Synthesis of phosphaisocoumarin amidates via DIBAL-H-mediated selective amidation of phosphaisocoumarin esters

Article abstract of DOI:10.1039/c4ob00663a

A series of phosphaisocoumarin amidates were synthesized for the first time via DIBAL-H-mediated direct amidation of phosphaisocoumarin esters under mild conditions in good to excellent yields. The present reaction showed high selectivity. In each case, the phostone ring was intact and only the exocyclic ethoxy group was amidated. A plausible mechanism of the reaction was provided. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00663a

Organic &
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Synthesis of phosphaisocoumarin amidates via
DIBAL-H-mediated selective amidation of
phosphaisocoumarin esters†
Cite this: Org. Biomol. Chem., 2014,
12, 5458
Yu-Juan Guo, Pei-Jiang Chen, Bo Wang and Ai-Yun Peng*
Received 29th March 2014,
Accepted 29th May 2014
A series of phosphaisocoumarin amidates were synthesized for the first time via DIBAL-H-mediated direct
amidation of phosphaisocoumarin esters under mild conditions in good to excellent yields. The present
reaction showed high selectivity. In each case, the phostone ring was intact and only the exocyclic ethoxy
group was amidated. A plausible mechanism of the reaction was provided.
DOI: 10.1039/c4ob00663a
www.rsc.org/obc
Introduction
Carboxamides are key structural units in many biologically
active compounds (i.e. proteins) and modern pharmaceuticals,
and the carboxamide-forming reactions have been extensively
investigated.1 Phosphonamidates, as important carboxamide
analogues, have also gained considerable research interest in
organic chemistry and biology, because they may mimic the
tetrahedral transition states of carboxamide hydrolysis and
may be used as potential probes and inhibitors of various
enzymes.2
Scheme 1 Typical procedure for the synthesis of phosphonamidates.
Despite the broad application prospects of phosphon-
amidates, only a few methods for their synthesis have been
reported. The typical approach to obtain phosphonamidates is
the coupling of amines with phosphonochloridates, which are
usually formed by the hydrolysis of the corresponding phos-
phonic acid diesters to monoesters followed by treatment with
thionyl chloride or oxalyl chloride (Scheme 1).3 The limitations
of this traditional route include lengthy steps, relatively low
total yields, strict reaction conditions and tedious workup,
which largely restrict the applications of phosphonamidates.
Although some new methods starting from trivalent phos-
phorus species have been developed by several groups,4
efficient, general and atom-economical methods for the syn-
thesis of phosphonamidates under mild conditions are still in
high demand.
Scheme 2 Some attempts to direct amidation of phosphonates.
the subsequent synthesis of unstable phosphonochloridates
are avoided. However, to date, little is known about such con-
version. In 1987, Froneman et al. reported that Ti(NEt2)4 and
Mn(NEt2)2 were unreactive with PhCH2P(O)(OEt)2,5 but reacted
smoothly with (EtO)2P(O)CH(OH)Ph to give the amidated pro-
ducts (Scheme 2). They thought that these processes might
involve the anchimeric assistance of the hydroxy with the
metal, which mediated the exchange of one or both EtO
groups for the NEt2 substituent. Unfortunately, the scope of
this inspirational method is very limited, and no subsequent
studies were reported thereafter.
Theoretically, direct amidation of phosphonic acid diesters
is a more desirable protocol to synthesize phosphonamidates
since the hydrolysis to the phosphonic acid monoesters and
School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi
In recent years, we synthesized a series of phosphaiso-
coumarin esters as isocoumarin analogues.6 It has been reported
that isocoumarins could be readily converted into the corres-
ponding isoquinolones by treatment with primary amines in
Lu, Guangzhou, 510275, China. E-mail: cespay@mail.sysu.edu.cn;
Fax: +86 020 84112245; Tel: +86 020 84110918
†Electronic supplementary information (ESI) available: NMR spectra for 2a–2k.
See DOI: 10.1039/c4ob00663a
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alcohols or other solvents,7 but we found that the reactions of found that the choice of the aluminium reagent was crucial for
phosphaisocoumarin esters with ethylamine in ethanol did the success of this reaction. With no aluminium reagent or the
not lead to any amidation products but the ring-opened alco- use of AlMe3, Et2AlCl and AlCl3, the reaction did not afford any
holysis products (Scheme 2).8 This result indicated that the amidation product (entries 1–6). Gratifyingly, the reaction
direct formation of phosphonamidates from phosphonates is of 1a with the aluminium amide (i-Bu2AlNHBun), generated
very challenging, probably due to the steric encumbrance from DIBAL-H (i-Bu2AlH, 1.0 mmol) and n-butylamine
around the phosphonyl group and the stronger affinity of (1.2 mmol) in THF accompanied by hydrogen evolution,
phosphorus to oxygen than to nitrogen.
proceeded smoothly at room temperature to give the corres-
The aluminium amide intermediates, generated from ponding phosphaisocoumarin amidate 2a in high yield
amines or amine hydrochloride and aluminium reagents, such (entries 7 and 8). Screening the solvents showed that the reac-
as AlMe3,9 Me2AlCl10 and DIBAL-H,11 were reported to react tion was sluggish in toluene (entry 9), but there were no appar-
with inactive lactones, esters, and acid chlorides,12 leading to ent differences in THF, CHCl3 and CH2Cl2 (entries 8, 10 and 11).
various carboxamides in moderate to excellent yields. We Taking into account that the aluminium reagent has better
reasoned that such aluminium amide species may promote solubility in THF, we selected THF as the solvent for the follow-
the direct amidation of phosphonates. However, to our sur- ing reactions. Surprisingly, when the amount of i-Bu2AlNHBun
prise, this kind of aluminium-mediated amidation of phos- was decreased to 0.15 mmol (1.5 equiv.), the yield of 2a was
phonates or phosphates has never been explored thus far. We significantly reduced even after doubling the reaction time
herein present our findings about the DIBALH-mediated direct (entry 12). Further studies indicated that excess i-Bu2AlNHBun
amidation of phosphaisocoumarin esters, affording a series of was necessary and six equiv. of i-Bu2AlNHBun were sufficient
phosphaisocoumarin amidates in this study.13
to drive the reaction to completion (entries 13–16).
To explore the scope and limitations of this reaction, the
reactions of a series of phosphaisocoumarin esters 1 and
primary aliphatic amines were then investigated using
DIBAL-H as an aluminium reagent and THF as a solvent and
the results are shown in Table 2. Under the optimized reaction
conditions, phosphaisocoumarin esters 1a–1h could react
smoothly with benzylamine and n-butyl amine, producing the
desired products phosphaisocoumarin amidates 2a–2k in
good to excellent yields (entries 1–11). The reaction was not
very sensitive to the electronic nature of the substrates. Various
functionalities were all able to withstand the reaction con-
Results and discussion
We first examined the amidation of 1a (0.1 mmol) with n-butyl-
amine under various conditions and the results are summar-
ized in Table 1. A slight excess of amine (amine–Al = 1.2 : 1)
was used in each case to exclude the effects of the free
aluminium reagent on the subsequent amidation reaction. We
Table 1 Optimization of the amidation reaction of 1aa
Table 2 DIBAL-H-mediated amidation of phosphaisocoumarin esters
with primary aminesa
Aluminium reagent
Entry (equiv.)
Solvent
T/°C Time/h Yieldb (%)
1
2
3
4
5
6
7
8
None
AlCl3 (10)
AlCl3 (10)
AlCl3 (10)
THF
THF
CHCl3
THF
THF
THF
THF
THF
0–rt
0–rt
0–rt
12
12
12
NRc
NR
NR
NR
NR
NR
91
92
53
90
83
Entry
R1
R2
X
R3
Time/h
Yieldb (%)
0–50 12
AlMe3 (10)
0–rt
0–rt
0–rt
rt
12
12
3
3
3
3
3
6
6
1
2
3
4
5
6
7
8
H
H
H
Cl
Cl
Cl
CH3O
CH3O
H
Ph
Ph
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
Ph
Ph
H (1a)
H (1a)
H (1b)
H (1c)
H (1c)
H (1d)
H (1e)
H (1e)
Cl (1f)
Br (1g)
I (1h)
n-Bu
3
1
3
4
5
4
6
8
4
4
4
77 (2a)
91 (2b)
64 (2c)
83 (2d)
72 (2e)
81 (2f)
81 (2g)
90 (2h)
73 (2i)
76 (2j)
84 (2k)
Et2AlCl (10)
DIBAL-H (10)
DIBAL-H (10)
DIBAL-H (10)
DIBAL-H (10)
DIBAL-H (10)
DIBAL-H (1.5)
DIBAL-H (2)
DIBAL-H (4)
DIBAL-H (5)
DIBAL-H (6)
PhCH2
PhCH2
PhCH2
n-Bu
n-Bu
PhCH2
n-Bu
PhCH2
PhCH2
PhCH2
9
Toluene rt
10
11
12
13
14
15
16
CHCl3
CH2Cl2
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
35
38
70
87
9
10
11
6
3
3
H
H
Ph
92
a The reaction was carried out in the presence of DIBAL-H (6 equiv.),
primary amine (7.2 equiv.), N2 at 0 °C in anhydrous THF for 1–2 h
followed by phosphaisocoumarin ester 1 in anhydrous THF at room
temperature. b Isolated yield.
a The reaction of the aluminium reagent, amine (1.2 equiv. of the
aluminium reagent) was carried out under N2 for 1–2 h followed by
addition of 1a (0.1 mmol). b Yield based on 31P NMR. c No reaction.
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ditions, e.g. R1 is electron-rich methoxy, electron-poor chlorine, amine, but also enhance the electrophilicity of the phosphorus
neutral hydrogen, R2 is aryl, alkyl, and X is chloro, bromo, by coordination with the phosphonyl oxygen (intermediate A).
iodo. The substrate 1e with an electron-donating methoxy The attack of the activated amine on the phosphorus leads to
group could transform to the desired products smoothly, but intermediate B, which collapses to the desired product 2 upon
needed a little longer reaction time (entries 7 and 8). Further- hydrolytic workup. The reaction of DIBAL-H and amines could
more, the reactivity of benzylamine is relatively higher than generate aluminium amides and hydrogen,14 but AlMe3,
that of n-butyl amine since the latter needed a longer time to Et2AlCl, AlCl3 could not afford the aluminium amides but the
complete the reactions (compare entries 1 and 2, 4 and 5, 7 1 : 1 aluminium amine adducts (Scheme 4).15 In the adducts,
and 8).
the nucleophilicity of the amine was greatly decreased by co-
Next, we examined the amidation of 1a with less reactive ordinating with the electron-weak aluminium, which might
aromatic amines and secondary aliphatic amines. Unfortu- account for the results that only DIBAL-H could facilitate the
nately, when using phenylamine, N-methoxy-N-methyl present reaction (entries 2–7, Table 1). Besides, the fact that
(Weinreb) amine and diethyl amine as the amine source this reaction needed excess aluminium amide might be
(Scheme 3), no desired amidation products but some decom- explained by the following two aspects. First, compared to the
posed unidentified compounds were observed. Extending the carboxylic esters, the more hindered phosphaisocoumarin
reaction time and increasing the reaction temperature did not esters are less reactive and need more nitrogen nucleophile to
make the reactions proceed. We speculated that it should be accelerate the reaction. Huang et al.11 reported that the amino-
the steric hindrance of the secondary amines or aromatic lysis of less reactive aromatic esters needed an excess of the
amines that prevented them from approaching the phos- DIBAL-H-amine reagents (up to 5 equiv.), which was consistent
phorus center.
with our results. Second, the coordination of additional alu-
Based on the above results, a plausible mechanism was pro- minium amide with the ethoxy might make it easier to leave
posed in Scheme 4. The formation of the aluminium amide is (Scheme 4).
the key to the success of the reaction, probably because the
It is noteworthy that whereas the amidation of lactones
aluminium might not only increase the nucleophilicity of often leads to lactams or ring opened amidated products, the
present reaction showed high selectivity for phosphaiso-
coumarin amidates. In each case, only the exocyclic ethoxy
group was amidated and no ring opened or other aminolysis
products were detected by TLC and NMR monitoring of the
crude reaction mixture.
The structures of 2 were determined by spectroscopic
1
methods, especially by H NMR spectral analysis and ESI-MS
analysis. For example, the structure of 2a was confirmed by the
disappearance of ethyl protons of P–OEt and the appearance
of n-butyl protons of P–NHBun, and the existence of the vinylic
Scheme 3 DIBAL-H-mediated amidation of 1a with phenylamine and
secondary amines.
1
proton at the 4 position from its H NMR spectrum, which is
consistent with the proposed structure.
Conclusion
In summary, we have developed a direct way to convert phos-
phaisocoumarin esters to phosphaisocoumarin amidates
using aluminium amides (i-Bu2AlNHR) as amidating reagents.
The present amidation reaction showed high selectivity, in
which the phostone ring of phosphaisocoumarin esters was
not opened and only the exocyclic ester group was amidated
under the reaction conditions. Further studies on the appli-
cations of this reaction and the amidation of other phostones
and acyclic phosphonates are underway in our group.
Experimental
General
1
The H, 13C and 31P NMR spectra were recorded on a Varian
Scheme 4 Plausible mechanism of the aluminium amide-mediated
amidation of 1.
Mercury-Plus 300 or a Varian INOVA 400 NMR instrument. All
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melting points are uncorrected. 31P NMR spectra used 85% 103.7 (d, J = 12.0 Hz), 45.4 (s); 31P NMR (121 MHz, CDCl3)
H3PO4 as the external reference. ESI-mass spectra were δ 17.9 (s); MS (ESI): m/z: 346 [M − 1]−, 348 [M + H]+, 370
recorded on a LCMS-2010A liquid chromatography mass [M + Na]+, 386 [M + K]+; Anal. Calcd for C18H20NO2P: C, 72.61;
spectrometer. Elemental analysis was performed using a Vario H, 5.22; N, 4.03. Found: C, 72.89; H, 5.02; N, 4.08.
1-Benzylamino-3-butylbenzo[c][1,2]oxaphosphinine
1-oxide
EL elemental analyzer. HRMS was determined using a Thermo
MAT95XP high resolution mass spectrometer. IR spectra were
recorded as KBr pellets on a Bruker Equinox 55 FT/IR spectro-
meter. Solvents were purified and dried according to standard
procedures. All commercially available reagents were used
as received. Column chromatography was performed on
200–300 mesh silica gel. Thin-layer chromatography was con-
ducted on a Kieselgel 60 F254. The starting materials 1 were
prepared according to our previous procedures.6
Typical procedures for the preparation of phosphaiso-
coumarin amidates 2a–k. A solution of DIBAL-H (1.0 M in
hexane, 1.8 mL, 1.8 mmol) was added to a cooled (0 °C) solu-
tion of n-butylamine (0.22 mL, 2.3 mmol) in anhydrous THF
(1.0 mL) under nitrogen. The mixture was allowed to warm up
and stirred at rt for 1–2 h. To this prepared i-Bu2AlNHBun solu-
tion was added a solution of 1 (0.3 mmol) in anhydrous THF
(1.0 mL) under nitrogen at room temperature. After stirring at
room temperature for an appropriate time (see Table 2), the
reaction mixture was cooled to 0 °C, and then quenched with
H2O (3.5 mL) and saturated NH4Cl (4 mL). The resulting
mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated. The residue was purified by flash chromato-
graphy (EtOAc–PE: 1/6–1/4) to give the corresponding phos-
phaisocoumarin amides 2a–2k. The isolated yield and the
spectral data for 2a–2k are as follows:
(2c). Oil. Yield: 64%. IR (film): 3183, 3065, 2959, 2930, 2872,
1725, 1656, 1596, 1468, 1428, 1379, 1343, 1227, 1148, 1106,
1045, 964, 912 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J =
14.0, 7.6 Hz, 1H), 7.54–7.43 (m, 1H), 7.37–7.07 (m, 7H), 5.86 (s,
1H), 3.96 (dd, J = 11.5, 6.7 Hz, 2H), 3.91–3.77 (m, 1H),
2.44–2.24 (m, 2H), 1.67–1.52 (m, 2H), 1.37 (dq, J = 14.1, 7.1 Hz,
2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 155.2
(d, J = 10.5 Hz), 139.3 (d, J = 5.7 Hz), 138.6 (d, J = 7.2 Hz), 132.8
(s), 129.9 (d, J = 9.2 Hz), 128.7 (s), 127.5 (s), 127.3 (s), 127.1 (s),
126.1 (d, J = 11.2 Hz), 121.2 (d, J = 164.3 Hz), 104.2 (d, J =
11.9 Hz), 45.2 (s), 34.9 (d, J = 4.5 Hz), 28.9 (s), 22.5 (s), 14.2 (s);
31P NMR (121 MHz, CDCl3) δ 17.9 (s); MS (ESI): m/z: 328
[M + H]+; HRMS (EI): calcd for C19H22NO2P (M+): 327.1383;
found: 327.1384.
1-Benzylamino-7-chloro-3-butylbenzo[c][1,2]oxaphosphinine
1-oxide (2d). White solid, mp: 74–77 °C. Yield: 83%. IR (KBr):
3155, 2956, 2927, 1722, 1661, 1528, 1459, 1385, 1344, 1218,
1
1160, 1099, 1004, 973 cm−1; H NMR (300 MHz, CDCl3) δ 7.71
(dd, J = 14.6, 2.0 Hz, 1H), 7.44 (dd, J = 8.4, 2.2 Hz, 1H),
7.36–7.21 (m, 5H), 7.12 (dd, J = 8.4, 5.9 Hz, 1H), 5.86 (s, 1H),
4.00 (d, J = 11.6 Hz, 2H), 3.63 (s, 1H), 2.35 (td, J = 7.4, 3.5 Hz,
2H), 1.68–1.53 (m, 2H), 1.37 (ddt, J = 8.6, 7.2, 4.1 Hz, 2H), 0.92
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 155.6 (d, J =
10.5 Hz), 138.9 (d, J = 5.1 Hz), 136.8 (d, J = 6.7 Hz), 133.0 (d, J =
1.5 Hz), 132.9 (s), 132.6 (s), 129.6 (d, J = 10.5 Hz), 128.7 (s),
127.7 (s), 127.5 (s), 123.0 (d, J = 163.4 Hz), 103.5 (d, J = 11.7
1-Butylamino-3-phenylbenzo[c][1,2]oxaphosphinine
1-oxide
(2a). White solid, mp: 122–125 °C. Yield: 77%. IR (KBr): 3193, Hz), 45.3 (s), 34.9 (d, J = 4.9 Hz), 28.8 (s), 22.5 (s), 14.2 (s);
3061, 2957, 1629, 1594, 1553, 1492, 1467, 1340, 1286, 1205, 31P NMR (121 MHz, CDCl3) δ 15.9 (s); MS (ESI): m/z: 362
1
1130, 1097, 1084, 1022, 982 cm−1; H NMR (300 MHz, CDCl3) [M + H]+, 384 [M + Na]+; Anal. Calcd for C19H21ClNO2P:
δ 7.92–7.75 (m, 3H), 7.57 (td, J = 7.6, 1.1 Hz, 1H), 7.48–7.30 (m, C, 63.07; H, 5.85; N, 3.87. Found: C, 63.21; H, 5.58; N, 3.79.
1-Butylamino-7-chloro-3-butylbenzo[c][1,2]oxaphosphinine
5H), 6.67 (s, 1H), 3.14 (s, 1H), 2.96–2.72 (m, 2H), 1.55–1.40 (m,
2H), 1.31 (dq, J = 13.8, 6.9 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 150.6 (d, J = 9.5 Hz), 138.4 (d, J =
7.2 Hz), 133.8 (d, J = 5.7 Hz), 132.8 (s), 129.9 (d, J = 9.3 Hz),
129.6 (s), 128.8 (s), 127.8 (d, J = 14.7 Hz), 127.1 (d, J = 11.1 Hz),
125.3 (s), 122.0 (d, J = 164.7 Hz), 103.7 (d, J = 11.8 Hz), 41.2 (s),
34.0 (d, J = 5.8 Hz), 20.0 (s), 14.0 (s); 31P NMR (121 MHz,
CDCl3) δ 18.5 (s); MS (ESI): m/z: 314 [M + H]+, 336 [M + Na]+,
352 [M + K]+; Anal. Calcd for C18H20NO2P: C, 69.00; H, 6.43;
N, 4.47. Found: C, 68.78; H, 6.56; N, 4.45.
1-oxide (2e). Oil. Yield: 72%. IR (film): 3208, 2957, 2869, 1721,
1
1656, 1471, 1384, 1343, 1285, 1230, 1103, 1047, 962 cm−1; H
NMR (300 MHz, CDCl3) δ 7.73 (d, J = 14.3 Hz, 1H), 7.41 (d, J =
8.3 Hz, 1H), 7.09 (dd, J = 8.1, 6.0 Hz, 1H), 5.84 (s, 1H), 3.74 (s,
1H), 2.83–2.64 (m, 2H), 2.50–2.28 (m, 2H), 1.63 (dt, J = 15.4,
7.6 Hz, 2H), 1.51–1.22 (m, 6H), 0.88 (dt, J = 26.2, 7.2 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 155.6 (d, J = 10.7 Hz), 136.8 (d, J =
6.7 Hz), 132.7 (s), 132.5 (s), 129.4 (d, J = 10.4 Hz), 127.6 (d, J =
12.2 Hz), 123.4 (d, J = 163.3 Hz), 103.5 (d, J = 11.7 Hz), 41.1 (s),
35.0 (d, J = 4.8 Hz), 33.9 (d, J = 5.7 Hz), 28.9 (s), 22.4 (s), 20.0
1-Benzylamino-3-phenylbenzo[c][1,2]oxaphosphinine
1-oxide
(2b). White solid, mp: 147–148 °C. Yield: 91%. IR (KBr): 3267, (s), 14.2 (s), 14.0 (s); 31P NMR (121 MHz, CDCl3) δ 16.2 (s); MS
3057, 3026, 2910, 1624, 1492, 1472, 1447, 1413, 1332, 1287, (ESI): m/z: 328 [M + H]+, 350 [M + Na]+; Anal. Calcd for
1241, 1217, 1148, 1112, 1075, 1051, 1023, 914 cm−1; H NMR C16H23ClNO2P: C, 58.63; H, 7.07; N, 4.27. Found: C, 58.65;
1
(300 MHz, CDCl3) δ 7.85 (ddd, J = 14.1, 7.6, 0.5 Hz, 1H), H, 7.08; N, 3.98.
7.76–7.69 (m, 2H), 7.53 (td, J = 7.6, 0.7 Hz, 1H), 7.44–7.06 (m,
1-Butylamino-7-chloro-3-phenylbenzo[c][1,2]oxaphosphinine
10H), 6.64 (s, 1H), 4.13(s, 1H), 4.07–4.01 (m, 2H); 13C NMR 1-oxide (2f). White solid, mp: 110–112 °C. Yield: 81%. IR
(75 MHz, CDCl3) δ 150.7 (d, J = 9.7 Hz), 139.4 (d, J = 5.4 Hz), (KBr): 3232, 3061, 2967, 2929, 2869, 1629, 1580, 1492, 1467,
138.4 (d, J = 7.1 Hz), 133.8 (d, J = 5.5 Hz), 132.9 (s), 130.0 (d, J = 1446, 1427, 1385, 1336, 1281, 1235, 1195, 1149, 1124, 1043,
9.3 Hz), 129.61(s), 128.7 (s), 127.9 (s), 127.7 (s), 127.5 (s), 127.5 1022, 979 cm−1 1H NMR (300 MHz, CDCl3) δ 7.88–7.72 (m,
;
(s), 127.2 (d, J = 11.4 Hz), 125.3 (s), 122.0 (d, J = 165.2 Hz), 3H), 7.50 (dd, J = 8.4, 1.7 Hz, 1H), 7.46–7.35 (m, 3H), 7.29 (dd,
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J = 8.4, 5.8 Hz, 1H), 6.63 (d, J = 1.7 Hz, 1H), 3.53 (s, 1H), 2.84
(m, 2H), 1.54–1.40 (m, 2H), 1.40–1.25 (m, 2H), 0.85 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 150.8 (d, J = 9.3 Hz),
136.7 (d, J = 6.4 Hz), 133.4 (d, J = 15.4 Hz), 133.1 (s), 132.9 (s),
129.8 (s), 129.4 (d, J = 10.4 Hz), 128.8 (s), 128.6 (s), 125.3 (s),
124.2 (d, J = 160.8 Hz), 102.9 (d, J = 11.6 Hz), 41.2 (s), 33.9 (d,
J = 5.5 Hz), 20.0 (s), 14.0 (s); 31P NMR (121 MHz, CDCl3) δ 16.1
(s); MS (ESI): m/z: 348 [M + H]+, 370 [M + Na]+, 386 [M + K]+;
Anal. Calcd for C18H19ClNO2P: C, 62.16; H, 5.51; N, 4.03.
Found: C, 61.97; H, 5.556; N, 3.94.
1-Benzylamino-3-phenyl-4-bromobenzo[c][1,2]oxaphosphinine
1-oxide (2j). White solid, mp: 149–151 °C. Yield: 76%.
IR (KBr): 3179, 2895, 1587, 1490, 1454, 1282, 1248, 1222, 1151,
1118, 1068, 1002, 938 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 7.98–7.92 (m, 1H), 7.80 (dd, J = 14.6, 7.5 Hz, 1H), 7.67–7.63
(m, 3H), 7.42 (t, J = 7.0 Hz, 4H), 7.23 (s, 5H), 4.48 (s, 1H), 4.06
(dd, J = 11.4, 1.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 148.5 (d,
J = 10.0 Hz), 139.0 (d, J = 5.6 Hz), 137.7 (d, J = 6.6 Hz), 135.1 (d,
J = 4.7 Hz), 133.2 (s), 129.9 (s), 129.8 (s), 129.6 (s), 128.8 (s),
128.7 (d, J = 14.1 Hz), 128.5, 128.3, 128.0 (s), 127.6 (s), 122.8 (d,
1-Benzylamino-7-methoxy-3-phenylbenzo[c][1,2]oxaphosphinine J = 165.6 Hz), 104.2 (d, J = 12.2 Hz), 45.5 (s); 31P NMR
(121 MHz, CDCl3) δ 16.5 (s); MS (ESI): m/z: 424 [M − H]−, 428
1-oxide (2g). White solid, mp: 172–176 °C. Yield: 81%. IR
[M + H]+, 450 [M + Na]+; Anal. Calcd for C21H17BrNO2P:
(KBr): 3161, 3026, 3004, 2916, 1955, 1893, 1736, 1631, 1598,
1552, 1489, 1452, 1415, 1330, 1313, 1287, 1265, 1215, 1180,
C, 59.17; H, 4.02; N, 3.29. Found: C, 59.21; H, 4.141; N, 3.24.
1-Benzylamino-3-phenyl-4-iodobenzo[c][1,2]oxaphosphinine
1-oxide (2k). White solid, mp: 127–128 °C. Yield: 84%. IR (KBr):
3179, 2894, 1574, 1547, 1488, 1453, 1280, 1252, 1217, 1151,
1
1122, 1077, 1038, 1022, 920 cm−1; H NMR (400 MHz, CDCl3)
δ 7.78–7.72 (m, 2H), 7.45–7.21 (m, 10H), 7.14 (ddd, J = 8.4, 2.8,
0.4, 1H), 6.64 (d, J = 1.9 Hz, 1H), 4.18–4.00 (m, 2H), 3.83 (s,
3H), 3.69–3.60 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 159.0 (d,
J = 18.1 Hz), 148.6 (d, J = 9.7 Hz), 139.1 (d, J = 5.9 Hz), 133.6 (d,
J = 6.1 Hz), 131.3 (d, J = 6.9 Hz), 129.1 (s), 128.9 (s), 128.7 (s),
128.6 (d, J = 6.0 Hz), 127.4 (s), 127.3 (s), 124.8 (s), 122.8 (d, J =
164.7 Hz), 120.8 (d, J = 2.8 Hz), 112.5 (d, J = 10.7 Hz), 103.1 (d,
J = 11.7 Hz), 55.6 (s), 45.0 (s); 31P NMR (121 MHz, CDCl3)
δ 22.6 (s); MS (ESI): m/z: 378 [M + H]+; Anal. Calcd for
C22H20NO3P: C, 70.02; H, 5.34; N, 3.71. Found: C, 70.06;
H, 5.39; N, 3.58.
1
1118, 1062, 1025, 1000, 925 cm−1; H NMR (300 MHz, CDCl3)
δ 7.98–7.89 (m, 1H), 7.78 (dd, J = 14.6, 7.5 Hz, 1H), 7.68–7.56
(m, 3H), 7.48–7.39 (m, 4H), 7.32–7.20 (m, 5H), 4.22–3.99 (m,
2H), 3.73 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 151.1 (d, J =
10.0 Hz), 139.3 (d, J = 6.8 Hz), 138.9 (d, J = 6.5 Hz), 137.7 (d, J =
4.4 Hz), 133.4 (s), 133.3 (d, J = 10.6 Hz), 130.2 (s), 129.9 (s),
129.6 (d, J = 9.3 Hz), 128.9 (s), 128.7 (s), 128.1 (s), 127.6 (s),
127.5 (s), 122.5 (d, J = 165.6 Hz), 80.3 (d, J = 11.7 Hz), 45.5 (s);
31P NMR (121 MHz, CDCl3) δ 16.2 (s); MS (ESI): m/z: 474
[M + H]+, 496 [M + Na]+, 512 [M + K]+; Anal. Calcd
for C21H17INO2P: C, 53.30; H, 3.52; N, 2.96. Found: C, 52.95;
H, 3.629; N, 2.85.
1-Butylamino-7-methoxy-3-phenylbenzo[c][1,2]oxaphosphinine
1-oxide (2h). White solid, mp: 158–161 °C. Yield: 90%. IR
(KBr): 3235, 3071, 3009, 2960, 2932, 2870, 1886, 1756, 1632,
1596, 1552, 1485, 1335, 1284, 1268, 1212, 1178, 1128, 1105,
1079, 1037, 1021, 977 cm−1 1H NMR (400 MHz, CDCl3)
;
δ 7.84–7.79 (m, 2H), 7.46–7.28 (m, 5H), 7.14 (dd, J = 8.6,
2.4 Hz, 1H), 6.64 (d, J = 1.4 Hz, 1H), 3.89 (s, 3H), 3.33 (s, 1H),
2.96–2.75 (m, 2H), 1.53–1.41 (m, 2H), 1.38–1.25 (m, 2H), 0.84
(t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.0 (d, J =
18.0 Hz), 148.6 (d, J = 9.6 Hz), 133.8 (d, J = 5.9 Hz), 131.3 (d, J =
6.8 Hz), 129.0 (s), 128.7 (d, J = 13.4 Hz), 128.5 (s), 124.8 (s),
123.2 (d, J = 164.4 Hz), 120.4 (d, J = 1.9 Hz), 112.7 (d, J =
10.5 Hz), 103.1 (d, J = 11.6 Hz), 55.6 (s), 40.8 (s), 33.7 (d, J =
5.8 Hz), 19.6 (s), 13.6 (s); 31P NMR (121 MHz, CDCl3) δ 18.0 (s);
MS (ESI): m/z: 344 [M + H]+; Anal. Calcd for C19H22NO3P:
C, 66.46; H, 6.46; N, 4.08. Found: C, 66.37; H, 6.50; N, 4.00.
1-Benzylamino-3-phenyl-4-chlorobenzo[c][1,2]oxaphosphinine
1-oxide (2i). White solid, mp: 158–159 °C. Yield: 73%. IR (KBr):
3162, 2898, 1592, 1491, 1445, 1224, 1151, 1117, 1072, 1004,
963 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.97–7.90 (m, 1H), 7.83
(dd, J = 14.6, 7.5 Hz, 1H), 7.76–7.63 (m, 3H), 7.48–7.41 (m, 4H),
7.25–7.23 (m, 5H), 4.45 (s, 1H), 4.07 (dd, J = 11.8, 7.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 147.3 (d, J = 10.4 Hz), 139.1 (d, J =
5.6 Hz), 137.1 (d, J = 6.5 Hz), 133.6 (d, J = 4.6 Hz), 133.1 (s),
129.9 (s), 129.7 (s), 129.6 (s), 128.8 (s), 128.6 (s), 128.1 (s), 127.6
(s), 125.8, 125.7, 122.7 (d, J = 165.3 Hz), 113.4 (d, J = 12.4 Hz),
45.5 (s); 31P NMR (121 MHz, CDCl3) δ 16.4 (s); MS (ESI): m/z:
380 [M − H]−, 382 [M + H]+, 404 [M + Na]+, 420 [M + K]+; Anal.
Calcd for C21H17ClNO2P: C, 66.06; H, 4.49; N, 3.67. Found: C,
66.144; H, 4.606; N, 3.60.
Acknowledgements
This work was supported by research grants from the National
Natural Science Foundation of China (grant no. 20602043).
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