Rhodium-Catalyzed Asymmetric Synthesis of β-Branched Amides

Article abstract of DOI:10.1002/anie.201610500

A general asymmetric route for the one-step synthesis of chiral β-branched amides is reported through the highly enantioselective isomerization of allylamines, followed by enamine exchange, and subsequent oxidation. The enamine exchange allows for a rapid and modular synthesis of various amides, including challenging β-diaryl and β-cyclic.

Full text of DOI:10.1002/anie.201610500

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International Edition: DOI: 10.1002/anie.201610500
German Edition: DOI: 10.1002/ange.201610500
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Synthesis of b-Branched Amides
Zhao Wu, Summer D. Laffoon, Trang T. Nguyen, Jacob D. McAlpin, and Kami L. Hull*
Abstract: A general asymmetric route for the one-step syn-
thesis of chiral b-branched amides is reported through the
highly enantioselective isomerization of allylamines, followed
by enamine exchange, and subsequent oxidation. The enamine
exchange allows for a rapid and modular synthesis of various
amides, including challenging b-diaryl and b-cyclic.
E
nantiopure b-branched amides are common motifs in
natural products and biologically active molecules[1]
(Figure 1) and are useful synthetic intermediates for the
Scheme 1. Enantioselective b-branched amide syntheses.
coupling reagents are often required which leads to poor atom
economy.[8]
Figure 1. Biologically active compounds containing chiral b-branched
Considering the dearth of approaches for the direct
asymmetric synthesis of chiral b-branched amides, we pro-
posed that allylic alcohols could serve as a chiral aldehyde
precursor, which upon asymmetric isomerization and subse-
quent oxidative amidation with an amine, affords the desired
product in a single step (Scheme 1c). We recently reported
a cationic Rh/BINAP complex as an effective catalyst for this
transformation, converting primary and secondary amines as
well as anilines into amides.[9] However, only moderate er was
observed when using trisubstituted allylic alcohols as sub-
strates.[10] As an enamine intermediate is formed over the
course of the reaction, we hypothesized that utilizing Noyoriꢀs
asymmetric isomerization of allyl amines, a highly enantiose-
lective process and the key step in the Takasago Process,
could allow for the formation of identical intermediates with
improved enantioselectivity.[11] To avoid preinstallation of the
amine functionality on the substrate, we further proposed
a domino process: enantioselective isomerization of an allylic
amine, enamine exchange with an external amine nucleo-
phile, and oxidation of enamine to afford enantiopure b-
branched amides in a single step (Scheme 1d).
The key challenge for this tandem process is identifying an
appropriate allyl amine precursor, as it must: isomerize with
high enantioselectivity, afford an enamine (ii) which is slow to
oxidize and instead undergo enamine exchange with an
external amine nucleophile to afford the desired intermediate
(i) (Scheme 2). We hypothesized that acyclic dialkyl amines
could serve as precursors as they are good substrates in
related Rh-catalyzed asymmetric isomerization reactions[11]
and are not reactive in the oxidative amidation of allyl
alcohols.[9] Several allylic dialkyl amines(1a–1d) were
amides.
construction of g-branched chiral amines.[2] However, exam-
ples of the direct asymmetric synthesis of chiral b-branched
amides are rare. Although asymmetric hydrogenation or
conjugate addition of a,b-unsaturated carbonyls are common
strategies toward b-stereocenters, a,b-unsaturated amides
intrinsically display low reactivity.[3] Only a few examples of
unsaturated acyclic amides have been documented, including
Co-catalyzed asymmetric reduction[4] and Rh-catalyzed con-
jugate addition.[5] For a general and modular synthesis of
enantiopure b-branched amides, a multistep sequence is often
required via carboxylic acid intermediates (Scheme 1).[1c] For
example, asymmetric hydrogenation of b,b-disubstituted
unsaturated acrylic acid or ester has been extensively studied
to reach high conversion and excellent enantioselectivity via
Rh, Ir, and Ru catalysis (Scheme 1a).[6] The same chiral acid
intermediate could be prepared through a copper-catalyzed
asymmetric 1,4-addition of an alkylzinc to a unsaturated N-
acyloxazolidione followed by hydrolysis (Scheme 1b).[7] For
the synthesis of the desired amide products, stoichiometric
[*] Z. Wu, S. D. Laffoon, T. T. Nguyen, J. D. McAlpin, Prof. Dr. K. L. Hull
Department of Chemistry, University of Illinois, Urbana-Champaign
600 S. Mathews, Urbana, IL 61821 (USA)
E-mail: kamihull@illinois.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610500.
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hydrogen acceptor, consistent with our allylic alcohol amida-
tion (Table S6).[9]
With the optimized conditions in hand, the amine
nucleophile scope was investigated (Table 2): cyclic amines
such as piperidine (2b), indoline (2e), and 2-(piperazin-1-yl)
pyrimidine (2 f) and acyclic amines, including dimethyl amine
Table 2: Scope of amine nucleophiles.
Scheme 2. Proposed reaction pathway.
screened for this tandem process (Table 1). Under slightly
modified conditions from the allylic alcohol amidation,[12] the
desired morpholine amide (3a) was formed in moderate
yields from all the allylic amine precursors. Only cinnamyl
dimethylamine (1a) provided 9% byproduct 4a, consistent
with dimethyl amine being an effective nucleophile in our
allylic alcohol amidation.[9] We chose to further optimize this
reaction with cinnamyl diethylamine (1b), as it forms a low
molecular weight byproduct (NHEt2) which is easily
removed.
Table 1: Rhodium-catalyzed allylic dialkylamine amidation.[a]
Entry
R
Yield of 3a [%][b]
Yield of 4a–4d [%][c]
[a] Condition a: secondary amines (1.05 equiv), Cs2CO3 (20 mol%),
styrene (1.5 equiv), THF/H2O (1:0.2). [b] Condition b: anilines
(3.0 equiv), Cs2CO3 (90 mol%), styrene (1.5 equiv), THF/H2O (1:0.3).
[c] Condition c: primary alkyl amine (1.0 equiv), KOH (2.5 equiv),
acetone (1.0 equiv), THF/H2O (1:1), 1008C.
1
2
3
4
Me
Et
i-Pr
Bn
64
77
71
74
9
<1
<1
<1
[a] General reaction conditions: cinnamyl dialkylamine (1) (0.12 mmol,
1.0 equiv), morpholine (2a) (1.5 equiv), CsOAc (1.5 equiv), styrene
(1.5 equiv), THF (1.2m), DI H2O. [b] In situ yield determined by GC
analysis. [c] In situ yield determined by NMR.
(2c) and N-benzyl methyl amine (2d) all gave excellent yields
of desired products. Moderate yields were obtained with
aniline derivatives (2g–2j). Electron-deficient (2i) and steri-
cally hindered anilines (2j) afford slightly diminished yields.
Primary amines are relatively challenging nucleophiles for
this reaction and 3k and 3l were obtained in 64% and 39%,
respectively. Unsurprisingly, diethyl and dibenzyl amines
showed no reactivity under optimized conditions, consistent
with results in Table 1.
The enantioselectivity of this transformation was explored
under optimized conditions with different amine nucleophiles
(Table 3). Excellent enantioselectivities (> 96:4 er) were
observed in the asymmetric oxidative amidation of (E)-
geranyl diethyl amine with morpholine, aniline, and benzyl
amine, affording 6aa, 6af, and 6ak in fair to excellent yields.
Using either (S)-BINAP or the (Z)-allyl diethylamine affords
the opposite enantiomer in identically excellent enantiose-
lectivity.[13]
The further optimization of reaction conditions was
elaborated in Tables S1–S6 (see Supporting Information):
Cs2CO3 proved superior to CsOAc for secondary amine
nucleophiles and only substoichiometric amount (20 mol%)
is required (Tables S2 and S4). A variety of hydrogen
acceptors were examined showing styrene to be superior, as
it was reduced faster than the substrate (Table S3). Further,
decreasing the equivalents of amine nucleophile (1.05 equiv)
led to only slightly diminished yields (Table S2).
Slight modification of the reaction conditions was
required for other amine nucleophiles. For less nucleophilic
aniline derivatives, excess nucleophile (3.0 equiv) and
increased base (0.9 equiv) were required to prevent unpro-
ductive reaction pathways (Table S5). With primary alkyl
amine nucleophiles, a stronger base and higher temperature
were essential, which presumably aid in the conversion of the
less electrophilic imine intermediate to the hemiaminal
intermediate. Additionally, acetone proved to be the better
Focusing our efforts on substrates not previously shown in
the Noyori isomerization, the scope of prochiral allylamines
was next explored (Table 4). A variety of substrates were
transformed to the corresponding b-branched amides with
high enantioselectivities in moderate to very good yields.
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Table 3: Enantioselective isomerization/amidation of (E)-geranyl diethyl
Heterocycles such as thiophene were tolerated and compat-
amine.[a]
ible with both secondary cyclic (6oa) and acyclic (6od) amine
nucleophiles. Further, a chroman-derived b-cyclic substrate
(5p) afforded the chiral amide product with excellent
enanotioselectivity, demonstrating an improvement over
other approaches, for example, chiral resolution.[16]
The diastereoselectivity of this reaction was investigated
with enantiopure amine nucleophiles (Table 5). When chiral
a-branched amines 2m and 2n were used as nucleophiles,
6bm and 6bn were formed in high er (> 99:1) and dr (> 96:4).
Further, both the enantiomer of ligand, (R)- or (S)-BINAP,
and the enantiomer of amine employed dictate which
diastereomer is formed. This indicates both that the stereo-
center a to the amine are unepimerized under the reaction
conditions, even with the relatively activated chiral benzylic
[a] For conditions see Table 2.[14] Isolated yield, average of two runs.
Absolute configuration is assigned by analogy to 6oa (see below).
[b] With (S)-BINAP.
Table 5: Diastereoselectivity with enantiopure amine nucleophiles.[14]
Various 3,3-aryl,alkyl allylic diethylamines were investigated
(5b–5h); stereocenters bearing both small (Me, Et) and large
(iPr) substituents uniformly give excellent enantiomeric
ratios (6ba-6da).[16] Aryl halides were tolerated under the
optimized conditions, although some protodebromination
product was observed from aryl bromides (6gg). When b-
dialkyl allylic diethylamines (5i–5l) were exposed to the
reaction conditions, chiral amides bearing a dialkyl stereo-
center were obtained with excellent enantioselectivity, even
with minimally differentiated substituents (6la, nBu vs.
nPent).
Additionally, 3,3-diaryl allylic diethylamines also undergo
this asymmetric isomerization/oxidation reaction. Substrates
bearing electron-rich (6ma) and electron-poor (6na) aryl
substituents afforded good yields and enantiomeric ratios.
[a] with (R)-BINAP. [b] with (S)-BINAP.
Table 4: Scope of one-step asymmetric isomerization/amidation of allylic amines.[a]
[a] For conditions see Table 2.[14] Isolated yield, average of two runs. [b] Determined from the dr of transamidation product from 6la.[14] [c] Absolute
configuration of 6oa was determined by X-ray crystallography.[14] [d] 96:4 E/Z ratio of starting material.
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amine (2m), and that it has no effect on the selectivity of the
isomerization reaction.
Next the isomerization of allylic amine with proximal
stereocenters was examined (Scheme 3). Interestingly, the
In conclusion, we have developed a Rh-catalyzed one-step
synthesis of chiral b-branched amides. This method allows for
the installation of a stereocenter and amide functionality in
a single step under mild conditions. Excellent enantio- and
diastereoselectivity was observed for a variety of allylic amine
substrates and amine nucleophiles. The expansion of this
methodology to other types of stereocenters and nucleophiles
currently is under investigation.
Acknowledgements
We thank the University of Illinois, ACS PRF (54007-DNI1),
and NSF CAREER (0332333) for their generous support.
S.D.L. and J.D.M. are grateful to the NSF GRFP (DGE-
1144245).
Keywords: amidation · asymmetric isomerization ·
b-branched amides
Scheme 3. Diastereoselectivity with enantiopure allyl amines.[14]
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diastereoselecitivity of the isomerization of 5q and 5r with
(Æ)-BINAP favored the formation of (3S,5R)-6qa (56:44 dr)
and (3S,4S)-6ra (14:85 dr), respectively, where the closer
stereocenter in 5r has a greater effect on the diastereoselec-
tivity of the reaction. Excitingly, both 5q and 5r undergo the
Rh-catalyzed isomerization/oxidation to afford desired prod-
ucts with excellent diastereoselectivities (> 97.5:2.5) when
enantioenriched ligands are employed. The isomerization
reaction proved to be ligand-controlled, as the mismatched
combination of (R)-BINAP and 5r decreased the yield of
(3R,4S)-6ra, rather than the diastereoselectivity.
As shown in Scheme 4, isotope labelling studies were
carried out using H218O and D2O respectively. The H218O
labelling study (Scheme 4a) confirms that the oxygen in the
product originates from the water. Similarly, deuterium
incorporation at the a-position of the amide was observed
(Scheme 4b), as it was in the allylic alcohol amidation,[9]
supporting the reversible formation of enamine intermediate
i (Scheme 2).
[6] Ref. [3a,b] and references therein.
[7] A. W. Hird, A. H. Hoveyda, Angew. Chem. Int. Ed. 2003, 42,
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FÀ
[12] Initial counter ion screens show BAr4 gives much higher
reactivity for allylic amine isomerization. See Table S1 for
details.
Scheme 4. Isotope labelling study.
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[13] (Z)-Geranyl diethyl amine combined with (R)-BINAP under
[16] For examples of other asymmetric allylic isomerizations see: P.
optimized conditions afforded (R)-6aa in 78% yield and 3.5:96.5
er.
[14] See Supporting Information for details.
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Manuscript received: October 26, 2016
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
A domino process: A RhI/chiral BINAP
catalysis is reported for the one-step
modular synthesis of chiral b-branched
amides with various amine nucleophiles.
b-dialkyl, b-diaryl, and b-alkylaryl stereo-
centers are established under identical
conditions with excellent enantio- and
diastereoselectivity in a ligand-controlled
manner.
Z. Wu, S. D. Laffoon, T. T. Nguyen,
J. D. McAlpin, K. L. Hull*
&&&& — &&&&
Rhodium-Catalyzed Asymmetric
Synthesis of b-Branched Amides
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