Highly efficient synthesis of quaternary α-hydroxy phosphonates via lewis acid-catalyzed hydrophosphonylation of ketones

Article abstract of DOI:10.1002/adsc.200900531

A Lewis acid catalyst has been first applied to the hydrophosphonylation of ketones, giving the corresponding quaternary a-hydroxy phosphonates in high yields (up to 98%). The present method was highly tolerable for functionalized ketones. Moreover, the f

Full text of DOI:10.1002/adsc.200900531

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DOI: 10.1002/adsc.200900531
Highly Efficient Synthesis of Quaternary a-Hydroxy
Phosphonates via Lewis Acid-Catalyzed Hydrophosphonylation
of Ketones
Xin Zhou,a Yanling Liu,a Lu Chang,a Jiannan Zhao,a Deju Shang,a Xiaohua Liu,a
Lili Lin,a and Xiaoming Fenga,b,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
b
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: July 30, 2009; Published online: October 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900531.
Abstract: A Lewis acid catalyst has been first ap-
plied to the hydrophosphonylation of ketones,
giving the corresponding quaternary a-hydroxy
phosphonates in high yields (up to 98%). The pres-
ent method was highly tolerable for functionalized
ketones. Moreover, the first catalytic enantioselec-
tive hydrophosphonylation of an unactivated
ketone was also realized by using a tridentate Schiff
base-titanium complex.
of products were sometimes obtained due to the low
reactivity of ketones, retro-hydrophosphonylation re-
actions [Scheme 1, Eq. (1)],[11] phospha-Brook rear-
rangements [Scheme 1, Eq. (2)][12] and so on [for ex-
ample, Scheme 1, Eq. (3)].[13] Furthermore, the strong
basic catalysts potentially excluded the hydrophos-
phonylation of base-sensitive ketones, even mild
bases such as tertiary amines may also cause side re-
actions.[14] Thus, searching for a catalyst that could
achieve high reactivity and wide applicability, espe-
cially for functionalized ketones, was still challenging
and interesting. Since Lewis acids have long been
proved to be effective for the hydrophosphonylation
of aldehydes, it was surprising that they have never
been applied in the reaction of ketones. It was sur-
mised that a suitable Lewis acid could not only effec-
Keywords: asymmetric synthesis; functionalized ke-
tones; hydrophosphonylation; ketones; titanium
The a-hydroxy phosphonates have exhibited intrigu- tively activate the dialkyl phosphite and ketone but
ing biological activities,[1] and are widely applied in also potentially suppress or avoid the shortcomings of
pharmaceutical chemistry as bio-phosphate mimics,[2] the base-catalyzed reaction. Moreover, the Lewis-acid
antibiotics,[3] anti-virals[4] and anti-tumour agents.[5] catalyzed process could also provide the potential for
Particularly, as analogues of quaternary a-hydroxy an asymmetric version by incorporating a suitable
acids, the quaternary a-hydroxy phosphonates are of chiral ligand. Herein, we describe the first Lewis acid-
considerable value because they may potentially in- catalyzed, highly efficient hydrophosphonylation of
crease the rigidity and resistance to protease enzymes ketones. The present method was suitable for a wide
and enhance bioactivity. As a consequence, the syn- range of substrates, and especially for functionalized
thesis of quaternary a-hydroxy phosphonates has at- ketones. The first catalytic asymmetric hydrophospho-
tracted significant attention.[6] To the best of our nylation of acetophenone is also presented.
knowledge, the hydrophosphonylation of ketones pro-
vides one of the most efficient methods for their prep- acidic Ti
aration.[7] However, due to the low reactivity of ke- drophosphonylation of acetophenone (Table 1,
A preliminary survey revealed that the mildly
AHCTUNGTRENNUNG
tones, an efficient catalyst for such a reaction was entry 1). With 5 mol% TiACTHUNRGTNEUNG(O-i-Pr)4, the corresponding
scarcely developed,[8] which was in sharp contrast to product was obtained with 58% isolated yield for
the hydrophosphonylation of aldehydes.[9] Whereas 12 h. In contrast, other Lewis acids which were effec-
strong bases were hitherto the most general catalysts tive for the hydrophosphonylation of aldehydes or al-
for the synthesis of quaternary a-hydroxy phospho- dimines gave 3a with ꢀ16% yield (Table 1, entries 2–
nates,[10] the yields were not always good and mixtures 8).[15a]
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Scheme 1. Towards related reactions for the hydrophosphonylation of ketones.
Table 1. Catalytic hydrophosphonylation of acetophenone.[a]
Entry
Metal
Ti(O-i-Pr)4
Yield [%]
Entry
Metal
Al(O-i-Pr)3
Yield [%]
1
3
5
7
G
58
16
2
4
6
8
E
6
12
In(OTf)3
Yb(OTf)3
TiCl4
R
Sc(OTf)3
La(OTf)3
Zr(O-i-Pr)4
R
A
10
N
7
N.R[b]
R
N.R[b]
[a]
Reactions were carried out with 1a (0.5 mmol), 2 (100 mL) and Lewis acid (5 mol%) in toluene (1.0 mL) at 238C for 12 h.
No reaction occurred.
[b]
An intensive investigation of the reaction condi- yield was dramatically improved. The hydrophospho-
tions revealed that the concentration of acetophenone nylation of acetophenone was complete within 10 min
played a crucial role on the reactivity (Figure 1).[15b] under neat conditions.[15c] In sharp contrast to such
By increasing the concentration of acetophenone, the solvent-free conditions, when the reaction was per-
Figure 1. The concentration effect in the hydrophosphonylation of acetophenone.[16a]
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Highly Efficient Synthesis of Quaternary a-Hydroxy Phosphonates
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formed at a low concentration of acetophenone (cꢀ of aromatic ketones showed high reactivities (prod-
1.0 mol/L), the quaternary a-hydroxy phosphonate 3a ucts 3a–j). The current system could be further ex-
was only obtained with poor to moderate yield (33– tended to the hydrophosphonylation of condensed
72%) albeit with a prolonged reaction time (12 h).[15d] ring, diaryl, conjugated and heteroaromatic ketones,
The substrate scope of catalytic hydrophosphonyla- giving the corresponding products with up to 95%
tion of ketone was then investigated under solvent- yield (products 3k–o). The aliphatic ketones were also
free conditions, and the corresponding quaternary a- effective substrates for the reaction albeit with re-
hydroxy phosphonates were obtained with high yields duced reactivities owing to their intrinsic lower reac-
(Figure 2).[17] Irrespective of the electronic nature of tivity (products 3p–r). It was most exciting that the
the aryl substituents and their location, the reaction present protocol for the catalytic hydrophosphonyla-
Figure 2. Substrate scope for the catalytic hydrophosphonylation of ketones.[16b,17]
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Scheme 2. Scaled-up version of the hydrophosphonylation of acetophenone.
Scheme 3. Catalytic asymmetric hydrophosphonylation of acetophenone.
tion of ketones was highly tolerable for functional ke- nylation of ketones. Significant progress has been ob-
tones (products 3t–v). In particular, the mild acidity tained with an extremely broad substrate scope,
of Ti
action of ketone 1s, which contained an acid-sensitive phonates with high yields. Particularly, the present
functional goup [CH(OEt)2]. The ethyl acetoacetate method showed a good tolerance of functionalized
ACHTUNGTRENNUNG(O-i-Pr)4 made it an effective catalyst for the re- giving the corresponding quaternary a-hydroxy phos-
AHCTUNGTRENNUNG
derivative 1v, which reacted sluggishly or did not ketones. Moreover, the first catalytic asymmetric hy-
react with dimethyl phosphite under basic conditions drophosphonylation of unactivated ketones has also
owing to the enolization, was also proved to be an ex- been developed by using a tridentate Schiff base-
cellent substrate for the reaction. Moreover, the b-hy- TiACHTNURGTNEUNG(O-i-Pr)4 complex as the catalyst. Further studies
droxy ketone 1w underwent the hydrophosphonyla- on the mechanism of the reaction as well as the asym-
tion smoothly, giving the quaternary 1,3-dihydroxy metric synthesis of quaternary a-hydroxy phospho-
phosphonate 3w with 89% yield. It should be men- nates are in progress.
tioned that the current strategy completely avoided
the retro-aldol reaction which rapidly proceeds under
strong basic conditions.
Experimental Section
To test the synthetic potential of the present ap-
proach, a large-scale synthesis of quaternary a-hy-
droxy phosphonate was performed (Scheme 2). By
treatment of 10 mmol of acetophenone under the op-
timal reaction conditions, the desired product was
produced with 96% yield within 15 min.
Based on the observations above, a preliminary in-
vestigation on the catalytic asymmetric version was
performed (Scheme 3). The tridentate Schiff base 6-
All reactions were carried out under an atmosphere of nitro-
gen in dry glassware with magnetic stirring. Ketone
(0.5 mmol) and dimethyl phosphite (75–200 mL) were added
to a dry flask, then TiACHTNUGTRNEUNG(O-i-Pr)4 was added under a nitrogen
atmosphere. The reaction mixture was stirred at 308C or
608C. When the reaction was completed, the product was di-
rectly purified by column chromatography on silica gel
(ethyl acetate/petroleum ether 1:1-ethyl acetate).
TiACHTUNGTRENNUNG(O-i-Pr)4 complex catalyzed the asymmetric hydro-
phosphonylation of acetophenone smoothly under
neat conditions, giving the corresponding quaternary
a-hydroxy phosphonate in high yield with 55% ee.[15e]
Although the enantioselectivity was moderate, it
should be noted that this is the first example of the
catalytic asymmetric hydrophosphonylation of an un-
activated ketone.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (Nos. 20732003 and 20872096) and the Ministry of
Education (No. 20070610019) for financial support. We also
thank Sichuan University Analytical & Testing Center for
In conclusion, we have demonstrated the first
highly efficient, Lewis acid-catalyzed hydrophospho- NMR analysis.
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Highly Efficient Synthesis of Quaternary a-Hydroxy Phosphonates
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ACHTUNGTRNE(NGNU O-i-Pr)4. d) Such a
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Pr)4 as the catalyst. The yields had no obvious improve-
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e) Using 4-methoxybenzoic acid as the additive, the
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b) See Experimental Section.
[17] a) Half of the products were unknown previously, and
only six products were reported to be prepared via hy-
drophosphonylation of ketones with moderate to good
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