Cu/Fe-cocatalyzed meyer-schuster-like rearrangement of propargylic amines: Direct access to e -β-aminoacryaldehydes

Article abstract of DOI:10.1021/ol5029805

A simple and efficient method for the synthesis of β-aminoacryaldehydes via Cu(OAc)₂·H₂O and FeCl₃ cocatalyzed Meyer-Schuster-Like rearrangement of propargylic amines was developed. The reactions proceed selectively as the E-isomers in generally good yields under aerobic conditions, and are compatible with a broad range of functional groups. This method combines C-N bond cleavage as well as the N-aryl group migration and provides a practical and mild synthetic approach to α,β-unsaturated carbonyl compounds, which are useful precursors in a variety of functional group transformations.

Full text of DOI:10.1021/ol5029805

Letter
pubs.acs.org/OrgLett
Cu/Fe-Cocatalyzed Meyer−Schuster-like Rearrangement of
Propargylic Amines: Direct Access to E‑β-Aminoacryaldehydes
Ming Chen, Jiangling Peng, Tingting Mao, and Jinbo Huang*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190
Kaiyuan Avenue, Guangzhou 510530, China
S
* Supporting Information
ABSTRACT: A simple and efficient method for the synthesis
of β-aminoacryaldehydes via Cu(OAc)2·H2O and FeCl3
cocatalyzed Meyer−Schuster-Like rearrangement of propar-
gylic amines was developed. The reactions proceed selectively
as the E-isomers in generally good yields under aerobic
conditions, and are compatible with a broad range of
functional groups. This method combines C−N bond cleavage as well as the N-aryl group migration and provides a practical
and mild synthetic approach to α,β-unsaturated carbonyl compounds, which are useful precursors in a variety of functional group
transformations.
earrangement reactions are useful for the preparation of
synthetically challenging products from readily accessible
Scheme 1. Transition-Metal Catalyzed Meyer−Schuster
R
Rearrangement Reactions
precursors.1 The classical Meyer−Schuster (M.S.) rearrange-
ment of propargylic alcohols, furnishing the corresponding α,β-
unsaturated aldehydes or ketones, was first reported by K. H.
Meyer and K. Schuster in 1922.2 This reaction has been
extensively applied in organic synthesis due to high atom
economy and high efficiency for converting readily available
materials into versatile enone products. Strong protic or Lewis
acids were mostly used as promoters in the earliest versions of the
M.S. reaction,3 which generally afforded products in poor yields,
due to unselective rearrangements and side reactions. Such
rearrangements were better catalyzed by oxo complexes of
transition metals, such as vanadium,4 molybdenum,5 rhenium,6
and titanium,7 which required an elevated temperature (100 °C)
and/or acidic conditions. Later on, many other transition metals8
such as mercury, ruthenium, gold, silver, and indium complexes
were explored to promote the direct M.S. rearrangement of
propargylic alcohols or esters. In this context, a gold-catalyzed
conversion of propargylic esters into 1,3-ynone derivatives in
combination with PhI(OAc)2 as an oxidant was reported by
Hashmi and co-workers (Scheme 1).9 Additionally, Baba
developed an indium chloride catalyzed alkylative rearrangement
of propargylic acetates into α-alkyl-α,β-unsaturated carbonyl
compounds.8i Furthermore, a copper-catalyzed arylative Meyer−
Schuster rearrangement of propargylic alcohols was notably
developed by Gaunt,10 and a novel domino copper-catalyzed
trifluoromethylated Meyer−Schuster rearrangement reaction
with Togni’s reagent was developed by Liu and Tan, in which
the active allenol intermediate is involved.11
corresponding propargylamines, perhaps because the active
enaminol intermediate are unstable and the multireactive centers
of enone or propargylicamines are difficult to control.
Encouraged by the results from Meyer−Schuster rearrangement
of propargylic alcohols9−11 and in connection with our
continuous efforts devoted to metal-catalyzed reactions,13 we
herein present the first example of a new type of Cu/Fe-
cocatalyzed oxidative Meyer−Schuster-like rearrangement re-
action of propargylic amines, in many cases forming β-
aminoacryaldehydes that would be difficult to synthesize by
other means,14 selectively as the E-isomers with moderate to
good yields. Importantly, the formation of aminoacryaldehyde
moieties can serve as versatile intermediates for the synthesis of a
wide variety of heterocycles contained in biologically active
Propargylamines are important building blocks for a variety of
organic transformations and are also valuable precursors for
therapeutic drug molecules.12 In contrast, while there are
numerous reports on Meyer−Schuster rearrangement, partic-
ularly involving propargylic alcohols or esters as substrates,4−11
much less is known about the rearrangement of the
Received: October 9, 2014
© XXXX American Chemical Society
A
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Letter
compounds.14c,15 Notably, a highly efficient and practical FeCl3-
catalyzed domino synthesis of acrylonitriles by using propargylic
alcohols and para-tolylsulfonohydrazide as a combined cyano
source was developed by Zhang.16 This cyanation reaction
proceeds through a domino regioselective propargylic sub-
stitution/aza-Meyer−Schuster rearrangement route.
We began our study by investigating the Cu(OAc)2 and FeCl3
cocatalyzed Meyer−Schuster-Like rearrangement of propargylic
amines 1a in air at 90 °C. Initially, a number of common solvents
were examined in this reaction, but no desired product was
detected (Table 1, entries 1−3). To our delight, when DMSO
mol % of Cu(OAc)2·H2O are used for the process (Table 1,
entries 7 vs 10). Further screenings of the cocatalysts revealed no
better results (Table 1, entries 11−13). Finally, a variety of
additives including bases and acids were also examined (Table 1,
entries 14−17). To our surprise, using 1.0 equiv of PivOH
afforded 2a in an excellent yield of 70% (Table 1, entry 15),
whereas other additives such as TFA, TsOH, and K2CO3
inhibited the reaction severely. In addition, we found that
increasing or decreasing the amount of PivOH does not benefit
the formation of 2a (see SI, Table S1). When the reaction was
operated in argon, the rearrangement was considerably less
efficient, suggesting that O2 played a vital role in the catalytic
cycle (Table 1, entry 18). Air (O2) is mandatory to obtain the
product, and we have detected Me2S as a byproduct during the
reaction by GC−MS.
a
Table 1. Optimization of the Reaction Conditions
Having identified the optimal conditions, we next examined
the substrate scope for this new reaction. As shown in Scheme 2,
a
Scheme 2. Scope of Aryl Amines Moiety
yield
b
entry
cd
catalyst 1
catalyst 2
FeCl3
additive
solvent
[%]
,
1
2
3
4
5
6
7
8
9
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(OAc)2
−
THF
n.d.
n.d.
n.d.
48
cd
,
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
−
CH3CN
DCE
cd
,
d
d
d
DMSO
MeOH
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
8
4
44
n.d.
30
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
10
11
FeCl3
62
Fe(NO3)3·
9H2O
trace
12
13
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Fe2(SO4)3
DMSO
DMSO
trace
n.r.
La(NO3)3·
9H2O
14
15
16
17
18
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
TFA
DMSO
DMSO
DMSO
DMSO
DMSO
n.d.
70
PivOH
TsOH
K2CO3
PivOH
n.d.
<10
<10
a
Reaction conditions: 1a (0.2 mmol), Cu(OAc)2·H2O (0.01 mmol),
FeCl3 (0.08 mmol), and PivOH (0.2 mmol) in 2.0 mL of DMSO at
100 °C, in air, for 22 h.
e
a
Reaction conditions: 1a (0.2 mmol), catalyst 1 (0.01 mmol), catalyst
2 (0.08 mmol), additive (0.2 mmol), solvent (2 mL), at 100 °C, in Ar,
for 22 h. Isolated yield. At 90 °C. Cu(OAc)2·H2O (0.02 mmol) and
FeCl3 (0.02 mmol) were used. Under argon.
b
c
d
the transformation for the substrates with substituents at the
para-position of aryl amines moiety proceeded quite smoothly
and afforded the desired β-aminoacryaldehydes 2a−d in good
yields, selectively as the E-isomers. Electron-donating groups
such as the methyl group and electron-withdrawing substituents
such as F and Cl in the propargylamines of 1 were tolerant, and
electronic effects had no significant impact on the yields.
However, the steric effect of the meta-substituted groups on the
phenyl ring of the aryl amines moiety lowered the yields (2e, 2f)
dramatically compared to their para-analogues. Somewhat
disappointingly, when a substituted group was installed on the
ortho-position of aryl amines moiety, only a trace amount of the
desired product was detected (2g, 2h) probably due to the steric
hindrance of the substrates.
The effect of the substituents on the phenyl ring of aromatic
alkyne moiety was also studied (Scheme 3). We were pleased to
see that this Cu/Fe cocatalyzed rearrangement reaction
displayed good functional-group tolerance and proved to be a
facile and general protocol for the synthesis of substituted β-
aminoacryaldehydes. The substrates containing electron-donat-
ing groups such as OMe and Me at the aryl ring could be
e
was used as the oxidant, the valuable β-aminoacryaldehydes 2a
was detected and isolated in 48% yield (Table 1, entry 4). In
addition, a higher temperature was not beneficial to the
transformation (see Supporting Information (SI), Table S1).
Other commonly used solvents such as methanol and toluene
were less effective, and only poor yields were obtained (Table 1,
entries 5−6). Then, we focus on the metal catalyst, which was
vital to the catalytic cycle. Various copper catalysts were
evaluated. The use of CuCl2, CuBr2, CuSO4, Cu(NO3)2, or
CuO was detrimental to this reaction (see SI, Table S1), whereas
Cu(OAc)2 and Cu(TFA)2 were effective for this transformation,
providing 2a in yields of 44% and 48%, respectively (Table 1,
entry 4 vs 7). A control reaction without Cu(OAc)2 did not
proceed, indicating that these catalysts are essential for oxidative
rearrangement reaction (Table 1, entry 8). Surprisingly, the
reaction did take place without FeCl3, albeit affording the
products with diminished yields (Table 1, entry 9). The yield of
2a was further increased to 62% when 40 mol % of FeCl3 and 5
B
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Letter
a
product (2q) in moderate yield. Interestingly, heteroaryl groups,
such as 3-thienyl (2r) and 3-pyridyl (2s) groups, can be
incorporated into the substituted β-aminoacryaldehydes scaffold
by using corresponding propargylic amines, albeit in lower yields,
thus enhancing the scope of our reaction. Importantly, all the
catalytic reactions proceeded with excellent E selectivity, and the
Z isomers were not detected presumably due to the steric
hindrance. Additionally, it was found the substituents on the
methylene such as benzyl, phenyl, and CF3 significantly effected
the reaction, with no desired product being detected.
Scheme 3. Scope of Aromatic Alkyne Moiety
To further extend the synthetic utility of 2, we studied the
palladium-catalyzed oxidative cyclization of N-aryl enamines
(Scheme 4).17 After a quick screening of the reaction conditions,
Scheme 4. Palladium-Catalyzed Synthesis of Indole-3-
carbaldehyde Derivatives from E-β-Aminoacryaldehydes
it was found that reaction of E-β-aminoacryaldehyde derivatives
(2a, 2i, 2l), conducted with a combination of 2.0 equiv of
Cu(OAc)2 as the catalyst and 2.0 equiv of PivOH as the additive
in DMF at 120 °C, resulted in conversion into the indole-3-
carbaldehyde derivatives (3a−c). As we know, indole derivatives
were useful nitrogen-containing structural units, which were
widely applied in synthetic and medicinal chemistry. Thus, this
new protocol could hold great potential for applications in the
discovery of lead compounds and other biologically active
indole-based molecules in organic chemistry as well as biology.
In order to explore the possible mechanism, two 18O-labeling
experiments were performed as described in Scheme 5. When
a
Reaction conditions: 1a (0.2 mmol), Cu(OAc)2·H2O (0.01 mmol),
FeCl3 (0.08 mmol), and PivOH (0.2 mmol) in 2.0 mL of DMSO at
100 °C, in air, for 22 h.
transformed to the desired products 2i and 2j in good yields,
respectively. Meanwhile, substrates with electron-deficient aryl
substituents such as Br, F, and NO2 in the 4′-position also
worked well to give 2k−m, respectively. The structure of 2k was
unambiguously determined by X-ray crystallography (Figure 1)
Scheme 5. Experiments for Mechanistic Studies
Figure 1. Crystal structure of 2k. Hydrogen atoms are omitted for
clarity.
and HRMS (see SI). It is noteworthy that the substrates with
aromatic halides performed well in this transformation
generating halo-substituted products (2k, 2l, 2p), thereby
providing possibilities for subsequent chemical transformations.
Additionally, propargylic amines having methyl substituents at
the meta-position of the aryl groups could also be transferred
through this protocol, although reduced yields of the
corresponding products 2n,o were observed. Similarly, ortho-
substituents including Cl (2p vs 2o and 2j) were generally
detrimental to this reaction, suggesting that this reaction is
sensitive to the steric bulk on the aromatic ring. Notably, a
benzylic C−H bond adjacent to the alkyne was less compatible
with the oxidative and acidic conditions, affording the oxidized
H2O18 (5.0 equiv) was added into the reaction, 82% of the 18O-
labeled product was detected (Scheme 5, eq 1). In the oxygen
exchange experiments, we could detect 9% of the 18O-labeled
product in the standard reaction conditions (Scheme 5, eq 2).
These results indicated that the oxygen source in 2a was from
water wich may come from the acid or Cu(OAc)2·H2O. In
addition, radical-trapping experiments were performed in the
reaction. As a result, the reactions were not suppressed (see SI,
Table S2). However, a tentative mechanism involving radical
intermediates was not excluded under the present reaction
conditions.18
On the basis of our observations and previous reports,8−10,19
a
plausible reaction mechanism is proposed in Scheme 6. Initially,
C
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Letter
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In summary, we have developed a novel approach to transform
readily accessible and inexpensive propargylic amines into β-
aminoacryaldehydes using copper and iron catalysis. This
protocol provided a broad scope of the desired enaminal
products in moderate to good yields with good E-isomeric
selectivity, rendering this method a valuable addition to the
synthetic chemist’s toolbox. The highly functionalized E-
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be readily transformed into important heterocyclic motifs.
Further developments of this method and elucidation of the
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ASSOCIATED CONTENT
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* Supporting Information
́
́
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Experimental procedure, and copies of H and 13C spectra for
1
́
compounds 2a−s, 3a−c. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
Z.-P. Chem.Eur. J. 2012, 18, 6453.
*E-mail: huang_jinbo@gibh.ac.cn.
Notes
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The authors declare no competing financial interest.
(18) (a) Li, Y.; Ma, L.; Jai, F.; Li, Z. J. Org. Chem. 2013, 78, 5638. (b) Li,
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ACKNOWLEDGMENTS
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This work was supported by the National Science Foundation of
China (NSFC) (Grant No. 21202167). The authors gratefully
thank Prof. Jinsong Liu and Dr. Yongzhi Lu for X-ray
measurements (Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences).
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