BF3·OEt2-Catalyzed Unexpected Stereoselective Formation of 2,4-trans-Diallyl-2-methyl-6-aryltetrahydro-2 H-pyrans with Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.joc.1c00352

The present manuscript describes a convenient, mild, and highly stereoselective method for the allylation of δ-hydroxy-α,β-unsaturated ketones having a benzylic hydroxyl group at the δ-position using allyltrimethylsilane mediated by BF3·OEt2, leading to 2,4-diallyl-2-methyl-6-aryltetrahydro-2H-pyran ring systems with quaternary carbon stereogenic centers. This represents the first example of a tandem isomerization followed by one C-O and two C-C bond-forming reactions in one pot. The isolation of TMS-protected lactol as an intermediate from the reaction strongly supports the proposed mechanistic pathway.

Full text of DOI:10.1021/acs.joc.1c00352

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BF ·OEt ‑Catalyzed Unexpected Stereoselective Formation of 2,4-
3
2
trans-Diallyl-2-methyl-6-aryltetrahydro‑2H‑pyrans with Quaternary
Stereocenters
∇
∇
D. Srinivas Reddy, Beduru Srinivas, Kavitha Rachineni, Bharatam Jagadeesh, Ariel M. Sarotti,
and Debendra K. Mohapatra*
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*
sı Supporting Information
ABSTRACT: The present manuscript describes a convenient, mild, and highly stereoselective method for the allylation of δ-
hydroxy-α,β-unsaturated ketones having a benzylic hydroxyl group at the δ-position using allyltrimethylsilane mediated by BF ·OEt ,
3
2
leading to 2,4-diallyl-2-methyl-6-aryltetrahydro-2H-pyran ring systems with quaternary carbon stereogenic centers. This represents
the first example of a tandem isomerization followed by one C−O and two C−C bond-forming reactions in one pot. The isolation of
TMS-protected lactol as an intermediate from the reaction strongly supports the proposed mechanistic pathway.
INTRODUCTION
medicinal chemistry and promote important organism
functions.
While several methods are already reported in the literature
■
8
1
Recent developments in glycobiology have increased the
demand for the synthesis of structurally distinct carbohydrates
and their analogues. Among them, C-glycosides constitute a
major class of glycomimetics, in which the anomeric oxygen
atom in O-glycosides is substituted with a methylene group.
Such a modification confers C-glycosides with improved
for the synthesis of 2,6-disubstituted tetrahydropyrans/
9
dihydropyrans, very few approaches are established for the
synthesis of tetrahydropyrans/dihydropyrans containing qua-
10
ternary stereocenters either at the C2 or C6 position.
2
General methods for the synthesis of these compounds involve
the nucleophilic addition on the oxocarbenium ion generated
on the THP ring (Scheme 1a). Although, the synthesis of some
of the quaternary carbon containing compounds were made
from glycosides, very few reports have addressed the synthesis
stability toward chemical and enzymatic hydrolysis, providing
useful avenues of study regarding carbohydrate-processing
3
enzymes. In principle, the augmented chemical and enzymatic
stability of C-glycosides has prompted synthetic organic
chemists and biologists to search for new C-glycosidic
structures. This has also encouraged the exploration of these
glycomimetics as small-molecule inhibitors of cell surface
recognition events, glycoside metabolism, and treatment of
various viral diseases and immunological disorders.
Substituted tetrahydropyrans/dihydropyrans are ubiquitous
structural units found in several simple to complex natural
products, especially those containing quaternary substitutions
either at the 2- or 6-position. These scaffolds are key
constituents of therapeutically important polyether containing
natural products, which include lituarine C (1), thyrsiferol (2),
11−13
of simple THPs.
Very recently, Compain and Kern et al. have reported an
iron-mediated hydrogen atom transfer or Michael/Giese
coupling strategy for the construction of C,C-glycoside
building blocks via the intermediacy of tertiary pseudoano-
4
5
14
meric radicals (Scheme 1b). A few years ago, we reported a
facile synthesis of 2,6-trans-disubstituted dihydropyrans from
enantiopure δ-hydroxy-α,β-unsaturated aldehydes. The process
involved the allylation of an oxocarbenium ion generated from
6
and brevenal (3) (Figure 1). The ability to rapidly increase
molecular complexity around tetrahydropyran/dihydropyran
ring systems is of great significance in synthetic chemistry as
well as in medicinal chemistry. In particular, the use of
Received: February 12, 2021
Published: April 27, 2021
7
optically active cyclic molecules containing multiple chiral
carbons with quaternary carbon stereogenic centers could
address three-dimensional conformational constraint issues in
©
2021 American Chemical Society
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the Supporting Information). At the outset, the initial reaction
of δ-hydroxy-α,β-unsaturated ketone 8, following our earlier
15f
approach,
with allyltrimethylsilane under different Lewis
acid catalysis, including 20 mol % iodine, did not provide any
product (Scheme 2).
Scheme 2. Synthesis of 6-Methyl 2,6-trans-Disubstituted
3
,6-Dihydropyran
However, the reaction of the enone (10a) having a benzylic
hydroxyl group at the δ-position (prepared via asymmetric
Keck allylation of aromatic aldehyde with more than 95% ee,
Jin’s one-pot oxidation, and keto phosphonate Wittig
16
reaction) with allyltrimethylsilane in THF in the presence
of 20 mol % molecular iodine afforded a product that was an
unexpected, 2,4-diallyl-2-methyl-6-(4-(trifluoromethyl)-
phenyl)tetrahydro-2H-pyran (12a) (dr ≥ 95:5) (Scheme 3).
Figure 1. Predominance of quaternary C,C-glycoside scaffolds in
bioactive natural products.
Scheme 3. Synthesis of 2,4-trans-Diallyl-2-methyl-6-
phenyltetrahydro-2H-pyran
Scheme 1. Background and Present Work
To ascertain the relative configuration in 12a, we undertook
DFT calculations of NMR chemical shifts coupled with DP4+
17
probability analysis. The four possible diastereoisomers were
built by keeping fixed the absolute configuration at C2, and a
systematic conformational sampling was done at the MMFF
level with a cutoff value of 10 kcal/mol. The resulting
conformers (about 3000 structures) were fully optimized at the
B3LYP/6-31G* level of theory, and after removing duplicates,
the isotropic shielding constants were computed at the PCM/
mPW1PW91/6-31+G** level using chloroform as a solvent.
The Boltzmann-averaged chemical shifts were correlated with
the experimental values, and compound 12a-SS (Figure 2a)
showed the best match with CMAE (corrected mean absolute
δ-hydroxy-α,β-unsaturated aldehydes using allyltrimethylsilane
catalyzed by molecular iodine. We have successfully utilized
the procedure for the synthesis of the macrolide natural
products and several other natural products. In continuation
of these studies, herein, we report our preliminary studies on
the formation of 2,6-disubstituted THPs containing a
quaternary stereocenter.
1
3
1
errors) values of 1.5 and 0.08 ppm for C and H data,
respectively. These values were considerably lower than those
computed for the other isomers (2.1−2.6 and 0.12−0.17 ppm,
respectively), suggesting an anti/syn relationship for the
unsaturated substituents. Therefore, DP4+ calculations
strongly supported this assignment (>99.9% overall proba-
15
RESULTS AND DISCUSSION
To verify the hypothesis, δ-hydroxy-α,β-unsaturated ketone 8
was prepared starting from a known epoxide 4, accessed from
18
■
bility). We speculated that the selectivity toward the 4(S)
configuration is related with the higher stability of the resulting
isomer, being >3 kcal/mol lower in energy than the
corresponding 4(R) compound. Detailed NMR spectroscopic
16
but-3-en-1-ol, following a three-step protocol (for details, see
6
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Figure 2. (a) DFT-derived lowest-energy structures of compound 12a and schematic representation of compound 12a depicting the observed key
1
1
nOes. (b) H− H expanded NOESY spectra of compound 12a in a CDCl solution at 700 MHz.
3
1
studies, viz., 1D- H and 2D-gDQFCOSY, gHSQC, and
gNOESY, were also carried out to explore this possibility.
The observed strong nOe cross-peaks, H4-H6, H7-H6, and
H7-H4, strongly supported a 4(S) configuration for compound
Table 1. Optimization for the Synthesis of 2,4-trans-Diallyl-
a
2-methyl-6-aryl-tetrahydropyrans
1
2a (Figure 2b) (also see the Supporting Information).
Moreover, the RCM reaction of 12a with Grubbs’ second-
generation catalyst did not provide the ring-closing product,
further supporting the trans nature of both the allyl groups.
With control over relative and absolute configurations, the
transformation simultaneously resulted in three bonds and two
stereogenic centers, one of which is a quaternary stereogenic
carbon center. The formation of this interesting trisubstituted
tetrahydropyran skeleton prompted us to investigate the
optimized reaction conditions and its mechanism in detail.
To optimize the reaction, we conducted systematic screen-
ing of Lewis acid catalysts with δ-hydroxy-α,β-unsaturated
ketone 10a and allyltrimethylsilane in THF at room temper-
ature. Employing TMSI, instead of molecular iodine as a
catalyst, under a nitrogen atmosphere at room temperature
furnished 12a in 40% yield (Table 1, entry 2). By changing the
solvent to CH Cl from THF, there was a little improvement
b
entry
catalyst (mol %)
(20)
TMSI (20)
TMSI (20)
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
I
THF
THF
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
04
24
24
31
40
45
NR
NR
20
48
NR
18
45
27
<20
NR
05
2
2
CH Cl2
AuCl (10)
THF
3
AuCl (10)
CH Cl2
3
2
ZnBr (20)
THF
2
ZnBr (10)
CH Cl2
2
2
ZnBr (20)
DMF
2
Zn(OTf) (20)
CH Cl2
2
2
2
2
2
2
10
11
12
13
14
15
16
17
18
Sc(OTf) (20)
CH Cl2
3
Sn(OTf) (20)
CH Cl2
3
Ce(OTf) (20)
CH Cl2
3
2
2
La(OTf) (20)
CH Cl2
in the yield (Table 1, entry 3). Next, the reaction was tried
with AuCl either in THF or CH Cl at room temperature. In
3
Er(OTf) (20)
CH Cl2
3
2
3
2
2
BF ·OEt (10)
THF
46
87
both cases, no transformation occurred even after 24 h (Table
, entries 4 and 5). When the reaction was performed with
3
2
c
BF ·OEt (10)
CH Cl2
1
3
2
2
BF ·OEt (20)
dioxane
15
29
3
2
ZnBr in THF, the reaction was found to be slow and ended
2
TiCl (20)
CH Cl2
4
2
up with a low yield after 24 h (Table 1, entry 6). There was a
dramatic improvement of yield when the reaction was carried
out in CH Cl (Table 1, entry 7). No reaction was observed
a
Reaction conditions: 10a (0.2 mmol) and allyltrimethylsilane (3.0
equiv) in a solvent (1.0 mL) at room temperature under a N
2
2
2
b
c
atmosphere. Yields after column purification. Gram-scale synthesis.
when CH Cl was replaced with DMF as the solvent (Table 1,
2
2
entry 8). Among the Lewis acids, such as Zn(OTf) , Sc(OTf) ,
2
3
Sn(OTf) , Ce(OTf) , La(OTf) , and Er(OTf) , Sc(OTf) was
entry 18). Finally, inspection of different parameters revealed
that the optimal reaction conditions were 10a (1 mmol) and
allyltrimethylsilane (3 mmol) with 10 mol % BF ·OEt in
3
3
3
3
3
found to be the best Lewis acid catalyst for the allylation
reaction (Table 1, entries 9−14). When the reaction was
conducted in the presence of BF ·OEt , among three different
3
2
CH Cl at room temperature for the formation of 12a in 87%
3
2
2
2
solvents tried, CH Cl was found out to be the best solvent for
yield.
2
2
the isomerization followed by C−O and C−C bond-forming
reactions (Table 1, entries 15−17). The reaction was found to
be slow with TiCl in CH Cl at room temperature (Table 1,
Encouraged by these results, we then turned our attention to
examine the substrate scope and limitations of this reaction
and the results are summarized in Table 2. The reaction in
4
2
2
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Table 2. Substrate Scope for the Synthesis of 2,4-Diallyl-2-
methyl-tetrahydropyran
Scheme 4. Substrate Scope with Electron-Donating Groups
a
2
H-pyran (12b) in 20 and 24% yield, respectively (Scheme 5).
The isolated TMS-protected lactol 13 when treated with
Scheme 5. Control Experiment
allyltrimethylsilane (1.2 equiv) and 10 mol % BF ·OEt in
3
2
CH Cl at room temperature afforded (2R,4S,6S)-2,4-diallyl-6-
a
2
2
Reaction conditions: 10 (0.2 mmol), allyltrimethylsilane (3.0 equiv),
(
4-bromophenyl)-2-methyltetrahydro-2H-pyran (12b) in 85%
BF ·OEt (10 mol %), CH Cl (1.0 mL) at rt under a N atmosphere;
yields were reported after column chromatography; dr through NMR
data.
3
2
2
2
2
yield, which clearly indicated that TMS-protected lactol is one
of the intermediates in the reaction.
In the second control experiment, reduction of the double
19
bond in the presence of PtO2 under a hydrogen atmosphere
led to the formation of six-membered hemiacetal 14, which, on
treatment with allyltrimethylsilane (1.5 equiv) and BF ·OEt
general proceeded well, affording the desired products in good
yields and with excellent diastereoselectivity. An aromatic ring
bearing an electron-withdrawing group proved to be more
compatible, and the reaction proceeded smoothly to furnish
product 12c in 86% yield (Table 2). Similarly, an aryl group
containing F, Cl, and Br substitutions resulted in the
corresponding products in good yields.
However, an aromatic ring possessing an electron-donating
group (compounds 10l and 10m), when treated with
allyltrimethylsilane in the presence of a catalytic amount of
BF ·OEt , did not produce even a trace amount of the
corresponding diallyl tetrahydropyran (Scheme 4). Instead, it
led to an intractable mixture of compounds at room
temperature. It might be due to the delocalization of electron
toward the tetrahydropyran ring, leading to the possibility of
tetrahydropyran ring-opening.
To verify the possible mechanistic pathway, some control
experiments were conducted. The keto compound 10b was
treated with allyltrimethylsilane (1.2 equiv) and 20 mol %
molecular iodine in THF at room temperature. After 24 h, we
were able to isolate the TMS-protected lactol 13 along with
3
2
(
10 mol %) in CH Cl at room temperature, furnished the
2 2
monoallylated compound 15 in 90% yield. Even the use of 3
equivalent of allyltrimethylsilane under the same reaction
conditions led to the formation of 15 only in 91% yield with a
9
7:3 ratio of diastereomers (Scheme 6).
On the basis of the above results and as for the mechanism,
we propose a plausible reaction pathway of the tandem
process, which is shown in Figure 3. We presume that the
reaction proceeds through the intermediacy of the unsaturated
oxocarbenium ion(II), the formation of which can be expected
3
2
from the reaction of enone with BF ·OEt . An encouraging
3
2
support for this intermediate can be drawn with the fact the
silyloxy acetal could be isolated. The unsaturated oxocarbe-
nium ion reacts with allyltrimethylsilane at the less hindered γ-
position first (III) followed by the second allylation at the α-
center to obtain 12b. We anticipate that the stereochemistry at
the γ-position is favored by the chiral center in the substrate,
while the stereochemistry in the subsequent α-allylation is
dictated by both chiral centers present at C2 and C4.
(
2R,4S,6S)-2,4-diallyl-6-(4-bromophenyl)-2-methyltetrahydro-
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Scheme 6. Control Experiment
an all-carbon quaternary stereocenter at C2, which could be
utilized for the synthesis of complex natural products and
designed molecules of medicinal values.
EXPERIMENTAL SECTION
■
General Information. All air- and/or moisture-sensitive reactions
were carried out in anhydrous solvents under an inert atmosphere in
flame-dried glassware. All commercially available starting materials
and reagents were used as received and without further purification.
Anhydrous solvents were distilled prior to use: THF from Na and
benzophenone; DMF, CH Cl from CaH ; MeOH from Mg cake.
2
2
2
Column chromatography was carried out by using silica gel (60−120
mesh). Thin layer chromatography (TLC) was run on plates (0.25
mm) with pre-coated silica gel GF254, for monitoring the reactions.
Specific rotations [α] were recorded with an Anton Paar MCP 200
D
−
1
3
−1
digital polarimeter at 20 °C and reported in deg dm cm g .
Diastereomeric ratio was analyzed by a Shimadzu LC-MS-8040
instrument. Infrared spectra were recorded in CHCl and reported in
3
−
1
wavenumber (cm ). HRMS spectra were recorded by using a Waters
Q-TOF mass spectrometer. H and C NMR chemical shifts were
1
13
reported in ppm downfield from tetramethylsilane relative to CDCl ,
3
1
13
7
.26 ppm for H NMR and 77.00 ppm for C NMR, respectively, and
coupling constants (J) were reported in hertz (Hz). The following
abbreviations were used to designate signal multiplicity: s = singlet, d
=
doublet, t = triplet, q = quartet, m = multiplet, br = broad.
General Procedure for δ-Hydroxyl α,β-Unsaturated Ketones
(
P1). To a stirred solution of β-hydroxy aldehydes (1.0 mmol) in
toluene (4.0 mL) was added 1-triphenylphosphoranylidene-2-
propanone (0.47 g, 1.5 mmol) at room temperature and stirred for
6
−10 h at room temperature. After the completion of the reaction
(monitored by TLC), the solvent was evaporated under reduced
pressure and the remaining oil was triturated with cold hexane. Then,
the insoluble triphenylphosphine oxide was precipitated out. The
reaction mixture was filtered through a sintered funnel (washing with
cold hexane), and the filtrate was concentrated to furnish the crude
product, which was purified using flash silica gel chromatography
(hexane/ethyl acetate = 2:1) to furnish δ-hydroxy α,β-unsaturated
ketones in 75−80% of isolated yield.
General Procedure for 2,4-Diallyl-2-methyl-6-aryltetrahy-
dro-2H-pyran (P2). To a stirred solution of δ-hydroxyl α,β-
unsaturated aldehyde (1.0 mmol), BF ·OEt (13 μL, 0.1 mmol),
3
2
and allyltrimethylsilane (0.48 mL, 3.0 mmol) was added CH Cl (8
2
2
mL) at 0 °C and allowed to stir at room temperature. After
completion of the reaction (monitored by TLC; 4−6 h), the reaction
mixture was quenched with a saturated solution of NaHCO (10 mL).
3
Figure 3. Plausible mechanistic pathway.
The reaction mixture was extracted with CH Cl (3 × 15 mL). The
2
2
combined organic layers were washed with brine (20 mL), dried over
anhydrous Na SO , and evaporated under reduced pressure. The
CONCLUSIONS
2
4
■
crude product was purified by silica gel column chromatography with
% ethyl acetate/hexane as an eluent to produce the cyclized product
In summary, under different Lewis acid-catalyzed tandem
isomerization followed by C−O and C−C bond-forming
reactions, starting from a δ-hydroxy-α,β-unsaturated ketone
having an aliphatic hydroxyl group at the δ-position with
allyltrimethylsilane as part of a planned stereoselective
synthesis did not provide 2,6-trans-disubstituted dihydropyran
ring systems with an all-carbon quaternary stereocenter at C2.
However, the reaction of the enone having a benzylic hydroxyl
group at the δ-position with allyltrimethylsilane in THF in the
presence of 10 mol % BF ·OEt afforded a product that was an
unexpected, 2,4-trans-diallyl-2-methyl-6-pheyltetrahydro-2H-
pyran (four reaction sequences in one pot) at ambient
temperature with excellent diastereoselectivity and yields.
The isolated TMS-protected lactol intermediate and the
control experiment strongly supported the proposed mecha-
nistic pathway. This protocol is simple and proceeds readily at
ambient temperature with excellent diastereoselectivity and
yields. This reaction establishes a new transformation of 2,4,6-
trisubstituted tetrahydropyran ring systems and incorporates
1
in 70−87% of isolated yield.
Characterization Data of δ-Hydroxyl α,β-Unsaturated
Ketones and 2,4-Diallyl-2-methyl-6-aryltetrahydro-2H-pyran
Compounds. (S,E)-8-(Benzyloxy)-6-hydroxyoct-3-en-2-one (8).
Following the general procedure P1, 8 (234 mg, 82%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 3:1)
25
as a viscous liquid. [α]D +52.2 (c 1.0, CHCl ); IR (neat): υ 3340,
3
max
−1
1
2
940, 2868, 1495, 1453, 1275, 1087 cm ; H NMR (CDCl 500
3,
MHz): δ 7.39−7.27 (m, 5H), 6.83 (m, 1H), 6.12 (d, J = 16.0 Hz,
3
2
1H), 4.53 (s, 2H), 4.00 (m, 1H), 3.78−3.62 (m, 2H), 3.21 (br s, 1H),
1
3
1
2.44−2.37 (m, 2H), 2.26−2.24 (s, 3H), 1.83−1.67 (m, 2H); C{ H}
NMR (CDCl3, 75 MHz): δ 198.3, 144.3, 137.7, 133.1, 128.3, 127.6,
1
27.5, 73.2, 69.8, 68.5, 40.2, 36.1, 26.6; ESI-HRMS: m/z calcd for
+
C H O [M + H] 249.1491, found 249.1490.
1
5
21
3
(
S,E)-6-Hydroxy-6-(4-(trifluoromethyl)phenyl)hex-3-en-2-one
(
10a). Following the general procedure P1, 10a (198 mg, 77%) was
obtained after silica gel column chromatography (hexane/ethyl
25
acetate = 2:1) as a colorless liquid. [α]D +44.2 (c 2.0, CHCl ); IR
3
−
1
(neat): υ 3422, 2917, 1668, 1626, 1479, 1427, 1256, 1044 cm ;
H NMR (CDCl 300 MHz): δ 7.62 (d, J = 7.6 Hz, 2H), 7.48 (d, J =
max
1
3
,
6
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−
1 1
7
.6 Hz, 2H), 6.80 (m, 1H), 6.13 (dd, J = 14.4, 1.5 Hz, 1H), 4.92 (br t,
2916, 1675, 1526, 1174, 1097 cm ; H NMR (CDCl 300 MHz): δ
3,
1
3
1
J = 5.7 Hz, 1H), 2.68−2.61 (m, 2H), 2.23 (s, 3H); C{ H} NMR
7.53 (s, 1H), 7.43 (m, 1H), 7.31−7.19 (m, 2H), 6.85−6.72 (m, 1H),
2
(CDCl 75 MHz): δ 198.6, 147.4, 143.2, 133.6, 130.0 (q, J
= 32.7
6.14 (dt, J = 1.3, 16.0 Hz, 1H), 4.83 (t, J = 6.0 Hz, 1H), 2.69−2.59
3,
C−F
3
1
13
1
Hz), 128.5 (d, J
= 11.8 Hz), 125.9, 125.5, 125.4, 124.1 (q, J
=
(m, 2H), 2.24 (s, 3H); C{ H} NMR (CDCl 75 MHz): δ 198.5,
C−F
C−F
3,
72.2 Hz), 72.3, 41.9, 26.9; ESI-HRMS: m/z calcd for C H F O Na
145.7, 143.2, 133.6, 130.9, 130.1, 128.7, 124.2, 122.7, 72.3, 41.9, 26.9;
1
3
13
3
2
+
+
ESI-HRMS: m/z calcd for C H BrO [M + H] 269.0176, found:
1
2
14
(
269.0165.
lowing the general procedure P1, 10b (204 mg, 76%) was obtained
(R,E)-6-(4-Fluorophenyl)-6-hydroxyhex-3-en-2-one (10h). Fol-
lowing the general procedure P1, 10h (158 mg, 76%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 2:1)
after silica gel column chromatography (hexane/ethyl acetate = 2:1)
2
5
as a yellow liquid. [α]D −34.1 (c 1.0, CHCl ); IR (neat): υ 3419,
3
max
−
1
1
25
2
3
923, 1023, 2854, 1713, 1632, 1452, 1274 cm ; H NMR (CDCl
00 MHz): δ 7.41 (d, J = 6.7 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 6.77
as a gummy liquid. [α]D +14.2 (c 2.0, CHCl ); IR (neat): υ 3424,
3
,
3
max
−
1 1
3052, 1672, 1434, 1184, 1014 cm ; H NMR (CDCl 300 MHz): δ
3,
(
6
m, 1H), 6.12 (dt, J = 15.8, 1.5 Hz, 1H), 4.82 (t, J = 6.0 Hz, 1H), 2.
7.35−7.30 (m, 2H), 7.07−7.02 (m, 2H), 6.78 (m, 1H), 6.12 (dt, J =
13.2, 1.3 Hz, 1H), 4.84 (dd, J = 5.0, 2.7 Hz, 1H), 2.70−2.58 (m, 2H),
1
3
1
9−2.57 (m, 2H), 2.22 (s, 3H); C{ H} NMR (CDCl 75 MHz): δ
3
,
1
3
1
1
98.4, 143.1, 142.3, 133.6, 131.7, 127.3, 121.7, 72.4, 41.9, 27.0; ESI-
2.23 (s, 3H); C{ H} NMR (CDCl 75 MHz): δ 198.4, 158.7 (d,
3,
+
1
3
HRMS: m/z calcd for C H BrO [M + H] 269.0176, found
JC−F = 287.7 Hz), 143.4, 139.2, 133.6, 127.3 (d, J
= 21.5 Hz), 72.5, 42.0, 26.9; ESI-HRMS: m/z calcd for
C H FO Na [M + Na] 231.0797, found 231.0791.
= 7.7 Hz),
C−F
1
2
14
2
2
69.0155.
115.5 (d, J
C−F
+
(S,E)-6-Hydroxy-6-(3-nitrophenyl)hex-3-en-2-one (10c). Follow-
12 13 2
ing the general procedure P1, 10c (215 mg, 80%) was obtained after
silica gel column chromatography (hexane/ethyl acetate = 3:1) as a
(S,E)-6-Hydroxy-6-phenylhex-3-en-2-one (10i). Following the
general procedure P1, 10i (150 mg, 76%) was obtained after silica
2
5
gummy liquid. [α]D −14.8 (c 1.5, CHCl ); IR (neat): υ 3422,
gel column chromatography (hexane/ethyl acetate = 3:1) as a thick
3
max
−
1 1
2
5
3
3
1
057, 1670, 1527, 1436, 1350, 1182, 1180 cm ; H NMR (CDCl
3,
liquid. [α]D +29.2 (c 0.5, CHCl ); IR (neat): υ 3421, 3030, 2923,
1
3
3 max
−
1 1
00 MHz): δ 8.25 (s, 1H), 8.17 (m, 1H), 7.71 (m, 1H), 7.55 (m,
H), 6.82 (m, 1H), 6.15 (m, 1H), 5.00 (t, J = 6.2 Hz, 1H), 2.71−2.66
669, 1626, 1423, 1362, 1258, 1197, 1048 cm ; H NMR (CDCl
3,
00 MHz): δ 7.41−7.28 (m, 5H), 6.81 (m, 1H), 6.12 (dd, J = 16.1,
1
3
1
(
m, 2H), 2.25 (s, 3H); C{ H} NMR (CDCl 75 MHz): δ 198.1,
3,
1.2 Hz, 1H), 4.85 (dd, J = 5.1, 2.2 Hz, 1H), 2.74−2.60 (m, 2H), 2.23
13 1
1
43.8, 133.1, 132.2, 131.2, 128.7, 121.6, 120.5, 71.0, 41.9, 26.3; ESI-
(
s, 3H); C{ H} NMR (CDCl 75 MHz): δ 198.5, 143.8, 143.4,
3,
+
HRMS: m/z calcd for C H NO Na [M + Na] 258.0740, found
1
2
13
4
133.4, 128.6, 127.9, 125.6, 73.1, 41.9, 26.8; ESI-HRMS: m/z calcd for
+
2
58.0742.
C H O Na [M + Na] 213.0892, found 213.0890.
1
2
14
2
(
S,E)-6-(2-Fluorophenyl)-6-hydroxyhex-3-en-2-one (10d). Fol-
(S,E)-6-(2-Chlorophenyl)-6-hydroxyhex-3-en-2-one (10j). Follow-
lowing the general procedure P1, 10d (156 mg, 75%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 2:1)
as a colorless liquid. [α]D +26.8 (c 1.0, CHCl ); IR (neat): υ
ing the general procedure P1, 10j (174 mg, 78%) was obtained after
silica gel column chromatography (hexane/ethyl acetate = 2:1) as a
2
5
2
5
3
max
viscous liquid. [α]D +45.7 (c 1.0, CHCl ); IR (neat): υ 2924,
3 max
−
1 1
−
1 1
3
3
1
5
451, 2925, 1668, 1513, 1356, 1066, 1039 cm ; H NMR (CDCl
3,
2870, 1720, 1453, 1273, 3434, 1094, 1028 cm ; H NMR (CDCl
3,
00 MHz): δ 7.48 (td, J = 1.5, 7.6 Hz, 1H), 7.28 (m, 1H), 7.18 (m,
H), 7.04 (m, 1H), 6.83 (m, 1H), 6.14 (dt, J = 1.5, 14.4 Hz, 1H),
3
00 MHz): δ 7.58 (dd, J = 6.4, 1.3, Hz, 1H), 7.41−7.17 (m, 3H), 6.87
(
m, 1H), 6.14 (d, J = 15.8 Hz, 1H), 5.27 (dd, J = 4.1, 3.9 Hz, 1H),
.80−2.52 (m, 2H), 2.25 (s, 3H); C{ H} NMR (CDCl 75 MHz):
1
3
1
1
3
1
.19 (brt, J = 6.8 Hz, 1H), 2.74−2.67 (m, 2H), 2.24 (s, 3H); C{ H}
2
3
,
1
NMR (CDCl 75 MHz): δ 198.5, 159.5 (d, J
= 245.5 Hz), 143.4,
= 12.7 Hz), 129.2 (d, J = 8.1 Hz), 127.0
C−F C−F
3
,
C−F
δ 198.6, 143.7, 140.7, 133.6, 131.5, 129.4, 128.8, 127.2, 126.8, 69.4,
40.3, 26.8; LRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C H ClO Na 247.05; Found 247.01.
2
3
1
(
33.8, 130. 2 (d, J
3
3
2
d, J
= 3.9 Hz), 124.4 (d, J
= 2.7 Hz), 115.4 (d, J
= 21.7
C−F
C−F
C−F
1
2
13
2
Hz), 67.1, 40.9, 26.9; ESI-HRMS: m/z calcd for C H FO Na [M +
Na] 231.0797, found 231.0792.
R,E)-6-(2,6-Difluorophenyl)-6-hydroxyhex-3-en-2-one (10e).
Following the general procedure P1, 10e (178 mg, 79%) was
obtained after silica gel column chromatography (hexane/ethyl
acetate = 2:1) as a viscous liquid. [α]D −67.7 (c 1.0, CHCl ); IR
(
(
1
2
13
2
(S,E)-6-(2,6-Dichlorophenyl)-6-hydroxyhex-3-en-2-one (10k).
Following the general procedure P1, 10k (199 mg, 77%) was
+
(
obtained after silica gel column chromatography (hexane/ethyl
26
acetate = 2:1) as a viscous liquid. [α]D +34.8 (c 1.0, CHCl ); IR
(
3
−1
1
neat): υmax 3418, 3031, 2923, 2863, 1653, 1453, 1081 cm ; H
2
5
3
NMR (CDCl 300 MHz): δ 7.32 (m, 2H), 7.17 (dd, J = 7.6, 0.7 Hz,
3
,
−
1
1
neat): υmax 3462, 2925, 1672, 1248, 1067, 1034 cm ; H NMR
1H), 6.83 (m, 1H), 6.12 (dt, J = 13.2, 1.3, Hz, 1H), 5.59 (m, 1H),
CDCl 300 MHz): δ 7.25−7.15 (m, 2H), 7.02 (m, 1H), 6.81 (m,
13
1
3,
3.04 (m, 1H), 2.81 (m, 1H), 2.25 (s, 3H); C{ H} NMR (CDCl 75
3,
1
2
1
H), 6.13 (dt, J = 13.4, 1.3 Hz, 1H), 5.37 (m, 1H), 2.96 (m, 1H),
MHz): δ 198.5, 143.1, 136.4, 134.0, 133.6, 129.4, 129.2, 70.6, 38.3,
1
3
1
.76 (m, 1H), 2.25 (s, 3H); C { H} NMR (CDCl 75 MHz): δ
+
3
,
26.5; ESI-HRMS: m/z calcd for C H Cl O Na [M + Na]
1
2
12
2
2
1
3
98.6, 161.6 (d, J
= 248.6 Hz), 143.0, 133.6, 133.2 (d, J
= 10.3 Hz), 127.8 (d, J
= 6.6
C−F
C−F
281.0112, found 281.0109.
3
2
Hz), 129.5 (d, J
= 13.9 Hz), 125.8 (d,
C−F
C−F
(S,E)-6-Hydroxy-6-(3,4,5-trimethoxyphenyl)hex-3-en-2-one (10l).
Following the general procedure P1, 10l (224 mg, 80%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 3:2)
3
3
2
JC−F = 2.9 Hz), 125.5 (d, J
= 11.0 Hz) 115.1 (d, J
= 22.7
C−F
C−F
Hz), 68.6, 39.4, 26.6; ESI-HRMS: m/z calcd for C H F O Na [M +
Na] 249.0703, 249.0710.
S,E)-6-(2,4-Dichlorophenyl)-6-hydroxyhex-3-en-2-one (10f). Fol-
lowing the general procedure P1, 10f (202 mg, 78%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 2:1)
as a colorless liquid. [α]D +32.7 (c 1.0, CHCl ); IR (neat): υ
3
NMR (CDCl 300 MHz): δ 7.53 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3
1
2
12
2
2
+
26
as a colorless liquid. [α]D −74.8 (c 1.0, CHCl ); IR (neat): υ
3
max
−
1 1
(
3
3
421, 2919, 2943, 2863, 1673, 1453, 1041 cm ; H NMR (CDCl
00 MHz): 7.69−7.45 (m,2H), 6.83 (m, 1H), 6.58 (s, 2H), 6.16 (d, J
15.8 Hz, 1H), 4.78 (dd, J = 12.6, 2.6 Hz, 1H), 3.86 (d, J = 11.8 Hz,
3,
=
2
5
3
max
9H), 2.74−2.56 (m, 2H), 2.24 (s, 3H); ESI-HRMS: m/z calcd for
−
1
1
+
419, 2924, 1667, 1629, 1562, 1432, 1257, 1186, 1047 cm ; H
C H O [M + H] 281.1387, found 281.1382.
1
5
21
5
3,
(R,E)-6-(7-Bromobenzo[d][1,3]dioxol-5-yl)-6-hydroxyhex-3-en-2-
one (10m). Following the general procedure P1, 10m (244 mg, 78%)
Hz, 1H), 7.29 (dd, J = 8.3, 1.8 Hz, 1H), 6.84 (m, 1H), 6.12 (dt, J =
4.6, 1.2 Hz, 1H), 5.22 (m, 1H), 2.84 (br s, 1H), 2.68 (m, 1H), 2.55
1
was obtained after silica gel column chromatography (hexane/ethyl
1
3
1
25
(m, 1H), 2.24 (s, 3H); C{ H} NMR (CDCl 75 MHz): δ 198.5,
acetate = 3:2) as a viscous liquid; [α]D +35.4 (c 1.2, CHCl ); IR
3
,
3
−
1
1
1
43.2, 139.4, 133.8, 133.7, 132.0, 129.1, 127.9, 127.5, 68.9, 40.2, 26.9;
(neat): υmax 3462, 2929, 1671, 1248, 1067, 1039 cm ; H NMR
+
ESI-HRMS: m/z calcd for C H Cl O Na [M + Na] 281.0112,
(CDCl 500 MHz): 6.96 (d, J = 0.9 Hz, 1H), 6.80−6.73 (m, 2H),
1
2
12
2
2
3,
found 281.0114.
R,E)-6-(3-Bromophenyl)-6-hydroxyhex-3-en-2-one (10g). Fol-
lowing the general procedure P1, 10g (201 mg, 75%) was obtained
after silica gel column chromatography (hexane/ethyl acetate = 2:1)
as a viscous liquid. [α]D +39.7 (c 1.0, CHCl ); IR (neat): υ 3432,
6.12 (dt, J = 16.0, 1.2 Hz, 1H), 6.04 (s, 2H), 4.73 (dd, J = 5.1, 2.5 Hz,
1H), 2.66−2.55 (m, 2H), 2.24 (s, 3H); ESI-HRMS: m/z calcd for
(
+
C H BrO [M + H] 313.0071, found 313.0079.
1
3
14
4
(2R,4S,6S)-2,4-Diallyl-2-methyl-6-(4-(trifluoromethyl)phenyl)-
tetrahydro-2H-pyran (12a). Following the general procedure P2, 12a
2
5
3
max
6
523
https://doi.org/10.1021/acs.joc.1c00352
J. Org. Chem. 2021, 86, 6518−6527

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(
(
0
2
7
4
281 mg, 87%) was obtained after silica gel column chromatography
(2R,4S,6S)-2,4-Diallyl-2-methyl-6-(3-nitrophenyl)tetrahydro-2H-
2
5
hexane/ethyl acetate = 99:1) as a pale yellow liquid. [α]D +41.6 (c
.8, CHCl ); IR (neat): υ 1718, 1015, 1619, 1325, 1126, 1067,
pyran (12c). Following the general procedure P2, 12c (258 mg, 86%)
was obtained after silica gel column chromatography (hexane/ethyl
3
max
−
1
1
26
929 cm ; H NMR (CDCl 400 MHz): δ 7.58 (d, J = 8.1 Hz, 2H),
acetate = 99:1) as a colorless liquid. [α]
D
+14.2 (c 1.0, CHCl ); IR
3
3
,
−
1 1
(
(
7
neat): υmax 2925, 1037, 2854, 1611, 1513, 1247,1149 cm ; H NMR
CDCl 300 MHz): δ 8.24 (m, 1H), 8.10 (m, 1H), 7.69 (m, 1H),
.48 (d, J = 8.1 Hz, 2H), 5.92−5.70 (m, 2H), 5.12−4.99 (m, 4H),
.67 (dd, J = 11.7, 1.3 Hz, 1H), 2.63 (dd, J = 14.1, 6.6 Hz, 1H), 2.33
3,
.48 (t, J = 7.7 Hz, 1H), 5.87−5.72 (m. 2H), 5.14−4.99 (m, 4H),
(
(
(
1
dd, J = 14.1, 7.7 Hz, 1H), 2.09−1.92 (m, 3H), 1.89 (m, 1H), 1.72
13 1
4.70 (dd, J = 9.6, 2.2 Hz, 1H), 2.63 (dd, J = 7.3, 6.8 Hz, 1H), 2.31
(dd, J = 7.6, 6.4, Hz, 1H), 2.06−1.98 (m, 2H), 1.92 (m, 1H), 1.73 (m,
m, 1H), 1.27 (s, 3H), 1.08 (dd, J = 12.8, 5.1 Hz, 2H); C{ H} NMR
2
CDCl 100 MHz): δ 147.5, 136.0, 133.9, 129.3 (q, J
= 32.4 Hz),
3,
C−F
1
3
1
3
1
1H), 1.64−1.55 (m, 1H), 1.28 (s, 3H), 1.08 (m, 2H); C{ H} NMR
26.3, 126.1 (q, J
= 14.6), 125.2, 125.1, 124.2. (q, J
= 271.8
C−F
C−F
(
CDCl 75 MHz): δ 148.2, 145.7, 135.8, 133.7, 132.2, 129.1, 122.1,
Hz), 117.5, 116.5, 74.5, 71.8, 41.4, 41.2, 39.9, 38.9, 31.2, 28.6; ESI-
HRMS: m/z calcd for C H F ONa [M + Na] 347.1596, found
3
3,
+
121.0, 117.6, 116.6, 74.7, 71.4, 41.3, 41.1, 39.9, 38.8, 31.1, 28.5; ESI-
1
9
23 3
+
HRMS: m/z calcd for C H NO Na [M + Na] 324.1575, found
47.1592.
18 23
3
3
24.1571.
(
((6S)-6-(4-Bromophenyl)-2-methyl-5,6-dihydro-2H-pyran-2-yl)-
(
2R,4S,6S)-2,4-Diallyl-6-(2-fluorophenyl)-2-methyltetrahydro-
oxy)trimethylsilane (13). To a stirred solution of δ-hydroxy α,β-
unsaturated ketone 10b (268 mg, 1.0 mmol) in THF (10 mL), were
added allyltrimethylsilane (0.19 mL, 1.2 mmol) and iodine (50 mg,
2
7
H-pyran (12d). Following the general procedure P2, 12d (200 mg,
3%) was obtained after silica gel column chromatography (hexane/
2
5
ethyl acetate = 99:1) as a colorless liquid. [α]D −37.5 (c 0.3,
0
.2 mmol) at room temperature. The reaction mixture was allowed to
−
1
CHCl ); IR (neat): υ 3459, 2924, 2074, 1634, 1460, 1030 cm ;
3
max
stir for 24 h at room temperature. The reaction was quenched with an
aqueous saturated solution of Na S O (10 mL) and diluted with
ethyl acetate (10 mL). The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (2 × 10 mL). The
combined organic layers were dried over anhydrous Na SO and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography (hexane/ethyl acetate = 99:1 to
2
protected lactol 13 (68 mg, 20%) (not stable enough), and recovered
starting material 10b (120 mg, 45%). 13: H NMR (CDCl 300
MHz): 7.45 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.72 (m,
1
2
1
H NMR (CDCl 300 MHz): δ 7.53 (td, J = 5.7, 1.6 Hz, 1H), 7.20
3
,
2
2
3
(
5
(
m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 5.79 (m, 2H), 5.13−4.81 (m,
H), 2.60 (m, 1H), 2.34 (m, 1H), 2.16 (m, 1H), 1.98 (m, 2H), 1.90
m, 1H), 1.69 (m, 1H), 1.52−1.37 (m, 1H), 1.26 (s, 3H), 1.12 (m,
2
4
13
1
1
H), 1.09 (m, 2H); C{ H} NMR (CDCl 75 MHz): δ 159.4 (d,
3,
1
2
JC−F = 245.2 Hz), 136.1, 134.1, 130.7 (d, J
JC−F = 8.1 Hz), 127.5 (d, J
17.4, 116.3, 114.9 (d, J
38.9, 31.1, 28.6; ESI-HRMS: m/z calcd for C H FONa [M + Na]
= 12.7 Hz), 128.3 (d,
C−F
3
3
3
= 3.6 Hz), 124.5 (d, J
= 2.7 Hz),
:1) to afford the diallylated product 12b (80 mg, 24%), TMS-
C−F
C−F
2
1
= 22.7 Hz), 74.5, 65.8, 41.4, 41.2, 39.1,
C−F
+
1
18 23
3
,
2
97.1630, found 297.1642.
(
2S,4R,6R)-2,4-Diallyl-6-(2,6-difluorophenyl)-2-methyltetrahy-
H), 6.05 (m, 1H), 4.73 (dd, J = 12.2, 1.8 Hz, 1H), 2.62−2.47 (m,
+
dro-2H-pyran (12e). Following the general procedure P2, 12e (233
H), 2.21 (s, 3H), 0,03 (s, 9H); LRMS (ESI-TOF) m/z: [M] Calcd
mg, 80%) was obtained after silica gel column chromatography
for C H BrO Si 342.04; Found 342.11.
15
21
2
25
(
1
1
hexane/ethyl acetate = 99:1) as a colorless liquid. [α]D +13.6 (c
(
2S,6S)-2-Allyl-6-(4-bromophenyl)-2-methyltetrahydro-2H-pyran
15). Following the general procedure P2, 15 (87 mg, 93%) was
obtained from hemiacetal 14 after silica gel column chromatography
.0, CHCl ); IR (neat): υ 3412, 2992, 2927, 1714, 1453, 1369,
3 max
(
−
1
1
272, 1015 cm ; H NMR (CDCl 300 MHz): δ 7.18−7.11 (m,
3
,
1
2H), 6.95 (m, 1H), 5.80 (m, 2H), 5.24 (dd, J = 11.5, 3.3 Hz, 1H),
(hexane/ethyl acetate = 99:1) as a colorless liquid. H NMR (CDCl ,
3
5
(
1
.15−5.00 (m, 4H), 2.66 (m, 1H), 2.32 (m, 1H), 2.14 (m, 1H), 2.02
4
(
=
1
1
00 MHz): δ 7.39 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.75
td, J = 17.0, 6.7 Hz, 1H), 5.04 (dd, J = 14.3, 7.7 Hz, 2H), 4.51 (dd, J
11.7, 1.7 Hz, 1H), 2.61 (dd, J = 14.1, 6.7 Hz, 1H), 2.25 (dd, J =
4.1, 7.8 Hz, 1H), 1.77−1.71 (m, 2H), 1.56 (dd, J = 10.1, 7.4 Hz,
m, 2H), 1.93 (m, 1H), 1.71−1.62 (m, 2H), 1.23 (s, 3H), 1.18 (m,
1
3
1
1
H); C{ H} NMR (CDCl 75 MHz): δ 162.2 (d, J
= 253.0
=
C−F
3
,
C−F
3
3
Hz), 136.2, 134.2 (dd, J
9.5 Hz), 125.6 (d, JC−F = 2.9 Hz), 117.6, 116.2 (d, JC−F = 19.7 Hz),
15.3 (d, J
= 14.6, 6.6 Hz), 133.9, 129.0 (d, J
C−F
3
2
1
3
1
H), 1.35 (ddd, J = 41.2, 21.2, 13.4 Hz, 3H), 1.18 (s, 3H); C{ H}
2
3
1
=
= 22.7 Hz), 74.7, 68.2, 41.4, 41.0, 38.6, 35.2 (d, J
C−F C−F
NMR (CDCl 100 MHz,): δ 142.8, 134.1, 131.3, 127.8, 120.8, 117.4,
7
C H BrO [M + H] 295.0692, found 295.0685.
3,
2.2 Hz), 31.2, 28.5; ESI-HRMS: m/z calcd for C H F ONa [M +
18 22 2
4.1, 71.7, 38.2, 34.3, 33.2, 28.7, 19.8; ESI-HRMS: m/z calcd for
+
Na] 315.1538, found 315.1542.
+
15
20
(
2R,4S,6S)-2,4-Diallyl-6-(2,4-dichlorophenyl)-2-methyltetrahy-
(
2R,4S,6S)-2,4-Diallyl-6-(4-bromophenyl)-2-methyltetrahydro-
dro-2H-pyran (12f). Following the general procedure P2, 12f (253
2
8
H-pyran (12b). Following the general procedure P2, 12b (274 mg,
mg, 78%) was obtained after silica gel column chromatography
2%) was obtained after silica gel column chromatography (hexane/
25
(
hexane/ethyl acetate = 99:1) as a colorless liquid. [α]D +43.4 (c
2
5
ethyl acetate = 99:1) as a colorless liquid. [α]D −46.2 (c 1.0,
CHCl ); IR (neat): υ 2975, 2926, 1718, 1452, 1265, 1184, 1065
cm ; H NMR (CDCl 300 MHz): δ 7.43 (d, J = 8.3 Hz, 2H), 7.24
1
1
1
5
(
(
1
3
.5, CHCl ); IR (neat): υ 3029, 2921, 1414, 1319, 1222, 1170,
3 max
3
max
−1
1
101 cm ; H NMR (CDCl 300 MHz): δ 7.54 (dd, J = 7.7, 0.4 Hz,
−
1
1
3,
3
,
H), 7.32 (d, J = 2.1 Hz, 1H), 7.25 (dd, J = 6.4, 1.9 Hz, 1H), 5.85−
(
1
1
d, J = 8.3 Hz, 2H), 5.77 (m, 2H), 5.17−4.95 (m, 4H), 4.56 (dd, J =
.73 (m, 2H), 5.14−4.95 (m, 5H), 2.60 (m, 1H), 2.39 (m, 2H), 2.20
.7, 11.8 Hz, 1H), 2.61 (m, 1H), 2.29 (m, 1H), 2.06−1.84 (m, 4H),
m, 1H), 2.03−1.94 (m, 3H), 1.75 (m, 1H), 1.60−1.51 (m, 2H), 1.26
13 1
.69 (m, 1H), 1.26 (m, 1H), 1.24 (m, 3H), 1.04 (m, 1H); C{ H}
13 1
s, 3H); C{ H} NMR (CDCl 75 MHz): δ 139.8, 135.9, 133.9,
3
,
NMR (CDCl 75 MHz): δ 142.6, 136.0, 134.0, 131.2, 127.8, 117.4,
1
calcd for C H BrONa [M + Na] 357.0825, found 357.0831.
3,
32.9, 132.0, 128.7, 128.6, 127.4, 117.6, 116.4, 74.7, 68.6, 41.3, 41.0,
16.4, 74.4, 71.7, 41.4, , 41.2, 39.9, 38.9, 31.2, 28.6; ESI-HRMS: m/z
8.9, 38.6, 31.0, 28.6; ESI-HRMS: m/z calcd for C H Cl ONa [M +
1
8
22
2
+
+
18
23
Na] 347.0945, found: 347.0944.
Gram-Scale Preparation of 12b. To a stirred solution of δ-
(
2S,4S,6R)-2,4-Diallyl-6-(3-bromophenyl)-2,6-dimethyltetrahy-
hydroxyl α,β-unsaturated aldehyde 10b (2.0 g, 7.7 mmol) in CH Cl
(
mL, 23.1 mmol) were added at 0 °C and allowed to stir at room
temperature. After completion of the reaction (monitored by TLC), it
was quenched with saturated aqueous NaHCO solution (40 mL) and
diluted with CH Cl (50 mL). The organic layer was separated, and
the aqueous layer was extracted with CH Cl (2 × 50 mL). The
combined organic layer was washed with brine (50 mL), dried over
anhydrous Na SO , and evaporated under reduced pressure. The
2
2
dro-2H-pyran (12g). Following the general procedure P2, 12g (241
40 mL) BF ·OEt (0.1 mL, 0.77 mmol), and allyltrimethylsilane (3.7
3 2
mg, 72%) was obtained after silica gel column chromatography
2
5
(hexane/ethyl acetate = 99:1) as a colorless liquid. [α]D +18.4 (c
1.0, CHCl ); IR (neat): υmax, 3029, 2922, 1455, 1375, 1212, 1150,
3
−
1
1
3
1106 cm ; H NMR (CDCl 300 MHz): δ 7.52 (m, 1H), 7.36 (m,
3,
2
2
1H), 7.26 (m, 1H), 7.18 (m, 1H), 5.90−5.72 (m, 2H), 5.13−4.95 (m,
1H), 4.57 (dd, J = 9.4, 2.1 Hz, 1H), 2.60 (m, 1H), 2.30 (m, 1H), 2.18
(m, 1H), 2.03−1.96 (m, 2H), 1.69 (dq, J = 9.4, 1.8 Hz, 1H), 1.47 (m,
2
2
1
3
1
2
4
1H), 1.25 (s, 3H), 1.05 (m, 1H); C{ H} NMR (CDCl 75 MHz): δ
3,
crude product was purified by silica gel chromatography (hexane/
ethyl acetate = 99:1) to obtain the cyclized product 12b (2.05 g, 83%)
as a pale yellow liquid.
145.9, 136.0, 134.0, 130.2, 129.8, 129.7, 129.1, 124.7, 122.4, 117.5,
116.4, 74.5, 71.7, 41.3, 41.2, 40.0, 38.8, 31.2, 28.6; ESI-HRMS: m/z
+
calcd for C H BrO [M + H] 335.1010, found 335.1032.
1
8
24
6
524
https://doi.org/10.1021/acs.joc.1c00352
J. Org. Chem. 2021, 86, 6518−6527

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(
2S,4R,6R)-2,4-Diallyl-6-(4-fluorophenyl)-2-methyltetrahydro-
and Innovative Research (AcSIR), Ghaziabad 201002,
India; orcid.org/0000-0002-9515-826X;
Email: mohapatra@iict.res.in
2
7
H-pyran (12h). Following the general procedure P2, 12h (208 mg,
6%) was obtained after silica gel column chromatography (hexane/
ethyl acetate = 99:1) as a colorless liquid. [α]D +19.6 (c 0.8,
CHCl ); IR (neat): υ 2918, 1762, 1452, 1313, 1065, 1010 cm ;
2
5
−
1
3
max
Authors
1
H NMR (CDCl 300 MHz): δ 7.39−7.30 (m, 2H), 7.07−6.95 (m,
3,
D. Srinivas Reddy − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India; orcid.org/0000-
0003-3987-4680
Beduru Srinivas − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
Kavitha Rachineni − Centre for NMR and Structural
Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India
Bharatam Jagadeesh − Centre for NMR and Structural
Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India
2
H), 5.92−5.70 (m, 2H), 5.21−5.15 (m, 4H), 4.60 (dd, J = 9.8, 1.7
Hz, 1H), 2.64 (m, 1H), 2.32 (m, 1H), 2.02, (m, 1H), 1.87 (m, 1H),
1
.72 (m, 1H), 1.61−1.52 (m, 2H), 1.26 (s, 3H), 1.14 (m, 2H);
C{ H} NMR (CDCl 75 MHz): δ: 162.0 (d, J
39.2, 136.4 (d, J
17.4, 116.3, 115.0 (d, J
13
1
1
= 244.8 Hz),
3
,
C−F
2
3
1
1
3
2
= 33.5 Hz), 134.1, 127.7 (d, J
= 7.0 Hz),
C−F
C−F
2
= 21.2 Hz), 74.4, 71.7, 41.4, 41.3, 40.0,
C−F
+
8.9, 31.2, 28.6; ESI-HRMS: m/z calcd for C H FO [M + H]
1
8
24
75.1811, found 275.1817.
2R,4S,6S)-2,4-Diallyl-2-methyl-6-phenyltetrahydro-2H-pyran
12i). Following the general procedure P2, 12i (179 mg, 70%) was
obtained after silica gel column chromatography (hexane/ethyl
(
(
2
5
acetate = 99:1) as a colorless liquid. [α]D +13.9 (c 0.8, CHCl );
IR (neat): υ 3419, 2923, 2854, 1713, 1632, 1452, 1274, 1023 cm ;
H NMR (CDCl 300 MHz): δ 7.41−7.21 (m, 5H), 5.90−5.73 (m,
3
−
1
max
1
3,
Ariel M. Sarotti − Instituto de Química Rosario (CONICET),
Facultad de Ciencias Bioquímicas Farmacéuticas,
Universidad Nacional de Rosario, 2000 Rosario, Argentina;
orcid.org/0000-0002-8151-0306
2
1
(
3
1
3
2
H), 5.14−4.99 (m, 4H), 4.61 (dd, J = 9.4, 2.2 Hz, 1H), 2.64 (m,
H), 2.36−2.28 (m, 1H), 2.03−1.97 (m, 2H), 1.87 (m, 1H), 1.70
dd, J = 8.0, 1.9 Hz, 1H), 1.58 (m, 1H), 1.31−1.27 (m, 1H), 1.25 (s,
13 1
H), 1.13 (m, 1H); C{ H} NMR (CDCl 75 MHz): δ 143.5, 136.2,
3,
34.2, 128.2, 127.1, 126.0, 117.3, 116.2, 74.3, 72.3, 41.4, 41.3, 40.0,
8.9, 31.3, 28.7; ESI-HRMS: m/z calcd for C H ONa [M + Na]
79.1724, found 279.1729.
+
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00352
1
8
24
(
2R,4S,6S)-2,4-Diallyl-6-(2-chlorophenyl)-2-methyltetrahydro-
2
7
H-pyran (12j). Following the general procedure P2, 12j (208 mg,
Author Contributions
D.S.R. and B.S. contributed equally.
Notes
∇
2%) was obtained after silica gel column chromatography (hexane/
ethyl acetate = 99:1) as a colorless liquid. [α]D −19.8 (c 0.8,
CHCl ); IR (neat): υ 2915, 2857, 2359, 1713, 2342, 1453, 1219,
2
5
3
max
−
1
1
The authors declare no competing financial interest.
1
8
5
1
2
3
024, cm ; H NMR (CDCl 300 MHz): δ 8.23 (t, J = 1.8 Hz, 1H),
3,
.10 (m, 1H), 7.69 (dd, J = 1.5, 6.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H),
.90−5.78 (m, 2H), 5.18−4.98 (m, 4H), 4.70 (dd, J = 2.2, 11.9 Hz,
H), 2.60 (dd, J = 7.1, 6.7 Hz, 1H), 2.38−2.27 (m, 1H), 2.02 (m,
H), 1.92 (m, 1H), 1.77−1.69 (m, 1H), 1.55−1.65 (m, 1H), 1.26 (m,
H), 1.25 (m, 1H), 1.03−1.12 (m, 1H); C{ H} NMR (CDCl 75
MHz): δ 136.1, 134.1, 129.0, 128.0, 127.5, 127.1, 117.5, 116.2, 74.6,
8.9, 41.4, 41.1, 39.0, 38.7, 31.1, 28.7; ESI-HRMS: m/z calcd for
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support
received from the Department of Science and Technology-
Science and Engineering Research Board (DST-SERB), New
Delhi, India, through grant no. EMR/2017/002298 (manu-
script communication number IICT/Pubs/2021/086). We are
thankful to the Director for his constant support and providing
excellent research facility. D.S.R., B.S., and K.R. thanks the
CSIR and UGC, New Delhi, India, for financial assistance in
the form of fellowships.
1
3
1
3
,
6
+
C H ClONa [M + Na] 313.1335, found 313.1339.
1
8
(
23
2R,4S,6S)-2,4-Diallyl-6-(2,6-dichlorophenyl)-2-methyltetrahy-
dro-2H-pyran (12k). Following the general procedure P2, 12k (253
mg, 78%) was obtained after silica gel column chromatography
hexane/ethyl acetate = 99:1) as a colorless liquid. [α]D −13.4 (c
.0, CHCl ); IR (neat): υ 1109, 1170, 1222, 1354, 1412, 2928,
3 max
2
5
(
1
3
(
1
(
1
1
3
3
−
1 1
022 cm ; H NMR (CDCl 300 MHz): δ 7.28−7.25 (m, 2H), 7.08
3
,
DEDICATION
■
t, J = 7.7 Hz, 1H), 5.86−5.74 (m, 2H), 5.45 (dd, J = 9.1, 2.9 Hz,
H), 5.15−5.00 (m, 4H), 2.64 (q, 7.0 Hz, 1H), 2.33 (m, 1H), 2.04
m, 2H), 1.95 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.26 (s, 3H),
Dedicated to Dr. Jhillu S. Yadav, Former Director, CSIR-IICT,
on the occasion of his 70th birthday.
1
3
1
.15−1.25 (m, 2H); C{ H} NMR (CDCl 75 MHz): δ 136.1,
33.9, 129.3, 128.6, 117.7, 116.3, 74.7, 69.9, 41.4, 40.7, 38.7, 33.4,
0.9, 28.1; ESI-HRMS: m/z calcd for C H Cl ONa [M + Na]
47.0945, found 347.0941.
3
,
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1
8
22
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sı Supporting Information
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