Copper-catalyzed aerobic C-C bond cleavage of lactols with N-hydroxy phthalimide for synthesis of lactones

Article abstract of DOI:10.1002/asia.201403196

The transformation of cyclic hemiacetals (lactols) into lactones has been achieved by Cu-catalyzed aerobic C-C bond cleavage in the presence of N-hydroxy phthalimide (NHPI). The present process is composed of a multistep sequence including a) formation of exo-cyclic enol ethers by dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trapping of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent β-radical fragmentation to generate lactones.

Full text of DOI:10.1002/asia.201403196

DOI: 10.1002/asia.201403196
Communication
Copper Catalysis
Copper-Catalyzed Aerobic CÀC Bond Cleavage of Lactols with N-
Hydroxy Phthalimide for Synthesis of Lactones
Ya Lin Tnay and Shunsuke Chiba*[a]
Abstract: The transformation of cyclic hemiacetals (lactols)
into lactones has been achieved by Cu-catalyzed aerobic
CÀC bond cleavage in the presence of N-hydroxy phthali-
mide (NHPI). The present process is composed of a multi-
step sequence including a) formation of exo-cyclic enol
ethers by dehydration; b) addition of phthalimide N-oxyl
radical to the enol ethers followed by trapping of the re-
sulting C-radicals with molecular oxygen to form peroxy
radicals; c) reductive generation of oxy radicals and subse-
quent b-radical fragmentation to generate lactones.
Molecular transformations involving fission of inert CÀC bonds
provide new methods for the synthetic design of the target
molecules. Therefore, a variety of methods realizing efficient
CÀC bond cleavage and functionalization have been exploited,
in which catalytic processes using transition metals [M] are
a recent main trend in the method development.[1] These reac-
tions are commonly driven by release of ring strain, diminution
of steric congestion, or generation of a relatively stable CÀ[M]
Scheme 1. Preliminary finding for the formation of lactone 2a by oxidative
CÀC bond cleavage from 1a.
bond as the driving force of the inert CÀC bond cleavage.
Our group has been working on the development of aliphat-
ic CÀH oxidation using hetero-atom radicals generated under
Cu-catalyzed aerobic reaction conditions.[2,3] In this context, we
recently disclosed a Cu-catalyzed aerobic oxygenation of ali-
phatic CÀH bonds through 1,5-H radical transfer of the
oxygen-centered radical generated from peroxy derivatives
(Scheme 1).[4,5] For example, the reaction of alkane 1,1-diphe-
nylpentane under Cu-catalyzed aerobic reaction conditions in
the presence of N-hydroxyphthalimide (NHPI) delivered lactol
1a in 41% yield after 24 h. This alkane oxygenation takes
place through a step-wise radical sequence involving 1) phtha-
limide N-oxyl radical-mediated intermolecular benzylic CÀH
oxygenation with molecular oxygen (at the carbon marked in
green); 2) generation of oxygen-centered radical and its 1,5-H
radical abstraction (at the carbon marked in red) followed by
aerobic oxygenation (Scheme 1). During the course of this
study, it was surprisingly found that prolonging the reaction
time to 36 h gave rise to another product, namely, a,b-unsatu-
rated lactone 2a in 19% yield along 1a in 26% yield. It was as-
sumed that a,b-unsaturated lactone 2a was formed from
lactol 1a through an unstrained CÀMe bond cleavage as well
as a,b-unsaturation under the present reaction conditions. We
therefore became interested in this unprecedented molecular
transformation and aimed at developing a new chemical trans-
formation of lactols to the corresponding lactones by the CÀC
bond fission. Optimization of the reaction conditions and
scope of the reaction as well as the detailed reaction mecha-
nism are described herein.
We began our investigation using lactol 1a[6] to optimize
the reaction conditions for the synthesis of lactone 2a
(Table 1). It was found that the presence of Cu-catalysts, NHPI,
and molecular O2 was essential for the reaction to occur.
Indeed, treatment of lactol 1a with CuCl (20 mol%) and NHPI
A (1 equiv) in MeCN under an O2 atmosphere at 508C provided
a,b-unsaturated lactone 2a in 49% yield (Table 1, entry 1). Rais-
ing the reaction temperature to 808C improved the yield of 2a
to 71% yield (Table 1, entry 2). Screening the Cu salts and sol-
vents revealed that the reaction performs best with CuCl in
[a] Y. L. Tnay, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403196.
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Table 1. Optimization of the reaction conditions.[a]
Entry [Cu]
(mol%)
Additive [equiv] Solvent
T
t
Yield [%]
[8C] [h]
1
2
3
4
5
6
7
8[b]
9
10
11
12
CuCl (20)
CuCl (20)
CuBr (20)
CuI (20)
A (1)
A (1)
A (1)
A (1)
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
50
80
80
80
80
80
80
80
80
80
80
80
7
6
49
71
Scheme 2. Synthetic scope of a,b-unsaturated-g-butyrolactones 2. [a] Lactols
1 except for 1k exist as an equilibrium mixture with their acyclic forms, g-
hydroxy ketones (see the Supporting Information for more details).
19 50
19 11
19 11
20 55
24 64
12 72
24 72
48 45
48 13
Cu(OAc)2 (20) A (1)
CuCl (20)
CuCl (20)
CuCl (10)
CuCl (5)
CuCl (20)
CuCl (20)
CuCl (20)
A (1)
A (1)
A (1)
A (1)
B (1)
C (1)
D (1)
24
0
[a] The reactions were carried out using 0.5 mmol of 1a in 5 mL of sol-
vent (0.1m) under an O2 atmosphere (1 atm). Lactol 1a exists as an equi-
librium mixture with its acyclic form, g-hydroxy ketone (see the Support-
ing Information for more details). [b] Phthalimide (3) was isolated in 20%
yield.
Scheme 3. The reaction of d-hydroxy ketone 1l.
product, which is likely formed through dehydration followed
by subsequent allylic oxygenation.
MeCN (Table 1, entries 3–7). The catalyst loading of CuCl could
be lowered to 5 mol% while maintaining the yield of 2a,
albeit with a longer reaction time (Table 1, entries 8 and 9). It is
noteworthy that in the reaction using 10 mol% CuCl and one
equivalent of NHPI, phthalimide (3) was isolated in 20% yield
(Table 1, entry 8).[7] The effect of additives was next examined.
Use of N-hydroxysuccinimide B or N-hydroxybenzotriazole C,
instead of NHPI A, was not optimal for the present transforma-
tion (Table 1, entries 10 and 11). Lactone 2a was not formed in
the reaction with TEMPO D (Table 1, entry 12).
The effect of the hemiacetal substituent R4 was then exam-
ined (Table 2). Changing the methyl group (1a) to ethyl (1aa)
and isopropyl (1ab) lowered the mass-balance of the products
(Table 2, entries 1 and 2), but intriguingly delivered not only
a,b-unsaturated lactone 2a but also a,b-saturated lactone (g-
butyrolactone) 5a in the ratio of about 2:1. The reaction with
Table 2. Effect of hemiacetal substituent for the formation of lactones 2a
and 5a.[a]
Having optimized the reaction conditions (Table 1, entry 8
with 10 mol% of CuCl), we next investigated the substrate
scope of hemiacetals 1 (Scheme 2). It was found that the g-po-
sition should be fully substituted (R1 and R2) to enable the
present catalytic CÀC bond fission and a,b-unsaturation for the
synthesis of lactone 2.[8] Various aryl groups including a thienyl
moiety could be installed at the g-position to afford the corre-
sponding lactone 2 in good to moderate yields. The reactions
of g-dialkyl lactols 1i and 1j also proceeded to afford the cor-
responding a,b-unsaturated lactones 2i and 2j in acceptable
yields, respectively. Installation of a methyl group at the b-posi-
tion (R3) did not disturb the process, thereby affording lactone
2k in 62% yield.
Entry
1 (R4)
T [8C]
t [h]
2a [%]
5a [%]
1
2
3[b]
4
5
6
7
1aa (R4 =Et)
80
80
80
80
80
50
50
7
3
8
48
24
72
168
25
24
0
20
8
13
10
0
60
52
70
61
1ab (R4 =iPr)
1ac (R4 =Ph)
1ad (R4 =CH2OBn)
1ae (R4 =CH2OMe)
1ae (R4 =CH2OMe)
1af (R4 =CH2OTBS)
5
1
[a] The reactions were carried out using 0.5 mmol of 1a in 5 mL of sol-
vent (0.1m) under an O2 atmosphere (1 atm). Lactols 1 (except for 1ac)
exist as an equilibrium mixture with their acyclic forms, g-hydroxy ke-
tones (see the Supporting Information for more details). [b] 1ac is ob-
served as a sole acyclic form without its lactol form (see the Supporting
Information for more details).
The reaction of d-hydroxy ketone 1l (that is observed as
a sole acyclic form without 6-membered ring hemiacetal)
under the present reaction conditions delivered the desired
a,b-unsaturated lactone 2l in only 22% yield (Scheme 3). In
this case, 1,3-diketone 4l was isolated in 23% yield as a major
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lactol 1ac with a phenyl group was unsuccessful (Table 2,
entry 3). It is noteworthy that the reactions with lactols 1ad–
1af bearing alkoxymethyl functions as R4 delivered saturated
g-butyrolactone 5a as a major product despite longer reaction
times (Table 2, entries 4–7).
units and lactol (hemiacetal) 9 bearing one N-oxyphthalimide
moiety in 15% and 13% yields, respectively.[9]
We thus wondered if acetals 8 and 9 are the key intermedi-
ates in the main stream of the present catalytic cycle for the
formation of phthalide 7. Thus, 8 and 9 were subjected to the
present Cu-catalyzed aerobic reaction conditions (Scheme 6).
This saturated lactone synthesis was applied for the transfor-
mation of optically active lactol 1m derived from d-(+)-ribonic
g-lactone. The reaction proceeded selectively to produce the
desired lactone 5m, while the reaction became very slow and
did not reach completion even after stirring over 7 days
(Scheme 4).
Scheme 6. Conversion of 8 and 9 under the present reaction conditions.
Our results showed that both of the reactions provided phtha-
lide 7, while longer reaction times were required especially for
the reaction of 9a and the yields were moderate (42% and
51% yields, respectively). These experimental results implied
that N-oxyphthalimide installed acetals 8 and 9 are not likely
the key intermediates for the present CÀC bond cleavage, but
the side-products formed during the course of the major cata-
lytic pathway.
Scheme 4. Synthesis of lactone 5m.
To gain mechanistic insights into the reaction, especially on
the CÀC bond fission process, the reactions of benzoannulated
lactol 6 were examined under the present reaction conditions.
Indeed, 3,3-dimethyl phthalide 7 was formed in good yields
(Scheme 5a) and monitoring of the reaction progress by
1H NMR spectroscopy revealed that lactol 6 was consumed
quickly within 10–15 min along with generation of several de-
rivatives (see the Supporting Information for more details). To
isolate these derivatives, we stopped the reaction of 6 after
10 min (Scheme 5b). In addition to phthalide 7 and phthali-
mide (3), we could isolate acetal 8 with two N-oxy-phthalimide
When the reaction of 6 was conducted in the presence of
benzene (Scheme 7), N-phenylphthalimide (10) was isolated in
15% yield along with the formation of phthalide 7 as well as
phthalimide (3). Compound 10 was formed presumably by ad-
dition of the phthalimide radical to benzene. Thus, the free
radical mechanism is likely operating for the present CÀC bond
cleavage event.
Taking these observations into consideration, proposed reac-
tion pathways for lactone formation through CÀC bond fission
are described in Scheme 8. These pathways are categorized
into the formation of a,b-unsaturated lactones 2 (Scheme 8b)
and a,b-saturated lactones 5 (Scheme 8c). It is known that
NHPI could be oxidized under Cu-catalyzed aerobic reaction
conditions to generate the corresponding O-radical (the PINO
Scheme 5. Reactions of benzoannulated lactol 6.
Scheme 7. The reaction of 6 in the presence of benzene.
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a-oxy radical I (Scheme 8c). The same transformation including
dioxygenation and radical fragmentation takes place, resulting
in formation of saturated lactone 5a as a major product.
These proposed reaction mechanisms including enol ethers
as one of the key intermediates could be further supported by
the reaction of methyl enol ether 11 under the present reac-
tion conditions (Scheme 9). The reaction proceeded very rapid-
Scheme 9. Reaction of enol ether 11.
ly (within 15 min) to give methyl ester 12 in 49% yield through
the CÀC bond cleavage along with acetal 13 in 15% yield.[17]
In summary, we have described an unprecedented aerobic
Cu-catalyzed NHPI-mediated synthesis of g-butyrolactones
(mainly butenolides) from the corresponding hemiacetals
through radical-mediated CÀC bond cleavage. The g-butyrolac-
tone skeleton is prevalent in biologically active natural prod-
ucts[18] and thus a variety of construction methods of these
scaffolds have been developed mainly by transition-metal
mediated cyclization/cyclo-addition reactions.[19,20] The present
method associated with inert CÀC bond cleavage of readily
available cyclic hemiacetals offers a new retrosynthetic analysis
for construction of g-butyrolactone structures. Further investi-
gation on application of this radical strategy for more practical
CÀC bond cleavage and other types of molecular transforma-
tion is now under way in our laboratory.
Scheme 8. Proposed mechanistic rationales for the reactions. See Table 2 for
nature of the R group.
radical) (Scheme 8a).[10,11] Concerning the formation of a,b-un-
saturated lactones 2, a,b-unsaturation likely takes place prior
to the CÀC bond fission. Thus, lactol 1a first undergoes dehy-
dration to give endo-cyclic enol ether A (that is thermodynami-
cally more stable than the corresponding exo-cyclic enol ether;
Scheme 8b). Abstraction of the H-radical at the allylic positon
by the PINO radical[12] results in alkene migration to form a-
oxy radical B that is subsequently oxidized to carbocation C
under the present reaction conditions. Deprotonation of C
forms exo-cyclic alkene D, which is trapped with the PINO radi-
cal, resulting in installation of the N-oxy-phthalimide moiety
and regeneration of a-oxy radical E. Dioxygenation of the a-
oxy radical E with molecular O2 gives peroxy radical F, the
Fenton-like reduction[13] of which generates O-radical G. Finally,
b-radical fragmentation[14,15] of O-radical G induces subsequent
CÀC and OÀN bond cleavage to form a,b-unsaturated lactone
2a, formaldehyde, and phthalimidoyl radical (that abstracts
a hydrogen radical forming phthalimide (3)).[16]
Experimental Section
Synthesis of 5,5-diphenylfuran-2(5H)-one (2a) (Table 1,
entry 8). For further procedures, see the Supporting Information.
Typical Procedure: Lactol 1a (0.127 g, 0.50 mmol), N-hydroxyphtha-
limide (81.5 mg, 0.5 mmol, 1.0 equiv) and CuCl (5.1 mg, 0.05 mmol,
0.1 equiv), were added to a 25 mL Schlenk tube, and back filled
with oxygen before addition of solvent MeCN (5.0 mL). The reac-
tion mixture was stirred at 808C under an oxygen atmosphere
(1 atm) for 12 h. After the complete consumption of lactol 1a, as
judged by thin layer chromatography anyalysis, the reaction was
cooled to room temperatures before quenching with pH 9 aq. am-
monium buffer and the organic materials were extracted with
ethyl acetate three times. The combined extracts were washed
twice with water and once with brine, and dried over MgSO4. Vola-
tile materials were removed in vacuo and the resulting crude mate-
rial was subjected to flash column chromatography (hexane/ethyl
In the reactions of alkoxymethyl lactols 1ad–1af (Table 2,
entries 4–7), the first dehydration selectively generates exo-
cyclic enol ether H, which is trapped by PINO radical to form
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[10] For reviews on the use of NHPI with metal co-catalyst, see: a) F. Recu-
pero, C. Punta, Chem. Rev. 2007, 107, 3800; b) R. A. Sheldon, I. W. C. E.
Arends, J. Mol. Catal. A 2006, 251, 200; c) R. A. Sheldon, I. W. C. E.
Arends, Adv. Synth. Catal. 2004, 346, 1051; d) F. Minisci, F. Recupero,
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Liang, Bull. Korean Chem. Soc. 2012, 33, 459; b) C. A. Correia, C.-J. Li, Tet-
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hall, K. U. Ingold, J. Org. Chem. 2005, 70, 4629; b) Y. Ishii, T. Iwahama, S.
Sukaguchi, K. Nakayama, Y. Nishiyama, J. Org. Chem. 1996, 61, 4520;
c) Y. Ishii, K. Nakayama, M. Takeno, S. Sukaguchi, T. Iwahama, Y. Nishiya-
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acetate=80:20) to afford 5,5-diphenylfuran-2(5H)-one (2a)
(85.0 mg, 0.36 mmol) in 72% yield as a white solid.
Acknowledgements
This work was supported by funding from Nanyang Technolog-
ical University and Singapore Ministry of Education (Academic
Research Fund Tier 2: MOE2012-T2-1-014). We thank Dr. Yong-
xin Li and Dr. Rakesh Ganguly (Division of Chemistry and Bio-
logical Chemistry, Nanyang Technological University) for assis-
tance in X-ray crystallographic analysis.
[13] For a recent report on the Fenton mechanism, see: S. Rachmilovich-
Calis, A. Masarwa, N. Meyerstein, D. Myerstein, R. van Eldik, Chem. Eur. J.
2009, 15, 8303.
Keywords: CÀC bond cleavage · copper · homogeneous
catalysis · lactones · radicals
[14] For reviews on b-radical fragmentation of alkoxyl radicals, see: a) J. Har-
ˇ
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[2] For an account, see: S. Chiba, Bull. Chem. Soc. Jpn. 2013, 86, 1400.
[3] a) Y.-F. Wang, H. Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134,
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[16] 18O-labelling experiments of 1a, 6, and 11 under an 18O2 atmosphere
delivered the corresponding lactones 2a and 7 as well as ester 12 with
incorporation of an 18O atom. These results could support the proposed
reaction mechanism involving peroxy radicals such as F and J as the re-
action intermediate. See the Supporting Information for more details.
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[6] Lactols 1 exist as an equilibrium mixture with the corresponding acylic
forms, g-hydroxy ketones. See the Supporting Information for more de-
tails.
[20] For recent reports for synthesis of g-butyrolactones, see: a) E. L. McIn-
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[7] Formation of phthalimide (3) was observed in all the reactions with
NHPI. Phthalimide (3) is easily solidified with poor solubility towards or-
ganic solvents so that it is easily lost during the work-up process.
Therefore, we did not pursue to elucidate the yield of phthalimide (3)
in the other cases.
[8] For example, the reaction of hemiacetal 1n (that is in equilibrium with
its acyclic form) under the present reaction conditions gave 1,4-dike-
tone 1n’ as a sole product. For the report on oxidation of secondary
benzylic alcohols under the Cu–NHPI system, see: G. Yang, L. Wang, J.
Li, Y. Zhang, X. D. Ying, S. Gao, Res. Chem. Intermed. 2012, 38, 775.
Received: October 17, 2014
Revised: November 3, 2014
Published online on && &&, 0000
[9] The structure of acetal 8 was secured by X-ray crystallographic analysis.
See the Supporting Information for the proposed mechanism for the
formation of acetals 8 and 9.
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COMMUNICATION
Let’s get physical: A Cu-catalyzed aero-
bic CÀC bond cleavage of cyclic hemia-
cetals (lactols) into lactones was ach-
ieved in the presence of N-hydroxy
phthalimide (NHPI). This reaction is
composed of a multistep sequence in-
cluding a) formation of exo-cyclic enol
ethers through dehydration; b) addition
of phthalimide N-oxyl radical to the
enol ethers followed by trap of the re-
sulting C-radicals with molecular oxygen
to form peroxy radicals; c) reductive
generation of oxy radicals and subse-
quent b-radical fragmentation to gener-
ate lactones.
&
Copper Catalysis
Ya Lin Tnay, Shunsuke Chiba*
&& – &&
Copper-Catalyzed Aerobic CÀC Bond
Cleavage of Lactols with N-Hydroxy
Phthalimide for Synthesis of Lactones
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