Synthesis of an unusual dinuclear chiral iron complex and its application in asymmetric hydrophosphorylation of aldehydes

Article abstract of DOI:10.1039/c2ob25810b

An unusual dinuclear chiral iron complex has been synthesized and effectively utilized in the asymmetric hydrophosphorylation of aldehydes to synthesize optically active α-hydroxy phosphonates with excellent yield and good enantioselectivity.

Full text of DOI:10.1039/c2ob25810b

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Organic &
Biomolecular
Chemistry
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Volume 10 | Number 28 | 28 July 2012 | Pages 5317–5472
ISSN 1477-0520
COMMUNICATION
Govindasamy Sekar
Synthesis of an unusual dinuclear chiral iron complex and its application
in asymmetric hydrophosphorylation of aldehydes

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COMMUNICATION
Synthesis of an unusual dinuclear chiral iron complex and its application in
asymmetric hydrophosphorylation of aldehydes†
Pandi Muthupandi and Govindasamy Sekar*
Received 27th April 2012, Accepted 9th May 2012
DOI: 10.1039/c2ob25810b
optically active α-hydroxy ketones and α-hydroxy esters,9 herein
An unusual dinuclear chiral iron complex has been syn-
we report the synthesis of an unusual dinuclear chiral iron
complex and its application as a catalyst in asymmetric hydro-
phosphorylation of aldehydes for the synthesis of optically
active α-hydroxy phosphonates. To the best of our knowledge,
this report uses a chiral iron complex as a catalyst for the first
time in asymmetric hydrophosphorylation of aldehydes.
thesized and effectively utilized in the asymmetric hydro-
phosphorylation of aldehydes to synthesize optically active
α-hydroxy phosphonates with excellent yield and good
enantioselectivity.
Introduction
Results and discussion
Development of iron catalysts has been one of the primary long-
term goals in synthetic organic chemistry. While iron is inexpen-
sive, non-toxic, more abundant and environmental friendly, iron
based catalysts are underutilized in organic synthesis, especially
in the field of asymmetric synthesis.1 On the other hand, opti-
cally active α-hydroxy phosphonates have proven to be an
efficient structural unit in the pharmaceutical industry. Also, they
are part of several biologically important molecules such as
renin inhibitors, agonists of calcium transfer, inhibitors of HIV
protease, anti-viral drugs and anti-cancer drugs.2 Among the
available methods, the asymmetric addition of phosphite to alde-
hyde is the most straightforward method for the synthesis of
optically active α-hydroxy phosphonates.3 In recent years, a set
of different catalytic systems has emerged for this purpose which
includes chiral bases,4 Ti,4b,5 La,5a,6 and Yb7 complexes.
In addition, chiral Al complexes8 have been widely utilized as
effective catalysts for this reaction. However, most of these chiral
complexes are either derived from rare metal salts like Yb(OTf)3
and LaCl3 or metal salts that are highly sensitive to handle such
as Ti(OiPr)4 and Et2AlCl. Therefore, an iron complex with a
readily available chiral ligand, which is easily tunable by means
of steric and electronic factors, will be a highly desirable catalyst
for the synthesis of optically active α-hydroxy phosphonates.
As part of our continuing interest in the development of cost
effective and easily accessible catalysts for the synthesis of
Recently, we have used Fe(OAc)2 in combination with salen
ligand L1 as an effective catalyst for the synthesis of optically
active α-hydroxy ketones through oxidative kinetic resolution
(OKR).10 To extend the application of this catalyst, we went on
to use the same catalyst for the asymmetric hydrophosphoryla-
tion of aldehydes by reacting 10 mol% of Fe(OAc)2 and
10 mol% of salen ligand L1 with 4-nitrobenzaldehyde and
diethyl phosphite in THF at room temperature. The reaction pro-
vided the corresponding α-hydroxy phosphonate as a racemic
product with 22% yield and the starting material remained
unconsumed even after 2 days (Table 1, entry 1).
The low yield and longer duration of the reaction could be
attributed to the less availability of nucleophilic phosphite in
dialkyl phosphite, which exists in equilibrium with phosphate. We
envisaged that the efficiency of the reaction can be increased by
addition of base, which in turn will shift the equilibrium in favour
of active nucleophilic phosphite (Scheme 1). True to our presump-
tion, addition of 1 equivalent of Na2CO3 increased the yield to
78% albeit there was no asymmetric induction (Table 1, entry 2).
When the ligand L1 was replaced with valinol derived salen
ligand L2, the reaction provided the corresponding α-hydroxy
phosphonate with 16% ee (entry 3). In the reaction medium,
Fe(OAc)2 and ligand L2 may form chiral Fe complex 1 which
might catalyze the reaction through activation of electrophile
leading to partial destruction of the chiral environment in a cata-
lyst (Scheme 1, path I, TS-1) and this could be the reason for
low enantioselectivity.
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, 600 036, India. E-mail: gsekar@iitm.ac.in;
Fax: +91 44 2257 4202; Tel: +91 44 2257 4229
†Electronic supplementary information (ESI) available: HPLC chroma-
togram, copy of 1H and 13C NMR spectra for all compounds. CCDC
843428. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25810b
To overcome this problem, we planned to synthesize chiral
Fe complex 2 to trap a phosphite anion by replacing the chloride
ligand. Thereby the catalyst can activate both the electrophile
and nucleophile, so that the reaction can proceed in a more
enantioselective fashion (Scheme 1, path II, TS-2). To synthesize
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Table 1 Optimization of asymmetric hydrophosphorylation reaction
Entry
Catalyst
Ligand
Na2CO3
Temp.
Time
Yielda
Ee
1
2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Chiral Fe complex 3
FeCl3
FeCl2
FeBr3
FeCl3
FeCl3
FeCl3
FeCl3
L1
L1
L2
—
L2
L2
L2
L2
L2
L2
L2
L2
L2
—
rt
rt
rt
rt
rt
rt
rt
rt
2 days
26 h
26 h
26 h
26 h
26 h
38 h
26 h
48 h
26 h
26 h
10 h
10 h
22%
78%
90%
92%
95%
89%
76%
93%
64%
41%
94%
96%
98%
0
0
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
0.5 equiv.
0.25 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
3
16%
57%
56%
28%
38%
52%
27%
18%
49%
64%
52%
4b
5
6
7
8
9
10
11
12
13
rt
10 °C
45 °C
55 °C
60 °C
FeCl3
FeCl3
a Isolated yield. b 5 mol% of chiral Fe complex 3 was used.
Scheme 2 Synthesis of a chiral iron complex.
Fig. 1 ORTEP diagram of chiral Fe complex 3. Ellipsoids represent
30% probability level (CCDC No. 843428). Hydrogen atoms are
omitted for clarity.
Scheme 1
chiral Fe complex 2, FeCl3 was reacted with ligand L2 in the pres-
ence of Et3N in THF at room temperature. Surprisingly, chiral Fe
complex 2 did not form but intriguingly we isolated an unusual
dinuclear chiral Fe complex 3 (Scheme 2). The complex formation
was confirmed by paramagnetic 1H NMR and high-resolution
mass spectrometry. The single crystal X-ray analysis showed that
chiral Fe complex 3 was crystallized in an orthorhombic manner
with space group P212121 (Fig. 1). The two iron atoms (Fe1 and
Fe2) are separated by a distance of 3.1115(7) Å and bridged by
two oxygen atoms (O2 and O4) of valinol through a two
electron three centred bond by an average distance of 1.977(2) Å.
This is longer than the Fe–O bond length (1.860(2)) where the
oxygen atom (O1) is from the phenolic part of the ligand.
square pyramidal and τ = 1 means trigonal bipyramidal geome-
try.8a,11 While the bond angles for O1–Fe1–O2 and N1–Fe1–O4
are 143.3(β) and 142.8(α), those for O4–Fe2–O3 and O2–Fe2–
N2 are 135.0(α) and 148.7(β). Calculated τ values of chiral Fe
complex 3 showed that iron (Fe1) in one part of the complex has
adopted perfect square pyramidal geometry with τ = 0.008 and
iron (Fe2) in another part of the complex has adopted distorted
square pyramidal geometry with τ = 0.23. A chloride ligand
occupies the axial position of each iron in their square pyramidal
geometry but pointing towards opposite directions to each other
with a bond length of 2.212 Å which is longer than the Fe1–O1
bond. The weaker Fe–Cl bond may help the catalyst to trap the
phosphite anion by replacing the chloride ligand so that better
enantioselectivity can be achieved.
The geometry parameter τ = (β − α)/60 was used to deduce
the structure of the five coordinated complex where τ = 0 means
5348 | Org. Biomol. Chem., 2012, 10, 5347–5352
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In order to test the feasibility of our hypothesis, the chiral Fe
complex 3 was used as a catalyst in the asymmetric hydrophos-
phorylation reaction. Interestingly, as we predicted, the enantio-
meric excess was increased to 57% (Table 1, entry 4). To study
the efficiency of in situ generated catalyst over synthesized chiral
Fe complex 3, FeCl3 and ligand L2 were employed to generate
the in situ catalyst. The results obtained were comparable with
synthesized chiral Fe complex 3 (entry 4 vs. 5), which encour-
aged us to move on with in situ generated catalyst for further
optimization of reaction. The importance of the extra chloride
ligand in the catalyst to enhance enantioselectivity was further
realized by replacing FeCl3 with FeCl2 where enantiomeric
excess was reduced to 28% (entry 5 vs. 6). The reaction with
FeBr3 in place of FeCl3 provided the product with 38% ee (entry
5 vs. 7), which indicates that the enhancement in enantioselectiv-
ity also depends on the properties of the counterion.
The ligand L2 was modified by means of the steric/electronic
factor (Fig. 2) and the reaction was screened with these modified
ligands to increase the enantiomeric excess but none of these
ligands were superior to ligand L2. Similarly, the study of the
reaction with different parameters such as solvents, bases and
ratios of metal salt and ligand also failed to increase the enantio-
meric excess. The use of 0.5 equivalent of base in the reaction
was found to be as good as 1 equivalent of base (entry 5 vs. 8).
However, the reactivity and enantioselectivity were decreased
when 0.25 equivalent of base was used (entry 9). Likewise, the
reaction at 10 °C diminished both reactivity and enantioselectiv-
ity (entry 10). Though the reaction at 45 °C decreased the selec-
tivity (entry 11), the reaction at 55 °C amplified the
enantioselectivity and offered the product with 64% ee (entry 8
vs. 12). Further rise in temperature only lessened the enantio-
selectivity (entry 13). Thus, 10 mol% of FeCl3 and 10 mol% of
ligand L2 with 0.5 equivalent of Na2CO3 in THF at 55 °C
became the optimized reaction condition for this hydrophosphor-
ylation of aldehydes.
phosphonates with good enantiomeric excess. All the substituted
α-hydroxy phosphonates were obtained with excellent yield and
good enantiomeric excess.12 The absolute stereochemistry of the
major enantiomer of all α-hydroxy phosphonates was found to
be “S”, which was determined from signs of specific rotation in
comparison with the literature values. Enantiomeric excess was
determined by HPLC using chiral columns.
The stereochemical outcome of chiral iron catalyzed asym-
metric hydrophosphorylation of aldehydes can be explained as
shown in Scheme 4. In situ generated chiral Fe complex 3 in the
presence of aldehyde and phosphite leads to TS-3 or TS-4
where chloride is replaced with phosphite as mentioned in path
II of Scheme 1. Subsequently, aldehyde coordinates with iron in
such a way that the bulkier group is away from the tertiary butyl
group of the ligand (TS-3), thereby generating a more favourable
transition state which could be responsible for the major enantio-
mer. If the bulkier group of the aldehyde points towards the ter-
tiary butyl group of the ligand (TS-4), the steric repulsion
between these groups leads to the formation of a less favourable
transition state which could be responsible for the minor enantio-
mer. It is also assumed that the reaction may take place at both
To explore the application of the catalytic system, the opti-
mized condition was used for the asymmetric synthesis of differ-
ent substituted α-hydroxy phosphonates and the results are
summarized in Scheme 3. The reactions proceeded smoothly
with all structurally varied aldehydes to afford the corresponding
α-hydroxy phosphonates with excellent yield and good enantio-
selectivity. The rate of reaction was found to be higher in the
case of aldehydes with stronger electron withdrawing substitu-
ents (1a–b) than in aldehydes with other substituents (1c–h).
Very importantly, the reaction with highly electron rich aldehyde
(1i), bulkier aldehyde (1j) and heterocyclic aldehydes (1k–l)
also proceeded effortlessly to give the corresponding α-hydroxy
Scheme 3 Chiral iron catalyzed hydrophosphorylation of aldehydes.
Fig. 2 Modified chiral ligands for asymmetric hydrophosphorylation.
Scheme 4 Elucidation of stereochemical outcome.
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Synthesis of chiral Fe complex 3
iron centers as 5 mol% of the chiral Fe complex 3 provided
similar results compared with 10 mol% of FeCl3 and 10 mol%
of L2 (Table 1, entry 4 vs. 5).
Et3N (137 μL, 0.99 mmol) was added dropwise to a mixture of
FeCl3 (81 mg, 0.5 mmol) and ligand L2 (144 mg, 0.45 mmol)
in THF (10 mL) solvent under a nitrogen atmosphere and stirred
for 8 h at room temperature. The reaction mixture was then con-
centrated and water was added to the resulting residue. The
aqueous mixture was extracted with CH2Cl2 and the combined
organic layer was dried over Na2SO4 and evaporated in vacuo to
give chiral Fe complex 3 in 62% yield. The single crystal suit-
able for X-ray analysis was obtained by recrystallization of
chiral Fe complex 3 in a CH2Cl2–hexanes mixture. HRMS (m/z):
[M + H]+ calcd for C40H63N2O4Cl2Fe2, 817.2864; found,
817.2866.
Conclusion
Asymmetric hydrophosphorylation of aldehydes using a chiral
iron catalyst has been successfully achieved for the first time. An
unusual dinuclear chiral Fe complex 3 was isolated and used as a
catalyst in asymmetric synthesis of optically active α-hydroxy
phosphonates. The additional chloride ligand in chiral Fe
complex 3 enhanced the enantioselectivity by activating both
electrophile and nucleophile. All the substituted α-hydroxy phos-
phonates were obtained with excellent yield and good enantio-
meric excess.12
General procedure for synthesis of optically active α-hydroxy
phosphonates
Experimental section
To a mixture of chiral Fe complex 3 (5 mol%) or FeCl3
(10 mol%), ligand L2 (10 mol%) and Na2CO3 (0.5 equiv.) in THF
(5 mL) were added diethyl phosphite (0.6 mmol) and aldehyde
(0.5 mmol) at room temperature and further stirred for 10–29 h
at 55 °C. The reaction mixture was then concentrated in vacuo
and the resulting residue was purified by silica gel column
chromatography (eluents: hexanes–ethyl acetate) to give opti-
cally active α-hydroxy phosphonate.
General considerations
FeCl3 (reagent grade, 97%) and dialkyl phosphite were pur-
chased from Aldrich Chemicals and used as received. Thin-layer
chromatography (TLC) was performed using Merck silica gel
60 F254 precoated plates (0.25 mm) and visualized by UV fluore-
scence quenching. Silica gel for column chromatography (par-
ticle size 100–200 mesh) was purchased from SRL India. 1H
and 13C NMR spectra were recorded on a Bruker 400 MHz
instrument. 1H NMR spectra were reported relative to Me4Si
(δ 0.0 ppm) or residual CDCl3 (δ 7.26 ppm). 13C NMR spectra
were reported relative to CDCl3 (δ 77.16 ppm). FTIR spectra
were recorded on a Nicolet 4100 spectrometer and are reported
in frequency of absorption (cm−1). High resolution mass spectra
(HRMS) were recorded on a Q-Tof Micro mass spectrometer.
Optical rotations were measured with an Autopol IV – Rudolph
Research Analytical Polarimeter. The enantiomeric excess
(% ee) of all the compounds was determined by SHIMADZU
HPLC using Daicel Chiral columns. 1H and 13C NMR and
HRMS spectral data have been included for all compounds. The
ligands L1 and L3–L10 were prepared using procedures avail-
able in the literature.13–18
Diethyl hydroxy(4-nitrophenyl)methylphosphonate (2a). Rf
0.21 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −31.8 (c = 2.0
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.22–1.30 (m, 6H),
4.03–4.17 (m, 4H), 5.16 (d, J = 12.4 Hz, 1H), 7.66 (dd, J = 2.0,
9.8 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 16.5 (t, J = 4.6 Hz), 63.5 (d, J = 7.5 Hz), 64.2 (d, J =
6.9 Hz), 70.2 (d, J = 156.9 Hz), 123.5, 127.8 (d, J = 4.9 Hz),
144.3, 147.7; IR (neat) 751, 1019, 1257, 3278 cm−1; HRMS
(m/z): [M + H]+ calcd for C11H17NO6P, 290.0794; found,
290.0791. The enantiomeric excess (% ee) was determined to be
64% by HPLC using a Daicel ChiralPAK AS-H column (20%
i-PrOH–hexanes, 1 mL min−1, 254 nm): tR (major, 10.915 min),
tR (minor, 8.577 min).
Diethyl (3-cyanophenyl)(hydroxy)methylphosphonate (2b). Rf
0.31 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −16.8 (c = 1.4
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.20–1.32 (m, 6H),
Synthesis of ligand L2
4.01–4.18 (m, 4H), 5.07 (d, J = 11.2 Hz, 1H), 7.45 (t, J =
7.6 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H),
7.82 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 16.5, 63.4 (d, J =
7.3 Hz), 64.0 (d, J = 7.1 Hz), 69.8 (d, J = 159.0 Hz), 112.4,
118.9, 129.0, 130.6 (d, J = 5.2 Hz), 131.6, 138.8; IR (neat) 732,
1038, 1230, 2236, 3252 cm−1; HRMS (m/z): [M + H]+ calcd for
C12H17NO4P, 270.0895; found, 270.0899. The enantiomeric
excess (% ee) was determined to be 60% by HPLC using a
Daicel ChiralCEL OD-H column (10% i-PrOH–hexanes, 0.5 mL
min−1, 254 nm): tR (major, 15.426 min), tR (minor, 18.266 min).
A mixture of valinol (1 g, 10 mmol) and 2,5-di-tert-butylsalicyl-
aldehyde (2.3 g, 10 mmol) in EtOH (50 mL) was refluxed for
12 h. The reaction mixture was then concentrated and the result-
ing residue was purified by silica gel column chromatography
(eluents: hexanes–ethyl acetate) to give ligand L2 in 78% yield.
Yellow solid, Mp: 107–109 °C, Rf 0.21 (hexanes–ethyl acetate,
40 : 60 v/v); [α]D = −30.9 (c = 1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): δ 0.97 (t, J = 6.4 Hz, 6H), 1.32 (s, 9H),
1.46 (s, 9H), 1.50–1.70 (m, 1H), 1.88–2.02 (m, 1H), 2.98–3.09
(m, 1H), 3.71–3.90 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 7.41 (d,
J = 2.4 Hz, 1H), 8.38 (s, 1H), 13.59 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 18.9, 19.9, 29.4, 29.6, 30.2, 31.6, 34.3,
35.2, 64.9, 78.1, 117.8, 126.3, 127.3, 136.9, 140.3, 158.3, 167.2.
HRMS (m/z): [M + H]+ calcd for C20H34NO2, 320.2590; found,
320.2578.
Diethyl (4-fluorophenyl)(hydroxy)methylphosphonate (2c). Rf
0.27 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −15.5 (c = 2.6
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.16–1.31 (m, 6H),
3.93–4.12 (m, 4H), 4.53 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 7.04
(t, J = 8.0 Hz, 2H), 7.40–7.52 (m, 2H); 13C NMR (100 MHz,
5350 | Org. Biomol. Chem., 2012, 10, 5347–5352
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CDCl3): δ 16.5 (d, J = 5.1 Hz), 63.1 (d, J = 7.1 Hz), 63.6 (d, J =
6.9 Hz), 70.1 (d, J = 161.4 Hz), 115.2 (d, J = 21.3 Hz), 128.9 (t,
J = 6.8 Hz), 132.7, 162.6 (d, J = 245.2 Hz); IR (neat) 747, 1026,
enantiomeric excess (% ee) was determined to be 58% by HPLC
using a Daicel ChiralPAK AS-H column (20% i-PrOH–hexanes,
1 mL min−1, 254 nm): tR (major, 5.679 min), tR (minor,
4.794 min).
1223, 3264 cm−1
; HRMS (m/z): [M +
H]+ calcd for
C11H17O4FP, 263.0849; found, 263.0845. The enantiomeric
excess (% ee) was determined to be 58% by HPLC using a
Daicel ChiralPAK AS-H column (10% i-PrOH–hexanes, 0.5 mL
min−1, 254 nm): tR (major, 17.492 min), tR (minor, 14.155 min).
Diethyl hydroxy(m-tolyl)methylphosphonate (2h). Rf 0.36
(hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −16.1 (c = 1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.03–1.17 (m, 6H),
2.24 (s, 3H), 3.79–4.04 (m, 4H), 4.87 (d, J = 11.6 Hz, 1H), 5.31
(s, 1H), 6.99 (d, J = 6.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H),
7.14–7.23 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 16.4 (t, J =
4.0 Hz), 21.5, 63.1 (d, J = 7.2 Hz), 63.5 (d, J = 7.0 Hz), 70.7 (d,
J = 158.6 Hz), 124.3 (d, J = 5.9 Hz), 127.8 (d, J = 5.9 Hz),
Diethyl (4-chlorophenyl)(hydroxy)methylphosphonate (2d). Rf
0.36 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −18.9 (c = 2.0
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.16–1.29 (m, 6H),
3.95–4.12 (m, 4H), 4.98 (d, J = 10.8 Hz, 1H), 7.30 (d, J = 7.2
Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 16.4 (d, J = 4.8 Hz), 63.2 (d, J = 7.2 Hz), 63.7 (d, J =
6.8 Hz), 70.0 (d, J = 160.2 Hz), 128.4, 128.5 (d, J = 5.4 Hz),
133.8, 135.6; IR (neat) 730, 1046, 1239, 3274 cm−1; HRMS
(m/z): [M + H]+ calcd for C11H17O4ClP, 279.0553; found,
279.0551. The enantiomeric excess (% ee) was determined to be
53% by HPLC using a Daicel ChiralPAK AS-H column (20%
i-PrOH–hexanes, 1 mL min−1, 254 nm): tR (major, 5.878 min),
tR (minor, 4.907 min).
128.1, 128.9, 136.6; IR (neat): 786, 1021, 1238, 3323 cm−1
;
HRMS (m/z): [M + H]+ calcd for C12H20O4P, 259.1099; found,
259.1094. The enantiomeric excess (% ee) was determined to be
71% by HPLC using a Daicel ChiralPAK AS-H column (10%
i-PrOH–hexanes, 0.5 mL min−1
14.567 min), tR (minor, 12.819 min).
, 254 nm): tR (major,
Diethyl (2,3,4-trimethoxyphenyl)(hydroxy)methylphosphonate
(2i). Rf 0.35 (hexanes–ethyl acetate, 20 : 80 v/v); [α]D = −9.4
1
(c = 2.4 in CHCl3); H NMR (400 MHz, CDCl3): δ 1.13 (t, J =
Diethyl (4-bromophenyl)(hydroxy)methylphosphonate (2e). Rf
0.29 (hexanes–ethyl acetate, 50 : 50 v/v); [α]D = −17.4 (c = 1.4
7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 3.78 (s, 3H), 3.84 (s, 3H),
3.82–3.92 (m, 4H), 3.92–4.04 (m, 1H), 4.04–4.16 (m, 2H), 5.22
(d, J = 11.6 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 16.5 (d, J = 5.8 Hz),
16.6 (d, J = 5.8 Hz), 56.0, 60.8, 61.5, 63.0 (d, J = 7.0 Hz), 63.2
(d, J = 6.9 Hz), 65.5 (d, J = 162.6 Hz), 107.4, 122.6, 123.4 (d,
J = 4.6 Hz), 141.7, 151.7 (d, J = 7.3 Hz), 153.8; IR (neat) 746,
1021, 1269, 3285 cm−1; HRMS (m/z): [M + H]+ calcd for
C14H24O7P, 335.1260; found, 335.1259. The enantiomeric
excess (% ee) was determined to be 52% by HPLC using a
Daicel ChiralCEL AS-H column (10% i-PrOH–hexanes, 0.5 mL
min−1, 254 nm): tR (major, 21.322 min), tR (minor, 17.296 min).
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.18–1.29 (m, 6H),
3.95–4.12 (m, 4H), 4.86 (s, 1H), 4.97 (d, J = 11.2 Hz, 1H), 7.33
(dd, J = 2.4, 8.8 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ 16.5 (d, J = 5.4 Hz), 63.2 (d, J = 7.4 Hz),
63.7 (d, J = 7.4 Hz), 70.1 (d, J = 159.1 Hz), 122.0, 128.5 (d, J =
5.6 Hz), 131.4, 136.0; IR (neat) 758, 1020, 1237, 3254 cm−1
;
HRMS (m/z): [M + H]+ calcd for C11H17O4BrP, 323.0048;
found, 323.0041. The enantiomeric excess (% ee) was deter-
mined to be 61% by HPLC using a Daicel ChiralPAK AS-H
column (10% i-PrOH–hexanes, 0.5 mL min−1, 254 nm): tR
(major, 17.857 min), tR (minor, 14.089 min).
Diethyl (anthracen-9-yl)(hydroxy)methylphosphonate (2j). Rf
0.38 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −3.3 (c = 1.0 in
Diethyl hydroxy(phenyl)methylphosphonate (2f). Rf 0.38
(hexanes–ethyl acetate, 50 : 50 v/v); [α]D = −14.9 (c = 2.1 in
CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.13–1.30 (m, 6H),
3.54 (s, 1H), 3.89–4.14 (m, 4H), 5.02 (d, J = 10.4 Hz, 1H),
7.27–7.40 (m, 3H), 7.42–7.53 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 16.4, 63.2 (d, J = 7.2 Hz), 63.5 (d, J = 7.0 Hz), 70.8
(d, J = 158.4 Hz), 127.2 (d, J = 5.6 Hz), 128.1, 128.3, 136.8;
IR (neat): 734, 1261, 3289 cm−1; HRMS (m/z): [M + Na]+ calcd
for C11H17O4PNa, 267.0762; found, 267.0768. The enantiomeric
excess (% ee) was determined to be 50% by HPLC using a
Daicel ChiralPAK AS-H column (10% i-PrOH–hexanes, 0.5 mL
min−1, 254 nm): tR (major, 17.403 min), tR (minor, 14.175 min).
1
CHCl3); H NMR (400 MHz, CDCl3): δ 0.91 (t, J = 6.8 Hz,
3H), 1.16 (t, J = 6.8 Hz, 3H), 3.57–3.73 (m, 1H), 3.74–4.15 (m,
4H), 6.59 (d, J = 16.0 Hz, 1H), 7.38–7.58 (m, 4H), 7.98 (d, J =
8.0 Hz, 2H), 8.07–8.54 (m, 2H), 9.04 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 16.2 (d, J = 5.6 Hz), 16.5 (d, J = 5.8 Hz),
63.0 (d, J = 7.2 Hz), 63.3 (d, J = 7.0 Hz), 68.3 (d, J = 162.8
Hz), 125.0, 125.9, 127.4, 129.1, 129.4 (d, J = 4.3 Hz), 130.5,
131.6; IR (neat) 738, 1046, 1230, 3281 cm−1; HRMS (m/z):
[M + H]+ calcd for C19H21O4PNa, 367.1075; found, 367.1069.
The enantiomeric excess (% ee) was determined to be 56% by
HPLC using a Daicel ChiralPAK AS-H column (20% i-PrOH–
hexanes, 1 mL min−1, 254 nm): tR (major, 13.141 min),
tR (minor, 8.383 min).
Diethyl hydroxy(p-tolyl)methylphosphonate (2g). Rf 0.39
(hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −22.4 (c = 1.0 in
1
CHCl3); H NMR (400 MHz, CDCl3): δ 1.22 (t, J = 7.2 Hz,
Diethyl (thiophen-2-yl)(hydroxy)methylphosphonate (2k). Rf
0.28 (hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −13.3 (c = 1.6
3H), 1.27 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 3.91–4.11 (m, 4H),
4.97 (d, J = 10.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 7.36 (d, J =
6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 16.5 (t, J =
4.6 Hz), 21.3, 63.2 (d, J = 7.1 Hz), 63.4 (d, J = 6.8 Hz), 70.9 (d,
J = 158.4 Hz), 127.1 (d, J = 5.9 Hz), 129.2, 133.5, 138.1; IR
(neat) 743, 1029, 1232, 3283 cm−1; HRMS (m/z): [M + H]+
calcd for C11H17NO6P, 290.0794; found, 290.0797. The
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 1.14–1.26 (m, 6H),
3.94–4.11 (m, 4H), 4.78 (s, 1H), 5.16 (d, J = 10.8 Hz, 1H), 6.92
(t, J = 3.6 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.16–7.24 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 16.5, 63.5 (d, J = 7.1 Hz), 63.8
(d, J = 7.0 Hz), 67.1 (d, J = 166.1 Hz), 125.8 (d, J = 3.0 Hz),
126.2 (d, J = 7.3 Hz), 126.9, 139.7; IR (neat): 731, 1037, 1219,
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3272 cm−1; HRMS (m/z): [M + H]+ calcd for C9H16O4SP,
251.0507; found, 251.0516. The enantiomeric excess (% ee) was
determined to be 68% by HPLC using a Daicel ChiralPAK
AS-H column (10% i-PrOH–hexanes, 0.5 mL min−1, 254 nm):
tR (major, 20.268 min), tR (minor, 15.147 min).
4 (a) F. Yang, D. Zhao, J. Lan, P. Xi, L. Yang, S. Xiang and J. You, Angew.
Chem., Int. Ed., 2008, 47, 5646; (b) D. Uraguchi, T. Ito and T. Ooi,
J. Am. Chem. Soc., 2009, 131, 3836.
5 (a) T. Yokomatsu, T. Yamagishi and S. Shibuya, J. Chem. Soc., Perkin
Trans. 1, 1997, 1527; (b) K. V. Zaitsev, M. V. Bermeshev,
A. A. Samsonov, J. F. Oprunenko, A. V. Churakov, J. A. L. Howard,
S. S. Karlov and G. S. Zaitsevaa, New J. Chem., 2008, 32, 1415.
6 (a) C. Qian, T. Huang, C. Zhu and J. Sun, J. Chem. Soc., Perkin Trans. 1,
1998, 2097; (b) A. J. Wooten, P. J. Carroll and P. J. Walsh, J. Am. Chem.
Soc., 2008, 130, 7407.
Diethyl (furan-2-yl)(hydroxy)methylphosphonate (2l). Rf 0.44
(hexanes–ethyl acetate, 40 : 60 v/v); [α]D = −11.3 (c = 1.0 in
1
CHCl3); H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 6.8 Hz,
7 W. Chen, Y. Hui, X. Zhou, J. Jiang, Y. Cai, X. Liu, L. Lin and X. Feng,
Tetrahedron Lett., 2010, 51, 4175.
3H), 1.32 (t, J = 7.2 Hz, 3H), 3.98–4.24 (m, 4H), 4.99 (d, J =
13.2 Hz, 1H), 6.37 (d, J = 1.6 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H),
7.42 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 15.5 (t, J =
6.8 Hz), 63.5 (d, J = 6.9 Hz), 63.6 (d, J = 6.6 Hz), 64.9 (d, J =
165.4 Hz), 109.5 (d, J = 6.3 Hz), 110.9, 142.9, 150.1; IR (neat)
729, 1028, 1215, 3274 cm−1; HRMS (m/z): [M + Na]+ calcd for
C9H15O5PNa, 257.0555; found, 257.0554. The enantiomeric
excess (% ee) was determined to be 52% by HPLC using
a Daicel ChiralCEL OD-H column (10% i-PrOH–hexanes,
0.5 mL min−1, 254 nm): tR (major, 17.126 min), tR (minor,
12.569 min).
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10 P. Muthupandi, S. K. Alamsetti and G. Sekar, Chem. Commun., 2009,
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Acknowledgements
11 (a) A. W. Addison, T. N. Rao, J. Reedijk, J. Rijn and G. C. Verschoor,
J. Chem. Soc., Dalton Trans., 1984, 1349; (b) T. Kurahashi, K. Oda,
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12 Though enantiomeric excess using our chiral iron catalyst for asymmetric
hydrophosphorylation is moderate compared to the chiral aluminum and
titanium catalytic systems reported by Katsuki8 and You4 in which more
than 90% ee were obtained, this is the first chiral iron catalytic system
developed for asymmetric hydrophosphorylation which will pave the way
for better selectivity in the near future.
We thank CSIR (Project No. CHY/10-11/264/CSIR/GSEK),
New Delhi for the financial support. PM thanks UGC,
New Delhi for a senior research fellowship. We thank DST,
New Delhi for the funding towards the 400 MHz NMR instru-
ment to the Department of Chemistry, IIT Madras under the
IRPHA scheme and ESI-MS facility under the FIST programme.
13 M. J. McKennon and A. I. Meyers, J. Org. Chem., 1993, 58, 3568.
14 S. Ay, M. Nieger and S. Brase, Chem.–Eur. J., 2008, 14, 11539.
15 K. Alexander, S. Cook, C. L. Gibson and A. R. Kennedy, J. Chem. Soc.,
Perkin Trans. 1, 2001, 1538.
Notes and references
1 For review, see: (a) C. Bolm, J. Legros, J. L. Paih and L. Zani, Chem.
Rev., 2004, 104, 6217; (b) S. Enthaler, K. Junge and M. Beller, Angew.
Chem., Int. Ed., 2008, 47, 3317 and references therein; (c) Iron Cataly-
sis, ed. B. Plietker, Wiley-VCH, Weinheim, 2008.
16 Y. N. Belokon, D. Chusov, D. A. Borkin, L. V. Yashkina, P. Bolotov and
T. Skrupskaya, Tetrahedron: Asymmetry, 2008, 19, 459.
17 J. Chin, D. C. Kim, F. Panosyan and K. M. Kim, Org. Lett., 2004, 6,
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2 O. I. Kolodiazhnyi, Tetrahedron: Asymmetry, 2005, 16, 3295.
3 H. Gröger and B. Hammer, Chem.–Eur. J., 2000, 6, 943.
18 S. Zhu, C. Wang, L. Chen, R. Liang, Y. Yu and H. Jiang, Org. Lett.,
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5352 | Org. Biomol. Chem., 2012, 10, 5347–5352
This journal is © The Royal Society of Chemistry 2012