Synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides

Article abstract of DOI:10.1016/j.tetlet.2009.11.010

The method for the synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones is described. It is shown that the reaction of phosphorus trichloride, 2-pyrrolidones and 6-aminopyrimidines brings to condensation producing 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides. The reaction of 6-imino-1,3-dimethyl-5-tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinedione with benzoyl chloride produces 10-benzoyl-2,4-dimethyl-6-phenyl-1,2,3,4,8,9-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]pyrimidine-1,3-dione. A method for the selective reduction of the carbomethoxy group of methyl 5-(4-imino-1,3-dimethyl-2,6-dioxohexahydro-5-pyrimidinyliden)-2-pyrrolidine carboxylate by system NaBH₄/1,4dioxane/CoCl₂/PEG-400 is described.

Full text of DOI:10.1016/j.tetlet.2009.11.010

Tetrahedron Letters 51 (2010) 231–233
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Tetrahedron Letters
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Synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-
pyrimidinediones as intermediates for the synthesis of C-azanucleosides
b
a
a
b
Ashot Martirosyan a, , Rafael Tamazyan , Sahak Gasparyan , Marina Alexanyan , Henry Panosyan ,
*
Vahan Martirosyan a, Raymond Schinazi c
a Institute of Fine Organic Chemistry, National Academy of Sciences RA, Azatutyan Avenue 26, 0014 Yerevan, Armenia
b Molecular Structure Research Center, National Academy of Sciences RA, Azatutyan Avenue 26, 0014 Yerevan, Armenia
c Emory University School of Medicine, Veterans Affairs, Medical Center 1670, Clairmont Road, 151-H Decatur, Georgia 30033-4004, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The method for the synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones
is described. It is shown thatthe reaction of phosphorus trichloride, 2-pyrrolidones and 6-aminopyrimidines
brings to condensation producing 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinedi-
ones as intermediates for the synthesis of C-azanucleosides. The reaction of 6-imino-1,3-dimethyl-5-tetra-
hydro-2-pyrrolylidenhexahydro-2,4-pyrimidinedione with benzoyl chloride produces 10-benzoyl-2,
4-dimethyl-6-phenyl-1,2,3,4,8,9-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]pyrimidine-1,3-dione. A method
for the selective reduction of the carbomethoxy group of methyl 5-(4-imino-1,3-dimethyl-2,6-dioxo-
hexahydro-5-pyrimidinyliden)-2-pyrrolidine carboxylate by system NaBH4/1,4dioxane/CoCl2/PEG-400 is
described.
Received 4 September 2009
Revised 30 October 2009
Accepted 3 November 2009
Available online 10 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The structural determination of the synthesized compounds
was performed using X-ray crystallography, IR, and NMR spectro-
The modification of nucleosides has long been recognized as an
important approach to improve their antiviral or anticancer activ-
ities.1 In contrast to natural nucleosides, in C-nucleosides the ribo-
furanosyl moieties are linked to the heterocyclic base through a
carbon–carbon bond and they possess a more stable glycosidic
bond toward hydrolysis and enzymic reaction. Furthermore, the
sugar residue of C-nucleosides where the oxygen is replaced by a
nitrogen atom constitutes an another important class of C-azanu-
cleosides able to inhibit glycohydrolases which are responsible
for the cleavage of glycosidic bonds.2
scopic methods.
2. Results and discussion
It is well known that the condensation of imino ethers or imino
chlorides, particularly derived from pyroglutamic acid, with active
methylene reagents such as Meldrum’s acid and methyl cyanoace-
tate, lead to corresponding b-enaminoesters.4 This precedent al-
lowed us to postulate a one-step condensation of 2-pyrolidones
with 6-aminopyrimidines 1a–b to prepare 6-imino-5-tetrahydro-
2-pyrrolylidenhexahydro-2,4-pyrimidinediones 2a–d by interac-
tion with phosphorus trichloride, probably through the formation
of intermediates such as the corresponding imino chlorides and
Vilsmeier-type complexes.5(Scheme 1).
The known methods for the synthesis of C-azanucleosides such
as Heck-coupling reactions, 1,3-dipolar cycloadditions, Mannich-
type C-nucleosidations, and Staudinger-aza-Wittig cyclization of
c
-azido ketones have been described in the literature.3 These
methods are multistage and complicated. Consequently, develop-
ment of new more readily accessible methods for their synthesis
becomes actual.
In this Letter, we report a one-step simple synthesis of 6-imino-
5-tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as
intermediates for the synthesis of C-azanucleosides and some fur-
ther transformations specific for these systems. The proposed ap-
proach assumes the application of hydrogenation processes in
the final stage of synthesis of C-azanucleosides.
It should be noted that the usage of 2-pyrrolidone instead of
1,4-dioxane brings to small increase of yields of synthesis of 2a–
b (Table 1). We believe that the low yields of 2b and 2d are caused
by bad solubility of the starting pyrimidines 1b, while the com-
pounds 2a and 2c were synthesized in good yields (Table 1).6
The condensation of 1a–b with 2-pyrrolidones gave only 2a–d,
and other isomers containing double bonds with the pyrrolidine
ring were not detected.
The method for selective reduction of amide and nitrile groups
by NaBH4/CH3OH/CoCl2 is well established.7 On the other hand, it
is known that cyclic polyethers (crown ethers) are able to acceler-
ate the reaction rates and induce high selectivity in reactions by
* Corresponding author.
E-mail address: ashot@enzymebiosystems.com (A. Martirosyan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.010

232
A. Martirosyan et al. / Tetrahedron Letters 51 (2010) 231–233
O
R N
O
R
N
O
O
X
O
X
R
O
R
O
N
H
N
H
N
N
NH2
OH
N
R
NH
N
R
NH2
,1,4 Dioxane
PCl3
N
H
C-Azanucleosides
2a-d
1a-b
(a) R=CH3, X=H; (b) R=H, X=H;
(c) R=CH3, X=COOCH3; (d) R=H, X=COOCH3
Scheme 1.
Table 1
Synthesis of 6-imino-5-tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinediones
2a–d
Compd no.
Solvent
Yield (%)
O
O
O
2a
2a
2b
2b
2c
2d
1,4-Dioxane
2-Pyrrolidone
1,4-Dioxane
2-Pyrrolidone
1,4-Dioxane
1,4-Dioxane
75
80
30
35
70
28
COCl
N
H
N
N
N
TEA, CHCl3
O
N
NH
N
N
O
4
2a
the crown ether-activated anion species. Polyethylene glycol (PEG-
400) is an excellent substitute for crown ethers and it has been
used as a co-solvent in the reduction of carbon–carbon triple or
double bonds by NaBH4/PdCl2 in PEG-400/CH2Cl2, where PdCl2 is
used in catalytic quantities.8 Using the system of NaBH4/1,4-diox-
ane/CoCl2/PEG-400 we anticipated a simple and selective reduc-
tion of the 6-imino group of 2c.
However, the 6-imino group of 2c had shown stability in the
conjugated system with carbon–carbon double bond, we observed
the reduction of the ester moiety of 2c with 3 equiv of NaBH4/1,4-
dioxane/CoCl2/PEG-400 in 80% yield (Scheme 2).9
In an attempt to increase the reductive activity of the 6-imino
group we used benzoyl chloride to acylate 2a. Surprisingly, we
found that a double incorporation of the benzoyl moiety had oc-
curred involving migration of C–C double bond into pyrrolidine
ring accompanied by an acylation of the enamine and condensa-
tion to give 4 (Scheme 3).10
It should be noted that a thin layer chromatography (TLC) con-
trol of the course of the reaction shows only the presence of the
starting and the final compounds. The final compound 4 was con-
sumed completely after the addition of 2 equiv of benzoyl chloride.
This observation allows supposing that all the above-mentioned
processes take place simultaneously.
Scheme 3.
C30
C29
C28
C6
C31
N3
O8
N5
C26
C27
C7
C2
N1
C4
C13
C11
N9
C17
C14
C15
C10
O12
C21
C16
C22
C24
C18
C20
C23
O19
C25
The assignment of the structure was further confirmed by X-ray
structure analysis of 4 as shown in Figure 1. The diffraction exper-
iment was carried out on CAD4 ‘Enraf-Nonius’ diffractometer. The
compound 4 C24H20N4O3 is crystallized in monoclinic C 2/c space
group (a = 36.230(7) Å, b = 5.4187(11) Å, c = 21.741(4) Å, b =
Figure 1.
110.43(3)°). A total of 9159 reflections were collected and 4763
are unique (Rint = 0.057). R1 and wR2 are 0.0549 [I > 2 (I)] and
r
0.1188 (all data), respectively. All observed interatomic distances
were in good agreement with their mean statistical values.11
It should be noted that all these compounds showed moderate
activity in primary lymphocytes infected with human immunode-
ficiency virus type 1 (HIV-1).12 HIV drug susceptibility assay was
done as previously described.13
O
O
N
N
N
N
NaBH4, CoCl2,
PEG-400
HN
HN
MeOOC
O
HN
HN
O
1,4-Dioxan
3. Conclusion
HO
2c
The synthesis of novel 6-imino-5-tetrahydro-2-pyrrolyliden-
hexahydro-2,4-pyrimidinediones as intermediates for the synthe-
sis of C-azanucleosides has been accomplished. The application
3
Scheme 2.

A. Martirosyan et al. / Tetrahedron Letters 51 (2010) 231–233
233
2,4-pyrimidinedione (2b): Product 2b was prepared in 30% of yield. Mp = 300–
305 °C; 1H NMR (DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 11.62 (1H, br, NH); 11.34 (1H,
br, NH);8.28 (2H, br, NH2);3.76(2H, t, J = 7.5, NCH2);3.30 (2H, t, J = 7.5, CH2);2.08
(2H, k, J = 7.5, CH2CH2CH2): 13C NMR (DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 20.0
(CH2); 35.6 (CH2); 50.4 (br, NCH2); 83.2 (C–CO); 147.9 (NC); 158.7 (NC); 164.0
(NC); 173.9 (NC). IR (thin film): 3330, 3295, 3110, 1736, 1709, 1651, 1529, 1467,
1384 cmÀ1. Anal. Calcd for C8H10N4O2: C, 49.48; H, 5.19; N, 28.85. Found: C,
49.77; H, 5.35; N, 28.73. Methyl 5-(4-imino-1,3-dimethyl-2,6-dioxohexahydro-5-
pyrimidinyliden)-2-pyrrolidine carboxylate (2c): Product 2c was prepared in 70%
of yield. Mp = 220–221 °C; 1HNMR (DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 11.92 (1H,
br, NH); 7.72 (1H, br, @NH); 4.64 (1H, ddt, J1 = 8.8, J2 = 6.6, J3 = 1.5, NCH); 3.69
(3H, s, OCH3); 3.37 (3H, s, NCH3); 3.18 (3H, s, NCH3); 3.22 (1H, m) and 3.16 (1H, m,
CH2); 2.15 (1H, m) and 1.90 (1H, m, CH2CH): 13C NMR (DMSO-d6/CCl4 1/3), d, ppm
(J, Hz): 25.6 (CH2); 27.1 (CH3); 29.0 (CH3); 38.5 (CH2); 51.0 (OCH3); 70.3 (CH);
83.7 (C–CO);149.5(NC);155.7(NC); 160.4(NC); 172.8(NC);175.6(OCO). IR(thin
film): 3500–3100 (br, s), 1743, 1700, 1610, 1568, 1534, 1460, 1380 cmÀ1. Anal.
Calcd for C12H16N4O4: C, 51.42; H, 5.75; N, 19.99. Found: C, 51.67; H, 5.61; N,
20.12. Methyl5-(4-imino-2,6-dioxohexahydro-5-pyrimidinyliden)-2-pyrrolidine-
carboxylate (2d): Product 2d was prepared in 28% of yield. Mp = 280–281 °C;
1H NMR (DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 10.71 (1H, br, NH); 10.54 (1H, br,
NH); 10.41 (1H, br, NH); 7.03 (1H, br, @NH); 4.63 (1H, dd, J1 = 8.6, J2 = 6.4, NCH);
3.65 (3H, s, OCH3); 3.35–2.97 (2H, m, CH2C@); 2.08 (1H, m, CHCH2); 1.82 (1H, m,
CHCH2). 13C NMR (DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 25.5 (CH2); 38.4 (CH2); 51.7
(OCH3); 70.8 (NCH); 83.0 (C–CO); 149.2 (NC); 156.5 (NC); 163.0 (NC); 175.1 (NC).
IR (thin film):3520, 3380, 3290, 3110, 1746, 1663, 1631, 1602, 1520, 1460,
1384 cmÀ1. Anal. Calcd for C10H12N4O4: C, 47.62; H, 4.80; N, 22.21. Found: C,
47.84; H, 4.67; N, 22.08.
of hydrogenation on the final stage of the synthesis of C-azanucle-
osides provides wide choice of catalysts for stereo selective and
asymmetric synthesis.
Described above, examples of transformations specific for these
systems (2a–d) such as the reaction of 6-imino-1,3-dimethyl-5-
tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinedione with
benzoyl chloride and a method for the selective reduction of the
carbomethoxy group of methyl 5-(4-imino-1,3-dimethyl-2,6-
dioxohexahydro-5-pyrimidinyliden)-2-pyrrolidine carboxylate by
system NaBH4/1,4dioxane/CoCl2/PEG-400 may play an essential
role in understanding and planning future investigations of similar
systems.
Studies on the extension of these reactions for the synthesis of
various C-aza nucleoside derivatives and 1,2,3,4,8,9-hexahydropy-
rimido[5,4-e]pyrrolo[1,2-c]pyrimidine-1,3-diones are in progress.
Acknowledgment
The authors are grateful to the Civilian Research and Develop-
ment Foundation (CRDF) (Grant No. ARB2-2701-YE-05).
7. (a) Satoh, T.; Suzuki, S. Tetrahedron Lett. 1969, 1931; (b) Shinichi, I.; Yoshiki, S.;
Koichi, I. Synthesis 1988, 995; (c) Akabori, S.; Takanoshi, Y. J. Chem. Soc., Perkin
Trans. 1 1991, 479.
Supplementary data
8. Suzuki, N.; Kaneko, Y.; Tsukanaka, T.; Nomoto, T.; Ayaguchi, Y.; Izawa, Y.
Tetrahedron 1985, 41, 2387.
13C and 1H NMR spectra14 for the compounds 2a–d, 3, 4 are
available. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.11.010.
9. 5-(5-Hydroxymethyltetrahydro-1H-2-pyrrolyliden)-6-imino-1,3-dimethylhexahy-
dro-2,4-pyrimidinedione 3: The mixture of 2c 2.8 g (10 mmol), NaBH4 1.1 g
(30 mmol), CoCl2Á6H2O 0.35 g (1.5 mmol), and PEG-400 4 g (10 mmol) in 10 mL
of 1,4-dioxane was stirred under reflux for 2 h. The mixture was concentrated
under reduced pressure. To the crude mixture was added 10 mL of ice water
and filtered. The residue was purified by crystallization from ethanol to give
2.0 g of 3 in 80% yield. Mp = 174–175 °C: 1H NMR (DMSO-d6/CCl4 1/3), d, ppm
(J, Hz): 12.31 (1H, br, NH); 7.49 (1H, br, @NH); 4.23 (1H, t, J = 5.5, OH); 4.04 (1H,
m, NCH); 3.44 (2H, m, OCH2); 3.35 (3H, s, NCH3); 3.17 (3H, s, NCH3); 3.21 (1H,
m) and 3.06 (1H, m, CH2C@); 1.90 (1H, m) and 1.58 (1H, m, CHCH2): 13C NMR
(DMSO-d6/CCl4 1/3), d, ppm (J, Hz): 23.97 (CH2); 27.02 (CH3); 28.78 (CH3);
37.96 (CH2); 65.10 (OCH2); 70.43 (CH); 83.82 (@C); 149.78 (N–C@); 155.68
(N@C); 160.59 (CO); 173.17 (CO). IR (thin film): 3345, 3270, 3190, 1703, 1624,
1560, 1549, 1470, 1380 cmÀ1. Anal. Calcd for C11H16N4O3: C, 52.37; H, 6.39; N,
22.21; Found: C, 52.22; H, 6.45; N, 22.50.
References and notes
1. (a) Slater, M. J.; Amphlett, E. M.; Andrews, D. M. J. Med. Chem. 2007, 50, 897; (b)
Butora, G.; Olsen, D. B.; Carroll, S. S. Bioorg. Med. Chem. 2007, 15, 5219; (c)
Guntaka, R. V.; Varma, B. R.; Weber, K. T. Int. J. Biochem. Cell Biol. 2003, 35, 22.
2. (a) Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Togo, H. J. Chem. Soc., Perkin
Trans. 1 1997, 29; (b) Ganem, B.; Papandreou, G. J. Am. Chem. Soc. 1991, 113,
898; (c) Schramm, V. L. Annu. Rev. Biochem. 1998, 67, 693.
3. (a) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L. Tetrahedron 1997,
53, 2915; (b) Yokoyama, M.; Ikeue, T.; Ochiai, Y. J. Chem. Soc., Perkin Trans. 1
1998, 2185; (c) Wong, C.-H.; Provencher, L.; Poroco, J. A. J. Org. Chem. 1995, 60,
1492; (d) Chen, X. Y.; Link, T. M.; Schramm, V. L. J. Am. Chem. Soc. 1996, 118,
3067; (e) Hainke, S.; Arndt, S.; Seitz, O. Org. Biomol. Chem. 2005, 3, 4233; (f)
Wellington, K. W.; Benner, S. A. Nucleosides, Nucleotides, Nucleic Acids 2006, 25,
1309; (g) Häberli, A.; Leumann, C. J. Org. Lett. 2001, 3, 489; (h) Kim, D. C.; Yoo, K.
H.; Kim, D. J.; Chung, B. Y.; Park, S. W. Tetrahedron Lett. 1999, 40, 4825.
4. Fasseur, D.; Rigo, B.; Leduc, C.; Cauliez, P.; Couturier, D. J. Heterocycl. Chem.
1992, 29, 1285.
10. 10-Benzoyl-2,4-dimethyl-6-phenyl-1,2,3,4,8,9-hexahydropyrimido[5,4-e]pyrrolo-
[1,2-c]pyrimidine-1,3-dione 4: To a CHCl3 (20 mL) solution of 2a 2.2 g (10 mmol)
and TEA 1.0 g (10 mmol) at room temperature was added benzoyl chloride
2.8 g (20 mmol). The mixture was stirred under reflux for 2 h. The organic
solution was washed with water, dried with MgSO4, and concentrated under
reduced pressure. The crude mixture was purified by crystallization from
methanol to give 2.7 g of 4 in 67% of yield. Mp = 249–250 °C: 1H NMR (DMSO-
d6/CCl4 1/3), d, ppm (J, Hz): 7.74 (2H, m, Haryl); 7.63 (2H, m, Haryl); 7.58–7.50
(3H, m, Haryl); 7.38–7.27 (3H, m, Haryl); 4.14 (2H, t, J = 9.2, NCH2); 3.45 (3H, s,
CH3); 3.02 (2H, dd, J1 = 9.8, J2 = 8.4, CH2); 1.82 (3H, s, CH3). 13C NMR (DMSO-d6/
CCl4 1/3), d, ppm (J, Hz): 27.1 (CH3); 28.9 (CH3); 29.3 (CH2); 49.2 (NCH2); 104.7
and 104.8 (C–CO); 126.9, 127.2, 127.6 and 128.0 (ortho and meta CH); 129.8
and 130.5 (para-CH); 132.8; 139.4; 140.8; 150.1; 154.9; 157.0; 160.7; 190.7
5. Black StC, D.; Bowyer, C. M.; Ivory, A. J.; Jolliffe, K. A.; Kumar, N. Tetrahedron
1996, 52, 4687.
6. Typical experimental procedure for preparation of 2a–d: To a 1,4-dioxane (10 mL)
solutionof 2-pyrrolidone or pyroglutamicacid methylether (0.3 mmol) at 0–5 °C
was added PCl3 (0.3 mmol). The mixture was stirred at room temperature for
10 min, and 1a–b (2 mmol) in 1,4-dioxane (10 mL) was added over a period of
10 min. The stirring was continued at 90–95 °C for 5 h. The mixture was
concentrated under reduced pressure. To the crude mixture was added 20 mL of
ice water, filtered, and neutralized with 30% NH4OH. The residue was separated
by filtration and purified by crystallization from the convenient solvent. 6-Imino-
1,3-dimethyl-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinedione
(2a): Product 2a was prepared in 75% of yield. Mp = 214–215 °C; 1H NMR (DMSO-
d6/CCl4 1/3), d, ppm (J, Hz): 12.22 (1H, br, NH); 7.51 (1H, br, NH); 3.79 (2H, tt,
J1 = 7.5, J2 = 1.7, NCH2); 3.35 (3H, s, CH3); 3.17 (3H, s, CH3); 3.12 (2H, tt, J1 = 8.2,
J2 = 1.7, CH2C@N); 1.82 (2H, J1 = 8.2, J2 = 7.5, CH2CH2CH2); 13C NMR (DMSO-d6/
CCl4 1/3), d, ppm (J, Hz): 21.5 (CH2); 27.0 (CH3); 28.9 (CH3); 38.1 (CH2); 57.0
(NCH2); 83.8 (C–CO); 149.7 (NC); 155.6 (NC); 160.4 (NC); 173.2 (NC). IR (FT-IR
Necsus Nicolet spectrometer, thin film):3320, 3297, 1699, 1620, 1567, 1528,
1470, 1385 cmÀ1. Anal. Calcd for C10H14N4O2: C, 54.04; H, 6.35; N, 25.21. Found:
C, 54.22; H, 6.57; N, 25.03. 6-Imino-5-tetrahydro-1H-2-pyrrolylidenhexa hydro-
(CO-Ph). IR (thin film):1704, 1669, 1604, 1560, 1501, 1468, 1380 cmÀ1 Anal.
.
Calcd for C24H20N4O3: C, 69.89; H, 4.89; N, 13.58. Found: C, 69.72; H, 4.93; N,
13.75.
11. CCDC 655561 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
12. The antiviral 50% effective concentration (EC50) was determined from the
concentration–response curve using the median effect method. EC50 for
compounds 2a––57
>100 M, 4––4.5 M.
lM, 2b––>100 lM, 2c––32 lM, 2d––>100 lM, 3––
l
l
13. Schinazi, R. F.; Sommadossi, J. P.; Saalmann, V.; Cannon, D. L.; Xie, M.-W.; Hart,
G. C.; Smith, G. A.; Hahn, E. F. Antimicrob. Agents Chemother. 1990, 34, 1061.
14. 1H and 13C NMR spectra were recorded on a Varian Mercury-300Vx instrument
(300.077 and 75.462 MHz, respectively) at 30 °C.