Selective C(sp3)?H Functionalization of Alkyl Esters with N-/S-/O-Nucleophiles Using Perfluoroalkyl Iodide as Oxidant

Article abstract of DOI:10.1002/adsc.202000199

An efficient transition metal-free approach to achieve the selective cleavage of the α-carbonyl C(sp³)?H bond in alkyl esters by using inexpensive, low-toxic, and insensitive perfluoroalkyl iodide as the radical initiator has been developed. A variety of enamides, N-heterocycles, amides, thiophenols, and phenols could be successfully incorporated into functionalized alkyl groups by intermolecular amination, thioetherification, and etherification. The distinguishing features of this CDC reaction are its broad substrate scope, synthetic simplicity, and mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000199

Title: Selective C(sp3)-H Functionalization of Alkyl Esters with N-/S-/O-
Nucleophiles Using Perfluoroalkyl Iodide as Oxidant
Authors: Shi-Wen Zhao, Song-Zhou Cai, Mao-Lin Wang, Weidong
Rao, Hai-Yan Xu, Lei Zhang, Xue-Qiang Chu, and Zhi-Liang
Shen
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000199
Link to VoR: https://doi.org/10.1002/adsc.202000199

10.1002/adsc.202000199
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Selective C(sp3)-H Functionalization of Alkyl Esters with N-/S-
/O-Nucleophiles Using Perfluoroalkyl Iodide as Oxidant
Shi-Wen Zhao,a Song-Zhou Cai,a Mao-Lin Wang,a Weidong Rao,b Haiyan Xu,c Lei
Zhang,a Xue-Qiang Chu,*a and Zhi-Liang Shen*a
a
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
E-mail: xueqiangchu@njtech.edu.cn; ias_zlshen@njtech.edu.cn;
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, College of Chemical Engineering,
b
Nanjing Forestry University, Nanjing 210037, China
School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu
c
212003, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient transition metal-free approach to intermolecular
amination,
thioetherification,
and
achieve the selective cleavage of the α-carbonyl C(sp3)-H etherification. The distinguishing features of this CDC
bond in alkyl esters by using inexpensive, low-toxic, and reaction are its broad substrate scope, synthetic simplicity,
insensitive perfluoroalkyl iodide as the radical initiator has and mild reaction conditions.
been developed. A variety of enamides, N-heterocycles,
Keywords: alkyl esters; C(sp3)-H functionalization;
amides, thiophenols, and phenols could be successfully
incorporated into functionalized alkyl groups by
perfluoroalkyl iodide; CDC reaction; transition metal-free
simple alkyl esters under classical conditions, such
as transition metal catalysis, an excess amount of
strong oxidants, UV light irradiation, and high
Introduction
The direct transformation of C-H bonds to C-X (X temperature.[10]
= C, O, N, S) bonds has advanced significantly by
developing efficient and practical strategies for the
In 2014, Ji and coworkers reported a radical
addition/1,2-aryl migration cascade of -diaryl
,
synthesis of complex compounds with high atom- allylic alcohol with carbonyl compound in the
/step-economy, such as materials, pharmaceuticals, presence of tert-butylperoxybenzoate (TBPB, 2
and natural products, starting from readily
equiv.) at 120 oC (Scheme 1, 2a).[10a] However, the
available molecules.[1] Among them, oxidative regioselectivity of hydrogen abstraction in the
cross-dehydrogenative-coupling (CDC) reactions alkyl esters was problematic due to the similar
involving the activation of less reactive C(sp3)-H bond dissociation energies (BDEs) of substrates’
bonds via radical pathway have been recognized
as ideal and environmentally attractive tools
because these methods usually does not require
prefunctionalization of coupling partners and
multiple C(sp3)-H bonds. Instead, the cleavage of
the C-H bond could also occur competitively at the
α-position of the ethoxy group.[10b-c] In 2019, Tang
group developed
a
site-selective α-alkoxy
defunctionalization of directing groups.[2] In this alkynylation of alkyl sulfones with alkynyl esters
context, an impressive range of synthetic strategies
which was mediated by stoichiometric pyridine-
via free radical-initiated C(sp3)-H bond ligated boryl radicals (Scheme 1, 2b).[10d]
functionalization of ethers,[3] alkyl nitriles,[4] Compared with the complicated boryl reaction
alcohols,[5] amines,[6] ketones,[7] alkanes,[8] and system, soon after, a visible-light-promoted
active methylene compounds[9] have been alkylheteroarylation of unactivated olefins with
developed in the past few decades (Scheme 1, 1).
Nevertheless, there are still many issues associated
with the generation of α-carbonyl radicals from photocatalyst and explosive peroxides should be
esters was discovered by Xu and co-workers
(Scheme 1, 2c).[10e] In their case, expensive
1
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10.1002/adsc.202000199
Advanced Synthesis & Catalysis
t
Table 1. Oxidative C(sp3)-H functionalization of BuOAc
employed. Therefore, the development of new
synthetic approach to achieve the selective
functionalization of alkyl esters are still urgently
demanded.
with enamide 1a: optimization of reaction conditionsa
Entry
Additive
(x equiv.)
Base
(y equiv.)
NaOH (2.5)
Et3N (2.5)
Yield
(%)b
31
0
0
0
0
0
99 (93)c
21
trace
0
99 (93)c
70
48
52d
58
47
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (2.0)
nC4F9I (1.5)
nC4F9I (2.0)
nC6F13I (2.0)
nC8F17I (2.0)
nC4H9I (2.0)
C6F5I (2.0)
I2 (2.0)
DABCO (2.5)
Cs2CO3 (2.5)
NaOAc (2.5)
K3PO4 (2.5)
tBuONa (2.5)
tBuOK (2.5)
tBuOLi (2.5)
LDA (2.5)
tBuONa (2.0)
tBuONa (1.5)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
trace
29c
10e
16f
nC4F9I (2.0)
nC4F9I (2.0)
a Reaction conditions: 1a (0.3 mmol), 2a (2 mL), additive
(0.45-0.6 mmol), and base (0.45-0.75 mmol) at room
temperature for 24 h under N2. b Yields were determined
by NMR analysis with 1,4-dimethoxybenzene as an
c
d
internal standard. Isolated yield. For 12 h. e tBuOAc
(20 equiv.) was used in DCE (2 mL). f tBuOAc (20 equiv.)
was used in PhCF3 (2 mL).
Scheme 1. General strategies for the functionalization of the
acidic C(sp3)-H bond.
Perfluoroalkyl halide, as a low-toxic and
environmentally friendly perfluoroalkyl radical
precursor,[11] has been extensively utilized as a
unique promoter in the C(sp3)-H bonds
conversions through abstracting hydrogen atoms
to afford hydrodehalogenated products over the
direct perfluoroalkylated products.[12] Herein, we
report a radical-type transformation[13] which
involves site-selective oxidative C(sp3)-H
functionalization of alkyl esters with various N-, S-
, and O-nucleophiles (Scheme 1, 3). The synthetic
linchpin for realizing the incorporation of the alkyl
ester moieties on N-/S-/O-atom centres[14] largely
relies on the use of perfluorobutyl iodide (nC4F9I)
as an efficient oxidant. Moreover, this transition-
metal-free approach involved new C(sp3)–X (X =
N, S, O) bond formations through a single electron
transfer (SET) pathway, which overcomes the
difficulty of the previously reported methods[10]
and features broad substrate scope, good
functional group compatibility, and synthetic
simplicity in a green manner.
Initially, we started our investigation by using N-(1-
phenylvinyl)acetamide
(1a)
as
a
nitrogen
nucleophile,[15] along with tert-butyl acetate (2a, 2 mL)
as both the reactant and solvent, in the presence of 2.0
n
equiv. of C4F9I and 2.5 equiv. of NaOH at room
temperature for 24 h under N2 (Table 1, entry 1).
Gratifyingly, it was found that the desired CDC
reaction proceeded smoothly to afford the C–N bond-
forming product 3aa in 31% NMR yield (entry 1).
Evaluation of various organic and inorganic bases
t
(entries 2-10) led to the discovery of BuONa as the
best base for the oxidative coupling, whose loading
could be further decreased to 2 equiv. (entries 11-12),
affording the product 3aa in 99% NMR yield and 93%
isolated yield (entry 11). In addition, attempts to
n
reduce either the amount of C4F9I (1.5 equiv., entry
13) or the reaction time (12 h, entry 14) only gave rise
to the corresponding product 3aa in 48% and 52%
NMR yields, respectively. Furthermore, low reaction
efficiency was observed when other perfluoroalkyl
n
n
iodides such as C6F13I and C8F17I were introduced
into the reaction (entries 15-16). Interestingly, non-
n
fluorinated C4H9I[16] and perfluoroaryl iodide were
found to be inferior to perfluoroalkyl iodide as the
reaction promoters (entries 17-18). It might be due to
Results and Discussion
2
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10.1002/adsc.202000199
Advanced Synthesis & Catalysis
the formed reactive and strongly electrophilic Rf
radicals[12] that perfluoroalkyl iodides (RfI) could
facilitate the activation of the C(sp3)–H bond in tert-
butyl acetate (2a). However, only 29% yield of product
3aa was obtained by using I2 as a promoter (entry 19).
It should be noted that no competitive reaction
occurred at the terminal C-C double bond of the N-acyl
enamides under the optimized reaction conditions.[15]
Moreover, performing the reaction with stoichiometric
amounts of tBuOAc (20 equiv.) in 1,2-dichloroethane
(DCE) or trifluorotoluene (PhCF3) has been proven to
be fruitless (entries 20-21).
enamides could also deliver the products 3ia-3ka in
71-90% yields. Furthermore, the presence of α-
substituent in N-vinylacetamide did not interfere with
the intermolecular reaction, as cyclic substrate 1l
efficiently
underwent
the
present
organic
transformation to provide the product 3la in 46% yield.
t
Table 3. Oxidative C(sp3)-H functionalization of BuOAc
with various enamides 1a
Table 2. Oxidative C(sp3)-H functionalization of various
aliphatic C-H components 2 with enamide 1aa
a
Standard reaction conditions (0.3 mmol scale); isolated
yield.
a
Standard reaction conditions (0.3 mmol scale); isolated
Subsequently, the present protocol was successfully
extended to the use of a wide range of structurally
varied N-, S-, and O-nucleophiles (Table 4).
Heterocyclic compounds bearing free N-H motifs,
such as benzimidazoles and 1,5,6,7-tetrahydro-4H-
indol-4-one, were transformed into the N-alkylated
products 5a-5d in 34-51% yields after a prolonged
reaction time. In addition, by switching to acetyl-
substituted sulfonamide, moderate conversion to the
amination product 5e was still achieved. Based on
diverse structural library design for pharmaceutical
chemistry, important S-nucleophiles were selected as
coupling partners to accomplish thioetherification of
tert-butyl acetate. For instance, thiophenols containing
different substituents (halides, methyl, and methoxy
group) well participated in this reaction, leading to
thioethers 6a–6g in 56-95% yields. Additionally,
heteroaryl S-nucleophiles including 2-methylfuran-3-
thiol and benzo[d]thiazole-2-thiol were compatible
with the mild reaction conditions to give the
corresponding heterocyclic variants 6h and 6i in 43%
and 51% yields, respectively. In a same manner, the
reaction of 4-methoxyphenol worked equally well
with tBuOAc to afford the etherification product 7a in
41% yield.
yield. b Cs2CO3 (3.3 equiv.) instead of tBuOK was used.
With the optimal reaction conditions in hand, we
continued our task to explore the substrate scope of the
present -C(sp3)-H amination, which delivered
functionalized alkyl groups by intermolecular C-N
bond formation. As summarized in Table 2, several
commercially available alkyl acetates 2b-2e were first
applied to the reactions with enamide 1a. Notably, in
these cases, the methyl group adjacent to carbonyl
group was the sole reactive site without affecting the
existing ester functionality, and exclusive products
3ab-3ae were produced in moderate to good yields.
However, other variants such as methyl propionate (2f),
lactone 2g, and acetamide 2h were proven to be
inappropriate candidates for the present reaction
system. Nevertheless, acetone was found to be suitable
for this oxidative C-N coupling reaction, furnishing
the product 3ai in 66% yield by using Cs2CO3 as the
base.
Next, the substrate generality with respect to various
enamides 1 was examined in the perfluorobutyl iodide-
mediated oxidative coupling (Table 3). To our delight,
a variety of N-vinylacetamides 1 containing different
substituents with varying electronic characteristics
(electron-donating or electron-withdrawing) or steric
demands (para-, meta-, and ortho-) on the aryl
We also performed the large-scale synthesis of tert-
butyl N-acetyl-N-(1-phenylvinyl)glycinate (3aa),
which could serve as versatile building block to
prepare various multi-substituted amines and olefin
derivatives 8,[15] leading to 61% yield of the
corresponding product 3aa (Scheme 2, 1). In order to
clarify the putative mechanism of the selective C(sp3)-
t
moieties smoothly coupled with BuOAc (2a) to
furnish the corresponding products 3aa–3ha in 51-96%
yields. Impressively, functional moieties of synthetic
potential such as F, Cl, Br, and I were well-tolerated,
which could be retained for late-stage manipulation. In
H
functionalization process, several control
addition,
the
use
of
naphthalenyl,
experiments were performed. Firstly, when radical
scavenger of 2,2,6,6-tetramethylpiperidin-1-oxyl
benzo[d][1,3]dioxoly, and pyridinyl substituted
3
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10.1002/adsc.202000199
Advanced Synthesis & Catalysis
(TEMPO, 3 equiv) was added to the model reaction
under standard reaction conditions, the yield of
product 3aa was dramatically decreased to 24%,
indicative of the involvement of a radical-type
mechanism in the reaction (Scheme 2, 2). Meanwhile,
the formation of TEMPO-adduct 9-11 were detected
by LC-MS which suggested that N-centered radical,[17]
nC4F9 radical, and -C-centered radical of alkyl ester[10]
might be involved in this process (see the Supporting
Information for more details). Secondly, the addition
of 3.0 equiv. of 2,6-di-tert-butyl-4-methylphenol
(BHT) as radical scavenger completely suppressed the
formation of 3aa. Moreover, 1,1,1,2,2,3,3,4,4-
nonafluorobutane (12, Rf-H) was detected in these
reactions by LC-MS, implying that nC4F9I might work
as the H-abstraction reagent (see Supporting
Information for more details). Thirdly, we found that
the addition of 0.1 mol% of Pd(PPh3)4, CuCl2,
Fe(acac)3, Co(acac)3, or NiCl2(PPh3)2 to the reaction
system did not obviously enhance the reaction
performance, and in some cases the reaction efficacy
was even reduced, which indicated that the
transformation was not catalyzed by trace metal
impurities possibly brought from the added reagents
and solvent (Scheme 2, 3). Finally, the aminated
product 3aa was obtained in a relatively low yield
when 1-iodobutane, instead of nC4F9I, was used
(Scheme 2, 4). In contrast, the direct alkylated product
13 was not formed in the reaction, indicating that N-
nucleophilic substitution of enamides might not be the
main reaction pathway.
observed a red shift of absorption and color change
when enamide 1a, nC4F9I, and tBuONa were combined
t
in BuOAc (Scheme 3, 2). These results indicated the
formation of EDA complex between 1a and nC4F9I.
t
Table 4. Oxidative C(sp3)-H functionalization of BuOAc
with various N-/S-/O-nucleophilesa
Scheme 2. A large-scale synthesis and control experiments
a
Standard reaction conditions (0.3 mmol scale); isolated
yield. b tBuOK (3.3 equiv.) was used.
The 19F NMR titration experiment and UV-Vis
spectroscopic measurement were performed on
various combinations of N-(1-phenylvinyl)acetamide
(1a), nC4F9I, and tBuONa, which proved the formation
of electron donor-acceptor (EDA) complex in the
reaction (Scheme 3). First, the 19F NMR signal of CF2I
moiety shifted upfield when the amount of 1a and
tBuONa increased (Scheme 3, 1). Second, we also
Scheme 3. Studies of the EDA complex. 1) 19F NMR
4
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10.1002/adsc.202000199
Advanced Synthesis & Catalysis
titration by using PhOCF3 as an internal standard in CDCl3.
2) Optical absorption spectra recorded and the color change
t
of different combinations of 1a, C4F9I, and BuONa in
tBuOAc.
The radical nature of this reaction was further
confirmed by electron paramagnetic resonance (EPR)
experiment (Scheme 4). A strong single EPR signal (g
t
= 2.00) was observed in BuOAc solution of N-(1-
n
t
phenylvinyl)acetamide (1a), C4F9I, and BuONa at
room temperature (black line). We also found that the
EPR signal was attenuated after 12 h (red line).
Scheme 5. Proposed mechanism.
Conclusion
In summary, we have developed an oxidative strategy
for C(sp3)-H functionalization of alkyl esters with
various N-/S-/O-nucleophiles under transition metal-
free conditions. Adistinguishing feature of this method
is that the inexpensive, low-toxic, and insensitive
perfluoroalkyl iodide could be used as efficient
oxidant to selectively abstract the less reactive α-
C(sp3)-H of carbonyl group rather than the α-C(sp3)-H
of alkoxy group in alkyl esters, leading to
regioselective C-X (X = N, S, O) bond formation.
Moreover, the broad substrate scope, mild reaction
conditions, and synthetic simplicity inarguably
provides chemists an alternative entry for site-
selective alkylation by using simple alkyl esters. In
addition, mechanistic studies revealed that the reaction
presumably proceeded via a radical chain propagation
process.
Scheme 4. Electron paramagnetic resonance (EPR)
experiment
On the basis of above control experiments and
literature survey,[11-14] a plausible mechanism of radical
chain process was depicted in Scheme 5. The initiation
of the reaction begins with the deprotonation of
nucleophiles 1 or 4 under basic conditions. Next, the
interaction of transiently formed anion A with
perfluorobutyl iodide leads to the generation of EDA
complex B, which subsequently affords strongly
n
reactive C4F9 radical D and N-/S-/O-centered radical
Experimental Section
General procedures for the oxidative C(sp3)-H
functionalization of aliphatic C-H components with N-
/S-/O-nucleophiles
C after an intramolecular single electron transfer from
n
anion A to C4F9I.[12] Due to its high electrophilicity
and pyramidal geometry, the perfluoroalkyl radical D
could then selectively abstract the -C(sp3)-H of alkyl
ester 2 adjacent to the carbonyl site to produce the
hydrofluorocarbon E (Rf-H) and alkyl radical F.[11] The
latter could be trapped by another molecule of
nucleophilic anion from EDA complex B to generate the
unstable radical anion G, which could be easily
A solution of N-/S-/O-nucleophile (0.3 mmol), aliphatic C-
H component (2 mL), perfluorobutyl iodide (208 mg, 0.6
t
mmol), and BuONa (58 mg, 0.6 mmol) was stirred under
nitrogen atmosphere at room temperature for 24-36 h. The
reaction was then quenched by saturated NH4Cl solution (20
mL) and diluted with EtOAc (20 mL). The organic layer was
washed with saturated brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (300-400
mesh) using petroleum ether/ethyl acetate or
dichloromethane/methanol as eluent to afford the pure
products 3 or 5-7.
n
oxidized by the C4F9I oxidant to give the CDC
product and regenerate the radical species D (pathway
a). Alternatively, the direct cross-coupling of the
radicals C and F could also lead to the formation of
final product (pathway b). However, the low
concentration of these open-shell radical species made
it difficult for the intermolecular coupling to take
place.[18]
Acknowledgements
We gratefully acknowledge the financial support from Nanjing
Tech University (Start-up Grant No. 39837118 and 39837146),
National Natural Science Foundation of China (21901087),
Natural Science Foundation of Jiangsu Province (BK20180690
and
BK20190951),
Jiangsu
Education
Department
(19KJB150008), and Nanjing Forestry University.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000199
Advanced Synthesis & Catalysis
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