ. After heating
at 140 °C for 3 days, no retro-DA reaction was detected. To
further study the kinetic-controlled regio- and stereo-selectivity
in the reactions, the energies of the reactions of 2a/2d and 1h
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13C NMR, HR-MS, 2D-NOESY NMR and single crystal X-ray
diffraction analysis. This study not only provides the first
report of synthesizing anti-1,4-adducts and achieving other-
wise unattainable regio- and stereo-selectivity, but also eluci-
dates the relationship between combining the steric effects of
two reactants and shifting the products toward 1,4-adducts.
Moreover, the resulting 1,4-adducts could easily be further
functionalized through their halogen groups via carbon–
carbon coupling reactions.
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Acknowledgements
This research was financially supported by the National
Natural Science Foundation (no. 21074004 and 91227202) and
the National Basic Research Program (2013CB933500) of the
Ministry of Science and Technology of China.
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the electron-withdrawing effect of fluorine atoms at 3,4,5-
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29 The relative activation free energies ΔΔG≠ were calculated
by DFT at M06-2X/6-31G(d) level of theory. DFT predicted
kinetic controlled product ratios of k9,10-adduct/kanti-1,4-adduct
were 51 and 1600 for 4d/3d and 4a/3a at 383 K, respectively
(see Tables S2 and S3†).
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