Asymmetric synthesis of allylic amines: Via hydroamination of allenes with benzophenone imine

Article abstract of DOI:10.1039/c5sc04984a

Rhodium-catalyzed highly regio- and enantioselective hydroamination of allenes is reported. Exclusive branched selectivities and excellent enantioselectivities were achieved applying a rhodium(i)/Josiphos catalyst. This method permits the practical synthesis of valuable α-chiral allylic amines using benzophenone imine as ammonia carrier.

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ARTICLE TYPE
Asymmetric Synthesis of Allylic Amines via Hydroamination of
Allenes with Benzophenone Imine
Kun Xu, YuꢀHsuan Wang, Vahid Khakyzadeh and Bernhard Breit*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
benzophenone with ammonia;[12] 2) the sp2 hybridized imine
Rhodiumꢀcatalyzed highly regioꢀ and enantioselective
nitrogen is more reactive towards allenes in the presence of a
suitable transition metal catalyst; 3) the final αꢀchiral primary
45 allylic amines can be obtained via simple hydrolysis, and the
benzophenone can be recycled (Scheme 2).
hydroamination of allenes is reported. Exclusive branched
selectivities and excellent enantioselectivities were achieved
applying a rhodium(I)/Josiphos catalyst. This method permits
10 the practical synthesis of valuable αꢀchiral allylic amines
using benzophenone imine as ammonia carrier.
αꢀChiral amines are of wide interest in organic synthesis[1a] due to
their broad application in pharmaceutical research[1bꢀc]
,
catalysis[1dꢀe] and natural product synthesis[1f] (Scheme 1). Among
15 them, the synthesis of αꢀchiral allylic amines is particularly
important because of the versatility of the allylic moiety for
further structural elaboration.[2] In the past decades, significant
efforts have advanced the efficiency towards their synthesis.
Many elegant approaches including allylic substitution,[3]
20 Overman rearrangements,[4] allylic CꢀH amination[5] and imine
vinylation[6] have been reported. However, these methods need
preꢀinstallation of a leaving group or stoichiometric amounts of
an oxidant/metalꢀcontaining reagent. In this regard, efficient
synthetic methods for the synthesis of α–chiral allylic amines are
25 highly desirable.
Scheme 2. Proposed synthesis of α–chiral allylic amines using
benzophenone imine as ammonia carrier.
50
The initial assessment was performed by coupling
cyclohexylallene and benzophenone imine using
[{Rh(COD)Cl}2] (2.5 mol%) and racemic ligand 1,4ꢀ
bis(diphenylphosphino)butane (L1, 10 mol%) in 1,2ꢀ
°
dichloroethane (DCE) at 80 C (Table 1, entry 1). The reaction
55 afforded the desired product with 10% NMR yield. We wondered
whether addition of acid would facilitate the reaction by
promoting the catalytic cycle. Indeed, both trifluoroacetic acid
(TFA) and pyridinium pꢀtoluenesulfonate (PPTS) could
significantly improve the yield, while the addition of pꢀ
60 toluenesulfonic acid (PTSA) had no effect (Table 1, entry 2−4).
These promising results encouraged us to test the feasibility of its
asymmetric variant. The (S)ꢀSegphos ligand (L2) only led to 10%
of the desired product. The (R,R)ꢀDIOP (L3) gave 76% of the
isolated amide product 1a, while only moderate ee was obtained.
Scheme 1. Applications of αꢀchiral amines.
The catalytic and enantioselective addition of simple ammonia
(NH3) to allenes would represent one of the most atomꢀeconomic 65 Further screening led to the discovery of Josiphos (L4), which
30 transformation towards the synthesis of αꢀchiral allylic amines.[7ꢀ9]
However, initial experiments revealed this transformation to be
very challenging, presumably due to the following reasons: 1) the
volatility and toxicity of gaseous NH3 makes it less interesting in
terms of practicality; 2) the catalytic systems were inactive in the
35 presence of ammonia, possibly due to the high basicity of sp3
hybridized nitrogen atom, and its difficulty to undergo oxidative
addition to a transition metal center.[10]
afforded 1a with 72% yield and 92% ee.[13]
Table 1. Reaction development.
To address these issues, we assumed that the easyꢀtoꢀuse and
Nꢀsp2ꢀhybridized benzophenone imine[11] could serve as an
40 ammonia carrier: 1) benzophenone imine is commercially
available and can be easily prepared via condensation of
Entry
x
Ligand (y)
Additive
Yield/%[d]
ee/% [e]
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DOI: 10.1039/C5SC04984A
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.0
2.0
2.0
2.0
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (4.0)
L2 (4.0)
L3 (4.0)
L4 (4.0)
ꢀ
(10)
(11)
(50)
(65)
(59)
(10)
76[f]
72[f]
ꢀ
amides and allenes was difficult. However, a oneꢀpot synthesis of
25 branched allylic amides or carbamate can be achieved easily upon
acylation or sulfonylation of the crude allylic amine with the
corresponding acyl/sulfonyl chlorides or anhydride, respectively
(Scheme 3, 2a−d).
Hydroamination with bioactive moieties containing substrates
30 using the scope conditions resulted in the desired branched allylic
amines with high yields and excellent enantioselectivities
(Scheme 3, 3a−c).
PTSA
TFA
ꢀ
ꢀ
PPTS
PPTS
PPTS
PPTS
PPTS
ꢀ
ꢀ
ꢀ
54[g]
92
[a] Benzophenone imine (1.0 equiv), cyclohexylallene (1.5 equiv). [b] Et2O (2.0 ml),
HCl aq. (2.0 ml, 2.0 M, 4.0 mmol), room temperature, 24 hours. [c] CH2Cl2 (2.0 ml),
Et3N (223 ꢁl, 1.6 mmol, 4.0 equiv), benzoyl chloride (84.3 mg, 0.6 mmol, 1.5 equiv).
[d] 1H NMR yield of the coupling product (hydroamination step) in the crude
reaction mixture using 1,3,5ꢀtrimethoxybenzene as internal standard. [e] ee of 1a
was determined by chiral HPLC. [f] Yield is that of the isolated product of 1a. [g]
Acetonitrile was used as solvent.
To test the practicality of this method for primary amine
synthesis, chiral allylic amine HCl salt 4 was synthesized under
35 scope conditions in a 1.1 gram scale with 86% yield and 95% ee.
The released ammonia carrier (benzophenone) can be recycled
after hydrolysis with 96% yield (Scheme 5).
5
With the optimized conditions in hand, we then investigated
the feasibility of various allene substrates (Scheme 3, 1a−i).
10 Interestingly, in basically all cases perfect regioselectivities and
excellent enantioselectivities were observed. Allenes containing
alkyl substituents as well as ether, thio ether, phthalimide and
sulfone functional groups were well tolerated.
Scheme 4. Large scale synthesis of primary allylic amine. [a]
40 Scope conditions. [b] Determined by its amide derivative 1e via
chiral HPLC.
Ph
[Rh]-catalyzed
To exemplify the utility of chiral allylic amines, derivatization
of compound 2a was performed (Scheme 6). Ozonolysis of 2a
followed by treatment with triphenylphosphine and NaBH4 gave
45 βꢀamino alcohol 5a and αꢀamino aldehyde 5b, respectively.
Direct oxidation of 2a could afford α–amino acid 5c.
Hydroboration of 2a using 9ꢀborabicyclo(3.3.1)nonane (9ꢀBBN),
then oxidation with H2O2 led to the formation of γ–amino alcohol
5d, which could be further oxidized to the corresponding β–
50 amino aldehyde 5e and β–amino acid 5f.
•
R
NHBz
hydroamination[a]
(a) Et2O, HCl aq.
(b) Et3N, R'Cl
Ph
N
R
1a-i, 2a-d,
3a-d
Ph2C=NH
R
NHBz
NHBz
NHBz
NHBz
NHBz
H3C
Ph
Ph
12
2
3
1a, 92% ee[b]
72% yield[c]
1b, 94% ee
1c, 96% ee
1d, 95% ee
1e, 95% ee
85% yield[d]
64% yield
85% yield
76% yield
NHBz
NHBz
NHBz
NHBz
PhthN
PhO
PhS
PhO2S
6
2
3
3
1f, 84% ee
1g, 97% ee
1h, 96% ee
1i, 93% ee
85% yield
78% yield
60% yield
85% yield
O
O
NHBoc
NHTs
HN
HN
Ph
Ph
Ph
Ph
3
3
3
3
2a, 95% ee
80% yield[e]
2b, 95% ee
2c, 95% ee
2d, 95% ee
75% yield
75% yield
70% yield
O
O
O
NHBz
NHBz
Scheme 5. Synthetic transformations of chiral allylic amines. (a)
O3, CH2Cl2, − 78 oC; then NaBH4, CH3OH, 0 oC to r.t.; 90% yield,
95% ee (5a). (b): O3, CH2Cl2, − 78 oC; then PPh3, − 78 oC to r.t.;
55 85% yield, 95% ee (5b). (c): RuCl3, NaIO4, MeCN/CCl4/H2O
3c, 85% yield
3
95% ee
O
n
H
H
3a (n = 2)
H
78% yield, 92% ee
3b (n = 3)
o
3d, 70% yield
96% ee
(1/1/1.5), r.t.; 82% yield, 95% ee (5c). (d) 9ꢀBBN, THF, − 78 C
O
NHBz
H
to r.t.; then EtOH, NaOH, H2O2 (30%), − 10 oC to r.t.; 95% yield,
91% yield, 97% ee
O
3
H
o
95% ee (5d). (e): C5H5NSO3, Et3N, DMSO, 0 C to r.t.; 88%
15 Scheme 3. Scope of allenes and oneꢀpot synthesis of allylic
amides. [a] Benzophenone imine (1.0 equiv, 0.4 mmol), allene
(1.5 equiv), [{Rh(COD)Cl}2] (2.0 mol%), L4 (4.0 mol%), PPTS
(20 mol%), DCE (1.0 ml). [b] Determined by chiral HPLC. [c]
Yield is that of the isolated product. [d] The reaction was
20 performed in 0.2 mmol scale. [e] Boc2O was used in the
protection step. Phth = phthaloyl; Ts = 4ꢀmethylbenzeneꢀ1ꢀ
sulfonyl.
yield, 95% ee (5e) (f) PhI(OAc)2, TEMPO, CH3CN/H2O (1/1),
60 r.t.; 48% yield, 95% ee (5f).
Isotopic labeling experiments using deuterated benzophenone
imine (Ph2C=ND) and deuterated PPTS (DꢀPPTS) were
conducted under scope conditions.[13] Deuterium incorporation
was only observed at the internal position of the allylic double
65 bond. Hence, we suggest that the mechanism follows a similar
pathway as for previously reported coupling reactions.[9e]
Oxidative addition of the benzophenone imine NꢀH bond to Rh(I)
Direct synthesis of branched allylic amides using simple
2
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substituted double bond could generate σꢀallylꢀRh complex,
which is in equilibrium with the π–allylꢀRh complex. Reductive
elimination of the allylꢀRh complexes generates the branched Nꢀ
allylic amine.
To conclude, we have developed the first highly regioꢀ and
enantioselective hydroamination of allenes using benzophenone
imine as an ammonia carrier via a rhodium/Josiphos catalyst
system. The reaction gave valuable αꢀchiral primary allylic
10 amines and αꢀchiral allylic amides in a practical manner. Recycle
of the ammonia carrier with high yield maximized the atomꢀ
economy of this protocol. Applications of this method in target
oriented synthesis and using more challenging terminal alkyne as
the coupling partner for the enantioselective synthesis of
15 branched allylic amines are currently under way in our
laboratories and will be reported in due course.
65
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Acknowledgements
85
This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
20 Synthesis” (IRTG 1038) and the Krupp Foundation. We thank
Umicore, BASF and Wacker for generous gifts of chemicals.
90
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Institut für Organische, Chemie Albert-Ludwigs-Universität Freiburg,
Albertstrasse 21, 79104 Freiburg, Germany. Fax: (+)49-761-203 8715;
25 E-mail: bernhard.breit@chemie.uni-freiburg.de
† Electronic Supplementary Information (ESI) available: experimental
procedures and detailed characterization data of all new compounds. See
DOI: 10.1039/b000000x/
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