A novel intermolecular synthesis of γ-lactones via visible-light photoredox catalysis

Article abstract of DOI:10.1021/ol402954t

Direct γ-lactone formation via visible-light photoredox catalysis has been achieved efficiently including hydroxylalkylation of aromatic alkenes and transesterification. The present photocatalytic protocol has good regioselectivity and substrate compatibility, affording a novel way to intermolecular γ-lactone synthesis by the reaction of styrenes with α-bromo esters in the absence of any external oxidants.

Full text of DOI:10.1021/ol402954t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Novel Intermolecular Synthesis of
γ‑Lactones via Visible-Light Photoredox
Catalysis
Xiao-Jing Wei,† Deng-Tao Yang,† Lin Wang,† Tao Song,† Li-Zhu Wu,*,‡ and Qiang Liu*,†
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, PR China, and Key Laboratory of Photochemical Conversion and
Optoelectronic Materials, Technical Institute of Physics and Chemistry,
Chinese Academy of Sciences, Beijing 100190, PR China
liuqiang@lzu.edu.cn; lzwu@mail.ipc.ac.cn
Received October 13, 2013
ABSTRACT
Direct γ-lactone formation via visible-light photoredox catalysis has been achieved efficiently including hydroxylalkylation of aromatic alkenes
and transesterification. The present photocatalytic protocol has good regioselectivity and substrate compatibility, affording a novel way to
intermolecular γ-lactone synthesis by the reaction of styrenes with R-bromo esters in the absence of any external oxidants.
γ-Lactones are basicstructuralelements inmany natural
products and are prevalently used building blocks in
agrichemicals, pharmaceuticals and organic materials.1 A
tremendous amount of effort has been devoted and much
progress has been made to introduce the γ-lactone moiety
into organic molecules,2 among which the intra- or inter-
molecular reactions of alkenes with nucleophiles3 or radi-
cal precursors4 are most common approaches to construct
the skeletons. However, stoichiometric oxidants and harsh
reaction conditions are always employed to activate alke-
nyl moieties or produce radicals in the transformations.
Moreover, the addition of oxidant tends to cause a crisis of
undesired side reactions and may lead to pollution of the
environment. As a result, an efficient and environmentally
friendly method should be developed.
As an efficient and sustainable method to perform
organic reactions, visible-light photoredox catalysis has
attracted widespread research interest owing to its attrac-
tive features such as mild and green conditions, excellent
functional group tolerance, and high reactivity.5 In addi-
tion, as the main wave band of solar energy, visible light is
generally readily available and can easily be used without
the need of a special instrument or apparatus. Moreover,
compared to ultraviolet irradiation, the transparent prop-
erties of most organic substrates for visible light minimize
the side reactions.
† Lanzhou University.
‡ Technical Institute of Physics and Chemistry.
(1) (a) Nefkens, G. H. L.; Thuring, J. W. J. F.; Beenakkers, M. F. M.;
Zwanenburg, B. J. Agric. Food Chem. 1997, 45, 2273. (b) Mangnus,
E. M.; Zwanenburg, B. J. Agric. Food Chem. 1992, 40, 1066. (c) Fang, B.;
Xie, X.; Zhao, C.; Jing, P.; Li, H.; Wang, Z.; Gu, J.; She, X. J. Org. Chem.
2013, 78, 6338.
(2) (a) Gil, S.; Parra, M.; Rodriguez, P.; Segura, J. Mini-Rev. Org.
Chem. 2009, 6, 345. (b) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang,
J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 1236. (c) Newhouse, T. R.; Kaib, P. S. J.; Gross, A. W.; Corey,
E. J. Org. Lett. 2013, 15, 1591.
Over these years, a variety of elegant chemical transfor-
mationsviavisible-light photoredoxhavebeendeveloped.6
Seminal works by MacMillian,7a,b Stephenson,7c,d and
ꢀ7e
Gagne et al. have demonstrated that activated haloalkanes
such as carbonyl, benzyl, alkenyl, aryl, and heteroatom
(3) (a) Huang, L.; Jiang, H.; Qi, C.; Liu, X. J. Am. Chem. Soc. 2010,
132, 17652. (b) Xie, X.; Li, Y.; Fox, J. M. Org. Lett. 2013, 15, 1500.
(4) (a) Powell, L. H.; Docherty, P. H.; Hulcoop, D. G.; Kemmitt,
P. D.; Burton, J. W. Chem. Commun. 2008, 2559. (b) Wang, W.; Xu,
M.-H.; Lei, X.-S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773. (c) Iwahama, T.;
Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 613.
(5) Reviews: (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
Soc. Rev. 2011, 40, 102. (b) Prier, C. K.; Rankic, D. A.; MacMillan,
D. W. C. Chem. Rev. 2013, 113, 5322. (c) Yoon, T. P.; Ischay, M. A.; Du,
J. Nat. Chem. 2010, 2, 527. (d) Xuan, J.; Xiao, W.-J. Angew. Chem. 2012,
124, 6934. Angew. Chem., Int. Ed. 2012, 51, 6828. (e) Shi, L.; Xia, W.
Chem. Soc. Rev. 2012, 41, 7687.
r
10.1021/ol402954t
XXXX American Chemical Society

Table 1. Screening of Reaction Conditionsa
Table 2. Scope of Visible-Light-Induced γ-Lactones Synthesis
with R-Bromo Esters 2a
entry
conditions
(CH3)2CO:H2O = 9:1
yield (%)b
1
28
2
DMF:H2O = 9:1
74
3
CH3CN:H2O = 9:1
80
4
CH3CN:H2O = 4:1
82
5
CH3CN:H2O = 4:1; LiBr (1.2 equiv)
CH3CN:H2O = 4:1; LiCl (1.2 equiv)
CH3CN:H2O = 4:1; LiBF4 (1.2 equiv)
CH3CN:H2O = 4:1; LiBF4 (0.5 equiv)
CH3CN, LiBF4 (1.2 equiv) (no H2O)
CH3CN:H2O = 4:1, LiBF4 (1.2 equiv)
CH3CN:H2O = 4:1, LiBF4 (1.2 equiv)
79
6
84
7
93
8
87
9e
10c,f
11d,f
N.D.
N.R.
N.R.
a Reaction conditions: a mixture of 1a (0.20 mmol), 2a (0.24 mmol)
and photocatalyst fac-Ir(ppy)3 (0.5 mol %) in solvent was irradiated
with a 3 W blue LEDs at room temperature for 24 h. b Isolated yield.
c Irradiated without fac-Ir(ppy)3. d The reaction was conducted in the
dark. e N.D. = not detected. f N.R. = no reaction.
halides are efficient precursors for the generation of carbon-
centered radicals under photoredox catalytic conditions. In
some of these reactions both the quenching and the regen-
eration of the photocatalyst are promoted by the substrates
or intermediates of the catalyzed reaction; therefore, external
reductants or oxidants are no longer needed.7
With this in mind, we initiated the study by using 1,1-
diphenylethylene 1a and R-bromo diethyl malonate 2a
with catalytic amount of fac-Ir(ppy)3. It was encouraging
to see that the aimed product 3a was obtained in 28% yield
after 24 h of irradiation (blue LEDs, λ = 450 nm) at room
temperature when the reaction was performed in a mixture
of acetone and water (9:1 v/v) (Table 1, entry 1). The replace-
ment of acetone by N,N-dimethylformamide (DMF) or
acetonitrile resulted in a significant improvement of the
yield (Table 1, entries 2 and 3), and acetonitrile was chosen
as the ideal organic solvent for the reaction. Next, we
investigated the amount of water for the transformation;
the result proved that acetonitrile/water (4:1) gained a
better result (Table 1, entry 4). Considering the activation
a Reaction conditions: a mixture of 1 (0.20 mmol), 2 (0.24 mmol),
LiBF4 (0.24 mmol) and photocatalyst fac-Ir(ppy)3 (0.5 mol %) in
CH3CN/H2O (4:1 v/v) was irradiated with a 3 W blue LEDs at room
temperature for 24 h. b Isolated yield.
of carbonyl moiety may be beneficial for the production of
γ-lactones, a brief screen of lithium salts additives was
performed (Table 1, entries 5À7). The best result was
achieved when 1.2 equiv of LiBF4 was introduced to the
system. In this case we obtained the desired γ-lactone 3a in
93% isolated yield. In addition, the attempt to reduce the
amout of LiBF4 slightly decreased the yield (Table 1, entry 8).
It was worth noting that no product was detected when the
reaction was carried out in dry acetonitrile (Table 1, entry 9).
Moreover, when the reaction was carried out in the absence
of fac-Ir(ppy)3 (Table 1, entry 10) or in the dark (Table 1,
entry 11), no conversion could be observed, which indicated
that the reaction was indeed a visible-light-driven photoredox
process.
(6) Selected recent examples: (a) Nagib, D. A.; MacMillan, D. W. C.
Nature 2011, 480, 224. (b) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon,
T. P. J. Am. Chem. Soc. 2008, 130, 12886. (c) Cai, S.; Zhao, X.; Wang, X.;
Liu, Q.; Li, Z.; Wang, D. Z. Angew. Chem., Int. Ed. 2012, 51, 8050. (d)
€
Hari, D. P.; Schroll, P.; Konig, B. J. Am. Chem. Soc. 2012, 134, 2958. (e)
Sun, H.; Yang, C.; Gao, F.; Li, Z.; Xia, W. Org. Lett. 2013, 15, 624. (f)
Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M. J. Am.
Chem. Soc. 2013, 135, 1823. (g) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc.
2012, 134, 9034.
(7) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(b) Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2010, 132, 13600. (c) Narayanam,
J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009,
131, 8756. (d) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.;
Stephenson, C. R. J. Nat. Chem. 2012, 4, 854. (e) Andrews, R. S.; Becker,
On submission to the optimized conditions, we next
investigated the scope of R-bromo esters 2 for the reaction.
R-Bromo dimethyl malonate 2b can also react with 1a to
produce 3b in excellent yield (Table 2, entry 2). Moreover,
this kind of reaction was successfully applied to ethyl
ꢀ
J. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2010, 49, 7274. (f) Liu, Q.; Yi,
H.; Liu, J.; Yang, Y.; Zhang, X.; Zeng, Z.; Lei, A. Chem.;Eur. J. 2013,
19, 5120. (g) Su, Y.; Zhang, L.; Jiao, N. Org. Lett. 2011, 13, 2168.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Reaction of 1a with Various Alkyl Bromoacetatesa
Table 4. Scope of Visible-Light-Induced γ-Lactones Synthesis
with Styrenes 1a
entry
bromoacetate
yield (%)b
1
2
3
4
5
6
2i (R = Et)
99
2j (R = Me)
99
2k (R = tBu)
2l (R = TMS)
2m (R = Ph)
2n (R = p-NO2Ph)
29 (67)c
70
75
23
a The reaction conditions as described in Table 2. b Isolated yields.
c Yield in bracket performed with 2.0 equiv of 2,6-lutidine.
bromoacetate with substituted groups such as methyl and
phenyl group. The corresponding γ-lactone products 3cÀ3e
were obtained in excellent yields (98À94%). Reaction of 2f
and 2g proceed effectively, and lactones with fluorine group
such as 3f, 3g might be helpful in the pharmaceutical
and agrochemical fields (Table 2, entries 6 and 7). Ethyl
2-bromo-2-methylpropanoate 2h was also smoothly
transformed to corresponding lactone with excellent
yield (Table 2, entry 8).
We next studied the reactivities of bromoacetates with
various alkoxyl groups8 in the visible-light-promoted
γ-lactone synthesis. The results showed that methyl and
ethyl 2-bromoacetate were completely converted into
γ-lactones, respectively (Table 3, entries 1 and 2). Trimethyl-
silyl and phenyl 2-bromoacetate could also produce the
same product 3i, even though the reaction proceeded less
efficiently than the former cases (Table 3, entries 4 and 5).
Finally, we found the tert-butyl and p-nitrophenyl just could
afford small amount of target compound (Table 3, entries 3
and 6), but in the case of tert-butyl 2-bromoacetate the yield
could be improved to 67% by addition of a base 2,6-lutidine.
Having found a broad range of R-carbonyl alkyl bro-
mides, the substrate scope with regard to substituted styrene
was examined. As shown in Table 4, both styrene and
p-methoxy-substituted styrene could obtain the γ-lactones
with good yields (Table 4, entries 1 and 2). Not surprisingly,
the R and β methyl substituted styrene yielded the aimed
products with good to excellent yields (Table 4, entries 3 and
4). Biaryl lactone 3n was obtained in similar way (Table 4,
entry 5). It is noteworthy that when conjugated benzyl diene
(E)-buta-1,3-dien-1-ylbenzene 1g was used, the desired pro-
duct 3o was isolated in 78% yield with exclusive regioselec-
tivity toward the terminal olefin (Table 4, entry 6). At the
same time, benzocycloalkene (Table 4, entries 7 and 8) gave
a The reaction conditions as described in Table 2. b Isolated yield. c dr
and E/Z were determined by 1H NMR spectrum.
the tricyclic γ-lactones with moderate to good yields, which
had been employed as starting materials for the synthesis of
strigolactone analogues.1a
Since both bromoacetates and styrenes are transparent
to 450-nm photons (see the Supporting Information), only
the photocatalyst fac-Ir(ppy)3 can be excited under the
(10) For representative alkene difunctionalization examples with
photoredox catalysis, see: (a) Yasu, Y.; Koike, T.; Akita, M. Org. Lett.
2013, 15, 2136. (b) Fumagalli, G.; Boyd, S.; Greaney, M. F. Org. Lett.
2013, 15, 4398. (c) Sahoo, B.; Hopkinson, M. N.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 5505. (d) Yasu, Y.; Koike, T.; Akita, M. Angew.
Chem., Int. Ed. 2012, 51, 9567. (e) Wilger, D. J.; Gesmundo, N. J.;
Nicewicz, D. A. Chem. Sci. 2013, 4, 3160. (f) Yoo, W.-J.; Kobayashi, S.
Green Chem. 2013, 15, 1844.
(8) Yoo, D.-W.; Han, J.-H.; Nam, S. H.; Kim, H. J.; Kim, C.; Lee,
J. K. Inorg. Chem. Commun. 2006, 9, 654.
ꢀ
ꢁ ꢀ
(9) (a) Maslak, V.; Matovic, R.; Saicic, R. N. Tetrahedron 2004, 60,
8957. (b) Bercot, E. A.; Kindrachuk, D. E.; Rovis, T. Org. Lett. 2005, 7,
107. (c) Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 613.
(d) Ko, Y. O.; Chun, Y. S.; Kim, Y.; Kim, S. J.; Shin, H.; Lee, S.-g.
Tetrahedron Lett. 2010, 51, 6893.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Proposed Mechanism Cycle
Figure 1. Photoluminescence quenching experiments. (A) Lu-
minescence quenching of fac-Ir(ppy)3 (2.00 Â 10À4 M) with
progressive addition of bromoacetate 2a. (B) Luminescence
quenching of fac-Ir(ppy)3 (2.00 Â 10À4 M) with progressive
addition of styrene 1a.
irradiation of blue LEDs (blue LEDs, λ = 450 nm). As
shown in Figure 1, excitation of the characteristic absorp-
tion of fac-Ir(ppy)3 resulted in a maximal photolumines-
cence at 513 nm in acetonitrile/water (4:1, v/v) solution,
which was quenched by bromoacetate 2a with a rate
constant of6.00Â 104 LmolÀ1. Although theluminescence
of fac-Ir(ppy)3 can also be quenched by styrene 1a, the rate
was smaller (2.90 Â 104 L molÀ1). As the spectral overlap
of absorption of bromoacetate 2a and photoluminescence
of fac-Ir(ppy)3 is rather small, the energy transfer from the
excited fac-Ir(ppy)3 to 2a would be negligible. The photo-
luminescence quenching is therefore attributed to the elec-
tron transfer from the excited fac-Ir(ppy)3 to bromoacetate
2a. The ET procedure generates electron-deficient radical 4
along with fac-IrIV(ppy)3. Then intermolecular π-addition
of the radical 4 to styrene 1a produces a benzylic radical
5. Further ET from radical 5 to fac-IrIV(ppy)3 affords
carbocation 6 and regenerates the photocatalyst. The
nucleophilic attack of the carbocation 6 by water
results in the hydroxyalkylation of styrene, which was
proved by H218O labeling experiment (see the Support-
ing Information). Finally, a spontaneous intramolecu-
lar transesterfication promoted by LiBF4 provided the
desired γ-lactone 3a (Scheme 1).9
In summary, we have developed a catalytic, external-
oxidant-free method for the construction of aryl-substi-
tuted γ-lactone via photoredox catalysis for the first time.
The highlight of this operationally simple reaction is the
avoidance of stoichiometric oxidants, low catalyst loading,
and the generation of γ-lactone in high yields under mild
conditions. Moreover, the photocatalytic transformation
is also a beneficial supplement for alkene difunctionaliza-
tion with photoredox catalysis.10 Further explorations on
the method to build δ-lactone mediated by visible light is
under investigation in our laboratory.
Acknowledgment. We are grateful for financial support
of NSFC (No. 21172102, 21090343), the Ministry of Science
and Technology of China (2013CB834804), and the Funda-
mental Research Funds for the Central Universities.
Supporting Information Available. Experimental pro-
cedure, characterization data for the products and UV/vis
absorption spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX