Diastereoselective Synthesis of trans-2,3-Diaryl(heteroaryl)-3,6-dihydropyrans by an Allylboration/Ring-Closing-Metathesis Sequence

Article abstract of DOI:10.1002/ejoc.201700448

trans-2,3-Diaryl(heteroaryl)-dihydropyrans were synthesized by an allylboration/ring-closing-metathesis sequence, using allylboranes formed in situ from the corresponding allylic alcohols. Aryl(heteroaryl) substituents were thus installed diastereoselectively onto dihydropyran rings in a trans fashion. These disubstituted dihydropyrans were further transformed into monosaccharide-like tetrahydropyrans.

Full text of DOI:10.1002/ejoc.201700448

A Journal of
Accepted Article
Title: Diastereoselective Synthesis of trans-2,3 Diaryl(heteroaryl)
3,6-Dihydropyrans by an Allylboration/Ring-Closing Metathesis
Sequence
Authors: Pierre-Antoine Nocquet, Andrei Corbu, Lieven Meerpoel, Ian
Stansfield, Didier Berthelot, Patrick Angibaud, and Janine
Cossy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700448
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700448
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
Diastereoselective Synthesis of trans-2,3 Diaryl(heteroaryl) 3,6-
Dihydropyrans by an Allylboration/Ring-Closing Metathesis
Sequence
Pierre-Antoine Nocquet,[a] Andrei Corbu,[a] Lieven Meerpoel,[b] Ian Stansfield,[c] Didier Berthelot,[c]
Patrick Angibaud[c] and Janine Cossy*[a]
Abstract:
trans-2,3-Diaryl(heteroaryl)
dihydropyrans
were
heteroaryl substituent (Figure 1).
synthesized by an allylboration/ring-closing metathesis sequence,
using allylboranes formed in situ from the corresponding allylic
alcohol. Aryl(heteroaryl) substituents were thus installed dia-
stereoselectively on dihydropyran rings in a trans fashion. These
disubstituted dihydropyrans were further transformed into
monosaccharide-like tetrahydropyrans.
Ar
HetAr
Ar
HetAr
O
O
A1
A2
Figure 1. 2,3-Diarylated dihydropyrans A1, A2.
The synthetic strategy to access compounds of type A was
based on a ring-closing metathesis applied to allyl ethers B to
form the pyran ring (Scheme 1).9 The homoallylic fragment
bearing two vicinal aromatic/heteroaromatic substituents of
these ethers B would come from homoallylic alcohols C. A
allylboration was planned to access C, involving arylated allylic
pinacol boronates D and various aryl(heteroaryl) aldehydes E.10
It is worth noting that the reactivity of such complex boronates
was seldom used in the synthesis of heteroaryl substrates.11 The
stereochemical outcome of the allylboration would depend on
the configuration of the in situ generated allylboronates D. To
access our targets, a palladium-catalyzed transformation of the
corresponding allylic alcohols F would selectively grant E-allylic
boronates D, that will inherently lead to the required homoallylic
alcohol anti stereoisomers C.
Introduction
Functionalized dihydropyrans are important targets in
organic synthesis as they can be transformed to a variety of
natural products and/or bioactive compounds including glycals,
pseudo-glycals, glycosides. As C-aryl glycosides have been
recently reported to have important biological properties,1
a
number of synthetic methods have been developed to access
these compounds, including cross-coupling reactions.2 So far
the arylation of glycals and glycosides has been restricted to
monoarylation.3 Very recently, vicinal diarylation of glycals and
pseudo-glycals has been reported, leading to cis-diaryl glycals
and pseudo-glycals.4 These compounds can also be obtained by
construction of the oxygen-containing 6-membered rings.5 It is
worth noting that mainly cis-2,3-diaryl derivatives have been
obtained, the trans-isomers, with one or two heteroaryl
substituents, have rarely been reported to our knowledge.6
As part of innovative efforts, pharmaceutical companies are
constantly searching for novel building blocks. The presence of
aryl and heteroaryl groups can have a huge influence on the
bioactivity of molecules due to the binding affinities with the
biological targets. Recently, 2-aryl(heteroaryl) glycosides have
been reported to be useful kinase inhibitors.7 In addition, 2,3-
diaryl 3,6-dihydropyrans can be seen as surrogates of
chromenes8 and, as the presence of heteroaryl groups can
reduce the lipophilicity and help creating binding interactions
with biological targets, we embarked on the synthesis of trans-
2,3-aryl(heteroaryl) DHPs of type A1, A2 with one aryl and one
(Het)Ar2
(Het)Ar1
(Het)Ar2
(Het)Ar1
(Het)Ar2
(Het)Ar1
RCM
O
OH
O
B
C
A
Brown allylation
H
Ar2(Het)
OH
Ar2(Het)
Bpin
+
(Het)Ar1
O
D
F
E
Scheme 1. Retrosynthetic analysis of di-aryl(heteroaryl) DHPs.
Results and Discussion
[a]
Laboratoire de Chimie Organique, Institute of Chemistry, Biology
and Innovation (CBI), ESPCI Paris, PSL Research University,
CNRS, 10 rue Vauquelin, 75231 Paris, France,
For the synthesis of DHPs A1, arylated allylic alcohols
1a-d were directly transformed into the corresponding pinacol-
boronates using Szabó et al. and Kirschning et al. conditions.12
These boronates were then converted to the bis-aryl(heteroaryl)
homoallylic alcohols 3a-3f by addition on various aromatic and
heteroaromatic aldehydes. At first, the (3-phenylallyl)borane was
prepared in situ by treatment of 1a with the bis-pinacolborane
[(Bpin)2 (2.25 equiv)] in the presence of a palladium catalyst
[Pd(CH3CN)4(BF4)2] in a mixture DMSO/MeOH (1:1) at 50 °C.
janine.cossy@espci.fr; https://www.lco.espci.fr/
[b]
[c]
Janssen Research & Development, Division of Janssen
Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
Janssen Research & Development, Division of Janssen-Cilag S.A.,
Oncology and Medicinal Chemistry, Campus de Maigremont, 27106
Val de Reuil, Cedex, France
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
After
2
h, the reaction mixture was worked-up and the
aryl(heteroaryl) aldehydes 2a-f were reacted with the crude
pinacol boronates in CH2Cl2 to produce the desired homoallylic
alcohols 3a-3f in good yields (87-99%). The results are reported
in Table 1. To access the homoallylic alcohols 3g-3j, the allylic
alcohols 1b-1d were transformed to the corresponding
boronates and further added to aldehyde 2f and benzaldehyde
to produce the corresponding homoallylic alcohols 3g-3j in
moderate to good yields (53%-93%). High diastereoselectivities
were obtained (dr > 98:2) for 3a-3j but at this stage the relative
configuration of the two aryl(heteroaryl) groups could not be
determined (cf vide infra).13 The results are summarized in
Table 1.
To access DHPs A2 (Figure 1), allylic alcohol 1e was
prepared from N-tosyl β-indolylaldehyde by using a Wittig
reaction and a DIBAL-H reduction. By applying the same
conditions as reported in Table 1, homoallylic alcohol 3k,
bearing the heteroaryl at the C2-position, was obtained in a
modest yield of 32% (Scheme 2).
Table 1. Allylation of various (hetero)aromatic aldehydes using in situ
generated allylboronates.
1) Pd(CH3CN)4(BF4)2 (7.5 mol %)
Ar
OH
Ar
(Bpin)2 (2.2 equiv)
DMSO/MeOH (1:1), 50 °C
2) Ar(Het)CHO, 2 (1 equiv)
CH2Cl2, rt, time
1
Ar(Het)
OH
3
Ar
OH
time
3 (yield)
Entry
Ar(Het)CHO
2
1
Ph
H
22 h
1
Ph
OH
O
OH
1a
F
F
3a (99%)
2a
Ph
Cl
Cl
H
Cl
H
46 h
45 h
94 h
90 h
1a
2
N
O
N
OH
N
2b
N
Cl
3b (88%)
Ts
Ts
N
N
Ph3PCHCO2Me (1.5 equiv)
Ph
THF, rt, 24 h
90%
3
1a
CHO
2c
2c'
O
O
OH
CO2Me
N
2c
N
DIBAL-H
THF, –78 °C
3c (97%)
Ts
Ts
48%
Ts
N
Ph
Ts
N
H
Cl
H
1) Pd(CH3CN)4(BF4)2 (7.5 mol %)
(Bpin)2 (2.25 equiv)
1a
4
OH
OH
DMSO/MeOH (1:1), 50 °C, 1 h
N
2d
N
Cl
1e
H
OH
3d (87%)
F
3k
2)
O
Ph
CH2Cl2, rt
Cl
Cl
2a
F
1a
5
32%
OH
O
N
N
N
2e
N
Scheme 2. Synthesis 2-indolyl homoallylic alcohol 3k.
Me
Me 3e (97%)
Ph
H
1a
O
6
Having the homoallylic alcohols 3a-3k in hand, their
transformation to compounds A was examined. At first, the
formation of the corresponding allylic ethers B was achieved via
22 h
40 h
40 h
40 h
43 h
OH
N
Cl
N
Cl
2f
2f
3f (92%)
OMe
a
conventional allylation using allylbromide under basic
OMe
conditions (NaH, THF). The corresponding allylic ethers 4 were
obtained in moderate to good yields (45%-83%), however, under
these conditions 3b, 3d and 3e could not be transformed to the
corresponding allyl ethers 4 (Table 2).14
7
OH
OH
1b
N
N
Cl
3g (61%)
MeO
Table 2. Synthesis of Allyl-ethers 4.
MeO
8
2f
2f
(Het)Ar2
(Het)Ar2
(Het)Ar1
Br
OH
NaH,
OH
1c
1d
1c
(Het)Ar1
O
THF
OH
Cl
4
3
3h (87%)
F3C
F3C
OMe
9
Ph
Ph
Ph
OH
OH
OH
O
O
O
O
N
N
Cl
N
F
Cl
N
Cl
4g (69%)
Ts
4c (45%)
3i (53%)
MeO
4a (77%)
4f (59%)
H
MeO
Ts
10
N
MeO
F3C
O
OH
O
O
O
3j (93%)
N
N
F
Cl
Cl
4h (83%)
4i (32%)
4k (26%, 50% brsm)
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
acryloyl chloride, Et3N
DMAP
Ph
Ph
Compounds 4a, 4c, 4f-4i, and 4k were then involved in a ring-
closing metathesis using the 2nd generation Grubbs catalyst (GII).
The corresponding DHPs were isolated in good to excellent
yields even for nitrogen containing heterocycles, as their
inherent Lewis basicity was decreased by the presence of an
adjacent chloride atom (5f-5i) (87-98%) or by the presence of a
N-tosyl group (5c, 85%; 5k, 93%).15 The results are reported in
Table 3.
(Het)Ar
O
O
CH2Cl2, 0 °C, 18-47 h
(Het)Ar
OH
3b
3d
3e
6b (43%)
6d (41%)
6e (88%)
Cl
Cl
N
N
Me
N
H-G II (4 mol %)
toluene, 100 °C, 15-48 h
(Het)Ar=
N
Cl
N
Cl
b
d
e
Ph
Ph
(Het)Ar
Table 3. Synthesis of 2,3 di(hetero)aryl substituted DHPs by RCM.
1) DIBAL-H (1.2 equiv)
CH2Cl2, –78 °C, 1-3 h
(Het)Ar2
(Het)Ar1
(Het)Ar
O
O
O
(Het)Ar2
(Het)Ar1
G II (2 mol %)
2) Et3SiH (1.5 equiv)
BF3•Et2O (2.0 equiv)
CH2Cl2, –78 °C to rt, 1-22 h
7b (64%)
7d (63%)
7e (65%)
CH2Cl2, rt, 20-24 h
5b (39%)
5d (50%)
5e (75%)
O
O
4
5
Scheme 3. Alternative route towards 5b, 5d, 5e DHPs, via a pyranone
OMe
intermediate.
Ph
Ph
Ph
3
O
O
O
2
O
It is worth noting that the anti-isomers 3 can be transformed to
their epimers at the C2 position, by an oxidation step (DMP,
CH2Cl2, 0 °C to rt) followed by a reduction with L-selectride (THF,
-78 °C). Compound 2-epi-3a was obtained in a good overall
yield as a single diastereomer (Scheme 4).16 Allylation of 2-epi-
3a generated 2-epi-4a in 72% yield, which was cyclized into the
desired DHP cis-5a in 79% yield by using the 2nd generation
Grubbs catalyst (GII). The cis-relative configuration was
established by measuring the coupling constant between the
protons H2 and H3 (JH2,3=3.4 Hz) and by a NOESY experiment.
N
N
Cl
F
Ts
N
5g (90%)
Cl
5f (98%)
5a (97%)
5c (85%)
Ts
N
MeO
F3C
O
O
O
N
Cl
F
N
Cl
5k (93%)
5h (92%)
5i (87%)
It is worth mentioning that the value of the coupling constant
between H2 and H3 in compounds is around Hz,
establishing the trans relationship between the aryl(heteroaryl)
substituents on the DHP rings.
1) DMP (1.5 equiv)
CH2Cl2, 0 °C to rt, 2 h
5
9
Ph
Ph
88%
3
OH
2
2
OH
2) L-selectride (1.5 equiv)
F
As ethers 4b, 4d and 4e could not be obtained by the
conventional allylation under basic conditions, an alternative
route was devised, by synthesizing acrylates 6b, 6d and 6e from
homoallylic alcohols 3b, 3d and 3e respectively (41%-88%)
(Scheme 3). The pyranones 7b (64%), 7d (63%) and 7e (65%)
were then obtained by realizing a ring-closing metathesis using
the 2nd generation Hoveyda-Grubbs catalyst (H-GII) in refluxing
toluene. After reduction of the pyranones, using DIBAL-H to
THF, –78 °C, 3 h
79%
F
2-epi-3a
3a
NaH (1.55 equiv)
allyl bromide (1.50 equiv)
THF, 0 °C to rt, 40 h
72%
Ph
Ph
G II (2 mol %)
3
CH2Cl2, rt, 23 h
2
O
O
79%
generate the intermediate lactols, followed by
a Et3SiH/
F
F
2-epi-4a
cis-5a
BF3!Et2O reduction, the targeted DHPs 5b, 5d and 5e were
obtained (39%-75%).
Scheme 4. Synthesis of cis-bis-arylated DHP cis-5a by an oxidation/reduction
sequence.
As it was intended to reach glycoside-type compounds, further
functionalization of the obtained DHPs was investigated. Thus,
homoallylic alcohol 3j was transformed to pyranone 7j, using the
previously described conditions (acylation, followed by a ring-
closing metathesis, 65% over 2 steps). The reduction of the
double bond present in 7j was effected using the Wilkinson
catalyst, generating lactone 8 (85%) that was treated with the
lithiated 1,3-dithiane (53% yield) and the intermediate lactol was
reduced using Et3SiH/BF3!Et2O, to produce the homologated
DHP 9 (50%).17 Dithiane 9 was deprotected using MeI under
basic conditions and the intermediate aldehyde 10 was reduced
in situ by NaBH4 to the 2,3-diaryl tetradeoxy carbohydrate 11
(57%, over the
2 steps) (Scheme 5). The cis-relative
configuration of the phenyl and hydroxymethyl substituents at
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
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General procedure 2 (GP2). Synthesis of esters 6
C2 and C6 was respectively proven by a NOESY correlation of
the protons H2 and H6.
1) acryloyl chloride (4 equiv)
Et3N (5 equiv)
Acryloyl chloride (4 equiv) was added to a solution of alcohol 3 (1 equiv),
Et3N (5 equiv) and DMAP (0.1 equiv) in CH2Cl2 (0.12M) cooled at 0 °C.
The solution was allowed to warm up to rt and stirred until complete
consumption of starting material (18-48 h). A saturated aqueous solution
of NaHCO3 was then added and the product was extracted with CH2Cl2
(3 times). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE) to afford ester
6.
DMAP (0.05 equiv)
MeO
MeO
CH2Cl2, rt, 29 h
69%
OH
2) H-G II (3 mol %)
toluene, 100 °C, 27 h
Ph
O
Ph
O
7j
3j
94%
(Ph3P)3RhCl (5 mol %)
H2
85%
1) 1,3-dithiane (1.1 equiv)
n-BuLi (1.1 equiv)
THF, –78 °C to 0 °C, 4 h
toluene, rt, 4 d
MeO
MeO
53%
(1R*,2S*)-1-(4-fluorophenyl)-2-phenylbut-3-en-1-ol (3a).
S
2) BF3•Et2O (4 equiv)
Et3SiH (5 equiv)
Ph
O
Ph
O
O
Compound 3a was prepared according to GP1 from cinnamyl alcohol
(0.15 mL, 1.19 mmol) and p-fluorobenzaldehyde (86 µL, 0.795 mmol).
The crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:6 to 1:5) to afford homoallylic alcohol 3a (190 mg, 99%)
as a slightly yellow oil. Rf = 0.31 (EtOAc/PE = 1:6); IR (film) 3428, 1603,
S
CH2Cl2, –78 °C to rt, 16 h
50%
9
8
1) MeI (2 equiv)
Na2CO3 (1.2 equiv)
acetone/H2O (9:1), 35 °C, 26 h
1509, 1220, 1156, 1032, 919 cm–1 1H NMR (400 MHz, CDCl3) δ 7.23 –
;
7.11 (m, 3H), 7.09 – 7.05 (m, 2H), 7.02 – 7.00 (m, 2H), 6.90 – 6.82 (m,
2H), 6.22 (ddd, J = 17.1, 10.2, 9.0 Hz, 1H), 5.28 – 5.21 (m, 2H), 4.78 (d,
J = 8.0 Hz, 1H), 3.46 (tapp, J = 8.5 Hz, 1H), 1.9 (br s, 1H, OH); 13C NMR
(100 MHz, CDCl3) δ 161.9 (d, J = 245.2 Hz), 140.3, 137.7, 137.5 (d, J =
3.2 Hz), 128.3 (2C), 128.2 (d, J = 8.0 Hz, 2C), 128.1 (2C), 126.7, 118.7,
114.7 (d, J = 21.4 Hz, 2C), 76.65, 59.65; EI–MS m/z (relative intensity)
125 (99), 118 (100), 117 (54), 115 (34), 97 (63), 95(20), 91 (19), 77 (27);
HRMS the compound was not detected.
MeO
MeO
2) NaBH4 (2 equiv)
OH
O
Et2O/MeOH (1:1)
0 °C to rt, 4 h
Ph
O
Ph
O
H
H
11
H
57% (from 9)
NOESY
10
Scheme 5. Synthesis of complex tetrahydropyrans, as glucoside analogs.
(1R*,2S*)-1-(4,6-Dichloropyrimidin-5-yl)-2-phenylbut-3-en-1-ol (3b).
Compound 3b was prepared according to GP1 from cinnamyl alcohol
(0.13 mL, 0.983 mmol) and 4,6-dichloropyrimidine-5-carbaldehyde (116
mg, 0.655 mmol). The crude product was purified by flash
Conclusions
chromatography on silica gel (EtOAc/PE
= 1:4 to 1:3) to afford
In summary, we have shown that trans-2,3-
diarylated(heteroarylated) DHPs can be synthesized from
aromatic and heteroaromatic aldehydes by using an
homoallylic alcohol 3b (171 mg, 88%) as a white solid. mp 91–92 °C; Rf
= 0.36 (EtOAc/PE = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.20
– 7.09 (m, 5H), 6.31 (m, 1H), 5.53 (dd, J = 10.2, 6.4 Hz, 1H), 5.41 (dtapp
,
J = 6.2, 0.9 Hz, 1H), 5.38 (dapp, J = 0.9 Hz, 1H), 4.27 (dd, J = 9.9, 8.4 Hz,
1H), 2.73 (d, J = 6.4 Hz, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 161.4
(2C), 156.3, 138.4, 137.3, 131.4, 128.7 (2C), 127.7 (2C), 127.5, 119.3,
72.8, 54.2; IR (film) 3397, 1532, 1515, 1415, 1334, 1214, 1130, 1048,
922, 854 cm–1; EI–MS m/z (relative intensity) 175 (18), 118 (22), 117 (10),
116 (24), 115 (53), 91 (18), 86 (29), 85 (23), 51 (31); HRMS the
compound was not detected.
allylboration followed by
a
ring-closing metathesis. The
compatibility of the Hoveyda-Grubbs catalysts with the complex
nitrogen-based heterocycles is assured by lowering the Lewis
basicity of the nitrogen atom with electron-withdrawing groups.
This versatile strategy provides an opportunity to obtain various
original structures and substitution patterns on pyran rings in a
diastereoselective manner. Further functionalization of the
obtained
DHPs
and
dihydropyranones
can
afford
(1R*,2S*)-2-Phenyl-1-(1-tosyl-1H-indol-3-yl)but-3-en-1-ol (3c).
C-diaryl(heteroaryl) tetradeoxy-glycosides.
Compound 3c was prepared according to GP1 from cinnamyl alcohol
(0.21 mL, 1.61 mmol) and aldehyde 2c (321 mg, 1.07 mmol). The crude
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:4 to 1:3) to afford homoallylic alcohol 3c (434 mg, 97%) as a viscous
colorless oil. Rf = 0.30 (EtOAc/PE = 1:3); IR (film) 3548, 1446, 1365,
1172, 1121, 1019, 972, 907 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J
= 8.3, 1H), 7.59 (br d, J = 7.7 Hz, 1H), 7.49 (br d, J = 8.4 Hz, 2H), 7.26 –
7.21 (m, 2H), 7.17 (m, 1H), 7.15 – 7.08 (m, 5H), 7.04 – 7.00 (m, 2H),
6.20 (ddd, J = 17.1, 10.2, 8.7 Hz, 1H), 5.21 (dd, J = 10.1, 1.5 Hz, 1H),
5.14 (ddd, J = 17.1, 1.6, 0.8 Hz, 1H), 5.06 (d, J = 7.7 Hz, 1H), 3.76 (tapp, J
= 8.2 Hz, 1H), 2.52 (br s, 1H, OH), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 144.6, 140.7, 137.5, 135.0, 134.9, 129.6, 128.9 (2C), 128.4
(2C), 127.9 (2C), 126.5, 124.5, 124.0, 123.1, 123.0, 120.5, 118.4, 113.5,
71.0, 56.7, 21.4; EI–MS m/z (relative intensity) 299 (13), 155 (30), 116
(11), 91 (100), 89 (15), 65 (25), 63 (10); HRMS calcd for C25H23NO3SNa
(M+Na+): 440.12909. Found: 440.12910.
Experimental Section
General procedure 1 (GP1). Synthesis of homoallylic alcohols 3. Allyl
alcohol 1 (1.2 equiv) was added to a solution of Pd(CH3CN)4(BF4)2 (10
mol %) and (Bpin)2 (2.5 equiv) in DMSO/MeOH (1:1, 0.25M). The
solution was heated at 50 °C under air. After complete consumption of
the starting material (1-5 h), the solution was cooled at rt and filtered
through
a pad of Celite and washed with Et2O. The filtrate was
concentrated under reduced pressure. Water was added and the product
was extracted with Et2O (3 times). The combined organic phases were
dried over MgSO4, filtered and concentrated under reduced pressure.
The crude boronate was diluted in CH2Cl2 (0.16 M) and aldehyde 2 (1
equiv) was added. The solution was stirred at rt, and after 22-90 h, H2O
was then added to the reaction mixture and the solution was stirred at rt
for 1 h. The product was extracted with CH2Cl2 (3 times). The combined
organic layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (EtOAc/PE) to afford homoallylic alcohol 3.
(1R*,2S*)-1-(2-Chloroquinolin-3-yl)-2-phenylbut-3-en-1-o (3d).
Compound 3d was prepared according to GP1 from cinnamyl alcohol
(0.15 mL, 1.17 mmol) and 2-chloroquinoline-3-carbaldehyde (150 mg,
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
0.783 mmol). The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:6 to 1:5) to afford homoallylic alcohol 3d (212
mg, 87%) as a white solid. mp 147–152 °C; Rf = 0.39 (EtOAc/PE = 1:3);
IR (film) 3341, 1590, 1492, 1396, 1326, 1138, 1039, 921, 752, 727, 699
cm–1; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H),
7.85 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.56
(ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.42 – 7.39 (m, 2H), 7.37 – 7.33 (m, 2H),
7.26 (m, 1H), 6.30 (ddd, J = 17.1, 10.3, 9.1 Hz, 1H), 5.47 (tapp, J = 3.8 Hz,
1H), 5.14 (dd, J = 10.3, 1.7 Hz, 1H), 4.91 (ddd, J = 17.2, 1.6, 0.9 Hz, 1H),
3.94 (dd, J = 9.2, 3.8 Hz, 1H), 1.79 (br s, 1H, OH); 13C NMR (100 MHz,
CDCl3) δ 148.6, 146.9 (2C), 141.2, 137.2, 134.4, 133.8, 130.3, 128.8
(2C), 128.2, 128.1 (2C), 127.8, 127.1 (2C), 119.6, 73.8, 54.9; EI–MS m/z
(relative intensity) 169.1 (21), 168.2 (35), 151.2 (45), 142.2 (33), 140.2
(100), 134.3 (34), 132.2 (58), 117.2 (30), 116.1 (62), 115.1 (26), 104.2
(46), 102.2 (37.4), 90.2 (19), 89.2 (40), 78.1 (24), 77.2 (37), 76.1 (29),
75.2 (24), 63.1 (31), 51.1 (56), 50.2 (39); HRMS calcd for C19H17ClNO
(M+H+): 310.09932. Found: 310.09915.
120.8, 118.6, 110.7, 71.9, 55.2, 50.4; EI–MS m/z (relative intensity) 289
(0.19), 148 (46), 147 (100), 131 (13), 117 (12), 115 (20), 91 (43), 78 (18),
77 (10), 51 (13); HRMS calcd for C16H17ClNO2 (M+H+): 290.09423.
Found: 290.09455.
(1R*,2S*)-1-(2-Chloropyridin-3-yl)-2-(4-methoxyphenyl)but-3-en-1-ol
(3h).
Compound 3h was prepared according to GP1 from alcohol 1c (174 mg,
0.706 mmol) and 2-chloropyridine-3-carbaldehyde (100 mg, 1.06 mmol).
The crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:4 to 1:3) to afford homoallylic alcohol 3h (178 mg, 87%)
as a yellow oil. Rf = 0.58 (EtOAc/PE = 1:1); IR (film) 3343, 1609, 1580,
1567, 1510, 1464, 1408, 1245, 1178, 1054, 1034, 910 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 8.25 (dd, J = 4.8, 2.0 Hz, 1H), 7.86 (ddd, J = 7.7, 2.0,
0.6 Hz, 1H), 7.26 – 7.21 (m, 3H), 6.87 – 6.83 (m, 2H); 6.21 (ddd, J = 17.1,
10.2, 9.1 Hz, 1H), 5.27 (dd, J = 4.2, 3.0 Hz, 1H), 5.15 (ddd, J = 10.3, 1.7,
0.6 Hz, 1H), 4.94 (ddd, J = 17.1, 1.7, 0.9 Hz, 1H), 3.78 (s, 3H), 3.73 (dd,
J = 9.1, 4.6 Hz, 1H), 2.41 (br d, J = 3.5 Hz, 1H, OH); 13C NMR (100 MHz,
CDCl3) δ 158.5, 148.9, 148.2, 137.6, 136.5, 135.2, 132.7, 129.0 (2C),
122.3, 119.0, 114.0 (2C), 73.5, 55.2, 54.3; EI–MS m/z (relative intensity)
289 (0.5), 148 (14), 147 (10), 115 (15), 91 (26), 78 (14); HRMS calcd for
C16H17ClNO2 (M+H+): 290.09423. Found: 290.09466.
(1R*,2S*)-1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-2-phenylbut-3-en-1-
ol (3e).
Compound 3e was prepared according to GP1 from cinnamyl alcohol
(0.40 mL, 3.11 mmol) and aldehyde 2e (300 mg, 2.08 mmol). The crude
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:1) to afford homoallylic alcohol 3e (529 mg, 97%) as a white solid. mp
81–83 °C; Rf = 0.28 (EtOAc/PE = 1:1); IR (film) 3361, 1557, 1407, 1172,
1003, 910 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.23 (m, 2H), 7.20 –
7.16 (m, 4H), 6.21 (ddd, J = 17.1, 10.2, 8.8 Hz, 1H), 5.24 (ddd, J = 10.3,
1.6, 0.7 Hz, 1H), 5.19 (ddd, J = 17.1, 1.7, 1.0 Hz, 1H), 4.89 (d, J = 7.0 Hz,
1H), 3.72 (s, 3H), 3.66 (dd, J = 9.1, 6.9 Hz, 1H), 2.46 – 2.36 (br s, 1H,
OH); 13C NMR (100 MHz, CDCl3) δ 140.6, 137.2, 136.8, 130.2, 128.5
(2C), 128.1 (2C), 126.7, 119.6, 118.4, 68.7, 56.8, 39.4; EI–MS m/z
(relative intensity) 246 (22), 245 (15), 244 (68), 210 (14), 209 (100), 208
(16), 194 (17), 168 (14), 145 (79), 144 (21), 143 (21), 142 (46), 141 (20),
140 (14), 139 (17), 131 (32), 129 (80), 52 (17), 51 (47), 50 (14); HRMS
calcd for C14H16ClN2O (M+H+): 263.09457. Found: 263.09475.
(1R*,2S*)-1-(2-Chloropyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)but-3-
en-1-ol (3i).
Compound 3i was prepared according to GP1 from alcohol 1d (257 mg,
1.27 mmol) and 2-chloropyrine-3-carbaldehyde (120 mg, 0.848 mmol).
The crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:4 to 1:2) to afford homoallylic alcohol 3i (146 mg, 53%) as
a white solid. mp 131–133 °C ; Rf = 0.29 (EtOAc/PE = 1:3); IR (film)
3282, 1617, 1570, 1411, 1324, 1163, 1121, 1068, 1018, 925 cm–1 1H
;
NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 4.7, 1.9 Hz, 1H), 7.89 (ddd, J =
7.7, 2.0, 0.7 Hz, 1H), 7.61 – 7.57 (m, 2H), 7.50 – 7.46 (m, 2H), 7.28 (m,
1H), 6.25 (ddd, J = 17.2, 10.3, 9.1 Hz, 1H), 5.33 (tapp, J = 4.0 Hz, 1H),
5.21 (ddd, J = 10.2, 1.5, 0.6 Hz, 1H), 4.95 (ddd, J = 17.2, 1.5, 0.9 Hz, 1H),
3.82 (dd, J = 9.1, 4.0 Hz, 1H), 2.31 (d, J = 4.0 Hz, 1H, OH); 13C NMR
(100 MHz, CDCl3) δ 148.7, 148.6, 145.2 (d, J = 1.6 Hz), 137.6, 136.2,
133.9, 129.2 (d, J = 32.6 Hz), 128.5 (2C), 125.5 (q, J = 3.8 Hz, 2C),
122.5, 121.2 (d, J = 269 Hz), 120.0, 73.2, 54.8; EI–MS m/z (relative
intensity) 196 (32), 166 (11), 144 (32), 142 (100), 117 (13), 116 (10), 115
(18), 106 (50), 78 (41), 51 (21); HRMS calcd for C16H14ClF3NO (M+H+):
328.07105. Found: 328.07124.
(1R*,2S*)-1-(2-Chloropyridin-3-yl)-2-phenylbut-3-en-1-ol (3f).
Compound 3f was prepared according to GP1 from cinnamyl alcohol
(0.15 mL, 1.18 mmol) and 2-chloropyridine-3-carbaldehyde (111 mg,
0.784 mmol). The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:4 to 1:3) to afford homoallylic alcohol 3f (185 mg,
92%) as a colorless oil. Rf = 0.33 (EtOAc/PE = 1:3); IR (film) 3296, 1579,
1567, 1494, 1452, 1408, 1183, 1120, 1054, 1000, 919 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 8.20 (dd, J = 4.7, 2.0 Hz, 1H), 7.86 (dd, J = 7.6, 2.0
Hz, 1H), 7.34 – 7.28 (m, 4H), 7.26 – 7.20 (m, 2H), 6.25 (ddd, J = 17.1,
10.2, 9.1 Hz, 1H), 5.29 (tapp, J = 3.9 Hz, 1H), 5.15 (dd, J = 10.2, 1.7 Hz,
1H), 4.93 (ddd, J = 17.1, 1.7, 0.9 Hz, 1H), 3.76 (dd, J = 9.2, 4.3 Hz, 1H),
2.69 (d, J = 3.7 Hz, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 148.7, 148.3,
140.8, 137.6, 136.4, 134.8, 128.7 (2C), 128.0 (2C), 127.0, 122.4, 119.4,
73.5, 55.1; EI–MS m/z (relative intensity) 118 (100), 117 (93), 115 (55);
HRMS calcd for C15H15ClNO (M+H+): 260.08367. Found: 260.08397.
(1R*,2S*)-2-(4-Methoxyphenyl)-1-phenylbut-3-en-1-ol (3j).
Compound 3j was prepared according to GP1 from alcohol 1c (1.13 g,
6.89 mmol) and benzaldehyde (0.46 mL, 4.59 mmol). The crude product
was purified by flash chromatography on silica gel (EtOAc/PE = 1:7 to
1:5) to afford homoallylic alcohol 3j (1.09 g, 93%) as a yellow oil. Rf =
0.36 (EtOAc/PE = 1:5); IR (film) 3443, 1610, 1583, 1510, 1454, 1302,
1243, 1178, 1033, 917 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.12 (m,
5H), 6.96 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.21 (ddd, J = 17.0,
10.2, 8.8 Hz, 1H), 5.27 – 5.17 (m, 2H), 4.80 (d, J = 7.6 Hz, 1H), 3.74 (s,
3H), 3.51 (t, J = 8.3 Hz, 1H), 2.30 (br d, J = 2.5 Hz, 1H, OH); 13C NMR
(100 MHz, CDCl3) δ 158.1, 141.9, 138.0, 132.6, 129.2 (2C), 127.8 (2C),
127.3, 126.7 (2C), 118.0, 113.7 (2C), 77.3, 58.2, 55.1; EI–MS m/z
(relative intensity) 149 (12), 148 (100), 147 (70), 117 (14), 115 (18), 107
(30), 105 (11), 91 (30), 79 (31), 78 (11), 77 (30), 51 (10); HRMS calcd for
C17H18O2Na (M+Na+): 277.11990. Found: 277.77996.
(1R*,2S*)-1-(2-Chloropyridin-3-yl)-2-(2-methoxyphenyl)but-3-en-1-ol
(3g).
Compound 3g was prepared according to GP1 from alcohol 1b (174 mg,
1.06 mmol) and 2-chloropyridine-3-carbaldehyde (100 mg, 0.706 mmol).
The crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:4 to 1:3) to afford homoallylic alcohol 3g (125 mg, 61%)
as a yellow oil. Rf = 0.61 (EtOAc/PE = 1:1); IR (film) 3311, 1581, 1567,
1491, 1462, 1409, 1243, 1184, 1052, 1029, 909, 751, 726 cm–1; 1H NMR
(400 MHz, CDCl3) δ 8.18 (br d, J = 2.7 Hz, 1H), 7.88 (dd, J = 7.7, 1.9 Hz,
1H), 7.24 (dd, J = 7.6, 1.8 Hz, 1H), 7.21 – 7.17 (m, 2H), 6.90 (td, J = 7.5,
1.1 Hz, 1H), 6.82 (dd, J = 8.2, 1.2 Hz, 1H), 6.29 (ddd, J = 17.1, 10.2, 9.0
Hz, 1H), 5.35 (dd, J = 4.9, 2.0 Hz, 1H), 5.11 (dd, J = 10.2, 1.8 Hz, 1H),
4.96 (ddd, J = 17.1, 1.8, 1.0 Hz, 1H), 4.13 (dd, J = 9.0, 4.9 Hz, 1H), 3.78
(s, 3H), 3.24 (br d, J = 2.9 Hz, 1H, OH); 13C NMR (100 MHz, CDCl3) δ
156.4, 149.0, 147.9, 137.7, 136.8, 135.1, 129.6, 128.8, 128.1, 122.0,
(1R*,2S*)-1-(4-Fluorophenyl)-2-(1-tosyl-1H-indol-3-yl)but-3-en-1-ol
(3k).
Compound 3k was prepared according to GP1 from alcohol 1e (266 mg,
0.811 mmol) and p-fluorobenzaldehyde (58 µL, 0.541 mmol). The crude
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:7 to 1:3) to afford a mixture of homoallylic alcohol 3k and pinacol (78
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
mg, 32%, 3% pinacol) as a soft white foam. The separation of pinacol
was carried out in the subsequent step. Rf = 0.33 (EtOAc/PE = 1:3); IR
(film) 3547, 1601, 1509, 1446, 1364, 1278, 1219, 1171, 1121, 1093,
1019, 979 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.93 (dtapp, J = 8.4, 0.9 Hz,
1H), 7.58 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.26
(m, 1H), 7.18 – 7.13 (m, 3H), 7.09 – 7.04 (m, 2H), 6.79 – 6.73 (m, 2H),
6.16 (ddd, J = 17.1, 10.2, 8.3 Hz, 1H), 5.24 (ddd, J = 10.2, 1.5, 0.8 Hz,
equiv) was added and the solution was stirred at rt for 15 h. The reaction
mixture was quenched with H2O (1 mL) then it was extracted with Et2O (3
× 2 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE = 17:83 to
25:75) to afford ether 4f (33 mg, 59%) as a yellow oil. Rf 0.66 (EtOAc/PE
= 1:5); IR (film) 1639, 1601, 1579, 1563, 1494, 1453, 1407, 1335, 1182,
1119, 1088, 1059, 998, 920 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd,
J = 4.7, 2.0 Hz, 1H), 7.78 (dd, J = 7.5, 1.9 Hz, 1H), 7.38 – 7.34 (m, 2H),
7.32 – 7.20 (m, 4H), 6.27 (ddd, J = 17.2, 10.2, 8.9 Hz, 1H), 5.74 (ddt, J =
17.2, 10.6 and 5.4 Hz, 1H), 5.18 (dqapp, J = 17.2, 1.7 Hz, 1H), 5.13 – 5.06
(m, 2H), 4.99 (d, J = 3.7 Hz, 1H), 4.78 (ddd, J = 17.2, 1.8, 1.0 Hz, 1H),
3.85 (ddt, J = 12.9, 5.2, 1.5 Hz, 1H), 3.71 (ddt, J = 12.9, 5.7, 1.5 Hz, 1H),
3.62 (dd, J = 8.9, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.8, 148.4,
141.6, 137.8, 135.5, 135.1, 134.0, 128.3 (2C), 128.2 (2C), 126.7, 122.3,
118.0, 117.0, 80.6, 70.6, 54.8; EI–MS m/z (relative intensity) 184 (32),
182 (100), 140 (32), 117 (55), 116 (17), 115 (60), 91 (30); HRMS calcd
for C18H19ClNO (M+H+): 300.11497. Found: 300.11503.
1H), 5.16 (dtapp, J = 17.1, 1.3 Hz, 1H), 4.96 (d, J = 7.4 Hz, 1H), 3.75 (tapp
,
J = 8.3 Hz, 1H), 2.49 (br s, 1H, OH), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.0 (d, J = 245.5 Hz), 144.8, 137.6, 137.6, 135.8, 134.9,
129.8, 129.7 (2C), 128.0 (d, J = 8.1 Hz, 2C), 126.5 (2C), 124.7, 123.9,
123.0, 121.6, 119.8, 119.0, 114.8 (d, J = 21.3 Hz, 2C), 113.7, 75.0, 49.8,
21.4; EI–MS m/z (relative intensity) 311 (26), 157 (14), 156 (100), 155
(33), 154 (32), 129 (22), 128 (46), 127 (15), 102 (10), 91 (59), 77 (18), 65
(34), 63 (11), 51 (14); HRMS calcd for C25H22FNO3SNa (M+Na+):
458.11966. Found: 458.11951.
1-((1R*,2S*)-1-(Allyloxy)-2-phenylbut-3-en-1-yl)-4-fluorobenzene (4a).
3-((1R*,2S*)-1-(Allyloxy)-2-(2-methoxyphenyl)but-3-en-1-yl)-2-
chloropyridine (4g).
A solution of alcohol 3a (200 mg, 0.83 mmol, 1 equiv) in THF (2 mL) was
added to a suspension of NaH (60% in oil, 51 mg, 1.28 mmol, 1.55 equiv)
in THF (1 mL) cooled at 0 °C. The solution was stirred at rt for 1 h. Allyl
bromide (0.11 mL, 1.24 mmol, 1.5 equiv) was then added and the
solution was stirred at rt for 15 h. Water (1 mL) was added and the
product was extracted with Et2O (3 × 2 mL). The combined organic layers
were dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:99 to 2:98) to afford ether 4a (181 mg, 77%) as
a yellow oil. Rf = 0.36 (EtOAc/PE = 2:98); IR (film) 1639, 1603, 1508,
NaH (60% in oil, 12 mg, 0.296 mmol, 1.55 equiv) was added to a solution
of alcohol 3g (55 mg, 0.191 mmol, 1 equiv) in THF (0.72 mL) cooled at
0 °C. The solution was stirred at rt for 1 h, then allyl bromide (25 µL,
0.286 mmol, 1.5 equiv) was added to the solution. After stirring for 38 h,
H2O (1 mL) was added to the reaction mixture and the product was
extracted with Et2O (3 × 2 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:7 to 1:5) to afford ether 4g (43 mg, 69%) as a colorless oil.
Rf = 0.61 (EtOAc/PE = 1:3); IR (film) 1599, 1580, 1563, 1491, 1462, 1408,
1333, 1289, 1243, 1183, 1082, 1058, 1030, 999, 921 cm–1; 1H NMR (400
MHz, CDCl3) δ 8.23 (dd, J = 4.7, 2.0 Hz, 1H), 7.84 (dd, J = 7.6, 2.0 Hz,
1H), 7.34 (dd, J = 7.6, 1.7 Hz, 1H), 7.21 (dd, J = 7.7, 4.6 Hz, 1H), 7.15
(ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 6.87 (tdapp, J = 7.5, 1.2 Hz, 1H), 6.76 (dd,
J = 8.2, 1.1 Hz, 1H), 6.31 (ddd, J = 17.1, 10.2, 8.6 Hz, 1H), 5.74 (dddd, J
= 17.2, 10.5, 5.8, 5.2 Hz, 1H), 5.18 (dqapp, J = 17.2, 1.7 Hz, 1H), 5.12 –
5.04 (m, 3H), 4.89 (ddd, J = 17.2, 1.8, 1.1 Hz, 1H), 4.19 (dd, J = 8.6, 5.5
Hz, 1H), 3.84 (ddt, J = 12.9, 5.2, 1.5 Hz, 1H), 3.74 (s, 3H) ; 3.74 – 3.60
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.3, 150.1, 148.3, 138.1, 136.5,
135.5, 134.2, 129.5, 129.1, 127.6, 122.0, 120.3, 117.4, 116.9, 110.3,
79.1, 70.4, 55.1, 47.5; EI–MS m/z (relative intensity) 329 (0.37), 184 (20),
182 (63), 148 (11), 147 (100), 140 (17), 134 (11), 131 (15), 115 (20), 91
(40), 78 (10), 77 (10); HRMS calcd for C19H21ClNO2 (M+H+): 330.12553.
Found: 330.12562.
1453, 1418, 1221, 1155, 1077, 990, 918 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 7.22 – 7.09 (m, 3H), 7.07 – 7.03 (m, 4H), 6.88 (tapp, J = 8.7 Hz,
2H), 6.28 (ddd, J = 17.6, 10.3 and 7.9 Hz, 1H), 5.85 (m, 1H), 5.21 (br d, J
= 17.2 Hz, 1H), 5.13 (d, J = 10.3 Hz, 2H), 4.99 (d, J = 17.2 Hz, 1H), 4.51
(d, J = 7.2 Hz, 1H), 3.92 (dd, J = 13.0, 4.5 Hz, 1H), 3.72 (dd, J = 13.0, 6.0
Hz, 1H), 3.53 (tapp, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.0
(d, J = 245.2 Hz), 141.2, 138.1, 136.1 (d, J = 3.1 Hz), 134.6, 128.9 (d, J =
8.0 Hz, 2C), 128.6 (2C), 128.1 (2C), 126.4, 116.6 (2C), 114.8 (d, J = 21.2
Hz, 2C), 83.9, 69.6, 57.5; EI–MS m/z (relative intensity) 165 (75), 123
(100), 117 (20), 115 (30), 109 (34), 91 (20) ; HRMS the compound was
not detected.
3-((1R*,2S*)-1-(Allyloxy)-2-phenylbut-3-en-1-yl)-1-tosyl-1H-indole (4c).
NaH (60% in oil, 14 mg, 0.36 mmol, 1.55 equiv) was added to a solution
of alcohol 3c (96 mg, 0.23 mmol, 1 equiv) in THF (0.9 mL) cooled at 0 °C.
The solution was stirred at rt for 1 h. Allyl bromide (30 µL, 0.34 mmol, 1.5
equiv) was added and the solution was stirred at rt for 90 h. Water (1 mL)
was added and the product was extracted with Et2O (3 × 2 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE = 1:9 to 1:8) to afford ether
4c (48 mg, 45%) as a slightly pink oil. Rf = 0.40 (EtOAc/PE = 1:7); IR
(film) 1598, 1446, 1367, 1268, 1173, 1121, 1085, 976, 909 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.86 (dtapp, J = 8.2, 0.8 Hz, 1H), 7.64 (ddd, J = 7.9,
1.2, 0.7 Hz, 1H), 7.48 (br dapp, J = 8.4 Hz, 2H), 7.26 (ddd, J = 8.3, 7.2, 1.6
Hz, 1H), 7.21 – 7.14 (m, 4H), 7.13 – 7.09 (m, 3H), 7.02 – 6.98 (m, 2H),
6.29 (ddd, J = 17.2, 10.3, 7.8 Hz, 1H), 5.84 (dddd, J = 16.4, 10.8, 6.1, 4.9
Hz, 1H), 5.19 (dqapp, J = 17.2, 1.7 Hz, 1H), 5.16 – 5.11 (m, 2H), 4.96
(dtapp, J = 17.2, 1.2 Hz, 1H), 4.79 (d, J = 7.8 Hz, 1H), 3.95 (ddtapp, J =
13.0, 4.9, 1.6 Hz, 1H), 3.82 – 3.73 (m, 2H), 2.35 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.6, 141.3, 138.2, 135.2, 135.0, 134.6, 129.7 (2C),
129.2, 128.3 (2C), 128.2 (2C), 126.6 (2C), 126.4, 124.9, 124.5, 123.0,
121.3, 120.7, 116.8, 116.7, 113.5, 78.3, 69.7, 55.3, 21.5; HRMS calcd for
C28H27NO3SNa (M+Na+): 480.16039. Found: 480.16016.g
3-((1R*,2S*)-1-(Allyloxy)-2-(4-methoxyphenyl)but-3-en-1-yl)-2-
chloropyridine (4h).
NaH (60% in oil, 12 mg, 0.310 mmol, 1.55 equiv) was added to a solution
of alcohol 3h (58 mg, 0.200 mmol, 1 equiv) in THF (0.76 mL) cooled at
0 °C. The solution was stirred at rt for 1 h and allyl bromide (26 µL, 0.300
mmol, 1.5 equiv) was added. The solution was stirred at rt for 63 h,
quenched with H2O (1 mL) and the product was extracted with Et2O (3 ×
2 mL). The combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE = 1:7 to 1:6) to afford ether
4h (55 mg, 83%) as a colorless oil. Rf = 0.40 (EtOAc/PE = 1:5); IR (film)
1610, 1579, 1563, 1510, 1463, 1408, 1337, 1247, 1179, 1059, 1035, 998,
920 cm–1 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 4.7, 2.0 Hz, 1H),
;
7.77 (ddd, J = 7.6, 2.0, 0.6 Hz, 1H), 7.28 – 7.23 (m, 3H), 6.83 (dapp, J =
8.9 Hz, 2H), 6.23 (ddd, J = 17.1, 10.2, 8.8 Hz, 1H), 5.76 (dddd, J = 17.2,
10.4, 5.7, 5.2 Hz, 1H), 5.20 (app dq, J = 17.2, 1.5 Hz, 1H), 5.12 (dqapp, J
= 10.4, 1.5 Hz, 1H), 5.06 (ddd, J = 10.2, 1.8, 0.7 Hz, 1H), 4.95 (br d, J =
3.9 Hz, 1H), 4.77 (ddd, J = 17.2, 1.7, 1.0 Hz, 1H), 3.85 (ddtapp, J = 12.9,
5.2, 1.5 Hz, 1H), 3.79 (s, 3H), 3.72 (ddtapp, J = 12.8, 5.7, 1.5 Hz, 1H),
3.57 (dd, J = 8.8, 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4, 149.9,
148.4, 137.8, 135.9, 135.2, 134.0, 133.7, 129.2 (2C), 122.3, 117.7, 117.0,
113.7 (2C), 80.7, 70.6, 55.2, 54.0; EI–MS m/z (relative intensity) 329
3-((1R*,2S*)-1-(Allyloxy)-2-phenylbut-3-en-1-yl)-2-chloropyridine (4f).
NaH (60% in oil, 11 mg, 0.29 mmol, 1.55 equiv) was added to a solution
of alcohol 3f (48 mg, 0.18 mmol, 1 equiv) in THF (0.7 mL) and the
solution was stirred at rt for 1 h. Allyl bromide (24 µL, 0.28 mmol, 1.5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
C19H21ClNO2 (M+H+): 330.12553. Found: 330.12578.
(0.16), 182 (10), 148 (11), 147 (100), 115 (10), 91 (18); HRMS calcd for
2:98); IR (film) 1505, 1510, 1452, 1222, 1157, 1114, 1049, 1025, 829 cm–
1
;
1H NMR (400 MHz, CDCl3) δ 7.22 – 7.16 (m, 3H), 7.03 – 6.98 (m, 2H),
6.92 – 6.86 (m, 4H), 6.03 (m, 1H), 5.93 (dqapp, J = 10.2, 2.0 Hz, 1H), 4.51
– 4.39 (m, 2H), 4.31 (d, J = 9.2 Hz, 1H), 3.54 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 162.1 (d, J = 245.3 Hz), 140.5, 136.3 (d, J = 3.2 Hz),
128.9, 128.6 (2C), 128.5 (d, J = 8.0 Hz, 2C), 128.2 (2C), 126.7, 126.4,
114.7 (d, J = 21.2 Hz, 2C), 82.6, 66.4, 49.2; EI–MS m/z (relative
intensity) 130 (100), 129 (62), 128 (20), 115 (30); HRMS the product was
not detected.
3-((1R*,2S*)-1-(Allyloxy)-2-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)-2-
chloropyridine (4i).
NaH (60% in oil, 11 mg, 0.286 mmol, 1.55 equiv) was added to a solution
of alcohol 3i (60 mg, 0.184 mmol, 1 equiv) in THF (0.70 mL) cooled at
0 °C. The solution was stirred at rt for 1 h and allyl bromide (24 µL, 0.276
mmol, 1.5 equiv) was added. After 60 h at rt, H2O (1 mL) was added and
the product was extracted with Et2O (3 × 3 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:7 to 1:5) to afford ether 4i (21 mg, 32%) as a
colorless oil. Rf = 0.27 (EtOAc/PE = 1:5); IR (film) 1618, 1565, 1409,
1325, 1123, 1068, 1018, 925 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.32 (dd,
J = 4.7, 2.0 Hz, 1H), 7.78 (dd, J = 7.6, 2.0 Hz, 1H), 7.58 (br d, J = 8.1 Hz,
2H), 7.50 (br d, J = 8.1 Hz, 2H), 7.28 (m, 1H), 6.25 (ddd, J = 17.2, 10.2,
9.0 Hz, 1H), 5.73 (dddd, J = 17.2, 10.6, 5.8, 5.2 Hz, 1H), 5.19 (dqapp, J =
17.2, 1.7 Hz, 1H), 5.15 – 5.08 (m, 2H), 4.96 (d, J = 3.2 Hz, 1H), 4.78
(dtapp, J = 17.1, 1.3 Hz, 1H), 3.87 (ddt, J = 12.8, 5.2, 1.5 Hz, 1H), 3.72 –
3.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 149.6, 148.7, 145.8, 137.7,
134.6, 134.4, 133.7, 129.0 (d, J = 32.2 Hz), 128.6 (2C), 125.2 (q, J = 3.8
Hz, 2C), 124.2 (d, J = 272 Hz), 122.4, 119.0, 117.4, 80.2, 70.6, 54.5; EI–
MS m/z (relative intensity) 185 (16), 184 (32), 183 (11), 182 (100), 165
(15), 142 (10), 140 (25), 116 (12), 115 (17); HRMS calcd for
C19H18ClF3NO (M+H+): 368.10235. Found: 368.10270.
3-((2R*,3S*)-3-Phenyl-3,6-dihydro-2H-pyran-2-yl)-1-tosyl-1H-indole
(5c).
The 2nd generation Grubbs catalyst (1.5 mg, 1.75 µmol, 2 mol %) was
added to a solution of diene 4c (40 mg, 0.087 mmol, 1 equiv) in
degassed CH2Cl2 (0.42 mL). After 23
h at rt, the solution was
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE = 1:9 to 1:7) to afford
dihydropyran 5c (32 mg, 85%) as a slightly yellow oil. Rf = 0.27
(EtOAc/PE = 1:7); IR (film) 1597, 1447, 1366, 1273, 1172, 1122, 1094,
1022, 979, 909 cm–1 1H NMR (400 MHz, CDCl3) δ 7.90 (dtapp, J = 8.4,
;
0.9 Hz, 1H), 7.59 (br d, J = 8.4 Hz, 2H), 7.51 (br d, J = 7.9 Hz, 1H), 7.28
– 7.24 (m, 1H), 7.21 (s, 1H), 7.19 – 7.12 (m, 6H), 6.94 – 6.91 (m, 2H),
6.04 (ddtapp, J = 10.3, 3.3, 2.0 Hz, 1H), 5.95 (dqapp, J = 10.3, 2.1 Hz, 1H),
4.64 (d, J = 8.6 Hz, 1H), 4.45 (ddtapp, J = 16.7, 4.0, 2.0 Hz, 1H), 4.35
(dddd, J = 16.7, 5.1, 3.0, 2.0 Hz, 1H), 3.85 (m, 1H), 2.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 144.7, 140.9, 135.1, 135.0, 129.7 (2C), 129.3,
128.4, 128.4 (2C), 128.3 (2C), 126.8, 126.7 (2C), 126.4, 124.6, 124.1,
123.1, 121.4, 120.8, 113.4, 76.5, 65.7, 46.7, 21.5; HRMS calcd for
C26H23NO3SNa (M+Na+): 452.12909. Found: 452.12916.
3-((1R*,2S*)-1-(Allyloxy)-1-(4-fluorophenyl)but-3-en-2-yl)-1-tosyl-1H-
indole (4k).
2-Chloro-3-((2R*,3S*)-3-phenyl-3,6-dihydro-2H-pyran-2-yl)pyridine
(5f).
NaH (60% in oil, 10 mg, 0.240 mmol, 1.55 equiv) was added to a solution
of alcohol 3k (67 mg, 0.155 mmol, 1 equiv) in THF (0.59 mL) cooled at
0 °C. The solution was stirred at rt for 1 h and allyl bromide (20 µL, 0.232
mmol, 1.5 equiv) was added. After stirring the solution at rt for 18 h, H2O
(1 mL) was added to the reaction mixture and the product was extracted
with Et2O (3 × 2 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:9 to 1:3) to afford ether 4k (19 mg, 26%) as a colorless oil and the
recovered starting material 3k (32 mg, 47%) was isolated as an orange
oil. Rf = 0.44 (EtOAc/PE = 1:5); IR (film) 1602, 1508, 1446, 1368, 1278,
1173, 1121, 1086, 983, 918 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.92 (br d,
J = 8.3 Hz, 1H), 7.58 (dapp, J = 8.3 Hz, 2H), 7.44 (br d, J = 8.1 Hz, 1H),
7.28 – 7.26 (m, 1H), 7.24 (s, 1H), 7.20 – 7.15 (m, 3H), 7.06 – 7.01 (m,
2H), 6.82 – 6.76 (m, 2H), 6.24 (ddd, J = 17.4, 10.3, 7.3 Hz, 1H), 5.86
(dddd, J = 17.3, 10.8, 6.0, 5.0 Hz, 1H), 5.23 (dqapp, J = 17.2, 1.7 Hz, 1H),
5.16 (dqapp, J = 10.8, 1.6 Hz, 1H), 5.12 (dtapp, J = 10.3, 1.3 Hz, 1H), 4.95
(dtapp, J = 17.2, 1.4 Hz, 1H), 4.63 (d, J = 7.0 Hz, 1H), 3.92 (ddt, J = 12.9,
5.0, 1.6 Hz, 1H), 3.79 (m, 1H), 3.73 (ddtapp, J = 12.9, 6.0, 1.4 Hz, 1H),
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.0 (d, J = 245.3 Hz), 144.7,
136.2, 135.9 (d, J = 3.2 Hz), 135.2, 135.0, 134.4, 130.1, 129.7 (2C),
128.7 (d, J = 8.0 Hz, 2C), 126.6 (2C), 124.5, 124.2, 122.8, 121.9, 120.2,
117.2, 116.9, 114.8 (d, J = 21.3 Hz, 2C), 113.6, 82.6, 69.8, 48.3, 21.5;
EI–MS m/z (relative intensity) 310 (13), 262 (21), 261 (10), 260 (12), 166
(10), 165 (71), 155 (27), 154 (41), 128 (10), 127 (10), 124 (17), 123 (74),
109 (20), 95 (18), 91 (100), 75 (10), 65 (26), 57 (28); HRMS calcd for
C28H26FNO3SNa (M+Na+): 498.15096. Found: 498.15037.
The 2nd generation Grubbs catalyst (1.7 mg, 2.06 µmol, 2 mol %) was
added to a solution of diene 4f (31 mg, 0.10 mmol, 1 equiv) in degassed
CH2Cl2 (0.49 mL). After 8 h at rt, a second portion of Grubbs 2nd
generation catalyst (1.7 mg, 2.06 µmol, 2 mol %) was added. After
another 15 h, the solution was concentrated under reduced pressure and
the crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:5) to afford dihydropyran 5f (27 mg, 98%) as a yellow oil.
Rf = 0.32 (EtOAc/PE = 1:5); IR (film) 1584, 1565, 1492, 1463, 1415, 1341,
1288, 1244, 1190, 1179, 1109, 1071, 1050, 1026, 916 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 8.27 (dd, J = 4.7, 2.0 Hz, 1H), 7.96 (dd, J = 7.7, 2.0
Hz, 1H), 7.29 (dd, J = 7.7, 4.7 Hz, 1H), 7.20 – 7.17 (m, 3H), 6.93 – 6.89
(m, 2H), 6.06 (m, 1H), 5.98 (dqapp, J = 10.2, 2.0 Hz, 1H), 4.86 (d, J = 9.3
Hz, 1H), 4.50 (dddd, J = 16.8, 4.1, 2.3, 1.7 Hz, 1H), 4.41 (dddd, J = 16.7,
3.0, 3.3, 1.9 Hz, 1H), 3.62 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 150.6,
148.7, 139.0, 137.6, 135.0, 128.7, 128.5 (2C), 128.4 (2C), 127.1, 126.5,
122.7, 78.0, 66.5, 48.6; EI–MS m/z (relative intensity) 130 (100), 129 (55),
128 (17), 115 (25); HRMS calcd for C16H15ClNO (M+H+): 272.08702.
Found: 272.08403.
2-Chloro-3-((2R*,3S*)-3-(2-methoxyphenyl)-3,6-dihydro-2H-pyran-2-
yl)pyridine (5g).
The 2nd generation Grubbs catalyst (2.5 mg, 2.95 µmol, 2 mol %) was
added to a solution of diene 4g (43 mg, 0.131 mmol, 1 equiv) in
degassed CH2Cl2 (0.70 mL). After stirring at rt for 22 h then refluxed for 8
h, the solution was concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:4) to afford dihydropyran 5g (36 mg, 90%) as a colorless oil. Rf = 0.38
(EtOAc/PE = 1:3); IR (film) 1584, 1565, 1493, 1463, 1416, 1341, 1288,
1245, 1190, 1179, 1109, 1071, 1051, 1027, 916 cm–1;1H NMR (400 MHz,
CDCl3) δ 8.23 (dd, J = 4.7, 2.0 Hz, 1H), 7.99 (dd, J = 7.7, 2.0 Hz, 1H),
7.25 (ddd, J = 7.6, 4.7, 0.5 Hz, 1H), 7.20 (dd, J = 7.5, 1.7 Hz, 1H), 7.16
(ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 6.90 (tdapp, J = 7.5, 1.1 Hz, 1H), 6.64 (dd,
J = 8.2, 1.1 Hz, 1H), 6.01 (dddd, J = 10.3, 3.4, 2.6, 1.8 Hz, 1H), 5.89
(dqapp, J = 10.3, 2.1 Hz, 1H), 4.86 (d, J = 9.2 Hz, 1H), 4.49 (dddd, J =
16.6, 4.1, 2.4, 1.8 Hz, 1H), 4.39 (dddd, J = 16.6, 3.4, 3.0, 2.0 Hz, 1H),
(2R*,3S*)-2-(4-Fluorophenyl)-3-phenyl-3,6-dihydro-2H-pyran (5a).
The 2nd generation Grubbs catalyst (6.7 mg, 7.88 µmol, 2 mol %) was
added to a solution of diene 4a (111 mg, 0.39 mmol, 1 equiv) in
degassed CH2Cl2 (1.9 mL). The solution was stirred at rt for 4 h, then it
was concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE = 3:97) to afford
dihydropyran 5a (97 mg, 97%) as a yellow oil. Rf = 0.40 (EtOAc/PE =
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
4.22 (m, 1H), 3.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 150.1,
148.3, 138.2, 135.4, 129.3, 129.2, 128.2, 127.5, 125.9, 122.2, 120.7,
110.2, 77.8, 66.4, 54.7, 40.1; EI–MS m/z (relative intensity) 302 (0.03),
161 (12), 160 (100), 159 (57), 145 (21), 144 (18), 129 (46), 128 (17), 127
(10), 117 (12), 115 (24), 91 (17); HRMS calcd for C17H17ClNO2 (M+H+):
302.09423. Found: 302.09452.
122.9, 121.9, 119.9, 114.8 (d, J = 21.3 Hz, 2C), 113.7, 80.5, 66.5, 40.8,
21.5; EI–MS m/z (relative intensity) 220 (27), 206 (17), 205 (100), 177
(12), 145 (14), 105 (12), 91 (12), 81 (14), 67 (12), 57 (48), 55 (14); HRMS
calcd for C26H22FNO3SNa (M+Na+): 470.11966. Found: 470.11967.
(1R*,2S*)-1-(4,6-Dichloropyrimidin-5-yl)-2-phenylbut-3-en-1-yl
acrylate (6b).
2-Chloro-3-((2R*,3S*)-3-(4-methoxyphenyl)-3,6-dihydro-2H-pyran-2-
yl)pyridine (5h).
This compound was prepared according to GP2 from alcohol 3b (371 mg,
1.26 mmol). The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:7 to 1:5) to afford ester 6b (187 mg, 43%) as a
white solid. mp 62–63 °C; Rf = 0.80 (EtOAc/PE = 1:3); IR (film) 1727,
1537, 1514, 1415, 1404, 1360, 1338, 1295, 1255, 1215, 1173, 1132,
The Grubbs 2nd generation catalyst (5.5 mg, 6.50 µmol, 4 mol %) was
added to a solution of diene 4h (54 mg, 0.163 mmol, 1 equiv) in
degassed CH2Cl2 (0.87 mL). The solution was stirred at rt for 24 h and
then concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE = 1:7 to 1:5) to
afford dihydropyran 5h (45 mg, 92%) as a slightly brown oil. Rf = 0.27
(EtOAc/PE = 1:5); IR (film) 1612, 1583, 1566, 1510, 1415, 1380, 1302,
1246, 1176, 1109, 1033, 909 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd,
J = 4.7, 2.0 Hz, 1H), 7.95 (dd, J = 7.7, 2.0 Hz, 1H), 7.28 (dd, J = 8.1, 4.9
Hz, 1H), 6.86 (dapp, J = 8.7 Hz, 2H), 6.72 (dapp, J = 8.7 Hz,2H), 6.03
(dddd, J = 10.2, 3.3, 2.5, 1.6 Hz, 1H), 5.95 (dqapp, J = 10.3, 1.8 Hz, 1H),
4.82 (d, J = 9.2 Hz, 1H), 4.48 (dddd, J = 16.7, 4.1, 2.3, 1.7 Hz, 1H), 4.39
(dddd, J = 16.7, 3.2, 3.0, 1.9 Hz, 1H), 3.73 (s, 3H), 3.57 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 150.6, 148.6, 137.6, 135.1, 131.0, 129.4
(2C), 129.0, 126.3, 122.6, 113.8 (2C), 78.2, 66.5, 55.1, 47.7; EI–MS m/z
(relative intensity) 301 (0.07), 161 (11), 160 (100), 159 (43), 145 (18),
144 (18), 129 (36), 128 (13), 117 (16), 115 (19), 91 (13); HRMS calcd for
C17H17ClNO2 (M+H+): 302.09423. Found: 302.09474.
1045, 984 cm–1 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.22 – 7.13
;
(m, 5H), 6.59 (d, J = 10.6 Hz, 1H), 6.50 (dd, J = 17.3, 1.3 Hz, 1H), 6.25 –
6.14 (m, 2H), 5.92 (dd, J = 10.4, 1.3 Hz, 1H), 5.26 (m, 1H), 5.23 (m, 1H),
4.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 165.0, 156.6 (3C), 137.6,
136.6, 132.3, 129.0, 128.6 (2C), 128.0 (2C), 127.7, 127.4, 118.1, 72.8,
51.3; EI–MS m/z (relative intensity) 117 (78), 115 (25), 91 (10), 55 (100);
HRMS calcd for C17H15Cl2N2O2 (M+H+): 349.05051. Found: 349.05053.
(1R*,2S*)-1-(2-Chloroquinolin-3-yl)-2-phenylbut-3-en-1-yl
acrylate
(6d).
This compound was prepared according to GP2 using alcohol 3d (423
mg, 1.36 mmol). The crude product was purified by flash chromatography
on silica gel (EtOAc/PE = 1:7 to 1:3) to afford ester 6d (201 mg, 41%) as
a colorless oil. Rf = 0.54 (EtOAc/PE = 1:5); IR (film) 1726, 1619, 1592,
1562, 1490, 1453, 1402, 1330, 1294, 1258, 1169, 1137, 1039, 981 cm–1
;
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.78
(d, J = 8.2 Hz, 1H), 7.68 (ddd, J = 8.6, 7.0, 1.6 Hz, 1H), 7.51 (tapp, J = 7.0
Hz, 1H), 7.32 – 7.24 (m, 4H), 7.19 (m, 1H), 6.60 (d, J = 5.0 Hz, 1H), 6.47
(dd, J = 17.3, 1.3 Hz, 1H), 6.29 (ddd, J = 17.1, 10.2, 9.0 Hz, 1H), 6.21 (dd,
J = 17.3, 10.4 Hz, 1H), 5.89 (dd, J = 10.4, 1.3 Hz, 1H), 5.15 (dd, J = 10.2,
1.6 Hz, 1H), 4.95 (dtapp, J = 17.0, 1.2 Hz, 1H), 4.04 (dd, J = 9.0, 5.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 164.5, 148.5, 146.9, 139.7, 136.9,
134.7, 131.8, 131.0, 130.5, 128.5 (2C), 128.1, 128.0 (2C), 127.7, 127.5,
127.1, 127.0, 126.6, 119.1, 75.0, 53.8; EI–MS m/z (relative intensity) 291
(10), 192 (21), 117 (32), 115 (15), 55 (100); HRMS calcd for
C22H18ClNO2Na (M+Na+): 386.09183. Found: 386.09205.
2-Chloro-3-((2R*,3S*)-3-(4-(trifluoromethyl)phenyl)-3,6-dihydro-2H-
pyran-2-yl)pyridine (5i).
The 2nd generation Grubbs catalyst (1.9 mg, 2.19 µmol, 4 mol %) was
added to a solution of diene 4i (20 mg, 54.7 µmol, 1 equiv) in degassed
CH2Cl2 (0.29 mL). The solution was stirred at rt for 26 h, then
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE
dihydropyran 5i (16 mg, 87%) as a colorless oil. Rf = 0.25 (EtOAc/PE =
1:5); IR (film) 1619, 1566, 1416, 1324, 1164, 1112, 1068, 1018 cm–1 1H
= 1:6) to afford
;
NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 4.7, 2.0 Hz, 1H), 7.97 (dd, J = 7.7,
2.0 Hz, 1H), 7.45 (br d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.7, 4.7 Hz, 1H),
7.04 (br d, J = 7.9 Hz, 2H), 6.12 (dddd, J = 10.2, 3.4, 2.5, 1.8 Hz, 1H),
5.95 (dqapp, J = 10.3, 2.2 Hz, 1H), 4.86 (d, J = 9.2 Hz, 1H), 4.52 (dddd, J
= 16.8, 4.0, 2.4, 1.8 Hz, 1H), 4.43 (dqapp, J = 16.9, 2.7 Hz, 1H), 3.68 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 150.4, 149.0, 143.2, 137.6, 134.6,
129.5 (d, J = 32.5 Hz), 128.9 (2C), 127.7, 127.3, 125.4 (q, J = 3.9 Hz,
2C), 124.2 (d, J = 276 Hz), 122.8, 77.7, 66.5, 48.7; EI–MS m/z (relative
intensity) 198 (44), 130 (11), 129 (100), 128 (17); HRMS calcd for
C17H14ClF3NO (M+H+): 340.07105. Found: 340.07112.
(1R*,2S*)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-phenylbut-3-en-1-
yl acrylate (6e).
This compound was prepared according to GP2 from alcohol 3e (369 mg,
0.998 mmol). The crude product was purified by flash chromatography on
silica gel (EtOAc/PE = 1:5 to 1:1) to afford ester 6e (278 mg, 88%) as a
colorless oil. Rf = 0.62 (EtOAc/PE = 1:1); IR (film) 1722, 1638, 1560,
1405, 1295, 1269, 1179, 1043, 984, 969 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 7.27 – 7.22 (m, 2H), 7.20 – 7.15 (m, 3H), 7.04 (s, 1H), 6.42 (dd,
J = 17.3, 1.5 Hz, 1H), 6.15 – 6.05 (m, 3H), 5.84 (dd, J = 10.4, 1.4 Hz, 1H),
5.15 (br s, 1H), 5.12 (ddd, J = 8.2, 1.5, 0.8 Hz, 1H), 3.97 (tapp, J = 8.6 Hz,
1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 139.6, 137.3,
137.1, 131.1, 131.0, 128.4 (2C), 128.2, 128.1 (2C), 126.8, 117.5, 116.1,
69.7, 54.2, 39.3; EI–MS m/z (relative intensity) 244 (15), 209 (22), 199
(11), 129 (21), 115 (13), 72 (13), 55 (100); HRMS calcd for C17H18ClN2O2
(M+H+): 317.10513. Found: 317.10513.
3-((2R*,3S*)-2-(4-Fluorophenyl)-3,6-dihydro-2H-pyran-3-yl)-1-tosyl-
1H-indole (5k).
The 2nd generation Grubbs catalyst (0.58 mg, 0.685 µmol, 2 mol %) was
added to a solution of diene 4k (16 mg, 34.3 µmol, 1 equiv) in degassed
CH2Cl2 (0.16 mL). The solution was stirred at rt for 25 h, then
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE = 1:9 to 1:7) to afford
dihydropyran 5k (14 mg, 93%) as a colorless oil. Rf 0.23 (EtOAc/PE, 1:7);
IR (film) 1603, 1511, 1446, 1368, 198, 1224, 1173, 1119, 1094, 1048,
(5S*,6R*)-6-(4,6-dichloropyrimidin-5-yl)-5-phenyl-5,6-dihydro-2H-
pyran-2-one (7b).
A solution of diene 6b (106 mg, 0.304 mmol, 1 equiv) and 2nd generation
Hoveyda-Grubbs catalyst (7.6 mg, 12.1 µmol, 4 mol %) in CH2Cl2 (1.5
mL) was heated at 60 °C in a sealed tube. After 48 h, the solution was
concentrated under reduced pressure and the crude product was purified
by flash chromatography on silica gel (EtOAc/PE = 1:7 to 1:5) to afford
lactone 7b (62 mg, 64%) as a white solid. mp 163–165 °C; Rf = 0.19
(EtOAc/PE = 1:5 ; IR (film) 1735, 1541, 1515, 1416, 1369, 1242, 1210,
1023, 973 cm–1 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 1H),
;
7.59 (br d, J = 8.4 Hz, 2H), 7.25 (m, 1H), 7.21 – 7.15 (m, 3H), 7.13 (s,
1H), 7.08 (m, 1H), 6.93 – 6.87 (m, 2H), 6.75 – 6.70 (m, 2H), 6.03 (dqapp, J
= 10.2, 2.8 Hz, 1H), 5.93 (dqapp, J = 10.0, 2.0 Hz, 1H), 4.54 – 4.43 (m,
3H), 3.73 (m, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.1 (d, J
= 245.5 Hz), 144.8, 136.4 (d, J = 3.1 Hz), 135.2, 135.2, 129.9, 129.7 (2C),
128.2 (d, J = 8.0 Hz, 2C), 128.1, 126.63 (2C), 126.60, 124.6, 124.2,
1162, 1054, 1041, 925 cm–1 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H),
;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
7.34 – 7.26 (m, 3H), 7.06 (dd, J = 9.9, 2.0 Hz, 1H), 7.03 – 7.00 (m, 2H),
6.33 (dd, J = 9.9, 2.9 Hz, 1H), 6.09 (d, J = 12.2 Hz, 1H), 4.71 (ddd, J =
12.2, 2.8, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.2, 162.0 (2C),
157.5, 149.1, 135.5, 129.2 (2C), 128.7, 128.4 (2C), 126.7, 121.2, 79.4,
42.7; EI–MS m/z (relative intensity) 145 (12), 144 (100), 116 (51), 115
(59); HRMS calcd for C15H10Cl2N2O2Na (M+Na+): 343.00115. Found:
343.00112.
(EtOAc/PE = 1:7); IR (film) 1538, 1514, 1492, 1453, 1414, 1369, 1330,
1216, 1138, 1104, 1051, 1025, 919 cm–1 1H NMR (400 MHz, CDCl3) δ
;
8.61 (s, 1H), 7.22 – 7.18 (m, 3H), 7.00 – 6.95 (m, 2H), 6.09 (dqapp, J =
10.3, 2.5 Hz, 1H), 6.00 (dqapp, J = 10.2, 2.0 Hz, 1H), 5.10 (d, J = 9.9 Hz,
1H), 4.46 – 4.44 (m, 2H), 4.36 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
162.0, 156.6 (2C), 138.8, 129.9, 128.6 (2C), 128.3 (2C), 128.0, 127.5,
126.6, 78.0, 66.4, 43.1; EI–MS m/z (relative intensity) 131 (10), 130 (100),
129 (48), 128 (15), 115 (27); HRMS calcd for C15H13Cl2N2O1 (M+H+):
307.03994. Found: 307.04030.
(5S*,6R*)-6-(2-Chloroquinolin-3-yl)-5-phenyl-5,6-dihydro-2H-pyran-2-
one (7d).
2-Chloro-3-((2R*,3S*)-3-phenyl-3,6-dihydro-2H-pyran-2-yl)quinolone
A solution of diene 6d (235 mg, 0.645 mmol, 1 equiv) and 2nd generation
Hoveyda-Grubbs catalyst (12 mg, 19.4 µmol, 4 mol %) in toluene (5 mL)
was heated at 100 °C. After 21 h, the solution was concentrated under
reduced pressure and the crude product was purified by flash
chromatography on silica gel (EtOAc/PE = 1:3 to 1:2) to afford lactone 7d
(137 mg, 63%) as a white solid. mp 146–149 °C; Rf = 0.16 (EtOAc/PE =
1:3); 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H),
7.87 (dd, J = 8.3, 0.9 Hz, 1H), 7.77 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.61
(ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.30 – 7.25 (m, 3H), 7.09 – 7.05 (m, 2H),
7.00 (dd, J = 9.8, 3.0 Hz, 1H), 6.36 (dd, J = 9.8, 2.4 Hz, 1H), 6.02 (d, J =
9.1 Hz, 1H), 4.14 (dt, J = 9.1, 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
163.0, 148.7, 148.4, 147.3, 138.0, 136.0, 131.2, 129.5, 129.1 (2C), 128.5
(2C), 128.3, 128.2, 127.8, 127.6, 126.7, 121.2, 81.4, 47.1; IR (film) 1731,
1620, 1592, 1567, 1491, 1454, 1415, 1375, 1266, 1241, 1158, 1045,
1031, 965 cm–1; HRMS calcd for C20H14ClNO2Na (M+Na+): 358.06053.
Found: 358.06066.
(5d).
DIBAL-H (1M in hexane, 0.48 mL, 0.481 mmol, 1.2 equiv) was added to
a solution of lactone 7d (135 mg, 0.401 mmol, 1 equiv) in CH2Cl2 (1.8
mL) cooled at –78 °C. The solution was stirred at –78 °C and after 3 h, it
was quenched with an aqueous solution of Rochelle salt (2 mL). The
mixture was stirred at rt until two limpid phases were obtained. The
product was extracted with EtOAc (3 x 4 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced
pressure to give the crude lactol. Et3SiH (97 µL, 0.602 mmol, 1.5 equiv)
and BF3•Et2O (51 µL, 0.401 mmol, 1 equiv) were added to a solution of
the previously formed lactol in CH2Cl2 (0.89 mL) cooled at –78 °C. The
solution was stirred at –78 °C for 2 h. A second equivalent of BF3•Et2O
(51 µL, 0.401 mmol, 1 equiv) was added and the solution was allowed to
warm up to rt for 19 h. A saturated aqueous solution of NH4Cl (1 mL) was
then added and the product was extracted with CH2Cl2 (3 x 2 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE = 1:7 to 1:3) to afford
dihydropyran 5d (69 mg, 50%) as a white solid. mp 138–141 °C; Rf =
0.16 (EtOAc/PE = 1:3); IR (film) 1620, 1591, 1561, 1489, 1409, 1383,
(5S*,6R*)-6-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-5-phenyl-5,6-
dihydro-2H-pyran-2-one (7e).
1326, 1203, 1176, 1130, 1108, 1049, 916 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 8.42 (s, 1H), 7.95 (dd, J = 8.4, 1.0 Hz, 1H), 7.85 (dd, J = 8.2,
1.3 Hz, 1H), 7.69 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.53 (ddd, J = 8.1, 6.9,
1.2 Hz, 1H), 7.18 – 7.13 (m, 3H), 6.96 – 6.92 (m, 2H), 6.08 (m, 1H), 6.01
(dqapp, J = 10.2, 1.9 Hz, 1H), 5.02 (d, J = 9.2 Hz, 1H), 4.54 (dddd, J =
16.8, 4.0, 2.0,1.5 Hz, 1H), 4.43 (dqapp, J = 16.8, 2.6 Hz, 1H), 3.77 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 150.2, 146.9, 139.1, 137.5, 133.0,
130.4, 128.8, 128.5 (2C), 128.4 (2C), 128.2, 127.6, 127.2, 127.1, 126.9,
126.5, 78.1, 66.6, 49.0; EI–MS m/z (relative intensity) 131 (11), 130 (100),
129 (45), 128 (16), 127 (10), 115 (24); HRMS calcd for C20H17ClNO
(M+H+): 322.09932. Found: 322.09933.
A solution of diene 6e (278 mg, 0.877 mmol, 1 equiv) and 2nd generation
Hoveyda-Grubbs catalyst (16 mg, 26.3 µmol, 4 mol %) in toluene (5.0
mL) was heated at 100 °C. After 15 h, the solution was concentrated
under reduced pressure and the crude product was purified by flash
chromatography on silica gel (EtOAc/PE = 1:3 to 1:1) to afford lactone 7e
(164 mg, 65%) as a colorless oil. Rf = 0.33 (EtOAc/PE = 1:1); IR (film)
1720, 1562, 1494, 1413, 1376, 1264, 1223, 1179, 1057, 1014, 964, 913
cm–1 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.32 – 7.25 (m, 3H),
;
7.11 – 7.06 (m, 2H), 6.94 (dd, J = 9.8, 2.5 Hz, 1H), 6.23 (dd, J = 9.8, 2.5
Hz, 1H), 5.37 (d, J = 10.3 Hz, 1H), 4.05 (dtapp, J = 10.3, 2.5 Hz, 1H), 3.78
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4, 149.1, 137.6, 136.9, 131.0,
128.9 (2C), 128.3 (2C), 128.0, 121.0, 115.3, 77.0, 46.2, 39.6; EI–MS m/z
(relative intensity) 244 (65), 209 (100), 194 (15), 168 (17), 167 (30), 166
(17), 165 (19), 153 (22), 142 (49), 141 (19), 140 (17), 139 (19), 131 (26),
129 (84), 76 (18); 65 (16), 63 (30), 51 (43), 50 (16); HRMS calcd for
C15H13ClN2O2Na (M+Na+): 311.05578. Found: 311.05583.
3-Chloro-1-methyl-4-((2R*,3S*)-3-phenyl-3,6-dihydro-2H-pyran-2-yl)-
1H-pyrazole (5e).
DIBAL-H (1M in hexane, 0.93 mL, 0.931 mmol, 1.2 equiv) was added to
a solution of lactone 7e (224 mg, 0.776 mmol, 1 equiv) in CH2Cl2 (3.4
mL) cooled at –78 °C. The solution was stirred at –78 °C and after 2 h, it
was quenched with an aqueous solution of Rochelle salt (3 mL). The
mixture was stirred at rt until two limpid phases were obtained. The
product was extracted with EtOAc (3 x 5 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced
pressure to give the crude lactol. Et3SiH (0.19 mL, 1.16 mmol, 1.5 equiv)
and BF3•Et2O (0.01 mL, 0.776 mmol, 1 equiv) were added to a solution of
the previously formed lactol in CH2Cl2 (3.4 mL) cooled at –78 °C. The
solution was stirred and allowed to warm up to rt. After 22 h a saturated
aqueous solution of NH4Cl (3 mL) was added and the product was
extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:5 to 1:3) to afford dihydropyran 5e (159 mg, 75%) as a
slightly yellow oil. Rf = 0.27 (EtOAc/PE = 1:3); IR (film) 1563, 1492, 1443,
4,6-Dichloro-5-((2R*,3S*)-3-phenyl-3,6-dihydro-2H-pyran-2-
yl)pyrimidine (5b).
DIBAL-H (1M in hexane, 0.24 mL, 0.242 mmol, 1.2 equiv) was added to
a solution of lactone 7b (65 mg, 0.202 mmol, 1 equiv) in CH2Cl2 (0.89
mL) cooled at –78 °C. The solution was stirred at –78 °C and after 1 h
was quenched with a saturated aqueous solution of Rochelle salt (2 mL).
The mixture was stirred at rt until two limpid phases were obtained. The
product was extracted with EtOAc (3 x 4 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced
pressure to give the crude lactol. Et3SiH (49 µL, 0.303 mmol, 1.5 equiv)
and BF3•Et2O (26 µL, 0.202 mmol, 1 equiv) were added to a solution of
the previously formed lactol in CH2Cl2 (0.89 mL) cooled at –78 °C. The
solution was stirred at –78 °C and after 1 h a saturated aqueous solution
of NH4Cl (1 mL) was added and the product was extracted with CH2Cl2 (3
x 2 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE = 6:94 to 12:88)
to afford dihydropyran 5b (24 mg, 39%) as a yellow oil. Rf = 0.49
1407, 1328, 1241, 1179, 1094, 1075, 1051, 1026, 985 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 7.31 (s, 1H), 7.26 – 7.17 (m, 3H), 7.07 – 7.05 (m,
2H), 5.99 (m, 1H), 5.90 (dqapp, J = 10.3, 2.1 Hz, 1H), 4.47 – 4.40 (m, 1H),
4.44 (d, J = 8.9 Hz, 1H), 4.32 (m, 1H), 3.78 (s, 3H), 3.67 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 140.5, 138.1, 130.2, 128.6, 128.4 (2C), 128.4
(2C), 126.8, 126.3, 118.2, 73.7, 65.9, 47.6, 39.5; EI–MS m/z (relative
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
HRMS calcd for C15H16ClN2O (M+H+): 275.09457. Found: 275.09520.
intensity) 131 (11), 130 (100), 129 (62), 128 (19), 115 (34), 51 (12);
J = 21.3 Hz, 2C), 83.4, 69.4, 57.3; EI–MS m/z (relative intensity) 165
(100), 123 (96), 117 (21), 115 (30), 91 (17); HRMS the compound was
not detected.
1-(4-Fluorophenyl)-2-phenylbut-3-en-1-one.
(2S*,3S*)-2-(4-Fluorophenyl)-3-phenyl-3,6-dihydro-2H-pyran (cis-5a).
Dess-Martin periodinane (176 mg, 0.415 mmol, 1.5 equiv) was added to
a solution of alcohol 2a (67 mg, 0.277 mmol, 1 equiv) in CH2Cl2 (2.3 mL)
cooled at 0 °C and the solution was stirred at rt. After 2 h, the reaction
mixture was quenched with a saturated aqueous solution of Na2S2O3 (2
mL). The product was extracted with CH2Cl2 (3 × 5 mL). The combined
The 2nd generation Grubbs catalyst (1.4 mg, 1.68 µmol, 2 mol %) was
added to a solution of diene epi-4a (24 mg, 83.9 µmol, 1 equiv) in
degassed CH2Cl2 (0.45 mL). The solution was stirred at rt and after 23 h,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (CH2Cl2/pentane = 5:95 to
13:87) to afford dihydropyran epi-5a (17 mg, 79%) as a white solid. mp
71–73 °C; Rf = 0.64 (acetone/PE = 4:96); GC rt 6.503 min; IR (film) 1603,
organic layers were washed with
a saturated aqueous solution of
NaHCO3 (5 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (EtOAc/PE = 2:98 to 4:96) to afford the
intermediate ketone (59 mg, 88%) as a colorless oil. Rf = 0.37 (EtOAc/PE
= 4:96); IR (film) 1680, 1636, 1596, 1505, 1453, 1408, 1312, 1288, 1226,
1510, 1492, 1451, 1280, 1219, 1179, 1156, 1124, 1092, 1050 cm–1 1H
;
NMR (400 MHz, CDCl3) δ 7.12 – 7.06 (m, 3H), 6.93 – 6.88 (m, 2H), 6.88
– 6.82 (m, 2H), 6.81 – 6.75 (m, 2H), 6.09 – 6.02 (m, 2H), 4.92 (d, J = 3.4
Hz, 1H), 4.60 – 4.46 (m, 2H), 3.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
161.6 (d, J = 244.6 Hz), 138.2, 136.2 (d, J = 3.2 Hz), 139.9 (2C), 127.9,
127.5 (d, J = 8.0 Hz, 2C), 127.4 (2C), 126.5, 126.4, 114.3 (d, J = 21.3 Hz,
2C), 78.6, 67.2, 47.4; EI–MS m/z (relative intensity) 254 (0.02), 131 (11),
130 (100), 129 (63), 128 (20), 115 (29); HRMS the compound was not
detected.
1206, 1156, 1075, 988, 923 cm–1 1H NMR (400 MHz, CDCl3) δ 8.04 –
;
7.95 (m, 2H), 7.36 – 7.26 (m, 4H), 7.24 (m, 1H), 7.11 – 7.01 (m, 2H),
6.35 (ddd, J = 17.5, 10.1, 7.7 Hz, 1H), 5.24 – 5.20 (m, 2H), 5.09 (d, J =
17.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 196.8, 165.5 (d, J = 255.0
Hz), 138.1, 136.9, 132.6 (d, J = 3.1 Hz), 131.5 (d, J = 9.3 Hz, 2C), 129.0
(2C), 128.2 (2C), 127.2, 117.2, 115.6 (d, J = 21.9 Hz, 2C), 57.9; EI–MS
m/z (relative intensity) 240 (0.7), 123 (100), 115 (12), 95 (30); HRMS the
compound was not detected.
(1R*,2S*)-2-(4-Methoxyphenyl)-1-phenylbut-3-en-1-yl acrylate.
(1S*,2S*)-1-(4-Fluorophenyl)-2-phenylbut-3-en-1-ol (anti-3a).
(1R*,2S*)-2-(4-Methoxyphenyl)-1-phenylbut-3-en-1-yl
acrylate
was
prepared according to GP2 from alcohol 3j (223 mg, 0.877 mmol). The
crude product was purified by flash chromatography on silica gel
(EtOAc/PE = 1:7) to afford the corresponding acrylate (186 mg, 69%) as
a colorless oil. Rf = 0.47 (EtOAc/PE = 1:5); IR (film) 1721, 1611, 1511,
L-Selectride (1M in THF, 0.73 mL, 0.730 mmol, 2 equiv) was added
dropwise to a solution of the previously obtained ketone (87 mg, 0.364
mmol, 1 equiv) in THF (0.88 mL) cooled at –78 °C. The solution was
stirred at –78 °C and, after 3 h, H2O (0.01 mL) was added and the
solution was warmed up to 0 °C. A 35% aqueous H2O2 solution (0.03 mL)
was added and the solution was diluted with EtOAc (5 mL). The organic
layer was washed with a saturated aqueous solution of Na2S2O3 (2 mL),
then with a saturated aqueous solution of NaHCO3 (2 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (acetone/PE =
1:9 to 1:7) to afford alcohol anti-3a (70 mg, 79%) as a white solid. mp
61–63 °C; Rf = 0.31 (EtOAc/PE = 1:5); IR (film) 3429, 1637, 1603, 1510,
1403, 1247, 1177, 1035, 982 cm–1 1H NMR (400 MHz, CDCl3) δ 7.23 –
;
7.11 (m, 5H), 6.95 (br d, J = 8.5 Hz, 2H), 6.72 (br d, J = 8.5 Hz, 2H), 6.43
(dd, J = 17.3, 1.5 Hz, 1H), 6.20 – 6.08 (m, 2H), 6.05 (d, J = 8.5 Hz, 1H),
5.84 (dd, J = 10.4, 1.5 Hz, 1H), 5.15 – 5.06 (m, 2H), 3.77 – 3.71 (m, 1H),
3.73 (s, 3H) ; 13C NMR (100 MHz, CDCl3) δ 165.2, 158.2, 138.6, 137.6,
131.8, 130.9, 129.4 (2C), 128.6, 127.9 (2C), 127.7, 127.1 (2C), 117.0,
113.7 (2C), 78.4, 55.6, 55.1; EI–MS m/z (relative intensity) 236 (20), 148
(11), 147 (100), 115 (10), 91 (21), 55 (78); HRMS calcd for C20H20O3Na
(M+Na+): 331.13047. Found: 331.13036.
1453, 1380, 1223, 1157, 1044, 1013, 920 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 7.38 – 7.33 (m, 2H), 7.30 – 7.22 (m, 5H), 7.04 – 6.98 (m, 2H),
5.88 (ddd, J = 17.1, 10.3, 8.0 Hz, 1H), 5.00 (dtapp, J = 10.3, 1.5 Hz, 1H),
4.91 – 4.83 (m, 2H), 3.58 (tapp, J = 8.0 Hz, 1H), 1.95 (br s, 1H, OH); 13C
NMR (100 MHz, CDCl3) δ 162.3 (d, J = 245.6 Hz), 140.0, 137.5 (d, J =
3.1 Hz), 137.3, 128.8 (2C), 128.7 (2C), 128.6 (d, J = 8.2 Hz, 2C), 127.2,
117.5, 114.9 (d, J = 21.2 Hz, 2C), 76.8, 58.7; EI–MS m/z (relative
intensity) 125 (100), 118 (95), 117 (46), 115 (28), 97 (54), 95 (13), 91
(15), 77 (21); HRMS the compound was not detected.
(5S*,6R*)-5-(4-Methoxyphenyl)-6-phenyl-5,6-dihydro-2H-pyran-2-one
(7j).
A solution of the previously obtained acrylate (288 mg, 0.933 mmol, 1
equiv) and 2nd generation Hoveyda-Grubbs catalyst (18 mg, 30.0 µmol, 3
mol %) in toluene (5.3 mL) was heated at 100 °C. After 26 h, the solution
was concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/PE = 1:3) to afford
lactone 7j (246 mg, 94%) as a slightly brown solid. mp 123–125 °C; Rf =
0.38 (EtOAc/PE = 1:2); IR (film) 1726, 1611, 1512, 1455, 1375, 1303,
1-((1S*,2S*)-1-(Allyloxy)-2-phenylbut-3-en-1-yl)-4-fluorobenzene (anti-
4a).
1249, 1178, 1157, 1056, 1031, 968 cm–1 1H NMR (400 MHz, CDCl3) δ
;
7.29 – 7.20 (m, 3H), 7.11 – 7.05 (m, 2H), 6.91 (dd, J = 9.8, 2.2 Hz, 1H),
6.82 (br d, J = 8.5 Hz, 2H), 6.75 (br d, J = 8.5 Hz, 2H), 6.23 (dd, J = 9.8,
2.6 Hz, 1H), 5.26 (d, J = 10.7 Hz, 1H), 3.84 (dtapp, J = 10.8, 2.5 Hz, 1H),
3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 1637, 159.0, 149.6, 137.0,
129.5 (2C), 129.0, 128.4, 128.0 (2C), 127.0 (2C), 120.9, 114.0 (2C), 86.0,
55.1, 47.0; EI–MS m/z (relative intensity) 280 (0.10), 174 (100), 159 (20),
131 (39), 103 (28), 77 (21); HRMS calcd for C18H17O3 (M+H+): 281.11722.
Found: 281.11722.
NaH (60% in oil, 18 mg, 0.459 mmol, 1.55 equiv) was added to a solution
of alcohol anti-3a (72 mg, 0.296 mmol, 1 equiv) in THF (1.1 mL) cooled
at 0 °C. The solution was stirred at rt for 1 h, then allyl bromide (39 µL,
0.445 mmol, 1.5 equiv) was added. The solution was stirred at rt and
after 39 h, H2O (2 mL) was added and the product was extracted with
Et2O (3 × 5 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (CH2Cl2/pentane =
2:98 to 4:96) to afford ether anti-4a (60 mg, 72%) as a white solid. mp
37–39 °C; Rf = 0.19 (CH2Cl2/PE, 4:96); IR (film) 1639, 1603, 1509, 1453,
(5S*,6R*)-5-(4-Methoxyphenyl)-6-phenyltetrahydro-2H-pyran-2-one
(8).
1419, 1221, 1156, 1076, 990, 920 cm–1 1H NMR (400 MHz, CDCl3) δ
;
7.31 – 7.24 (m, 2H), 7.24 – 7.09 (m, 5H), 7.01 – 6.94 (m, 2H), 5.93 (ddd,
J = 17.0, 10.3, 8.2 Hz, 1H), 5.70 (ddtapp, J = 17.6, 10.5, 5.1 Hz, 1H), 5.11
– 5.03 (m, 2H), 4.96 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 17.1 Hz, 1H), 4.55
(d, J = 7.4 Hz, 1H), 3.86 (br dd, J = 13.0, 4.2 Hz, 1H), 3.65 (dd, J = 13.2,
6.0 Hz, 1H), 3.59 (tapp, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
162.3 (d, J = 245.2 Hz), 140.8, 138.1, 136.0 (d, J = 3.0 Hz), 134.6, 129.1
(d, J = 8.0 Hz, 2C), 128.8 (2C), 128.0 (2C), 126.4, 116.6, 116.5, 114.8 (d,
Wilkinson catalyst (13 mg, 13.7 µmol, 2.5 mol %) was added to a solution
of lactone 7j (154 mg, 0.549 mmol, 1 equiv) in toluene (6.4 mL). The
solution was purged with H2 and stirred at rt, and after 24 h, a second
portion of Wilkinson catalyst (13 mg, 13.7 µmol, 2.5 mol %) was added.
The solution was stirred for 3 days. The reaction was filtered through a
pad of Celite and concentrated under reduced pressure. The crude
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
product was purified by flash chromatography on silica gel (EtOAc/PE =
1:3 to 1:2) to afford lactone 8 (132 mg, 85%) as a white solid. mp 111–
113 °C; Rf = 0.30 (EtOAc/PE = 1:2); IR (film) 1730, 1512, 1455, 1348,
1331, 1275, 1247, 1194, 1180, 1061, 1029, 987 cm–1; 1H NMR (400 MHz,
CDCl3) δ 7.21 – 7.16 (m, 3H), 7.05 – 7.00 (m, 2H), 6.87 (dapp, J = 8.9 Hz,
2H), 6.72 (dapp, J = 8.9 Hz, 2H), 5.29 (d, J = 10.3 Hz, 1H), 3.71 (s, 3H),
3.02 (ddd, J = 11.0, 10.3, 4.7 Hz, 1H), 2.88 (ddd, J = 17.9, 6.4, 4.4 Hz,
1H), 2.74 (ddd, J = 17.8, 10.1, 6.9 Hz, 1H), 2.28 (dddd, J = 13.9, 11.0,
10.0, 6.5, Hz, 1H), 2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.8,
158.5, 138.2, 131.3, 128.7 (2C), 128.1, 128.0 (2C), 126.7 (2C), 113.8
(2C), 87.1, 55.0, 46.4, 30.0, 27.0; EI–MS m/z (relative intensity) 282 (3),
176 (20), 135 (10), 134 (100); HRMS calcd for C18H19O3 (M+H+):
283.13257. Found: 283.13298.
MeI (85 µL, 0.137 mmol, 2 equiv) and Na2CO3 (8.7 mg, 82.0 µmol, 1.2
equiv) were added to a solution of dithiane 9 (26 mg, 68.3 µmol, 1equiv)
in a mixture of acetone/H2O (9:1, 8.6 mL). The solution was heated at
35 °C and after 26 h it was concentrated under reduced pressure. EtOAc
(5 mL) and H2O (2 mL) were then added, and the mixture vigorously
stirred. The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure to give a crude aldehyde 10.
NaBH4 (5.2 mg, 0.137 mmol, 2 equiv) was added to a solution of
aldehyde 10 in a cooled (0 °C) mixture of Et2O/MeOH (1:1, 0.76 mL). The
solution was stirred at rt and after 4 h, acetone (1 mL) was added and the
solution was concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (acetone/pentane =
1:5 to 1:3) to afford alcohol 11 (12 mg, 57%) as a colorless oil. Rf = 0.33
(EtOAc/PE, 1:3); GC rt 8.164 min; IR (film) 3430, 1611, 1583, 1512, 1454,
1265, 1244, 1178, 1111, 1069, 1037 cm–1 1H NMR (400 MHz, CDCl3) δ
;
(5S*,6R*)-2-(1,3-Dithian-2-yl)-5-(4-methoxyphenyl)-6-
phenyltetrahydro-2H-pyran-2-ol.
7.18 – 7.12 (m, 3H), 7.07 – 7.02 (m, 2H), 6.84 (dapp, J = 8.4 Hz, 2H), 6.67
(dapp, J = 8.4 Hz, 2H), 4.39 (d, J = 10.1 Hz, 1H), 3.77 (m, 1H), 3.71 (s,
3H), 3.70 – 3.60 (m, 2H), 2.71 (ddd, J = 12.1, 10.1, 3.9 Hz, 1H), 2.22 (br
s, 1H, OH), 2.10 (dqapp, J = 13.4, 4.3 Hz, 1H), 1.99 (qdapp, J = 12.9, 4.1
Hz, 1H), 1.74 (ddtapp, J = 13.2, 4.1, 2.6 Hz, 1H), 1.63 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 157.9, 140.9, 134.0, 128.9 (2C), 127.7 (2C), 127.3,
127.2 (2C), 113.5 (2C), 85.4, 78.5, 66.2, 55.0, 49.2, 31.5, 27.6; EI–MS
m/z (relative intensity) 298 (6), 147 (15), 135 (10), 134 (100), 119 (11),
91 (17); HRMS calcd for C19H22O3Na (M+Na+): 321.14612. Found:
321.14606.
n-BuLi (2.2M, 0.19 mL, 0.426 mmol, 1.1 equiv) was added to a solution
of 1,3-dithiane (51 mg, 0.426 mmol, 1.1 equiv) in THF (1.9 mL) cooled at
–78 °C. The solution was stirred at –78 °C, and after 15 min a solution of
lactone 8 (109 mg, 0.387 mmol, 1 equiv) in THF (1.4 mL) was added.
The solution was stirred at 0 °C and after 2.5 h, a saturated aqueous
solution of NH4Cl (2 mL) was added and the product was extracted with
Et2O (3 × 5 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (EtOAc/PE = 1:7 to
1:5) to afford an intermediate lactol (83 mg, 53%) as a white solid. mp
154–157 °C; Rf = 0.19 (EtOAc/PE = 1:5); IR (film) 3437, 1611, 1512,
1452, 1386, 1246, 1136, 1113, 1060, 1035, 993, 970 cm–1; 1H NMR (400
MHz, CDCl3) δ 7.17 – 7.09 (m, 5H), 6.90 (br d, J = 8.6 Hz, 2H), 6.67 (br d,
J = 8.6 Hz, 2H), 5.00 (d, J = 10.6 Hz, 1H), 4.19 (d, J = 2.6 Hz, 1H, OH),
3.70 (s, 3H), 3.53 (s, 1H), 3.44 (m, 1H), 3.05 (m, 1H), 2.82 (ddd, J = 12.9,
10.8, 4.1 Hz, 1H), 2.66 (tddapp, J = 13.3, 4.6, 2.6 Hz, 1H), 2.51 (dtapp, J =
13.3, 4.4 Hz, 1H), 2.40 (m, 1H), 2.30 (dtapp, J = 13.3, 4.4 Hz, 1H), 2.01 –
1.89 (m, 3H), 1.72 (ddd, J = 12.9, 4.2, 2.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.9, 140.8, 134.0, 128.9 (2C), 127.7 (2C), 127.5 (2C), 127.2,
113.4 (2C), 99.8, 78.9, 55.0, 50.3, 48.3, 31.1, 27.8, 26.5, 26.0, 24.8; EI–
MS m/z (relative intensity) 176 (18), 135 (11), 134 (100); HRMS calcd for
C22H26O3S2Na (M+Na+): 425.12156. Found: 425.12164.
Acknowledgements
Janssen Pharmaceutica is thanked for financial support.
Keywords: dihydropyrans • tetrahydropyrans • heterocycles •
allylboration • ring-closing metathesis
(2R*,3S*,6S*)-6-(1,3-Dithian-2-yl)-3-(4-methoxyphenyl)-2-
phenyltetrahydro-2H-pyran (9).
Et3SiH (0.13 mL, 0.774 mmol, 5 equiv) and BF3•Et2O (78 µL, 0.619 mmol,
4 equiv) were added to a solution of the previously obtained lactol (62 mg,
0.155 mmol, 1 equiv) in CH2Cl2 (2 mL) cooled at –78 °C. The solution
was stirred at –78 °C for 1 h and then it was slowly allowed to warm up to
rt. After 12 h a saturated aqueous solution of NaHCO3 (0.5 mL) was
added to the reaction mixture that was concentrated under reduced
pressure. CH2Cl2 (5 mL) was added and the organic layer was washed
with H2O (2 mL), brine (2 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (EtOAc/PE
= 1:5) to afford
tetrehydropyran 9 (30 mg, 50%) as a white solid. mp 143–145 °C; Rf =
0.45 (EtOAc/PE = 1:5); IR (film) 1611, 1512, 1453, 1276, 1244, 1178,
1105, 1066, 1034, 907 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.09 (m,
3H), 7.05 – 7.01 (m, 2H), 6.82 (br d, J = 8.6 Hz, 2H), 6.66 (br d, J = 8.6
Hz, 2H), 4.40 (d, J = 10.1 Hz, 1H), 4.29 (d, J = 4.8 Hz, 1H), 3.92 (ddd, J =
10.8, 4.8, 2.3 Hz, 1H), 3.71 (s, 3H), 2.99 – 2.89 (m, 2H), 2.89 – 2.79 (m,
2H), 2.69 (m, 1H), 2.16 – 2.05 (m, 2H), 2.03 – 1.87 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 157.9, 140.7, 133.8, 128.8 (2C), 127.7 (2C), 127.1,
127.0 (2C), 113.4 (2C), 85.9, 80.7, 55.0, 51.7, 49.1, 31.6, 30.1, 29.9,
28.9, 26.2; EI–MS m/z (relative intensity) 386 (5), 173 (10), 134 (52), 121
(19), 119 (100), 91 (16); HRMS calcd for C22H26O2S2Na (M+Na+):
409.12664. Found: 409.12682.
((2S*,5S*,6R*)-5-(4-Methoxyphenyl)-6-phenyltetrahydro-2H-pyran-2-
yl)methanol (11).
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10.1002/ejoc.201700448
European Journal of Organic Chemistry
FULL PAPER
GC/MS the starting homoallylic alcohols as well as desired ethers 4
could not be detected.
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