UV light-mediated difunctionalization of alkenes through aroyl radical addition/1,4-/1,2-Aryl shift cascade reactions

Article abstract of DOI:10.1021/acs.orglett.5b00144

UV light-mediated difunctionalization of alkenes through an aroyl radical addition/1,4-/1,2-aryl shift has been described. The resulted aroyl radical from a photocleavage reaction added to acrylamide compounds followed by cyclization led to the formation of oxindoles, whereas the addition to cinnamic amides aroused a unique 1,4-aryl shift reaction. Furthermore, the difunctionalization of alkenes of prop-2-en-1-ols was also achieved through aroyl radical addition and a sequential 1,2-aryl shift cascade reaction.

Full text of DOI:10.1021/acs.orglett.5b00144

Letter
pubs.acs.org/OrgLett
UV Light-Mediated Difunctionalization of Alkenes through Aroyl
Radical Addition/1,4-/1,2-Aryl Shift Cascade Reactions
Lewei Zheng,† Hongli Huang,† Chao Yang,* and Wujiong Xia*
State Key Lab of Urban Water Resource and Environment, the Academy of Fundamental and Interdisciplinary Sciences, Harbin
Institute of Technology, Harbin 150080, China
S
* Supporting Information
ABSTRACT: UV light-mediated difunctionalization of alkenes through an aroyl
radical addition/1,4-/1,2-aryl shift has been described. The resulted aroyl radical
from a photocleavage reaction added to acrylamide compounds followed by
cyclization led to the formation of oxindoles, whereas the addition to cinnamic
amides aroused a unique 1,4-aryl shift reaction. Furthermore, the difunctionaliza-
tion of alkenes of prop-2-en-1-ols was also achieved through aroyl radical addition
and a sequential 1,2-aryl shift cascade reaction.
a
Table 1. Screening for Optimal Reaction Conditions
ifunctionalization of alkenes has become increasingly
Dpopular because of their high efficiency in the preparation
of significant building blocks of natural products and
pharmaceutical molecules.1 Thus, considerable efforts were
made for the development of novel and highly efficient methods
in this field. Recent studies mainly focused on transition-metal
catalyzed C−H functionalization/carbocyclization of alkenes by
simultaneous formation of two C−C bonds.2 Yet, to our
knowledge, work on the carbonylarylation of alkenes is quite rare.
In this context, Li et al. developed oxidative coupling of alkene
with an aldehyde C(sp2)−H bond and aryl C(sp2)−H bond to
form two C(sp2)−C(sp3) bonds using TBHP at 105 °C.3
Subsequently, the Duan and Li groups respectively reported Ag
and Fe catalyzed carbonylarylation of alkenes of acrylamides to
synthesize oxindoles4 under heating.5 Despite these advances,
room still exists for developing more alternative and environ-
mentally friendly approaches associated with this field.
Recently, organic photochemical reactions have attracted
considerable interest from chemists in the realm of organic
synthesis, synthetic methodologies, and radical chemistry, and
therefore a variety of photoreactions have been reported up to
now.6 Based upon our previous work on the chemical behavior of
radicals,7 we envisioned that a benzoyl radical selectively
generated from a photochemical cleavage reaction might add
to an alkene followed by C−C bond formation to realize the
difunctionalization of alkenes.
a
Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), hv, solvent
b
c
(anhydrous 50 mL) under N2 for 1 h. Isolated yield. Product 4a
(40%). 5 h, 76% conversion. 2d (0.9 mmol). 2d (1.5 mmol).
d
e
f
Therefore, we initially chose 2,2-dimethyl-1-phenylpropan-1-
one 2a (Table 1, entry 1, R = tBu) as the source of the benzoyl
radical and acrylamide 1a as the radical acceptor. Irradiation of
the mixture of the above two compounds in acetonitrile with a
450 W high-pressure mercury lamp using a Pyrex filter led to the
desired product 3a in 20% yield accompanied by the
alkylarylation product 4a as well as the product of the
photoreaction of 1a itself (Table 1, entry 1).8
compound 2a over compound 1a, and finally a 350 nm
wavelength was chosen as the light source. Irradiation of the
same reaction mixture with a 350 nm wavelength afforded 3a in
51% and 4a in 40% yield (entry 2). A solvent screening, including
toluene, methanol, and benzene, led to lower yields (entries 3−
Such a result prompted us to improve the selectivity of the
photoreaction by screening the wavelength to selectively excite
Received: January 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00144
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Letter
a b
,
5). After examination of other benzoyl radical sources (entries
6−10), the reaction conditions were optimized to use 350 nm
wavelength as the light source, 5 equiv of benzoin 2d as the
benzoyl radical source, and acetonitrile as the solvent.
Scheme 2. Scope of N-Arylacrylamides 1
With these optimized reaction conditions, we focused on the
scope of substrates (Schemes 1 and 2). As shown in Scheme 1, a
a b
,
Scheme 1. Scope of Substrates 2
a
Reaction conditions: 1a (0.3 mmol), 2 (1.5 mmol), hv (350 nm),
b
MeCN (anhydrous 50 mL) under N2 for 1 h. Isolated yield.
variety of substituted benzoins, including 2-hydroxy-2-phenyl-1-
m-tolylethanone (2da), 2-hydroxy-1-(4-methoxyphenyl)-2-
phenylethanone (2 db), 1-(4-chlorophenyl)-2-hydroxy-2-
phenylethanone (2dc), and 1-(4-fluorophenyl)-2-hydroxy-2-
phenylethanone (2dd), were successfully reacted with acryl-
amide 1a to give the desired products in moderate to good yields.
Interestingly, 2-hydroxy-1-(naphthalen-1-yl)-2-phenylethanone
(2de) was also suitable for the reaction in moderate yield, making
this method more potentially useful.
Next we set out to investigate the scope of acrylamides. As
shown in Scheme 2, compounds bearing different N-protecting
groups including alkyl, aryl, and benzyl are viable substrates for
the reaction to lead to the corresponding products (3a, 3b, 3c,
and 3s) in good yields. The substrates bearing electron-
withdrawing and/or -donating groups at the para position of
the nitrogen atom were also tolerant of the reaction conditions to
provide the desired products (3d−3i) in moderate to good
yields. When the meta-position was substituted with methyl or Cl
groups, the reaction went smoothly to afford the regioisomers
with a ratio of 2:1 (3o and 3p). However, no reaction was
observed for the ortho-substituted substrates owing to the effect
of the steric bulk. When the benzene ring of the substrate was
replaced by a naphthalene, the substrate was also suitable for the
reaction (3r). In addition, a tetrahydroquinoline derivative
furnished the tricyclic oxindole in moderate yield (3q).
Substrates with two groups on the aryl ring (1t and 1u) are
still good for the transformation to form the desired products;
however, the reaction of 1u afforded the mixture of 3u and 3u′
with a ratio of 4:1. Importantly, a pyridine group was also
tolerated under the optimal conditions (3w). Furthermore, a
series of α-substituted olefins bearing different functional groups,
such as benzyl, ester, alcohol, and ether, were still tolerant with
the reaction conditions to yield the corresponding products (3j−
3n). Interestingly, cinnmic amide compound 1v was also reactive
with the benzoyl radical to form a six-membered ring compound
3v. Such a unique and interesting result intrigues us to explore
the chemical behavior of cinnamic amides further.
a
Reaction conditions: 1 (0.3 mmol), 2d (1.5 mmol), hv (350 nm),
b
MeCN (anhydrous 50 mL) under N2 for 1 h. Isolated yield.
Sequentially, a cinnamic amide 5a (Scheme 3, R1 = H, R2, R3 =
phenyl) was prepared and submitted to the optimal reaction
conditions. To our surprise, the reaction led to the amide
compound 6a in 53% yield through a benzoyl radical addition/
1,4-aryl shift cascade reaction over the formation of a six-
membered ring. Such a serendipitous and new result, to our
knowledge, has not been reported up to now. Inspired by this, we
therefore explored this new protocol in detail by preparation of a
variety of cinnamic amides 5 and reaction with benzoin 2d, and
the results are listed in Scheme 3. As shown in Scheme 3, the aryl
group at the β-position of acrylamide substituted with electron-
withdrawing or -donating groups, including methyl, F, Cl, Br,
methoxy, were smoothly converted to the corresponding
products in moderate to good yields (6a−6h), which also
indicated that the position of the substituents on the aryl group
has no significant influence on the reaction. The structure of one
of the products 6a was further confirmed by X-ray single crystal
analysis (see the Supporting Information (SI)).9 However, when
the aryl group was replaced by a methyl or carbonyl group, no
desired product was formed. The substrates with the nitrogen
atom substituted with different aryl groups are also tolerant of the
optimized conditions (6i−6k), among which, for the unsym-
B
DOI: 10.1021/acs.orglett.5b00144
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the solvent, and the reaction results were summarized in Scheme
4.
Scheme 3. Scope of UV Light-Mediated 1,4-Aryl Shift
Reaction
a b
,
Scheme 4. Scope of the Reaction of Symmetric and
a
Unsymmetric Prop-2-enols
a
Reaction conditions: 7 (0.3 mmol), 2d (1.5 mmol), hv (350 nm),
b
benzene (anhydrous 15 mL) under N2. Ratio of isomers.
As shown in Scheme 4, for the symmetric substituents, the
corresponding products were obtained in good isolated yields
(8a−h). For the unsymmetric substituents, the electronic effect
plays an important role in the aryl migration. For example, the
electron-deficient aryl group was preferentially shifted over the
phenyl and/or the aryl ring substituted with an electron-donating
group (8i, 8k−m, 8o), and the phenyl group was prior to the
electron-enriched aryl ring (8j, 8n, 8p). Notably, when the
substituent contained a cyclopropanyl group, the corresponding
product was formed in low yield with the ring unopened (8q).
Such a result suggested the phenyl shift and formation of ketone
might happen synchronously.
a
Reaction conditions: 5 (0.3 mmol), 2d (1.5 mmol), hv (350 nm),
b
MeCN (anhydrous 50 mL), N2, irradiation for 1 h. Isolated yield.
Before the mechanism was proposed, the kinetic isotope effect
experiments were conducted using the deuterated derivatives of
1a as shown in Scheme 1 (see the SI). Both the intermolecular
(kH/D = 1.2) and intramolecular (kH/D = 1.3) isotopic effect
indicated that the C−C bond formation occurs before C−H
cleavage. The intramolecular KIE experiment result also
suggested that the rate of the reaction was determined by the
elimination of the hydrogen after C−C bond formation. The
intramolecular KIE experiment result also suggested that the rate
of the reaction was determined by the elimination of the
hydrogen after C−C bond formation.
According to the above results, the possible mechanism is
proposed as shown in Scheme 5. At first, benzoyl radical was
generated through the photochemical cleavage reaction upon
irradiation, which was then added to β-position of acrylamide 1
providing the intermediate A (blue). The addition of a radical to
the aromatic ring produced the intermediate B, which lost a
hydrogen radical rapidly to afford the oxindole 3. In contrast, for
cinnamic amide 5, the benzoyl radical was added to the α-
metric amides, the compound containing an electron-with-
drawing group, e.g. F, exhibited excellent regioselectivity and
afforded the single product with a phenyl group shift (6i); in
contrast, the compound containing an electron-donating group,
e.g. OMe, yielded a mixture with a ratio of 1:1 (6k, 6k′). Such a
result suggested the stability of the nitrogen atom radical
involved in the reaction procedure might play an important role
in the regioselectivity.
To further investigate the applicability of this protocol, 1,1-
diphenylprop-2-enol 7a was therefore prepared and subjected to
the reaction conditions. We envision that, with the generated
benzoyl radical addition to the double bond of 7a, a subsequent
1,2-phenyl shift might occur. To our delight, the desired product
8a was obtained in 54% yield after reaction for 34 h. When the
solvent CH3CN was replaced by benzene, the yield was
improved to 65%. Then a variety of symmetrically and
unsymmetrically substituted prop-2-enols were prepared and
submitted to the standard reaction conditions using benzene as
C
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Letter
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position to form the intermediate C (black), and sequential
cyclization led to intermediate D. Then a 1,2-H shift happened
instead of loss of the hydrogen radical to afford the intermediate
E. The final product 6 was formed by C−N bond cleavage
followed by hydrogen radical abstraction. For prop-2-enol
substrates 7, the benzoyl radical was added to the C−C double
bond to lead to the intermediate G (green); subsequently, the
radical cyclization to the aryl ring occurred to form the
intermediate H containing a cyclopropanyl ring. Synchronous
formation of a carbonyl group through the cleavage of the O−H
bond and ring opening of cyclopropane led to the final product 8.
In summary, we have developed a novel protocol for the
difunctionalization of alkenes through an aroyl radical addition/
1,4-/1,2-aryl shift cascade. The method is highlighted by the use
of the milder reaction conditions and is environmentally benign
by using economic available benzoin as the benzoyl precursor. In
addition the unique 1,2-/1,4-aryl shift reactions have been
discovered through a radical pathway. Further studies on the use
of these reactions are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
General procedures, materials, instrumentation, synthesis, H,
13C NMR and 2D spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xyyang@hit.edu.cn.
*E-mail: xiawj@hit.edu.cn.
Author Contributions
†L.W.Z and H.L.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from China NSFC (Nos.
21002018, 21072038, and 21472030), SKLUWRE (No.
2014DX01), the Fundamental Research Funds for the Central
Universities (Grant No. HIT.BRETIV.201310), and HLJNSF
(B201406).
REFERENCES
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■
̌
z, K. In Catalyzed Carbon-
D
DOI: 10.1021/acs.orglett.5b00144
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