Topically resolved intramolecular CH-π interactions in phenylalanine derivatives

Article abstract of DOI:10.1039/b916021n

NMR spectra of imines and nitrones derived from benzophenone and phenylalanine or tyrosine show clear evidence of an aromatic edge-to-face interaction in solution. At low temperatures the two ortho protons of the edge interacting phenyl ring become topica

Full text of DOI:10.1039/b916021n

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Topically resolved intramolecular CH-p interactions in
phenylalanine derivatives†
W. Brian Jennings,*a Noel J. P. McCarthy,a Padraig Kellya and John F. Malone*b
Received 4th August 2009, Accepted 24th September 2009
First published as an Advance Article on the web 27th October 2009
DOI: 10.1039/b916021n
NMR spectra of imines and nitrones derived from benzophenone and phenylalanine or tyrosine show
clear evidence of an aromatic edge-to-face interaction in solution. At low temperatures the two ortho
protons of the edge interacting phenyl ring become topically resolved with the ortho proton NMR signal
involved in the CH-p interactions shifted well upfield (d 5.4–5.8 at -88 ◦C) of the other ortho signal.
Introduction of a para substituent into the phenylalanine ring has a modest effect on the upfield shift.
The edge-to-face arrangement also manifests in the X-ray crystal structures of two of these compounds.
Barriers to rotation around the syn phenyl-imino bond are also reported (10.5–11.1 kcal mol-1).
single ortho proton directed away, could reduce the magnitude of
the observed upfield shift.
Introduction
General interest in aromatic CH-p interactions was largely initi-
ated in the 1980s by recognition of their importance in protein
structure1 and host binding in supramolecular systems.2 These
interactions are also important in crystal engineering,3 molecular
recognition4 and some drug receptor binding interactions.5,6
Further insight into the nature and strength of these weak
interactions has been provided by molecular orbital calculations
on the benzene dimer system.7 Several model systems have
been synthesised where single intramolecular aromatic CH-p
interactions can be assessed in solution by NMR and/or in the
solid state by X-ray crystallography.8 These include the Grossel
aryl cyclohexadiene model,9 the conformationally restricted cy-
clophanes of Kim, Fukazawa and Gellman,10 the Wilcox ‘torsion
balance’,11 the Gellman carboxylic acid and amides,12 the Gung
triptycene system,13 and our own imino and biaryl systems.14,15
Hunter and co-workers have devised an interesting alternative
procedure involving mutant cycles for assessing intermolecular
aromatic CH-p interactions.16
We now report an improved ‘topically resolved’ model where
rotation of the edge orientated phenyl ring is sufficiently restricted
to enable the interacting ortho proton to be independently
observed by NMR investigations at low temperature.
Results and discussion
Compounds 1–3 (Fig. 1) were prepared by a transimination
procedure devised by O’Donnell and Polt.17 Direct imination of
benzophenone with amino acid esters is problematic due to the
low reactivity of diaryl ketones and the tendency of amino acid
esters to dimerise on heating in the presence of Lewis acid catalysts
such as titanium tetrachloride.
In previous model compounds where intramolecular edge-to-
face interactions involving phenyl rings have been observed by
NMR in solution, the edge orientated ortho (or meta) proton is
in a fast dynamic exchange with the other ortho (or meta) proton
due to rapid rotation of the phenyl ring about its two-fold axis.
This leads to a single time averaged signal for these two protons,
and any observed upfield shift due to ring current shielding from
a face oriented aromatic ring is thereby reduced by 50%. In
order to circumvent this problem, our previous investigations14,15
in this area employed compounds where one ortho position was
blocked by a substituent. Nevertheless the possibility remains that
a significant population of a second conformation with the ortho
substituent directed towards the second aromatic ring, and the
Fig. 1 Structures of compounds 1–6
1
aDepartment of Chemistry and Analytical & Biological Chemistry Research
Facility, University College Cork, Cork, Ireland. E-mail: brianj@ucc.ie
The H NMR spectra of these three compounds in deuterio-
chloroform at ambient temperature were in agreement with their
structures except that an anomalous broadened doublet signal
integrating for two protons was observed at d 6.6–6.7 for imines 1,
2, and 3 (Table 1). Imines 1 and 2 have been reported previously,18,19
but the broadening and unusual upfield shift of this signal was not
bSchool of Chemistry & Chemical Engineering, The Queen’s University
of Belfast, Belfast, Northern Ireland, UK, BT9 5AG. E-mail: j.malone@
qub.ac.uk
† CCDC reference numbers 739741–739743. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b916021n
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Table 1 Selected 13C and 1H chemical shifts for compounds 1–6
dichloromethane-d2. On lowering the temperature the upfield
aromatic signal broadened further and below -30 ◦C it split into
two widely separated broad components. These component signals
were well resolved at -88 ◦C into an upfield doublet at d 5.5–5.8
integrating for one proton, and a lower field signal at d 7.14–7.17
also integrating for one proton (Table 1). The position of the latter
signal was confirmed by a 2D EXSY spectrum on imine 1 at -88 ◦C
as it lay underneath a doublet signal from the two ortho protons
of the benzyl ring. Variable temperature spectra of imine 1 are
depicted in Fig. 3.
13
13
=
=
C
N
N- C
Ho + Ho¢
Ho
Ho¢
Compd
(25 ◦C)a
(25 ◦C)a
(25 ◦C)a
(-88 ◦C)b (-88 ◦C)b
1
2
3
4
5
6
170.9
171.3
171.6
147.5
148.0
148.0
67.2
67.4
66.3
73.8
73.8
72.9
6.60
6.64
6.69
6.58
6.65
6.70
5.52
5.78
5.71
5.26
5.45
5.49
7.14
7.14
7.17
7.45
7.41
7.50
a Solvent CDCl3. b Solvent CD2Cl2 set at d 5.32.
commented upon. A 2D-COSY spectrum of imine 1 confirmed
that this broad signal was from aromatic protons as it was
coupled to a signal at d 7.27 in the normal aromatic envelope.
A HMBC experiment on 1 was conducted at 70 ◦C in 1,1,2,2-
tetrachloroethane-d2, where the upfield aromatic signal was a well
resolved doublet. The imino carbon signal at d 170.7 gave a three-
bond correlation with the upfield aromatic doublet (2H) at d 6.72
and with a second 2H aromatic doublet at d 7.61. Accordingly
these doublet signals can be confidently assigned to the ortho
protons on the imino phenyl rings. A third 2H doublet at d
7.07 showed a three-bond HMBC correlation with the benzylic
methylene carbon at d 39.6, indicating that this 2H doublet belongs
to the ortho protons on the N-terminal benzyl ring.
Previously reported imines derived from ortho-substituted ace-
tophenones and phenylalanine esters also exhibit a similar upfield
doublet signal in the Z-isomer where the aromatic ring is syn to the
N-alkyl substituent.14 Hence the upfield 2H doublet in the present
series of compounds can be confidently assigned to the equivalent
ortho hydrogens Ho and Ho¢ on the phenyl ring located syn to the
amino acid ester side chain (Fig. 2). The position of this signal is
well upfield of the region (ca. d 7.5–8.0) where ortho hydrogens
would normally be expected for a phenyl ring attached to an
=
electron withdrawing C N moiety. Indeed the ortho hydrogens
of the anti phenyl ring in imines 1–3 resonate at d 7.56–7.59 in
deuteriochloroform.
Fig. 3 Variable temperature 1H NMR spectra of imine 1 in CD2Cl2
(s denotes the residual solvent signal).
Clearly the two ortho hydrogens (Ho and Ho¢) on the syn
phenyl ring (Fig. 2) have become diastereotopically resolved on
the NMR timescale at low temperature due to slow rotation about
the phenyl-imino bond combined with the stereogenic centre in the
amino-ester moiety. These signals are unusually widely separated
by 1.62, 1.36 and 1.46 ppm in 1, 2 and 3, respectively, and the higher
field signal (Ho) is far outside the normal region for the aromatic
signals. An upfield shift of this magnitude can only be rationalised
by a well populated edge-to-face molecular conformation in
solution where one ortho proton (Ho) in the syn imino phenyl
ring is positioned above, and relatively close to, the face of the
terminal phenyl ring of the phenylalanine moiety (Fig. 2). This
does not necessarily mean that the edge-to-face conformer is the
only populated conformation in solution. Indeed we believe that at
least one other conformation is significantly populated especially
at higher temperature. The signal position of the upfield Ho signal
below coalescence moves steadily further upfield by ca. 0.06 ppm
for each 10◦ decrease in temperature. This is consistent with a
rapid dynamic conformational equilibrium between the ‘closed’
Fig. 2 Illustration showing the edge-to-face CH-p interaction involving
close contact with Ho.
Abnormal signal broadening as observed for the upfield aro-
matic signal in compounds 1–3 can be indicative of an exchange
process that is becoming slow on the NMR timescale. Accordingly
a low temperature study was conducted on compounds 1–3 in
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edge-to-face conformer and a second higher enthalpy ‘open’
conformer where the phenylalanine moiety is remote from the
ortho proton Ho.8,14 There is considerable conformational freedom
in solution about the sidechain N–CH, CH–CH2 and CH2–phenyl
single bonds, and indeed more than one alternative conformer
could be appreciably populated, especially at higher temperatures.
The alternative ‘open’ conformation(s) are likely to be entropically
favoured over the constrained edge-to-face conformation, and
therefore more populated at higher temperatures.8,14
It is evident from Table 1 that the para substituent on the facially
orientated benzylic ring has a modest effect on the chemical shift
of the Ho signal at -88 ◦C. This signal moves further downfield by
0.26 and 0.19 ppm when the para hydrogen is replaced by an OH or
NO2 group respectively. A similar trend is present in the nitrones
4–6 (see below), indicating that this relatively small substituent
effect is not an artefact. The effect can be attributed to a slight
weakening of the edge-to-face interaction by both these para sub-
stituents. An alternative possibility that the chemical shift changes
are primarily due to alterations in the ring current shielding of Ho
can probably be excluded as the p-donating OH and electron with-
drawing NO2 substituents would have opposite effects on the ring
current density. The weakening of the CH-p interaction is likely to
be manifested in an increase of the population of the alternative
open conformer(s) in dynamic equilibrium with the major closed
form, or possibly a slightly increased contact distance between the
phenyl rings. Molecular orbital calculations on model systems20
indicate that introduction of a nitro group into the face orientated
ring reduces the energy of the CH-p interaction by ca. 0.23–
0.30 kcal mol-1 in chloroform solution which would be consistent
with the present experimental observations. However the MO
calculations also predict that an OH substituent should have a very
small effect (< 0.1 kcal mol-1) on the interaction energy in solution,
in contrast to the present results. Experimental investigations on
the Wilcox system by Diederich and co-workers also indicate that
a nitro substituent on the face orientated ring appreciably weakens
the CH-p interaction but a hydroxyl substituent has only a very
minor weakening effect.11 However the Wilcox system has an
edge-tilted-T geometry with two intramolecular CH-p interactions
whereas the present system has face-tilted-T geometry and a single
intramolecular CH-p interaction. More recently Cockroft and
Hunter have postulated that solvent effects play a significant role
in determining the magnitude of substituent effects in the Wilcox,
and possibly other systems.11 Further experimental investigations
of substituent effects on aromatic CH-p interactions may be
required to clarify the situation.
Fig. 4 X-Ray structure of imine 2.
ring located syn to the amino acid ester side-chain lies above
the face of the phenyl ring of the tyrosine moiety. With Ho
˚
positioned to give a C–H bond length of 1.083 A (i.e. the standard
value obtained from neutron diffraction determination of the
position of the hydrogen nucleus, and used in earlier studies as a
normalised distance8) the geometry of the edge-to-face interaction
is as follows: the Ho to ring centroid distance is 2.60 A; the
perpendicular distance from Ho to the ring plane is 2.59 A and
˚
˚
the point of intersection of this perpendicular onto the ring plane
˚
is offset by 0.24 A from the ring centroid. These distances are
among the shortest found in previous edge-to-face contacts8 and
represent a substantial interaction. Moreover the dihedral angle
between the interacting ring planes is 50◦, typical of angles found
in earlier examples of edge-to-face interactions with face-tilted-T
geometry.8
Nitrones 4–6
Imines 1–3 were oxidised with meta-chloroperoxybenzoic acid or
its complex with potassium fluoride. NMR spectra of the resulting
crude products indicated the presence of some of the desired
nitrone together with a mixture of diastereoisomeric oxaziridines.
The more polar nitrones 4–6 (Fig. 1) were readily isolated from
the mixture by flash column chromatography. The H and 13C
1
NMR spectra of the nitrones showed broadly similar features to
the parent imines except that the low field 13C N signal at d 171
=
The co-ordinates of Ho relative to the tyrosine ring centre,
determined from X-ray crystallographic data (see below) for
compound 2 and the Johnson–Bovey ring current tables,21 gives a
predicted estimate of a ca. 2.6 ppm upfield shift of proton Ho in the
observed edge-to-face arrangement (see below). This is somewhat
greater than the measured upfield shift of 1.36 ppm for Ho relative
to Ho¢ in imine 2 measured at -88 ◦C (Table 1). This could be due
to inaccuracies in ring current model and/or a time averaged shift
contribution from one (or more) open conformers in solution,
even at this low temperature where entropy contributions (TDS)
to conformational free energies are reduced.
in the imines was absent in the nitrones. A HMBC spectrum was
recorded on nitrone 4 at -88 ◦C in dichloromethane-d2 (where
the exchanging Ho and Ho¢ doublet signals were well resolved). It
exhibited cross peaks due to 3JCCCH coupling between a quaternary
carbon at d 147.5 and the syn phenyl Ho and Ho¢ protons at d 5.26
and d 7.45, plus a 2H doublet signal at d 7.78 assigned to the ortho
protons on the phenyl ring anti to the N-alkyl moiety. Accordingly
the quaternary carbon at d 147.5 can be assigned to an unusually
=
shielded C N resonance in nitrones. It can also be seen (Table 1
and NMR data in the Experimental Section) that the N–13C and
NCH proton signals are shifted further downfield in the nitrones
(by ca. 6.5 and 0.67 ppm respectively) due to the adjacent polar
N-oxide moiety. As in the imines, the 1H NMR spectra of nitrones
A single-crystal X-ray structure analysis of imine 2 showed that,
in the solid state, the molecule adopts a closed conformation in
which the ortho proton Ho (on C3, Fig. 4) of the benzophenone
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4–6 recorded at ambient temperature in deuteriochloroform
displayed a broad upfield aromatic signal at d 6.58–6.70 which
integrated for two protons (Table 1). This signal was broader than
that observed in the imines 1–3 due to a slightly higher barrier
to rotation about the syn phenyl imino bond in the nitrones (see
below).
Nitrone crystal structures
A single-crystal X-ray structure analysis of nitrone 6 showed that,
in the solid state, the molecule adopts a closed conformation
very similar to that of imine 2. The ortho proton Ho (on C3,
Fig. 6) of the benzophenone ring located syn to the amino acid
ester side-chain lies above the face of the phenyl ring of the
On cooling samples of nitrones 4, 5 and 6 in dichloromethane-
d2 this signal collapsed into the baseline, and below -30 ◦C it
split into two equally intense components (Fig. 5). At -88 ◦C
two new doublet signals were evident at d 5.26–5.49 and d 7.4–7.5
assigned to Ho and Ho¢ respectively (Table 1). Unlike the situation
in the imines the downfield Ho¢ signal was not overlapped by other
aromatic signals, but nevertheless the assignment of this signal as
the exchanging partner of Ho was confirmed by a 2D EXSY
experiment on nitrone 4 at -88 ◦C. The Ho signal in nitrones 4–6
is ca. 0.3 ppm upfield from the corresponding imines 1–3 while
the Ho¢ signal is 0.2–0.3 ppm further downfield in the nitrones
(Table 1). Accordingly the chemical shift separation between Ho
and Ho¢ (1.96–2.19 ppm) in the nitrones is significantly larger
than that in the imines. This could indicate a stronger edge-to-
face interaction and/or a reduced population of alternative open
conformers in the nitrones. The predicted ring current shielding
of Ho for nitrone 6 using the Johnson–Bovey model21 and the
X-ray co-ordinates (see below) is 2.0 ppm. This is in excellent
agreement with the measured chemical shift difference of 2.01 ppm
(Table 1) between Ho and Ho¢ in 6. As discussed in the imine
section, the presence of a para-nitro or para-hydroxy substituent
on the terminal benzyl ring somewhat reduces the upfield shift of
Ho¢ in nitrones 5 and 6. This may be due to a slight weakening of
the CH-p interaction.
˚
˚
phenylalanine moiety. The Ho to ring centroid distance is 2.86 A;
the perpendicular distance from Ho to the ring plane is 2.85 A
and the point of intersection of this perpendicular to the plane is
˚
offset by 0.17 A from the ring centroid. The inter-plane angle is
39◦. While the distances are longer than those of imine 2, and the
inter-plane angle is shallower, these dimensions are still consistent
with a face-tilted-T edge-to-face interaction.8
Fig. 6 X-Ray structure of nitrone 6.
Nitrone 4 (Fig. 7), on the other hand, adopts a conformation in
the solid state which puts the corresponding dimensions beyond
the distances appropriate to an edge-to-face interaction. The
conformational differences are illustrated by the torsion angles
in Table 2 and by Fig. 4, 6 and 7 which show imine 2 and nitrones
6 and 4, respectively, from a similar perspective with respect to the
imine/nitrone planes.
Table 2 Selected bond angles and torsion angles from X-ray crystallo-
graphic data
Angle (◦)
Imine 2
Nitrone 6
Nitrone 4
C1-N1-C14
N1-C1-C2
N1-C1-C8
120.1
125.7
117.6
110.5
-60.3
-100.8
81.7
11.6
-169.1
83.3
122.5
119.1
122.3
116.6
-68.0
-96.3
86.5
20.8
-159.4
93.5
122.6
121.6
120.6
116.7
-48.7
-121.6
63.6
C1-N1-C14-C15
N1-C14-C15-C16
N1-C1-C2-C3
N1-C1-C2-C7
N1-C1-C8-C9
N1-C1-C8-C13
C14-C15-C16-C17
C14-C15-C16-C21
40.0
-144.5
121.7
-58.4
Fig. 5 Variable temperature 1H NMR spectra of nitrone 4 in CD2Cl2
(s denotes the residual solvent signal).
-95.6
-87.0
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moiety and the geminal anti phenyl ring as the syn phenyl ring
rotates through the imino plane. The calculated phenyl rotational
barrier (molecular mechanics and ab initio MO) in benzophenone
-1 22
=
(Ph2C O) is very small (1.3–1.6 kcal mol ), hence the major
contribution to the syn phenyl rotational barrier in compounds
1–6 is likely to be the passing interaction with the N-alkyl moiety
The steric effects in the rotational transition state may be slightly
offset by increased conjugation between the co-planar syn phenyl
and imino systems, but this is likely to be reduced by a loss in
conjugation involving the anti phenyl group which will probably
twist out of plane to minimise steric contact with co-planar
syn phenyl group. The CH-p interaction may make a minor
contribution to the syn phenyl rotational barrier as this stabilising
interaction is likely to be lost in the rotational transition state. The
NMR data indicate that rotation about the much less hindered
anti phenyl-imino bond in 1–6 remains fast on the NMR timescale
down to -88 ◦C as the ortho proton doublet signal from this ring
does not broaden and split into two components.
Fig. 7 X-Ray structure of nitrone 4.
Phenyl-imino rotational barriers
Experimental
Preparation of imines 1–3
Rates of rotation around the phenyl-imino bond syn to the N-alkyl
group were determined for the representative imines 1 and 2 and
nitrones 4 and 6 by computer assisted analysis of the coalescing
Ho and Ho¢ doublet signals. An additional signal collapse and
eventual modest splitting involving triplet signals was also evident
in the central aromatic region of the imines and nitrones at low
temperature. This was due to the meta protons on the syn phenyl
ring also becoming non-equivalent due to the slow phenyl-imino
bond rotation.
The results (Table 3) show that the remote para substituents on
the N-terminal benzylic ring have a negligible effect on the imino-
phenyl rotational barrier. However, the rotational barrier in the
nitrones 4 and 6 is appreciably higher (by 0.6 kcal mol-1) than in
the imines 1 and 2. Buttressing effects from the N–O group in the
nitrones and associated bond angle changes at the imino carbon
are probably responsible for the increased rotational barriers in the
These imines were prepared from benzophenone imine and the
appropriate phenylalanine methyl ester hydrochloride by the tran-
simination methodology of O’Donnell and Polt,17,18 and purified
by flash column chromatography on silica gel using hexane–ethyl
acetate as eluent (yields 75–90%).
Methyl N-diphenylmethylene-L-phenylalaninate 1. Previously
characterised;18 dH (500 MHz, CDCl3) 3.18 (1 H, dd, J 13.3 and
9.4, HA of CH2), 3.28 (1H, dd, J 13.3 and 4.2, HB of CH2), 3.73
(3H, s, OCH3), 4.27 (1H, dd, J 9.4 and 4.2, NCHX), 6.60 (2H,
br d, o-Ph syn), 7.03 (2H, d, o-benzyl), 7.2–7.4 (9H, m, m- and
p-Ph/Bn), 7.57 (2H, d, o-Ph anti); dC (125.8 MHz, CDCl3) 39.8
(CH2), 52.2 (OCH3), 67.2 (NCH), 126.3 (CH), 127.6 (2CH), 128.0
(2CH), 128.13 (2CH), 128.15 (2CH), 128.3 (CH), 128.8 (2CH),
129.8 (2CH), 130.3 (CH), 136.0 (Ph Cq), 137.9 (Ph Cq), 139.4 (Bn
=
=
Cq), 170.9 (C N), 172.3 (C O).
=
Methyl N-diphenylmethylene-L-tyrosinate 2. Colourless crys-
tals, mp 130–131 ◦C (from hexane–ether), (Found: C, 76.7; H, 5.9;
N, 3.95. C23H21NO3 requires C, 76.9; H, 5.9; N, 3.9); dH (500 MHz,
CDCl3) 3.10 (1H, dd, J 13.5 and 9.4, HA of CH2), 3.19 (1H, dd,
J 13.5 and 4.3, HB of CH2), 3.72 (3H, s, OCH3), 4.22 (1H, dd, J
9.4 and 4.3, NCHX), 4.79 (1H, s, OH), 6.65 (2H, d, Bn ortho to
OH), 6.66, (2H, d, o-Ph syn), 6.89 (2H, d, Bn meta to OH), 7.3–
7.4 (6H, m, m- and p-Ph), 7.57 (2H, d, o-Ph anti); dC (75.5 MHz,
CDCl3) 38.8 (CH2), 52.2 (OCH3), 67.4 (NCH), 115.0 (2CH), 127.6
(2CH), 128.0 (2CH), 128.2 (2CH), 128.4 (CH), 128.8 (2CH), 129.5
(Bn Cq), 130.3 (CH), 130.9 (2CH), 136.0 (Ph Cq), 139.2 (Ph Cq),
nitrones. Thus the X-ray data (Table 2) show that the syn Ph–C N
bond angle (N1–C1–C2) is reduced in nitrones 4 and 6 by 4–6◦
compared with imine 2. This places the syn phenyl group closer to
the N-alkyl moiety thereby increasing the passing interactions in
the rotational transition state.
=
The Ph2C X torsional system can be described as a two-
bladed propeller. The rotational barriers in these compounds will
be dominated by steric passing interactions between the ortho
hydrogens Ho and Ho¢ and the hydrogens on the syn N-alkyl
Table 3 Barriers to rotation around the syn phenyl-imino bonda
=
=
154.4 (Bn Cq-OH), 171.3 (C N), 172.5 (C O).
Compound
T/◦C
k/s-1
DGπ/kcal mol-1
Crystal data for 2
1
2
4
6
-30b
-42c
-15b
-15b
1400
590
2400
2200
10.6
10.5
11.1
11.1
C23H21NO3, M = 359.4, orthorhombic, a = 9.212(2), b =
3
˚
˚
10.822(3), c = 19.309(5) A, U = 1924.9(9) A , T = 150(2) K,
˚
Mo-Ka radiation, l = 0.71073 A, space group P212121 (no. 19),
a Determined in CD2Cl2 by 500 MHz 1H NMR lineshape analysis.
b Coalescence temperature. c Lineshape analysis performed around 10◦
below coalescence due to overlap with tyrosinate ring signals.
Z = 4, F(000) = 760, Dx = 1.240 g cm-3, m = 0.082 mm-1, Bruker
SMART CCD area detector diffractometer, f/w scans, 4.2◦
<
2q < 52.8◦, measured/independent reflections: 20 500/3936,
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Rint = 0.038, direct methods solution, full-matrix least squares
refinement on Fo2, anisotropic displacement parameters for non-
hydrogen atoms; all hydrogen atoms located in a different Fourier
synthesis but included at positions calculated from the geometry
of the molecules using the riding model, with isotropic vibration
parameters. R1 = 0.035 for 3447 data with Fo > 4s(Fo), 246
SMART CCD area detector diffractometer, f/w scans, 4.3◦
<
2q < 52.8◦, measured/independent reflections: 19 868/3843,
Rint = 0.021, direct methods solution, full-matrix least squares
refinement on Fo2, anisotropic displacement parameters for non-
hydrogen atoms; all hydrogen atoms located in a different Fourier
synthesis but included at positions calculated from the geometry
of the molecules using the riding model, with isotropic vibration
parameters. R1 = 0.031 for 3457 data with Fo > 4s(Fo), 246
parameters, wR2 = 0.085 (all data), GoF = 1.05, Drmin,max
=
-3
˚
-0.14/0.15 e A . CCDC 739743.
parameters, wR2 = 0.080 (all data), GoF = 1.05, Drmin,max
=
Methyl
N-diphenylmethylene-L-4-nitrophenylalaninate
3.
-3
˚
-0.17/0.16 e A . CCDC 739741.
Colourless crystals, mp 78–80 ◦C (from hexane), (Found: C,
71.25; H, 5.2; N, 7.1. C23H20N2O4 requires C, 71.1; H, 5.2; N,
7.2); dH (500 MHz, CDCl3) 3.30 (1 H, dd, J 13.3 and 9.0, HA
of CH2), 3.35 (1H, dd, J 13.3 and 4.3, HB of CH2), 3.75 (3H, s,
OCH3), 4.32 (1H, dd, J 9.0 and 4.3, NCHX), 6.69 (2H, br d,
o-Ph syn), 7.21 (2H, d, Bn meta to NO2) 7.3–7.4 (6H, m, m- and
p-Ph), 7.56 (2H, d, o-Ph anti) 8.06 (2H, d, Bn ortho to NO2); dC
(125.8 MHz, CDCl3) 39.5 (CH2), 52.5 (OCH3), 66.3 (NCH), 123.3
(2CH), 127.5 (2CH), 128.2 (2CH), 128.4 (2CH), 128.8 (2CH),
128.8 (CH), 130.65 (2CH), 130.7 (CH), 135.7 (Ph Cq), 138.9 (Ph
Methyl N-diphenylmethylene-L-tyrosinate-N-oxide 5. Colour-
less crystals, mp 79–81 ◦C from hexane–EtOAc; dH (500 MHz,
CDCl3) 3.13 (1 H, dd, J 14.1 and 3.5, HA of CH2), 3.72 (1H,
dd, J 14.1 and 11.2, HB of CH2), 3.85 (3H, s, OCH3), 4.90 (1H,
dd, J 11.2 and 3.6, NCHX), 6.65 (2H, br s, o-Ph syn), 6.72 (2H,
d, Bn ortho to OH), 7.05 (2H, d, Bn meta to OH), 7.3–7.4 (6H,
m, m- and p-Ph), 7.91 (2H, d, o-Ph anti); dC (75.5 MHz, CDCl3)
34.2 (CH2), 53.1 (OCH3), 73.8 (NCH), 115.4 (2CH), 127.8 (2CH),
128.7 (2CH), 129.3 (CH), 129.5 (2CH), 130.0 (CH), 130.4 (2CH),
130.7 (2CH), 132.4 (Bn Cq), 133.2 (Ph Cq), 134.9 (Ph Cq), 155.2
=
Cq), 146.0 (Bn Cq), 146.7 (Bn Cq-NO2), 171.58 (C N), 171.63
=
=
=
(C O).
(Bn Cq-OH), 148.0 (C N), 167.7 (C O); m/z (EI) 376.1551 (M +
H+), C23H22NO4 requires 376.1549.
Preparation of nitrones. Nitrones 4 and 5 were obtained by
stirring an equimolar mixture of the appropriate imine 1 or 2
with m-chloroperoxybenzoic acid (m-CPBA) in dichloromethane
for ca. 24 h. The required quantity of commercial 70–75%
m-CPBA was first dissolved in dichloromethane and dried over
MgSO4 to remove the water present in the m-CPBA, followed
by filtration and addition of the imine. After standing for 24 h
the reaction mixture was washed with aqueous sodium sulfite
(1.0 M), then aqueous sodium bicarbonate (1.0 M), water, and
dried (MgSO4). 1H NMR spectra of the crude product indicated
the presence of the desired nitrone together with a mixture of
diastereoisomeric oxaziridines produced by epoxidation of the
imino bond in competition with N-oxidation. Flash column
chromatography on silica gel eluting with hexane-ether afforded
the more polar nitrone as the last eluted material. Due partly to
the formation of considerable oxaziridine co-products the isolated
yield of nitrone was low (ca. 10%).
Methyl N-diphenylmethylene-L-4-nitrophenylalaninate-N-oxide
6. Was obtained by stirring freshly prepared solid m-CPBA/KF
complex (1.07 g, 3.6 mmol) with imine 3 in dry dichloromethane
(10 cm3) at 0 ◦C for 12 h, followed by filtration and removal
of solvent. Flash column chromatography on silica gel afforded
nitrone 6 as colourless crystals (0.17 g, 29%), mp 142–143 ◦C
(Found: C, 68.3; H, 4.9; N, 7.0. C23H20N2O5 requires C, 68.3; H,
5.0, N, 6.9%); dH (500 MHz, CDCl3) 3.32 (1 H, dd, J 13.8 and
3.7, HA of CH2), 3.92 (1H, dd, J 13.8 and 11.0, HB of CH2), 3.88
(3H, s, OCH3), 5.02 (1H, dd, J 11.0 and 3.8, NCHX), 6.70 (2H,
br d, o-Ph syn), 7.3–7.4 (8H, m), 7.90 (2H, d, o-Ph anti), 8.13
(2H, d, Ar ortho to NO2); dC (75.5 MHz, CDCl3) 34.9 (CH2), 53.5
(OCH3), 72.9 (NCH), 123.7 (2CH), 127.9 (2CH), 129.0 (2CH),
129.3 (2CH), 129.7 (CH), 130.3 (2CH), 130.4 (CH), 130.5 (2CH),
132.8 (Ph Cq), 134.7 (Ph Cq), 144.2 (Bn Cq), 147.2 (Bn Cq-NO2),
=
=
148.1 (C N), 167.2 (C O).
Methyl N-diphenylmethylene-L-phenylalaninate-N-oxide 4.
Colourless crystals, mp 139–140 ◦C from hexane–EtOAc (Found:
C, 77.35; H, 5.9; N, 3.9. C23H21NO3 requires C, 76.9; H, 5.9; N,
3.9%); dH (500 MHz, CDCl3) 3.16 (1 H, dd, J 13.8 and 3.6, HA
of CH2), 3.69 (1H, dd, J 13.8 and 11.1, HB of CH2), 3.81 (3H, s,
OCH3), 4.93 (1H, dd, J 11.1 and 3.6, NCHX), 6.58 (2H, br s, o-Ph
syn), 7.14 (2H, d, o-benzyl), 7.2–7.4 (9H, m, m- and p-Ph/Bn),
7.87 (2H, d, o-Ph anti); dC (75.5 MHz, CDCl3) 35.1 (CH2), 53.2
(OCH3), 73.8 (NCH), 127.1 (CH), 127.8 (2CH), 128.5 (2CH),
128.7 (2CH), 129.2 (CH), 129.5 (2CH), 129.6 (2CH), 129.9 (CH),
Crystal data for 6
C23H20N2O5, M = 404.4, monoclinic, a = 9.094(2), b = 11.642(3),
3
˚
˚
c = 9.371(2) A, b = 91.370(4), U = 991.9(4) A , T = 150(2)
˚
K, Mo-Ka radiation, l = 0.71073 A, space group P21 (no. 4),
Z = 2, F(000) = 424, Dx = 1.354 g cm-3, m = 0.097 mm-1,
Bruker SMART CCD area detector diffractometer, f/w scans,
4.3◦ < 2q < 52.8◦, measured/independent reflections: 8232/3955,
Rint = 0.009, direct methods solution, full-matrix least squares
refinement on Fo2, anisotropic displacement parameters for non-
hydrogen atoms; all hydrogen atoms located in a difference Fourier
synthesis but included at positions calculated from the geometry
of the molecules using the riding model, with isotropic vibration
parameters. R1 = 0.030 for 3698 data with Fo > 4s(Fo), 272
130.3 (2CH), 133.3 (Ph Cq), 135.0 (Ph Cq), 136.4 (Bn Cq),
+
=
=
147.5 (C N), 167.8 (C O); m/z (EI) 359.1498 (M ), C23H21NO3
requires 359.1521.
Crystal data for 4
parameters, wR2 = 0.077 (all data), GoF = 1.06, Drmin,max
=
-3
˚
-0.17/0.13 e A . CCDC 739742.
C23H21NO3, M = 359.4, orthorhombic, a = 9.729(2), b =
3
˚
˚
10.168(2), c = 18.965(4) A, U = 1876.1(7) A , T = 150(2) K,
NMR lineshape analysis. Exchange mediated low temperature
1
˚
Mo-Ka radiation, l = 0.71073 A, space group P212121 (no. 19),
500 MHz H NMR spectra of the ortho-proton signals in the
Z = 4, F(000) = 760, Dx = 1.272 g cm-3, m = 0.084 mm-1, Bruker
phenyl ring cis to the N-phenethyl group at (or 10◦ below
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in the case of 2) the coalescence temperature in CD2Cl2 were
analysed using the lineshape fitting programme INMR.23 The
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overlap from other aromatic signals only the upfield section of
the coalescing signal was analysed, but this was sufficient to
afford a reasonably accurate rate constant ( 10%). The probe
temperature at coalescence was calibrated using an external digital
thermocouple with a fine copper-constantan lead inserted into the
sample tube following acquisition of the spectra.
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Acknowledgements
We thank Mr. Richard Murphy, Queen’s University for assistance
with the low temperature and 2D NMR experiments.
13 B. W. Gung, X. Xue and H. J. Reich, J. Org. Chem., 2005, 70, 3641–
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21 The ring current shielding was determined from the tabular data given
in J. W. Emsley, J. Feeney, and L. H. Sutcliffe, Nuclear Magnetic
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5162 | Org. Biomol. Chem., 2009, 7, 5156–5162
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©