Iridium-catalyzed enantioselective allylic substitution with aqueous solutions of nucleophiles

Article abstract of DOI:10.1021/jacs.9b05830

The iridium-catalyzed asymmetric allylic substitution under biphasic conditions is reported. This approach allows the use of various unstable and/or volatile nucleophiles including hydrazines, methylamine, t-butyl hydroperoxide, N-hydroxylamine, α-chloroacetaldehyde and glutaraldehyde. This transformation provides rapid access to a broad range of products from simple starting materials in good yields and up to >99% ee and 20:1 d.r. Additionally, these products can be elaborated efficiently into a diverse set of cyclic and acyclic compounds, bearing up to four stereocenters.

Full text of DOI:10.1021/jacs.9b05830

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Communication
Iridium-Catalyzed Enantioselective Allylic
Substitution with Aqueous Solutions of Nucleophiles
Tobias Sandmeier, F. Wieland Goetzke, simon krautwald, and Erick M Carreira
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05830 • Publication Date (Web): 18 Jul 2019
Downloaded from pubs.acs.org on July 18, 2019
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Iridium-Catalyzed Enantioselective Allylic Substitution with
Aqueous Solutions of Nucleophiles
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Tobias Sandmeier, F. Wieland Goetzke, Simon Krautwald and Erick M. Carreira*
ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
Supporting Information Placeholder
ABSTRACT: The iridium-catalyzed asymmetric allylic
substitution under biphasic conditions is reported. This approach
Scheme 1. Iridium-Catalyzed Allylic Substitution Using
Nucleophiles or their Hydrates in Aqueous Solutions.
allows the use of various unstable and/or volatile nucleophiles
including hydrazines, methylamine, t-butyl hydroperoxide, N-
hydroxylamine, α -chloroacetaldehyde and glutaraldehyde. This
transformation provides rapid access to a broad range of products
from simple starting materials in good yields and up to >99% ee
and 20:1 d.r. Additionally, these products can be elaborated
efficiently into a diverse set of cyclic and acyclic compounds,
bearing up to four stereocenters.
Unknown or Incompatible with Current Enantioselective Allylation
N2H4, RO2H, MeNH2, NH2OH
(available & safe in H2O)
MeSH (gas)
(available as thilate in H2O)
ClCH2CHO, BrCH2CHO,
OHC(CH2)3CHO
(hydrates available as aq solutions)
Cl2CHCHO
(solid hydrate)
This work
OH
H2O-ClCH2CH2Cl
Biphase
[Ir(cod)Cl]2 (3 mol%)
+
(S)-L
(12 mol%), H
R
Enantioselective, transition metal-catalyzed allylic substitution
has emerged as a powerful tool for the synthesis of chiral building
blocks from simple starting materials and a wide range of
nucleophiles.1 The electrophilic nature of the η3-organometal
intermediate typically restricts the conditions to non-nucleophilic
organic solvents and with few exceptions prescribes rigorous
exclusion of water.2 Yet, there are a number of highly reactive
and/or unstable small molecules such as chloroacetaldehyde,
hydrazines or N-hydroxylamine that due to their reactivity or
limited stability in pure form are stored, sold, and most safely
handled as aqueous solutions. To date, only protected versions of
these reagents including hydroxamic acids and hydrazones have
been employed in transition metal-catalyzed allylic substitution.2d,3
Developing methods which employ the commercially available
aqueous solutions of these unstable molecules, however, would
significantly expand the synthetic utility of enantioselective
catalysis.
O
O
OH
NH2
HN
X
HN
OHC
H
H
R
R
R
R
Ot-Bu
NHMe
O
X = Cl, Br, H
R
O
R
R
O
Cl
P
N
O
H
SMe
Cl
R
H
(S)-L
Excess water can pose a challenge in transition metal-catalyzed
allylic substitution not only because it can lead to decomposition of
the η3-organometal intermediate but also due to its inherent
nucleophilicity.2g,10 Thus, for a productive catalytic cycle with
nucleophiles in aqueous solutions, the nucleophilic addition of
water to the activated allyl-metal complex needs to be either
kinetically disfavored or reversible. This makes allylic substitution
reactions employing branched, unactivated allylic alcohols prime
targets for the development of biphasic reactions, as nucleophilic
attack by water would regenerate the starting material. With these
considerations in mind, we set out to develop a general approach to
biphasic allylic substitutions using the complex derived from
[Ir(cod)Cl]2/(S)-L and nucleophiles in aqueous solutions.11
In general, organocatalytic methods based on enamine catalysis
or hydrogen bonding catalysts have been shown to be compatible
with aqueous media.4 For instance, aqueous chloroacetaldehyde
has been employed as an electrophile in enzymatic or
organocatalytic aldol reactions but its use as an nucleophile remains
elusive.5 In the field of asymmetric transition-metal catalysis,
biphasic systems for enantioselective oxidations6 and
hydrogenations7 have garnered significant attention, but
transformations generating carbon-carbon bonds under aqueous
conditions remain scarce.8 Herein we report the asymmetric
substitution reaction of racemic allylic alcohols with aqueous
nucleophiles such as hydrazines, N-hydroxylamines, and α-halo-
acetaldehydes catalyzed by a chiral Ir(P,olefin) complex under
aqueous biphasic conditions (Scheme 1). The transformations
employ aqueous solutions that the reagents are supplied in, and thus
avoid laborious extraction and dehydration techniques.9 Our
approach delivers products in good yields and high regio- and
enantioselectivities for nucleophiles that have been rarely
employed to date.
Our group has previously developed an Ir(P,olefin) complex
derived from phosphoramidate ligand (S)-L and iridium(I) for the
displacement of allylic alcohols with various nucleophiles.11 Key
features of this catalytic system are its high robustness and its use
of branched, unactivated allylic alcohols as substrates, activated by
Brønsted acids.11b Therefore, we envisioned that this system would
be well suited to explore allylic substitutions under biphasic
conditions with nucleophiles that are stabilized in water and thus
readily available as aqueous solutions. To demonstrate the
feasibility of this approach, we initially focused on aqueous
hydrazine. Chiral hydrazine derivatives are used in stereoselective
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Page 2 of 7
[3+2]-cycloadditions,12
as
organocatalysts,13
and
as
(NaCl, Na2SO4, MgSO4) increased the overall conversion of the
reaction. Presumably, an increase of ionic strength facilitates
transfer of the water-soluble aldehyde to the organic phase.27
commercialized drugs for the treatment of Parkinson’s disease.14
Hydrazine is a colorless liquid that decomposes explosively and is
commonly used as a rocket fuel.15 Thus, aqueous solutions of
hydrazine find widespread applications in organic synthesis. When
a 51% aqueous solution of hydrazine was used in combination with
the Ir(P,olefin) complex, allylic alcohol 1a (R = 2-Np) and 3,5-
dichlorobenzoic acid as a Brønsted acid promoter adduct 2a was
obtained in 61 % yield and 94% ee (Table 1).16 This result
encouraged us to investigate aqueous solutions of various
substituted hydrazine derivatives (Table 1, 2b-2e). Of particular
interest are substrates 2d and 2e. Such 1-amino piperazine and 4-
amino-1,2,3-triazole derivatives have garnered significant attention
from medicinal chemists and can be found in commercial drugs.17
Due to their limited solubility in aprotic, non-nucleophilic organic
solvents and the fact that they are freely soluble in water, these
substrates demonstrate the synthetic power of a biphasic approach
1
2
3
4
5
6
7
8
Table 1. Scope of the Biphasic Iridium-Catalyzed
Allylation of N-, O- and S-Nucleophiles.a
[Ir(cod)Cl]2 (3 mol%)
Y
OH
L
(S)- (12 mol%)
X
Y
+
HX
acidic promoter
R
R
1
2
water
21-70% in
9
(1.1 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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30
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Me
Me
NH2
HN
NH
N
HN
HN
Me
2-Np
2-Np
2-Np
2c:
51%, 97% ee
b
c
d
2a:
2b:
61%, 94% ee
73%, 98% ee
Subsequently, we examined methyl, ethyl and dimethyl amine,
which are gases at room temperature but are readily available as
aqueous solutions. Interestingly, for these more basic and less
nucleophilic reagents, kinetic resolution of allylic alcohol 1a was
observed, and the enantioselectivity and conversion was found to
strongly depend on the acidic promoter used (see supplementary
information). With 3,5-dichlorobenzoic acid the corresponding
secondary and tertiary amines were obtained in good yields along
with the enantioenriched starting material. We then aimed to
expand the scope of aqueous nucleophiles to other heteroatoms.
Interestingly, tert-butyl hydroperoxide and sodium thiomethoxide,
sold as 70% and 21% aqueous solutions respectively, afforded the
corresponding adducts (2p and 2q) in good yield and
stereoselectivity. It is noteworthy, that the catalytic system
described herein is compatible with both reductants (hydrazines)18
and oxidants (t-butyl hydroperoxide).
Me
N
N
N
N
N
HN
HN
2-Np
2-Np
d
d
2d:
2e:
66%, >99% ee
63%, >99% ee
Me
HN
Et
Me
Me
HN
N
2-Np
2-Np
2-Np
e
e,f
e
2f:
2g:
1a:
2h:
1a:
41%, >99% ee
45%, 95% ee
42%, 93% ee
45%, 97% ee
45%, 94% ee
43%, 94% ee
1a:
O
Me
S
t-Bu
O
Encouraged by these results, N-hydroxylamine was also
investigated as nucleophile for iridium-catalyzed allylic
substitution. N-alkylated hydroxylamines are useful precursors for
chiral nitrones and find application in the synthesis of complex
molecules.19 Similarly to hydrazine, hydroxylamine is preferably
used as an aqueous solution or its hydrochloride salt since the pure
compound is unstable.20 Recently Zhao reported the
enantioselective allylation of H2NOH·HCl requiring DMSO as
solvent and triethyl amine to liberate hydroxyl amine.21 Hence, we
believe the biphasic system utilizing aqueous N-hydroxylamine
complements this approach. When a 50% aqueous solution of N-
hydroxylamine was used in combination with the Ir(P,olefin)
complex, allylic alcohol 1a (R = 2-Np) and dibenzenesulfonamide
as a Brønsted acid promoter a adduct 2k was obtained in 64% yield
and 93% ee. This transformation was found to be compatible with
a series of allylic alcohols with excellent selectivity for N-
alkylation (Table 1, and supporting information).
2-Np
2-Np
g
h
2i:
2j:
78%, 90% ee
86%, 80% ee
OH
OH
HN
HN
OH
HN
2-Np
I
F
2m:
i
i
i
2k:
2l:
64%, 93% ee
81%, 95% ee
67%, 94% ee
OH
OH
HN
HN
F3C
S
i
i
2o:
2n:
73%, 97% ee
57%, 96% ee
a 0.25 mmol scale. Isolated Yields. ee determined SFC on a chiral
stationary phase. 2-Np= 2-naphthyl. (PhSO2)2NH (1.3 equiv),
isolated after benzoylation. DCBA (1.3 equiv), yield determined
We next focused on the construction of carbon-carbon bonds
under biphasic conditions. Since the synthesis of halogenated,
biologically active molecules has been an ongoing field of research
in our group,22 we first investigated chloracetaldehyde (3) as
nucleophile. Due to its high reactivity chloroacetaldehyde is only
commercially available as a 50% aqueous solution.23-25 Notably,
the asymmetric α-functionalization of chloracetaldehyde is not
known. thus, our approach provides a complementary approach to
optically active chlorides which are traditionally obtained by
organocatalytic α-halogenation.26
b
c
1
by H NMR with an internal standard, isolated after acetylation.
dDCBA (1.8 equiv). e2.0 equiv. of nucleophile, DCBA (2.3 equiv).
f2.0 equiv. of nucleophile, DCBA (2.8 equiv). (PhSO2)2NH (0.5
g
equiv). h(PhO)2P(O)OH (1.8 equiv). acid. i(PhSO2)2NH (1.3 equiv).
DCBA = 3,5-dichlorobenzoic
With optimized conditions in hand, the substrate scope of the
reaction with regard to allylic alcohols was explored (Table 2).
Electron-poor as well as electron-rich substrates were tolerated,
resulting in good yields (41-81%), d.r. values between 5:1 and 20:1
and excellent enantioselectivity (>99% ee) (4c-4j). Additionally,
hetereoaromatic allylic alcohols (1k and 1l) afforded the respective
products in good yields and excellent selectivities.
We found that using 1b (R
=
Ph) and aqueous
chloroacetaldehyde in combination with proline derived amine
A1,26b ligand (R)-L, and dimethylphosphate afforded aldehyde 4b
in 82% yield, 10:1 d.r. and >99% ee. Optimization studies revealed
that using solvents that give a homogenous reaction mixture such
as 1,4-dioxane or acetone did not lead to any product formation,
indicating that biphasic conditions were essential for this
transformation. Furthermore, we found that inorganic salt additives
When dichloroacetaldehyde (3b), commercially available as its
solid hydrate, was employed under identical reaction conditions, no
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Journal of the American Chemical Society
allylated product was obtained. Optimization studies revealed that
for this sterically hindered aldehyde, primary amine catalysts were
required. The iridium-catalyzed reaction of solid
dichloroacetaldehyde hydrate, diphenylmethane amine, allylic
alcohol 1a and Zn(OTf)2 as a Lewis acid promoter afforded the
corresponding dichlorinated aldehyde, which was isolated as
primary alcohol 4m in 55% yield and >99% ee after reduction with
NaBH4. Bromoacetaldehyde could also be allylated by slight
alteration of the reaction conditions and several adducts (4n-4w)
could be obtained in 62–83% yield, high diastereomeric ratios
(10:1–20:1 d.r.) and excellent enantioselectivity (98 - >99% ee).
1
2
3
4
5
6
7
Table 2. Allylic Alcohol Scope of the α-Allylation of Aqueous Chloro- and Bromoacetaldehyde.a
8
9
[Ir(cod)Cl]2 (3 mol%)
O
Ar
Ar
OSiMe3
Ar = 3,5-(CF3)2-Ph
L
(R)- (12 mol%)
OH
O
X
A1
(S)-
(10 mol%)
H
10
11
12
13
14
15
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17
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+
N
R
H
R
(MeO)2PO2H (75 mol%)
MgSO4, DCE (0.5 M)
rt, 14 - 26 h
H
X
X
X
water
50 % in
3a
, 2.0 equiv
: X = Cl, Cl
3bb
1a-q
4
A1
(S)-
: X = Cl, H,
3cc
: X = Br, H
O
O
O
O
O
H
H
H
H
H
Cl
Cl
4d:
Cl
Cl
Cl
F
CHO
OMe
65%, 10:1 d.r.
4a:
4b:
4c:
4e:
74%, 10:1 d.r.
>99% ee
82%, 10:1 d.r.
>99% ee
61%, 7:1 d.r.
>99% ee
41%, 5:1 d.r.
>99% ee
>99% ee
O
OMe
O
OMe
O
O
Me
O
O
B
H
O
H
H
H
O
H
Cl
Cl
MeO
Cl
Cl
O
CO2Me
Cl
OMe
63%, 5:1 d.r.
>99% ee
4f:
4g:
4h:
4i:
4j:
77%, 12:1 d.r.
>99% ee
54%, 15:1 d.r.
>99% ee
71%, 7:1 d.r.
>99% ee
81%, 2:1 d.r.
>99% ee
O
O
H
HO
H
Cl
S
Cl Cl
Cl
NBoc
[X-Ray]
4m:
55%
>99% ee
of a derivative
4b
4k:
4l:
73%, 10:1 d.r.
>99% ee
75%, 20:1 d.r.
>99% ee
of
O
O
O
O
Me
O
OMe
O
O
H
H
H
H
H
Br
Br
Br
Br
Br
Br
4q:
4n:
4o:
4p:
4r:
75%, 20:1 d.r.
>99% ee
72%, 16:1 d.r.
>99% ee
80%, 10:1 d.r.
>99% ee
83%, 17:1 d.r.
98% ee
72%, 10:1 d.r.
>99% ee
O
O
O
O
O
Br
H
H
H
H
H
Br
Br
Br
Br
Br
S
I
F
CO2Me
4s:
4t:
4u:
4v:
4w:
62%, 19:1 d.r.
>99% ee
71%, 13:1 d.r.
>99% ee
75%, 14:1 d.r.
>99% ee
47%, 12:1 d.r.
>99% ee
73%, 19:1 d.r.
>99% ee
a
1
0.25 mmol scale. Isolated yields. ee SFC on a chiral stationary phase. Diastereomeric ratios (d.r.) determined by H NMR analysis of
isolated products. DCE = 1,2-dichloroethane. The (R)-L, (R)-A1 or (S)-L, (S)-A1 ligand combination resulted in a d.r. of approximately 1:1.
Reaction conditions: bBenzhydrylamine (0.1 equiv), ZnBr2 (50 mol%), 40°C, then NaBH4, MeOH. c(S)-L, (R)-A1, (PhSO2)2NH (50 mol%)
and Na2SO4.
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In an effort to demonstrate the synthetic versatility of the product
chiral α-chloro- and α-bromoaldehydes, variety of
To further extend the synthetic potential of this iridium-catalyzed
α-allylation of aldehydes in biphasic media, glutaraldehyde was
a
1
2
3
4
5
6
7
8
functionalization reactions were carried out (Scheme 2). Diverse
heterocycles with various ring sizes including aziridines (8),
tetrahydrofurans (10) and β-lactams (7) could be accessed
efficiently. Addition of acetophenone to 4b followed by syn-
selective reduction allowed the installation of two additional
stereocenters with good selectivity (product 5). Furthermore,
reduction of 4b and 4o to the primary alcohol with NaBH4 enables
the synthesis of β-chloronitrile 6 and hydroxylthio ether 11.
examined as
a substrate. Like many small dialdehydes,
glutaraldehyde is unstable and readily forms polymeric solids.28 In
aqueous solutions, glutaraldehyde forms cyclic hydrate 13 which
can be stored for extended periods of time (Scheme 3).29
We found that 13 also participates in dual-catalytic α-allylation
reactions with allylic alcohol 1b. Interestingly, the reaction
proceeds with high selectivity for the mono-allylated aldehyde.
Since attempts to isolate the resulting dialdehyde were
unsuccessful, the crude reaction mixture was reduced to the
corresponding diol 14, which could be further elaborated into
tetrahydropyran 15 Alternatively, the mono-allylated aldehyde
could be reductively aminated in one pot to afford piperidine 16,
demonstrating the synthetic potential of the method for the
enantioselective synthesis of chiral saturated heterocycles.
Additionally, we found that with an excess of allylic alcohol bis-
allylated product 17 could be obtained with high enantio- and
9
Scheme 2. Functionalization of γ,δ-Unsaturaded
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Aldehydesa
OH OH
a) b)
NC
diastereoselectivity.
Oxidation
of
diol
17
using
Cl
Cl
tetrapropylammonium perruthenate afforded unsymmetrical,
lactone 18. Sequential addition of two distinct allylic alcohols,
followed by reduction furnished asymmetric diol 19 in >99:1 ee
and >10:1 d.r., which is remarkable considering that the reaction
could in principle afford 16 different stereoisomers.
5:
6:
8:
68%, 8:1 d.r.
63%, 10:1 d.r.
O
N
In conclusion, we have developed a biphasic aqueous system for
the enantioselective iridium-catalyzed allylic substitution. This
approach allows the use of readily available aqueous solutions of
various nucleophiles which are otherwise highly volatile or
unstable when anhydrous. These biphasic conditions rely on a
robust catalyst system and allow for the synthesis of a broad range
of synthetically useful chiral intermediates such as hydrazines,
peroxides, N-hydroxylamines, α-halo-aldehydes, and diols. Their
use in asymmetric transition-metal catalysis has been largely
unexplored because of the requirements to use them in anhydrous
forms for most other catalyst systems. We believe that the concepts
disclosed in this report will serve as inspiration for other transition
metal-catalyzed transformations employing these readily available,
yet rarely used reagents.
N
BnO
7:
H
Cl
73%, 5.5:1.5:1 d.r.
41%, 10:1 d.r.
c)
d)
f)
X = Cl
X = Br
O
H
e)
X
4b
4n
: X = Cl; : X = Br
O
HO
O
I
Br
O
EtO
N
O
9:
10:
72%, 19:1 d.r.
68%, 8:1 d.r.
S
g) h)
O
OH
12:
61%, 10:1 d.r.
11:
76%, 13:1 d.r.
aReagents and conditions: For detailed experimental procedures see
supporting information. (a) 1) 4b, acetophenone, LDA; 2) DIBAL-
H. (b) 1) 4b, NaBH4; 2) Tf2O, 2,6-lutidine, then KCN, 18-crown-
6. (c) 4b, cyclohexylamine, MgSO4, then 2-(benzyloxy)acetyl
chloride, NEt3. (d) 1) 4b, NaBH4; 2) Tf2O, 2,6-lutidine, then
H2NBn. (e) 4n, imidazole, ethyl nitroacetate. (f) 1) 4n, NaBH4; 2)
K2CO3, I2. (g) 1) 4n, NaBH4; 2) PhSH, NaOH. (h) 1) 4n, NaBH4;
2) NaOH.
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Scheme 3. Iridium-Catalyzed α-Allylation of Glutaraldehyde a
1
2
3
50% in water (1-2 equiv)
OH
HO
O
OH
OH
O
O
O
4
5
HO
H
H
H
1s
13
TsN
6
7
L
A1
1b 1s
/
[Ir/(R)- ], (S)-
8
9
1s
then
2) LiAlH4
1)
(1.0 equiv)
1b
2) LiAlH4
1b
2) LiAlH4
1b
1) , (1.0 equiv)
2) (BnO)NH, NaBH(CN)3
1b
1)
(1.0 equiv)
1)
(1.0 equiv)
1) , (2.0 equiv)
2) LiAlH4
1b
(1.5 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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48
49
50
51
52
53
54
55
56
57
58
59
60
HO
OH
OBn
HO
OH
HO
OH
HO
OH
N
Ph
H
Ph
Ph
Ph
Ph
(S,S)-14b,c
Ph
TsN
(S,R)-14b
15b
17d
19b
: 71%,
>10:1 d.r., >99% ee
: 69%
: 63%, 5:1 d.r.
>99% ee
: 61%, >10:1 d.r.
>99% ee
: 44%, >10:1 d.r.
>99% ee
>10:1 d.r., >99% ee
O
O
O
p-TsOH
MgSO4
(n-Pr)4NRuO4,
NMO, 4 Å MS
H
H
H
Ph
: 83%, 14:1 d.r.
Ph
18
Ph
14
X-ray of
15
: 63%, 5:1 d.r.
aFor detailed experimental procedures see supporting information. Ellipsoids shown at 50% probability. Ts = toluenesulfonyl, NMO = 4-
methylmorpholine N-oxide. b2.0 equiv. of 19. c(R)-A was used.d1.0 equiv. of 19.
Rev. 2019, 119, 1855. For selected examples on formation of carbon-carbon
bonds see: (f) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M.
Construction of vicinal tertiary all-carbon quaternary stereocenters via Ir-
ASSOCIATED CONTENT
catalyzed regio- diastereo-, and enantioselective allylic alkylation and
applications in sequential Pd catalysis. J. Am. Chem. Soc. 2013, 135,
10626. (g) Jiang, X.; Beiger, J. J.; Hartwig, J. F. Stereodivergent allylic
substitutions with aryl acetic acid esters by synergistic iridium and lewis
base catalysis. J. Am. Chem. Soc. 2017, 139, 87. (h) Hethcox, J. C.;
Shockley, S. E.; Stoltz, B. M. Enantioselective synthesis of vicinal all-
carbon quaternary stereocenters via iridium-catalyzed allylic alkylation.
Angew. Chem. Int. Ed. 2018, 57, 8664. For selected examples on formation
of carbon-heteroatom bonds see: (i) Ohmura, T.; Hartwig, J. F. Regio- and
enantioselective allylic amination of achiral allylic esters catalyzed by an
iridium−phosphoramidite complex. J. Am. Chem. Soc. 2002, 124, 15164.
(j) Shu, C.; Hartwig, J. F. Iridium-catalyzed intermolecular allylic
etherification with aliphatic alkoxides: Asymmetric synthesis of
dihydropyrans and dihydrofuranes. Angew. Chem. Int. Ed. 2004, 43, 4794.
(k) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-L.
Iridium-catalyzed allylic vinylation and asymmetric allylic amination
reactions with o-aminostyrenes. J. Am. Chem. Soc. 2011, 133, 19006.
(2) For a general review see: (a) Lindström, U. M. Stereoseletive organic
reactions in water. Chem. Rev. 2002, 102, 2751. For selected examples see:
(b) Trost, B. M.; McEachern, E. J. Inorganic carbonates as nucleophiles for
the asymmetric synthesis of vinylglycidols. J. Am. Chem. Soc. 1999, 121,
8649. (c) Liu, W.; Zhao, X.; Zhang, H.; Zhang, L.; Zhao, M. Asymmetric
synthesis of allylic sulfonic acids: Enantio- and Regioselective iridium-
catalyzed allylations of Na2SO4. Chem. Eur. J. 2014, 20, 16873. (d) Miyabe,
H.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. Hydroxylamines as oxygen
atom nucleophiles in transition-metal-catalyzed allylic substitution. J. Org.
Chem. 2005, 70, 2148. (e) Ueda, M.; Hartwig, J. F. Iridium-catalyzed,
regio- and enantioselective allylic substitution with aromatic and aliphatic
sulfonates. Org. Lett. 2010, 12, 92. (f) Zhen, S.; Huang, W.; Gao, N.; Cui,
R.; Zhang, M.; Zhao, X. One pot iridium-catalyzed asymmetrical double
allylations of sodium sulfide: a fast and economic way to construct chiral
C2-symmetric bis(1-substituted-allyl)sulfane Chem. Commun. 2011, 47,
6969. (g) Gärtner, M.; Mader, S.; Seehafer, K.; Helmchen, G. Enantio- and
regioselective iridium-catalyzed allylic hydroxylation. J. Am. Chem. Soc.
2011, 133, 2072.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
General methods, detailed experimental procedures, spectral data
and X-ray crystallographic data.
AUTHOR INFORMATION
Corresponding Author
*E-mail: erickm.carreira@org.chem.ethz.ch
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to the ETH Zürich and the Swiss National Science
Foundation (200020_172516) for financial support. We also thank
Dr. N. Trapp and M. Solar for X‐ray crystallographic analyses.
Tobias Schnitzer and Greta Vastakaite are acknowledged for their
support with chiral chromatography analysis and Prof. Helma
Wennemers (ETH Zürich) is thanked for HPLC access.
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Journal of the American Chemical Society
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SYNOPSIS TOC
OH
H2O-ClCH2CH2Cl
Biphase
NH2
NHMe
HN
HN
R
R
[Ir(cod)Cl]2 (3 mol%)
R
OH
+
(S)-L
(12 mol%), H
Ot-Bu
Nu-H
+
SMe
O
R
21–70%
R
water
in
R
X
R
O
OHC
aqueous solutions of unstable/volatile
nucleophiles
O
H
O
Cl
Cl
H
Nu-H
: HONH2, H2N-NH2, R2NH,
ROOH, RSH, RCH2CHO
H
R
H
R
X = Cl, Br
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