N, N -Bis-(dimethylfluorosilylmethyl)amides of N -organosulfonylproline and sarcosine: Synthesis, structure, stereodynamic behaviour and in silico studies

Article abstract of DOI:10.1039/c6ra14450k

(O→Si)-Chelate difluorides R₃R₂NCH(R₁)C(O)N(CH₂SiMe₂F)₂ (9a-c, R₁R₂ = (CH₂)₃, R₃ = Ms (a), Ts (b); R₁ = H, R₂ = Me, R₃ = Ms (c)), containing one penta- and one tetracoordinate silicon atoms were synthesized by silylmethylation of amides R₃R₂NCH(R₁)C(O)NH₂, subsequent hydrolysis of unstable intermediates R₃R₂NCH(R₁)C(O)N(CH₂SiMe₂Cl)₂ (7a-c) into 4-acyl-2,6-disilamorpholines R₃R₂NCH(R₁)C(O)N(CH₂SiMe₂O)₂ (8a-c) and the reaction of the latter compounds with BF₃·Et₂O. The structures of disilamorpholines 8a,c and difluoride 9a were confirmed by an X-ray diffraction study. According to the IR and NMR data, the O→Si coordination in solutions of these compounds was weaker than that in the solid state due to effective solvation of the Si-F bond. A permutational isomerisation involving an exchange of equatorial Me groups at the pentacoordinate Si atom in complexes 9a-c was detected, and its activational parameters were determined by ¹H DNMR. In silico estimation of possible pharmacological effects and acute rat toxicity by PASS Online and GUSAR Online services showed a potential for their further pharmacological study.

Full text of DOI:10.1039/c6ra14450k

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N,N-Bis-(dimethylfluorosilylmethyl)amides of N-
organosulfonylproline and sarcosine: synthesis,
Cite this: RSC Adv., 2016, 6, 75315
structure, stereodynamic behaviour and in silico
studies†
a
Alexey A. Nikolin, Eugenia P. Kramarova,a Alexander G. Shipov,a Yuri I. Baukov,a
*
Vadim V. Negrebetsky,a Dmitry E. Arkhipov,b Alexander A. Korlyukov,b
Alexey A. Lagunin,cd Sergey Yu. Bylikin,e Alan R. Bassindalee and Peter G. Taylore
(O/Si)-Chelate difluorides R3R2NCH(R1)C(O)N(CH2SiMe2F)2 (9a–c, R1R2 ¼ (CH2)3, R3 ¼ Ms (a), Ts (b); R1 ¼
H, R2 ¼ Me, R3 ¼ Ms (c)), containing one penta- and one tetracoordinate silicon atoms were synthesized by
silylmethylation of amides R3R2NCH(R1)C(O)NH2, subsequent hydrolysis of unstable intermediates
R3R2NCH(R1)C(O)N(CH2SiMe2Cl)2
(7a–c)
into
4-acyl-2,6-disilamorpholines
R3R2NCH(R1)C(O)
N(CH2SiMe2O)2 (8a–c) and the reaction of the latter compounds with BF3$Et2O. The structures of
disilamorpholines 8a,c and difluoride 9a were confirmed by an X-ray diffraction study. According to the
IR and NMR data, the O/Si coordination in solutions of these compounds was weaker than that in the
solid state due to effective solvation of the Si–F bond. A permutational isomerisation involving an
exchange of equatorial Me groups at the pentacoordinate Si atom in complexes 9a–c was detected, and
its activational parameters were determined by 1H DNMR. In silico estimation of possible
pharmacological effects and acute rat toxicity by PASS Online and GUSAR Online services showed
a potential for their further pharmacological study.
Received 3rd June 2016
Accepted 22nd July 2016
DOI: 10.1039/c6ra14450k
www.rsc.org/advances
molecule remain virtually unknown. Among these compounds
are N,N-bis(dimethylhalogenosilylmethyl)amides, where two
Introduction
silicon centres compete for a single carbonyl group. One of the
Si atoms in these amides extends its coordination number to
ve and forms an (O/Si)-chelate ring while another Si atom
remains tetracoordinate. Up to date, very few examples of such
compounds have been reported,6 with the structures of only
four complexes (1,6b 2,6b 3 (ref. 6e) and 4 (ref. 6e)) determined by
X-ray method.
Since each of the two silicon atoms in dihalides 1–4 can
potentially form a coordination bond with the carbonyl group,
these compounds are particularly interesting as models for
studying stereodynamic processes in solutions (such as alter-
nating coordination or permutational isomerisation), pathways
of SN2–Si reactions, relative contributions of the silicon centres
to O/Si coordination and the effects of such coordination on
the reactivity of SiIVMe2Hal and SiVMe2Hal groups within
a single molecule.
Hypercoordinate silicon compounds are the focus of intense
research due to the diversity of their structures, chemical
properties,1 stereodynamic behaviour2 and practical use in
stereoselective synthesis3 and medical diagnostics.4 In recent
years a large number of new types of pentacoordinate silicon
compounds have been synthesized, including complexes with
ve different atoms in the silicon environment, compounds
with SiO5, SiS2N2C, SiS2O2C, SiN4X (X ¼ S, Se, Te) skeletons and
others.5
At the same time, certain classes of organosilanes containing
both penta- and tetracoordinate silicon atoms in the same
aDepartment of Chemistry, N.I. Pirogov Russian National Research Medical University,
Ostrovityanov St. 1, Moscow 117997, Russian Federation. E-mail: nikson1111@yahoo.
com
bA. N. Nesmeyanov's Institute of Organoelement Compounds, RAS, Vavilova St. 28,
119991 Moscow, Russian Federation
Earlier we described (O/Si)-monochelate uorosilanes RSO2-
Pro-N(Me)CH2SiMe2F (5), containing an electron-withdrawing
organosulfonyl group at the nitrogen atom of the amino acid
fragment.7 In the present work, we report the synthesis, structures
and stereodynamic behaviour of dinuclear uorosilyl derivatives
of proline and sarcosine R3R2NCH(R1)C(O)N(CH2SiMe2F)2 (9),
synthesised by bis-silylmethylation of N-organosulfonyl-(S)-proline
cDepartment of Bioinformatics, N.I. Pirogov Russian National Research Medical
University, Ostrovityanov St. 1, Moscow 117997, Russian Federation
dInstitute of Biomedical Chemistry, Pogodinskaya Str., 10/8, Moscow, 119121, Russian
Federation
eDepartment of Chemistry, Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
† Electronic supplementary information (ESI) available. CCDC 1059570–1059573.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ra14450k
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and N-mesylsarcosine amides R3R2NCH(R1)C(O)NH2 (6) via 7a, which was typical O/Si chelates of pentacoordinate sili-
unstable dichlorides R3R2NCH(R1)C(O)N(CH2SiMe2Cl)2 (7) and con.6b,9 IR spectra of all 4-acyl-2,6-disilamorpholines 8a–c
isolable N-substituted 2,6-disilamorpholines R3R2NCH(R1)C(O) showed a strong absorption of the NCO fragment at 1630 cmꢀ1
N(CH2SiMe2O)2 (8).
.
In the 1H NMR spectra of chiral proline derivatives 8a,b, the
signals of two SiMe2 groups appear as four singlets.
The 29Si NMR spectra of disilamorpholines 8a–c in solutions
contain two signals at approximately 8 and 10 ppm, which are
almost independent of the amino acid or N-substituent nature.
The same chemical shis of 29Si are observed in the solid-state
CP/MAS spectra of these compounds (see Experimental
section). Therefore, the solvation of tetracoordinate silicon
atoms has no noticeable effect on their chemical shis.
The above data suggest that both silicon atoms in
compounds 8a–c are tetracoordinate.6c Similar to the double set
Discussion of the results
Synthesis of disilamorpholines
Disilamorpholines 8 were prepared by the general synthetic
approach developed by us for various silacyclanes.6d,e,8 The
starting compounds, primary amides 6, were silylmethylated by
a mixture of chloro(chloromethyl)dimethylsilane and hexame-
thyldisilazane with subsequent hydrolysis of unstable dichlor-
ides 7 into target 4-acyl-2,6-disilamorpholines 8 (Scheme 1).
Mesyl and tosyl derivatives of (S)-proline, Ms-Pro-N(CH2-
SiMe2)2O (8a) and Ts-Pro-N(CH2SiMe2)2O (8b), and mesyl
derivative of sarcosine, MsN(Me)CH2C(O)N(CH2SiMe2)2O (8c),
were obtained by one-pot syntheses with yields of 75, 78 and
80%, respectively. The composition and structures of
1
of signals of SiMe2 groups in H NMR spectra, the presence of
two signals in 29Si NMR spectra of these compounds is probably
caused by the hindered amide rotation.
Synthesis of diuorides
compounds 8 were conrmed by the elemental analysis, IR and In contrast to hydrolytically labile Si–Cl bonds in pentacoordi-
multinuclear (1H, 13C, 29Si and CP/MAS 29Si) NMR spectroscopy. nate dichlorides 7a–c, the Si–F bonds in their diuoro
The structures of compounds 8a and 8c were also determined by analogues 9a–c were expected to be more stable. (O/Si)-
X-ray method (see below).
The formation of hydrolytically unstable dichloride 7a was (S)-prolinamides
Chelate N0,N0-bis(dimethyluorosilylmethyl)-N-organosulfonyl-
(9a,b) and
N0,N0-bis(dimethyl-
detected by IR spectroscopy. When a mixture of amide 6a with uorosilylmethyl)-N-mesylsarcosinamide (9c) were prepared by
three equivalents of ClCH2SiMe2Cl and one equivalent of the reaction of disilamorpholines 8a–c with BF3$Et2O in aceto-
(Me3Si)2NH was reuxed in benzene or toluene, the absorption nitrile (Scheme 2).
of the NCO fragment in 6a was gradually replaced by two
The composition and structure of diuorides 9a–c were
absorptions (at 1590 and 1505 cmꢀ1) of the same fragment in determined by the elemental analysis, IR and multinuclear (1H,
Scheme 1
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Scheme 2
1
13C and 29Si) NMR spectroscopy. The coordination states of
Direct spin–spin coupling constants JSiF in NMR spectra of
both silicon atoms in compound 9a in the solid state was compounds 9 for tetracoordinate silicon (230–260 Hz) were
further conrmed by X-ray single-crystal study (see below) and generally lower than those for pentacoordinate silicon (ca. 280
29Si CP/MAS NMR.
Hz; see Experimental section). Such difference, observed both in
solutions and solid state, reected the weakening of the Si–F
bond at SiV in comparison with SiIV (see X-ray data for 9a).2b,c For
Multinuclear NMR spectroscopy
3
the same reason, the spin–spin coupling constant JHF was
1H NMR spectra of diuorides 9a–c contain two signals of the
SiMe2 groups in the upeld region. These signals can be
attributed to specic SiMe2 groups using Bruker 2D pulse
sequence {1H-29Si}HMBS. For example, the cross-peaks in the
2D spectrum of 9b (Fig. 1) indicate that the upeld signal of
SiMe2 protons corresponds to the signal of pentacoordinate 29Si
at ꢀ20 ppm while the downeld signal of SiMe2 protons
corresponds to the signal of tetracoordinate 29Si at +30 ppm.2b,c
observed at ambient temperature only for the SiIVMe2 group but
not for the SiVMe2 group. Finally, the weakening of the SiV–F
2
bonds affected the JCF constants in 13C NMR spectra: the
observed spin–spin coupling frequencies at SiV centres (10–15 Hz)
were signicantly lower than those at the SiIV centres (ca. 30 Hz).
Intramolecular O/Si coordination in complexes 9 in solu-
tions was further conrmed by the down eld shi of the C]O
Fig. 1 Two-dimensional NMR spectrum of 9b (Bruker {1H-29Si}HMBS, CDCl3, 600 MHz).
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signal in their 13C NMR spectra. The characteristic patterns of and NCH2 signals in 1H NMR spectra of diuorides 9a–c. Such
SiV(CH3)2 and NCH2SiV signals in 1H NMR spectra of diuorides broadening was indicative of a permutational isomerisation at
9a,b (two singlets of equal intensity and an AB-system quartet, the SiV coordination set of these compounds.
respectively) indicated the presence of a chiral carbon atom in
their molecules.
The activation parameters of the permutation were calcu-
lated by a 1H DNMR method using a full line-shape analysis of
The 29Si signals in solid-state NMR spectra of compounds 9 the signals. For all studied compounds, the stereodynamic
had greater upeld shis (ca. ꢀ40 ppm) than the same signals processes in CDCl3 were characterised by a narrow range of
in solutions (ca. ꢀ10 ppm). Similar effect was observed for activation energies (ꢂ24 kcal molꢀ1 or greater) and high nega-
monouorides 5 and was probably caused by effective solvation tive values of the entropy of activation (ca. ꢂ ꢀ20 cal molꢀ1 Kꢀ1).
of pentacoordinate silicon.7a
These values were very similar to the activation parameters of N-
Using the difference between the observed chemical shis of (dimethyluorosilylmethyl)- and N-[uoro(methyl)(phenyl)silyl-
a SiV atom and the typical chemical shi of a SiIV atom (ca. 30 methyl]amides and -lactams,2a,12–15 as well as RSO2-Pro-N(Me)
ppm), the coordination contribution (ꢀDd ¼ dSiV ꢀ dSiIV)2a in CH2SiMe2F (5),6a where R ¼ Me, Ph, 4-MeC6H4, 4-ClC6H4, 4-
diuorides 9 can be estimated to be approximately 50 ppm. The BrC6H4 or 4-NO2C6H4.
comparison of this value to coordination contributions in
chlorosilanes RSO2-Pro-N(Me)CH2SiMe2Cl (70–75 ppm), sily-
XRD studies
loxonium halides [R-Pro-N(Me)CH2SiMe2OH2]X (R ¼ AlkSO2,
ArSO2, Ac; X ¼ Cl, Br) (70–80 ppm)10 and theoretical data for
Disilamorpholine 8a (Fig. 2) crystallizes in two polymorph
modications (8a and 8a0).
The orthorhombic (P212121) crystals 8a were obtained from
a heptane–benzene mixture with a molar ratio of 3 : 1, whereas
monouorosilanes 5 (ref. 7b) and MeC(O)N(Me)CH2SiMe2F11
(same as above) indicates a relatively weak coordination in
diuorides 9.
All diuorides have two signals in their 19F NMR spectra: one
at approximately ꢀ159 ppm and another at ꢀ119 O ꢀ125 ppm.
According to literature data, these signals belong to SiIVMe2F
and SiVMe2F groups, respectively.2b,c
1
Variable-temperature H, 19F and 29Si NMR studies
The strength of intramolecular coordination in monochelates
of pentacoordinate silicon strongly depends on the nature of
the substituent X (Scheme 3; see2c,7a and references therein).
In the case of compounds with the OSiC3X coordination set
and X ¼ Hal or OTf, structures A and B are typical for uorides,
C for chlorides, D for bromides, and E for iodides and triates.
To study the temperature effects on the coordination set
structure in diuorides 9a–c, the temperature-dependent 1H,
19F and 29Si NMR spectra of these compounds in CDCl3 were
ꢁ
obtained. The decrease in temperature from +20 to ꢀ60 C led
1
to reversible downeld shis of H and 19F signals (by ca. 0.03
and 3–4 ppm, respectively) of the SiVMe2F group. At the same
time, the chemical shi of 19F in the SiIVMe2F group was not
affected by the temperature. Such behaviour of 1H and 19F
signals suggests an increased contribution of form B (Scheme 3)
at low temperatures.
Similar to monouorosilanes,7a the increase in temperature
Fig. 2 Molecular structure of 8a with thermal ellipsoids shown at the
to +60 ꢁC caused very small reversible broadening of the SiMe2 50% probability level.
Scheme 3
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monoclinic (P21) crystals 8a0 were obtained from ethanol. There
are two crystallographically independent molecules in the
asymmetric unit of 8a; its volume is 3.84 times larger than that
3
0
0
˚
of 8a , because the cell 8a contains a void of about 40 A . The
structure of the 2,6-disilamorpholine fragment in compounds
8a, 8a0 and 8c (Fig. 3) is analogous to the previously published
ve structures (CSD refcodes:16 QOMTAN, QOMTER, XATQIT,
XULNAT, XULNEX).
The mesyl group and 2,6-disilamorpholine fragment have
syn-conformation relative to the proline ring: the corresponding
torsion angles C8–N2–S1–C12 and C20–N4–S2–C24 in 8a are
95.3(2)ꢁ and 88.8(2)ꢁ for two crystallographically independent
molecules, respectively, and the torsion angle C8–N2–S1–C12 in
8a0 is 94.7(5)ꢁ.
An asymmetric unit of diuoride 9a contains two crystallo-
graphically independent molecules, which differ by mutual
orientation of the proline moiety and Me2FSiCH2 group relative
to the chelate ring. In the case of syn-conformation, the inter-
˚
atomic distance S1/Si2 is 5.387(1) A, whereas for anti-congu-
˚
ration the distance S2/Si4 is 6.340(1) A. In 9a (Fig. 4), one of the
silicon atoms is pentacoordinated, and its coordination poly-
hedron is a distorted trigonal bipyramid (axial angles O1–Si1–F1
and O4–Si3–F3 are 172.1(1)ꢁ and 171.9(1)ꢁ, the deviations of Si1
and Si3 atoms from the planes of equatorial substituents toward
Fig. 4 Molecular structure of 9a with thermal ellipsoids shown at the
50% probability level.
˚
˚
uorine atoms are 0.167(1) A and 0.176(1) A for two crystallo-
graphically independent molecules, respectively).
boron group while the coordination with the silicon atom is very
The structures of coordination polyhedra of Si1 and Si2
atoms in 9a are noticeably different from those in the series of
˚
weak. Thus, the axial Si–O bonds are shortened by 0.07–0.17 A,
V
˚
and Si –F bonds lengthened by 0.02–0.04 A compared to similar
(O/Si)-chelate
N0-(dimethyluorosilylmethyl)-N0-methyl-N-
bonds in prolinamide derivatives and diuoride 1. The SiIV–F
(organosulfonyl)prolinamides,7a complexes 1 (ref. 6d) and 3 (ref.
6e) (selected bond lengths are given in Table 1).
˚
bonds are lengthened by 0.05–0.10 A in comparison with
similar bonds in diuorides 1 and 3. Atoms Si2 and Si4 are not
The structure of 3 differs signicantly from other diuorides
due to the coordination of amide oxygen atom with the diuoro-
coordinated by any oxygen atoms, with the shortest intermo-
˚
lecular contact Si4/O2 of 3.538(1) A.
Quantum-chemical studies of the permutational
isomerization
To test the applicability of the mechanism (Scheme 4) previ-
ously suggested for the permutational isomerisation of N-
(dimethyluorosilylmethyl)amides1
to
N,N-bis-(dimethyl-
uorosilylmethyl)amides, we carried out quantum chemical
studies of molecule 9a.
At higher temperatures, the equilibrium B # A (Schemes 3
and 4) shis towards the tetracoordinate topomer A. The
nucleophilic attack at the Si atom by a uoride anion (F*ꢀ)
produces pentacoordinate diuoride G, which subsequently
loses the Fꢀ anion and forms tetracoordinate intermediate H.
The rotation around the Si–CH2 bond produces topomer A0 and
Table 1 Selected bond lengths for structures 9a, 1, 3 and prolinamide
derivatives
9a (mean values) 1 (ref. 6d) 3 (ref. 6e) Monouorides7a
SiIV–F 1.613(1)
SiV–F
1.693(1)
Si/O 2.062(1)
1.603
1.668
2.187
1.608
1.620
2.918
—
1.651–1.671
2.131–2.220
Fig. 3 Molecular structure of 8c with thermal ellipsoids shown at the
50% probability level.
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Scheme 4
nally complex B0 with inverted orientation of the methyl 311G(d,p) basis set were utilized for structure optimization,
groups at silicon. hessian calculations, relaxed potential energy scans and tran-
According to our previous study, the external uorine anion sition state search. To account for the effect of nonspecic
can attack tetracoordinated silicon, and the dissociation energy solvation, the PCM model was applied (the value of dielectric
of resulting Si–F bond in gas phase is equal to ꢂ90 kcal molꢀ1
.
constant corresponded to chloroform). All calculations was
Solvation of the Fꢀ anion leads to signicant decrease of the Si–F performed with tight optimization criteria (Opt ¼ tight) and
dissociation energy. It is reasonable to assume that similar precise grid for computation of two-electron integrals (Int(Grid
processes can occur in solution of 9a in CDCl3. Due to the ¼ Ultrane)). Molecular graphics was drawn with ChemCra
presence of two dimethyluorosilylmethyl and one bulky tosyl program.19 General views of calculated structures, atomic
groups, the silicon atoms seems to be less accessible for nucle- coordinates and total energies can be found in ESI.†
ophilic attack as compared to N-(dimethyluorosilylmethyl)
Analysis of potential energy surface for 9a in its isolated
amides, where only one dimethyluorosilylmethyl group molecule and CDCl3 (PCM calculation) has shown that the
is present. Hence, the stereodynamic processes in solution presence of two conformational isomers correspond to the
of 9a can be more complex as compared to N-(dimethyl- cyclic structures (where the Si–O coordination bond is present)
uorosilylmethyl)amides.7a
and two other conformers belong are acyclic (Si–O coordination
An alternative mechanism can involve the carbonyl group bond is absent). According to quantum chemical calculations,
migration from one dimethyluorosilyl to another (similarly to the inuence of dielectric continuum used in PCM model leads
derivatives urea17) (Scheme 5).
to signicant changes in molecular structure of 9a. The most
In any case, the cleavage of the Si–O coordination bond and noticeable change is the decrease of Si1/O1 distance from
˚
the certain conformational changes are necessary to the transfer 2.36–2.37 to 2.25 A. Cyclic conformers are more favourable as
the carbonyl oxygen atom from one dimethyluorosilylmethyl to compared to the acyclic conformers. The difference between
another. Thus, the detailed inspection of these processes can be two isolated most stable cyclic and acyclic structures is 2.51 kcal
very useful for understanding the nature of permutational iso- molꢀ1. The use of PCM model for the description of solvation
merisation in the solution of 9a.
increases this difference to 4.37 kcal molꢀ1, which is in good
Quantum-chemical calculations of 9a were carried out using agreement with our earlier calculations.7a All cyclic conformers
Gaussian 03W program.18 Hybrid PBE0 functional and 6- can be characterized by the same geometry of coordination
Scheme 5
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polyhedra of silicon atoms, so their 19F and 29Si chemical shis this assumption was obtained by the localization of transition
should be very close. states (Fig. 11S and 12S†). The modes of negative vibrations
Other differences are related to mutual orientation of N- (ꢀ67.0 and ꢀ62.8 cmꢀ1 for isolated molecule and CDCl3 solu-
organosulfonyl and dimethyluorosilyl groups. In isolated tion, respectively) correspond to the rotation around the N1–C4
cyclic and acyclic forms of 9a, these fragments are much closer bond and formation/dissociation of Si–O coordination bonds.
to each other than in the solution. In two conformers (9a-cyclic2 The difference between energies of the most favourable cyclic
and 9a-acyclic2, Fig. 5S and 6S, see ESI†), the Si2/O2 distances conformers and transition state is 28.4 and 29.3 kcal molꢀ1 for
between one of the SiMe2F groups and the oxygen atom of the isolated molecules and solution of 9a, respectively. These values
˚
sulfonyl group are 3.698 and 3.720 A, respectively. The optimi- are in agreement with the results of DNMR study. At the same
zation of these conformers in terms of PCM model (9a-cyclic2- time, the DS value calculated as the difference between the
CDCl3 and 9a-acyclic2-CDCl3, Fig. 7S and 8S†) increases the transition state and cyclic isomer is ꢂꢀ2 kcal molꢀ1 Kꢀ1, which
separation of the above fragments (the Si2/O2 distances is much lower than the experimental value. In our opinion, this
˚
become 4.533 and 3.962 A). Conformers 9a-cyclic and 9a-acyclic difference can be explained by specic solvation (for instance,
(Fig. 1S and 2S†) are stabilized by weak C–H/O bonds between H-bonds between CDCl3 and carbonyl or sulfonyl groups, which
sulfonyl and methyl groups, so the Si2/O2 distances are 3.724 can be responsible for stabilization of particular conformers).
˚
and 4.450 A. Again, the application of PCM model increases
˚
Si2/O2 distances to 4.292 and 4.376 A (9a-cyclic-CDCl3 and 9a-
In silico estimation of possible pharmacological applications
acyclic-CDCl3, Fig. 3S and 4S†). Thus, the effect of nonspecic
Possible applications of synthesized complexes were evaluated
by the search for similar compounds with known activities and
solvation prevents the formation of Si2/O2 interactions, so the
permutational isomerisation involving the sulfonyl group is
computational prediction of biological activity based on
unlikely to take place.
“structure–activity” relationships (SAR) models. Such analysis
The information about the barrier of rotation around Si1–C3
provides a reasonable basis for planning further experimental
and N1–C4 bonds can be useful to understand the mechanism
of permutational isomerisation of 9a. These barriers were
studies of biological activity.
In this study, we used the PubChem structural search for
calculated by the relaxed potential energy surface scan of CNCO
identication of equivalent and similar structures (https://
and F1Si1C3N1 torsion angles (the plots of the energy vs. scan
coordinate are placed in ESI (Fig. 9S and 10S†)). The value of the
rotation barrier around the Si1–C3 bond in isolated molecule 9a
pubchem.ncbi.nlm.nih.gov).20 The similarity was assessed by
the Tanimoto equation and the PubChem dictionary-based
is approximately 7 kcal molꢀ1 (Fig. 9S†), so the rotation around
binary ngerprint analysis (https://pubchem.ncbi.nlm.nih.gov/
search/help_search.html). The search results for similar
the Si–C bond is possible despite the presence of an Si1–O1
coordination bond. In solution, the value of this barrier is even
compounds are shown in Table 3.
lower than that in isolated molecule (ꢂ5.1 kcal molꢀ1). It is not
According to Table 3, the studied complexes have different
similar compounds with variable known activities. No two
surprising that the rotation around the N1–C4 bond is less
favourable than the rotation around the Si1–C3 bond. Firstly,
the N1–C3 bond is intermediate between ordinary and double
(Table 2). Secondly, the rotation around the N1–C3 bond is
attributed to the formation and cleavage of Si1–O1 and Si2–O1
coordination bonds. Our calculation gave the values of 26.3 kcal
complexes have the same most similar compound, which could
indicate their similar biological potentials.
Computational prediction of biological activity for studied
complexes was carried out using SAR-based online services.
Possible therapeutic effects and mechanisms of action were
evaluated by PASS Online21 (http://www.way2drug.com/
PASSOnline) while the LD50 values for acute rat toxicity were
estimated by GUSAR Online22 (http://www.way2drug.com/gusar/
acutoxpredict.html). The results of these predictions are
summarized in Table 4.
molꢀ1 for isolated molecule 9a and 24.8 kcal molꢀ1 for its
solution in chloroform (Fig. 10S†). These values are very close to
the permutational barriers measured for 9a–c by 19F DNMR
study. Thus, the internal rotation can be responsible for the
permutational isomerisation of 9a. Additional justication for
The prediction results suggest that synthesized compounds
may possess cardiovascular and CNS properties. Low levels of
predicted acute rat toxicity makes them suitable for all routes of
administration.
Table 2 Calculated bond distances and angles in conformers of 9a
Conformer
Si1/O1 Si2/O2 Si1–F1 Si2–F2 O1Si1F1
Conclusions
9a-cyclic
9a-acyclic
9a-cyclic-CDCl3
9a-acyclic-CDCl3
9a-cyclic2
9a-acyclic2
9a-cyclic2-CDCl3
9a-acyclic2-CDCl3 3.175
9a-ts
2.368
3.130
2.248
3.222
2.356
2.984
2.250
4.450
3.724
4.533
3.962
3.698
3.720
4.292
4.376
3.969
3.777
1.665
1.638
1.686
1.652
1.667
1.637
1.686
1.644
1.638
1.645
1.632
1.646
1.640
1.644
1.637
1.639
1.643
1.644
1.637
1.648
169.20
79.69
170.25
78.82
168.96
76.09
169.97
77.90
New diuorides R3R2NCH(R1)C(O)N(CH2SiMe2F)2 (9a–c) with
one pentacoordinate and one tetracoordinate silicon atoms
were synthesized by silylmethylation of amides R3R2NCH(R1)
C(O)NH2, subsequent hydrolysis of unstable intermediates
R3R2NCH(R1)C(O)N(CH2SiMe2Cl)2 (7a–c) into 4-acyl-2,6-
disilamorpholines R3R2NCH(R1)C(O)N(CH2SiMe2O)2 (8a–c)
and the reaction of the latter compounds with BF3$Et2O.
4.828
4.947
112.44
115.07
9a-ts-CDCl3
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Table 3 The search results for similar compounds in PubChema
The most similar compound with data on
ID
Hits (probability)
patents or activity
8a
0 (90%); 161 (80%)
N-[(3S)-1-Methyl-2-oxopiperidin-3-yl]-N-(2-
oxopropyl)methanesulfonamide (CID 58869395)
Patent description: sulfonylaminovalerolactams
and derivatives thereof as factor Xa inhibitors
4,40-Ethylenebis(1-methyl-2,6-piperazinedione)
(CID 97592)
8b
216 (90%)
Patent description: novel drug targets to
overcome de novo drug-resistance in multiple
myeloma; method of reducing amyloid-beta
peptide levels using a bisdioxopiperazine;
abatement process for contaminants; bis-
dioxopiperazines and their use as protection
agents bis-dioxopiperazines and their use as
protection agents
Known activity: small molecule inhibitors of
FGF22-mediated excitatory synaptogenesis &
epilepsy measured in biochemical system using
RT-PCR – 7012-
01_Inhibitor_SinglePoint_HTS_Activity
2-(4-Acetylpiperazin-1-yl)-N-
8c
9a
0 (90%); 19 (80%)
0 (90%); 74 (80%)
methylsulfonylacetamide (CID 89504348)
Patent description: dual-acting antihypertensive
agents having angiotensin II type receptor
antagonist activity and neprilysin-inhibition
activity
(1) N-(4-Amino-5-oxo-5-pyrrolidin-1-ylpentyl)
methanesulfonamide (CID 17960593)
Patent description: alpha-amino acid sulphonyl
compounds
(2) (2S)-1-[2-[Methyl(methylsulfonyl)amino]
ethyl]pyrrolidine-2-carboxamide (CID 57572120)
Patent description: quinolinone compounds as
5-HT4 receptor agonists
9b
59 (90%)
Azepan-1-yl-[1-(4-methylphenyl)
sulfonylpyrrolidin-2-yl]methanone (CID
2964486)
Known activity: active in HTS assay for activators
of cytochrome P450 2A9
9c
0 (90%); 10 (80%)
N,N-Dimethyl-2-[methyl(methylsulfonyl)amino]
acetamide (CID 57682568)
Patent description: HIV integrase inhibitors
a
Hits – number of similar compounds ($90% or $ 80% Tanimoto index); CID – PubChem Compound ID.
According to IR and NMR data, the O/Si coordination in in CDCl3 and DMSO-d6 were recorded on a Bruker Avance II 300
solutions of these compounds was weaker than in the solid state (1H, 300 MHz; 13C, 75.6 MHz; 19F, 282.2 MHz) and Jeol JNM-
due to effective solvation of the Si–F bond. The absence of spin– EX400 (1H, 400 MHz; 13C, 100.6 MHz; 19F, 376.3 MHz) instru-
3
spin coupling constants JHF of the methyl groups at SiV and ments using standard pulse sequences. 29Si NMR spectra were
their retention at SiIV indicates a signicant weakening of the recorded using the 1H-29Si HSQC pulse sequence supplied with
1
Si–F bond at pentacoordinate silicon, which favours its ioniza- the Bruker Avance II 600 instrument.23 The H, 13C, 29Si chem-
tion. Based on in silica analysis, the synthesized compounds ical shis were measured using Me4Si as internal reference. The
show a potential for pharmacological studies.
19F chemical shis were measured using BF3 as external refer-
ence. Negative values are to high eld. 29Si NMR CP/MAS
spectra in the solid state were recorded on a Jeol JNM-EX-400
instrument using 5 mm zirconia rotors and a Doty probe.
The temperature calibration of the NMR spectrometers was
performed by measuring the differences in chemical shis
between non-equivalent protons in methanol (ꢀ90.+30 ꢁC)
Experimental section
IR-spectra of compounds in solution and in the solid state were
recorded on a Bruker Tensor-27 spectrometer using KBr cells
and an APR element, respectively. 1H, 13C and 19F NMR spectra
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Table 4 Prediction of therapeutic effects and mechanisms of action (PASS Online) and LD50 values of acute rat toxicity (GUSAR Online)a
Predicted LD50 values in mg kgꢀ1
,
Top 5 predicted therapeutic effects
with probability > 50%
Top 5 predicted mechanisms of
action with probability > 50%
type of administration, class of
toxicity
ID
8a
8b
8c
Not predicted
Not predicted
Spasmolytic
Acetylcholine neuromuscular
blocking agent
Acetylcholine neuromuscular
blocking agent
Acetylcholine neuromuscular
blocking agent, anaphylatoxin
receptor antagonist
IP – out of AD, 127, IV, 4 class, 904,
PO, 4 class, SC – out of AD
IP – out of AD, 96, IV, 4 class, 1270,
PO, 4 class, SC – out of AD
IP – out of AD, 156, IV, 4 class, 453,
PO, 4 class, 250, SC, 4 class
9a
Antianginal, multiple sclerosis
treatment, antiparkinsonian,
neurodegenerative diseases
treatment
Phosphatidylinositol 3-kinase
C2beta inhibitor, RANTES
antagonist, insulin growth factor
agonist, insulin like growth factor 1
agonist
IP – out of AD, 80, IV, 4 class, PO –
out of AD, 487, SC, 4 class
9b
9c
Antianginal, cardiovascular
analeptic, multiple sclerosis
treatment, cell adhesion molecule
inhibitor
Integrin alpha2 antagonist,
calmodulin antagonist, nicotinic
alpha4beta4 receptor agonist
IP – out of AD, 101, IV, 4 class, PO –
out of AD, SC – out of AD
Antianginal
Anaphylatoxin receptor antagonist,
phospholipid-translocating ATPase
inhibitor, 2-haloacid dehalogenase
inhibitor,
IP – out of AD, 130, IV, 4 class, PO –
out of AD, 225, SC, 4 class
glycosylphosphatidylinositol
phospholipase D inhibitor, NADPH
peroxidase inhibitor
a
IP – intraperitoneal route of administration; IV – intravenous route of administration; PO – oral route of administration; SC – subcutaneous route
of administration; out of AD – compound is out of applicability domain of QSAR models.
and ethyleneglycol (+30.+85 ꢁC).24 The activational parameters 0.10 mol) and triethylamine (10.1 g, 0.10 mol) in diethyl ether
of the permutational isomerisation were calculated using (80 mL). The mixture was stirred at ambient temperature for 2
DNMR-SIM soware25 and a modied Eyring equation.26 In each h, the precipitate formed was ltered off, washed with ether (15
case, at least twelve temperature points were obtained to ach- mL), and the combined organic solutions were evaporated in
ieve a correlation coefficient of 0.997–0.999.
vacuum. The residue was distilled to afford 13.7 g (70%) of
Chloro(chloromethyl)dimethylsilane, (S)-proline hydrochlo- ethyl-N-mesyl-N-methylglycinate with b.p. 144–145 ꢁC (9 torr)
ride, sarcosine and all solvents were purchased from Acros and and m.p. 34–35 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1750 (C]O),
Sigma-Aldrich. Ethyl esters of N-mesyl-(S)-proline and N-tosyl- 1360 and 1160 (SO2). 1H NMR spectrum (CDCl3, d, ppm (J, Hz)):
(S)-proline were synthesised as described earlier.10
1.25 (3H, t, 3J 7.3, CH2CH3); 2.77 (3H, s, CH3N); 2.87 (3H, s,
CH3S); 4.05 (2H, s, NCH2). 13C NMR spectrum (CDCl3, d, ppm):
8.9 (CH2CH3); 35.3 (CH3N); 38.1 (CH3S); 51.4 (NCC(O)); 55.5
(CH2CH3); 173.9 (C]O). Found, %: C 37.08; H 6.65; N 7.11.
C6H13NO4S. Calculated, %: C 36.91; H 6.71; N 7.17.
Ethyl-N-mesyl-N-methylglycinate
Thionyl chloride (83.3 g, 0.27 mol) was added dropwise to
a solution of N-methylglycine (44.5 g, 0.50 mol) in absolute
ethanol (200 mL). The mixture was reuxed for 5 h, then the
volatiles were removed in vacuum. The residue was sus-
N-Mesyl-(S)-prolinamide (6a)
pended in an ice-cold mixture of water (20 mL) and diethyl Ethyl ester of N0-mesyl-(S)-proline (6.6 g, 30 mmol) was stirred
ether (100 mL), and a solution of potassium hydroxide (28.0 g, with 50 mL of a 25% aqueous ammonia solution for 5 days at
0.50 mol) in water (20 mL) was added over 5 min at 0 ꢁC, ambient temperature. The precipitate formed was isolated by
followed by 250 g of anhydrous potassium carbonate. The ltration, dried in the open air and used without further puri-
organic layer was separated, the residue was washed with cation. Yield 5.5 g (96%), m.p. 156–157 ꢁC (from EtOH),
ether (2 ꢃ 50 mL), and the combined organic solutions were [a]2D5 ꢀ101.3ꢁ (c 1.93, H2O). IR spectrum (KBr, n, cmꢀ1): 3449,
1
dried over magnesium sulfate. The solvent was removed in 3170 (NH2); 1619 (NCO), 1321 and 1140 (SO2). H NMR spec-
vacuum, and the residue was distilled to afford 38.0 g (65%) of trum (DMSO-d6, d, ppm (J, Hz)): 1.75–2.25 (4H, m, 3,4-CH2); 2.83
ethyl N-methylglycinate with b.p. 43–45 ꢁC (12 torr) and nD (3H, s, CH3); 3.25–3.47 (2H, m, 5-CH2); 3.96–4.09 (1H, m, 2-CH);
(ref. 20) 1.4105. Literature data:27 b.p. 46 C (12 torr), nD (ref. 6.1 and 6.7 (2H, two broad s, NH2). 13C NMR spectrum (DMSO-
ꢁ
20) 1.4144.
d6, d, ppm): 22.0 (Me); 26.0 (C-4); 32.3 (C-3); 50.7 (C-5); 63.5 (C-
Methanesulfonyl chloride (11.5 g, 0.10 mmol) was added 2); 175.8 (C]O). Found, %: C 37.35; H 6.39; N 14.50.
dropwise to a cooled solution of ethyl-N-methylglycinate (11.7 g, C6H12N2O3S. Calculated, %: C 37.49; H 6.29; N 14.57.
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remaining solution was evaporated in vacuum, the residue was
dissolved in chloroform (30 mL) and stirred with a solution of
NaHCO3 (0.84 g, 10 mmol) in water (10 mL) for 2 h. The organic
layer was separated, the aqueous layer was extracted with
chloroform (20 mL), and the combined organic solutions were
evaporated in vacuum. Recrystallisation of the residue from
heptane/benzene (3 : 1) mixture afforded 1.32 g (75%) of
compound 8a with m.p. 121–124 ꢁC and [a]D25 ꢀ55.0ꢁ (c 1.31,
CHCl3). Found, %: C 41.25, H 7.56, N 7.80, S 9.03. C12H26N2-
O4SSi2. Calculated, %: C 41.11, H 7.48, N 7.99, S 9.15. IR spec-
trum (KBr, n, cmꢀ1): 1631 s (C]O), 1325 s, 1148 s (SO2). 1H NMR
spectrum (CDCl3, d, ppm): 0.18, 0.19, 0.21 and 0.31 (four s, 12H,
2Si(CH3)2); 1.88–2.34 (m, 4H, C3H2 and C4H2 Pro); 2.7 and 3.42
N-Tosyl-(S)-prolinamide (6b)
Prepared similar to 6a. Yield 6.2 g (93%), m.p. 161–162 ꢁC (from
EtOH), [a]2D5 ꢀ134.6ꢁ (c 1.06, H2O). IR spectrum (KBr, n, cmꢀ1):
1
1643 (NCO), 1344, 1156 (SO2). H NMR spectrum (DMSO-d6, d,
ppm (J, Hz)): 1.31–1.83 (4H, m, 3,4-CH2); 2.43 (3H, s, CH3); 3.11–
3.22 and 3.35–3.55 (2H, m, 5-CH2); 3.91–4.01 (1H, m, 2-CH); 5.95
and 6.71 (2H, two broad s, NH2); 7.36 (2H, d, 3J ¼ 8.3, H Ar); 7.72
(2H, d, 3J 8.3, H Ar). 13C NMR spectrum (DMSO-d6, d, ppm): 22.0
(Me); 25.7 (C-4); 31.8 (C-3); 50.9 (C-5); 63.7 (C-2); 129.2 (C-3,5 Ar);
131.4 (C-2,6 Ar); 135.4 (C-1 Ar); 145.8 (C-4 Ar); 175.5 (C]O).
Found, %: C 37.58, H 6.27, N 14.50. C6H12N2O3S. Calculated, %:
C 37.49, H 6.29, N 14.57.
3
3
(dd, 2H, NCH2Si, JHH 15.34 Hz); 2.83 (dd, 2H, NCH2Si, JHH
15.34 Hz); 3.01 (s, 3H, SCH3); 3.45–3.52 and 3.56–3.63 (two m,
2H, C5H2 Pro); 4.80–4.87 (m, 1H, C2H Pro). 13C NMR spectrum
(CDCl3, d, ppm): –0.76 O 0.00 (m, 2SiMe2); 24.65 (4C Pro); 30.79
(3C Pro); 39.9 (SC); 38.1 and 40.29 (two s, NCH2Si); 47.54 (5C
Pro); 58.92 (C2 Pro); 169.64 (C]O). 29Si NMR spectrum (CDCl3,
d, ppm): 8.0, 10.5.
N-Mesyl-N-methylglycinamide (6c)
Prepared similar to 6a. Yield 4.1 g (82%), m. p. 170–171 ꢁC
(EtOH). IR spectrum (KBr, n, cmꢀ1): 3315, 3170 (NH2); 1657
1
(NCO), 1320 and 1150 (SO2). H NMR spectrum (DMSO-d6, d,
ppm (J, Hz)): 2.79 (3H, s, CH3); 2.87 (3H, s, CH3S); 3.58 and 3.71
(2H, two s, NCH2); 5.5 and 6.1 (2H, two broad s, NH2). 13C NMR
spectrum (DMSO-d6, d, ppm): 34.3 (CH3N); 37.1 (CH3S); 50.9
(NCC(O)); 174.9 (C]O). Found, %: C 29.18, H 5.92, N 16.81.
C4H10N2O3S. Calculated, %: C 28.91, H 6.06, N 16.86.
2,2,6,6-Tetramethyl-4-[N-tosyl-(S)-prolinyl]-2,6-
disilamorpholine (8b)
Prepared similar to 8a from 1.34 g of 6b. Yield 1.66 g (78%) with
m. p. 110–112 ꢁC (from heptane–benzene, 10 : 1) and
[a]2D5 ꢀ2.92ꢁ (c 1.85, CHCl3). Found, %: C 50.51, H 7.24, N 6.62, S
2,2,6,6-Tetramethyl-4-[N-mesyl-(S)-prolinyl]-2,6-
disilamorpholine (8a)
A mixture of 6a (0.96 g, 5 mmol), hexamethyldisilazane (0.81 g, 5 7.45. C18H30N2O4SSi2. Calculated, %: C 50.67, H 7.09, N 6.57, S
mmol), chloro(chloromethyl)dimethylsilane (2.15 g, 15 mmol) 7.52. IR spectrum (KBr, n, cmꢀ1): 1629 s (C]O), 1580 m (Ar),
1
and toluene (10 mL) was reuxed for 4 h, then allowed to cool 1325 s, 1148 s (SO2). H NMR spectrum (CDCl3, d, ppm): 0.17,
down, and the precipitate formed was ltered out. The 0.21, 0.23 and 0.34 (four s, 12H, 2Si(CH3)2); 1.88–2.05 (m, 4H,
Table 5 Crystallographic data and refinement parameters for the structures 8a, 8a0, 8c and 9a
8a
8a0
8c
9a
Molecular formula
Formula weight
Crystal system
Space group
Flack parameter
Z
C
12H26N2O4SSi2
C12H26N2O4SSi2
350.59
Monoclinic
P21
0.03(9)
2
7.436(4)
9.474(6)
14.125(9)
90
104.082(9)
90
C10H24N2O4SSi2
324.55
Monoclinic
P21/n
—
4
15.1089(9)
6.6275(4)
16.4442(10)
90
98.7620(10)
90
1627.41(17)
1.325
3.57
C12H26F2N2O3SSi2
372.59
Orthorhombic
P212121
0.016(13)
8
13.0441(9)
15.9282(11)
18.2980(13)
90
90
90
3801.8(5)
1.302
3.25
350.59
Orthorhombic
P212121
0.027(18)
8
9.6000(5)
14.2422(7)
27.0844(14)
90
90
90
3703.1(3)
1.258
3.19
˚
a, A
˚
b, A
˚
c, A
a, ꢁꢁ
b,
g, ꢁ
3
˚
V, A
965.2(10)
1.206
3.06
rcalc (g cmꢀ3
)
m, cmꢀ1
F(000) ꢁ
1504
61.03
376
60.22
696
60.06
1584
61.06
2qmax
,
Reections collected
Independent reections (Rint
Number of reections with I > 2s(I)
Parameters
50 072
11 308 (0.0355)
10 588
389
10 584
5331 (0.00)
3228
30 094
4740 (0.0311)
3981
65 941
11 597 (0.0327)
10 557
)
195
178
411
R1 [I > 2s(I)]
wR2 (all independent reections)
GOF
rmin/rmax (e A
0.0344
0.0793
1.071
0.556/ꢀ0.323
0.0579
0.1168
1.000
0.873/ꢀ0.494
0.0484
0.1022
1.034
0.565/ꢀ0.358
0.0266
0.0698
1.084
0.381/ꢀ0.197
ꢀ3
˚
)
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C3H2 and C4H2 Pro); 2.42 (s, 3H, ArCH3); 2.95 and 3.14 (dd, 2H, s, 1151 s (SO2). 1H NMR spectrum (CDCl3, d, ppm): 0.18 and 0.22
NCH2Si, JHH 15.0 Hz); 2.99 and 3.04 (dd, 2H, NCH2Si, JHH (two s, 6H, SiV(CH3)2); 0.41–0.44 (m, 6H, SiIV(CH3)2); 1.83–1.93
15.95 Hz); 3.39–3.46 and 3.50–3.57 (two m, 2H, C5H2 Pro); 4.87– and 2.05–2.16 (two m, 4H, C3H2 and C4H2 Pro); 2.43 and 2.51
4.92 (m, 1H, C2H Pro); 7.28 and 7.79 (two d, 4H, Ar, 3JHH 8 Hz). (dd, 2H, NCH2SiV, 3JHH 15.74 Hz); 2.45 (s, 3H, ArCH3); 3.04–3.08
13C NMR spectrum (CDCl3, d, ppm): –0.57 O 0.00 (m, 2SiMe2); and 3.52–3.59 (two m, 2H, NCH2SiIV); 3.35–3.4 and 3.46–3.52
21.47 (Me); 24.75 (4C Pro); 30.89 (3C Pro); 37.96 and 40.41 (two s, (two m, 2H, C5H2 Pro); 4.78–4.81 (m, 1H, C2H Pro), 7.32 (d, 2H,
3
3
3
3
NCH2Si); 48.09 (5C Pro); 57.60 (C2 Pro); 127.48 (C2 and C6 Ar), Ar, JHH 8.07 Hz), 7.75 (d, 2H, Ar, JHH 8.07 Hz). 13C NMR
129.30 (C3 and C5 Ar), 136.50 (C1 Ar), 143.04 (C4 Ar), 169.52 (C] spectrum (CDCl3, d, ppm): ꢀ1.92 O ꢀ1.78 (m, SiIVCH3); 1.20–
O). 29Si NMR spectrum (CDCl3, d, ppm): 7.9, 10.4.
1.37 (m, SiVCH3); 21.46 (ArMe); 24.89 (C4 Pro); 30.63 (C3 Pro);
41.27 (d, CH2SiIV, 3JCF 16.69 Hz); 41.36–41.47 (m, CH2SiV); 48.24
(C5 Pro); 55.45 (C2 Pro); 127.31 (C2 and C6 Ar), 129.64 (C3 and C5
Ar), 135.89 (C1 Ar), 143.74 (C4 Ar); 172.39 (C]O). 19F NMR
spectrum (CDCl3, d, ppm): ꢀ159.47; ꢀ119.31. 29Si NMR spec-
2,2,6,6-Tetramethyl-4-(N-mesylsarcosinyl)-2,6-
disilamorpholine (8c)
Prepared similar to 8a from 0.83 g of 6c. Yield 1.3 g (80%) with
m.p. 151–153 ꢁC (from heptane–benzene, 7 : 1). Found, %: C
37.28, H 7.24, N 8.64, S 9.51. C10H24N2O4SSi2. Calculated, %: C
37.01, H 7.45, N 8.63, S 9.88. IR spectrum (KBr, n, cmꢀ1): 1628 s
(C]O), 1323 s, 1153 s (SO2). 1H NMR spectrum (CDCl3, d, ppm):
0.18 and 0.23 (two s, 12H, 2Si(CH3)2); 2.79 and 3.06 (two s, 4H,
NCH2Si); 2.98 (s, 3H, NCH3); 2.99 (s, 3H, SCH3); 4.13 (s, 2H,
NCH2). 13C NMR spectrum (CDCl3, d, ppm): –0.37 and ꢀ0.19
(two s, 2Si(CH3)2); 35.44 (NMe); 37.95 and 39.70 (two s, NCH2Si);
38.15 (SMe); 51.56 (NCC]O); 165.58 (C]O). 29Si NMR spec-
trum (CDCl3, d, ppm): 8.3, 10.4.
1
1
trum (CDCl3, d, ppm): ꢀ19.1 (d, JSiF 236 Hz), 28.1 (d, JSiF 276
Hz). 29Si NMR CP/MAS spectrum (d, ppm): ꢀ32.0 (d, JSiF 251
1
1
Hz), 30.7 (d, JSiF 292 Hz).
N0,N0-Bis(dimethyluorosilylmethyl)-N-mesylsarcosinamide
(9c)
Prepared similar to 9a from 0.80 g of 8c. Yield 0.73 g (85%) with
m. p. 135–136 ꢁC (from heptane). Found, %: C 34.61, H 6.88, N
7.86, S 8.92. C10H24F2N2O3SSi2. Calculated, %: C 34.66, H 6.98,
N 8.08, S 9.25. IR spectrum (KBr, n, cmꢀ1): 1610 s, 1505 w (C]
O), 1319 s, 1134 s (SO2). 1H NMR spectrum (CDCl3, d, ppm): 0.30
(two s, 6H, Si(CH3)2); 0.39–0.43 (m, 6H, SiIV(CH3)2); 2.56 and
3.05 (two s, 4H, NCH2Si); 2.96 (s, 3H, NCH3); 2.98 (s, 3H, SCH3);
4.17 (s, 2H, NCH2). 13C NMR spectrum (CDCl3, d, ppm): ꢀ1.8 (d,
N0,N0-Bis(dimethyluorosilylmethyl)-N-mesyl-(S)-prolinamide
(9a)
Boron triuoride (0.36 g, 2.5 mmol) was added dropwise to
a solution of 8a (0.88 g, 2.5 mmol) in acetonitrile (5 mL). The
reaction mixture was reuxed for 2 h, then evaporated in
vacuum. The remaining oil was reuxed with benzene (15 mL),
the precipitate was ltered out, and the solution was evaporated
in vacuum. The residue was recrystallised from heptane to
afford 0.76 g (82%) of 9a with m.p. 100–101 ꢁC. Found, %: C
34.61, H 6.88, N 7.86, S 8.92. C10H24F2N2O3SSi2. Calculated, %:
C 34.66, H 6.98, N 8.08, S 9.25. IR spectrum (KBr, n, cmꢀ1): 1610
s, 1505 w (C]O), 1319 s, 1134 s (SO2). 1H NMR spectrum
(CDCl3, d, ppm): 0.22 and 0.31 (two s, 6H, SiV(CH3)2); 0.41 and
0.46 (dd, 6H, SiIV(CH3)2, 3JHF 7.67 Hz); 1.86–1.93, 2.03–2.18 and
2.28–2.36 (m, 4H, C3H2 and C4H2 Pro); 2.44 and 2.59 (dd, 2H,
NCH2SiV, 3JHH 15.74 Hz); 2.98 (s, 3H, SCH3); 3.00–3.05 and 3.25–
3.30 (two m, 2H, NCH2SiIV); 3.44–3.5 and 3.58–3.63 (two m, 2H,
C5H2 Pro); 4.75–4.77 (m, 1H, C2H Pro). 13C NMR spectrum
(CDCl3, d, ppm): ꢀ1.9 O ꢀ1.7 (m, SiIVCH3); 1.1–1.7 (m, SiVCH3);
24.95 (C4 Pro); 30.93 (C3 Pro); 39.23 (SC); 41.1 O 41.5 (m, CH2SiV
and CH2SiIV); 47.72 (C5 Pro); 56.59 (C2 Pro); 172.51 (C]O). 19F
NMR spectrum (CDCl3, d, ppm): ꢀ159.15; ꢀ121.88. 29Si NMR
2
SiMe2, JCF 14.5 Hz), 1.2 (s, SiMe2); 35.3 (NMe); 37.9 and 40.8
(two s, NCH2Si); 41.4 (SMe); 49.7 (NCC]O); 168.6 (C]O). NMR
19F spectrum (CDCl3, d, ppm): ꢀ159.15; ꢀ125.46. 29Si NMR
1
1
spectrum (CDCl3, d, ppm): ꢀ10.5 (d, JSiF 248 Hz), 29.2 (d, JSiF
287 Hz).
Single crystals suitable for X-ray diffraction analysis were
obtained by recrystallisation from: orthorhombic 8a—heptane/
benzene 3 : 1; monoclinic 8a0—ethanol; 8c—heptane/benzene
7 : 1; 9a—heptane. X-ray diffraction measurements were
carried out using Bruker Smart 1000 CCD and Bruker Smart
Apex II CCD diffractometers at 100 K. The frames were inte-
grated using SMART and APEX2 program packages.28 The
correction for absorption was made using SADABS program.29
The details of crystallographic data and experimental condi-
tions are given in Table 5.
The structures were solved by the direct method by XS
program30 and rened by full-matrix least-squares technique
against F2 in the anisotropic–isotropic approximation using XL
program.30 Atom H20 in s was located from the difference
Fourier maps and rened freely. All remaining hydrogen atoms
were placed in geometrically calculated positions and rened in
rigid body model (Uiso(H) ¼ 1.2Ueq(CH, CH2), Uiso(H) ¼
1.5Ueq(CH3)). The Flack parameter conrms (S)-conguration of
the proline fragment. Preparation of graphic materials was
1
1
spectrum (CDCl3, d, ppm): ꢀ15.5 (d, JSiF 252 Hz), 28.9 (d, JSiF
1
284 Hz). 29Si NMR CP/MAS spectrum (d, ppm): ꢀ37.2 (d, JSiF
1
880 Hz), 32.7 (d, JSiF 1024 Hz).
N0,N0-Bis(dimethyluorosilylmethyl)-N-tosyl-(S)-prolinamide
(9b)
Prepared similar to 9a from 1.1 g of 8b. Yield 0.9 g (80%) with m. performed using OLEX2 soware package.31 Crystallographic
p. 87–88 ꢁC (from heptane). Found, %: C 48.23, H 6.80, N 6.15, S data for the structural analysis of 8a, 8a0, 8c and 9a have been
7.20. C18H30F2N2O3SSi2. Calculated, %: C 48.18, H 6.74, N 6.24, deposited with the Cambridge Crystallographic Data Centre
S 7.15. IR spectrum (KBr, n, cmꢀ1): 1602 s, 1515 w (C]O), 1336 (CCDC nos 1059570–1059573).
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A. A. Korlyukov, K. A. Lyssenko, M. Y. Antipin,
A. G. Shipov, O. A. Zamyshlyaeva, E. P. Kramarova,
V. V. Negrebetsky, S. A. Pogozhikh, Y. E. Ovchinnikov and
Y. I. Baukov, Russ. Chem. Bull., 2004, 53(9), 1924–1931.
7 (a) A. A. Nikolin, E. P. Kramarova, A. G. Shipov, Y. I. Baukov,
V. V. Negrebetsky, A. A. Korlyukov, D. E. Arkhipov,
A. Bowden, S. Y. Bylikin, A. R. Bassindale and P. G. Taylor,
Organometallics, 2012, 31(14), 4988–4997; (b) A. A. Nikolin,
O. V. Kuznetsova, D. E. Arkhipov, E. P. Kramarova,
A. G. Shipov, A. N. Egorochkin, A. A. Korlyukov,
Y. I. Baukov and V. V. Negrebetsky, Russ. Chem. Bull., 2013,
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Khim, 1994, 64, 1222–1223; (b) Y. I. Baukov, A. G. Shipov,
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Acknowledgements
This work was carried out as a part of the research activities of
the Science and Education Centre for the Synthesis and Inves-
tigation of Biologically Active Compounds at the N. I. Pirogov
Russian National Research Medical University and supported by
the Russian Foundation for Basic Research (grants nos 16-03-
00957, 16-33-60168 and 16-33-00956).
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