Visible-light photocatalytic α-amino C(sp3)–H activation through radical translocation: a novel and metal-free approach to α-alkoxybenzamides

Article abstract of DOI:10.1016/j.tetlet.2016.02.108

Visible-light photocatalytic, metal-free synthesis of valuable α-alkoxybenzamides starting with readily prepared o-aminobenzamides and alcohols through radical translocation under mild conditions is reported. This protocol employs eosin Y as an organophot

Full text of DOI:10.1016/j.tetlet.2016.02.108

Accepted Manuscript
Visible-light photocatalytic α-amino C(sp3)-H activation through radical trans-
location: a novel and metal-free approach to α-alkoxybenzamides
Feng-Qing Huang, Xin Dong, Lian-Wen Qi, Bo Zhang
PII:
S0040-4039(16)30217-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.108
TETL 47383
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 November 2015
23 February 2016
29 February 2016
Please cite this article as: Huang, F-Q., Dong, X., Qi, L-W., Zhang, B., Visible-light photocatalytic α-amino
C(sp3)-H activation through radical translocation: a novel and metal-free approach to α-alkoxybenzamides,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.108
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Tetrahedron Letters
Visible-light photocatalytic α-amino C(sp3)-H activation through radical
translocation: a novel and metal-free approach to α-alkoxybenzamides
Feng-Qing Huang, Xin Dong, Lian-Wen Qi,* Bo Zhang*
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Visible-light photocatalytic, metal-free synthesis of valuable α-alkoxybenzamides starting with
readily prepared o-aminobenzamides and alcohols through radical translocation under mild
conditions is reported. This protocol employs eosin Y as an organophotoredox catalyst and
readily available tert-butyl nitrite as the nitrosating reagent. These transformations occur in the
absence of any transition metal and the title compounds are obtained in moderate to good yields.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Photochemistry
C–H activation
C-O bond formation
Radical reactions
Visible light
Saturated nitrogen heterocycles are ubiquitous in natural products, bioactive molecules, and drugs.[1] Among them, benzamides
as a highly important class of saturated nitrogen heterocycles have attracted significant interest from the medicinal chemistry
community because of their diverse and prominent biological activities such as enzyme inhibition or nootropic and antimicrobial
activity (Figure 1).[2] Because of its importance, there is continuing interest in the development of synthetic methods for
diversification of benzamides.[3] The development of novel methodology for the introduction of a substituent into α-position of
benzamides is beneficial for the adjustment of bioactivities of parent molecules. Importantly, the construction of the related
compound library might offer a lot of opportunities of application to discover new lead compounds. Therefore, uncovering novel
and efficient approaches to construct α-substituted benzamides is important.
Figure 1. Representative biologically active compounds containing benzamide scaffold.
Scheme 1. Visible-light photocatalytic synthesis of α-alkoxybenzamides through radical translocation.

3
In recent years, a variety of methods have been established for the preparation of α-substituted saturated amines through a
C(sp3)-H functionalization strategy.[4,5] However, to date, none of these methods has been successfully applied to the preparation of
α-substituted benzamides. As a complementary way, C(sp3)-H functionalization of saturated amines through radical translocation
provides an efficient strategy for the preparation of α-substituted benzamides.[6.7] For example, the Curran group[6a] and the Undheim
group[6b] independently reported tin-mediated synthesis of α-alkylated benzamides through radical translocation. Moreover, Weinreb
and co-workers described a metal-catalyzed approach to prepare α-methoxybenzamides through radical translocation under strongly
acidic conditions.[6c,d] Despite these significant advances, the reported approaches also revealed some drawbacks: (a) the use of
environmentally harmful metal reagents or catalysts; (b) the need for harsh reaction conditions; (c) limited substrate scope.
Therefore, developing novel ways to prepare α-substituted benzamides under mild and environmentally benign conditions is still of
great interest.
Visible-light photoredox catalysis using photosensitizers to activate organic compounds has in recent years emerged as a
powerful tool for mild and environmentally benign organic transformations.[8] However, only a few studies on C(sp3)-H
functionalization through radical translocation under visible-light photoredox catalysis have been reported.[7i] In this context, we
became interested in constructing α-alkoxybenzamides through radical translocation using visible-light photoredox catalysis.
Herein, we disclose the first results on the visible-light photocatalytic synthesis of α-alkoxybenzamides through radical
translocation catalyzed by eosin Y under mild and metal-free conditions (Scheme 1).
Table 1. Optimization of reaction conditionsa
entry
X
Y
nitrosating amount of 2a
solvent
yieldb
(%)
12
80
20
10
72
62
54
67
55
61
76
0
agent
1
5
5
0
5
5
5
5
5
5
5
5
5
5
1
0
5
5
5
5
5
5
5
5
5
5
5
5
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
tBuONO
NaNO2
2.0 mL
none
2
2.0 mL
none
3
4c
2.0 mL
none
2.0 mL
none
5
5.0 equiv
3.0 equiv
1.5 equiv
5.0 equiv
5.0 equiv
5.0 equiv
5.0 equiv
5.0 equiv
5.0 equiv
5.0 equiv
CH3CN
CH3CN
CH3CN
DCM
6
7
8
9
DMF
10
11
12
13
14
DMSO
CH3NO2
CH3NO2
CH3NO2
amylONO
18
2.5 tBuONO
CH3NO2 81
a Reaction conditions: 1a (0.4 mmol), 2a, eosin Y, TsOH·H2O, and nitrosating agent (0.6 mmol) in the given solvent (2.0 mL) were irradiated with 10 W
blue LEDs (450 nm) at room temperature under N2 for 24 h. b Isolated yields. c The reaction was conducted in the absence of light.
We decided to use eosin Y as the organophotoredox catalyst because it has been already demonstrated that the aryl radicals can
be generated by reaction of aryl diazonium salts with eosin Y.[9] tBuONO was chosen as the commercially available nitrosating
agent. Radical translocation of readily prepared o-aminobenzamide 1a with methanol 2a in the presence of blue LED lights (450
nm) at room temperature under N2 was investigated first. Gratifyingly, the desired product 3a was obtained in 12% yield (Table 1,
entry 1). Based on this promising result, we next screened a large number of reaction conditions and found that catalytic amounts of
TsOH is very important for improving the transformation (Table 1, entry 2). When the reaction was run in the absence of eosin Y or
light, the yield of 3a was dramatically decreased to 20% or 10% (Table 1, entry 3 and 4). These results imply that both eosin Y and
light are essential for this transformation. To make the alcohol as a reagent rather than a solvent, further optimization of reaction
conditions was conducted. When the reaction was carried out with 5.0 equiv of methanol 2a in CH3CN, 3a was isolated in 72%
yield (Table 1, entry 5). Lowering the amounts of 2a to 3.0 equiv or 1.5 equiv resulted in poorer results (Table 1, entry 6 and 7).
Solvent effects were then investigated, and the results indicate that CH3NO2 is the best solvent for this transformation (Table 1,
entry 8-11). However, the reaction did not perform well in the presence of other nitrosating agents, such as NaNO2 and amylONO
(Table 1, entry 12 and 13). Organophotoredox catalyst and acid loading could be further lowered to 1 mol% and 2.5 mol% without
affecting the yield (Table 1, entry 14).
With optimized reaction conditions in hand, the scope and limitations of the α-alkoxybenzamide synthesis were investigated

4
Table 2. Various α-alkoxybenzamides prepareda,b
a Reaction condition: 1 (0.4 mmol), 2 (2.0 mmol), eosin Y (0.004 mmol), TsOH·H2O (0.01 mmol), and tBuONO (0.6 mmol) in CH3NO2 (2.0 mL) were
irradiated with 10 W blue LEDs (450 nm) at room temperature under N2 for 24 h. b Isolated yields.
(Table 2). We first investigated the scope with respect to the o-aminobenzamides 1. Five-, six-, and eight-membered cyclic amines
1b-1d proceeded well with moderate to good yields. When the reaction was conducted on three and four-membered cyclic amines,
the desired products were not obtained likely due to the instability of starting materials under current reaction system. The
thiomorpholine derivative 1e is a suitable substrate and afforded the desired product 3e in 42% yield. The piperazine derivative 1f
provided a low yield due to some side reactions. The substituted cyclic amines 1g-1i underwent this transformation smoothly to
provide the corresponding products 3g-3i in moderate to good yields, which are formed as a single diastereomer with rotamerism. In
addition, the reaction of α-substituted amine was investigated. Unfortunately, the reaction provided a mixture, which could not be
identified as the targeted product. When the reaction was conducted on the acyclic aliphatic amine 1j, the targeted product 3j was
obtained in 55% yield. For diethyl amine as the substrate, the reaction only provided the dealkylated product rather than the desired
cross-coupling product. For substrates 1b-1j providing 3b-3j, we also tested these substrates by using methanol as the solvent.
Compared to these reactions in CH3NO2 as the solvent, lower yields were obtained (these results are not shown in Table 2).
We then surveyed the scope of alcohols 2 (Table 2). Different aliphatic alcohols worked well and afforded the corresponding α-
alkoxybenzamides 3k-3m in good yields (54-71%). In addition, alcohols containing alkene and alkyne were tolerated under
optimized conditions, leading to the targeted products in good yields (3n: 78%, 3o: 76%). The sterically more hindered alcohol
equally served as a good substrate and provided the product 3p in 45% yield. Notably, this photocatalytic system can be applied to
the late-stage functionalization of natural alcohols. For instance, (-)-carveol was proved to be competent and was successfully
converted to the desired product 3q in 51% yield. The feasibility for the introduction of natural alcohols into biologically important
benzamides is very important for structure-activity relationship (SAR) studies and discovery of new lead compounds. It is important
to note that regiocontrol of the current method was very high. All of the reactions preferably occurred at the α-position of aliphatic
amines. We did not observe any β-substituted product in these reactions.
To gain mechanistic insights into the reaction pathway, some preliminary studies were conducted. The reaction of 1a with 2a
was conducted in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the radical scavenger. When TEMPO was
added to the reaction mixture, the formation of 3a was suppressed, and the TEMPO-adduct 4 was isolated in 40% yield (Scheme 2,
a). This result supports the hypothesis that sequential generation of aryl radical and 1,5-hydrogen-atom transfer may be involved in
this transformation.
On the basis of the above experiments and previous reports,[6,9] a plausible reaction mechanism is proposed. First, the o-
aminobenzamide 1 reacts with tBuONO and sequentially takes place anion exchange with the anion of TsOH to the diazonium salt I

5
and tBuOH.[10] Subsequently, the diazonium salt I is reduced through single electron transfer (SET) process by the excited state of
eosin Y to the aryl radical II,[9] which abstracts a hydrogen atom from a remote aliphatic C-H bond to the alkyl radical III (racial
translocation event). The alkyl radical III was further oxidized through SET by eosin Y radical cation to the iminium intermediate
IV. However, an alternative pathway
Scheme 2. a) Mechanistic studies. b) Proposed reaction mechanism.
involving the transformation of III into IV by radical chain propagation cannot be excluded at the current stage.[11] Finally, IV is
trapped by alcohol 2 to form the product 3. Further studies are ongoing to understand the mechanism in more detail.
In summary, we have presented the first visible-light photocatalytic synthesis of valuable α-alkoxybenzamides starting with
readily prepared o-aminobenzamides and alcohols through radical translocation. These transformations proceed efficiently under
metal-free and mild conditions. Reactions are very easy to conduct, and products were obtained in moderate to good yields.
Acknowledgments
This work was financially supported in part by the National Natural Science Foundation of China (No. 81222052 and 81421005),
and Jiangsu Province Science Fund for Distinguished Young Scholars (BK20130025). We thank Dr. R. N. Alolga in this group for
proofreading the manuscript.
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Visible-light photocatalytic α-amino C(sp3)-
H activation through radical translocation: a
novel and metal-free approach to α-
alkoxybenzamides
Leave this area blank for abstract info.
Feng-Qing Huang, Xin Dong, Lian-Wen Qi,* Bo Zhang*

Tetrahedron Letters
8
Highlights
•Metal-free approach to α-alkoxybenzamides
through radical translocation.
•This photocatalytic system can be applied to the
late-stage functionalization of nature alcohols.
•The reaction features complete regioselectivity,
operational simplicity, and good practicality.