NHC-copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2013.10.158

N-Heterocyclic carbene-copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones was developed for the synthesis of chiral phosphorus derivatives in high yields with moderate enantioselectivity under mild conditions.

Full text of DOI:10.1016/j.tetlet.2013.10.158

Tetrahedron Letters 55 (2014) 595–597
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NHC–copper-catalyzed asymmetric 1,4-addition of diarylphosphines
to a,b-unsaturated ketones
Yun-Rong Chen a, Jian-Jun Feng b, Wei-Liang Duan a,
⇑
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 LingLing Road, Shanghai 200032, China
b School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Heterocyclic carbene–copper-catalyzed asymmetric 1,4-addition of diarylphosphines to
rated ketones was developed for the synthesis of chiral phosphorus derivatives in high yields with mod-
erate enantioselectivity under mild conditions.
a,b-unsatu-
Received 27 August 2013
Revised 1 October 2013
Accepted 14 October 2013
Available online 28 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Addition
Copper
N-Heterocyclic carbene
Chiral phosphine
Enone
Chiral phosphorus compounds are widely useful ligands for
transition-metals in catalysis, and they are also capable of acting
as organocatalysts for asymmetric reactions.1 Therefore, the devel-
opment of new methods for the synthesis of chiral phosphines for
asymmetric catalysis is of great interest. Asymmetric hydropho-
sphination of electron-deficient alkenes with phosphorus nucleo-
philes is a direct pathway for the preparation of optically active
phosphorus compounds.2,3 In the past decade, research on this
reaction with excellent enantioselectivity has been reported.
Typical examples include transition metal-catalyzed addition of
secondary trivalent phosphines or phosphine oxides to electron-
deficient alkenes and organocatalyst-promoted phosphorus
addition reactions.4 Recently, we developed an efficient pincer-Pd
catalyst for asymmetric phosphorus addition reactions to diverse
electron-deficient alkenes.5 At the same time, we are investigating
alternative catalytic systems, with particular attention focused on
the first row transition metals because of their ready availability
and economical advantage compared with precious metals.
for asymmetric 1,4-addition of diarylphosphines to a,b-unsatu-
rated ketones in high yields with moderate enantioselectivity.
Initially, we examined the addition reaction of diphenylphos-
phine with cyclohexen-1-one 1a to test the catalytic activity of var-
ious copper catalysts.7 The use of nitrogen ligands such as (S,S)-Ph-
Box and (S)-i-Pr-Phox in combination with CuCl in the presence of
5 mol % K2CO3 did not result in the desired product (Table 1, en-
tries 1 and 2). The chiral bisphosphines Binap and Segphos only
produced the racemic product in low yields (entries 3 and 4).8
Notably, monitoring the reaction through TLC or NMR analysis re-
vealed that free chiral bisphosphine was generated, which is due to
the replacement of the chiral ligands on the copper atom by
diphenylphosphine or its 1,4-adduct. NHCs are known to be stron-
ger binding ligands to transition metals than phosphorus ligands,9
and this feature of NHC may ensure that its copper complex is the
stable catalyst in the current reaction. Hence, we prepared achiral
copper/NHC catalysts to examine their catalytic activity in the cur-
rent reaction. Screening various copper–NHC complexes indicated
that SIPrCuCl catalyst provided better results than others, affording
the 1,4-adduct in 96% yield in 1 h without the addition of base (en-
try 8).10 By contrast, CuCl without the aid of the ligands is not
effective (entry 10). After extensive examination of several chiral
copper/NHC catalysts, a copper complex of bisoxazoline-based car-
bene (S,S)-4 was found to generate the product with 6% ee (entry
11).11 Increasing the size of the substituted group from isopropyl
to tert-butyl group, catalyst (S,S)-5 was used, and ee of the product
was enhanced to 13% (entry 12). Instead of cyclic enones, linear en-
one such as chalcone 1b was employed, and the 1,4-adduct was
Copper complexes coordinated with chiral ligands have been
widely used catalysts for asymmetric 1,4-addition reactions. The
reported systems always involved carbon-, boron-, and silyl-cen-
tered nucleophiles.6 Phosphorus nucleophiles have not been used
in copper-catalyzed asymmetric addition reactions to date, which
may be due to the strong binding ability of the phosphorus atom
to metal catalysts. Thus, we report the first chiral copper catalysts
⇑
Corresponding author. Tel.: +86 21 54925203; fax: +86 21 64166128.
E-mail address: wlduan@mail.sioc.ac.cn (W.-L. Duan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.158

596
Y.-R. Chen et al. / Tetrahedron Letters 55 (2014) 595–597
Table 1
Copper-catalyzed asymmetric 1,4-addition of diphenylphosphine to enonesa
(1) 5 mol % CuCl, 6 mol % ligand
or 5 mol % copper complex
solvent, temp
O
O
O
PPh2
R2
+
HPPh2
2a
R1
1.2 equiv
R2
(2) aq H2O2
R1
3
1a: 2-cyclohexen-1-one
O
O
O
O
1b: chalcone
N
N
N
N
Cu
Cl
Cu
Cl
(S,S)-4
(S,S)-5
Entry
Enone
Ligand or copper complex
Solvent
Temp (°C)/time (h)
Yieldb/eec (%)
1d
2d
3d
4d
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
(S,S)-Ph-box
(S)-iPr-Phox
(R)-Binap
(R)-Segphos
IMesCuCl
SIMeCuCl
IPrCuCl
SIPrCuCl
SIPrCuCl
CuCl
(S,S)-4
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Acetone
Toluene
DME
THF
Et2O
Dioxane
i-PrOH
THF
rt (36)
rt (17)
rt (48)
rt (48)
rt (1)
rt (1)
rt (1)
rt (1)
rt (2)
rt (10)
rt (36)
rt (20)
rt (3)
0
0
25 (0)
13 (0)
67
68
90
96
96
0
58 (6)
92 (13)
94 (28)
99 (5)
93 (31)
96 (43)
94 (42)
94 (50)
91 (47)
98 (47)
99 (22)
97 (62)
82 (63)
rt (3)
rt (0.5)
rt (0.5)
rt (0.2)
rt (0.2)
rt (0.2)
rt (0.2)
rt (0.2)
À20 (2)
À40 (6)
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
THF
a
b
c
For the reaction of cyclohexen-1-one with diphenylphosphine, the product was isolated as the trivalent phosphine without addition of H2O2.
Isolated yield.
Determined by HPLC with hexane/2-propanol.
5 mol % K2CO3 was used.
d
Table 2
O
O
O
O
Copper-catalyzed asymmetric 1,4-addition of diarylphosphines to enones
HPAr2
-HCl
N
N
N
N
O
(1) 5 mol–% (S,S)-5
O
O
PAr2
R2
Cu
Cl
Cu
P
THF, 20 °C
(2) aq H2O2
+
HPAr2
R1
R2
R1
Ar
Ar
O
PAr2
R2
1.2 equiv
O
O
O
O
O
R1
R1
R2
N
N
N
N
Entry
R1
R2
Ar
Yielda (%)
eeb,c (%)
vs
R2
R2
Cu
Cu
HCl
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
p-BrC6H4
m-BrC6H4
p-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
99
97
97
98
98
97
97
97
96
99
88
93
92
62
63
64
63
66
53
52
51
73
61
58
69
46
P
P
Ar
Ar
O
Ar
O
Ar
R1
R1
favorable
unfavorable
o-BrC6H4
m-BrC6H4
p-BrC6H4
p-O2NC6H4
o-MeOC6H4
p-MeC6H4
p-BrC6H4
Ph
Enantioselectivity-Determining Step
Scheme 1. Proposed catalytic cycle.
After establishing the optimal reaction conditions, we examined
the scope of enones and phosphorus nucleophiles. As shown in Ta-
ble 2, various enones bearing electron-donating or electron-with-
drawing groups were tolerated with high yields and moderate
stereoselection (88–99% yield, 51–73% ee; entries 1–11). For the
nucleophilic components, phosphines bearing methoxy or chloride
both reacted with chalcone smoothly, affording the desired prod-
ucts in excellent yields (92–93% yield, 46–69% ee; entries 12–13).
A plausible catalytic cycle is proposed in Scheme 1. First, the
diarylphosphorus group transfers to the copper atom to afford a
copper diarylphosphido intermediate.12 Then, the diarylphospho-
rus group on the copper atom proceeds on a nucleophilic attack
to the Si face of the enone, followed by protonolysis with HCl in
p-MeOC6H4
p-ClC6H4
Ph
a
b
c
Isolated yields.
Determined by HPLC with hexane/2-propanol.
The absolute configurations of products were determined to be S by comparison
of the specific optical rotation of the adduct (entry 1) with the value reported in the
literature; see Supporting Information for details.
obtained with 28% ee (entry 13). Further screening the reaction
solvents and temperature revealed that THF and À20 °C are the
optimum conditions for this reaction, affording the product in
97% yield with 62% ee (entry 22).

Y.-R. Chen et al. / Tetrahedron Letters 55 (2014) 595–597
597
Int. Ed. 2007, 46, 4507; (c) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Mazzanti, A.; Sambri, L.; Melchiorre, P. Chem. Commun. 2007, 722; (d) Fu, X.;
Jiang, Z.; Tan, C.-H. Chem. Commun. 2007, 5058; (e) Ibrahem, I.; Hammar, P.;
Vesely, J.; Rios, R.; Eriksso, L.; Córdova, A. Adv. Synth. Catal. 2008, 350, 1875; (f)
Zhao, D.; Mao, L.; Yang, D.; Wang, R. J. Org. Chem. 2010, 75, 6756; (g) Wen, S.; Li,
L.; Wu, H.; Yu, F.; Liang, X.; Ye, J. Chem. Commun. 2010, 4806; (h) Huang, Y.;
Pullarkat, S. A.; Li, L.; Leung, P.-H. Chem. Commun. 2010, 6950; (i) Russo, A.;
Lattanzi, A. Eur. J. Org. Chem. 2010, 6736; (j) Luo, X.; Zhou, Z.; Li, X.; Liang, X.; Ye,
J. RSC Adv. 2011, 1, 698; (k) Yang, M.-J.; Liu, Y.-J.; Gong, J.-F.; Song, M.-P.
Organometallics 2011, 30, 3793; (l) Huang, Y.; Chew, R. J.; Li, Y.; Pullarkat, S. A.;
Leung, P.-H. Org. Lett. 2011, 13, 5862; (m) Huang, Y.; Pullarkat, S. A.; Li, Y.;
Leung, P.-H. Inorg. Chem. 2012, 51, 2533; (n) Zhao, D.; Wang, L.; Yang, D.; Zhang,
Y.; Wang, R. Chem. Asian J. 2012, 7, 881; (o) Huang, Y.; Pullarkat, S. A.; Teong, S.;
Chew, R. J.; Li, Y.; Leung, P.-H. Organometallics 2012, 31, 4871; (p) Huang, Y.;
Pullarkat, S. A.; Chew, R. J.; Li, Y.; Leung, P.-H. J. Org. Chem. 2012, 77, 6894; (q)
Hatano, M.; Horibe, T.; Ishihara, K. Angew. Chem., Int. Ed. 2013, 52, 4549.
5. (a) Feng, J.-J.; Chen, X.-F.; Shi, M.; Duan, W.-L. J. Am. Chem. Soc. 2010, 132, 5562;
(b) Du, D.; Duan, W.-L. Chem. Commun. 2011, 11101; (c) Chen, Y.-R.; Duan, W.-
L. Org. Lett. 2011, 13, 5824; (d) Feng, J.-J.; Huang, M.; Lin, Z.-Q.; Duan, W.-L. Adv.
Synth. Catal. 2012, 354, 3122; (e) Huang, M.; Li, C.; Duan, W.-L.; Xu, S. Chem.
Commun. 2012, 11148.
the system and the eventual release of the 1,4-adduct with the S
configuration and the regenerated original copper catalyst.
In summary, we have developed a copper/NHC-catalyzed asym-
metric 1,4-addition of diarylphosphines to
a,b-unsaturated
ketones, furnishing the chiral phosphorus derivatives in high
yields with moderate enantioselectivity. Attempts to develop
new copper/NHC catalysts for improving the stereoselectivity of
this reaction will be pursued in our laboratory.
Acknowledgments
We thank the National Basic Research Program of China (973
Program 2010CB833300), NSFC (20902099, 21172238), and SIOC
for financial support.
Supplementary data
6. For selected reviews, see (a) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824; (b) Alexakis, A.;
Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796;
(c) von Zezschwitz, P. Synthesis 2008, 1809; (d) Dang, L.; Lin, Z.; Marder, T. B.
Chem. Commun. 2009, 3987; (e) Schiffner, J. A.; Müther, K.; Oestreich, M. Angew.
Chem., Int. Ed. 2010, 49, 1194; (f) Hartmann, E.; Vyas, D. J.; Oestreich, M. Chem.
Commun. 2011, 7917; For recent examples, see: (g) Mun, S.; Lee, J.-E.; Yun, J.
Org. Lett. 2006, 8, 4887; (h) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145;
(i) Bos, P. H.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2008, 10, 4219; (j) Wilsily,
A.; Lou, T.; Fillion, E. Synthesis 2009, 2066; (k) Lee, K.; Hoveyda, A. H. J. Org.
Chem. 2009, 74, 4455; (l) Feng, X.; Yun, J. Chem. Commun. 2009, 6577; (m) Chen,
I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664; (n) Bos, P. H.; Maciá, B.; Fernández-Ibánez, M. Á.; Minnaard, A. J.;
Feringa, B. L. Org. Biomol. Chem. 2010, 8, 47; (o) Palais, L.; Babel, L.; Quintard, A.;
Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 1988; (p) Endo, K.; Ogawa, M.; Shibata,
T. Angew. Chem., Int. Ed. 2010, 49, 2410; (q) Müller, D.; Hawner, C.; Tissot, M.;
Palais, L.; Alexakis, A. Synlett 2010, 1694; (r) Tissot, M.; Müller, D.; Belot, S.;
Alexakis, A. Org. Lett. 2010, 12, 2770; (s) O Brien, J. M.; Lee, K.; Hoveyda, A. H. J.
Am. Chem. Soc. 2010, 132, 10630; (t) den Hartog, T.; Rudolph, A.; Maciá, B.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2010, 132, 14349; (u) Takatsu, K.;
Shintani, R.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50, 5548; (v) Yoshida, M.;
Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2012, 134, 11896.
7. For copper-catalyzed non-asymmetric hydrophosphination of alkynes and
alkenes, see: (a) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007,
129, 4099; (b) Leyva-Perez, A.; Vidal-Moya, J. A.; Cabrero-Antonino, J. R.; Al-
Deyab, S. S.; Al-Resayes, S. I.; Corma, A. J. Organomet. Chem. 2011, 696, 362.
8. For an example of copper/triphosphine-catalyzed alkylation of
diphenylphosphine, see, Lane, E. M.; Chapp, T. W.; Hughes, R. P.; Glueck, D.
S.; Feland, B. C.; Bernard, G. M.; Wasylishen, R. E.; Rheingold, A. L. Inorg. Chem.
2010, 49, 7650.
9. N-Heterocyclic Carbenes in Transition Metal Catalysis In Topics in
Organometallic Chemistry; Glorius, F., Ed.; Springer: Heidelberg, 2007; Vol. 21,.
10. The product was obtained with a similar yield in the presence of 5 mol %
K2CO3.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.10.158.
References and notes
1. Phosphorus Ligands in Asymmetric Catalysis Synthesis and Applications; Börner,
A., Ed.; Wiley-VCH: Weinheim, 2008; Vols 1–3,.
2. For a review of 1,4-addition reaction of phosphorus nucleophiles to electron-
deficient olefins, see: Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J.
Org. Chem. 2006, 29.
3. For reviews on catalytic asymmetric synthesis of chiral phosphanes see: (a)
Glueck, D. S. Synlett 2007, 2627; (b) Glueck, D. S. Chem. -Eur. J. 2008, 14, 7108;
(c) Harvey, J. S.; Gouverneur, V. Chem. Commun. 2010, 7477; (d) Zhao, D.; Wang,
R. Chem. Soc. Rev. 2012, 41, 2095; For leading examples, see: (e) Kovacik, I.;
Wicht, D. K.; Grewal, N. S.; Glueck, D. S.; Incarvito, C. D.; Guzei, I. A.; Rheingold,
A. L. Organometallics 2000, 19, 950; (f) Moncarz, J. R.; Laritcheva, N. F.; Glueck,
D. S. J. Am. Chem. Soc. 2002, 124, 13356; (g) Sadow, A. D.; Haller, I.; Fadini, L.;
Togni, A. J. Am. Chem. Soc. 2004, 126, 14704; (h) Sadow, A. D.; Togni, A. J. Am.
Chem. Soc. 2005, 127, 17012; (i) Scriban, C.; Kovacik, I.; Glueck, D. S.
Organometallics 2005, 24, 4871; (j) Chan, V. S.; Stewart, I. C.; Bergman, R. G.;
Toste, F. D. J. Am. Chem. Soc. 2006, 128, 2786; (k) Scriban, C.; Glueck, D. S. J. Am.
Chem. Soc. 2006, 128, 2788; (l) Blank, N. F.; Moncarz, J. R.; Brunker, T. J.; Scriban,
C.; Anderson, B. J.; Amir, O.; Glueck, D. S.; Zakharov, L. N.; Golen, J. A.; Incarvito,
C. D.; Rheingold, A. L. J. Am. Chem. Soc. 2007, 129, 6847; (m) Chan, V. S.;
Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 15122; (n) Butti, P.;
Rochat, R.; Sadow, A. D.; Togni, A. Angew. Chem., Int. Ed. 2008, 47, 4878; (o)
Chan, V. S.; Chiu, M.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
6021; (p) Hong, L.; Sun, W.; Liu, C.; Zhao, D.; Wang, R. Chem. Commun. 2010,
2856; (q) Sun, W.; Hong, L.; Liu, C.; Wang, R. Org. Lett. 2010, 12, 3914.
4. For catalytic asymmetric 1,4-addition of substituted phosphines or phosphine
oxides to electron-deficient alkenes, see: (a) Carlone, A.; Bartoli, G.; Bosco, M.;
Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 4504; (b) Ibrahem, I.;
Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Córdova, A. Angew. Chem.,
11. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704.
12. Fortman, G. C.; Slawin, A. M. Z.; Nolan, S. P. Organometallics 2010, 29, 3966.