Cavity-promoted Diels - Alder reactions of unsubstituted naphthalene: Fine reactivity tuning by cavity shrinkage

Article abstract of DOI:10.1246/cl.150351

By finely tuning the cavity volume of a coordination cage, the Diels - Alder reactivity of aromatic compounds was enhanced. Even unsubstituted naphthalene could be made to undergo the Diels - Alder reaction with N-tert-butylmaleimide, with perfectly controlled syn-selectivity. M₆L₄ cages with standard and contracted cavities had opposite effects on the reaction: the former favored larger Diels - Alder substrates, whereas the latter favored smaller ones.

Full text of DOI:10.1246/cl.150351

Received: April 15, 2015 | Accepted: May 14, 2015 | Web Released: May 21, 2015
CL-150351
Cavity-promoted Diels-Alder Reactions of Unsubstituted
Naphthalene: Fine Reactivity Tuning by Cavity Shrinkage#
Yu Fang,1 Takashi Murase,2 and Makoto Fujita*1
1Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
2Department of Material and Biological Chemistry, Faculty of Science, Yamagata University,
1-4-12 Kojirakawa-machi, Yamagata 990-8560
(E-mail: mfujita@appchem.t.u-tokyo.ac.jp)
O
R2
By finely tuning the cavity volume of a coordination cage,
R2
N
N
R1
R1
cage 1a or 1b
the Diels-Alder reactivity of aromatic compounds was
enhanced. Even unsubstituted naphthalene could be made to
undergo the Diels-Alder reaction with N-tert-butylmaleimide,
with perfectly controlled syn-selectivity. M6L4 cages with
standard and contracted cavities had opposite effects on the
reaction: the former favored larger Diels-Alder substrates,
whereas the latter favored smaller ones.
+
O
O
O
R1
R1
2a : R1 = H
3a : R2 = t-Bu
3b: R2 = c-C6H11
4a : R1 = H, R2 = t-Bu
2b: R1 = Me
2c : R1 = Et
4b: R1 = Me, R2 = t-Bu
4c : R1 = Et, R2 = t-Bu
4d: R1 = H, R2 = c-C6H11
4e : R1 = Me, R2 = c-C6H11
4f : R1 = Et, R2 = c-C6H11
Well-defined cage cavities can activate otherwise inert
substrates to accelerate chemical reactions with high regio- and
stereoselectivity.1 The close proximity of the substrates’ reaction
sites in the cavity is indispensable, and fine tuning of substrate
structures is often required to achieve highly efficient reactions.
In our previous studies on the Diels-Alder reactions of aromatic
compounds within M6L4 cage 1b (Figure 1),2 unnecessary alkyl
substituents had to be introduced into the substrates to enhance
their reactivity.2c Here, we report that the substrate reactivity
can be changed dramatically without modifying the substrate
structures but by finely tuning the cavity volume of cage 1.
Recently, we have shown that the effective cavity volume
of cage 1 is easily contracted by functionalizing the 1,10-
phenanthroline ancillary ligand on the Pd(II) units with sterically
demanding groups.3 The cavity volume is, in particular,
significantly reduced (by as much as ca. 20%) with mesityl
(Mes) group functionalization (Figure 1).4 Contracted cage 1a
showed binding behavior different from that of 1b toward large
organic guests, but we have not previously examined the effect
of the cavity contraction on reactivity control. Here, we show
Scheme 1. Cavity-promoted Diels-Alder reactions of naphthalene 2
with N-alkyl maleimide 3.
that in the contracted cavity, even unsubstituted naphthalene
smoothly undergoes the Diels-Alder reaction, and suggest a
catalytic cycle for the reaction (Scheme 1).5
Expecting enhanced reactivity for the Diels-Alder reaction,
unsubstituted naphthalene 2a (20 ¯mol), which was inert in cage
1b,2c was treated with N-tert-butylmaleimide (3a, 10 ¯mol) in
an aqueous solution of cage 1a (1.0 mM, 10.0 mL, 10 ¯mol) at
80 °C.6 Unlike its inclusion in cage 1b, in which a ternary
complex [namely, 1b¢(2a¢3a)] is easily formed, after 1 h
stirring, contracted cage 1a bound only one molecule of 2a to
form inclusion complex 1a¢2a in 60% yield. Maleimide 3a,
though slightly soluble in water, remained largely unbound and
suspended in the reaction solution. A small portion of dissolved
3a may have formed ternary complex 1a¢(2a¢3a), as the signals
of 3a were slightly shifted upfield (¦¤ = ¹0.24 ppm for the
olefin protons). When this mixture was heated at 100 °C for 24 h,
however, the pale yellow solution turned cloudy. In a control
experiment in D2O, a new set of signals appeared in the 1H NMR
spectrum at this stage, strongly indicating that the Diels-Alder
reaction started to occur at 100 °C. The reaction mixture was
filtered, and the filtrate was extracted with chloroform. 1H NMR
spectroscopy of the filtrate showed the formation of Diels-Alder
product 4a. The filtered solid also included 4a as a major
component. The combined crude product was purified by
column chromatography and gel permeation chromatography
to give pure 4a in 46% isolated yield. When the reaction was
carried out at 110 °C, the yield was increased to 58%.
N
N
Pd
12+
–
Pd =
Pd
Pd =
Pd
N
N
N
N
12NO3
N
N
N
N
N
N
N
Pd
N
N
N
N
Pd
Pd
N
N
Pd
N
N
N
N
N
N
N
N
N
Pd
1
The syn stereochemistry of 4a was deduced from the
upfield-shifted N-tert-butyl protons (¤ = 1.17 ppm), which are
located above the benzene ring. An NOE correlation between
the vinyl protons and the bridgehead protons also supported the
stereochemistry. No anti isomer was detected by NMR spec-
troscopy. With the sterically unbiased cage 1b, 2a, and 3a were
coencapsulated to give ternary complex 1b¢(2a¢3a) in 71%
1a
(380 Å3)
1b
(462 Å3)
Figure 1. Self-assembled coordination cages 1. The cavity volume
of 1 shown in parentheses was calculated based on each X-ray crystal
structure using the VOIDOO program (probe radius: 3.36 ¡). For
details, see ref 3.
Chem. Lett. 2015, 44, 1095–1097 | doi:10.1246/cl.150351
© 2015 The Chemical Society of Japan | 1095

Table 1. Isolated yields of Diels-Alder adducts 4 generated in the
standard (1a) and contracted (1b) cavitiesa
O
N
O
N
O
+
Yield of 4c/%
Substrate
(Volumeb/Å3)
Product
(Volumeb/Å3)
O
With 1a
With 1b
O
O
O
1a•2a
3a
1a•(2a•3a)
N
O
2a + 3a
(315)
4a
46 (58)d
0
Scheme 2. Equilibrium of ternary complex 1a¢(2a¢3a) with in-
clusion complex 1a¢2a and free 3a.
(293)
151 + 164
yield, but no Diels-Alder products were formed after heating
the inclusion complex at 100 °C. We thus presume that ternary
complex 1a¢(2a¢3a), which is indispensable for the formation
of 4a, is in equilibrium with inclusion complex 1a¢2a and
free 3a. Though the equilibrium is much in favor of 1a¢2a
(Scheme 2), the tightly preorganized 2a¢3a pair in the minor
1a¢(2a¢3a) component rapidly undergoes the reaction at 100-
110 °C.
It is noteworthy that subtle changes in the Diels-Alder
substrate or cavity volume result in large differences in the
reactivity. The total volume of 2a + 3a (315 ¡3) seems to be the
best fit for cage 1a, allowing a tight fit and close proximity of the
reaction sites, thus giving the highest yield of adduct 4a. With
increasing volume, the substrate pairs were not well accom-
modated or no longer fit in the cavity, and the yields of the
products decreased significantly (Table 1). In contrast, the guest
pair 2a + 3a is loosely bound in the cavity of standard cage 1b
and no reaction takes place. The Diels-Alder reaction occurs in
1b only when substrates are modified with alkyl substituents, so
they can be tightly bound in the larger cavity (see the formation
of 4e and 4f in Table 1).
N
O
2b + 3a
(351)
187 + 164
4b
(332)
35
29
0
0
0
N
O
2c + 3a
(387)
223 + 164
4c
(368)
O
O
O
N
O
2a + 3b
(340)
151 + 189
4d
(317)
0
N
O
2b + 3b
(376)
187 + 189
4e
(357)
0
5
N
O
2c + 3b
(412)
223 + 189
4f
(374)
0
43
We also note that product 4a was released to some extent
from the cavity of 1a under the reaction conditions. The
spontaneous product release is a crucial step for accomplishing
a catalytic cycle for the reaction (Figure 2). Thus, the reaction
of 2a and 3a was examined with a catalytic amount (5 mol %)
of cage 1a. The mixture of 2a (50 ¯mol) and maleimide 3a
(50 ¯mol) was suspended in an aqueous solution of 1a
(0.25 mM, 10.0 mL, 2.5 ¯mol) and stirred at 110 °C for 48 h.
From the reaction mixture, Diels-Alder product 4a was isolated
in 33% yield; this corresponds to a turnover number (TON) of
6.6 based on cage catalyst 1a. The reaction was very slow but
did proceed catalytically at 110 °C.
aReaction conditions: cage 1 (10 ¯mol), naphthalene 2 (20 ¯mol),
and maleimide 3 (10 ¯mol) in D2O (10.0 mL) at 100°C for 24 h.
bvan der Waals volumes calculated from structures optimized using
SPARTAN’10 with MP2 using a 6-31G* basis set. cIsolated yields.
dIsolated yield in the reaction at 110 °C.
O
N
O
2a
The fine tuning of the cavity volume is also effective for the
activation of other inert aromatics. For example, the Diels-Alder
reaction of triphenylene 5 with maleimide 3a proceeded to give
adduct 6 in only 40% yield within cage 1b but in 75% yield
within cage 1a. This is presumably because the substrate pair
was more closely packed in the contracted cavity of 1a
(Scheme 3).2b The 1H NMR spectrum of inclusion complex
1a¢6 showed a severe splitting pattern of the host signals,
revealing strong host-guest interactions. Thus, the catalytic
cycle was hampered by product inhibition.
4a
1a
O
N
O
1a•4a
1a•2a
O
N
O
N
O
In summary, we succeeded in performing the Diels-Alder
reaction of unsubstituted naphthalene by shrinking the cavity of
a self-assembled M6L4 cage. Previously, the only way to achieve
preorganized orientation of substrates in this cavity had been
through the introduction of substituents onto the substrates
themselves. We now have another option: the cage cavity can be
homogeneously deformed and contracted by functionalizing the
O
3a
1a•(2a•3a)
Figure 2. Proposed mechanism for the catalytic Diels-Alder
reaction of naphthalene 2a with maleimide 3a in the presence of cage
1a.
1096 | Chem. Lett. 2015, 44, 1095–1097 | doi:10.1246/cl.150351
© 2015 The Chemical Society of Japan

O
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O
N
N
O
O
100 °C, 20 h
2
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1•(5•3a)
1•6
75%
40%
With 1a
With 1b
Scheme 3. Cavity-promoted Diels-Alder reaction of triphenylene 5
with N-tert-butylmaleimide 3a.
3
4
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gradually shrinks as the bulkiness of the substituents of the
phenanthroline ancillary ligand increases,3b a variety of substrate
pairs can, in principle, be accommodated and reacted within the
M6L4 cage without modifying the substrates themselves. We
believe that the present method expands the possibilities for and
the effectiveness of cavity-directed reactions.
Other groups also use the VOIDOO program to estimate the
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This research was supported by Grants-in-Aid for Specially
Promoted Research (No. 24000009) and for Young Scientists
(A) (No. 25708008).
Supporting Information is available electronically on J-STAGE.
5
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References and Notes
#
Dedicated to Professor Iwao Ojima on the occasion of his
70th birthday.
1
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Chem. Lett. 2015, 44, 1095–1097 | doi:10.1246/cl.150351
© 2015 The Chemical Society of Japan | 1097