Catalytic Regio- and Enantioselective Alkylation of Conjugated Dienyl Amides

Article abstract of DOI:10.1002/anie.201808392

A method for catalytic asymmetric alkylation of conjugated dienyl amides has been developed and it allows efficient and high-yielding transformations of a wide range of polyconjugated amides into the corresponding chiral products. Smooth addition of organomagnesium reagents to relatively unreactive dienyl amides with excellent 1,6- and 1,4-selectivities, as well as enantioselectivites above 90 %, is achieved owing to the complementary action of the Lewis acid and a chiral copper-based catalyst.

Full text of DOI:10.1002/anie.201808392

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Accepted Article
Title: Catalytic regio- and enantioselective alkylation of conjugated
dienyl amides
Authors: Syuzanna R. Harutyunyan, Yafei Guo, and Johanan Kootstra
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10.1002/anie.201808392
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Catalytic regio- and enantioselective alkylation of conjugated
dienyl amides
Yafei Guo,[a] Johanan Kootstra,[a] Syuzanna R. Harutyunyan *[a]
Dedicated to Professor Yuri N. Belokon on the occasion of his 80th birthday
Abstract: We have developed a method for catalytic asymmetric
alkylation of conjugated dienyl amides that allows efficient and high
yield transformations of a wide range of policonjugated amides to the
and has become common practice in organic synthesis.[6] In our
previous research we found that strong LA can be used in
combination with organomagnesium reagents.[7] The role of LA
in these reports was twofold: prevention of side reactions by
effectively acting as an in-situ protecting group, and activation of
unreactive substrates towards nucleophilic attack.
Here we show that the synergistic action of boron-based LA and
a readily accessible chiral copper-based catalyst allows to
overcome the reactivity and selectivity issues associated with
dienyl amides. This finding led us to develop a highly regio- and
enantioselective protocol for 1,6- and 1,4-additions of
organomagnesium reagents with considerable scope and good
yields.
corresponding
chiral
products.
Smooth
addition
of
organomagnesium reagents to relatively unreactive dienyl amides
with excellent 1,6- and 1,4- selectivities and enantioselectivites
above 90% is achieved owing to the complementary action of Lewis
acid and a chiral copper-based catalytic system.
Simultaneous catalytic control of regio- and enantioselectivities
in reactions that involve molecules featuring several reactive
sites remains a major challenge in chemical synthesis. Catalytic
asymmetric addition of organometallics to dienyl acceptors is an
important example that manifests this challenge.[1] Complete
regiocontrol towards either 1,2-, 1,4- or 1,6-additions combined
with high stereocontrol over the addition process is hard to attain
in these systems due to the presence of a supplementary double
bond.
We first examined the addition of ethylmagnesium bromide to
-unsaturated N,N-dimethyl amide 1a (Table 1). To
evaluate the reactivity of the amide towards nucleophilic addition,
we carried out the initial reaction in the absence of a catalyst at
o
o
0 C and at cryogenic temperatures (entries 1 and 2). At 0 C
mainly 1,4-addition product was obtained with 38% yield, similar
to the result obtained by Miginiac et al.[8] while at -78 oC no
substrate conversion was observed. Copper-based catalysts are
known to promote the addition of various organometallics,
including organomagnesium reagents, to extended conjugated
enones and enoates with very good selectivities.[4,9] Adding
various copper-based catalysts to the above mentioned
reactions afforded results similar to those obtained in their
absence (entries 3 and 4). Suspecting the poor reactivity of the
substrate to be the main cause of the inability of the catalyst to
promote the reaction, we also carried out the non-catalytic
reaction in the presence of 2 equivalents of BF3·Et2O under
cryogenic conditions(entry 5). However, also in this case the
substrate 1a was not converted, highlighting the low reactivity
issue associated with amides. Gratifyingly, combining BF3·Et2O
with chiral copper catalyst Cu/L1 led to an immense acceleration
of the addition rate (entry 6). The reaction was completed in a
few hours and the 1H NMR analysis of the crude reaction
mixture revealed predominant formation of the 1,6-addition
product 2a. Furthermore, the product 2a was obtained with a
promising enantioselectivity of 85%. Encouraged by these
results we investigated the effect of the type of LA, the catalyst
structure, and the nature of the solvent on the stereochemical
outcome and on the overall reactivity of the catalytic system.
Silicon-based LA led to worse reaction outcomes with decreased
regioselectivity as well as reduced enantioselectivity (entries 7-
9). A large screening of chiral ligands for the copper catalyst
(only selected examples are shown) revealed ferrocenyl- and
binaphtyl- based ligand L1 to be the best in terms of
enantioselectivity, while similarly high levels of regioselectivities
were obtained for most other chiral ligands (entries 6, 10, and
11). Importantly, switching from dichloromethane to ethereal
solvents was found to be detrimental for the reactivity, leading to
lower substrate conversion, but highly beneficial for the
Scheme 1. Conjugate addition of organometallics to Michael acceptors with
extended conjugated double bonds.
Following impressive advances in catalytic asymmetric
conjugate additions (1,4-additions) of organometalics to Michael
acceptors,[2] several chiral transition metal catalysts have been
shown to be effective for overcoming these regioselectivity and
stereoselectivity issues when using Michael acceptors with
extended conjugated double bonds.[3-5] Although this has
enabled the selective introduction of carbanionic nucleophiles,
these reactions are confined to reactive polyconjugated Michael
acceptors, such as dienones, dienoates and nitrodienes
(Scheme 1). Catalytic asymmetric additions of organometallics
to less reactive polyconjugated systems, for example N,N-dialkyl
dienyl carboxamides or dienyl heteroarenes, are unknown.
Furthermore, to overcome the poor electrophilicity of adjacent
dienyl moieties the reactions need to be carried out at relatively
high temperatures, resulting in poor stereocontrol and reduced
yields under catalytic condition and consequently limiting
developments in this area.
Lewis acid (LA) activation of molecules towards nucleophilic
addition is a powerful tool that has been used for many decades
[a]
Y. Guo, J. Kootstra, Prof. Dr. S. R. Harutyunyan
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
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10.1002/anie.201808392
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COMMUNICATION
stereochemical outcome of the reaction when using L1 (entries
12 and 14). In particular, when the reaction was carried out in
diethyl ether the regioselectivity of the addition reaction
remained practically the same but the enantioselectivity
increased to 93% (entry 14). Finally, increasing the LA amount
enantioselectivities (80%-99%). On the other hand, highly
regioselective 1,4-addition (more than 92%) was observed with
amide substrates featuring electron rich and electron poor
aromatics, heteroaromatics and branched aliphatic substituents
at the -position. The corresponding 1,4-adducts 3k-3p, were
obtained with high yields and excellent 94% to 99%
enantioselectivities.
Next, we studied substrates with various substituents at the N-
atom using dienyl amides with a linear aliphatic substituent at
the -position. We found that incorporation of various
substituents at the nitrogen atom is well tolerated and excellent
selectivities and yields were obtained for N-dialkyl, N-phenyl-N-
methyl, N-diallyl, substituted compounds (2a, 2j, 2g, and 2h).
to
3 equivalents led to higher reaction rate and higher
selectivities, namely a regioselectivity of 1,6:1,4 = 96:4, 81%
isolated yield and and excellent 95% enantioselectivity for the
addition product 2a (entry 15).
Table 1. Optimization of the enantioselective 1,6-addition of EtMgBr to
substrate 1a.[a]
T
Cu/
L
LA
(2 equiv.)
2a:3a
ee 2a
Entry
Solvent
(oC)
(ratio)[b,c]
(%)[d,e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[f]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
Et2O
0
-78
0
-
-
L1
L1
-
L1
L1
L1
L1
L2
L3
L1
L3
L1
L1
-
2:98 (38)
-
9:91 (nd)
-
nd
-
nd
-
-
-
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
BF3∙Et2O
BF3∙Et2O
TMSOTf
TMSBr
TBSOTf
BF3∙Et2O
BF3∙Et2O
BF3∙Et2O
BF3∙Et2O
BF3∙Et2O
BF3∙Et2O
-
-
94: 6 (92)
33:67 (58)
41:59 (nd)
68:32 (nd)
99: 1 (93)
95: 5 (90)
90:10 (60)
87:13 (51)
93: 7 (66)
96: 4 (81)
85
72
nd
nd
54
86
90
86
93
95
Et2O
Et2O
[a] Reaction conditions: the LA (2 equiv.), EtMgBr (2 equiv.), ligand L (6 mol%),
CuBr∙SMe2 (5 mol%) and 1a (0.2 mmol) in 2 mL of solvent, overnight. [b]
1,6:1,4 ratio was determined by 1H NMR.[c] The values in brackets correspond
to the isolated yield (%) of the major product. [d] The ee values were
determined using chiral HPLC on
a chiral phase. [e] The absolute
configuration was determined by conversion of product 2a into a known
compound (see supporting information). [f] 3 equiv. of BF3∙Et2O was used in
this case
With the optimized set of conditions in hand, we investigated the
generality of this methodology and the results of this scope
study are shown on schemes 2 and 3. Generally speaking, this
catalytic, highly regio- and enantioselective reaction reaches
nearly full conversion in 10-16 h using 5 mol% of copper catalyst
Cu/L1 with regioselectivities above 90%, in some cases even
reaching 100%. A broad substrate and organomagnesium
reagent scope is tolerated, while we observed an interesting
correlation between substrate substituents and regioselectivity
as detailed in the following.
Evaluation of the addition reaction using EtMgBr and a number
of dienyl amides differing by the substituent at the δ-position
revealed a strong influence of the substitution pattern on the
regioselectivity (Scheme 2). In particular addition reactions with
amide substrates featuring linear as well as functionalized
aliphatic substituents at the -position led to predominantly
(more than 90%) 1,6-adducts (2a-2e) with high yields, and
Scheme 2. Scope of the reaction with respect to dienyl amides. Reaction
conditions: dienyl amide 1 (0.2 mmol) in 2 mL Et2O, -78 oC, overnight. Yields
are for the isolated products; ee values were determined using chiral HPLC;
1,6:1,4 ratios were determined by 1H NMR. [a] The absolute configuration was
determined by conversion into
a known compound (see supporting
information). [b] CH2Cl2 (2 mL) and TMSOTf (2 equiv.) were employed instead
of Et2O and BF3∙Et2O.
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10.1002/anie.201808392
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Importantly, the addition to morpholine-substituted enamide
leads to 1,6-addition product 2f, which is amenable to further
synthetic transformations, with a 78% isolated yield and 91% ee.
Remarkably, even the addition of EtMgBr to a secondary amide
bearing an acidic proton was possible. Also in this case the
corresponding 1,6-addition product 2i was obtained with high
regio- and enantioselectivity.
Having established the substrate scope, we moved to assess
the scope of organomagnesium reagents. For this purpose we
selected two substrates, aliphatic dienyl amide 1a and aromatic
dienyl amide 1k, as substrates in order to study both 1,6- and
1,4-additions, respectively (Scheme 3). Our catalytic system
enables the introduction of organomagnesium reagents of
various chain lengths, e.g Et, nBu, nHex and iPent, affording the
corresponding products 4a-6a with high regio- and
enantioselectivities as well as yields. When using β-branched
organomagnesium reagent, the increase in steric hindrance
caused by the branching led to diminished enantioselectivity
(76%) for product 7a. No reaction was observed with PhMgBr
under various reaction conditions.
organomagnesium reagents to this demanding substrate affords
predominantly
1,4-addition
products
2q-4q
with
enantioselectivities above 93% and high yields.
Finally, we applied our methodology to the synthesis of an
important precursor for the synthesis of natural product
Penicillenol A (Scheme 4b).[11] This compound (8) was obtained
in two steps, namely catalytic asymmetric 1,6-addition to
substrate 1a, followed by the oxidation of the double bond
product 5a.[12]
Scheme 4. Application of the methodology: a) conjugate addition of
organomagnesium reagents to carboxamide derivative of (2E,4E)-Muconic
acid 1q ; b) towards the synthesis of the natural product Penicillenol A.
In summary, we have developed the first catalytic asymmetric
addition of organometallics to various dienyl caroboxamides
leading to --, or -substituted chiral functionalized amides
with excellent 1,6- or 1,4-regioselelectivity. The combination of
Lewis acid activation and the high reactivity of reagents lies at
the basis of this feat, as it overcomes the low reactivity of the
amide substrates. Although the substrate structure can strongly
affect the regioselectivity outcome we have shown that under
our catalytic conditions almost exclusively one regioisomer is
formed with excellent enantioselectivity.
Scheme 3. Scope of the reaction with respect to organomagnesium reagents.
Reaction conditions: dienyl amide 1 (0.2 mmol) in 2 mL Et2O, -78 oC, overnight.
Yields are for the isolated products; ee values were determined using chiral
HPLC; 1,4:1,6 ratios were determined by 1H NMR. [a] CH2Cl2 (2 mL) and
TMSOTf (2 equiv.) were employed instead of Et2O and BF3∙Et2O in order to
enhance the substrate conversion.
Methylations have always been challenging due to the
diminished reactivity of the corresponding organometallics
compared to those with higher carbon number.[10] We were
pleased to observe smooth addition of MeMgBr to the natural
product Piperine, providing the addition product 4p with
excellent 1,4-regioselectivity, and remarkable enantioselectivity
of more than 99%.
Next we wonder if we can extend our methodology to
nucleophilic additions to dicarboxylic acid derivatives, namely to
carboxamide derivative of Muconic acid 1q (Scheme 4a). This
substrate represents quite some challenges with respect to both
reactivity and selectivity control. Therefore we were pleased to
find that using our catalytic system addition of various
Acknowledgements
Financial support from The Netherlands Organization for
Scientific Research (NWO-ECHO to S.R.H.), the China
Scholarship Council (CSC, to Y. G.), and the Ministry of
Education, Culture and Science (Gravity program 024.001.035
to S.R.H.) is acknowledged. Solvias is acknowledged for the
supply of chiral ferrocenyl diphosphine ligands.
Keywords: polyconjugated systems • copper catalysis •
muconic acid • organomagnesium reagent • asymmetric
alkylation
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