The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

Article abstract of DOI:10.1055/s-2003-43345

Two new heterocyclic diphenylphosphinooxazolines derived from thiophene and benzothiophene were prepared in moderate to good yield and these, and a range of related HETPHOX ligands, were applied in the intermolecular asymmetric Heck reaction. Phenylation of 2,3-dihydrofuran with the t-butyl-substituted thiophene-oxazoline ligand gave (R)-2-phenyl-2,3-dihydrofuran highly regioselectively with excellent enantioselectivity (91-95% ee) and in good yields (70-97%). In addition, cyclohexenylation of 2,3-dihydrofuran proceeded with enantioselectivities of up to 97% ee in excellent (97%) yields, again with the t-butyl-substituted thiophene-oxazoline ligand proving optimal over a range of reaction conditions investigated.

Full text of DOI:10.1055/s-2003-43345

1
06
LETTER
The Application of HETPHOX Ligands to the Asymmetric Intermolecular
Heck Reaction
a
b
c
a
The
A
pplication
i
of
H
E
m
TPH
O
X
Ligands G. Kilroy, Pier Giorgio Cozzi, Nicole End, Patrick J. Guiry*
a
Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research, Department of Chemistry,
University College Dublin, Belfield, Dublin 4, Ireland
E-mail: P.Guiry@ucd.ie
b
c
Dipartimento di Chimica , ‘G. Ciamician’, Via Selmi 2, 40126 Bologna, Italy
Ciba Speciality Chemicals, Group Research, K-420.2.18, 4002 Basel, Switzerland
Received 29 September 2003
Since that study a range of oxazoline-containing ligands
have been applied to this reaction by the groups of
Gilbertson, Hashimoto, and Hou with similar high levels
of regioselectivity and enantioselectivities.5 We also re-
Abstract: Two new heterocyclic diphenylphosphinooxazolines de-
rived from thiophene and benzothiophene were prepared in moder-
ate to good yield and these, and a range of related HETPHOX
ligands, were applied in the intermolecular asymmetric Heck reac-
–9
tion. Phenylation of 2,3-dihydrofuran with the t-butyl-substituted ported the application of diphenylphosphinoferrocenyl-
thiophene-oxazoline ligand gave (R)-2-phenyl-2,3-dihydrofuran oxazoline ligands which gave (R)-2 in moderate to good
highly regioselectively with excellent enantioselectivity (91–95%
yields of up to 72% with good regioselectivity for phenyl-
ee) and in good yields (70–97%). In addition, cyclohexenylation of
ations with consistently high ees of up to 99%, while
2
,3-dihydrofuran proceeded with enantioselectivities of up to 97%
cyclohexenylations gave the related cyclohexenylated ki-
netic isomer in moderate to good yields of up to 75% and
ee in excellent (97%) yields, again with the t-butyl-substituted
thiophene-oxazoline ligand proving optimal over a range of reac-
tion conditions investigated.
10
good ees up to 85%. We subsequently extended the ap-
plication of diphenylphosphinoaryloxazolines to intermo-
lecular Heck reactions employing 2,2-dialkyl-2,3-
Key words: P,N ligands, oxazoline, asymmetric catalysis, inter-
molecular Heck reaction, palladium
1
1
dihydrofurans as substrates and to the asymmetric in-
tramolecular Heck reaction.12 Related (phosphino-
phenyl)benzoxazine ligands from Kündig and Meier and
iso-PINPHOS ligands from Kocovsky followed the same
pattern of both high regioselectivity and enantioselectivi-
ty in the intermolecular Heck reaction.1
The Heck reaction is the palladium(0) catalysed coupling
of an aryl or alkenyl halide with an alkene and has proven
to be a highly versatile procedure for C-C bond forma-
3,14
1
tion. Since the first enantioselective intermolecular Heck
2
reactions by Hayashi, several new chiral ligands have The ligand used in the first example of the asymmetric in-
3
been developed and employed successfully. The first use termolecular Heck reaction by Hayashi was the axially
of P,N ligands in this reaction was reported by Pfaltz in chiral diphosphine ligand, BINAP. This was the ligand of
1
996 who described the arylation and cyclohexenylation choice for many subsequent studies but a more recent re-
of 2,3-dihydrofuran (1), Scheme 1. In contrast to the re- lated axially chiral example by Tietze, the thiophene con-
4
gioisomer problem encountered by Hayashi who formed taining ligand BITIANP, showed higher selectivity and
15
both the kinetic and thermodynamic products 2 and 3, the reactivity. In 2002, the same group subsequently report-
application of palladium complexes of diphenylphosphi- ed the synthesis of novel chiral thiophene-, ben-
nooxazoline ligands 4 produced only (R)-2 in 97% ee.
zothiophene- and benzofuran-oxazoline ligands 5–10 and
their application to palladium catalysed allylic allyla-
1
6
tions. These ligands differ in the substitution pattern of
the oxazoline unit and diphenylphosphino substituent on
the heterocyclic ring.
O
[Pd(ligand)]
O
O
R
+ R
+
ROTf
base, solvent, 30–80 °C
We have independently prepared the HETPHOX ligands
(8–10) and recently applied them to the iridium catalysed
asymmetric hydrogenation of olefins and imines.17 The
oxazoline unit, an important structural feature of the high-
ly successful series of ligands prepared by Pfaltz, coupled
with the electronic effect of the sulfur atom would provide
an interesting combination of factors whose effects we
were interested in studying in the intermolecular Heck re-
action.
1
(R)-2
(R)-3
O
4
a: R = i-Pr
PPh2
N
4b: R = t-Bu
R
Scheme 1
SYNLETT 2004, No. 1, pp 0106–0110
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43345; Art ID: D23703ST.pdf
Georg Thieme Verlag Stuttgart · New York
©

LETTER
The Application of HETPHOX Ligands
107
t-Bu
Asymmetric Phenylation of 2,3-Dihydrofuran (1)
PPh2
N
t-Bu
N
O
Using 3 mol% palladium(0) complexes formed in situ
Ph2P
O
from Pd (dba) and ligands 8 to 12, the initial phenyla-
2
3
X
tions were carried out in toluene at reflux, conditions
which previously afforded our optimal results using
S
1
0
diphenylphosphinoferrocenyloxazolines ligands. These
reaction conditions generally gave (R)-phenyl-2,5-dihy-
drofuran (2) and (R)-phenyl-2,3-dihydrofuran (3) in low
yields with poor regioselectivities and moderate enantio-
selectivities. It was found that the catalyst systems were
more reactive in benzene in which shorter reaction times
of 7 days were required and therefore benzene was the
solvent employed in our further studies, see Scheme 3 and
Table 1.21
5
6: X = S
: X = O
7
R
O
PPh2
N
N
R
S
PPh2
O
S
8
9
1
: R = i-Pr
: R = t-Bu
1: R = Ph
10: R = t-Bu
12: R = i-Pr
O
[Pd(ligand)] 3 mol% Ph
base, benzene,
O
O
+ Ph
Figure 1
+
PhOTf
8
0 °C, 7d
In this letter, we wish to report the synthesis of a further
two examples of HETPHOX ligands (11, 12) and the ap-
1
(R)-2
(R)-3
plication of the thiophene- and benzothiophene-oxazoline Scheme 3
containing ligands 8–12 in the asymmetric phenylation
and cyclohexenylation of 2,3-dihydrofuran (1).
Table 1 Phenylation of 2,3-Dihydrofuran (1) with Palladium
Complexes of Ligands (8–12)
Entry
Ligand Base
Yield (%)a Ee (%)b
(3)
Synthesis of Ligands18
2
(R)-2 [(R)-3]
77 (nd)c
68 (nd)
75 (nd)
70 (nd)
89 (nd)
87 (nd)
43 (16)
27 (13)
33 (21)
81 (nd)
82 (nd)
78 (nd)
95 (nd)
91 (nd)
95 (nd)
1
2
3
4
5
6
7
8
9
11
11
11
8
i-Pr NH
66 (8)
62 (2)
48 (7)
46 (7)
23 (6)
33 (7)
8 (19)
8 (30)
7 (11)
17 (1)
18 (2)
57 (6)
90 (9)
72 (8)
97 (2)
The benzo[b]thiophene ligand 11 was prepared from ben-
zo[b]thiophene carboxylic acid which was transformed
into the 3-oxazoline using standard reactions conditions
2
Proton sponged
1
9
(
Scheme 2). The metalation of the benzo[b]thiophene-
Et N
3
oxazoline occurs in diethyl ether at –78 °C and after the
Et N
3
addition of Ph PCl the benzo[b]thiophene phosphino-ox-
2
azoline 11 was isolated in a good yield of 78%. In the case
of ligand 12 with a thiophene backbone, we started from
8
Proton sponge
8
i-Pr NH
2
2
-cyano thiophene, which was converted into the corre-
2
0
sponding thiophene-oxazoline as previously reported.
9
Et N
3
Selective metalation of thiophene-oxazoline in the 3-posi-
9
Proton sponge
tion followed by the addition of Ph PCl, afforded the de-
2
sired ligand 12 in a moderate yield of 34%, see Scheme 2.
9
i-Pr NH
2
1
1
0
1
12
12
12
10
10
10
Et N
3
Ph
Ph
Proton sponge
O
O
N
N
CO2H
12
i-Pr NH
2
a, b, c
1. n-BuLi
1
1
1
3
4
5
Et N
PPh2
3
2
. ClPPh2
S
S
S
Proton sponge
1
1
i-Pr NH
2
PPh2
a
Conversions by GC (SE-30, 30 m, 11 psi He).
d
1. n-BuLi
b
N
N
Enantiomeric excesses were determined by GC on a Chiraldex g-cy-
i-Pr
i-Pr
CN
2
. ClPPh2
S
S
S
clodextrin TFA capillary column (30 m × 0.25 m, 15 psi He); 80 °C,
O
O
–1 –1
0
.3 °C min up to 90 °C, 5 °C min up to 120 °C, [t = 31.80 (S) and
R
1
2
34.0 (R) min for 2 and t = 23.30 (S) and 24.6 (R) min for 3].
R
c
Enantiomeric excess not detected.
Scheme 2 a) SOCl ; b) (S)-phenylglycinol; c) MesCl, NaOH; d)
d
2
Proton sponge = 1,8-bis(dimethylamino)naphthalene.
ZnCl , (S)-valinol, chlorobenzene, reflux, 24 h.
2
Synlett 2004, No. 1, 106–110 © Thieme Stuttgart · New York

1
08
T. G. Kilroy et al.
LETTER
The catalyst derived from ligand 11, containing the phe- Asymmetric Cyclohexenylation of 2,3-Dihydrofuran
nyl-substituted oxazoline ring, gave consistently good (1)
yields ranging from 48–66% of the kinetic isomer 2. The
enantioselectivities were also good ranging from 68–77% The asymmetric cyclohexenylation of 2,3-dihydrofuran
(
entries 1–3). The i-Pr-substituted ligand 8 was found to (1) was also tested using palladium complexes of ligands
give lower yields (23–46%), although with higher ees of 9–12, see Scheme 4 and Table 2.
0–89% (entries 4–6). The use of diisopropylamine as
7
base gave the optimum result of 33% yield and 87% ee al-
though proton sponge gave a slightly higher ee of 89% but
a considerably lower yield of 23%. The bulky t-butyl sub-
stituted benzothiophene analogue 9 gave opposite regio-
selectivity in all cases, with the thermodynamic isomer 3
being favoured over 2 and the highest yield of the thermo-
dynamic isomer 3 was 30%. Moderate ees of regioisomer
OTf
O
[Pd(ligand)] 3 mol%
base, benzene,
O
O
+
+
8
0 °C, 7d
(R)-23
(R)-24
1
Scheme 4
[
7
(R)-3] were also obtained ranging from 13-21% (entries
–9). Interestingly, although lower yields of the kinetic
isomer 2 were seen, higher ees of 27–43% were obtained.
Table 2 Cyclohexenylation of 2,3-Dihydrofuran (1) with Palladium
Complexes of Ligands (9–12)
Yield (%)a Ee (%)b
(R)-23 [(R)-24]
These results are in contrast to those reported by Pfaltz, Entry Ligand Base
which showed increased reactivity and enantioselectivi-
ties with the ligand possessing the more bulky substituent.
The thiophene containing ligands 12 and 10 were also
tested for their enantiodifferentiating ability in the pheny-
lation of 2,3-dihydrofuran. Ligand 12, containing a
thiophene ring and an i-Pr substituted oxazoline ring, pro-
vided a catalyst, which gave moderate yields but quite
high enantioselectivities of between 78–82% (entries 10–
23 (24)
78 (10)
20 (29)
89 (5)
3 (49)
21 (26)
30 (41)
36 (9)
49 (4)
13 (5)
96 (4)
97 (3)
69 (3)
1
2
3
4
5
6
7
8
9
0
1
2
11
11
11
9
i-Pr NH
76 (nd)c
34 (20)
54 (nd)
nd (61)
61 (40)
55 (51)
55 (nd)
47 (nd)
50 (nd)
97 (nd)
95 (nd)
89 (nd)
2
Proton sponged
Et N
3
Et N
3
9
Proton sponge
1
2). The use of diisopropylamine as base again gave the
best yield (57%) for ligand 12 and a reasonable ee of 78%.
The other bases tested, triethylamine and proton sponge
gave slightly higher ees of 81% and 82%, but consider-
ably lower yields (17% and 18%) respectively. Reactions
using ligand 10 gave both good to excellent yields (up to
9
i-Pr NH
2
12
12
12
10
10
10
Et N
3
Proton sponge
i-Pr NH
9
9
7%) and high ees irrespective of base employed (up to
5%) in all cases (entries 13–15). Our optimal result used
2
1
1
1
Et N
3
diisopropylamine as the base with a palladium complex of
ligand 10 in benzene, providing (R)-2 in 97% yield with
excellent regioselectivity and in 95% ee in 7 days (entry
Proton sponge
i-Pr NH
2
1
5).
Of the benzothiophene-oxazoline containing ligands 8, 9,
1, reactions with ligand 11 were found to give the opti-
mum results with both good ees and yields, unlike those 0.3 °C min up to 90 °C, 5 °C min up to 120 °C, [t = 22.20 (S) and
a
Conversions by GC (SE-30, 30 m, 11 psi He).
Enantiomeric excesses were determined by GC on a Chiraldex g-cy-
b
1
clodextrin TFA capillary column (30 m × 0.25 m, 15 psi He); 80 °C,
–1
–1
R
with ligand 8, which, despite having been found to give 24.9 (R) min for 23 and t
= 18.0 (S) and 18.3 (R) min for 24].
Enantiomeric excess not detected.
Proton sponge = 1,8-bis(dimethylamino)naphthalene.
R
c
slightly higher ees, gave poorer yields. Complexes de-
rived from ligand 9, however, although expected to give
higher enantioselectivities, a feature noted from our work
d
with diphenylphosphinoferrocenyloxazoline ligands and Complexes derived from ligand 11 gave quite high yields
Pfaltz in his work with ligands 4, gave both poor yields (78% and 89%) in the cases where diisopropylamine and
and ees in the intermolecular asymmetric Heck reaction. triethylamine were used as base, respectively, although
Of the thiophene-oxazoline containing ligands 10 and 12, the ees obtained were reasonable (54% to 76%). An unex-
ligand 12 gave good yields and high ees but was out- pected result was obtained in the case where proton
performed by ligand 10, the optimal ligand overall, in all sponge was used as base in that the major regioisomer
cases.
formed was that of the thermodynamic isomer 24 in 29%
yield as opposed to 20% of the kinetic isomer 23 formed.
The ee of the major thermodynamic isomer 24 was found
to be quite low (20%) although interestingly a higher ee of
the minor regioisomer 23 was observed (34%, entry 2).
Application of ligand 9 proved again to give low yields
ranging from 26–9% of the thermodynamic regioisomer
Synlett 2004, No. 1, 106–110 © Thieme Stuttgart · New York

LETTER
4 but gave higher ees than for the corresponding phenyl-
ations in all cases (entries 4–6). Triethylamine was found
to be the base of choice, giving the highest ee and yield
with this particular ligand (49% yield of 24 and 61% ee,
entry 4).
The Application of HETPHOX Ligands
109
2
(7) Gilbertson, S. R.; Fu, Z.; Xie, D. Tetrahedron Lett. 2001, 42,
65.
8) Hashimoto, Y.; Horie, Y.; Hayashi, M.; Saigo, K.
Tetrahedron: Asymmetry 2000, 11, 2205.
9) Tu, T.; Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Dong, X.-C.
Chem.–Eur. J. 2003, 9, 3073.
3
(
(
(
(
10) Kilroy, T. G.; Hennessy, A. J.; Malone, Y. M.; Farrell, A.;
Guiry, P. J. J. Mol. Catal. A: Chem. 2003, 196, 65.
11) (a) Hennessy, A. J.; Malone, Y. M.; Farrell, A.; Guiry, P. J.
Tetrahedron Lett. 1999, 40, 9163. (b) Hennessy, A. J.;
Malone, Y. M.; Farrell, A.; Guiry, P. J. Tetrahedron Lett.
Using ligand 12, the highest yield of the major regioiso-
mer 23 was obtained with proton sponge as base of 49%
(
entry 8) but the highest ee obtained was using triethyl-
amine as base of 55% (entry 7). A substantial drop in yield
to 13% of 23 was observed when diisopropylamine was
used as base, although little effect was seen with the ee
2000, 41, 2261. (c) Hennessy, A. J.; Connolly, D. J.;
Malone, Y. M.; Farrell, A.; Guiry, P. J. Tetrahedron Lett.
2000, 41, 7757.
(
entry 9). Once again the ligand 10 gave the best results
with ees in the range 89–97% and yields 69–96% (entries
0–12). The optimum result with this ligand was using tri-
(12) (a) Kiely, D.; Guiry, P. J. Tetrahedron Lett. 2002, 43, 9545.
(b) Kiely, D.; Guiry, P. J. Tetrahedron Lett. 2003, 44, 7377.
1
(
(
13) Kündig, P. E.; Meier, P. Helv. Chim. Acta 1999, 82, 1360.
14) Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P.
Tetrahedron Lett. 2001, 42, 3045.
ethylamine as base and this gave (R)-2-cyclohex-1¢-en-1¢-
yl-2,5-dihydrofuran (23) in 96% yield and 97% ee after 7
days (entry 10).
(
15) (a) Tietze, L. F.; Thede, K.; Sannicolò, F. Chem. Commun.
1
999, 1811. (b) Tietze, L. F.; Thede, K. Synlett 2000, 1470.
In conclusion, we have prepared two new HETPHOX
ligands (11, 12) and applied a series of thiophene- and
benzothiophene-oxazoline containing ligands in the inter-
molecular asymmetric Heck phenylation and cyclohex-
enylation of 2,3-dihydrofuran (1). Although most ligands
performed satisfactorily in this transformation, ligand 10
was the ligand of choice, giving the highest yields, regio-
selectivities and enantioselectivities, irrespective of the
base employed. Further studies are now in progress with
other substrates using these ligands and the results of
these investigations will be reported in due course.22
(
(
(
16) Tietze, L. F.; Lohmann, J. K. Synlett 2002, 2083.
17) Cozzi, P. G.; Menges, F.; Kaiser, S. Synlett 2003, 833.
18) Typical Experimental Procedure for the Preparation of
2-(2-Diphenylphosphino)-benzo[b]thiophene-3-yl-4S-
phenyl-4,5-dihydrooxazole (11).
To a solution of the benzo[b]thiophene-oxazoline (1.0 g,
3.58 mmol) in Et O (10 mL) at –78 °C a solution of 1.6 M
2
BuLi in hexane (2.3 mL, 3.70 mmol) were added and the
resulting suspension was agitated at –78 °C for 1 h and 30
min. Diphenylchlorophosphine (0.62 mL, 3.36 mmol) was
added at –78 °C and the reaction mixture was warmed at r.t.
and stirred for 30 min. The reaction was quenched by adding
pentane (40 mL) and H O (30 mL). The organic phase was
2
separated and dried over Na SO and purified by chromato-
2
4
Acknowledgement
graphy (hexane:Et O, 9:1). Yield 78%; [a] –5.4 (c 0.92,
2
D
1
CHCl ). H NMR (300 MHz, CDCl ): d = 3.96 (dd, 1 H,
J = 8.3, 8.8 Hz), 4.56 (dd, 1 H, J = 8.3, 10.3 Hz), 5.34 (dd, 1
H, J = 8.8, 10.3 Hz), 7.04–7.09 (m, 2 H), 7.22–7.52 (m, 15
T. G. K. thanks Enterprise Ireland for the award of a Research
Scholarship (BR/99/240) and Merck Sharp and Dohme (Ireland) for
their support of our asymmetric Heck research.
3
3
1
3
H), 7.58–7.72 (m, 1 H), 8.60–8.66 (m, 1 H). C NMR (75
MHz, CDCl ): d = 70.1, 74.1, 121.7, 125.0, 125.1, 125.3,
3
References
126.9, 127.5, 127.8, 128.7, 128.8 (d, J = 7.7 Hz), 129.6 (d,
J = 10.9 Hz), 133.9 (d, J = 21.3 Hz), 134.3 (d, J = 21.3 Hz),
(
1) For extensive reviews of the Heck reaction see: (a) Heck,
R. F. Acc. Chem. Res. 1979, 146. (b) De Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 28, 2379.
1
37.0 (J = 20.6 Hz), 137.2 (d, J = 16.6 Hz), 139.8, 142.0,
31
142.6, 148.9 (d, J = 42.8 Hz), 161.3. P (124 MHz, CDCl ):
3
+
d = –12.4. MS (EI): m/z (%) = 463 (4) [M ], 358 (100), 296
(
(
c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
d) Guiry, P. J.; Hennessy, A. J.; Cahill, J. P. Top. Catal.
(
12) and 239 (18).
Typical Experimental Procedure for the Preparation of
1997, 4, 311. (e) Jeffrey, T. Advances in Metal-Organic
4-iso-Propyl-2-(3-diphenylphosphino-thiophene-2-yl)-
Chemistry, Vol 5; JAI Press Inc.: Conneticut, 1996, 153.
2) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett. 1992,
4,5-dihydrooxazole (12).
(
(
Thiophene-2-oxazoline (0.418 g, 2.14 mmol) was dissolved
33, 1485.
in Et O (5 mL) and the resultant solution was cooled at –78
2
3) (a) Hennessy, A. J.; Malone, Y. M.; Guiry, P. J. Tetrahedron
Lett. 2000, 41, 2261. (b) Ozawa, F.; Kubo, A.; Matsumoto,
Y.; Hayashi, T. Organometallics 1993, 12, 4188.
°
C. A solution of 2.5 M n-BuLi in hexane (1.6 mL, 4 mmol)
was added dropwise and the yellow solution was stirred at
78 °C for 30 min. The reaction was warmed up at 0 °C and
–
(
c) Tschoerner, M.; Pregosin, P. S.; Albinati, A.
stirred at this temperature for 30 min. The yellow-green
Organometallics 1999, 18, 670. (d) Tietze, L. F.; Thede, K.;
Sannicolò, F. Chem. Commun. 1999, 1811. (e) Cho, S. Y.;
Shibisaki, M. Tetrahedron Lett. 1998, 39, 1773.
solution was finally cooled to –78 °C then ClPPh (0.74 mL,
2
4
mmol) was added. The reaction was allowed to warm to r.t.
during 20 h and then quenched with H O. The phases were
2
(
f) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A.
separated and the aqueous phase was extracted with Et O
2
Synthesis 1997, 1338. (g) Ozawa, F.; Kobatake, Y.;
Hayashi, T. Tetrahedron Lett. 1993, 34, 2505. (h) Ozawa,
F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267.
4) Loiseleur, O.; Meier, O.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 200.
(
2 × 5 mL) the the organic phases were combined, dried over
Na SO and evaporated under reduced pressure to give an oil
then was purified by chromatography (cyclohexane: Et O,
9
2
4
2
(
:1) to give a clear oil that slowly turned into a waxy white
1
solid, yield 34%; [a] –99.0 (c 0.99, CHCl ). H NMR (300
D
3
(
(
5) Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161.
6) Gilbertson, S. R.; Xie, D.; Fu, Z. J. Org. Chem. 2001, 66,
MHz, CDCl ): d = 0.71 (d, 1 H, J = 6.6 Hz), 0.74 (d, 3 H,
3
J = 6.6 Hz), 1.6 (m, 1 H), 3.92 (q, 1 H, J = 7.8 Hz), 4.02 (q,
7420.
Synlett 2004, No. 1, 106–110 © Thieme Stuttgart · New York

1
10
T. G. Kilroy et al.
LETTER
1
H, J = 7.8 Hz), 4.22 (dt, 1 H, J = 7.8, 1.8 Hz), 6.38 (dd, 1
mmol) and n-tridecane (10.0 mg, 0.054 mmol) in benzene
1
3
H, J = 5.2, 0.8 Hz), 7.40–7.30 (m, 11 H). C NMR (75 MHz,
(0.5 mL) was added to a schlenk containing Pd (dba) (2.3
2
3
CDCl ): d = 17.10, 17.78, 31.86, 71.61, 126.20, 127.41,
mg, 0.004 mmol) and ligand (0.008 mmol) under nitrogen.
To this was then added the 2,3-dihydrofuran (0.65 mmol)
and base (0.39 mmol). The resulting solution was then
degassed by three freeze-thaw cycles at 0.01 mbar and then
left to stir under nitrogen at 80 °C for 7 d giving a red
solution with precipitation of Base·HOTf. Pentane (10 mL)
was then added to the reaction mixture and the resulting
suspension was filtered through 2 cm of silica with further
3
1
27.17 (d, J = 13 Hz), 126.60 (d, J = 6 Hz), 132.10, 132.11
(
d, J = 23.4 Hz), 132.50 (d, J = 20.8 Hz), 136.15 (d, J = 10.3
Hz), 137 (d, J = 11.8 Hz), 140.00 (d, J = 27 Hz), 157.11 (d,
J = 3.5 Hz). 31P NMR (124 MHz, CHCl ): d = –13.15. MS
3
+
(
EI): m/z (%) = 379 (2) [M ], 364 (4), 336 (19), 308 (100),
288 (53), 234 (9) and 89 (18).
(
19) (a) Della Vecchia, L.; Vlattas, I. J. Org. Chem. 1977, 42,
2649. (b) Ennis, D. S.; Gilchrist, T. L. Tetrahedron 1990, 46,
elution using Et O (10 mL). This solution was then
2
2
623.
concentrated and the yield calculated using GC (Se-30, 11
psi, 50 °C, 4 min, 15 °C/min, 170 °C, 10 min) by the internal
standard method.
(
(
20) Frost, C. G.; Williams, J. M. J. Tetrahedron Lett. 1993, 34,
015.
2
21) Typical Experimental Procedure for the Asymmetric
Heck Reaction.
(22) Kilroy, T. G.; End, N.; Cozzi, P. G.; Guiry, P. J. unpublished
results.
A solution of aryl or alkenyl trifluoromethanesulfonate (0.13
Synlett 2004, No. 1, 106–110 © Thieme Stuttgart · New York