Catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines using chiral tert-butanesulfinylphosphine ligands

Article abstract of DOI:10.1016/j.tetlet.2008.09.111

A class of novel chiral tert-butanesulfinylphosphine ligands were designed and synthesized by a concise two-step route with high yields. High activities and enantioselectivities (up to 94% ee) were achieved when using them in catalytic asymmetric diethylz

Full text of DOI:10.1016/j.tetlet.2008.09.111

Tetrahedron Letters 49 (2008) 6921–6923
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Tetrahedron Letters
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Catalytic asymmetric diethylzinc addition to diphenylphosphionyl
imines using chiral tert-butanesulfinylphosphine ligands
Junmin Chen a,b,c, Dong Li a,b, Haifeng Ma a, Linfeng Cun a, Jin Zhu a,b, Jingen Deng a,b, Jian Liao a,b,
*
a National Engineering Research Center of Chiral Drugs and Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate School of Chinese Academy of Science, Beijing 100049, China
c College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2008
Revised 17 September 2008
Accepted 19 September 2008
Available online 23 September 2008
A class of novel chiral tert-butanesulfinylphosphine ligands were designed and synthesized by a concise
two-step route with high yields. High activities and enantioselectivities (up to 94% ee) were achieved
when using them in catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines.
Ó 2008 Elsevier Ltd. All rights reserved.
a
-Branched chiral amines play an important role in the synthe-
elegant catalytic asymmetric oxidation route to prepare tert-butyl
tert-butanethiosulfinate with good enantioselectivity, which was
then readily converted to enantiomerically pure tert-butanesulfi-
namide, it has been widely employed as chiral auxiliary in stereo-
selective carbon–carbon bond formation.1c,17 Furthermore, tert-
butanesulfinyl moiety was also utilized for the designation of C2-
symmetric sulfinyl imines,16 P, N; N, N; P, S; N, S-ligands and
widely used in catalytic asymmetric reactions.18 In this letter, we
would like to present novel phosphino sulfoxide ligands, of which
both sulfoxide and chirality environment are provided by a chiral
tert-butylsulfinyl moiety and their copper complexes are applied
sis of many modern active pharmaceutical ingredients and drug
candidates.1 Various methods have been developed to prepare
a-
branched chiral amines enantioselectively, such as asymmetric
reduction of imines, resolution of racemates, and enantioselective
addition of alkylmetals to imines. Remarkably, the most attractive
and effective method for a convenient synthesis of a-branched chi-
ral amines is based on enantioselective addition of diorganozinc
reagents to activated amines catalyzed by chiral metal-complexes,
such as Zr–peptide,2 copper–amidophosphine,3 thiophosphora-
mide,4 Me–Duphos,5 Me–Duphos monoxide metal complex,6 N,O-
ligand catalysis,7 and Rh–diene complexes.8,9 For most of these
catalysis complexes, ligands are hard to obtain in a convenient
way. It is still worthwhile to design and develop novel and effective
ligands that can be prepared through concise routes. P,O-ligands,
such as Me–Duphos monoxide,10,11 display good coordination
capacities with copper ion from one P atom and one O atom of
phosphine oxide.12 Could the coordinating oxygen atom be replaced
by other heteroatoms like sulfur atom (sulfoxides)? Actually, chiral
sulfur ligands are widely used in catalytic asymmetric reactions.13
Particularly, chiral phosphino sulfoxides and their palladium com-
plexes are used in catalytic asymmetric allylic nucleophilic substi-
tution reactions.14 Up to date, there is no literature reports about
the applications of chiral phosphino sulfoxide ligands coordinated
with other transition metals like copper ion in catalytic asymmet-
ric reactions. Although both oxygen and sulfur atoms can coordi-
nate with different transition metals,15 in sulfoxide–Cu(II)
complex,16 it is oxygen but not sulfur atom that coordinated with
copper ion very well, therefore, phosphino sulfoxide ligands might
also act as a new type of P,O-ligands. Since Ellman developed an
in catalytic asymmetric synthesis of a-branched chiral amines.
The synthesis of the novel phosphino sulfoxide ligands was
accomplished through two steps using bromo-arene derivatives 1
as the starting materials. Standard bromo-lithium exchange pro-
ceeded at low temperature followed by addition of thiosulfinate
2, which can be readily obtained in optical form according to our
method19 to give the desired product 3 in high yield (Scheme 1).
Deprotonation of 3a has been reported with n-BuLi, but 3b and
3c reacted more readily with LDA in THF at ꢀ78 °C.20 It should
be emphasized that the chiral ligands 4b and 4c are quite stable
at ambient temperature due to electronic effect of the meta-OCH3
and OCH2OCH3 group on tert-butanesulfinyl group. In fact, no
phosphine oxide was detected after keeping them in desiccator
for three months.
With the ligands 4 in hand, we chose diphenylphosphionyl imi-
nes as amine precursors, in which N-phosphinionyl-protecting
group can be easily cleaved under mild acidic conditions to provide
a-branched chiral amines. As showed in Table 1, the model reac-
tion is carried out at a 0.5 mmol scale of diphenylphosphionyl
imine 5a with 4.0 equiv diethylzinc, 3 mol % ligands 4b, and
6 mol % copper salt in anhydrous toluene. The desired product 6a
was obtained within 15 h. Except CuI (25% yield, 53% ee, Table 1,
* Corresponding author. Tel.: +86 28 85229250; fax: +86 28 85223978.
E-mail address: jliao10@cioc.ac.cn (J. Liao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.111

6922
J. Chen et al. / Tetrahedron Letters 49 (2008) 6921–6923
t-Bu
S
t-Bu
Br
S
O
O
1) n-BuLi/THF, -78 ºC
1) LDA/THF, -78 ºC
2) Ph2PCl
PPh2
O
S
2)
R
R
R
a: R=H 87%
S
a: R=H 92%
b: R=OCH3 85%
c: R=OCH2OCH3 89%
3 a-c
1a-c
b: R=OCH3 94%
c: R=OCH2OCH3 91%
4a-c
2
Scheme 1. Synthesis of chiral phoshino sulfoxide ligands 4a–c.
Table 1
Table 2
Enantioselective addition of Et2Zn to diphenylphosphionyl imine 5a catalyzed by
Enantioselective addition of Et2Zn to diphenylphosphionyl imines 5 catalyzed by
copper salts and ligands 4a–ca
Cu(O2CCF3)2ꢁxH2O and ligand 4ba
O
O
O
O
PPh2
PPh2
PPh2
PPh2
N
HN
Ph
N
4b
4
Cu- complex
HN
Cu- complex
Et2Zn/Toluene
Et2Zn/Toluene
Ph
H
Ar
H
Ar
*
*
6
5a
6a
5
Yieldb (%)
eec,d (%)
Entry
Imines
Ar
Ph
Yieldb (%)
89
eec (%)
Configurationd
Entry
L
Cu salts
T (°C)
Time (h)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
92
93
89
89
94
80
83
73
80
R
R
R
R
R
R
R
R
1
2
3
4
5
6
7
8
9
4b
4b
4b
4b
4b
4a
4c
4b
4b
4b
4b
4b
CuI
0
0
0
0
0
0
0
ꢀ20
rt
rt
rt
rt
15
15
15
15
15
15
15
24
15
6
25
82
81
87
89
52
86
Trace
81
85
81
80
53
80
85
85
92
47
89
ndf
89
86
88
87
CuTCe
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
2-FC6H4
3-ClC6H4
2-Furyl
2-Thienyl
87
83
84
80
84
80
81
84
CuOTf
Cu(OTf)2
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
Cu(II)ꢁxH2O
(—)
10g
11h
12i
a
Reactions performed at a 0.5 mmol scale of 5 with 4.0 equiv Et2Zn, 3 mol % 4b
and 6 mol % Cu(O2CCF3)2ꢁxH2O (x = 0.56) in 5.0 mL toluene for 15 h.
15
15
b
Isolated yield.
c
a
Determined by HPLC with chiral columns (see: Supplementary data for details).
The absolute configuration except 6i was assigned by comparison of the optical
Reactions performed at a 0.5 mmol scale of 5a with 4.0 equiv Et2Zn, 3 mol %
d
ligand and 6 mol % copper salt in 5.0 mL toluene.
rotation with literature.22
b
Isolated yield.
Determined by HPLC with Daicel Chiralcel OD column.
The absolute configuration is R-form which was assigned by comparison of the
c
d
tries 11 and 12). Thus, the best reaction condition was to use ligand
4b (3 mol %) and Cu(O2CCF3)2ꢁxH2O (6 mol %) in toluene at 0 °C.
Under the optimized conditions, we investigated the scope of
imines derived from aryl-, furyl- and thienyl aldehydes, and the re-
sults are summarized in Table 2. Most reactions demonstrated high
activities and high enantioselectivities (Table 2, entries 1–5).
Ortho-F, meta-Cl substituent on phenyl ring, 2-furyl- and 2-thienyl
gave similar yields and moderate enantioselectivities (Table 2, en-
tries 6–9).
In conclusion, we have designed and synthesized a class of novel
tert-butanesulfinylphosphine ligands, of which both sulfoxide and
chirality environment are provided by a chiral tert-butylsulfinyl
moiety. The ligands can be conveniently prepared in high yields
through two steps. And using the chiral ligand 4b in the copper-cat-
alyzed addition of diethylzinc to diphenylphosphionyl imines dem-
onstrated high activities and up to 94% enantioselectivities. Further
studies on mechanism and on other catalytic asymmetric reactions
of these ligands are currently underway in our laboratory.
optical rotation with literature 19.
e
CuTC = copper thiophene-2-carboxylate.
nd = not determined.
f
g
6 mol % 4b and 12 mol % = Cu(O2CCF3)2ꢁxH2O was used.
h
3 mol % 4b and 3 mol % = Cu(O2CCF3)2ꢁxH2O was used.
i
6 mol % 4b and 3 mol % = Cu(O2CCF3)2ꢁxH2O was used.
entry 1), other copper salts CuTC, CuOTf, and Cu(OTf)2 showed
similar catalytic activities and good enantioselectivities (Table 1,
entries 2–4). It is interesting that copper(II) trifluoro-acetate
hydrate, Cu(O2CCF3)2ꢁxH2O (x = 0.56),21 gave the best result (89%
yield and 92% ee, Table 1, entry 5). We next examined the effect
of ligands, catalyst loading, and temperature on the reactivities
and enantioselectivities. Ligand 4c manifested similar catalytic
activity and high enantioselectivity (86% yield and 89% ee, Table
1, entry 7). However, ligand 4a gave the product in a low yield
and enantioselectivity (52% yield and 47% ee, Table 1, entry 6).
The meta-substituted groups might exert electronic effect and
steric hindrance. We found that the reaction was inert when the
temperature was decreased to ꢀ20 °C even after 24 h (Table 1,
entry 8). No obvious variation on activity and slight decrease on
enantioselectivity were observed when the temperature was
increased to room temperature (81% yield and 89% ee, Table 1,
entry 9). Furthermore, the reaction went faster (6 h) without
affecting the enantioselectivity or on yield when the catalyst
loading was doubled (6 mol % 4b and 12 mol % Cu(O2CCF3)2ꢁxH2O,
Table 1, entry 10). In addition, there was also no effect on enantio-
selectivity or yield when the mole ratio of ligand 4b and
Cu(O2CCF3)2ꢁxH2O was changed from 3:6 to 3:3 or 6:3 (Table 1, en-
Acknowledgment
Financial supports from the National Natural Science Foundation
of China (Grant No. 20872139) and National Engineering Research
Center of Chiral Drugs are greatly acknowledged by the authors.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.111.

J. Chen et al. / Tetrahedron Letters 49 (2008) 6921–6923
6923
7066; (e) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46, 5020; (f)
Sun, X. W.; Liu, M.; Xu, M. H.; Lin, G. Q. Org. Lett. 2008, 10, 1259.
References and notes
18. (a) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3; (b) Schenkel,
L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545; (c) Souers, A. J.; Owens, D. T.; Ellman,
A. J. Inorg. Chem. 2001, 40, 5299; (d) Schenkel, L. B.; Ellman, J. A. J. Org. Chem.
2004, 69, 1800; (e) Mancheno, O. G.; Priego, J.; Cabrera, S.; Arrayas, R. G. J. Org.
Chem. 2003, 68, 3679; (f) Fur, N. L.; Mojovic, L.; Ple, N.; Turck, A.; Reboul, V.;
Metzner, P. J. Org. Chem. 2006, 71, 2609.
1. For reviews see: (a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069; (c) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984; (d) Enders, D.; Reindhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895; (e) Brase, S.; Baumann, T.; Dahmen, S.; Vogt, H. Chem.
Commun. 2007, 1881; (f) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63,
2541; (g) Ferraris, D. Tetrahedron 2007, 63, 9581.
2. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001,
123, 984.
3. Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055.
4. Shi, M.; Wang, C. J. Adv. Synth. Catal. 2003, 345, 971.
5. Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692.
6. (a) Cote, A.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int. Ed. 2004, 43, 6525;
(b) Boezio, A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2003,
125, 14260; (c) Cote, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. 2004,
101, 5405; (d) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8, 2743.
7. Dahmen, S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940.
8. Nishimura, T.; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.
9. Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
10. Grushin, V. V. Chem. Rev. 2004, 104, 1629.
11. Selective examples: (a) Trost, B. M.; Breit, B.; Organ, M. G. Tetrahedron Lett.
1994, 35, 5817; (b) Clayden, J.; Johnson, J. P.; Pink, J. H.; Helliwell, M. J. Org.
Chem. 2000, 65, 7033; (c) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237; (d)
Dai, W. M.; Yeung, K.; Liu, J. T.; Zhang, Y.; Williams, I. D. Org. Lett. 2002, 4, 1615.
12. Cote, A.; Charette, A. B. J. Org. Chem. 2005, 70, 10864.
13. Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133.
14. (a) Hiroi, K.; Suzuki, Y.; Kawagishi, R. Tetrahedron Lett. 1999, 40, 715; (b) Hiroi,
K.; Suzuki, Y.; Abe, I.; Kawagishi, R. Tetrahedron 2000, 56, 4701; (c) Hiroi, K.;
Suzuki, Y.; Kaneko, Y.; Kato, F.; Abe, I.; Kawagishi, R. Polyhedron 2000, 19, 525.
15. (a) Kagan, H. B. Rev. Heteroat. Chem. 1992, 7, 92; (b) Calligaris, M. Coord. Chem.
Rev. 2004, 248, 351; (c) Alessio, E. Chem. Rev. 2004, 104, 4203.
19. Liao, J.; Sun, X. X.; Cui, X.; Yu, K. B.; Zhu, J.; Deng, J. G. Chem. Eur. J. 2003, 9, 2611.
20. Characterization data of 4a–c: Compound 4a: Colorless oil. ½a D25
ꢀ13.2 (c 0.4,
ꢂ
EtOH). 1H NMR (CDCl3): d 7.92–7.95 (br, 1H), 7.45 (t, J = 7.3 Hz, 1H), 6.99–7.31
(m, 12H), 1.26 (s, 9H). 13C NMR (CDCl3): d 161.7, 151.1, 150.7, 137.1, 134.4,
134.3, 132.7, 132.5, 132.4, 132.1, 131.8, 131.3, 128.1, 127.9, 127.8, 127.7 119.4,
119.2, 114.1, 58.3, 55.1, 24.0. 31P NMR (CDCl3): d ꢀ14.6; IR (liquid film) (cmꢀ1
)
3051, 2960, 2921, 1582, 1432, 1432, 1047, 741,694. HRMS: calcd for
C22H23OPS+Na: 389.1099, found: 389.1111.
Compound 4b: White solid. ½a D25
ꢂ
ꢀ165.1 (c 0.1, EtOH), mp: 114–115 °C. 1H NMR
(CDCl3): 7.21–7.61 (m, 12H), 6.93 (d, J = 8.0 Hz 1H), 3.32 (s, 3H),1.22 (s, 9H). 13
C
NMR (CDCl3): d 161.6, 161.5, 150.9, 150.5, 137.2, 134.3, 132.6, 132.4, 132.3,
132.2, 132.1, 130.4, 130.3, 130.2, 128.0, 127.9, 127.8, 127.7, 127.6, 119.2, 119.1,
114.0, 55.0, 23.9. 31P NMR (CDCl3): d ꢀ18.7; IR (KBr) (cmꢀ1): 3058, 2978, 1570,
1453, 1451, 1264, 1176, 1039, 1025, 789, 743, 693. HRMS: calcd for
C23H25O2PS+Na: 419.1205, found: 419.1210.
Compound 4c: White solid. ½a D25
ꢂ
ꢀ195.2 (c 0.1, EtOH), mp: 117–118 °C. 1H NMR
(CDCl3): d 7.21–7.72 (m, 13H), 4.61 (m, 2H), 2.95 (s, 3H), 1.23(s, 9H). 13C NMR
(CDCl3): d 59.6, 151.0, 150.6, 137.1, 136.9, 134.0, 133.9, 132.4, 132.3, 132.2,
132.1, 130.6, 130.4, 130.2, 128.0, 127.9, 127.8, 127.7, 120.4, 120.1, 116.5, 94.0,
58.3, 55.7, 23.8. 31P NMR (CDCl3): d ꢀ18.5. IR (KBr) (cmꢀ1): 3056, 2970, 2896,
1571, 1435, 1252, 1152, 1137, 1079, 1031, 998, 789, 750, 693. HRMS: calcd for
C24H28O3PS+H: 427.1491, found: 427.1496.
21. Copper(II) trifluoroacetate hydrate(Cu(O2CCF3)2ꢁxH2O) was purchased from
Alfa Aesar, x = 0.56. For literatures about improving enantioselectivities of
dialkylzinc addition by adding trace water or by using metal complex hydrate,
see: (a) Keller, E.; Maurer, J.; Naasz, R.; Schader, T.; Meetsma, A.; Feringa, B. L.
Tetrahedron: Asymmetry 1998, 9, 2409; (b) Delapierre, G.; Constantieux, T.;
Brunel, J. M.; Buono, G. Eur. J. Org. Chem. 2000, 2507; (c) Alexakis, A.; Benhaim,
C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262.
16. Owens, T. D.; Hollander, F.; Oliver, A.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
1539.
17. Selected literatures for applications of tert-butanesulfinamide: (a) Kochi, T.;
Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276; (b) Kells, K. W.;
Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666; (c) Zhong, Y. W.; Dong, Y. Z.;
Fang, K.; Izumi, K.; Xu, M. H.; Lin, G. Q. J. Am. Chem. Soc. 2005, 127, 11956; (d)
Unthank, M. G.; Hussain, N.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2006, 45,
22. Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364.