Stacked naphthyls and weak hydrogen-bond interactions govern the conformational behavior of p -resolved cyclic phosphonamides: A combined experimental and computational study

Article abstract of DOI:10.1021/jo502094g

P-Enantiomerically pure cyclic phosphonamides have been synthesized via a cyclization reaction of (S,S)-aminobenzylnaphthols with chloromethylphosphonic dichloride. The reaction is highly stereoselective and gives almost exclusively (S,S,S_P)-cyclic phosphonamides in good yields. Analysis of the X-ray crystal structures shows clearly that the cyclization reaction forces the two naphthyl rings into a stable parallel displaced stacking assembly and indicates also the existence of intramolecular CH···π interactions and weak forms of intermolecular hydrogen bondings, involving the oxygen and the chlorine atoms. QM computations and NMR spectra in solution confirm the stacked molecular assembly as the preferred arrangement of the two naphthyl groups.

Full text of DOI:10.1021/jo502094g

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Article
Stacked naphthyls and weak hydrogen bond interactions
govern the conformational behavior of P-resolved cyclic
phosphonamides: a combined experimental and computational study
Maria Annunziata M Capozzi, Francesco Capitelli, Andrea Bottoni, Matteo Calvaresi, and Cosimo Cardellicchio
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502094g • Publication Date (Web): 23 Oct 2014
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Stacked naphthyls and weak hydrogen bond interactions govern the
conformational behavior of P-resolved cyclic phosphonamides: a
combined experimental and computational study
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Maria Annunziata M. Capozzi,§ Francesco Capitelli,‡ Andrea Bottoni, † Matteo Calvaresi, † Cosimo
Cardellicchio.* ||
(
§
) Dipartimento di Chimica, Università di Bari, via Orabona 4, Bari, Italy.
(‡) CNR IC, via Salaria, Km 29.300, Monterotondo (Rome), Italy.
) Dipartimento di Chimica G. Ciamician, via Selmi 2, Università di Bologna, Bologna, Italy
(
†
(||) CNR ICCOM, Dipartimento di Chimica, Università di Bari, via Orabona 4, 70125 Bari, Italy.
Corresponding author eꢀmail address: cardellicchio@ba.iccom.cnr.it
Abstract
Pꢀenantiomerically pure cyclic phosphonamides have been synthesized via a cyclisation reaction of
(S, S)ꢀaminobenzylnaphthols with chloromethylphosphonic dichloride. The reaction is highly
stereoselective and gives almost exclusively (S, S, SP)ꢀcyclic phosphonamides in good yields.
Analysis of the Xꢀray crystal structures shows clearly that the cyclisation reaction forces the two
naphthyl rings into a stable parallel displaced stacking assembly and indicates also the existence of
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intraꢀmolecular CH…π interactions and weak forms of interꢀmolecular hydrogen bondings,
involving the oxygen and the chlorine atoms. QM computations and NMR spectra in solution
confirm the stacked molecular assembly as the preferred arrangement of the two naphthyl groups.
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Introduction
Organic derivatives of phosphonic acid have been commonly employed in organic synthesis.1ꢀ3 The
practical utility of these compounds can be ascribed to the capacity of the phosphonyl moiety to
stabilize carbanions and to the degree of asymmetric induction produced by the phosphorus
stereogenic center.1ꢀ3
Moreover, since the phosphonyl group represents an isostere of the carbonyl group, many
applications of these molecules to medicinal chemistry have been described in literature.4 One
interesting example is provided by αꢀaminophosphonic acids: these phosphonic compounds are the
isosteric analogues of αꢀaminoacids and can influence a considerable number of physiologic and
pathologic processes by inhibiting some specific enzymes.5ꢀ6
A particularly interesting class of phosphorus bioactive molecules is represented by the cyclic
phosphonamides, which are sixꢀmember rings characterized by the NꢀP(O)ꢀO scaffold. Some of
them were reported to be active against various disease states, such as the hepatitisꢀB virus.7 The
most representative member of this class is “cyclophosphamide”, one of the best known anticancer
chemotherapeutic agents.8 Its mechanism of action is related to the in vivo production of a powerful
anticancer nitrogen mustard. Thanks to its proven biological activity, “cyclophosphamide” is linked
to a long list of structurally similar prodrugs8ꢀ9 and has inspired many investigations,8 as to its
mechanism of action.
It is worth noting that, in addition to “cyclophosphamide”, other cyclic phosphonamides exhibit a
marked anticancer action. This action is related to the ability of these compounds to inhibit Matrix
Metalloproteinase (MMP). It is known that the uncontrolled expression and activity of MMPs is
responsible for a number of diseases among them tumor growth and metastasis.10 In particular,
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cyclic aryl phosphonamides have been shown to have increased citoxicity, because the electron
poor aryl ring favors the proꢀdrug cleavage and the formation of an active mustard.11
Considering the interest shown in these compounds as bioactive molecules, therapeutic agents, and
their potential synthetic applications, the present work examines the possibility for synthesis of new
Pꢀchiral cyclic phosphonamides.
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The synthesis of Pꢀchiral intermediates12 is generally associated with a multiꢀstep process. First,
diastereomeric phosphorus intermediates must be prepared with the aid of a chiral auxiliary; then,
the separation of the resulting epimers with different chirality at the phosphorus center must be
carried out. Finally, stereoꢀcontrolled reaction steps complete the synthetic procedure leading to the
target Pꢀresolved product. In the previous work on this topic, natural menthol was used as a chiral
auxiliary to synthesize Pꢀchiral phospine oxides13 or sulfinylmethylphosphonates.14
In the course of our research on asymmetric synthesis, the Betti reaction was reꢀdiscovered.15ꢀ16
Since then, this procedure has been applied by others17 for the synthesis of new
aminobenzylnaphthols, that were employed as chiral auxiliaries.
Using the Betti procedure for the synthesis of (S, S)ꢀaminobenzylnaphthols,18 it was decided to
investigate the possibility of producing cyclic phosphonamides, with formation of a novel
stereogenic center at the phosphorus atom, by reacting these aminobenzylnaphthols with a
phosphonic dichloride. Herein, we report the results of this ringꢀclosing reaction, which
demonstrated an unexpected high stereoꢀselection towards the (S, S, SP)ꢀepimers. The synthetic
work was accompanied by a structural analysis of the crystals of these compounds and by a detailed
conformational study based on Density Functional Theory (DFT) computations.
Results and discussion
1. Chiral auxiliaries via Betti reaction: synthesis of aminobenzylnaphthols
Aminobenzylnaphthols 1aꢀ4a18 were obtained after reaction of 2ꢀnaphthol, (S)ꢀ1ꢀ
naphthylethylamine and benzaldehyde (1a) or 4ꢀhalobenzaldehyde (2aꢀ4a), as shown in Scheme 1.
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NH2
CHO
X
OH
60 °C
+
+
NH
OH
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X
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1aꢀ4a
X= H, F, Cl, Br
Scheme 1. The Betti reaction; X = H (1a); X = F (2a); X = Cl (3a); X = Br (4a)
This multicomponent but straightforward condensation, performed without solvent, led exclusively
to formation of the (
S, S)ꢀaminobenzylnaphthols in satisfactory isolated yields (51ꢀ68%). Only a
simple crystallization of the crude reaction mixture was carried out.18 Convergence of the Betti
reaction towards the (
S, S)ꢀ or (R, R)ꢀstereoisomers was explained by Palmieri et al by invoking the
preferential crystallization of these diastereoisomers in the reaction mixture.19 Investigation of the
crystal structures of (
S, S)ꢀaminobenzylnaphthol highlighted many shortꢀdistance interactions
involving the aryl groups.18 These interactions can be reasonably assumed to be one of the keyꢀ
factors that contribute to the crystal stability of the (
S, S)ꢀstereoisomers, and thus to high stereoꢀ
selection of the Betti reaction towards these stereoisomers.18
2. Synthesis of (
S, S, SP)-cyclic phosphonamides
Cyclic phosphonamides 1bꢀ4b were obtained via the ring closing reaction of (
S, S)ꢀ
aminobenzylnaphthols 1aꢀ4a with chloromethylphosphonic dichloride (Scheme 2). This phosphonic
dichloride was selected as the electrophilic reactant just like the procedure described in the work
carried out by Sisti et al.20 Hanessian et al21ꢀ22 and Lopez et al 23
,
in which potential precursors of
antiviral agents were prepared.
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X
X
*
*
O
N
NH
ClCH2P(O)Cl2
*
*
P
*
CH2Cl
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PyH, Toluene
OH
O
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1a-4a
1b-4b
X=H, F, Cl, Br
Scheme 2. Ring closing reaction of aminobenzylnaphthols 1aꢀ4a using chloromethylphosphonic dichloride.
After a preliminary screening of the reaction conditions, cyclized products were obtained using
toluene as a reaction solvent in the presence of pyridine (Scheme 2). Under these conditions, the
reaction led to good isolated yields (73ꢀ91%, see Experimental Section) of the valuable (
cyclic phosphonamides 1bꢀ3b. The only exception was the reaction affording cyclic
phosphonamide 4b (50% yield). No trace of the ( p)ꢀepimers of cyclic phosphonamides 1b-2b
was detected for the reaction starting from 1a-2a. Small amounts (<5%) of side products having
NMR spectra compatible with the structure of the ( Rp)ꢀepimers of cyclic phosphonamides 3bꢀ
S, S, Sp)ꢀ
S, S, R
S, S,
4b were observed, and they were easily separated from the main reaction product. Investigations
associated with these products were not carried out at this time, even if some considerations about
them are developed later.
In conclusion, with the use of the ringꢀclosing reaction described above, the difficult task was
achieved of obtaining in a single step and in good yields cyclic phosphonamides with three resolved
stereogenic centers including the just formed
absence (or with negligible levels) of different
P
ꢀstereogenic centre. This result was obtained in the
Pꢀepimers.
As a result of the high stereoꢀselection of the cyclisation reaction towards the (S, S, Sp)ꢀcyclic
phosphonamides, we decided to investigate the crystal structures of the synthesized intermediates
1b-4b to identify specific interactions (solid phase) that might be responsible for the observed
stereochemical outcome.
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3. Crystal structures of (S, S, SP)-cyclic phosphonamides: intra- and inter-molecular
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interactions.
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We found that crystals of cyclic phosphonamides 1bꢀ4b were suitable for Xꢀray diffraction analysis
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and could establish the configuration of these stereocenters in the cyclic phosphonamide products is
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(S, S, SP). The crystal structures of 1b, 3b and 4b are orthorhombic (space group is P212121) and a
single molecule is hosted in the asymmetric unity. Two molecules are hosted in the asymmetric unit
in the case of 2b (see Table S1 and Figures S1, S2, S3, S4 of the Supporting Information).
In all species, the sixꢀmember ring including oxygen, phosphorus and nitrogen atoms (CꢀCꢀCꢀOꢀPꢀ
N) dictates the central features of the entire structure. The two sp2 carbon atoms are shared with the
adjacent naphthyl group and the oxygen lies approximately in the plane of the three carbon atoms of
the cycle: the measured dihedral angles between the plane of these carbon atoms and the reference
plane of the oxygen atom (angle between the two planes CꢀCꢀC and CꢀCꢀO) are in the range 3°ꢀ5°
in all cases (1bꢀ4b). The phosphorus and nitrogen atoms force the ring into a twisted boat
conformation, which is reported elsewhere for related cyclic phosphonamides.24ꢀ25 These structural
features are evident in the prototype cyclic phosphonamide 1b depicted in Figure 1 as a
representative example.
Figure 1. Crystal structures of cyclic phosphonamides 1b
The (SP) configuration in the twisted boat conformation of the cyclic phosphonamide ring is
characterized by axial and equatorial positions of the phosphonic oxygen and chloromethyl group,
respectively (Figure 1).
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It is apparent that the twisted boat conformation of the sixꢀmember ring has a moderate
conformational freedom. However, two conformational motifs are of particular interest in 1b-4b.
The first one is the rotation of the 1ꢀnaphthylethyl moiety around the bond between the nitrogen and
the exocyclic carbon atom. Crystal structure analysis shows that, thanks to this conformational
freedom, the two naphthyl groups preferentially form intraꢀmolecular parallel displaced stacking
structure as shown, for example, in Figure 1.
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Even in the crystal structures where the phenyl group and the two naphtyl groups of the starting (
S,
S
)ꢀaminobenzylnaphthols 1aꢀ4a are arranged anti one from the other,18 the cyclization reaction with
chloromethylphosphonic dichloride has the effect of forcing the naphthyl moieties into a particular
stacking arrangement that promotes ꢀstacking interactions.
π
The second conformational motif is rotation of the chloromethyl group around the bond between
phosphorus and the chloromethyl carbon atom. The crystal structure analysis suggests the existence
of a CH…π interaction26ꢀ28 between one hydrogen of the methylene moiety and the phenyl group. A
schematic representation of this intraꢀmolecular interaction in 1b, chosen as a representative
example, is given in Figure 2, where 1b is just represented in a different 3ꢀD perspective with
respect to Figure 1.
Figure 2. Intraꢀmolecular CH···π interactions in cyclic phosphonamides 1b.
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The nature of CH…π interactions has been thoroughly investigated26ꢀ28 and it has become evident
that, in spite of their weakness, these interactions can play a significant role in many different fields
of research.26ꢀ28 The importance of CH…π interactions in determining the high enantioselectivity
observed in the asymmetric oxidation of aryl benzyl sulfides using hydroperoxides in the presence
of a titanium catalyst has recently described.29ꢀ31 In some recent studies, CH…π interactions were
indicated as “CH…π hydrogen bondings”, to denote them as the weakest form of the hydrogen
bonds.28
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As shown in Figure 2, one hydrogen atom of the methylene group of 1bꢀ4b points towards the
plane of the phenyl group. The distances between the methylene hydrogen atom and the phenyl
plane are in the range 2.69ꢀ2.72 Å. Geometrical parameters that characterize this interaction are
reported in the Supporting Information (Table S2 and Figure S5). The values of these parameters
are in agreement with the existence of a nonꢀnegligible interaction26ꢀ28 that should restrain the
rotation around the carbonꢀphosphorus bond, and that should provide a further energetic
stabilization to the structure. In fact, in the (S, S, RP)ꢀcyclic phosphonamides epimers, that are
characterized by equatorial and axial positions of the phosphonic oxygen and chloromethyl group
respectively, the CH…π interaction involving the methylene hydrogen atoms is not present, because
the hydrogen atoms have no proximity with phenyl or naphthyl rings. Consequently, energetic
stabilization of the structure due to CH…π interactions is missing in (
phosphonamides, and this fact might explain the stereoꢀselection of the ringꢀclosing reaction
towards the stabilized ( P)ꢀstereoisomers.
S, S, RP)ꢀcyclic
S, S, S
The crystal structures of cyclic phosphonamides 1b-4b are built up by interꢀmolecular CH…O weak
hydrogen bondings32 involving the phosphonyl oxygen atom and one naphthyl hydrogen atom of
two adjacent molecules, as shown in Figure 3. Geometrical parameters describing the most
important CꢀH…O interactions are summarized in Table 1.
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Figure 3. Interꢀmolecular CH···O short contacts in cyclic phosphonamide 1b.
Table 1. Distance (Å) and angles (°) for interꢀmolecular hydrogen bond interactions.
Entry Compound
D-X···
A
H
···
A
D
···
A
Symmetry
-x+1/2,-y,+z-1/2;
x+1/2,-y+1/2+1,-z+1
x+1/2,-y+1/2+1,-z+1
x-1/2,-y-1/2,-z+2;
∠ D-H···
160.7
A
1
2
3
4
C9ꢀH9···O2 (a)
C6ꢀH6···O2 (b)
C6ꢀH6···O2 (b)
C6ꢀH6···Cl1 (c)
2.61
2.51
2.56
2.95
3.499(5)
3.411(6)
3.459(8)
3.627(5)
1b
3b
4b
1b
162.2
161.4
130.8
The crystallographic notation corresponds to the following interactions: (a) phosphonyl oxygen atom with hydrogen
atom in position 8 of naphthyl group that is a part of cyclophosphonamide ring; (b) phosphonyl oxygen atom with
hydrogen atom in position 4 of naphthyl group that is a part of cyclophosphonamide ring; (c) chlorine atom of
chloromethyl group with hydrogen atom in position 4 of the naphthyl group that is a part of cyclophosphonamide ring.
Given the common features of the crystal structures of cyclic phosphonamides 1bꢀ4b, the presence
of the halogen atom in the paraꢀposition of the phenyl group in molecules 2bꢀ4b, resulting as a
consequence of the employment of pꢀhalobenzaldeydes in the Betti condensation reaction, affords
further minor structural differences. The main difference is that, in compound 1b, the chlorine atom
of the chloromethyl group of one molecule and one naphthyl hydrogen atom of an adjacent
molecule are involved into a CH···Cl interaction33 (Table 1, entry 4). This interaction is another
example of hydrogen bonding in which the chlorine atom behaves as an acceptor. On the other
hand, in the almost isostructural cyclic phosphonamides 3b and 4b, the chlorine atom of the
chloromethyl group interacts with the naphthyl
πꢀsystem of another molecule. This interaction can
be considered one form of the halogen bonding.34
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4. Quantum Mechanical (QM) and NMR analysis on the main conformers
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QM conformational analysis and NMR experiments have been carried out to investigate the two
above described conformational motifs and compare the behavior of cyclic phosphonamides in solid
phase and solution in which the constraints of the crystal packing disappear. In the following, we
use the labels reported in Figure 4 and 6 (and in figure S7 of the Supporting Information) to denote
the various atoms involved in the discussion.
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4.1. NMR spectra. General aspect. The 1HꢀNMR spectra (see Experimental Section and
Supporting Information, Figures S6ꢀS16) show a characteristic pattern of the alkyl hydrogen atoms
for each molecule 1bꢀ4b. The hydrogen bond to the exocyclic carbon Hb is a multiplet in the range
6.20ꢀ6.11 ppm (dq when better resolved, see compound 2b) due to the coupling of Hb with the
phosphorus atom and the hydrogen atoms of the methyl group. The hydrogen bond to the
endocyclic carbon Ha is a doublet in the range 5.61ꢀ5.53 ppm, due to the coupling with the
phosphorus atom. The methylene hydrogen atoms is a dd, due to the geminal coupling with the
other hydrogen and with the phosphorus nucleus. One of them has a chemical shift in the range
3.28ꢀ3.34 ppm. The other one moves to high field (2.61ꢀ2.69 ppm), thus producing an almost 0.7
ppm difference between these chemical shifts. This shift can be considered a clear indication that
also in solution the hydrogen atom having a high field signal is facing the phenyl group26ꢀ28 (see
Figure S7 of the Supporting Information for more details).
As previously noted, the less abundant stereoisomers (
S
,
S
,
R
P)ꢀ3b and 4b were obtained in so small
1
quantities that a complete characterization was not achieved. However, the section of the HꢀNMR
spectrum between 6.3 and 2.4 ppm was free from unrelated signals and was analyzed (see
1
Supporting Information, Figure S15, in which the HꢀNMR spectrum of (
S
,
S,
S
P)ꢀ4b and of (
S
,
S,
R
P)ꢀ4b are compared). The position of the signals related to hydrogen atoms Ha and Hb is inverted,
but the most interesting feature is that the methylene hydrogen atoms of ( P)ꢀ4b have a similar
chemical shift (3.57 and 3.34 ppm), i.e. there is no high field shift of one of them, as occurs in (
P)ꢀ4b. These similar chemical shifts can be justified on the basis of the fact that the methylene
S, S, R
S, S,
S
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group of (
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,
S
,
R
P)ꢀ4b is placed in an apical position and, thus, it cannot interact with the phenyl
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moiety, with the consequent high field shift.
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4.2 Rotation of the 1-naphthylethyl group. We have first analyzed the rotational motion of the
1ꢀnaphthylethyl group around the bond between nitrogen and the exocyclic carbon atom Cb in the
prototype molecule 1b. This motion determines the relative orientation of the two naphthyl groups
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and is described by the dihedral angle
angle. The nature of this rotation is depicted in Figure 4, as well as the diagram (top right) that
describes the optimized energy profile obtained for discrete increments of dihedral angle
φ defined by the two planes PꢀNꢀCb and NꢀCbꢀC [Pꢀ(NꢀCb)ꢀC]
φ.
Figure 4. Conformational analysis along the dihedral angle φ. Schematic representation of conformers A, B and C. C is
obtained along a different conformational coordinate describing the rotation of the phenyl group and orthogonal to φ.
Energy values are expressed in kcal molꢀ1 and distances in Ångstroms.
The QM computations indicate that, as found in solid phase, the most stable structure in solution is
Conformer A (φ = ꢀ128.3°), which favors the πꢀstacking interactions between the two naphthyl
groups. These interactions are represented in Figure 4 where we have evidenced two of the shortest
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distances between the carbon atoms of the two naphthyl groups. Recent calculations showed that
the entity of the interaction between two naphthalenes in a naphthalene dimer is 5.51 and 5.62 kcal
molꢀ1 for the crossed and graphiteꢀtype dimers, respectively.35ꢀ36 When the two naphtyl moieties in
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1b are far away and cannot interact, as found in Conformer B (minimum at
φ = 51.7° as shown in
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Figure 4), the energy becomes 6.5 kcal molꢀ1 higher than Conformer A, in agreement with the
previously reported computed values. Partial stabilization is obtained after rotation of the phenyl
ring in Conformer B to afford Conformer C, where a Tꢀshaped interaction between the phenyl and
one of the napthyl groups is established. Conformer C is not represented in the diagram of Figure 4
since it exists along a different conformational coordinate describing the rotation of the phenyl
group and orthogonal to φ
. Conformer C is 1.3 kcal molꢀ1 lower than Conformer B, but remains 5.2
kcal molꢀ1 less stable than Conformer A. On the basis of this energy difference, we obtain a
population of 99.98% for the crystallographic Conformer A versus a value of 0.02% for Conformer
C. Thus, the results of our computational investigations demonstrate that even in solution the
molecule appears to be “frozen” in a conformation in which the relative arrangement of the two
naphthyl groups is a parallelꢀdisplaced stacking structure, very similar to that found in the crystal
structure. The solvent effects (chloroform) have been taken into account in our computations using
the Polarizable Continuum Model (PCM) approach with a dielectric constant ε of 4.71 (see the final
Computational Methods section for more details).
The NMR spectra were used as a further experimental validation of the computational results. In a
3
first instance, we thought to study the rotation of the 1ꢀnaphthylethyl group by analyzing the J
coupling constants of the phosphorus nucleus with the Hb hydrogen atom (bonded to the exocyclic
carbon Cb). However, the attempt to discriminate between Conformer A and Conformer B with this
technique cannot be successful because, as previously reported, the dihedral angle
φ is –128.3° and
51.7° for A and B, respectively. Since the Karplusꢀlike behavior of this coupling constants follows a
cos2φ trend,37 it is reasonable to believe that the coupling constants will have similar values.
Analogous arguments hold also for the 3J constant between the phosphorus nucleus and two carbon
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atoms. On the other hand, the comparison between the experimental (see Experimental Section) and
calculated 1HꢀNMR chemical shifts of the two hydrogen atoms Ha (bonded to the endocyclic carbon
Ca) and Hb (bonded to the exocyclic carbon Cb) validates our hypothesis pointing to Conformer A
as the dominant structure in solution. The computed chemical shifts of Ha and Hb for conformers A
are 5.57 and 6.12 ppm, respectively, which agree very well with the corresponding experimental
values of 5.61 and 6.15 ppm (see also Figure 5). Since the agreement between computation and
experiment is poor in the case of Conformer B (the computed values are 6.01 and 5.17 ppm,
respectively), this result is again consistent with Conformer A as being the true structure present in
solution.
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Further validation is provided by NOESY NMR experiments on cyclic phosphonamide 1b. In
Conformer A, where the two naphthyl groups are constrained in a stacked structural arrangement,
Ha and Hb are far away (where the distance estimated from the crystallographic analysis is 3.37 Å
and the computed distance is 3.52 Å), while in Conformer B and C these two hydrogen atoms are
…
close together in space (i.e., the computed Ha Hb distance in Conformer B and C are 2.03 and 2.20
1
Å, respectively). As reported above, in the HꢀNMR spectrum of 1b, the signals of the two
methylene hydrogen atoms are centered at 3.28 and 2.61 ppm. The NOESY experiment clearly
confirms that Ha and Hb are not close together (see expansion of the NOESY data in Figure 5: no
cross peaks are observed between the signals at
δ 5.61 and 6.15 ). In contrast, the experiment states
the expected proximity of the two chloromethyl hydrogen atoms (interaction between the signals at
3.28 and 2.61 ppm).
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Figure 5. NOESY experiment for molecule 1b. Only the signals at δ 3.28 and 2.61 ppm (geminal methylene
protons) exhibit close spacial proximity.
4.3 Rotation of the chloromethyl group. The second conformational motif that was investigated is
rotation of the chloromethyl group around the bond connecting phosphorus and the chloromethyl
carbon atom C’. This rotation is described by the dihedral angle
ψ defined by the two planes ClꢀC’ꢀ
P and C’ꢀPꢀN (dihedral angle [Clꢀ(C’ꢀP)ꢀN]) and illustrated in Figure 6. In the same figure we have
reported the energy profile obtained in an optimized scan using angle
(diagram in the top right part).
ψ as rotational coordinate
The potential surface exhibits the presence of three conformational minima: previously discussed
Conformation A and two additional conformations A1 and A2. Conformation A and A1 are
characterized by CH…π interactions between one of the two methylene hydrogen atoms and the
π
system of the phenyl group (see Figure 4 and 6). The strength of these interactions, which are
consistent with the crystal structure, is approximately equivalent in A and A1, as suggested by the
shortest distances (reported in the figures) between one methylene hydrogen and the phenyl carbon
atoms (2.67 and 2.73 Å in A and 2.66 and 2.81 Å in A1). The presence in A of two interactions
between the methylene hydrogen atoms and the endocyclic oxygen (CH…O distance = 2.75 and
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2.81 Å) and that involving one methylene hydrogen with the exocyclic oxygen (CH…O distance =
2.98 Å) suggest that the gauche arrangement (torsional angle is 61.7°) of the chlorine atom with the
exocyclic oxygen can be considered as a generalized anomeric effect,38ꢀ39 which stabilizes A with
respect to A1. In conformer A2 the CH…π interactions disappear and the chlorine atom is now
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facing the benzene
π system (see Figure 5), thus increasing the energy of the system.
Figure 6. Conformational analysis along the dihedral angle ψ. Schematic representation of conformers A1 and A2.
Energy values are expressed in kcal molꢀ1 and distances in Ångstroms.
The structure of the most stable conformer obtained from the computational results on the isolated
molecule (i.e. Conformer A) does not correspond to the crystallographic structure. This structure
appears to match Conformer A1 of Figure 6, which is approximately 2.0 kcal molꢀ1 higher in energy
than Conformer A. Even if A and A1 are both characterized by a stabilizing CꢀH…π interaction
(involving a proꢀ(R) and proꢀ(S) hydrogen of the chloromethyl moiety and the phenyl group,
respectively), the solid phase Conformer A1 is favored by intermolecular interaction involving the
chlorine atom of one molecule and a naphthyl CꢀH bond of an adjacent molecule (see previous
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section and data reported in Table 1). This interaction is however lost in solution. Also, rotation
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around the PꢀC’ bond (in the transformation A1
ꢀ A) activates a hydrogen interaction involving the
chlorine atom and one hydrogen atom of the methyl group (CꢀH…Cl distance = 3.00 Å, see Figure
4),33 which further stabilizes A with respect to A1.
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An energy difference of about 2.0 kcal molꢀ1 between A and A1 gives for the former structure a
population of 96.7%, which indicates that in solution the molecule practically exists in a unique
molecular conformation (since the low conformational barriers can be easily overcome at room
temperature, this group is free to rotate and the molecule spends the major part of its time in
conformation A).
The chemical shifts of the two chloromethyl hydrogen atoms computed for the most stable
conformer A (3.47 and 1.80 ppm) can be considered consistent with the experimentally observed
values (3.28 and 2.61 ppm respectively, as previously reported). This result enforces the hypothesis
that conformer A represents the structure present in solution.
To conclude, the previously discussed stabilising interactions involving either the two naphthyl
rings or the chloromethyl group and the oxygen atoms (and, additionally, the interꢀmolecular
CꢀH…Cl hydrogenꢀbond) seem to be a keyꢀfactor in determining the stability of specific structures
found in solid phase.
Conclusions
In the present work, we have described high stereoselective cyclisation of aminobenzylnaphthols
with chloromethylphosphonic dichloride which yields almost exclusively aryl (S, S, SP)ꢀcyclic
phosphonamides. These molecules are valuable intermediates with potential applications in
asymmetric synthesis and medicinal chemistry. The Xꢀray diffraction analysis shows that the solid
phase structures of these intermediates are characterized by a twisted boat conformation of the CꢀCꢀ
CꢀOꢀPꢀN ring and an arrangement of the two naphthyl moieties, which represents a departure from
the conformation of the starting materials to form parallel displaced stacking assemblies. This
arrangement activates intraꢀmolecular stabilizing
π stacking interactions between the two aryl π
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systems. Analysis of the solid state structures also suggest the existence of stabilizing CH…π
interaction between one hydrogen of the chloromethyl group and a phenyl ring.
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The QM computations and the NMR analysis confirm that, even in solution, the most stable
structure is consistent with a parallelꢀdisplaced stacking arrangement of the two naphthyl groups,
which is similar to that found in solid state (Conformer A). In contrast, the most favored
conformation of the chloromethyl group present in solution does not match that of the
crystallographic structure that corresponds to conformer A1. This is due to an absence in solution of
specific interꢀmolecular interactions which are present only in the solid state.
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The results further indicate that the previously discussed stabilizing interactions involving either the
two naphthyl rings or the chloromethyl group and, additionally, the interꢀmolecular hydrogenꢀbonds
are responsible for the stability of specific structures found in solid phase. Also, it is reasonable to
extrapolate that these stabilizing effects could have been responsible for the high stereoꢀselection
observed in this reaction.
Experimental Section.
Chemicals were used as received. Elemental analyses were performed on a CHNSꢀO
1
Elemental Analyzer. NMR spectra were recorded on a Hꢀ500 MHz spectrometer. Only the
absolute value of each coupling constant was reported. HMBC and HSQC experiments were
employed for the attribution of the resonances. NOESY experiment of cyclic phosphonamide
1b was performed on an accurately degassed sample, with a mixing time optimized for the
alkyl hydrogen nuclei.
Materials
Aminobenzylnaphthols 1aꢀ4a were synthesized according to methods previously reported.18
Cyclic phosphonamides 1bꢀ4b were obtained from starting materials 1aꢀ4a with the following
procedure. A solution of chloromethylphosphonic dichloride (1 mmol) and pyridine (2 mmol),
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in 3 mL of toluene was cooled to 0°C. Then, a solution of aminobenzylnaphthols 1aꢀ4a (1.1
mmol) in 12 mL of toluene was slowly added with stirring. After 30 minutes stirring, the
reaction was allowed to reach room temperature and was stirred overnight. The mixture was
quenched with a solution of HCl 1 N, and extracted three times with ethyl acetate. The
organic phase was washed with water and dried (Na2SO4). The crude reaction mixture was
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separated with column chromatography (silica gel, eluent
further purified by crystallization.
nꢀhexane/ethyl acetate 7:3) and
(S
P)-2-Chloromethyl-3-((
S
)-1-naphthalen-1-yl-ethyl)-((
S)-4-phenyl)-3,4-dihydro-1-oxa-3-
aza-2-phospha-phenanthrene 2-oxide (1b).
25
Isolated yield: 0.365 g (73%). Mp 183ꢀ184°C (from
n
ꢀhexane/ethyl acetate 9:1). [α]D = +
349.1 (c=0.8 in CHCl3). Anal. Calcd for C30H25ClNO2P: C 72.36; H 5.06; N 2.81. Found C
72.16; H 4.82; N 3.11. 1HꢀNMR (500 MHz, CDCl3,)
δH 8.19ꢀ8.12 (1H, m), 7.84ꢀ7.76 (1H, m),
7.50ꢀ7.42 (3H, m), 7.41ꢀ7.36 (1H, m), 7.32ꢀ7.24 (3H, m), 7.20ꢀ7.08 (5H, m), 6.99ꢀ6.94 (1H,
m), 6.91ꢀ6.83 (2H, m), 6.44ꢀ6.39 (1H, m), 6.20ꢀ6.11 (1H, m), 5.61 (1H, d, = 25.6 Hz), 3.28
= 13.6 Hz), 2.20 (3H, d, = 6.9
= 9.7 Hz), 138.8, 133.9 (d, = 3.5 Hz),
= 1.4 Hz), 128.8, 128.2, 127.8, 127.7, 127.1,
J
(1H, dd,
J
= 11.6 Hz,
J
= 13.6 Hz), 2.61 (1H, dd,
J
= 8.9 Hz,
J
J
Hz). 13CꢀNMR (125 MHz, CDCl3) δC 147.4 (d,
J
J
133.2, 131.4, 129.7, 129.6, 129.4, 129.3 (d,
126.4, 125.7, 125.6, 125.2, 124.4, 124.2, 124.1 (d,
Hz), 53.7 (d, = 2.1 Hz), 51.8 (d, = 4.2 Hz), 36.8 (d,
NMR (202 MHz, CDCl3) P 23.5.
P)-2-Chloromethyl-(( )-4-(4-fluorophenyl))-3-((S)-1-naphthalen-1-yl-ethyl)-3,4-
J
J
= 8.8 Hz), 123.1, 121.3, 118.7 (d,
J = 4.2
J
J
J = 154.7 Hz), 22.1 (d, J
= 2.1 Hz). 31Pꢀ
δ
(S
S
dihydro-1-oxa-3-aza-2-phospha-phenanthrene 2-oxide (2b).
ꢀhexane/acetone 1:1). [α]D25 = +322.9 (
c=
Isolated yield: 0.47 g (91%). Mp 191ꢀ193°C (from
n
0.7, CHCl3). Anal. Calcd for C30H24ClFNO2P: C 69.84; H 4.69; N 2.71. Found C 69.61; H
1
4.57; N 3.00. HꢀNMR (CDCl3, 500 MHz) δH 8.16ꢀ8.12 (1H, m), 7.81ꢀ7.76 (1H, m), 7.50ꢀ
7.43 (3H, m), 7.41ꢀ7.36 (1H, m), 7.21ꢀ7.15 (1H, m), 7.14ꢀ7.07 (4H, m), 7.00ꢀ6.93 (3H, m),
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6.92ꢀ6.84 (2H, m), 6.41ꢀ6.36 (1H, m), 6.14 (1H, dq,
J = 9.5 Hz, J = 6.9 Hz), 5.57 (1H, d, J
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5
6
7
8
=25.5 Hz), 3.32 (1H, dd,
J
= 11.7 Hz,
J
= 13.6 Hz), 2.63 (1H, dd,
J
J
= 8.9 Hz,
J = 13.6 Hz),
2.18 (3H, d,
J
= 6.9 Hz). 13CꢀNMR (CDCl3, 125 MHz)
δC 162.4 (d,
= 248 Hz), 147.3 (d,
J
J
=
=
9
9.0 Hz), 134.7 (d,
7.6 Hz), 129.4, 129.1 (d,
123.9 (d, = 9.0 Hz), 123.0, 121.1, 118.7 (d,
2.8 Hz), 51.9 (d, = 4.2 Hz), 36.8 (d,
CDCl3) P 23.2.
P)-2-Chloromethyl-((
dihydro-1-oxa-3-aza-2-phospha-phenanthrene 2-oxide (3b).
Isolated yield: 0.405 g (76%). Mp 215ꢀ216 °C (from ꢀhexane/ethyl acetate 1:1). [α]D = +
J = 3.5 Hz), 133.7 (d, J = 2.8 Hz), 133.2, 131.3, 129.7, 129.6, 129.5 (d,
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J
= 1.4 Hz), 127.8, 127.1, 126.6, 125.7, 125.6, 125.3, 124.5, 124.2,
J
J
= 4.2 Hz), 115.7 (d,
J = 21.5 Hz), 53.1 (d, J =
J
J = 154.7 Hz), 22.1 (d, J
= 2.8 Hz). 31PꢀNMR (202 MHz,
δ
(S
S)-4-(4-chlorophenyl))-3-((S)-1-naphthalen-1-yl-ethyl)-3,4-
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n
332.5 (c=0.7, CHCl3). Anal. Calcd for C30H24Cl2NO2P: C 67.68; H 4.54; N 2.63. Found C
67.77; H 4.42; N 2.93. 1HꢀNMR (500 MHz, CDCl3)
δH 8.15ꢀ8.11 (1H, m), 7.80ꢀ7.76 (1H, m),
7.50ꢀ7.43 (3H, m), 7.41ꢀ7.36 (1H, m), 7.28ꢀ7.21 (2H, m), 7.20ꢀ7.16 (1H, m), 7.14ꢀ7.04 (4H,
m), 6.99ꢀ6.95 (1H, m), 6.90ꢀ6.83 (2H, m), 6.39ꢀ6.35 (1H, m), 6.17ꢀ6.11 (1H, m), 5.56 (1H, d,
J
= 25.4 Hz), 3.34 (1H, dd,
J = 11.6 Hz, J = 13.6 Hz), 2.68 (1H, dd, J = 8.6 Hz, J = 13.6 Hz),
2.18 (3H d,
J
= 6.8 Hz). 13CꢀNMR (CDCl3, 125 MHz)
δC 147.3 (d,
J
= 9.0 Hz), 137.6, 134.2,
133.7 (d,
127.9, 127.2, 126.6, 125.8, 125.6, 125.3, 124.6, 124.3, 123.7 (d,
J = 3.5 Hz), 133.3, 131.4, 129.8, 129.7, 129.3, 129.2 (d, J = 1.4 Hz), 129.1, 129.0,
J
= 9.0 Hz), 123.1, 121.0,
118.7 (d,
= 2.8 Hz). 31PꢀNMR (202 MHz, CDCl3)
P)ꢀ3b has an [α]D25 = + 187 (
J
= 4.6 Hz), 53.2 (d,
J
=2.1 Hz), 52.0 (d,
J
= 4.2 Hz), 36.9 (d, = 155.4 Hz), 22.1 (d,
J
J
δP 22.8.
A small sample of (
S
,
S,
R
c
=0.06, CHCl3).
)-1-naphthalen-1-yl-ethyl)-3,4-
dihydro-1-oxa-3-aza-2-phospha-phenanthrene 2-oxide (4b).
Isolated yield: 0.29 g (50)%. Mp 209ꢀ211 °C (from ꢀhexane/ethyl acetate 2:1). [α]D = +
δP 18.0.
(SP)-2-Chloromethyl-((S)-4-(4-bromophenyl))-3-((S
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308.7 (
c
=1.0, CHCl3). Anal. Calcd for C30H24BrClNO2P: C 62.46; H 4.19; N 2.43. Found C
4
5
6
7
8
9
62.57; H 4.29; N 2.23. 1HꢀNMR (500 MHz, CDCl3)
7.50ꢀ7.44 (3H, m), 7.42ꢀ7.37 (3H, m), 7.21ꢀ7.16 (1H, m), 7.14ꢀ7.09 (2H, m), 7.02ꢀ6.95 (3H,
m), 6.91ꢀ6.84 (2H, m), 6.38ꢀ6.35 (1H, m), 6.17ꢀ6.11 (1H, m), 5.53 (1H, d, = 25.6 Hz), 3.34
= 13.6 Hz), 2.17 (3H d, = 6.9
= 9.7 Hz), 138.2, 133.7 (d, = 2.8 Hz),
δH 8.14ꢀ8.11 (1H, m), 7.80ꢀ7.76 (1H, m),
J
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(1H, dd,
J
= 11.6 Hz,
J
= 13.6 Hz), 2.69 (1H, dd,
J
= 8.8 Hz,
J
J
Hz). 13CꢀNMR (CDCl3, 125 MHz) δC 147.3 (d,
J
J
133.3, 132.0, 131.4, 129.8, 129.7, 129.4, 129.2 (m), 127.9, 127.2, 126.7, 125.8, 125.7, 125.3,
124.6, 124.3, 123.7 (d,
Hz,), 52.0 (d,
CDCl3) P 22.8.
A small sample of (
X-ray experiments.
J
= 8.3 Hz), 123.1, 122.3, 121.0, 118.8 (d,
J = 4.9 Hz), 53.3 (d, J = 2.1
J
= 4.2 Hz), 36.9 (d,
J
= 155.4 Hz), 22.1 (d,
J
= 2.8 Hz). 31PꢀNMR (202 MHz,
δ
S, S, R c=0.45, CHCl3). δP 18.0.
P)ꢀ4b has an [α]D25 = + 108 (
XꢀRay data were collected at 293 K by means of single crystal Xꢀray diffractometer, with
= 0.71073 Å); data collection: COLLECT;40 cell refinement and data
MoꢀK
α radiation (λ
reduction: EvalCCD.41 Data were corrected for Lorentz and polarization effects, and for
absorption effects.42 Unit cell parameters are reported in Table S1 (Supporting Information.
The structures were solved by the direct method procedure of SIR97,43 and refined by a fullꢀ
matrixꢀleastꢀsquare technique based on F2 (SHELXLꢀ97).44 In the refinement of the crystal
structures, the hydrogen atoms were placed in idealized positions riding on their attached
atoms (C–HAr 0.93 Å, CꢀHMethyl 0.96 Å, CꢀHAlk = 0.98 Å, Uiso(H) = 1.2Uiso(C)). The nonꢀ
hydrogen atoms were refined with anisotropic thermal parameters. Data collection and
refinement are likewise reported in Table S1. The molecules are depicted in Fig. S1, S2, S3,
S4 (Supporting Information). Complete crystallographic data are available upon request from
the Cambridge Crystallographic Data Centre (12 Union Road, Cambridge, CB2 1EZ, UK;
email: deposit@ccdc.cam.ac.uk), by quoting the depository numbers CCDCꢀ1013329 (1b),
1013323 (2b), 1013325 (3b) and 1013324 (4b).
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Computational methods.
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All DFT computations reported were performed with the Gaussian 09 series of programs45 using the
M06ꢀ2X functional46 and the 6ꢀ311++G** basis set.47 The geometries of the various critical points
on the potential surface were fully optimized with the gradient method available in Gaussian 09 and
harmonic vibrational frequencies were computed to evaluate the nature of all critical points. Since
NMR experiments were carried out in deuterated chloroform, the solvent effects was taken into
account during optimization using the Polarizable Continuum Model (PCM) using the integral
equation formalism variant (IEFPCM).48 A values of 4.71 was employed for the dielectric constant
ε. NMR shielding tensors were computed with the GaugeꢀIndependent Atomic Orbital (GIAO)
method.49
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Acknowledgements.
We thank Mr Giuseppe Chita (CNR, Istituto di Cristallografia, Bari, Italy) for the Xꢀray data
collection, and Dr. Angel AlvarezꢀLarena (Universitat Autònoma de Barcelona, Spain) for
helpful discussions on the singleꢀcrystal Xꢀray structures. Thanks are due to CINMPIS
consortium and to “Phoebus” Project “Tecnologie plastiche per la realizzazione di celle solari
e sorgenti organiche per illuminazione ad elevata efficienza, uniformità e brillanza” in the
framework of the Reti di Laboratori Pubblici di Ricerca.
Supporting Information. Crystallographic data and ORTEP plot of cyclic phosphonamides
1bꢀ4b. Graphical representation and geometrical parameters of the CH…π interaction in
compound 1b. Graphical representation of the 1H and 13C NMR spectra of cyclic
phosphonamides 1bꢀ4b. This material is available free of charge via the Internet at
http://pubs.acs.org
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