Visible-Light Photocatalytic Decarboxylative Alkyl Radical Addition Cascade for Synthesis of Benzazepine Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03588

A visible-light photocatalytic decarboxylative alkyl radical addition cascade reaction of acrylamide-tethered styrenes for the synthesis of benzazepine derivatives is described. This protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions, affording the seven-membered rings in good yields. This method was also applied for efficient grafting of the benzazepine scaffold into the pharmaceutically active ursolic acid scaffold.

Full text of DOI:10.1021/acs.orglett.7b03588

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light Photocatalytic Decarboxylative Alkyl Radical Addition
Cascade for Synthesis of Benzazepine Derivatives
Yu Zhao,† Jia-Rong Chen,† and Wen-Jing Xiao*,†,‡
†Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticides
and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan
430079, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A visible-light photocatalytic decarboxylative
alkyl radical addition cascade reaction of acrylamide-tethered
styrenes for the synthesis of benzazepine derivatives is
described. This protocol features broad substrate scope,
excellent functional group tolerance, and mild reaction
conditions, affording the seven-membered rings in good
yields. This method was also applied for efficient grafting of
the benzazepine scaffold into the pharmaceutically active
ursolic acid scaffold.
adical cascade reactions serve as an excellent way to
Rconstruct various structually diverse and complex carbo-
cycles and heterocycles, which exist in many pharmaceuticals,
bioactive molecules, and natural products.1 This strategy can
usually meet a criteria of ideal synthesis,2 enabling the design of
an atom-, step-, and redox-economic process. In order to
develop more environmentally friendly alternatives, we need to
avoid the use of harsh reaction conditions and stoichiomeric
radical initiators that are typically involved in the traditional
methods for radical generation. Toward this target, visible-light
photoredox catalysis provides an attractive tool to produce
various reactive radicals for initiating radical reactions and
assembly of diverse carbocyclic and heterocyclic skeletons.3 In
this context, we also have a longstanding interest in visible light
Figure 1. Examples of biologically active compounds containing
benzazepine scaffold.
photocatalytic heterocycle synthesis.
Benzazepine derivatives are a significant family of seven-
membered heterocycles that exhibit unique bioactive and
pharmaceutical properties (Figure 1).4 The development of
novel and efficient methods for their synthesis has attracted
considerable attention from the synthetic community.
Typically, the benzazepine skeletons could be assembled by
transition-metal-catalyzed coupling,5 Beckmann rearrangemen-
t,4a radical reactions,6 and others.7 For instance, the Shi group
reported an elegant Fe- or Cu salt-catalyzed CF3 radical
addition cascade for the synthesis of CF3-containing polycyclic
benzazepine derivatives in a highly chemoselective fashion
(Scheme 1a).6c Recently, the Li group has also developed a Ag-
mediated decarboxylative radical addition/annulation cascade
for construction of 2H-benzo[b]azepin-2-ones using stoichio-
meric K2S2O8 as oxidant (Scheme 1b).6d Inspired by these
impressive advances, we envisaged that visible light induced
redox-neutral radical addition cascade would provide a facile
route to benzazepine skeletons.
Carboxylic acids are abundant and inexpensive chemical
feedstocks. With the development of visible-light photoredox
catalysis, carboxylic acids and their derivatives can undergo
single-electron transfer to form the alkyl radicals by
decarboxylation. As such, synthetically useful transformations
can take place,3h,8 such as atom abstraction, radical−radical
cross coupling, radical addition, and radical transmetalation.9 In
terms of the radical addition reactions, we found that the alkyl
radicals could directly add to activated or unactivated alkenes.10
Inspired by these contributions, we anticipated that the visible
light induced decarboxylative alkyl radical chemoselective
addition casacde to acrylamide-tethered styrene would lead to
Received: November 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
none or very low yield of 3a was observed, confirming that this
radical cascade reaction was a photocatalytic process (entries
8−10).
With the optimized reaction established, we examined the
substrate scope for the reaction of acrylamide-tethered styrenes
1 with 2a (Scheme 2). It was found that this reaction can
Scheme 1. Intermolecular Radical Addition Cascade for the
Construction of the Benzazepine Scaffolds
a,b
Scheme 2. Scope of Acrylamide-Tethered Styrenes 2a
benzazepine derivatives. Herein, we describe our preliminary
results.
The investigation of the alkyl radical addition cascade began
with acrylamide-tethered styrene and cyclohexyl N-(acyloxy)-
phthalimide (NHP ester) as model substrates, 1 mol % of
Ir(ppy)2(dtbbpy)PF6 as photocatalyst, and CH3CN as the
solvent under irradiation of 2*3 W blue LEDs (Table 1).11
a
Table 1. Reaction Optimization
a
1 (0.20 mmol), 2a (0.22 mmol) and Ir(ppy)2(dtbbpy)PF6 (1 mol %),
10 equiv of water, 1.2 equiv of pyridine, in MeCN (2.0 mL) at rt under
b
irradiation by 2*3 W blue LEDs overnight. Isolated yield.
tolerate a variety of substituents on the benzene ring tethered
alkene. Reactions of 1b−e containing an electron-donating
(e.g., methyl) or electron-withdrawing (e.g., fluoro, chloro,
bromo) functional groups worked well to deliver the
corresponding products 3b−e in 58−70% yields. When R3 is
a chloro group, product 3f can be isolated in 65% yield.
Subsequently, we investigated the influence of the N-protected
groups. It was found that with those groups, such as ethyl,
benzyl and allyl, the reaction could give the desired products
3g−i in 64−73% yields. In contrast, the reaction of N-free
acrylamide-tethered styrene did not work under the standard
conditions. Surprisingly, when we utilized the 1,1-phenylmethyl
alkene tethered acrylamide as a radical acceptor, no desired
product 3k was observed, probably because the benzyl radical
intermediate was not sufficiently stable. Note that the acrylate-
tethered styrene 1l could also react with 2a to give the product
3l in 31% yield. Importantly, the X-ray crystal structure analysis
of product 3c was determined, thus demonstrating the
feasibility of this strategy for the construction of benzazepines.
For the next stage of this investigation, a set of radical
sources was assessed by examining the generality of the alkyl
radical addition cascade (Scheme 3). We were pleased to
observe that this reaction exhibited broad substrate scope, and
the aliphatic primary, secondary, and tertiary carboxylic acids
reacted smoothly with 1a. For example, the reaction with the
primary carbon-centered radical derived from phenylpropionic
acid gave rise to desired product 4a in 40% yield. Moreover, the
acyclic and cyclic secondary carbon-centered radicals worked
well to afford the products 4b−i in 49−73% yields. Functional
b
entry
H2O (x equiv)
base
yield (%)
1
2
3
4
5
6
5
10
50
10
10
10
10
10
10
no
no
no
69
71
62
74
69
43
75
no
no
19
pyridine
NaHCO3
K2CO3
c
7
pyridine
pyridine
pyridine
pyridine
d
8
e
9
f
10
a
1a (0.20 mmol), 2a (0.22 mmol), photocatalyst (1 mol %), 2.2 equiv
b
of base, 2.0 mL of MeCN, overnight, 2*3 W blue LEDs, rt. Isolated
c
d
yield. 1.2 equiv of pyridine was added. Without photocatalyst.
e
f
Without visible light irradiation. Without H2O.
When 10 equiv of H2O were added to this system, the desired
product 3a was obtained in 71% yield. Addition of less or more
distilled water led to a slight decrease to 69% and 62% yields,
respectively (entries 1−3). Subsequently, the addition of extra
bases to this system, including organic and inorganic bases, led
to a significant change in the reaction efficiency (entries 4−6).
When pyridine was used as the base, the yield of the desired
product 3a rose to 74%. By decreasing the loading of pyridine
to 1.2 equiv, the desired product 3a was obtained in 75% yield
(entry 7). Control experiments of this radical addition cascade
were performed, either without the photocatalyst, in the
absence of visible light irradiation, or without extra H2O, and
B
DOI: 10.1021/acs.orglett.7b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
To gain further insight into the mechanism, we have
performed some control experiments, including addition of
TEMPO as radical-trapping agent, with D2O and without extra
H2O.11 The experimental results suggested the involvement of
radical intermediates and activation of the alkyl N-(acyloxy)-
phthalimide by its hydrogen-bonding interaction with water.10d
Accordingly, we proposed a plausible mechanism forthe
photocatalytic chemoselective alkyl radical addition cascade
(Scheme 5). First, this photocatalyst (PC) is photoexcited to its
Scheme 3. Scope of the Alkyl Radical Precursors 2
Scheme 5. Proposed Mechanism
a
1a (0.20 mmol), 2 (0.22 mmol) and Ir(ppy)2(dtbbpy)PF6 (1 mol %),
10 equiv of water, 1.2 equiv of pyridine, in MeCN (2.0 mL) at rt under
b
c
irradiation by 2*3 W blue LEDs overnight. Isolated yield. The ratio
d
of 1a to 2 is 1.5:1. 5 mol % of Ir(ppy)2(dtbbpy)PF6 was used.
Diastereomeric ratio was 1:1, which was determined by H NMR
excited state (PC*) and oxidized by a complex of 2a binded by
hydrogen bonding. This reducing complex B undergoes
decarbonation, to afford the alkyl radical intermediate.
Subsequently, this alkyl radical reacts with 1a, followed by
the chemoselective radical addition cascade process, to form the
benzyl radical intermediate D. Finally, this key intermediate D
further undergoes oxidation and dehydrogen, completing the
photocatalytic cycle by affording the final product 3a. As
demonstrated in Scheme 2, the reaction of substrates with
electron-rich aryl groups (e.g., 3a and 3e) gave better yields
than those with electron-deficient groups (e.g., 3b−d,f),
indicating that the stability of D is essential and the formation
of D should be the rate-determining step.
In conclusion, we have successfully developed a novel and
efficient method for the facile synthesis of benzazepine
derivatives. The key to success is the photocatalytic
decarboxylative alkyl radical generation and its chemoselective
addition cascade to the alkene. This protocol features broad
substrate scope and excellent functional group tolerance under
very mild reaction conditions. Furthermore, application of this
method enables access to the efficient installation of the
pharmaceutically active ursolic group onto the benzazepine
scaffold.
e
1
f
analysis. 37 h.
groups, such as vinyl, ether, Boc-protected amine, and carbonyl,
can be toleranted in this reaction. Tertiary radical sources,
including the sterically hindrance radical containing the 1-
adamantyl group, could be employed for this reaction to
generate the corresponding products 4i−k in 54−83% yields.
In addition, when we utilized NHP ester 2m of cyclopropyl
acetic acid as a radical precursor, a 28% yield of ring-opened
product 4m was obtained, confirming the involvement of
radical intermediate in the process.
To showcase the scalability of this photocatalytic radical
addition cascade, a gram-scale reaction was performed using the
model substrates 1a and 2a, giving the product 3a in 74% yield
(Scheme 4, eq 1). Furthermore, it is well-known that ursolic
acid has excellent pharmaceutical activity.12 Using this radical
addition cascade, we were able to assemble the “two privileged
scaffolds” between ursolic group and benzazepine, providing 7
in 58% isolated yield by using the Ac-protected ursolic acid as
starting material (Scheme 4, eq 2).
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Synthetic Application
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03588.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
Accession Codes
CCDC 1582448 contains 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
C
DOI: 10.1021/acs.orglett.7b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wxiao@mail.ccnu.edu.cn.
ORCID
Jia-Rong Chen: 0000-0001-6054-2547
Wen-Jing Xiao: 0000-0002-9318-6021
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21772053, 21472057, 21472058, 21232003, and
21622201) and the Science and Technology Department of
Hubei Province (2017AH047) for support of this research. The
Program of Introducing Talents of Discipline to Universities of
China (111 Program, B17019) is also acknowledged. We thank
Professor Howard Alper of University of Ottawa for helpful
discussions.
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