New syntheses of haloketo acid methyl esters and their transformation to halolactones by reductive cyclization

Article abstract of DOI:10.1007/s11172-020-2965-6

A new method for haloketo acid methyl ester synthesis on the basis of the ring-opening of cyclic α,β-unsaturated ketones followed by halogenation under mild conditions is reported. Di- and tri-haloketo acid methyl esters are conveniently synthesized via the hydrolytic ring-opening reaction through this method. Halolactones were readily obtained from these haloketo acid methyl esters by reductive cyclization employing NaBH₄ and trifluoroacetic acid. Derivatizations of the obtained halolactone utilizing the exo-halomethylene moiety were also demonstrated.

Full text of DOI:10.1007/s11172-020-2965-6

Russian Chemical Bulletin, International Edition, Vol. 69, No. 9, pp. 1804—1810, September, 2020
1804
New syntheses of haloketo acid methyl esters and their
transformation to halolactones by reductive cyclization*
H. China,a H. Yatabe,a N. Kageyama,a M. Fujitake,b K. Kikushima,a and T. Dohia
aCollege of Pharmaceutical Sciences, Ritsumeikan University,
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
Tel.: +81 77 561 4908. E-mail:hchina7a@fc.ritsumei.ac.jp; td1203@ph.ritsumei.ac.jp
bOsaka University of Pharmaceutical Sciences,
4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
A new method for haloketo acid methyl ester synthesis on the basis of the ring-opening of
cyclic ,-unsaturated ketones followed by halogenation under mild conditions is reported.
Di- and tri-haloketo acid methyl esters are conveniently synthesized via the hydrolytic ring-
opening reaction through this method. Halolactones were readily obtained from these halo-
keto acid methyl esters by reductive cyclization employing NaBH4 and trifluoroacetic acid.
Derivatizations of the obtained halolactone utilizing the exo-halomethylene moiety were also
demonstrated.
Key words: haloketo acid methyl ester, halolactone, hydrolytic ring-opening reaction, reduc-
tive cyclization, cyclic -diketone.
Halolactones are useful synthetic intermediates1 for
involved the use of diazomethane as the C(1)-carbon
source.25,26 On the next step, diazomethyl ketone, gener-
ated from acyl chloride, is converted to monohaloketo
acid methyl ester by the reaction with dry hydrogen halide.
Alternatively, monobromoketo acid alkyl esters can
be synthesized from keto acids by their reactions with
molecular bromine using alcohol as a co-solvent un-
der heating.27 There is only one example of the synthe-
sis of dichloroketo acid methyl ester by the ring-open-
ing of bicyclic compound.28 However, selective synthesis
of substituted dichloroketo acid methyl esters may be
difficult through this method, because regioisomers of
silyl enol ethers may be formed during the synthesis of the
substrate.
In this study, we have developed a new synthetic route
to haloketo acid methyl esters through the ring-open-
ing of cyclic ,-unsaturated ketones and cyclic -di-
ketones and their sequential transformation to halolac-
tones by reductive cyclization. The halolactone forma-
tion belongs to the condensation-type cyclization with-
out the potent problem of regioselectivity (see Scheme 1,
B). The monohaloketo acid methyl esters can be ob-
tained by regioselective halogenation of the corresponding
keto acid methyl ester precursors that are accessible
by oxidative cleavage29 of 3-methyl-2-cyclohexenones
(Scheme 1, D). Di- and tri-haloketo acid methyl es-
ters can be alternatively synthesized by the hydrolytic
ring-opening of 2,2-dichlorocyclohexane-1,3-diones (see
Scheme 1, D).
derivatization to various compounds including natural
products with interesting biological activities. Recently,
several biologically active halolactones have also been
reported.2—4 Halolactones are typically synthesized by
halocyclizations of olefinic acids, such as iodo-, bromo-,
and chlorolactonizations (Scheme 1, A).5—15. However,
the halolactonization reaction offers limited control of the
regioselectivity of endo- and exo-cyclizations in the case
of internal alkenes. The classical intramolecular cyclization
strategies based on the condensation of hydroxy acids are
advantageous since a mixture of these exo- and endo-
lactones are not formed in principle. This halolactoniza-
tion requires an excess amount of an organic base and
diluted hydroxy acids in order to avoid dimer forma-
tion,16—20 whereas the cyclization of hydroxy acid methyl
esters under acidic or basic conditions readily provides
lactones without a dimer byproduct.21—24 Moreover, the
strategy of halolactone synthesis using carboxylic acid
methyl esters with a halohydrin moiety derived by the
reduction of haloketo acid methyl esters as a synthetic
intermediate does not produce the corresponding dimer
and regioisomeric byproducts (Scheme 1, B).
The previously reported method for the synthesis of
monohaloketo acid methyl esters (Scheme 1, C) typically
* Based on the materials of the International Conference "Catalysis
and Organic Synthesis" (ICCOS-2019) (September 15—20, 2019,
Moscow, Russian Federation).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1804—1810, September, 2020.
1066-5285/20/6909-1804 © 2020 Springer Science+Business Media LLC

Halolactones
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
1805
Scheme 1
Results and Discussion
the chlorination of dimedone,30 using Na2HPO4 in MeOH
afforded dichloroketo acid methyl ester 5a in 97% yield
(Scheme 3). In addition, this ring-opening alcoholysis in
the presence of N-chlorosuccinimide (NCS) and NBS,
respectively, gave pure trichloroketo acid methyl ester 5b
and monobromo dichloroketo acid methyl ester 5c in high
yields (see Scheme 3).
Next, the reductive cyclization of the thus-obtained
haloketo acid methyl esters 4 and 5 using NaBH4 and
trifluoroacetic acid (TFA) to produce halolactones was
examined (Scheme 4). After the reduction of the substrates
using NaBH4 in MeOH at 0 C, the intramolecular con-
densation reaction of the resulting methyl esters with the
halohydrin moiety was subsequently carried out by the
treatment with TFA at room temperature. This method
The representative scheme for the preparation of
monohaloketo acids as a substrate for a reductive lactoni-
zation is illustrated in Scheme 2. Keto acid 2a was pro-
duced by the oxidative cleavage of cyclic ,-unsaturated
ketone 1.29 Keto acid methyl ester 3 derived from keto
acid 2a in 87% yield was converted to monochloroketo
acid methyl ester 4a and monobromoketo acid methyl
ester 4b in good yield by reacting with 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) and N-bromosuccinimide
(NBS), respectively, in the presence of silica gel. Mono-
iodoketo acid methyl ester 4c was prepared by the Fin-
kelstein reaction of compound 4a. The ring-opening al-
coholysis of dichloro--diketone, which was obtained by

China et al.
1806
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
Scheme 2
Reagents and conditions: i. Oxone®, RuCl3, MeCN, H2O, RT, 3 h; ii. CDI, MeOH, RT, 30 min; iii. DCDMH, MeOH, SiO2;
iv. NaI, acetone, RT, 1 h; v. NBS, MeOH, SiO2, RT, 6 h.
Scheme 3
Scheme 4
Compounds 5
X
H
Cl
Br
Yield (%)
a
b
c
97
96
89
Reagents and conditions: i. aq. NaOCl, AcOH, MeOH, 0 C,
30 min; ii. Na2HPO4, MeOH (for 5a) or Na2HPO4, MeOH,
NCS (for 5b), or Na2HPO4, MeOH, NBS (for 5c), room tem-
perature (RT), 0.5—1 h.
afforded highly pure halolactones 6 and 7 without chrom-
atographic purification in both the reduction and cycliza-
tion steps. Thus, 3,3-dimethyl-substituted monochloro-
-lactone 6a and monobromo--lactone 6b were obtained
by the lactonization of the corresponding methyl esters 4a
and 4b in high yield. However, monoiodoketo acid methyl
ester 4c did not form monoiodo--lactone 6c. This is
because the elimination of the iodine atom in the substrate
4c was caused during the reduction with NaBH4.
Unsubstituted monobromo--lactone 6d and mono-
bromo--lactone 6e were obtained in satisfactorily yields
by the lactonizations of the corresponding methyl esters
4d and 4e, respectively. 4-Methyl-substituted mono-
bromo--lactone 6f and 3-methyl-substituted mono-
bromo--lactone 6g were also obtained in good yields from
the corresponding methyl esters 4f and 4g, respectively;
no significant difference in the cis/trans ratio of products
6f and 6g was observed. 3,3-Dimethyl-substituted di-
chloro--lactone 7a and trichloro--lactone 7b were af-
forded in high yields by the lactonization of the corre-
sponding dichloro- and trichloromethyl esters 5a and 5b,
respectively. Whereas monobromo dichloro--lactone 7c
R1 = R2 = H (4e), R1 = H, R2 = Me (4f), R1 = Me, R2 = H (4g)
X = H (7a), Cl (6a, 7b), Br (6b, 7c), I (6c)
n = 1 (6d), 2 (6e)
Compound Yield (%)
Compound Yield (%)
6a
6b
6c
6d
6e
98
99
0
90
97
6f
96
99
97
99
0
6g
7a
7b
7c

Halolactones
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
1807
was not detected during the lactonization of monobromo
dichloroketo acid methyl ester 5c due to the facile reduc-
tion of the weak carbon—bromine bond. Instead, in this
case dichloro--lactone 7a was obtained in 96% yield.31—33
This method is particularly convenient to synthesize lac-
tones 7a and 7b since no purification was required in all
steps from dimedone (see Schemes 3 and 4).
this method: purification is not necessary for the lactoni-
zation sequence and di- and tri-chlorolactones can be
readily obtained in high yields. Regarding the halogen
functionality, derivatizations are possible while maintain-
ing the lactone structure. Therefore, this method would
become a practical and convenient alternative to synthe-
size haloketo acid methyl esters and halolactones.
Finally, derivatizations of 6e were demonstrated in
Scheme 5. The bromo-substitution reaction for the de-
rivatization of bromolactone must be conducted under
mild pH conditions because the ring-opening of lactone
would occur under strong basic conditions. The treatment
of 6e with potassium thioacetate (AcSK) in THF at 60 C
quantitatively afforded lactone 8 tethered with the thioester
moiety. Halogen substitution to produce iodolactone 9
was accomplished by the Finkelstein reaction at 60 C.
Such iodolactones can be converted to aryl lactones34 and
olefinic lactones35 by C(sp3)—C(sp2) cross-coupling reac-
tions. In addition, iodolactones are known as the useful
precursor of lactones with thioether34 and ester34,36,37
moieties. The reaction between 6e and NaN3 in DMF at
80 C under neutral pH conditions afforded azide lactone
10 in moderate yield. The C—N coupling between 6e and
aniline to form the amine lactone 11 occurred under weak
basic conditions at reflux. In the synthesis of biologically
active compounds, bromolactones were sometimes used
for the elongation of aliphatic side chains.38—40
Experimental
1H and 13C NMR spectra were recorded on an ECS 400
NMR spectrometer (JEOL Ltd., Tokyo, Japan) at 400 and 100
MHz, respectively, using CDCl3 as a solvent. The chemical shifts
are given in the  scale relative to Me4Si as an internal standard.
Steric and interactive analyses were performed by 1D nuclear
Overhauser enhancement and exchange spectroscopy (NOESY)
using the double pulsed field gradient spin echo-nuclear Over-
hauser effect (DPFGSE-NOE) method under the appropriate
mixing time and relaxation delay. Infrared (IR) spectra were
recorded by a JASCO FT/IR-4200 spectrometer (JASCO Co.,
Tokyo, Japan) on diffuse reflectance method using KBr pellets.
Electron impact high resolution mass spectra (HRMS) obtained
by the electron ionization (EI) method were recorded on
a JMS-700 spectrometer (JEOL).
Methyl 5-bromo-4-oxopentanoate (4d), methyl 6-bromo-5-
oxohexanoate (4e), methyl 6-bromo-3-methyl-5-oxohexanoate
(4f), and methyl 6-bromo-2-methyl-5-oxohexanoate (4g) were
synthesized from the corresponding keto acids 2b—e by the
earlier reported method.27
Methyl 3,3-dimethyl-5-oxohexanoate (3). To a solution of
3,3-dimethyl-5-oxo-hexanoic acid 2a29 (3.95 g, 25.0 mmol) in
CH2Cl2 (62.5 mL), 1,1´-carbonyldiimidazole (CDI, 4.46 g,
27.5 mmol) was added. The mixture was stirred at room tem-
perature for 0.5 h and MeOH (12.5 mL) was added. After 15 min
of continuous stirring, the solvent was removed by evaporation.
The product was extracted with hexane by sonication and the
extract was filtered through filter paper. Removal of the solvent
by evaporation gave product 3 (3.75 g, 87%) as a colorless oil.
1H NMR, : 1.09 (s, 6 H), 2.12 (s, 3 H), 2.46 (s, 2 H), 2.57
(s, 2 H), 3.64 (s, 3 H). 13C NMR, : 28.0, 31.9, 32.5, 44.3, 51.2,
Scheme 5
52.3, 172.7, 208.2. H and 13C NMR data are consistent with
1
those reported in the literature.30
Methyl 6-bromo-3,3-dimethyl-5-oxohexanoate (4b). To a so-
lution of compound 3 (517 mg, 3.00 mmol) in MeOH (30 mL)
containing silica gel (3.0 g), NBS (1.34 g, 7.50 mmol) was
added. After the mixture was stirred at room temperature for 6 h,
the silica gel was removed by filtration, washed with MeOH and
the solvent was removed by evaporation. The product was ex-
tracted with hexane by sonication and the extract was filtered
through filter paper for dehydration. The filtrate was concen-
trated by evaporation and the residue was purified by silica gel
chromatography with AcOEt—hexane (1 : 9) to afford product
Reagents and conditions: i. AcSK, THF, 60 C, 12 h; ii. NaI,
acetone, 60 C, 6 h; iii. NaN3, DMF, 80 C, 7 h; iv. PhNH2,
NaHCO3, MeCN, reflux, 24 h.
In summary, herein we reported the reductive cycliza-
tion using NaBH4 and TFA for haloketo acid methyl es-
ters 4 and 5 obtainable by new synthetic routes to synthe-
size halolactones 6 and 7; this method differs from the
conventional method based on the halolactonization
strategy employing olefinic acids. Our methodology pro-
vides versatility for the introduction of the substituents in
the halolactone structures because the halolactones derived
from cyclic olefins and cyclic -diketones can be obtained
in good yields. There is a remarkable advantage in using
1
4b (568 mg, 75%) as a colorless oil. H NMR, : 1.11 (s, 6 H),
2.47 (s, 2 H), 2.78 (s, 2 H), 3.65 (s, 3 H), 3.91 (s, 2 H). 13C NMR,
: 28.2, 32.8, 35.9, 44.0, 48.4, 51.3, 172.6, 200.9. IR, /cm–1
:
3651, 3559, 3444, 2960, 2876, 2638, 2327, 2029, 1733, 1437,
1390, 1356, 1232, 1156, 1052, 1026, 887, 812, 737, 640, 619.
HR-MS (EI), found: m/z 251.0279 [M + H]+. Calculated for
C9H16BrO3: 251.0283.
Methyl 6-iodo-3,3-dimethyl-5-oxohexanoate (4c). To a solu-
tion of methyl 6-chloro-3,3-dimethyl-5-oxohexanoate (4a)

China et al.
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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
(82.7 mg, 0.40 mmol) in acetone (4 mL), NaI (71.9 mg,
0.48 mmol) was added. After the mixture was stirred at room
temperature for 1 h, the solvent was removed by evaporation.
The product was extracted with CH2Cl2 and the extract was
filtered through filter paper. Removal of the solvent by evapora-
tion gave product 4c (116.4 mg, 98%) as a pale-yellow oil. 1H NMR,
: 1.10 (s, 6 H), 2.47 (s, 2 H), 2.86 (s, 2 H), 3.65 (s, 3 H), 3.82
(s, 2 H). 13C NMR, : 8.4, 28.0, 32.7, 44.1, 48.1, 51.3, 172.6,
202.0. IR, /cm–1: 3649, 3545, 3434, 2953, 2874, 2020, 1728,
1436, 1357, 1231, 1159, 1022, 928, 885, 720, 598. HR-MS (EI),
found: m/z 298.0066 [M]+. Calculated for C9H15O3I: 298.0066.
Preparation of keto acid 2b—e (general procedure). Keto
acids 2b—e were synthesized by a modified version of the previ-
ously described procedure.29 To a solution of the correspond-
ing ,-unsaturated ketone (5.0 mmol) and RuCl3 (10.4 mg,
0.05 mmol) in a mixture of MeCN (30 mL) and water (20 mL),
a mixture of Oxone® (4.61 g, 7.5 mmol) and NaHCO3 (1.93 g,
23 mmol) was added by portions over a period of 10 min at room
temperature. After the mixture was stirred at room temperature
for 21 h, the solvent was removed by evaporation. The resulting
aqueous solution was acidified by addition of concentrated H2SO4
(0.25 mL). The product was extracted with CH2Cl2 (580 mL)
and the extracted product was purified by extraction with a satu-
rated NaHCO3 aqueous solution (80 mL). After washing with
CH2Cl2 (10 mL), the aqueous solution was acidified to pH 1 with
concentrated H2SO4. The product was extracted with CH2Cl2
(540 mL) and the extract was filtered through filter paper for
dehydration. Removal of the solvent by evaporation gave the
corresponding keto acids 2b—e.
temperature for 0.5 h, the residual Na2HPO4 was removed by
filtration and washed with MeOH. The solvent was removed by
evaporation, the product was extracted with hexane by sonication,
and the extract was filtered through filter paper. Removal of the
solvent by evaporation gave ester 5a (466 mg, 97%) as a colorless
oil. 1H NMR, : 1.14 (s, 6 H), 2.50 (s, 2 H), 2.97 (s, 2 H), 3.65
(s, 3 H), 5.83 (s, 1 H). 13C NMR, : 28.1, 32.6, 44.0, 44.3, 51.3,
1
70.5, 172.4, 195.7. H and 13C NMR data are consistent with
those reported in the literature.30
Methyl 6,6,6-trichloro-3,3-dimethyloxohexanoate (5b). To
a solution of 2,2-dichloro-5,5-dimethyl-cyclohexane-1,3-dione30
(2.09 g, 10.0 mmol) and NCS (1.60 g, 12.0 mmol) in MeOH
(100 mL), Na2HPO4 (7.10 g, 5.0 mmol) was added. After the
mixture was stirred at room temperature for 1 h, the residual
Na2HPO4 was removed by filtration and washed with MeOH.
The solvent was removed by evaporation, the product was ex-
tracted with hexane by sonication and the extract was filtered
through filter paper. Removal of the solvent by evaporation gave
ester 5b (2.65 g, 96%) as a colorless oil. 1H NMR, : 1.17 (s, 6 H),
2.58 (s, 2 H), 3.23 (s, 2 H), 3.66 (s, 3 H). 13C NMR, : 27.7,
32.8, 42.7, 44.1, 51.3, 96.7, 172.3, 189.2. IR, /cm–1: 2953, 2879,
1735, 1437, 1391, 1353, 1230, 1196, 1153, 1121, 1075, 1012, 881,
831, 748, 696, 651, 624, 555. HR-MS (EI), found: m/z 275.0016
[M + H]+. Calculated for C9H14Cl3O3: 275.0009.
Methyl 6-bromo-6,6-dichloro-3,3-dimethyl-5-oxohexanoate
(5c). To a solution of 2,2-dichloro-5,5-dimethylcyclohexane-
1,3-dione30 (418 mg, 2.0 mmol) and NBS (534 mg, 3.0 mmol) in
MeOH (10 mL), Na2HPO4 (142 mg, 1.0 mmol) was added. After
the mixture was stirred at room temperature for 0.5 h, the re-
sidual Na2HPO4 was removed by filtration and washed with
MeOH. The solvent was removed by evaporation, the product
was extracted with hexane by sonication and the extract was
filtered through filter paper. Removal of the solvent by evapora-
tion gave ester 5c (568 mg, 89%) as a colorless oil. 1H NMR, :
1.18 (s, 6 H), 2.59 (s, 2 H), 3.30 (s, 2 H), 3.67 (s, 3 H). 13C NMR,
4-Oxopentanoic acid (2b) was synthesized from 3-methyl-
1
cyclopent-2-enone in 49% yield as a colorless oil. H NMR, :
2.20 (s, 3 H), 2.63 (t, 2 H, J = 6.4 Hz), 2.76 (t, 2 H, J = 6.6 Hz),
7.5—12.0 (br.s, 1 H). 13C NMR, : 27.8, 29.8, 37.7, 178.7, 206.7.
1H and 13C NMR data are consistent with those reported in the
literature.41
5-Oxohexanoic acid (2c) was synthesized from 3-methyl-
: 27.7, 32.9, 42.3, 44.1, 51.4, 81.7, 172.3, 189.5. IR, /cm–1
:
2954, 2877, 1738, 1437, 1392, 1348, 1230, 1153, 1072, 1013, 930,
888, 826, 705, 625, 536. HR-MS (EI), found: m/z 318.9499
[M + H]+. Calculated for C9H14BrCl2O3: 318.9503.
1
cyclohex-2-enone in 64% yield as a colorless oil. H NMR, :
1.90 (quint, 2 H, J = 7.3 Hz), 2.16 (s, 3 H), 2.40 (t, 2 H,
J = 7.3 Hz), 2.55 (t, 2 H, J = 7.3 Hz), 7.4—11.8 (br.s, 1 H).
1
13C NMR, : 18.5, 30.0, 32.9, 42.3, 179.3, 208.2. H and 13C
Lactonization (general procedure). To a solution of haloketo
acid methyl ester (0.20 mmol) in anhydrous MeOH (1 mL),
NaBH4 (9.1 mg, 0.24 mmol) was added. After the mixture was
stirred at 0 C for 0.5 h, the reaction was quenched by addition
of water (200 L) and 2M HCl aqueous solution (200 L). The
product was extracted with CH2Cl2 (220 mL). The extract was
filtered with filter paper for dehydration and the solvent was
removed by evaporation to obtain the corresponding alcohol. To
the thus obtained alcohol, TFA (0.5 mL) was added, the result-
ing mixture was stirred at room temperature for 1 h and then
diluted with CH2Cl2 (20 mL). After the reaction was quenched
by addition of a saturated NaHCO3 solution (20 mL), the prod-
uct was extracted with CH2Cl2 (220 mL) and the extract was
filtered with filter paper for dehydration. The removal of the
solvent by evaporation gave the corresponding lactones 6a,b,d—g
and 7a,b.
NMR data are consistent with those reported in the literature.41
3-Methyl-5-oxohexanoic acid (2d) was synthesized from
3,5-dimethylcyclohex-2-enone in 61% yield as a colorless oil.
1H NMR, : 1.01 (d, 3 H, J = 6.9 Hz), 2.15 (s, 3 H), 2.27 (dd,
1 H, J = 15.6 Hz, J = 6.9 Hz), 2.37 (d, 1 H, J = 5.9 Hz), 2.40
(d, 1 H, J = 7.8 Hz), 2.44—2.61 (m, 2 H). 13C NMR, : 19.9,
26.0, 30.4, 40.5, 49.7, 178.6, 208.1. IR, /cm–1: 2962, 1709,
1407, 1370, 1162, 1087, 957, 911. HR-MS (EI), found: m/z
144.0787 [M]+. Calculated for C7H12O3: 144.0786.
2-Methyl-5-oxohexanoic acid (2e) was synthesized from
3,6-dimethylcyclohex-2-enone42 in 66% yield as a colorless oil.
1H NMR, : 1.21 (d, 3 H, J = 7.3 Hz), 1.72—1.84 (m, 1 H),
1.84—1.96 (m, 1 H), 2.16 (s, 3 H), 2.44—2.61 (m, 3 H).
13C NMR, : 17.1, 27.1, 30.0, 38.5, 41.0, 182.4, 208.3. IR,
/cm–1: 2973, 1707, 1464, 1415, 1362, 1170, 1127, 1068, 910,
810, 747. HR-MS (EI), found: m/z 145.0864 [M + H]+.
Calculated for C7H13O3: 145.0865.
Methyl 6,6-dichloro-3,3-dimethyl-5-oxohexanoate (5a). To
a solution of 2,2-dichloro-5,5-dimethylcyclohexane-1,3-dione30
(418 mg, 2.0 mmol) in MeOH (10 mL), Na2HPO4 (142 mg,
1.0 mmol) was added. After the mixture was stirred at room
6-Chloromethyl-4,4-dimethyltetrahydropyran-2-one (6a) was
synthesized from compound 4a in 98% as a colorless oil.
1H NMR, : 1.11 (d, 6 H, J = 3.2 Hz), 1.66 (dd, 1 H, J = 13.9 Hz,
J = 12.3 Hz), 1.81 (dq, 1 H, J = 14.0 Hz, J = 2.0 Hz), 2.26
(d, 1 H, J = 17.2 Hz), 2.41 (dd, 1 H, J = 17.2 Hz, J = 2.1 Hz),
3.68 (d, 2 H, J = 4.6 Hz), 4.62 (ddd, 1 H, J = 11.9 Hz, J = 9.0 Hz,

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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
1809
J = 4.8 Hz). 13C NMR, : 26.8, 29.8, 30.8, 39.0, 43.7, 46.3, 76.2,
170.6. IR, /cm–1: 3493, 2961, 2873, 1739, 1469, 1431, 1373,
1313, 1239, 1208, 1153, 1087, 1058, 1034, 966, 924, 822, 732,
654, 628, 577. HR-MS (EI), found: m/z 177.0685 [M + H]+.
Calculated for C8H14ClO2: 177.0682.
6-Bromomethyl-4,4-dimethyltetrahydropyran-2-one (6b) was
synthesized from compound 4b in 99% as a colorless oil.
1H NMR, : 1.10 (d, 6 H, J = 4.1 Hz), 1.62 (dd, 1 H, J = 14.0 Hz,
J = 11.9 Hz), 1.86 (dq, 1 H, J = 14.2 Hz, J = 2.0 Hz), 2.26
(d, 1 H, J = 17.2 Hz), 2.40 (dd, 1 H, J = 16.9 Hz, J = 2.1 Hz),
3.53 (d, 2 H, J = 5.0 Hz), 4.59 (dtd, 1 H, J = 11.9 Hz, J = 5.0 Hz,
J = 4.0 Hz). 13C NMR, : 26.9, 29.8, 30.8, 34.5, 40.1, 43.7, 75.8,
170.5. IR, /cm–1: 3476, 3030, 2957, 2871, 2732, 1468, 1421,
1372, 1308, 1239, 1197, 1151, 1083, 1043, 991, 966, 925, 858,
817, 788, 676, 641. HR-MS (EI), found: m/z 221.0179 [M + H]+.
Calculated for C8H14BrO2: 221.0177.
1H NMR, : 1.14 (d, 6 H, J = 8.5 Hz), 1.81 (dd, 1 H, J = 14.0 Hz,
J = 11.7 Hz), 1.98 (dq, 1 H, J = 14.0 Hz, J = 2.4 Hz), 2.29 (dd,
1 H, J = 17.3 Hz, J = 0.7 Hz), 2.43 (dd, 1 H, J = 17.3 Hz,
J = 2.3 Hz), 4.74 (ddd, 1 H, J = 11.6 Hz, J = 3.7 Hz, J = 4.6 Hz),
5.89 (d, 1 H, J = 3.7 Hz). 13C NMR, : 26.3, 29.6, 30.6, 35.0,
43.7, 72.5, 79.4, 169.3. IR, /cm–1: 3476, 2959, 2874, 1742,
1469, 1373, 1234, 1152, 1096, 1054, 994, 964, 920, 896, 824,
770, 751, 656, 574. HR-MS (EI), found: m/z 211.0289 [M + H]+.
Calculated for C8H13Cl2O2: 211.0293.
4,4-Dimethyl-6-trichloromethyltetrahydropyran-2-one (7b)
was synthesized from compound 5b in 99% as a white powder.
1H NMR, : 1.15 (s, 3 H), 1.17 (s, 3 H), 1.81 (dd, 1 H, J = 14.0 Hz,
J = 11.4 Hz), 2.23 (ddd, 1 H, J = 14.0 Hz, J = 2.5 Hz, J = 4.8 Hz),
2.31 (dd, 1 H, J = 17.4 Hz, J = 0.7 Hz), 2.47 (dd, 1 H, J = 17.4 Hz,
J = 2.5 Hz), 4.86 (dd, 1 H, J = 11.4 Hz, J = 4.8 Hz). 13C NMR,
: 26.1, 29.8, 30.5, 37.3, 43.3, 85.1, 99.4, 168.6. IR, /cm–1
:
5-Bromomethyldihydrofuran-2-one (6d) was synthesized from
compound 4d43 in 90% as a colorless oil. 1H NMR, : 2.08—2.19
(m, 1 H), 2.40—2.51 (m, 1 H), 2.53—2.73 (m, 2 H), 3.55 (dd, 1 H,
J = 11.0 Hz, J = 5.7 Hz), 3.58 (dd, 1 H, J = 11.0 Hz, J = 4.6 Hz),
4.72—4.80 (m, 1 H). 13C NMR, : 26.2, 28.4, 34.1, 77.9, 176.3.
1H and 13C NMR data are consistent with those reported in the
literature.44
6-Bromomethyltetrahydropyran-2-one (6e) was synthesized
from compound 4e45 in 97% as a colorless oil. 1H NMR, :
1.67—1.78 (m, 1 H), 1.82—2.05 (m, 2 H), 2.09—2.18 (m, 1 H),
2.48 (ddd, 1 H, J = 18.1 Hz, J = 9.8 Hz, J = 7.1 Hz), 2.63 (dddd,
1 H, J = 18.1 Hz, J = 6.6 Hz, J = 4.6 Hz, J = 1.2 Hz), 3.49 (dd,
1 H, J = 10.8 Hz, J = 6.1 Hz), 3.55 (dd, 1 H, J = 11.0 Hz,
J = 4.6 Hz), 4.48—4.56 (m, 1 H). 13C NMR, : 18.2, 26.3, 29.4,
33.8, 78.6, 170.4. 1H and 13C NMR data are consistent with those
reported in the literature.46
3468, 2961, 2874, 1756, 1471, 1371, 1268, 1226, 1155, 1107,
1068, 1031, 969, 924, 901, 822, 783, 768, 678, 635, 615, 583,
534. HR-MS (EI), found: m/z 244.9910 [M + H]+. Calculated
for C8H12Cl3O2: 244.9903.
S-[(6-Oxotetrahydro-2H-pyran-2-yl)methyl] ethanethioate
(8). To a solution of compound 6e (38.6 mg, 0.20 mmol) in THF
(1 mL), AcSK (30.4 mg, 0.40 mmol) was added. After the mixture
was stirred at 60 C for 12 h, the solvent was removed by evapo-
ration. The product was dissolved in CH2Cl2 and the extract
was filtered through filter paper. Removal of the solvent by
evaporation gave product 8 (37.7 mg, quantitative yield) as a pale-
yellow oil. 1H NMR, : 1.58 (dtd, 1 H, J = 13.8 Hz, J = 11.1 Hz,
J = 5.4 Hz), 1.79—2.07 (m, 3 H), 2.38 (s, 3 H), 2.46 (ddd, 1 H,
J = 18.1 Hz, J = 9.2 Hz, J = 7.1 Hz), 2.59 (dddd, 1 H, J = 17.9 Hz,
J = 7.1 Hz, J = 5.0 Hz, J = 1.2 Hz), 3.14 (dd, 1 H, J = 14.3 Hz,
J = 6.3 Hz), 3.22 (dd, 1 H, J = 14.3 Hz, J = 5.4 Hz), 4.36—4.45
(m, 1 H). 13C NMR, : 18.2, 26.7, 29.3, 30.5, 33.6, 78.9, 170.9,
195.1. IR, /cm–1: 3509, 2952, 1732, 1693, 1419, 1356, 1239,
1138, 1044, 960, 934, 754, 631. HR-MS (EI), found: m/z
189.0584 [M + H]+. Calculated for C8H13O3S: 189.0585.
6-(Iodomethyl)tetrahydro-2H-pyran-2-one (9). To a solution
of compound 6e (38.6 mg, 0.20 mmol) in acetone (4 mL), NaI
(149.9 mg, 1.00 mmol) was added. After the mixture was stirred
at 60 C for 6 h, the solvent was removed by evaporation. The
product was dissolved in CH2Cl2 and the extract was filtered
through filter paper. Removal of the solvent by evaporation gave
product 9 (48.0 mg, quantitative yield) as a pale-yellow oil.
1H NMR, : 1.26 (dtd, 1 H, J = 14.2 Hz, J = 11.1 Hz, J = 5.4 Hz),
1.83—2.04 (m, 2 H), 2.14—2.24 (m, 1 H), 2.47 (ddd, 1 H,
J = 18.1 Hz, J = 9.7 Hz, J = 7.2 Hz), 2.64 (dddd, 1 H, J = 18.1 Hz,
J = 6.9 Hz, J = 4.8 Hz, J = 1.4 Hz), 3.33 (dd, 1 H, J = 18.1 Hz,
J = 6.5 Hz), 3.38 (dd, 1 H, J = 18.1 Hz, J = 4.7 Hz), 4.25—4.35
(m, 1 H). 13C NMR, : 7.5, 18.2, 28.0, 29.2, 78.8, 170.5. IR,
/cm–1: 3433, 2953, 1734, 1461, 1440, 1415, 1351, 1245, 1170,
1077, 1026, 933, 870, 854, 818, 757, 621, 530. HR-MS (EI),
found: m/z 239.9644 [M]+. Calculated for C6H9O2I: 239.9647.
6-(Azidomethyl)tetrahydro-2H-pyran-2-one (10). To a solu-
tion of compound 6e (38.6 mg, 0.20 mmol) in DMF (1 mL),
NaN3 (26.0 mg, 0.40 mmol) was added. After the mixture was
stirred at room temperature for 7 h, the solvent was removed by
evaporation. The product was dissolved in CH2Cl2 and the extract
was filtered through filter paper. The filtrate was concentrated
by evaporation and the residue was purified by silica gel chro-
matography (CH2Cl2) to obtain product 10 (19.2 mg, 62%) as
6-Bromomethyl-4-methyltetrahydropyran-2-one (6f) was
synthesized from compound 4f in 96% as a colorless oil. IR,
/cm–1: 3442, 2958, 1733, 1457, 1422, 1382, 1234, 1086, 1053,
1022, 989, 926, 890, 869, 796, 658. HR-MS (EI), found: m/z
207.0018 [M + H]+. Calculated for C7H12BrO2: 207.0021.
1
trans-Isomer of 6f. H NMR, : 1.13 (d, 3 H, J = 6.9 Hz),
1.71—1.81 (m, 1 H), 1.97—2.06 (m, 2 H), 2.17—2.31 (m, 1 H),
2.56—2.66 (m, 1 H), 3.47 (dd, 1 H, J = 10.8 Hz, J = 6.7 Hz),
3.55 (dd, 1 H, J = 10.8 Hz, J = 5.1 Hz), 4.58—4.68 (m, 1 H).
13C NMR, : 20.9, 23.7, 32.9, 33.3, 37.3, 75.7, 170.9.
1
cis-Isomer of 6f. H NMR, : 1.08 (d, 3 H, J = 6.2 Hz),
1.33—1.46 (m, 1 H), 2.04—2.16 (m, 4 H), 2.65—2.77 (m, 1 H),
3.47—3.55 (m, 2 H), 4.46—4.55 (m, 1 H). 13C NMR, : 21.4,
26.4, 34.2, 35.1, 37.9, 78.4, 170.3.
6-Bromomethyl-3-methyltetrahydropyran-2-one (6g) was
synthesized from compound 4g in 99% as a colorless oil. 1H and
13C NMR data for compound 6g are consistent with those re-
ported in the literature.47
1
trans-Isomer of 6g. H NMR, : 1.32 (d, 3 H, J = 7.1 Hz),
1.53—1.69 (m, 2 H), 2.02—2.20 (m, 2 H), 2.41—2.54 (m, 1 H),
3.51 (dd, 2 H, J = 5.7 Hz, J = 2.3 Hz), 4.47—4.58 (m, 1 H).
13C NMR, : 17.2, 27.5, 27.7, 34.5, 36.0, 79.3, 173.3.
1
cis-Isomer of 6g. H NMR, : 1.25 (d, 3 H, J = 6.8 Hz),
1.73—1.88 (m, 2 H), 2.07—2.20 (m, 2 H), 2.56—2.68 (m, 1 H),
3.45 (dd, 1 H, J = 10.9 Hz, J = 6.1 Hz), 3.53 (dd, 1 H, J = 11.0 Hz,
J = 5.3 Hz), 4.47—4.58 (m, 1 H). 13C NMR, : 16.2, 25.06,
25.10, 33.1, 33.3, 76.7, 174.9.
6-Dichloromethyl-4,4-dimethyltetrahydropyran-2-one (7a)
was synthesized from compound 5a in 97% as a colorless oil.
1
a colorless oil. H NMR, : 1.58—1.80 (m, 1 H), 1.80—2.06

China et al.
1810
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 9, September, 2020
(m, 3 H), 2.42—2.55 (m, 1 H), 2.57—2.70 (m, 1 H), 3.46 (dd, 1 H,
J = 13.2 Hz, J = 5.1 Hz), 3.52 (dd, 1 H, J = 13.0 Hz, J = 4.6 Hz),
4.41—4.50 (m, 1 H). 13C NMR, : 18.4, 25.1, 29.5, 54.4, 78.6,
170.5. IR, /cm–1: 3452, 2941, 2104, 1720, 1445, 1250, 1189,
1162, 1059, 974, 934, 845, 781, 668, 634, 557. HR-MS (EI),
found: m/z 156.0771 [M + H]+. Calculated for C6H10N3O2:
156.0773.
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6-[(Phenylamino)methyl]tetrahydro-2H-pyran-2-one (11).
To a solution of compound 6e (38.6 mg, 0.20 mmol) in MeCN
(1 mL), aniline (93.1 mg, 1.00 mmol) and NaHCO3 (84.0 mg,
1.00 mmol) were added. After the mixture was refluxed with
stirring for 24 h, the solvent was removed by evaporation. The
filtrate was concentrated by evaporation and the residue was
purified by silica gel chromatography (AcOEt—hexane (1 : 1)) to
obtain product 11 (23.4 mg, 57%) as a white powder. 1H NMR,
: 1.50—1.78 (m, 1 H), 1.78—2.02 (m, 3 H), 2.36—2.55 (m, 1 H),
2.55—2.68 (m, 1 H), 3.31 (dd, 1 H, J = 13.7 Hz, J = 7.3 Hz),
3.44 (dd, 1 H, J = 14.2 Hz, J = 3.7 Hz), 4.51—4.60 (m, 1 H),
6.66 (d, 2 H, J = 7.8 Hz), 6.76 (t, 1 H, J = 7.5 Hz), 7.20 (dd, 2 H,
J = 10.5 Hz, J = 9.6 Hz). 13C NMR, : 18.3, 25.5, 29.5, 48.4,
78.9, 113.4, 118.4, 129.4, 147.2, 171.4. IR, /cm–1: 3383, 3050,
2951, 1731, 1603, 1507, 1461, 1439, 1378, 1328, 1241, 1166,
1058, 1030, 992, 933, 876, 755, 696, 666, 639, 613, 598, 564,
535, 515. HR-MS (EI), found: m/z 205.1100 [M]+. Calculated
for C12H15NO2: 205.1103.
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This work was financially supported by a Grant-in-Aid for
Scientific Research C (JSPS KAKENHI (C) Grant Number
19K05466) from JSPS and the Uruma Fund for the Promotion
of Science. T.D. acknowledges support from the Ritsumeikan
Global Innovation Research Organization (R-GIRO) project.
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Received September 30, 2019;
in revised form March 18, 2020;
accepted July 8, 2020