Highly enantioselective asymmetric hydrogenation of (E)-β,β- disubstituted α,β-unsaturated Weinreb amides catalyzed by Ir(i) complexes of SpinPhox ligands

Article abstract of DOI:10.1039/c2cc30812f

The Ir(i) complexes of chiral spiro phosphino-oxazoline ligands (SpinPhox) have demonstrated good to excellent enantioselectivity in the asymmetric hydrogenation (AH) of a variety of (E)-β,β-disubstituted α,β-unsaturated N-methoxy-N-methylamides, affording the corresponding optically active Weinreb amides with up to 97% ee.

Full text of DOI:10.1039/c2cc30812f

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COMMUNICATION
Highly enantioselective asymmetric hydrogenation of
(E)-b,b-disubstituted a,b-unsaturated Weinreb amides catalyzed
by Ir(I) complexes of SpinPhox ligandsw
Jian Shang, Zhaobin Han, Yang Li, Zheng Wang and Kuiling Ding*
Received 4th February 2012, Accepted 2nd April 2012
DOI: 10.1039/c2cc30812f
The Ir(I) complexes of chiral spiro phosphino–oxazoline ligands
(SpinPhox) have demonstrated good to excellent enantioselectivity
in the asymmetric hydrogenation (AH) of a variety of (E)-b,b-
disubstituted a,b-unsaturated N-methoxy-N-methylamides, affording
the corresponding optically active Weinreb amides with up to 97% ee.
The a,b-unsaturated Weinreb amide substrates 1a–r were
readily synthesized in good to high yields by following a
literature method (see ESIw).14 The chiral iridium complexes
(R,S)-3a–e and (S,S)-3b–e were synthesized according to our
previously published procedure.13a To examine the feasibility of
the catalysis, initial investigations were performed with 1a as the
model substrate and (R,S)-3a as the catalyst. As shown in
Table 1, the solvent effect is dramatic for this reaction
(entries 1–7), and dichloromethane was found to be the superior
solvent (92% conversion, 89% ee). Lowering the initial hydrogen
pressure from 50 to 20 atm resulted in a marked decline in
the substrate conversion (92 vs. 66%, entries 1 and 8), albeit the
effect on the enantioselectivity is only marginal (89 vs. 87% ee).
N-Methoxy-N-methylamides, well-known as Weinreb amides,1
have been established as an important class of acylating agents
with numerous synthetic utilities.2 Given the wide utilities of
optically active Weinreb amides as a stable chiral acylating
agent in asymmetric synthesis, development of novel and efficient
methodologies for their synthesis would be highly desirable. Among
the rare examples, Hayashi et al. reported in 2005 a Rh-catalyzed
highly enantioselective asymmetric 1,4-addition of arylboronic acids
to a,b-unsaturated Weinreb amides.3 Very recently, Takacs et al.
demonstrated that b,g-unsaturated Weinreb amides are amenable
to Rh-catalyzed asymmetric hydroboration, to afford chiral
organoboronates that can be easily transformed into chiral ketones
or aldehydes.4 Clarke et al. reported an Rh/diphosphine catalyzed
highly regioselective asymmetric hydroformylation of acrylic
Weinreb amide to give the enantio-enriched aldehyde.5 We
envisioned that transition metal catalyzed AH6 of the readily
accessible prochiral unsaturated N-methoxy-N-methylamides
would be an efficient and atom-economical route to optically
active Weinreb amides. While some excellent Ir-based catalytic
systems have been reported for AH of CQC double bonds in
a,b-unsaturated carbonyl compounds in general,7 examples that
are especially effective for the AH of a,b-unsaturated amides are
relatively rare.8 In particular, to the best of our knowledge,
there has been no systematic study on the catalytic AH of
unsaturated Weinreb amides so far.9 Herein, we present the
iridium-catalyzed AH10 of (E)-b,b-disubstituted a,b-unsaturated
Weinreb amides with iridium(I) complexes 3 bearing a spiro P4N
ligand11,12 (SpinPhox)13 as the catalysts.
Table 1 Screening of reaction conditions for (R,S)-3a-catalyzed AH
of a,b-unsaturated Weinreb amide 1aa
Entry
Solvent
P(H2)/atm
T/1C
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
DCE
CHCl3
PhCH3
Et2O
EtOAc
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
50
50
50
50
50
50
20
20
50
50
20
50
25
25
25
25
25
25
25
25
40
40
50
25
25
92
74
57
26
14
38
33
66
32
70
77
5
89
89
89
77
6
66
20
87
81
89
88
N.D.
89
9
10
11
12d
13e
>99
a
Unless otherwise specified, all reactions were carried out with
0.1 mmol of the substrate ([1a] = 0.1 M) in 1.0 ml of the solvent for
24 h, in the presence of 0.001 mmol (1 mol%) of the Ir catalyst (R,S)-3a.
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai, 200032, P.R. China.
b
c
Determined by 1H NMR analysis. Determined by HPLC on a
E-mail: kding@mail.sioc.ac.cn; Fax: +86 21 64166128
chiral AD-H column. In all cases, the absolute configuration of 2a was
determined to be (R) by comparison of the corresponding specific
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for all new compounds. CCDC
822915 ((R,S)-3a) and 865426 ((S,S)-3c). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc30812f
d
rotations with the literature value. Ir(I)/(S)-tBuPHOX was used as
e
the catalyst. N.D. = not determined. [(R, S)-3a] = 2 mM (2 mol%).
c
5172 Chem. Commun., 2012, 48, 5172–5174
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Table 2 Catalyst optimization for the SpinPhox–Ir-catalyzed AH of 1aa
Table 3 (R,S)-3b catalyzed AH of (E)-b,b-disubstituted a,b-unsatu-
rated Weinreb amidesa
Entry Substrate R1
R2
Conv.b (%) eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
4-MeC6H4
4-MeOC6H4
2,4-(MeO)2C6H3 Me >99
4-i-BuC6H4
4-FC6H4
4-ClC6H4
4-IC6H4
4-F3CC6H4
3-MeOC6H4
3-ClC6H4
2-MeC6H4
Naphthalen-2-yl Me >99
Naphthalen-1-yl Me >99
Benzyl
t-Bu
Me >99
Me >99
Me >99
95 (R)
97 (R)
96 (R)
83 (+)
96 (+)
96 (+)
94 (+)
94 (+)
92 (+)
95 (+)
95 (+)
82 (+)
95 (R)
79 (+)
91 (+)
N.D.d
96 (+)
90
Me >99
Me >99
Me >99
Me >99
Me >99
Me >99
Me >99
Me >99
Entry
Catalyst
Conv.b (%)
eec (%)
9
10
11
12
13
14
15
16
17
18
19e
20f
1j
1k
1l
1
2
3
4
5
6
7
8
(R,S)-3a
(R,S)-3b
(R,S)-3c
(R,S)-3d
(R,S)-3e
(S,S)-3b
(S,S)-3c
(S,S)-3d
(S,S)-3e
(R,S)-3b
(R,S)-3b
>99
>99
36
29
70
18
>99
6
89 (R)
95 (R)
79 (R)
82 (R)
77 (R)
61 (S)
84 (S)
50 (S)
45 (S)
94 (R)
94 (R)
1m
1n
1o
1p
1q
1r
1s
1a
Me >99
Me 12
Et >99
i-Pr 94
Me >99
Me >99
C6H5
C6H5
n-Bu
9
34
88
98
65 (+)
97
10d
11e
C6H5
For reaction conditions, see footnote a in Table 2. b Determined by
1H NMR analysis. c Determined by HPLC on a chiral AD-H column. The
absolute configurations were assigned by comparison of the corresponding
specific rotations with the literature values. d Not determined. e The
catalyst loading is 6 mol%. f The quantity of 1a in this case is 1.0 mmol.
a
a
Reaction conditions: [1a] = 0.1 M, [3] = 2 mM (2 mol%), T = 25 1C,
P(H2) = 50 atm, t = 24 h, dichloromethane solvent. Determined by
b
1H NMR analysis. Determined by HPLC (chiral AD-H column). The
absolute configuration was assigned by comparison of the specific
c
d
e
rotation with the literature value. t = 12 h. T = 0 1C.
a,b-unsaturated Weinreb amides 1a–s. As shown in Table 3, for
the reactions of substrates with a Me group at their b-position
(1a–o), quantitative conversions were generally attained in 24 h,
and enantioselectivities were good to excellent, ranging from 79
to 97% ee (entries 1–15). Among these substrates, reactions
involving those with a para- or meta-substituted b-phenyl ring
(1a–c and 1e–k) afforded uniformly high ee values (92–97%,
entries 1–3 and 5–11), irrespective of the electron-donating or
electron-withdrawing nature of the substituent. In contrast, the
enantioselectivities were slightly lower for reactions involving 1d
and 1l, both having a sterically somewhat more demanding
ortho-substituent on their b-phenyl rings. These observations
suggest that the steric properties of the b-substituent seem to
play a more substantial role than the electronic ones in
determining the enantioselectivity, and the steric congestion
of the b-substituent should have a negative impact on the
catalysis. This was also confirmed by the performance of
reactions involving 1m and 1n with a b-2- or b-1-naphthyl
substituent (95 vs. 79% ee, entries 13 and 14), which can
formally be viewed as 3,4- or 2,4-disubstituted phenyl rings,
respectively. Furthermore, the reactions involving (E)-b,b-dialkyl
substituted amides 1o, 1p, and 1s are also consistent with this
generalized trend. While AH of 1o afforded the corresponding
product in full conversion with 91% ee (entry15), the reaction
with 1p that bears a bulky b-t-Bu group proceeded much more
sluggishly to afford only a poor conversion (12%, entry 16), and
the reaction with 1s needs higher catalyst loading (6 mol%) for
full conversion (entry 19). In addition, AH of substrate 1q gave a
result comparable to that of its homologue 1a (entries 17 vs. 1),
Elevation of the reaction temperature from rt to 50 1C also
exhibited a minor effect on the enantioselectivity, however, the
conversion of 1a decreased considerably presumably as a result of
catalyst decomposition (entries 1 vs. 10 and 11, entries 8 vs. 9). The
use of an Ir(I) complex of an analogous tBuPHOX ligand11a
afforded only 5% conversion of 1a under the identical experimental
conditions (entry 12). Finally, the full conversion of 1a in 24 h was
realised under 50 atm of H2 in CH2Cl2 by increasing the catalyst
(R,S)-3a loading from 1 to 2 mol% (entry 13).
To further improve the enantioselectivity of the catalysis, a range
of (R,S)-3 or (S,S)-3 catalysts were screened in the AH of 1a under
the above-mentioned optimized reaction conditions. As shown in
Table 2, the chirality at the spiro backbone of the ligands obviously
plays a key role in determining the stereochemical outcome of the
asymmetric induction, as the (R,S)- and (S,S)-catalysts 3 always
afforded the hydrogenation product 2a with opposite absolute
configurations (entries 1–5 vs. 6–9). The (R,S)-3b, 3d, and 3e
generally demonstrated a higher conversion and ee value than their
corresponding (S,S)-analogues (entries 2, 4 and 5 vs. 6, 8 and 9,
respectively), even though irregularities do exist for the catalysis by
(R,S)- or (S,S)-3c (entries 3 vs. 7). This observation suggests
that the (R,S)-3 tend to be the chirality-matched catalysts for
enantioselectivity control. Among the Ir complexes (R,S)-3a–e
bearing various oxazolinyl substituents, (R,S)-3b turned out to
be optimal in terms of both reactivity and enantioselectivity
(>99% conversion, 95% ee, entry 2).
With these results in hand, we proceeded to further extend
the substrate scope by examining AH of (E)-b,b-disubstituted
c
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Chem. Commun., 2012, 48, 5172–5174 5173

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Financial support from NSFC (No. 21172237, 21121062,
21032007), the Major Basic Research Development Program
of China (Grant No. 2010CB833300), and the Chinese Academy
of Sciences is gratefully acknowledged.
Notes and references
1 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
2 For reviews, see: (a) M. P. Sibi, Org. Prep. Proced. Int., 1993,
25, 15; (b) M. Mentzel and H. M. R. Hoffmann, J. Prakt. Chem.,
1997, 339, 517; (c) J. Singh, N. Satyamurthi and I. S. Aidhen,
J. Prakt. Chem., 2000, 342, 340; (d) S. Balasubramaniam and
I. S. Aidhen, Synthesis, 2008, 3707.
3 R. Shintani, T. Kimura and T. Hayashi, Chem. Commun., 2005,
3213.
4 S. M. Smith, M. Uteuliyev and J. M. Takacs, Chem. Commun.,
2011, 47, 7812.
5 G. M. Noonan, D. Newton, C. J. Cobley, A. Suarez, A. Pizzano
´
and M. L. Clarke, Adv. Synth. Catal., 2010, 352, 1047.
6 For reviews, see: (a) Handbook of Homogeneous Hydrogenation, ed.
J. G. de Vries and C. J. Elsevier, Wiley VCH, Weinheim, 2007;
(b) G. Shang, W. Li and X. Zhang, in Catalytic Asymmetric Synthesis,
ed. I. Ojima, Wiley, Hoboken, 3rd edn, 2010, pp. 343–436.
Fig. 1 (a) X-Ray structures of (R,S)-3a (left) and (S,S)-3c (right),
H atoms, BArFÀ anion, and 1,5-cyclooctadiene are omitted for clarity.
(b) Schematic model for enantioselection of (R,S)- and (S,S)-3.
7 For examples, see: (a) S.-M. Lu and C. Bolm, Angew. Chem., Int. Ed.,
2008, 47, 8920; (b) W. Lu, Y. Chen and X. Hou, Angew. Chem., Int. Ed.,
2008, 47, 10133; (c) S. M. Lu and C. Bolm, Chem.–Eur. J., 2008,
14, 7513; (d) F. T. Tian, D. M. Yao, Y. Y. Liu, F. Xie and W. B. Zhang,
Adv. Synth. Catal., 2010, 352, 1841; (e) D. Liu, W. J. Tang and
X. Zhang, Org. Lett., 2004, 6, 513; (f) J. G. Zhou, J. W. Ogle,
Y. B. Fan, V. Banphavichit, Y. Zhu and K. Burgess, Chem.–Eur. J.,
2007, 13, 7162; (g) S. Li, S. F. Zhu, C. M. Zhang, S. Song and
Q. L. Zhou, J. Am. Chem. Soc., 2008, 130, 8584; (h) S. Li, S. F. Zhu,
J. H. Xie, S. Song, C. M. Zhang and Q. L. Zhou, J. Am. Chem. Soc.,
2010, 132, 1172; (i) D. H. Woodmansee, M. A. Muller, M. Neuburger
and A. Pfaltz, Chem. Sci., 2010, 1, 72; (j) D. Rageot, D. H.
Woodmansee, B. Pugin and A. Pfaltz, Angew. Chem., Int. Ed., 2011,
50, 9598.
8 W.-J. Lu and X.-L. Hou, Adv. Synth. Catal., 2009, 351, 1224 and
the references therein.
9 Burgess reported an example of chiral NHC–Ir catalyzed AH of a
Weinreb amide derivative with a moderate ee value (46%), see ref. 7f.
10 For reviews, see: (a) S. J. Roseblade and A. Pfaltz, Acc. Chem.
Res., 2007, 40, 1402; (b) X. Cui and K. Burgess, Chem. Rev., 2005,
whereas the reaction with sterically somewhat more crowded
1r resulted in incomplete conversion (94%) and a slightly
declined ee value (90%, entry 18). Finally, the procedure can
be scaled up to 1.0 mmol of the substrate, with even a slightly
higher ee value being obtained in the case of 1a (entry 20 vs. 1).
The structures of catalyst precursors (R,S)-3a and (S,S)-3c
have been determined by single crystal X-ray diffraction
(Fig. 1a, see ESIw for details).15 Inspired by the elegant DFT
study reported recently by Andersson et al.16 on the mechanism of
Ir/P4N catalyzed hydrogenation of unfunctionalized olefins as well
as the structures of (R,S)-3a and (S,S)-3c (Fig. 1a), we tentatively
propose a schematic model to account for the stereoselection in the
(R,S)- or (S,S)-3 catalyzed hydrogenation of unsaturated amides 1,
a class of trisubstituted olefins. As shown in Fig. 1b, the bulky
oxazolyl substituent is forced to situate either above or below the
equatorial plane defined by N–Ir–P of the catalytic intermediates
{[(R,S)-3]Ir(H)2(H2)(1)}+ or {[(S,S)-3]Ir(H)2(H2)(1)}+, respectively,
as a result of the constraints of the rigid spiro ligand backbone. The
unsaturated amide is coordinated trans to the phosphorous moiety,
and oriented with the smallest substituent (H atom) pointing
towards the oxazoline fragment. The sense of enantioselection
predicted on the basis of this model can rationalize the
opposite asymmetric inductions in AH of 1a using (R,S)- or
(S,S)-3 catalysts (Table 2).
105, 3272; (c) K. Kallstrom, I. Munslow and P. G. Andersson,
¨
¨
Chem.–Eur. J., 2006, 12, 3194; (d) Y.-G. Zhou, Acc. Chem. Res.,
2007, 40, 1357; (e) D. H. Woodmansee and A. Pfaltz, Chem.
Commun., 2011, 47, 7912.
11 For reviews, see: (a) G. Helmchen and A. Pfaltz, Acc. Chem. Res.,
2000, 33, 336; (b) H. A. McManus and P. J. Guiry, Chem. Rev.,
2004, 104, 4151; (c) I. D. Kostas, Curr. Org. Synth., 2008, 5, 227.
12 The spirobackbone based chiral ligands in asymmetric catalysis, see:
(a) Privileged Chiral Ligands and Catalysts, ed. Q.-L. Zhou, Wiley-VCH,
Weinheim, 2011; (b) A. S. C. Chan, W. Hu, C.-C. Pai, C.-P. Lau,
Y. Jiang, A. Mi, M. Yan, J. Sun, R. Lou and J. Deng, J. Am. Chem.
Soc., 1997, 119, 9570; (c) J.-H. Xie and Q.-L. Zhou, Acc. Chem. Res.,
2008, 41, 581; (d) K. Ding, Z. Han and Z. Wang, Chem.–Asian J., 2009,
4, 32; (e) G. B. Bajracharya, M. A. Arai, P. S. Koranne, T. Suzuki,
S. Takizawa and H. Sasai, Bull. Chem. Soc. Jpn., 2009, 82, 285.
13 (a) Z. Han, Z. Wang, X. Zhang and K. Ding, Angew. Chem., Int.
Ed., 2009, 48, 5345; (b) Y. Zhang, Z. Han, F. Li, K. Ding and
A. Zhang, Chem. Commun., 2010, 46, 156; (c) X. Wang, Z. Han,
Z. Wang and K. Ding, Angew. Chem., Int. Ed., 2012, 51, 936.
14 W. S. Wadsworth, Organic Reactions, J. R. Wiley and Sons,
New York, 1977, vol. 25, pp. 73–253.
In summary, catalytic AH of a,b-unsaturated Weinreb amides
using chiral Ir catalysts 3 has provided an efficient and clean
route to enantio-enriched Weinreb amides. Full conversions and
excellent ee values (up to 97%) can be obtained under the
optimized conditions, and the sterically less bulky substituents
at the b-position seem to be more amenable to the present
catalytic protocol. Given the easy access to various unsaturated
Weinreb amide substrates, such a catalytic AH methodology
is expected to find broad applications in the preparation of
optically active Weinreb amides.
15 CCDC 822915 ((R,S)-3a) and CCDC 865426 ((S,S)-3c) contain the
supplementary crystallographic data for this paper.
16 T. L. Church, T. Rasmussen and P. G. Andersson, Organometallics,
2010, 29, 6769 and the references cited therein.
c
5174 Chem. Commun., 2012, 48, 5172–5174
This journal is The Royal Society of Chemistry 2012