Evaluating hydrogen bonding control in the diastereoselective Diels-Alder reactions of 9-(2-aminoethyl)-anthracene derivatives

Article abstract of DOI:10.1039/c5ob01343g

Several 9-(2-aminoethyl)anthracene derivatives were prepared with different nitrogen substitutents including alkyl, acetamide, trifluoroacaeamide and t-butyl carbamate. The selectivity in Diels-Alder cyclodaddition reaction with N-methyl maleimide was evaluated through single crystal X-ray analysis of the products. Models for the change in selectivity with hydrogen bond acceptor are proposed, supported by DFT level calculations.

Full text of DOI:10.1039/c5ob01343g

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ARTICLE
Evaluating hydrogen bonding control in the diastereoselective
Diels-Alder reactions of 9-(2-aminoethyl)-anthracene derivatives
R. A. Bawa,a F.-M. Gautier,a H. Adams,a A. J. H. M. Meijera,* and S. Jonesa,*
Received 00th January 20xx,
Accepted 00th January 20xx
Several 9-(2-aminoethyl)anthracene derivatives were prepared with different nitrogen substitutents including alkyl,
acetamide, trifluoroacaeamide and t-butyl carbamate. The selectivity in Diels_alder cyclodaddition reaction with N-methyl
maleimide was evaluated thorugh single crystal x-ray analysis of the products. Models for the change in selectivity with
hydrogen bond acceptor are proposed, supported by DFT level calculations.
DOI: 10.1039/x0xx00000x
www.rsc.org/
hydrogen-bond donor and acceptor should change the
diastereoselectivity. This effect can straight forwardly be
achieved by replacing the oxygen atom in 1a and 1b with
Introduction
Hydrogen bonding has been known to play a pivotal role in
helping to control the stereochemical outcome of many
chemical transformations, including the Diels-Alder reaction. In
this respect, a number of seminal studies have investigated the
nature of this control,1–3 applied it in the design of catalysts,4,5
and used it to access complex target molecules.6 Previous
work described from these laboratories7–11 and others12–17 on
nitrogen, that would then allow control of the availability of
the lone-pair on the nitrogen atom (i.e. the hydrogen-bond
acceptor) in going from a secondary amine to an amide. The
strength of the hydrogen-bond donor (the N-H) can be then be
further attenuated by changing that nature of the amide
group. It should be noted that in the case of a secondary
amine, such as benzyl amine, there will be a number of
additional possible H-bond donors (C-H) groups on the
stereodirecting group to consider. The synthesis and reactions
of these systems are described herein, supported with DFT
calculations that attempt to elucidate the relative importance
of H-bond donor and H-bond acceptor in these processes.
the cycloaddition of dienophiles to chiral anthracenes (eg 1, 2)
has demonstrated an inherent preference of the
stereodirecting group to deliver a single diastereoisomer of
cycloadduct. This is caused by the subtle interplay of a number
of interactions in the transition state connecting reactants and
products, including a hydrogen bond, initiated by the group at
the 9-position of the anthracene 1a
/ 1b, framed against a
hydrogen bond from a C-H bond of the incoming dienophile
with a lone pair on an electronegative element on the 9-
position. A similar effect was also observed in 9-amino
anthracene derivatives 2a whereby this balance could be
disrupted by methylation of the nitrogen atom 2b, removing
the hydrogen bond (Figure 1).18,19,20,21,22,23
Results and discussion
Synthesis of the key α-methyl-9-anthracenemethanamine
3
was first attempted, which could then serve as a common
intermediate for several of the diene substrates (Scheme 1).
1) BnNH2, MgSO4,
THF, rt, 2 h, 98%
2) MeLi, BF3.OEt2, PhMe,
-78 oC, 21 h, 82%
O
4
Ph
N
H
Me
5
2a R = H
2b R = Me
1a R = Me
1b R = H
Me
N
R
R
O
Me
Pd/C, H2,
AcOH
Ph
Figure 1 Anthracene derivative previously investigated
Na(CN)BH3, AcOH
72 h, 90%
3
H2N
Me
Thus, changing the relative position and strength of the
MeMgI, Et2O,
ꢀ, 72 h, 57%
CN
6
7
NH
Scheme 1 Synthesis of α-methyl-9-anthracenemethanamine 1
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The condensation of 9-anthraldehyde
4
with benzylamine in
the presence of MgSO4, followed by a Lewis acid mediated
addition of MeLi to the resultant imine afforded the amine in
5
an overall yield of 80%. However, attempts to remove the
benzyl group under standard hydrogenation conditions failed.
Therefore, an alternative route was targeted, where 9-
anthracenecarbonitrile
addition of methylmagnesium iodide, and subsequent
reduction with Na(CN)BH3 furnished the desired amine in
90% yield. With amine in hand, functionalization of the
amine was achieved by treatment with the appropriate
6 was first converted to the imine 7 by
3
1
anhydride to generate the amides
(Scheme 2).
8
and 9, and carbamate 10
Figure 2 Representative X-ray crystal structure of cycloadduct 12.
Reagents
should be noted that in all structures obtained, steric
influences from packing and / or intermolecular hydrogen
bonds appear to override any preference to form
intramolecular hydrogen bonds. The terms anti and syn used
throughout refer to the relative orientation of the maleimide
carbonyl group and the nitrogen atom attached to the 9-
position of the anthracene, when the methyl group is placed
perpendicular to the plane of the anthracene ring.
H2N
Me
3
8
9
R = Me
R = CF3
HN
R
Me
10 R = Ot-Bu
8
9
Ac2O, rt, 2 h, 36%
(CF3CO)2O, CH2Cl2, rt, 24 h, 88%
O
10 Boc 2O, NaHCO3, EtOH, rt, 72 h, 56%
Scheme 2 Synthesis of amides 8 & 9 and carbamate 10
Each of the amine derivatives was subsequently subjected to
o
Diels-Alder reactions by heating at 80 C in toluene with one
Table 1 Conversion and diastereomeric ratio from Diels-Alder reactions, as in Scheme 3
equivalent of N-methyl maleimide. For comparison purposes,
the methoxyethyl anthracene 1a used extensively in previous
work was also considered (Table 1).
Entry
R
Conversion (%)a
Product
11
antib
72
synb
18
90
75
80
0
1
2
3
4
5
BnNH
84
MeC(O)NH
CF3C(O)NH
84
12
10
100
13
25
t-BuOC(O)NH 78
MeO 100
14
20
+
O
O
N
15
100
Me
a Determined from comparison of the integrals of the residual starting material
and product(s) in the 1H NMR spectrum of the crude reaction mixture. b Ratio
determined by comparison of the integrals for the syn and anti isomers from in
the 1H NMR spectrum of the crude reaction mixture. The identity of the isomers
was determined by single crystal x-ray diffraction.
R
N
H
Me
N
5, 8 - 10
C6H5CH3,
80 - 85 oC, 2 h
O
O
H
Me
Me
N
O
O
In all cases, purification invariably led to samples of scalemic
mixtures with diastereomeric ratios different to those
obtained from the reaction. When such samples were
subjected to the original reaction condition, no change in the
diastereomeric ratio was observed, indicating that the reaction
appears to proceed under kinetic control. The amine (Table 1,
entry 1) gave the anti isomer as the major product, in-line with
what would be expected by comparison with the ether 1a. All
other compounds (entries 2-4) show a reversal in the sense of
diastereoselectivity.
+
H
N
H
H
N
5, 11 R = Bn
8, 12 R = MeC(O)
9, 13 R = CF3C(O)
R
R
Me
Me
10, 14 R= -BuOC(O)
t
syn - 11 - 14
anti - 11 - 14
O
Me
O
N
C6H5CH3,
80 - 85 oC, 2 h
1a
+
N
Me
O
To further substantiate this, the Gibbs energy for reaction,
O
H
OMe
15
ꢀꢁꢂ, and the corresponding Gibbs energy of activation, ꢀꢂ‡
were calculated by Density Functional Theory (DFT) methods
for each of the substrates 8-10 (Table 2, for complete
,
Me
Scheme 3 Evaluation of anthracene derivatives in Diels-Alder reactions.
5,
details, see experimental section). As in previous studies, the
lowest energy conformation leading to each of the syn and
anti-products that locates one of the groups attached to the 9-
position orthogonal to the plane of ring was considered.
In all cases, the conversion and diastereoselectivity was
calculated by comparison of the integrals in the 1H NMR
spectrum of the crude reaction mixture, and the identity of the
major diastereoisomer confirmed by single crystal x-ray
diffraction (see Figure 2 for a representative structure). It
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In panel (a), a CH from the phenyl ring serves as the H-bond
donor, whereas in panel (b) it is a CH from the methylene
bridge unit. This leads to a barrier height for panel (a) being
0.01 kJ mol-1 lower than for panel (b). It is also noticeable that
in panel (b) the transition state is essentially synchronous,
compared to the clearly asynchronous one in panel (a),
Table 2. Computational data for reaction outlined in Scheme 3.
anti
synb
Anthracene
Approacha
ꢀꢁꢂꢃ
1.7
ꢀꢂ‡,ꢃ
140.4
163.4
157.0
ꢀꢁꢂꢃ
23.5
24.1
6.9
ꢀꢂ‡,ꢃ
5
α
β
γ
142.4
171.3
148.6
12.0
33.7
showing that (a)synchronicity for this system is not
diagnostic for the barrier height.21
a
8
α
β
γ
13.8
-0.9
24.1
148.3
152.6
153.0
16.1
22.8
0.6
138.3
138.3c
145.3
In the case of the lowest transition states for the syn-isomer
[Figure 3, panels (c) and (d)] the conformation of the
stereodirecting group has clearly changed compared to the
anti to avoid clash of the methyl group with the incoming
dienophile. As a consequence, the stereochemistry around the
nitrogen atom is inverted, to facilitate NH interactions with the
maleimide, thus eliminating any maleimide interactions with
the lone pair of the nitrogen atom, which instead accepts a
hydrogen bond from a C-H on the anthracene backbone.
Another aromatic C-H interaction with the maleimide is also
observed, as in panel (a). Finally, in panel (d), the benzyl unit
rotates away, allowing the transition state to be more
synchronous. However, the slightly longer NH…O bond means
that this transition state is 1.31 kJ mol-1 higher in energy, but
since this is less than the thermal energy of the reaction
temperature, it will still have a role to play. These conclusions
are consistent with the experimental results previously
obtained for the ether 1a and alcohol 1b. In the case of the
ether 1a, the hydrogen-bond donor and acceptor components
9
α
β
γ
9.6
146.2
153.9
153.1
14.9
23.6
-0.3
143.0
165.2
145.9
-4.7
23.3
10
α
β
γ
12.6
-0.5
23.4
147.1
154.0
149.7
18.8
21.7
-1.0
142.7
164.7
145.5
a Orientation of group placed orthogonal to plane of anthracene ring; in ‘α’ Me is
orthogonal, ‘β’ R is orthogonal and in ‘γ’ the H atom is orthogonal. b in kJ mol-1. c
Converts to approach syn-α during optimization.
Benzyl amine
5 bears the closest similarity to the ether 1a
which has been previously investigated, and contains a
hydrogen-bond accepting electronegative nitrogen atom and a
hydrogen-bond donor (CH) adjacent to this atom, as in the
case of the ether 1a. However, in contrast to the ether 1a, the
amine
to the alcohol, 1b. Comparing the different energies, ꢀꢂ‡, for
the benzyl amine , it is clear that it behaves more like ether
5 can function as a hydrogen-bond donor as well, akin
are not directly connected. As
a consequence, the
stereodirecting group has enough flexibility to form a pincer-
like conformation and stabilize the transition state that leads
8
1a than the alcohol 1b. The relevant structures for the lowest
transition state for anti and syn isomers clearly show that in
the lowest energy transition state, the stereodirecting group is
able to adopt a pincer-like conformation, where the nitrogen
atom, acting as a hydrogen-bond acceptor and the hydrogen-
bond donor are not connected to each other, leading to two
possible cooperative conformations [Figure 3, panels (a) and
(b)].
to the anti-isomer as the major product. For the alcohol 1b
,
the hydrogen-bond donor and acceptor are both associated
with the hydroxyl group. As a consequence, only one of these
two functionalities can be used to stabilize the transition state,
which turns out to be the hydrogen-bond donating ability.
Given this and the geometric constraints of the stereogenic
centre, the major product will be syn.
Based on these arguments, a number of predictions for amide
derivatives 8-10 can be made. Here, the conjugation of the
nitrogen atom in the amide group can only lead to this
functioning as a hydrogen-bond donor. In addition, the planar
nature of this functional group means that the alkyl and alkoxy
groups attached will be too far away to interact directly with
the functional groups of the dienophile and may only influence
the hydrogen-bond donating ability of the amide NH subgroup.
Thus, one would expect these systems to behave as the
alcohol 1b and give the syn-isomer as the major product. The
experimental (Table 1) and computational data (Table 2)
confirm this. For example, the lowest transition state for
trifluoroacetamide
9
clearly shows this predicted behaviour
[Figure 4, panel (a)].
Figure 3 Different possible transition states for N-methyl maleimide with anthracene 5.
Panel (a): lowest TS for the anti approach (140.39 kJ mol-1). Panel (b): Second-lowest
TS for the anti approach (140.40 kJ mol-1). Panel (c): Lowest TS for the syn approach
(142.4 kJ mol-1). Panel (d): Second-lowest TS for the syn approach (143.7 kJ mol-1).
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Figure 5. Transition state geometries and final geometries for two isomers of the
MeC(O)NH cycloaddition reaction. Panels (a) and (b) show the transition state for the
syn conformation (α-approach, 138.3 kJ mol-1), and anti-conformation (β-approach,
152.6 kJ mol-1), respectively. Panel (c) and (d) show the corresponding final products
syn-12 (16.1 kJ mol-1 ) and anti 12 (-0.9 kJ mol-1).
Figure 4. Transition state geometries and final geometries for two isomers of the
CF3C(O)NH cycloaddition reaction. Panels (a) and (b) show the transition state for the
syn conformation (α-approach, 143.0 kJ mol-1), and anti-conformation (β-approach,
153.9 kJ mol-1), respectively. Panel (c) and (d) show the corresponding final products
syn-13 (14.9 kJ mol-1 ) and anti 13 (-4.7 kJ mol-1).
If it is assumed that the Eyring-Polyani equation holds, the
relative rate of formation for the syn and anti isomers can be
written as:
This data also reaffirms earlier reported work that the lowest
transition state does not necessarily correlate to the most
stable product in these reactions, confirming the experimental
observation that the reaction occurs under kinetic control. For
example, if the two lowest energy transition states for the
ꢄꢅꢆꢇꢈ
ꢍꢎꢎꢏ‡
ꢋ ꢌ
ꢄꢉꢊꢆ
trifluoroacetamide
9 and associated products are compared
where ꢀꢀꢂ‡ is defined as ꢀꢂꢅ‡ꢆꢇꢈ ꢐ ꢀꢂꢉ‡ꢊꢆ. However, it needs
to be noted that in the case of BnNH, in particular, one needs
to take account of all thermally accessible transition states.
Also, for completeness and comparison purposes, results from
earlier work on the MeO derivative 1a are included (Table 3).18
(Figure 4), it is clear for the syn addition shown in panels (a)
and (c) that the most important distances are very similar,
whereby the distances for the anti conformation shown in
panels (b) and (d) are consistently larger, making the transition
state earlier, i.e. more reactant-like. This is probably caused by
the fact that for the anti-approach, the methyl group clashes
with a hydrogen atom on the incoming maleimide. For the syn-
approach shown in panel (a) the distance between hydrogen
atom at the stereogenic centre and the hydrogen atom on the
maleimide is 2.9 Å, leading to a lower transition state energy.
It should be noted that both cases are equally asynchronous,
suggesting again that the synchronicity of the transition state
is not necessarily a marker for the height of the transition
state. In contrast the Gibbs energy of the final product for the
anti-configuration is 19.6 kJ mol-1 lower. Again, this is not due
to the amide, but rather that in the anti-approach [panel (b)]
the two halves of the anthracene ‘hinge’ can come closer
together, because the hydrogen atom on the stereogenic
centre is pointing down, rather than the methyl group as in
panel (a). This is reflected in the fact that in panel (c) the
hydrogen atoms marked α and β are 4.93 Å apart, whereas in
panel (d) the equivalent distance is 4.53 Å. Similar conclusions
can be drawn for the MeC(O)NH and t-BuOC(O) substrates (see
Figure 5 and 6, respectively).
Figure 6. Transition state geometries and final geometries for two isomers of the t-
BuO(O)NH cycloaddition reaction. Panels (a) and (b) show the transition state for the
syn conformation (α-approach, 142.7 kJ mol-1), and anti-conformation (β-approach,
154.0 kJ mol-1), respectively. Panel (c) and (d) show the corresponding final products
syn-14 (18.8 kJ mol-1 ) and anti 14 (-0.5 kJ mol-1).
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In conclusion we have demonstrated that the stereoselectivity
of Diels-Alder reactions of suitably constructed anthracenes
may be controlled through judicious choice of the protecting
group used on the nitrogen atom. We have examined these
processes in depth using computational methods to develop
and substantiate the key control elements in these reactions
that may pave the way in helping to develop more
sophisticated stereoselective processes.
Table 3 Comparison of computed ratios for two different approaches with
experimental results
Lowest TS
only
Experimental
All TSs
Entry
R
anti : syn
66:34
anti : syn
74:26
2:98
anti : syn
72:18
1
2
3
4
5
BnNH
MeC(O)NH
CF3C(O)NH
t-BuOC(O)NH
MeOa
3:97
10:90
25:75
22:78
19:81
100:0
25:75
18:82
20:80
100:0
100:0
Experimental
aIn this case only one transition state really needs to be considered.
Materials and methods
Comparison of the two sets of transition state energy data
shows that only for BnNH (Table 3, entry 1) there is more than
All solvents were obtained dry from a Grubbs dry solvent
system and glassware was flame dried and cooled under
vacuum before use. All dry reactions were carried out under
nitrogen. TLC was carried out using Merck aluminium TLC
sheets (silica gel 60 F254), visualisation of TLC plates was
performed using a UV lamp or by dipping in KMnO4 then
exposure to heat. Flash column chromatography was carried
60Å (Fluorochem Limited). 1H and 13
out with silica gel 40-63ꢁ C
NMR spectra were measured using CDCl3 as solvent unless
otherwise stated, on a Brüker 250 or 400 MHz machine with
an automated sample changer (unless otherwise stated).
a
single transition state of importance. For the other
compounds the effects are much less significant. If these data
are compared to the experimentally obtained ratios (Table 1),
the calculated ratios agree well with experiment.
Finally, other groups have noted that there is a direct
correlation between the strength of the hydrogen bond
initiated from the chiral ligand and the stereoselectivity,21 and
therefore the partial charges have been calculated, through
the Merz-Kollman scheme (Table 4). It should be noted that for
BnNH the NH moieties can function both as a hydrogen-bond
donor and as a hydrogen bond acceptor, making it unclear
whether it can be compared directly with the other three
groups studied.
Chemical shifts for carbon and hydrogen are given on the
δ
scale relative to TMS (tetramethylsilane, δ = 0 ppm). Coupling
constants were measured in Hz. 13C NMR spectra were
recorded using the JMOD method. Specific rotations were
performed on an Optical Activity Ltd. AA-10 automatic
polarimeter at 589nm (Na D-Line) and measured at 20 oC
Table 4 Polarity of the NH bonds in auxiliary ligands.
Entry
R
qN
qH
Δq
unless otherwise stated. [α]D values are given in 10-1 deg cm2 g-
1. Infrared spectra were recorded on a Perkin-Elmer 100 FT-IR
machine using attenuated total reflectance (ATR). Mass
spectra were either recorded on a micromass autospec (EI+) or
Waters LCT Classic (TOF ES+). All chemicals were used as
received without further purification. The preparation of
compounds 3, 7 and 8 were carried out by literature methods and
are detailed in the supplementary information.
1
2
3
4
BnNH
-0.48
-0.76
-0.55
-0.78
0.27
0.34
0.28
0.36
0.75
1.09
0.82
1.14
MeC(O)NH
CF3C(O)NH
t-BuOC(O)NH
The data shows that the partial charge on H, qH, is not affected
much by the nature or oxidation level of the attached group,
whereas the partial charge on N, qN, changes significantly,
reflecting the fact that for the amides, the nitrogen is part of a
conjugated system. It is also clear that the electron-
withdrawing effect of the trifluoroacetamide group lowers the
charge of the nitrogen atom and thereby lowers the bond
polarity (Δq), i.e. the difference in the partial charges on H and
X-ray crystallographic data collected were measured on a
Bruker Smart 1000 CCD area detector with Oxford
Cryosystems low temperature system held at 150K. Reflections
were measured from a hemisphere of data collected of frames
each covering 0.3 degrees in omega, all of which were
corrected for Lorentz and polarisation effects and for
absorption by semi empirical methods based on symmetry-
equivalent and repeated reflections (SADABS). All structures
were solved by direct methods and refined by full matrix least
squares methods on F2. Hydrogen atoms were calculated and
refined in riding mode. Complex scattering factors were taken
from the program package SHELXTL24 as implemented on the
Viglen Pentium computer.
N. The result should be
interaction, leading to poorer selectivity. The bond polarity for
both and 10 is higher than for , which indeed correlates to
a weaker hydrogen-bonding
8
9
the higher selectivity for the former two over the latter. There
may be limits to using a relatively crude measure like bond
polarity, given that it ignores all other effects and does not
take into account experimental error bars as well. Thus, for
example, experimentally acetamide
8
provides higher
selectivity than the carbamate 10, which is not reflected in a
Synthetic procedures
higher bond polarity.
N-Benzyl-α-methyl-9-anthracenemethanamine 5 Magnesium
sulfate (0.50 g, 4.86 mmol) was added to a stirred solution of
9-anthraldehyde
4
(3.00 g, 14.6 mmol) in dry THF (60 mL).
Conclusions
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Benzylamine (1.8 mL, 16.2 mmol) was added drop-wise at
room temperature. The resulting mixture was stirred for
further 2 h at room temperature, filtered through Celite and
the solvent removed under vacuum to give the imine as a
yellow solid with no further purification required (4.30 g,
ArCH), 123.0 (2 × ArCH), 115.8 (q, JC-F 288.0, CF3), 46.1 (CHNH), 21.0
(CH3); m/z (TOF ES+) 360 (10%), 356 (30), 340 (60, MNa+), 355 (100),
318.1095 (52%, MH+. C18H15F3NO requires 318.1106), 205 (85).
(±)-(1-Anthracen-9-yl-ethyl)-carbamic acid tert-butyl ester 10
Sodium hydrogen carbonate (3.10 g, 22.4 mmol) and di-tert-butyl
dicarbonate (2.41 g, 11.0 mmol) were added to a stirred solution of
9-anthrylethylamine 3 (1.58 g, 7.14 mmol) in EtOH (50 mL). After 72
h at room temperature, the suspension was concentrated under
reduced pressure, redissolved in diethyl ether (100 mL) and filtered
through a Celite® plug. The filtrate was dried over sodium sulfate,
filtered and evaporated. The solid was purified by flash
>99%); mp 86
Me4Si) 9.57 (1 H, t, J 1.4, CH=N), 8.56
8.04 7.98 (2 H, m, ArCH), 7.55 7.28 (9 H, m, ArCH), 5.16 (2 H,
−
87
°
C (lit.25 90
−
91
°C); δH (250 MHz; CDCl3;
−
8.50 (3 H, m, ArCH),
−
−
s, PhCH2); δC (62.5 MHz; CDCl3; Me4Si) 161.0 (CH=N), 139.1
(ArC), 131.1 (ArC), 130.0 (ArC), 129.4 (ArCH), 128.9 (ArCH),
128.7 (ArCH), 128.6 (ArCH), 128.3 (ArCH), 128.1 (ArCH), 127.0
(ArCH), 126.6 (ArCH), 125.5 (ArCH), 125.1 (ArCH), 124.7 (ArCH),
66.7 (PhCH2). NMR data was in broad accordance with the
literature. The complexity of the 13C NMR region precludes
accurate assignment.
chromatography on silica gel eluting with 10% EtOAc / petroleum
ether 40-60 to yield the title compound 10 as orange yellow crystals
(1.29 g, 56%). A sample was crystallised from toluene for
characterization purposes. Mp (toluene) 148–149 oC; (Found: C,
78.23; H, 7.39; N, 4.29. C21H23NO2 requires C, 78.47; H, 7.21; N,
4.36); νmax/cm-1 3686, 3447, 3054, 2985, 1708; δH (400 MHz; CDCl3;
Me4Si) 8.45 (2 H, d, J 9.1, ArCH), 8.41 (1 H, s, ArCH), 8.02 (2 H, d, J
8.2, ArCH), 7.45–7.60 (4 H, m, ArCH), 6.36 (1 H, br s, CHCH3), 5.53 (1
H, br s, NH), 1.94 (3 H, d, J 6.9, CHCH3), 1.42 [9 H, s, C(CH3)3]; δC (100
MHz; CDCl3; Me4Si) 155.5 (NHCO), 134.5 (ArC), 131.8 (2 × ArC),
129.7 (2 × ArCH), 128.7 (2 × ArC), 127.9 (ArCH), 126.0 (2 × ArCH),
124.8 (2 × ArCH), 124.2 (2 × ArCH), 79.6 [OC(CH3)3], 46.0 (CHNH),
28.4 [C(CH3)3], 22.1 (CHCH3); m/z (TOF ES+) 344.1633 (90%, MNa+
requires 344.1626), 205 (100).
This product (1.00 g, 3.40 mmol) was immediately dissolved in dry
toluene (40 mL) and cooled to -20 °C and BF3.OEt2 (1.0 mL, 6.80
mmol) was added. The reaction mixture was stirred for 5 min at -20
°C, cooled to -78 °C and MeLi (1.6 M in Et2O, 17.6 mL, 27.2 mmol)
was added drop-wise. The resulting mixture was stirred for 6 h,
allowed to warm to room temperature and stirred for further 12 h.
The reaction was quenched with saturated NaHCO3(aq) (30 mL), the
organic layer was separated, the aqueous layer was extracted with
EtOAc (3 × 15 mL). The organic phases were combined, washed
with brine (2 × 30 mL), and dried over Na2SO4. Filtration and
evaporation of the solvent in vacuo gave the crude material that
was purified by chromatography on silica gel (5% EtOAc / petroleum
ether 40−60 °C) to give the title compound 5 as dark brown oil
(±)-(3aR,9aR)-rel-3a,4,9,9a-tetrahydro-4-[(1R)-1-N-
benzylaminoethyl]-2-methyl-,4,9[1',2']-benzeno-1H-
benz[f]isoindole-1,3(2H)-dione 11
(0.45 g, 40%); νmax /cm-1 2920, 2905, 2860, 1662, 1600;
δH (250
MHz; CDCl3; Me4Si) 8.40 (1 H, s, ArCH), 8.04−7.99 (2 H, m, ArCH),
7.55−7.40 (4 H, m, ArCH), 7.38−7.19 (7 H, m, ArCH), 5.54 (1 H, q, J
6.9, CH3CH), 3.75 (1 H, d, J 12.4, PhCHH), 3.62 (1 H, d, J 12.4,
Benzylamine 5 (0.30 g, 0.97 mmol) was dissolved in dry toluene (10
mL) and the resulting solution was heated to 80−85 °C. N-
Methylmaleimide (0.11 g, 1.00 mmol) was added as a solid and the
reaction mixture was stirred for 4 h at 80−85 °C. The reaction
mixture was allowed to cool to room temperature, and the solvent
was removed under reduced pressure to afford the title
PhCHH), 1.90 (1 H, br s, NH), 1.81 (3 H, d, J 6.9, CH3); δC (62.5 MHz;
CDCl3; Me4Si) 140.9 (ArC), 135.7 (ArC), 129.9 (ArC), 129.3 (ArCH),
128.3 (ArCH), 128.2 (ArCH), 127.5 (ArCH), 126.8 (ArCH), 124.7
(ArCH), 52.9 (CH), 52.6 (CH2), 22.3 (CH3); m/z (TOF ES+) 312.1748
(15%, MH+. C23H22N requires 312.1752), 205 (100).
cycloaddition adduct as two diastereoisomers in ratio of 73:27 in
favour of the anti-isomer. The crude material was dissolved in
toluene (8 mL) and diethyl ether (10 mL) was added slowly at room
temperature. After standing, the major diastereoisomer
(±)-N-(1-Anthracen-9-yl-ethyl)-trifluoroacetamide 9
precipitated as a white solid (0.25 g, 61% yield). The major isomer
anti 11 was further purified for analytical purposes by diffusion
recrystallisation using CH2Cl2 / petroleum ether 40−60, mp 200−202
oC; νmax /cm-1 2950, 2873, 1769, 1695; 1453, 1429; δH (250 MHz;
CDCl3; Me4Si) 7.76–7.71 (1 H, m, ArCH), 7.49 (2 H, d, J 7.0, ArCH),
7.42−7.23 (6 H, m, ArCH), 7.22−7.11 (4 H, m, ArCH), 4.71 (1 H, d, J
3.3, CH), 4.61 (1 H, q, J 6.7, CH3CH), 4.30 (1 H, d, J 17.6, PhCHH),
4.15 (1 H, d, J 17.6, PhCHH), 3.89 (1 H, d, J 8.3, CH), 3.15 (1 H, dd, J
8.3, 3.3, CH), 2.47 (3 H, s, NCH3), 1.84 (3 H, d, J 6.7, CH3), 1.66 (1 H,
br s, NH); δC (62.5 MHz; CDCl3; Me4Si) 177.0 (CO), 176.2 (CO), 143.0
(ArC), 141.4 (ArC), 140.0 (ArC), 139.5 (ArC), 139.0 (ArC), 128.4 (4 ×
ArCH), 127.0 (ArCH), 126.7 (ArCH), 126.6 (ArCH), 126.4 (ArCH),
126.0 (ArCH), 125.8 (ArCH), 125.1 (ArCH), 124.4 (ArCH), 123.9
(ArCH), 118.9 (ArCH), 55.2 (C), 53.2 (PhCH2), 51.4 (CH3CH), 48.8
(CH), 47.1 (CHCO), 46.5 (CHCO), 24.1 (NCH3), 19.2 (CH3); m/z (TOF
ES+) 423.2081 (100%, MH+. C28H27N2O2 requires 423.2073). Selected
Trifluoroacetic anhydride (1.3 mL, 9.3 mmol) was added drop-wise
to a solution of 9-anthrylethanamine 3 (1.04 g, 4.69 mmol) in CH2Cl2
(20 mL) and left to stir under a nitrogen atmosphere at room
temperature for 24 h. The solvent was evaporated and the solid
obtained purified by column chromatography on silica gel, eluting
with 10% EtOAc / petroleum ether 40-60 to yield the title
compound 9 as yellow crystals (1.31g, 88%). A sample was
crystallized from toluene for characterization purposes. mp 162–
163 oC; (Found: C, 67.75; H, 4.48; N, 4.31. C18H14F3NO requires: C,
68.13; H, 4.45; N, 4.41); νmax /cm-1 3431, 3054, 1724; δH (400 MHz;
CDCl3; Me4Si) 8.43 (1 H, s, ArCH), 8.27 (2 H, d, J 9.2, ArCH), 8.01 (2
H, d, J 8.0, ArCH), 7.57–7.41 (4 H, m, ArCH), 7.25 (1 H, br s, NH), 6.54
(1 H, quin, J 6.9, CHN), 1.97 (3 H, d, J 6.9, CH3); δC (100 MHz; CDCl3;
Me4Si) 156.8 (q, JC-F 37.1, COCF3), 131.7 (ArC), 131.1 (ArC), 130.1
(ArCH), 129.0 (ArCH), 128.8 (ArC), 127.0 (2 × ArCH), 125.1 (2 ×
6 | J. Name., 2012, 00, 1-3
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(CHCH3); m/z (TOF ES+) 451 (100%, MNa+), 429.1429 (74, MH+.
1H NMR signals for the minor diastereoisomer syn 11, δH (250 MHz;
CDCl3; Me4Si) 3.86 (1H, d, J 3.3, CH), 3.22 (1H, dd, J 8.4, 3.3, CH),
1.86 (3H, d, J 3.1, CH3).
C23H20F3N2O3 requires 429.1426). Selected 1H NMR signals for the
minor diastereoisomer anti 13, δH (250 MHz; CDCl3; Me4Si) 4.67 (1
H, d, J 2.8, CH), 3.57 (1 H, d, J 8.5, COCH), 3.40 (1 H, dd, J 8.5, 2.8,
COCH), 2.71 (3 H, s, CH3N), 1.83 (3 H, d, J 6.9, CH3).
(±)-(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1R)-ethylacetamido]-2-
methyl-4,9-[1’,2’]benzeno-1H-benzo[f]isoindole-1,3-(2H)-dione 12
rac-N-[1-(9-anthryl)ethyl]acetamide 8 (0.26 g, 0.97 mmol) was
dissolved in dry toluene (10 mL) and the resulting solution was
heated to 80−85 °C. N-Methylmaleimide (0.11 g, 1.00 mmol) was
added as a solid and the reaction mixture was stirred for 4 h at
80−85 °C The reaction mixture was allowed to cool to room
temperature, and the solvent was removed under reduced pressure
to afford the title cycloaddition adduct as two diastereoisomers in
ratio of 90:10 in favour of the syn-isomer. The crude material was
(±)-(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1R)-ethyl-tert-
butylcarbamato]-2-methyl-4,9-[1’,2’]benzeno-1H-
benzo[f]isoindole-1,3-(2H)-dione 14 rac-N-[1-(9-Anthryl)ethyl]-
carbamic acid tert-butyl ester 10 (0.31 g, 0.97 mmol) was dissolved
in dry toluene (10 mL) and the resulting solution was heated to
80−85 °C. N-Methylmaleimide (0.11 g, 1.00 mmol) was added as a
solid and the reaction mixture was stirred for 4 h at 80−85 °C The
reaction mixture was allowed to cool to room temperature, and the
recrystallised from CH2Cl2/hexane to afford a single diastereoisomer solvent was removed under reduced pressure to afford the title
of the title compound syn 12 as a white powder (0.20 g, 55% yield);
mp 299−303 °C; νmax /cm-1 3505, 3050, 1693, 1669; δH (250 MHz;
CDCl3; Me4Si) 7.63–7.57 (1 H, m, ArCH), 7.44–7.41 (1 H, m, ArCH),
7.27−7.15 (3 H, m, ArCH), 7.13−7.05 (3 H, m, ArCH), 6.12 (1 H, d, J
7.3, NH), 5.60 (1 H, quint, J 6.7, CH3CH), 4.69 (1 H, d, J 2.4, CH),
3.27−3.05 (2 H, m, 2 × CH), 2.40 (3 H, s, NCH3), 1.91 (3 H, s, COCH3),
1.89 (3 H, d, J 6.7, CH3); δC (63 MHz; CDCl3; Me4Si) 176.2 (CO), 174.5
(CO), 169.5 (CO), 143.5 (ArC), 138.8 (ArC), 138.5 (ArC), 127.5 (ArCH),
127.2 (ArCH), 127.1 (ArCH), 126.5 (ArCH), 125.5 (ArCH), 125.0
(ArCH), 124.0 (ArCH), 123.5 (ArCH), 118.9 (ArC), 52.1 (C), 48.5 (CH),
47.0 (CH), 45.9 (CH), 44.9 (CH), 24.3 (CH3), 23.7 (CH3), 17.1 (CH3);
m/z (EI+) 374.1627 (4%, M+. C23H22N2O3 requires 374.1630), 331
(10), 264 (37), 263 (100), 220 (59), 206 (45), 179 (30), 112 (12).
Selected 1H NMR signals for the minor diastereoisomer anti 12, δH
(250 MHz; CDCl3; Me4Si) 4.59 (1H, d, J 3.1, CH), 2.29 (3H, s, NCH3),
1.74 (3H, s, COCH3), 1.68 (3H, d, J 6.4, CH3).
cycloaddition adduct as two diastereoisomers in a ratio of 80:20 in
favour of the syn-isomer. The crude material was recrystallised
from CH2Cl2/hexane to afford a single diastereoisomer of the title
compound syn 14 as white crystals (0.23 g, 54% yield); mp 235–236
oC; νmax /cm-1 3684, 3027, 1775, 1700; δH (500 MHz; CDCl3; Me4Si
)
7.66 (1 H, d, J 6.8, ArCH); 7.45 (1 H, dd, J 7.2, 2.1, ArCH), 7.31-7.20
(4 H, m, ArCH), 7.09–7.06 (2 H, m, ArCH), 5.48-5.38 (1 H, br m,
NCHCH3), 5.31-5.23 (1 H, br m, NH), 4.73 (1 H, s, CH), 3.22 (2 H, s, 2
× CH), 2.46 (3 H, s, NCH3), 1.94 (3 H, d, J 6.8, NCHCH3), 1.45 [9 H, br
s, (CH3)3C]; δC (125 MHz; CDCl3; Me4Si) 176.3 (MeNC=O), 174.6
(MeNC=O), 155.4 (tBuOC=O), 143.3 (ArC), 138.8 (ArC), 138.7 (ArC),
138.5 (ArC), 127.3 (ArCH), 127.1 (ArCH), 126.9 (ArCH), 126.4 (ArCH),
125.2 (ArCH), 124.9 (ArCH), 124.4 (ArCH), 123.8 (ArCH), 79.5 (OC),
52.5 (C), 48.5 (CH), 47.1 (CH), 45.9 (CH), 28.4 [(CH3)3], 24.2 (NCH3),
17.7 (CHCH3); m/z (TOF ES+) 455 (30%, MNa+), 450 (100), 433.2137
(10, MH+. C26H29N2O4 requires 433.2127), 377 (22), 333 (20).
Selected 1H NMR signals for the minor diastereoisomer, as a
mixture of rotamers, δH (250 MHz; CDCl3; Me4Si) 4.64 (1 H, d, J 3.1,
CH), 3.46 (1 H, d, J 8.9, CH), 3.13 (1 H, dd, J 8.2, 3.1, CH), 1.86 (3 H,
d, J 6.4, CH3 rotamer A), 1.73 (3 H, d, J 6.4, CH3, rotamer B).
Crystallography
(±)-(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1R)-ethyl-
trifluoroacetamido]-2-methyl-4,9-[1’,2’]benzeno-1H-
benzo[f]isoindole-1,3-(2H)-dione 13 rac-N-[1-(9-
Anthryl)ethyl]trifluoroacetamide 9 (0.31 g, 0.97 mmol) was
dissolved in dry toluene (10 mL) and the resulting solution was
heated to 80−85 °C. N-Methylmaleimide (0.11 g, 1.00 mmol) was
added as a solid and the reaction mixture was stirred for 4 h at
80−85 °C The reaction mixture was allowed to cool to room
Crystal data for 11 (coded as OSJ27) C28H26N2O2; M = 422.51;
crystallises from dichloromethane/petroleum ether as
colourless plates; crystal dimensions 0.43 x 0.32 x 0.32 mm3.
temperature, and the solvent was removed under reduced pressure Triclinic, a = 10.2636(18), b = 10.7862(18), c = 11.475(2) Å,
α=
96.250(3)°, β= 98.454(3)° γ
= 104.549(3)°, U = 1202.0(4) Å3, Z =
to afford the title cycloaddition adduct as two diastereoisomers in
ratio of 75:25 in favour of the syn-isomer. The crude material was
recrystallised from CH2Cl2/hexane to afford a single diastereoisomer
of the title compound syn 13 as white crystals (0.25 g, 60% yield);
mp 250–251 oC; νmax /cm-1 3684, 3433, 3024, 1776, 1725, 1701; δH
(250 MHz; CDCl3; Me4Si) 7.61–7.48 (2 H, m, ArCH), 7.33–7.24 (3 H,
m, ArCH), 7.20–7.16 (2 H, m, ArCH), 7.11–7.03 (1 H, m, ArCH), 6.96
(1 H, d, J 6.9, NH), 5.72 (1 H, quin, J 6.9, NHCH), 4.78 (1 H, d, J 2.9,
CH), 3.31–3.22 (2 H, m, 2 × CH), 2.48 (3 H, s, CH3N), 2.03 (3 H, d, J
6.9, CHCH3); δC (125 MHz; CDCl3; Me4Si) 175.9 (NCO), 174.5 (NCO),
156.7 (q, JC-F 37, COCF3), 143.4 (ArC), 138.5 (ArC), 137.8 (ArC), 137.6
(ArC), 127.6 (2 × ArCH), 127.5 (ArCH), 126.9 (ArCH), 125.9 (ArCH),
125.4 (ArCH), 123.1 (ArCH), 122.7 (ArCH), 115.7 (q, JC-F 288, CF3),
51.6 (C), 48.3 (CH), 46.9 (CH), 46.1 (CH), 45.8 (CH), 24.4 (NCH3), 16.4
2, Dc = 1.167 Mg/m3, space group P-1 (C1i , No. 2) , Mo-K
α
−
radiation (
λ
= 0.71073 Å), ꢁ ( Mo-Kα
) = 0.0741 mm-1, F(000) =
448. Final R = 0.0539 (wR2 = 0.1683, for all 4236 data, 294
parameters, mean and maximum δ/σ 0.000,0.000) with
allowance for the thermal anisotropy of all non-hydrogen
atoms. Minimum and maximum final electron density -0.556
and 0.668 e.Å-3. A weighting scheme w = 1/[σ2 (Fo2)
+(0.0954*P)2+0.4985*P] where P=(Fo2+ 2 * Fc2)/3 was used in
the latter stages of refinement
Crystal data for 12 (coded as osj19) C23H22N2O3; M = 374.43.
Crystallises from dichloromethane/petroleum ether as
colourless block; crystal dimensions 0.41 x 0.32 x 0.23 mm.
Orthorhombic, a = 17.583(2), b = 11.5915(14), c = 17.893(2) Å,
U = 3646.9(8) Å3, Z = 8, Dc = 1.364 Mg/m3, space group Pbca
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
−
15
2
(D , No.61), Mo-K
α
radiation (
λ
= 0.71073 Å),
ꢁ
(Mo-K
α
) =
activation used is defined as the difference in free energy
0.091 mm-1, F(000) = 1584. Data collected were measured on a between the transition state and infinitely separated
Bruker Smart CCD area detector with Oxford Cryosystems low
temperature system. Cell parameters were refined from the
reactants. It is noted that the formation of a pre-collision
complex was found to be endergonic in all cases. Transition
setting angles of 3981 reflections (θ range 2.28 < 25.00°). Final states were identified by their single imaginary frequency. A
R = 0.0506 (wR2 = 0.1470, for all 3215 data, 256 parameters,
mean and maximum δ/σ 0.000,0.000) with allowance for the
thermal anisotropy of all non-hydrogen atoms. Minimum and
maximum final electron density -0.237 and 0.755e. Å-3. A
molecule of acetonitrile was found to be present. A weighting
scheme w = 1/[σ2(Fo2) +(0.0549*P)2+ 4.0964*P] where
P=(Fo2+ 2 * Fc2)/3 was used in the latter stages of refinement.
visual inspection was carried out for each of the transition
states to confirm it connected the correct reactants and
products.
Acknowledgements
We thank the Committee of Higher Education in Libya and the
Libyan Arab Peoples Bureau for a scholarship (RAB) and the
University of Sheffield (FMG) for funding. Calculations were
performed on the ‘Sol’ cluster of the Theoretical Chemistry
Group at the University of Sheffield (UoS) and on the central
‘Iceberg’ cluster of the UoS.
Crystal data for 13 (coded as OSJ51) C23H19F3N2O3; M = 425.
Crystallises from chloroform and 40/60 petroleum ether as
pale yellow needles; crystal dimensions 0.30 x 0.06 x 0.06
mm3. Orthorhombic, a = 14.680(3), b = 17.220(3), c = 15.260(3)
Å, U = 3857.6(13) Å3, Z = 8, Dc = 1.475 Mg/m3, space group
−
Pbca (D152 , No.61), Mo-K
α
radiation (
λ
= 0.71073 Å), ꢁ (Mo
Kα
) = 2.208 mm-1, F(000) = 1776. Final R = 0.0458 (wR2 =
Notes and references
0.1299, for all 2977 data, 281 parameters with allowance for
the thermal anisotropy of all non-hydrogen atoms. Minimum
and maximum final electron density -0.289 and 0.277e. Å-3. A
weighting scheme w = 1/[σ2 (Fo2) + (0.0326*P)2+ 0.00*P]
where P=(Fo2+ 2 * Fc2)/3 was used in the latter stages of
refinement.
1.
M. J. Fisher, W. J. Hehre, S. D. Kahn, and L. E. Overman, J.
Am. Chem. Soc., 1988, 110, 4625–4633.
2.
S. C. Datta, R. W. Franck, R. Tripathy, G. J. Quigley, L.
Huang, S. Chen, and A. Sihaed, J. Am. Chem. Soc., 1990,
112, 8472–8478.
Crystal data for 14 (coded as OSJ53) C26H28N2O4; M = 432.50,
crystallises from dichloromethane as colourless blocks; crystal
dimensions 0.32 x 0.14 x 0.06 mm3. Monoclinic, a =
3.
4.
B. M. Trost and D. C. Lee, J. Org. Chem., 1989, 54, 2271–
2274.
14.9540(12), b = 9.4917(8), c = 16.5072(6) Å,
= 2229.4(3) Å3, Z = 4, Dc = 1.289 Mg/m3, space group P21/c
β = 107.913(3)° U
−
5
2
(C h, No.14), Mo-K
α
radiation (
λ
= 0.71073 Å), ꢁ(Mo-Kα) =
H. Jiang, C. Rodríguez-Escrich, T. K. Johansen, R. L. Davis,
and K. A. Jørgensen, Angew. Chem. Int. Ed. Engl., 2012, 51,
10271–4.
0.087 mm-1, F(000) = 920. Final R = 0.0517 (wR2 = 0.1555, for
all 3916 data, 294 parameters, mean and maximum
δ/σ 0.000,0.000) with allowance for the thermal anisotropy of
all non-hydrogen atoms. Minimum and maximum final
electron density -0.284 and 0.242 e.Å-3. A weighting scheme w
= 1/[σ2(Fo2) + (0.0729*P)2 + 0.2665*P] where P = (Fo2+ 2 *
Fc2)/3 was used in the latter stages of refinement.
5.
6.
7.
8.
T. R. Kelly, P. Meghani, and V. S. Ekkundi, Tetrahedron
Lett., 1990, 31, 3381–3384.
M. Shoji, H. Imai, I. Shiina, H. Kakeya, H. Osada, and Y.
Hayashi, J. Org. Chem., 2004, 69, 1548–56.
Computational
All of the calculations were performed using density functional
theory (DFT) with the B3LYP hybrid functional26–29 using the 6-
311G(d,p) basis set30 for all atoms as implemented in Gaussian 09.31
Solvent effects were included in all of the calculations through the
IEF-PCM32 model as implemented in Gaussian 0931 with toluene as
the solvent. These computational parameters were chosen to allow
comparison with previous work.18 Moreover, B3LYP has been found
to determine stereoselectivities accurately and has been used in the
past in the study of Diels-Alder reactions.18,20,21,33
J. C. Christian Atherton and S. Jones, J. Chem. Soc. Perkin
Trans. 1, 2002, 2166–2173.
H. Adams, S. Jones, A. J. H. M. Meijer, Z. Najah, I. Ojea-
Jimenez, and A. T. Reeder, Tetrahedron Asymmetry, 2011,
22, 1620–1625.
9.
S. A. Hasbullah and S. Jones, Tetrahedron: Asymmetry,
2010, 21, 2719–2725.
All of the reactant, transition state, and product structures
were fully optimized without any symmetry restrictions.
Transition states were located using the QST3 algorithm.34
Frequency calculations were carried out to characterize all
stationary points obtained to confirm them as either local
minima or transition states. Frequencies were used to
calculate free energies in the standard way. The free energy of
10.
11.
J. C. Ball, R. Gleave, and S. Jones, Org. Biomol. Chem., 2011,
9, 4353–4360.
H. Adams, S. Jones, and I. Ojea-Jimenez, Org. Biomol.
Chem., 2006, 4, 2296–2303.
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB01343G
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COMMUNICATION
12.
K. L. Burgess, N. J. Lajkiewicz, A. Sanyal, W. Yan, and J. K.
Snyder, Org. Lett., 2005, 7, 31–34.
31.
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M.
A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
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