Asymmetric 1,4-addition of organoboron reagents to quinone monoketals catalyzed by a chiral diene/rhodium complex: A new synthetic route to enantioenriched 2-aryltetralones

Article abstract of DOI:10.1002/adsc.200600632

A novel synthetic approach to 2-aryltetra-lones with high ee has been developed through asymmetric 1,4-addition of arylboronic acids to naphthoquinone monoketals catalyzed by a rhodium complex with the (R,R)-Ph-bod* ligand. The asymmetric addition proceed

Full text of DOI:10.1002/adsc.200600632

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DOI: 10.1002/adsc.200600632
Asymmetric 1,4-Addition of Organoboron Reagents to Quinone
Monoketals Catalyzed by a Chiral Diene/Rhodium Complex: A
New Synthetic Route to Enantioenriched 2-Aryltetralones
Norihito Tokunagaa and Tamio Hayashia,*
a
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax : (+81)-75-753-3988; e-mail: thayashi@kuchem.kyoto-u.ac.jp
Received: December 11, 2006
Dedicated to Professor Masakatsu Shibasaki on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel synthetic approach to 2-aryltetra-
lones with high ee has been developed through
asymmetric 1,4-addition of arylboronic acids to
naphthoquinone monoketals catalyzed by a rhodi-
um complex with the (R,R)-Ph-bod* ligand. The
asymmetric addition proceeded in high yields with
excellent enantioselectivity.
metric synthesis of a-aryl ketones. Herein we report
that the asymmetric 1,4-addition of aryl- and alkenyl-
boron reagents to quinone monoketals[10] is efficiently
catalyzed by a chiral diene/rhodium complex[11–14] and
one of the enantioenriched addition products (96–
99% ee) is readily converted into a 2-aryltetralone
without loss of enantiomeric purity.
Naphthoquinone monoketal 1a, which is readily ac-
Keywords: asymmetric catalysis; boron; chiral
diene ligands; conjugate addition; quinone monoke-
tals; rhodium
cessible from 1-naphthol by oxidation with PhI(OAc)2
A
in ethylene glycol,[15] was allowed to react with
PhB(OH)2 (2m) in the presence of rhodium catalysts
coordinated with some of the chiral ligands which
have been reported to be effective for rhodium-cata-
lyzed asymmetric 1,4-addition reactions[8,9] (Table 1).
The best result was obtained with chiral diene ligand
Enantiomerically pure carbonyl compounds bearing (R,R)-2,5-diphenylbicyclo
aryl or alkenyl groups at the a position to the carbon- (Ph-bod*).[11] Thus, a rhodium complex generated
yl moiety, which are represented by the 2-aryltetra- from [RhCl(C2H4)2]2 (3 mol% Rh) and (R,R)-Ph-
[2.2.2]bicycloocta-2,5-diene
AHCTREUNG
lones, constitute key intermediates to biologically im- bod* (1.1 equivs. to Rh) catalyzed the reaction in 1,4-
portant compounds.[1] Although their preparation dioxane/H2O (10/1) at 208C to give a 98% yield of
using a stoichiometric amount of chiral reagents has the phenylation product 3am which is 98% enantio-
been reported,[1,2] their catalytic asymmetric synthesis merically pure (entry 1). Another chiral diene ligand,
has not been well developed. The palladium- or (R,R)-Bn-bod*,[12] which is the dibenzyl analogue of
nickel-catalyzed asymmetric a-arylation[3] and a-alke- (R,R)-Ph-bod*, was not as effective (entry 2). The
nylation[4] of carbonyl compounds provides an effi- chemical yield and enantioselectivity were lower in
cient method for the synthesis of chiral ketones sub- the reaction with phosphine-based ligands, (R)-
stituted with quaternary stereogenic centers, but their BINAP[16] and (S)-phosphoramidite[17] (entries 3 and
application to the asymmetric synthesis of products 4).
containing hydrogen at the chiral carbon should pres-
Under similar reaction conditions using (R,R)-Ph-
ent a problem due to the difficulty in keeping the ste- bod* as a ligand, various aryl groups were introduced
reogenic character of the chiral carbon center bound onto naphthoquinone monoketal 1a in high yields
to an acidic hydrogen under basic conditions at a high with excellent enantioselectivity (96–99% ee)
reaction temperature. Another important method of (Table 2). The presence of electron-withdrawing or
providing a-chiral ketones is the catalytic asymmetric -donating groups on the aryl group (2n–s) did not dis-
protonation of enolates,[5–7] but the asymmetric syn- turb the high efficiency of the present asymmetric 1,4-
thesis at the stage of carbon-carbon bond formation is addition (entries 2–7). The enantioselectivity was kept
more desirable. Our approach is to apply the rhodi- high in the addition of sterically demanding o-tolyl
um-catalyzed asymmetric 1,4-addition[8,9] to the asym- (2t), 2-naphthyl (2u), and 3-thienyl (2v) groups (en-
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Table 1. Rhodium-catalyzed asymmetric 1,4-addition of phe-
nylboronic acid (2m) to monoketal 1a.[a]
Table 2. Asymmetric 1,4-addition of arylboronic acids 2 to
naphthoquinone monoketals 1 catalyzed by Rh/(R,R)-Ph-
A
bod*.[a]
Entry
Ligand
(R,R)-Ph-bod*
(R,R)-Bn-bod*
(R)-BINAP
Yield [%][b]
ee [%][c]
1
2
3
4
N
98
91
68
35
98 (R)
87 (R)
92 (R)
33 (S)
(S)-phosphoramidite
Entry
1
2
Yield [%][b]
ee [%][c]
[a]
The reaction was carried out with 0.10 mmol of 1a and
0.15 mmol of 2m in 1,4-dioxane/H2O (10/1) at 208C for
1[d]
2[d]
3[e]
4[f]
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2q
98 (3am)
94 (3an)
93 (3ao)
95 (3ap)
94 (3aq)
86( 3ar)
95 (3as)
96( 3at)
97 (3au)
87 (3av)
95 (3bq)
98 (R)
99 (R)
98 (R)
99 (R)
98 (R)
97 (R)
96 R)
99 (R)
98 (R)
98 (R)
98 (R)
20 h in the presence of [RhCl(C2H4)2]2 (3 mol% Rh),
A
ligand [3.3 mol% of chiral diene ligands and (R)-
BINAP; 6.6 mol% of (S)-phosphoramidite], and KOH
(20 mol%).
Isolated yields purified by preparative thin-layer chroma-
tography on silica gel (eluent: n-hexane/ethyl acetate=2/
1).
Determined by HPLC analysis with a chiral stationary
phase column (Chiralpak AD-H, eluent: n-hexane/2-
propanol=90/10).
5[e]
6[e]
7[e]
8[g]
9[f]
[b]
[c]
(
10[e]
11[h]
[a]
The reaction was carried out with 0.30 mmol of 1 and
0.45 mmol of 2 in 1,4-dioxane/H2O (10/1) for 20 h in the
tries 8–10). The addition to monoketal 1b which is
substituted with a methylenedioxy group on naphtho-
quinone is slower, but the reaction was completed
within 20 h by use of 10 mol% of the rhodium cata-
lyst (entry 11). It is remarkable that the addition to
monoketals 1 containing the bulky ethylene ketal
moiety in close proximity to the reacting b-position of
the enone takes place in high yields under mild condi-
tions by use of the chiral diene/rhodium catalyst. The
absolute configurations of these arylation products
were assigned as (R) by correlation of compound 3bq
with a 2-aryltetralone derivative (vide infra).
presence of [RhCl
A
G
Rh) complex and KOH (20 mol%).
Isolated yields purified by preparative thin-layer chroma-
tography on silica gel (eluent: n-hexane/ethyl acetate).
Determined by HPLC analysis with a chiral stationary
phase column (Chiralpak AD-H).
With 3 mol% Rh at 208C.
With 6mol% Rh at 30 8C.
With 6mol% Rh at 20 8C.
With 3 mol% Rh at 308C.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
With 10 mol% Rh at 208C.
Asymmetric alkenylation of the monoketal 1a also although the chemical yields are a little lower
proceeded with high enantioselectivity by use of alke- (Scheme 2).
nylboron reagents and the Rh/
A
The asymmetric arylation products obtained here
alyst to give the corresponding 1,4-adducts 5 of 96– from naphthoquinone monoketals by the rhodium-
99% ee (Scheme 1). For the introduction of the un- catalyzed asymmetric 1,4-addition can be converted
substituted vinyl group, potassium vinyltrifluorobor- into 2-aryltetralones without loss of the enantiomeric
ate[18](4n) was used conveniently. Dihydroquinone purity. As an example, the synthesis of chiral ketone
monoketal 1c[19] is another good substrate which un- 9,[1] which is a key intermediate to hexahydroben-
dergoes the asymmetric 1,4-addition of arylboronic zo[c]benzophenanthridine alkaloids, is shown in
acids 2m–o with high enantioselectivity (96–98% ee), Scheme 3. Reduction of ketone 3bq (98% ee, Table 2,
514
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Asymmetric 1,4-Addition of Organoboron Reagents to Quinone Monoketals
Scheme 1. Asymmetric 1,4-addition of alkenylborons 4 to
monoketal 1a catalyzed by Rh/(R,R)-Ph-bod*.
A
Figure 1. Enantioselection in the rhodium-catalyzed asym-
metric 1,4-addition.
is important to prevent the reaction from racemiza-
tion (85% ee at 288C and 92% ee at 08C). The abso-
lute configuration of 9 was determined to be (R) by
correlation with (S)-9,[1] indicating that the 1,4-addi-
tion product 3bq obtained with (R,R)-Ph-bod* has
the (R) configuration.
Scheme 2. Asymmetric 1,4-addition of arylboronic acids 2 to
dihydrobenzoquinone monoketal 1c.
The (R) configuration of the 1,4-addition product 3
obtained with (R,R)-Ph-bod* is consistent with the
steric features of the Rh/(R,R)-Ph-bod* complex
A
(Figure 1).[20] The coordination of the carbon-carbon
double bond on monoketal 1 with its a-si face is
much more favorable than that with its a-re face due
to the steric repulsions caused by one of the phenyl
rings of the chiral diene ligand.
In summary, we found that the asymmetric 1,4-ad-
dition of arylboronic acids to naphthoquinone mono-
ketals proceeds with high enantioselectivity by use of
a Rh/(R,R)-Ph-bod* complex as a catalyst. The reac-
A
tion provides a new efficient synthetic route to enan-
tiomerically enriched a-arylated tetralones, which are
valuable chiral building blocks for the synthesis of
biologically active compounds.
Scheme 3. Transformation of 3bq to 2-aryltetralone 9. a)
LiAlH4, THF, 08C, 1 h, 94%; b) n-BuLi, THF, 08C, 0.5 h;
then TsCl, 08C to room temperature, 12 h; c) NaBHEt3, tol-
uene, 08C to room temperature, 2.5 h, 61% (2 steps), 98%
ee; d) 10% aqueous HCl, MeOH, À158C, 1 h, 81%, 98%
ee.
Experimental Section
Typical Procedure
entry 11) with LiAlH4 in THF at 08C gave the cis-hy-
droxy ketal 6 (94% yield) as a single isomer. A crude
mixture of chloride 7, which was obtained by treat-
ment of 6 with n-BuLi in THF at 08C followed by ad-
dition of p-toluenesulfonyl chloride, was subjected to
the reduction with NaBHEt3 in toluene to give a 61%
yield of ketal 8. Deprotection of the ketal in 8 with
10% HCl in methanol at À158C for 1 h provided an
81% yield of the a-aryl ketone 9 which is 98% ee. In
To a solution of [RhCl(C2H4)2]2 (1.8 mg, 0.0045 mmol, 3
A
mol% Rh) and (R,R)-Ph-bod* (2.6mg, 0.0099 mmol, 1.1
equivs. to Rh) in 1,4-dioxane (0.60 mL) was added aqueous
KOH (30 mL, 2.0M, 20 mol% KOH) at room temperature
and the mixture was stirred for 5 min. Monoketal 1a
(60.2 mg, 0.30 mmol) and PhB(OH)2 (2m) (55.3 mg,
0.45 mmol, 1.5 equivs. to 1a) were added to this catalyst so-
lution with 1,4-dioxane (1.5 mL) and H2O (0.18 mL) at
room temperature. After 20 h stirring at 208C, water was
this acidic deprotection, the low reaction temperature added, the mixture was extracted with Et2O, and the ex-
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Norihito Tokunaga and Tamio Hayashi
tracts were dried over MgSO4. Evaporation of the solvent
followed by preparative thin-layer chromatography on silica
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meric excess of 3am was determined to be 98% ee on a
Chiralpak AD-H column (eluent: n-hexane/2-propanol=90/
10).
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search, the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (21 COE on Kyoto University Alli-
ance for Chemistry). N.T. thanks the Japan Society for Pro-
motion of Science for the award a fellowship for graduate
students.
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Adv. Synth. Catal. 2007, 349, 513 – 516