Design of N-sulfinyl homoallylic amines as novel sulfinamide-olefin hybrid ligands for asymmetric catalysis: Application in Rh-catalyzed enantioselective 1,4-additions

Article abstract of DOI:10.1039/c1cc12322j

Here we show that simple and readily available chiral sulfinamide-olefins can display great catalytic activities and enantioselectivities in rhodium-catalyzed 1,4-addition reactions. This study represent the first example of chiral sulfur-based olefin ligand class for transition metal-catalyzed asymmetric transformation.

Full text of DOI:10.1039/c1cc12322j

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COMMUNICATION
Design of N-sulfinyl homoallylic amines as novel sulfinamide-olefin
hybrid ligands for asymmetric catalysis: application in Rh-catalyzed
enantioselective 1,4-additionsw
Shen-Shuang Jin, Hui Wang and Ming-Hua Xu*
Received 21st April 2011, Accepted 10th May 2011
DOI: 10.1039/c1cc12322j
Here we show that simple and readily available chiral sulfinamide-
olefins can display great catalytic activities and enantioselectivities
in rhodium-catalyzed 1,4-addition reactions. This study represent
the first example of chiral sulfur-based olefin ligand class for
transition metal-catalyzed asymmetric transformation.
for asymmetric synthesis of various important chiral amines.8,9
In considering the idea of designing chiral sulfur-olefins, we
became intrigued by the possibility of combing olefin and
N-tert-butanesulfinamide elements into a candidate ligand
molecule, in which the reaction stereocontrol through stereo-
genic sulfur might be expected. With this structure profile in
mind, we further envisioned that easily accessed N-sulfinyl
homoallylic amines10 might be a deserving choice (Fig. 2).
The conjugate addition of 2-cyclohexenone with phenyl-
boronic acid was chosen as a model reaction.11 We began our
investigation by examining readily available N-tert-butane-
sulfinyl homoallylic amine 19a as possible ligand in the presence
of [RhCl(C2H4)2]2 under aqueous K3PO4/dioxane (Scheme 1).
To our great delight, despite the simple and flexible structure
of 1, the reaction proceeded smoothly at 60 1C and went to
completion in an hour, giving the corresponding product in
99% yield and with a promising 82% ee. To ensure that the
sulfinamide and allylic double bond are both involve closely in
coordination to rhodium in the catalytic process, we designed
compounds 2 and 3 lacking either of the functional groups for
control experiments. Indeed, the reaction did not work with 2
as ligand, and only 25% yield of racemic product was obtained
while utilizing 3 as ligand. Surprisingly, the use of ligand 4 with
an additional methyl substitution at the sulfinamide nitrogen
resulted in a very poor conversion of the reaction, possibly due
to unfavourable coordination geometry.12 These results suggest
that conformationally appropriate sulfinamide-olefins can be
new potential ligands for asymmetric catalysis.
Development of highly selective and active chiral catalysts for
asymmetric transformations has been a challenging topic of
intense current interest in the field of synthetic organic chemistry
and pharmaceutical chemistry.1 With respect to transition
metal-catalyzed asymmetric reactions, design of efficient chiral
ligands is particularly important and intriguing.1b,e Since the
pioneering work of Hayashi and Carreira,2 chiral dienes have
emerged as novel exciting ligands for asymmetric catalysis. In
the past several years, design and use of chiral chelating olefins
as steering ligands in asymmetric catalysis have become an
active and vibrant area with impressive progress.3 Compared
to chiral diene systems, the development of related chiral olefin-
heteroatom hybrid ligands is much less studied, although
Grutzmacher and others have demonstrated that phosphorus- or
¨
nitrogen-containing olefins can serve as new promising ligands
for asymmetric catalysis.4 On the other hand, the use of sulfur-
containing ligands in asymmetric catalysis is rapidly increasing
nowadays.5 Despite the high potential of chiral sulfur ligands,
however, there are no examples of sulfur-based chiral olefin
ligands reported to date. In this context, we have been interested
in the development of chiral sulfur-olefins as a significantly
new and attractive class of ligands (Fig. 1). Herein we disclose
our discovery of sulfinamide-olefins as novel efficient hybrid
ligands for highly enantioselective rhodium-catalyzed asymmetric
reactions.
With the encouraging findings, we prepared a series of chiral
N-tert-butanesulfinyl homoallylic amines bearing different
substitution patterns on the C-1 and C-2 positions9c,d (Fig. 3)
and evaluated them as ligands in the same reaction (Table 1).
It was interesting that the use of compound 5, the diastereo-
isomer of 1, also furnished the addition product in 99% yield
and with a similar 85% ee (entry 2). Gratifyingly, when 6 was
employed, the reaction exhibited great yield (99%) and excellent
improved enantioselectivity (94% ee) (entry 3). Varying the
Recently, we have reported the design and synthesis of a
new type of C2-symmetric chiral diene ligands bearing a simple
bicyclic [3.3.0] backbone and their successful applications in
several important asymmetric reactions.6 In addition, we have
been exploring the chemistry of N-tert-butanesulfinyl imines7
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China.
E-mail: xumh@mail.shcnc.ac.cn; Fax: + 86 215080 7388;
Tel: + 86 215080 7388
w Electronic supplementary information (ESI) available: Experimental
details, characterization data, copies of HPLC, NMR spectra. See
DOI: 10.1039/c1cc12322j
Fig. 1 Chiral chelating olefin ligand design.
c
7230 Chem. Commun., 2011, 47, 7230–7232
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yield and enantioselectivity (ligand 12) (entry 9). On the other
hand, upon further evaluation on 2-cyclopentenone, sterically
hindered 10 appeared to be the optimal ligand (entries 10–12).
To investigate the effect of match/mismatch on stereo-
chemistry, diastereoisomer 11 with opposite configurations
compared to 10 at the both two carbon stereocenters was
subjected to catalysis. As a result, almost the same high yield
(99%) and enantioselectivity (94% ee) were obtained (entry 8),
which is similar to that found using 1 and 5 (entries 1 and 2),
suggesting that the substituents on the C-1 and C-2 positions
are relatively far away from the rhodium catalytic site, therefore
these carbon chiralities may not be necessary for excellent
enantioselectivity. In fact, the use of the mixed 10 and 11 as
ligand also allowed for the highly enantioselective formation
of addition product in 99% yield and 95% ee (entry 13). These
observations illustrate that the reaction enantioselectivity was
primarily controlled by the stereochemistry of the N-sulfinyl
group, but it is presently not clear how other factors such as
substituent nature or molecular geometry may have influenced
the stereo outcome and reactivity of the transformation.13
Nevertheless, we were pleased to note that the product (11)
afforded by Zn-mediated simple benzoyloxyallylation of
(R)-N-tert-butanesulfinyl imine in THF at room temperature
can be suitable ligand, without concerning about the reaction
stereoselectivity.14
Fig. 2 Chiral sulfinamide-olefin ligand proposal.
Scheme 1 Initial attempts on using N-sulfinyl homoallylic amine as
ligand.
With 11 identified as the optimal novel sulfinamide-olefin
ligand, we then turned our attention to pursue the reaction
generality of this rhodium-catalyzed asymmetric 1,4-addition
(Table 2). In all cases, the reaction proceeded well, affording
the corresponding products in high yields with good to
excellent enantioselectivities. Among them, 2-cyclohexenone
(13a) was found to be particularly effective substrate (92–99%
yield except entry 7, 95–98% ee; entries 1–10). The steric and
electronic properties of the aryl boronic acids did not appear
to affect the reaction. When it came to 2-cyclopentenone (13b),
slightly better enantiomeric excesses of the adducts were
achieved with the sterically more hindered 1-naphthylboronic
acid or 3-tolylboronic acid (entries 15 and 16). Notably, in
addition to cyclic enones, this catalytic system is also applicable
for asymmetric addition of a,b-unsaturated cyclic ester 13c
and amide 13d, providing the products with high enantio-
selectivities. Unfortunately, when linear enone (E)-2-heptenone
was subjected to react with phenyl boronic acid, both low yield
(51%) and selectivity (38% ee) were afforded.
Fig. 3 Sulfinamide-olefins evaluated in this study.
Table 1 Screening of sulfinamide-olefin ligandsa
Entry
n
Ligand
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
1
1
1
2
1
5
6
7
8
9
10
11
12
6
99
99
99
99
99
99
99
99
21
99
99
99
99
82
85
94
94
95
94
95
94
In summary, we have demonstrated that simple and readily
available chiral sulfinamide-olefins can display great catalytic
activities and enantioselectivities in rhodium-catalyzed asymmetric
reactions. This study represent the first example of chiral sulfur-
olefin ligand class for transition metal-catalyzed asymmetric
transformation. Compared to the known chiral dienes and
pnictogen-based olefin ligands with the chirality being introduced
in the carbon backbone, it is noteworthy that the use of stereo-
genic sulfinamide as key chiral directing group provides an inno-
vative design of chiral sulfur ligands and has a great advantage in
terms of easy and practical ligand synthesis. We expect that this
type of novel sulfur-containing olefin ligand, and particularly
its design principles will find wide applications in asymmetric
catalysis. Our continued efforts to apply and develop sulfur-based
olefin ligands will be reported in due course.
9
À26
10
11
12
13
88
89
8
10
10 + 11
90
95
a
The reaction was carried out with 0.25 mmol of enone, 2 equiv. of
phenylboronic acid in the presence of 3 mol% of [Rh], 3 mol% of
b
ligand, 1.5 M aq K3PO4 (83 ml) in dioxane (0.5 mL). Isolated
yield. Determined by chiral HPLC.
c
aromatic moiety (ligands 7–10) gave the same level of enantio-
selectivity (94–95% ee) (entries 4–7). In contrast, alteration of
the –OBz portion of the ligand led to a significant loss in both
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7230–7232 7231

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Table 2 Asymmetric 1,4-addition of arylboronic acids to a,b-unsa-
turated cyclic carbonyl compounds catalyzed by [RhCl(C2H4)2]2/11a
F. Lang, H. Ruegger, D. Stein, M. Worle and H. Grutzmacher,
¨ ¨
¨ ¨
Chem.–Eur. J., 2006, 12, 5849; (c) R. Shintani, W.-L. Duan,
T. Nagano, A. Okada and T. Hayashi, Angew. Chem., Int. Ed.,
2005, 44, 4611; (d) C. Defieber, M. A. Ariger, P. Moriel and
E. M. Carreira, Angew. Chem., Int. Ed., 2007, 46, 3139;
(e) B. T. Hahn, F. Tewes, R. Frohlich and F. Glorius, Angew.
Chem., Int. Ed., 2010, 49, 1143.
¨
5 (a) Organosulfur Chemistry in Asymmetric Synthesis, ed. T. Toru
and C. Bolm, Wiley-VCH, Weinheim, Germany, 2008; (b) Chiral
Sulfur Ligands: Asymmetric Catalysis, ed. H. Pellissier, Royal
Society of Chemistry, Cambridge, UK, 2009; (c) M. Mellah,
A. Voituriez and E. Schulz, Chem. Rev., 2007, 107, 5133.
6 (a) Z.-Q. Wang, C.-G. Feng, M.-H. Xu and G.-Q. Lin, J. Am.
Chem. Soc., 2007, 129, 5336; (b) C.-G. Feng, Z.-Q. Wang, P. Tian,
M.-H. Xu and G.-Q. Lin, Chem.–Asian J., 2008, 3, 1511;
(c) C.-G. Feng, Z.-Q. Wang, C. Shao, M.-H. Xu and G.-Q. Lin,
Org. Lett., 2008, 10, 4101; (d) Z.-Q. Wang, C.-G. Feng,
S.-S. Zhang, M.-H. Xu and G.-Q. Lin, Angew. Chem., Int. Ed.,
2010, 49, 5780; (e) L. Wang, Z.-Q. Wang, M.-H. Xu and G.-Q. Lin,
Synthesis, 2010, 3263; (f) S.-S. Zhang, Z.-Q. Wang, M.-H. Xu and
G.-Q. Lin, Org. Lett., 2010, 12, 5546; (g) H.-Y. Yang and
M.-H. Xu, Chem. Commun., 2010, 46, 9223.
Entry
13
Ar
14
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13b
13b
13b
13b
13b
13b
13c
13c
13c
13c
13d
C6H5
4-MeC6H4
4-FC6H4
14a
14b
14c
14d
14e
14f
14g
14h
14i
99
98
99
99
98
98
53
92
99
98
99
96
96
98
99
93
91
85
74
86
88
95
96
97
95
95
98
98
97
98
97
92
88
92
87
93
98
78
89
94
84
85
4-ClC6H4
4-MeOC6H4
3-MeC6H4
2-MeC6H4
2-MeOC6H4
1-Naphthyl
2-Naphthyl
C6H5
4-MeC6H4
4-ClC6H4
4-MeOC6H4
1-Naphthyl
3-MeC6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
14j
14k
14l
7 For recent reviews on the chemistry of N-tert-butanesulfinimines,
see: (a) C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Han
and E. Gallon, Aldrichimica Acta, 2005, 38, 93; (b) F. Ferreira,
´
C. Botuha, F. Chemla and A. Perez-Luna, Chem. Soc. Rev., 2009,
38, 1162; (c) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem.
Rev., 2010, 110, 3600.
14m
14n
14o
14p
14q
14r
14s
14t
14u
8 (a) Y.-W. Zhong, M.-H. Xu and G.-Q. Lin, Org. Lett., 2004, 6,
3953; (b) Y.-W. Zhong, K. Isumi, M.-H. Xu and G.-Q. Lin, Org.
Lett., 2004, 6, 4747; (c) Y.-W. Zhong, Y.-Z. Dong, K. Fang,
K. Isumi, M.-H. Xu and G.-Q. Lin, J. Am. Chem. Soc., 2005,
127, 11956; (d) R.-H. Liu, K. Fang, B. Wang, M.-H. Xu and
G.-Q. Lin, J. Org. Chem., 2008, 73, 3307; (e) R. Wang, K. Fang,
B.-F. Sun, M.-H. Xu and G.-Q. Lin, Synlett, 2009, 2301;
(f) G.-Q. Lin, M.-H. Xu, Y.-W. Zhong and X.-W. Sun, Acc. Chem.
Res., 2008, 41, 831; (g) A. Shen, M. Liu, Z.-S. Jia, M.-H. Xu and
G.-Q. Lin, Org. Lett., 2010, 12, 5154; (h) D.-M. Ji and M.-H. Xu,
Chem. Commun., 2010, 46, 1550; (i) S.-S. Jin and M.-H. Xu, Adv.
Synth. Catal., 2010, 352, 3136; (j) L. Wang, C. Shen and M.-H. Xu,
Sci. China Chem., 2011, 54, 61.
9 (a) X.-W. Sun, M.-H. Xu and G.-Q. Lin, Org. Lett., 2006, 8, 4979;
(b) X.-W. Sun, M. Liu, M.-H. Xu and G.-Q. Lin, Org. Lett., 2008,
10, 1259; (c) M. Liu, X.-W. Sun, M.-H. Xu and G.-Q. Lin,
Chem.–Eur. J., 2009, 15, 10217; (d) M. Liu, A. Shen, X.-W. Sun,
F. Deng, M.-H. Xu and G.-Q. Lin, Chem. Commun., 2010, 46, 8460.
10 In our previous studies, we reported our successful development of
simple approaches for highly diastereoselective synthesis of chiral
homoallylic amines including densely functionalized a-vinyl-b-amino
alcohols by Zn- or In-mediated allylation at room temperature,
see ref. 9.
4-ClC6H4
2-MeOC6H4
3-MeC6H4
C6H5
a
The reaction was carried out with 0.25 mmol of 13, 2 equiv. of
arylboronic acid in the presence of 3 mol% of [Rh], 3 mol% of ligand,
b
1.5 M aq K3PO4 (83 ml) in dioxane (0.5 mL) at 60 1C. Isolated
yield. Determined by chiral HPLC.
c
This work was generously supported by the National Natural
Science Foundation of China (20972172, 21021063), the Chinese
Academy of Sciences, and National Science & Technology Major
Project.
Notes and references
1 (a) Asymmetric Catalysis on Industrial Scale, ed. H. U. Blaser and
E. Schmidt, Wiley-VCH, 2004; (b) New Frontiers in Asymmetric
Catalysis, ed. K. Mikami and M. Lautens, Wiley, New Jersey,
2007; (c) Catalysis in Asymmetric Synthesis, ed. V. Caprio and
J. M. J. Williams, Wiley, New Jersey, 2nd edn, 2009; (d) Catalytic
Asymmetric Synthesis, ed. I. Ojima, Wiley, New Jersey, 3rd edn,
2010; (e) in Privileged Chiral Ligands and Catalysts, ed. Q.-L. Zhou,
Wiley, New Jersey, 2011.
11 For leading reviews on rhodium-catalyzed asymmetric conjugate
addition, see: (a) K. Fagnou and M. Lautens, Chem. Rev., 2003,
103, 169; (b) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103,
2829; (c) J. Christoffers, G. Koripelly, A. Rosiak and M. Rossle,
¨
2 (a) T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida, J. Am.
Chem. Soc., 2003, 125, 11508; (b) C. Fischer, C. Defieber, T. Suzuki
and E. M. Carreira, J. Am. Chem. Soc., 2004, 126, 1628.
3 For leading reviews on chiral diene ligands in asymmetric catalysis,
see: (a) F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 3364;
Synthesis, 2007, 1279; (d) Rhodium- and Palladium-Catalyzed
Asymmetric Conjugate Additions, ed. G. Berthon and T. Hayashi,
Wiley-VCH, 2010.
12 We also prepared the corresponding N-free and N-acetyl homoallylic
amines for catalysis test, but no reaction occurred. These results
suggest involvement of amide NH in chelation can be excluded.
13 For ligand 12, the low reactivity is probably due to the
syn-orientation between the two phenyl substituents, which would
disfavor the six-membered ring transition state.
(b) C. Defieber, H. Grutzmacher and E. M. Carreira, Angew.
¨
Chem., Int. Ed., 2008, 47, 4482; (c) R. Shintani and T. Hayashi,
Aldrichimica Acta, 2009, 42, 31.
4 For some recent promising examples, see: (a) P. Maire, S. Deblon,
F. Breher, J. Geier, C. Bohler, H. Ruegger, H. Schonberg and
¨
14 In general, this reaction in THF gives around 80% de, see ref. 9c
for details.
¨
H. Grutzmacher, Chem.–Eur. J., 2004, 10, 4198; (b) E. Piras,
¨
¨
c
7232 Chem. Commun., 2011, 47, 7230–7232
This journal is The Royal Society of Chemistry 2011