Chiral Benzoquinones as a New Class of Ligands for Asymmetric Catalysis: Synthesis and Application to the Palladium(II)-Catalyzed 1,4-Dialkoxylation of 1,3-Dienes

Article abstract of DOI:10.1021/jo980561x

Chiral C₂-symmetric 2,5-bisamide hydroquinone ligands, with β-amino alcohols as chiral building units, were synthesized in excellent overall yields. The ligands gave up to 54.4% ee in the palladium-catalyzed 1,4-dialkoxylation of 1,3-dienes. These findings demonstrate the potential of asymmetric induction utilizing chiral benzoquinones as ligands in palladium(II) catalysis, albeit with modest enantiomeric excesses. Weakly coordinating hydroxyl groups of the ligand appear to be crucial for the success of the reaction. Mechanistic aspects and the origin of enantioselectivity are also discussed.

Full text of DOI:10.1021/jo980561x

6466
J . Org. Chem. 1998, 63, 6466-6471
Ch ir a l Ben zoqu in on es a s a New Cla ss of Liga n d s for Asym m etr ic
Ca ta lysis: Syn th esis a n d Ap p lica tion to th e
P a lla d iu m (II)-Ca ta lyzed 1,4-Dia lk oxyla tion of 1,3-Dien es
Kenichiro Itami, Andreas Palmgren,† Atli Thorarensen, and J an-E. Ba¨ckvall*,†
Department of Organic Chemistry, University of Uppsala, Box 531, SE-751 21 Uppsala, Sweden, and
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
Received March 26, 1998
Chiral C2-symmetric 2,5-bisamide hydroquinone ligands, with â-amino alcohols as chiral building
units, were synthesized in excellent overall yields. The ligands gave up to 54.4% ee in the palladium-
catalyzed 1,4-dialkoxylation of 1,3-dienes. These findings demonstrate the potential of asymmetric
induction utilizing chiral benzoquinones as ligands in palladium(II) catalysis, albeit with modest
enantiomeric excesses. Weakly coordinating hydroxyl groups of the ligand appear to be crucial for
the success of the reaction. Mechanistic aspects and the origin of enantioselectivity are also
discussed.
In tr od u ction
asymmetric reactions, the most desirable and the most
challenging is catalytic asymmetric synthesis. Therefore,
new types of chiral ligands were called for in order to
realize a catalytic asymmetric 1,4-oxidation of 1,3-dienes.
Since p-benzoquinone is known to be an essential ligand
for inducing nucleophilic attack3,5 in the palladium(II)-
catalyzed 1,4-oxidations of 1,3-dienes, chiral benzoquino-
nes are potential ligands in the asymmetric version of
these reactions.6
We have recently reported our preliminary results7 on
the palladium(II)-catalyzed asymmetric 1,4-diacetoxyla-
tion of 2-phenyl-1,3-cyclohexadiene, utilizing chiral sul-
foxide and amide-substituted benzoquinones as ligands,
which indicated that a coordinating group in the side
chain of the benzoquinone is required. Since amides are
known to be good ligands to palladium(II),8 we decided
to explore the use of 1,4-benzoquinones with chiral
amides in the 2- and 5-positions. In this paper, we report
on a general methodology for the synthesis of chiral C2-
symmetric 2,5-bis-amide hydroquinone ligands and our
preliminary results on the use of these ligands in the
palladium(II)-catalyzed asymmetric 1,4-dialkoxylation of
1,3-dienes.
The molecular design of enantiomerically pure chiral
auxiliaries and ligands for use in asymmetric reactions
is arguably one of the most important issues in modern
organic chemistry.1 Chiral ligands with phosphine and
nitrogen functionalities constitute successful classes of
compounds for achieving a high degree of asymmetric
induction.2 However, there are transition metal-cata-
lyzed reactions where the ordinary chiral ligands cannot
be used because of their low catalytic activity toward a
desired reaction pathway. For example, the 1,4-oxida-
tions of 1,3-dienes catalyzed by the palladium(II)-
benzoquinone system (eq 1) developed in our laboratory
are among such reactions.3 Although a number of
natural products were synthesized using this methodol-
ogy, we had to rely on an enzymatic transformation to
make enantiomerically enriched final products.4 Among
Resu lt a n d Discu ssion
A. Syn t h esis of Ch ir a l C2-Sym m et r ic 2,5-Bis-
a m id e Hyd r oqu in on e Liga n d s. Chiral benzoquinones
of general motive were designed where the use of chiral
2,5-bis-amide units would create the C2 symmetry, and
in addition, the chiral portion of the ligands could be
easily varied by appropriate choice of â-amino alcohols
(Figure 1). The advantage of using â-amino alcohols as
chiral building units is apparent, as they are readily
† Current address: Stockholm University.
(1) (a) Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asym-
metric Synthesis; J ohn Wiley and Sons: New York, 1995. (b) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; J ohn Wiley and Sons:
New York, 1994. (c) Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH Publishers: New York, 1993.
(2) For a review: Brunner, H. Top Stereochem. 1988, 18, 129.
(3) (a) Ba¨ckvall, J . E. Palladium-Catalyzed 1,4-Additions to Conju-
gated Dienes. Review in Metal-catalyzed Cross Coupling Reactions;
Stang, P., Diederich, F., Eds.; Wiley-VCH: Weinheim, 1998; pp 339-
385. (b) Ba¨ckvall, J . E.; Bystro¨m, S. E.; Norberg, R. E. J . Org. Chem.
1984, 49, 4619.
(4) (a) Ba¨ckvall, J . E.; Tanner, D. Palladium-mediated synthesis of
alkaloids. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1995; Vol. 16, pp 415-452. (b) Andersson,
P. G.; Ba¨ckvall, J . E. Synthesis of heterocyclic natural products via
regio- and stereocontrolled palladium-catalyzed reactions. In Advances
in Heterocyclic Natural Product Synthesis; Pearson, W. H., Ed.; J AI
Press: Greenwich, CT, 1996; Vol. 3, pp 179-215. (c) Ba¨ckvall, J . E.;
Gatti, R.; Schink, H. E. Synthesis 1993, 343.
(5) Grennberg, H.; Gogoll, A.; Ba¨ckvall, J . E. J . Org. Chem. 1991,
56, 5808.
(6) Review on chiral ligand acceleration: Berrisford, D. J .; Bolm,
C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.
(7) Thorarensen, A.; Palmgren, A.; Itami, K.; Ba¨ckvall, J . E.
Tetrahedron Lett. 1997, 38, 8541.
(8) (a) Sigel, H.; Martin, R. B. Chem. Rev. 1982, 82, 385. (b) Conti,
F.; Donati, M.; Pregaglia, G. F.; Ugo, R. J . Organomet. Chem. 1971,
30, 421.
S0022-3263(98)00561-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

Palladium(II)-Catalyzed 1,4-Dialkoxylation of 1,3-Dienes
J . Org. Chem., Vol. 63, No. 19, 1998 6467
removed by basic hydrolysis with LiOH in THF, and the
bis acid 417 was isolated in 91% yield as a tan solid.
The bis acid 4 was utilized as a common intermediate
for the preparation of all the ligands. Syntheses of the
desired chiral C2-symmetric 2,5-bis-amide hydroquinone
ligands are depicted in Table 1. The bis acid chloride
generated by refluxing the bis acid 4 in SOCl2 was
allowed to react with the appropriate amino alcohol to
give the allyl-protected 2,5-bis-amide hydroquinones 5 in
excellent yields. The allyl group was subsequently
removed by the Pd(PPh3)4/NaBH4 system18 to give the
chiral C2-symmetric 2,5-bis-amide hydroquinones 6a -f
in good overall yields. In the present study, the in situ
oxidation of hydroquinones 6 to the corresponding C2-
symmetric chiral benzoquinones by molecular oxygen,
activated by iron phthalocyanine (Fe(Pc)),5,7,19 was em-
ployed. This allows the use of hydroquinone ligands 6
in catalytic amounts in the 1,4-oxidation of 1,3-dienes.
F igu r e 1. Symmetric 2,5-bisamide benzoquinone ligands.
Sch em e 1
B. P a lla d iu m (II)-Ca ta lyzed Asym m etr ic 1,4-Di-
a lk oxyla tion of 1,3-Dien es. An evaluation of ligand
architecture was done by application to the palladium-
(II)-catalyzed 1,4-dialkoxylation20 of 2-phenyl-1,3-cyclo-
hexadiene 7. The reactions were carried out in EtOH at
room temperature using 10 mol % of Pd(OAc)2, 10 mol %
of ligand 6, 20 mol % of MeSO3H, and 3 mol % of Fe(Pc)
under an oxygen atmosphere. The results are depicted
in Table 2. Unfortunately, ligands 6a ,b were found to
be totally ineffective in terms of asymmetric induction
giving racemic product (entries 1 and 2). We next
examined the ligands without any substituents in the
â-position of the amides (entries 3-5). Ligand 6c having
benzyl groups at the R-position of the amides provided 8
in 30.9% ee and in 41% yield. Increasing the steric bulk
of the R-substituent employing i-Pr (6d ) and t-Bu (6e)
groups had beneficial effects in enantioselectivities, 36.3%
and 41.2% ee, respectively. Conformationally fixed ligand
6f, on the other hand, provided 8 in a lower ee (24.8%).
During the studies of the controlling factors in this
reaction, it was observed that the use of solvents, other
than the nucleophile itself, affects the enantioselectivities
of the reaction. Several different solvents were examined
for the reaction using 6d as a ligand, and the results are
given in Table 3. Most of the nonpolar solvents21 gave
higher enantioselectivities than EtOH. Among them,
CH2Cl2 was found to provide the best result (54.4% ee).
It is interesting to note that the observed enantioselec-
tivities correlate with the polarity of the solvent em-
ployed. Other reaction parameters were also examined,
but the effects were not as dramatic as those of the
solvent.
available in enantiomerically pure form either from
natural sources9 or by asymmetric synthesis.9-13 The
synthesis of the benzoquinone scaffold is shown in
Scheme 1. Aldol condensation of ethyl succinate accord-
ing to the description by Nielsen14 furnished the cyclo-
hexanedione 1, which was then oxidized to hydroquinone
2 in 50% yield utilizing freshly prepared manganese
dioxide.15 Having a suitable benzoquinone core in hand,
a hydroxyl protection was required during the transfor-
mation of the bis-acid chloride to chiral bis-amide. After
many attempts, it was found that the allyl protecting
group was a good choice due to its easy and selective
deprotection.16 Thus, treating hydroquinone 2 in DMF
with allyl bromide and K2CO3 afforded the protected
product 3 in 91% yield. The ethyl ester groups were then
(9) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835
and references therein.
(10) Asymmetric aminohydroxylation of alkenes: (a) Li, G.; Chang,
H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451. (b)
Rudolph, J .; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2810. (c) Li, G.; Angert, H. H.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. (d)
Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1483.
(11) Ring opening of epoxides: (a) Nugent, W. A. J . Am. Chem. Soc.
1992, 114, 2768. (b) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.;
J acobsen, E. N. J . Am. Chem. Soc. 1995, 117, 5897. (c) Larrow, J . F.;
Schaus, S. E.; J acobsen, E. N. J . Am. Chem. Soc. 1996, 118, 7420.
(12) Ring opening of aziridines: (a) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J . Am. Chem. Soc.
1993, 115, 5328. (b) Hwang, G.-I.; Chung, J .-H.; Lee, W. K. J . Org.
Chem. 1996, 61, 6183. (c) Du Bois, J .; Tomooka, C. S.; Hong, J .;
Carreira, E. M. J . Am. Chem. Soc. 1997, 119, 3179.
(16) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley and Sons: New York, 1991 and
references therein.
(17) Noh, H.-G.; Shim, H.-K.; Chang, J .-H.; J in, J .-I. Mol. Cryst. Liq.
Cryst. 1996, 280, 103.
(18) (a) For a review see: Giube´, F. Tetrahedron 1997, 53, 13509.
(b) Dessolin, M.; Guillerez, M. G.; Thieriet, N. Guibe´, F.; Loffet, A.
Tetrahedron Lett. 1995, 32, 5741. (c) Four, P.; Guibe´, F. Tetrahedron
Lett. 1982, 23, 1825. (d) Beugelmans, R. Bourdet, S.; Bigot, A.; Zhu, J .
Tetrahedron Lett. 1994, 35, 4349.
(19) (a) Ba¨ckvall, J . E.; Hopkins, R. B.; Grennberg, H.; Mader, M.;
Awasthi, A. K. J . Am. Chem. Soc. 1990, 112, 5160. (b) Ba¨ckvall, J . E.;
Awasthi, A. K.; Renko, Z. D. J . Am. Chem. Soc. 1987, 109, 4750.
(20) (a) Ba¨ckvall, J . E.; Vågberg, J . O. J . Org. Chem. 1988, 53, 5695.
(b) Ba¨ckvall, J . E.; Andersson, P. G. J . Am. Chem. Soc. 1992, 114, 6374.
(c) Itami, K.; Palmgren, A.; Ba¨ckvall, J . E. Tetrahedron Lett. 1998,
39, 1223.
(13) Asymmetric aldol and Mannich-type reactions: (a) Ito, Y.;
Sawamura, M.; Hayashi, T. J . Am. Chem. Soc. 1986, 108, 6405. (b)
Shibasaki, M.; Sasai, H. Pure Appl. Chem. 1996, 68, 523. (c) Kobayashi,
S.; Ishitani, H.; Ueno, M. J . Am. Chem. Soc. 1998, 120, 431.
(14) Nielsen, A. T.; Carpenter, W. R. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 288.
(15) (a) Fatiadi, A. J . Synthesis 1976, 65. (b) No reaction with
commercial MnO2.
(21) Employment of polar solvent such as CH3CN did not give the
product.

6468 J . Org. Chem., Vol. 63, No. 19, 1998
Ta ble 1. Syn th esis of Ch ir a l C2-Sym m etr ic 2,5-Bisa m id e Hyd r oqu in on e Liga n d s
Itami et al.
Ta ble 2. P a lla d iu m -Ca ta lyzed Asym m etr ic
1,4-Dia lk oxyla tion a
Ta ble 3. Effect of Solven ta
entry
solvent
yieldb (%)
% ee of 8c
1
2
3
4
5
6
7
EtOH
acetone
DME
57
47
42
46
50
45
28
36.3
31.2
41.4
41.7
47.2
54.4
51.9
CCl4
CHCl3
CH2Cl2
toluene
a
entry
ligand
yieldb (%)
% ee of 8c
All reactions were run at room temperature using 10 mol %
of Pd(OAc)2, 20 mol % of MeSO3H, 10 mol % of 6d , 3 mol % of
Fe(Pc), and EtOH in solvent (EtOH/solvent ) 1:4) under an oxygen
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
51
42
41
57
32
31
0
0
30.9
36.3
41.2
24.8
b
atmosphere. Isolated yield by column chromatography. c Deter-
mined by HPLC analysis.
states of the first irreversible step.22 In the 1,4-dialkoxy-
lation, there are two stereocenter-creating steps (i.e., first
and second nucleophilic attack). The catalyst may dif-
ferentiate the enantiotopic faces of 7 leading preferen-
tially to (π-allyl)palladium complex 9 or 10 (eq 2).
However, the two diastereomeric (π-allyl)palladium com-
plexes 9 and 10 are in equilibrium23 with one another
a
All reactions were run at room temperature using 10 mol %
of Pd(OAc)2, 20 mol % of MeSO3H, 10 mol % of chiral ligand, and
3 mol % of Fe(Pc) in EtOH under an oxygen atmosphere. b Isolated
yield by column chromatography. c Determined by HPLC analysis.
C. Mech a n ist ic Con sid er a t ion s a n d Or igin of
En a n tioselectivity. Enantioselectivity in a multistep
asymmetric reaction is not necessarily determined by the
initial enantiodifferentiating event, but rather by the
relative energy difference of the diastereomeric transition
(22) Landis, C. R.; Halpern, J . J . Am. Chem. Soc. 1987, 109, 1746.
For an exception, see: Zhang, W.; Lee, N. H.; J acobsen, E. N. J . Am.
Chem. Soc. 1994, 116, 425.

Palladium(II)-Catalyzed 1,4-Dialkoxylation of 1,3-Dienes
Sch em e 2
J . Org. Chem., Vol. 63, No. 19, 1998 6469
via the (η4-diene)palladium complex, and the enantio-
differentiation most likely occurs by preferential second
nucleophilic attack on either 9 or 10.
The effect of solvent is also in line with the suggested
mechanism. Employment of a polar solvent such as
EtOH would shift the equilibrium in Scheme 2 toward
complex B. On the other hand, the use of nonpolar
solvent, such as CH2Cl2, might help the intramolecular
coordination of the hydroxyl groups to palladium, there-
fore giving rise to a larger bias in the enantioselection.
However, there is still the unavoidable question to be
addressed of whether the hydroxyl group is coordinated
to the palladium or not. Therefore, ligand 12 having no
additional coordinating groups26 at the â-position of the
amides was synthesized according to eq 4. When sub-
sequently subjected to the 1,4-dialkoxylation of diene 7,
it gave 8 as a racemate in 35% yield. We believe that
this pronounced difference between 6d and 12 supports
our hypothesis about the requirement of a hydroxyl group
coordination for asymmetric induction. Thus, the hy-
droxyl group on the ligand appears to be essential in
order to obtain a fixed conformation (intermediate A),
thereby achieving more efficient chirality transmission
from the ligand.
A tentative rationalization of our results in the palla-
dium(II)-catalyzed 1,4-dialkoxylation of 7 is given in
Scheme 2. Since benzoquinones are rate-accelerating
ligands in the second nucleophilic attack,24 the most
important intermediates to be considered are (π-allyl)-
palladium complexes A and B resulting from the first
nucleophilic attack on 1,3-diene. We hypothesized that
the hydroxyl group is coordinating25 to the palladium
(intermediate A), therefore bringing the sterically de-
manding group at the R-position of the amide in closer
proximity to the π-allyl group. Besides, the noncoordi-
nated complex B should result in a less efficient asym-
metric induction.
Some insight about the coordination was available from
the disappointing results of ligands 6a ,b. These led us
to examine the configuration of the coordinated ligand
(eq 3). In the case of 6a , the equilibrium of eq 3 is shifted
Con clu sion
A methodology for the synthesis of a new type of chiral
2,5-disubstituted 1,4-hydroquinones was developed, em-
ploying â-amino alcohols as chiral building units. The
ligands gave up to 54.4% ee in the palladium(II)-
catalyzed 1,4-dialkoxylation of 1,3-dienes. These findings
demonstrate the potential of asymmetric induction utiliz-
ing chiral benzoquinones as ligands in palladium(II)
catalysis, albeit with modest enantiomeric excesses. We
further demonstrated that asymmetric induction for
palladium(II)-catalyzed 1,4-dialkoxylation can only be
achieved by the use of ligands with appropriately placed
hemilabile coordinating groups. It is noteworthy that
such a control element has not been exploited extensively
in asymmetric catalysis.27 Moreover, it is noteworthy
that asymmetric induction in the palladium(II)-catalyzed
1,4-dialkoxylation of 1,3-dienes is a difficult task because
the chiral ligand is located far from both reactive sites
of the substrate. Since palladium(II)-catalyzed asym-
to the right (noncoordinated complex, type B) due to the
steric repulsion. On the other hand, in the case of 6c-
e, the equilibrium is expected to be shifted to the left
(coordinated complex, type A) due to the absence of
substituents at R to the hydroxyl group on the amino
alcohol moiety, which should make a gauche conforma-
tion between the nitrogen and oxygen function more
likely. In agreement with these assumptions, ligand 6f,
in which the configuration is fixed to give a gauche
conformation between the amide and the alcohol, did
provide 8 in 24.8% ee, despite having a substituent
similar to that of ligand 6a in the R-position.
(23) Thorarensen, A.; Palmgren, A.; Ba¨ckvall, J . E. Unpublished
results. See also: Szabo´, K. J . Chem. Eur. J . 1997, 3, 592.
(24) The complexation of the benzoquinone or the subsequent second
nucleophilic attack is believed to be the rate-determining step of the
process.4b
(25) (a) An example of hydroxyl group coordination to (π-allyl)-
palladium complex: Nordstro¨m, K.; Macedo, E.; Moberg, C. J . Org.
Chem. 1997, 62, 1604. (b) The hydroxyl group is also used as a directing
group for diastereo- and enantioselective hydrogenation; see: Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307 and references
therein.
(26) Several attempts to introduce alkoxy groups into the â-position
of the amides met with no success.
(27) Nomura, N.; J in, J .; Park, H.; RajanBabu, T. V. J . Am. Chem.
Soc. 1998, 120, 459.

6470 J . Org. Chem., Vol. 63, No. 19, 1998
Itami et al.
Hz, 6H); 13C NMR (CDCl3) δ 165.6, 151.5, 132.7, 125.0, 117.6,
metric reactions lag far behind those of palladium(0), this
study opens up a new frontier for the development of
asymmetric palladium(II) chemistry.7,28 The design and
the preparation of a new generation of ligands as well
as their application to other reactions are currently under
investigation.
117.3, 70.6, 61.4, 14.2; IR (KBr) 1708 cm-1
.
1,4-Dia llyloxy-2,5-ben zen ed ica r boxylic Acid (4). To a
solution of 3 (5.66 g, 16.9 mmol) in THF (100 mL) was added
LiOH (2.49 g, 50.7 mmol) in H2O (25 mL). The mixture was
stirred for 5 h under reflux and then allowed to cool to room
temperature. The reaction mixture was acidified with 2 N HCl
and then concentrated under reduced pressure to ca. 20 mL
followed by filtration to afford 4.54 g (96%) of 4 as a beige
solid: mp 173-174 °C; 1H NMR (CDCl3) δ 7.46 (s, 2H), 6.11-
6.01 (m, 2H), 5.46 (ddd, J ) 17.2, 3.5, 1.7 Hz, 2H), 5.26 (ddd,
J ) 10.6, 3.1, 1.5 Hz, 2H), 4.63 (dt, J ) 5.1, 1.6 Hz, 4H); 13C
NMR (CDCl3) δ 168.6, 152.6, 134.2, 126.4, 118.1, 118.0, 71.5;
IR (KBr) 1673 cm-1. Anal. Calcd for C14H14O6: C, 60.43; H,
5.07. Found: C, 60.55; H, 5.13.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
1
on a Varian Unity-400 (400 MHz H, 100 MHz 13C) spectrom-
eter in CDCl3, CD3OD, THF-d8, and acetone-d6 with internal
1
standards as follows: CDCl3 (7.26 ppm H, 77.0 ppm 13C), CD3-
1
OD (4.78, 3.30 ppm H, 49.0 ppm 13C), THF-d8 (3.58, 1.73 ppm
1H, 67.4, 25.3 ppm 13C), and acetone-d6 (2.04 ppm 1H, 206.0,
29.8 ppm 13C). Infrared spectra were recorded on a Perkin-
Elmer 1600 series FTIR spectrophotometer, and the samples
were examined as KBr plates. Analytical thin-layer chroma-
tography was performed on Merck silica gel plates with F-254
indicator. Column chromatography was performed with 230-
400 mesh silica gel (Woelm). Melting points (mp) were
determined on a hot-stage capillary melting point apparatus
and are uncorrected. Analytical high-pressure liquid chroma-
tography (HPLC) was performed on a Waters liquid chromato-
graph using a Daicel Chiralcel OD-H column. Optical rota-
tions were obtained on a Perkin-Elmer 241 Polarimeter and
are reported as follows [R]temperaturewavelength, concentration (c )
g/100 mL), and solvent. Elemental analyses were performed
by Analytische Laboratorien, Lindlar, Germany.
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification.
Tetrahydrofuran (THF), and diethyl ether (Et2O) were freshly
distilled from sodium benzophenone ketyl prior to use. Tolu-
ene was distilled from sodium, and methylene chloride (CH2-
Cl2) was distilled from calcium hydride. Pd(PPh3)4 was
prepared according to the literature method.29 2-Phenyl-1,3-
cyclohexadiene 7 was prepared by procedures recently devel-
oped in our laboratory.30 Cyclohexanedione 1 was obtained
according to the procedure described by Nielsen.14
(+)-N-[(1R,2S)-1,2-Dip h en yl-2-h yd r oxyet h yl]-1,4-d ia l-
lyloxy-2,5-ben zen ed ica r boxa m id e (5a ). Gen er a l P r oce-
d u r e. The bis acid 4 (593 mg, 2.13 mmol) was stirred for 3 h
under reflux in SOCl2 (6 mL). After the acid was cooled to
room temperature, the solvent was removed under reduced
pressure. Azeotropical removal of residual SOCl2 with toluene
(5 mL × 2) under reduced pressure afforded bis acid chloride
as a brown solid. To a solution of (1S,2R)-(+)-2-amino-1,2-
diphenylethanol (1.00 g, 4.69 mmol) and Et3N (1.5 mL, 10.65
mmol) in CH2Cl2 (15 mL) was slowly added a solution of bis
acid chloride in CH2Cl2 (15 mL) at 0 °C. The reaction mixture
was stirred for 12 h at room temperature. The mixture was
diluted with CHCl3 (50 mL) and washed with H2O (50 mL), 2
N HCl (50 mL), and brine (50 mL). Drying over MgSO4
followed by removal of solvent afforded 1.32 g (93%) of 5a as
a white solid: mp 237 °C; [R]25D +138.1° (c 1.00, THF); 1H NMR
(CDCl3) δ 8.99 (d, J ) 8.0 Hz, 2H), 7.86 (s, 2H), 7.25-7.18 (m,
12H), 7.10-7.03 (m, 8H), 6.00-5.88 (m, 2H), 5.59 (dd, J ) 8.0,
3.6 Hz, 2H), 5.40 (d, J ) 17.6 Hz, 2H), 5.33 (d, J ) 10.4 Hz,
2H), 5.22 (d, J ) 3.6 Hz, 2H), 4.72-4.60 (m, 4H), 3.24 (br, 2H);
13C NMR (CDCl3) δ 164.3, 150.8, 139.8, 137.2, 131.9, 128.1,
128.0, 127.9, 127.74, 127.69, 126.8, 124.6, 120.2, 116.6, 77.2,
70.9, 60.4; IR (KBr) 1639, 1531 cm-1
.
(+)-N-[(1S,2R)-1-Meth yl-2-p h en yl-2-h yd r oxyeth yl]-1,4-
d ia llyloxy-2,5-ben zen ed ica r boxa m id e (5b). According to
the procedure given for the preparation of 5a , 5b (89% based
on 4) was obtained from (1R,2S)-(-)-norephedrine as a white
Dieth yl 1,4-Dih yd r oxy-2,5-ben zen ed ica r boxyla te (2).
To a solution of the cyclohexanedione 114 (10.28 g, 40 mmol)
in toluene (200 mL) was added freshly prepared MnO2 (14.0
g, 160 mmol), and the resulting brown suspension was stirred
for 17 h under reflux. The reaction mixture was cooled to room
temperature and filtered through Celite, followed by washing
with EtOAc (100 mL). The combined organic phases were
concentrated under reduced pressure to afford 5.1 g (50%) of
2 as yellow crystals: mp 125-127 °C; 1H NMR (CDCl3) δ 10.14
(s, 2H), 7.47 (s, 2H), 4.42 (q, J ) 7.2 Hz, 4H), 1.42 (t, J ) 7.1
Hz, 6H); 13C NMR (CDCl3) δ 169.1, 152.9, 118.5, 117.7, 62.0,
solid: mp 135 °C; [R]25 +37.3° (c 1.63, MeOH); 1H NMR
D
(CDCl3) δ 8.26 (d, J ) 7.2 Hz, 2H), 7.44 (d, J ) 7.2 Hz, 4H),
7.35-7.23 (m, 8H), 6.01-5.90 (m, 2H), 5.47 (d, J ) 17.2 Hz,
2H), 5.32-5.28 (m, 4H), 5.27 (d, J ) 10.8 Hz, 2H), 4.56-4.38
(m, 4H), 4.37-4.30 (m, 2H), 1.02 (d, J ) 6.4 Hz, 6H); 13C NMR
(CDCl3) δ 163.3, 149.7, 141.5, 131.4, 127.8, 126.7, 125.9, 123.7,
119.1, 115.3, 73.4, 70.0, 51.9, 12.2; IR (KBr) 1634, 1532 cm-1
.
(-)-N-[(S)-1-Ben zyl-2-h yd r oxyeth yl]-1,4-d ia llyloxy-2,5-
ben zen ed ica r boxa m id e (5c). According to the procedure
given for the preparation of 5a , 5c (99% based on 4) was
obtained from L-phenylalaninol as a white solid: mp 161 °C;
[R]25D -103.3° (c 1.61, MeOH); 1H NMR (CDCl3) δ 8.39 (d, J )
7.2 Hz, 2H), 7.71 (s, 2H), 7.32-7.16 (m, 10H), 5.99-5.86 (m,
2H), 5.38 (d, J ) 17.2 Hz, 2H), 5.31 (d, J ) 10.4 Hz, 2H), 4.65-
4.52 (m, 4H), 4.45-4.34 (m, 2H), 3.88-3.82 (m, 2H), 3.64 (dd,
J ) 11.2, 5.6 Hz, 2H), 3.02-2.86 (m, 2H), 2.94 (d, J ) 7.2 Hz,
4H);); 13C NMR (CDCl3) δ 164.4, 150.6, 137.7, 131.9, 129.3,
128.5, 126.6, 124.5, 119.4, 116.6, 70.6, 64.2, 53.6, 37.3; IR (KBr)
14.1; IR (KBr) 1687 cm-1
.
Dieth yl 1,4-Dia llyloxy-2,5-ben zen ed ica r boxyla te (3).
To a suspension of 2 (4.88 g, 19.2 mmol) and K2CO3 (7.95 g,
57.6 mmol) in DMF (45 mL) was added allyl bromide (5.0 mL,
57.6 mmol), and the reaction mixture was stirred at room
temperature for 13 h. The mixture was diluted with CH2Cl2
and then washed with H2O and brine. The organic layer was
dried over MgSO4. Removal of solvent under reduced pressure
followed by silica gel chromatography (pentane/EtOAc 8/1-
2/1) afforded 5.83 g (91%) of 3 as white crystals: mp 50-52
1634, 1540 cm-1
.
1
°C; H NMR (CDCl3) δ 7.38 (s, 2H), 6.10-6.00 (m, 2H), 5.48
(-)-N-[(S)-1-(Hyd r oxym eth yl)-2-m eth ylp r op yl]-1,4-d i-
a llyloxy-2,5-ben zen ed ica r boxa m id e (5d ). According to the
procedure given for the preparation of 5a , 5d (98% based on
4) was obtained from L-valinol as a white solid: mp 172-175
°C; [R]20D -35.2° (c 0.27, CHCl3); 1H NMR (CDCl3) δ 8.38 (d, J
) 7.8 Hz, 2H), 7.80 (s, 2H), 6.15-6.06 (m, 2H), 5.49 (d, J )
16.1 Hz, 2H), 5.40 (d, J ) 10.4 Hz, 2H), 4.76-4.66 (m, 4H),
4.07-4.01 (m, 2H), 3.88 (dd, J ) 11.3, 3.2 Hz, 2H), 3.71 (dd, J
) 11.3, 7.3 Hz, 2H), 2.91 (s, 2H), 1.98 (m, 2H), 1.01 (d, J ) 6.7
Hz, 6H), 0.99 (d, J ) 6.9 Hz, 6H); 13C NMR (CDCl3) δ 165.1,
150.6, 131.8, 124.4, 120.2, 116.5, 70.8, 64.5, 58.1, 29.5, 19.6,
18.5; IR (KBr) 1617, 1552 cm-1. Anal. Calcd for C24H36N2O6:
C, 64.26; H, 8.09. Found: C, 64.01; H, 7.91.
(ddd, J ) 17.3, 2.7, 1.7 Hz, 2H), 5.30-5.27 (m, 2H), 4.58 (dt,
J ) 4.9, 1.4 Hz, 4H), 4.37 (q, J ) 7.2 Hz, 4H), 1.38 (t, J ) 7.2
(28) (a) Uozumi, Y.; Kato, K.; Hayashi, T. J . Am. Chem. Soc. 1997,
119, 5063. (b) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J . Am.
Chem. Soc. 1981, 103, 2318. (c) Hosokawa, T.; Okuda, C.; Murahashi,
S.-I. J . Org. Chem. 1985, 50, 1282. (d) Calter, M.; Hollis, T. K.;
Overman, L. E.; Ziller, J .; Zipp, G. G. J . Org. Chem. 1997, 62, 1449.
(e) Hollis, T. K.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8837.
(29) Coulson, D. R. Inorg. Synth. 1972, 13, 121.
(30) (a) Karlstro¨m, A. S. E.; Ro¨nn, M.; Thorarensen, A.; Ba¨ckvall,
J . E. J . Org. Chem. 1998, 63, 2517. (b) Karlstro¨m, A. S. E.; Ba¨ckvall,
J . E. Unpublished results.

Palladium(II)-Catalyzed 1,4-Dialkoxylation of 1,3-Dienes
J . Org. Chem., Vol. 63, No. 19, 1998 6471
(+)-N-[(S)-2,2-Dim eth yl-1-(h yd r oxym eth yl)p r op yl]-1,4-
d ia llyloxy-2,5-ben zen ed ica r boxa m id e (5e). According to
the procedure given for the preparation of 5a , 5e (100% based
on 4) was obtained from (S)-tert-leucinol as a white solid: mp
83-85 °C; [R]25D +4.8° (c 1.93, CHCl3); 1H NMR (CDCl3) δ 8.33
(d, J ) 9.6 Hz, 2H), 7.59 (s, 2H), 6.12-5.99 (m, 2H), 5.45 (d, J
) 17.2 Hz, 2H), 5.33 (d, J ) 10.4 Hz, 2H), 4.71 (dd, J ) 12.0,
5.2 Hz, 2H), 4.56 (dd, J ) 12.0, 6.0 Hz, 2H), 4.35 (br, 2H),
4.07-3.96 (m, 4H), 3.60-3.50 (m, 2H), 0.92 (s, 18H); 13C NMR
(CDCl3) δ 164.8, 150.2, 131.9, 123.9, 119.9, 116.5, 70.7, 62.4,
) 7.2, 3.6 Hz, 2H), 3.84 (dd, J ) 11.6, 3.6 Hz, 2H), 3.62 (dd, J
) 11.6, 7.2 Hz, 2H), 1.01 (s, 18H); 13C NMR (CD3OD) δ 168.3,
150.9, 123.5, 118.6, 62.6, 61.0, 35.1, 27.4; IR (KBr) 1622 cm-1
.
(+)-N-[(1S,2R)-2-Hyd r oxy-1-in da n yl]-1,4-dih yd r oxy-2,5-
ben zen ed ica r boxa m id e (6f). According to the procedure
given for the preparation of 6a , 6f (93%) was obtained from
5e as a white solid: mp 152-154 °C; [R]25 +64.6° (c 1.51,
D
THF); 1H NMR (CD3OD) δ 9.26 (d, J ) 7.8 Hz, trace of amide
proton), 7.61 (s, 2H), 7.31-7.14 (m, 8H), 5.53 (d, J ) 4.4 Hz,
2H), 4.65 (dd, J ) 4.8, 4.4 Hz, 2H), 3.18 (dd, J ) 16.4, 4.8 Hz,
2H), 2.96 (d, J ) 16.4 Hz, 2H); 13C NMR (CD3OD) δ 167.7,
150.9, 142.5, 141.6, 128.9, 127.9, 126.2, 125.2, 123.4, 118.9,
60.4, 33.9, 26.8; IR (KBr) 1644, 1538 cm-1
.
(+)-N-[(1S,2R)-2-Hyd r oxy-1-in d a n yl]-1,4-d ia llyloxy-2,5-
ben zen ed ica r boxa m id e (5f). According to the procedure
given for the preparation of 5a , 5f (99% based on 4) was
obtained from (1S,2R)-(-)-cis-1-amino-2-indanol as a white
74.1, 59.3, 40.8; IR (KBr) 1629, 1522 cm-1
.
(-)-N-[(S)-1-(Ch lor om eth yl)-2-m eth yl-p r op yl]-1,4-d ia l-
lyloxy-2,5-ben zen ed ica r boxa m id e (11). To a solution of 5d
(1.00 g, 2.22 mmol) in CH2Cl2 (20 mL) was added SOCl2 (0.81
mL, 11.1 mmol) at 0 °C. The mixture was allowed to warm to
room temperature over 17 h. After removal of solvent under
reduced pressure, the residue was subjected to silica gel
chromatography (pentane/EtOAc 4/1-1/1) to afford 1.00 g
solid: mp 330 °C; [R]25 +76.5° (c 1.56, THF); 1H NMR (THF-
D
d8) δ 8.91 (d, J ) 7.6 Hz, trace of amide proton), 7.97 (s, 2H),
7.33 (d, J ) 6.8 Hz, 2H), 7.22-7.08 (m, 6H), 6.15-6.03 (m,
2H), 5.52 (d, J ) 4.8 Hz, 2H), 5.35 (d, J ) 17.2 Hz, 2H), 5.14
(d, J ) 10.4 Hz, 2H), 4.75-4.67 (m, 4H), 4.64-4.58 (m, 2H),
4.48 (d, J ) 5.2 Hz, 2H), 3.17 (dd, J ) 16.4, 5.2 Hz, 2H), 2.92
(d, J ) 16.4 Hz, 2H); 13C NMR (THF-d8) δ 164.3, 151.8, 143.7,
141.5, 134.1, 128.1, 127.2, 126.3, 125.7, 125.5, 118.6, 117.7,
(93%) of 11 as a white solid: mp 148-149 °C; [R]20 -59.2° (c
D
0.40, CHCl3); 1H NMR (CDCl3) δ 8.40 (d, J ) 8.7 Hz, 2H), 7.92
(s, 2H), 6.17-6.08 (m, 2H), 5.49 (d, J ) 17.2 Hz, 2H), 5.40 (d,
J ) 10.3 Hz, 2H), 4.75 (d, J ) 5.9 Hz, 4H), 4.23 (m, 2H), 3.81
(dd, J ) 11.3, 3.7 Hz, 2H), 3.75 (dd, J ) 11.3, 4.2 Hz, 2H),
2.12-2.03 (m, 2H), 1.05 (d, J ) 6.7 Hz, 6H), 1.01 (d, J ) 6.9
Hz, 6H); 13C NMR (CDCl3) δ 163.9, 150.8, 131.9, 124.7, 120.1,
73.7, 71.6, 59.0, 41.1; IR (KBr) 1631, 1540 cm-1
.
(+)-N-[(1R,2S)-1,2-Dip h en yl-2-h yd r oxyeth yl]-1,4-d ih y-
d r oxy-2,5-ben zen ed ica r boxa m id e (6a . Gen er a l P r oce-
d u r e. A suspension of 5a (1.30 g, 1.94 mmol), Pd(PPh3)4 (280
mg, 0.16 mmol), and NaBH4 (378 mg, 10.0 mmol) in Et2O (30
mL) was stirred at room temperature for 14 h under an argon
atmosphere. The reaction was quenched with MeOH (20 mL),
and the mixture was acidified with 2 N HCl. After concentra-
tion under reduced pressure, the residue was purified by silica
gel chromatography (CH2Cl2/MeOH, 100/0-19/1) to afford
116.8, 70.9, 55.5, 46.4, 29.3, 19.4, 18.7; IR (KBr) 1628 cm-1
.
(+)-N-[(S)-1-(Ch lor om eth yl)-2-m eth ylp r op yl]-1,4-d ih y-
d r oxy-2,5-ben zen ed ica r boxa m id e (12). According to the
procedure given for the preparation of 6a , 12 (94%) was
obtained from 11 as a white solid: mp 264-268 °C; [R]25D +6.2°
1
(c 1.63, acetone); H NMR (acetone-d6) δ 8.08 (d, J ) 8.4 Hz,
886.3 mg (78%) of 6a as a cream-colored solid: mp 266 °C;
2H), 7.41 (s, 2H), 4.26-4.17 (m, 2H), 3.92-3.82 (m, 4H), 2.18-
2.06 (m, 2H), 1.03 (d, J ) 6.4 Hz, 6H), 1.02 (d, J ) 6.4 Hz,
6H); 13C NMR (acetone-d6) δ 170.0, 153.6, 120.1, 115.7, 57.3,
46.4, 30.8, 19.6, 18.9; IR (KBr) 1622, 1558 cm-1. Anal. Calcd
for C18H26N2O4Cl2: C, 53.34; H, 6.47. Found: C, 53.50; H, 6.42.
cis-1,4-Dieth oxy-2-p h en yl-2-cycloh exen e (8. Gen er a l
P r oced u r e. To a solution of Pd(OAc)2 (11.2 mg, 0.05 mmol),
ligand 6d (18.4 mg, 0.05 mmol), Fe(Pc) (8.5 mg, 0.015 mmol),
and EtOH (0.5 mL, 8.5 mmol) in CH2Cl2 (2 mL) was added
MeSO3H (9.6 mg, 0.1 mmol) followed by 2-phenyl-1,3-cyclo-
hexadiene 7 (78.1 mg, 0.5 mmol). The mixture was stirred
for 24 h at room temperature under an oxygen atmosphere.
The reaction mixture was filtered through a short silica gel
column with Et2O as eluent. Evaporation of the solvent and
subsequent purification by silica gel chromatography (pentane/
Et2O 9/1) afforded 8 (55.4 mg, 0.23 mmol, 45%) as a colorless
oil: 1H NMR (CDCl3) δ 7.50-7.45 (m, 2H), 7.35-7.22 (m, 3H),
6.18 (d, J ) 2.4 Hz, 1H), 4.21 (t, J ) 3.2 Hz, 1H), 4.04-3.98
(m, 1H), 3.67-3.55 (m, 3H), 3.48-3.38 (m, 1H), 2.22-2.12 (m,
1H), 1.95-1.82 (m, 2H), 1.70-1.58 (m, 1H), 1.25 (t, J ) 6.8
Hz, 3H), 1.13 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3) δ 140.4,
139.7, 129.9, 128.0, 127.1, 126.2, 74.5, 72.6, 64.2, 63.0, 25.2,
23.6, 15.7, 15.6. Anal. Calcd for C16H22O2: C, 78.01; H, 9.00.
Found: C, 77.80; H, 9.02. The product was found to be of
54.4% ee as determined by HPLC analysis using a Chiralcel
OD-H column (flow rate 0.5 mL/min, 98/2 hexane/2-pro-
panol): tR(minor) ) 9.6 min; tR(major) ) 15.6 min.
1
[R]25 +69.2° (c 1.00, THF); H NMR (CD3OD) δ 7.46 (s, 2H),
D
7.22-7.16 (m, 12H), 7.14-7.09 (m, 8H), 5.39 (d, J ) 5.2 Hz,
2H), 5.10 (d, J ) 5.2 Hz, 2H); 13C NMR (CD3OD) δ 166.6, 150.6,
142.1, 140.0, 129.2, 128.84, 128.82, 128.5, 128.2, 128.0, 123.6,
118.9, 77.2, 61.1; IR (KBr) 1617, 1541 cm-1
.
(+)-N-[(1S,2R)-1-Meth yl-2-p h en yl-2-h yd r oxyeth yl]-1,4-
d ih yd r oxy-2,5-ben zen ed ica r boxa m id e (6b). According to
the procedure given for the preparation of 6a , 6b (96%) was
obtained from 5b as a white solid: mp 105-108 °C; [R]25
D
1
+60.6° (c 1.08, MeOH); H NMR (CD3OD) δ 8.70 (d, J ) 8.0
Hz, trace of amide proton), 7.39-7.33 (m, 6H), 7.29-7.22 (m,
4H), 7.20-7.14 (m, 2H), 4.82-4.78 (m, 2H), 4.38-4.26 (m, 2H),
1.05 (d, J ) 6.8 Hz, 6H); 13C NMR (CD3OD) δ 167.8, 150.6,
143.4, 128.9, 128.2, 127.0, 122.7, 118.1, 72.1, 62.4, 58.7; IR
(KBr) 1627, 1539 cm-1
.
(+)-N-[(S)-1-Ben zyl-2-h yd r oxyeth yl]-1,4-d ih yd r oxy-2,5-
ben zen ed ica r boxa m id e (6c). According to the procedure
given for the preparation of 6a , 6c (90%) was obtained from
5c as a white solid: mp 204-206 °C; [R]25 +41.8° (c 2.02,
D
THF); 1H NMR (CD3OD) δ 7.35 (s, 2H), 7.26 (s, 4H), 7.26-
7.22 (m, 4H), 7.20-7.13 (m, 2H), 4.36-4.28 (m, 2H), 3.61 (d,
J ) 5.2 Hz, 4H), 2.98 (dd, J ) 13.6, 6.4 Hz, 2H), 2.88 (dd, J )
13.6, 8.0 Hz, 2H); 13C NMR (CD3OD) δ 168.4, 151.6, 139.6,
130.4, 129.4, 127.4, 122.6, 117.7, 63.7, 54.6, 38.0; IR (KBr)
1626, 1548 cm-1. Anal. Calcd for C26H28N2O6: C, 67.23; H,
6.08. Found: C, 67.36; H, 5.96.
(-)-N-[(S)-1-(Hyd r oxym eth yl)-2-m eth ylp r op yl]-1,4-d i-
h yd r oxy-2,5-ben zen ed ica r boxa m id e (6d ). According to the
procedure given for the preparation of 6a , 6d (91%) was
Ackn owledgm en t. Financial support from the Swed-
ish Natural Science Research Council and the Swedish
Research Council for Engineering Sciences is gratefully
acknowledged. K.I. thanks the J apan Society for the
Promotion of Science for a predoctoral fellowship.
obtained from 5d as a white solid: mp 233-234 °C; [R]20
D
-62.6° (c 0.27, MeOH); 1H NMR (CD3OD) δ 7.48 (s, 2H), 3.94
(dd, J ) 11.8, 5.1 Hz, 2H), 3.72-3.64 (m, 4H), 2.02 (m, 2H),
1.01 (d, J ) 6.9 Hz, 6H), 0.98 (d, J ) 6.7 Hz, 6H); 13C NMR
(CD3OD) δ 168.3, 151.2, 123.1, 118.3, 63.0, 58.2, 30.0, 20.2,
18.8; IR (KBr) 1621, 1559 cm-1. Anal. Calcd for C18H28N2O6:
C, 58.68; H, 7.66. Found: C, 58.50; H, 7.64.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 5a -c,e,f, 6a ,b,e,f, and 11 (20
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(+)-N-[(S)-2,2-Dim eth yl-1-(h yd r oxym eth yl)p r op yl]-1,4-
d ih yd r oxy-2,5-ben zen ed ica r boxa m id e (6e). According to
the procedure given for the preparation of 6a , 6e (87%) was
obtained from 5e as a white solid: mp 266-269 °C; [R]25D +5.4°
1
(c 0.41, MeOH); H NMR (CD3OD) δ 7.52 (s, 2H), 4.01 (dd, J
J O980561X