TETRAHEDRON

Tetrahedron 54 (1998) 13073-13078

Pergamon

Silver Salt Effects on an Asymmetric Heck Reaction.

Catalytic Asymmetric Total Synthesis of (+)-Xestoquinone.

Futoshi Miyazaki, Koichiro Uotsu, and Masakatsu Shibasaki*

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo I 13-0033, Japan

Received 16 July 1998; accepted 18 August 1998

Abstract: An enantioselective total synthesis of (+)-xestoquinone has been achieved using a cascade-type asymmetric
Heck reaction (in up to 63% ee and 39% chemical yield (66% conversion yield)) of the aryl bromide derivative(4). The

use of a larger amount of silver exchanged zeolite resulted in a decrease in ee and yield. This is the first example of an effect

of the amount of a silver salt on the ee and yield of a product. © 1998 Elsevier Science Ltd. All rights reserved.

Keywords: Asymmetric reactions, Heck reactions, Naturalproducts, Palladium trodcompounds

INTRODUCTION

Asymn~tric Heck reactions are one of the most important C-C bond-forming reactions known to date.
The first examples of asymmetric Heck reactions were reported in 1989, concurrently and independently by
ourselves 2 and O v e r m a n . 3 Since then we ~'4 have demonstrated, along with others, 5 that this type of catalytic
asymmetric C-C bond forming reaction is useful for the synthesis of various optically active compounds.
In 1996, Keay and co-workers reported an elegant catalytic asymmetric total synthesis of (+)-xestoquinone
(6), in which a highly efficient cascade-type asymmetric Heck reaction was developed. 6 In that synthesis, high
chemical yield and modest to good enantioselectivity (up to 68% ee) were achieved when aryl triflates were used
as substrates. However, the use of the corresponding aryl halides resulted in only poor enantioselectivities (5-
13% eel Therefore, there remained room for improvement for reactions starting from aryl halides, which are
obtained more readily than the corresponding aryl triflates. Recently we have developed 2,2'-
bis(diphenylarsino)-l, l'-binaphthyl (BINAs), and have found that BINAs is more useful than BINAP in the
catalytic asymmetric synthesis of c/s-decalin derivatives from alkenyl iodidesfl Thus, investigations were
carried out in an attempt to enhance the cascade-type asymmetric Heck reaction with aryl halides. In this note,
we report a much improved cascade-type asymmetric Heck reaction of aryl halides, in which highly interesting
and useful silver salt effects are discussed.

RESULTS AND D I S C U S S I O N

The starting aryl bromide 4 was fwst prepared according to the procedure developed by Keay6' sL Sb and
Wallace s°'sd, in which the one step (2"-"3) reaction conditions were improved for the large-scale synthesis of 4
(Scheme 1). The cascade-type asymmetric Heck reaction of 4 was then examined USing BINAs and/or BINAP.
It has been well established that the addition of a silver salt is essential to form cationic palladium intermediates
with 16-electron configurations, leading to products with high enantiomeric excesses. 9 Among the many silver
salts available, the use of silver phosphate or silver exchanged zeolite has been found to give the best results?' 4
0040-4020/98/$ - see front matter © 1998 Elsevier Science Ltd. All fights reserved.
Pll: S0040-4020(98)00797-2
13074 F. Miyazaki et al. /Tetrahedron 54 (1998) 13073-13078

OCH3 OCH3 10% Pd-C OCH3

CHO "- ,. [ ~ . / ~ COOH NH4+HCO2 = L ~ C O O H
I=
y "NO2 EtOH, 70°C "T" NH2
OCH3 OCH3 (98%) OCH3
1 2 3

? CH3 ~ ~ Pd2(dba)3*CHCl
3 (5mol %) OCH3 =
~ , ~ B r "~ (S)-BINAP (15 mol '/,) 1) H2,Pd/C
j~ . , . ', J ' ~ k ~ ,2 CaCO3 (2.2 mol equiv) ,~/JJ~/~..~ .,,,,JL_d 2) CAN
I I1 u Ag exchanged zeolite (1.0 mol equiv)"r" v ..~ -
OCH 3 O NMP, 80 °C, 4 days OCH 3 O O O
4 ( 39%, 63% ee) 5
6, Xestoqulnone
Scheme l

~
Table 1. AsymmetricHeck Reactionof 4 using (S)-BINAs

Pd2(dba)3,,CHCI3 (5 mol %) entry temperature yield ee recoveryof 4

(S)-BINAs (15 mol %) (oc) (%) (%) (%) AsPh2
It

4 CaCO 3 (2.2 mol equiv) 5 1 60 trace 69

Ag3PO4 (2.0 mol equiv) 2 80 11 50 38 AsPh2
NMP, 4 days 3 100 7 37 5
(S)-BINAs

As shown in Table 1, a cascade-type asymmetric Heck reaction of 4 was initially carded out under the well
established conditions of [Pd2(dba)3"CHC13 (5 tool %), (S)-BINAs (15 mol %), Ag3PO4 (2.0 mol equiv), CaCO 3
(2.2 mol equiv) and 1-methyl-2-pyrrolidinone (NMP)]. However, at 60 °C only a trace amount of the desired
product 5 was obtained and 69% of starting material 4 was recovered '° (entry 1, Table 1). This was the best
temperature previously reported by ourselves for alkenyl halide systems./'4 When the temperature was increased
to 80 ¢C, we succeeded in obtaining 5 in 11% yield and 50% ee, with a 38% recovery of starting material 4.
When the reaction was carried out at 100 ~C, however, the yield and ee of the product was lower compared to the
values obtained at 80 ~C. These results suggest that 4 and 5 might be decomposed by silver phosphate at 100 °C.
The absolute configuration of 5 was determined by comparison with an authentic sample, 6 and the ee of 5 was
determined by HPLC analysis using a DAICEL CHIRALCEL OJ column. Although the chemical yield of 5
was poor, our ee was much better than Keay's reported result using 4 as a substrate, 6 encouraging us to further
improve the cascade-type asymmetric Heck reaction of the aryl bromide 4.
Due to the possible decomposition of 4 and 5 by an excess amount of silver phosphate, even at 80 'U, we
next investigated the amount of silver phosphate required for this reaction (entries 1-3, Table 2). As a result
(entry 3, Table 2), using BINAs as a ligand, we were pleased to find that the chemical yield and enantioselectivity
were improved by decreasing the amount of silver phosphate. The highest yield (16%) and enantioselectivity
(63%) were obtained using 0.33 moi equiv of silver phosphate (corresponding to ca~ 1.0 equiv of Ag*). We
also examined the use of BINAP as an asymmetric ligand and tried to optimize the amount of silver phosphate
(entries 4-7, Table 2). The best chemical yield (35%) was obtained when 4.0 mol equiv of silver phosphate
(entry 4, Table 2) was used and the best enantioselectivity (49%) was obtained when 2.0 mol equiv of Ag3PO4
was used (entry 5, Table 2). These results might be reasonably explained by considering that, in the presence of
Ag3PO4, the chemical stability of the BINAs-Pd complex is slightly lower than that of the BINAP-Pd complex, t l
In other words, it is likely that the transfer of B1NAs from Pd ° to silver phosphate occurs more readily than with
BINAP. Furthermore, the unexpected observation that BtNAP is more effective than BINAs might be
understood by the fact that the present cascade type asymmetric Heck reaction requires a higher temperature (80
°C) than generally required (60 ~ ) . 7, At 80 °C, a small amount of undesired ligand transfer of BINAs from Pd °
 F. Miyazaki et aL / Tetrahedron 54 (1998) 13073-13078 13075

to silver phosphate appears to happen. Interestingly, the amount of silver phosphate that produces the best result
depends upon the type of asynmletric ligand employed.

Table 2. Asymmetric Heck Reaction of 4 under Various Reaction Conditions

Pd2(dba)a*CHCI3 (5 mol %) ~~I ~ L - / P P h 2

(S)-Iigand (15 mol %) _L
4 CaCO3(2.2toolequiv) " 5 ~f -~ ~r_PPh2
Ag reagent
NMP, 80 °C, 4 days (S)-BINAP
entry Ag reagent ligand yield ee recovery of 4 conversion
(mol equiv) (%) (%) (%) (%)

I Ag3PO4 ( 2 . 0 ) (S)-B1NAs 11 50 38 18
2 Ag3PO4 ( 0 . 6 7 ) (S)-BINAs 12 59 65 34
3 Ag3PO4 (0.33) (S)-BINAs 16 63 55 36
4 Ag3PO,,( 4 . 0 ) (S)-BINAP 35 44 32 51
5 Ag3PO4 ( 2 . 0 ) (S)-BINAP 29 49 23 38
6 Ag3PO4 ( 0 . 6 7 ) (S)-BINAP 25 47 45 45
7 Ag3PO4 ( 0 . 3 3 ) (S)-BINAP 21 46 33 3I
8 Ag exchanged zeolite (6.0)a (S)-BINAs trace 39 45 trace
9 Ag exchanged zeolite (2.0)° (S)-BINAs 24 52 31 35
10 Agexchanged zeolite (1.0)a (S)-BINAs 21 53 54 46
11 Ag exchanged zeolite (6.0)a (S)-BINAP 9 I1 trace 9
12 Ag exchanged zeolite (2.0)a (S)-BINAP 28 47 33 42
13 Ag exchanged zeolite (I .0)a (S)-BINAP 39 63 41 66
a Aid 36,660-9, Ag content; typically 20-25%, 100 mesh powder.

In an attempt to further improve the cascade-type asymmetric Heck reaction of 4, we next examined the
effect of silver exchanged zeolite on this reaction. This effect is known to accelerate the asymmetric Heck
reaction of alkenyl iodides. "4s When BINAs was employed as an asymmetric ligand, in the presence of 1.0
equivalent of silver exchanged zeolite, the desired product 5 was formed in 21% chemical yield (46% conversion
yield) and 53% ee (entry 10, Table2). As expected, the use of larger amounts of silver exchanged zeolite
produced only a trace amount of 5 (entry 8, Table 2). Quite surprisingly, even when BINAP was used as an
asymmetric ligand, 1.0 equivalent of silver exchanged zeolite gave the best result, affording 5 in 39% chemical
yield (66% conversion yield) and in 63% ee (entry 13, Table 2). When 2.0 or 6.0 equivalents of silver
exchanged zeolite were used, less satisfactory results were obtained (entries 11 and 12, Table 2). This suggests
that excess amounts of silver exchanged zeolite might lead to the undesired ligand transfer, even in the case of
BINAP as a ligand. These observations are in accordance with the fact that silver exchanged zeolite accelerates
asymmetric Heck reactions of alkenyl iodides, j' 4g by working as a more naked and reactive Ag÷ than silver
phosphate. The above mentioned result is quite useful for determining the best reaction conditions for
asymmetric Heck reactions employing aryl halides and/or alkenyl halides.
The results discussed herein appear to suggest the following possibilities. Firstly, undesired asymmetric
ligand exchange might take place between Pd ° and Ag÷, t2 which suggests that the amount of a silver salt
employed is very important. Secondly, considering the electronegativities of both metals (Pd; I. 35, Ag; 1.42),
undesired electron transfer might occur from Pd ° to Ag ÷ at relatively high temperature, causing the decomposition
of an asymmetric catalyst. Finally an excess amount of a silver salt might decompose 4 and 5. The cascade-
type asymmetric Heck reaction product 5 was finally converted to (+)-xestoquinone (6) according to the
procedure developed by Keay and co-workers (Scheme I ).6

SUMMARY

Although aryl bromide 4 was reported to be an ineffective substrate for cascade-type asymrrwaric Heck
reactions, 6 we have succeeded in greatly improving the reaction of 4 by modifying the reaction conditions.
13076 F. Miyazaki et al. / Tetrahedron 54 (1998) 13073-13078

Desired product 5 has been isolated in up to 63% ee albeit in modest chemical yield. Moreover, these studies
have revealed for the first time that the amount of silver salt is quite important for an a s y ~ c Heck reaction
using aryl halides. The amount of a silver salt required depends not only on the type of silver salt, but also on the
type of asymmetric ligand. These results would be useful for further development of an asymmetric Heck
reaction. Further studies along this line are currently under investigation.

EXPERIMENTAL SECTION

General Methods. Pd2(dba)3.CHCl 3, (S)-BINAP, Ag3PO4. silver exchanged zeolite (Aid 36,660-9), 10%
Pd-C, ammonium formate, EtOH (99.9% pure) and Et20 (99.8% pure) used are available from commercially
sources. These reagents and solvents were used without further purification, except for CaCO 3 which was dried
with heating under vacuum at 80 ~C before use. Toluene, 1,2-diehloroethane, hexane, ethyl acetate,
dichloromethane and 1-rnethyl-2-pyrrolidinone were distilled before use. Preparative TI.,C (Merck 60 F2~4
precoated silica gel plates (0.25 mm thickness)) and silica gel (Merck silica gel 60 (230-400 mesh)) for
chromatography was washed with diehlorornethane before use. BINAs was prepared according to the reported
procedure. 7a Synthesis of (+)-xestoquinone (6) was carded out according to the procedure reported by Keay6' s,.
Sb and Wallace8c'8d except for 2--*3 and 4"*5. All experiments were performed under an argon atmosphere,
unless otherwise mentioned, and monitored with analytical TLC (Merck Art. 5715, silica gel 60 F25, plates) All
products were previously known, and their JH NMR, ~3C NMR, IR spectra and Mass spectra were consistent
with literature spectral data. 6 tH NMR and t3C NMR were taken in CDCI3 or DMSO-d 6 at 500 and 125 Mhz,
respectively.

2-Amino-3,6-dimethoxybenzoic acid (3). To a solution of 28c (20 g, 88 mmol) in ethanol (99.9% pure,
500 mL) was added 10% Pd-C (9.4 g, 8. 8 mmol) and this rrtixture was stirred at 0 K2. To this mixture was then
added ammonium formate (22 g, 350 retool) and the suspension was stirred at 70 ~C for 7 h. The catalyst was
removed by filtration and washed with ethanol ( 100 mL), and the filtrate was evaporated under reduced pressure
to give the crude amino acid, which was separated from a trace amount of the 4-amino isomer by silica gel
chromatography (ether) to give the title compound 3 (17 g, 98%). The spectral data of 3 thus obtained were
superimposable with those of an authentic sample, sc tH NMR (500 MHz, DMSO-d~) ~ 6.83 (IH, d, J= 8.9
Hz), 6.15 (IH, d, J = 8.9 Hz), 3.74 (3H, s), 3.72 (3H, s); ~3C NMR (125 MHz) d~ 168.6, 152.8, 141.4,
140.5, 112.9, 103.9, 97.2, 56.2, 56.1; MS (El) ndz 197 (M*, 66), (M*-33, 100), (M*-63, 51); IR (KBr, cm~)
3496, 3363, 1692.

5-((3-Bromo-5,8-dimethoxynaphth-2-yl)carbonyl)-3-ethenyl.4-(propen.2.yl)furtm (4). tH NMR (500

MHz, CDCI3) d 8.44 (s, IH), 8.24 (s, 1H), 7.64 (s, IH), 6.79 (d, IH, J = 8.3 Hz), 6.74 (d, IH, J = 8.4 Hz),
6.38 (dd, 1H, J = 11, 18 Hz), 5.61 (dd, IH, J = 1.3, 18 Hz), 5.25 (dd, IH, J = 1.3, 11.2 Hz), 5.09 (d, 1H, J=
1.5 Hz), 4.97 (d, 1H, J--- 1.7 Hz), 3.96 (s, 3H), 3.92 (s, 3H), 1.94 (s, 3H); ~3C NMR (125 MHz) t~ 184.1,
150.1, 148.6, 147.8, 143.2, 137.2, 136.4, 135.9, 127.9, 126.6, 126.5, 125.5, 124.4, 124.0, 118.6, 117.4,
116.6, 106.1, 104.6, 56.1, 56.0, 23.0; MS (El, m/z) 428, 426 (M*, 13), 18 (H20, 100); IR (KBr, cm1) 1637,
1463, 1264, 1108. The spectral data of 4 thus obtained were superimposable with those of an authentic
sample.6

(12bS)-8, l l-Dimethoxy-12b-methyl- l H-benzo[ 6, 7]phenanthro-[ l O,l-bc ]furan-6(12bH )-one ((+)-5).

1. Representative procedure using BINAP. Pd2(dba)3"CHCl 3 (4.8 nag, 5.0 rnol %), (S)-BINAP (8.8 nag,
15 tool %), CaCO 3 (21 rag, 2.2 mol eq), a silver salt and substrate 4 (40 mg, 0.094 retool) were placed in a
reaction flask. To this mixture was added distilled NMP (1.3 mL). The mixture (0.072 M) was degassed by
freeze-pump-thaw cycles, and stirred at 80 qC for 4 days. The crude reaction mixture was filtered through a pad
of silica gel (dichloromethane) to afford a yellow solid which was purified by preparative TLC (fast, hexane :
ethyl acetate = 3:1 and then toluene : 1,2-dichloroethan¢ = 1:1).
 F. Miyazaki et al. /Tetrahedron 54 (1998) 13073-13078 13077

2. Using BINAs. Pd2(dba)3.CHCl~ (4.8 mg, 5.0 mol %), (S)-BINAs (10 mg, 15 mol %), C.aC~3 (21 mg,
2.2 tool eq) and a silver salt were placed in a reaction flask. To this mixture was added degassed NMP (0.50 mL).
The mixture was degassed by freeze-pump-thaw cycles, and stirred at 60 ~C for 30 rain. To this mixture was
added a solution of the substrate 4 (40 rag, 0.094 mmol) in degassed NMP (0.80 mL). The mixture was
degassed by freeze-pump-thaw cycles, and stirred at 80 qC for 4 days. The crude reaction mixture was f'dtered
through a pad of silica gel (dichloromethane) to afford a yellow solid which was purified by preparative TLC
(first, hexane : ethyl acetate = 3:1 and then toluene : 1,2-dichloroethane = 1:1). The enantiopurity was assessed
by dissolving the sample in CH2CI2 and separating the enantiomers by a Daieel CHIRAI.~EL OJ column
(hexane:ethanol=85 : 15; a=350nm, flowrate= 1.3mlJmin). The relative peak areas (12.0and 15.5 rain)
indicated an ee of 5. The spectral data of 5 thus obtained were superimposable with those of an authentic
sample. 6 ]H NMR (500 MHz, CDCI3) 3 9.30 (s, 1H), 8.26 (s, IH), 7.57 (s, 1H), 6.82 (d, IH, J = 8.4Hz),
6.71 (d, IH, J = 8.4 Hz), 6.62 (dd, IH, J = 3.1, 9.8 Hz), 6.11 (ddd, 1H, J = 2.5, 6.1, 9.8 Hz), 4.00 (s, 3H),
3.99(s, 3H), 3.15 (dd, 1H, J=6.1, 17Hz), 2.67 (brd, IH, J = 17Hz), 1.53 (s, IH);~3CNMR (125 Ml-Iz) 6'
173.0, 151.1, 149.0, 146.0, 144.6, 144.5, 141.7, 131.6, 129.0, 127.8, 125.1, 124.5, 121.3, 118.5, 117.8,
106.4, 103.7, 56.0, 56.0, 35.7, 35.7, 32.4; MS (El, m/z) 346 (M÷, 86), 331 (M*-I5, 100); IR (KBr, an ~) 1667,
1623, 1595.

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OCH 3 O

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