Catalytic asymmetric hydrophosphinylation of α,β-unsaturated N -acylpyrroles: Application of dialkyl phosphine oxides in enantioselective synthesis of chiral phosphine oxides or phosphines

Article abstract of DOI:10.1021/ol100504h

Dialkyl phosphine oxides were introduced in catalytic asymmetric transformations for the first time. An unprecedented phospha-Michael reaction of dialkyl phosphine oxide with α,β-unsaturated N-acylpyrroles was disclosed. Excellent enantioselectivities (94→99% ee) and chemical yields (up to 99%) were achieved with a broad substrate scope of the N-acylpyrroles. Importantly, pyridine was found to be critical to achieve good results for the present reaction.

Full text of DOI:10.1021/ol100504h

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1880-1882
Catalytic Asymmetric
Hydrophosphinylation of
r,ꢀ-Unsaturated N-Acylpyrroles:
Application of Dialkyl Phosphine Oxides
in Enantioselective Synthesis of Chiral
Phosphine Oxides or Phosphines
Depeng Zhao, Lijuan Mao, Yuan Wang, Dongxu Yang, Quanliang Zhang, and
Rui Wang*
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 March 1, 2010
ABSTRACT
Dialkyl phosphine oxides were introduced in catalytic asymmetric transformations for the first time. An unprecedented phospha-Michael reaction
of dialkyl phosphine oxide with r,ꢀ-unsaturated N-acylpyrroles was disclosed. Excellent enantioselectivities (94f99% ee) and chemical yields
(up to 99%) were achieved with a broad substrate scope of the N-acylpyrroles. Importantly, pyridine was found to be critical to achieve good
results for the present reaction.
Chiral phosphorus-containing compounds have attracted
intense interest in recent years owing to their wide applica-
tions as ligands for metal-catalyzed asymmetric reactions1
and their potential biological activities.2 These compounds
are generally prepared by resolution, employing stoichio-
metric amounts of chiral auxiliaries or enantiopure substrates.
The catalytic asymmetric addition of phosphorus nucleophiles
to electrophiles is one of the most powerful methods to
provide such compounds.3 Indeed, numerous reports have
been focused on the asymmetric additions of dialkyl phos-
phites [(RO)2P(O)H]3a-d in the past decades, and recently
secondary phosphines4 (R2PH) have been applied in synthesis
of chiral phosphines. However, few reports have been
focused on other phosphorus nucleophiles such as secondary
phosphine oxides [R2P(O)H].5 To date, Shibasaki’s hetero-
bimetallic catalyst5a and chiral guanidines5b-d were success-
(3) For reviews, see: (a) Ordo´n˜ez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17–49. (b) Ma, J. A. Chem. Soc. ReV. 2006, 35,
630–636. (c) Merino, P.; Marque´s-Lo´pez, E.; Herrera, R. P. AdV. Synth.
Catal. 2008, 350, 1195–1208. (d) Gro¨ger, H.; Hammer, B. Chem.sEur. J.
2000, 6, 943–948. (e) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen,
A. Eur. J. Org. Chem. 2006, 2, 9–49.
(4) (a) Sadow, A. D.; Haller, I.; Fadini, L.; Togni, A. J. Am. Chem.
Soc. 2004, 126, 14704–14705. (b) Sadow, A. D.; Togni, A. J. Am. Chem.
Soc. 2005, 127, 17012–17024. (c) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar,
P.; Eriksson, L.; Himo, F.; Co´rdova, A. Angew. Chem., Int. Ed. 2007, 46,
4507–4510. (d) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre,
P. Angew. Chem., Int. Ed. 2007, 46, 4504–4506. (e) Bartoli, G.; Bosco,
M.; Carlone, A.; Locatelli, M.; Mazzanti, A.; Sambri, L.; Melchiorre, P.
Chem. Commun. 2007, 722–724.
(1) For reviews, see: (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103,
3029–3069. (b) Hayashi, T. Acc. Chem. Res. 2000, 33, 354–362.
(2) (a) The role of phosphonates in liVing systems; Hildebrand, P. L.,
Ed.; CRC Press: Boca Raton, FL, 1983. (b) Engel, R. Chem. ReV. 1977,
77, 349–367. (d) Romanenko, V. D.; Kukhar, V. P. Chem. ReV. 2006, 106,
3868–3935.
10.1021/ol100504h  2010 American Chemical Society
Published on Web 03/25/2010

fully used to synthesize chiral phosphine oxides employing
diaryl phosphine oxides. However, less reactive dialkyl
phosphine oxides, in comparison with diaryl phosphine
oxides, are still challenging for chemists and no report has
been presented yet. Herein, we report for the first time the
application of dialkyl phosphine oxides in catalytic asym-
metric reactions.
Table 1. Optimization of the Phospha-Michael Reaction
It is commonly accepted that secondary phosphine oxides
undergo phosphine oxide-phosphinous acid (R2POH) tau-
tomerism with the phosphinous acid tautomer as the nucleo-
philic form and the phosphine oxide tautomer as the almost
exclusively favored but non-nucleophilic form under neutral
conditions (eg, R ) Et, eq 1).6 Thus, the activation of
phosphine oxide employing an appropriate base is expected
to be an effective approach to activate the nucleophile since
the equilibrium could shift toward the reactive phosphinous
acid form under such conditions. In connection with our
previous work on zinc catalyzed phospha-Michael reactions
of dialkyl phosphite,7 we chose Et2Zn as a base to investigate
the hydrophosphinylation reaction of dialkyl phosphine
oxides.
entrya
additive (mol %)
none
none
none
none
none
4 Å MS (100 mg)
iPrOH (20)
p-cresol (20)
PhCOOH (20)
ZnCl2 (20)
AlCl3 (20)
Ph3PO (20)
Ph3PS (20)
solvent
yield (%)b
ee (%)c
1
2
3
toluene
THF
ether
95
71
90
90
99
83
84
trace
5
n.r.
n.r.
84
83
83
59
91
85
99
99
95
99
68
60
67
33
94
64
60
n.d.
70
-
4
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5d
6
7
8
9
10
11
12
13
14
15e
16
17
18
19
20
21f
-
68
68
62
64
60
86
93
94
95
97
Et3N (20)
NMI (20)
The preliminary study indicated that diethyl phosphine
oxide underwent deprotonation in the presence of Et2Zn with
liberation of 1 equiv of ethane (eq 1). Intrigued by this
phenomenon, we tried to monitor this process using 31P
NMR. When diethyl phosphine oxide was mixed with Et2Zn
(1 equiv) in toluene, the original signal at 40.3 ppm
underwent a significant downfield shift to 103.1 ppm, which
indicated the formation of the corresponding zincate.8 This
intermediate is highly nucleophilic and it undergoes addition
to R,ꢀ-unsaturated N-acylpyrrolessan equivalence of Wein-
reb amide.9
2,2′-bipyridine (20)
pyridine (20)
pyridine (1 equiv)
pyridine (5 equiv)
pyridine (10 equiv)
pyridine (10 equiv)
a All reactions were carried out with 1a (0.375 mmol, 1.5 equiv), L3/
Et2Zn (20 mol %) and 2a (0.25 mmol) in 2.5 mL solvent at rt for 12 h.
b Yield of isolated product. c The enantiomeric excess was determined by
HPLC analysis. d One equivalent of L3/Et2Zn was employed. e NMI )
N-methyl-imidazol. f Reaction was carried out with L3/Me2Zn and 4.0 mL
toluene at rt for 12 h.
Encouraged by this finding, we envisioned the catalytic
version. The preliminary study indicated (S,S)-ProPhenol
L310 was the best ligand among the ligands investigated
(95%, 68% ee). The following examination of solvents
suggested toluene was the best solvent with respect to
enantioselectivity. In order to test the chiral inducing ability
of the catalyst, 1 equiv L3/Et2Zn was employed. We were
pleased to find the enantioselectivity increased remarkably
to 94% ee (Table 1, entry 5). On the basis of the result, we
speculated that the product formed in the reaction may have
a negative feedback to the catalyst and thereby affected the
enantioselectivity. So an additional reagent might be required
in the reaction to prevent the unfavorable binding of the
product to the catalyst. After careful screening of a series of
additives,11 including molecular sieves, alcohols, carboxylic
(5) (a) Yamakoshi, K.; Harwood, S. J.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 1999, 40, 2565–2568. (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, 7387–7390. (c) Leow, D.; Lin, S.; Chittimalla, S.; Fu, X.; Tan,
C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641–5645. (d) Fu, X.; Jiang, Z.;
Tan, C.-H. Chem. Commun. 2007, 5058–5060.
(6) (a) Chatt, J.; Heaton, B. T. J. Chem. Soc. A 1968, 2745–2757. (b)
Ivanova, N. I.; Gusarova, N. K.; Nikitina, E. A.; Albanov, A. I.;
Sinegovskaya, L. M.; Nikitin, M. V.; Konovalova, N. A.; Trofimov, B. A.
Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 7–18.
(7) (a) Zhao, D.; Yuan, Y.; Chan, A. S. C.; Wang, R. Chem.sEur. J.
2009, 15, 2738–2741. (b) Zhao, D.; Wang, Y.; Mao, L.; Wang, R.
Chem.sEur. J. 2009, 15, 10983–10987.
(10) For recent examples of the bis-ProPhenol in asymmetric catalysis:
(a) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131,
1674–1675. (b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572–
4573. (c) Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem.sEur.
J. 2008, 14, 7648–7657. (d) Trost, B. M.; Muller, C. J. Am. Chem. Soc.
2008, 130, 2438–2439. (e) Trost, B. M.; Shin, S. H.; Sclafani, J. A. J. Am.
Chem. Soc. 2005, 127, 8602–8603. (f) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778–2779. (g) Trost, B. M.;
Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8–9. (h)
Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023–2026. See also ref 7.
(8) For details, see Figure S1 in the Supporting Information.
(9) (a) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2003, 42, 4680–4684. (b) Mita, T.; Sasaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514–515. (c)
Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 13419–13427. (d) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2002, 41, 3188–3191.
Org. Lett., Vol. 12, No. 8, 2010
1881

N-acylpyrroles, regardless of the electronic nature or positions
of the substituents on the phenyl ring, heteroaromatic and
aliphatic N-acylpyrroles were all applicable to the present
catalysis with excellent enantioselectivities (94f99% ee,
entries 1-18). Other phosphine oxides were also examined
under the same conditions.12 We found that dipropyl and
dibutyl phosphine oxides were also excellent substrates for
the reaction (entries 19, 20). Interestingly, diallyl phosphine
oxide also provided the desired adducts in 96% ee (entry
21). The versatility of the allyl group facilitates further
transformations of the phosphorus adducts.
Table 2. Substrate Scope of the Phospha-Michael Reaction
Finally, the synthetic utility of the products can be
demonstrated by the following transformations. Phosphine
oxide 3a can be reduced to phosphine by HSiCl3, and the
phosphine can be transformed in situ to air-stable borane
phosphine 4. Then 4 can be readily converted into the
corresponding methyl ester 5 in the presence of MeONa.
Scheme 1. Transformations of the Products
a Unless otherwise noted, reactions were carried out with 1 (0.375 mmol,
1.5 equiv) and 2 (0.25 mmol) in 4.0 mL toluene at rt for 12 h. b Yield of
isolated product. c Enantiomeric excess was determined by HPLC analysis.
d Absolute configuration of 3h was determined to be S by X-ray analysis.
In conclusion, we report for the first time the application
of dialkyl phosphine oxides in catalytic asymmetric reactions.
An unprecedented phospha-Michael reaction of dialkyl
phosphine oxide with R,ꢀ-unsaturated N-acylpyrroles was
disclosed. Excellent enantioselectivities (94f99% ee) and
chemical yields (up to 99%) were achieved with a broad
substrate scope of the N-acylpyrroles. Importantly, the
products can be readily reduced to chiral phosphines by
HSiCl3. We believe this study will greatly facilitate the
asymmetric synthesis of tertiary phosphine oxide or phos-
phines and arouse a new interest of dialkyl phosphine oxides.
acids, Lewis acids, Ph3PO/S, amines, and pyridines (entries
6-17), we were pleased to find pyridine gave the best result
(86% ee, entry 17). The enantioselectivity increased favorably
with the amount of pyridine increased and the best result
was attained when 10 equivalents of pyridine was employed
(95% ee, entry 20). The enantioselectivity further increased
to 97% ee when the concentration of reaction was changed
from 0.1 to 0.0625 M and Me2Zn instead of Et2Zn was used
to form the zinc catalyst (97% ee, entry 21).
With the optimal conditions established above, we then
examined the scope of the phospha-Michael reaction of 1
and 2. In general, all reactions proceeded smoothly to give
the desired product in high chemical yields and excellent
enantioselectivities. The scope of N-acylpyrroles was tested
using 1a as a nucleophile. As shown in Table 2, aromatic
Acknowledgment. We gratefully acknowledge financial
support from NSFC (20932003 and 90813012) and the
National S&T Major Project of China (2009ZX09503-017).
Supporting Information Available: Experimental details,
characterization data for new compounds, and a CIF. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100504H
(11) For an excellent review on additives and cocatalysts in asymmetric
catalysis, see: Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int.
Ed. 1999, 38, 1570–1577.
(12) Diaryl phosphine oxides are not applicable to the present catalysis,
only racemic products were obtained.
1882
Org. Lett., Vol. 12, No. 8, 2010