Synthesis of Baylis-Hillman-derived phosphonated 3-(benzylaminomethyl) coumarins

Article abstract of DOI:10.1080/00397910903531649

Treatment of Baylis-Hillman-derived 3-(chloromethyl)coumarins with benzylamine has afforded benzylamino derivatives, sequential chloroacetylation and Michaelis-Arbuzov phosphonation of which have provided access to a series of phosphonate esters as potent

Full text of DOI:10.1080/00397910903531649

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Synthesis of Baylis–Hillman-
Derived Phosphonated 3-
(Benzylaminomethyl)coumarins
Thompo J. Rashamuse a , Rosalyn Klein a & Perry T. Kaye a
a Department of Chemistry and Centre for Chemico- and
Biomedicinal Research , Rhodes University , Grahamstown, South
Africa
Published online: 09 Nov 2010.
To cite this article: Thompo J. Rashamuse , Rosalyn Klein & Perry T. Kaye (2010) Synthesis of
Baylis–Hillman-Derived Phosphonated 3-(Benzylaminomethyl)coumarins, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:24, 3683-3690,
DOI: 10.1080/00397910903531649
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Synthetic Communications1, 40: 3683–3690, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531649
SYNTHESIS OF BAYLIS–HILLMAN-DERIVED
PHOSPHONATED 3-(BENZYLAMINOMETHYL)-
COUMARINS
Thompo J. Rashamuse, Rosalyn Klein, and Perry T. Kaye
Department of Chemistry and Centre for Chemico- and Biomedicinal
Research, Rhodes University, Grahamstown, South Africa
Treatment of Baylis–Hillman-derived 3-(chloromethyl)coumarins with benzylamine has
afforded benzylamino derivatives, sequential chloroacetylation and Michaelis–Arbuzov
phosphonation of which have provided access to a series of phosphonate esters as potential
HIV-1 protease inhibitors.
Keywords: Amides; Baylis–Hillman; coumarins; Michaelis–Arbuzov phosphonation
Coumarin (2H-1-benzopyran-2-one) 1 was first isolated, in 1822, from the tonka
bean,[1] and many of its naturally occurring derivatives have been found to exhibit
interesting and useful biological activity. Warfarin 2,[2] for example, is not only used
medicinally as a blood anti-coagulant but also as a rodenticide; dicoumarol 3, found
in sweet clover hay, acts as an anti-coagulant but is also responsible for sweet clover
disease in cattle,[3,4] Warfarin 2 and its ‘‘deacetylated’’ analogue, phenprocoumon 4
both exhibit activity against HIV-1 protease,[5] the latter with an inhibition potential
of 1 mM. Binding of these compounds in the HIV-1 protease receptor cavity is con-
sidered to involve hydrogen-bonding interactions between the 4-hydroxy group
and the catalytic aspartic residues, and between the coumarin carbonyl group and
an Ile-50 residue.[6] Kostova et al.[7] have reported the anti-HIV activity of various
synthetic coumarins, and our own research on the development of novel HIV-1
protease inhibitors[8,9] has led us to explore the potential of coumarin derivatives
as scaffolds for the construction of truncated analogues of the hydroxyethylene
dipeptide isosteres currently in clinical use as HIV-1 protease inhibitors. In this
paper, we discuss the preparation of a series phosphonated 3-(benzylaminomethyl)-
coumarin derivatives as potential protease inhibitors.
We have previously reported the application of Baylis-Hillman methodology in
the construction of 3-(chloromethyl)coumarin derivatives 7 via the DABCO-catalysed
reaction of salicylaldehyde derivatives 5 with t-butyl acrylate (Scheme 1).[10] This
Received June 9, 2009.
Address correspondence to Perry T. Kaye, Department of Chemistry and Centre for Chemico- and
Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. E-mail: p.kaye@ru.ac.za
3683

3684
T. J. RASHAMUSE, R. KLEIN, AND P. T. KAYE
Scheme 1. Reagents and conditions: i) t-Butyl acrylate, DABCO, CHCl3; ii) HCl, Ac2O, AcOH, reflux; iii)
PhCH2NH2, THF; iv) ClCH2COCl, THF, reflux; v) P(OEt)3, N2, reflux.
approach permits isolation of the Baylis–Hillman adducts 6, acid-catalysed cyclisation
of which affords the 3-(chloromethyl)coumarin derivatives 7 in good yields (86% to
90%) and without the concomitant formation of isomeric chromenes.
The 3-(chloromethyl)coumarin derivatives 7 were reacted with benzylamine
using THF as solvent (Scheme 1) and, following evaporation of the solvent in vacuo,
the 3-(benzylaminomethyl)coumarin derivatives 8a–d were isolated by flash chroma-
tography in yields of up to 74% (Table 1). The 1H-NMR spectra of the benzylamino
derivatives 8a–d are characterised by the presence of two, methylene proton singlets
Table 1. Isolated yields (%) of compounds 8a–d, 9a–d, and 10a–d (Scheme 1)
R
8
9
10
a
b
c
H
74
61
64
35
64
72
70
56
60
77
77
86
8-OEt
6-Cl
6-Br
d

SYNTHESIS OF PHOSPHONATED 3-(BENZYLAMINOMETHYL)COUMARINS
3685
at ca. 3.7 and 3.8 ppm, and the 13C-NMR spectra by the corresponding methylene
carbon signals at ca. 53 and 48 ppm.
The 3-(benzylaminomethyl)coumarin derivatives 8a-d were then heated under
nitrogen with chloroacetyl chloride in THF for 45 minutes to afford the chloroace-
1
tamide derivatives 9a–d in yields of up to 72% (Table 1). The H- and 13C-NMR
spectra were complicated by the presence of additional signals, which are attributed
to the presence of rotamers arising from hindered rotation about the N-CO amide
bond—a conclusion supported by the fact that when samples were run at higher tem-
perature, the signals began to broaden and then coalesce (see Figure 1). Although
complicated by the presence of signals corresponding to both rotamers, the COSY,
HSQC and HMBC spectra were consistent with the assigned structures and the
molecular formulae are supported by the HRMS data.
Figure 1. 400 MHz 1H NMR spectra of compound 9d in DMSO-d6 at: a) 30 ꢀC; and b) 100 ꢀC.

3686
T. J. RASHAMUSE, R. KLEIN, AND P. T. KAYE
Figure 2. A schematic diagram of potential hydrogen-bonding interactions between the hydrolysed
analogue of ligand 10d and structural water molecules in the active site of the HIV-1 PR enzyme.[12]
In an earlier study,[11] we reported Michaelis–Arbuzov reactions of 3-(iodo-
methyl)- and 3-(chloromethyl)coumarins, the regiosectivity of which is determined
by various factors; in the present study, however, direct (SN) displacement of chlor-
ide by phosphite is the only option. Thus, when the chloroacetamide derivatives 9a–d
were heated under nitrogen with two equivalents of triethyl phosphite at 120–130 ꢀC,
flash chromatography afforded the phosphonated derivatives 10a–d in good yields of
up to 86% (Table 1). The 1H– and 13C–NMR spectra of the phosphonate esters were
also complicated – not only by the presence of amide rotamers, but also by the
1
expected H–31P and 13C–31P spin-spin coupling of proximate nuclei. Nevertheless,
the 1- and 2-D NMR and HRMS data permitted unambiguous characterization
of the products.
In vivo metabolism may be expected to effect hydrolysis of the phosphonate
diester moiety, and preliminary in silico modelling of the hydrolysed analogue of
ligand 10d revealed several potential hydrogen-bonding interactions with structural
water molecules in the active site of the HIV-1 PR enzyme (Figure 2).
Baylis–Hillman methodology has thus been used to provide access to precur-
sors, which have been subjected, successfully, to tandem amination, chloroacetylation
and Michaelis–Arbuzov phosphonation reactions to afford a series of phosphonated
coumarin derivatives. Enzyme-binding, enzyme-inhibition and in silico enzyme
receptor-site docking studies of these compounds are expected to elucidate their
potential as readily accessible HIV-1 protease inhibitors. The 2-chloroacetamides 9
are also expected to serve as useful precursors for the construction of more complex
derivatives.
EXPERIMENTAL
NMR spectra were recorded on Bruker AMX 400 and Biospin 600 spectro-
meters at 303 K in DMSO-d6 or CDCl3 and calibrated using solvent signals [7.25
(CHCl3) and 2.50 ppm (DMSO-d6) for 1H NMR; 77.0 (CDCl3) and 34.5 ppm
(DMSO-d6) for 13C NMR]. 31P NMR spectra were recorded using phosphoric acid
(H3PO4) as an internal reference. Melting points were measured using a hot-stage
apparatus and are uncorrected. Flash chromatography was performed using Merck
Silica gel 60 [particle size 0.040–0.063 mm (230–400 mesh)] and MN Kieselgel 60
(particle size 0.063–0.200 mm). Infrared spectra were obtained on a Perkin Elmer

SYNTHESIS OF PHOSPHONATED 3-(BENZYLAMINOMETHYL)COUMARINS
3687
FT-IR Spectrum 2000 spectrometer using nujol mulls. Low-resolution (EI) mass
spectra were obtained on a Finnigan-Mat GCQ mass spectrometer and high-
resolution (EI) mass spectra on a VG70-SEQ Micromass double-focussing magnetic
sector spectrometer (University of the North-West Mass Spectrometry Unit). The
reagents used in the present study were supplied by Aldrich and used without further
purification.
Docking of the hydrolysed derivative of ligand 10d into the receptor cavity of
an HIV-1 protease X-ray diffraction structure11 was explored using the Ligandfit
module in the Accelrys Cerius2 platform on an SG-O2 computer.
Compounds 6a–d, 7a–d, and 8a–d are known and were prepared following
reported methods.[10,11,13] The procedures used for the preparation of the com-
pounds reported in this study are illustrated by the following examples.
N-Benzyl-2-chloro-N-[(6-bromo-2-oxo-2H-chromen-3-yl)-
methyl]acetamide 9d
Chloroacetyl chloride (0.32 ml, 2 mmol) was added to 3-(benzylaminomethyl)-6-
bromocoumarin 8d (0.49 g, 1.4 mmol) in THF (6 ml) under nitrogen, and the mixture
was boiled under reflux for 45 minutes. After cooling, the solvent was removed in
vacuo and the residue crystallized from EtOH to afford N-benzyl-2-chloro-N-[(-
6-bromo-2-oxo-2H-chromen-3-yl)methyl]acetamide 9d as a white solid (0.34 g, 56%),
m.p. 109–111ꢀC (Found Mþ: 418.990988. C19H15BrClNO3 requires M:
418.992382); n (nujol)=cmꢁ1 OꢁC O (1721) and NꢁC O (1658); dH (400 MHz;
=
=
max
DMSO-d6) 4.27–4.71 (6H, series of signals, 3 ꢂ CH2), 7.23–7.80 (8H, overlapping mul-
tiplets, Ar-H) and 7.99 (1H, s, 4-H); m=z 421 (M þ 1, 18%) and 182 (100%).[14]
Diethyl N-Benzyl-N-[(6-bromo-2-oxo-2H-chromen-3-yl)-
methyl]carbamoylmethylphosphonate 10d
Triethyl phosphite (0.2ml, 0.8 mmol) was added to N-benzyl-2-chloro-N-
[(6-bromo-2-oxo-2H-chromen-3-yl)methyl]acetamide 9d (0.157g, 0.4 mmol), and the
mixture was boiled under reflux, under nitrogen, for 4 hours. After cooling to room
temperature, the crude mixture was flash chromatographed [on silica; elution with ethyl
acetate-hexane (1:2)] to afford diethyl N-benzyl-N-[(6-bromo-2-oxo-2H-chromen-
3-yl)methyl]carbamoylmethylþphosphonate 10d as a pale yellow solid (0.168g, 86%),
m.p. 137–139 ꢀC (Found M : 521.058999. C23H25BrNO6P requires M: 521.060287);
nmax (nujol)=cmꢁ1 OꢁC O (1721), NꢁC O (1658) and 1244 (P O); (400MHz;
CDCl3) 1.32 (6H, overlapping triplets, J ¼ 7 Hz, 2 ꢂ OCH2CH3), 3.10 (2H, d,
JP,H ¼ 22 Hz, CH2P), 4.17 (2H, overlapping multiplets, 2 ꢂ CH2OP), 4.50 and 4.83
(4H, 2 ꢂ s, 2 ꢂ CH2N), 7.19–7.60 (7H, m, Ar-H), 7.67 (1H, s, 5-H), and 7.93 (1H, s,
4-H); dC (100MHz; CDCl3)15 16.3 (d, JP,C ¼ 6.2 Hz, 2 ꢂ OCH2CH3), 33.6 (d,
JP,C ¼ 140 Hz, CH2P), 45.9 and 52.8 (2 ꢂ CH2N), 62.9 (d, JP,C ¼ 6.4 Hz, 2 ꢂ CH2OP),
117.0, 118.0, 120.9, 124.2, 126.2, 127.9, 129.1, 130.2, 133.9, 135.7, 138.0, and 151.9
=
=
=
=
(Ar-C), 160.5 and 166.2 (C O); m=z 523 (M þ 1, 16%) and 106 (100%).
Analytical data for other compounds isolated in this study are as follows.

3688
T. J. RASHAMUSE, R. KLEIN, AND P. T. KAYE
N-Benzyl-2-chloro-N-[(2-oxo-2H-chromen-3-yl)methyl]acetamide 9a
The procedure described for the synthesis of compound 9d was followed using
3-[(benzylamino)methyl]coumarin 8a (0.35 g, 1.3 mmol) and chloroacetyl chloride
(0.30 ml, 2.6 mmol) in THF (6 ml). Crystallization from ethanol afforded N-
benzyl-2-chloro-N-[(2-oxo-2H-chromen-3-yl)methyl]acetamide 9a as a white solid
(0.29 g, 64%), m.p. 98–100 ꢀC (Found Mþ: 341.083861. C19H16ClNO3 requires M:
341.081871); nmax(nujol)=cmꢁ1 OꢁC O (1721) and NꢁC O (1658); dH (400 MHz;
CDCl3) 4.15–4.45 (6H, series of signals, 3 ꢂ CH2), 7.23–7.57 (9H, overlapping multi-
plets, Ar-H) and 7.84 (1H, s, 4-H);14 m=z 341 (M þ 1, 22%) and 182 (100%).
=
=
N-Benzyl-2-chloro-N-[(8-ethoxy-2-oxo-2H-chromen-3-yl)-
methyl]acetamide 9b
The procedure described for the synthesis of compound 9d was followed using
3-[(benzylamino)methyl]-8-ethoxycoumarin 8b (0.54 g, 1.7 mmol) and chloroacetyl
chloride (0.4 ml, 4 mmol) in THF (8 ml). Chromatography [elution with ethyl
acetate-hexane (1:4)] afforded N-benzyl-2-chloro-N-[(8-ethoxy-2-oxo-2H-chromen-
3-yl)methyl]acetamide 55b as a brown oil (0.48 g, 72%) (Found Mþ: 385.108324.
C21H20ClNO4 requires M: 385.980888); nmax(nujol)=cmꢁ1 OꢁC O (1721) and
=
=
NꢁC O (1658); dH (400 MHz; DMSO-d6): 1.38 (3H, t, J ¼ 6.6 Hz, OCH2CH3),
4.17 (2H, q, J ¼ 6.8 Hz, OCH2CH3), 4.17–4.59 (6H, series of signals, 3 ꢂ CH2),
7.26–7.38 (8H, overlapping multiplets, Ar-H) and 7.78 (1H, s, 4-H);14 m=z 385
(M þ 1, 25%) and 182 (100%).
N-Benzyl-2-chloro-N-[(6-chloro-2-oxo-2H-chromen-3-yl)-
methyl]acetamide 9c
The procedure described for the synthesis of compound 9d was followed using
3-[(benzylamino)methyl]-6-chlorocoumarin 8c (0.18 g, 0.6 mmol) and chloroacetyl
chloride (0.13 ml, 1.2 mmol) in THF (4 ml). Crystallization from ethanol afforded
N-benzyl-2-chloro-N-[(6-chloro-2-oxo-2H-chromen-3-ylþ)methyl]acetamide 9c as
a
white solid (0.156 g, 70%), m.p. 120–122 ꢀC (Found M : 377.040222. C19H15Cl2NO3
requires M: 377.039949); nmax(nujol)=cmꢁ1 OꢁC O (1721) and NꢁC O (1658);
dH (400 MHz; CDCl3) 4.17–4.45 (6H, series of signals, 3 ꢂ CH2), 7.27–7.48 (8H,
overlapping multiplets, Ar-H), 7.74 (1H, s, 4-H);14 m=z 377 (M þ 1, 13%) and 91
(100%).
=
=
Diethyl N-Benzyl-N-[(2-oxo-2H-chromen-3-yl)-
methyl]carbamoylmethylphosphonate 10a
The procedure described for the synthesis of compound 10d was followed
using N-benzyl-2-chloro-N-[(2-oxo-2H-chromen-3-yl)methyl]acetamide 9a (0.16 g,
0.5 mmol) and triethyl phosphite (0.2 ml, 0.9 mmol). Chromatography afforded
diethyl
N-benzyl-N-[(2-oxo-2H-chromen-3-yl)methyl]carbamoylmethylphosphonate
10a as a yellow solid (0.134 g, 60%), m.p. 138–140 ꢀC (Found Mþ: 443.152637.
C23H26NO6P requires M: 443.149776); nmax(nujol)=cmꢁ1: OꢁC O (1721), NꢁC O
=
=

SYNTHESIS OF PHOSPHONATED 3-(BENZYLAMINOMETHYL)COUMARINS
3689
=
(1658) and 1244 (P O); (400 MHz; CDCl3) 1.31 (6H, overlapping triplets,
2 ꢂ OCH2CH3), 3.10 (2H, d, JP,H ¼ 22 Hz, CH2P), 4.09 (2H, overlapping signals,
2 ꢂ CH2OP), 4.51 and 4.85 (4H, 2 ꢂ s, 2 ꢂ CH2N), 7.22–7.67 (9H, overlapping multi-
plets, Ar-H) and 7.98 (1H, s, 4-H); dC (100 MHz; CDCl3)15 16.3 (d, JP,C ¼ 6.3 Hz,
2 ꢂ OCH2CH3), 33.6 (d, JP,C ¼ 130 Hz, CH2P), 45.8 and 52.7 (2 ꢂ CH2N), 62.9 (d,
JP,C ¼ 6.6 Hz, 2 ꢂ CH2OP), 116.3, 119.3, 123.5 124.4, 126.2, 128.0, 128.7, 129.1,
=
131.2, 135.9, 139.6 and 153.1 (Ar-C), 161.3 and 166.1 (C O); m=z 443 (M þ 1,
10%) and 106 (100%).
Diethyl N-Benzyl-N-[(8-ethoxy-2-oxo-2H-chromen-3-yl)-
methyl]carbamoylmethylphosphonate 10b
The procedure described for the synthesis of compound 10d was followed
using N-benzyl-2-chloro-N-[(8-ethoxy-2-oxo-2H-chromen-3-yl)methyl]acetamide 9b
(0.30 g, 0.8 mmol) and triethyl phosphite (0.26 ml, 2 mmol). Chromatography
afforded diethyl N-benzyl-N-[(8-ethoxy-2-oxo-2H-chromen-3-yl)methyl]carbamoyl-
methylphosphonate 10b as a brown oil (0.19 g, 77%) (Found Mþ: 487.174816.
C25H30NO7P requires M, 487.175991); nmax (nujol)=cmꢁ1 OꢁC O (1721), NꢁC O
=
=
=
(1658) and 1244 (P O); (400 MHz; CDCl3) 1.28 (6H, overlapping triplets,
2 ꢂ OCH2CH3), 1.46 (3H, t, J ¼ 7 Hz, Ar-OCH2CH3), 3.1 (2H, d, JP,H ¼ 22 Hz,
CH2P), 4.17 (6H, overlapping multiplets, 2 ꢂ CH2OP and Ar-OCH2CH3), 4.50
and 4.82 (4H, 2 ꢂ s, 2 ꢂ CH2N), 7.10–7.43 (8H, overlapping multiplets, Ar-H),
7.92 (1H, s, 4-H); dC (100 MHz; CDCl3)15 14.7 (Ar-OCH2CH3), 16.3 (d,
JP,C ¼ 4.2 Hz, 2 ꢂ OCH2CH3), 27.4 (d, JP,C ¼ 298 Hz, CH2P), 45.8 and 52.7
(2 ꢂ CH2N), 62.8 (d, JP,C ¼ 4.3 Hz, 2 ꢂ CH2OP), 65.0 (Ar-OCH2CH3), 119.5,
120.1, 124.2, 124.6, 126.3; 127.9, 128.0, 128.7, 129.1, 136.0, 139.8 and 146.3
=
(Ar-C), 160.9 and 166.1 (C O); m=z 487 (M þ 1, 24%) and 106 (100%).
Diethyl N-Benzyl-N-[(6-chloro-2-oxo-2H-chromen-3-yl)-
methyl]carbamoylmethylphosphonate 10c
The procedure described for the synthesis of compound 10d was followed
using N-benzyl-2-chloro-N-[(6-chloro-2-oxo-2H-chromen-3-yl)methyl]acetamide 9c
(0.46 g, 1.2 mmol) and triethyl phosphite (0.40 ml, 2 mmol). Chromatography afforded
diethyl N-benzyl-N-[(6-chloro-2-oxo-2H-chromen-3-yl)methyl]carbamoylmethylphoþs-
phonate 10c as a yellow solid (0.455 g, 77%), m.p. 165–167 ꢀC (Found M :
477.111852. C23H25ClNO6P requires M: 477.110804); nmax (nujol)=cmꢁ1 OꢁC O
=
=
=
(1721), NꢁC O (1658) and 1244 (P O); (400 MHz; CDCl3) 1.35 (6H, overlapping
triplets, 2 ꢂ OCH2CH3), 3.14 (2H, d, JP,H ¼ 22 Hz, CH2P), 4.09 (4H, overlapping mul-
tiplets, 2 ꢂ CH2OP), 4.55 and 4.87 (4H, 2 ꢂ s, 2 ꢂ CH2N), 7.27–7.49 (7H, m, Ar-H),
7.56 (1H, s, 5-H) and 7.93 (1H, s, 4-H); dC (100 MHz; CDCl3)15 16.3 (d, JP,C ¼ 6.2 Hz,
2 ꢂ OCH2CH3), 33.6 (d, JP,C ¼ 130 Hz, CH2P), 45.9 and 52.8 (2 ꢂ CH2N), 62.9 (d,
JP,C ¼ 6.5 Hz, 2 ꢂ CH2OP) 117.8, 120.4, 124.9, 127.2, 127.9, 128.7, 129.1, 129.7,
=
131.1, 135.8, 138.1 and 151.4 (Ar-C), 160.6 and 166.2 (C O); m=z 477 (M þ 1, 10%)
and 106 (100%).

3690
T. J. RASHAMUSE, R. KLEIN, AND P. T. KAYE
ACKNOWLEDGMENTS
The authors thank the Medical Research Council of South Africa (MRC),
the National Research Foundation (NRF: GUN 2069255), and Rhodes University
for generous bursary and financial support. Miss Yi-Chen Lee’s assistance with the
collection of some of the NMR data is gratefully acknowledged.
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13
14. C data not cited due to multiplicity of signals arising from rotamers at 30 ꢀC.
15. 13C data cited for major rotamer.