Phosphonated benzoxazole derivatives: Synthesis and metal-complexing properties

Article abstract of DOI:10.1055/s-0032-1318500

Phosphonated benzoxazole derivatives are good candidates as ligands for metal complexes. Two regioisomers were synthesized with the phosphonate function at the C-4 and C-7 positions. Different alkyl chains were also introduced at the C-2 position to functionalize these two regioisomers and increase their complexation properties. The formation of coordination complexes of selected benzoxazoles with M²⁺ and M³⁺ metal cations has been screened in solution using HRMS (high-resolution mass spectrometry) as the analytical tool. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318500

LETTER
▌817
letter
Phosphonated Benzoxazole Derivatives: Synthesis and Metal-Complexing
Properties
Novel Phosphonated Benzoxazoles: Synthesis and Properties
Elodie Lagadic,a Frédéric Bruyneel,a Noémie Demeyer,a Marie-France Hérent,b Yann Garcia,a Jacqueline Marchand-
Brynaert*a
a
Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place
Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)474168; E-mail: jacqueline.marchand@uclouvain.be
b
Louvain Drug Research Institute (LDRI), Université catholique de Louvain, Avenue Mounier 73.40, 1200 Bruxelles, Belgium
Received: 30.01.2013; Accepted: 07.03.2013
a related class of benzoxazoles, i.e. the phosphonated de-
Abstract: Phosphonated benzoxazole derivatives are good candi-
rivatives. To the best of our knowledge, such functional-
dates as ligands for metal complexes. Two regioisomers were syn-
ized benzoxazoles have not been disclosed in the previous
literature (Figure 2). The introduction of the phosphonate
thesized with the phosphonate function at the C-4 and C-7 positions.
Different alkyl chains were also introduced at the C-2 position to
functionalize these two regioisomers and increase their complex- function on the benzoxazole core has a double interest:
ation properties. The formation of coordination complexes of se-
beside the possibility to finely tune the solubility proper-
ties of the molecules in polar and/or aqueous media (going
lected benzoxazoles with M2+ and M3+ metal cations has been
screened in solution using HRMS (high-resolution mass spectrom-
from diester to monoester and free phosphonic acid), the
etry) as the analytical tool.
phosphonate function displays an excellent coordinating
P=O motif9 for making complexes with transition metal
Key words: benzoxazole, phosphonate, regioselectivity, coordina-
tion complex, metal ligand
and lanthanide cations, in synergy with the oxazole ring
when placed either at the C-4 or C-7 position.
The benzoxazole framework is found in various biologi-
cally active compounds of natural or synthetic origin,
such as cancer drugs, antifungal, antiviral and antimicro-
bial agents.1 Most of the remarkable activities of 2-(het-
ero)arylbenzoxazoles are linked to their capacity of
complexing metal cations; typical N,N and N,O ligands
are shown in the Figure 1.2 For instance, the cytotoxicity
of UK-1 (a metabolite of Streptomyces cultures) results
from DNA intercalation which correlates with its ability
of Cu2+ chelation.3 Benzoxazole-based Pt2+ complexes an-
alogues of cisplatine (drug used in cancer chemotherapy)
are investigated for medical purpose.2c,4 Other useful ap-
plications of metal complexes of benzoxazole ligands are
described in the fields of catalysis,2a,b photoluminescent
materials5 and environmental sensors,6 among others.
OR1
OR1
R1O
5
P
O
4
R1O
6
P
O
7
O1
N3
2
CH2R2
CH2R2
2
O
1
N
3
5
6
7
4
Figure 2 Novel phosphonated benzoxazoles disclosed in this work
(R1 = Et, H; R2 = H, Br, OH, OCOCH2PO3Et2)
We have selected two precursors featuring a methyl sub-
stituent at the C-2 position (Figure 2, R1 = Et, H and R2 =
H) with the aim of further lengthening this one-carbon
chain and introducing an additional function for metal
chelation.
In this article, we describe the synthesis of 2-methylben-
zoxazoles of both regioisomeric series and their function-
alization via the 2-hydroxymethyl key intermediates
(Figure 2, R1 = Et; R2 = OH). The complexing properties
of the novel compounds versus M2+ and M3+ cations, in
ethanol solution, have been examined by HRMS (high-
resolution mass spectrometry) in the ESI mode (electro-
spray ionization).
HO
4
N3
O1
N
5
6
N
O
2
7
Figure 1 Typical benzoxazole-based N,N and N,O ligands found in
the literature
We have previously described the preparation of 2-amino-
3-hydroxy-1-benzenephosphonic acid (1)8b by applying
the strategy of ortho-metallation.10 Reaction of 1 with tri-
ethyl orthoacetate in excess led simultaneously to the ox-
azole ring formation and bisesterification of the
phosphonic function, with 78% yield (Scheme 1). We first
tried to functionalize 2 by bromination of the C-2 methyl
group. Using radicalar conditions [NBS (2.0 equiv),
AIBN (0.2 equiv), CCl4, 80 °C], we obtained 2-(bromo-
We have recently reported the synthesis of C-4 and C-7
sulfonylated benzoxazoles with a view to increase the hy-
drophilicity of the compounds.7 Our interest in the phos-
phonate chemistry8 prompted us to examine the entry into
SYNLETT 2013, 24, 0817–0822
Advanced online publication: 18.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318500; Art ID: ST-2013-B0102-L
© Georg Thieme Verlag Stuttgart · New York

818
E. Lagadic et al.
LETTER
EtO
EtO
Me
Me
OH
O
N
O
N
N
MeC(OEt)3
MeCN, reflux
NaIO4
THF–H2O
Me
Me
Me
NH2
N
12 h
78%
r.t., 2 h
MeCN, reflux
12 h
PO3Et2
PO3Et2
PO3H2
80%
1
2
3
O
O
P
O
N
O
N
O
N
OEt
O
HO
NaBH4, MeOH
O
OEt
OH
O
r.t., 2 h
84%
DCC, DMAP
CH2Cl2, r.t., 12 h
PO3Et2
PO3Et2
PO3Et2
PO3Et2
98%
4
5
6
Scheme 1 Synthesis of 2-functionalized 4-phosphonated benzoxazoles
methyl)-4-(diethylphosphonate)benzoxazole in a low fluxing acetonitrile afforded 3 in 80% yield after purifica-
1
yield [≤20%; H NMR (δ): signal of CH2Br at δ = 4.60 tion by flash chromatography on silica gel. Oxidation of 3
ppm] and with arduous purification (see Scheme S1 in with sodium metaperiodate followed by reduction with
Supporting Information). Methyl deprotonation with a sodium borohydride gave the alcohol 5 in 84% overall
strong base [n-BuLi (1.1 equiv), THF, –78 °C] followed yield. The aldehyde intermediate 4 was identified by the
by anion quenching with bromine failed to give the ex- usual spectroscopic methods, but neither purified, nor
pected 2-(bromomethyl)-benzoxazole. Opening of the ox- stored. Lastly, to exemplify the introduction of an addi-
azole ring occurred, giving after aqueous workup, tional complexing function, we have coupled (diethoxy-
diethyl 2-(acetylamino)-3-hydroxy-1-benzenephospho- phosphoryl)acetic acid with the alcohol 5, using
nate (Scheme S1). The use of functionalized triethyl dicyclohexylcarbodiimide and dimethylaminopyridine as
orthoacetates, such as (EtO)3CCH2Br,11 for the direct for- activation method. The final bisphosphonated ligand 6
mation of C-2 functionalized benzoxazoles, was rapidly was recovered in nearly quantitative yield (Scheme 1).
abandoned due to the difficulty to prepare the reagent and Other esterification protocols afforded lower yields, for
the tenuous yield of pure cyclized product formed by re- instance: N-(3-dimethylaminopropyl)-N′-ethylcarbodi-
action with 1 (Scheme S1).
imide hydrochloride and 1-hydroxybenzotriazole as acti-
vating agents, and activated esters of (diethoxy-
phosphoryl)acetic acid made with oxalyl chloride, penta-
fluorophenol or chloroacetonitrile.
After screening for optimal conditions, compatible with
the stability of the phosphonated heterocycle 2, we select-
ed the Bredereck’s reagent,12 namely diethylacetal of di-
methylformamide, for making the versatile enamine The synthesis of the regioisomeric series (i.e. 7-phospho-
intermediate 3 (Scheme 1). The reaction performed in re- nated benzoxazoles) required another synthetic route be-
Cl
PO3Et2
PO3H2
OH
MeC(OEt)3
MeCN, reflux
1) n-BuLi, THF
–78 to –45 °C, 2 h
12 M HCl
reflux, 12 h
O
t-Bu
12 h
63%
2) ClPO(OEt)2, THF
–78 to 25 °C, 12 h
57%
42%
N
NHCOt-Bu
NH2
7
8
9
EtO
EtO
Me
Me
PO3Et2
PO3Et2
PO3Et2
N
1) NaIO4, THF–H2O
r.t., 2 h
O
O
OH
O
Me
Me
MeCN, reflux
12 h
2) NaBH4, MeOH
r.t., 2 h
N
N
N
N
Me
27%
10
11
12
63%
O
O
P
PO3Et2
PO3Et2
OEt
OH
O
HO
PO3Et2
O
O
+
OEt
PO3Et2
O
DCC, DMAP
CH2Cl2, r.t., 12 h
75%
O
N
N
H
O
13
14
column chromatography
Scheme 2 Synthesis of 2-functionalized 7-phosphonated benzoxazoles
Synlett 2013, 24, 817–822
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Phosphonated Benzoxazoles: Synthesis and Properties
819
cause the directing effect of ortho-aminophenol es from the solution in the gas phase with the conservation
derivatives in metallation reactions is never in favor of the of non-covalent bonds. Five equivalents of cation (per-
position next to the oxygen-substituted one13 (see Sup- chlorate salt of M2+ and nitrate salt of M3+) were added to
porting Information). The synthetic route outlined in a 0.5 mM solution of ligand (L) in ethanol. The reference
Scheme 2 is based on a benzyne intermediate, intramolec- ligands 2 (Table 2) and 10 (Table S1 in Supporting Infor-
ularly quenched by the amide anion to form the oxazole mation), devoid of C-2 functional group (R2 = H), gave
ring (Scheme S2). Thus, 3-chloro-2-(pivaloyl)aminoben- mixtures of L2:M (two ligands for one metal) and L1:M
zene (7) was treated with n-BuLi at low temperature, fol- complexes (one ligand for one metal) detected by HRMS–
lowed by addition of diethyl chlorophosphate to furnish ESI as single charged species due to the presence of one
the benzoxazole 8 in 57% yield after purification by chro- perchlorate counteranion in the case of divalent cations,
matography. Refluxing 8 in 12 M HCl led to 3-amino-2- and two nitrate anions in the case of trivalent cations. A
hydroxy-1-benzenephosphonic acid (9) which was puri- residual solvent molecule (EtOH) could be observed for
fied by precipitation from a dichloromethane–methanol the L1:M complexes. The predominant species were the
(6:1) mixture. The following steps were similar to Scheme L1:M complexes with divalent cations, and the L2:M com-
1; however the same experimental conditions led here sys- plexes with trivalent cations (Table 2 and Table S1). The
tematically to lower yields of products 10 (2-methylben- easiness of complexation was estimated from the ratios of
zoxazole), 11 (enamine) and 12 (2-hydroxymethyl- complexes versus the free cations. The results show that:
benzoxaole), in the regioisomeric series. The purifications (1) the benzoxazole 2 behaved as a better ligand than its
were more difficult and the oxazole ring appeared more regioisomer 10; (2) complexes with 3d ions such as Fe2+,
sensitive to hydrolysis. This was particularly true for the Co2+, Ni2+ were highly favorable; (3) all trivalent cations
last step of the synthesis, giving the bisphosphonated li- behaved quite similarly.
gand 13. After purification by column chromatography,
Considering the C-2 functionalized ligands 5 (R2 = OH)
13 was contaminated by varying amounts of the amide 14
and 6 (R2 = OCOCH2PO3Et2), we detected the L1:M com-
resulting from the hydrolysis of the five-membered het-
plexes formed with divalent cations as the single species
erocycle on silica gel (Scheme 2). This result suggests that
in solution (Table 3). This is consistent with the presence
the presence of an electron-withdrawing group (PO3Et2)
of an additional chelating function on the ligands. More-
over, from the ratios of complexes versus free metals, we
could conclude that the bisphosphonated molecule 6 be-
haves as the best ligand, in particular for the complexation
on the benzene ring, in ortho position with respect to the
oxygen substituent, strongly favors the cleavage of the ox-
azole O1–C2 bond (Scheme S3).
The novel compounds have been characterized by the usu- of Fe2+, Co2+ and Ni2+. The complexation of trivalent cat-
al spectroscopic methods;14 some NMR data of the substi- ions by 5 and 6 appeared less efficient (see Table S2, in
tuted benzoxazoles are summarized in the Table 1.
Supporting Information). With the regioisomer 12 (R2 =
OH), complexes were observed by HRMS–ESI in few
cases only (L1:M complex with Co2+ and Lu3+). The exact
masses of the main identified complexes are given in the
Supporting Information (Tables S3–S7).
A screening of complexes formation with series of M2+
and M3+ cations was then performed in ethanol solution
using high resolution mass spectrometry (HRMS) cou-
pled with electrospray ionization (ESI) as the analytical
tool. This mild method allows the transfer of the complex-
Table 1 Typical NMR Data (ppm) of the C-2 Substituents and Aryl-P Recorded in CDCl3 for the C-4 and C-7 Phosphonated Series, Respec-
tively
Substituents
δC–H(2)
δC(2)
δP
4-P
7-P
4-P
7-P
4-P
7-P
Me
s, 2.69 (2)a
s, 2.71 (10)
14.2 (2)a
14.8 (10)
16.6 (2)a
13.8 (10)
H
d, 7.58 (3)
d, 7.64 (11)
149.3 (3)
149.4 (11)
n.d.
17.4 (3)
15.0 (11)
n.d.
(J = 13.3 Hz)
(J = 13.2 Hz)
NMe2
H
s, 10.09 (4)
s, 5.01 (5)
n.d.
179.5 (4)
58.0 (5)
13.6 (4)
15.3 (5)
O
H
H
H
s, 4.98 (12)
57.9 (12)
13.3 (12)
OH
H
s, 5.43 (6)
s, 5.39 (13)
s, 4.73 (14)
59.1 (9)
n.d.
15.3 and 19.1 (6)
13.1 and 19.4 (13)
19.3 and 22.6 (14)
O
O
–
–
64.0 (14)
–
a Recorded in CD3OD.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 817–822

820
E. Lagadic et al.
LETTER
Table 2 [M(II)(2)n(ClO4)(EtOH)m]+ and [M(III)(2)n(NO3)2(EtOH)m]+ Complexes formed with the Ligand (L) 2 (see Scheme 1 for the Structure
of 2)
M(II) (Atomic number) L2:L1a,b complexes
∑complexes:M(II)c M(III) (Atomic number) L2:L1a,b complexes ∑complexes:M(III)d
Mg (12)
Ca (20)
Mn (25)
Fe (26)
Co (27)
Ni (28)
Cu (29)
Zn (30)
Cd (48)
Ba (56)
57:43 (55:45)
36:64 (55:45)
52:48 (91:9)
56:44 (99:1)
55:45 (90:10)
52:48 (98:2)
12:88 (100:0)
25:75 (99:1)
47:53 (95:5)
19:81 (99:1)
57:43
31:67
52:48
81:19
83:17
99:≤1
63:37
59:41
48:52
25:75
La (57)
Ce (58)
Pr (59)
Sm (62)
Eu (63)
Gd (64)
Er (68)
Tm (69)
Lu (71)
66:34 (77:23)
64:36 (77:23)
49:51 (74:26)
65:35 (67:33)
68:32 (65:35)
79:21 (62:38)
76:24 (59:41)
75:25 (62:38)
73:27 (60:40)
63:37
60:40
49:51
55:45
57:43
69:31
79:21
74:26
70:30
a For L2 complexes (n = 2), there is no EtOH associated (m = 0).
b For L1 complexes (n = 1), the ratio of solvent-free (m = 0) and EtOH-associated complex (m = 1) is given into parenthesis.
c Ratio of M(II) complexes (L2 + L1 complexes) vs. M(II)ClO4(EtOH)m (m = 1, 2, 3).
d Ratio of M(III) complexes (L2 + L1 complexes) vs. M(III)(NO3)2(EtOH)m (m = 1, 2, 3).
In conclusion, the regioisomeric 2-methylbenzoxazoles 2
and 10 are readily accessible from 2-amino-3-hydroxy-
and 3-amino-2-hydroxybenzenephosphonic acids 1 and 9,
respectively (Schemes 1 and 2). The methyl group dis-
plays a nucleophilic reactivity thanks to the tautomeric
form 2′ (or 10′) and reacts easily with the Bredereck’s re-
agent under neutral conditions to furnish the N-(dimeth-
yl)enamine intermediate 3 (or 11) (Scheme S4). A
sequence of oxidation and reduction, compatible with the
+
O
N
Me
O
P
OEt
OEt
P
Fe2+
OEt
EtO
O
N
O
–
ClO4
Me
+
H
Table 3 [M(II)(5)(ClO4)(EtOH)m]+ and [M(II)(6)(ClO4)(H2O)m]+
Complexes (See Scheme 1 for the Structures of 5 and 6)
O
H
OEt
Fe2+
OEt
P
Complex 5a:M(II)
Complex 6b:M(II)
O
M(II) (Atomic number)
EtO
O
P
Mg (12)
Ca (20)
Mn (25)
Fe (26)
Co (27)
Ni (28)
Cu (29)
Zn (30)
Cd (48)
Ba (56)
6:94
31:69c
6:94
63 (27:73):37
51 (19:81):49
60 (17:83):40
99 (35:65):≤1
99 (0:100):≤1
99 (0:100):≤1
10 (0:100):90
25 (0:100):75
22 (0:100):78
21 (4:96):79
O
EtO
O
N
–
ClO4
O
:92
Figure 3 Postulated structures of L2:M and L1:M complexes formed
with Fe(II) and ligands 2 and 6, respectively
27:73
15:85
9:91
stability of the phosphonated benzoxazole core, com-
pletes the synthesis of the 2-hydroxymethyl derivative 5
(or 12). In our opinion this derivative (or its aldehyde pre-
cursor 4) constitutes the best entry into the 2-functional-
ized benzoxazoles. Due to the presence of the
phosphonate substituent and the oxazole heterocycle, 2 is
particularly suitable for metal cations complexation. The
chelation capacity has been improved by the functional-
ization of the C-2 position with a phosphonated arm, giv-
ing the ligand 6. Based on the HRMS–ESI results, we
have identified L2:M and L1:M complexes whose possible
structures are depicted in Figure 3 with M(II) = Fe. The in-
15:85
7:93
5:95
a m = 0 for all the complexes, except for Ca complex (m = 0:m = 1
ratio is 35:65), Zn complex (ratio 89:11) and Cd complex (ratio
50:50) which contain ethanol.
b The complexes from 6 can contain one water molecule; the ratio of
complexes with m = 0 and m = 1 is given into parenthesis.
c The Ca complex was contaminated by 12% of [Ca(5)2(ClO4)]+.
Synlett 2013, 24, 817–822
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Phosphonated Benzoxazoles: Synthesis and Properties
821
(b) Bruyneel, F.; D’Auria, L.; Payen, O.; Courtoy, P. J.;
Marchand-Brynaert, J. ChemBioChem 2010, 11, 1451.
(11) The reagent was prepared from triethyl orthoacetate,
troduction of these molecules (2, 6) as ligands in MOFs
(Metal Organic Frameworks)15 is under investigation,
with a particular interest for iron(II) complexes with tri-
azole derivatives as co-ligands.16
bromine and pyridine according to: Mike, J. F.; Makowski,
A. J.; Jeffries-El, M. Org. Lett. 2008, 10, 4915.
(12) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
(13) Maggi, R.; Schlosser, M. J. Org. Chem. 1996, 61, 5430.
(14) 1H NMR, 13C NMR and 31P NMR spectra were recorded on
Bruker Avance 300 and 500 spectrometers. Spectra were
obtained in CDCl3 or CD3OD. Chemical shifts are reported
in ppm relative to the solvent signals. High Resolution Mass
Spectrometry (HRMS) analyses were performed on a LTQ-
orbitrap XL hybrid mass spectrometer (Thermo Fisher
Scientific, Bremen, Germany). Infrared spectra were
performed on a FTIR-84005 equipment using ATR mode.
Analytical grade solvents and commercially available
reagents were used without further purification.
Acknowledgment
This work was supported by the ARC program 08/13-009 (Commu-
nauté Française, Belgium) entitled ‘New hybrid inorganic-organic
materials with functional properties modulated through the supra-
molecular architecture’. J.M.-B. is senior research associate of the
F.R.S.-FNRS (Belgium).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Chromatography was carried with Rocc silica gel, 40–63 μm
or 60–200 μm.
References and Notes
Diethyl 2-Methylbenzoxazole-4-phosphonate (2): The
glassware was flame-dried under an argon atmosphere. To a
solution of 2-amino-3-hydroxybenzenephosphonic acid
(1.00 g, 5.29 mmol) in anhyd MeCN (10.00 mL) was added
triethyl orthoacetate (5.0 equiv, 4.90 mL). The mixture was
heated at 80 °C overnight and then evaporated to give an
orange oil. The crude product was purified by flash
chromatography on silica gel (cyclohexane–EtOAc, 1:1,
then EtOAc). The title compound was isolated as an orange
oil with 78% yield (1.11 g). IR (film): 1677, 1568, 1415,
1244, 1230, 1020, 973, 790, 761 cm–1. 1H NMR (300 MHz,
CD3OD): δ = 1.30–1.35 [m, 6 H, PO(OCH2CH3)2], 2.69 (s,
3 H, Me), 4.16–4.22 [m, 4 H, PO(OCH2CH3)2], 7.48 (td,
3JH–H = 7.9 Hz, 4JH–P = 3.7 Hz, 1 H, H-6), 7.74–7.85 (m, 2 H,
H-5, H-7). 13C NMR (75 MHz, CD3OD): δ = 14.2 (s, Me),
16.6 [d, 3JC–P = 6.3 Hz, PO(OCH2CH3)2], 64.1 [d, 2JC–P = 5.6
Hz, PO(OCH2CH3)2], 116.2 (d, 4JC–P = 3.1 Hz, C-7), 119.6
(d, 1JC–P = 190.2 Hz, C-4), 125.6 (d, 3JC–P = 14.9 Hz, C-6),
130.1 (d, 2JC–P = 7.8 Hz, C-5), 143.7 (d, 2JC–P = 6.8 Hz, C-9),
152.4 (d, 3JC–P = 15.9 Hz, C-8), 167.6 (s, C-2). 31P NMR (121
MHz, CD3OD): δ = 16.6 [s, PO(OEt)2]. HRMS (ESI): m/z
[M + Na]+ calcd for C12H16NO4NaP: 292.0715; found:
292.0716.
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1977. (b) Milewska, M.; Guzow, K.; Wiczk, W. Cent. Eur.
J. Chem. 2010, 8, 674. (c) Oliveira, E.; Costa, S. P. G.;
Raposo, M. M. M.; Faza, O. N.; Lodeiro, C. Inorg. Chim.
Acta 2011, 366, 154.
(7) (a) Bruyneel, F.; Payen, O.; Rescigno, A.; Tinant, B.;
Marchand-Brynaert, J. Chem. Eur. J. 2009, 15, 8283.
(b) Bruyneel, F.; Marchand-Brynaert, J. Synlett 2010, 1974.
(8) (a) Villemin, E.; Herent, M.-F.; Marchand-Brynaert, J. Eur.
J. Org. Chem. 2012, 6165; and references cited therein.
(b) Lagadic, E.; Garcia, Y.; Marchand-Brynaert, J. Synthesis
2012, 44, 93; and references cited therein . (c) Villemin, E.;
Elias, B.; Robiette, R.; Herent, M.-F.; Habib-Jiwan, J.-L.;
Marchand-Brynaert, J. Tetrahedron Lett. 2011, 52, 5140.
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202, 563. (b) Galezowska, J.; Janicki, R.; Kozlowski, H.;
Mondry, A.; Mlynarz, P.; Szyrwiel, L. Eur. J. Inorg. Chem.
2010, 1696.
Diethyl 2-(N,N-Dimethyl-1-ethylen-1-amino)benzox-
azole-4-phosphonate (3): The glassware was flame-dried
under an argon atmosphere. To a solution of 2 (0.1 g, 0.4
mmol) in anhyd MeCN (2.0 mL) was added
dimethylformamide diethylacetal (DMFDEA; 3.0 equiv, 0.2
mL). The mixture was heated at reflux overnight and then
evaporated to give an orange oil. The crude product was
purified by flash chromatography on silica gel (EtOAc, then
EtOAc–i-PrOH, 95:5) to give the title compound as a yellow
oil with 80% yield (0.09 g). IR (film): 1633, 1547, 1537,
1414, 1387, 1240, 1227, 1107, 1047, 1024, 968, 787, 764
cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.31–1.37 [m, 6 H,
PO(OCH2CH3)2], 2.98 (s, 6 H, Me), 4.12–4.27 [m, 4 H,
PO(OCH2CH3)2], 5.19 (d, 3JH–H = 13.3 Hz, 1 H, C=CH), 7.15
(td, 3JH–H = 7.8 Hz, 4JH–P = 3.6 Hz, 1 H, H-6), 7.47 (ddd,
3JH–H = 7.9 Hz, 4JH–H = 5JH–P = 1.2 Hz, 1 H, H-7), 7.58 (d,
3JH–H = 13.3 Hz, 1 H, CH=C), 7.70 (ddd, 3JH–P = 13.8 Hz,
3JH–H = 7.7 Hz, 4JH–H = 1.1 Hz, 1 H, H-5). 13C NMR (125
MHz, CDCl3): δ = 16.4 [d, 3JC–P = 6.5 Hz, PO(OCH2CH3)2],
62.3 [d, 2JC–P = 5.1 Hz, PO(OCH2CH3)2], 81.7 (s, C=C),
112.8 (d, 4JC–P = 2.7 Hz, C-7), 116.2 (d, 1JC–P = 186.9 Hz,
C-4), 121.4 (d, 3JC–P = 15.0 Hz, C-6), 128.6 (d, 2JC–P = 8.4
Hz, C-5), 145.3 (d, 2JC–P = 6.8 Hz, C-9), 149.3 (s, C=C),
149.9 (d, 3JC–P = 16.0 Hz, C-8), 167.8 (s, C-2). 31P NMR (121
MHz, CDCl3): δ = 17.4 [s, PO(OEt)2]. HRMS (ESI): m/z [M
(10) (a) Bruyneel, F.; Enaud, E.; Billottet, L.; Vanhulle, S.;
Marchand-Brynaert, J. Eur. J. Org. Chem. 2008, 72.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 817–822

822
E. Lagadic et al.
LETTER
+ H]+ calcd for C15H22O4N2P: 325.1312; found: 325.1317.
Diethyl 2-Formylbenzoxazole-4-phosphonate (4): To a
solution of 3 (0.083 g, 0.255 mmol) in THF–H2O (1:1;
5.4/5.4 mL) was added sodium periodate (4.0 equiv, 0.218 g,
1.024 mmol). The reaction mixture was stirred at r.t. for 2 h.
Then the crude mixture was extracted with CH2Cl2 (3 ×),
dried over Na2SO4, filtered and evaporated to give the title
compound as a yellow oil. It was used in the next step
without further purification. 1H NMR (500 MHz, CDCl3): δ
= 1.35–1.40 [m, 6 H, PO(OCH2CH3)2], 4.20–4.36 [m, 4 H,
PO(OCH2CH3)2], 7.66 (td, 3JH–H = 7.5 Hz, 4JH–P = 3.3 Hz, 1
H, H-6), 7.88 (ddd, 3JH–H = 8.4 Hz, 4JH–H = 5JH–P = 0.9 Hz, 1
CDCl3): δ = 15.3 [s, PO(OEt)2]. HRMS (ESI): m/z [M + H]+
calcd for C12H17O5NP: 286.0839; found: 286.0841.
Diethyl 2-[(Methoxycarbonyl)methyl(diethoxy-
phosphoryl)]benzoxazole-4-phosphonate (6): To a
solution of 5 (0.048 g, 0.17 mmol) in CH2Cl2 (1.00 mL) was
added (diethoxyphosphoryl)acetic acid (1.1 equiv, 0.03 mL)
and then N,N′-dicyclohexylcarbodiimide (DCC; 1.1 equiv,
0.038 g) and 4-(dimethylamino)pyridine (DMAP; 1.1 equiv,
0.023 g). The reaction mixture was stirred at r.t. overnight
and then filtered to eliminate the N,N′-dicyclohexylurea
(DCU) formed. The filtrate was evaporated and purified by
flash chromatography on silica gel (MeCN–i-PrOH, 95:5).
The title compound was isolated as a yellow oil with 98%
yield (0.058 g). IR (film): 2905–2926, 1749, 1602, 1570,
1444, 1414, 1392, 1228–1290, 1161, 1111, 931–1047, 866,
731–789 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.27–1.33
{m, 12 H, [PO(OCH2CH3)2]2}, 3.07 (d, 2JH–P = 21.6 Hz, 2 H,
COCH2P), 4.13–4.26 {m, 8 H, [PO(OCH2CH3)2]2}, 5.43 (s,
2 H, CH2O), 7.45 (td, 3JH–H = 7.9 Hz, 4JH–P = 3.4 Hz, 1 H, H-
6), 7.71 (d, 3JH–H = 8.2 Hz, 1 H, H-7), 7.88 (dd, 3JH–P = 14.0
Hz, 3JH–H = 7.4 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3):
δ = 16.3–16.4 [m, PO(OCH2CH3)2], 34.0 (d, 2JC–P = 133.8
Hz, COCH2P), 59.1 (s, CH2O), 62.8 [d, 2JC–P = 5.3 Hz,
PO(OCH2CH3)2], 63.0 [d, 2JC–P = 6.2 Hz, PO(OCH2CH3)2],
115.2 (d, 4JC–P = 2.8 Hz, C-7), 120.9 (d, 2JC–P = 188.6 Hz, C-
4), 125.5 (d, 3JC–P = 14.9 Hz, C-6), 130.1 (d, 2JC–P = 7.8 Hz,
C-5), 141.7 (d, 2JC–P = 6.3 Hz, C-9), 150.9 (d, 3JC–P = 15.4
H, H-7), 8.03 (ddd, 3JH–P = 14.2 Hz, 3JH–H = 7.4 Hz, 4JH–H
=
0.9 Hz, 1 H, H-5), 10.09 (s, 1 H, CHO). 13C NMR (125 MHz,
CDCl3): δ = 16.4 [d, 3JC–P = 6.3 Hz, PO(OCH2CH3)2], 62.9
[d, 2JC–P = 5.5 Hz, PO(OCH2CH3)2], 116.4 (d, 4JC–P = 3.0 Hz,
C-7), 123.6 (d, 1JC–P = 189.0 Hz, C-4), 128.8 (d, 3JC–P = 14.9
Hz, C-6), 131.4 (d, 2JC–P = 7.5 Hz, C-5), 141.3 (d, 2JC–P = 6.2
Hz, C-9), 150.5 (d, 3JC–P = 14.8 Hz, C-8), 157.8 (s, C-2),
179.5 (s, CHO). 31P NMR (121 MHz, CDCl3): δ = 13.6 [s,
PO(OEt)2].
Diethyl 2-Hydroxymethylbenzoxazole-4-phosphonate
(5): To a solution of crude 4 (0.072 g, 0.254 mmol) in MeOH
(22.0 mL) was added NaBH4 (5.0 equiv, 0.038 g, 1.017
mmol). The solution was stirred for 2 h. Then cold H2O was
added and the mixture was extracted with CH2Cl2 (3 ×),
dried over Na2SO4, filtered and evaporated to give the title
compound as a yellow oil with 84% yield for two steps
(0.061 g). IR (film): 1749, 1633, 1608, 1570, 1414, 1392,
1246, 1049, 1020, 970, 789, 760 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.31–1.37 [m, 6 H, PO(OCH2CH3)2], 4.14–4.29
[m, 4 H, PO(OCH2CH3)2], 5.01 (s, 2 H, CH2), 7.41 (td, 3JH–
H = 7.5 Hz, 4JH–P = 3.5 Hz, 1 H, H-6), 7.70 (ddd, 3JH–H = 8.3
Hz, 4JH–H = 5JH–P = 1.3 Hz, 1 H, H-7), 7.83 (ddd, 3JH–P = 13.9
Hz, 3JH–H = 7.5 Hz, 4JH–H = 1.0 Hz, 1 H, H-5), 8.24 (br s, 1 H,
OH). 13C NMR (125 MHz, CDCl3): δ = 16.4 [d, 3JC–P = 6.4
Hz, PO(OCH2CH3)2], 58.0 (s, CH2), 62.8 [d, 2JC–P = 5.3 Hz,
PO(OCH2CH3)2], 115.1 (d, 4JC–P = 2.8 Hz, C-7), 120.0 (d,
1JC–P = 189.1 Hz, C-4), 124.8 (d, 3JC–P = 14.9 Hz, C-6), 129.4
(d, 2JC–P = 7.6 Hz, C-5), 142.1 (d, 2JC–P = 6.7 Hz, C-9), 150.9
(d, 3JC–P = 15.6 Hz, C-8), 167.1 (s, C-2). 31P NMR (121 MHz,
Hz, C-8), 161.2 (s, C-2), 165.1 (d, 2JC–P = 5.9 Hz, CO). 31
P
NMR (121 MHz, CDCl3): δ = 15.3 [s, PhPO(OEt)2], 19.1 [s,
CH2PO(OEt)2]. HRMS (ESI): m/z [M + H]+ calcd for
C18H28NO9P2: 464.1239; found: 464.1231.
Compounds 7–14 (Scheme 2) are described in the
Supporting Information.
(15) Naik, A. D.; Dîrtu, M. M.; Raillet, A. P.; Marchand-
Brynaert, J.; Garcia, Y. Polymers 2011, 3, 1750.
(16) (a) Dirtu, M. M.; Schmit, F.; Naik, A. D.; Rotaru, A.;
Marchand-Brynaert, J.; Garcia, Y. Int. J. Mol. Sci. 2011, 12,
5339. (b) Boland, Y.; Tinant, B.; Safin, D. A.; Marchand-
Brynaert, J.; Garcia, Y. Cryst. Eng. Commun. 2012, 14,
8153. (c) Raillet, A. P.; Naik, A. D.; Rotaru, A.; Marchand-
Brynaert, J.; Garcia, Y. Hyperfine Interact. 2012, 205, 51.
Synlett 2013, 24, 817–822
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