Strategy for Overcoming Full Reversibility of Intermolecular Radical Addition to Aldehydes: Tandem C-H and C-O Bonds Cleaving Cyclization of (Phenoxymethyl)arenes with Carbonyls to Benzofurans

Article abstract of DOI:10.1021/acs.orglett.8b01207

An intermolecular addition of carbon radicals enabled by a cascade radical coupling strategy is developed. It includes an intermolecular alkyl radical addition to a carbonyl group followed by an intramolecular alkoxy radical addition to haloarenes and produces substituted benzofurans in high yields. The radical nature of this reaction is explored by radical trapping experiments and EPR analysis. The mechanism is investigated by KIE experiments and control experiments. This method could provide rapid and practical access to the key intermediate of TAM-16, a safe and potent antibacterial agent for treating tuberculosis, and, therefore, is of great importance for organic synthesis and the pharmaceutical industry.

Full text of DOI:10.1021/acs.orglett.8b01207

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strategy for Overcoming Full Reversibility of Intermolecular Radical
Addition to Aldehydes: Tandem C−H and C−O Bonds Cleaving
Cyclization of (Phenoxymethyl)arenes with Carbonyls to Benzofurans
Hong-Xing Zheng,† Xiang-Huan Shan,† Jian-Ping Qu,*,‡ and Yan-Biao Kang*,†
†Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: An intermolecular addition of carbon radicals enabled by a cascade radical coupling strategy is developed. It
includes an intermolecular alkyl radical addition to a carbonyl group followed by an intramolecular alkoxy radical addition to
haloarenes and produces substituted benzofurans in high yields. The radical nature of this reaction is explored by radical trapping
experiments and EPR analysis. The mechanism is investigated by KIE experiments and control experiments. This method could
provide rapid and practical access to the key intermediate of TAM-16, a safe and potent antibacterial agent for treating
tuberculosis, and, therefore, is of great importance for organic synthesis and the pharmaceutical industry.
he addition of carbon radicals to substituted carbonyls is
Talways a challenging mission in organic reactions and,
thus, has been barely reported.1−3 Despite the fact that radical
addition to the simplest aldehydes, formaldehyde, has been
frequently reported,4−9 the intermolecular addition to sub-
stituted carbonyls of ketones and substituted aldehydes majorly
remains unrevealed.4 The challenge lies in the instability of
alkoxy radical compared to its carbon radical donor which
makes this addition fully reversible. The alkoxy radical
intermediate is thermodynamically unfavorable and preferably
decays via homolytic cleavage to form a more stable alkyl
radical species (Figure 1). Although utilizing substituted
aldehydes as intramolecular radical acceptors has been well
developed,10−18 research on intermolecular addition of carbon
radical to carbonyls remains limited.19 Therefore, the
exploration of such a reaction is highly desirable.
On the other hand, aldehydes and ketones are useful
feedstocks in organic synthesis, as important acceptors as
electrophiles. However, in radical addition reactions, compared
to C−C and C−N double bonds, C−O double bonds have
been less explored as radical acceptors, especially for substituted
aldehydes and ketones. Here, we report our recent results on
benzofuran synthesis via a cascade radical addition strategy
(Scheme 1). In this reaction the alkoxy radical B generated
from the intermolecular addition of alkyl radical A to carbonyls
Scheme 1. Tandem Strategy for Radical Addition to
Aldehydes
Figure 1. Selected nature products, pharmaceuticals, and biologically
active compounds.
Received: April 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01207
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
is trapped by a fast subsequent intramolecular radical addition
to aryl halide to form stable radical C. This trapping strategy via
the addition of unstable alkoxy radicals to holoarenes enables
the accomplishment of “mission impossible”. This transition-
metal-free and toxic-free method provides a rapid, versatile, and
practical access to pharmaceuticals containing a substituted
benzofuran skeleton. Substituted benzofurans are useful
feedstocks in organic synthesis, as they represent convenient
intermediates for manufacturing biologically active molecules,
pharmaceuticals, and organic functional molecules (Figure 1).
Development of a practical and straightforward strategy to
construct a benzofuran skeleton would benefit both pharma-
ceutical research and material studies and consequently has
attracted more interest from synthetic chemists.
Scheme 3. Radical Trapping Experiments
To investigate the conditions, 1-iodo-2-(phenoxymethyl)-
benzene 1a and benzaldehyde 2a were subjected to various
reaction conditions in the presence of base under argon (Table
1). Potassium tert-butoxide turned out to be the best base, and
The reaction carried out in oxygen yields only trace 3a
(Scheme 3A). The TEMPO trapping experiments afforded the
adduct 4 (Scheme 3B). In the EPR test for the reaction
between 1ab and 2a, a strong signal of radical 5 from 1ab is
observed (Scheme 3C).
On the basis of experimental evidence, a cascade radical
addition to carbonyls and arenes is proposed (Scheme 4, path
a
Table 1. Reaction Conditions
b
entry
solvent
x
solvent
3a (%)
1
2
3
4
tBuOK
tBuOK
tBuONa
tBuOLi
tBuOK
none
2.4
2.0
2.4
2.4
2.4
−
DMF
DMF
DMF
DMF
DMF
DMF
other
86
80
Scheme 4. Proposed Mechanism
23
trace
80
c
5
6
0
d
7
tBuOK
2.4
trace
a
Reaction conditions: 1a (0.5 mmol), 2a (1.2 mmol), DMF (1 mL),
b
c
d
1
argon. Determined by H NMR. At 70 °C. Other solvents include
DMA, DMSO, DME, toluene, and dioxane.
dimethylformamide, the best solvent. A 2.4 equiv amount of
base is necessary for the improved yield. Thus, the reaction
conditions demonstrated in entry 1 were then chosen as the
standard conditions.
Recently, we have reported that potassium tert-butoxide
promoted a series of useful transformations, such as allylic
isomerization of alcohols20 and dehalogenation of aryl halide.21
In this work, a base-promoted working model via a radical
intermediate was proposed based on systematical kinetic study,
isotope-labeling experiments, a radical trapping experiment, and
a control experiment and EPR experiments. In the isotope
labeling experiments, a KIE of 1 is established for 1ab (Scheme
2), indicating the C−H cleavage step is not the rate-
determining step. A slightly higher KIE of 1.3 is observed for
aldehyde 2a. The radical nature of this reaction is confirmed by
EPR experiments and radical trapping experiments (Scheme 3).
t
a). Radical A is generated by the BuOK−DMF system under
heating conditions.20−27 Trace alkoxy radical B is formed
reversibly from the addition of radical A to carbonyl of 2.
Alkoxy radical B is not thermodynamically favorable and tends
to go back to A or be trapped by the haloarene moiety of B via
an intramolecular radical addition process to form C. Allyl
radical C is more stable than alkoxyl radical B and turns to D
with the regeneration of A. Dihydrobenzofuran D is converted
to final product 3 via an E2 process. The detailed mechanism
for the regeneration of A is not clear, which probably involves a
halogen radical or a benzoyl radical.28 However, only 1.2 equiv
Scheme 2. Isotope Labeling Experiments
t
of aldehydes were used, and no PhCO2 Bu was detected in the
reaction. Therefore, the benzoyl radical should not be involved.
An alternative path b might evolve an anionic addition of
deprotonated 1 to aldehydes. In the control experiments, the
hypothesized intermediate 7 (intermediate IV) cannot be
observed in the reaction of 1ab and 2a under standard
conditions (Scheme 5A). Compound 7 cannot be converted to
B
DOI: 10.1021/acs.orglett.8b01207
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 5. Control Experiments
Scheme 6. Substrate Scope
3a (Scheme 5B). Compound 6 (intermediate II) cannot afford
3a either (Scheme 5C). Compound 8 affords only elimination
products 10 and 11 (Scheme 5D). Therefore, the anionic
process should not be involved in this reaction.
Leaving groups (LG) of 2-halogen benzyl ether 1were
investigated. Substrates 1 and PhCHO were heated at 90 °C for
the desired time in the presence of 2.4 equiv of tBuOK in DMF
(Table 1). A wide range of iodides and bromides could
generate benzofuran products from moderate to good yields
(Table 2, entries 1−9). Chlorides could also afford the desired
a
Table 2. Screening Leaving Groups
b
entry
X
LG
time (h)
3a (%)
1
2
3
4
5
6
7
8
9
10
I
PhO
4
87
89
73
15
59
87
48
36
79
34
I
4-MeC6H4O
4-MeOC6H4O
4-CF3C6H4O
4-FC6H4O
1,1′-biphenylO
nBuO
4
I
6
I
1
I
4
I
4
a
Conditions: 1 (0.5 mmol), RCHO (0.6 mmol; 0.75 mmol for 3t−w),
I
1.5
4
b
tBuOK (1.2 mmol). tBuOLi instead of BuOK.
t
Br
Br
Cl
pyrrolidin-1-yl
PhO
4
feature of substituents on both substrates. A very strong
electron-withdrawing group (EWG) such as nitro is not
favorable in this reaction (3q), but other EWGs such as CF3
and CN have no negative effect (3f and 3n). The aliphatic
aldehydes with α-active protons are not suitable for this
reaction. One example using pivalaldehyde as a radical acceptor
affords 2-tert-butyl benzofuran 3z in 46% yield. Alkenyl
aldehydes do not work for this reaction. When benzophenone
is used instead of aldehydes, 2,3-dihydrobenzofuran 12 is
yielded.
PhO
2
a
Standard conditions: 1a (0.5 mmol), DMF (1 mL), argon.
Determined by H NMR.
b
1
product, but with decreased yield (entry 10). The amine leaving
group gives a much lower yield (entry 8). Considering the
lower price of PhOH and the comparable yields presented in
entries 1 and 2, substrates bearing a phenoxy were chosen for
further investigation. The standard conditions have been
established as listed in entry 1.
Using benzaldehyde 2a as a model radical acceptor, various
substrates 1 were subjected to the standard conditions and
generally good yields were achieved (Scheme 6). The
benzofurans bearing a C4−C7 bromo-group were obtained in
84% to 97% yields (3b−3e). Such bromobenzofurans could be
further transformed to various products via cross-coupling
reactions. Either electron-rich or electron-deficient aldehydes
afford the desired products (3a, 3l, 3o, 3p, and 3x). The
heteroaryl products can also be obtained in high yields (3i, 3j,
3k−3m). Generally, this reaction is not sensitive to the electron
This reaction has been applied in the synthesis of
pharmaceuticals under transition-metal-free conditions. Started
from 1c, 2 g of 3s are obtained in 90% of yield (Scheme 7).
After a three-steps transformation, the key intermediate 15 for
TAM-16, a safe and potent antibacterial agent for treating
tuberculosis,29 is produced.
C
DOI: 10.1021/acs.orglett.8b01207
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ketones via a cascade radical addition/cyclization reaction. This
reaction provides rapid, versatile, and practical access to
pharmaceuticals containing a substituted benzofuran skeleton.
The radical nature of this reaction is proved by a radical
trapping experiment and EPR analysis. The mechanism is
investigated by kinetic study, KIE experiments, and control
experiments. Such a strategy might be used as a general scaffold
to develop other radical additions to carbonyls.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01207.
(25) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018−
5022.
(26) Zhou, S.; Anderson, G. M.; Mondal, B.; Doni, E.; Ironmonger,
V.; Kranz, M.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2014, 5, 476−482.
(27) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.;
Lei, A. Chem. Rev. 2017, 117, 9016−9085.
(28) Kippo, T.; Kimura, Y.; Ueda, M.; Fukuyama, T.; Ryu, I. Synlett
2017, 28, 1733−1737.
(29) Aggarwal, A.; Parai, M. K.; Shetty, N.; Wallis, D.; Woolhiser, L.;
Hastings, C.; Dutta, N. K.; Galaviz, S.; Dhakal, R. C.; Shrestha, R.;
Wakabayashi, S.; Walpole, C.; Matthews, D.; Floyd, D.; Scullion, P.;
Riley, J.; Epemolu, O.; Norval, S.; Snavely, T.; Robertson, G. T.;
Rubin, E. J.; Ioerg, T. R.; Sirgel, F. A.; van der Merwe, R.; van Helden,
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ybkang@ustc.edu.cn.
*E-mail: ias_jpqu@njtech.edu.cn.
ORCID
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Notes
P. D.; Keller, P.; Botter, E. C.; Karakousis, P. C.; Lenaerts, A. J.;
̈
Sacchettini, J. C. Cell 2017, 170, 249.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21672196, 21602001, U1463202) for financial support.
■
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D
DOI: 10.1021/acs.orglett.8b01207
Org. Lett. XXXX, XXX, XXX−XXX