Efficient Oxidative Cleavage of Tetrahydrofuran-2-methanols to γ-Lactones by a 2-Iodobenzamide Catalyst in Combination with Oxone

Article abstract of DOI:10.1002/adsc.201500795

An environmentally friendly oxidative cleavage of tetrahydrofuran-2-methanols to the corresponding γ-lactones using a catalytic amount of 2-iodo-N-isopropylbenzamide has been developed. The reaction of various tetrahydrofuran-2-methanols with the catalyst in the presence of Oxone (2 KHSO₅·KHSO₄·K₂SO₄) as a co-oxidant in DMF at room temperature successfully affords the corresponding lactones in good to high yields, and recovery of the catalyst is readily accomplished using a reductive work-up. This method is notable because it enables the transformation of tetrahydrofuran-2-methanols to γ-lactones under mild conditions without the use of any toxic heavy metals.

Full text of DOI:10.1002/adsc.201500795

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DOI: 10.1002/adsc.201500795
Efficient Oxidative Cleavage of Tetrahydrofuran-2-methanols to
g-Lactones by a 2-Iodobenzamide Catalyst in Combination with
Oxoneꢀ
Takayuki Yakura,a,* Yuto Horiuchi,a Yushi Nishimura,a Akihiro Yamada,a
Hisanori Nambu,a and Tomoya Fujiwaraa
a
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
Fax: (+81)-76-434-5053; phone: (+81)-76-434-7555; e-mail: yakura@pha.u-toyama.ac.jp
Received: August 25, 2015; Revised: December 9, 2015; Published online: February 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500795.
Abstract: An environmentally friendly oxidative
cleavage of tetrahydrofuran-2-methanols to the cor-
responding g-lactones using a catalytic amount of 2-
iodo-N-isopropylbenzamide has been developed.
The reaction of various tetrahydrofuran-2-metha-
nols with the catalyst in the presence of Oxoneꢀ
(2KHSO5·KHSO4·K2SO4) as a co-oxidant in DMF
at room temperature successfully affords the corre-
sponding lactones in good to high yields, and recov-
ery of the catalyst is readily accomplished using a re-
ductive work-up. This method is notable because it
enables the transformation of tetrahydrofuran-2-
methanols to g-lactones under mild conditions with-
out the use of any toxic heavy metals.
the synthesis of biologically active compounds
(Scheme 1a).[8]
Pentavalent iodine reagents such as Dess–Martin
periodinane (DMP)[9] and 2-iodoxybenzoic acid
(IBX)[10] have been widely employed by synthetic or-
ganic chemists as environmentally friendly oxidants
because they are non-metallic, less toxic, easy to
handle, and they often enable mild reaction condi-
Keywords: green chemistry; hypervalent com-
pounds; iodobenzamides; organic catalysis; oxida-
tive cleavage reaction
The direct transformation of oxacycle-2-methanols
1 to the corresponding lactones 2 via oxidative cleav-
age (Scheme 1a)[1,2] has often been used for the syn-
thesis of various biologically active compounds.[3–6] In
our synthesis of 2-epi-cinatrin C1 dimethyl ester,[7] the
oxidative cleavage of a substituted tetrahydrofuran-2-
methanol was accomplished using 16 equiv. of pyridi-
nium dichromate (PDC) at 1508C. Other procedures
for this general transformation have also been devel-
oped. However, all the reported reactions require an
excess amount of hexavalent chromium oxidants such
as PDC[1,4,7] and pyridinium chlorochromate
(PCC)[2,3,5,6] and most are performed at high tempera-
ture.[2,4–7] In addition, the yields of 2 are often
low.[1a,3,6] To avoid these drawbacks, some researchers
Scheme 1. Strategy for efficient and environmentally friend-
ly oxidative cleavage of tetrahydrofuran-2-methanols 1 to g-
have employed stepwise transformations of 1 to 2 for lactones 2.
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Takayuki Yakura et al.
tions.[11] Catalytic systems using iodine(V) species room temperature (258C) (entry 4). Fortunately, the
generated in situ from the corresponding iodine(I) re- desired oxidative cleavage of 1a successfully proceed-
agents have also been developed to minimize the ed to provide the corresponding g-lactone 2a in 71%
amount of potentially explosive iodine(V) species yield after 60 h. When 2-iodobenzoic acid (7),[12a,b]
during the reaction.[11,12] As a part of our efforts to de- a known catalyst for alcohol oxidation, was used in-
velop multi-functionalized organocatalysts based on stead of 3, the oxidative cleavage reaction was very
hypervalent iodine chemistry,[13] we recently reported slow and afforded only a 17% yield of 2a and a 57%
2-iodobenzamide 3 as an effective catalyst for alcohol yield of the recovered starting material 1a after 60 h
oxidation (Scheme 1b).[14] In the presence of Oxoneꢀ (entry 5). The reaction of 1a in the presence of
(2KHSO5·KHSO4·K2SO4) as a co-oxidant, oxidation 2.5 equiv. of Oxoneꢀ and 1 equiv. of Bu4NHSO4 with-
of primary alcohols using a catalytic amount of 3 pro- out any iodine reagent resulted in no detectable prod-
ceeded smoothly, even at room temperature, to pro- uct formation (entry 6). These results strongly indicat-
vide the corresponding carboxylic acids. Here, we ed that 3 would be an effective reagent for the oxida-
report the mild and effective oxidative cleavage of tive cleavage reaction. When the reaction of 1a with
tetrahydrofuran-2-methanols 1 to g-lactones 2 at 1 equiv. of 3 in the presence of 5 equiv. of Oxoneꢀ
room temperature using a combination of 3 and was conducted, the reaction time (33 h) was much
Oxoneꢀ (Scheme 1c).
shorter than that with 2.5 equiv. of Oxoneꢀ (entry 7).
First, the reaction of tetrahydrofuran-2-methanol 1a The use of 10 equiv. of Oxoneꢀ, however, was not as
with several oxidizing reagents was examined effective for shortening the reaction time (entry 8).
(Table 1). Reaction of 1a with 4 equiv. of PCC in the The reaction without Bu4NHSO4 afforded the best
presence of MS 3Š in CH2Cl2 under reflux condi- result, with 2a obtained in 73% yield after 26 h
tions[2b] afforded a complex mixture (entry 1). When (entry 9), indicating that Bu4NHSO4 is not necessary
1a was treated with 2.5 equiv. of DMP (5) or IBX (6) for this reaction.
in MeNO2, the corresponding aldehyde 4 was ob-
An interesting solvent effect was observed in this
tained in 55 and 38% yields, respectively, without the oxidative cleavage reaction (Table 2). While changing
formation of 2a (entries 2 and 3). Based on our previ- the ratio of MeNO2 and water from 8:3 to 3:8 did not
ously reported conditions for alcohol oxidation using affect the yield of 2a or the reaction time (entry 2),
3 and Oxoneꢀ,[14] 1a was treated with 1 equiv. of 3 in the reaction in water was complete within 28 h but
the presence of 2.5 equiv. of Oxoneꢀ and 1 equiv. of with a very low yield of the desired product (entry 3).
Bu4NHSO4 in an 8:3 mixture of MeNO2 and water at In contrast, when MeNO2 was employed as the sole
Table 1. Oxidation of tetrahydrofuran-2-methanol 1a to g-lactone 2a with various oxidizing reagents at room temperature.[a]
Entry Reagent (equiv.) Oxoneꢀ (equiv.) Bu4NHSO4 (equiv.) Solvent
Time [h] Products [yield (%)][b]
1[c]
2
3
4
5
6
7
8
9
PCC (4)
5 (2.5)
6 (2.5)
3 (1)
7 (1)
none
3 (1)
3 (1)
3 (1)
none
none
none
2.5
2.5
2.5
5
none
none
none
1
1
1
1
1
CH2Cl2
MeNO2
MeNO2
MeNO2-H2O (8:3) 60
MeNO2-H2O (8:3) 60
MeNO2-H2O (8:3) 60
MeNO2-H2O (8:3) 33
MeNO2-H2O (8:3) 27
MeNO2-H2O (8:3) 26
24
24
24
complex mixture
4 [55]
4 [38]+1a [38]
2a [71]
2a [17]+1a [57]
no reaction
2a [60]
10
5
2a [67]
2a [73]
none
[a]
[b]
[c]
All reactions were performed on a 0.25-mmol scale unless otherwise specified.
Isolated yield.
The reaction was performed using 1a (0.40 mmol), PCC (1.60 mmol), and MS 3Š (85 mg) in CH2Cl2 (3 mL) under reflux
conditions.[2b]
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Efficient Oxidative Cleavage of Tetrahydrofuran-2-methanols
Table 2. Effect of solvent on the oxidative cleavage of 1a to
a using 3 and Oxoneꢀ.[a]
Table 3. Oxidative cleavage of various tetrahydrofuran-2-
methanols 1b–l to g-lactones 2b–l using 3 and Oxoneꢀ.[a]
Entry Solvent
3
Time Yield
[equiv.] [h]
[%][b]
1
2
3
4
5
6
7
8
MeNO2-H2O (8:3)
MeNO2-H2O (3:8)
H2O
MeNO2
MeCN
CF3CH2OH
toluene
DMSO
DMF
DMA
DMF
DMF
DMF
1
1
1
1
1
1
1
1
1
1
0.3
0.1
0.3
26
28
28
24
25
25
48
48
9
10
15
25
21
73
73
35
81
69
54
29[c]
no reaction[c]
9
73
67
67
63
73
10
11
12
13[d]
[a]
All reactions were performed using 1a (0.25 mmol), 3
and Oxoneꢀ (1.25 mmol) in solvent (1.1 mL) at room
temperature unless otherwise specified.
Isolated yield.
The starting 1a was recovered.
The reaction was performed using 1.00 mmol of 1a.
[b]
[c]
[d]
solvent, 2a was obtained in 81% yield after 24 h
(entry 4). Use of MeCN, 2,2,2-trifluoroethanol, and
toluene produced unsuccessful results (entries 5–7).
The reaction in DMSO also did not proceed, presum-
ably due to oxidation of DMSO by Oxoneꢀ
(entry 8).[15] Interestingly, DMF[16] and DMA drasti-
cally accelerated the reaction, which was complete
within just 9 and 10 h, respectively (entries 9 and 10).
The catalytic use of 3 was then tested; when the reac-
tion was performed using 0.3 equiv. of 3 in DMF, 2a
was obtained in 67% yield after 15 h (entry 11). Even
with 0.1 equiv. of 3, the reaction was complete within
25 h and afforded 2a in 63% yield (entry 12). When
1 mmol of 1a was reacted with 0.3 equiv. of 3, the
longer reaction time (21 h) was required to give 2a in
slightly increased yield (entry 13).
[a]
All reactions were performed using 1 (0.40 mmol), 3
(0.12 mmon) and Oxoneꢀ (2 mmol) in DMF (1.8 mL) at
room temperature.
[b]
Isolated yield.
The reaction was performed using 0.20 mmol of 3.
Complex mixture was obtained.
[c]
[d]
Next, the tetrahydrofuran-2-methanols 1b–l were
oxidized using 0.3 equiv. of 3 in the presence of (entries 5 and 6). Reactions of 4-substituted 2-metha-
5 equiv. of Oxoneꢀ in DMF at room temperature nols 1h and 1i proceeded to give 2h and 2i in 67%
(Table 3). When 1b and 1c bearing an acyloxymethyl and 70% yields, respectively (entries 7 and 8). Bicyclic
group at the 5-position were allowed to react with 3 1j and 5,5-disubstituted methanol 1k were oxidized to
and Oxoneꢀ for 22 and 24 h, respectively, the corre- lactones (entries 9 and 10). On the other hand, the re-
sponding lactones 2b and 2c were each obtained in action of 1l bearing a silyloxymethyl group afforded
73% yield (entries 1 and 2). Oxidation of phthalimide a complex mixture without the formation of the de-
1d gave 2d in high yield (entry 3), although tosyloxy sired product 2l (entry 7), presumably due to removal
derivative 1e required 0.5 equiv. of 3 to complete the of the silyl group under the reaction conditions. Cata-
reaction (entry 4). Alkylated 1f and 1g were smoothly lyst 3 was recovered in high yields after reductive
converted to the the corresponding lactones 2f and 2g treatment in all cases.
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Takayuki Yakura et al.
Having obtained these results, the focus shifted to oxidized by Oxoneꢀ to iodine(V) species 11, which
understanding the reaction mechanism. Considering reacts with 1 to generate aldehyde 12 as a key inter-
the mechanism of alcohol oxidation with 3,[14] alde- mediate.[17] Compound 12 would then react with
hyde 4 and/or carboxylic acid 8 were proposed as pos- Oxoneꢀ to generate not carboxylic acid 14[18] but
sible reaction intermediates in the present oxidative rather formate 13[8c] which is further oxidized to lac-
cleavage reaction. Thus, 4 and 8 were reacted with tone 2. The iodine(III) species 10 derived during the
1 equiv. of 3 in the presence of 5 equiv. of Oxoneꢀ in reaction of 11 and 1 is re-oxidized by Oxoneꢀ to
DMF at room temperature (Table 4). While the reac- reform 11.
tion of 4 afforded 2a in 77% yield only after 1 h
In summary, we have developed a mild and effi-
(entry 1), the reaction of 8 did not proceed (entry 2). cient oxidative cleavage reaction for the conversion of
Interestingly, the reaction of 4 in the absence of 3 was 1 to 2 using 3 and Oxoneꢀ. In this reaction, the trans-
also complete within 1 h and afforded 2a in 75% yield formation of 1 to 2 is accomplished at room tempera-
(entry 3).
ture without the use of any toxic heavy metals, and 2
Based on the above results, we propose a possible is obtained in good to high yields. This method pro-
mechanism for the oxidative cleavage of 1 using 3 and vides a new environmentally friendly procedure for
Oxoneꢀ as shown in Scheme 2. Iodobenzamide 3 is the synthesis of g-lactones 2 with various functionali-
ties.
Table 4. Oxidation of aldehyde 4 and carboxylic acid 8 using
3 and Oxoneꢀ.[a]
Experimental Section
Typical Experimental Procedure for the Oxidative
Cleavage of Tetrahydrofuran-2-methanols
To a solution of 1 (0.40 mmol) in anhydrous DMF (1.8 mL)
Entry
Substrate
3 (equiv.)
Time [h]
Yield [%][b]
were added 3 (35 mg, 0.12 mmol) and Oxoneꢀ (1.23 g,
2.0 mmol) at room temperature. After completion of the re-
action (checked by TLC), the mixture was diluted with
EtOAc and water. The organic layer was then separated,
washed with saturated aqueous Na2S2O3, saturated aqueous
NaHCO3, water, and brine, then dried over magnesium sul-
fate, filtered, and concentrated under reduced pressure. The
residue was purified via silica gel column chromatography
to afford lactone 2 and recover 3.
1
2
3
4
8
4
1
1
1
24
1
77
no reaction
75
none
[a]
Reaction conditions: 4 or 8 (0.25 mmol), 3 and Oxoneꢀ
(1.25 mmol) in DMF (1.1 mL) at room temperature.
Isolated yield.
[b]
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecu-
lar Transformations by Organocatalysts” from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
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