Site-Tunable Csp3 -H Bonds Functionalization by Visible-Light-Induced Radical Translocation of N-Alkoxyphthalimides

Article abstract of DOI:10.1021/acs.orglett.9b03524

Site-tunable functionalization of C(sp³)-H bonds has been accomplished through radical translocation and cross-coupling. Upon irradiation with visible light, copper-based photocatalyst [Cu(Xantphos)(dmp)]BF₄ enabled cross-coupling of N-alkoxyphthalimides with amino acid esters or amino acids to provide δ-C(sp³)-H alkylated alcohols (31 examples, up to 92% yield) with additive BNDHP or α-C(sp³)-H alkylated alcohols (18 examples, up to 86% yield) with additive DABCO in a highly regioselective fashion.

Full text of DOI:10.1021/acs.orglett.9b03524

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
3
Site-Tunable Csp −H Bonds Functionalization by Visible-Light-
Induced Radical Translocation of N‑Alkoxyphthalimides
Chuanyong Wang,* Yangyang Yu, Wen-Long Liu, and Wei-Liang Duan*
College of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Road, Yangzhou 225002, China
S
* Supporting Information
ABSTRACT: Site-tunable functionalization of C(sp3)−H bonds has been accomplished through radical translocation and
cross-coupling. Upon irradiation with visible light, copper-based photocatalyst [Cu(Xantphos)(dmp)]BF4 enabled cross-
coupling of N-alkoxyphthalimides with amino acid esters or amino acids to provide δ-C(sp3)−H alkylated alcohols (31
examples, up to 92% yield) with additive BNDHP or α-C(sp3)−H alkylated alcohols (18 examples, up to 86% yield) with
additive DABCO in a highly regioselective fashion.
Scheme 1. Visible-Light-Induced Selective
Functionalization of C(sp3)−H of Alcohols or Their
Derivates
lcohols are one of the most common and important
Asynthetic materials in organic and pharmaceutical
chemistry.1 While the hydroxy group can be readily trans-
formed into various functional groups, the C(sp3)−H bond
transformation of alcohols is less investigated but more
challenging especially for achieving high site selectivity and
chemoselectivity.2 Recently, radical approaches for selective
functionalization of α-C(sp3)−H and remote C(sp3)−H bonds
of alcohols and alcohol derivatives have received more
attention due to the development of robust methods for
generation of radical intermediates under mild photoredox
conditions toward versatile hydrogen atom transfer (HAT)
reactivity.3−5 Among these, MacMillan introduced an elegant
work based on the visible-light-induced direct α-alkylation/
lactonization of alcohols through the synergistic combination
of an iridium-based photocatalyst, a HAT reagent, and a
hydrogen-bonding catalyst (Scheme 1a).6 While, Chen,7a
Meggers,7b Hong,7c Zhu,7d Zuo,7e and others,7e,f respectively,
developed effective strategies to achieve δ-C(sp3)−H bond
activation of free alcohols or their derivates based on the
sequence of 1,5-HAT of visible-light-generated alkoxyl radical
intermediates8 and the follow-up transformations of the
resultant alkyl radicals such as radical conjugate additions,
Minisci-type reactions, and cross-couplings (Scheme 1b).
Besides, photoinduced alkoxyl radicals have led to new
advancements in C(sp3)−H bond cleavage reactions involving
HAT and β-fragmentation reactivity by Zhu9a and Zuo.9b,c
Although several methods have been established for selective
functionalization of alcohols, the use of earth-abundant copper
as a photoredox catalyst10 to achieve the site-tunable C(sp3)−
H bond alkylation of alcohols, to the best of our knowledge, is
still unknown.11
Scheme 1c. This protocol employs simple activating groups,
namely N-alkoxyphthalimides as recently developed redox-
active radical precursors.7a,b,12 It features the advantageous use
of a Cu(I) complex as a photocatalyst along with (R)-BNDHP
or DABCO to assist a challenging switchable alkylation of C−
H bond at room temperature. Remarkably, our catalytic
manifold is endowed with reaction scalability and a broad
substrate scope allowing late-stage functionalization of diverse
peptides in good yields.
Herein, we report the visible-light-induced α-/δ-selective
Received: October 6, 2019
functionalization of C(sp3)−H bonds of alcohols as shown in
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03524
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We started our investigation with readily prepared
heteroleptic Cu(I)-based complex [Cu(Xantphos)(dmp)]BF4
as a photocatalyst.13 When N-alkoxyphthalimide 1a reacted
with 2-(phenylamino)acetate 2a in the presence of [Cu-
(Xantphos)(dmp)]BF4 (10 mol %) under visible-light
irradiation with a 24 W blue LEDs, we were disappointed to
not observe even traces of the desired product 3a (Table 1,
with other dinitrogen and diphosphine ligands, the reaction
proceeded less efficiently (Table S1; see the Supporting
Information).
Under the optimized conditions (Table 1, entry 11), we next
tested the substrate scope of the photoinduced C(sp3)−C(sp3)
formation reaction using (R)-BNDHP as an additive which is
shown in Scheme 2. Primary, secondary, and tertiary N-
a
Table 1. Reaction Development
Scheme 2. Substrate Scope for δ-C(sp3)−H Alkylation
Using (R)-BNDHP as Additive
b
b
entry
additive (equiv)
no
(R)-BNDHP (0.2)
nBu2PO2H (0.2)
PhCO2H (0.2)
PivOH (0.2)
(R)-BNDHP (0.2)
(R)-BNDHP (0.2)
(R)-BNDHP (0.2)
(R)-BNDHP (0.2)
(R)-BNDHP (0.2)
(R)-BNDHP (0.2)
DABCO (2.0)
solvent (M)
3a (%)
4a (%)
1
2
3
4
5
6
7
8
DMA (0.2)
DMA (0.2)
DMA (0.2)
DMA (0.2)
DMA (0.2)
THF (0.2)
DCM(0.2)
toluene (0.2)
CH3CN (0.2)
DMA (0.1)
DMA (0.05)
DMA (0.2)
DMA (0.2)
DMA (0.2)
DMA (0.2)
DMA (0.05)
DMA (0.2)
DMA (0.05)
DMA (0.2)
0
0
0
0
0
0
0
0
0
0
0
0
48
20
14
0
trace
0
0
9
20
53
60
0
0
0
0
0
0
0
10
11
12
13
14
15
c
74 (1.5:1)
Et3N (2.0)
Na2CO3 (2.0)
NaOAc (2.0)
(R)-BNDHP (0.2)
DABCO (2.0)
trace
c
c
34 (1.5:1)
52 (1.5:1)
d
16
0
0
0
0
d
alkoxyphthalimides were applied to the reaction, affording the
cross-coupling products in moderate to good yields (3a−3e,
2.0:1 dr of 3b and 3c). Notably, the substrates bearing cyclic,
heterocyclic, and alkenyl groups were well tolerated (3f−3h).
Furthermore, α-sulfur C−H bonds also worked well under
standard conditions (3i and 3j). With respect to the coupling
partner, various 2-(aromaticamino)acetates with electron-rich
or electron-withdrawing aromatic substituents were found to
be tolerated (3k−3n). Besides esters, α-amino amide, ketone,
and nitrile also exhibited good reactivity to provide the
expected products in 40−92% yields (3o−3s). The structure of
3q was determined by X-ray diffraction (CCDC 1923105).
Having obtained the δ-C(sp3)−H alkylation of alcohols, we
next investigated the substrate scope of α-C(sp3)−H
functionalization using DABCO as an additive. As shown in
Scheme 3, under the optimized conditions (Table 1, entry 12),
N-alkoxyphthalimides with aliphatic groups reacted smoothly
with 2-(phenylamino)acetate to form β-amino alcohols with
moderate to good yields as diastereomeric mixtures (44−70%
yield, 3.0:1−1.1:1 dr) (4b−4f). The conditions clearly enabled
the functionalization of the alcohol α-oxy C−H bond in the
presence of other functional groups, including thioether (4g)
as well as acyclic and cyclic ether (4h−4l). Besides, N-
alkoxyphthalimides with aromatic substituents also worked
well with 2-(1-naphthylamino)acetate to offer the C(sp3)−
C(sp3) bond formation products with isolated yields of up to
85% and 2.8:1 dr (4m and 4n). Moreover, heteroaromatics
such as furan, thiophene, quinoline, and benzothiazole were
successfully applied to this transformation (4o−4r). Addition-
ally, tertiary amine N,N-dimethylaniline was also suitable for
the reaction albeit with a lower yield (4s).15
17
18
e
(R)-BNDHP (0.2)
DABCO (2.0)
e
19
0
a
Reaction conditions: N-alkoxyphthalimide 1a (0.40 mmol) and 2-
(phenylamino)acetate 2a (0.20 mmol) with Cu catalyst (10.0 mol %)
and additive ((R)-BNDHP (0.2 equiv) or DABCO (2.0 equiv)) in
DMA (4.0 or 1.0 mL) under light irradiation using 24 W blue LEDs at
b
room temperature for 65 h under a nitrogen atmosphere. Isolated
c
yield. Dr value shown in parentheses determined by crude 1H NMR.
d
e
No light. No Cu catalyst. Xantphos = 4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene; dmp = 2,9-dimethyl-1,10-phenanthroline; phth
= phthalimide; (R)-BNDHP = (R)-(−)-1,1′-binaphthyl-2,2′-diyl
hydrogenphosphate; PivOH = pivalic acid; DABCO = 1,4-diaza-
bicyclo[2.2.2]octane.
entry 1). Encouragingly, with the addition of (R)-BNDHP14
(0.2 equiv), the C(sp3)−C(sp3) bond formation product 3a
was obtained in 48% yield (entry 2). Other tested acids did not
provide satisfactory results (entries 3−5). Further optimization
showed that the reaction is very sensitive to solvent effects
(entries 6−10), and the best result was obtained by using
DMA as solvent with a decreased concentration of 0.05 mol·
L−1 (entry 11). Interestingly, when DABCO (2.0 equiv)
instead of (R)-BNDHP was applied to this system, the reaction
afforded the α-alkylation product 4a with a 74% yield and 1.5:1
dr (entry 12). Replacing DABCO with other bases resulted in
significantly lower yields (entries 13−15). Control experiments
verified that both visible light and a copper-based photocatalyst
are essential for product formation (entries 16−19). When
[Cu(Xantphos)(dmp)]BF4 was replaced by other commonly
used photocatalysts or dmp and Xantphos were interchanged
B
DOI: 10.1021/acs.orglett.9b03524
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for α-C(sp3)−H Alkylation
Using DABCO as Additive
Scheme 5. δ-C(sp3)−H Alkylation of Complex Settings
yields (7g and 7h). Importantly, the reaction was amenable to
scale-up to gram quantity (7i).18
A plausible mechanism is shown in Scheme 6 and starts with
the photoactivation of [Cu(Xantphos)(dmp)]BF4 [CuI] to its
Scheme 6. Proposed Mechanism
α-Amino acids, well-known radical precursors for decarbox-
ylative radical additions and cross-coupling reactions,16 reacted
quite efficiently under modified reaction conditions (Scheme
4). Without any additives, the reaction of N-alkoxyphthalimide
1d with α-amino acids 5 afforded the decarboxylated radical−
radical cross-coupling products 6 in moderate yields.
Scheme 4. δ-C(sp3)−H Alkylation with Respect to α-Amino
Acids
excited state [CuI]*, which serves as a reducing agent and
transfers a single electron to N-alkoxyphthalimide 1.19 Then
the N-alkoxyphthalimide radical anion A fragments to form a
carbon-centered radical in two pathways depending on the acid
or base additive: (1) In the presence of acid BNDHP, the
intermediate A is subsequently protonated and then undergoes
a homolytic N−O cleavage under formation of an alkoxy
radical B and phthalimide. This intermediate B engages in an
intramolecular 1,5-HAT to yield a remote carbon-centered
radical C.7 (2) In the presence of DABCO as a base,
intramolecular proton transfer of intermediate A followed by
N−O bond homolytic cleavage generates radical anion
intermediate D which could exist in its more stable resonance
structure α-oxy carbon-centered radical anion D′.20 Simulta-
neously, [CuII] oxidizes N-aryl glycine ester 2 to generate an
amino radical cation E, along with regeneration of [CuI].21
The intermediate E is deprotonated to provide an α-amino
carbon-centered radical F. Finally, the radical−radical cross-
coupling between α-aminoalkyl radical F and alkyl radical C
provides δ-functionalized product 3, while the coupling with
radical D′ and concurrent protonation deliver α-alkylated
product 4.22
Given the good regioselectivity, we subsequently examined
the δ-C(sp3)−H alkylation of more complex settings, as it
represents an attractive approach for late-stage modification of
complex molecules (Scheme 5).17 For example, 2-
(phenylamino)acetates, which were prepared from readily
available (−)-menthol and (−)-borneol, reacted smoothly with
N-alkoxyphthalimide 1g to furnish the products in moderate
yields as diastereomeric mixtures (7a and 7b). Dipeptides
containing glycine (7c), valine (7d), phenylalanine (7e), and
proline (7f) units underwent selective δ-C(sp3)−H alkylation
on the Ph-glycine unit with good yields (64−82%). It is worth
noting that the presence of a proline unit is beneficial to
improve the diastereoselectivity (10.0:1 dr for 7f). The
robustness of this method was further demonstrated by the
site-selective functionalization of tripeptides in reasonable
C
DOI: 10.1021/acs.orglett.9b03524
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
Several experiments were performed to probe the mecha-
nism. First, the presence of air or TEMPO (2.5 equiv)
completely inhibited the formation of 3a or 4a, which might
indicate a radical pathway (Scheme 7a). Second, the proposed
CCDC 1923105 and 1959513 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 7. Mechanistic Investigations
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: wangchuanyong@yzu.edu.cn.
*E-mail: duanwl@yzu.edu.cn.
ORCID
Chuanyong Wang: 0000-0001-9576-8589
Wei-Liang Duan: 0000-0003-2791-1931
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Professor Qi Shen on the occasion of her 80th
birthday. This work was financially supported by the National
Natural Science Foundation of China (21801220, 21472218,
and 21672183), the Natural Science Foundation of Jiangsu
Province (BK20180892), the Priority Academic Program
Development of Jiangsu Higher Education Institutions, and
Top-notch Academic Programs Project of Jiangsu Higher
Education Institutions. We thank Dr. Xiaoqiang Huang
(UIUC) for discussions during the preparation of the
manuscript.
carbon-centered radical C which formed by 1,5-HAT was
verified by a trapping experiment with isoquinoline (Scheme
7b).7d Third, the homocoupling of proposed intermediate α-
amino carbon radical F (Scheme 7c) and side product
aldehyde derived from radical intermediate D or D′ (see the
Supporting Information) were isolated under standard
conditions. Moreover, deuterium labeling studies involving
1q and 1q-d2 yielded a KIE value of 6.0 (Scheme 7d),
suggesting that cleavage of the α-C(sp3)−H bond is likely the
rate-determining step.23 Finally, the quantum yield Φ < 1 (0.10
and 0.12; see the Supporting Information) indicated the radical
chain process might not be involved in the reaction.24
In summary, we demonstrated a visible-light-induced site-
tunable functionalization of alcohols by using N-alkoxyph-
thalimides and N-aryl glycine esters as redox-active radical
precursors. This method features mild radical conditions and
employs a Cu(I) complex as a photocatalyst along with
BNDHP or DABCO to assist the regioselective amino-
alkylation of δ- or α-C(sp3)−H bonds of alcohols. Our
catalytic manifold is endowed with a broad substrate scope and
reaction scalability. Peptides could also be site-selectively
functionalized. The application of this method in asymmetric
catalysis is underway in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03524.
Experimental procedures, character of new starting
materials and products, NMR spectra, and X-ray
structure (PDF)
D
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