An Ni-PyBisulidine complex for the asymmetric hydrophosphonylation of aldehydes

Article abstract of DOI:10.1039/c6ob01750a

A novel Ni-PyBisulidine complex has been developed for the asymmetric hydrophosphonylation of aldehydes. A variety of aromatic, heteroaromatic, condensed-ring, α,β-unsaturated, and aliphatic aldehydes are found to be suitable substrates for the reaction,

Full text of DOI:10.1039/c6ob01750a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Zeng, P. Deng,
S. Zhang, H. Yan, G. Liang, Y. Xiong and H. Zhou, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB01750A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C6OB01750A
Journal Name
COMMUNICATION
A Ni-PyBisulidine complex for the asymmetric
hydrophosphonylation of aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
Youmao Zeng,a‡ Ping Deng,a‡ Shixiong Zhang,a Hong Yan,a Guojuan Liang,a Yan Xiongb and Hui
Zhou*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel Ni-PyBisulidine complex has been developed for the
asymmetric hydrophosphonylation of aldehydes. A variety of
aromatic, heteroaromatic, condensed-ring, α,β-unsaturated, and
aliphatic aldehydes are found to be suitable substartes for the
reaction, and the desired α-hydroxy phosphonates are obtained in
up to 99% yield and 97% ee.
R
R
O2S
SO2
CH2Cl2 or THF, 1h
in situ, 35 o
+
Ni(OAc)2
Ni-L
N
N
N
Ph
Ph
C
NH
HN
Ph
Ph
L1, R = CH3
L2, R = H
L3, R = NO2
L4, R = t-Bu
Chiral α-hydroxy phosphonates and phosphonic acids usually
show potent biological activity.1 The asymmetric
hydrophosphonylation of aldehydes is a powerful and direct
reaction for forming α-hydroxy phosphonates.2 Since the first
asymmetric hydrophosphonylation by Shibuya group3 in 1993
and the first highly enantioselective hydrophosphonylation by
Ts
Ts
N
N
filtration
MeOH, 4h
N
+
Ni(OAc)2
Ni-L1
Ph
Ph
Shibasaki group4 using
a BINOL-derived heterometallic
reflux
NH
HN
Ph
Ph
L1
complex (BINOL = 1,1’-bi-2-naphthol) in 1996, various types of
catalyst systems, containing metal complexes (such as Ti,5 Al,6
Yb,7 Zn,8 Fe,9 Cu10), and organocatalysts11 have been studied.
Although great progress has been achieved, developing new
catalysts for the enantioselective hydrophosphonylation of
aldehydes is still challenging and interesting. Recently, a novel
sulfonylated pyridine bisimidazolidine (PyBisulidines) ligand
was reported and exploited in Fe-catalyzed dehydrogenative
α-oxygenation of ethers and selective oxidation of olefins to
carbonyls by Xiao group.12 We hypothesized that this
PyBisulidine ligand would afford a high level of chiral induction
in the hydrophosphonylation of aldehydes for the bulky,
flexible Pyridine bisimidazolidine (PyBidine)13 skeleton and the
electron-withdrawing group. Herein, we present a highly
efficient asymmetric hydrophosphonylation of aldehydes
catalyzed by Ni-PyBisulidines (Scheme 1). 14
HRMS (ESI) for Ni-L1: m/z Calcd. For C51H48N5NiO6S2 [M + H]+: 948.23940, Found: 948.23941
Scheme 1 Syntheses of Ni-PyBisulidine complexes.
acetates to form complexes that catalyze the asymmetric
hydrophosphonylation of benzaldehyde (Table 1, entries 1-8).
Complex Ni-L1 catalyzed the reaction smoothly, giving the
desired product with 87% ee (Table 1, entry 1). Complex Zn-L1
,
Co-L1 and Mn(II)-L1 could promoted the conversation with
moderate enantioselectivity (Table 1, entries 2, 3 and 8). When
Fe(II), Pd(II), Cu(I), Cu(II) were used as the central metal, the
low chiral induction was observed (Table 1, entries 4-7).
Subsequently, the benzenesulfonyl moiety of the ligands was
examined (Table 1, entries 1, 9-11). Different substituent on
the benzenesulfonyl provided different reactivity while the
substituent hardly affected the enantioselectivity. Considering
the reactivity and economy, L1 was selected for further
optimization.
A survey of various solvents revealed that chlorinated
hydrocarbons showed a strong solvent effect (Table 2, entries
1-6). Chloroform provided the best enantioselectivity and
CH2ClCH2Cl gave the best reactivity. CH2Cl2 was found to be
favourable considering the reactivity and enantioselectivity
Initially, PyBisulidine L1 reacted in situ with various metal
a.School of Pharmaceutical Science, Chongqing Research Center for Pharmaceutical
Engineering, Chongqing Key Laboratory of Biochemistry and Molecular
Pharmacology, Chongqing Medical University, Chongqing 400016, P. R. China. E-
mail: hzhou@cqmu.edu.cn.
b.School of Chemistry and Chemical Engineering, Chongqing University, Chongqing
400030, P. R. China.
‡These authors contributed equally.
†Electronic Supplementary Information (ESI) available: General experimental
information, and NMR, MS, and HPLC spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
Table
1 The Screening of metals and ligands for the hydrophosphonylation of
decreased reactivity (Table 2, entry 9 vs. entry 8). It should be
View Article Online
benzaldehydea
note that the process is air and moistureDtoOlIe: r1a0.n10t.39/C6OB01750A
In addition, the present Ni-L1 complex could be pre-
prepared in MeOH by filtration (Scheme 1). The complex
prepared in situ and the complex pre-prepared provided the
same results (Table 2, entry 9 vs. 10). The using of pre-
prepared catalyst could greatly facilitate the operation.
Substrate scope in Table 3 was investigated using the pre-
prepared complex.16 To gain some insight into the complex,
ESI-HRMS analyses of the Ni-L1 complex was carried out. The
spectrum displayed the ion at m/z 948.23941, which
corresponded to NiOAc/L1 (Calcd. For C51H48N5NiO6S2,
[Ni(OAc)2 + ML1 – HOAc + H]+: 948.23940).17
OH
Metal salt 10 mol%
Ligand 10 mol%
O
P
CHO
+
P(OPh)2
H
OPh
THF, 0 oC,
OPh
O
1a
2a
Entry
1
Metal salts
Ni(OAC)2
Zn(OAc)2
Co(OAc)2
Fe(OAc)2
Pd(OAc)2
CuOAc
Ligand
Time (h)
16
Yield (%)b
98
ee (%)c
87
55
50
11
10
2
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
2
3
4
5
6
7
8
9
20
20
20
20
20
20
20
40
43
75
52
14
22
10
90
94
Table
3 Substrate scope of the catalytic asymmetric hydrophosphonylation of
Cu(OAc)2
Mn(OAc)2
Ni(OAC)2
Ni(OAC)2
Ni(OAC)2
0
aldehydesa
50
84
87
88
OH
O
P
O
Ni-L1 10 mol%
CH2Cl2, -10 o
*
10
11
14
40
98
88
+
R
P(OPh)2
H
OPh
C
R
H
OPh
O
a
The reactions were carried out on a 0.2 mmol scale (benzaldehyde) with
diphenylphosphite (0.24 mmol) in THF (1.0 mL) in the presence of metal-
1
2
b
c
PyBisulidines prepared in situ. Isolated yield. Enantiomeric excesses were
Entry
R
Ph
2-MeC6H4
3-MeC6H4
Product Time (h) Yield (%)b ee (%)c
determined by HPLC analysis on
a Chiralcel OD-H column; the absolute
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
14
22
41
33
10
48
39
37
40
41
41
44
40
36
29
36
92
93
99
99
95
93
94
98
99
98
90
99
91
99
87
99
95 (R)d
96
configuration was established as R by comparison with literature data. 11d,11e
95
Table 2 Further optimization of reaction conditionsa
4-MeC6H4
4-CF3C6H4
4-FC6H4
95 (R) d
95
OH
O
P
CHO
Ni-L1 10 mol%
90
+
P(OPh)2
H
OPh
4-BrC6H4
4-ClC6H4
2-thienyl
2-furyl
95 (R) d
95 (R) d
95
Solvent, 14-16h
OPh
O
1a
2a
91
1-naphthyl
2-naphthyl
PhCH=CH
Cyclohexyl
CH3(CH2)2
CH3(CH3)4
97 (R) d
96
The molar ratio of
benzaldehyde and
T
Yield
(%)b
ee
Entry
Solvent
(oC)
(%)c
diphenylphosphite
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1
93
71 (S) d
79
1
2
3
4
5
6
7
THF
MeOH
Toluene
CH2Cl2
CHCl3
CH2ClCH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
0
0
0
0
0
-10
-10
98
97
88
90
66
99
90
98
92
92
87
83
91
93
95
92
93
93
95
95
81
a
The reactions were carried out: aldehyde (0.2 mmol), diphenylphosphite (0.2
mmol), 0.5 mL CH2Cl2; the catalyst was pre-pared in MeOH by filtration. b Isolated
yield. Enantiomeric excesses were determined by HPLC analysis. d The absolute
c
configurations were determined by comparison with literature data.11d,11e
8d
9d
10d,e
1 : 1
1 : 1
1 : 1
With the optimized reaction conditions in hand, the
substrate scope was explored. The results were summarized in
Table 3. No matter aryl aldehydes with an ortho substituent or
a meta substituent or a para substituent or an electron-
withdrawing substituent as well as heteroaryl aldehyde
afforded the corresponding product in excellent yields with
excellent enantioselectivities (Table 3, entries 1-10). The
bulkier aldehydes, such as 1-naphthaldehyde and 2-
naphthaldehyde, also gave excellent results (Table 3, entries
11 and 12). The α,β-unsaturated aldehyde, cinnamaldehyde,
gave product 2m with excellent yield and ee (Table 3, entry 13).
The aliphatic aldehydes showed reduced enantioselectivity, in
which the nonbranched aliphatic aldehydes gave higher ee
than branched aliphatic aldehydes (Table 3, entries 14-16).
a
Unless otherwise noted, the reactions were performed with Ni-L1 complex
prepared in situ on a 0.2 mmol (benzaldehyde) in 1.0 mL solvent. b isolated yield.
c
d
Enantiomeric excesses were determined by HPLC analysis.
0.4 mmol
e
benzaldehyde was used. The Ni-L1 complex was pre-prepared in MeOH by
filtration. For details, see supporting information.
(Table 2, entry 4 vs. entries 5 and 6). The molar ratio of
benzaldehyde and diphenylphosphite could reduce to 1:1
without any loss of the reactivity and enantioselectivity (Table
2, entry 7 vs. 4). Furthermore, increasing the concentration of
the benzaldehyde from 0.2 M to 0.4 M led to higher reactivity
and the same enantioselectivity (Table 2, entry 8 vs. 7).15 The
improving enantioselectivity was obtained when reducing the
reaction temperature from 0 oC to -10 oC with a slightly
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
Although the detailed reaction mechanism remains unclear, training project for young teacher of School of Pharmaceutical
View Article Online
the proposed transition state for the reaction using Ni-L1 as Science, Chongqing Medical University (YDXOY2I:0101.410Q3N9/SCZ60O1B)0.1750A
the catalyst is shown in Figure 1.18 The benzaldehyde
coordinated to the chiral Ni(II) catalyst in the equatorial
position by avoiding the steric repulsion of PyBisulidine (TS1 vs
Notes and references
TS2 and TS3, Figure 1). Coordination of oxygen in phosphite to
Ni(II) and the deprotonation of phosphite affords the
phosphonates, which attacks to the aldehyde in the
coordination sphere of chiral Ni-PyBisulidine salt and leads to
chiral addition products.
1
(a) T. Wang, H. J. Huang, J. Luo, D. H. Yu, Phosphorus Sulfur
Silicon Relat. Elem., 2012, 187, 135-141; (b) C. Jin, H. He,
Phosphorus Sulfur Silicon Relat. Elem., 2011, 186, 1397-1403;
(c) T. Wang, D. Y. Lei, Y. Huang, L. H. Ao, Phosphorus Sulfur
Silicon Relat. Elem., 2009, 184, 2777-2785; (d) A. Szymanska,
M. Szymczak, J. Boryski, J. Stawinski, A. Kraszewski, G. Gollu,
G. Sanna, G. Giliberti, R. Loddo, P. L. Colla, Bioorg. Med.
Chem., 2006, 14, 1924-1934; (e) J. Stawinski, A. Kraszewski,
Acc. Chem. Res., 2002, 35, 952-960; (f) J. A. Sikorski, M. J.
Miller, D. S. Braccolino, D. G. Cleary, S. D. Corey, J. L. Font, K.
J. Gruys, C. Y. Han, K. C. Lin, P. D. Pansegrau, J. E. Ream, D.
Schnur, A. Shah, M. C. Walker, Phosphorus Sulfur Silicon
Relat. Elem., 1993, 76, 115-118; (g) B. Stowasser, K.-H. Budt,
L. Jian-Qi, A. Peyman, D. Ruppert, Tetrahedron Lett., 1992, 33
6625-6628.
p-Toly
OAc
p-Toly
O
N
S
N
O
N
S
N
N
Ni
O
AcO
N
N
NH
O
Ni
O
P
O
O
O
P
Ph
OPh
OPh
H
,
Ph
H
OPh
PhO
OH
TS1 favored
2
For recent reviews, see: (a) M. Dzięgielewski, J. Pięta, E.
Kamińska, Ł. Albrecht, Eur. J. Org. Chem., 2015, 677-702; (b)
P(OPh)2
O
D. Zhao, R. Wang, Chem. Soc. Rev., 2012, 41, 2095-2108; (c) P.
Merino, E. Marqués-López, R. P. Herrera, Adv. Synth. Catal.,
2008, 350, 1195-1208; (d) H. Gröger, B. Hammer, Chem. -Eur.
(R)
p-Toly
J., 2000, 6, 943-948; (e) Ł. Albrecht, A. Albrecht, H. Krawczyk,
p-Toly
O
p-Toly
N
O
p-Toly
S
N
O
K. A. Jørgensen, Chem. -Eur. J., 2000, 16, 28-48.
O
S
S
N
N
O
N
O
AcO
N
S
3
4
T. Yokomatsu, T. Yamaishi, S. Shibuya, Tetrahedron:
AcO
N
NH
O
N
NH
Ni
O
Asymmetry, 1993, 4, 1779-1782.
Ni
O
O
O
(a) T. Arai, M. Bougauchi, H. Sasai, M. Shibasaki, J. Org.
Chem., 1996, 61, 2926-2927; (b) H. Sasai, M. Bougauchi, T.
Arai, M. Shibasaki, Tetrahedron Lett., 1997, 38, 2717-2720.
(a) M. D. Groaning, B. J. Rowe, C. D. Spilling, Tetrahedron
Lett., 1998, 39, 5485-5488; (b) F. Yang, D. Zhao, J. Lan, P, Xi, L.
Yang, S. Xiang, J. You, Angew. Chem., Int. Ed., 2008, 47, 5646-
5649; (c) X. Zhou, Y. Liu, L. Chang, J. Zhao, D. Shang, X. Liu, L.
Lin, X. Feng, Adv. Synth. Catal., 2009, 351, 2567-2572.
O
P
Ph
Ph
H
PhO
OPh
PhO
OPh
5
TS2 disfavored
TS3 disfavored
Figure 1 The Proposed mechanistic hypothesis.
6
(a) J. P. Duxbury, A. Cawley, M. Thornton-Pett, L. Wantz, J. N.
D. Warne, R. Greatrex, D. Brown, T. P. Kee, Tetrahedron Lett.,
1999, 40, 4403-4406; (b) C. V. Ward, M. Jiang, T. P. Kee,
Tetrahedron Lett., 2000, 41, 6181-6184; (c) B. Saito, T.
Katsuke, Angew. Chem., Int. Ed., 2005, 44, 4600-4602; (d) K.
Ito, H. Tsutsumi, M. Setoyama, B, Saito, T. Katsuki, Synlett,
2007, 1960; (e) X. Zhou, X. Liu, X. Yang, D. Shang, J. Xin, X.
Feng, Angew. Chem., Int. Ed., 2008, 47, 392-394; (f) S. Gou, X.
Zhou, J. Wang, X. Liu, X. Feng, Tetrahedron, 2008, 64, 2864-
2870; (g) J. P. Abell, H. Yamamoto, J. Am. Chem. Soc., 2008,
130, 10521-10523; (h) B. Hoge, P. Garcia, H. Willner, H.
Oberhammer, Chem. -Eur. J., 2006, 12, 3567-3574; (i) K.
Suyama, Y. Sakai, K. Matsumoto, B. Saito, T. Katsuki, Angew.
Chem., Int. Ed., 2010, 49, 797-799; (j) X. Zhou, Q. Zhang, Y.
Hui, W. Chen, J. Jiang, L. Lin, X. Liu, X. Feng, Org. Lett., 2010,
12, 4296-4299; (k) C. Wang, C. Xu, X. Tan, H. Peng, H. He, Org.
Biomol. Chem., 2012, 10, 1680-1685.
W. Chen, Y. Hui, X. Zhou, J. Jiang, Y. Cai, X. Liu, L. Lin, X. Feng,
Tetrahedron Lett., 2010, 51, 4175-4178.
L. Sun, Q. Guo, X. Li, L. Zhang, Y. Li, C. Da, Asian J. Org. Chem.,
2013, 2, 1031-1035.
(a) R. Boobalan, C. Chen, Adv. Synth. Catal., 2013, 355, 3443-
3450; (b) P. Muthupandi, G. Sekar, Org. Biomol. Chem., 2012,
10, 5347-5352; (c) F. Xu, Y. Liu, J. Tu, C. Lei, G. Li, Tetrahedron:
Asymmetry, 2015, 26, 891-896.
Conclusions
We have developed a new chiral Ni-PyBisulidine (sulfonylated
pyridine bisimidazolidine) complex for the asymmetric
hydrophosphonylation of aldehydes. Various α-hydroxy
phosphonates were obtained in good to excellent yields with
moderate to excellent enantioselectivities. It is a more
environmentally friendly method for the synthesis of α-
hydroxy aromatic phosphonates, because of the excellent
yields and enantioselectivities of aromatic aldehydes as well as
the 1:1 molar ratio of aldehydes and diphenylphosphite. The
pathway was air-tolerant and easily manipulated. Further
investigations are underway in our laboratory for the detailed
mechanism and the application of the desired catalyst to other
reactions.
7
8
9
Acknowledgements
We are grateful for the generous financial support by the
National Nature Science Foundation of China (21672031,
21372265), Fundamental and Advanced Research Projects of
10 T. Deng, C. Cai, RSC Adv., 2014, 4, 27853-27856.
11 (a) H. Wynberg, A. A. Smaardijk, Tetrahedron Lett., 1983, 24
Chongqing
City
(cstc2016jcyjA0250),
Scientific
and
,
Technological Research Program of Chongqing Municipal
Education Commission (KJ120307 and KJ1500221), and
5899-5900; (b) A. A. Smaardijk, S. Noorda, F. Bolhuis, H.
Wynberg, Tetrahedron Lett., 1985, 26, 493-496; (c) D.
Uraguchi, T. Ito, T. Ooi, J. Am. Chem. Soc., 2009, 131, 3836-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
3837; (d) J. V. Alegre-Requena, E. Marqués-López, P. J. S.
Miguel, R. P. Herrera, Org. Biomol. Chem., 2014, 12, 1258-
1264; (e) S. Hirashima, R. Arai, K. Nakashima, N. Kawai, J.
View Article Online
DOI: 10.1039/C6OB01750A
Kondo, Y. Koseki, T. Miura, Adv. Synth. Catal., 2015, 357
,
3863-3867; (f) J. Guin, Q. Wang, M. van Gemmeren, B. List,
Angew. Chem., Int. Ed., 2015, 54, 355-358.
12 (a) A. Gonzalez-de-Castro, C. M. Robertson, J. Xiao, J. Am.
Chem. Soc., 2014, 136, 8350-8360; (b) A. Gonzalez-de-Castro,
J. Xiao, J. Am. Chem. Soc., 2015, 137, 8206-8218.
13 Examples of asymmetric catalysis using the PyBidines as the
ligand, see: (a) T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki, H.
Sato, J. Am. Chem. Soc., 2010, 132, 5338-5339; (b) T. Arai, A.
Mishiro, E. Matsumura, A. Awata, M. Shirasugi, Chem. -Eur. J.,
2012, 18, 11219-11222; (c) T. Arai, Y. Ogino, Molecules, 2012,
17, 6170-6178; (d) T. Arai, S. Kajikawa, E. Matsumura, Synlett,
2013, 24, 2045-2048; (e) T. Arai, E. Matsumura, H. Masu, Org.
Lett., 2014, 16, 2768-2711; (f) T. Arai, K. Tsuchiya, E.
Matsumura, Org. Lett., 2015, 17, 2416-2419; (g) T. Arai, H.
Ogawa, A. Awata, M. Sato, M. Watabe, M. Yamanaka, Angew.
Chem., Int. Ed., 2015, 54, 1595-1599.
14 For a related enantioselective Kabachnik-Fields reaction
catalyzed by chiral Pyridine Bisimidazoline (Pybim)-Zn, see:
M. Ohara, S. Nakamura, N. Shibata, Adv. Synth. Catal., 2011,
353, 3285-3289.
15 For the detailed data of the effects of the catalyst loading and
the concentration of aldehyde, see Supporting Information.
16 The stability test of the pre-prepared complex is in progress.
The current result is the complex can be storable under air at
4 oC for about a month without any loss of activity.
17 For the discussion of the speculated structure of the complex,
see Supporting Information.
18 For
a theoretical study on the mechanism for the
hydrophosphonylation of aldehydes using aluminium
catalysts, see: W. Li, S. Qin, Z. Su, H. Yang, C. Hu,
Organometallics, 2011, 30, 2095-2104.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins