Amide α,β-Dehydrogenation Using Allyl-Palladium Catalysis and a Hindered Monodentate Anilide

Article abstract of DOI:10.1021/jacs.5b12924

A practical and direct method for the α,β-dehydrogenation of amides is reported using allyl-palladium catalysis. Critical to the success of this process was the synthesis and application of a novel lithium N-cyclohexyl anilide (LiCyan). The reaction conditions tolerate a wide variety of substrates, including those with acidic heteroatom nucleophiles.

Full text of DOI:10.1021/jacs.5b12924

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Communication
Amide #,#-Dehydrogenation Using Allyl-Palladium
Catalysis and a Hindered Monodentate Anilide
Yifeng Chen, Aneta Turlik, and Timothy R. Newhouse
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12924 • Publication Date (Web): 14 Jan 2016
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Amide α,β-Dehydrogenation Using Allyl-Palladium Catalysis and a
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Yifeng Chen, Aneta Turlik, and Timothy R. Newhouse*
Department of Chemistry, Yale University, 275 Prospect St., New Haven, Connecticut 06520-8107
Supporting Information Placeholder
ABSTRACT: A practical and direct method for the α,β-
dehydrogenation of amides is reported using allyl-palladium
catalysis. Critical to the success of this process was the synthe-
sis and application of a novel lithium N-cyclohexyl anilide (Li-
Cyan). The reaction conditions tolerate a wide variety of sub-
strates, including those with acidic heteroatom nucleophiles.
A greater number of modes of reactivity become available by
increasing the oxidation state of organic compounds through
dehydrogenation. Dehydrogenation methodologies for the
conversion of alcohols to ketones, amines to imines, and al-
kanes to alkenes can be made more sustainable through the
development of transition metal catalyzed reactions.1 Palladi-
um complexes have emerged as the most practical metal cata-
lysts for the introduction of alkenes adjacent to carbonyls,2,3
including α,β-dehydrogenation via the enoxysilane by the two-
step Saegusa oxidation.3d Stahl and co-workers obviated the
requirement for the synthesis of the enoxysilane by developing
a method that oxidizes ketones and aldehydes directly by a C-
H insertion mechanism.3f,g Recently we reported conditions for
Figure 1. (a) LiTMP is an efficient base for ester and nitrile
dehydrogenation, but ineffective for amide dehydrogenation.
(b) Recently commercialized CyanH allows for facile amide
dehydrogenation using allyl acetate as a stoichiometric oxi-
dant. (c) Amides are selectively dehydrogenated in the pres-
ence of unprotected heteroatom nucleophiles.
α,β-dehydrogenation of the more electron-deficient and less
acidic esters and nitriles using allyl-palladium catalysis (Figure
1a).4
Despite the prevalence of amides in proteins,5 bioactive mol-
ecules,6 and polymers,7 a general and direct method for amide
α,β-dehydrogenation has not been developed.8-10 A commonly
employed strategy relies on the Sharpless process which re-
quires α-selenation followed by a second oxidation step where-
in selenoxide elimination occurs, generating a stoichiometric
and toxic byproduct.3a,b Bromination and elimination se-
quences also have been employed, but use strong oxidants and
produce undesirable halogen waste.11 While these processes
have been useful for the two-step introduction of alkenes con-
jugated to amides, these methodologies do not generally toler-
ate nucleophillic and reactive functional groups (e.g. alcohols
and amines).12
planned – a process that typically requires a four-step se-
quence.
Attempts to apply our previously developed oxidation sys-
tem for the α,β-dehydrogenation of esters and nitriles to am-
ides were unsuccessful, and are summarized in Figure 2. The
previously disclosed reaction conditions generate a zinc eno-
late by sequential addition of LiTMP (lithium 2,2,6,6-
tetramethylpiperidine) and ZnCl2, followed by oxidation with
π-allyl-palladium chloride dimer and allyl acetate:4 for the
model amide substrate 1a, use of previously described LiTMP
(3a) resulted in a yield of only 26% with 53% conversion of the
starting material. Attempts to improve these results through
modification of standard reaction variables (oxidant, equiva-
lents, temperature, time, etc.) were unsuccessful. Reasoning
that the lithium amide base may play a role in determining the
coordination sphere of the allyl-palladium reactive species and
may impact the observed efficiency, we examined alternative
lithium amide bases.
Herein we report a novel lithium anilide, lithium cyclohex-
yl(2,6-diisopropylanilide), LiCyan, that allows for the direct
palladium-catalyzed α,β-dehydrogenation of amide substrates
(Figure 1b). Furthermore, we demonstrate a generalized meth-
od for carbonyl-selective dehydrogenation of substrates with
reactive heteroatom nucleophiles, including alcohols and
amines (Figure 1c). These advancements eliminate the need to
include inefficient protection and deprotection strategies in
synthetic design where dehydrogenation of amide substrates is
Varying the structure of the lithium amide base in the em-
ployment of alternative commercial lithium amide bases, LDA
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Scheme 1. Amide α,β-dehydrogenation scopea
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Figure 2. LiCyan is optimal for dehydrogenation.a
(3b, 64%) and LiNCy2 (3c, 66%), was also unsuccessful. Addi-
tional structural modification focused on introduction of an
arene into the lithium amide in order to provide an additional
means to make structural modifications: unfortunately, only
54% of the desired oxidized product was obtained using lithi-
um N-cyclohexyl anilide (3d). However, introduction of 2,6-
diisopropyl groups on the aryl ring, LiCyan (3e), resulted in
complete conversion and a 1H-NMR yield of 99%. Exchange of
the isopropyl groups for isopropoxy groups by using lithium N-
cyclohexyl 2,6-diisopropoxyanilide (3f) resulted in a decreased
yield of 62%. Optimization of the alkyl fragment established
that the yield increased in the order Ph < t-Bu << i-Pr ~ Cy.13
When the catalyst loading was reduced by an order of magni-
tude to 0.25 mole percent with LiCyan as base, a yield of 99%
was still obtained.14 CyanH is readily synthesized on prepara-
tive scale via reductive amination and recrystallization. Follow-
ing dehydrogenation reactions, it is routinely recovered in
yields up to 99%.
After efficient conditions for amide α,β-dehydrogenation
were determined, we investigated the scope of this transfor-
mation (Scheme 1). It was found that a number of different
amides were tolerated in addition to the dibenzyl amide func-
tionality in 2a, which on a 10-mmol scale was produced in 99%
yield. This methodology can access a morpholine amide (2b),
which could be converted to an enone using an organometallic
nucleophile.15 Activated substrates, such as the acyl oxazoli-
dinone 1c, could also be dehydrogenated to provide 2c,16 which
have been used to effect diastereoselective 1,4-conjugate addi-
tions.17 While incomplete conversion was observed at room
temperature, increasing the temperature to 60 °C resulted in
full conversion. A Boc-protected piperazine underwent dehy-
drogenation to provide 2d in 90% yield. Synthesis of conjugat-
ed systems with electron-rich and -deficient substitution at the
β-position had minimal impact on formation of the dehydro-
genated products 2e-h. Products derived from competitive
oxidative addition of the aryl chloride (2i) and aryl bromide
(2j) functionality were not observed under the optimized
reaction conditions. Formation of enyne (2k) and diene (2l),
which could be useful as substrates for alternative modes of
reactivity, proceeded in excellent yield, 86% and 95%, respec-
tively. A brief investigation of lactam substrates revealed that
normal- and medium-sized rings (5-8 membered rings) with
alkyl, allyl, and benzyl functional groups at nitrogen were via-
ble substrates for α,β-dehydrogenation (2m-2q). An amino
group at the β-position of the amide did not prevent formation
of the product 2r. It has previously been shown that amide
α,β-dehydrogenation with DDQ is facile when aromaticity is a
driving force;18 likewise, our optimized conditions can provide
such substrates in good yield (e.g. 2s). Over-oxidation of com-
pounds that can become aromatic (e.g. 2n and 2q) was not
observed under the conditions employed. Dehydrogenation of
mono-β-substituted amides provided exclusively E-selective
products.19 Although the dehydrogenation conditions de-
scribed herein are mild and allow for the selective dehydro-
genation of a wide variety of amides, one limitation is that α,α-
disubstituted amides are generally not viable substrates due to
the difficult deprotonation of these compounds. In addition,
dehydrogenation adjacent to tosyl-protected and carbamate-
protected amides (e.g. Boc, Cbz) was not possible under the
conditions employed.
With a preliminary understanding of the constraints on the
scope for α,β-dehydrogenation of amides, we began to investi-
gate substrates that contain nucleophillic heteroatoms
(Scheme 2). While a multitude of synthetic technologies can
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Scheme
2.
Carbonyl-selective
amide
α,β-
Scheme
dehydrogenation
3.
Protecting-group
controlled
α,β-
dehydrogenationa
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sulfonamide (2ab), an anilide (2ac), and a carbamate (2ad) are
tolerated. The secondary-amine containing product 2ae could
be isolated in good yield (52%), which is surprising given
amines are known to undergo oxidation catalyzed by palladi-
um.22 Although oxidation and the nucleophilicity of the amine
functionality can be suppressed under acidic conditions by
protonation,23 this mode of reactivity is unavailable under the
basic conditions of the present oxidation system.
Scheme 3 demonstrates that amide or lactam protecting
group selection can determine which carbonyl in a substrate
with more than one carbonyl undergoes dehydrogenation.
While mono N-substituted amides are tolerated as spectator
groups, they cannot be α,β-dehydrogenated under the reaction
conditions. Substrate 2af can be formed in an excellent 87%
yield. Even a lactam that is more easily oxidized by virtue of
the byproduct being aromatic does not interfere in the dehy-
drogenation of the N,N-disubstituted amide 2ag. This trend
can be reversed to the more typical selectivity mode24 through
the introduction of a PMB protecting group on the lactam
nitrogen and by using a limited quantity of LiCyan, which re-
sults in formation of 2ah in an isolated yield of 48% as the
single dehydrogenated product in addition to 41% recovered
starting material, 1ah. These examples clarify how choice of
protecting group and equivalents of base can determine the
reaction outcome.
oxidize or functionalize alcohols in the presence of carbonyl
functionality,20 methods for the opposite mode of dehydro-
genation selectivity have been elusive except for a small num-
ber of specialized substrates.12 Such a methodology would im-
prove the synthetic efficiency of accessing α,β-dehydrogenated
carbonyl compounds by averting protection and deprotection
concession steps. It was hypothesized that the optimized reac-
tion conditions with additional anilide base would tolerate
acidic and nucleophillic heteroatom functionality prone to
oxidation.21 The substrate 1t (Scheme 2a) was subjected to the
standard reaction conditions, and it was found that the prima-
ry alcohol functionality remained intact, providing the product
2t in 59% yield. This selectivity trend was also observed for the
α,β-dehydrogenation of lactams, as evidenced by the formation
of 2u in 82% yield. Secondary alcohols did not interfere with
amide α,β-dehydrogention, as seen with the formation of the
diol product 2v in 76% yield and the hemiaminal substrate 2w.
The hemiaminal substrate 2w is notable as this functionality
readily undergoes oxidation by an even wider variety of oxi-
dants than do simple alcohols. In a similar vein, activated
benzylic alcohols were not converted to phenyl ketones, but
provided the α,β-unsaturated amide, as in 2x (83%) derived
from the Myers’ pseudophedrin auxiliary. Akin to alcohols,
phenols are also prone to oxidation, but the product 2y could
be obtained in 57% yield.
Employing allyl-palladium catalysis, a method for the dehy-
drogenation of amides has been developed using a novel, recy-
clable anilide base, LiCyan. Because alcohols and amines are
tolerated under these reaction conditions, it is not necessary to
subdue these readily oxidized functionalities through tedious
multiple-step protecting group sequences. Moreover, CyanH
may have future use in alternative base-mediated processes or
transition-metal catalyzed reactions as a hindered, monoden-
tate anilide ligand.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data for all new
1
compounds including H- and 13C-NMR spectra. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
In addition to substrates that contain O–H functionality, it
was found that the N–H functional group is also tolerated.
Scheme 2b illustrates that unprotected indoles (2z-aa), a
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(10) For the α,β-dehydrogenation of more acidic and more easily
oxidized lactams, see: Bhattacharya, A.; DiMichele L. M.; Dolling,
U. H.; Douglas, A. W.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988,
110, 3318.
(11) For the use of elemental halogens for α,β-dehydrogenation
of lactams, see: King, A. O.; Anderson, R. K.; Shuman, R. F.;
Karady, S.; Abramson, N. L.; Douglas, A. W. J. Org. Chem. 1993, 58,
3384.
(12) For a rare α,β-dehydrogenation of a lactam in the presence
of an unprotected alcohol, see: Shams, N. A. J. Prakt.
Chem. 1985, 327, 536.
(13) In addition to the slightly improved yield with 3e relative to
3g, the aniline precursor of 3e is a crystalline solid (M.P. = 67 – 68
°C) whereas that of 3g is an oil.
(14) Dehydrogenation under the standard conditions was also
viable for esters (tert-butyl hydrocinnamate, 90% yield) and ni-
triles (cyclohexanecarbonitrile, 95% yield).
(15) Martín, R.; Romea, P.; Tey, C.; Urpí, F.; Vilarrasa, J. Synlett
1997, 12, 1414.
(16) For NMR yields for α,β-dehydrogenation of the more acidic
and more easily oxidized imides, see: Matsuo, J.-i.; Aizawa, Y. Tet-
rahedron Lett. 2005, 46, 407.
(17) For asymmetric conjugate additions with similar products,
see: (a) Nicolás, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993,
58, 766. (b) Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org. Chem.
2004, 69, 5374.
(18) For an example of dehydrogenation to form a pyridone, see:
Tanaka, T.; Mashimo, K.; Wagatsuma, M. Tetrahedron Lett. 1971, 12,
2803.
(19) Dehydrogenation to form N,N-dibenzyl-β-methylcinnamide
provided a yield of 95% (E:Z = 4:1).
(20) For reviews on Pd-catalyzed alcohol oxidation, see: (a) Mu-
zart, J. Tetrahedron 2003, 59, 5789. (b) Sigman, M. S.; Schultz, M. J.
Org. Biomol. Chem. 2004, 2, 2551. (c) Ebner, D. C.; Bagdanoff, J. T.;
Ferreira, E. M.; McFadden, R. M.; Caspi, D. D.; Trend, R. M.; Stoltz,
B. M. Chem. Eur. J. 2009, 15, 12978.
(21) In addition to the mild nature of the allyl oxidant, the lig-
and environment of the palladium-bound substrate allows for
selective amide dehydrogenation, rather than alcohol oxidation or
allylation. For a related reaction involving the oxidation of allyl
carbonates to ketones, see: Minami, I.; Tsuji, J. Tetrahedron, 1987,
43, 3903.
(22) For a review on amine oxidation, including with Pd, see:
Murahashi, S.-I. Angew. Chem. Int. Ed. 1995, 34, 2443.
(23) For two recent examples of this strategy, see: (a) Lee, M.;
Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 12796. (b) Howell, J. M.;
Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White, M. C. J. Am. Chem.
Soc. 2015, 137, 14590.
(24) For lactam α,β-dehydrogenation in the presence of amides,
see: Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton,
E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J.
R.; Berman, C. J. Med. Chem. 1986, 29, 2298.
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AUTHOR INFORMATION
Corresponding Author
timothy.newhouse@yale.edu
Notes
The authors declare no competing financial interests.
9
ACKNOWLEDGMENTS
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We gratefully acknowledge Yale University, the NSF (GRF
to A.T., DGE-1122492) and the Anderson Foundation (post-
doctoral fellowship to Y.C.) for funding.
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