Intramolecular Transamidation of Secondary Amides via Visible-Light-Induced Tandem Reaction

Article abstract of DOI:10.1021/acs.orglett.8b02303

Transformation of secondary amides to N-acylimines was used as an effective strategy to activate otherwise unreactive amide bonds. In this tandem reaction, the Rose Bengal-catalyzed photo-oxidative coupling of arylglycine esters and enamides generates N-acylimines, which undergo intramolecular transamidation and imine hydrolysis to afford bioactive acyl Mannich base derivatives under metal-free and mild conditions.

Full text of DOI:10.1021/acs.orglett.8b02303

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intramolecular Transamidation of Secondary Amides via Visible-
Light-Induced Tandem Reaction
Li Tang,† Xing-Meng Li,† Jack H. Matuska,‡ Yan-Hong He,*,† and Zhi Guan*,†
†Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, China
‡Department of Chemistry, College of Saint Benedict and Saint John’s University, Collegeville, Minnesota 56321, United States
S
* Supporting Information
ABSTRACT: Transformation of secondary amides to N-
acylimines was used as an effective strategy to activate
otherwise unreactive amide bonds. In this tandem reaction,
the Rose Bengal-catalyzed photo-oxidative coupling of
arylglycine esters and enamides generates N-acylimines,
which undergo intramolecular transamidation and imine
hydrolysis to afford bioactive acyl Mannich base derivatives
under metal-free and mild conditions.
Scheme 1. Two Main Challenges and Various Means of
Secondary Amide Transamidation
mide bonds not only are the key linkages of peptides,
Aproteins, and some synthetic polymers but are also present
in a great number of modern pharmaceuticals and biologically
active compounds.1 Traditional methods for construction of
amidebondsareoften associatedwithsignificant drawbackssuch
as waste, expense, and harsh reaction conditions. Therefore,
development of new approaches to amide bond formation is one
of the highest priority areas in sustainable organic synthesis.2
Transamidation can serve as an attractive strategy to prepare
amides, avoiding the use of carboxylic acids which need harsh
conditions or stoichiometric coupling agents.3 However, trans-
amidation is hindered by its kinetic and thermodynamic
challenges (Scheme 1a).4 The high kinetic barrier is due to the
amide N−C(O) bond resonance stabilization, which makes the
amide bond robust.3a,5 Transamidation is a mostly thermoneu-
tral process and tends toward an equilibrium between substrates
and products.3b,6 Primary amide transamidation is relatively
common,7 but transamidation of secondary amides that are
ubiquitous in proteins and synthetic amide derivatives is still a
great challenge. To the best of our knowledge, only a few
secondary amide transamidations have been reported.8−11
Catalytic direct transamidation by Lewis acidic metal complexes
was developed by Gellman and Stahl, but mixed amides of
reactants and products were obtained due to the equilibrium
betweensubstratesandproducts(Scheme1b).8 Veryrecently,an
elegant two-step strategy was used for secondary amide
transamidation, which involves first preparing Boc-activated
secondary amide derivatives. With this strategy, Garg’s group
developed the Ni-catalyzed secondary amide transamidation,9
and Szostak’s group reported the Pd/NHC complexes catalyzed
secondary amide transamidation.10 The Szostak group also
developed metal-free transamidation of secondary amides by
nucleophilic addition (Scheme 1c).11 Therefore, development of
efficient and mild methods for transamidation of secondary
amides is desirable.
We assumed that the ground state N−C(O) can be
destabilized when secondary amides are transformed to N-
acylimines, and transamidation equilibrium can be driven
forward by hydrolysis of imines to release NH3 just like primary
Received: July 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02303
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amide transamidation. Therefore, to verify our idea, we designed
a tandem reaction in which the visible-light-induced aerobic
oxidative coupling of arylglycine esters with enamides forms N-
acylimines, which undergo intramolecular transamidation,
producing corresponding imines; the hydrolysis of the imines
gives the final product Mannich base derivatives (Scheme 1d). In
the past decade, visible-light-induced photoredox catalysis has
emergedasapowerfulplatformfordesignandimplementationof
valuable transformations through single electron transfer path-
ways.12 From the viewpoint of green chemistry, organic dyes as
photocatalysts are cheap and environmentally friendly.13 Rose
Bengal (RB) as a common organic dye has been widely used in
photo-oxidative reactions.14 Furthermore, Mannich base de-
rivatives are highly important and useful compounds because
aminoalkyl chain motifs exist widely in a variety of natural
products, pharmaceuticals, agrochemicals, andsoforth.15 N-Acyl
Mannich bases have specifically been found to be potential
antimicrobial agents16 and useful synthetic intermediates.17 This
reaction has three key features: (1) direct synthesis of acyl
Mannich bases via the visible-light photocatalytic N−H
functionalization of secondary amines; (2) one-step trans-
amidation of secondary amides under mild conditions; (3)
atom economy and using oxygen and water as clean, abundant,
and sustainable chemical reagents.18
desired product ethyl 4-oxo-4-phenyl-2-(N-(p-tolyl)-
acetamido)butanoate (3aa) was obtained in 53% yield (Table
1, entry 1). Several other common metal and organo-photo-
catalysts were examined (Table 1, entries 2−6), and RB was
found to be the most effective for this reaction (Table 1, entry 6).
Thus, RB was chosen as the photocatalyst for the reaction. Next,
other common solvents were also screened, but none achieved
the yield observed with MeCN (Table 1, entries 7−11). Notably,
a good yield of 79% was obtained when a MeCN/AcOH (9:1, v/
v) solventsystemwas used (Table 1, entry 12). Wespeculate that
acidic solventmay promote the intramolecular transamidation,19
and acidic conditions favor hydrolysis of imines. Interestingly, no
reaction was observed when AcOH alone was used as a solvent
(Table1,entry13).Asexpected,nodesiredproductwasdetected
in the absence of water, and the reaction became messy (Table 1,
entry 14). Finally, the control experiments suggested that
photocatalyst, light, and oxygen were essential for this reaction
to proceed (Table 1, entries 15−17).
With the optimized conditions in hand (Table 1, entry 12), we
decided to examine the arylglycine ester scope (Scheme 2). First,
different ester groups (Me, Bn) were explored, and correspond-
ing products 3ba and 3ca were obtained. Second, a range of
groups at the para-position of the benzene rings of arylglycine
esters were surveyed, andboth electron-withdrawing (Cl and Br)
and electron-donating groups (Me and OMe) were compatible
with this reaction under applied conditions, affording corre-
sponding products 3aa and 3da−3ga. Next, mono- and di-Me
substituents on meta-position of the benzene rings of arylglycine
esters were tested, and they proved suitable for this reaction,
affording the corresponding products 3ha and 3ia. However, no
desired products were detected for the reactions with ortho-Me-
substituted N-phenylglycine ester and N-naphthylglycine ester,
probablyduetothestereohindranceeffect. Tofurtherinvestigate
the generality and practicability of this photoinduced tandem
reaction, an array of enamides 2 was examined (Scheme 2).
Phenyl enamides with both electron-donating and electron-
withdrawing groups at the para-position of the benzene rings
worked smoothly, affording the corresponding acyl Mannich
bases (3ab−3ag) in moderate to good yields. Because phenyl
bromides are widely known as electrophiles in traditional cross-
coupling reactions, to further capitalize these products, phenyl
enamides 2 with meta-bromo and ortho-bromo at the benzene
rings were examined. The meta-bromophenyl enamide afforded
the desired product 3ah in good yield, but the corresponding
product 3an of ortho-bromophenyl enamide could not be
detected, potentially duetothe stereohindranceeffect. The meta-
and para-dichlorophenyl enamides were tested, which gave the
corresponding product 3ai. Notably, xenyl and 2-naphthyl
enamides were compatible with the reaction under the applied
conditions (3aj and 3ak). The heterocycle-based enamide also
reacted smoothly with 1a, affording product 3al. This reaction
was also applicable to N-propionyl enamide, and the propionyl
Mannich base 3am was obtained. In addition to aliphatic acyl
enamides, both electron-donating and electron-withdrawing
aromatic acyl enamides worked well in this reaction to give
aromatic acyl Mannich bases 3aq and 3ar in good yields. In
addition,notethatthenonterminalolefin-derivedenamideswere
not effective with this tandem reaction (3ao and 3ap), probably
because of the steric hindrance of the substituent group at
nonterminal olefins. For those reactions where the desired
products were not obtained, most of the starting materials
(enamides 2) were consumed; the reaction got very messy. We
Our initial investigation focused on the reaction between ethyl
p-tolylglycinate 1a and N-(1-phenylvinyl)acetamide 2a (Table
1). In the presence of 3 mol % of Ru(bpy)3Cl2, a solution of 1a
(0.4mmol), 2a (0.2mmol), andwater(0.6mmol)inMeCN(1.0
mL) was irradiated with a 32 W compact fluorescent light bulb
(CFL) under oxygen at ambient temperature for 24 h, and the
a
Table 1. Selected Optimization Experiments
entry
photocatalyst
Ru(bpy)3Cl2
solvent
MeCN
yield (%)
1
53
2
methylene blue
MeCN
13
3
fac-Ir(ppy)3
MeCN
21
4
eosin Y
MeCN
39
5
Ir(ppy)2(dtbbpy)PF6
MeCN
48
6
7
8
9
10
11
12
13
14
15
RB
RB
RB
RB
RB
RB
RB
RB
RB
MeCN
acetone
DMSO
DMF
ethanol
THF
MeCN/AcOH 9:1
AcOH
9:1 MeCN/AcOH
9:1 MeCN/AcOH
9:1 MeCN/AcOH
9:1 MeCN/AcOH
65
56
43
38
35
26
79
nr
messy
trace
trace
nr
b
c
d
16
17
RB
RB
e
a
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), H2O (0.6
mmol), and photocatalyst (3 mol %) in solvent (1.0 mL) were
irradiated using a 32 W CFL in O2 at room temperature for 24 h;
b
isolated yields are provided. Standard conditions without water.
c
d
Standard conditions without photocatalyst. Standard conditions
e
without O2. Standard conditions without light.
B
DOI: 10.1021/acs.orglett.8b02303
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Organic Letters
Letter
a
Scheme 2. Scope of Substrates
Scheme 3. Scale-up Experiment and X-ray Analysis
Scheme 4. O-Labeling Experiment
Scheme 5. Proposed Possible Mechanism
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), H2O (0.6 mmol),
and RB (3 mol %) in MeCN/AcOH = 9:1 (1.0 mL) was irradiated
using a 32 W CFL in O2 at room temperature for 24 h; isolated yields
are provided.
to be excited from its ground state to its excited state RB*
(Ered[RB*/RB•−] = +0.99 V vs SCE in MeCN).20 RB* is single
electron reduced by arylglycine ester 1 ((Eox[1a/1a•+] = +0.83 V
vs SCE in MeCN) (see Figure S4) to form RB•−, and 1 is
converted into N-cation radical 1-A. Then, RB•− is single
electron oxidized by oxygen, leading to the ground state RB and
superoxide anion radical (O2•−). Subsequently, cation radical 1-
A is deprotonated by O2•− to give arylglycine ester radical 1-B
and hydroperoxyl radical HOO•. Then enamide 2 as a radical
acceptor reacts with 1-B to form the intermediate 3-A. Hydrogen
atomtransferbetween3-AandHOO• givesN-acylimine3-Cand
H2O2. Intramolecular transamidation of 3-C generates the imine
intermediate 3-E. Finally, the N-acyl Mannich base 3 is obtained
by the hydrolysis of 3-E.
In summary, we have developedthe first visible-light-mediated
intramolecular transamidation of secondary amides under metal-
free and mild conditions. Most crucially, we have demonstrated a
new design idea for transamidation through conversion of
secondary amides to N-acylimines, which can activate the
otherwise unreactive amide bonds. In this strategy, the visible-
light-induced aerobic oxidative coupling of arylglycine esters
tried to isolate the produced substances but failed because the
reactions were too complicated.
Next, a scale-up experiment of this visible-light induced
tandem reaction was conducted. A gram-scale reaction between
1aand2ewascarriedoutunderthestandardconditions(Scheme
3), and product 3ae was obtained in 72% isolated yield, which
proved the efficacy of this protocol. Because all of the products
are liquid, in order to undoubtedly determine the structure of the
products, 3ae was converted to its corresponding oxime 4ae
which is a solid. The crystallographic data of 4ae is shown in
Scheme 3.
Togaininsightintothereactionmechanism,weperformedthe
18O-labeling experiment (Scheme 4). When the reaction was
carried out in the presence of H218O instead of H216O, 18O
product 3aa-18O was obtained mostly (Figure S11), proving that
the oxygen atom in the ketone carbonyl of products originated
from H2O.
After other control experiments were conducted (see
Supporting Information), a plausible mechanism was proposed
(Scheme 5). Upon visible-light irradiation, RB accepts a photon
C
DOI: 10.1021/acs.orglett.8b02303
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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transamidation, producing the corresponding imines. The
hydrolysis of the imines gives the final product Mannich base
derivatives. This work also provides a new method for the
synthesis of acyl Mannich bases, which are valuable in
pharmaceutical chemistry and important intermediates in
organic synthesis. In the future, we will focus on developing
more intermolecular transamidation of secondary amides under
mild conditions.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02303.
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Accession Codes
CCDC 1823107 contains the supplementary crystallographic
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AUTHOR INFORMATION
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Corresponding Authors
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Chen, L.; Tan, C.-H. Green Chem. 2011, 13, 2682. (d) Shi, Q.; Li, P.;
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Org. Chem. Front. 2018, 5, 92. (f) Zhang, M.-J.; Schroeder, G. M.; He, Y.-
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*E-mail: heyh@swu.edu.cn.
*E-mail: guanzhi@swu.edu.cn.
ORCID
Yan-Hong He: 0000-0002-6405-285X
Zhi Guan: 0000-0002-0369-6141
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21472152 and 21672174),
the Basic and Frontier Research Project of Chongqing
(cstc2015jcyjBX0106), and the Innovation Foundation of
Chongqing for Postgraduate (CYB18097).
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