Organoselenium Accelerated Bromolactonization Reaction

Article abstract of DOI:10.1021/acs.joc.9b01294

A highly efficient and regioselective bromolactonization protocol is reported. The quantitative formation of synthetically versatile bromolactones occurs in the presence of only 0.1 mol % of an organoselenium compound, coined DECAD herein, within 90 min.

Full text of DOI:10.1021/acs.joc.9b01294

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An Organoselenium Accelerated Bromolactonization Reaction
Jørn Eivind Tungen, Renate Kristianslund, Anders Vik, and Trond Vidar Hansen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01294 • Publication Date (Web): 26 Aug 2019
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The Journal of Organic Chemistry
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An Organoselenium Accelerated Bromolactonization Reaction
Jørn E. Tungen,*,† Renate Kristianslund,† Anders Vik, Trond V. Hansen
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Department of Pharmacy, Section of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316, Oslo,
Norway.
Supporting Information Placeholder
ABSTRACT: A highly efficient and regioselective bromolactonization protocol is reported. The quantitative formation of
synthetically versatile δ-bromolactones occurs in the presence of only 0.1 mol% of an organoselenium-compound, coined
DECAD herein, within 90 minutes. DECAD is conveniently prepared on multi-gram scale from cheap racemic camphor. The
presented protocol was easy to scale up and performed equally well on gram scale. Investigation of the mechanism revealed
that DECAD forms a selenonium ylen in situ.
INTRODUCTION
Scheme 1. Preparation of bromolactones.
The synthesis of lactones via halolactonization is a
classical method1 that has been known for more than 165
H
years. This useful reaction has been widely employed in
0.1 mol%
This work:
Se)2
total syntheses of natural products.2 Over the years
diastereo-, and more recently, enantioselective versions
have emerged,3,4 enabling the synthesis of a variety of
valuable intermediates and products. Throughout our
studies related to the development of enantioselective
organocatalyzed halolactonization reactions,5 we noticed
that the preparation of several racemic bromolactones
from substituted unsaturated carboxylic acids in particular
required prolonged reaction times and addition of
Brønsted bases for completion. The same observations
have been reported by others.6 One approach to enhance
the reactivity and diminish the reaction time is to activate
the bromenium species prior to addition. Organoselenium
compounds are versatile reagents which have been used to
catalyze a variety of synthetically useful transformations.7-9
In this regard, the activation of unreactive electrophiles in
alkene addition reactions is of particular interest.8a,8c
Diaryl diselenides (ArSeSeAr) and arylselenides halides
(ArSeX) are known to react with halogenation reagents to
produce intermediates that may transfer a halogenium ion
(X+) to alkenes.7 Halolactonization catalyzed by other
chalcogens have been met with considerable success,
including enantioselective protocols.10 However, scarce
efforts have been made to utilize organoselenium catalysts
in bromolactonization reactions.11 Existing protocols
frequently suffer from lack of regiocontrol, dihalogenation
and low yields due to unwanted selenolactone formation.11
Recently, Einaru et al. disclosed that reduced reaction
times in bromolactonization reactions of unsaturated
carboxylic acids were possible to achieve in an
organocatalyzed protocol.6c Still, reaction times of 6-12
hours were needed. Herein we report our results using an
organoselenium catalyst for the cyclization of unsaturated
carboxylic acids (Scheme 1).
O
O
NBS (1.1 equiv.),
4Å MS, MeCN, rt., 1 h
O
Br
O
OH
96%
new catalysis
rapid and clean reaction
RESULTS AND DISCUSSION
Based on the aforementioned rationale for
organoselenium catalysis, we first designed, prepared and
investigated a collection of organoselenium based catalysts
1-4 as a basis for further developments (Figure 1). 5 mol%
of each of the diselenide compounds 1-4 was then tested in
the bromolactonization reaction of 5-phenylhex-5-enoic
acid (5a) (Table 1). Initial investigations revealed that all
four diselenide compounds efficiently catalysed the
bromolactonization reactions leading to racemic product
6a. Monitoring the initial reaction progress with respect to
the starting material 5a using GLC-analyses revealed
complete conversion of 5a within 15 minutes to the
bromolactone 6a and its aryl- or alkylselenium analog 7a-
d. In the absence of 1-4, the preparation of racemic 6a
required 24
CF3
OMe
H
O
Se)2
Se)2
Se)2
F3C
N
N
Se)2
H
H
O
1
3
2
4
Figure 1. Organoselenium compounds 1-4 as putative
halolactonization catalysts.
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full conversion of 5a to lactone 6a (entry 5). Substantial
1
2
3
4
5
6
7
8
loss of reactivity was observed when 0.1 mol% of either
diselenide catalyst 2 or 3 were employed, affording
bromolactone 6a in only 34% and 27% yield after 2 h
(entry 6 and 7). The same was the case when 4 was used
as catalyst (entry 8). Of note, dropwise addition of NBS in
solution and addition of molecular sieves were crucial in
order to achieve high and consistent yields of the
bromolactone 6a at lower catalyst loadings. Elevated
concentrations of NBS probably inhibits the reactivity of
the selenyl bromide formed in the reaction.12
hours in order to obtain, at best, 47% yield after
purification by column chromatography (entry 9).
Although disappointed with the lack of enantioselectivity,
we were intrigued by the remarkably short reaction times
and the magnitude of conversion, i.e. full conversion after
15 minutes (entry 1-4), compared to several hours or days
for other catalysts (see Table 2). Addition of diaryl
diselenides to Br+-sources produce arylselenide halides
which in the presence of alkenes are known to afford the
corresponding vicinally-functionalized selenides.8a,11b
Thus, the formation of selenolactone 7 should be
dependent exclusively on the amount of 1-4. This was
confirmed by varying the loading of catalyst 1 which
revealed that the isolated yield of the selenolactone 7a
obtained was strictly dependent on the amount of 1. Using
the diselenide 1 in 5, 10, 15, 25 and 50 mol% in the
reaction always returned twice the amount of the
selenolactone 7a as the catalyst loading, as determined by
HPLC- and GLC-analyses. Consequently, reducing the
catalyst loading would diminish the formation of this
undesired selenolactone.
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The efficiency of 1 was found to be favorable to other
known catalysts or additives when tested in the
bromolactonization reaction of 5-phenylhex-5-enoic acid
(5a) (see Table 2). This was especially evident in terms of
turnover frequencies as most catalysts failed to reach
completion even after 24 hours (entry 2-7). Using an
indole-based catalyst13 or vanadium (IV) oxide14 provided
the bromolactones in high yields, although extended
reaction times and tenfold amount of the catalysts were
required compared to 1 (entry 9 and 10).
Table 2. Screening of known catalysts in the bromo-
lactonization reaction.
Table 1. Screening of diselenide catalysts in the
bromo-lactonization reaction.
catalyst
O
NBS (1.1 equiv.),
Br
O
O
Ph
OH
Ph
6a
cat. 1-4,
NBS (1.1 equiv.),
O
4Å MS, MeCN, rt.
5a
RSe
OH
Br
O
O
O
O
Ph
4Å MS,
MeCN, 0 °C
yield (%)a
Ph
entry
catalyst
DECAD (1)
pyridine
catalyst loading reaction time
5a
6a
7a-d
1
2
3
4
5
6
7
8
0.1 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
1 h
94
52
77
51
61
79
71
92
24 h
24 h
24 h
24 h
24 h
24 h
8 h
7a, R =
7b, R =
OMe
7c, R =
7d, R =
CF3
pyridine/DMAP
2,6-lutidine
thiourea
H
O
F3C
N
N
H
H
O
quinuclidine
Ph3P=S
catalyst
loading
ratio
yield
entry
catalyst
time
[6:7]a
91:9
(%)b
94
89
94
93
96
34
27
37
47
Me2S
ethyl 2-
methylindole-3-
carboxylate
1
2
3
4
5
6
7
8
9
1
2
5 mol%
5 mol%
5 mol%
5 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
-
15 min
15 min
15 min
15 min
1 h
9b
1 mol%
1 mol%
24 h
18 h
89
90:10
91:9
3
10c
V2O5, UHPd
90
4
89:11
>99:1
>99:1
>99:1
>99:1
-
b
c
aIsolated material. The reaction was run in heptane. The
1
reaction was run in acetone:H2O and NH4Br was used as
d
2
2 h
the bromonium source. UHP = urea-hydrogen peroxide
complex
3
2 h
4
2 h
none
24 h
The conversion of carboxylic acid 5a to bromolactone
6a was monitored using GLC with the optimized amount of
DECAD (1) (Figure 2). The reaction is remarkably rapid
and proceeds to 50% conversion after only ca 4 minutes.
Under these conditions, complete conversion was reached
within 70 minutes.
aDetermined by either 1H NMR or HPLC. bCombined isolated
yield of 6a and 7a-7d.
The catalyst loading could be decreased to only 0.1
mol% without appreciable loss of reactivity when using
di(endo-3-camphoryl) diselenide catalyst 1 (DECAD).
However, an extended reaction time (1 h) was needed for
After being content with the catalytic performance
and excellent regioselectivity of 1, the scope of the
protocol was tested with a range of substrates. The results
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are summarized in Table 3. Overall, all of the substituted 5- bromolacactone is initially produced as observed by TLC
1
2
3
4
5
6
7
hexenoic acids reacted rapidly with high to excellent
chemical yields. The para- and ortho-tolyl-substituted
lactones
and NMR, but was very difficult to isolate as it hydrolyses
readily.
When 8 was treated with DECAD (1) under precisely
the same conditions, the corresponding bromolactone 9
Table 3. Bromolactonization of δ-unsaturated acids 5a-
5l catalyzed by DECAD (1)
8
9
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
O
Br
O
O
R
OH
R
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4Å MS, MeCN, rt.
5a-l
6a-l
entrya
R
reaction time (min)
yield (%)b
96
1
5a, 6a: phenyl
60
90
90
90
90
60
60
60
60
60
60
60
2
5b, 6b: 4-CH3-C6H4
5c, 6c: 2-CH3-C6H4
5d, 6d: 2-naphtyl
5e, 6e: 4-OMe-C6H4
5f, 6f: 4-F-C6H4
70
3
85
4
91
5
77
6
96
7
5g, 6g: 4-Cl-C6H4
5h, 6h: 4-Br-C6H4
5i, 6i: 3-F-C6H4
93
Figure 2. Conversion of carboxylic acid 5a to bromolactone
6a with respect to time.
8
93
9
91
10
11
12
13
14
15
16
17c
5j, 6j: 3,4,5-F-C6H2
5k, 6k: 4-NO2-C6H4
5l, 6l: 3-NO2-C6H4
94
96
6b and 6c were isolated in somewhat diminished yields,
70% and 85%, respectively (entry 2 and 3). Prolonged
reaction times (90 min) were also necessary to achieve
satisfactory results. Electron donating substituent may
accelerate the reaction due to activation of the olefin.
However, when an electron donating para-methoxy group
was employed, the same results as for the tolyl-substrates
were observed (entry 5). The slightly reduced yield is most
likely connected to incomplete conversion as no other side
products were detected. With the same short reaction
time, product 6c was formed in 91% yield (entry 4). When
a halogen-substituent was present in the para- or meta-
position of the bromolactones (entry 6-9), near
quantitative chemical yields were observed in all cases.
Similar results were achieved using a 3,4,5-trisubstituted
fluorophenyl substrate (entry 10). A nitro-group in the
para- or meta-position gave some of the highest yields
among all substrates investigated (entry 11 and 12). The
same trend, i.e excellent conversion and swift reactions
times, was observed for other electron deficient
substrates. The meta-cyano-para-tolyl- and the meta-
acetylphenyl substituted lactones were formed in 85% and
92% yields, respectively, within 60 minutes (entry 13 and
14). Aliphatic substrates are generally less reactive than
their aromatic counterparts towards bromolactonization
and extended reaction times with harsh conditions are
often necessary. However, comparable results as for the
aryl subtrates, in terms of reactivity and yields, were
observed when an isopropyl- or a cyclohexyl-substituent
was investigated (entry 15 and 16). Furthermore, the
seleno-catalyzed bromolactonization reaction performs
excellent on gram scale, affording bromolactone 6a in
quantitative yield (>95%) (entry 17). When hex-5-enoic
acid (R = H) is applied, using the disclosed conditions, the
hydrolytic product of the bromolactone is formed. The
94
5m, 6m: 3-CN-4-CH3-C6H3
5n, 6n: 3-acetylphenyl
5o, 6o: iPr
60
60
90
60
60
85
92
92
5p, 6p: cyclohexyl
5a, 6a: phenyl
97
95
aThe reactions were performed on a 0.13 mmol scale.
bIsolated material. The reaction was performed on a 5.78
c
mmol scale (1.1 g of 5a)
was obtained in 95% yield in less than one hour, see
Scheme 2 A. Using a phenyl 1,2-disubstituted E-configured
substrate (10a) at ambient temperature resulted in a 2:1
mixture of the δ- and γ-lactone, respectively. The
regioisomeric ratio could be considerably improved at
lower temperature (-35 ˚C) producing the lactones 11a
and 11b in a 20.5:1 ratio in favor of the δ-lactone 11a, as
1
determined by H NMR-analysis. The regioselectivity was
shifted towards the γ-lactone without an activated benzylic
position, as seen for the methyl-substituted substrate 10b.
The lactones were obtained in an 1:8 ratio and in 92%
combined chemical yield. Of note, an extended reaction
time of two hours was required to acquire comparable
yields for both E-configured substrates (Scheme 2, B) The
same swift conversion and excellent chemical yield was
observed when a Z-internal olefin was used as the
substrate (Scheme 2, C). Halolactonization of allenoic
acids are difficult to realize and are often associated with
deprived conversion of the substrate. When allenoic acid
14 was subjected to the disclosed conditions the
lactonization went remarkable efficiently, affording the
sensitive lactone 15 in 92% yield. (Scheme 2, D). The cis-
configured substrate 16 afforded the γ-lactone 17b as the
sole product in 95% yield and in only 30 min when treated
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1
2
3
Br
I
1
1
96
89
with DECAD (1) (Scheme 2, E). This is interestingly in
contrast to the trans-configured substrate 10a which
returned the δ-lactone as the main product.
1
2
3
4
5
6
7
8
Cl
24
trace
Exchanging NBS with NIS and using otherwise the
same conditions, produced the corresponding iodo-
aIsolated material.
Scheme 2. Selenium catalyzed bromolactonization of
various unsaturated acids.
Next, we turned our attention to explore the reaction
mechanism of this rapid and synthetically useful reaction.
Rapid conversion rates are frequently associated with
A:
Ph
O
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
mechanisms.15
Thus,
the
developed
O
radical
9
O
Ph
9, 95%
Br
O
bromolactonization reaction was executed in the presence
of several radical scavengers in order to determine
whether the reaction proceeds through such a mechanism.
Experiments with butylated hydroxytoluene (BHT) gave
somewhat inconclusive results (70% yield). In the absence
of light and in the presence of ascorbic acid or δ-
tocopherol, the reaction proceeded in the same high
yielding manner as without a scavenger, rendering support
for an ionic mechanism. Addition of the radical initiator
2,2’-azobis(2-methylpropionitrile) (AIBN), at elevated
temperature, did not accelerate the poor conversion of 5a
into the chlorolactone, further supporting an ionic
mechanism (see Supporting Information). Using 5 mol% of
the diselenide 1 constantly yielded 10% of selenolactone
7a while excess of 1 afforded 7a, almost exclusively. This
inclines that the formation of the selenolactone proceeds
considerably faster than the formation of 6a. By this
rationale, the bromolactonization reaction should cease
after consumption of 1. As this is not the case, we
hypothesized that the selenolactone 7a most likely is the
catalytic specie generated in situ. Selenolactone 7a was
then synthesized on a preparative scale to test our
assumption. As expected, 0.5 equivalents of the diselenide
1 in the presence of 5a afforded the selenolactone 7a in
less than 15 minutes and in near quantitative yield.
Gratifyingly, 0.1 mol% of 7a performed equally well as the
OH
10
11
12
13
14
15
16
17
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22
23
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4Å MS, MeCN
rt, 1 h
8
B:
Br
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
O
O
Br
O
R
OH
R
O
R
4Å MS, MeCN
-35 °C, 2 h
(rt for 10b)
()-11a and ()-11b,
R = Ph, 94%, 20.5:1
()-11c and ()-11d,
R = Me, 92%, 1:8
10a, R = Ph
10b, R = Me
C:
DECAD (1) 0.1 mol%, Br
NBS (1.1 equiv.),
O
O
O
OH
4Å MS, MeCN
rt, 1 h
Br
Br
12
()-13, 90%
D:
Br
•
O
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
OH
O
tBu
tBu
4Å MS, MeCN
rt, 1 h
O
14
15, 92%
E:
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
Br
O
Br
O
OH
Ph
O
O
Ph
O
4Å MS, MeCN
rt, 0.5 h
16
()-17a and ()-17b, 93%, >1:20
diselenide
1 itself, giving full conversion to the
bromolactone 6a within 60 minutes, and thereby
confirming our hypothesis. DECAD (1) should therefore be
considered as a precatalyst rather than a catalyst. Further
clues regarding the mechanism were revealed by NMR
experiments. An equimolar mixture of selenolactone 7a
and NBS in MeCN-d3 showed significant shifts of several
characteristic signals of this selenolactone, see Supporting
Information. Noteworthy, complete conversion of NBS to
succinimide was also observed. These observations led us
to propose the mechanistic cycle shown in Scheme 3, in
which selenonium ylen intermediate I is formed by the
reaction between 7a and NBS. The likely role of the
molecular sieves is to reduce the hydrolysis of the putative
labile intermediate I. The existence of complex I was later
confirmed by HRMS-analysis (Supporting information).
This intermediate should render the bromenium specie
electrophilic and reactive towards alkenes (II).7
Intramolecular ring closure of 5a is then enabled through a
concerted mechanism, which in turn produces the
bromolactone and selenolactone enol III. The catalytic
specie 7a is then regenerated through rapid
tautomerization. The possibility to form a selenonium ylen
may explain the high turnover frequency of 1 compared to
congener 6q in 89% isolated yield (Table 4, entry 2).
Disappointingly, the disclosed protocol could not be
directly transferred to form chlorolactones even at
prolonged reaction times or with higher catalyst loadings.
Other chlorinating reagents such as 5-chlorobenzotriazole
and 1,3-dichloro-5,5-dimethylhydantoin or those in
combination with bases did not improve the outcome. Of
interest, the bromo- and iodolactonization performed
equally well with Br2 or I2 as the halogen source.
Table 4 Halolactonization of 5a catalyzed by DECAD
(1)
DECAD (1) 0.1 mol%,
NXS (1.1 equiv.),
O
X
O
O
Ph
OH
Ph
4Å MS, MeCN, rt.
5a
6a, X = Br
6q, X = I
6r, X = Cl
entrya
X
reaction time (h)
yield (%)a
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2-4, as the latter catalysts are unable to form such material. Melting points were measured using a Barnstead
1
2
3
4
5
6
7
intermediates. An acetophenone-derived selenide catalyst
was prepared17 to test this hypothesis. Bromolactone 6a
was obtained in 91% yield in less than 60 minutes in the
presence of 0.1 mol% of this diselenide catalyst, further
strengthening the assumption of the involvement of a
selenonium ylen specie.
Electrothermal IA9200 melting point apparatus. Thin layer
chromatography was performed on silica gel 60 F254
aluminum-backed plates fabricated by Merck. Flash
column chromatography was performed on silica gel 60
(40-63 µm) produced by Merck. NMR spectra were
recorded on a Bruker AVII400 or a Bruker DPX300
1
spectrometer at 400 MHz or 300 MHz respectively for H
NMR and at 100 MHz or 75 MHz respectively for 13C NMR.
Coupling constants (J) are reported in hertz and chemical
shifts are reported in parts per million () relative to the
central residual protium solvent resonance in 1H NMR
(CDCl3 =  7.27, MeOD-d4 = δ 3.31 and CD3CN =  1.94) and
the central carbon solvent resonance in 13C NMR (CDCl3 = 
77.00, MeOD-d4 = δ 49.00 and CD3CN =  1.32). Mass
spectra and high resolution mass spectra were recorded at
70 eV on Micromass Prospec Q or Micromass QTOF 2W
spectrometer using ESI as the method of ionization. GC was
performed on an Aglient Technologies 7820A GC
instrument with split (1:30) injection and flame ionization
detector, and equipped with an achiral column (Aglient J &
W GC columns 19091J-413 HP-5).
8
9
Scheme 3. Proposed mechanism of the selenium
catalyzed bromolactonization reaction.
10
11
12
13
14
15
16
17
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19
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23
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51
52
53
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57
58
59
60
Fast
DECAD (1) 0.1 mol%,
NBS (1.1 equiv.),
O
Ph
O
O
Se
Ph
OH
O
4Å MS, MeCN, rt.
5a
()7a
Ph
O
Br
O
Ph
O
O
Se
6a
HO
III
Di(endo-3-camphoryl) diselenide (1). Prepared
according to the procedure by Back and co-workers.16
Camphor (2.00 g, 13.1 mmol, 1.00 equiv.) in THF (15 mL)
was added to a flask containing LDA (15.8 mL, 1.20 equiv.,
1.0 M in THF/hexane) at – 40 °C, and stirred for 2 h.
Selenium (1.35 g, 17.0 mmol, 1.30 equiv.) was added, and
the resulting suspension was stirred for 5 h at – 40 °C. The
reaction was quenched with sat. aq. NH4Cl (50 mL),
warmed to room temperature, and air was bubbled
through the reaction mixture overnight. The mixture was
then added to ether (50 mL), washed with brine (50 mL),
dried (Na2SO4), filtered through a plug of celite and
concentrated in vacuo. The residue was purified by flash
chromatography on silica (5-10% EtOAc in hexane), and
further purified by recrystallization from methanol to
afford the title compound 1 as bright yellow crystals. TLC
(hexanes/EtOAc 9:1): Rf = 0.30, visualized with CAM stain;
1H NMR (400 MHz, CDCl3) δ 4.50 (dd, J = 4.8, 2.2 Hz, 2H),
2.42 – 2.35 (m, 2H), 1.87 – 1.75 (m, 4H), 1.69 (ddd, J = 15.3,
10.9, 4.4 Hz, 2H), 1.39 (ddd, J = 13.9, 8.7, 5.5 Hz, 2H), 1.03
(s, 6H), 0.98 (s, 6H), 0.93 (s, 6H).13C{1H} NMR (101 MHz,
CDCl3) δ 216.3, 58.4, 56.5, 48.8, 46.7, 30.6, 23.0, 19.8, 19.6,
9.7. HRMS (ESI+): Exact mass calculated for C20H30O2Se2Na
[M+Na]+: 485.0468, found 485.0468. The diselenide 1 was
prepared starting from either (±)-camphor or (+)-
camphor. When starting from (+)-camphor, the specific
optical rotation of the resulting diselenide product was: [α]
tautomerization
Ph
O
O
Se
Br
O
H
Ph
O
Ph
O
O
Se
II
O
O
()7a
Br
O
O
N
O
Ph
O
O
O
Se
H
O
N
HO
Ph
O
Br
5a
I
CONCLUSIONS
In summary, we have developed an extremely rapid
organoselenium accelerated method for preparing racemic
bromo- and iodolactones in excellent yields and
regioselectivity. Our approach compares exceedingly well
with those methods already published in terms of yields
and reaction time as well as regioselectivity. The DECAD-
catalyst is conveniently prepared in an one-pot protocol
from commercially available inexpensive racemic
camphor. A plausible mechanism was outlined based on
experimental results, NMR- and MS-data. Studies towards
an asymmetric version is ongoing and will be reported in
due time.
25 = 234.1 (c = 3.20, CHCl3).
퐷
(S)-1-Bromo-2-(1-methoxyethyl)benzene
(18).
Prepared from commercially available (S)-(−)-2-bromo-α-
methylbenzyl alcohol according to the procedure by
Resnick and co-workers.18 Spectroscopic data is in
EXPERIMENTAL SECTION
1
agreement with literature18. H NMR (400 MHz, CDCl3) δ
General Information. Unless stated otherwise, all
commercially available reagents and solvents were used in
the form they were supplied without any further
purification. The stated yields are based on isolated
7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.47 (dd, J = 7.8, 1.8 Hz, 1H),
7.34 (td, J = 7.4, 1.2 Hz, 1H), 7.12 (ddd, J = 7.9, 7.2, 1.8 Hz,
1H), 4.71 (q, J = 6.4 Hz, 1H), 3.26 (s, 3H), 1.41 (d, J = 6.4 Hz,
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The Journal of Organic Chemistry
Page 6 of 12
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.6, 132.7, 128.7,
127.8, 126.9, 122.6, 78.22, 56.7, 22.5.(R,R)-Bis[2-(1-
methoxyethyl)phenyl] diselenide (2). Prepared from
bromide 18 according to the procedure by Wirth and
Fragale.19 Spectroscopic data is in agreement with
literature.19 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.8,
1.3 Hz, 1H), 7.33 (dd, J = 7.7, 1.6 Hz, 1H), 7.29 – 7.23 (m,
1H), 7.18 – 7.12 (m, 1H), 4.73 (q, J = 6.5 Hz, 1H), 3.20 (s,
3H), 1.44 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 143.7, 133.2, 129.5, 128.3, 128.1, 126.2, 78.89, 56.44,
22.37. HRMS (ESI+): Exact mass calculated for
C18H22NaO2Se2 [M+Na]+: 452.9842, found 452.9845.
Preparation of starting materials. The following
1
2
3
4
5
6
7
8
substrates were prepared as previously reported: 5a, 5b,
5d, 5e, 5f, 5g, 5h, 5i, 5k, 5o and 5p.5c Substrate 85a and
10a6c were prepared as previously described.
5-(o-Tolyl)hex-5-enoic
acid
(5c).
Prepared
according to the previously reported general method B.5c
Step 2: Yield: 324 mg (87%) of colourless oil. TLC
1
(hexanes/EtOAc 9:1): Rf = 0.34, visualized with KMnO4; H
NMR (400 MHz, CDCl3) δ 7.20 – 7.10 (m, 3H), 7.09 – 7.01
(m, 1H), 5.20 (q, J = 1.5 Hz, 1H), 4.90 (d, J = 1.9 Hz, 1H),
3.66 (s, 3H), 2.40 – 2.31 (m, 4H), 2.29 (s, 3H), 1.73 (p, J =
7.6 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 149.0,
142.6, 134.8, 130.1, 128.3, 126.9, 125.4, 114.4, 51.5, 37.0,
33.6, 23.0, 19.8. HRMS (ESI+): Exact mass calculated for
C14H18NaO2 [M+Na]+: 241.1199, found 241.1199. Step 3:
Yield: 286 mg (94%) of colourless oil. TLC (hexanes/EtOAc
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)-3-(1-(2-
bromophenyl)ethyl)urea (19).
A solution of 3,5-
bis(trifluoromethyl)phenyl isocyanate (0.405 g, 1.59 mmol,
1.00 equiv.) in CH2Cl2 (2 mL) was added dropwise to a
solution of (S)-1-(2-bromophenyl)ethylamine (0.318 g,
1.59 mmol, 1.00 equiv.) in CH2Cl2 (2 mL). The reaction was
stirred until completion as judged by TLC. The solvent was
removed in vacuo to afford the title compound as a white
solid. The product 19 was sufficiently pure, as judged by
NMR, and used in the next step without further
purification. Yield: 719 mg (99%). TLC (hexanes/EtOAc
1
1:1): Rf = 0.44, visualized with KMnO4; H NMR (400 MHz,
CDCl3) δ 7.22 – 7.10 (m, 3H), 7.11 – 6.96 (m, 1H), 5.21 (q, J
= 1.6 Hz, 1H), 4.92 (d, J = 1.8 Hz, 1H), 2.48 – 2.34 (m, 4H),
2.29 (s, 3H), 1.74 (p, J = 7.5 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 179.3, 148.8, 142.5, 134.8, 130.1, 128.3,
126.9, 125.5, 114.6, 36.8, 33.4, 22.7, 19.8. HRMS (ESI+):
Exact mass calculated for C13H16NaO2 [M+Na]+: 227.1043,
found 227.1042.
4:1): Rf = 0.38, visualized with CAM stain; [α] 25 = 27.0 (c =
퐷
5-(3,4,5-Trifluorophenyl)hex-5-enoic acid (5j).
Prepared according to the previously reported general
method B.5c Step 2: Yield: 156 mg (35%) of colourless oil.
TLC (hexanes/EtOAc 9:1): Rf = 0.27, visualized with
1
1.0, CHCl3); H NMR (600 MHz, CDCl3) δ 7.80 (s, 2H), 7.57
(dd, J = 8.1, 1.2 Hz, 1H), 7.48 (s, 1H), 7.38 (dd, J = 7.8, 1.7
Hz, 1H), 7.33 (td, J = 7.4, 1.2 Hz, 1H), 7.15 (ddd, J = 8.0, 7.3,
1.7 Hz, 1H), 6.62 (s, 1H), 5.29 – 5.13 (m, 2H), 1.53 (d, J = 6.8
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.4, 141.8,
140.1, 133.5, 132.22 (q, 2JCF = 33.4 Hz), 129.3, 128.2, 127.1,
1
KMnO4; H NMR (400 MHz, CDCl3) δ 7.07 – 6.96 (m, 2H),
5.29 (s, 1H), 5.14 (s, 1H), 3.67 (s, 3H), 2.50 – 2.41 (m, 2H),
2.34 (t, J = 7.3 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 173.6, 152.3 (dd, J = 9.9, 4.2 Hz), 149.8
(dd, J = 10.1, 4.5 Hz), 144.8 (d, J = 2.2 Hz), 140.3 (t, J = 15.5
Hz), 137.8 (t, J = 15.5 Hz), 136.9 (td, J = 7.3, 4.6 Hz), 114.7
(d, J = 1.7 Hz), 110.3 – 109.9 (m), 51.6, 34.1, 33.1, 23.1.
HRMS (ESI+): Exact mass calculated for C13H13F3NaO2
[M+Na]+: 281.0760, found 281.0760. Step 3: Yield: 143 mg
(97%) of white solid. TLC (hexanes/EtOAc 6:4): Rf = 0.35,
1
122.41, 123.0 (q, JCF = 275.1 Hz), 118.6, 116.2, 50.49,
21.72. HRMS (ESI+): Exact mass calculated for
C17H13BrF6N2NaO [M+Na]+: 477.0008, found 477.0007.1,1'-
((1S,1'S)-(Diselanediylbis(2,1-phenylene))bis(ethane-
1,1-diyl))bis(3-(3,5-bis(trifluoromethyl)phenyl)urea)
(3). The bromide 19 (732 mg, 1.61 mmol, 1.00 equiv.) was
dissolved in THF (16 mL, 0.1 M) and cooled to - 78 °C
before dropwise addition of tBuLi (1.7 M in pentane, 2.84
mL, 4.82 mmol, 3.00 equiv.). The resulting bright yellow
solution was stirred at 0 °C for 30 min. Subsequently,
selenium (140 mg, 1.77 mmol, 1.10 equiv.) was added and
the resulting brown suspension was stirred at ambient
temperature for 3 h, and 1M HCl was added. The reaction
mixture was extracted with CH2Cl2 (2x50 mL) and the
combined organic extracts were dried (MgSO4). Powdered
KOH (93 mg) was added before filtration and removal of
solvents in vacuo. The residue was purified by flash
chromatography on silica (10-20% EtOAc in hexane) to
afford 3 as a light yellow solid. Yield: 504 mg (34%). TLC
(hexanes/EtOAc 4:1): Rf = 0.38, visualized with CAM stain;
1
visualized with KMnO4; Mp: 66-69 °C; H NMR (600 MHz,
CDCl3) δ 7.04 – 6.98 (m, 2H), 5.31 (s, 1H), 5.15 (s, 1H), 2.49
(t, J = 7.5 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.78 (p, J = 7.4 Hz,
2H). 13C{1H} NMR (151 MHz, CDCl3) δ 151.9 (dd, J = 10.0,
4.3 Hz), 150.3 (dd, J = 10.0, 4.2 Hz), 145.0 – 144.2 (m),
139.9 (t, J = 15.5 Hz), 138.2 (t, J = 15.5 Hz), 136.8 (td, J =
7.3, 4.6 Hz), 110.1 (dd, J = 17.0, 4.4 Hz). HRMS (ESI+): Exact
mass calculated for C12H11F3NaO2 [M+Na]+: 267.0601,
found 267.0602.
5-(3-Nitrophenyl)hex-5-enoic acid (5l). Prepared
according to the previously reported general method B.5c
Step 2: Yield: 193 mg (32%) of colourless oil. TLC
[α] 20 = - 51.6 (c = 2.68, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1
(hexanes/EtOAc 9:1): Rf = 0.17, visualized with KMnO4; H
퐷
NMR (400 MHz, CDCl3) δ 8.25 (t, J = 2.0 Hz, 1H), 8.15 – 8.10
(m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 5.43 (s, 1H), 5.24 (q, J = 1.2
Hz, 1H), 3.68 (s, 3H), 2.65 – 2.52 (m, 2H), 2.36 (t, J = 7.3 Hz,
2H), 1.80 (p, J = 7.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 173.6, 148.4, 145.5, 142.6, 132.1, 129.3, 122.3, 121.0,
115.4, 51.6, 34.3, 33.2, 23.2. HRMS (ESI+): Exact mass
calculated for C13H15NNaO4 [M+Na]+: 272.0893, found
272.0894. Step 3: Yield: 79 mg (91%) of white solid. TLC
8.20 (s, 1H), 7.55 (s, 2H), 7.37 (s, 1H), 7.30 – 7.09 (m, 5H),
6.39 (bs, 1H), 4.79 (q, J = 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz,
3H). .13C NMR (101 MHz, CDCl3) δ 155.4, 143.4, 140.1,
132.0 (q, 2JCF = 33.3 Hz), 128.7, 127.5, 125.4, 123.0 (q, 1JCF
=
272.6 Hz), 118.5, 115.85, 50.3, 22.8. HRMS (ESI+): Exact
mass calculated for C34H26F12N4NaO2Se2 [M+Na]+:
933.0087, found 933.0099.
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The Journal of Organic Chemistry
(hexanes/EtOAc 1:1): Rf = 0.39, visualized with KMnO4;
Mp: 102-105 ºC; H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H),
acetonitrile (0.5 mL) was added dropwise and the
resulting mixture was stirred at ambient temperature until
full conversion as judged by TLC (60 – 90 min). The
reaction mixture was treated with sat. aq. Na2S2O3 (5 ml)
and EtOAc (5 ml) was subsequently added. The phases
were separated and the organic phase was washed with
aq. NaOH (2 x 5 ml, 1.0 M) and brine (5 ml). The organic
phase was dried (Na2SO4), filtered and evaporated in
vacuo. The residue was purified by column
chromatography on silica (hexanes/EtOAc 5:1) to afford
the corresponding bromolactones. The chemical purities
1
1
2
3
4
5
6
7
8
8.26 (t, J = 2.0 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.50 (t, J = 8.0
Hz, 1H), 5.44 (s, 1H), 5.25 (d, J = 1.1 Hz, 1H), 2.69 – 2.52 (m,
2H), 2.41 (t, J = 7.3 Hz, 2H), 1.81 (p, J = 7.4 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 13C{1H} NMR (101 MHz, CDCl3) δ 179.2,
148.4, 145.3, 142.4, 132.0, 129.3, 122.3, 120.9, 115.5, 34.1,
33.1, 22.8. HRMS (ESI+): Exact mass calculated for
C12H13NNaO4 [M+Na]+: 258.0737, found 258.0736.
5-(3-Cyano-4-methylphenyl)hex-5-enoic
acid
9
(5m) Prepared according to the previously reported
general method B.5c Step 2: Yield: 135 mg (36%) of
colourless oil. TLC (hexanes/EtOAc 85:15): Rf = 0.20,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
and diastereomeric ratios were determined by H NMR
and/or HPLC analysis (Eclipse XDB-C18, MeOH:H2O 55:45,
1 mL/min, 217 nm for purified materials), (Eclipse XDB-
C18, MeCN:MeOH:H2O 60:10:30, 1 mL/min, 217 nm for
crude materials).
1
visualized with KMnO4; H NMR (400 MHz, CDCl3) δ 7.61
(d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.1, 2.0 Hz, 1H), 7.29 – 7.26
(m, 1H), 5.32 (s, 1H), 5.13 (q, J = 1.2 Hz, 1H), 3.67 (s, 3H),
2.55 – 2.48 (m, 5H), 2.33 (t, J = 7.4 Hz, 2H), 1.76 (p, J = 7.5
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.7, 145.4,
140.9, 139.1, 130.3, 130.0, 118.2, 114.2, 112.9, 51.6, 34.2,
33.2, 23.1, 20.1. HRMS (ESI+): Exact mass calculated for
C15H17NNaO2 [M+Na]+: 266.1151, found 266.1151. Step 3:
Yield: 105 mg (95%) of white solid. TLC (hexanes/EtOAc
6-(Bromomethyl)-6-phenyltetrahydro-2H-pyran-
2-one (6a). Prepared according to the general method.
Spectroscopic data is in agreement with literature.10c,20
Yield: 34 mg (96%) of colourless oil; TLC (hexanes/EtOAc
1
6:4): Rf = 0.27, visualized with CAM stain; H NMR (400
MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 3.68 (d, J = 11.2 Hz, 1H),
3.63 (d, J = 11.2 Hz, 1H), 2.56 – 2.32 (m, 4H), 1.89 – 1.77
(m, 2H), 1.66 – 1.52 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 170.6, 140.4, 129.1, 128.7, 125.5, 85.3, 41.7, 30.2,
29.2, 16.4.
1
6:4): Rf = 0.24, visualized with KMnO4; Mp: 82-85 °C; H
NMR (600 MHz, CDCl3) δ 7.62 (d, J = 2.0 Hz, 1H), 7.50 (dd, J
= 8.1, 2.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 5.33 (d, J = 1.0 Hz,
1H), 5.14 (q, J = 1.2 Hz, 1H), 2.56 – 2.52 (m, 5H), 2.39 (t, J =
7.3 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ 178.0, 145.3, 140.9, 139.0, 130.3, 130.3, 130.0,
118.1, 114.4, 112.9, 34.1, 32.9, 22.9, 20.1. HRMS (ESI+):
Exact mass calculated for C14H15NNaO2 [M+Na]+: 252.0995,
found 252.0994.
6-(Bromomethyl)-6-(p-tolyl)tetrahydro-2H-
pyran-2-one (6b). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c,20 Yield: 26 mg (70%) of white solid; Mp.: 59-
61 °C. TLC (hexanes/EtOAc 6:4): Rf = 0.35, visualized with
1
CAM stain; H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 6.5 Hz,
5-(3-Acetylphenyl)hex-5-enoic acid (5n). Prepared
according to the previously reported general method B.5c
Step 2: Yield: 206 mg (49%) of colourless oil. TLC
2H), 7.21 (d, J = 8.2 Hz, 2H), 3.67 (d, J = 11.2 Hz, 1H), 3.61
(d, J = 11.1 Hz, 1H), 2.55 – 2.29 (m, 7H), 1.90 – 1.74 (m,
1H), 1.69 – 1.53 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
170.7, 138.6, 137.4, 129.8 (2C), 125.4 (2C), 85.3, 41.8, 30.1,
29.2, 21.2, 16.4.
1
(hexanes/EtOAc 4:1): Rf = 0.27, visualized with KMnO4; H
NMR (400 MHz, CDCl3) δ 7.99 (t, J = 1.9 Hz, 1H), 7.85 (dt, J
= 7.8, 1.4 Hz, 1H), 7.62 – 7.57 (m, 1H), 7.43 (t, J = 7.7 Hz,
1H), 5.36 (s, 1H), 5.15 (q, J = 1.3 Hz, 1H), 3.66 (s, 3H), 2.62
(s, 3H), 2.60 – 2.54 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 1.78 (p,
J = 7.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.1,
173.8, 146.8, 141.4, 137.3, 130.7, 128.6, 127.4, 125.8,
114.0, 51.5, 34.5, 33.3, 26.7, 23.3. HRMS (ESI+): Exact mass
calculated for C15H18NaO3 [M+Na]+: 269.1148, found
269.1149. Step 3: Yield: 189 mg (97%) of white solid. TLC
(hexanes/EtOAc 1:1): Rf = 0.23, visualized with KMnO4;
6-(Bromomethyl)-6-(o-tolyl)tetrahydro-2H-
pyran-2-one (6c). Prepared according to the general
method. Yield: 31 mg (85%) of white solid; Mp.: 57-59 °C.
TLC (hexanes/EtOAc 1:1): Rf = 0.55, visualized with
1
KMnO4; H NMR (400 MHz, CDCl3) δ 7.38 – 7.32 (m, 1H),
7.25 – 7.18 (m, 3H), 3.79 (d, J = 11.3 Hz, 1H), 3.74 (d, J =
11.3 Hz, 1H), 2.61 (dt, J = 14.6, 4.4 Hz, 1H), 2.50 (s, 3H),
2.41 – 2.25 (m, 2H), 1.94 – 1.83 (m, 1H), 1.78 – 1.63 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 137.1, 135.3,
133.7, 128.8, 127.1, 126.4, 86.1, 39.7, 29.6, 28.6, 22.6, 16.0.
HRMS (ESI+): Exact mass calculated for C13H15BrNaO2
[M+Na]+: 305.0148, found 305.0148.
1
Mp: 48-50 °C; H NMR (400 MHz, CDCl3) δ 7.99 (t, J = 1.9
Hz, 1H), 7.85 (dt, J = 7.7, 1.4 Hz, 1H), 7.62 – 7.57 (m, 1H),
7.42 (t, J = 7.7 Hz, 1H), 5.37 (s, 1H), 5.18 – 5.13 (m, 1H),
2.62 (s, 3H), 2.39 (t, J = 7.4 Hz, 2H), 1.79 (p, J = 7.4 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 198.3, 179.4, 146.6, 141.3,
137.2, 130.8, 128.6, 127.5, 125.8, 114.2, 34.4, 33.1, 26.7,
22.9. HRMS (ESI+): Exact mass calculated for C14H16NaO3
[M+Na]+: 255.0992, found 255.0992.
6-(Bromomethyl)-6-(naphthalen-2-yl)tetrahydro-
2H-pyran-2-one (6d). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c,20 Yield: 38 mg (91%) of pale yellow solid;
Mp.: 116-118 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.35,
General procedure for bromolactonization. The
unsaturated carboxylic acid (0.13 mmol, 1.0 equiv.) was
dissolved in acetonitrile (1.0 mL) and molecular sieves
(4Å) were added, followed by addition of diselenide pre-
catalyst 1 (0.06 mg, 0.13 μmol, 0.1 mol%). Subsequently, a
solution of NBS (26 mg, 0.14 mmol, 1.1 equiv.) in
1
visualized with CAM stain; H NMR (400 MHz, CDCl3) δ
7.93 – 7.83 (m, 4H), 7.57 – 7.50 (m, 2H), 7.43 (dd, J = 8.7,
2.0 Hz, 1H), 3.75 (s, 2H), 2.59 – 2.43 (m, 4H), 1.92 – 1.82
(m, 1H), 1.69 – 1.57 (m, 1H). 13C{1H} NMR (101 MHz,
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Page 8 of 12
1
2
CDCl3) δ 170.6, 137.7, 133.2, 133.1, 129.2, 128.5, 127.7,
127.1, 127.0, 125.5, 122.6, 85.4, 41.5, 30.2, 29.3, 16.4.
Hz), 115.7 (d, JCF = 21.1 Hz), 113.1 (d, JCF = 23.4 Hz), 84.8
(d, 4JCF = 1.9 Hz), 41.2, 30.4, 29.3, 16.4.
1
2
3
4
5
6
7
8
9
6-(Bromomethyl)-6-(4-
methoxyphenyl)tetrahydro-2H-pyran-2-one
Prepared according to the general method. Spectroscopic
data is in agreement with literature.10c,20 Yield: 30 mg
(77%) of white solid; Mp.: 83-84 °C. TLC (hexanes/EtOAc
6-(Bromomethyl)-6-(3,4,5-
trifluorophenyl)tetrahydro-2H-pyran-2-one
Prepared according to the general method. Yield: 40 mg
(94%) of colourless solids; Mp.: 148-150 °C. TLC. TLC
(hexanes/EtOAc 3:2): Rf = 0.38, visualized with KMnO4; H
NMR (400 MHz, CDCl3) δ 7.12 – 7.02 (m, 2H), 3.61 (d, J =
11.1 Hz, 1H), 3.56 (d, J = 11.1 Hz, 1H), 2.57 – 2.46 (m, 2H),
2.44 – 2.25 (m, 2H), 1.98 – 1.83 (m, 1H), 1.68 – 1.51 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.1, 152.6 (dd, J =
10.0, 4.1 Hz), 150.1 (dd, J = 9.9, 4.0 Hz), 140.8, 138.3, 137.3
– 136.6 (m), 110.7 – 109.8 (m), 84.0, 40.4, 30.1, 29.1, 16.3.
HRMS (ESI+): Exact mass calculated for C12H10BrF3NaO2
[M+Na]+: 344.9708, found 344.9708.
(6e).
(6j).
1
1
7:3): Rf = 0.17, visualized with CAM stain; H NMR (400
MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz,
2H), 3.82 (s, 3H), 3.66 (d, J = 11.1 Hz, 1H), 3.59 (d, J = 11.1
Hz, 1H), 2.55 – 2.29 (m, 4H), 1.89 – 1.78 (m, 1H), 1.70 –
1.58 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.6, 159.8,
132.3, 126.9, 114.5, 85.1, 55.5, 41.9, 30.0, 29.2, 16.4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(Bromomethyl)-6-(4-flurophenyl)tetrahydro-
2H-pyran-2-one (6f). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c,20 Yield: 36 mg (96%) of white solid; Mp.: 97-
99 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.34, visualized with
CAM stain; 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H),
7.08 – 6.98 (m, 2H), 3.65 (d, J = 11.1 Hz, 1H), 3.60 (d, J =
11.1 Hz, 1H), 2.50 – 2.22 (m, 4H), 1.85 – 1.73 (m, 1H), 1.60
– 1.49 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1,
Bromomethyl)-6-(4-nitrophenyl)tetrahydro-2H-
pyran-2-one (6k). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.5c Yield: 38 mg (94%) of pale yellow solid; Mp.:
110-111 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.14, visualized
with CAM stain; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.9
Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 3.68 (d, J = 11.2 Hz, 1H),
3.65 (d, J = 11.2 Hz, 1H), 2.48 – 2.39 (m, 4H), 1.97 – 1.87
(m, 1H), 1.64 – 1.54 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 169.4, 148.1, 147.6, 126.9, 124.2, 84.9, 40.4, 30.7,
29.3, 16.5.
1
4
162.6 (d, JCF = 248.7 Hz), 136.1 (d, JCF = 2.9 Hz), 127.4 (d,
2
3JCF = 8.2 Hz,), 116.0 (d, JCF = 21.6 Hz), 84.8, 41.4, 30.1,
29.1, 16.2.
6-(Bromomethyl)-6-(4-chlorophenyl)tetrahydro-
2H-pyran-2-one (6g). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c,20 Yield: 37 mg (93%) of white solid; Mp.: 102-
104 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.15, visualized with
CAM stain; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m, 4H),
3.65 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 2.56 –
2.30 (m, 4H), 1.91 – 1.81 (m, 1H), 1.67 – 1.55 (m, 1H),
13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 139.0, 134.9, 129.3,
127.1, 84.9, 41.3, 30.3, 29.2, 16.4.
6-(Bromomethyl)-6-(3-nitrophenyl)tetrahydro-
2H-pyran-2-one (6l). Prepared according to the general
method. Yield: 38 mg (94%) of pale yellow solid; Mp.: 133-
135 °C. TLC (hexanes/EtOAc 6:4): Rf = 0.21, visualized with
CAM stain; 1H NMR (400 MHz, CDCl3) δ 8.31 – 8.23 (m, 2H),
7.89 – 7.81 (m, 1H), 7.69 – 7.62 (m, 1H), 3.72 (d, J = 11.2
Hz, 1H), 3.68 (d, J = 11.1 Hz, 1H), 2.70 – 2.42 (m, 4H), 2.02 –
1.90 (m, 1H), 1.68 – 1.56 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 169.3, 148.7, 142.9, 132.0, 130.3, 123.8, 120.7,
84.6, 40.7, 30.4, 29.4, 16.5. HRMS (ESI+): Exact mass
calculated for C12H12BrNO4Na [M+Na]+: 335.9842, found
335.9842.
6-(Bromomethyl)-6-(4-bromophenyl)tetrahydro-
2H-pyran-2-one (6h). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.20 Yield: 42 mg (93%) of white solid; Mp.: 180-
182 °C decomp. TLC (hexanes/EtOAc 7:3): Rf = 0.33,
5-(2-(Bromomethyl)-6-oxotetrahydro-2H-pyran-
2-yl)-2-methylbenzonitrile (6m). Prepared according to
the general method. Yield: 34 mg (85%) of colourless oil.
TLC (hexanes/EtOAc 3:2): Rf = 0.32, visualized with
KMnO4; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.1 Hz, 1H),
7.55 (dd, J = 8.2, 2.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 3.64
(d, J = 11.1 Hz, 1H), 3.59 (d, J = 11.1 Hz, 1H), 2.56 (s, 3H),
2.53 – 2.34 (m, 4H), 1.96 – 1.83 (m, 1H), 1.64 – 1.51 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.4, 142.4, 139.0,
131.0, 129.9, 129.4, 117.5, 113.6, 84.3, 40.7, 30.1, 29.1,
20.1, 16.3. HRMS (ESI+): Exact mass calculated for
C14H14BrNNaO2 [M+Na]+: 330.0100, found 330.0100.
1
visualized with CAM stain; H NMR (400 MHz, CDCl3) δ
7.60 – 7.44 (m, 2H), 7.31 – 7.26 (m, 2H), 3.67 (d, J = 11.2
Hz, 1H), 3.62 (d, J = 11.2 Hz, 1H), 2.60 – 2.25 (m, 4H), 1.94 –
1.78 (m, 1H), 1.65 – 1.50 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 170.1, 139.5, 132.3, 127.4, 123.0, 85.0, 41.2, 30.2,
29.2, 16.4.
6-(Bromomethyl)-6-(3-fluorophenyl)tetrahydro-
2H-pyran-2-one (6i). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.5c Yield: 34 mg (91%) of colourless solids; Mp.:
90-91 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.35, visualized
6-(3-Acetylphenyl)-6-(bromomethyl)tetrahydro-
2H-pyran-2-one (6n). Prepared according to the general
method. Yield: 37 mg (92%) of colourless oil. TLC
1
with CAM stain; H NMR (400 MHz, CDCl3) δ 7.39 (td, J =
8.1, 5.9 Hz, 1H), 7.18 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.12 (dt,
J = 10.0, 2.2 Hz, 1H), 7.06 (tdd, J = 8.2, 2.5, 0.9 Hz, 1H), 3.66
(d, J = 11.2 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 2.58 – 2.30 (m,
4H), 1.92 – 1.81 (m, 1H), 1.67 – 1.56 (m, 1H). 13C{1H} NMR
1
(hexanes/EtOAc 1:1): Rf = 0.31, visualized with KMnO4; H
1
NMR H NMR (400 MHz, CDCl3) δ 7.99 (t, J = 1.9 Hz, 1H),
7.85 (dt, J = 7.7, 1.4 Hz, 1H), 7.60 (dt, J = 7.7, 1.5 Hz, 1H),
7.42 (t, J = 7.7 Hz, 1H), 5.37 (s, 1H), 5.18 – 5.13 (m, 1H),
2.68 – 2.52 (m, 5H), 2.39 (t, J = 7.4 Hz, 2H), 1.79 (p, J = 7.4
1
(101 MHz, CDCl3) δ 170.0, 163.2 (d, JCF = 247.6 Hz), 143.2
(d, 3JCF = 6.8 Hz), 130.8 (d, 3JCF = 8.2 Hz), 121.2 (d, 4JCF = 3.0
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The Journal of Organic Chemistry
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.2, 178.2,
146.6, 141.3, 137.3, 130.8, 128.6, 127.5, 125.8, 114.2, 34.4,
32.9, 26.7, 23.0. HRMS (ESI+): Exact mass calculated for
C14H15BrNaO3 [M+Na]+: 333.0097, found 333.0096.
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.6, 140.9, 129.0,
128.8, 125.1, 86.6, 41.2, 32.5, 29.2.
1
2
3
4
5
6
7
8
5-
Bromotetrahydro-6-phenyl-2H-pyran-2-one
(11a). Prepared according to the general method at – 30
°C. The regioisomeric ratio of δ-lactone:γ-lactone was 20:1
as determined by HPLC and NMR. Spectroscopic data is in
agreement with literature.10a Yield: 30 mg (90%) of white
solid; TLC (hexanes/EtOAc 7:3): Rf = 0.28, visualized with
CAM stain; 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.30 (m, 5H),
5.57 (d, J = 6.3 Hz, 1H), 4.39 (td, J = 6.6, 4.3 Hz, 1H), 2.96
(ddd, J = 18.2, 8.5, 7.1 Hz, 1H), 2.72 (dt, J = 18.2, 6.1 Hz, 1H),
2.42 (dddd, J = 14.8, 8.5, 6.5, 4.3 Hz, 1H), 2.33-2.22 (m, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 169.0, 137.3, 129.1, 128.8,
126.4, 85.6, 47.2, 28.4, 27.6.
6-(Bromomethyl)-6-isopropyltetrahydro-2H-
pyran-2-one (6o). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c Yield: 28 mg (92%) of colourless oil; TLC
(hexanes/EtOAc 7:3): Rf = 0.37, visualized with CAM stain;
1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 2.61 – 2.49 (m,
1H), 2.48 – 2.36 (m, 1H), 2.18 (hept, J = 6.9 Hz, 1H), 2.10 –
2.01 (m, 1H), 1.95 – 1.78 (m, 3H), 1.01 (dd, J = 6.9, 5.9 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 85.9, 37.6,
35.2, 29.9, 25.9, 17.1, 16.9, 16.7.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Bromomethyl)-6-cyclohexyltetrahydro-2H-
pyran-2-one (6p). Prepared according to the general
method. Spectroscopic data is in agreement with
literature.10c,20 Yield: 35 mg (97%) of colourless oil; TLC
(hexanes/EtOAc 7:3): Rf = 0.41, visualized with CAM stain;
1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 2.60 – 2.48 (m,
1H), 2.47 – 2.36 (m, 1H), 2.09 – 1.65 (m, 10H), 1.36 – 1.03
(m, 5H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 85.7, 45.5,
38.1, 30.0, 26.9, 26.6, 26.5, 26.5, 26.3, 26.2, 17.2.
5-Bromo-6-methyltetrahydro-2H-pyran-2-one
(11c)
and
5-Bromoethyl)dihydrofuran-2(3H)-one
(11d). Prepared according to the general method from
10b.6c The regioisomeric ratio of δ-lactone:γ-lactone was
1:8 as determined by HPLC and NMR. Spectroscopic data is
in agreement with literature.6c Yield: 31 mg (92%) of
colourless oils; TLC (hexanes/EtOAc 1:1): Rf = 0.49,
visualized with CAM stain; 11c: 1H NMR (400 MHz,
Chloroform-d) δ 4.56 (dq, J = 8.4, 6.4 Hz, 1H), 3.95 (td, J =
8.3, 5.0 Hz, 1H), 2.77 (dt, J = 17.6, 6.8 Hz, 1H), 2.59 – 2.46
(m, 2H), 2.35 – 2.22 (m, 1H), 1.53 (d, J = 6.4 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 169.7, 80.5, 47.1, 29.6, 29.2, 20.5.
11d: 1H NMR (400 MHz, Chloroform-d) δ 4.45 (q, J = 7.0 Hz,
1H), 4.14 (p, J = 6.8 Hz, 1H), 2.68 – 2.50 (m, 2H), 2.48 – 2.38
(m, 1H), 2.21 – 2.06 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 176.4, 82.6, 50.6, 28.7, 25.8,
22.23.
6-(Iodomethyl)-6-phenyltetrahydro-2H-pyran-2-
one (6q). Prepared according to the general method, by
substituting NBS with NIS. Spectroscopic data Is in
agreement with literature.5a Yield: 37 mg (89%) of
colourless oil; TLC (hexanes/EtOAc 4:1): Rf = 0.16,
1
visualized with CAM stain; H NMR (400 MHz, CDCl3) δ
7.47 – 7.31 (m, 5H), 3.57 (s, 2H), 2.57 – 2.27 (m, 4H), 1.90 –
1.74 (m, 1H), 1.65 – 1.47 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 170.4, 140.2, 129.0, 128.4, 125.2, 84.4, 32.1, 29.0,
17.6, 16.6.
(Z)-6-(4-Bromophenyl)hex-5-enoic acid (12). To a
solution of the methyl ester21 (100 mg, 0.35 mmol, 1.0
equiv.) in THF/MeOH/H2O (3/1/1, c = 0.25 M), solid
LiOH·H2O (2.5 equiv.) was added at rt. The mixture was
stirred until TLC indicated full conversion. The solution
was acidified with sat. aq. NaH2PO4 (10 mL) and then
EtOAc (10 mL) was added. The layers were separated and
the water phase was extracted with EtOAc (2 x 10 mL). The
combined organic layer was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The alkenoic acid was
used without further purfication. Yield: 92 mg (97%) of
white solid. Mp.: 57-59 °C. TLC (hexanes/EtOAc 1:1): Rf =
0.40, visualized with CAM stain; 1H NMR (400 MHz,
Chloroform-d) δ 7.44 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.4 Hz,
2H), 6.39 (d, J = 11.6 Hz, 1H), 5.66 (dt, J = 11.6, 7.3 Hz, 1H),
2.42 – 2.28 (m, 4H), 1.79 (p, J = 7.5 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 179.5, 136.4, 132.3, 131.4, 130.5,
129.0, 120.7, 33.5, 27.9, 24.8. HRMS (ESI+): Exact mass
calculated for C12H13BrNaO2 [M+Na]+: 290.9991, found
290.9990.
6-Phenyl-6-((((1S,2S,4S)-4,7,7-trimethyl-3-
oxobicyclo[2.2.1]heptan-2-
yl)selanyl)methyl)tetrahydro-2H-pyran-2-one (±7a).
Prepared according to the general method, by using 50
mol% (30 mg) of the diselenide pre-catalyst. Yield: 53 mg
(97%) of colourless oil; TLC (hexanes/EtOAc 3:2): Rf =
0.38, visualized with CAM stain; 1H NMR (400 MHz, CD3CN)
δ 7.49 – 7.27 (m, 10H), 3.68 – 3.63 (m, 1H), 3.52 – 3.46 (m,
1H), 3.40 – 3.22 (m, 4H), 2.57 – 2.21 (m, 9H), 2.14 – 2.10
(m, 1H), 1.97 – 1.95 (m, 1H), 1.85 – 1.57 (m, 8H), 1.55 –
1.38 (m, 2H), 1.31 – 1.17 (m, 2H), 0.98 (s, 3H), 0.95 (s, 3H),
0.82 (s, 3H), 0.82 (s, 3H), 0.78 (s, 3H), 0.74 (s, 3H). 13C{1H}
NMR (101 MHz, CD3CN) δ 218.5, 218.4, 171.5, 171.4, 144.0,
143.9, 129.5, 129.5, 128.7, 126.3, 126.3, 87.9, 87.7, 58.9,
58.8, 49.0, 48.9, 48.4, 48.3, 47.6, 47.3, 37.8, 37.5, 33.0, 32.8,
31.3, 31.3, 29.8, 23.7, 23.7, 19.8, 19.8, 17.3, 9.9. HRMS
(ESI+): Exact mass calculated for C22H28 NaO3Se [M+Na]+:
443.1096, found 443.1096.
6-(Bromo(4-bromophenyl)methyl)tetrahydro-
2H-pyran-2-one (13) Prepared according to the general
method from 12. Yield: 41 mg (90%) of colourless oil; TLC
(hexanes/EtOAc 1:1): Rf = 0.41, visualized with CAM stain;
1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 8.5 Hz, 2H),
7.35 (d, J = 8.5 Hz, 2H), 4.92 (d, J = 5.3 Hz, 1H), 4.60 (ddd, J
= 11.4, 5.3, 3.1 Hz, 1H), 2.68 – 2.50 (m, 1H), 2.42 (ddd, J =
17.7, 9.7, 7.0 Hz, 1H), 1.96 – 1.76 (m, 3H), 1.65 – 1.51 (m,
5-(Bromomethyl)-5-phenyldihydrofuran-2(3H)-
one (9). Prepared according to the general method.
Spectroscopic data is in agreement with literature.10d Yield:
32 mg (95%) of colourless oil; TLC (hexanes/EtOAc 8:2): Rf
1
= 0.18, visualized with CAM stain; H NMR (400 MHz,
CDCl3) δ 7.46 – 7.32 (m, 5H), 3.75 (d, J = 11.4 Hz, 1H), 3.69
(d, J = 11.4 Hz, 1H), 2.89 – 2.75 (m, 2H), 2.62 – 2.47 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.2, 136.6, 132.0,
ACKNOWLEDGMENT
130.4, 123.2, 82.1, 54.3, 29.6, 25.8, 18.3. HRMS (ESI+):
Exact mass calculated for C12H12Br2NaO2 [M+Na]+:
368.9096, found 368.9100.
1
2
3
4
5
6
7
8
The Research Council of Norway is gratefully acknowledged
for funding of a doctoral fellowship to R. K. (FRIPRO-
FRINATEK 230470). We are thankful to the Department of
Pharmacy, University of Oslo, for a scholarship to J. E. T. as
well as for the generous support from the Norwegian Ph.D.
School in Pharmacy (Nasjonal forskerskole i farmasi, NFIF) for
a travel grant to R. K.
6-(1-Bromovinyl)-6-(4-(tert-
butyl)phenyl)tetrahydro-2H-pyran-2-one
(15).
Prepared according to the general method from 145d with
the exception that the organic phase was not washed with
NaOH during work-up. Yield: 40 mg (92%) of colourless
oil; TLC (hexanes/EtOAc 1:1): Rf = 0.58, visualized with
CAM stain; 1H NMR (400 MHz, Methanol-d4) δ 7.53 – 7.41
(m, 4H), 6.04 (d, J = 2.6 Hz, 1H), 5.78 (d, J = 2.5 Hz, 1H),
2.73 – 2.61 (m, 1H), 2.62 – 2.56 (m, 1H), 2.55 – 2.49 (m,
1H), 2.49 – 2.42 (m, 1H), 1.99 – 1.87 (m, 1H), 1.87 – 1.74
(m, 1H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, MeOD) δ
172.9, 152.8, 138.2, 137.0, 127.1, 126.4, 120.1, 89.7, 35.4,
31.7, 31.1, 29.8, 17.3. HRMS (ESI+): Exact mass calculated
for C17H21BrNaO2 [M+Na]+: 359.0617, found 359.0617.
Notice! This bromolactone is very labile in the condensed
state under vacuum. Thus, to avoid decomposition, great
care had to be taken when evaporating the solvent in vacuo
after isolation by flash chromatography.
REFERENCES
9
(1) Selected reviews concerning halolactonization: (a) Snyder,
S. A.; Treitler, D. S.; Brucks, A. P. Halonium-induced cyclization
reactions. Aldrichimica Acta 2011, 44, 27; (b) Ranganathan, S.;
Muraleedharan, K. M; Vaish, N. K.; Jayaraman, N. Halo- and
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12
13
14
15
16
17
18
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21
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24
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30
31
32
33
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36
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42
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selenolactonization:
the
two
major
strategies
for
cyclofunctionalization. Tetrahedron 2004, 60, 5273; (c) Nolsøe, J.
M. J.; Hansen, T. V. Asymmetric Iodolactonization: An
Evolutionary Account. Eur. J. Org. Chem. 2014, 15, 3051.
(2) Selected reviews concerning halolactonization reactions
used in natural product synthesis: (a) Laya, M. S.; Banerjee, A. K.;
Cabrera, E. V. Iodolactonization. Past and present examples. Curr.
Org. Chem. 2009, 13, 720; (b) French, A. N. Bissmire, S.; Wirth, T.
Iodine electrophiles in stereoselective reactions: recent
developments and synthetic applications. Chem. Soc. Rev. 2004,
33, 354.
5-(Bromo(phenyl)methyl)dihydrofuran-2(3H)-
one (17b). Prepared according to the general method
from 16.6c Spectroscopic data is in agreement with
literature.6c Yield: 31 mg (93%) of white solid; Mp.: 121-
123 °C. TLC (hexanes/EtOAc 1:1): Rf = 0.52, visualized with
CAM stain; 1H NMR (400 MHz, Chloroform-d) δ 7.50 – 7.43
(m, 2H), 7.39 – 7.31 (m, 3H), 5.00 (d, J = 5.5 Hz, 1H), 4.92
(ddd, J = 7.5, 6.7, 5.5 Hz, 1H), 2.54 – 2.33 (m, 2H), 2.30 –
2.19 (m, 1H), 2.13 – 2.02 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 176.1, 137.0, 129.3, 129.0, 128.6, 82.1, 55.3, 28.5,
25.8.
(3) Examples of recent enantioselective halolactonization
protocols: (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan,
B. An Organocatalytic Asymmetric Chlorolactonization. J. Am.
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Hethcox, J. C.; Paull, D. H.; Fang, C.; Donald, J. R.; Shugrue, C. R.;
Pansick, A. D.; Martin, S. F. Enantioselective Halolactonization
Reactions using BINOL-Derived Bifunctional Catalysts:
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Yeung, Y.-Y. Recent advances in asymmetric intra- and
intermolecular halofunctionalizations of alkenes. Org. Biomol.
Chem. 2014, 12, 2333; (c) Kristianslund, R.; Tungen, J. E.; Hansen,
T. V. Catalytic enantioselective iodolactonization reactions. Org.
Biomol. Chem. 2019, 17, 3079 and references cited therein.
(5) (a) Tungen, J. E.; Nolsøe, J. M. J.; Hansen, T. V. Asymmetric
Iodolactonization Utilizing Chiral Squaramides. Org. Lett. 2012,
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asymmetric iodolactonization reaction catalyzed by a zinc bis-
proline-phenol complex. Tetrahedron Lett., 2014, 55, 419; (c)
Aursnes, M.; Tungen, J. E.; Hansen, T. V. Enantioselective
Organocatalyzed Bromolactonizations: Applications in Natural
Product Synthesis. J. Org. Chem. 2016, 81, 8287; (d) Kristianslund,
R.; Aursnes, M.; Tungen, J. E.; Hansen, T. V. Squaramide catalyzed
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Lett. 2016, 57, 5232; (e) Kristianslund, R.; Aursnes, M.; Tungen, J.
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1007.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full spectroscopic characterization (NMR spectra) of all new
products, and mechanistic studies (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.e.tungen@farmasi.uio.no
ORCID
Jørn Eivind Tungen: 0000-0002-6522-9661
Renate Kristianslund: 0000-0003-4397-3980
Anders Vik: 0000-0002-7864-3271
Trond Vidar Hansen: 0000-0001-5239-9920
(6) (a) Terashima, S.; Jew, S. Asymmetric Halolactonization
Reaction: A Highly Efficient Synthesis of Optically Active α,β-
Unsaturated Acids. Tetrahedron Lett. 1977, 11, 1005; (b) Jew, S.
Novel aspects of bromolactonization reaction using N-haloimides
in an aprotic polar solvent. Arch. Pharm. Res. 1982, 5, 97; (c)
Einaru, S.; Shitamichi, K.; Nagano, T.; Matsumoto, A.; Asano, K.
Author Contributions
†J.E.T and R.K contributed equally.
Notes
The authors declare no conflict of interest
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0.1 mol%
Se)2
O
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NBS (1.1 equiv.),
4Å MS, MeCN, rt.
CO2H
O
Br
O
R
R
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60-90 min
rapid and clean reactions
up to 96%
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