Enantioselective acylphosphonylation-dual lewis acid-lewis base activation of aldehyde and acylphosphonate

Article abstract of DOI:10.1021/jo500895u

Acetoxyphosphonates were obtained by a one-step procedure consisting of reaction of diethyl acetylphosphonate with prochiral aldehydes in the presence of a catalytic system comprising a chiral Lewis acid, an achiral Lewis base, and a Br?nstedt base. Best

Full text of DOI:10.1021/jo500895u

Article
pubs.acs.org/joc
Enantioselective AcylphosphonylationDual Lewis Acid−Lewis Base
Activation of Aldehyde and Acylphosphonate
Ye-Qian Wen, Robin Hertzberg, and Christina Moberg*
Department of Chemistry, Organic Chemistry, KTH Royal Institute of Technology, SE 10044 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Acetoxyphosphonates were obtained by a one-step procedure
consisting of reaction of diethyl acetylphosphonate with prochiral aldehydes in
the presence of a catalytic system comprising a chiral Lewis acid, an achiral
Lewis base, and a Brønstedt base. Best results were obtained using a tridentate
Schiff base aluminum(III) Lewis acidic complex, 1H-1,2,3-benzotriazole, and
a tertiary amine such as DBU. The target compounds were in most cases obtained in high yields, but with moderate enantiomeric
ratios (up to 78:22).
Whereas hydroxyphosphonates are accessible in enantio-
enriched form by reaction of aldehydes with dialkylphosphites
in the presence of a variety of different catalysts (the Pudovik
reaction9),10 no direct enantioselective methods have been
reported for the preparation of acylated derivatives.11 Enantio-
enriched acetoxyphosphonates are instead normally prepared
either from hydroxyphosphonates by acetylation12 or reaction
with ketene,13 or by lipase-catalyzed kinetic resolution of
racemic acetoxyphoshonates14 or hydroxyphosphonates.15 Both
types of compounds have interesting biological properties
and therefore constitute attractive synthetic targets. Acylated
derivatives have, for example, found use as herbicides,16 and
direct methods for the preparation of both types of compounds
are therefore desirable.
Since acylphosphonates are conveniently accessible by Arbuzov
reaction between a phosphite and an acid chloride, we thought
that a direct synthetic process employing acylphosphonates
would constitute an attractive method for the preparation of
α-acyloxyphosphonates. For this purpose, conditions resulting
in cleavage of the carbon−phosphorus bond of less reactive
phosphonates were required. The proximity of two electrophilic
groups in acylphosphonates results in enhanced reactivity of both
functional groups, at the same time as the carbon−phosphorus
bond linking the two groups is weakened.17 Most nucleophiles
attack the carbonyl group while the dialkylphosphoryl group
serves as leaving group. Reaction with primary or secondary
amines indeed results in cleavage of the carbon−phosphorus
bond and formation of amides.18 The order of reactivities of the
amines parallels their basicities, and primary amines react more
rapidly than secondary. Aromatic amines do not react under these
conditions. For our purpose, use of a tertiary amine was required
in order to obtain a reactive acylating agent.
INTRODUCTION
■
Synergistic catalysis whereby several reaction components are
simultaneously activated may allow otherwise unreactive species to
undergo a desired reaction.1 Activation of both electrophiles and
nucleophiles by combined use of Lewis acids (electron-pair
acceptors) and Lewis bases (electron-pair donors) is an attractive
way to enhance chemical reactivity.2 Whereas Lewis acids have
the ability to activate electrophiles, Lewis bases3 may enhance the
reactivity of both nucleophiles and electrophiles. We have
previously demonstrated that Lewis acid−Lewis base catalysis
allows enantioselective acylcyanation of prochiral aldehydes.4
Although the reaction occurs in the presence of only base,5 a
chiral Lewis acid is required in order to obtain enantioenriched
products. We assumed that acylphosphonates may exhibit a
reactivity similar to that of acyl cyanides and thus react with
aldehydes to form acetoxyphosphonates (Scheme 1); low-valent
Scheme 1. Analogy between Acylcyanation and
Acylphosphonylation of Aldehydes
achiral samarium compounds have indeed been shown to catalyze
this reaction, which however under the conditions used was
limited to racemic benzoyloxyphosphonates.6 Racemic α-acetoxy-
phosphonates have also been obtained by a one-step reaction of
diethylphosphite with certain aldehydes in the presence of acetic
anhydride employing metal oxides or carbonates as solid phase
catalysts,7 and, along with 1,4-addition products, from reaction of
a dialkyl acylphosphite with α,β-unsaturated aldehydes.8
With these known reactivities in mind, we decided to explore
whether acylphosphonates might serve as suitable starting materials
Received: April 22, 2014
© XXXX American Chemical Society
A
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Scheme 2. Reaction in the Presence of Titanium Salen Complex 3
a
for a more general direct preparation of acetoxyphosphonates
from aldehydes. The results are presented here.
Table 1. Optimization of Catalyst Composition
RESULTS AND DISCUSSION
■
In contrast to reactions with acetyl cyanide, a Lewis acid catalyst
is required for reaction of benzaldehyde (1a) with acylphos-
phonate 2 to occur. Attempted reaction in the presence of
only tertiary amine (TEA, DABCO, DMAP) led, according to
1H NMR, to reversible formation of a tetrahedral intermediate,19
1H-
benzotriazole
(mol %)
Brønstedt base
(mol %)
4a:5
Yield of
b
c
entry
(mol ratio) 4a (%)
R:S 4a
or, with the more basic DBU, also to enolate formation.20
Considering the weak acidity of dialkylphosphites,21 the
observation that reaction with a tertiary amine does not lead
to cleavage of the carbon−phosphorus bond is hardly surprising.
Use of a tertiary amine (DBU, TEA, DABCO, or DMAP) in
combination with (S,S)-[(4,6-bis(tert-butyl)salen)Ti(μ-O)]2
(3), a catalyst system which provided excellent reactivity and
selectivity in the cyanation of aldehydes with acyl cyanides,4
resulted in only trace amounts of product. Replacement of the
tertiary amine by 1H-1,2,3-benzotriazole, which is less
nucleophilic than DABCO, DBU, and DMAP,22 required the
presence of an additional base in order to react with the
acetylphosphonate. The N-acylated benzotriazole expected to
form is known to be an efficient O-acylating agent.23 Full
conversion of an independently prepared hydroxyphosphonate
to acylated product was indeed observed in toluene in the
presence of DBU; in the absence of DBU, the reaction was
exceedingly slow.
1
0
0
DBU (15)
DBU (50)
DBU (15)
DBU (15)
DBU (15)
DBU (30)
DBU (50)
DMAP (15)
DABCO (15)
DIPEA (15)
1:0.13
1:0.16
1:0.13
1:0.05
1:0
37
38
64:36
59:41
64:36
69:31
65:35
66:34
63:37
67:33
69:31
46:54
2
3
10
20
50
20
20
20
20
20
53
4
79
5
100
36
6
1:0
7
1:0
32
8
1:0.04
1:0.09
1:1.7
63
9
61
10
16
a
Reaction conditions: benzaldehyde (0.25 mmol), 8a (10 mol %),
toluene (1 mL), room temperature; acetyl phosphonate 2 (3 equiv)
diluted to 200 μL with toluene was added over 20 h using a syringe
b
pump. Determined by 1H NMR with 1-methoxynaphthalene as
c
internal standard. Determined by HPLC using chiral IA column.
Reaction of benzaldehyde (1a) with 2 in the presence of
10 mol % of each 1H-benzotriazole and DBU and 10 mol % of
titanium complex 3 (Scheme 2) afforded, however, after 24 h at
room temperature neither the desired product 4a, nor non-
acylated 5, but only 6, resulting from attack of the phosphite
anion on unreacted 2.24 In order to suppress this undesired
reaction, acylphosphonate 2 was added to the reaction mixture
over 20 h, thereby maintaining a low concentration of 2. This
procedure did indeed result in the formation of the desired
product 4a, but along with hydroxyphosponate 5 and appreci-
able amounts of 6.
Exchange of titanium complex 3 for aluminum salen complex
7 resulted, under otherwise identical conditions, in only trace
amounts of product 4a and compound 6. Superior results were
obtained when aluminum complex 8a, containing a tridentate Shiff
base derived from L-valinol and 3,5-di-tert-butylsalicylaldehyde,
was used as Lewis acid catalyst (Table 1). This complex, pre-
pared in situ, has previously been used for hydrophosphonyla-
tion of aldehydes, and has been shown to be a dimer.25 The
dimeric structure was shown by DFT calculations to be favored
over the monomer during the catalytic reaction,26 a result sup-
ported by the observation of a nonlinear effect.25 The cor-
responding bromide has been shown by X-ray crystallography to
be a dimer with the two bromine atoms positioned on the same
side of the molecular plane.27,28
Reactions without benzotriazole led to poor yields of 4a, even
in the presence of a large amount of DBU (entries 1 and 2).
Successive increase of the amount of benzotriazole resulted in
increasing yields (entries 3−5), whereas lower yields were
observed with increasing amounts of DBU (entries 4, 6, and 7):
the latter effect may be a result of extensive enolate formation.
A quantitative yield of 4a, with no trace of hydroxyphospho-
nate 5, was obtained using 50 mol % of benzotriazole and
15 mol % of DBU (entry 5), but the highest enantiomeric
ratio (69:31) was observed with merely 20 mol % benzotriazole
(entry 4).
In order to optimize the reaction conditions, the amounts
of benzotriazole and Brønstedt base were varied (Table 1).
B
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a
Somewhat inferior yields were obtained when DBU was
replaced by DMAP or DABCO (entries 8 and 9). With DIPEA,
hydroxyphosphonate 5 was the main product, obtained together
with essentially racemic 4a (entry 10). Minor effects on the
enantiomeric ratios were observed by use of chiral bases;
cinchonidine and cinchonine gave 4a with 66:34 and 63:37 er,
respectively, demonstrating that the chirality originates from the
chiral Lewis acid.
Although a quantitative yield could be obtained with the
optimal catalyst system, the enantiomeric ratios were unsatis-
factory. Attempts were therefore made to improve the enantio-
selectivity by using ligands with different steric and electronic
properties (Table 2). Unfortunately, neither variation of the
Table 4. Effect of Temperature
1H-
benzotriazole
(mol %)
4a:5
(mol
ratio)
temp
entry (°C)
DBU
(mol %)
yield of
b
c
4a (%)
R:S 4a
1
2
0
0
20
50
15
20
1:07
1:0
60
78:22
76:24
100
a
Reaction conditions: benzaldehyde (0.25 mmol) and 8a (10 mol %)
in dichloromethane (1 mL). Acetyl phosphonate 2 (3 equiv) diluted to
300 μL with dichloromethane was added over 45 h using a syringe
b
pump. Determined by 1H NMR with 1-methoxynaphthalene as
c
internal standard. Determined by HPLC using chiral IA column.
2 resulted in 35% yield after 47 h, as compared to ca. 5% in
toluene. Although 1.5 equiv of acylphosphonate proved sufficient
at room temperature, a larger excess was used in order to
ascertain acceptable conversions. 50 mol % of 1H-benzotriazole
and more base were required in order to achieve a quantitative
yield at 0 °C (entries 1 and 2). At −10 °C no further increase of
the selectivity was observed, and the yield was lower.
a
Table 2. Variation of Ligand Structure
b
c)
entry L (10 mol %) 4a:5 (mol ratio) yield of 4a (%)
er 4a
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
1:0.05
1:0.04
1:0.25
1:0.31
1:0.51
1:0.28
1:0
79
48
35
38
23
13
61
46
69:31 (R)
51:49 (R)
64:36 (R)
56:44 (R)
48:52 (S)
45:55 (S)
60:40 (R)
66:34 (R)
The optimized reaction conditions were applied to a range of
different aldehydes (Table 5). We were pleased to see that high
a
Table 5. Application to Different Aldehydes
8g
8h
1:0
a
Reaction conditions: benzaldehyde (0.25 mmol), 1H-benzotriazole
(20 mol %), DBU (15 mol %) in toluene (1 mL), room temperature,
acetyl phosphonate 2 (3 equiv) diluted to 200 μL with toluene was
b
added over 20 h using a syringe pump. Determined by 1H NMR with
c)
1-methoxynaphthalene as internal standard. Determined by HPLC
using chiral IA column.
yield of 4
isolated yield of 4
b
c
entry
R
product
(%)
(%)
R:S 4
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
98
96
84
83
83
83
89
72
60
15
53
75:25
73:27
69:31
75:25
75:25
77:23
78:22
79:21
66:34
steric properties of the substituent on the amino alcohol part
of the ligand (entries 1−3) and/or in the 3-position of the
aromatic ring (entries 4−6), nor the electronic properties
of the ligand (entries 7−8), led to any improvement of the
enantioselectivity.
Further optimization studies showed that the amount of 2
could be decreased by increasing the time of addition to 30 h.
As shown in Table 3, a quantitative yield of 4a was obtained
2-naphthyl
4-MeO-C6H4
3-MeO-C6H4
4-Me-C6H4
4−Cl-C6H4
2−Cl-C6H4
C2H5
93
92
100
84
4g
4h
4h
61
16
d
C2H5
61
a
a
Reaction conditions: aldehyde (0.25 mmol), 1H-benzotriazole
Table 3. Amount Acylphosphonate
(50 mol %), DBU (20 mol %), 8a (10 mol %) in dichlormethane (1 mL)
at 0 °C. Acetyl phosphonate 2 (3 equiv) diluted to 300 μL with
b
c
entry
2 (equiv)
4a:5 (mol ratio)
yield of 4a (%)
R:S 4a
b
dichlormethane and added over 45 h using a syringe pump. Determined
1
2
3
4
3
1:0
98
99
68:32
64:36
63:37
62:38
c
by 1H NMR with 1-methoxynaphthalene as internal standard. Determined
2
1:0
d
by HPLC or GC with chiral columns. Reaction at rt.
1.5
1.2
1:0
100
89
1:0.06
a
yields were obtained with most of the aldehydes tested, although
enantiomeric ratios were moderate. No hydroxyphosphonate 5 was
obtained in any of the reactions. The reaction was successful with
both electron-rich (entries 3−5) and electron-poor aromatic
aldehydes (entries 6−7), and substituents in the 2,3- or 4-positions
were tolerated (entries 2−7). The aliphatic substrate propanal
reacted more sluggishly and it was necessary to perform the reaction
at room temperature due to low conversion at 0 °C (entries 8−9).
Attempted reaction with (E)-2-butenal gave an impure product in
low yield, even after several attempts to improve the results.
Absolute Configuration. The products were shown to
have R absolute configuration by comparison of the sign of optical
rotation of the hydroxyphosphonates obtained by hydrolysis
(p-toluene sulfonic acid/ethanol/water) of 4a, 4e, and 4f with
literature data.25 The remaining compounds (4b, 4c, 4d, 4g,
and 4h) were assumed to have the same absolute configuration.
Reaction conditions: benzaldehyde (0.25 mmol), 1H-benzotriazole
(20 mol %), DBU (15 mol %), 8a (10 mol %) in toluene (1 mL) at
room temperature, acetyl phosphonate 2 diluted to 300 μL with
b
toluene was added over 30 h using a syringe pump. Determined by
c
1H NMR with 1-methoxynaphthalene as internal standard. Determined
by HPLC using chiral IA column.
when merely 1.5 equiv of 2 were used (entry 3), but under
these conditions the enantiomeric ratio was lower.
In order to attempt to increase the enantioselectivity, reactions
were run at lower temperatures (Table 4). The reagents had
insufficient solubility in toluene below room temperature, and
therefore dichloromethane was used as solvent; this solvent led
to somewhat decreased enantiomeric ratios at room temperature.
On the other hand, formation of 6 was somewhat suppressed in
dichloromethane: at room temperature instantaneous addition of
C
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This is opposite to the configuration of products obtained by
hydrophosphonylation using the same ligand (8a).25
Mechanistic Aspects. In line with the known reactivity of
acylphosphonates as well as the present results, we propose the
following mechanism (Scheme 3): The first step is suggested to
Shiff base aluminum complex 8a, DBU, and 1H-benzotriazole
provided an efficient catalyst system for the reaction. Although
moderate enantioselectivities were observed, high yields of
products from aldehydes with different substitution patterns
were obtained.
EXPERIMENTAL SECTION
General Information. H NMR spectra were recorded at 500 or
Scheme 3. Suggested Mechanism
■
1
400 MHz, 13C NMR spectra at 126 or 100 MHz, and 31P NMR
spectra at 202 MHz. Chemical shifts are reported in ppm with
reference to residual CHCl3 in CDCl3. Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q), septet (sept), and
multiplet (m). Broad signals are reported as (br). Enantiomeric ratios
(er) were determined by HPLC analyses with a UV-detector and a
chiral column (Daicel Chiralpak IA, 0.46 cm × 25 cm), or by gas
chromatography using a chiral column (30 m × 0.250 mm × 0.25 μm)
containing Cyclosil-B as the stationary phase. All aldehydes were
purified using known procedures. Triethyl phosphite was distilled
prior to use. Dry solvents were taken from a Glass Contour solvent
dispensing system. Complexes 329 and 7,30 and ligands used for
the preparation of 8a−f,31,32 8g,32,33 and 8h32−34 were synthesized
according to published procedures. Complexes 8a−h were prepared in
dichloromethane and used directly after evaporation of the solvent,
and complexes 8g−h were prepared in situ in toluene.
Complex 8a. S-Valinol (0.52 g, 5.0 mmol) was added to a solution
of 3,5-di-tert-butyl salicylaldehyde (1.17 g, 5.0 mmol) in EtOH (60 mL).
The resulting yellow solution was stirred for 5 h at rt, and then the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography using hexanes/ethyl acetate (5:1)
as eluent to give the ligand32 as a yellow solid (1.49 g, 94% yield).
1H NMR (500 MHz, CDCl3) δ 13.49 (brs, 1H), 8.38 (s, 1H), 7.43 (d,
J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 3.83 (A-part of ABX, J = 3.5,
11.3 Hz, 1H), 3.78 (B-part of ABX, J = 8.5, 11.3 Hz, 1H), 3.05 (ddd, J =
3.8, 6.0, 8.5 Hz, 1H), 1.96 (dsept, JHH = JHP = 6.6 Hz, 1H), 1.66 (brs,
1H), 1.45 (s, 9H), 1.31 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.96 (d, J =
7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 167.1, 158.1, 140.2, 136.8,
127.2, 126.2, 117.7, 77.9, 64.7, 35.1, 34.2, 31.5, 30.1, 29.5, 19.8, 18.8.
Et2AlCl (1 M hexane solution, 1.26 mL, 1.26 mmol) was added to
a solution of the ligand (0.38 g, 1.2 mmol) in dry CH2Cl2 (10 mL) in a
glovebox. The solution was stirred for 2 h before removing the solvent
under vacuum. The resulting pale yellow solid was used as the catalyst
without further purification.
involve deprotonation of 1H-benzotriazole by DBU; in contrast
to DABCO and DMAP, DBU is expected to be able to achieve
complete deprotonation. This is followed by attack of the anion
on acetyl phosphonate to give 1-acetylbenzotriazole and phos-
phonate ion which, like in hydrophosphonylation,26 probably
binds to an aluminum center. Nucleophilic addition of the anion
to the Lewis acid-activated aldehyde and subsequent acetylation
afford the final α-acetoxyphosphonate. Support for this
suggestion comes from 1H NMR of the crude reaction mixture,
which showed the presence of 1-acetylbenzotriazole, assumed
to be an intermediate of the catalytic reaction. Acetylation
probably does not occur within the same molecular complex as
P−C bond formation, as shown by the formation of mixed
products from reaction of benzaldehyde with 0.5 equiv each of
diisopropyl acetylphosphonate and diethyl propanoylphosphonate
(analyzed by GC-MS).
The hydrophosphonylation employing the same Al(III)
complex (8a), reported by Feng and co-workers, was shown by
DFT calculations to be catalyzed by the dimeric metal complex,26
a situation that gave rise to a pronounced positive linear effect.25
In our case, a very weak negative nonlinear effect was observed
(Figure 1). This result does, however, not allow any conclusions
whether dimeric species are involved in the catalytic reaction.
Diethyl Acetyl Phosphonate (2). Compound 2 was synthesized
by an Arbuzov reaction using a slightly modified literature procedure.35
Triethyl phosphite (3.0 mL, 18.0 mmol) was slowly added to a solution
of acetyl chloride (1.4 mL, 19.8 mmol) in CH2Cl2 (25 mL) at 0 °C
under N2. Then the mixture was stirred overnight at room temperature
before the solvent was removed under vacuum. The residue was
purified by column chromatography using hexanes/ethyl acetate (2:1)
1
as eluent to give 2 as a colorless liquid (2.7 g, 84% yield). H NMR
(500 MHz, CDCl3) δ 4.24 (dq, J = 7.1, JHP = 7.1 Hz, 4H), 2.48 (d, J =
5.0 Hz, 3H), 1.37 (t, J = 7.1 Hz, 6H); 31P NMR (202 MHz, CDCl3)
δ −2.87.
General Procedure for Synthesis of Racemic Acetoxy-
phosphonates.36 Aldehyde (20 mmol) and diethyl phosphite
(2.58 mL, 20 mmol) were dissolved in dry THF (20 mL) under N2,
and the solution was cooled to 0 °C before DBU (1.62 mL, 20 mmol)
was added. The resulting solution was stirred for 5 min at 0 °C, then
allowed to warm to room temperature and kept at that temperature for
15−60 min, during which time the aldehyde was consumed (TLC).
After removal of the solvent, CH2Cl2 (50 mL) was added, and the
solution was washed successively with 1 M HCl and brine, and dried
over MgSO4. After removal of the solvent, hydroxyphosphonates were
obtained.
Figure 1. Relation between product er and catalyst precursor er.
α-Acetoxyphosphonates could be obtained by any of the following
methods: Method A:12a Cu(OTf)2 (22 mg, 0.06 mmol) was added
to a mixture of hydroxyphosphonate (3 mmol) and Ac2O (1.4 mL,
15 mmol) at room temperature. The resulting mixture was stirred and
the reaction was monitored by TLC. After 1−2 h, diethyl ether was
CONCLUSION
■
A three-component catalyst system for a one-step synthesis of
enantioenriched α-acetoxyphosphonates from aldehydes and an
acetyl phosphonate was developed. The combination of tridentate
D
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added and the mixture was washed sequentially, with H2O, sat. aq.
NaHCO3, and brine, and dried over MgSO4. The solvent was removed
under reduced pressure to give the crude product. Further purification
by column chromatography using hexanes/ethyl acetate (1:1) as eluent
gave the racemic α-acetoxyphosphonates. This method was used for
benzaldehyde, 4-chlorobenzaldehyde, and 3-methoxybenzaldehyde.
Method B:37 To a solution of hydroxyphosphonate (1 mmol) in
ethyl acetate (20 mL), K2CO3 (276 mg, 2.0 mmol), N,N-dimethyl-
aminopyridine (6.1 mg, 0.05 mmol), and acetic anhydride (0.14 mL,
1.5 mmol) were added. The mixture was stirred at room temperature
until the starting materials disappeared by TLC. Then the mixture was
filtered to remove K2CO3 and the filtrate was washed with H2O. The
aqueous phase was extracted with ethyl acetate, the combined organic
phases were dried over MgSO4, and the solvent evaporated. The crude
product was purified by column chromatography using petroleum
ether/ethyl acetate (1:1 or 1:4) as eluent to get the product. This
method was used for 4-methoxybenzaldehyde, 4-methylbenzaldehyde,
2-chlorobenzaldehyde, 2-naphthaldehyde, and propionaldehyde.
General Procedure for Asymmetric Synthesis of α-Acetox-
yphosphonates. In a glovebox, the aldehyde (0.25 mmol), DBU
(7.5 μL, 0.050 mmol), and 1-methoxynaphthalene as internal standard
(10 μL) were added to a vial containing a solution of aluminum
complex 8a (9.5 mg, 0.025 mmol) and 1H-benzotriazole (14.9 mg,
0.125 mmol) in dichloromethane (1 mL). Then the vial was capped
and taken out of the glovebox, and the solution was cooled to the
indicated temperature. Acetyl phosphonate (122 μL, 0.750 mmol)
diluted to 300 μL with dichloromethane was added to the mixture
over the indicated time using a syringe pump. After the addition was
finished, a sample was taken and filtered through a plug of silica, which
was rinsed with ethyl acetate, the solvent evaporated, and the yield
(30.4 μL, 0.25 mmol). Chromatography: hexanes/ethyl acetate (1:1).
Colorless oil, 65.4 mg, 83% yield (93% yield by H NMR), (R:S) =
1
69:31. Chiral HPLC conditions (wavelength 220 nm): hexanes/
isopropanol = 97:3, rate = 0.7 mL/min, tR (minor) = 37.5 min, tR
(major) = 45.3 min. [α]D20 +16.6 (c 0.98 in CHCl3, for the compound
1
with 69:31 er). H NMR (500 MHz, CDCl3) δ 7.43 (dd, J = 1.7,
8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.07 (d, JHP = 13.1 Hz, 1H),
4.00−4.15 (m, 3H), 3.87−3.95 (m, 1H), 3.80 (s, 3H), 2.15 (s, 3H),
1.29 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 169.4 (d, JCP = 9.1 Hz), 160.0 (d, JCP = 2.5 Hz), 129.6
(d, JCP = 6.2 Hz), 125.4 (d, JCP = 1.8 Hz), 113.9 (d, JCP = 1.7 Hz), 70.1
(d, JCP = 172.7 Hz), 63.3 (d, JCP = 5.4 Hz), 63.2 (d, JCP = 6.0 Hz),
55.3, 20.9, 16.5 (d, JCP = 5.7 Hz), 16.3 (d, JCP = 5.7 Hz); 31P NMR
(202 MHz, CDCl3) δ 18.13.
Diethyl 1-Acetoxy-(3-methoxyphenyl)methylphosphonate
(4d).7b This compound was prepared from 3-methoxybenzaldehyde
(30.5 μL, 0.25 mmol). Chromatography: hexanes/ethyl acetate (1:1).
1
Colorless oil, 65.2 mg, 83% yield (92% yield by H NMR), (R:S) =
75:25. Chiral HPLC conditions (wavelength 220 nm): hexanes/
isopropanol = 97:3, rate = 0.7 mL/min, tR (minor) = 23.9 min, tR
(major) = 36.5 min. [α]D20 +16.4 (c 0.73 in CHCl3, for the compound
with 75:25 er). 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J = 7.9, 7.9 Hz,
1H, partly hidden by CHCl3), 7.06 (d (broad), J = 7.6 Hz, 1H), 7.03
(brs, 1H), 6.87 (d (broad), J = 8.3 Hz, 1H), 6.11 (d, JHP = 13.6 Hz,
1H), 4.03−4.12 (m, 3H), 3.92−3.99 (m, 1H), 3.81 (s, 3H), 2.18 (s,
3H), 1.28 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.3 (d, JCP = 8.9 Hz), 159.6 (d, JCP = 2.2 Hz), 134.9
(d, JCP = 1.9 Hz), 129.5 (d, JCP = 2.1 Hz), 120.2 (d, JCP = 5.9 Hz),
114.4 (d, JCP = 2.8 Hz), 113.3 (d, JCP = 5.6 Hz), 70.4 (d, JCP = 169.9
Hz), 63.4 (d, JCP = 2.6 Hz), 63.3 (d, JCP = 2.1 Hz), 55.3, 20.9, 16.4 (d,
JCP = 5.8 Hz), 16.3 (d, JCP = 5.8 Hz); 31P NMR (202 MHz, CDCl3)
δ 17.68.
1
determined by H NMR. The reaction was quenched by the addition
of a sat. aq. NaHCO3 solution, followed by diethyl ether. The mixture
was washed with sat. aq. NaHCO3 to remove diethyl phosphite which
had been formed by hydrolysis of remaining acetyl phosphonate.
Further purification by column chromatography gave the desired
product.
Diethyl 1-Acetoxy(4-methylphenyl)methylphosphonate
(4e).12b This compound was prepared from 4-methylbenzaldehyde
(29.6 μL, 0.25 mmol). Chromatography: hexanes/ethyl acetate (1:2).
1
Colorless oil, 66.4 mg, 89% yield (100% yield by H NMR), (R:S) =
Diethyl 1-Acetoxyphenylmethylphosphonate (4a).12b This
compound was prepared from benzaldehyde (25.5 μL, 0.25 mmol).
Chromatography: hexanes/ethyl acetate (1:1). Colorless oil, 60.1 mg,
75:25. Chiral HPLC conditions (wavelength 220 nm): hexanes/
isopropanol = 97:3, rate = 0.7 mL/min, tR (minor) = 24.7 min, tR
(major) = 31.6 min. [α]D20 +23.9 (c 0.80 in CHCl3, for the compound
1
1
84% yield (98% yield by H NMR), (R:S) = 75:25. Chiral HPLC
with 75:25 er). H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 1.6, 8.0
conditions (wavelength 220 nm): hexanes/isopropanol = 97:3, rate =
Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.10 (d, JHP = 13.3 Hz, 1H), 4.01−
4.13 (m, 3H), 3.89−3.97 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 1.28 (t,
J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.4 (d, JCP = 9.1 Hz), 138.7 (d, JCP = 2.9 Hz), 130.4 (d,
JCP = 1.9 Hz), 129.2 (d, JCP = 2.0 Hz), 128.0 (d, JCP = 5.9 Hz), 70.4 (d,
JCP = 171.0 Hz), 63.3 and 63.2 (2C), 21.2, 20.9, 16.4 (d, JCP = 5.6 Hz),
16.3 (d, JCP = 5.8 Hz); 31P NMR (202 MHz, CDCl3) δ 18.00.
Diethyl 1-Acetoxy (4-chlorophenyl)methylphosphonate
(4f).12b This compound was prepared from 4-chlorobenzaldehyde
(35.1 mg, 0.25 mmol). Chromatography: hexanes/ethyl acetate (1:1).
20
0.7 mL/min, tR (minor) = 20.6 min, tR (major) = 25.3 min. [α]D
1
+23.4 (c 0.99 in CHCl3, for the compound with 75:25 er). H NMR
(500 MHz, CDCl3) δ 7.48 (d (broad), J = 7.8 Hz, 2H), 7.31−7.38 (m,
3H), 6.14 (d, JHP = 13.6 Hz, 1H), 4.01−4.12 (m, 3H), 3.89−3.97 (m,
1H), 2.17 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 169.3 (d, JCP = 8.9 Hz), 133.5 (d,
JCP = 2.0 Hz), 128.7 (d, JCP = 2.8 Hz), 128.5 (d, JCP = 2.2 Hz), 127.9
(d, JCP = 5.8 Hz), 70.5 (d, JCP = 170.1 Hz), 63.4 (d, JCP = 2.3 Hz), 63.3
(d, JCP = 1.8 Hz), 20.9, 16.4 (d, JCP = 5.7 Hz), 16.3 (d, JCP = 5.8 Hz);
31P NMR (202 MHz, CDCl3) δ 17.78.
1
Colorless oil, 57.8 mg, 72% yield (84% yield by H NMR), (R:S) =
Diethyl 1-Acetoxy-(2-naphthyl)methylphosphonate (4b).12b
This compound was prepared from 2-naphthylaldehyde (39.0 mg,
0.25 mmol). Chromatography: hexanes/ethyl acetate (1:2). Colorless
oil, 70.1 mg, 83% yield (96% yield by 1H NMR), (R:S) = 73:27. Chiral
HPLC conditions (wavelength 220 nm): hexanes/isopropanol = 98:2,
rate = 0.7 mL/min, tR (minor) = 63.6 min, tR (major) = 67.7 min.
77:23. Chiral HPLC conditions (wavelength 220 nm): hexanes/
isopropanol = 97:3, rate = 0.7 mL/min, tR (minor) = 27.0 min, tR
(major) = 33.7 min. [α]D20 +27.1 (c 0.79 in CHCl3, for the compound
1
with 77:23 er). H NMR (500 MHz, CDCl3) δ 7.42 (dd, J = 1.8, 8.5
Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 6.08 (d, JHP = 13.8 Hz, 1H), 4.03−
4.13 (m, 3H), 3.93−4.01 (m, 1H), 2.17 (s, 3H), 1.28 (t, J = 7.0 Hz,
3H), 1.23 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2
(d, JCP = 9.0 Hz), 134.7 (d, JCP = 3.4 Hz), 132.1 (d, JCP = 2.0 Hz), 129.3
(d, JCP = 5.8 Hz), 128.7 (d, JCP = 2.1 Hz), 69.8 (d, JCP = 170.8 Hz), 63.5
(d, JCP = 6.6 Hz), 63.4 (d, JCP = 6.2 Hz), 20.8, 16.4 (d, JCP = 5.6 Hz),
16.3 (d, JCP = 5.6 Hz); 31P NMR (202 MHz, CDCl3) δ 17.25.
Diethyl 1-Acetoxy-(2-chlorophenyl)methylphosphonate
(4g).12b This compound was prepared from 2-chlorobenzaldehyde
(28.2 μL, 0.25 mmol). Chromatography: hexanes/ethyl acetate (1:2).
Colorless oil, 48.3 mg, 60% yield (61% yield by 1H NMR), (R:S) = 78:22.
Chiral HPLC conditions (wavelength 220 nm): hexanes/isopropanol =
97:3, rate = 0.7 mL/min, tR (minor) = 35.4 min, tR (major) = 37.6 min.
20
1
[α]D +33.4 (c 1.3 in CHCl3, for the compound with 73:27 er). H
NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.82−7.87 (m, 3H), 7.62 (d,
J = 8.5 Hz. 1H), 7.47−7.52 (m, 2H), 6.30 (d, JHP = 13.7 Hz, 1H),
4.02−4.15 (m, 3H), 3.89−3.98 (m, 1H), 2.21 (s, 3H), 1.28 (t, J = 7.1
Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
169.5 (d, JCP = 9.3 Hz), 133.5 (d, JCP = 1.7 Hz), 133.2 (d, JCP = 2.3
Hz), 131.1 (d, JCP = 2.2 Hz), 128.4 (d, JCP = 1.6 Hz), 128.3, 127.9,
127.6 (d, JCP = 7.5 Hz), 126.7, 126.5, 125.5 (d, JCP = 4.4 Hz), 70.8 (d,
JCP = 170.3 Hz), 63.53 (d, JCP = 4.5 Hz), 63.48 (d, JCP = 4.0 Hz), 21.1,
16.6 (d, JCP = 5.6 Hz), 16.5 (d, JCP = 5.8 Hz); 31P NMR (202 MHz,
CDCl3) δ 17.74.
20
[α]D +13.1 (c 0.83 in CHCl3, for the compound with 78:22 er).
Diethyl 1-Acetoxy-(4-methoxyphenyl)methylphosphonate
(4c).12b This compound was prepared from 4-methoxybenzaldehyde
1H NMR (500 MHz, CDCl3) δ 7.64 (dt, J = 1.8, 7.5 Hz, 1H),
E
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7.38 (d, J = 7.7 Hz, 1H), 7.27−7.32 (m, 2H), 6.62 (d, JHP = 13.7 Hz, 1H),
4.17 (dq, JHH = 7.1 Hz, JHP = 7.7 Hz, 2H), 4.00−4.06 (m, 1H), 3.89−3.97
(m, 1H), 2.16 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H);
(i) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53−57. (j) Dugal-
Tessier, J.; O’Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2012, 51, 4963−4967.
(3) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560−1638. (b) Beutner, G. L.; Denmark, S. E. Top. Organomet.
Chem. 2013, 44, 55−90.
(4) (a) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am.
Chem. Soc. 2005, 127, 11592−11593. (b) Lundgren, S.; Wingstrand,
E.; Moberg, C. Adv. Synth. Catal. 2007, 349, 364−372.
(5) (a) Marvel, C. S.; Brace, N. O.; Miller, F. A.; Johnson, A. R. J. Am.
Chem. Soc. 1949, 71, 34−36. (b) Okimoto, M.; Chiba, T. Synthesis
1996, 1188−1190. (c) Watahiki, T.; Ohba, S.; Oriyama, T. Org. Lett.
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(6) Takaki, K.; Itono, Y.; Nagafuji, A.; Naito, Y.; Shishido, T.;
Takehira, K.; Makioka, Y.; Taniguchi, Y.; Fujiwara, Y. J. Org. Chem.
2000, 65, 475−481.
13C NMR (126 MHz, CDCl3) δ 169.0 (d, JCP = 9.6 Hz), 133.7 (d, JCP
7.9 Hz), 132.0 (d, JCP = 1.0 Hz), 129.8 (d, JCP = 2.8 Hz), 129.7 (d, JCP
3.9 Hz), 129.5 (d, JCP = 1.9 Hz), 127.1 (d, JCP = 2.7 Hz), 66.9 (d, JCP
=
=
=
173.0 Hz), 63.5 (d, JCP = 3.4 Hz), 63.4 (d, JCP = 3.6 Hz), 20.8, 16.4 (d,
JCP = 5.8 Hz), 16.2 (d, JCP = 5.7 Hz); 31P NMR (202 MHz, CDCl3)
δ 17.20.
Diethyl 1-Acetoxypropanephosphonate (4h).38 This compound
was prepared from propanal (18.0 μL, 0.25 mmol). Chromatography:
hexanes/ethyl acetate (1:1). Colorless oil, 9.0 mg, 15% yield
(16% yield by 1H NMR), (R:S) = 79:21. Chiral GC conditions:
flow 1 mL/min, 50 °C for 10 min, 2 °C/min to 100 °C, hold for
20 min, 1 °C/min to 135 °C, 10 °C/min to 180 °C, tR (major) = 86.1
20
min, tR (minor) = 86.5 min. [α]D −32.1 (c 0.14 in CHCl3, for the
compound with 79:21 er). 1H NMR (500 MHz, CDCl3) δ 5.19 (ddd,
J = 4.2, 8.7, 9.6 Hz, 1H), 4.11−4.19 (m, 4H), 2.13 (s, 3H), 1.89−1.97
(m, 1H), 1.77−1.86 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2
Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
170.0 (d, JCP = 5.3 Hz), 69.2 (d, JCP = 167.7 Hz), 62.7 (d, JCP = 7.0
Hz), 62.6 (d, JCP = 6.3 Hz), 22.9, 20.7, 16.5 (d, JCP = 5.7 Hz), 16.4 (d,
JCP = 5.9 Hz), 10.3 (d, JCP = 12.6 Hz); 31P NMR (202 MHz, CDCl3)
δ 20.88.
(7) (a) Kaboudin, B.; Karimi, M. Bioorg. Med. Chem. Lett. 2006, 16,
5324−5327. (b) Kaboudin, B.; Karimi, M. Arkivoc 2007, xiii, 124−132.
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2694.
(9) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81−96.
́ ́
(10) Merino, P.; Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal.
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(11) (a) Kategaonkar, A. H.; Pokalwar, R. U.; Sonar, S. S.; Gawali, V.
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General Procedure for Hydrolysis of Acetoxyphosphonates
4a, 4e, and 4f. p-TsOH·H2O (27 mg, 0.14 mmol) was added to the
solution of acetoxyphosphonate (0.10 mmol) in EtOH (2 mL) at
room temperature. The resulting mixture was stirred for 3 d. Then the
solvent was evaporated and the crude product was purified by column
chromatography using hexanes/ethyl acetate (1:2) as eluent gave the
hydroxyphosphonates.
(12) (a) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.; Amoozgar, Z.
Synthesis 2004, 295−297. (b) Firouzabadi, H.; Iranpoor, N.; Sobhani,
S.; Amoozgar, Z. Synthesis 2004, 1771−1774.
(13) McConnell, R. L.; Coover, H. W., Jr. J. Am. Chem. Soc. 1957, 79,
1961−1963.
ASSOCIATED CONTENT
■
(14) Li, Y.-F.; Hammerschmidt, F. Tetrahedron: Asymmetry 1993, 4,
109−120.
S
* Supporting Information
1H NMR spectra of compounds 2, 4a−h, ligand for complex
8a, 31P NMR spectrum of compound 2, and HPLC and GC of
compounds 4a−h. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Khushi, T.; O’Toole, K. J.; Sime, J. T. Tetrahedron Lett. 1993,
34, 2375−2378.
(16) Peng, H.; Wang, T.; Xie, P.; Chen, T.; He, H.-W.; Wan, J. J.
Agric. Food Chem. 2007, 55, 1871−1880. (b) He, H.-W.; Yuan, J.-L.;
Peng, H.; Chen, T.; Shen, P.; Wan, S.-Q.; Li, Y.; Tan, H.-L.; He, Y.-H.;
He, J.-B.; Li, Y. J. Agric. Food Chem. 2011, 59, 4801−4813.
(17) Breuer E. in The Chemistry of Organophosphorus Compounds,
Hartley, F. R., Ed.; Wiley, 1996; Vol. 4, pp 653−729.
(18) Sekine, M.; Satoh, M.; Yamagata, H.; Hata, T. J. Org. Chem.
1980, 45, 4162−4167.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kimo@kth.se
■
Author Contributions
Ye-Qian Wen and Robin Hertzberg contributed equally.
(19) Katzhendler, J.; Ringel, I.; Karaman, R.; Zaher, H.; Breuer, E. J.
Chem. Soc., Perkin Trans. 2: Phys. Org. Chem. 1997, 341−349.
(20) Afarinkia, K.; Echenique, J.; Nyburg, S. C. Tetrahedron Lett.
1997, 38, 1663−1666.
(21) The pKa value of HCN (10.2 in DMSO) should be compared
to that of dimethylphosphite (18.4 in DMSO): Li, J.-N.; Liu, L.; Fu, Y.;
Guo, Q.-X. Tetrahedron 2006, 62, 4453−4462.
(22) (a) Baidya, M.; Brotzel, F.; Mayr, H. Org. Biomol. Chem. 2010, 8,
1929−1935. (b) Breugst, M.; Bautista, F. C.; Mayr, H. Chem.Eur. J.
2012, 18, 127−137.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Wenner-Gren Foundations and
from the Swedish Research Council (grant 621-2012-3391) is
gratefully acknowledged.
(23) (a) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656−
1665. (b) Rogge, T. M.; Stevens, C. V.; Colpaert, A.; Levecke, B.;
Booten, K. Biomacromolecules 2007, 8, 485−489. (c) Nagel, M. C. V.;
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