Microwave-assisted asymmetric intermolecular heck reaction using phosphine-thiazole ligands

Article abstract of DOI:10.1002/adsc.200700390

A series of new phosphine-thiazole compounds has been synthesized and used as efficient ligands in the palladium-catalyzed asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates and cyclohexenyl triflate. Microwave heating was used to accelerate the reactions and gave complete conversions in as little as one hour. Products were obtained with good to excellent enantioselectivities.

Full text of DOI:10.1002/adsc.200700390

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DOI: 10.1002/adsc.200700390
Microwave-Assisted Asymmetric Intermolecular Heck Reaction
using Phosphine-Thiazole Ligands
Päivi Kaukoranta,a Klas Källstrçm,b and Pher G. Anderssona,*
a
Department of Biochemistry and Organic Chemistry, Box 576, 75123 Uppsala, Sweden
Fax : (+46)-18-471-3818; e-mail: pher.andersson@biorg.uu.se
Biovitrum AB, 11276 Stockholm, Sweden
b
Received: August 6, 2007; Published online: November 27, 2007
Dedicated to Professor Jan-E. Bäckvall on his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A series of new phosphine-thiazole com- gave complete conversions in as little as one hour.
pounds has been synthesized and used as efficient li- Products were obtained with good to excellent enan-
gands in the palladium-catalyzed asymmetric inter- tioselectivities.
molecular Heck coupling of 2,3-dihydrofuran with
aryl triflates and cyclohexenyl triflate. Microwave Keywords: asymmetric catalysis; Heck reaction; mi-
heating was used to accelerate the reactions and crowave heating; phosphine-thiazole ligands
Introduction
tions have been reported and this transformation has
proven to be a valuable tool in the synthesis of natu-
One of the great challenges in modern synthetic or- ral products and other complex structures.[4a–d] How-
ganic chemistry concerns the enantioselective forma- ever, when bidentate phosphine ligands such as
tion of carbon-carbon bonds.[1] One way to achieve BINAP are used in the intermolecular coupling of
this is the asymmetric Pd-catalyzed Heck coupling of 2,3-dihydrofuran (1) and phenyl triflate (2), the com-
aryl and alkenyl halides or triflates to alkenes, a reac- pound with the migrated double bond, 2-phenyl-2,3-
tion known to be very versatile due to its high toler- dihydrofuran (4), is obtained as a major product
ance of functional groups.[2a–e] During the last decade (Scheme 1).[5,6]
chiral bidentate phosphine ligands have successfully
The first report on intermolecular Heck coupling of
been used as ligands in this coupling reaction.[3a–e] 1 and 2 employing N,P-donor ligands was published
Highly enantioselective intramolecular Heck reac- by Pfaltz and co-workers, who used their oxazoline-
Scheme 1. The asymmetric intermolecular Heck reaction with 2,3-dihydrofuran and phenyl triflate.
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based PHOX ligand.[7] After this initial report several ture.[13] As it is still important to find catalytic systems
N,P-donor ligands have been employed in the asym- that give high enantioselectivies with short reaction
metric Heck reaction.[8a–g] Many of these ligands pos- times in this coupling reaction, we decided to investi-
sess an oxazoline functionality but there are reports gate the use of microwave irradiation as a heating
concerning other N-donor functionalities, such as pyr- method when using our thiazole based ligands.
idine and quinoline.[2e,9] Surprisingly when N,P-donor
Herein we report the highly enantio- and regiose-
ligands are used, 2-phenyl-2,5-dihydrofuran (3) is lective MW-assisted asymmetric Heck coupling of 2,3-
formed predominantly and highly enantioselectively dihydrofuran 1 with different triflates (2, 23–26) by
(Scheme 1). The low tendency of N,P-donor ligated using thiazole phosphine ligands (5–10). The choice of
À
Pd catalysts to promote C C double bond migration the base and solvent and the impact of the ligand
is not yet fully understood.
structure on the reaction were studied. Both known li-
One of the drawbacks with N,P-donor ligands is the gands (5–7)[12a] and newly prepared ligands (8–10)
long reaction times required to achieve full conver- were used (Figure 1).
sion. Today it is known that by using controlled mi-
crowave dielectric heating, the reaction rates can be
accelerated. This is especially important in modern Results and Discussion
medicinal chemistry where MW-assisted synthesis has
aided in high-speed drug development. In a report by Synthesis of the N,P-ligands 8–10
Hallberg and co-workers it was demonstrated that the
use of MW heating in asymmetric intermolecular The synthesis of the new ligands started from the
Heck reactions greatly shorten the reaction times known compound 11[12a] which smoothly underwent
from several days to some hours and also reduced the Suzuki coupling with 3,5-dimethylphenylboronic acid
need for an inert atmosphere.[10,11] However, the enan- according to a standard protocol and gave 15 in high
tioselectivities in their study were lower than those yield (Scheme 2).[14] Very large arylboronic acids gave
obtained with thermal heating (Scheme 1). Recently diminished yields and therefore we turned our inter-
Pàmies et al. have reported on the MW-assisted asym- est to the catalytic systems developed by Buchwald
metric intermolecular Heck reaction, using sugar- and co-workers.[15] They have reported highly efficient
based phosphite-oxazoline ligands on Pd to achieve monophosphines for Suzuki cross-coupling and we
complete reactions in 10 min with excellent enantiose- chose to use 2-(2’,6’-dimethoxybiphenyl)dicyclohexyl-
lectivities.[8a]
phosphine (SPhos), which has given the best results
We have recently developed a novel class of phos- so far and is commercially available, as a ligand.[15]
phine thiazole ligands and applied them to the Ir-cata- Under Buchwald conditions, alcohol 11 did not give
lyzed asymmetric hydrogenation of olefins with great the desired product 16 in the reaction with mesityl-
success.[12] These structures provide a highly tunable boronic acid. However coupling of mesitylboronic
ligand scaffold and the substituents can be varied at acid and ester 12 worked well giving 13 in almost
both the thiazole and phosphine positions (Figure 1). quantitative yield. The ester 13 was reduced to alco-
We reasoned that these compounds might also serve hol 16, which was resolved in to its enantiomers by
as good ligands in other transition metal-catalyzed re- preparative chiral HPLC (Chiralcel OD). Alcohols
actions. Initial studies using phosphine thiazole li- 14–16, were converted to the corresponding tosylates
gands in the asymmetric intermolecular Heck cou- 17–19 in good yields. Treatment of tosylates 17–19
pling reaction of 1 and 2 showed similar selectivities with Ar2PACHTRE(UNG BH3)Li at 08C in THF, followed by stirring
and reaction rates similar to those as in the litera- at room temperature overnight in DMF, yielded the
P-borane protected phosphines 20–22 in high yields.
At this point, the borane adducts were stable to hy-
drolysis and oxidation. Removal of the borane-pro-
tecting group by stirring in neat Et2NH gave the de-
protected phosphines 8–10 (Scheme 2).
Asymmetric Heck Couplings
The Heck coupling between 2,3-dihydrofuran and
phenyl triflate with 3 mol% of catalyst, prepared in
situ from 1.5 mol% of [Pd2ACHTRE(UNG dba)3] and 6 mol% of
ligand 6 was chosen as the standard reaction to study
the influence of solvent and base (Table 1). The
choice of base did not dramatically change the iso-
Figure 1. Phosphine-thiazole ligands used in the asymmetric
intermolecular Heck reaction.
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Scheme 2. Reagents and conditions: a) ArB(OH)2, DPPF·PdCl2 (5 mol%), K2CO3 (aqueous), toluene, 808C; b) SPHOS (8
mol%), Pd2A(dba)3 (4 mol%), mesitylB(OH)2, K3PO4, toluene, reflux, overnight, 95%; c) LiAlH4, THF, r.t., overnight, then
CHTREUNG
preparative HPLC, Chiracel OD; d) TsCl, pyridine, 08C to r.t. overnight; e) Ar2P
overnight; f) Et2NH, r.t., overnight.
A
meric ratio of 3/4, but affected the reaction rates. Em-
ploying DIPEA as a base, the reaction proceeded to
completion within four hours, whereas using triethyl-
amine and proton sponge as bases gave lower conver-
sions of 80% and 11%, respectively with the same re-
action time (Table 1, entries 1–3). When proton
sponge was employed as a base lower enantioselectiv-
ity (ee 85%) was obtained whereas the enantioselec-
tivity was the same when triethylamine and DIPEA
were used (ee 89%). Even though the ratio of 3/4 was
not affected dramatically when different bases were
used it should be mentioned that slightly more 4 was
formed in the reaction when triethylamine and proton
sponge were used when compared to DIPEA. This
shows that the choice of base is important for the out-
come of the reaction. In our system DIPEA proved
superior among the bases employed (Table 1,
entry 1).
Table 1. Optimization of reaction conditions.
Entry Solvent Base
Time Conversion[a] Ratio[b] ee[b]
[h]
[%]
3/4
[%]
1
2
3
4
5
THF
THF
THF
DMF
THF
DIPEA 4
>99
80
11
18
>99
98/2
96/4
97/3
95/5
76/24
89
89
85
89
89
(76)
89
(40)
89
Et3N
PS[c]
4
4
DIPEA 4
DIPEA 12
6
7
THF
THF
DIPEA 5
>99
83/17
99/1
DIPEA 3
90
Varying the solvent also had a great impact on the
rate of the reaction. When THF was used as a solvent
the reaction was complete within 4 h (Table 1,
entry 1). When the more polar solvent DMF was used
the reaction gave only 18% conversion in four hours
(Table 1, entry 4). The enantiomeric excess remained
[a]
[b]
1
Determined by H NMR.
Determined by GC-MS (CHIRALDEX G-TA). Enantio-
meric excess of 3. Enantiomeric excess of 4 given in pa-
renthesis. Absolute configuration of 4 was not deter-
mined.
[c]
1,8-Bis(dimethylamino)naphthalene.
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Table 2. Pd-catalyzed phenylation of 2,3-dihydrofuran 1 with
ligands 5–10.
the same when DMF was used as solvent, but 4 was
formed even though the reaction did not proceed to
completion.
To our surprise in the commonly used solvent for
Heck reactions, benzene, the reaction proceeded
slowly when compared to THF and gave various con-
versions. The regioselectivity and enantioselectivity
(76% ee) were also lower in benzene.
Entry
Ligand
Conversion
[%]
ee
[%]
As seen in Table 1, the reaction time was crucial to
regioselectivity (Table 1, entries 1 and 5–7). Longer
reaction times resulted in lower regioselectivity
(entry 5 and 6) whereas the reaction was not complete
in 3 h (entry 7). The best results were obtained when
the reaction was run for 4 h; this afforded the two re-
gioisomers 3 and 4 in the ratio 98:2 (Table 1, entry 1).
The enantiomeric excess of 3 was 89%. Based on the
fact that the longer reaction time resulted in more for-
mation of isomer 4, the isomerization process takes
place after the initial formation of 3 in our catalytic
system. Lowering the reaction temperature from
1208C to 1008C did not enhance the enantioselectivi-
ty or regioselectivity, and the reaction proceeded
much more slowly.
1
2
3
4
(R)-5
(R)-6
(S)-7
(R)-8
98
98
29
98
85 (R)
87 (R)
80 (S)
87 (R)
Effect of Ligand Substituents in the Heck Reaction of
2,3-Dihydrofuran (1) and Phenyl Triflate (2)
5
(S)-9
98
98
87 (S)
96 (S)
After optimizing the reaction for the formation of 3,
we screened several ligands (5–10) in order to chart
the impact of the ligand structure on the reaction
(Table 2). When the substitution pattern on the phos-
phine was varied with different aromatic substituents
that is, phenyl, o-tolyl and 3,5-dimethylphenyl, the
enantioselectivity varied little, although it can be seen
that the ee values generally increased with bulkier
substituents (Table 2, entries 1, 2 and 4). Different ar-
omatic substituents on the phosphine moiety did not
impact on the regioselectivity of the reaction or on
the reactivity of the catalyst.
(S)-
10
6
[a]
Reactions were run for 4 h with ligands 5–9 and 1 hour
with ligand 10. Conversions to 3 were determined by
1H NMR based on the triflate. Enantiomeric excesses
were determined by GC-MS (CHIRALDEX G-TA) and
chiral HPLC. The absolute configurations were assigned
according to the literature.
However, varying the substituent at the 2-position
of the thiazole from hydrogen to mesityl affected the
enantioselectivity of the reaction remarkably. With
bulkier substituents, better enantioselectivities were conversion in four hours. The reaction was completed
obtained (Table 2, entries 2, 3, 5 and 6). This is in in one hour when ligand 10 was employed.
agreement with the findings of Pfaltz and co-workers,
who observed that bulkier substituents close to the ni-
trogen coordinating atom increased the enantioselec- Heck reaction of 2,3-Dihydrofuran (1) with Different
tivity.[7] When using ligand 7 the enantioselectivity Aryl Triflates and Cyclohexenyl Triflate
was lower (ee 80%) than when using the ligands with
aromatic substituents in the 2-position of the thiazole. In order to study further the steric and electronic
With ligand 10 the best enantioselectivity was ob- properties of the reaction, we tested the Heck reac-
tained, ee 96% (Table 2, entry 6). In our system the tion of 2,3-dihydrofuran (1)[16] with various aryl tri-
reaction rate was enhanced with bulkier substituents flates (2, 23–25) and cyclohexenyl triflate (26). Aryl
in the 2-position of the thiazole; which is in the con- triflates were varied from bulky ones (1-naphthyl) to
trast with the findings from Pàmies et al.[8a,b] The reac- electron-donating ones (p-MeOC6H4OTf and p-Me-
tions proceeded slowest with ligand 7, giving 29% C6H4OTf). In our system the best enantioselectivies
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were achieved when 1-naphthyl triflate (25) was used. bulky mesityl substituent gave excellent enantioselec-
Electron-donating substituents (23 and 24) on phenyl tivities (94–98%) with high reactivity.
gave generally higher ees compared to phenyl triflate.
Surprisingly, when cyclohexenyl triflate (26) was
Ligand substituent effects on the coupling with differ- employed in the Heck reaction the impact of the
ent aryl triflates were comparable to those observed ligand structure was not equivalent to what was seen
in the Heck reaction of 2,3-dihydrofuran and phenyl with aryl triflates. Reaction of 2,3-dihydrofuran (1)
triflate (Table 2). The ligand with the smallest sub- and cyclohexenyl triflate (26) gave dramatically in-
stituent on the thiazole moiety (7) gave the lowest ee creased ee values when the aromatic substituent on
values varying from 77–80% and the reactions did phosphine was changed from phenyl to the bulkier o-
not go to completion, whereas the ligand with the tolyl, 50% (Table 3, entry 1) to 80% respectively
Table 3. Evaluation of ligands 5–10 with various triflates 2, 23–26.
Entry Ligand/Triflate
2 Conv./ee [%] 23 Conv./ee [%] 24 Conv./ee [%] 25 Conv./ee [%] 26[b] Conv./ee [%]
1
2
3
4
(R)-5
(R)-6
(S)-7
(R)-8
98/85 (R)
98/87 (R)
29/80 (S)
98/87 (R)
98/88 (R)
98/87 (R)
28/77 (S)
98/92 (R)
98/88 (R)
98/86 (R)
No conv.
98/89 (R)
98/90 (R)
98/93 (R)
30/78 (S)
98/95 (R)
98/50 (R)
98/80 (R)
72/79 (S)
40/28 (R)
5
6
(S)-9
98/87 (S)
98/96 (S)
98/89 (S)
98/97 (S)
98/87 (S)
98/94 (S)
98/90 (S)
98/98 (S)
98/86 (S)
98/68 (S)
(S)-10
[a]
[b]
Reactions were run for 4 h with ligands 5–9 and 1 hour with ligand 10. Conversions to substituted 2,5-dihydrofurans were
determined by 1H NMR based on the triflate. Enantiomeric excesses were determined by GC-MS (CHIRALDEX G-TA)
and chiral HPLC. The absolute configurations were assigned according to literature.
Reactions were run 6 h with ligands 5–9 and 1.5 h with ligand 10.
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2’,6’-dimethoxybiphenyl [S-PHOS] (0.226 g, 0.552 mmol), 7
(2.0 g, 6.9 mmol), 2,4,6-trimethylphenylboronic acid (2.26 g,
13.8 mmol) and powdered, anhydrous K3PO4 (5.86 g,
27.6 mmol). The flask was capped with a rubber septum and
then evacuated and backfilled with nitrogen (three cycles).
Dry toluene (15 mL) was added and the septum was re-
placed by a condenser. The reaction mixture was heated to
reflux and the mixture was stirred for 16 h under nitrogen.
The reaction mixture was then allowed to cool down to
room temperature, diluted with diethyl ether and filtered
through Celite. The filtrate was concentrated under vacuum
giving the crude product. The crude product was purified by
flash chromatography (toluene:EtOAc, 90:10) giving prod-
uct 8 as an oil; yield: 2.16 g (95%). Rf =0.35 (toluene:
EtOAc, 90:10); IR (KBr): nmax =2937, 2864, 1731, 1462,
(Table 3, entry 2). However when the bulky substitu-
ent 3,5-dimethylphenyl on the phosphine was used in
the coupling of 1 and 26, the reaction proceeded in
low ee (28%) and low conversion (Table 3, entry 4).
With cyclohexenyl triflate (26), the substitution pat-
tern at the 2-position of the thiazole did not play as
crucial role as with aryl triflates.
Conclusions
In conclusion, we have shown that the phosphine-
thiazole ligands developed in our group for the Ir-cat-
alyzed hydrogenation of olefins also perform ex-
tremely well in the asymmetric Pd-catalyzed Heck
coupling between 2,3-dihydrofuran and various tri-
flates, giving enantioselectivities among the best re-
ported so far. We have also shown that, when using
microwaves as the source of heat, the reaction pro-
ceeds much faster and retains excellent enantioselec-
tivity, allowing for a highly selective, fast screening of
the asymmetric Heck coupling.
1
1218, 1177, 1158, 909 cmÀ1; H NMR: d=1.23 (t, J=7.2 Hz,
3H, CH2CH3), 1.88–1.95 (m, 1H, CH2), 1.99–2.07 (m, 1H,
CH2), 2.10–2.17 (m, s overlapping, 1H, CH2), 2.14 (s, m
overlapping, 6H, 2CH3), 2.21–2.27 (m, 1H, CH2), 2.30 (s,
3H, CH3), 2.91 (dddd, J=1.6, 5.7, 6.9, 13.6 Hz, 1H, CH2),
3.93–3.96 (m, 1H, CH), 4.12–4.22 (m, 2H, CH2CH3), 6.89–
6.90 (m, 2H, ArH); 13C NMR: d=14.2, 20.2, 21.1, 21.2, 23.4,
26.9, 43.0, 60.8, 128.2, 131.0, 132.4, 137.6, 138.8, 146.7, 163.5,
173.6; MS (EI): m/z (rel. intensity)=331.06 (MH+, 26%),
329.46 (M+, 100%), 256.54 (44%), 255.16 (80%), 253.17
(22%); anal. calcd. (%) for C19H23NO2S (329.1): C 69.27, H
7.04, N 4.25; found: C 69.25, H 7.28, N 4.37.
Experimental Section
All reactions were conducted under nitrogen using dried
glassware and magnetic stirring. THF was freshly distilled
from sodium-benzophenone ketyl under N2 prior to use.
CH2Cl2 was freshly distilled from powdered CaH2 under N2
prior to use. Benzene was freshly distilled from sodium
under N2 prior to use. Anhydrous dimethylformamide was
purchased from Sigma–Aldrich. Triflates 2, 23 and 25 were
purchased from Sigma–Aldrich and triflates 24 and 26 were
synthezised according to the literature procedures. 2,3-Dihy-
drofuran was purchased from Sigma–Aldrich. Diisopropyl-
ethylamine (DIPEA) was distilled from ninhydrin and then
from potassium hydroxide. Flash chromatography was per-
formed using silica gel 60 Š (37–70 mm). Analytical TLC
was carried out utilizing 0.25 mm precoated plates, silica gel
60 UV254 and spots were visualized by the use of UV light.
NMR samples were dissolved in CDCl3 or benzene-d6 and
run at room temperature; 1H (500 MHz), 13C (126 MHz)
NMR spectra were recorded on a 500 MHz spectrometer
whereas 31P (121 MHz) NMR spectra were recorded on a
300 MHz spectrometer. Chemical shifts for protons are re-
ported using the residual CHCl3 as internal reference (d=
7.26). Carbon spectra were referenced to the shift of the 13C
signal of CDCl3 (d=77.0). Microwave heating was carried
out using automatic single-mode synthesizer from Biotage,
which produces a radiation frequency of 2.45 GHz. Temper-
ature in the microwave oven was measured by an IR sensor
sitting in the reaction cavity. Melting points are reported as
their uncorrected values.
(S)-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydrobenzo-
[d]thiazol-4-yl]methanol (15)
To a solution of 11 (0.1 g, 0.4 mmol) in toluene (1.5 mL) was
added Na2CO3 (0.085 g, 0.8 mmol) followed by H2O
(0.35 mL), 3,5-dimethylphenylB(OH)2 (0.089 g, 0.6 mmol) and
PdCl2·dppf·CHCl3 (0.025 g, 0.030 mmol) and the resulting mix-
ture was degassed and vigorously stirred at 808C under nitro-
gen until TLC indicated complete disappearance of 11. H2O
(5 mL) and toluene (5 mL) were added followed by 1M
NaOH (5 mL). After separation, the aqueous layer was ex-
tracted with CHCl3 (3”10 mL) and the combined organic ex-
tracts were washed with H2O(10 mL), brine (10 mL), dried
(MgSO4) and evaporated to dryness. Purification by flash chro-
matography (toluene:EtOAc, 90:10) gave 15 as a white solid;
yield: 0.094 g (86%); mp 98.5–100.5; Rf =0.46 (toluene:EtOAc
80:20); [a]25: +84.98 (c 1.1, CHCl3); IR (KBr): nmax =3338,
3063, 2941,D2856, 1531, 1499, 1456, 1428, 1310, 1228, 1036, 763,
732, 691 cmÀ1; 1H NMR: d=1.34–1.46 (m, 1H, CH2), 2.78–1.89
(m, 1H, CH2), 1.95–2.10 (m, 2H, CH2), 2.36 (s, 6H), 2.69–2.90
(m, 2H), 3.03–3.09 (m, 1H), 3.68 (dd, J=4.8, 10.6 Hz, 1H,
CH), 3.82 (dd, J=9.7, 10.6 Hz, 1H, CH2OH), 4.77 (brs, 1H,
OH), 7.03 (m, 1H, ArH), 7.49 (m, 1H, ArH); 13C NMR: d=
21.2, 22.4, 23.6, 25.5, 39.4, 67.3, 124.0, 129.5, 131.6, 133.2, 138.5,
153.3, 165.7; MS (EI): m/z (rel. intensity)=274.1 (MH+, 41%),
243.2, (100%), 242.2 (62%) 200.1 (11%), 249.9 (18%), 132.2
(17%), 111.1 (22%); anal. calcd. (%) for C16H19NOS (273.1):
C 70.29, H 7.00, N 5.12; found: C 70.15, H 7.06, N 5.03.
Ethyl 2-(2,4,6-Trimethylphenyl)-4,5,6,7-tetrahydro-
benzo[d]thiazol-4-carboxylate (13)
(S)-[2-(2,4,6-Trimethylphenyl)-4,5,6,7-tetrahydro-
benzo[d]thiazol-4-yl]methanol (16)
An oven-dried, round-bottomed flask was charged with
Compound 13 (2.15 g, 6.53 mmol) was dissolved in dry THF
Pd
2A
(25 mL) and added to
a
slurry of LiAlH4 (0.50 g,
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Microwave-Assisted Asymmetric Intermolecular Heck Reaction
13.07 mmol) in THF (15 mL) at 08C. The temperature was
allowed to rise to room temperature and the mixture was
stirred overnight. The reaction mixture was recooled to 08C
and the reaction was quenched by slow addition of water
(0.5 mL), followed by 2M NaOH (1.0 mL) and additional
water (0.5 mL). The resulting mixture was stirred for 3 h at
room tempertaure. Filtration on Celite, followed by washing
of the filter cake with THF (2”15 mL) and evaporation of
the filtrate gave the crude product; yield: 1.65 g (90%).
The crude product was pure enough for the chiral separa-
tion. The two enantiomers were separated by semiprepara-
tive HPLC [Chiracel OD column (20”250 mm), hexane:i-
PrOH=95:5, 5 mLminÀ1, 30 mg loading, tR 21.08 (S) and
24.83 (R) (chirality decided assuming the same optical rota-
tion as for 14[12]] to afford a white solid; mp 149.6–150.4;
Rf =0.30 (toluene:EtOAc, 80:20); [a]2D5:3: +528 (S) (c 0.9,
CHCl3); IR (KBr): nmax =3402, 2927, 2860, 2246, 1447, 1041,
wave-heated at 120 8C for the given time. After cooling, the
mixture was diluted with diethyl ether and filtered through
a short column of silica. The filtrate was concentrated and
1
the residue was analyzed by H NMR and the enantioselec-
tivity was determined by the method reported in the litera-
ture or by the given method. The products were 2-phenyl-
2,5-dihydrofuran,[8e] 2-p-methoxyphenyl-2,5-dihydrofuran,[10]
and 2-(cyclohex-1’-en-1’-yl)-2,5-dihydrofuran.[8e]
2-p-Tolyl-2,5-dihydrofuran:[17] The same method as was
used for 2-phenyl-2,5-dihydrofuran; GC-MS (G-TA, 808C,
0.38C/min, 908C, 58C/min, 1258C, 15 psi): TR1 =32.7 min
(S), TR2 =34.3 min (R). The absolute configuration assumes
the same sense of asymmetric induction as with 2-phenyl-
2,5-dihydrofuran.
2-(1-Naphthyl)-2,5-dihydrofuran:[8e]
GC-MS
(G-TA
1208C, 18C/min, 1708C, 12 psi): TR1 =34.8 min (À), TR2
=
35.5 min (+). According to the literature (+) gives (R).[18]
1
978. 908 cmÀ1; H NMR: d=1.39–1.47 (m, 1H CH2), 1.81–
1.89 (m, 1H, CH2), 1.97–2.02 (m, 1H, CH2), 2.05–2.11 (m,
1H, CH2), 2.15 (s, 6H, CH3), 2.32 (s, 3H, CH3), 2.75–2.82
(m, 1H, CH2), 2.86–2.91 (m, 1H, CH2), 3.06–3.13 (m, 1H,
CH), 3.66 (ddd, J=1.6 Hz, 9.4 Hz, 10.5 Hz, 1H, CH2OH),
3.81 (ddd, J=4.2 Hz, 10.5 Hz, 1H, CH2OH), 4.55 (dd, J=
1.6 Hz, 10.5 Hz, 1H, OH), 6.93 (m, 2H, ArH); 13C NMR:
d=20.31, 21.13, 22.42, 23.52, 25.56, 39.44, 67.43, 128.36,
130.71, 130.83, 137.54, 139.01, 152.53, 163.83; MS (EI): m/z
(rel. intensity)=288.14 (MH+, 100%), 257.52 (32%), 255.84
(18%); anal. calcd. (%) for C17H21NOS (287.1): C 71.04, H
7.36, N 4.87; found: C 70.83, H 7.21, N 4.73.
Supporting Information
The characterization data of the compounds 17–22 and 8–10
are available in the Supporting Information.
Acknowledgements
This work was supported by grants from SSF SELCHEM
graduate research program and Swedish Research Council
(VR).
Compounds 17–22 and 8–10 were synthesized according
to the reported procedures.[12]
General Procedure for MW-Assisted Asymmetric
Intermolecular Heck Reaction (Table 1)
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