Application of 3,3′-disubstituted xylBINAP derivatives in inter- and intramolecular asymmetric Heck/Mizoroki reactions

Article abstract of DOI:10.1016/j.tetlet.2010.08.078

3,3′-Disubstituted xylBINAP derivatives were applied to inter- and intramolecular asymmetric Heck/Mizoroki reactions. The results from these reactions were compared to those obtained with (R)-xylBINAP, (S)-BINAP and 3,3′-disubstituted BINAP derivatives. C

Full text of DOI:10.1016/j.tetlet.2010.08.078

Tetrahedron Letters 51 (2010) 5724–5727
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of 3,30-disubstituted xylBINAP derivatives in inter-
and intramolecular asymmetric Heck/Mizoroki reactions
⇑
Danica A. Rankic, Daniela Lucciola, Brian A. Keay
Department of Chemistry, University of Calgary, 2500 University Drive NW Calgary, Alberta, Canada T2N 1N4
a r t i c l e i n f o
a b s t r a c t
3,30-Disubstituted xylBINAP derivatives were applied to inter- and intramolecular asymmetric Heck/
Mizoroki reactions. The results from these reactions were compared to those obtained with (R)-xylBINAP,
(S)-BINAP and 3,30-disubstituted BINAP derivatives. Catalysts derived from 3,30-disubstituted xylBINAP
ligands were found to be most effective in the arylation of 2,3-dihydrofuran in terms of reaction times,
conversions, and product enantioselectivity.
Article history:
Received 9 July 2010
Revised 20 August 2010
Accepted 24 August 2010
Available online 31 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heck/Mizoroki reactions
Polyene cyclization
BINAP
3,30-Disubstitution
3,5-Dialkyl meta effect
The modification of BINAP can be used to improve the enanti-
oselectivity of some asymmetric reactions.1–3 Notably, 3,30-disub-
stituted BINAP and xylBINAP ligands (Chart 1) have been shown
to afford superior enantioselectivities in the Rh-catalyzed hydroge-
nation of dehydroamino acids.2,3 Recently, our group showcased
the effects of 3,30-disubstitution of BINAP in inter- and intramolec-
ular Heck/Mizoroki reactions.4 In certain cases, both reversal in the
absolute enantiosense of product and enhancements in product
enantioselectivities were observed. In this report, we disclose an
extension of this work by utilizing 3,30-disubstituted xylBINAP
derivatives (2b–e) in inter- and intramolecular Heck/Mizoroki
reactions with the aim of assessing how combining 3,30-disubstitu-
tion with the 3,5-dialkyl meta effect5,6 influences the enantioselec-
tivity of these reactions.
BINAP series
xylBINAP series
R
R
PPh2
PPh2
Pxyl2
Pxyl2
R
1a R = H (BINAP)
1b R = OMe
1c R = OiPr
R
2a R = H (xylBINAP)
(Rax)-2b R = ONp*
ONp* =
O
(Sax)-2c R = ONp*
2d R = OiPr
1d R = OBn
1e R = OPiv
2e R = OPiv
OMe
Chart 1. 3,30-Disubstituted BINAP and xylBINAP derivatives.
The first reaction that we investigated was the cyclization of aryl
triflate 3 to polycycle 4, involving two consecutive Heck/Mizoroki
cyclizations. Hopkins et al. demonstrated that substituting the 3
and 30 positions of BINAP did not result in any improvements with
regard to enantioselectivity in the cyclization of triflate 3.4 The best
enantioselectivity obtained was with (S)-3,30-(OiPr)2-BINAP (1c),
which gave the cyclization adduct (R)-4 in 74% ee (Table 1, entry
3). Note that an enantiosense switch was observed upon installation
of groups in the 3,30-positions of BINAP; (S)-BINAP provided (R)-
product whereas (S)-3,30-substituted BINAP ligands provided (S)-
product. This enantiosense reversal has also been observed when
certain 3,30-disubstituted MeO-BIPHEP ligands have been utilized
in the cyclization of triflate 3 to polycycle 4.7,8 The OMe- and OPiv-
substituted BINAP ligands 2b and 2e performed quite poorly in this
reaction, affording tetracycle 4 in 0% and 14% ee, respectively (en-
tries 2 and 4).
When (R)-xylBINAP (2a) was used in the polyene cyclization of 3,
the enantiomeric excess of the product 4 was reduced by approxi-
mately 40% in comparison with (S)-BINAP, representative of a
strongly negative3,5-dialkyl meta effect9,10 (Table 1, entry 1 vs entry
6). However, the use of a BINAP ligand containing P-xylyl groups in-
stead of P-phenyl groups did not result in a reversal of product enan-
tiosense; product (R)-4 was obtained from (R)-xylBINAP. This is in
contrast to what was observed when xylBINAP was used in the
hydrogenation of dehydroamino acid derivatives.3
The use of 3,30-disubstituted xylBINAP ligands in the cyclization
of 3 to 4 led to slight improvements in selectivity over those ob-
served with xylBINAP. However, the high enantioselectivities seen
with (S)-BINAP and 3,30-disubstituted BINAP ligand 1c were not
⇑
Corresponding author. Tel.: +1 403 220 3293; fax: +1 403 289 9488.
E-mail address: keay@ucalgary.ca (B.A. Keay).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.078

D. A. Rankic et al. / Tetrahedron Letters 51 (2010) 5724–5727
5725
Table 1
Table 2
Asymmetric Pd-catalyzed intramolecular Heck/Mizoroki cyclization of polyene 3 to
tetracycle 4
Asymmetric Pd-catalyzed intramolecular Heck/Mizoroki reaction of iodoaniline 5 to
3,30-spirooxindoles 6a and 6b
Me
Pd2dba3 (5 mol%)
PMP, ligand (20 mol%)
O
N
OTf
O
O
toluene, 110 ºC
48 h
O
Me
Pd2dba3 (5 mol%)
O
N
O
6a
ligand (10 mol%)
I
3
4
PMP, DMA, 110 ºC
Entrya
Series
BINAP
Ligand
3,30-Group
Yield (%)
%ee (config)b
Me
18 h
O
1c
2c
3c
4
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
H
88
0
93
84
73
72 (S)
—
74 (R)
46 (R)
14 (R)
N
5
OMe
OiPr
OBn
OPiv
5c
6b
Entrya
Series
Ligand
3,30-Group
6a:6b
%ee (config)b
6
7
8
9
xylBINAP
(R)-2a
H
42
90
77
88
28 (R)
29 (S)
47 (R)
40 (S)
*
*
(Rax)-2b
(Sax)-2c
(R)-2d
ONp
ONp
OiPr
1
2
3
4
5
BINAPc
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
H
1.1:1
2.6:1
2.0:1
1.2:1
1.4:1
84 (S)
11 (R)
19 (R)
12 (R)
1 (S)
OMe
OiPr
OBn
OPiv
a
All catalysts were generated in situ by premixing Pd2dba3 and ligand for 30 min
at rt in toluene.
b
Measured by HPLC (9:1 hexanes/iPrOH, 1.0 mL/min, Chiralcel OD column).
Obtained from Ref. 4 for the purposes of comparison.
6
7
8
9
xylBINAP
(R)-2a
H
1.5:1
1.2:1
1:1.6
1:1.5
28 (R)
10 (S)
2 (S)
c
*
*
(Rax)-2b
(Sax)-2c
(R)-2d
ONp
ONp
OiPr
8 (S)
a
All catalysts were generated in situ by premixing Pd2dba3 and ligand for 30 min
achieved with this series of ligands. Ligand (Sax)-2c outperformed
all others in the xylBINAP series, providing tetracycle (R)-4 in
47% ee (Table 1, entry 8). Related diphosphine (Rax)-2b provided
the product in an enantioselectivity comparable to (R)-xyBINAP
(entries 6 and 7). Tetracycle 4 was generated in 40% ee when (R)-
3,30-(OiPr)2-xylBINAP (2d) was used, representing a reduction in
enantiomeric excess in comparison with its BINAP counterpart
(S)-1c (entry 3 vs entry 9). This indicated that the effects from
3,30-disubstitution and the 3,5-dialkyl meta effect are not cooper-
ative in the case of the Heck/Mizoroki cyclization of 3 to 4. The
attenuation of enantioselectivity when either 3,30-disubstitution
or P-xylyl groups are present on a BINAP ligand may be due to a
weak interaction between the metal and substrate due to the
excessive steric bulk present in the catalytic pocket.11
at 60 °C in DMA.
b
Measured by HPLC (9:1 hexanes/iPrOH, 1.0 mL/min, Chiralcel OD column).
Obtained from Ref. 4 for the purposes of comparison.
c
afforded spirocycles (S)-6 in 10% ee, demonstrating the same enan-
tiosense reversal observed in the cases of 3,30-disubstituted BINAP
ligands 1b–d. The diastereomer of (Rax)-2b, (Sax)-2c, afforded race-
mic product and OiPr-substituted xylBINAP (R)-2d gave (S)-prod-
uct 6 in 8% ee. This represents less than half the product ee that
was afforded by the related 3,30-disubstituted BINAP (R)-1c. Inter-
estingly, (Sax)-2c and (R)-2d caused the ratio of the double bond
isomers to switch, in favor of isomer 6b.
When a catalyst derived from (S)-BINAP and Pd2dba3 was used
to promote the cyclization of iodoaniline 5, developed by Overman
and co-workers,12 products 6 were obtained in 84% ee, as predom-
inantly the (S)-enantiomer (Table 2, entry 1). Moreover, cyclization
products 6 were isolated as a mixture of double bond isomers in a
1.1:1 ratio, as measured by HPLC.4 The substitution of the 3 and 30
positions of BINAP was not found to be an effective strategy for
increasing the enantioselectivity of the cyclization of 5. The best
result for the substituted BINAP ligands was obtained with OiPr-
substituted BINAP ligand (S)-1c, which provided the product (R)-
6 in 18.9% ee (entry 3). In all cases but one, (S)-3,30-disubstituted
BINAP derivatives provided spirocycles 6 in the opposite configura-
tion than that provided by (S)-BINAP; (S)-BINAP provided (S)-prod-
uct and (S)-3,30-disubstituted BINAP ligands provided (R)-product
(entries 2–4).
The intermolecular arylation of 2,3-dihydrofuran (7) catalyzed
by a Pd/(S)-BINAP catalyst system afforded phenyl-substituted
dihydrofurans 9 and 10 in a 91:9 ratio and in 32% conversion
(Table 3, entry 1).4 Phenylated dihydrofuran 9 was produced as
predominantly the (S)-enantiomer in 66% ee. Its double bond iso-
mer 10 was determined to be enriched in the (R)-enantiomer with
57% ee. The configurations of products 9 and 10 obtained with 3,30-
disubstituted BINAP derivatives 1b–e were consistent with the
product configurations obtained with (S)-BINAP. Hopkins et al.
found that product ratios also improved upon 3,30-disubstitution
of the BINAP scaffold, with ligands 1b–e providing anywhere from
96:4 up to 99:1 ratios of 9 to 10.4 In two instances, 3,30-disubstitu-
tion also improved the enantioselectivity of the major product 9.
OiPr- and OPiv-substituted BINAP derivatives 1c and 1e gave ary-
lated dihydrofuran 9 in 73% ee and 80% ee, respectively (entries
3 and 5). Isomer 10, however, was produced in a much lower ee
in reactions involving 1c and 1e than with the parent BINAP.
The use of a Pd/(S)-xylBINAP catalyst system resulted in a drastic
change in product ratios in comparison with (S)-BINAP (Table 1, en-
try 6). (S)-BINAP provided the mixture of arylated dihydrofurans 9
and 10 in a 91:9 ratio but using (S)-xylBINAP changed this ratio to
66:34. Interestingly, the ee of isomer 9 decreased considerably in
comparison with the BINAP system, yet isomer 10 was produced
with greater enantiomeric excess (83%). The stereochemical
preference was maintained for both isomers. In other words
2,3-dihydrofuran 9 was produced predominantly as the (S)-enantio-
mer and 3,4-dihydrofuran 10 were produced predominantly as the
Although 3,30-disubstitution of the BINAP skeleton failed to im-
prove the enantioselectivity of this cyclization, it did succeed in
increasing the preference for one double bond isomer over the
other. The best ratio was obtained with OMe-disubstituted BINAP
1b, which afforded a 2.6:1 ratio of double bond isomers, bettering
the 1.1:1 ratio obtained with BINAP (entry 2).4
All ligands belonging to the xylBINAP series failed to surpass
BINAP in the Pd-catalyzed cyclization of iodoanilide 5 to form spi-
rooxindoles 6. Parent ligand (R)-xylBINAP outperformed all 3,30-
disubstituted xylBINAP ligands, affording product (R)-6 in 28% ee
as a 1.5:1 mixture of double bond isomers (Table 2, entry 6).
Naproxen ether-substituted 3,30-disubstituted xylBINAP (Rax)-2b

5726
D. A. Rankic et al. / Tetrahedron Letters 51 (2010) 5724–5727
Table 3
Asymmetric Pd-catalyzed intermolecular arylation of 2,3-dihydrofuran (7) with phenyltriflate (8)
Pd(OAc)2 (3 mol%)
ligand (6 mol%)
OTf
Ph
Ph
O
O
O
DIPEA, benzene
40 ºC, 24 h
7
8
9
10
Entrya
Series
Ligand
3,30-Substituent
Conversion (%)
Product ratio (%ee, config)b
9
10
1
2
3
4
5
BINAPc
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
H
32
56
100
100
68
91 (66, S)
99 (7, S)
99 (73, S)
97 (40, S)
96 (80, S)
9 (57, R)
1 (22, R)
1 (2, R)
3 (16, R)
4 (16, R)
OMe
OiPr
OBn
OPiv
6
7
8
9
xylBINAP
(S)-2a
H
100
100
100
100
66 (21, S)
98 (90, R)
98.5 (>99, S)
99 (83, R)
34 (83, R)
2 (45, R)
1.5 (77, S)
1 (6, S)
(Rax)-2b
(Sax)-2c
(R)-2d
ONp*
ONp*
OiPr
a
b
c
All catalysts were generated in situ by premixing Pd(OAc)2 and ligand for 30 min at rt in benzene.
Measured by chiral GC (80 °C for 2 min, increase 1 °C/min for 38 min. Cyclodex-B column).
Obtained from Ref. 4 for the purposes of comparison.
(R)-enantiomer.Upon substitution of the 3 and 30 positions of xylB-
INAP, improvements in both product ratio and enantioselectivities
were achieved (Table 3, entries 7–9). The OiPr-substituted xylBINAP
2d outperformed its BINAP counterpart 1c, affording product 9 in
83% ee instead of 73% ee, however the product ratios and enantiose-
lectivity of product 10 were comparable between the two ligands
(entry 9). This seemed to indicate that the effects of 3,30-disubstitu-
tion and the 3,5-dialkyl meta effect operate synergistically in the
case of ligand 2d and for this reaction type. The most impressive re-
sults were obtained with diastereomeric ligands (Rax)-2b and (Sax)-
2c. Both afforded product 9 nearly exclusively (98:2 ratio of 9 to
10). Moreover, catalysts based on these ligands afforded the highest
ee’s for any 3,30-disubstituted BINAP or xylBINAP ligands. (Rax)-2b
gave arylated 2,3-dihydrofuran (R)-9 in 90% ee and (Sax)-2c provided
product (S)-9 in >99% ee (S) (entries 7 and 8). Note that 3,4-dihydro-
furan arylation product 10 was also produced with the same sense of
chirality as the configuration of the ligand used in both cases, with
moderate enantioselectivities of 45% ee and 77% ee obtained using
(Rax)-2b and (Sax)-2c, respectively.
The fact that arylation products 9 and 10 were produced with
same absolute configuration when ligands (Rax)-2b and (Sax)-2c
were utilized in the Pd-catalyzed arylation of 2,3-dihydrofuran
provides important mechanistic insight into the intermolecular
Heck/Mizoroki arylation of 2,3-dihydrofuran (7). Although not well
understood, it was originally proposed that the mechanism of this
intermolecular Heck/Mizoroki reaction proceeds via a kinetic reso-
lution.13 The evidence for this was a connection between the prod-
uct ratio and enantiomeric purity of 9. Hayashi and co-workers
observed that as the ratio of 10 to 9 increased, the enantiomeric ex-
cess of 9 increased as well. Their best results for the enantioselec-
tivity of 9 were obtained when Pd(OAc)2 was used as a precatalyst
and Proton Sponge™ was used as a base instead of DIPEA. They re-
ceived a 9:10 ratio of 71:29 with 9 being produced in >96% ee and
10 being produced in 17% ee after a reaction time of 216 h (9 days).
They postulated that if the coordination of 2,3-dihydrofuran (7) to
the Pd/(S)-BINAP catalyst after oxidative addition of phenyl triflate
(8) occurred via the pro-S face, the resulting metal alkyl was capa-
ble of undergoing a b-hydride elimination/re-insertion/b-hydride
elimination sequence to produce 9. Conversely, they thought that
if coordination of 2,3-dihydrofuran occurred via the pro-R face of
the olefin, the migratory insertion product underwent a single, fac-
ile b-hydride elimination to eject (R)-product 10. This explanation
accounted for why arylated dihydrofuran 9 was always produced
with the (S)-configuration and 10 was always produced with the
(R)-configuration when (S)-BINAP was used as a ligand in this
reaction.
In our study, when diastereomeric 3,30-disubstitutedxylBINAPli-
gands (Rax)-2b and (Sax)-2c were used, the absolute configuration of
the chiral axis was directly transferred to both the arylated products,
compounds 9 and 10. Moreover, high enantiomeric excesses of
product 9 could be accessed even when minute amounts of the min-
or isomer 10 were produced. These two pieces of evidence appear to
contradict the kinetic resolution argument put forth by Hayashi and
co-workers. We are currently investigating this phenomenon and
the results will be reported in a subsequent publication.
In conclusion, we have demonstrated that the incorporation of
3,5-(dimethylphenyl) groups on phosphorus in combination with
3,30-substituents on the BINAP framework was not beneficial for
intramolecular Heck/Mizoroki reactions. However, when an inter-
molecular Heck/Mizoroki reaction was performed, that is, the ary-
lation of 2,3-dihydrofuran, superior ee’s, and conversions were
observed in comparison with 3,30-disubstituted BINAPs and the
parent BINAP. Most notably we observed an interesting phenome-
non when diastereomeric 3,30-diastereomeric xylBINAP ligands
(Rax)-2b and (Sax)-2c were utilized. With these ligands, we found
that this reaction proceeded with high enantioselectivity and high
specificity for the major isomer 9, even with comparatively shorter
reaction times than those reported by Hiyashi and co-workers13
(24 h vs 216 h, vide supra). The small amount of isomer 10 that
was generated was found to be of the same configuration as isomer
9, which is in contrast to what was previously observed with BIN-
AP. This suggests that the Heck/Mizoroki reaction might not pro-
ceed via a kinetic resolution when (Rax)-2b and (Sax)-2c are used
as ligands for the arylation of 2,3-dihydrofuran. We propose that
this might be due to an interaction between the naproxen ether
substituents and the aryl triflate upon oxidative addition. We have
evidence for a similar interaction in the Rh-catalyzed asymmetric
hydrogenations of dehydroamino acids which will be reported
elsewhere in due course.
Acknowledgments
The University of Calgary and the Natural Science and Engineer-
ing Council of Canada (NSERC) are thanked for funding. D.A.R. and
D.L. authors thank both NSERC and Alberta Ingenuity Fund for stu-
dentships. Thanks are also extended to Professor Warren Piers for
use of his chiral HPLC.

D. A. Rankic et al. / Tetrahedron Letters 51 (2010) 5724–5727
5727
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Supplementary data associated with this article can be found, in
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