Intermolecular Tandem Addition/Esterification Reaction of Alkenes with Malonates Leading to γ-Lactones Mediated by Molecular Iodine under Visible Light Irradiation

Article abstract of DOI:10.1002/adsc.201700809

The iodine-mediated intermolecular C?C bond-forming/esterification reaction of various alkenes including α-olefins with malonates under irradiation using a compact fluorescent lamp has been developed to synthesize γ-lactones in moderate to excellent yield

Full text of DOI:10.1002/adsc.201700809

Title: Intermolecular tandem addition/esterification reaction of alkenes
with malonates leading to γ-lactones mediated by molecular
iodine under visible light irradiation
Authors: Saki Maejima, Eiji Yamaguchi, and Akichika Itoh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700809
Link to VoR: http://dx.doi.org/10.1002/adsc.201700809

10.1002/adsc.201700809
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Intermolecular Tandem Addition/Esterification Reaction of
Alkenes with Malonates Leading to -Lactones Mediated by
Molecular Iodine under Visible Light Irradiation
Saki Maejima, a Eiji Yamaguchi,a,* and Akichika Itoha,*
a
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax: (+81)-58-230-8108; phone: (+81)-58-230-8108; e-mail: yamaguchi@gifu-pu.ac.jp, itoha@gifu-pu.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
metal reagent, higher reaction temperature, and the
unpredictable diastereoselectivity. The pioneering
research by Wu and Liu on the lactonization reaction
of styrenes with -halo esters utilized Ir(III)
photoredox catalysis (Scheme 1b).[7] However, their
method required halogenation of -carbonyls to
generate a C-centered radical and an expensive and
potentially toxic transition metal-based photoredox
catalyst.[8] Therefore, the methods that are
straightforward, convenient, and mild leading to the
formation of -lactones are highly desirable.
Abstract. The iodine-mediated intermolecular C–C
bond-forming/esterification reaction of various alkenes
including -olefins with malonates under irradiation
using a compact fluorescent lamp has been developed to
synthesize -lactones in moderate to excellent yields. The
method developed in this research shows broad substrate
scope and moderate diastereoselectivity and constructs
valuable polyfunctionalized -lactones. Furthermore, the
developed methodology was comprehensively studied by
performing several control experiments, radical trapping,
and radical clock experiments. These experiments showed
that sequential iodination by an iodine radical is triggered
for the following C–C bond-forming reaction.γ
Keywords: iodine; lactones; olefins; photochemistry;
radical reactions
Polyfunctionalized -lactones are commonly found
in many naturally occurring compounds and show
important biological activities.[1] The structure of -
lactone is also present in a diverse range of
agrochemicals and pharmaceuticals.[2] Therefore,
various methods to synthesize lactones have been
developed via cyclization reaction of linear starting
materials.[3] Moreover, the enantioselective ketone
hydroacylation reaction from keto alcohol leading to
the formation of -lactones has been reported.[4]
Despite the significant progress made in the synthesis
of lactones via cyclization reaction, multi-step
syntheses to obtain linear starting materials are often
required.
Therefore,
the
diversity-oriented
and
Scheme 1. Direct synthesis of lactones via olefin
straightforward methodologies leading to -lactones
are highly desirable. For direct construction of -
lactones from readily available substrates, oxidative
transformation provides a privileged methodology.[5]
Jiang and coworkers reported Cu-catalyzed or Mn-
mediated intermolecular oxidative cycloaddition of
alkene with anhydrides (Scheme 1a).[6] Although this
transformation shows a broad substrate scope for direct
synthesis of lactones, the process requires a heavy
difunctionalization reaction.
We have focused on visible light-mediated
transformations and have reported several reactions
based on photooxidative/photoexcitation strategy.[9] In
our previous study on the photooxidative
dehydrogenative C–C bond-forming reaction of
heteroarenes with malonate, we found that the
exposure of olefin-bearing pendant malonate to the
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700809
Advanced Synthesis & Catalysis
optimized condition afforded bicyclic butyrolactone control experiments performed without iodine or
(Scheme 1c).[10] This result indicates that the Ca(OH)2 resulted in no reaction (entries 7 and 8,
intramolecular C–C bond formation occurred between respectively), thus indicating that the combination of
malonate with olefin in 5-exo-trig manner. iodine and base is crucial for this lactonization reaction.
Subsequently, the following C–O bond formation
Employing the optimized reaction conditions, we
produced corresponding lactones. We envisioned that evaluated the generality of the process. Table 2
a direct lactonization reaction could be realized if the summarized results of the reaction using various
intermolecular C–C bond formation between malonate olefins 1. Whether alkyl or halogen substituents on
with olefins occurs under similar reaction condition styrenes, the reaction proceeded to give the
(Scheme 1d).
corresponding lactones 3 in moderate to good yield
Herein, we report that the combination of visible with moderate dr values, respectively (Table 2, entries
light and molecular iodine is an efficient mediator of 1-8). Substrate 1i bearing ester group afforded the
the intermolecular C–C/C–O bond formation between desired product in 64% yield with similar
olefins with malonates, leading to the formation of diastereoselectivity (entry 9). Only in the case of 1j,
lactones. This method also shows moderate cis polymerization of 1j predominantly occurred, perhaps
diastereoselectivity.
due to the strongly electron-donating MeO group on
We initiated our research by focusing on the direct the styrene (entry 10). To our delight, the reaction also
lactonization reaction of styrene (1a) with methyl tolerated substrates 1 with different aryl groups,
dimethylmalonate (2a) irradiated with visible light leading to desired lactones 3k-m in moderate yields
using a compact fluorescent lamp (CFL) (Table 1).
with moderate dr (entries 11-13). Finally, the reaction
was also applicable to –olefin such as 1-dodecene
Table 1. Optimization study of lactone synthesis meditated (1n) to give lactone 3n in good yield (entry 14).
by iodine/visible light.
Table 2. Substrates scope using various olefins 1 with 2a[a]
entry
1
2
3
4
solvent
MeOH
EtOH
yield (%)[a]
dr (cis:trans)[b]
entry
R
yield
(%)[b]
83
65
46
64
76
40
62
57
64
trace
57
47
dr[c]
1
3
17
33:67
48:52
58:42
64:34
79:21
70:30
-
67[c]
85[c]
1
2
3
4
5
6
7
8
Ph
79:21
76:24
72:28
69:31
74:26
71:29
75:25
70:30
68:32
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
IPA
4-tBuC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
tAmylOH
tBuOH
tBuOH
tBuOH
tBuOH
74
83
23
5
6[d]
7[e]
8[f]
no reaction
no reaction
-
4-ClC6H4
4-BrC6H4
4-MeO2CC6H4
4-MeOC6H4
4-PhC6H4
2-Naph
[a] Isolated yield.
[b] Diasteromeric ratios were determined by 1H NMR
analysis of crude reaction mixture.
[c] Transesterification product was also included.
[d] 0.5 equiv of I2 was used.
9
10
11
12
13
14
82:18
73:27
38:62
67:33
[e] Without Ca(OH)2.
2-pyridyl
C10H21
51
82
[f] Without iodine.
[a] Reaction condition: 1 (2 equiv), 2a (0.3 mmol), I2 (0.3
mmol), and Ca(OH)2 (0.3 mmol) in BuOH (3 mL) and
t
The mixture of 1a, 2a, and molecular iodine with
Ca(OH)2 in solvent was stirred for 20 h (refer to S1 for
full details of optimization). Extensive experiments
revealed that the yield of corresponding lactone (3a)
was significantly affected by the use of the solvent. We
found that the use of a protic solvent, MeOH, was
effective for the reaction (Table 1, entry 1). To improve
on this result, a series of protic solvents, including
EtOH, IPA, tAmyl-OH, and tBu-OH, were evaluated in
stirred at ambient temperature irradiated with a compact
fluorescent lamp (CFL) for 20 h.
[b] Isolated yield.
Diasteromeric ratios were determined by 1H NMR
[c]
analysis of crude reaction mixture.
Using styrene 1a as the substrate, we subsequently
investigated the scope of malonate 2 to elucidate the
effect of the substituents on malonates (Table 3).
This intramolecular lactonization reaction smoothly
proceeded with the sterically hindered substrate 3o but
in lower diastereoselectivity (Table 3, entry 1 vs. entry
2). However, substrates bearing a benzyl group 3p or
phenethyl group 3q afforded the corresponding
t
this reaction, among which Bu-OH was the most
effective in generating the desired product with 83%
yield and 79:21 diastereoselectivity (entries 2–5). In
addition, loading 0.5 equiv of iodine displayed a
significant decrease in the reaction efficiency,
furnishing product 3a in 23% yield (entry 6). Finally,
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700809
Advanced Synthesis & Catalysis
product in lower yield with slightly higher promotes the generation of iodine radicals and that the
diastereoselectivity compared with 3a (entries 3 and 4). generated iodine adduct is intermediate for the reaction.
Unfortunately, this system was unable to facilitate the To gain more insight regarding the mechanism, 1-
lactonization
reaction
using
triethyl cyclopropyl-1-phenylethylene was subjected to our
methanetricarboxylate 3r at this stage (entry 5). The standard condition; the ring-opening products 5a and
t
ester-bearing sterically hindered Bu group produced 5b were obtained (Eq. 4). This result clearly confirms
lactones
with
low
yield
and
excellent the generation of an iodine radical intermediate.
On the basis of the results of these investigations, a
diastereoselectivity (entry 6). Gratifyingly, further
substrate scope studies revealed that while the reaction tentative mechanism is proposed in Scheme 3.
of methyl 2-methylacetoacetate readily proceeded and Molecular iodine and the iodine radical are in
gave the O-cyclization product 3t in 66% yield (entry equilibrium under visible right irradiation, and the
7), the corresponding 2-methylacetoacetic acid was not generated radical is sequentially added to styrene to
effective for the desired C–C bond forming reaction yield II. vic-Diiodoalkanes II, generated in situ, are
(entry 8).
generally unstable and tend to revert back to iodine and
the olefin.[13] In the presence of Ca(OH)2, compound II
Table 3. Scope of substrates using styrenes 1a with various reacts with malonate 2a, affording the corresponding
malonates 2.
product III. Finally, cyclization produces the desired
lactone 3.
entry R1
R2
R3
yield dr[b]
3
(%)[a]
1
2
3
4
5
6
7
8
Me
Ph
Bn
CO2Me Me
CO2Me Me
CO2Me Me
83
60
30
44
trace
35
66
8
79:21
3a
3o
3p
3q
3r
3s
3t
62:38
86:14
85:15
-
95:5
50:50
50:50
Ph(CH2)2 CO2Me Me
CO2Et
Me
CO2Et
CO2 Bu Me
COMe Me
Me
t
Me
Me
COMe
H
3t
[a] Isolated yield.
[b] Diasteromeric ratios were determined by 1H NMR
analysis of crude reaction mixture.
Furthermore, we focused on elucidating the reaction
mechanism (Scheme 2, refer to S2-4 for full details of
these study). First, the role of iodine was investigated
(Eq. 1). The reaction using cationic iodine source, such
−
as NIS or (lutidine)2I+BF4 , instead of molecular iodine
under optimized reaction condition significantly
decreased the yield of 3a.[11] However, two equivalents
of NIS produced similar yield of the product. Trace
amount of the product was observed when the reaction
condition was changed to the heating and dark
conditions. These observations revealed that olefin was
not activated by cationic iodine to form iodonium
intermediate and that visible light from the CFL could
increase the reaction efficiency. Then, we investigated
whether iodinated malonate 2a-I, which we previously
reported as the C-centered radical source, is generated
(Eq. 2).[9i, 10] The reaction of 2a-I with styrene under
optimized reaction condition resulted in no reaction.
To determine the key intermediate, the reaction under
an oxygen atmosphere was conducted (Eq. 3).
Phenacyl iodide 4a, which was synthesized by the
addition of iodine radical to styrene and by the addition
of triplet oxygen to benzyl radical generated followed
by dehydration, was obtained in 34% yield.[12]
Therefore, we hypothesized that the visible light
Scheme 2. Mechanistic investigation.
Scheme 3. Proposed mechanism for lactonization.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700809
Advanced Synthesis & Catalysis
In brief, we developed a photoinitiated method for [5] a) J. R. Peterson, H. D. Do, I. B. Surjasasmita, Synth.
the constructing polysubstituted -lactones via an
iodine-mediated C–C/C–O bond-forming sequence.
The highlight of this operationally straightforward
reaction is the avoidance of transition or heavy metal
reagent, use of abundant molecular iodine, and
generation of -lactone in high yields under mild
conditions. Moreover, the diastereoselectivity of the
desired lactones can be controlled by using an alkaline
metal or alkaline earth metal. Further studies on the
scope, more detailed mechanism, and synthetic
applications of this novel iodine/visible light chemistry
are under investigation in our laboratory.
Commun. 1988, 18, 1985-1993. b) A. Citterio, R.
Sebastiano, M. Nicolini, R. Santi, Synlett 1990, 42-43. c)
J. R. Peterson, H. D. Do, R. D. Rogers, Synthesis 1991,
275-277. d) E. Baciocchi, R. Ruzziconi, J. Org. Chem.
1991, 56, 4772-4778. e) M. Allegretti, A. D’Annibale, C.
Trogolo, Tetrahedron 1993, 49, 10705-10714. f) V. Nair,
J. Mathew, J. Org. Soc. Perkin. Trans. 1 1995, 1881-
1882. g) M. Horikawa, H. Shirahama, Synlett 1996, 95-
96. h) V. Nair, J. Mathew, L. G. Nair, Synth. Commun.
1997, 27, 3053-3064. i) L. Huang, H. Jiang, C. Qi, X. Liu,
J. Am. Chem. Soc. 2010, 132, 17652-17654. (j) D. Hulya,
A. Mustafa, Z. Mustafa, K. Mustafa, Lett. Org. Chem.
2011, 8, 488. (k) R. Matsumoto, H. Nishino, Synth.
Commun. 2015, 45, 1807. l) X.-J. Wei, D.-T. Yang, L.
Wang, T. Song, L.-Z. Wu, Q. Liu, Org. Lett. 2013, 15,
6054-6057. (m) G. Fumagalli, S. Boyd, M. F. Greaney,
Tetrahedron Lett. 2015, 56, 2571-2573.
Experimental Section
General procedure: A Pyrex® test tube (16.5 cm × 1.5 cm)
containing a mixture of dimethyl 2-methylmalonate 2 (0.3
mmol), I2 (76.2 mg, 1.0 epuiv., 0.3 mmol), calcium
hydroxide (22.2 mg, 1.0 equiv, 0.3 mmol) and styrene 1 (2.0
equiv, 0.6 mmol) in tert-butyl alcohol (3.0 mL) was
degassed via FPT cycling for three times and backfilled with
Ar. The resulting solution was stirred at ambient temperature
for 20 h. The reaction was quenched with sat. Na2S2O3 aq.
and extracted with Et2O (10 mL x 3). The combined organic
layers were washed with brine, dried over Mg2SO4, filtered
and concentrated in vacuo. The resulting mixture was
purified by flash column chromatography on silica gel (n-
hexane : EtOAc) to give 3.
[6] a) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc.
2010, 132, 17652. (b) L. Wu, Z. Zhang, J. Liao, J. Li, W.
Wua, H. Jiang, Chem. Commun. 2016, 52, 2628.
[7] X.-J. Wei, D.-T. Yang, L. Wang, T. Song, L.-Z. Wu, Q.
Liu, Org. Lett. 2013, 15, 6054-6057.
[8] H. Kruszyna, R. Kruszyna, J. Hurst, R. P. J. Smith,
Toxicol, Environ. Health. 1980, 6, 757-773.
[9] a) N. Kanai, H. Nakayama, N. Tada, A. Itoh, Org. Lett.
2010, 12, 1948-1951. b) N. Tada, M. Shomura, L. Cui,
T. Nobuta, T. Miura, A. Itoh, Synlett 2011, 19, 2896-
2900. c) N. Tada, T. Ishigami, L. Cui, K. Ban, T. Miura,
A. Itoh, Tetrahedron Lett. 2013, 54, 256-258. d) Y.
Nagasawa, Y. Matsusaki, T. Hotta, T. Nobuta, N. Tada,
T. Miura, A. Itoh, Tetrahedron Lett. 2014, 55, 6543-6546.
e) Y. Tachikawa, Y. Nagasawa, S. Furuhashi, L. Cui, E.
Yamaguchi, N. Tada, T. Miura, A. Itoh, RSC. Adv. 2015,
5, 9591-9593. f) Y. Sugiura, Y. Tachikawa, Y. Nagasawa,
N. Tada, A. Itoh, RSC Adv. 2015, 5, 70883-70886. g) K.
Usami, Y. Nagasawa, E. Yamaguchi, N. Tada, A. Itoh,
Org. Lett. 2016, 18, 8-11. h) T. Yamaguchi, K. Sakairi,
E. Yamaguchi, N. Tada, A. Itoh, RSC. Adv. 2016, 6,
56892-56895. i) Y. Sudo, E. Yamaguchi, A. Itoh, Org.
Lett. 2017, 19, 1610-1613.
Acknowledgements
This work was financially supported by Takeda science foundation.
References
[1] a) H. M. R. Hoffmann, J. Rabe, Angew. Chem. 1985, 97,
96-112; Angew. Chem. Int. Ed. 1985, 24, 94-110. b) A.
K. Picman, Biochem. Syst. Ecol. 1986, 14, 255-281.
[2] a) E. M. Mangnus, B. J. Zwanenburg, Agric. Food Chem.
1992, 40, 1066-1070. b) G. H. L. Nefkens, J. W. J. F.
Thuring, M. F. M. Beenakkers, B. J. Zwanenburg, Agric.
Food Chem. 1997, 45, 2273-2283. c) B. Fang, X. Xie, C.
Zhao, P. Jing, H. Li, Z. Wang, J. Gu, X. She, J. Org.
Chem. 2013, 78, 6338-6343.
[10] E. Yamaguchi, Y. Sudo, N. Tada, A. Itoh, Adv. Synth.
Catal. 2016, 358, 3191-3195.
[3] a) S. K. Taylor, N. H. Chmiel, L. J. Simons, J. R. Vyvyan,
J. Org. Chem. 1996, 61, 9084-9085. b) T. Dohi, N.
Takenaga, A. Goto, A. Maruyama, Y. Kita, Org. Lett.
2007, 9, 3129-3132. c) L. J. Goobn, D. M. Ohlmann, M.
Dierker, Green Chem. 2010, 12, 197-200. d) N. Tada, T.
-
[11] When (lutidine)2I+BF4 was used for the reaction, only
the corresponding iodohydrin was obtained (full details
are shown in S2). The result showed that the reaction did
not proceed via an iodonium intermediate.
Ishigami, L. Cui, K. Ban, T. Miura, A. Itoh, Tetrahedron [12] T. Nobuta, S. Hirashima, N. Tada, T. Miura, A. Itoh,
Lett. 2013, 54, 256-258. e) V. Valerio, D. Petkova, C.
Madelaine, N. Maulide, Chem. Eur. J. 2013, 19, 2606-
2610. f) H. K. Grover, M. R. Emmett, M. A. Kerr, Org.
Lett. 2013, 15, 4838-4841. g) J. Li, S. Yang, H. Jiang, W.
Wu, J. Zhao, J. Org. Chem. 2013, 78, 12477-12486. h)
A. Díaz-Rodríguez, W. Borzcka, I. Lavandera, V. Gotor,
ACS Catal. 2014, 4, 386-393. i) N. Sakai, S. Horikawa,
Y. Ogiwara, RSC Advances 2016, 6, 81763-81766.
Synlett 2010, 2335-2339.
[13] a) M. Zanger, J. L. Rabinowitz, J. Org. Chem. 1975, 40,
248-250. b) J. Barluenga, M. A. Rodriguez, P. J. Campos,
G. Asensio, J. Chem. Soc. Chem. Commun. 1987, 1491-
1492.
[4] S. K. Murphy, V. M. Diong, J. Am. Chem. Soc. 2013,
135, 5553-5556.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700809
Advanced Synthesis & Catalysis
COMMUNICATION
Intermolecular tandem addition/esterification
reaction of styrenes with malonates leading to -
lactones mediated by molecular iodine
Adv. Synth. Catal. Year, Volume, Page – Page
Saki Maejima, Eiji Yamaguchi* and Akichika
Itoh*
5
This article is protected by copyright. All rights reserved.