Switchable Decarboxylative Heck-Type Reaction and Oxo-alkylation of Styrenes with N-Hydroxyphthalimide Esters under Photocatalysis

Article abstract of DOI:10.1021/acs.orglett.8b01268

The switchable visible-light-mediated decarboxylative Heck-type reaction and oxo-alkylation reaction of N-hydroxyphthalimide esters under photocatalysis were developed. Disubstituted or trisubstituted alkenes were obtained in good yield with high E-select

Full text of DOI:10.1021/acs.orglett.8b01268

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Switchable Decarboxylative Heck-Type Reaction and Oxo-alkylation
of Styrenes with N‑Hydroxyphthalimide Esters under Photocatalysis
Zi-Hao Xia,†,‡ Chun-Lin Zhang,† Zhong-Hua Gao,*,†,‡ and Song Ye*,†,‡
†Beijing National Laboratory for Molecular Science, Key Laboratory of Molecular Recognition and Functional, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
‡University of Chinese Academy of Science, Beijing 100049, People’s Republic of China
S
* Supporting Information
ABSTRACT: The switchable visible-light-mediated decarboxylative Heck-type reaction and oxo-alkylation reaction of N-
hydroxyphthalimide esters under photocatalysis were developed. Disubstituted or trisubstituted alkenes were obtained in good
yield with high E-selectivity in the presence of Brønsted acid as the additive, while ketones resulted in the absence of the acidic
additive.
Scheme 1. Reactions of NHP Esters via Alkyl Radicals
he Mizoroki−Heck reaction, which involves the metal-
Tcatalyzed coupling of olefins and aryl/vinyl (pseudo)-
halides, is a powerful method for the synthesis of substituted
alkenes.1 Classically, this reaction utilizes aryl or vinyl
electrophiles. Alkyl halides, especially tertiary alkyl halides, are
challenging reagents, because of their slow oxidative addition
rates, inherent instability of alkyl palladium species, and
undesired premature β-hydrogen elimination process.2 Since
Fu’s pioneering work on palladium-catalyzed Heck reactions of
alkyl halides,3 great effort has been devoted to the reaction with
success.4 In 2017, Fu5 and Gevorgyan6 independently reported
the elegant photomediated Pd-catalyzed Heck reaction of alkyl
halides at room temperature. This success relies on the alkyl
radical-palladium(I) complex, which can suppress the undesired
β-hydrogen elimination.
reaction d).14 Very recently, Fu and Glorius independently
reported the visible-light-mediated palladium-catalyzed decar-
boxylative Heck-type reaction of NHP esters (Scheme 1,
reaction e).15 During the preparation of this paper, the oxo-
alkylation was also reported by Glorius et al.,16 prompting us to
report our results on the switchable Heck-type reaction in the
presence of Brønsted acid, and the oxo-alkylation reaction to
give ketones (Scheme 1, reactions f and g).
The model reaction of styrene 1a and N-hydroxyphalimide
2a was carried out using Ir(ppy)3 (1 mol %) as the
photocatalyst under irradiation with blue LEDs (see Table 1).
Although it is disappointing that no desired alkene 3a was
formed when base was added (Table 1, entries 1 and 2), the
reaction in the presence of 1.0 equiv of p-toluenesulfonic acid
gave alkene 3a in 46% yield (Table 1, entry 3). A series of acidic
Being inexpensive, stable, and readily available, carboxylic
acids are highly useful alternatives for organic halides in cross-
coupling reactions.7 In 2002, Myers et al. reported the first Pd-
catalyzed decarboxylative Heck reactions utilizing aromatic
carboxylic acids and alkenes as the substrates.8 However, this
transformation requires high temperature and only works for
C(sp2)−C(sp2) couplings. As a carboxylic acid derivative, N-
hydroxyphthalimide (NHP) esters can be easily reduced by
photocatalysts or low-valent transition metals to generate alkyl
radicals for various transformations (see Scheme 1). In 1988,
Okada and Oda et al. reported the photomediated decarbox-
ylation of NHP esters, following the abstraction of hydrogen to
give hydrocarbon (Scheme 1, reaction a).9 Recently, the C−C
coupling of the generated radicals with organometallic
compounds,10 aryl iodides,11 and C−H bond12 has been well-
established (Scheme 1, reaction b). In addition to the Michael
addition of the alkyl radicals (Scheme 1, reaction c),13 the
interesting oxy-alkylation of styrenes was realized (Scheme 1,
Received: April 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01268
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Heck-Type Reaction
b
b
entry
additive (X equiv)
solvent
3a yield (%) 4a yield (%)
1
2
K2CO3 (1.0)
Et3N (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCM
0
0
0
0
c
3
TsOH (1.0)
TFA (1.0)
46
0
c
c
c
c
c
4
48
53
6
0
5
TfOH (1.0)
CH3CO2H (1.0)
PhCO2H (1.0)
TfOH (0.5)
TfOH (0.5)
TfOH (0.5)
TfOH (0.5)
0
6
0
7
11
56
0
8
0
9
0
0
0
0
0
0
10
11
12
13
MeCN
acetone
DMSO
MeCN
0
0
66
0
a
General conditions: 1a (0.4 mmol), 2a (0.6 mmol), Ir(ppy)3 (1
mol %), and additives in 2.0 mL of solvent, and irradiated under 12 W
blue LEDs at room temperature for 12 h under nitrogen atmosphere.
b
c
Isolated yield. E/Z > 20:1, determined by 1H NMR spectroscopy of
the crude reaction mixture. TFA = trifluoroacetic acid; TsOH = p-
toluenesulfonic acid; TfOH = trifluoromethanesulfonic acid.
additives were then tested for the reaction (Table 1, entries 4−
7), and trifluoromethanesulfonic acid (TfOH) turned out to be
the best (Table 1, entry 5). Decreasing the loading of the acid
to 0.5 equiv resulted in no loss of the yield (Table 1, entry 8).
However, other solvents, such as DCM, MeCN, and acetone,
were not suitable for this transformation (Table 1, entries 9−
11). Investigation on the photocatalysts gave no better results
(see Table S1 in the Supporting Information).
Interestingly, ketone 4a was obtained in 66% without the
formation of alkene 3a when the reaction was carried out in the
absence of the acidic additives (Table 1, entry 12). Control
experiments revealed that no ketone was formed when other
solvents were used instead of DMSO (Table 1, entry 13),
which indicates that DMSO acts as both the solvent and the
oxidant for the reaction.17
The scope of the Heck-type reaction of styrenes with N-
hydroxyphthalimide esters was then investigated (Scheme 2). It
was found that all the precursors of primary, secondary, and
tertiary alkyl radicals worked for the reaction to give the desired
alkenes in moderate to good yields (3a−3h). The reaction with
γ-radicals of tetrahydropyran and piperidine gave the
corresponding alkenes in good to high yields (3i−3k). The
yield decreased when the esters containing a C−C double bond
or bromine substituent were used (3l and 3m), while keto and
ester groups were well-tolerated in the substrate (3n and 3o).
Note that only E-alkenes were isolated and no Z-isomer was
observed for all investigated cases. The styrenes with electron-
withdrawing groups resulted in low yields (3p and 3q), while
those with electron-donating groups gave the desired products
in much better yields (3r and 3s). The reaction of 1,1-
disubstituted alkenes worked very well (3u−3x). Notably, the
reaction of estrone-derived alkene molecule afforded the
corresponding product in 90% yield (3y). However, olefins
other than styrenes, such as acrylates and enol ethers, did not
work under current reaction condition.
Considering the wide applications of ketones in organic
synthesis,18 the oxo-alkylation of styrenes with NHP esters was
also investigated (see Scheme 3). It was found that all the
precursors of primary, secondary, and tertiary alkyl radicals
worked well for the reaction to give the desired oxo-alkylation
products (4a−4g) in good yields. A reaction of cyclic and
acyclic alkyl radicals containing carbon−carbon double bond
also went well (4h and 4i). The reaction via α-radical of
tetrahydrofuran afforded product (4j) in decreased yield, while
those via γ-radical resulted in good yields (4k and 4l). In
addition, keto and bromine were also tolerated for the reaction
(4m and 4n). All styrenes with para-electron-withdrawing (Ar
= 4-FC6H4, 4-ClC6H4, 4-BrC6H4), and electron-donating
groups (Ar = 4-MeC6H4, 4-MeOC6H4, 4-AcOC6H4) worked
B
DOI: 10.1021/acs.orglett.8b01268
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Oxo-alkylation Reaction
Scheme 4. Reactions on 1 mmol Scale
Scheme 5. Trapping of the Radical
ment of the cyclopropylmethyl radical in good yield (see
Scheme 6).
Scheme 6. Rearrangement of the Radical
A plausible mechanism for the switchable reactions is
depicted in Figure 1. Under visible-light irradiation, the catalyst
Ir(ppy)3 is excited and reduces the NHP ester to give alkyl
radical via elimination of phthalimide anion and carbon dioxide.
The addition of alkyl radical to styrene gives new alkyl radical
intermediate B, which is oxidized to a carbocation intermediate
C by IrIV. In the presence of acidic additive, the reaction goes
by elimination of a β-proton to afford the substituted alkene 3
and regenerates the photocatalyst. In absence of acidic additive,
the combination of carbocation C and DMSO affords the
alkoxylsulfonium intermediate D, which is fragmented to give
the ketone 4, which is a process known as Kornblum
oxidation.17 The key difference between these two reactions
may be the pH value of the reaction mixture in the presence or
absence of acidic additive. The high concentration of protons
may deter the depronation of alkoxylsulfonium intermediate D,
thereby disfavoring the formation of ketone 4.
In summary, we have developed a visible-light-mediated
Heck-type olefination and oxo-alkylation of styrenes with N-
hydroxyphthalimide esters as a mild radical precursor. The
reaction gives alkenes in the presence of acidic additive, while
ketones are obtained in the absence of acidic additive. The
reaction features readily available starting materials, mild
conditions and a broad scope of alkyl radicals, including
primary, secondary, and tertiary ones. Detailed mechanistic
for the oxo-alkylation reaction (4o−4u). Styrenes with meta-
and ortho- substituents and β-naphthyl resulted in low yields
(4v−4z).
Both the Heck-type reaction and oxo-alkylation reaction
could be carried out on 1 mmol scale (see Scheme 4).
Some control experiments were conducted to verify the
involvement of the alkyl radical for the reaction. When the
reaction was carried out under the standard conditions with the
addition of 2.0 equiv of TEMPO, which is a typical radical
scavenger, the formation of the adduct between TEMPO and
the alkyl radical derived from decarboxylation of NHP ester 1a
was detected by high-resolution mass spectroscopy (HR-MS)
(see the Supporting Information), while the corresponding
product 3a was not obtained (see Scheme 5).
The reaction with N-(2-cyclopropylacetyloxyl) phathimide 5
gave the corresponding product 4i via ring-opening rearrange-
C
DOI: 10.1021/acs.orglett.8b01268
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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Figure 1. Possible mechanism.
studies and other photocatalyzed functionalization reactions of
alkenes are currently underway in our laboratory.
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.8b01268.
Experimental details and NMR spectra for obtained
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gaozh@iccas.ac.cn (Z.-H. Gao).
*E-mail: songye@iccas.ac.cn (S. Ye).
ORCID
Song Ye: 0000-0002-3962-7738
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Nos. 21425207, 21521002, 21672216,
21702208), and the Chinese Academy of Sciences is greatly
acknowledged.
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DOI: 10.1021/acs.orglett.8b01268
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