Stereospecific transformation of protected Pa-H group into Pa-O or Pa-N group in one-pot reaction

Article abstract of DOI:10.1021/jo302140q

A general and efficient procedure for converting 1,1- diethoxyalkylphosphinates into phosphonates or phosphonamides is described by the application of bromine with moderate to high yields and good purity in a one-pot reaction. H-Phosphinate reacts stereospecifically with bromine and subsequently couples with nucleophile to form the corresponding optically active R¹P(O)(OEt)X with retention of configuration at the phosphorus center. For α-amino-H-phosphinates, the transformation could be realized without the protection of the amino group.

Full text of DOI:10.1021/jo302140q

Note
pubs.acs.org/joc
Stereospecific Transformation of Protected P−H Group into P−O or
P−N Group in One-Pot Reaction
Qiuli Yao and Chengye Yuan*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A general and efficient procedure for converting 1,1-diethox-
yalkylphosphinates into phosphonates or phosphonamides is described by the
application of bromine with moderate to high yields and good purity in a one-
pot reaction. H-Phosphinate reacts stereospecifically with bromine and
subsequently couples with nucleophile to form the corresponding optically
active R1P(O)(OEt)X with retention of configuration at the phosphorus center.
For α-amino-H-phosphinates, the transformation could be realized without the protection of the amino group.
rganophosphorus acid derivatives, more specifically α-
amino or α-hydroxy phosphonates or phosphonamides
phosphinates in our study. Above all, all of the described
processes need to have the α-amino group of the H-
phosphinates protected.
To determine the absolute configuration and d.r. values of α-
aminophosphinates, as was done by Haruki and co-workers,5
the α-aminophosphinates need to be converted to α-amino-
phosphonates and the amino group should be blocked (Scheme
2).
O
are useful as intermediates for the preparation of antibacterial,
antipsoriatic, anti-HIV, and anticancer agents, and they have
been found to possess herbicidal and defoliating activity.1
The transformation of the P−H group into a P−X group is
useful for the syntheses of various organophosphorus acid
derivatives, and the stereospecific transformation is especially
important for optically active compounds. The most common
strategies for such transformation are shown in Scheme 1 as
Scheme 2. Transformation of α-Aminophosphinates into α-
Amidophosphonate5
Scheme 1. Transformation of P−H Group to P−X Group
Here we report an efficient procedure for the stereospecific
transformation of 1,1-diethoxyalkyl protected H-phosphinates
into phosphonates or phosphonamides in the presence of
bromine and nucleophile in a one-pot reaction (Scheme 1).
Because H-phosphinates are sometimes unstable and the 1,1-
diethoxyalkyl group is easily introduced and labile to hydrolysis,
it is used as temporary protecting group for the P−H function.
In our previous study of converting α-aminophosphinate 1a
into α-aminophosphonate to determine the d.r. value of 1a, we
first hydrolyzed the 1,1-diethoxymethyl group of 1a by TMSCl
to give α-amino-H-phosphinate,6 which was too unstable to be
isolated. So it was directly subjected to the oxidization reaction
by bromine in dichloromethane and ethanol. Unexpectedly, the
diethylphosphonate 2a instead of ethyl hydrogen phosphonate
was separated in good yields (Table 1, entry 1, 2). The
transformation went through the formation of the P−H group,
and sequential bromination and in situ transferring into
diethylphosphonate 2a. During optimization studies, we
path A2 and path B,3 both of which require several steps.
Achieving these transformations is somewhat troublesome
because of the difficulties in purifying phosphonic acid (Path A)
and because of highly reactive phosphorochloridate or
phosphorobromidate. Although the Atherton−Todd reaction
provides direct transformation with the activation of the P−H
4
group by CCl4 (Scheme 1 Path C), this procedure could not
Received: October 8, 2012
be applied for the sterically hindered or unstable H-
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302140q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Transformation of α-Aminophosphinates to α-
Aminophosphonates and α-Aminophosphonamides
Table 2. Transformation of 3 to 4
a
b
entry
3
X−H
EtOH (5 equiv)
L-menthol (2 equiv)
4
yield (%)
c
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
4a
4b
4c
4d
4d
4e
4f
76 (61)
37
d
H-Gly-OEt·HCl (2 equiv)
n-C7H15NH2 (2 equiv)
61
70
e
n-C7H15NH2 (5 equiv)
77
df
,
(S)-α-methylbenzylamine (5 equiv)
quant.
ce
EtOH (10 mL mmol−1
)
73
quant.
,
ce
,
MeOH (10 mL mmol−1
)
4g
a
Reaction for step 2 was carried out with H-phosphinate after the
hydrolysis of 3 (0.1 mmol), appropriate X−H, NEt3 (0.2 mmol) and
b
bromine (0.15 mmol) in CH3CN (2 mL) at rt. Isolated yield for two
c
d
steps. Isolated yield in parentheses without NEt3. NEt3 (0.4 mmol)
e
f
was used. Bromine (0.2 mmol) was used. Bromine (0.5 mmol) was
used.
neutralize the acid generated from the bromination of H-
phosphinate. The sterically hindered L-menthol gave a slightly
low yield (entry 2), and the glycine ethyl ester, as well as amine,
gave corresponding phosphonamide with high purity and good
yields (entry 3−6). The addition of X−H from 2 to 5 equiv
would slightly improve the yield (entry 4, 5), and 3b was a
good substrate for this reaction with good yields (entry 7, 8).
The enantiomerically pure α-amidophosphinates 5,8 which
are important biologically active compounds, are difficult to be
converted into phosphonates or phosphonamides 6 for their
steric hindrance and low stability. Thus, an endeavor was made
to achieve the stereospecific transformation of 5 to prepare
optically active 6 by this procedure (Table 3). Gladly, the
conversion went through quite well at 0 °C within several hours
to generate 6 with moderate to high yields. Partly decomposed
H-phosphinates were detected, which could be ascribed to the
instability of these compounds. It should be pointed out that by
the procedure of CuCl2 (entry 2) or CCl4 (entry 3), no
product was given at all, which indicated the steric hindrance
and the low stability of these H-phosphinates. Each product
gave a single peak in its 31P NMR, indicating that its de % was
more than 95% and the transformation was stereospecific.
The single crystals of deprotected 5c, 6c and 6f indicate that
the products have retention of configuration at the phosphorus
center.9 Thus we are able to convert the stereospecific P−H
group into a P−X group with retention of configuration for
bulky and instable H-phosphinates. To achieve the stereo-
specific transformation with retention at the phosphorus center
is rather rare in the literature,10 so this reaction could provide a
protocol to investigate the stereochemistry of phosphorus
compounds.
a
Reaction for step 2 was carried out with H-phosphinate after the
hydrolysis of 1 (0.1 mmol), EtOH (1 mL) or MeOH (1 mL) or
corresponding RNH2 in DCM (1 mL, entry 1, 3−6) or CH3CN (1
mL, entry 2, 7−9), and a slight excess of bromine was added until
b
c
yellow color persisted at rt. Isolated yield for two steps. TMSCl for
d
e
step 1. Isolated yield in parentheses with 2 equiv of NEt3. BF3·Et2O
for step 1.
found the addition of NEt3 was disadvantageous and resulted in
lower yield (entry 2). Under the optimized conditions, the
substrate scope was studied, and it was proved that the reaction
could tolerate different protecting groups including benzyl,
phthalyl and alkoxylcarbonyl (entry 1, 3, 5, 6). Next, the
nucleophile was investigated, and methanol was a good
substrate for this reaction with good yield (entry 7).
Phosphonamides could be prepared as well when reacted
with amine or glycine ethyl ester, but the yields are low to
moderate (entry 8, 9).
As shown in Table 1, the process is direct and highly
efficient. This provides a convenient method to elucidate the
absolute configuration and d.r. values of α-aminophosphinates.
The partial protection of the amino group as a result of the
intramolecular hydrogen bonding of the amino group with the
phosphoryl group makes the protection of the α-amino group
not necessary.7 As far as we know, no report of such process
with the free α-amino group as substrate has been revealed yet,
and no method of direct conversion of the P−H group into a
P−O or P−N group by bromine has ever been developed.
Therefore, we decided to expand this procedure for special
phosphinate derivatives such as α-acetoxyphosphinate 3a and
α-Fmoc-oxyphosphinate 3b (Table 2) that constitute an
important class of biologically active compounds.
3c
4b
Following the progress of the reaction by 31P NMR
spectroscopy reveals several aspects of the mechanism (Scheme
3, Figure 1). Phosphinate 3a is hydrolyzed to H-phosphinate A
and then activated by Br2, producing an intermediate B, which
is phosphorobromidate and HBr. Since B is generated in the
presence of EtOH, it is coupled in situ and side reactions are
minimized (Scheme 3). If the nucleophile is omitted from the
reaction mixture, byproducts are formed because of inter-
molecular reactions of the phosphorus derivatives.
As described in Table 2, phosphinates 3 were converted to 4
in moderate to high yields in one pot reaction. For 3a, the
addition of NEt3 gave a higher yield (entry 1), which was the
opposite of the result of α-aminophosphinates 1. It might be
reasoned by the acid-capture nature of the amino group in α-
amino-H-phosphinates, whereas 3a needs additional base to
B
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The Journal of Organic Chemistry
Note
a
Table 3. Stereospecific Transformation of 5 to 6
Br2
b
entry
5
X−H
(equiv)
6
yield (%)
86
1
2
3
4
5
5a MeOH (10 mL mmol−1
5b MeOH (10 mL mmol−1
)
)
2
6a
6b
6c
6d
6e
c
2
86 (0)
d
e
5b H-Gly-OEt·HCl (2 equiv)
5b n-C7H15NH2 (5 equiv)
1.5
4
48 (0)
80
50
5b (S)-α-methylbenzylamine
4
(5 equiv)
Figure 1. 31P NMR of A reacted with Br2 (2 equiv) and EtOH (5
equiv).
6
5c MeOH (10 mL mmol−1
5d MeOH (10 mL mmol−1
5d n-C7H15NH2 (5 equiv)
)
)
2
2
4
6f
quant.
79
f
7
f
6g
6h
g
8
46
a
Reaction for step 2 was carried out with H-phosphinate after the
General Procedure for the Transformation of the P−H
Group into a P−O or P−N Group. H-Phosphinate (0.1 mmol)
generated by the hydrolysis of 1,1-diethoxyalkyl group11 was used
directly in the next step without further purification. H-Phosphinate
was dissolved in DCM (2 mL) or CH3CN (2 mL). The corresponding
X−H and, for some instances, NEt3 were added. Bromine was added at
room temperature, except for 5, where it was added at 0 °C. After
completion of the reaction monitored by TLC, it was quenched by 2
mL of 5% NaHCO3 and 2 mL of 5% Na2SO3 and extracted with ethyl
acetate. The combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The solvent was evaporated, and the
crude product was purified by silica gel column chromatography with
petroleum ether/ethyl acetate (1:1) or preparative TLC. Data for
compounds 2a,12 2c,13 2d,14 3a,5b 4a,15 5a8 and 5c8 were in
accordance with reported data.
hydrolysis of 5 (0.1 mmol), appropriate X−H and bromine in CH3CN
b
(2 mL) at 0 °C. Isolated yield; each product gave a single peak in its
c
31P NMR, indicating single diastereoisomer. Yield in parentheses with
the procedure of CuCl2 and then NEt3, MeOH and THF.3c NEt3 (0.4
d
mmol) was added, and the reaction was carried out at room
e
temperature. Yield in parentheses with the procedure of NEt3,
CH3CN, CH2Cl2, CCl4.4b CH2Cl2 (2 mL) was used instead of
f
g
CH3CN. The reaction was carried out at room temperature.
Scheme 3. Process Revealed by 31P NMR
Compound 2b. White solid (28 mg, 79%): mp 92−94 °C; IR
(film) 3463, 3383, 3305, 2981, 2934, 1771, 1716, 1397, 1055, 722
1
cm−1; H NMR (CDCl3, 400 MHz) δ 7.83 (q, J = 2.8 Hz, 2H), 7.73
(q, J = 2.8 Hz, 2H), 4.14 (m, 4H), 3.73 (t, J = 6.8 Hz, 2H), 3.02 (td, J1
= 10.4 Hz, J2 = 3.2 Hz, 1H), 2.02 (m, 1H), 1.84 (m, 2H), 1.65 (m,
2H), 1.56 (m, 1H), 1.33 (td, J1 = 7.0 Hz, J2 = 2.0 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) δ 168.2 (s), 133.8 (s), 132.0 (s), 123.1 (s), 62.0
(m), 48.1 (d, J = 148.1 Hz), 37.4 (s), 28.3 (s), 25.2 (d, J = 12.4 Hz),
16.4 (m); 31P NMR (CDCl3, 162 MHz) δ 28.42; MS (ESI) m/z (%)
355.1 [M + H]+; HRMS (MALDI) calcd for C16H24N2O5P 355.1417,
found 355.1432.
Compound 2e. Colorless oil (20 mg, 55%): IR (film) 3455, 2937,
1770, 1712, 1397, 1025 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.84 (q,
J = 2.8 Hz, 2H), 7.71 (q, J = 2.8 Hz, 2H), 4.14 (m, 4H), 3.71 (t, J = 7.2
Hz, 2H), 2.93 (td, J1 = 10.2 Hz, J2 = 3.6 Hz, 1H), 1.83 (m, 1H), 1.69
(m, 5H), 1.48 (m, 2H), 1.33 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3,
100 MHz) δ 168.5 (s), 133.9 (s), 132.1 (s), 123.2 (s), 62.1 (m), 48.6
(d, J = 148.0 Hz), 37.7 (s), 30.8 (s), 28.3 (s), 23.5 (d, J = 12.4 Hz),
16.6 (d, J = 5.1 Hz); 31P NMR (CDCl3, 162 MHz) δ 28.91; MS (ESI)
m/z (%) 369.3 [M + H]+; HRMS (MALDI) calcd for C17H26N2O5P
369.1574, found 369.1585.
In conclusion, this procedure offers a general and effective
method for the direct transformation of a protected P−H group
into a P−O or P−N group stereospecifically. Bromine is first
applied for such one-pot transformation. This is the first time
achieving the conversion of α-aminophosphinates without
protection of the amino group. Stereospecific retention at
phosphorus center in such chemical conversion is quite rare
and interesting. The high reactivity of phosphorobromidate
makes the preparation of sterically hindered phosphonates or
phosphonamides much more realizable.
EXPERIMENTAL SECTION
■
General Methods. Reactions were performed under nitrogen
unless otherwise noted. Materials were obtained from commercial
suppliers and used without further purification. Preparative thin-layer
chromatography (TLC) was performed with plates precoated with
silica gel G.F. Flash chromatography was performed using silica gel
(300−400 mesh). HRMS were detected by FT-ICR MS.
Compound 2f. Colorless oil (18 mg, 82%): Two diastereomers; IR
1
(film) 3465, 2957, 1637, 1236, 1057, 1028 cm−1; H NMR (CDCl3,
400 MHz) δ 4.16 (m, 2H), 3.78 (m, 3H), 3.06 (td, J1 = 10.8 Hz, J2 =
2.8 Hz, 1H), 1.91 (m, 1H), 1.54−1.43 (m, 4H), 1.35 (m, 3H), 0.93
(dd, J1 = 26.0 Hz, J2 = 6.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ
62.3 (m), 52.7 (m), 46.6 (d, J = 147.3 Hz), 39.9 (s); 24.1 (d, J = 13.1
C
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The Journal of Organic Chemistry
Note
Hz), 23.5 and 21.0 (s), 16.6 (m); 31P NMR (CDCl3, 162 MHz) δ
30.92, 30.87; MS (ESI) m/z (%) 210.1 [M + H]+; HRMS (MALDI)
calcd for C8H21NO3P 210.1254, found 210.1259.
15.2 (m); 31P NMR (CDCl3, 162 MHz) δ 21.11, 20.77, 20.64, 20.61;
MS (ESI) m/z (%) 396.2 [M + H]+; HRMS (MALDI) calcd for
C19H23NO4PClNa 418.0946, found 418.0944.
Compound 2g. Colorless oil (9 mg, 24%): Two diastereomers; IR
(film) 3222, 2926, 1454, 1208, 1039, 698 cm−1; 1H NMR (CDCl3, 400
MHz) δ 7.37−7.28 (m, 5H), 4.58−4.50 (m, 2H), 4.14−3.98 (m, 2H),
3.82−3.63 (m, 2H), 3.33−3.16 (m, 1H), 3.01−2.88 (m, 2H), 2.72 (m,
1H), 1.43 (m, 2H), 1.32−1.25 (m, 13H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 137.82 (s), 137.75 (s), 128.5 (s), 127.8
(s), 73.5 (m), 71.1 (d, J = 41.5 Hz), 60.2 (m), 50.5 and 50.0 (d, J =
136.4 and 139.2 Hz), 40.9 (s), 32.5 (m), 31.8 (s), 29.0 (s), 26.6 (s),
22.6 (s), 16.5 (m), 14.1 (s).; 31P NMR (CDCl3, 162 MHz) δ 33.52,
33.05 (1:1); MS (ESI) m/z (%) 357.3 [M + H]+; HRMS (ESI) calcd
for C18H34N2O3P 357.2302, found 357.2306.
Compound 4f. Colorless oil (34 mg, 73%): IR (film) 3479, 2983,
1754, 1258, 1050, 1023, 974, 741 cm−1; 1H NMR (CDCl3, 400 MHz)
δ 7.75 (d, J = 8.0 Hz, 2H), 7.59 (m, 2H), 7.53 (m, 2H), 7.42−7.35 (m,
5H), 7.32−7.25 (m, 2H), 5.96 (d, J = 13.6 Hz, 1H), 4.42 (m, 2H),
4.26 (t, J = 7.4 Hz, 1H), 4.14−3.95 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H),
1.23 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.4 (d, J =
1.2 Hz), 143.2 (d, J = 2.2 Hz), 141.3 (s), 133.0 (d, J = 1.5 Hz), 129.0
(d, J = 2.9 Hz), 128.6 (d, J = 2.2 Hz), 127.6 (d, J = 1.5 Hz), 127.8 (d, J
= 5.8 Hz), 127.2 (s), 125.2 (d, J = 3.7 Hz), 120.1 (s), 74.6 (d, J = 169.2
Hz), 70.6 (s), 63.7 and 63.5 (dd, J = 6.5 and 6.6 Hz), 46.7 (s), 16.4
and 16.3 (d, J = 5.1 and 5.8 Hz); 31P NMR (CDCl3, 162 MHz) δ
16.59; MS (ESI) m/z (%) 467.3 [M + H]+; HRMS (MALDI) calcd
for C26H27O6PNa 489.1438, found 489.1441.
Compound 2h. Colorless oil (12 mg, 42%): Two diastereomers;
1
IR (film) 3200, 2957, 2928, 1750, 1202, 1150, 1034 cm−1; H NMR
(CDCl3, 400 MHz) δ 4.21 (q, J = 7.2 Hz, 2H), 4.16−3.98 (m, 2H),
3.83 (dd, J1 = 9.6 Hz, J2 = 6.8 Hz, 2H), 3.12 (m, 1H), 3.02 (td, J1 =
10.4 Hz, J2 = 3.6 Hz, 1H), 1.88 (m, 1H), 1.59−1.36 (m, 2H), 1.30 (m,
6H), 0.96 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 172.1 (d, J = 4.4 Hz) and 171.9 (d, J = 5.2 Hz),
61.4 (m), 60.2 (m), 48.2 (d, J = 141.4 Hz) and 47.6 (d, J = 140.0 Hz),
43.0 (m), 40.1 and 39.4 (s), 24.3 and 24.2 (s), 23.6 and 21.0 (s), 16.4
(m), 14.2 (m); 31P NMR (CDCl3, 162 MHz) δ 33.52, 33.05; MS
(ESI) m/z (%) 281.2 [M + H]+; HRMS (MALDI) calcd for
C11H26N2O4P 281.1625, found 281.1626.
Compound 4b. Attained as four diastereomers; Light yellow oil
(16 mg, 37%): IR (film) 3480, 2956, 2928, 2870, 1752, 1223, 1014,
998 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.45−7.40 (m, 2H), 7.34−
7.31 (m, 2H), 6.03 (m, 1H), 4.30−4.17 (m, 1H), 4.14−3.91 (m, 2H),
2.15 (m, 3H), 2.03−1.74 (m, 1H), 1.65−1.24 (m, 10H), 1.20−1.12
(m, 1H), 0.91−0.88 (m, 3H), 0.83−0.55 (m, 6H) ; 13C NMR (CDCl3,
100 MHz) δ 168.2 (m), 133.5 (m), 131.4 (m), 128.6 (m), 127.5 (m),
77.7 (m), 70.0−68.1 (m), 62.6 (m), 47.3 (m), 42.0 (m), 32.8 (m),
30.4 (m), 28.6 (m), 24.5 (m), 21.7 (m), 20.8 (m), 19.8 (m), 15.4 and
14.5 (m); 31P NMR (CDCl3, 162 MHz) δ 16.54, 16.45, 16.28, 16.18;
MS (ESI) m/z (%) 453.2 [M + Na]+; HRMS (MALDI) calcd for
C21H32O5PClNa 453.1568, found 453.1563.
Compound 4c. Attained as two diastereomers; Light yellow oil
(23 mg, 61%): IR (film) 3222, 2983, 1747, 1226, 1031, 963 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 7.44−7.40 (m, 2H), 7.32 (d, J = 8.4 Hz,
2H), 6.08 and 6.03 (d, J = 12.4 Hz and J = 12.4 Hz, 1H), 4.19 (m,
2H), 4.14−4.03 (m, 2H), 3.77−356 (m, 2H), 3.21−3.10 (m, 1H),
2.165 and 2,160 (s, 3H), 1.30−1.24 (m, 6H); 13C NMR (CDCl3, 100
MHz) δ 171.0 (m), 169.5 and 169.4 (s), 134.5 (m), 132.4 and 132.4
(d, J = 2.9 Hz and J = 2.7 Hz); 129.2 (m), 128.7 (m), 71.6 and 70.9 (d,
J = 156.1 Hz and J = 156.1 Hz), 61.61 (m), 61.57 (m), 42.9 and 42.8
(s), 20.9 (s), 16.3 (m), 14.1 (s); 31P NMR (CDCl3, 162 MHz) δ
21.23, 21.18 (1.4:1); MS (ESI) m/z (%) 378.1 [M + H]+; HRMS
(MALDI) calcd for C15H21NO6PClNa 400.0687, found 400.0691.
Compound 4d. Attained as two diastereomers; Colorless oil (27
mg, 70%): IR (film) 3418, 2929, 1743, 1627, 1227, 1046, 564 cm−1;
1H NMR (CDCl3, 400 MHz) δ 7.42 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 6.05 and 6.01 (d, J = 12.4 Hz and J = 12.0 Hz,
1H), 4.13−3.96 (m, 2H), 2.94−2.82 (m, 2H), 2.53 and 2.44 (m, 1H),
2.17 (s, 3H), 1.40 (m, 2H), 1.29−1.22 (m, 11H), 0.88 (t, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 169.6 (m), 134.4 (m), 132.9
(m); 129.2 (s), 128.6 (s), 71.2 (m), 61.1 (m), 41.4 (d, J = 4.4 Hz),
32.2 (d, J = 4.3 Hz), 31.8 (s), 28.9 (s), 26.5 (s), 22.6 (s), 20.9 (m),
16.4 (m), 14.1 (s); 31P NMR (CDCl3, 162 MHz) δ 21.86, 21.71; MS
(ESI) m/z (%) 390.2 [M + H]+; HRMS (MALDI) calcd for
C18H29NO4PClNa 412.1415, found 412.1429.
Compound 4g. Colorless oil (45 mg, quantitative): IR (film)
3480, 2955, 1754, 1258, 1027, 742 cm−1; 1H NMR (CDCl3, 400
MHz) δ 7.75 (d, J = 8.0 Hz, 2H), 7.58 (m, 2H), 7.53 (m, 2H), 7.42−
7.35 (m, 5H), 7.27 (m, 2H), 5.98 (d, J = 13.6 Hz, 1H), 4.42 (m, 2H),
4.26 (t, J = 7.4 Hz, 1H), 4.16−4.02 (m, 2H), 3.68 (d, J = 10.8 Hz, 3H),
1.27 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.3 (d, J =
11.6 Hz), 143.2 (s), 141.3 (s), 132.7 (d, J = 2.2 Hz), 129.0 (d, J = 2.9
Hz), 128.7 (d, J = 2.2 Hz), 128.0 (d, J = 1.4 Hz), 127.8 (d, J = 5.8 Hz),
127.2 (s), 125.2 (d, J = 2.9 Hz), 120.1 (s), 74.3 (d, J = 169.2 Hz), 70.6
(s), 63.9 (d, J = 7.3 Hz), 53.7 (d, J = 6.5 Hz), 46.7 (s), 16.5 (d, J = 5.1
Hz); 31P NMR (CDCl3, 162 MHz) δ 17.87; MS (ESI) m/z (%) 453.3
[M + H]+; HRMS (MALDI) calcd for C25H25O6PNa 475.1281, found
475.1274.
Compounds 5 were prepared according to reported procedure8 as
single diastereomer.
Compound 5b. Colorless oil, yield 92% (477 mg): [α]D25.4 38.7 (c
1.0, CHCl3); IR (film) 3288, 2979, 2932, 1483, 1313, 1129, 1058
1
cm−1; H NMR (CDCl3, 400 MHz) δ 7.53 (dd, J1 = 8.8 Hz, J2 = 1.6
Hz, 2H), 7.50 (d, J = 9.2 Hz, 2H), 5.74 (d, J = 8.4 Hz, 1H), 4.40 (d, J
= 10.4 Hz, 1H), 4.12 (m, 2H), 3.87−3.70 (m, 2H), 3.64−3.43 (m,
2H), 2.13 (d, J = 15.2 Hz, 3H), 1.43 (s, 9H), 1.29(t, J = 7.0 Hz, 3H),
1.24 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 138.8 (s), 131.3 (s),
129.3 (s); 122.2 (d, J = 3.6 Hz), 100.8 (dd, J1 = 142.2 Hz, J2 = 4.4 Hz),
66.9 (m), 65.6 (m), 63.6 (m), 62.5 (d, J = 347.2 Hz), 60.5 (s), 24.3
(s), 19.8 (s), 16.7 (s), 15.1 (s); 31P NMR (CDCl3, 162 MHz) δ 33.94
ppm; MS (ESI) m/z (%) 536.1, 538.1 [M + Na]+; HRMS (MALDI)
m/z calcd for C19H33BrNO6PSNa 536.0842, found 536.0849.
25.2
Deprotected 5c. White solid (49 mg, 89%): mp 144 °C; [α]D
52.8 (c 0.94, CHCl3); IR (film) 3149, 2985, 2933, 1606, 1521, 1348,
1126 cm−1; H NMR (CDCl3, 400 MHz) δ 8.27 (d, J = 8.4 Hz, 2H),
1
7.79 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 580.0 Hz, 1H), 5.28 (d, J = 8.8
Hz, 1H), 3.98−3.78 (m, 2H), 2.09 (d, J = 20.4 Hz, 3H), 1.44 (s, 9H),
1.15 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 147.6 (s),
145.2 (d, J = 3.0 Hz), 128.5 (d, J = 4.4 Hz); 123.5 (d, J = 2.1 Hz), 64.1
(d, J = 7.3 Hz), 60.9 (s), 60.5 (d, J = 97.0 Hz), 24.3 (s), 19.3 (s), 16.1
(d, J = 5.1 Hz); 31P NMR (CDCl3, 162 MHz) δ 35.89; MS (ESI) m/z
(%) 379.3 [M + H]+; HRMS (MALDI) calcd for C14H23N2O6PSNa
401.0907, found 401.0905.
Compound 5d. Light yellow oil, yield 98% (365 mg): [α]D25.9 55.7
(c 1.0, CHCl3); IR (film) 3289, 2979, 1484, 1313, 1129, 1058, 1030
1
cm−1; H NMR (CDCl3, 400 MHz) δ 7.63 (dd, J1 = 8.8 Hz, J2 = 2.0
Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.03 (d, J = 7.6 Hz, 1H), 4.34 (d, J
= 11.6 Hz, 1H), 4.19 (m, 2H), 3.86 (m, 1H), 3.69 (m, 2H), 3.36 (m,
1H), 2.07 (d, J = 14.8 Hz, 3H), 1.44 (s, 9H), 1.31 (m, 6H), 1.22 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 139.1 (s), 131.5 (s),
129.2 (s); 122.2 (d, J = 3.6 Hz), 102.3 (s), 68.1 (d, J = 5.9 Hz), 66.1
(m), 63.8 (d, J = 8.0 Hz), 63.1 (d, J = 89.7 Hz), 60.3 (s), 24.2 (s), 19.2
(s), 16.7 (d, J = 5.1 Hz), 15.1 (d, J = 24.8 Hz); 31P NMR (CDCl3, 162
MHz) δ 32.80 ppm; MS (ESI) m/z (%) 536.2, 538.2 [M + Na]+.
Elemental analysis (%) calcd for C19H33BrNO6PS: C 44.36, H 6.47, N
2.72. Found: C 44.13, H 6.38, N 2.54.
Compound 4e. Attained as four diastereomers; Sticky white solid
(40 mg, quantitative): mp 62 °C; IR (film) 3218, 2977, 1745, 1492,
1225, 1038, 701 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.34−7.18 (m,
9H), 6.04−5.83 (m, 1H), 5.24−4.36 (m, 1H), 4.13−3.61 (m, 2H),
3.18−2.98 (m, 1H), 2.27−1.99 (m, 3H), 1.57−1.41 (m, 3H), 1.27−
1.02 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.9 (m), 143.8 (m),
133.3 (m), 131.8 (m), 131.5 (m), 128.2 (m), 127.5 (m), 126.3 (m),
124.6 (m), 71.3−69.0 (m), 60.2 (m), 50.2 (m), 24.8 (m), 19.7 (m),
Compound 6a. White solid (35 mg, 86%): mp 138−139 °C;
[α]D27.4 40.9 (c 0.93, CHCl3); IR (film) 3155, 2987, 1605, 1520, 1350,
1
1312, 1245, 1024 cm−1; H NMR (CDCl3, 400 MHz) δ 8.24 (d, J =
D
dx.doi.org/10.1021/jo302140q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8.8 Hz, 2H), 7.86 (dd, J1 = 9.6 Hz, J2 = 2.4 Hz, 2H), 5.22 (d, J = 8.8
Hz, 1H), 4.12 (m, 2H), 3.51 (d, J = 10.8 Hz, 3H), 2.14 (d, J = 16.8 Hz,
3H), 1.44 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 147.4 (s), 147.3 (s), 128.5 (d, J = 4.3 Hz), 123.3 (d, J = 2.9
Hz), 64.4 (d, J = 7.3 Hz), 61.1 (d, J = 148.8 Hz), 60.7 (s), 54.5 (d, J =
7.3 Hz), 24.3 (s), 20.5 (d, J = 6.5 Hz), 16.5 (d, J = 5.1 Hz); 31P NMR
(CDCl3, 162 MHz) δ 23.36; MS (ESI) m/z (%) 409.3 [M + H]+;
HRMS (MALDI) calcd for C15H25N2O7PSNa 431.1012, found
431.1008.
m/z (%) 409.3 [M + H]+; HRMS (MALDI) calcd for
C15H25N2O7PSNa 431.1012, found 431.1010.
Compound 6g. White solid (35 mg, 79%): mp 128−129 °C;
[α]D27.4 40.9 (c 0.93, CHCl3); IR (film) 3448, 2987, 1638, 1480, 1315,
1
1243, 1130, 1050, 1023 cm−1; H NMR (CDCl3, 400 MHz) δ 7.56−
7.49 (m, 4H), 5.15 (d, J = 8.8 Hz, 1H), 3.94−3.61 (m, 2H), 3.72 (d, J
= 10.8 Hz, 3H), 2.06 (d, J = 16.8 Hz, 3H), 1.41 (s, 9H), 1.15 (t, J =
13.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.8 (d, J = 2.2 Hz),
131.4 (s), 129.2 (d, J = 5.1 Hz); 122.3 (d, J =3.7 Hz), 64.4 (d, J =7.2
Hz), 60.8 (d, J = 150.2 Hz), 60.5 (s), 54.2 (m), 24.3 (s), 20.1 (d, J =
5.0 Hz), 16.3 (d, J = 4.2 Hz); 31P NMR (CDCl3, 162 MHz) δ 24.16;
MS (ESI) m/z (%) 442.0, 444.0 [M + H]+; HRMS (MALDI) calcd for
C15H25NO5PSBrNa 464.0267, found 464.0261.
26.5
Compound 6b. White solid (38 mg, 86%): mp 84−87 °C; [α]D
34.5 (c 0.5, CHCl3); IR (film) 3153, 2981, 1481, 1314, 1242, 1130,
1
1025, 967, 852 cm−1; H NMR (CDCl3, 400 MHz) δ 7.55−7.50 (m,
4H), 5.11 (d, J = 8.8 Hz, 1H), 4.09 (m, 2H), 3.44 (d, J = 10.8 Hz, 3H),
2.06 (d, J = 16.8 Hz, 3H), 1.41(s, 9H), 1.31 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 138.8 (d, J = 2.1 Hz), 131.4 (s), 129.1 (d,
J = 4.3 Hz); 122.3 (d, J = 3.7 Hz), 64.1 (d, J = 7.3 Hz), 61.1 (d, J =
90.9 Hz), 60.5 (s), 54.5 (m), 24.3 (s), 20.0 (d, J = 3.7 Hz), 16.5 (d, J =
5.1 Hz); 31P NMR (CDCl3, 162 MHz) δ 24.15; MS (ESI) m/z (%)
27.7
Compound 6h. Colorless oil (24 mg, 46%): [α]D 18.2 (c 1.0,
CHCl3); IR (film) 3307, 2928, 2856, 1647, 1312, 1128, 1034 cm−1; 1H
NMR (CDCl3, 300 MHz) δ 7.48 (br, 4H), 5.27 (d, J = 11.6 Hz, 1H),
3.88 (m, 2H), 3.83 (m, 2H), 2.47 (m, 1H), 2.05 (d, J = 16.8 Hz, 3H),
1.44−1.40 (m, 10H), 1.24 (s, 9H), 1.17 (t, J = 7.0 Hz, 3H), 0.87 (t, J =
6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 139.9 (d, J = 2.9 Hz),
131.1 (s), 129.2 (s); 121.8 (d, J = 3.6 Hz), 62.0 (d, J = 7.3 Hz), 61.7
(d, J = 135.6 Hz), 60.4 (s), 42.4 (s), 32.5 (d, J = 5.1 Hz), 31.7 (s), 28.9
(s), 26.5 (s), 24.3 (s), 22.6 (s), 20.2 (m), 16.2 (m), 14.0 (s); 31P NMR
(CDCl3, 162 MHz) δ 27.80; MS (ESI) m/z (%) 525.3, 527.3 [M +
H]+; HRMS (MALDI) calcd for C21H39N2O4PSBr 525.1546, found
525.1546.
442.2, 444.2 [M
+
H]+; HRMS (MALDI) calcd for
C15H25NO5PSBrNa 464.0267, found 464.0282.
Compound 6c. White solid (25 mg, 48%): mp 141−142 °C;
[α]D27.0 36.6 (c 0.93, CHCl3); IR (film) 3204, 2984, 2930, 1731, 1311,
1209, 1127, 1082, 851 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.56 (dd,
J1 = 8.8 Hz, J2 = 2.4 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 6.04 (d, J = 8.8
Hz, 1H), 4.18 (q, J = 9.3 Hz, 2H), 4.06 (m, 2H), 3.46 (m, 2H), 2.78
(m, 1H), 2.07 (d, J = 16.4 Hz, 3H), 1.42 (s, 9H), 1.31−1.25 (m, 6H);
13C NMR (CDCl3, 100 MHz) δ 172.2 (d, J = 4.3 Hz), 139.9 (s), 131.3
(d, J = 2.2 Hz); 129.2 (d, J = 4.4 Hz), 122.0 (d, J = 4.3 Hz), 61.88 (d, J
= 7.3 Hz), 61.87 (s), 61.8 (d, J = 139.3 Hz), 60.5 (s), 42.8 (s), 24.3
(s), 19.8 (d, J = 5.0 Hz), 16.3 (d, J = 6.5 Hz), 14.1 (s); 31P NMR
(CDCl3, 162 MHz) δ 26.89; MS (ESI) m/z (%) 513.1 [M + H]+;
HRMS (MALDI) calcd for C18H31N2O6PSBr 513.0818, found
513.0815.
Compound 6d. White solid (42 mg, 80%): mp 135−137 °C;
[α]D25.8 38.5 (c 1.04, CHCl3); IR (film) 3336, 2928, 2857, 1483, 1312,
1127, 1034, 547 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.52−7.47 (m,
4H), 5.27 (t, J = 8.4 Hz, 1H), 4.20−4.0 (m, 2H), 2.70 (m, 1H), 2.53
(m, 1H), 2.28 (m, 1H), 2.02 (d, J = 16.0 Hz, 3H), 1.40 (s, 9H), 1.32
(t, J = 7.0 Hz, 3H), 1.30−1.10 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 139.8 (d, J = 2.1 Hz), 131.2 (d, J = 3.0
Hz), 129.1 (d, J = 4.4 Hz); 122.0 (d, J = 3.7 Hz), 61.9 (d, J = 7.3 Hz),
61.8 (d, J = 134.9 Hz), 60.3 (s), 42.2 (s), 32.2 (d, J = 5.1 Hz), 31.7 (s),
28.8 (s), 26.4 (s), 24.3 (s), 22.6 (s), 20.0 (d, J = 5.1 Hz), 16.5 (d, J =
5.9 Hz), 14.0 (s); 31P NMR (CDCl3, 162 MHz) δ 28.06; MS (ESI) m/
z (%) 525.4, 527.4 [M + H]+; HRMS (MALDI) calcd for
C21H38N2O4PSBrNa 547.1366, found 547.1360.
Mechanism Studied by 31P NMR Spectroscopy. 3a (50 μmol)
was hydrolyzed by BF3·Et2O and concentrated to give crude H-
phosphinate A.
A (50 μmol in 0.5 mL of CDCl3) reacted with Br2 (100 μmol) and
EtOH (100 μmol). The progress of the reaction was monitored by 31P
NMR spectroscopy. After 2 h, the intermediate B and product 4a were
formed (Figure 1a). Twelve hours later, only 4a was detected (Figure
1b).
A (50 μmol in 0.5 mL of CDCl3) reacted with Br2 (100 μmol).
After 5 min, partial conversion of A to intermediate B and byproducts
was detected (Scheme S2a, Supporting Information). After 3 h, A was
completely consumed and 4a was detected which was from the
reaction of B with EtOH, a residue from the hydrolysis of 3a (Scheme
S2b, Supporting Information). After that, EtOH (100 μmol) was
added. Two hours later, B was partly consumed and 4a was formed
(Scheme S2c, Supporting Information). Twelve hours later, B was
completely consumed. However, the byproducts were present during
the entire process (Scheme S2d, Supporting Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
Compound 6e. White solid (27 mg, 50%): mp 172−174 °C;
NMR spectra of compounds 2b, 2e−h, 4b−g, 5b, deprotected
5c, 5d and 6a−h; crystallographic data for deprotected 5c, 6c
and 6f. This material is available free of charge via the Internet
at http://pubs.acs.org.
26.8
[α]D 32.9 (c 1.0, CHCl3); IR (film) 3340, 2979, 1455, 1310, 1127,
1
1031 cm−1; H NMR (CDCl3, 300 MHz) δ 7.38 (s, 4H), 7.36−7.23
(m, 3H), 7.08 (d, J = 6.8 Hz, 2H), 5.04 (d, J = 8.8 Hz, 1H), 4.21 (m,
1H), 4.05 (m, 1H), 3.81 (m, 1H), 2.70 (t, J = 10.4 Hz, 1H), 1.98 (d, J
= 16.8 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.31 (s, 9H), 1.21 (t, J = 7.0
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.0 (d, J = 3.6 Hz), 139.7
(d, J = 2.2 Hz), 131.1 (d, J = 2.9 Hz), 129.2 (d, J = 4.4 Hz), 128.8 (s),
127.4 (s), 125.4 (s), 122.0 (d, J = 3.6 Hz), 62.0 (d, J = 7.3 Hz), 61.8
(d, J = 137.1 Hz), 60.4 (s), 52.3 (s), 26.6 (d, J = 4.4 Hz), 24.2 (s), 19.9
(d, J = 5.1 Hz), 16.3 (d, J = 5.8 Hz); 31P NMR (CDCl3, 162 MHz) δ
26.70; MS (ESI) m/z (%) 531.3 [M + H]+; HRMS (MALDI) calcd
for C22H32N2O4PSBrNa 553.0896, found 553.0886.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yuancy@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Compound 6f. White solid (41 mg, quantitative): mp 129−130
■
24.8
°C; [α]D 47.9 (c 1.0, CHCl3); IR (film) 3444, 3150, 2986, 1606,
The project was supported by the National Science Foundation
of China (Grants No. 20672132; 20872165).
1
1520, 1349, 1311, 1245, 1022 cm−1; H NMR (CDCl3, 400 MHz) δ
8.24 (d, J = 8.8 Hz, 2H), 7.86 (dd, J1 = 9.6 Hz, J2 = 2.4 Hz, 2H), 5.26
(d, J = 8.8 Hz, 1H), 3.98−3.75 (m, 2H), 3.76 (d, J = 10.8 Hz, 3H),
2.14 (d, J = 16.8 Hz, 3H), 1.44 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 147.4 (s), 147.3 (d, J = 2.9 Hz), 128.6 (d,
J = 5.1 Hz), 123.2 (d, J = 2.1 Hz), 64.6 (d, J = 8.0 Hz), 61.1 (d, J =
148.8 Hz), 60.7 (s), 54.4 (d, J = 7.3 Hz), 24.3 (s), 20.5 (d, J = 6.6 Hz),
16.5 (d, J = 5.8 Hz); 31P NMR (CDCl3, 162 MHz) δ 23.40; MS (ESI)
REFERENCES
■
(1) (a) Berlicki, L.; Kafarski, P. Curr. Org. Chem. 2005, 9, 1829−
1850. (b) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 2005, 16, 3295−
3340. (c) Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629−
́
́
647. (d) Natchev, I. A. Liebigs Ann. Chem. 1988, 861−867.
E
dx.doi.org/10.1021/jo302140q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(2) (a) Winqvist, A.; Stromberg, R. Eur. J. Org. Chem. 2008, 1705−
̈
1714. (b) Dumy, P.; Escale, R.; Girard, J. P.; Parello, J.; Vidal, J. P.
Synthesis 1992, 1226. (c) Bartlett, P. A.; Giangiordano, M. A. J. Org.
Chem. 1996, 61, 3433−3438.
(3) (a) Au-Yeung, T. L.; Chan, K. Y.; Chan, W. K.; Haynes, R. K.;
Williams, I. D.; Yeung, L. L. Tetrahedron Lett. 2001, 42, 453.
(b) Drabowicz. J. Heteroatom. Chem. 2002, 13, 437. (c) Zhou, Y. B.;
Wang, G.; Saga, Y.; Shen, R. W.; Goto, M.; Zhao, Y. F.; Han, L. B. J.
Org. Chem. 2010, 75, 7924−7927.
(4) (a) Sampson, N. S.; Bartlett, P. A. J. Org. Chem. 1988, 53, 4500−
4503. (b) Wang, G.; Shen, R. W.; Xu, Q.; Goto, M.; Zhao, Y. F.; Han,
L. B. J. Org. Chem. 2010, 75, 3890−3892.
(5) (a) Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron:
Asymmetry 2007, 18, 2886−2893. (b) Yamagishi, T.; Miyamae, T.;
Yokomatsu, T.; Shibuya, S. Tetrahedron Lett. 2004, 45 (36), 6713−
6716.
(6) Similar structures were prepared, and the manuscript is in
preparation.
(7) Troev, K. D. Important classes of compounds. In Chemistry and
Application of H-Phosphonates; Elsevier Science Ltd.: Amsterdam,
2006; p 142.
(8) Zhang, D. H.; Yuan, C. Y. Chem.Eur. J. 2008, 14, 6049−6052.
(9) The deprotection of the 1,1′-diethoxyethyl group yields the
corresponding H-phosphinate with retention at the phosphorus center.
This is proved by the single crystal structure of the intermediate H-
phosphinate after hydrolysis of 5c by BF3·OEt2. See the Supporting
Information for details.
(10) Han, L. B.; Zhao, C. Q.; Onozawa, S.; Goto, M.; Tanaka, M. J.
Am. Chem. Soc. 2002, 124, 3842−3843.
(11) Zhang, D. H.; Yuan, C. Y. Chem.Eur. J. 2009, 15, 4088−4101.
(12) Tadeusz, G.; Maciej, M. Synth. Commun. 1992, 22 (15), 2193−
2203.
(13) Kudzin, Z. H.; Kotynski, A. Synthesis 1980, 12, 1028−1032.
(14) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117 (44), 10879−10888.
(15) Babak, K.; Masoumeh, K. Bioorg. Med. Chem. Lett. 2006, 16
(20), 5324−5327.
F
dx.doi.org/10.1021/jo302140q | J. Org. Chem. XXXX, XXX, XXX−XXX