Microwave-assisted enantioselective Heck reactions: Expediting high reaction speed and preparative convenience

Article abstract of DOI:10.1055/s-2002-33331

Palladium-catalyzed asymmetric Heck reactions have been performed using high temperature conditions with the aid of controlled microwave dielectric heating. Significant enantioselectivities of up to 92% ee were obtained under non-inert conditions utilizin

Full text of DOI:10.1055/s-2002-33331

SPECIAL TOPIC
1611
Microwave-Assisted Enantioselective Heck Reactions: Expediting High
Reaction Speed and Preparative Convenience
M
P
icrowave-As
e
siste
d
Enan
t
tiosele
e
ctive
H
eck
r
R
eaction Nilsson, Henrik Gold, Mats Larhed,* Anders Hallberg
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, P. O. Box 574, 75123 Uppsala,
Sweden
Fax +46(18)4714474; E-mail: mats@orgfarm.uu.se
Received 14 June 2002
Aryl triflates 1 were reacted with olefin 2 in the presence
of different palladium precatalysts to furnish the isomeric
products 3–5 (Scheme 1). The 0.6 mmol scale one-pot re-
actions were performed under air, in sealed microwave
Abstract: Palladium-catalyzed asymmetric Heck reactions have
been performed using high temperature conditions with the aid of
controlled microwave dielectric heating. Significant enantioselec-
tivities of up to 92% ee were obtained under non-inert conditions
utilizing the previously reported thermostable palladium- transparent reaction vessels, using controlled microwave
phosphineoxazoline catalytic system. With microwave irradiation, irradiation with a single-mode applicator. The preparative
reaction times of hours instead of days were obtained. Enantiomeric
results are summarized in the Table. The best conversions
purities and conversions were found to be strongly dependent on
both the choice of the aryl triflate, the reaction temperature, the sol-
vent and the base. Examples of asymmetric arylations of electron-
rich as well as neutral cyclic alkenes are presented.
were obtained in these high temperature reactions when
proton sponge was used as the base and benzene as the
solvent. To overcome the problem with double bond
isomerization, ligand A was first investigated. Increasing
the reaction temperature with 2 as olefin to 145 °C, from
5
Key words: asymmetric catalysis, Heck reaction, arylations, regio-
selectivity, palladium
7
0 °C as used originally by Pfaltz, resulted in an isolated
yield of 58% and an ee of 90% after only 55 minutes of
irradiation (entry 3). At higher reaction temperatures, the
catalytic system decomposed before complete conversion
was achieved. However, after lowering of the temperature
to 140 °C, the isolation of 3a in 66% yield and with 89%
ee was achieved (entry 2). A higher stereoselectivity
could be obtained in THF than in benzene, but lower con-
versions of 1a were experienced in all cases (entries 1–3).6
In modern medicinal and combinatorial chemistry, reac-
tion optimization and chemical rehearsal rear up as bottle-
necks that can severely restrict compound throughput.
Despite advances in parallel synthesis, the reaction times
1
can still be rate-limiting. Our research in microwave syn-
thesis is therefore devoted to the discovery and develop-
ment of high-speed methods of importance for lead
2
generation and lead optimization processes.
Pfaltz has reported that (R)-2-phenyl-2,5-dihydrofuran
Ph
O
(
3a) is produced from phenyl triflate (1a) and 2,3-dihy-
P
P
Ph
Ph
drofuran (2) in the presence of a palladium(0) precursor
and phosphineoxazoline A (Figure 1, Scheme 1). The
most impressive reaction was carried out in THF with
high regioselectivity and an impressive enantiomeric ex-
N
Ph2P
Ph
3
cess of 97%. The reaction time for this intermolecular
A
B
3
Heck reaction was reported to be 4 days. Previous utili-
Figure 1 The structures of phosphineoxazoline ligand A and di-
phosphine ligand B [(R)-BINAP].
zation of palladium-(phosphinophenyl)oxazoline based
catalytic systems in microwave promoted allylic substitu-
tion reactions have afforded up to 97% yield and 99% ee
4
after only 30 seconds of irradiation. Inspired by these re- The electronic properties of the aryl triflates were found to
sults, we decided to investigate whether the use of con- be important for the reactivity. In a novel asymmetric re-
trolled microwave heating in combination with action, the electron rich 1b reacted to produce high yields
thermostable catalytic systems could enable shortening (73–85%) and high ee (88%) of pure 3b after 1–4 hours
also of the Heck arylation reaction times with high reten- (entries 4 and 5) whereas the use of electron-poor 4-cy-
tion of enantioselectivity. This short communication is fo- anophenyl triflate gave only small amounts of an arylated
cused on acceleration of intermolecular asymmetric Heck Heck product. The sterically demanding 1c furnished the
processes under a non-inert atmosphere.
highest enantiomeric excess (92%) but also the lowest re-
action rate (entry 6). It is noteworthy that small amounts
of non-chiral 5a (Ar = Ph) but no 4a were formed in all of
the reactions between phenyl triflate (1a) and 2,3-dihy-
drofuran (2) (entries 1–3). Since the classic (70 °C) phos-
phinooxazoline controlled arylation of 2 proceeds without
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1611,1614,ftx,en;C02902SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1
612
P. Nilsson et al.
SPECIAL TOPIC
Scheme 1
3
affording the aryl-conjugated isomer 5, we find it diffi- These results are in accordance with the literature regard-
cult to rationalize the outcome in terms of the accepted ing both reaction rate1 and selectivity.
cationic Heck-cycle. Thus, the isomerization to 5a (Ar =
0a
10b
7
Asymmetric reactions with cyclopentene (6) were includ-
ed to provide data from reactions of a less electron-rich
cyclic olefin. With classical heating (70 °C, 5 d) this valu-
able extension of the Heck reaction is reported to furnish
Ph) ought to occur after insertion, -elimination and sub-
sequent release of the metal from the phenylated product
8
,9
3
a. The use of the diphosphine ligand B, (R)-BINAP
(
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) (Figure 1),
8
0% of 7 in 86% ee in THF (82% ee with benzene as sol-
allowed reduction of the reaction times (10–30 min), but
significantly lower yields and stereoselectivities were en-
countered. When Pd dba was used as the palladium
11
vent) employing ligand A (Scheme 2). Accordingly, mi-
crowave arylation of 6 resulted exclusively in the
formation of isomer 7 and only trace amounts (1–2%) of
isomers 8 and 9 were detected (Scheme 2, Table). The Ta-
ble reveals that the desired 7 was formed in high yield
2
3
source, the yield was 66% and the ee 43% (entry 7). The
use of Pd(OAc) gave 53% yield and 50% ee (entry 8).
2
Table Palladium-Catalyzed Asymmetric Arylation of the Prochiral Olefins 2 and 6 Using Microwave Irradiationa
e
Entry
1
Main Product
Pd/Ligand Temp (°C)
Time (h)b
Yield (%)c
Isomeric
Ratio
ee (%)
Optical
Rotation
d
Pd dba /A 120
3
64
3:5/90:10
90
2
3
3
3
a
2
3
4
Pd dba /A 140
1
66
58
85
3:5/96:4
3:5/90:10
3/100
89
90
88
2
3
Pd dba /A 145
55 min
4
2
3
Pd dba /A 120
2
3
b
5
6
Pd dba /A 140
1
73
80
3/100
3/100
88
92
2
3
Pd dba /A 120
8f
2
3
3
4
c
7
Pd dba /B
160
30 min
66
4:3/83:17
43
2
3
a
8
9
Pd(OAc) /B 160
10 min
8
53
80
4:3/94:6
50
2
Pd dba /A 120
7:8+9/99:1
45g
[ ]D23 +85
2
3
7
10
Pd dba /A 140
4
78
7:8+9/98:2
42g
[ ]D23 +90
2
3
a
b
c
d
e
f
All reactions were performed in benzene with proton sponge as base.
Reactions were irradiated until all of the starting aryl triflate 1 was consumed as deduced by GC/MS.
Main product after silica gel column chromatography (>95% pure according to GC/MS).
Measured by GC/MS, double bond isomers were assumed to have identical response factors.
Ee of major isomer as measured by chiral HPLC.
Small amounts of starting 1b remained.
Ee of major isomer as measured by optical rotation.
g
Synthesis 2002, No. 11, 1611–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwave-Assisted Enantioselective Heck Reaction
1613
Scheme 2
(
78%), but in moderate stereoselectivity (42%), after only Pyrex (5 mL, code no 351520, Smith process vial) with silicon sep-
tum were supplied by the same company. All reactions were con-
ducted under air. Enantiomerical purities of 3 and 4 were analyzed
by HPLC (Chiracel OD-H; 0.46 25 cm, PS = 5 m, degassed 2-
4
hours of microwave heating at 140 °C (entry 10).
Powerful heating ramps, good temperature control and
impressive superheating were readily obtained using the methylpentane–propan-2-ol, flowrate 0.5 mL/min, detection at 220
microwave synthesizer despite the use of weakly absorb- nm). The chiral HPLC column was protected by a guard column
1
3
1
1
2
(Chiralcel OD 0.46 5 cm, PS = 10 m). C and H NMR spectra
ing solvents (tan
(
an IR-sensor, positioned outside the reaction vessel.
= 0.047, tan
0)
THF
benzene
were obtained in CDCl at 100 and 400 MHz respectively. Low res-
olution mass spectra were recorded on a GC/MS instrument
equipped with a cross-linked methyl siloxane capillary column (25
3
Figure 2). The reaction temperatures were recorded with
m
0.22 mm 0.3 m film) operating at an ionization energy of 70
eV. The oven temperature was 70–315 °C (gradient 30 °C/min). Re-
gioisomers were assumed to have the same (GC/MS) response fac-
tor. Optical rotation was measured in CHCl (c = 1, T = 23 °C).
3
2
,8-Bis(dimethylamino)naphthalene; benzene (anhydrous); phenyl
trifluoromethanesulfonate (1a); 4-methoxyphenyl trifluo-
romethanesulfonate (1b); and 2,3-dihydrofuran, were purchased
from Aldrich Co and used as received. (R)-(+)-BINAP and cyclo-
pentene: Fluka; Pd dba and Pd(OAc) : Strem Chemicals. 1-Naph-
2
3
2
thyl trifluoromethanesulfonate (1c) was prepared from the
1
3
corresponding naphthol by a standard procedure. (–)-(4S)-4-tert-
Butyl-4,5-dihydro-2-[2 -(diphenylphosphino)phenyl]oxazole was
1
4
synthesized according to Koch et al. Flash column chromatogra-
phy: silica gel 60 0.040–0.063 mm, Merck.
Figure 2 Temperature (IR-sensor) and pressure profiles for an
asymmetric Heck coupling performed in benzene (bp 80 °C, Table,
entry 3).
Microwave-Assisted Enantioselective Heck Reaction; General
Procedure (Table)
The palladium source (0.03 equiv based on Pd) was stirred together
with the chiral ligand (0.06 equiv) in benzene (1 mL) in a Smith pro-
cess vial at r.t. for 10 min. After subsequent addition of base (3
equiv), olefin 2 or 6 (5 equiv) and aryl triflate 1 (0.60 mmol, 1
equiv) dissolved in benzene (1 mL), the mixture was microwave-
heated at the chosen temperature and time. After cooling, the reac-
Although reaction times were reduced from days to hours
and the preparative procedure simplified, the stereoselec-
tivity for phenylation of 2,3-dihydrofuran (2) was reduced
from 97% ee (70 °C) to 90% ee (145 °C). In light of this, tion mixture was filtered, evaporated and purified by column chro-
the high enantioselectivities (99% ee) that have been re- matography on silica gel (pentane–Et O, 95:5). The products were
2
1
5
16,17
identified by comparison with the literature data for 3a, 3b,
ported in microwave flash-heated allylic substitutions af-
1
8
15
18,19
ter only 30 seconds of irradiation are remarkable.4
3c, 4a, 7,
and the configuration was confirmed by optical ro-
tation measurements.
In short, the use of controlled microwave heating expe-
dites metal-catalyzed organic synthesis by increasing the (+)-(R)-2-Phenyl-2,5-dihydrofuran (3a)15
HPLC (2-methylpentane–propan-2-ol, 99:1): t 17.7 min (+), t 21.0
min (–).
reaction speed and reducing the need for an inert atmo-
sphere. In certain cases the requirement for good yield,
high ee (88–92%) and short reaction times can be fulfilled
with asymmetric Heck reactions. The preparative utility
of the presented microwave-assisted Heck reaction is,
however, limited to cases where there is not a strong de-
r
r
(
+)-(R)-2-(4-Methoxyphenyl)-2,5-dihydrofuran (3b)15–17
HPLC (2-methylpentane–propan-2-ol, 95:5): t 18.5 min (–), t 19.9
min (+).
r
r
mand for high enantioselectivity. We believe that an alter- (+)-2-(1-Naphthyl)-2,5-dihydrofuran (3c)18
HPLC (2-methylpentane–propan-2-ol, 90:10): t 23.3 min (+),
tr 28.3 min (–).
native
microwave-accelerated
auxiliary-controlled
r
stereoselective Heck procedure is worthy of investigation.
(
+)-(R)-2-Phenyl-2,3-dihydrofuran (4a)15
HPLC (2-methylpentane–propan-2-ol, 99.5:0.5): t
17.5 min (–).
Microwave heating was carried out using an automatic Smith sin-
gle-mode synthesizer from Personal Chemistry AB, Sweden, which
produces a radiation frequency of 2450 MHz. Reaction vessels in
15.6 min (+),
r
t
r
Synthesis 2002, No. 11, 1611–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

1
614
P. Nilsson et al.
SPECIAL TOPIC
Acknowledgement
(9) Alternatively product 5a (Ar = Ph) may be formed by a trans
Pd- -hydride elimination from the depicted intermediate -
complex (Figure 3).
We thank the Swedish Foundation for Strategic Research, Dr. Marc
Roddis, Dr. Lena Ripa, Dr. Vijay Gupta and Personal Chemistry
AB.
O
Ph
H
References
Pd
H
(
1) (a) Wathey, B.; Tierney, J.; Lidström, P.; Westman, J. Drug
Discovery Today 2002, 7, 373. (b) Lew, A.; Krutzik, P. O.;
Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95.
Figure 3
(
10) (a) Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. J.
Org. Chem. 1999, 64, 1082. (b) Ozawa, F.; Kubo, A.;
Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417.
11) Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.;
Pfaltz, A. J. Organomet. Chem. 1999, 576, 16.
12) (a) Loss tangents data in the literature are only available at
room temperature, see: Gabriel, C.; Gabriel, S.; Grant, E. H.;
Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
(
c) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(
2) (a) Larhed, M.; Hallberg, A. Drug Discovery Today 2001, 6,
(
(
406. (b) Schaal, W.; Karlsson, A.; Ahlsen, G.; Lindberg, J.;
Andersson, H. O.; Danielson, U. H.; Classon, B.; Unge, T.;
Samuelsson, B.; Hulten, J.; Hallberg, A.; Karlen, A. J. Med.
Chem. 2001, 44, 155.
(
(
3) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 200.
27, 213. (b) The loss tangent for benzene is assumed to be
approximately zero since the molecule lacks a permanent
dipole moment
4) (a) Bremberg, U.; Lutsenko, S.; Kaiser, N.-F. K.; Larhed,
M.; Hallberg, A.; Moberg, C. Synthesis 2000, 1004.
(
(
13) Sáa, J. M.; Dopico, M.; Martorell, G.; Garciaraso, A. J. Org.
Chem. 1990, 55, 991.
14) Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfaltz, A.;
Pretot, R.; Schaffner, S.; Schnider, P.; von Matt, P. Recl.
Trav. Chim. Pays-Bas 1995, 114, 206.
(
b) Kaiser, N.-F. K.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. J. Organomet. Chem. 2000, 603, 2.
5) The generic name of this base is 2,8-
(
(
bis(dimethylamino)naphthalene.
6) In THF, diisopropylamine gave an optimized ee of 94%
(
15) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka,
E.; Yanagi, K.; Moriguchi, K. Organometallics 1993, 12,
(
120 °C, 7 h), but the reaction suffered from incomplete
conversion of 1a. With proton sponge as the base the best ee
in THF was 93% (120 °C, 12 h).
4188.
(
(
(
16) Lee, T. D.; Doyle Daves, G. Jr. J. Org. Chem. 1983, 48, 399.
17) Schmidt, B.; Wildemann, H. Eur. J. Org. Chem. 2000, 3145.
18) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A.
Synthesis 1997, 1338.
(
7) This product has been reported as a sideproduct in similar
Heck arylations, see: (a) Andersen, N. G.; Parvez, M.; Keay,
B. A. Org. Lett. 2000, 2, 2817. (b) Hillers, S.; Sartori, S.;
Reiser, O. J. Am. Chem. Soc. 1996, 118, 2087.
8) For an example of a similar palladium catalyzed
isomerization see: Sonesson, C.; Hallberg, A. Tetrahedron
Lett. 1995, 36, 4505.
(
19) Braun v., J.; Kühn, M. Ber. Dtsch. Chem. Ges. 1927, 60,
(
2551.
Synthesis 2002, No. 11, 1611–1614 ISSN 0039-7881 © Thieme Stuttgart · New York