Zinc-mediated asymmetric additions of dialkylphosphine oxides to α,β-unsaturated ketones and N -sulfinylimines

Article abstract of DOI:10.1021/jo1014917

A catalyst was synthesized on the basis of Trosts dinuclear catalyst characterized by working well without pyridine in the present phospha-Michael reaction. Nevertheless, the presence of pyridine is still advantageous in the present system. The substrate scope was successfully extended to enones employing diallyl phosphine oxide as a nucleophile. Excellent yields and enantioselectivities (up to >99% ee) were achieved for a wide scope of enones employing the catalyst under mild conditions. The detailed reaction mechanism is also discussed herein. Finally, the unprecedented asymmetric additions of dialkylphosphine oxides to N-sulfinylimines were achieved by using Et ₂Zn as a base.

Full text of DOI:10.1021/jo1014917

pubs.acs.org/joc
Zinc-Mediated Asymmetric Additions of Dialkylphosphine Oxides to
r,β-Unsaturated Ketones and N-Sulfinylimines‡
Depeng Zhao, Lijuan Mao, Dongxu Yang, and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Medicine,
State Key Laboratory of Applied Organic Chemistry, and Institute of Biochemistry and Molecular Biology,
Lanzhou University, Lanzhou 730000, P. R. China
wangrui@lzu.edu.cn
Received July 29, 2010
A catalyst was synthesized on the basis of Trost’s dinuclear catalyst characterized by working well
without pyridine in the present phospha-Michael reaction. Nevertheless, the presence of pyridine is
still advantageous in the present system. The substrate scope was successfully extended to enones
employing diallyl phosphine oxide as a nucleophile. Excellent yields and enantioselectivities (up to
>99% ee) were achieved for a wide scope of enones employing the catalyst under mild conditions.
The detailed reaction mechanism is also discussed herein. Finally, the unprecedented asymmetric
additions of dialkylphosphine oxides to N-sulfinylimines were achieved by using Et2Zn as a base.
Introduction
to electrophiles is a convenient method to construct P-C
bonds. However, previous studies only focus on nucleophiles
such as dialkyl phosphites4 [(RO)2P(O)H], secondary phos-
phines5 (R2PH), and diarylphosphine oxides6 [Ar2P(O)H].
In addition, dialkylphosphine oxides [R2P(O)H] have
been much neglected even though the adducts possess syn-
thetic potential and may be used as useful analogues of
phosphonates.
The catalytic asymmetric synthesis of chiral organophos-
phorus compounds has attracted considerable attention in
the past decades, for these compounds can serve as precur-
sors of many biologically active molecules1 and play an
important role in metal-catalyzed2 and organocatalytic
reactions.3 The direct addition of phosphorus nucleophiles
‡ Dedicated to Professor Albert S. C. Chan on the occasion of his 60th
birthday.
(5) (a) Sadow, A. D.; Haller, I.; Fadini, L.; Togni, A. J. Am. Chem. Soc.
2004, 126, 14704. (b) Sadow, A. D.; Togni, A. J. Am. Chem. Soc. 2005, 127,
17012. (c) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo,
(1) (a) The role of phosphonates in living systems; Hildebrand, P. L., Ed.;
CRC Press: Boca Raton, 1983. (b) Engel, R. Chem. Rev. 1977, 77, 349.
(c) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868.
(2) For reviews on chiral phosphine ligands, see: (a) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029. (b) Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
(3) For reviews about phosphine-catalyzed reactions, see: (a) Lu, X.;
Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush,
W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Wei, Y.; Shi, M. Acc. Chem. Res.
2010, 43, 1005. For a review about phosphine oxide catalyzed reactions, see:
(d) Benaglia, M.; Rossi, S. Org. Biomol. Chem. 2010, 3824.
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2007, 46, 4504. (e) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
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hedron Lett. 1999, 40, 2565. (b) Fu, X.; Loh, W.-T.; Zhang, Y.; Chen, T.; Ma,
T.; Liu, H.; Wang, J.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 7387.
(c) Leow, D.; Lin, S.; Chittimalla, S.; Fu, X.; Tan, C.-H. Angew. Chem., Int.
Ed. 2008, 47, 5641. (d) Fu, X.; Jiang, Z.; Tan, C.-H. Chem. Commun. 2007,
5058. (e) Wen, S.; Li, P.; Wu, H.; Yu, F.; Liang, X.; Ye, J. Chem. Commun.
2010, 46, 4806. (f ) Hong, L.; Sun, W.; Liu, C.; Zhao, D.; Wang, R. Chem.
Commun. 2010, 2856.
ꢀ~
(4) For reviews, see: (a) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17. (b) Ma, J. A. Chem. Soc. Rev. 2006, 35, 630.
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(c) Merino, P.; Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal. 2008, 350,
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6756 J. Org. Chem. 2010, 75, 6756–6763
Published on Web 09/16/2010
DOI: 10.1021/jo1014917
r
2010 American Chemical Society

Zhao et al.
JOCFeatured Article
TABLE 1. Optimization of the Phospha-Michael Reaction
entrya
L
additive
C (M)
yield (%)
eeb (%)
1
2
3
4
5
6
L1
L2
L1
L2
L2
L2
pyridine
pyridine
0.0625
0.0625
0.1
0.1
0.05
0.03
97
98
91
89
80
77
93
99
53
82
93
93
aAll reactions were carried out with 1a (0.375 mmol, 1.5 equiv), L/Et2Zn (20 mol %), and 2a (0.25 mmol) at rt for 12 h. bThe enantiomeric excess was
determined by HPLC analysis.
Preliminary studies indicate that the nucleophilic reac-
tivity order toward electrophiles is Ar2P(O)H > (RO)2P(O)H >
R2P(O)H. Thus, in comparison with other commonly used
nucleophiles, dialkylphosphine oxides show the lowest re-
activity and are hard to activate. This might be a critical
reason for the lack of reports in this area.
Our group recently communicated for the first time the
application of dialkylphosphine oxides in catalytic asym-
metric reactions.7 We found that Et2Zn was able to activate
diethylphosphine oxide by deprotonation and formation of a
zincate intermediate (eq 1). With the aid of a bifunctional
catalyst, dialkylphosphine oxides were successfully added to
R,β-unsaturated N-acylpyrroles with high level of yields and
enantioselectivities. Importantly, we found pyridine was a
critical additive for the present reaction.
Finally, we achieved the asymmetric addition of dialkylphos-
phine oxides to N-sulfinylimines promoted by Et2Zn.
Results and Discussion
To further broaden the substrate scope of the phospha-
Michael reaction of dialkylphosphine oxides to enones, we
tried the reaction of diallyl phosphine oxide and enone 2a
under the optimal conditions established for R,β-unsatu-
rated N-acylpyrroles. The result indicated the enantioselec-
tivity was not as satisfactory as that in R,β-unsaturated
N-acylpyrroles, although excellent yield was achieved
(97%, 93% ee, Table 1, entry 1). By comparison of the
structure of R,β-unsaturated N-acylpyrroles and chalcones,
we speculated that a ligand incorporating less hindered aryl
groups instead of phenyl rings for L1 might be effective for
the present reaction. Consequently, we synthesized L2 bear-
ing four 2-thienyl groups. To our delight, the enantioselec-
tivity increased to 99% ee when L2 was used in the reaction
and similar yield was observed (Table 1, entry 2). Surpris-
ingly, when the reaction was conducted without pyridine, L2
gave a significantly higher enantioselectivity than L1 (82%
ee vs 53% ee, Table 1, entries 3 and 4). The enantioselectivity
further increased to 93% with good yield when the reaction
concentration was diluted to 0.05 M (Table 1, entry 5). This
interesting phenomenon will be discussed in the mechanism
consideration section.
With the new catalyst in hand, the reactions of various
enones with diallylphosphine oxide 1a were carried out
under the optimized reaction conditions (Table 1, entry 2),
affording the corresponding products 3a-u in 70%-98%
yields with enantiomeric excesses up to >99% ee (Table 2,
entries 1-21). The catalyst is especially effective for diaryl
enones irrespective of the electronic nature or positions of the
substituent on the phenyl ring. R-Heteroaromatic, β-hetero-
aromatic, and β-aliphatic enones were also applicable to the
present system (Table 2, entries 11, 17-19). To our great
delight, the addition of dialkylphosphine oxide to R-aliphatic
enones gave exclusive Michael adducts in moderate yields
with >99% ee (entries 20-22). This is completely different
from the addition of dialkyl phosphites, which always
The purpose of the present research is to further expand
our preliminary study in the following aspects. A catalyst
was synthesized based on Trost’s dinuclear catalyst.8 The
catalyst’s unique feature is that it works well without pyri-
dine in the present phospha-Michael reaction. In view of the
synthetic utilities of the allyl group, we then extended the
substrate scope to enones employing diallylphosphine oxide.
The detailed reaction mechanism is also discussed here.
(7) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.; Wang, R. Org.
Lett. 2010, 12, 1880.
(8) For recent examples of the dinuclear catalyst in asymmetric catalysis,
see: (a) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131,
1674. (b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572. (c) Trost,
B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem.;Eur. J. 2008, 14,
7648. (d) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438.
(e) Trost, B. M.; Shin, S. H.; Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602.
(f ) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc.
2006, 128, 2778. (g) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am.
Chem. Soc. 2006, 128, 8. (h) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9,
2023. (i) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010,
132, 5186.
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TABLE 2. Substrate Scope of the Phospha-Michael Reaction
aUnless otherwise noted, reactions were carried out with 1 (0.375 mmol, 1.5 equiv) and 2 (0.25 mmol) in 4.0 mL of toluene at rt for 12 h.
c
bThe enantiomeric excess was determined by HPLC analysis. Absolute configuration was not determined. It is assigned by analogy according to a
previous report.7 dThe reaction was performed at 50 °C in 2.5 mL of toluene.
facilitated 1,2-addition in the presence of Et2Zn for
R-aliphatic enones.9
Dialkylphosphine oxides 1b-d can be used in the catalysis
as well, but reactions proved to be somewhat less reactive
than the above-mentioned allyl counterpart. However, this
problem can be solved by raising the temperature to 50 °C
and changing the reaction concentration from 0.0625 to
0.1 M without any loss of ee (Table 2, entries 23-25).
Preliminary experiments indicate that the deprotonation
of the dialkylphosphine oxides is crucial for the addition to
enones. Thus, we suppose the mechanism of the present
(9) Zhao, D.; Yuan, Y.; Chan, A. S. C.; Wang, R. Chem.;Eur. J. 2009,
15, 2738.
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SCHEME 1. Proposed Mechanism of the Phospha-Michael Reaction
reaction is that one zinc of the catalyst functions as a base to
activate the dialkylphosphine oxides and the other one might
coordinate to enone 2, thus closing the distance between the
two substrates. Next, we tried to gain insight to the origin of
the beneficial effect of pyridine. It is well-known that tertiary
phosphine oxides may function as Lewis base3d,10,11 and
coordinate to Lewis acid such as zinc. Therefore, we believe
the products formed in the present reaction;chiral tertiary
phosphine oxides;might in turn bind to the catalyst, thereby
poisoning the catalyst. This can also be ascertained by the
fact that the using of stoichiometric amount of
L1/Et2Zn leads to excellent ee without additive in the pre-
vious report.7 Thus, the introduction of an additional Lewis
base to the system to prevent the binding of the product to
the catalyst is necessary. As shown in Scheme 1, for L1 in the
absence of pyridine, the product can be only afforded in 53%
ee in contrast to 93% ee for the presence of pyridine. This
phenomenon suggests that pyridine is a stronger Lewis base
and preferred to bind to the catalyst, thus preventing the
binding of the products.11
In the case of L2, the sulfur atom on the thienyl group may
serve as an intramolecular Lewis base and occupy the vacant
binding sites of the catalyst, thus facilitating the formation of
a stable structure. The unfavorable binding of the product to
the catalyst may also be avoided in this case, for no coordi-
nation sites are available. In contrast to L1, the product can
be obtained in 93% ee without the participation of pyridine.
Nevertheless, with regard to L2, the presence of pyridine is
still advantageous for its beneficial effect on improvement of
both yield and ee. These results indicate the significant
superiority of L2 in the present phospha-Michael reaction.
Although the attempt to apply the current catalysis to
imines failed,12 we tried the reaction of dialkylphosphine
oxides with chiral imines. On the basis of the high reactivity
of the zincate intermediate formed from Et2Zn and dialkyl-
phosphine oxide, we speculate it is reactive enough to add to
chiral imines such as N-tert-butanesulfinyl imines.13,14 Thus,
we investigated the reaction of diethylphosphine oxide and
Ellman’s N-tert-butanesulfinyl ketimine 4a in toluene at
0 °C. Fortunately, the reaction proceeded smoothly to afford
the corresponding phosphorus adduct in 97% de (Table 3,
entry 1).15 Although Et2Zn was previously found to be able
to reduce imines,16 we did not find any reduction product of
ketimine 4a in this reaction. The diastereoselectivity further
increased to >99% de when the reaction was performed at
-15 °C without substantial impact on yield (Table 3, entry 2).
(12) We failed to apply the current catalysis to imines for only racemic
product was afforded.
(13) For recent reviews related to the Ellman N-(tert-butanesulfinyl)-
imines, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (b) Senanayake, C. H.; Han, Z.; Krishnamurthy, D. In
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.;
Wiley-VCH: New York, 2008. (c) Morton, D.; Stockman, R. A. Tetrahedron
2006, 62, 8869. (d) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han,
Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93. (e) Ellman, J. A. Pure Appl. Chem.
2003, 75, 39. (f ) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem.
Soc. Rev. 2009, 38, 1162. (g) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron
2004, 60, 8003. (h) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600.
(14) For reactions of other phosphorus nucleophiles with N-tert-butane-
sulfinylimines, see: (a) Chen, Q. Y.; Yuan, C. Y. Synthesis 2007, 24, 3779.
(b) Zhang, D. H.; Yuan, C. Y. Chem.;Eur. J. 2008, 14, 6049.
(15) Other bases were also tested. Weak bases such as Na2CO3 and
K2CO3 cannot promote the reaction, whereas hash conditions (-78 °C)
are required for strong bases such as LDA and LiHMDS despite similar
results that were observed with Et2Zn.
(10) Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511.
(11) For an excellent review on additives and cocatalysts in asymmetric
€
catalysis, see: Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570.
(16) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006, 71,
1558.
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TABLE 3. Substrate Scope of the Phospha-Mannich Reaction
aUnless otherwise noted, reactions were carried out with 1 (0.75 mmol, 3.0 equiv) and 2 (0.25 mmol) in 2.5 mL of toluene at -15 °C for 3 h. bYield of
isolated product. cThe de was determined by 1H and 31P NMR analysis of the crude product. dThe reaction was performed at 0 °C. eThe excess phosphine
oxide cannot be separated completely by silica gel column chromatography. fThe absolute configuration of 3h was determined to be (R,SS).
SCHEME 2. Determination of Optical Purity of the Products
84% de for i-Bu (Table 3, entries 9 and 10). This is probably
because i-Bu is very similar in steric bulk with Me and the
corresponding imine is a rapidly equilibrating mixture of E/Z
isomers.17 The ketimine 4j bearing an ethyl group instead of a
methyl group can also be used in the present reaction with 99%
de. Good results were also observed for phosphine oxides 1c
and 1d. Unfortunately, aldimines did not give results as good as
those of ketimines, and only moderate to good diastereoselec-
tivities were achieved (Table 3, entries 14-16).
In order to verify the optical purity of the products, we
tried to oxidize the products and determine the enantioselec-
tivities. As shown in Scheme 2, 5a can be readily converted
into its corresponding sulfonylamide derivative 6 with
NaIO4/RuCl3. The HPLC analysis indicated the enantiomeric
With the optimized reaction conditions established, the
scope and limitations of the phospha-Mannich reaction were
then tested. As summarized in Table 3, perfect diastereo-
selectivities (>99% de) were observed for a series of aromatic
and heteroaromatic methyl ketimines with 77-92% yields
(Table 3, entries 2-8). For the two aliphatic ketimines inves-
tigated, imine bearing an i-Pr gave 97% de, whereas it is only
(17) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278.
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FIGURE 1. Determination of absolute configuration of 5n.
excess of 6 was >99% ee, and it was in agreement with
diastereomeric excess of 5a.
1.0 M in toluene, 0.1 mmol) under an argon atmosphere. The
mixture was stirred at room temperature for 0.5 h to generate the
zinc catalyst, and the resulting solution of catalyst was added
to a stirred mixture of pyridine (0.2 mL, 10 equiv), 2a (52.0 mg,
0.25 mmol), and diallyl phosphine oxide 1a (48.8 mg, 0.375
mmol) in toluene (3.5 mL) at 0 °C under an argon atmosphere.
After the addition, the mixture was stirred at room temperature
for 12 h. The reaction was quenched with aqueous HCl (1 M)
and extracted with CH2Cl2. The combined organic layer was
dried over Na2SO4 and concentrated under vacuum. The crude
product was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 4:1-ethyl acetate/methanol 40:1).
(S )-3-(Diallylphosphoryl)-1,3-diphenylpropan-1-one (3a): color-
less oil; 98% yield; 99% ee determined by HPLC on a Chiralpak
OD-H column (hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min, tminor = 14.4 min, tmajor =9.4min);[R]rtD =-45.1 (c= 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ = 7.94 (d, J = 7.2 Hz,
2H), 7.55 (t, J = 7.4 Hz, 1H), 7.49-7.38 (m, 4H), 7.32 (t, J =
7.4 Hz, 2H), 7.28-7.16 (m, 1H), 6.04-5.79 (m, 1H), 5.78-5.54 (m,
1H), 5.39-5.16 (m, 3H), 5.09 (ddd, J = 17.0, 4.2, 1.3 Hz, 1H),
3.97-3.73 (m, 3H), 2.86-2.61 (m, 2H), 2.50-2.21 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ = 196.5 (d, J = 10.6 Hz), 136.9 (d, J =
5.2 Hz), 136.3, 133.4, 129.2 (d, J = 5.7 Hz), 128.9 (d, J = 1.8 Hz),
128.6, 128.1, 127.7 (d, J = 8.0 Hz), 127.4 (d, J = 2.3 Hz), 127.3
(d, J = 8.2 Hz), 120.9 (d, J = 11.2 Hz), 120.7 (d, J= 11.5 Hz), 39.3
(d, J = 62.1 Hz), 38.7, 32.7 (d, J = 60.8 Hz), 32.4 (d, J = 63.8 Hz);
31P NMR (121 MHz, CDCl3) δ = þ46.7; IR (neat) 3417, 3063,
1686, 1231, 1159, 983, 921, 697, 615 cm-1; HRMS (ESI) C21H23-
O2P [M þ H]þ calcd 339.1508, found 339.1511.
The absolute configuration of 5n was determined by
1H NMR spectra.18 The tert-butylsulfinyl group of 5n can be
removed by HCl/dioxane, affording the amino phosphine
oxide 7. The absolute configuration of primary amine 7 was
then determined by using Boc-phenylglycine (BPG) for its
advantages of producing greater values and being inexpen-
sive.19 The primary amine 7 was then converted to (R)-BPG
amide 8 and (S)-BPG amide 9, respectively, and the 1H NMR
spectra of these two compounds were recorded. As shown in
Figure 1, the ΔδR,S value for the phosphine oxide group
is positive and it is negative for p-methoxyphenyl group.
By comparing these results with the model represented in
Figure 1, the stereochemistry of 7 is determined to be R.
Thus, the absolute configuration of 5n is (R,SS) and the rest
of the products are assigned by analogy.
Conclusion
In conclusion, we have synthesized a catalyst based on
Trost’s dinuclear catalyst. The catalyst works well with-
out pyridine in the present phospha-Michael reaction.
Nevertheless, pyridine is still a beneficial additive for the pres-
ent system. Furthermore, we have successfully extended the
substrate scope to enones employing diallyl phosphine oxide
as a nucleophile in view of the synthetic utilities of the allyl
group. Excellent yields and enantioselectivities (up to >99%
ee) were achieved for a wide scope of enones employing the
catalyst under mild conditions. The detailed reaction mech-
anism and the origin of the beneficial effects of pyridine and
L2 are also discussed here. Finally, we achieved the un-
precedented asymmetric addition of dialkylphosphine ox-
ides to N-sulfinyl imines using Et2Zn as a base, and good to
excellent diastereoselectivities were observed for a series of
N-tert-butanesulfinylimines. Further studies on synthetic
applications of the chiral phosphine oxides20 and lowering
the catalyst loading are ongoing.
(S )-3-(Diallylphosphoryl)-1-phenyl-3-p-tolylpropan-1-one (3b):
colorless oil; 96% yield; >99% ee determined by HPLC on a
Chiracel OD-H column (hexane/2-propanol =90/10, flow rate =
1.0 mL/min, tminor = 21.9 min, tmajor = 8.4 min); [R]rtD = -59.1
(c = 1.27, CHCl3); 1H NMR (300 MHz, CDCl3) δ = 7.94(d, J =
7.2 Hz, 2H), 7.55 (t, J =7.4 Hz, 1H), 7.43 (t, J =7.5 Hz, 2H), 7.32
(dd, J = 8.0, 1.6 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.03-5.80 (m,
1H), 5.80-5.55 (m, 1H), 5.38-5.16 (m, 3H), 5.11 (ddd, J = 17.0,
4.2, 1.3 Hz, 1H), 3.96-3.73 (m, 3H), 2.88-2.58 (m, 2H),
2.48-2.18 (m, 2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ = 196.7 (d, J = 10.8 Hz), 137.1 (d, J = 2.6 Hz), 136.4, 133.7 (d,
J = 5.4 Hz), 133.4, 129.6 (d, J = 1.9 Hz), 129.1 (d, J = 5.7 Hz),
128.6, 128.1, 127.7 (d, J = 8.0 Hz), 127.5(d, J = 8.1Hz), 120.9 (d,
J = 11.3 Hz), 120.7 (d, J = 11.4 Hz), 39.0 (d, J = 62.3 Hz), 38.7,
32.7 (d, J = 60.8 Hz), 32.3 (d, J = 64.5 Hz), 21.0; 31P NMR (121
MHz, CDCl3) δ = þ46.8; IR (neat) 3418, 2922, 1686, 1231, 1159,
920, 731 607 cm-1; HRMS (ESI) C22H25O2P [M þ H]þ calcd
353.1665, found 353.1657.
Experimental Section
General Procedure for Asymmetric Hydrophosphinylation of
r,β-Unsaturated Enones. To a stirred solution of L2 (33.1 mg,
0.05 mmol) in toluene (0.5 mL) was added diethylzinc (100 μL,
~ ꢀ
(18) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915.
(19) Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1999, 64, 4669.
(20) Currently, we have not successfully reduced the product 3 and 5 to
their corresponding phosphines. Inseparable mixtures were obtained for
both 3 and 5 using the method mentioned in ref 7.
(S )-3-(Diallylphosphoryl)-3-(4-methoxyphenyl)-1-phenylpropan-
1-one (3c): colorless oil; 97% yield; >99% ee determined by
HPLC on a Chiracel OD-H column (hexane/2-propanol =90/10,
flow rate = 1.0 mL/min, tminor = 22.8 min, tmajor = 11.5 min);
[R]rtD = -64.3 (c = 1.12, CHCl3); 1H NMR (300 MHz, CDCl3)
J. Org. Chem. Vol. 75, No. 20, 2010 6761

Zhao et al.
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δ = 7.94 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J =
7.5 Hz, 2H), 7.36 (dd, J = 8.6, 1.7 Hz, 2H), 6.85 (d, J = 8.6 Hz,
2H), 6.05-5.80 (m, 1H), 5.79-5.58 (m, 1H), 5.36-5.16 (m, 3H),
5.10 (ddd, J = 17.1, 4.2, 1.2 Hz, 1H), 3.90-3.68 (m, 3H), 3.77 (s,
3H), 2.82-2.61 (m, 2H), 2.48-2.21 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ = 196.7 (d, J = 11.0 Hz), 158.8 (d, J = 2.3 Hz), 136.4,
133.4, 130.3 (d, J = 5.7 Hz), 128.7 (d, J = 6.0 Hz), 128.6, 128.1,
127.7 (d, J = 8.0 Hz), 127.4 (d, J = 8.0 Hz), 120.8 (d, J = 11.2
Hz), 120.6 (d, J = 11.5 Hz), 114.3 (d, J = 1.7 Hz), 55.2, 38.8, 38.5
HRMS (ESI) C23H27O2P [M þ H]þ calcd 367.1821, found
367.1818.
(S )-4-(Diallylphosphoryl)-4-phenylbutan-2-one (3t): colorless
oil; 70% yield; >99% ee determined by HPLC on a Chiralpak
OJ-H column (hexane/2-propanol = 95/5, flow rate = 1.0 mL/
min, tminor = 11.7 min, tmajor = 12.4 min); [R]rtD = -21.7 (c =
1.15, CHCl3); 1H NMR (300 MHz, CDCl3) δ = 7.46-7.16 (m,
5H), 5.97-5.76 (m, 1H), 5.73-5.51 (m, 1H), 5.37-5.21 (m, 2H),
5.18 (dd, J = 10.1, 1.5 Hz, 1H), 5.06 (ddd, J = 17.0, 4.2, 1.2 Hz,
1H), 3.66 (td, J = 8.6, 4.4 Hz, 1H), 3.40-3.07 (m, 2H),
2.78-2.54 (m, 2H), 2.40-2.17 (m, 2H), 2.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ = 205.2 (d, J = 10.3 Hz), 136.6 (d,
J = 5.1 Hz), 129.0 (d, J = 5.6 Hz), 128.9 (d, J = 1.8 Hz), 127.6
(d, J = 8.1 Hz), 127.4 (d, J = 2.4 Hz), 127.2 (d, J = 8.2 Hz),
120.8 (d, J = 11.3 Hz), 120.6 (d, J = 11.5 Hz), 43.2, 39.3 (d, J =
61.7 Hz), 32.6 (d, J = 60.8 Hz), 32.2 (d, J = 64.5 Hz), 30.3;
31P NMR (121 MHz, CDCl3) δ = þ46.3; HRMS (ESI) C16H21-
O2P [M þ H]þ calcd 277.1352, found 277.1356.
(d, J = 63.0 Hz), 32.7 (d, J = 60.0 Hz), 32.3 (d, J = 64.5 Hz); 31
NMR (121 MHz, CDCl3) δ = þ47.1; IR (neat) 3417, 2905, 1686,
1512, 1251, 1180, 1156, 922 cm-1; HRMS (ESI) C22H25O3P [M þ
H]þ calcd 369.1614, found 369.1612.
P
(S )-3-(Diallylphosphoryl)-3-(4-fluorophenyl)-1-phenylpropan-
1-one (3d): white solid; mp 104-106 °C; 91% yield; 98% ee
determined by HPLC on a Chiralpak OD-H column (hexane/
2-propanol = 90/10, flow rate = 1.0 mL/min, tminor = 11.7 min,
t
major = 9.3 min); [R]rtD = -40.0 (c = 1.13, CHCl3); 1H NMR
General Procedure for Asymmetric Hydrophosphinylation of
N-tert-Butylsulfinylimines. To a stirred solution of 1b (80 μL,
0.75 mmol) in toluene (0.5 mL) was added diethylzinc (0.75 mL,
1.0 M in toluene, 0.75 mmol) at 0 °C under an argon atmo-
sphere. The mixture was stirred at room temperature for 1 h, and
then 4 (0.25 mmol) in toluene (1.25 mL) was added to the stirred
mixture at -15 °C under an argon atmosphere. After the
addition, the mixture was stirred at the same temperature for
3 h, and then the reaction was quenched with saturated NH4Cl
aqueous and extracted with ether. The combined organic layer
was dried over Na2SO4 and concentrated under vacuum. The
crude product was purified by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate 4:1 to ethyl acetate/
methanol 1:1).
(300 MHz, CDCl3) δ = 7.94 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.4 Hz,
1H), 7.44 (t, J = 7.3 Hz, 4H), 7.01 (t, J = 8.6 Hz, 2H), 6.00-5.79
(m, 1H), 5.78-5.56 (m, 1H), 5.38-5.16 (m, 3H), 5.09 (ddd, J =
17.0, 4.3, 1.3 Hz, 1H), 3.93-3.65 (m, 3H), 2.89-2.62 (m, 2H),
2.51-2.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 196.4
(d, J = 10.9 Hz), 162.1 (dd, J = 245.3, 3.0 Hz), 136.2, 133.6, 132.6
(dd, J = 5.3, 3.8 Hz), 130.9 (dd, J = 8.0, 5.8 Hz), 128.7, 128.1,
127.5 (d, J= 8.0 Hz), 127.1 (d, J = 8.0 Hz), 121.1 (d, J= 11.5 Hz),
120.9 (d, J = 12.0 Hz), 115.8 (dd, J = 21.0, 1.5 Hz), 38.9, 38.5
(d, J = 63.4 Hz), 32.6 (d, J = 60.0 Hz), 32.4 (d, J = 64.5 Hz);
31P NMR (121 MHz, CDCl3) δ = þ46.8; IR (neat) 3419, 2921,
1686, 1509, 1229, 1159, 922, 746 cm-1; HRMS (ESI) C21H22-
FO2P [M þ H]þ calcd 357.1414, found 357.1420.
(S )-3-(Diallylphosphoryl)-1-(furan-2-yl)-3-phenylpropan-1-one
(3k): colorless oil; 91% yield; 96% ee determined by HPLC on a
Chiralpak OD-H column (hexane/2-propanol =90/10, flow rate =
1.0 mL/min, tminor = 21.3 min, tmajor = 15.7 min); [R]rtD = -72.0
(c = 1.00, CHCl3); 1H NMR(300 MHz, CDCl3) δ = 7.56 (d, J =
1.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H),
7.27-7.20 (m, 1H), 7.18 (d, J = 3.2 Hz, 1H), 6.50 (dd, J = 3.6,
1.7 Hz, 1H), 6.03-5.78 (m, 1H), 5.76-5.51 (m, 1H), 5.37-5.23
(m, 2H), 5.19 (dd, J = 10.2, 1.7 Hz, 1H), 5.08 (ddd, J = 17.0, 4.3,
1.4 Hz, 1H), 3.92-3.77 (m, 1H), 3.76-3.50 (m, 2H), 2.86-2.54
(m, 2H), 2.45-2.21 (m, 2H); 13C NMR (75 MHz, CDCl3) δ =
185.6 (d, J = 11.3 Hz), 152.1, 146.7, 136.4 (d, J = 5.2 Hz), 129.2
(d, J = 5.7 Hz), 128.8 (d, J = 1.8 Hz), 127.52 (d, J = 11.3 Hz),
127.5, 127.2 (d, J = 8.1 Hz), 121.0 (d, J = 11.3 Hz), 120.7 (d, J =
11.6 Hz), 117.8, 112.3, 39.1 (d, J = 62.0 Hz), 38.3, 32.6 (d, J =
60.0Hz), 32.3 (d, J = 63.8Hz);31P NMR (121 MHz, CDCl3) δ =
(S )-N-((R)-1-(Diethylphosphoryl)-1-phenylethyl)-2-methyl-
propane-2-sulfinamide (5a): white solid; mp 123-125 °C; 82%
yield; >99% de determined by NMR; [R]rtD = 107.2 (c = 1.11,
CHCl3); 1H NMR (300 MHz, CDCl3) δ = 7.49 (d, J = 7.9 Hz,
2H), 7.38 (t, J = 7.3 Hz, 2H), 7.34-7.28 (m, 1H), 4.68 (d, J = 4.7
Hz, 1H), 2.11 (d, J = 13.3 Hz, 3H), 1.95-1.61 (m, 2H), 1.61-1.42
(m, 2H), 1.30 (s, 9H), 1.08 (dt, J = 15.5, 7.7 Hz, 3H), 1.03 (dt, J =
15.6, 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 138.4 (d,
J = 1.5 Hz), 128.3 (d, J = 2.4 Hz), 127.75 (d, J = 1.5 Hz),
127.73 (d, J = 3.8 Hz), 61.6 (d, J = 65.5 Hz), 56.8, 22.73, 22.66,
16.6 (d, J = 62.8 Hz, overlapped), 6.0 (d, J = 5.1 Hz), 5.9 (d,
J = 5.3 Hz); 31P NMR (121 MHz, CDCl3) δ = þ57.2; IR (neat)
3445, 2978, 1668, 1453, 1382, 1161, 1068, 794, 703 cm-1
;
HRMS (ESI) C16H28NO2PS [M þ Na]þ calcd 352.1471, found
352.1479.
(S )-N-((R)-1-(Diethylphosphoryl)-1-p-tolylethyl)-2-methyl-
propane-2-sulfinamide (5b): colorless oil; 91% yield; >99% de
determined by NMR; [R]rtD = 86.9 (c = 0.99, CHCl3); 1H NMR
(300 MHz, CDCl3) δ = 7.36 (d, J = 6.7 Hz, 2H), 7.18 (d, J =
8.0 Hz, 2H), 4.62 (d, J = 4.3 Hz, 1H), 2.35 (s, 3H), 2.09 (d, J =
13.2 Hz, 3H), 1.94-1.62 (m, 2H), 1.62-1.38 (m, 2H), 1.29 (s, 9H),
þ46.6; IR(neat) 3417, 2922, 1674, 1467, 1160, 918, 703, 611 cm-1
;
HRMS (ESI) C19H21O3P [M þ H]þ calcd 329.1301, found
329.1291.
(R)-3-(Diallylphosphoryl)-1,5-diphenylpentan-1-one (3r): color-
less oil; 92% yield; 90% ee determined by HPLC on a Chiralpak
AD-H column (hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min, tminor = 21.4 min, tmajor = 19.3 min); [R]rtD = -3.7 (c =
1.07 (dt, J = 15.6, 7.7 Hz, 3H), 1.05 (dt, J = 15.6, 7.7 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ = 137.6 (d, J = 3.0 Hz), 135.1, 129.0
(d, J = 2.5 Hz), 127.7 (d, J = 3.9 Hz), 61.5 (d, J = 66.5 Hz), 56.8,
22.7 (overlapped), 20.8, 16.52 (d, J = 61.5 Hz), 16.51 (d, J =
63.8 Hz), 6.0 (d, J = 5.3 Hz), 5.9 (d, J = 5.3 Hz); 31P NMR
(121 MHz, CDCl3) δ = þ57.2; IR (neat) 3441, 2976, 1459, 1161,
1070, 828, 768 cm-1; HRMS (ESI) C17H30NO2PS [M þ Na]þ
calcd 366.1627, found 366.1620.
(S )-N-((R)-1-(Diethylphosphoryl)-1-(4-methoxyphenyl)ethyl)-
2-methylpropane-2-sulfinamide (5c): colorless oil; 77% yield;
>99% de determined by NMR; [R]rtD = 78.3 (c = 1.03, CHCl3);
1H NMR (300 MHz, CDCl3) δ = 7.40 (dd, J = 8.9, 2.0 Hz, 2H),
6.90 (d, J= 8.9 Hz, 2H), 4.60 (d, J= 4.3 Hz, 1H), 3.82 (s, 3H), 2.08
(d, J = 13.2 Hz, 3H), 1.91-1.63 (m, 2H), 1.62-1.42 (m, 2H), 1.29
(s, 9H), 1.07 (dt, J = 15.6, 7.8 Hz, 3H), 1.06 (dt, J = 15.6, 7.8 Hz,
1
1.08, CHCl3); H NMR (300 MHz, CDCl3) δ = 8.01 (d, J =
7.2 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.5Hz, 2H), 7.26
(t, J = 7.2 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 6.9 Hz,
2H), 5.92-5.67 (m, 2H), 5.34-5.07 (m, 4H), 3.63 (ddd, J = 18.8,
15.6, 4.9 Hz, 1H), 3.25 (ddd, J = 18.7, 10.0, 6.2 Hz, 1H),
2.88-2.68 (m, 3H), 2.68-2.48 (m, 4H), 2.15-2.00 (m, 1H),
1.98-1.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ = 197.5 (d,
J = 7.6 Hz), 141.0, 136.3, 133.6, 128.7, 128.5, 128.4, 128.2, 127.63
(d, J = 8.3 Hz), 127.6 (d, J = 8.3 Hz), 126.2, 120.7 (d, J = 11.3
Hz), 120.6 (d, J = 11.3 Hz), 36.7, 33.9 (d, J = 11.2 Hz), 32.7
(d, J = 60.8 Hz), 32.3 (d, J = 61.5 Hz), 30.9 (d, J = 64.5 Hz),
30.8 (d, J = 1.5 Hz); 31P NMR (121 MHz, CDCl3) δ = þ49.0;
IR (neat) 3414, 2930, 1685, 1227, 1154, 920, 752, 698 cm-1
;
6762 J. Org. Chem. Vol. 75, No. 20, 2010

Zhao et al.
JOCFeatured Article
3H); 13C NMR (75 MHz, CDCl3) δ=159.0(d, J= 2.7 Hz), 129.9,
129.0 (d, J = 3.9 Hz), 113.6 (d, J = 2.3 Hz), 61.2 (d, J = 67.6 Hz),
56.7, 55.1, 22.8, 22.7, 16.6 (d, J = 62.3 Hz), 16.5 (d, J = 63.8 Hz),
6.04 (d, J = 5.3 Hz), 5.96 (d, J = 5.4 Hz); 31P NMR (121 MHz,
CDCl3) δ = þ57.3; IR (neat) 3437, 2976, 1609, 1513, 1461, 1255,
1160, 1069, 1030, 841, 771 cm-1; HRMS (ESI) C17H30NO3PS [M
þ H]þ calcd 360.1757, found 360.1752.
(S )-N-((R)-1-(4-Bromophenyl)-1-(diethylphosphoryl)ethyl)-
2-methylpropane-2-sulfinamide (5e): colorless oil; 84% yield;
>99% de determined by NMR; [R]rtD = 90.6 (c = 1.00, CHCl3);
1H NMR (300 MHz, CDCl3) δ = 7.51 (d, J = 8.6 Hz, 2H), 7.37
(dd, J = 8.8, 2.0 Hz, 2H), 4.70 (d, J = 5.1 Hz, 1H), 2.08 (d, J =
13.3 Hz, 3H), 1.96-1.77 (m, 1H), 1.76-1.40 (m, 3H), 1.28 (s, 9H),
1.11 (dt, J = 15.9, 7.8 Hz, 3H), 1.05 (dt, J = 15.6, 7.8 Hz, 3H); 13
C
(S )-N-((R)-1-(4-Chlorophenyl)-1-(diethylphosphoryl)ethyl)-
NMR (75 MHz, CDCl3) δ = 137.9, 131.4 (d, J = 2.4 Hz), 129.4
(d, J = 3.8 Hz), 122.1 (d, J = 3.5 Hz), 61.2 (d, J = 64.8 Hz), 56.8,
22.7, 22.4, 16.6 (d, J = 63.0 Hz, overlapped), 6.0 (d, J = 5.6 Hz),
5.9 (d, J = 5.7 Hz); 31P NMR (121 MHz, CDCl3) δ = þ56.8; IR
(neat) 3442, 2977, 1460, 1398, 1163, 1071, 836, 732 cm-1; HRMS
(ESI) C16H27BrNO2PS [M þ Na]þ calcd 430.0576, found 430.0570.
2-methylpropane-2-sulfinamide (5d): colorless oil; 91% yield; >99%
1
de determined by NMR; [R]rt = 109.7 (c = 1.00, CHCl3); H
D
NMR (300 MHz, CDCl3) δ = 7.44 (dd, J = 8.8, 1.9 Hz, 2H), 7.35
(d, J = 10.2 Hz, 2H), 4.70 (d, J = 5.0 Hz, 1H), 2.08 (d, J = 13.3
Hz, 3H), 1.95-1.76 (m, 1H), 1.73-1.43 (m, 3H), 1.28 (s, 9H), 1.11
(dt, J = 15.9, 7.7 Hz, 3H), 1.04 (dt, J = 15.9, 7.7 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ = 137.3, 133.9 (d, J = 3.3 Hz), 129.1
(d, J = 3.9 Hz), 128.4 (d, J = 2.4 Hz), 61.1 (d, J = 65.0 Hz), 56.8,
22.7, 22.5, 16.66 (d, J= 62.3 Hz), 16.65 (d, J= 63.0 Hz), 6.0 (d, J=
5.7 Hz), 5.9 (d, J = 5.9 Hz); 31P NMR (121 MHz, CDCl3) δ =
Acknowledgment. We gratefully acknowledge financial
support from NSFC (20932003 and 90813012) and the
National S&T Major Project of China (2009ZX09503-017).
þ56.9; IR (neat) 3441, 2977, 1460, 1163, 1070, 840, 764 cm-1
;
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
HRMS (ESI) C16H27ClNO2PS [M þ H]þ calcd 364.1261, found
364.1268.
J. Org. Chem. Vol. 75, No. 20, 2010 6763