Rubén Oswaldo Argüello-Velasco1, Błażej Dziuk2, Bartosz Zarychta2, Mario Ordóñez1, Paweł Kafarski3. 1. Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico. 2. Department of Crystallography, Faculty of Chemistry, University of Opole, 45-040 Opole, Poland. 3. Department of Bioorganic Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
Abstract
The reaction of the title lactams with triethyl phosphite prompted by phosphoryl chloride provided six-membered ring heterocyclic phosphonates or bisphosphonates. These novel scaffolds might be of interest as building blocks in medicinal chemistry. The course of the reaction was dependent on the structure of the used substrate. Thus, morpholin-3-one and thiomorpholin-3-one readily provided the corresponding 1,1-bisphosphonates (compounds 1, 2, 7, 14 and 16), whereas the protection of their nitrogen atom resulted in the formation of dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one reacted differently yielding mixture of cis- and trans- piperazine-2,3-diyl-bisphosphonates (compounds 10 and 11). Since cytosine could be considered as an analogue of piperin-2-one, its ditosyl derivative 18 was used as a substrate affording compound 19 being a product of phosphite addition to double bond. In dependence of their structures, hydrolysis of the obtained diethyl phosphonates resulted either in corresponding cyclic phosphonic acids or in the degradation of carbon-to-phosphorus bond.
The reaction of the title lactams with triethyl phosphite prompted by phosphoryl chloride provided six-membered ring heterocyclic phosphonates or bisphosphonates. These novel scaffolds might be of interest as building blocks in medicinal chemistry. The course of the reaction was dependent on the structure of the used substrate. Thus, morpholin-3-one and thiomorpholin-3-one readily provided the corresponding 1,1-bisphosphonates (compounds 1, 2, 7, 14 and 16), whereas the protection of their nitrogen atom resulted in the formation of dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one reacted differently yielding mixture of cis- and trans- piperazine-2,3-diyl-bisphosphonates (compounds 10 and 11). Since cytosine could be considered as an analogue of piperin-2-one, its ditosyl derivative 18 was used as a substrate affording compound 19 being a product of phosphite addition to double bond. In dependence of their structures, hydrolysis of the obtained diethyl phosphonates resulted either in corresponding cyclic phosphonic acids or in the degradation of carbon-to-phosphorus bond.
Heterocyclic
rings are key scaffold components in medicinal chemistry
and are the fundamental building blocks of many drugs. However, the
design and preparation of new heterocyclic building blocks is still
a challenging area in the early drug discovery phase.[1] The extensive literature focused on the synthesis and functionalization
of azaheterocyclic phosphonates is mostly concentrated on aromatic
compounds,[2] with heteroalicyclic ones being
less intensively studied.[3a] Anyway, numerous
synthetic procedures were elaborated for the syntheses of aziridin-,
azetidin-, pyrrolidin-, and piperidin-ylphosphonic acids and their
derivatives.[3] Syntheses of heteroalicyclic
phosphonates bearing a second heteroatom in the ring have been scarcely
described so far,[4] and there remains a
great need for further advance in this area.Since simple lactams
upon reaction with triethyl phosphite prompted
by phosphoryl chloride, a version of Vilsmeier–Haack reaction,[3h,5] readily provided cyclic aminobisphosphonates (Scheme ), the enlargement of the scope of this reaction
is a logic alternative.
Scheme 1
Reaction of Lactams by Vilsmeier–Haack-Like
Reaction
Therefore, we studied
the course of this reaction using morpholin-3-one,
thiomorpholin-3-one, and piperazin-2-one as substrates.
Results and Discussion
Morpholin-3-one
and Thiomorpholin-3-one as Substrates
As expected, the reaction
of morpholin-3-one and thiomorpholin-3-one
with triethyl phosphite and phosphoryl chloride afforded the corresponding
bisphosphonates 1 and 2 in satisfactory
yields (Scheme ).
These compounds decompose upon hydrolysis by concentrated hydrochloric
acid; therefore, the corresponding phosphonic acids 3 and 4 were obtained by classic dealkylation with trimethylbromosilane
followed by methanolysis of trimethylsilyl esters (Scheme ). When the amidenitrogen
atom in both substrates was blocked with benzyl moiety, the reaction
afforded corresponding diethyl N-benzyl-2,3-dehydromorpholyl-3-phosphonate
(compound 5) and N-benzyl-2,3-dehydrothiomorpholyl-3-phosphonate
(compound 6) (Scheme ) as major products.
Scheme 2
Reactions of Morpholin-3-one
and Thiomorpholin-3-one and Their Derivatives
These findings support the assumption that the mechanism
of this
reaction is similar to the one proposed earlier[3h] and is presented in Scheme for morpholin-3-one.
Scheme 3
Mechanism of Reaction
of Mopholin-3-one and N-benzylmopholin-3-one
It is worth to mention that
we were able to isolate only bisphosphonate 7 as a product
of the analogous reaction of N-benzylvalerolactam.
This product was, however, obtained in low (20%)
yield accompanied by many side-products (Scheme ).
Scheme 4
Reaction of N-benzylvalerolactam
Quite unexpectedly, the use of N-phenyl-morpholine-3-one
as a substrate provided monoethyl N-benzyl-2,3-dehydromorpholyl-3-phosphonate
(compound 8) (Scheme ). Tetraethyl N-benzyl-2,3-morpholyl-3,3-bisphosphonate
(compound 9) was obtained with a good yield in a separate
reaction according to the procedure proposed recently by Wang (Scheme ).[6] Unfortunately, attempts to use this procedure for other
substrates gave unsatisfactory results yielding mixtures of the inseparable
products.
Scheme 5
Synthesis of tetraethyl N-benzyl-2,3-morpholyl-3,3-bisphosphonate
(9) by procedure of Wang et al.[6]
Piperazin-2-one and Its
analogues as Substrates
The
reaction of piperazin-2-one gave the mixture of products: tetraethyl cis-piperazine-2,3-diyl-bisphosphonate 10,
which is a meso compound and trans-piperazine-2,3-diyl-bisphosphonate 11, which is a racemic mixture of RR and SS stereoisomers
(Scheme ).
Scheme 6
Products
of the Reaction of Piperazin-2-one as a Substrate
The isomers were separated by means of column
chromatography. It
is worth mentioning that the 1H and 13C spectra
of both (cis and trans) isomers are significantly different (Figures S1.10 and S1.17 in the Supporting Information),
which enabled their easy differentiation upon separation.We
speculate that the mechanism of the formation of a mixture of
compounds 10 and 11 conforms to the general
mechanism of the formation of bisphosphonates with the difference
being in a shift of keto-enol equilibrium toward enamine rather than
to imine upon the action of phosphoryl chloride. The addition of phosphite
to enamine favors the production of gen-bisphosphonates (Scheme ).
Scheme 7
Presumable Mechanism
of the Formation of gem-bisphosphonates 10 and 11
The hydrolysis of compounds 10 and 11 with concentrated hydrochloric acid provided the corresponding
acids 12 and 13 in good yields (Scheme ). Their structures
were unequivocally supported
by crystallographic studies (Figure ).
Figure 1
Crystal structures for compounds 12 (left
panel) and 13 (right panel).
Crystal structures for compounds 12 (left
panel) and 13 (right panel).The use of 4-ethyl-piperazin-2,3-dione as a substrate quite
readily
provided corresponding tetraethyl 4-ethyl-3-oxopiperazine-2,2-diyl-bisphosphonate 14 (Scheme ). The hydrolysis of this compound resulted in the degradation of
carbon-to-phosphorus bond and the product of this degradation, (N′-ethyl-2-aminoethyl)glycine 15, was
isolated and characterized by X-ray studies (Figure ).
Figure 2
Crystal structure of the product of the degradation
of C–P
bonds upon hydrolysis of compound 14.
Crystal structure of the product of the degradation
of C–P
bonds upon hydrolysis of compound 14.Similarly, the 3,4-dihydroqinoxline-2-one provided
low yield of
the corresponding bisphosphonate 16, which appeared to
be also unstable under hydrolytic conditions yielding products of
the breakage of the C–P bonds (Scheme ). Such instability of benzoannulated bisphosphonates
has been observed earlier.[3h]
Scheme 8
Reactions
of Derivatives of Piperazin-2,3-dione
Finally, when using 3-methyl-piperazin-3-one as the substrate,
only the product of monophosphonylation 17 was isolated,
albeit in a very small yield (Scheme ). The formation of this unexpected product suggests
that the reaction has, at least in part, radical mechanism.
Scheme 9
Reaction
of 3-methyl-piperazin-3-one
Cytosine as a Substrate
Cytosine could be also considered
as an analogue of piperin-2-one. Unprotected cytosine did not react,
but blocking of its amino groups by toluenesulfonyl chloride leads
to its ditosyl derivative 18, which reacted quite smoothly
yielding the product 19 of the addition of phosphite
to double bond (Scheme ). Its structure, as determined by crystallography, is shown
in Figure .
Scheme 10
Addition of Phosphite to Double Bond of Ditosyl–Cytosine
Figure 3
Crystal structure
of compound 19.
Crystal structure
of compound 19.This compound upon hydrolysis
with concentrated hydrochloric acid
yielded a mixture of unseparable products with 1-tosyl-2,4-dioxo-pirymidyn-6-ylphosphonic
acid 20 being one of the major components.
Conclusions
These, as well as previous studies, indicate that a version of
the Vilsmeier–Haack reaction of lactams with triethyl phosphite
prompted by phosphoryl chloride is a promising mean to synthesize
azaheterocyclic phosphonates. The course of this reaction is strongly
dependent on the structure of the starting lactam, and in some cases,
unexpected products are also formed. Thus, in the case of lactams
possessing unsubstituted nitrogen, the formation of amino-gem-bisphosphonates (compounds 1, 2, 7, 14, and 16) was observed
as the major products, whereas the use of N-substituted
lactams unusually resulted in dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one and
2-methyl-piperazin-3-one and cytosine reacted differently yielding
unexpected products. All of the obtained compounds might be considered
as novel building blocks for medicinal chemistry.
Experimental
Section
General Methods and Materials
All solvents and reagents,
purchased from commercial suppliers, were of analytical grade and
were used without further purification. Unless otherwise specified,
solvents were removed with a rotary evaporator. Infrared spectra were
measured on a 1600 FT-IR Perkin Elmer spectrometer. The 1H-, 31P-, and 13C NMR spectroscopic experiments
were performed on a Bruker Avance II Ultrashield Plus (Bruker, Rheinstetten,
Germany) operating at 600.58 MHz (1H), 243.12 MHz (31P{1H}), and 151.016 MHz (13C{1H}), on a Bruker Avance III HD operating at 500.13 MHz (1H), 202.46 MHz (31P{1H}), and 125.75 MHz (13C{1H}), or on a Jeol JNM-ECZ 400S Research FT
NMR Spectrometer (JEOL Ltd., Tokyo, Japan) operating at 399.78 MHz
(1H), 161.83 MHz (31P{1H}), and 100.53
(13C{1H}). Measurements were made in solutions
of CDCl3 or D2O + NaOD at 300 K, and solvents
were supplied by ARMAR AG (Dottingen, Switzerland). Chemical shifts
are reported in ppm relative to tetramethylsilane (TMS) and 85% H3PO4, used as external standards, and coupling constants
are reported in Hz. Melting points were determined on an SRS Melting
Point Apparatus OptiMelt MPA 100 (Stanford Research Systems, Sunnyvale,
CA) and are reported uncorrected. Mass spectra (MS) were recorded
at the Faculty of Chemistry, Wroclaw University of Science and Technology
using a Waters LCT Premier XE mass spectrometer (method of electrospray
ionization, ESI) (Waters, Milford, MA).
Synthetic Procedures
Synthesis
of Substrates
4-Benzylmorpholin-3-one
A round-bottom
flask was charged
with morpholin-3-one (1 g, 9.85 mmol) and N,N-dimethylformamide (30 mL). The resulting solution was
cooled to 0 °C, and sodium hydride (60% in mineral oil, 0.51
g, 12.85 mmol) was added. The suspension was allowed to warm to room
temperature, and benzyl bromide (2.47 mL, 20.77 mmol) was added. The
reaction mixture was stirred for 16 h. Upon completion, the reaction
was quenched with brine (10 mL), extracted with ethyl acetate (3 ×
20 mL), and dried over anhydrous Na2SO4. The
crude residue was purified by flash chromatography on silica using
40% acetone in pentane as eluent. Yield 1.88 g (100%) of a colorless
oil. 1H NMR (399.78 MHz, CDCl3, ppm): δ
= 3.25 (m, 2H, C2O), 3.82
(m, 2H, C2N), 4.23 (s, 2H,
C2O), 4.61 (s, 2H, C2Ph), 7.29 (m, 5H, Ar); 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ
= 45.56, 49.54, 64.01, 68.27, 127.84, 128.35, 128.85, 136.27, 166.90
ppm; high-resolution mass spectrometry (HRMS) (time-of-flight (TOF)
MS ESI): calcd for C11H14NO2 [M +
H]+, m/z 192.1024; found m/z 192.1024.
4-Benzylthiomorpholin-3-one
4-Benzylthiomorpholin-3-one
was obtained analogously as above yielding as a colorless oil; yield
1.88 g (99%). 1H NMR (500.13 MHz, CDCl3, ppm):
δ = 2.77 (m, 2H, C2S6), 3.39 (s, 2H, C2S),
3.54 (m, 2H, C2N), 4.65
(s, 2H, C2Ph), 7.30 (m,
5H, Ar) ppm. 13C{1H}NMR (125.75 MHz, CDCl3): δ = 26.6, 30.7, 48.8, 50.9, 127.9, 128.2, 129.0,
137.0, 166.8 ppm. HRMS (TOF MS ESI): calcd for C11H14NOS [M + H]+, m/z 208.0796; found m/z 208.0788.
A solution of
cytosine (1 g, 9 mmol) and tosyl chloride (7.72 g, 40.5 mmol) in dry
pyridine (135 mL) was stirred at room temperature for 6 h. The pyridine
was evaporated, the oily residue dissolved in ethyl acetate, and extracted
twice with water. The organic layer was dried over sodium sulfate,
filtered, and the solvent was evaporated. The dark brown oil was separated
and purified by column chromatography using silica/chloroform/methanol
(95:5) resulting in a white solid. Yield 1.56 g (68%); mp 169–172 °C. 1H NMR (399.78 MHz, CDCl3, ppm): δ = 2.39
and 2.46 (s, 3H each, C3), 7.28 (d, J = 8.00 Hz, 2H, Ar), 7.38 (d, J = 8.16
Hz, 2H, Ar), 7.77 (d, J = 8.34 Hz, 2H, Ar), 7.93
(d, J = 8.47 Hz, 2H, Ar), 7.98 (d, J = 8.32 Hz, 1H, C=C) ppm; 13C{1H}NMR (100.53 MHz, CDCl3, ppm):
δ = 21.7, 22.0, 126.9, 127.1, 129.8, 129.9, 130.1, 130.3, 132.3,
137.8, 147.6 ppm; HRMS (TOF MS ESI): calcd for C18H18N3O5S2 [M + H]+, m/z 420.0687; found m/z 420.0685.
General Procedure for Reacting
of Amides with Phosphoryl Chloride
and Triethyl Phosphite
Appropriate amide (5 mmol) and triethyl
phosphite (1.79 mL, 10.48 mmol) were mixed in an ice bath followed
by the dropwise addition of phosphoryl chloride (0.97 mL, 10.48 mmol)
for 20 min under an argon atmosphere. The solution was left for 24
h, and to the mixture was poured a cold solution of ammonia (final
pH 7). The product was extracted with methylene chloride (3 ×
50 mL). The methylene chloride layers were combined and dried over
sodium sulfate. The drying agent was then removed by filtration, and
the volatile components of the reaction mixture removed under reduced
pressure. The crude product was purified by column chromatography
using silica/chloroform/methanol.
Tetraethyl (cis-piperazine-2,3-diyl)bisphosphonate
(10) was obtained as a yellow oil. After column chromatography,
fractions of pure cis and trans isomers were obtained and a fraction
containing both isomers in a nonequimolar ratio. Yield 0.1 g (6%); 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.31
and 1.32 (d, J = 7.1 Hz, 6H each of 4 × C3), 2.82 and 2.94 (m, 2H each,
C2N), 3.29 and 3.32 (d, J = 14 Hz, 2H, 2 × CP), 4.18 (m, 8H, 4 × C2OP). 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.47 and 16.50 and 16.53 and 16.56 and 16.60 (d, J = 3 Hz; each of H3), 41.44 and 41.50 (d, J = 6 Hz, H2N), 44.9 (H2N) 46.2 (2 × HP), 62.98
and 63.03 and 63.86 and 63.89 (d, J = 3.0 Hz, each
of 4 × H2OP) ppm. 31P{1H}NMR (161.83 MHz, CDCl3, ppm):
δ = 21.31 ppm. HRMS (TOF MS ESI): calcd for C12H29N2O6P2 [M + H]+, m/z 359.1500; found for [M + H]+, m/z 359.1501.
4-Methyl-N-(2-oxo-6-(oxophosphanyl)-1-tosyltetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamide (19) was obtained
as a white solid. Yield 0.55 g (70%); mp 159–162 °C; 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.25
and 1.27 (t, J = 7.2, 7.8 Hz, 3H, 2 × C3), 2.40 and 2.42 (s, 3H each,
C3Ph), 3.07 (m, 2H, C2C=N), 4.09 (m, 4H, C2OP), 5.04 (m, 1H, CP), 7.29 and 7.33 (d, J = 8.17
Hz, 2H each, Ar), 7.78 (d, J = 8.24 Hz, 2H, Ar),
8.02 (d, J = 8.32, 2H, Ar); 13C{1H}NMR (100.53
MHz, CDCl3, ppm): δ = 16.3 and 16.4 (d, J = 5.5 Hz, each of H3),
21.7 and 21.8 (s, H3Ph),
32.0 (H2), 47.7 (d, J = 160.0 Hz, P), 63.82 and
64.21 (d, J = 7.0 Hz, each of H2OP), 126.5, 127.2, 129.4, 129.5, 129.7, 129.75, 129.81, 134.7,
136.9, 144.8, 145.9, 146.0, 158.0 (=O); 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 18.56. IR (ν cm–1): 1019 (P=OC), 1225 (P=O), 1661 (C=O), 3283
(N – H); HRMS (TOF MS ESI): calcd for C22H28N3NaO7PS2Na [M+ Na]+, m/z 564.1004; found m/z 564.1004.
Hydrolysis of Esters
Method
A
The obtained tetraethyl bisphosphonate (30
mmol) was refluxed for 12 h in 20 mL of 6 M aqueous hydrochloric acid
solution. Then, the volatile components were evaporated, and the resulting
crude product was recrystallized from water, anhydrous ethanol, or
water–ethanol mixture.
cis-(Piperazine-2,3-diyl)bisphosphonic
acid (13) was obtained as a white solid. Yield 100%;
mp 245–248 °C; very badly soluble, 1H NMR (399.78
MHz, D2O, very badly soluble, ppm): δ = 2.88 (m,
2H, C2NH), 3.13 (m, 2H,
CP), 3.36 (m, 2H, C2NH); 31P{1H}NMR (161.83
MHz, D2O, ppm): δ = 16.93; HRMS (TOF MS ESI): calcd
for C4H12N2NaO6P2 [M + Na]+, m/z 269.0068;
found m/z 269.0072.Appropriate bisphosphonate
(0.22 mmol) was dissolved in dry dichloromethane
(200 mL) under nitrogen, and the flask cooled to 0 °C. After
5 min, bromotrimethylsilane (4.4 mL, 3.3 mmol) was added dropwise
over 5 min. The reaction was carried out exactly, as described in
the literature.[5]
Method
B: Procedure for Dealkylation with TMSBr
Morpholine-3,3-diylbisphosphonic
Acid (3)
Morpholine-3,3-diylbisphosphonic acid
(3) was obtained
as a white solid. Yield 0.63 g (60%); mp 139–143 °C. 1H NMR (500.13 MHz, D2O, ppm): δ = 2.13 (s,
2H, C2O), 2.68 (dd, J = 11.82, 11.88 Hz, 2H, C2CP2), 2.86 (s, 2H, C2NH) ppm. 13C{1H}NMR (100.53
MHz, D2O, ppm): δ = 26.1, 28.86 and 28.94 (d, J = 9.9 Hz, each of CH2CP2), 40.7, 56.12 and 57.14 (d, J = 128.7 Hz, each of P2) ppm; 31P{1H}NMR (202.46 MHz, CDCl3, ppm): δ = 19.37 ppm. HRMS (TOF MS ESI): calcd for C4H12NO7P2Na [M + Na]+, m/z 269.9908; found m/z 269.9905.
Thiomorpholine-3,3-diylbisphosphonic Acid
(4)
Thiomorpholine-3,3-diylbisphosphonic acid
(4) was
obtained as a white solid. Yield 0.138 g (60%); mp 245–248
°C. 1H NMR (500.13 MHz, D2O, ppm): δ
= 2.81 (AB system, J = 5.2, 5.3 Hz, 2H, C2S), 3.19 (dd, J = 9.1, 12.4 Hz, 2H, C2CP2), 3.69 (AB system, J = 5.3, 5.4 Hz,
2H, C2NH) ppm; 13C{1H}NMR (125.75 MHz, D2O, ppm): δ =
23.86, 28.79, 42.0, 57.4 and 58.3 (d, J = 109.6 Hz,
each of P2) ppm; 31P{1H}NMR (202.46 MHz, D2O, ppm): δ =
10.99 ppm. HRMS (TOF MS ESI): calcd for C4H12NO6P2SNa [M + Na]+, m/z 285.9680; found m/z 285.9674.
Tetraethyl (4-Benzylmorpholine-3,3-diyl)bisphosphonate
(9) by Procedure of Wang et al.[6]
Trifluoromethanesulfonic anhydride (0.2 mL, 1.2 mmol, 1.2
equiv) was added dropwise to a cooled (−78 °C) solution
of 4-benzylmorpholin-3-one (0.28 g, 1.0 mmol, 1.0 equiv) and DTBMP
(0.82 g, 4.0 mmol, 4.0 equiv) in dichloromethane (5 mL) and stirred
for 30 min, then at 0 °C (in an ice bath) for 10 min. Then, diethyl
phosphite (0.386 mL, 3.0 mmol, 3.0 equiv) was added to the mixture
and stirred for 5 h. The reaction was quenched with a saturated sodium
hydrogen carbonate solution (10 mL) and extracted with dichloromethane
(3 × 10 mL). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfonate, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent: DCM/MeOH = 50:1) to afford 0.3 g (70%) of the
desired product as a colorless oil. 1H NMR (399.78 MHz,
CDCl3, ppm): δ = 1.35 (m, 12H 4 × C3), 2.87 (t, J = 5.2,
5.2 Hz, 2H, C2N), 3.72 (t, J = 5.2, 5.2 Hz, 2H, C2O), 4.25 (m, 8H, 4 × C2OP), 4.42 (s, 2H, C2Ph), 7.29 (m, 5H, Ph); 13C{1H}NMR(100.53
MHz, CDCl3, ppm): δ = 16.55 and 16.59 and 16.62 and
16.64 (d, J = 3 Hz, each of H3), 46.25 and 46.30 (d, J =
4.8 Hz, H2N), 58.6 (H2Ph), 62.91 and 62.95 and 63.31
and 63.34 (d, J = 3.3 Hz, CH2OP), 64.69 and 66.03 (d, J = 134.6 Hz, each of HP2), 67.5 (s, H2O), 69.61 and 69.64 (d, J = 3 Hz, each of CH2O), 127.25, 128.23, 129.20, 138.14; 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 20.91;
HRMS (TOF MS ESI): calcd for C19H34NO7P2 [M + H]+, m/z 450.1810; found m/z 450.1807.
Crystallography
Relevant crystallographic data for
the molecules and the full geometrical information are summarized
in Tables S2.1–S2.3 of the Supporting
InformationThe single-crystal X-ray diffraction experiments
were performed at 100.0(1) K (12, 13, and 19) and at 293(2) K (14) on an Xcalibur diffractometer
(Rigaku Oxford Diffraction, Sevenoaks, Kent, U.K.), equipped with
a CCD detector and a graphite monochromator (Rigaku Oxford Diffraction)
with Mo Kα radiation and furnished with an Oxford Cryosystem
N2 gas stream device. The reciprocal space was explored
by ω scans. The reflections were measured with a radiation exposure
time from 4 to 25 s, according to diffraction intensities. The detector
was positioned at a 60-mm distance from the crystal. Procession of
the diffraction data was performed using the CrysAlis CCD.[7] Structures for compounds 12, 13, and 19 were solved in the triclinic crystal
system, P̅1 space group. Compound 14 solved in the monoclinic crystal system, 21/c space group (Table S2.1), by direct methods and refined by a full-matrix least-squares
method using the SHELXL14 program.[8] Lorentz
and polarization corrections were applied. Nonhydrogen atoms were
refined anisotropically. In structures, H atoms were refined using
a riding model. The structure drawings were prepared using the OLEX2
program.[9] The crystallographic data for
all compounds have been deposited at the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC 1888865 (12), CCDC 1888866 (13), CCDC 1888867 (14),
CCDC 1888868 (19). These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk.
Authors: Alexandria P Taylor; Ralph P Robinson; Yvette M Fobian; David C Blakemore; Lyn H Jones; Olugbeminiyi Fadeyi Journal: Org Biomol Chem Date: 2016-07-12 Impact factor: 3.876
Authors: Gavin D Kenny; Karen P Shaw; Saranja Sivachelvam; Andrew J P White; Rene M Botnar; Rafael T M de Rosales Journal: J Fluor Chem Date: 2016-04 Impact factor: 2.050
Authors: José Luis Viveros-Ceballos; Lizeth A Matías-Valdez; Francisco J Sayago; Carlos Cativiela; Mario Ordóñez Journal: Amino Acids Date: 2021-03-01 Impact factor: 3.520
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Figure 1
Figure 2
Scheme 8
Scheme 9
Scheme 10
Figure 3