Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl)alkylphosphonate esters

Article abstract of DOI:10.1016/j.tet.2017.01.045

Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.

Full text of DOI:10.1016/j.tet.2017.01.045

Accepted Manuscript
Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl)alkyl-
phosphonate esters
Christiana M. Adeyemi, Michelle Isaacs, Dumisani Mnkandhla, Rosalyn Klein,
Heinrich C. Hoppe, Rui W.M. Krause, Kevin A. Lobb, Perry T. Kaye
PII:
S0040-4020(17)30068-6
10.1016/j.tet.2017.01.045
TET 28415
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 September 2016
Revised Date: 12 January 2017
Accepted Date: 19 January 2017
Please cite this article as: Adeyemi CM, Isaacs M, Mnkandhla D, Klein R, Hoppe HC, Krause RWM,
Lobb KA, Kaye PT, Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl)alkyl-
phosphonate esters, Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.045.
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ACCEPTED MANUSCRIPT
..
1

ACCEPTED MANUSCRIPT
Synthesis and Anti-parasitic Activity of
C-Benzylated (N-arylcarbamoyl)alkyl-phosphonate Esters
Christiana M. Adeyemia, Michelle Isaacsc, Dumisani Mnkandhlac, Rosalyn Kleina,c,
Heinrich C. Hoppeb,c, Rui W.M. Krausea,c, Kevin A. Lobba,c and Perry T. Kayea,c*
aDepartment of Chemistry, bDepartment of Biochemistry and Microbiology and cCentre for Chemico- and
Biomedicinal Research, Rhodes University, Grahamstown, 6140, South Africa.
Abstract. Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-
benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-
furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-
benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei
parasites which are responsible for African trypanosomiasis in cattle.
Keywords:
C-benzylation,
phosphonate esters
2-halogeno-3-phenylpropanoic acid
Michaelis-Arbuzov reaction
anti-parasitics
_________________
*Corresponding author:
Prof Perry Kaye.
E-mail. P.Kaye@ru.ac.za
Tel. +27 46 6037030; Fax. +27 466225109.
Dept. of Chemistry, Rhodes University,
Grahamstown, 6140, South Africa.
1

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1. Introduction
Malaria remains a major international health concern, particularly in developing countries,1
and the identification of new targets for therapeutic intervention provides opportunities for
discovering new antimalarial agents. The Plasmodium falciparum enzyme, 1-deoxy-1-D-
xylulose-5-phosphate reductoisomerase (PfDXR), has been identified as such a target.2
Fosmidomycin 1, a naturally occurring antibiotic, and its acetyl analogue FR900098 2 are
known to inhibit this enzyme3 and, in our research programme, we have been investigating
various ‘reverse’ fosmidomycin analogues 3 as potential PfDXR inhibitors (Figure 1).
In silico examination of the intramolecular topology of the PfDXR active-site4 has confirmed
the presence of nearby hydrophobic pockets, and N-benzylated phosphonate ester analogues,
containing a bimethylene spacer between the phosphonate and amide moieties, have been
prepared from N-benzylated arylamines in the expectation that the hydrophobic benzyl
moiety would occupy such a pocket.5,6 Surprisingly, while a number of these compounds
exhibited activity against the Pf parasite (IC50 ≥ 10.12 µM), they were inactive (as their
phosphonic acid derivatives) against the PfDXR enzyme, thus suggesting the involvement of
a different but, as yet, unknown mechanism. In this communication we report the preparation
of the series of C-benzylated analogues 6a-g in which the phosphonate and amide moieties
are separated by a single methylene spacer (Schemes 1 and 3).
OH
N
O
O
OH
N
O
O
H
P OH
OH
Ar
P OH
OH
( )n
N
P OH
OH
H
O
O
2
3
1
Figure 1.
2. Results and Discussion
Access to the desired C-benzylated phosphonate esters 6 proved unexpectedly frustrating.
Direct, base-catalysed benzylation of the (N-arylcarbamoyl)phosphonate esters 5a-f, which
we had synthesised previously,4 was considered a reasonable option, and exploratory studies
were undertaken using the available furfurylamine-derived phosphonate ester 5a as the
substrate. Five different methods (A-E; Scheme 1) were investigated. Reactions in dry THF
using pyridine (method A) or triethylamine (method B) as the base, both at room temperature
and at reflux, failed to afford any of the desired product. Refluxing a mixture of the
phosphonate ester 5a with benzyl bromide in 10% aqueous NaOH for ca 2 h (method C) was
similarly unsuccessful. Use of finely powdered KOH in dry THF (method D) afforded the
desired C-benzylated phosphonate ester 6a, but only in 10% yield. The benzylation of N-
arylcarboxamides under various conditions appears to favour the N-benzylated products − as
reflected in the reaction of N-arylacetamides with benzyl bromide and NaH in THF as
reported by Clarke et al.7 However, reaction of the (N-furfurylcarbamoyl)phosphonate ester
5a under similar conditions base (method E) gave a very different result. Thus, a solution of
the phosphonate ester 5a in dry THF was boiled under reflux with sodium hydride as base for
ca 6 hours and benzyl bromide (2.4 equivalents) was then added in two portions. After
2

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refluxing the mixture for 4 hours, work-up and chromatography afforded the desired C-
benzylated phosphonate ester 6a in 56% yield − not the N-benzylated analogue! C-
Benzylation is clearly supported by the NMR data. Thus, a P-methine proton multiplet at
1
δ 3.03 ppm in the H-NMR spectrum of the product 6a, replaces the P-methylene proton
doublet at δ 2.87 ppm observed in the spectrum of the precursor 5a, while DEPT-135 NMR
spectra show a P-methylene doublet for 5a at δ 34.2 ppm and a P-methine doublet for 6a at δ
47.1 ppm.8
O
O
O
O
Method
Yield/%
__________________________
P O
O
P O
O
N
N
H
H
A
: Et3N, BnBr, THF
0
0
O
O
B: Pyridine, BnBr, THF
C: 10% aq. NaOH, BnBr
D: KOH, BnBr, THF
E: NaH, BnBr, THF
Methods
A-E
5a
6a
0
10
56
Scheme 1.
Given its successful use in the α-benzylation of the furfurylamine-derived phosphonate ester
5a, method E (involving reaction with benzyl bromide in dry THF in the presence of NaH)
was applied to the (N-arylcarbamoyl)phosphonate esters 5b-e. However, 1H NMR analysis of
each of the purified products revealed the absence of the phosphonate ester moiety. Careful
examination of the experimenta data revealed that a totally unexpected transformation had
taken place to form the N-benzylated tetrahydrofuran-2-yl derivatives 7b-e (Scheme 2). The
origin of the tetrahydrofuran-2-yl moiety is attributed to the presence of the cyclic enol ether,
2,3-dihydrofuran, in the batch of THF used as the solvent in these reactions.8 Repetition of
the reaction with compound 5e using fresh THF, however, simply afforded the N-benzylated
product 8e rather than the desired C-benzylated analogues − and not the unusual
tetrahydrofuran-2-yl derivative 7e.8 It seems that the presence of the furfuryl group in
compound 5a decreases the acidity of the amide proton sufficiently,9 relative to the
methylene protons adjacent to the carbonyl group, to permit formation of the enolate I
(Figure 2) and subsequent C-benzylation to afford compound 6a. However, in compound 5e
(and, presumably, in the N-arylacetamides discussed by Clarke et al.7) the electron-
withdrawing N-aryl group enhances the acidity of the amide proton sufficiently (via both - I
and - M effects) to facilitate formation of the resonance-stabilised anion II and, hence, the
observed N-benzylation observed in this case and elsewhere.7
O
O
O
O
O
i
Ar
P O
O
Ar
P O
O
Ar
i
N
N
N
H
H
X
O
O
6b-e
5b-e
7b-e
_
_
Ar
ii
(for 5e)
_
_______________________
_
O
_
_
b
c
d
e
3-Bromophenyl
3-(Hydroxymethyl)phenyl
2-Pyridyl
_
Ar
P O
O
_
N
_
_
_
_
_
3-Hydroxyphenyl
8e
Scheme 2.
Reagents and conditions: i) NaH, BnBr, THF; ii) NaH, BnBr, fresh THF.
3

ACCEPTED MANUSCRIPT
OH
(b)
(a)
O
O
P
O
O
P
>
OEt
N
OEt
OEt
H
O
N
H
5e
5a
OEt
NaH
NaH
OH
OH
OH
O
O
O
O
P
O
O
P
O
O
P
P
OEt
OEt
OEt
OEt
N
H
N
N
N
OEt
OEt
OEt
OEt
ii
II
Resonance-stabilised anion
i
O
Enolate
intermediate
Ph
Br
Ph
Br
I
OH
O
O
O
O
P
OEt
P
OEt
N
H
N
OEt
OEt
O
C-Benzylated
product
N-Benzylated
product
Ph
Ph
8e
6a
Figure 2. a) C-Benzylation of the N-furfuryl derivative 5a. b) N-Benzylation of the N-(3-
hydroxyphenyl) derivative 5e.
Clearly, while the furfuryl derivative 6a could be obtained using method E (Scheme 1),
alternative approaches to an expanded series of the desired C-benzylated (N-arylcarbamoyl)-
phosphonate esters had to be explored. 2-Bromo-3-phenylpropanoic acid 11 was identified as
a possible key intermediate in the construction of the remaining targeted compounds (6)
(Scheme 3). Catalytic hydrogenation of cinnamic acid 9 afforded 3-phenyl-propanoic acid 10,
but attempted α-bromination of the latter compound using the Hell-Volhard-Zelinsky
reaction10 failed to afford compound 11. Attention was consequently turned to the preparation
of the α-chloro analogue 14 instead. N-Boc-phenylalanine 12 was de-protected by stirring
with 4
EtOAc afforded phenylalanine hydrochloride 13 in yields of up to 96%. Diazotisation of the
phenylalanine salt 13 in 6
-HCl afforded 2-chloro-3-phenylpropanoic acid 1411 which, on
M-HCl in dioxane for 2 hours at room temperature; work-up and trituration with
M
reaction with triethylphosphite, gave the corresponding ethyl ester 15 instead of expected
phosphonate ester 16. Consequently, amidation of 2-chloro-3-phenylpropanoic acid 14 was
effected via the acid chloride which was reacted directly with the aromatic amines, aniline
and 3-bromoaniline. Work-up and flash-chromatography afforded the corresponding, N-aryl-
2-chloro-3-phenylpropanamides 17g (which is known12), 17b and 17f in moderate yields (65-
71%). Michaelis-Arbuzov reactions of the intermediates 17f and 17g in refluxing
triethylphosphite (3 eq.) led to the targeted C-benzylated (N-arylcarbamoyl)phosphonate
esters 6f and 6g, but in low yields (25-45%).
Since bromide is generally a better leaving group than chloride, attention returned to the use
of 2-bromo-3-phenylpropanoic acid 11 in place of the 2-chloro analogue 14. In a variation of
the diazotisation conditions, a solution of phenylalanine hydrochloride 13 in 4
M
-H2SO4 (in
place of 6
M
-HCl) was treated with NaBr (3.5 eq) and NaNO2 (1.25 eq) in water at 0 ºC to
produce 2-bromo-3-phenylpropanoic acid 11 in 72% yield.13 The N-substituted 2-
bromopropanamides 19b-e,h were then obtained in 60-65% yield by reacting the
corresponding aromatic amines with 2-bromo-3-phenylpropanoic acid 11 in the presence of
the coupling agent 1,1'-carbonyldiimidazole (CDI) in DCM14 (instead of using the acid
chloride used to access to the 2-chloropropanamide analogues). Similar reaction of 3-
(hydroxymethyl)aniline, however, afforded the N,O-diacylated analogue, necessitating
4

ACCEPTED MANUSCRIPT
protection of the hydroxyl group prior to amidation. This was achieved by reacting 3-
(hydroxymethyl)aniline with tert-butyldimethylsilyl chloride (TBDMSCl; 1.1 eq) and
imidazole (1.5 eq) at 0 ºC in dry DCM, and the resulting TBDMS ether-protected derivative
18 was reacted with CDI and 2-bromo-3-phenylpropanoic acid 11 to afford (following in situ
cleavage of the unstable silyl ether 19h) 2-bromo-N-(hydroxymethyl)-2-phenylpropanamide
19c. Arbuzov reactions of the 2-bromo-2-phenyl-propanamides with triethylphosphite finally
afforded the phosphonate esters 6b,c,e,h in moderate yield (32-61%) following
13
chromatography. An interesting feature of the C-NMR spectra of the chiral C-benzylated
phosphonate esters (6) is that the inherently diastereotopic phosphonate O-methylene carbons
are observed to resonate as a pair of doublets exhibiting, in some cases, slightly different J,P,C
values.
Ph
O
O
O
Ar
P O
O
N
H
N
H
CO2H
CO2H
O
HO P O
OH
Ph
Ph
20b,e
x
5a
9
i
xi
Ph
O
Ph
Ph
O
ii
Ar
CO2H
Ar
N
H
ix
vii
N
X
H
Br
10
Br
EtO P O
OEt
11
6a-c,e-g
19b-e,h
viii
vii
O
Ar
CO2H
CO2H
CO2H
NH2..HCl
Ph
N
H
Ph
Ph
iv
Ph
iii
vi
Cl
NHBoc
Cl
17b,f,g
14
12
13
v
X
Ar
_______________________
a
b
c
d
e
f
Furfuryl
CO2H
CO2Et
Ph
3-Bromophenyl
Ph
15
3-(Hydroxymethyl)phenyl
2-Pyridyl
3-Hydroxyphenyl
3-Nitrophenyl
Phenyl
3-TBDMSO-phenyl
Cl
EtO P O
OEt
16
g
h
Scheme 3.
Reagents and conditions:- (i) H2, 10% Pd/C catalyst, AcOH; (ii) PBr3; (iii) 4
r.t., 2 h; (iv) 6
SOCl2, DMF, 70 ºC, 1 h, then ArNH2, DMF, overnight.; (vii) triethylphosphite, 120-150 ºC,
M
-HCl, dioxane,
M
-HCl, NaNO2, H2O, r.t., 24 h; (v) triethylphosphite, 120-150 ºC, 5 h; (vi)
10 h; (viii) NaBr, NaNO2, 4
(xi) NaH, BnBr, THF.
M
-H2SO4, H2O, r.t.; (ix) CDI, DCM, ArNH2; (x) TMSBr, DCM;
5

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Thus, while the furfuryl derivative 6a was readily obtained via direct N-benzylation of the
phosphonate ester precursor 5a (Scheme 1), the N-aryl analogues 6b-g had to be accessed by
very different routes, commencing from N-Boc-phenylalanine 12 (Scheme 3). Although the
purified phosphonate esters might have been expected to serve directly as possible pro-drugs
in the P.falciparum parasite (PfLDH) bioassays, in vitro evaluation of specific PfDXR
inhibition potential was expected to require the use of the phosphonic acid analogues. The
phosphonate ester 6e was hydrolysed to the corresponding, representative acid 20e using
bromotrimethylsilane in dry DCM.14 The phosphonic acid and the phosphonate esters were
then subjected to screening using a range of in vitro bioassays.15
None of the compounds tested (6a-c,e-g and 20e) exhibited significant cytotoxicity against
HeLa cells in concentrations of up to 100 µM; above this concentration, however, all nine
compounds were toxic. The C-benzylated (N-furfurylcarbamoyl)phosphonate ester 6a
exhibited low micromolar activity against malaria parasite lactate dehydrogenase (PfLDH)
(16.1% PfLDH viability at 20 µM; IC50 = 16.4 µM). This represents a marked improvement
in activity compared to the non-benzylated precursor 5a (64.1% PfLDH viability at 20 µM).
Surprisingly, the C-benzylated (N-arylcarbamoyl)phosphonate esters 6b,c,e-g − unlike the C-
benzylated (N-furfurylcarbamoyl)phosphonate ester 6a or the N-benzylated dimethylene-
linked analogues5 − failed to exhibit any significant PfLDH inhibition. The C-benzylated
phosphonic acid 20e also failed to inhibit PfDXR significantly at 20 µM. One of the
compounds, however, showed modest activity (6b: IC50 = 31 µM) against Nagana
Trypanosoma brucei (T.b.) parasites which are responsible for African trypanosomiasis in
cattle – an important agricultural problem.
In conclusion, convenient synthetic routes have been established to access a range of C-
benzylated diethyl phosphonate derivatives, and implicit regioselectivity issues have been
resolved. While the C-benzylated N-furfurylcarbamoyl derivative 6a exhibited encouraging
anti-malarial activity, the C-benzylated N-arylcarbamoyl derivatives 6b,c,e-g exhibited little
if any such activity. The observed inhibition of Nagana Trypanosoma brucei by one of the C-
benzylated N-arylcarbamoyl derivatives, however, raises interesting possibilities for parallel
studies on the development of novel trypanocides.
3. Experimental
1H and 13C NMR spectra were typically recorded on Bruker 300 or 400 MHz spectrometers
in CDCl3 and calibrated using solvent signals [δH: 7.26 ppm for residual CHCl3; δC: 77.0 ppm
(CDCl3)]. Melting points were measured using a hot stage apparatus and are uncorrected.
High-resolution mass spectra (HRMS) were recorded on a Waters API Q-TOF Ultima
spectrometer (University of Stellenbosch, Stellenbosch, South Africa). NMR spectra for new
compounds are available in the Supporting Information (File II). Methods for the preparation
and characterisation of new compounds are as follows.
3.1.
Diethyl 1-(N-furfurylcarbamoyl)-2-phenylethylphosphonate 6a. A solution of
diethyl (furfurylcarbamoyl)methylphosphonate 5a (0.35 g, 1.3 mmol) in THF (10 mL) was
added drop-wise over 10 min. to a stirred suspension of NaH (0.034 g, 1.4 mmol) in dry THF
(10 mL) under N2. The reaction mixture was stirred until the mixture became clear (30 min;
during which time, H2 was evolved), and a solution of benzyl bromide (0.19 mL, 1.7 mmol)
in THF (5 mL) was added drop-wise during 10 min. The resulting solution was refluxed for 4
6

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h, allowed to cool and then filtered. Water (10 mL) was added and the solvents evaporated in
vacuo. The crude product was chromatographed [PLC on silica gel; elution with hexane-
EtOAc (7:3)] to afford diethyl 1-(N-furfurylcarbamoyl)-2-phenylethyl-phosphonate 6a as an
orange oil (0.26 g, 56%); νmax/cm-1: 1675 (C=O); δH/ppm (300 MHz; CDCl3) 1.30 (6H, t, J =
6.0 Hz, 2 × CH3), 3.03 (1H, m, CHP), 3.08 and 3.32 (2H, 2 × m, CH2Ph), 4.09 (4H, m, 2 ×
OCH2CH3), 4.38 (2H, m, CH2N), 6.16 (lH, s, Ar-H), 6.28 (1H, s, Ar-H), 6.67 (lH, br s, NH)
and 7.20-7.32 (6H, overlapping m, Ar-H); δC/ppm (75 MHz; CDCl3) 16.4 (d, JP-C = 3.5 Hz, 2
× CH3), 32.8 (d, J = 9.1 Hz, CH2Ph), 36.9 (CH2N), 48.6 (d, JP-C = 129.5 Hz, CHP), 62.9 (d,
JP-C = 5.4 Hz, OCaH2CH3), 63.2 (d, JP-C = 6.8 Hz, OCbH2CH3), 107.5, 110.5, 126.7, 128.6,
128.9, 139.1, 142.1 and 151.3 (Ar-C) and 166.8 (C=O); HRMS (ESI) calc’d for C18H25NO5P
[M+H]+: 366.1470. Found 366.1466.
3.2. The general procedure for the synthesis of the N-benzylated 2-tetrahydrofuranyl
derivatives 7b-e is illustrated by the following example. A solution of diethyl [N-(3-
bromophenyl)carbamoyl]methylphosphonate 5b (0.10 g, 0.29 mmol) in dry THF (10 mL)
was added drop-wise over 10 min. to a stirred suspension of NaH (0.007 g, 0.3 mmol) in dry
THF (10 mL) under N2, The reaction mixture was stirred until a clear solution was obtained
(30 min.; during which time H2 was evolved), A solution of benzyl bromide (0.042 mL, 0.35
mmol) in dry THF (10 mL) was then added drop-wise during 10 min. , followed by further
benzyl bromide (0.19 mL, 1.7 mmol) in THF (5 mL), and the resulting solution was refluxed
for 4 h. After cooling, the mixture was filtered and water (10 mL) was added to the filtrate.
The solvents were evaporated in vacuo and the residue was chromatographed [PLC on silica
gel; elution with hexane-EtOAc (1:2)] to afford N-benzyl-N-(3-bromophenyl)-2-
(tetrahydrofuran-2-yl)acetamide 7b as an orange oil (0.034 g, 32%); νmax/cm-1: 1671 (C=O);
δH/ppm (400 MHz; CDCl3) 1.44 (2H, m, 3ʹ-CH2), 1.84 (2H, m, 4ʹ-CH2), 2.15 (1H, m, 2-CHa),
2.45 (1H, m, 2-CHb), 3.73 (2H, m, 5ʹ-CH2), 4.32 (1H, m, 2ʹ -CH), 4.88 (2H, m, CH2Ph), 6.91
(lH, d, J = 7.8 Hz, Ar-H), 7.15-7.22 (7H, overlapping m, Ar-H) and 7.43 (1H, d, J = 8.0 Hz,
Ar-H); δC/ppm (100 MHz; CDCl3) 25.8 (C-3ʹ), 31.6 (C-4ʹ), 40.5 (C-2), 53.1 (CH2Ph), 67.9
(C-5ʹ), 76.2 (C-2ʹ), 122.8, 127.6, 127.7, 128.6, 128.7, 128.9, 129.2, 130.8, 131.3, 132.0, 137.1
and 143.7 (Ar-C) and 170.5 (C=O); HRMS (ESI) calc’d for C19H21BrNO2 [M+H]+:
374.0756. Found 374.0749.
3.3.
The general procedure for the synthesis of the N-aryl-2-chloro-3-
phenylpropanamides (17) is illustrated by the following example. A mixture of 2-chloro-3-
phenylpropanoic acid 14 (0.1 g, 0.5 mmol), thionyl chloride (0.08 mL, 1.08 mmol) and a
catalytic amount of DMF (3 drops) was heated at 70 °C for 1 h. The resulting 2-chloro-3-
phenylpropanoic acid chloride was added dropwise to a stirred cold solution of 3-bromoaniline
(0.06 mL, 0.54 mmol) in DMF (1 mL), and the resulting mixture was stirred at rt overnight.
Excess water was added and the mixture extracted with EtOAc (3 × 15 mL). The organic layer
was dried over anhydr. MgSO4, filtered and concentrated in vacuo to afford N-(3-
bromophenyl)-2-chloro-3-phenylpropanamide 17b (0.12 g, 65%) as a brown oil; νmax/cm-1:
1668 (C=O); δH/ppm (600 MHz; CDCl3) 3.30 (1H, m, CHaPh), 3.51 (1H, m, CHbPh), 4.68
(1H, m, CHCl), 7.21-7.36 (8H, overlapping m, Ar-H), 7.73 (1H, s, Ar-H) and 8.05 (1H, s,
NH); δC/ppm (150 MHz; CDCl3) 41.5 (CH2Ph), 61.9 (CHCl), 118.8, 122.8, 123.3, 127.6,
128.3, 128.7, 129.9, 130.5, 135.8 and 138.0 (Ar-C) and 166.4 (C=O); HRMS (ESI) calc’d for
C15H14BrClNO [M+H]+: 337.9947. Found 337.9933.
7

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3.3.1 2-Chloro-N-(3-nitrophenyl)-3-phenylpropanamide 17f as a pale-yellow oil (0.31 g,
65%) following chromatography [PLC on silica gel; elution with EtOAc-hexane (5:5)];
νmax/cm-1 3486 (NH) and 1675 (C=O); δH/ppm (300 MHz; CDCl3) 3.27 (1H, dd, J = 13.5 and
7.5 Hz, CHaPh), 3.46 (1H, dd, J = 13.5 and 7.5 Hz, CHbPh), 4.66 (1H, dd, J = 7.5 and 4.5 Hz,
CHCl), 7.19-7.23 (5H, overlapping m, Ar-H), 7.45 (1H, m, Ar-H), 7.78 (1H, d, J = 9.0 Hz, Ar-
H), 7.94 (1H, d, J = 7.3 Hz, Ar-H), 8.15 (1H, br s, NH) and 8.27 (1H, m, Ar-H); δC/ppm (75
MHz; CDCl3) 41.4 (CH2Ph), 61.7 (CHCl), 115.3, 120.0, 120.1, 127.7, 128.7, 128.9, 129.6,
130.1, 135.6 and 138.0 (Ar-C) and 166.8 (C=O); HRMS (ESI-) calc’d for C15H12ClN2O3 [M-
H]- : 303.0536. Found 303.0534.
3.4.
tert-Butyldimethylsilyl ether-protected 3-aminobenzyl alcohol 18. Imidiazole (0.48
g, 7.14 mmol) was added to a solution of 3-aminobenzyl alcohol 5b (0.59 g, 4.8 mmol) in dry
°
DCM at 0 C. After stirring for 15 min., TBDMSCl (0.79 g, 5.23 mmol) was added in
portions and the reaction mixture was stirred overnight at room temperature. The solution
was diluted with DCM, washed with water and brine, dried over anhydr. MgSO4 and
evaporated in vacuo to afford the tert-butyldimethylsilyl ether-protected 3-aminobenzyl
alcohol 18 (1.08 g, 95%); νmax/cm-1: 3340 (NH); δH/ppm (300 MHz; CDCl3) 0.11 (6H, s,
Si(CH3)2), 0.95 [9H, s, C(CH3)3], 4.67 (2H, s, CH2OSi), 6.53 (1H, d, J = 8.7 Hz, Ar-H), 6.69-
6.72 (2H, overlapping m, Ar-H) and 7.11 (1H, t, J = 8.7 Hz, Ar-H); δC/ppm (75 MHz;
CDCl3) -5.10 [Si(CH3)2], 18.6 [C(CH3)3], 26.2 [C(CH3)3], 65.1 (CH2Ph), 112.9, 113.8, 116.4,
129.3, 142.9 and 146.5 (Ar-C); HRMS (ESI) calc’d for C13H24NOSi [M+H]+: 238.1627.
Found 238.1632.
3.5.
The general procedure for the preparation of propanamides (19) is illustrated by
the following example. 2-bromo-3-phenylpropanoic acid 11 (0.19 g, 0.81 mmol) was
dissolved in dry DCM and CDI (0.15 g, 0.89 mmol) was added in portions. The mixture was
stirred for 1 h before the tert-butyldimethylsilyl ether-protected amine 18 (0.19 g, 0.81 mmol)
was added and stirring was continued at room temperature for 48 h. The solution was
concentrated and the residue chromatographed [PLC chromatography] on silica gel; elution
with hexane-EtOAc (7:3)] to afford N-{[3-(tert-butyldimethylsilyloxy)methy]phenyl}-2-
bromo-3-phenylpropanamide 19h16 as a yellow oil 17 (0.16 g, 60%); νmax/cm-1: 1678 (C=O);
δH/ppm (300 MHz; CDCl3) 0.04 [6H, s, Si(CH3)2], 0.79 [9H, s, C(CH3)3], 3.20 (1H, dd, J =
15.0 Hz and 9.0 Hz CHbPh), 3.48 (1H, dd, J = 15.0 Hz and 6.0 Hz CHaPh), 4.46 (1H, m,
CHBr), 4.57 (2H, s, OCH2Ph), 7.98 (1H, d, J = 8.4 Hz, Ar-H), 7.11-7.26 (7H, overlapping m,
Ar-H), 7.38 (1H, s, Ar-H) and 7.71 (1H, br s, NH); δC/ppm (75 MHz; CDCl3) -5.12
[Si(CH3)2], 18.6 [C(CH3)3], 26.1 [C(CH3)3], 29.9 (CH2Ph), 52.0 (CHBr), 64.8 (CH2OSi),
117.7, 118.7, 122.8, 127.5, 128.2, 128.7, 129.1, 129.6, 137.1, 142.8 (Ar-C) and 166.1 (C=O);
HRMS (ESI) calc’d for C22H31BrNO2Si [M+H]+: 448.1307. Found 448.1301.
3.5.1. 2-Bromo-N-(3-bromophenyl)-3-phenylpropanamide 19b as a yellow solid (0.24 g,
69%), m.p. 116-118 °C; νmax/cm-1: 1670 (C=O); δH/ppm (600 MHz; CDCl3) 3.35 (1H, m,
CHaPh), 3.60 (1H, m, CHbPh), 4.60 (1H, m, CHBr), 7.26-7.36 (8H, overlapping m, Ar-H),
7.72 (1H, s, Ar-H) and 7.82 (1H, br s, NH); δC/ppm (150 MHz; CDCl3) 41.7 (CH2Ph), 51.7
(CHBr), 118.7, 123.2, 127.6, 128.2, 128.8, 129.0, 129.6, 130.5, 136.6 and 138.2 (Ar-C) and
166.3 (C=O); HRMS (ESI) calc’d for C15H14Br2NO [M+H]+: 381.9442. Found 381.9430.
3.5.2. 2-Bromo-N-[3-(hydroxymethyl)phenyl]-3-phenylpropanamide 19c16 as yellow oil
(0.16 g, 60%); νmax/cm-1: 1669 (C=O); δH/ppm (300 MHz; CDCl3) 3.34 (1H, dd, J = 12.0 Hz
and 6.0 Hz, CHaPh), 3.61 (1H, dd, J = 12.0 Hz and 4.5 Hz, CHbPh), 4.61 (1H, m, CHBr),
4.67 (2H, s, OCH2Ph), 7.14 (1H, d, J = 7.5 Hz, Ar-H), 7.25-7.31 (7H, overlapping m, Ar-H),
7.37 (1H, d, J = 8.2 Hz, Ar-H), 7.47 (1H, s, Ar-H) and 7.96 (1H, br s, NH); δC/ppm (150
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MHz; CDCl3) 41.7 (CH2Ph), 52.0 (CHBr), 65.1 (PhCH2OH), 118.7, 119.4, 123.6, 124.1,
125.0, 127.5, 128.7, 129.0, 129.6 and 130.2 (Ar-C) and 166.4 (C=O); HRMS (ESI) calc’d for
C16H17BrNO2 [M+H]+: 334.0443. Found 334.0429.
3.5.3. 2-Bromo-3-phenyl-N-(2-pyridyl)propanamide 19d as yellow oil (0.21 g, 62.5%);
νmax/cm-1: 1671 (C=O); δH/ppm (300 MHz; CDCl3) 3.24 (1H, dd, J = 13.5 Hz and 7.5 Hz,
CHaPh), 3.56 (1H, dd, J = 13.5 Hz and 7.5 Hz, CHbPh), 4.48 (1H, m, CHBr), 7.02 (1H, m,
Ar-H), 7.17-7.24 (5H, overlapping m, Ar-H), 7.67 (1H, t, J = 8.7 Hz, Ar-H), 8.12 (1H, d, J =
4.9 Hz, Ar-H), 8.21 (1H, d, J = 8.3 Hz, Ar-H) and 8.58 (1H, br s, NH); δC/ppm (75 MHz;
CDCl3) 41.3 (CH2Ph), 49.8 (CHBr), 127.5, 128.8, 129.1, 129.5, 129.7, 129.9, 136.8, 140.4,
143.3 and 150.4 (Ar-C) and 167.6 (C=O); HRMS (ESI) calc’d for C14H14BrN2O [M+H]+:
305.0290. Found 305.0294.
3.5.4. 2-Bromo-N-(3-hydroxyphenyl)-3-phenylpropanamide 19e as a brown solid (0.18
g, 63%), m.p. 118-120 °C; νmax/cm-1: 1677 (C=O); δH/ppm (300 MHz; CDCl3) 3.35 (1H, dd,
J = 15.0 Hz and 7.5 Hz, CHaPh), 3.61 (1H, dd, J = 13.5 Hz and 4.5 Hz, CHbPh), 4.61 (1H, m,
CHBr), 6.68 (2H, m, Ar-H), 7.17 (1H, t, J = 8.1 Hz, Ar-H), 7.28-7.32 (5H, overlapping m,
Ar-H) and 7.45 (1H, m, Ar-H); δC/ppm (150 MHz; CDCl3) 41.9 (CH2Ph), 51.9 (CHBr),
107.6, 111.9, 112.7, 127.6, 128.8, 129.6, 130.1, 136.6, 138.0 and 156.9 (Ar-C) and 166.8
(C=O); HRMS (ESI) calc’d for C15H15BrNO2 [M+H]+: 320.0286. Found 320.0275.
3.6.
The general procedure for Arbuzov reactions of the N-aryl-2-halogeno-3-phenyl-
propanamides 17b,g and 6b-f is illustrated by the following example. A mixture of 2-
bromo-N-[3-(hydroxymethyl)phenyl]-3-phenylpropanamide 19c (0.12 g, 0.35 mmol) and
triethylphosphite (0.2 mL, 1.1 mmol) under N2 was heated under reflux at 120-150 oC for 10
h. Preparative layer chromatography of the resulting mixture [on silica gel; elution with
EtOAc-hexane (6:4)] afforded diethyl 1-[N-(3-bromophenyl)carbamoyl]-2-phenylethyl-
phosphonate 6b as a pale white solid (0.086 g, 61%), m.p 108-110 °C; νmax/cm-1: 1671
(C=O); δH/ppm (600 MHz; CDCl3) 1.31 (3H, t, J = 5.1 Hz, CH3), 1.35 (3H, t, J = 5.5 Hz,
CH3), 3.13 and 3.20 (2H, 2 × m, CH2Ph), 3.43 (1H, m, CHP), 4.16 (4H, m, 2 × OCH2CH3),
7.07 (1H, m, Ar-H), 7.15 (1H, m, Ar-H), 7.21-7.26 (6H, overlapping m, Ar-H), 7.72 (1H, s,
Ar-H) and 8.73 (1H, br s, NH); δC/ppm (150 MHz; CDCl3) 16.40 and 16.44 (2xd, JP-C = 7.8
Hz, 2 × CH3), 32.5 (d, JP-C = 3.6 Hz, CH2Ph), 48.6 (d, JP-C = 127.1 Hz, CHP), 63.02 (d, JP-C
=
6.7 Hz, OCaH2CH3), 63.67 (d, JP-C = 6.7 Hz, OCbH2CH3), 118.3, 122.6, 122.8, 126.9, 127.3,
128.6, 128.6, 128.7, 130.2 and 139.2 (Ar-C) and 165.1 (C=O); HRMS (ESI) calc’d for
C19H24BrNO4P [M+H]+: 440.0626. Found 440.0634.
3.6.1. Diethyl 1-{N-[3-(hydroxymethyl)phenyl]carbamoyl}-2-phenylethylphosphonate
6c as a yellow oil (0.068 g, 48.9%) νmax/cm-1: 1694 (C=O); δH/ppm (600 MHz; CDCl3) 1.32
(6H, t, J = 6.8 Hz, 2 × CH3), 3.28 and 3.34 (2H, 2 × m, CH2Ph), 3.62 (1H, m, CHP), 4.10
(4H, m, 2 × OCH2CH3), 5.04 (2H, s, CH2OH), 7.26-7.37 (7H, overlapping m, Ar-H), 7.50
(2H, m, Ar-H) and 8.14 (1H, br s, NH); HRMS (ESI) calc’d for C20H25NO5P [M-1]+:
391.1470. Found 390.1454.17
3.6.2. Diethyl 1-[N-(3-hydroxyphenyl)carbamoyl]-2-phenylethylphosphonate 6e as a
white solid (0.095 g, 59%), m.p 158-160 °C; νmax/cm-1: 1677 (C=O); δH/ppm (600 MHz;
CDCl3) 1.28 and 1.29 (6H, 2xm, 2 × CH3), 3.13 (1H, m, CHP), 3.30 and 3.36 (2H, 2 × m,
CH2Ph), 4.13 (4H, m, 2 × OCH2CH3), 6.56 (1H, d, J = 7.6 Hz, Ar-H), 6.84 (1H, d, J = 7.3
Hz, Ar-H) 7.16-7.26 (5H, overlapping m, Ar-H), 7.47 (1H, s, Ar-H) and 8.47 (1H, br s, NH);
δC/ppm (150 MHz; CDCl3) 16.5 (d, JP-C = 5.4 Hz, 2 × CH3), 32.8 (d, JP-C = 3.2 Hz, CH2Ph),
49.5 (d, JP-C = 128.3 Hz, CHP), 63.3 (d, JP-C = 6.5 Hz, OCaH2CH3), 63.7 (d, JP-C = 6.5 Hz,
OCbH2CH3), 105.9, 107.2, 111.3, 112.1, 126.9, 128.7, 128.8, 123.0, 138.7 and 157.2 (Ar-C)
and 165.6 (C=O); HRMS (ESI) calc’d for C19H25NO5P [M+H]+: 378.1470. Found 378.1468.
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3.6.3. Diethyl 1-[N-(3-nitrophenyl)carbamoyl]-2-phenylethylphosphonate 6f as a yellow
oil (0.050 g, 45%); νmax/cm-1: 1667 (C=O); δH/ppm (300 MHz; CDCl3) 1.31 (6H, m, 2 ×
CH3), 3.24 and 3.26 (2H, 2 × m, CH2Ph), 3.48 (1H, m, CHP), 4.19 (4H, m, 2 × OCH2CH3),
7.13 (1H, s, Ar-H), 7.26-7.38 (5H, overlapping m, Ar-H), 7.51 (3H, m, Ar-H) and 8.6 (1H, br
s, NH); δC/ppm (150 MHz; CDCl3) 16.19 and 16.23 (2xd, JP-C = 6.7 Hz, 2 × CH3), 29.9
(CH2Ph), 61.2 (d, JP-C = 109.8 Hz, CHP), 64.7 (d, JP-C = 6.0 Hz, OCaH2CH3), 64.9 (d, JP-C
=
5.5 Hz, OCbH2CH3), 115.0, 119.5, 125.8, 127.3, 127.4, 128.5, 128.6, 129.7, 129.8, 130.0,
135.4 and 138.7 (Ar-C) and 167.8 (C=O). HRMS (ESI) calc’d for C19H22N2O7P [M+OH-2H]-
: 421.1165. Found 421.1159.
3.6.4. Diethyl 1-(N-phenylcarbamoyl)-2-phenylethylphosphonate 6g as a yellow oil
(0.08 g, 25%); νmax/cm-1: 1678 (C=O); δH/ppm (300 MHz; CDCl3) 1.33 (6H, m, 2 × CH3),
3.17 and 3.22 (2H, 2 × m, CH2Ph), 3.42 (1H, m, CHP), 4.12 (4H, m, 2 × OCH2CH3), 7.07
(1H, s, Ar-H), 7.20-7.32 (6H, overlapping m, Ar-H), 7.45 (2H, m, Ar-H) and 8.51 (1H, br s,
NH); δC/ppm (150 MHz; CDCl3) 16.38 and 16.42 (2 × CH3), 32.5 (d, JP-C = 4.1 Hz, CH2Ph),
48.6 (d, JP-C = 127.6 Hz CHP), 62.9 (d, JP-C = 6.4 Hz, OCaH2CH3), 63.3 (d, JP-C = 6.4 Hz,
OCbH2CH3), 119.7, 120.0, 124.3, 126.7, 127.9, 128.6, 128.6, 128.8, 137.8 and 139.0 (Ar-C)
and 165.0 (C=O); HRMS (ESI) calc’d for C19H25NO4P [M+H]+: 362.1521. Found 362.1519.
3.7.
1-{N-[3-Hydroxyphenyl)carbamoyl]}-2-phenylethylphosphonic acid 20e. Bromo-
trimethylsilane (0.15 mL, 1.1 mmol) was added to a solution of diethyl 1-{N-[(3-
bromophenyl)carbamoyl]}-2-phenylethylphosphonate 6b (0.10 g, 0.23 mmol) in dry DCM (5
mL) at 0 oC under N2. After 1 h., the solution was allowed to warm to room temperature and
stirred for an additional 24 h. The solvent was removed in vacuo and the residue dissolved in
THF (0.5 mL) and H2O (0.05 mL). After stirring for 1 h, the resulting mixture was
concentrated in vacuo and EtOAc was added to the residue; sonication of the mixture,
followed by cooling at -10 oC and the formation of a dense oil. The EtOAc was decanted and
the residual solvent was evaporated in vacuo to afford 1-{N-[3-hydroxyphenyl)carbamoyl]}-
2-phenylethylphosphonic acid 20e as a yellow oil (0.09 g, 86%); νmax/cm-1: 1674 (C=O) and
3450 (OH); δH/ppm (600 MHz; CD3OD) 2.99 and 3.02 (2H, 2 × m, CH2Ph), 3.24 (1H, m,
CHP), 6.38 (1H, s, Ar-H), 6.70 (1H, s, Ar-H), 6.93 (2H, m, Ar-H) and 7.06 (5H, overlapping
m, Ar-H); δC/ppm (150 MHz; CD3OD) 16.9 (d, JP-C = 5.6 Hz, CH2Ph), 34.1 (d, JP-C = 28.6
Hz, CHP), 108.4, 108.5, 112.4, 127.6, 127.7, 129.5, 129.6, 129.7, 130.3 and 130.4 (Ar-C) and
158.8 (C=O); HRMS (ESI) calc’d for C15H17NO5P [M+H]+: 322.0844. Found 322.0836.
4. Acknowledgements
The authors thank the South African Medical Research Council (SAMRC) for a bursary
(C.M.A.) and Rhodes University and the MRC for generous financial support. This research
project was supported by the South African Medical Research Council (SAMRC) with funds
from National Treasury under its Economic Competitiveness and Support Package.
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5. References and notes
1. http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/
2. Rohmer, M.; Seemann, M.; Horbach, S.; Bringer-Meyer, S.; Sahm, H. J. Am. Chem.
Soc. 1996, 118, 2564-2566.
3. Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz, M.;
Türbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E.
Science 1999, 285, 1573-1576.
4. Bodill, T.; Conibear, A.C.; Blatch, G.L.; Lobb, K.A.; Kaye, P.T. Bioorg. Med. Chem.,
2011, 19, 1321–1327.
5. Adeyemi, C.M.; Faridoon; Isaacs, M.; Mnkandhla, D.; Hoppe, H.C.; Krause, R.;
Kaye, P.T. Bioorg. Med. Chem., 2016, 64, 6131-6138..
6. Mutorwa, M. Ph.D. Thesis Rhodes University, Grahamstown, 2011.
7. Clark, A.J.; Curran, D.P.; Fox, D.J.; Ghel, F.; Guy, C.S.; Hay, B.; James, N.; Phillips,
J.M.Roncaglia, F.; Sellars, P.B.;Wilson, P,;Zhang, H. J. Org. Chem.,2016, 81, 5547-
5556.
8. Comparative NMR spectroscopic data for the C- and non-benzylated systems (6a and
5a, respectively), DEPT-135 and 2-D NMR spectra supporting the structural
assignment of the fully characterised representative compound 7b, a tentative
mechanistic proposal for the formation of the unexpected series of tetrafuranyl
products 7b-e, and spectroscopic data for compounds 7c-e and 8e are provided in the
Supporting Information (File I). Subsequent attempts to reproduce the formation of 8e
have, thus far, proved unsuccessful.
9. Amide pKa typically ca. 25. (F.G. Bordwell, and G.Z. Ji, J. Am. Chem. Soc., 1991,
113, 8398-8401).
10. http://www.organic-chemistry.org/namedreactions/hell-volhard-zelinsky-
reaction.shtm
11. Nisar, B.; Raza, R.A.; Black,STC. D.; Kumar, N.; Nawaz, M.T.; Chirality., 2013, 25,
865-870.
12. Vora, H.V.; Rovis, T. J. Am. Chem. Soc., 2007, 129(45), 13796-13797.
13. Rochon, K.; Proteau, G.A.; Bourassa P.; Nadon, J.F.; Cote, J.; Bournival, V.; Gobeil,
F; Guerin, B.; Dory, Y.L.; Gendron, L.; ACS Chem. Neurosci., 2013, 4(8): 1204-1216.
14. Mckenna, C.E.; Higa, M.T.; Cheung, N.H.; Mckenna, M.C.; Tetrahedron Lett., 1977,
155-158.
15. Bioassay procedures and data are provided in the Supporting Information: File III.
16. Compound 19h proved to be unstable, decomposing to afford compound 19c which
was purified and fully characterised.
17. The phosphonated products appear to be relatively unstable − evidenced, in this case,
13
by an unsatisfactory C NMR spectrum and an HRMS correlation based on a low-
intensity MS peak.
11