Manganese-Catalyzed Desaturation of N-Acyl Amines and Ethers

Article abstract of DOI:10.1021/acscatal.9b03457

Enamines and enol ethers are versatile synthons for chemical synthesis. While several methods have been developed to access such molecules, prefunctionalized starting materials are usually required, and direct desaturation methods remain rare. Herein, we report direct desaturation reactions of N-protected cyclic amines and cyclic ethers using a mild I(III) oxidant, PhI(OAc)₂, and an electron-deficient manganese pentafluorophenylporphyrin catalyst, Mn(TPFPP)Cl. This system displays high efficiency for α,β-desaturation of various cyclic amines and ethers. Mechanistic probes suggest that the desaturation reaction occurs via an initial α-C-H hydroxylation pathway, which serves to protect the product from overoxidation.

Full text of DOI:10.1021/acscatal.9b03457

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Letter
Manganese Catalyzed Desaturation of N-acyl Amines and Ethers
Gang Li, Patrick Kates, Andrew K. Dilger, Peter T.W. Cheng, William R. Ewing, and John T. Groves
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03457 • Publication Date (Web): 18 Sep 2019
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ACS Catalysis
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Manganese Catalyzed Desaturation of N-acyl Amines and Ethers
Gang Li,† Patrick A. Kates, † Andrew K. Dilger,‡ Peter T. Cheng,‡ William R. Ewing,‡ and John
T. Groves*†
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†Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
‡Bristol-Myers Squibb, P. O. Box 5400, Princeton, New Jersey 08543-5400, United States
homogenous catalysis, C-H activation, high-valent metal-oxo complexes, manganese porphyrins, desaturation
ABSTRACT: Enamines and enol ethers are versatile synthons for chemical synthesis. While several methods have been
developed to access such molecules, prefunctionalized starting materials are usually required and direct desaturation
methods remain rare. Herein, we report direct desaturation reactions of cyclic amines and cyclic ethers using a mild I(III)
oxidant, PhI(OAc)2, and an electron-deficient manganese pentafluorophenylporphyrin catalyst, Mn(TPFPP)Cl. This
system displays high efficiency for ,-desaturation of various cyclic amines and ethers. Mechanistic probes suggest that
the desaturation reaction occurs via an initial -C-H hydroxylation pathway, which serves to protect the product from
over-oxidation.
Olefins occupy a key nexus in organic synthesis and
process chemistry.1 Among them, functionalized olefins
such as enamines and enol ethers have attracted
considerable attention. Enamines are widely represented
in natural and synthetic compounds possessing useful
biological and physiological properties.2-7 Enol ethers are
used as cross-reaction partners in olefin metathesis,8 as
well as substrates for access to a variety of functional
polymers.9-10 In view of this level of utility, numerous
methods have been developed to access such olefins.
Typically, these methods require prefunctionalized
a minor pathway and olefin oxygenation typically
dominates. Thus, this unexpected observation
encouraged us to explore the scope of this manganese-
catalyzed, direct desaturation protocol.
We initiated this study by screening N-protecting groups
using proline derivatives as model substrates. Each
substrate resulted solely in desaturation products (Table
1, entries 1-5). Less electron-withdrawing protecting
groups (Boc, Bz, Ac) gave better conversions, while more
electron-withdrawing protecting groups (Ns, TFA)
suppressed the reaction.
11-19
starting materials, thus limiting their practicality.2-3,
Table 1. Manganese-catalyzed desaturation of N-
protected proline methyl esters with various
oxidants.a
Direct, catalytic dehydrogenation would be ideal for the
conversion of simple aliphatic starting materials into
valuable functionalized olefins, but such methods remain
rare. Very recently, Gevorgyan et al. reported a palladium-
catalyzed desaturation of aliphatic amines via a hydrogen
atom transfer mechanism.20 While efficient for a variety of
substrates, the method requires N-benzoyl protecting
groups, thus limiting its application due to the forcing
conditions required for the removal of that protecting
group. Moreover, the method has so far been limited to
amines. A more general desaturation method that is
applicable to both amines and ethers would be highly
valuable.
entry
R
oxidant
PhIO
conversion
35%
yield
30%
trace
32%
25%
trace
>95%
trace
10%
67%
trace
1
2
3
4
5
6
7
Boc
TFA
Bz
PhIO
trace
PhIO
34%
Our long-standing interest in aliphatic C-H
functionalization led us to examine manganese
porphyrins and heteroatom rebound catalysis as an
approach to amine and ether desaturation.21-28 In an
attempt to functionalize the -C-H bond of a protected
proline (1a) using a manganese(III) pentafluorophenyl
porphyrin, Mn(TPFPP)Cl, we observed ,-desaturation
with iodosylbenzene as the oxidant (Table 1, entry 1).
Although desaturations are commonly observed in
aliphatic C-H bond oxidation reactions,29-30 this is usually
Ac
PhIO
28%
Ns
PhIO
trace
Boc
Boc
PhI(OAc)2
PhI(TFA)2
>95%
trace
8
Boc
Boc
Boc
PhI(OPiv)2
MesI(OAc)2
H2O2/AcOH
12%
70%
trace
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aConditions: substrate (0.1 mmol), PhI(OAc)2 (0.2 mmol),
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Boc
Cbz
mCPBA
trace
trace
1
2
3
4
5
6
7
8
MeCN (0.5 mL), 50 oC, 2 h. Conversions and yields
determined by GC-MS using naphthalene as an internal
standard.
PhI(OAc)2
>95%
>95%
aConditions: substrate (0.1 mmol), PhI(OAc)2 (0.2 mmol),
Mn(TPFPP)Cl (0.005 mmol), MeCN (0.5 mL), 50 C, 2 h.
Conversions and yields determined by GC-MS using
naphthalene as an internal standard. Ns
nitrophenylsulfonyl, TFA = trifluoroacetate, Bz = benzoyl, Ac
= acetyl, Boc = tButyloxycarbonyl, Cbz = carboxybenzyl. Piv
= pivaloyl, Mes = mesityl, mCPBA = m-chloroperoxybenzoic
acid.
o
Inspired by the results for proline desaturation, we
further investigated the ability of Mn(TPFPP)Cl to catalyze
the ,-desaturation of other amines (Table 3).
=
4-
Generally, 5- and 6-membered cyclic amines reacted
efficiently, affording the desired desaturation products in
moderate to excellent yields (2a-2f). Morpholine 1g was
also reactive, producing the desired desaturation product
2g in good yield. It is interesting to note that when bis-N-
Boc piperazine 1h was subjected to the reaction
conditions, a double desaturation product 2h was
observed. Similar double desaturation was observed for
this substrate with palladium-catalyzed desaturation.20
Notably, substrate reactivity decreased significantly with
increasing ring size. Reaction of seven-membered rings
(1i and 1j) resulted in moderate yields (2i and 2j), while
reaction with a substrate with an eight-membered ring (1k)
resulted in less than a 20% yield. A non-cyclic amine 1l
was also tested, which only afforded trace desaturation
product 2l. We expect that the transition state for
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Carbamate protecting groups such as Boc or Cbz are
particularly useful because they can be removed easily.31
We then used N-Boc proline methyl ester (1a) as the
substrate to examine the effect of oxidants in the
desaturation reaction. When a milder and more soluble
oxidant such as PhI(OAc)2 was used, we observed
quantitative conversion to the desaturated product with no
side products (Table 1, entry 6, and Figure S1 in
Supporting Information). Switching to a more electrophilic
trifluoroacetate oxidant PhI(O2CCF3)2 (Table 1, entry 7)
severely suppressed the reaction. The bulkiness of the
oxidant was also found to affect the observed reactivity.
When PhI(OPiv)2 was employed as the oxidant (Table 1,
entry 8), the desired product was obtained in only 10%
yield. A less oxidizing mesityl iodinane also resulted in a
decreased yield (Table 1, entry 9). Other oxidants that
have been previously used in transition-metal-catalyzed
proline oxidation32 showed no reactivity under these
reaction conditions (Table 1, entries 10 and 11). Cbz-
protected proline methyl ester also showed superior
reactivity and a quantitative conversion was observed
(Table 1, entry 12). A more electron-rich manganese
catalyst, Mn(TMP)Cl, showed little catalytic activity (Table
S3, entry 2, optimization reactions are presented in the
Supporting Information).
desaturation requires
a conformation wherein the
incipient C=C bond is in conjugation with the amide group.
Such a conformation is readily achieved in small ring
substrates but would be more challenging or entropically
disfavored in larger ring or acyclic substrates, leading to a
lower yield of the enamide product.
Table 3. ,-Desaturation of amines catalyzed by
Mn(TPFPP)Cl.a
We were pleased to find the desaturation reaction
proceeded in good yields even with low catalyst loading
(Table 2). With 1 mol% catalyst, the reaction was
completed in 2 h. Decreasing the catalyst loading to 0.5%
still gave a yield of 90%, although a longer reaction time
was required. Further decreasing the catalyst loading to
0.1% led to a drastic decrease in yield, possibly due to
catalyst-bleaching. No reaction was observed without the
catalyst.
Table 2. The effect of catalyst loading on the
desaturation reaction.a
aConditions: substrate (0.2 mmol), PhI(OAc)2 (0.4 mmol),
Mn(TPFPP)Cl (0.002 mmol), MeCN (1 mL), 50 oC, 2 h,
b
isolated yield reported unless otherwise stated. 0.5 mmol
scale. cConversion and yield determined by GC-MS.
Considering the electronic similarities between cyclic
amines and cyclic ethers, we applied this desaturation
reaction to a panel of cyclic ether structures. Indeed, when
tetrahydropyran 1m was subjected to the desaturation
conditions with a higher catalyst loading, the desired
product 2m was observed in 55% NMR yield (eq. 3).
catalyst
loading
reaction
time
entry
conversion yield
1
2
3
4
5
6
5%
2h
2h
2h
4h
24h
>95%
>95%
>95%
95%
>95%
>95%
>95%
90%
12%
0%
2%
1%
0.5%
0.1%
16%
no catalyst 48h
<5%
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Similarly, the tetrahydropyran ester 1n afforded only the
1
desaturated product 2n, which was isolated in 62% yield
2
(eq. 4).
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Owing to the fact that ,-unsaturated cyclic ene-
carbamates are versatile intermediates for the synthesis
of various nitrogen-containing bioactive molecules,6, 33-37 it
would be highly advantageous if the viability of the
desaturation reaction was demonstrated on a larger scale.
Accordingly, we then carried out a gram-scale reaction on
1a to explore reaction scalability. The reaction worked
smoothly with no significant decrease in yield (Table 3,
condition b for 2a).
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Figure 1. UV-Vis spectra observed upon addition of
PhI(OAc)2 to Mn(TPFPP)Cl: a) Soret region; b) Q band
region. Solid line: Mn(TPFPP)Cl (10 M) in acetonitrile;
dotted line: 30 s after the addition of PhI(OAc)2 (20 equiv).
The reactivity of the Mn(TPFPP)Cl/PhI(OAc)2 system
indicates the involvement of an oxo-MnV intermediate.28,
39 The observed oxo-MnIV species is likely to be generated
upon rapid comproportionation of oxo-MnV with a MnIII
species43 and is unreactive toward these N-protected
amines.
We carried out the reaction under air-free conditions in
dry solvent to gain some mechanistic insight. No
conversion was observed under these conditions even
after heating for 24 h. However, upon addition of 10 equiv
of water, the desaturated product quickly appeared in
quantitative yield (eq. 5). We attribute this water
accelerating effect to slow hydrolysis of PhI(OAc)2 in wet
solvent to form PhIO or PhI(OH)(OAc), which has also
been observed in other metalloporphyrin-catalyzed
oxidation reactions using PhI(OAc)2 as oxidant.38-39
Oxo-MnV porphyrins have been shown to oxidize olefins
44-47
rapidly.26,
Also, PhI(OAc)2 is known to react with
enamines.48 Thus, we were curious as to why the
desaturated products could be isolated in such high yields.
Interestingly, when a reaction mixture with the N-benzoyl
substrate 1c was examined by mass spectrometry, a
hydroxylated product (presumably the hemi-aminal) was
observed (see Supporting Information). This result is
analogous to observations by White with a non-heme iron
catalyst.32 Bietti and Costas have also reported similar -
hydroxylations of amines using a non-heme manganese
catalyst.49-52 This unstable hemi-aminal product, or its
acyloxy derivative, is presumably converted rapidly into
the desired desaturated product during work-up. No
hydroxylated intermediate was observed for the
corresponding N-Boc protected substrate 1a, possibly
due to the greater instability of the corresponding hemi-
aminals. This hemi-aminal intermediate is likely converted
to an acyloxy-aminal intermediate in the presence of
excess PhI(OAc)2, which could suppress further oxidation
by the reactive oxo-MnV species due to its steric
hindrance and electron-deficiency. In contrast, when the
desaturated product 2a was directly subjected to this
Mn(TPFPP)Cl/PhI(OAc)2 system, it was further oxidized
and no substrate was recovered. Interestingly, when the
cyclic lactam substrate 1o was subjected to this
desaturation conditions, the -hydroxylated product 2o
was isolated in high yield (eq. 6), which also supports the
Examination of the reaction mixture by UV-Vis
spectroscopy was also informative. The Mn(TPFPP)Cl
catalyst displayed a split Soret band at 359 and 470 nm
and a Q band at 566 nm in acetonitrile, typical for
manganese(III) porphyrin complexes. After addition of
PhI(OAc)2 (10 equiv), the band at 470 nm disappeared
and a new band at 418 nm was formed. At the same time,
the Q band at 566 nm also faded while a new band was
observed at 540 nm (Figure 1). The new peaks match
previous reported values for oxo-MnIV species.40-43 Zhang
et al. have reported similar spectra in a previous study on
oxidation
of
alkenes
and
activated
benzylic
hydrocarbons.39
existence of
a
hemi-aminal intermediate in the
desaturation reaction.
In the case of cyclic ether 1m, the corresponding hemi-
acetal is stable. When this hemi-acetal was directly
reacted with PhI(OAc)2 in acetonitrile (eq 7), the
desaturated product was observed, indicating that hemi-
acetal could indeed be the intermediate of the
desaturation reaction.
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Detailed condition optimization; experimental procedures for
desaturation; and characterization data, including 1H and 13
NMR spectra (PDF)
1
2
C
3
4
AUTHOR INFORMATION
In accord with these results, we propose a mechanism
for this manganese-catalyzed desaturation reaction
(Figure 2). In the presence of oxidant, the manganese(III)
porphyrin will be oxidized to an oxo-MnV species that
abstracts the -hydrogen atom from the substrate,
resulting in a hydro-MnIV species and a substrate radical.
Oxygen rebound of the substrate radical forms the
unstable hemiaminal species, which dehydrates to yield
the desired desaturated product.
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8
Corresponding Author
*E-mail: jtgroves@princeton.edu
ORCID
John T. Groves: 0000-0002-9944-5899
Gang Li: 0000-0001-6680-961X
Notes
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The authors declare no competing financial interest.
Desaturation reactions of this type are commonly
observed with various heme53 and non-heme iron54
oxidases. It is noteworthy that assistance from the
adjacent heteroatom in C-C desaturation has also been
ACKNOWLEDGMENT
This research was supported by the US National Science
Foundation awards CHE-1464578 and CHE-1900048 (JTG)
and the BMS Center for Molecular Synthesis at Princeton
University.
54
observed in a non-heme Fe/2OG system. However, a
hydroxylated intermediate is not usually proposed in the
mechanism.54 Our result suggests that a hydroxylation
pathway may be taken into consideration in desaturations
in biological systems.
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Figure 2. Proposed mechanism for manganese-catalyzed
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In conclusion, we have demonstrated that an electron-
deficient manganese porphyrin, Mn(TPFPP)Cl, is a highly
efficient catalyst for the ,-desaturation of various cyclic
amines and cyclic ethers to afford a range of highly useful
functionalized olefins. The reaction protocol is simple, and
the reaction conditions are very mild and operationally
simple. The homogeneous conditions and tolerance of air
and moisture make this protocol amenable to automated
and high through-put procedures. We have also shown
that this reaction has the potential to be applied at larger-
scale. Our preliminary mechanistic studies indicate that
the reaction proceeds via
a
C-H hydroxylation-
dehydration pathway. An intermediate hemiaminal for
cyclic amine substrate is resistant to further oxidation,
resulting in a highly efficient desaturation. Further
extensions of this reaction are currently ongoing.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website.
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