Thiourea catalyzed organocatalytic enantioselective Michael addition of diphenyl phosphite to nitroalkenes

Article abstract of DOI:10.1039/c0ob01059f

Bifunctional thiourea catalyzes the enantioselective Michael addition reaction of diphenyl phosphite to nitroalkenes. This methodology provides a facile access to enantiomerically enriched β-nitrophosphonates, precursors for the preparation of synthetically and biologically useful β-aminophosphonic acids. DFT level of computational calculations invoke the attack of the diphenyl phosphite to the nitroolefin by the Re face, this give light to this scarcely explored process update in the literature. The computational calculations support the absolute configuration obtained in the final adducts.

Full text of DOI:10.1039/c0ob01059f

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PAPER
Thiourea catalyzed organocatalytic enantioselective Michael addition of
diphenyl phosphite to nitroalkenes†
Ana Alcaine,a Eugenia Marque´s-Lo´pez,a,b Pedro Merino,a Toma´s Tejeroa and Raquel P. Herrera*a,c
Received 21st November 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob01059f
Bifunctional thiourea catalyzes the enantioselective Michael addition reaction of diphenyl phosphite to
nitroalkenes. This methodology provides a facile access to enantiomerically enriched
b-nitrophosphonates, precursors for the preparation of synthetically and biologically useful
b-aminophosphonic acids. DFT level of computational calculations invoke the attack of the diphenyl
phosphite to the nitroolefin by the Re face, this give light to this scarcely explored process update in the
literature. The computational calculations support the absolute configuration obtained in the final
adducts.
interesting and pioneer organocatalytic enantioselective methods
Introduction
concerning Michael addition of diphenyl phosphite have been
reported using chiral guanidine 1 and quinine 2 (Fig. 1).8a,b Very
Due to the immense progress in the scientific community, the
claim in the organic synthesis has been shifted to the design
recently, Rawal and co-workers reported the Michael addition of
phosphite to nitroalkenes catalyzed by squaramide 3.8c Therefore,
and synthesis of more complex structures and important targets
making essential the search for new methods and new efficient
processes.1 Organocatalysis has emerged as a powerful tool
and as an efficient solution for the rapid and stereoselective
construction of significant chiral entities.2,3 In the last decade, the
the development of new and efficient catalytic methodologies
to obtain b-nitrophosphonates are still of remarked importance.
Among the great number of organocatalysts developed until now,
thioureas/ureas have attracted a great attention in the scientific
enantioselective synthesis of a- and b-aminophosphonic acids and
their phosphonate esters has received significant attention owing
to their biological activities as structurally analogues to a- and b-
amino acids.4,5 It is not surprising that the absolute configuration
of the stereogenic a- or b-carbon in these phosphonyl compounds
strongly influences their biological properties.6 In this context,
great efforts have been focused toward the development of ex-
cellent asymmetric methods for the synthesis of enantiomerically
pure a-aminophosphonic acids.5,7 However, the strategies for the
synthesis of b-aminophosphonic acids has been less studied4 and
only a few examples based in organocatalytic protocols have
been scarcely investigated to date.8 The Michael addition of
phosphorus compounds to nitroolefins provides a straightforward
and convenient method for synthesizing P–C bonds.9,10 Two
community from pioneering examples reported by Curran and
co-workers,11 as suitable catalysts for a great number of efficient
processes.12 Herein, we report the organocatalytic enantioselective
Michael addition of diphenyl phosphites to nitroolefins afford-
ing b-nitrophosphonates enantiomerically enriched using bifunc-
tional thiourea 4a. Michael adducts could be further conveniently
transformed to chiral b-aminophosphonic acids following the
procedures previously reported in the literature.8a,b
aLaboratorio de S´ıntesis Asime´trica, Departamento de Qu´ımica Orga´nica,
Instituto de Ciencia de Materiales de Arago´n, Universidad de Zaragoza-
CSIC, E-50009, Zaragoza, Arago´n, Spain. E-mail: raquelph@unizar.es;
Fax: +34 976762075; Tel: +34 976762281
bOrganische Chemie, Technische Universita¨t Dortmund, Otto-Hahn-Str. 6,
44227, Dortmund, Germany
cARAID, Fundacio´n Arago´n I+D, E-50004, Zaragoza, Spain
† Electronic supplementary information (ESI) available: Detailed ex-
perimental procedures and characterization data for new compounds
7e,j and HPLC chromatograms for all compounds 7a–l. See DOI:
10.1039/c0ob01059f
Fig. 1 Catalysts employed in the phospha-Michael addition reaction.
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Table 1 Screening of thiourea catalysts 4a–4ka
Entry
catalyst
yield (%)b
ee (%)c
Scheme 1 Synthesis of chiral thioureas.
1d
2
3
4
5
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
67
67
78
63
50
60
86
45
79
76
70
5
Rac.e
3
Among all thioureas tested in this process, only 4a afforded
promising results in terms of both reactivity and enantioselectivity
(Table 1, entry 1).16 In the other cases, the addition of an external
base was always required in order to observe reactivity,17 except for
catalyst 4h,18 which also has a Brønsted base moiety in its structure
(Table 1, entry 8). However unfortunately, the final products were
obtained with very poor enantioselectivities. On the basis of this
observation, it is conceivable that the presence of the Brønsted
base and the thiourea moiety placed on the right position in the
same molecular structure is crucial for the success of this protocol.
Maybe, due to formation of a rigid transition state, leading to
higher values of enantioselectivity.
Rac.e
Rac.e
Rac.e
9
6
7
8d
9
Rac.e
Rac.e
Rac.e
10
11
4j
4k
a Experimental conditions: To a solution of nitroalkene 5a (0.4 mmol)
and corresponding catalyst 4a–k (10 mol%) in CH2Cl2 (1 mL), iPr2EtN
(10 mol%) and diphenyl phosphite 6a (0.4 mmol) were added at room
temperature. b After isolation by column chromatography. c Determined
by chiral HPLC analysis (Chiralpak IA). d Reaction performed in absence
of iPr2EtN. e Racemic sample.
Catalysts 4c, 4e, and 4g were used expecting a bifunctional
mode of action of these structures, since the possible bifunctional
character of such catalysts has been already proposed when the
thiourea moiety and the hydroxy group, which would activate the
nucleophile, are present in the same skeleton (Fig. 3).13b,e However
in this case, the coordination of the nucleophile with the H of the
hydroxyl group seems to be neither effective nor efficient enough
to promote the reaction in an enantioselective way.
The bifunctional role that catalyst 4h may play in similar
processes has been also previously proposed and discussed.13d,18
In fact, in the current reaction, catalyst 4h gave slighlty the
second best result, which is in agreement with the importance
of having both moeties (the Brønsted base and the thiourea) in
the same structure. Furthermore, bis-thiourea catalyst 4d19 has
been also invoked to react as bifunctional catalyst interacting with
both nucleophile and electrophile by hydrogen-bonds. To further
explore the viability of this phospha-Michael addition, different
Results and discussion
Based on our experience using thiourea catalysts13 and the
demonstrated ability of these molecules activating nitro groups as
proposed by several authors,14,15 we decided to explore and study
these structures in the asymmetric phospha-Michael reaction
of nitroalkenes (Fig. 2, Table 1). Thioureas 4b–h were first
synthesized following our previously reported procedure, depicted
in Scheme 1.13b,e This easy method allows access to a great variety
of this kind of structures.
These synthesized thioureas (4b–h), as well as others commer-
cially available (4a and 4i–k) (Fig. 2) were tested as catalysts in a
model hydrophosphonylation reaction using trans-b-nitrostyrene
(5a) as substrate, and the results are summarized in Table 1.
Fig. 2 Thiourea catalysts tested.
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Table 2 Screening for the organocatalytic asymmetric Michael addition
reaction of phosphite 6a to trans-b-nitrostyrene (5a)a
Table 3 Screening of different reaction conditions using toluene as
solventa
Entry solvent (mL) 4a (%) T/◦C time (h) yield (%)b ee (%)c
Entry
solvent (mL)
6a (eq.)
time (h)
yield (%)b
ee (%)c
1
2
2
2.5
3
1
1
1
2
2
1
1
1
1
1
2
2
0.9
12
62
66
64
60
66
62
62
60
60
1
2
3
4
5
6
7
8
Xylene (1)
Toluene (1)
CH3CN (1)
CH2Cl2 (1)
CHCl3 (1)
THF (1)
10
10
10
10
10
10
10
15
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
r.t.
r.t.
-10
-10
-10
-10
10 min
10 min
24
72
96
96
96
72
72
72
48
12
120
72
24
12
85
85
25
90
58
60
60
70
54
n.r.d
n.r.d
68
66
68
72
60
78
76
72
72
120
120
72
34
3
n.d.d
n.d.d
78
4e
5f
6
12
26
n.r.d
n.r.d
85
5 min
5 min
12
84
80
80
7
8
Et2O (1)
CH2Cl2 (1)
CH2Cl2 (1)
CH2Cl2 (2)
CH2Cl2 (0.5) 10
CH2Cl2 (1)
CH2Cl2 (1)
CH2Cl2 (0.5) 10
CH2Cl2 (1)
CH2Cl2 (1)
9
n.d.e
n.d.e
85
a Experimental conditions: To a solution of nitroalkene (5a) (0.4 mmol) and
catalyst 4a (10 mol%) in toluene (1 mL), diphenyl phosphite 6a (0.4 mmol)
was added. b After isolation by column chromatography. c Determined
by chiral HPLC analysis (Chiralpak IA). d Not determined. e 5 mol% of
catalyst 4a. f Reaction performed at 0 ◦C.
10
11
12f
13
14
15
16f
10
10
10
85
39
95
65
20
20
85
in the asymmetric induction as well as in the the yield, providing
finally the best reaction conditions (entry 14). However, due to the
interesting short reaction time required when toluene was used
(Table 2, entry 2), we could not discard this solvent before further
investigations were carried out (Table 3).
Unfortunately, any of the variations performed in the concen-
tration of the solution (entries 1–3,7–8), catalyst loading (entry
4), temperature (entry 5), and amount of diphenyl phosphite
(6a) (entry 6–8) did not afford better results in comparison with
those achieved using CH2Cl2 as solvent. We observed the fast
precipitation of the final product in the reaction media, due to its
insolubility in toluene. This fact accelerates the process but it does
not provide better enantioselectivity.
a Experimental conditions (unless otherwise specified): To a solution of
nitroalkene 5a (0.4 mmol) and catalyst 4a (10 mol%) in the corresponding
solvent (1 mL), diphenyl phosphite 6a (0.4 mmol) was added at room
temperature. b After isolation by column chromatography. c Determined
by chiral HPLC analysis (Chiralpak IA). d No reaction observed. e Not
determined. f 2 equiv. of diphenyl phosphite 6a.
The effect of other different nucleophilic dialkyl phosphites
[diethyl phosphite (6b), dimethyl phosphite (6c), diisopropyl
phosphite (6d) and dibenzyl phosphite (6e)] were also explored
in order to improve the enantioselectivity of the Michael reaction
(Fig. 4).
Fig. 3 Bifunctional mode of action.
parameters were investigated using trans-b-nitrostyrene (5a) as the
test substrate and the best catalyst (4a) (Table 2).
In an initial screening of solvents at room temperature, while
THF and Et2O showed not to be effective for this reaction (entries
6–7), toluene, xylene, CH3CN, CHCl3, and CH2Cl2 provided the
final product with promising values of enantioselectivity (entries
1–5). Finally, CH2Cl2 was the solvent of choice for further
variations, since it led to the highest yield and enantioselectivity
(entry 4), even when longer reaction time was required compared
with toluene or xylene (entries 1–2). Variation of the catalyst
loading (entries 8–9), dilution of the reaction mixture (entry
10) or the addition of an excess of phosphite (entry 12) had a
negative effect on the enantioselectivity and the yield. On the
other hand, increasing the concentration accelerated the reaction
giving comparable results (entry 11). Lowering the temperature to
-10 ◦C improved the enantioselectivity at the expense of reactivity
and yield (entry 13). Thus, the combination of both variations
(concentration and cooling down to -10 ◦C) led to a slight increase
Fig. 4 Dialkyl phosphites tested.
However, under the best reaction conditions, after 3 days, any of
these dialkyl phosphites (6b–e) were reactive enough. Thus, only
diphenyl phosphite (6a) furnished the corresponding final product
7a with good results. The lack of reactivity and the dramatic
descent of the reaction rates using these dialkyl phosphites (6b–e)
might be due to the drastic variation of its pKa values,20 as we
observed in a previous work.21
Having established the optimal reaction conditions, we further
explored the scope of this 1,4-Michael addition for various
substituted nitroolefines 5b–l. Corresponding derivatives 7a–l were
furnished with very good yields and good enantioselectivities in
CH2Cl2 at -10 ◦C (Table 4).
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Table 4 Organocatalytic enantioselective 1,4-Michael addition of phos-
phite 6a to nitroalkenes 5a–l catalyzed by thiourea 4aa
upper attack (TS-1 and TS-2) are lower in energy (Fig. 5). The key
proton abstraction from the developing phosphite anion by the
dimethylamino group25 helps in stabilizing the transition states and
it is responsible of the enantioselective approach of the nucleophile
to the nitroalkene. From the two possible orientations of the
double bond, that corresponding to the Re attack and leading
to (R)-isomer, resulted the most stable by 1.39 kcal mol-1, thus
being in good qualitative agreement with the experimental results.
Entry
R
time (days)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph (7a)
3
3
3
3
3
3
4
3
3
3
3
3
95
81
79
75
79
87
60
67
79
81
82
60
76
74
78
73
76
73
72
76
76
78
72
68
4-MeC6H4 (7b)
4-MeOC6H4 (7c)
2-MeOC6H4 (7d)
2-CF3C6H4 (7e)
4-ClC6H4 (7f)
4-FC6H4 (7g)
2-furyl (7h)
9
4-BrC6H4 (7i)
4-BnOC6H4 (7j)
Cy (7k)
10
11
12
PhCH2CH2 (7l)
a See Experimental Section. b After isolation by column chromatography.
c Determined by chiral HPLC analysis (Chiralpak IA and IB).
An enantioselectivity/temperature profile showed that in all
cases a small improvement on the enantioselectivity was posible
after longer reaction time, by running the reactions at -10 ◦C. As
illustrated in Table 4, nitroolefines 5a–l underwent conjugate
addition with diphenyl phosphite 6a in the presence of catalyst
4a within 3 reaction days with high yields and good enantiomeric
ratio (up to 78%). The steric hindrance and the electronic
environment influence only slightly on the enantioselectivity of this
process, which was almost independent of the aryl group (entries
1–10). Although with alkyl substituents the enantioselectivity
seems to be somewhat lower (entries 11–12). These results are
comparable to those previously reported by Wang and co-
workers, but shor◦ter reaction times and a less drastic decrease in
temperature (-55 C) were required,8a which saves energy and time
management. Unfortunately, we could not improve the excellent
results reported by Terada,8b and Rawal8c groups. However, the
readily accessible thioureas, compared with the more tedious
preparation of their catalysts, reinforces the simplicity and viability
of our procedure. The absolute configuration of the Michael
adducts 7a–l was determined by comparison of the optical rotation
values with those previously reported in the literature for the same
products.8
On the basis of the obtained results, we envisioned that catalyst
4a could act in a bifunctional fashion, as previously proposed in
the literature.22 The activation of nitroolefins by thiourea 4a has
been demonstrated earlier in other processes16,23 and kinetic studies
indicated the bifunctional character of this structure in Michael
reactions.16c In order to give additional support to this hypothesis
we performed calculations at DFT level (B3LYP/6-31+G*).24 We
assumed that the enantioselectivity of the reaction is controlled
during the C–P bond formation between the activated nitroalkene
and the nucleophile. We have studied the approach of dimethyl
phosphite, which has been employed as the model reagent, to both
Re and Si faces of the nitroalkene. For each enantiotopic face, the
attack can occur from above or below, leading to four transition
states. Among these transition states, those corresponding to the
Fig. 5 Transition state models.
In contrast to the Si-facial attack, Re-facial approach of the
phosphite is located at the less sterically demanding upper right-
hand quadrant. Therefore, TS-1 is more stabilized than TS-2
because a lower steric repulsion between the phosphite nucleophile
and the inside-oriented phenyl group of the nitroalkene. These
results are also in agreement with similar theoretical studies
reported by Papai and co-workers25a for the thiourea catalyzed
nucleophilic addition of acetylacetone to nitrostyrene. The C–P
distances in the transition states were found to be very similar,
2.76 A and 2.80 A for TS-1 and TS-2, respectively indicating early
transition states in which the electrostatic interaction between the
phosphite and the dimethylamino group at the catalyst is crucial
for approaching the reagents. The possibility of hydrogen bonding
between the nitro group and the thiourea moiety through an only
oxygen atom as recently proposed by other authors26 has also been
considered, but in all cases higher energy stationary points have
been found in close agreement with previous calculations made by
Papai in which it was demonstrated the preference by a substrate
binding through bidentate H-bonds with the nitroalkene.25a Higher
level calculations considering solvent correction are underway in
our group to confirm these preliminary results and will be reported
in due course.
˚
˚
Conclusions
In summary, we have reported a simple and enantioselec-
tive organocatalytic phospha-Michael reaction catalyzed by
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commercially available Takemoto’s thiourea catalyst 4a. Thus,
this methodology provides a facile access to the corresponding
enantiomerically enriched b-nitrophosphonates in good yields.
The limited number of catalytic enantioselective methods for the
synthesis of b-nitrophosphonates by straightforward hydrophos-
phonylation of nitroalkenes,8,27 and the high synthetic versatility
of these products make this new approach very attractive for the
synthesis of optically active b-aminophosphonic acids. DFT level
of computational calculations appeal to the attack of the diphenyl
phosphite to the nitroolefin by the Re face, this shed light on
this process which has been scarcely explored up to now in the
literature. We have invoked the importance, efficiency and utility
of bifuctional catalysts and we will study the design and synthesis
of new bifuncional thioureas. Future research will be carried out
concerning the improvement of enanantiocontrol of this process.
Due to the extremely simple operational procedure our method-
ology is very accessible and it increases the utility and interest
of the work in this growing area of the use of thioureas as
organocatalysts.
at -10 ◦C as a white solid in 81% yield. M.p. 116–119 ◦C. The ee of
the product was determined by HPLC using a Daicel Chiralpak
IB column (n-hexane/i-PrOH = 90 : 10, flow rate 1 mL min-1,
l = 254 nm): tmajor = 22.1 min; tminor = 15.3 min. HRMS calcd
for C21H20NNaO5P 420.0977; found 420.0964 [M+ + Na]. [a]D22
=
1
-3.92 (c 1.0, CHCl3, 74% ee). The H and 13C NMR spectra are
consistent with values previously reported in the literature.8b
(R)-Diphenyl1-(4-methoxyphenyl)-2-nitroethylphosphonate(7c).
Following the general procedure, compound 7c was obtained
after 3 days at -10 ◦C as a white solid in 79% yield. M.p.
133–137 ◦C. The ee of the product was determined by HPLC
using a Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10,
flow rate 1 mL min-1, l = 254 nm): tmajor = 28.2 min; tminor
=
22.9 min. HRMS calcd C21H20NNaO6P 436.0926; found 436.0920
[M+ + Na]. [a]D22 = -0.48 (c 1.0, CHCl3, 78% ee). The 1H and 13
C
NMR spectra are consistent with values previously reported in the
literature.8a,b
(R)-Diphenyl
1-(2-methoxyphenyl)-2-nitroethylphosphonate
(7d). Following the general procedure, compound 7d was
obtained after 3 days at -10 ◦C as a white solid in 75% yield. M.p.
85–88 ◦C. The ee of the product was determined by HPLC using
a Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow
rate 1 mL min-1, l = 254 nm): tmajor = 17.6 min; tminor = 13.3 min.
HRMS calcd for C C21H20NNaO6P 436.0926; found 436.0929
Experimental section
General Information
Purification of reaction products was carried out by flash chro-
matography using silical gel (0.040–0.063 mm). Analytical thin
layer chromatography was performed on 0.25 mm silical gel 60-
F plates. 1H-NMR spectra were recorded at 400 MHz; 13C-NMR
spectra were recorded at 100 MHz and 75 MHz; CDCl3 as solvent.
Chemical shifts were reported in the d scale relative to residual
CHCl3 (7.26 ppm) for 1H-NMR and to the central line of CDCl3
(77.0 ppm) for 13C-NMR.
[M+ + Na]. [a]D22 = +10.5 (c 1.0, CHCl3, 73% ee). The 1H and 13
C
NMR spectra are consistent with values previously reported in
the literature.8a,b
(R)-Diphenyl 2-nitro-1-(2-trifluoromethyl)phenyl)ethylphospho-
nate (7e). Following the general procedure, compound 7e was
obtained after 3 days at -10 ◦C as a viscous yellow liquid in 79%
yield. The ee of the product was determined by HPLC using a
Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow rate
1 mL min-1, l = 254 nm): tmajor = 14.1 min; tminor = 10.5 min. HRMS
calcd for C21H17F3NNaO5P 474.0694; found 474.0684 [M+ + Na].
[a]2D2 = +10.3 (c 1.0, CHCl3, 76% ee). 1H NMR (400 MHz, CDCl3)
Materials. All commercially available solvents and reagents
were used as received. Chiral thioureas catalysts were obtained
following the literature procedure: 4b,28 4c,13e 4d,18a 4e–g,13e and
4h.29 The 1H and 13C-NMR spectra for the compounds 7a–d,h–i,k,l
are consistent with values previously reported in the literature.8
2
3
3
Representative experimental procedure for enantioselective 1,4-
addition reaction of diphenyl phosphite (6a) with nitroalkenes (5a–l)
catalyzed by thiourea 4a. To a solution of nitroalkene (5a–l) (0.4
mmol) and catalyst 4a (10 mol%) in CH2Cl2 (0.5 mL), in a test
tube, diphenyl phosphite (6a) (0.4 mmol) was added. After the
d 4.90 (ddd, JH–P = 24.3, JH–H = 9.6, JH–H = 5.3 Hz, 1H, CH),
5.02–5.10 (m, 1H, CH2), 5.19–5.26 (m, 1H, CH2), 6.64–6.65 (m,
1H, Ar), 6.65–6.67 (m, 1H, Ar), 7.01–7.06 (m, 1H, Ar), 7.09–7.16
(m, 4H, Ar), 7.17–7.22 (m, 1H, Ar), 7.30–7.35 (m, 2H, Ar), 7.42–
7.47 (m, 1H, Ar), 7.53–7.57 (m, 1H, Ar), 7.72–7.74 (m, 1H, Ar),
7.82–7.84 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3) d 38.8 (d, J =
143.4 Hz), 75.4 (d, J = 2.3 Hz), 119.7 (d, J = 4.6 Hz), 120.4 (d, J =
4.1 Hz), 123.8 (qd, J = 274.4, 1.4 Hz), 125.3 (d, J = 1.2 Hz), 125.9
(d, J = 1.2 Hz), 127.1 (m), 128.9 (d, J = 3.5 Hz), 129.6, 129.6, 129.7
(d, J = 4.8 Hz), 129.8 (qd, J = 30.0, 8.2 Hz), 130.0 (d, J = 1.2 Hz),
132.5 (d, J = 3.5 Hz), 147.8 (d, J = 9.8 Hz), 148.1 (d, J = 9.3 Hz).
◦
appropriate reaction time, at -10 C, the residue was purified by
silica gel chromatography (SiO2, hexane–EtOAc 7 : 3) to afford the
adducts 7a–l as white solid. Yields and spectral and analytical data
for compounds 7a–l are as follows:
(R)-Diphenyl 2-nitro-1-phenylethylphosphonate (7a). Follow-
ing the general procedure, compound 7a was obtained after 3 days
at -10 ◦C as a white solid in 95% yield. M.p. 154–160 ◦C. The ee of
the product was determined by HPLC using a Daicel Chiralpak
IA column (n-hexane/i-PrOH = 60 : 40, flow rate 0.5, mL min-1,
l = 254 nm): tmajor = 18.7 min; tminor = 21.0 min. HRMS calcd
(R)-Diphenyl 1-(4-chlorophenyl)-2-nitroethylphosphonate (7f).
Following the general procedure, compound 7f was obtained
after 3 days at -10 ◦C as a white solid in 87% yield. M.p. 134–
137 ◦C. The ee of the product was determined by HPLC using a
Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow rate
1 mL min-1, l = 254 nm): tmajor = 28.9 min; tminor = 17.8 min. HRMS
calcd for C20H17ClNNaO5P 440.0431; found 440.0430 [M+ + Na].
[a]2D2 = -6.2 (c 1.0, CHCl3, 73% ee). The 1H and 13C NMR spectra
are consistent with values previously reported in the literature.8a
for C20H18NNaO5P 406.0820; found 406.0812 [M+ + Na]. [a]D22
=
-1.24 (c 1.0, CHCl3, 76% ee). The H and 13C NMR spectra are
1
consistent with values previously reported in the literature.8a,b
(R)-Diphenyl 2-nitro-1-p-tolylethylphosphonate (7b). Follow-
ing the general procedure, compound 7b was obtained after 3 days
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(R)-Diphenyl 1-(4-fluorophenyl)-2-nitroethylphosphonate (7g).
Following the general procedure, compound 7g was obtained
after 4 days at -10 ◦C as a white solid in 60% yield. M.p. 130–
134 ◦C. The ee of the product was determined by HPLC using a
Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow rate
1 mL min-1, l = 254 nm): tmajor = 26.7 min; tminor = 15.0 min. HRMS
calcd for C20H17FNNaO5P 424.0726; found 424.0724 [M+ + Na].
[a]2D2 = +0.23 (c 1.0, CHCl3, 72% ee). The 1H and 13C NMR spectra
are consistent with values previously reported in the literature.8a
3 days at -10 ◦C as a white solid in 60% yield. M.p. 70–75 ◦C. The ee
of the product was determined by HPLC using a Daicel Chiralpak
IA column (n-hexane/i-PrOH = 95 : 5, flow rate 1 mL min-1, l =
254 nm): tmajor = 43.1 min; tminor = 47.1 min. HRMS calcd for
C22H22NNaO5P 434.1133; found 434.1145 [M+ + Na]. [a]D22 = +4.70
(c 1.0, CHCl3, 68% ee). The 1H and 13C NMR spectra are consistent
with values previously reported in the literature.8c
Acknowledgements
(S)-Diphenyl 1-(furan-2-yl)-2-nitroethylphosphonate (7h). Fol-
lowing the general procedure, compound 7h was obtained after
3 days at -10 ◦C as a white solid in 67% yield. M.p. 82–85 ◦C. The ee
of the product was determined by HPLC using a Daicel Chiralpak
IB column (n-hexane/i-PrOH = 90 : 10, flow rate 1 mL min-1, l =
254 nm): tmajor = 21.8 min; tminor = 12.1 min. HRMS calcd for
C18H16NNaO6P 396.0613; found 396.0620 [M+ + Na]. [a]D22 = -9.0
(c 1.0, CHCl3, 76% ee). The 1H and 13C NMR spectra are consistent
with values previously reported in the literature.8a,b
We thank the Ministry of Science and Innovation (MICINN,
Madrid, Spain. Projects CTQ2009-09028 and CTQ2010-19606)
and the Government of Arago´n (Zaragoza, Spain. Project
PI064/09 and Research Groups, E-10) for financial support of
our research. E. M.-L. thanks the Alexander von Humboldt
Foundation for a postdoctoral fellowship and CSIC for a JAE-Doc
contract. We are also grateful to David Roca-Lo´pez (Universidad
de Zaragoza) for his help and encouragement. R. P. H. thanks the
Arago´n I+D Foundation for her permanent contract.
(R)-Diphenyl 1-(4-bromophenyl)-2-nitroethylphosphonate (7i).
Following the general procedure, compound 7i was obtained
after 3 days at -10 ◦C as a white solid in 79% yield. M.p. 134–
137 ◦C. The ee of the product was determined by HPLC using a
Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow rate
1 mL min-1, l = 254 nm): tmajor = 30.6 min; tminor = 21.0 min. HRMS
calcd for C20H17BrNNaO5P 483.9925; found 483.9960 [M+ + Na].
[a]2D2 = -8.7 (c 1.0, CHCl3, 76% ee). The 1H and 13C NMR spectra
are consistent with values previously reported in the literature.8a,b
Notes and references
1 Asymmetric Synthesis: The Essentials, 2nd edition (Ed.: M. Christ-
mann, S. Bra¨se), Wiley-VCH, Weinheim, Germany, 2007.
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(R)-Diphenyl 1-(4-(benzyloxy)phenyl)-2-nitroethylphosphonate
(7j). Following the general procedure, compound 7j was ob-
tained after 3 days at -10 ◦C as a yellow solid in 81% yield. M.p.
122–126 ◦C. The ee of the product was determined by HPLC using
a Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow
rate 1 mL min-1, l = 254 nm): tmajor = 40.2 min; tminor = 28.1 min.
HRMS calcd for C27H24NNaO6P 512.1239; found 512.1242 [M+ +
1
Na]. [a]2D2 = -1.0 (c 1.0, CHCl3, 78% ee). H NMR (400 MHz,
CDCl3) d 4.37 (ddd, 2JH–P = 24.5, 3JH–H = 11.1, 3JH–H = 4.6 Hz, 1H,
CH), 5.00–5.10 (m, 1H, CH2), 5.04 (s, 2H, OCH2), 5.13–5.19 (m,
1H, CH2), 6.75–6.77 (m, 2H, Ar), 6.95–6.95 (m, 2H, Ar), 7.07–
7.10 (m, 3H, Ar), 7.15–7.20 (m, 3H, Ar), 7.28–7.43 (m, 9H, Ar).
13C NMR (100 MHz, CDCl3) d 42.7 (d, J = 141.9 Hz), 70.1, 75.2
(d, J = 5.9 Hz), 115.6 (d, J = 2.2 Hz), 115.8, 120.2 (d, J = 4.4 Hz),
120.4 (d, J = 4.4 Hz), 122.5 (d, J = 8.1 Hz), 125.5, 125.6 (d, J =
24.2 Hz), 127.5, 128.1, 128.7, 129.7, 130.0, 136.6, 130.5 (d, J = 6.6
Hz), 149.9 (d, J = 10.2 Hz), 150.0 (d, J = 9.5 Hz), 159.2 (d, J = 2.9
Hz).
(R)-Diphenyl 1-cyclohexyl-2-nitroethylphosphonate (7k). Fol-
lowing the general procedure, compound 7k was obtained after
3 days at -10 ◦C as a white solid in 82% yield. M.p. 108–
111 ◦C. The ee of the product was determined by HPLC using a
Daicel Chiralpak IB column (n-hexane/i-PrOH = 90 : 10, flow rate
1 mL min-1, l = 254 nm): tmajor = 7.5 min; tminor = 6.7 min. HRMS
calcd for C20H24NNaO5P 412.1290; found 412.1290 [M+ + Na].
[a]2D2 = -8.27 (c 1.0, CHCl3, 72% ee). The 1H and 13C NMR spectra
are consistent with values previously reported in the literature.8b
(R)-Diphenyl 1-nitro-4-phenylbutan-2-ylphosphonate (7l). Fol-
lowing the general procedure, compound 7l was obtained after
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This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2777–2783 | 2783
©