Arylation of 8-acetoxyoctalenone in a nickel-catalyzed coupling reaction with lithium arylborates

Article abstract of DOI:10.1002/1099-0690(200010)2000:20<3393::AID-EJOC3393>3.0.CO;2-C

In order to find a suitable organometallic compound and a catalyst for the arylation of 8-acetoxyoctalenone 4 (a stereoisomeric mixture of 4α and 4β), phenylation was first investigated with PhZnX (7: X = Cl; 8: X = Br)/Pd or Ni cat., PhSnBu₃ (9)/Pd cat. and LiCl, and [PhB(Bu)(OCHMeCH-MeO)]Li (10a)/Ni cat. Borate 10a provided the desired product 11a with high stereoselectivity. The stereochemical outcome was irrespective of the stereochemistry of the acetoxy group in 4. Four more aryl groups, p-R-C₆H₄ (R = Me, MeO, Ph, and Me₂N), were installed stereoselectively with this method.

Full text of DOI:10.1002/1099-0690(200010)2000:20<3393::AID-EJOC3393>3.0.CO;2-C

FULL PAPER
Arylation of 8-Acetoxyoctalenone in a Nickel-Catalyzed Coupling Reaction
with Lithium Arylborates
Yuichi Kobayashi*[a] and Michiko Ito[a]
Keywords: Arylation / Borates / CϪC coupling / Nickel / Steroids
In order to find a suitable organometallic compound and a
uct 11a with high stereoselectivity. The stereochemical out-
catalyst for the arylation of 8-acetoxyoctalenone 4 (a stereo- come was irrespective of the stereochemistry of the acetoxy
isomeric mixture of 4α and 4β), phenylation was first investi-
gated with PhZnX (7: X = Cl; 8: X = Br)/Pd or Ni cat.,
group in 4. Four more aryl groups, p-R-C6H4 (R = Me, MeO,
Ph, and Me2N), were installed stereoselectively with this
PhSnBu3 (9)/Pd cat. and LiCl, and [PhB(Bu)(OCHMeCH- method.
MeO)]Li (10a)/Ni cat. Borate 10a provided the desired prod-
Introduction
Since the Teutsch group reported the antiprogesterone
activity of 11-aryl-19-nor steroids,[1] they have attracted
much interest in the field of pharmaceutical chemistry,[2]
and in addition their biological activity as a fertility control
drug has prompted urgent elucidation of the biological role
of natural 11-substituted steroids (i.e., those possessing the
is desirable to find a reaction by which a substrate derived
19-methyl group).
from each stereoisomer of 2 (X ϭ OH) conveniently fur-
nishes the installation of an aryl group at the β side of the
octalenone framework. This stereochemical requirement is
of utmost importance. To this end, we studied a transition
metal catalyzed coupling reaction of 8-hydroxyoctalenone
derivatives with organometallics as illustrated in Equation
1. We expected that the π-allyl intermediate of the undesired
stereochemistry (the metal center projected to the α side of
the molecule) would be transformed into the desired inter-
mediate or remain unchanged. Results along this line are
described below.
The 11-substituted-19-nor steroids have been prepared
from 19-nor steroidal dienes by epoxidation followed by re-
action with an organometallic such as copper compounds,
and this methodology is now well established.[1,3] The
method is, however, limited to synthesis of the 19-nor ster-
oids. In order to develop a method for synthesis of natural
11-substituted steroids, we were interested in a substitution
reaction of 8-hydroxyoctalenone derivatives 2 (X ϭ leaving
group) as a model compound of the A-ring-nor enone 1.[4]
The parent alcohol 2 (X ϭ OH) is prepared by m-CPBA
oxidation of the dienol acetate derived from octalenone 3.[5]
However, the oxidation affords a stereoisomeric mixture
of 2 (X ϭ OH; α-OH/β-OH ϭ 3:7), though the stereoiso-
mers can be separated by chromatography. Consequently, it
Results and Discussion
Initially, installation of a phenyl group was examined us-
ing several organometallic compounds based on Zn,[6] Sn,[7]
and B,[8] which are highly reactive toward allylic esters in
the presence of appropriate catalysts, and the results are
summarized in Table 1. When PhZnCl (7), prepared from
PhLi and ZnCl2, was allowed to react with a stereoisomeric
mixture of acetate 4α (α-OAc) and 4β (β-OAc) (4α/4β ϭ
1:3) in the presence of a palladium or a nickel catalyst un-
der Negishi’s conditions,[6] a mixture of unidentified prod-
ucts (Entry 1) or the reduction compound 3 was obtained
as a major product (Entry 2), respectively.[9,10] Reactions
with PhZnCl (7), prepared from PhMgBr and ZnCl2, or
PhZnBr (8) from PhLi and ZnBr2 furnished similar results
(data not shown). Next, a phenylstannane was examined.
Hegedus carried out the coupling reaction between allylic
[a]
Department of Molecular Engineering, Tokyo Institute of
Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Fax: (internat.) ϩ 81-45/924-5789
E-mail: ykobayas@bio.titech.ac.jp
Eur. J. Org. Chem. 2000, 3393Ϫ3397
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/1020Ϫ3393 $ 17.50ϩ.50/0
3393

Y. Kobayashi, M. Ito
FULL PAPER
Table 1. Coupling reaction of substrates 4, 5, and 6 with phenylmetal compounds
Substrate
No.
Product ratio (%)
Entry[a]
α-/β-OR
Ph-met[b]
Catalyst[c]
11a (Yield,[d] β-/α-Ph[e])
3
1
2
3
4
5
6
7
8
9
10
4
mixture[f]
mixture
mixture
mixture
mixture
mixture
mixture
mixture
β-OAc
7[g]
7[g]
9
10a
10a
10a
10a
10a
10a
10a
Pd(tpp)4
0
0
4
NiCl2(tpp)2
Pd2(dba)3·CHCl3
NiCl2(dppf)
NiCl2(dppp)
NiCl2(tpp)2
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
5 (nd)[h]
32[i]
major[j]
18
4
0
4
82 (75%, 96:4)
59 (nd,[h] 96:4)
63 (nd,[h] 93:7)
64 (nd,[h] 93:7)
82 (63%, 95:5)
89 (80%, 96:4)
84 (76%, 94:6)
4
41
4
37
5
36
6
18
4β
4α
11
α-OAc
16
[b]
[c]
[d]
[a] Reactions were carried out in THF at 60 °C overnight. Ϫ 1.5Ϫ1.8 equiv. Ϫ 5Ϫ10 mol-%. Ϫ Isolated yield by chromatography.
Ϫ [e] Determined by H NMR spectroscopy. Ϫ [f] α-OR/β-OR ϭ 1:2 to 1:4. Ϫ [g] Prepared from PhLi and ZnCl2. Ϫ [h] Isolated yield and/
or ratio was not determined. Ϫ Substrate 4 was recovered in 55% yield. Ϫ Enone 3 was obtained as a major product.
1
[i]
[j]
acetates and organostannanes under forcing conditions resulted in worse and similar product ratios, respectively
[Pd(dba)2, LiCl, DMF].[7] However, reaction of acetate 4 (Entries 7 and 8).
and PhSnBu3 (9) under these conditions afforded a mixture
of products, in which 3 was the major product (Entry 3).
Finally, the borate reagent was examined, which is reac-
tive toward allylic esters only in the presence of a nickel
catalyst.[8] Reaction of phenylboronate ester 12a (Ar ϭ Ph)
and nBuLi[11] at room temperature for 15 min generated
lithium phenylborate 10a in situ, and further reaction with
acetate 4 at 60 °C afforded 11a (Ar ϭ Ph) as a major prod-
uct, for the first time (Entries 4Ϫ6).
The stereochemistry of the reaction was studied under
the conditions of Entry 4 by using the pure stereoisomers,
4α and 4β, which were prepared by separation of the ster-
eoisomers of alcohol 2 (X ϭ OH) followed by acetylation.
The stereochemistry of the product was independent of that
of the acetoxy group of 4, and the same stereoisomer 11a
was obtained in the same ratio from both isomers (Table 1,
Entries 9 and 10). Since the allylic coupling with hard nu-
cleophiles generally proceeds with inversion, the present re-
sult is an exceptional case and is probably explained by the
nickel enolate 15 of the half-chair conformation as illus-
trated in Scheme 1.[13] Thus, the reaction involves: (1)
formation of the nickel enolate 15 (X ϭ OAc) from acetates
4α and 4β through the initially formed π-allyl complexes 13
and 14; (2) transmetalation of 15 (X ϭ OAc) with borate
10a to generate 15 (X ϭ Ph); (3) peripheral change to the
stable π-allyl complexes 13 (X ϭ Ph), in which the NiϪPh
part is located on the less congested β side of the octalenone
plane; (4) reductive elimination affording the coupling
product 11a.
The stereochemical purity of 11a was higher than 93%,
and the stereochemistry of the major product was assigned
as depicted in 11a, with the phenyl group on the desired β
1
side of the ring, as determined by the H NMR coupling
constant of the proton at C-8 in the stable chair-like con-
former: δ ϭ 3.80 (t, J ϭ 3 Hz).[12] The signal at δ ϭ 3.38
(dd, J ϭ 12, 4 Hz) was assigned to the same proton of the
The optimized conditions summarized in Entry 4 of
minor product with the α-Ph group.[12] Although 3 was pro- Table 1 were applied to install other aryl groups onto the
duced as a by-product, use of dppf as a ligand suppressed octalenone by using borates 10bϪe. The boronate esters
its formation (Entry 4; cf. Entries 5 and 6), and the products 12d,e [p-PhC6H4, p-N(Me2)C6H4] were prepared in 94 and
were separated easily by chromatography on silica gel.
50% yields, respectively, by the method[8] for synthesis of
Leaving groups other than the acetoxy group were tested 12b,c (Ar ϭ p-MeC6H4, p-MeOC6H4) through lithiation of
under the reaction conditions used in Entry 4. Reactions of the corresponding aryl bromides followed by reaction with
carbonate 5 (5α/5β ϭ 1:2) and pivaloate 6 (6α/6β ϭ 1:4) B(OiPr)3 and esterification with 2,3-butanediol. As sum-
3394
Eur. J. Org. Chem. 2000, 3393Ϫ3397

Arylation of 8-Acetoxyoctalenone in a Nickel-Catalyzed Coupling Reaction
FULL PAPER
Scheme 1. Plausible pathway for formation of 11a
cording to the literature methods.[15,16] Boronate esters 12aϪc of
Ar ϭ Ph, p-MeC6H4, and p-MeOC6H4 were prepared by the litera-
ture procedures,[8] while 12d,e were prepared by the procedure de-
scribed below. ∆1(9)-Octalone-2 (3) was prepared by the literature
method.[17] Routinely, an organic extract was dried with MgSO4
and concentrated by using a rotary evaporator to leave a residue,
which was purified by chromatography on silica gel.
Table 2. Reaction between acetate 4 and borates 10bϪe
Product 11
Yield of 3
Entry[a] Ar
No. Yield (%)[b] β-/α-Ar[c] (%)
1
2
3
4
p-MeC6H4
11b 69
11c 63
11d 80
94:6
93:7
94:6
90:10
17
20
15
22
p-MeOC6H4
p-PhC6H4
p-(NMe2)C6H4 11e 54
8α- and 8β-Acetoxy-∆1(9)-octalone-2 (4α,β). ؊ I: 8-Hydroxy-∆1(9)
-
octalone-2 (2) (X ϭ OH) was prepared by a literature method[5a]
with modification. In summary, concentrated H2SO4 (0.4 mL) was
added to a mixture of ∆1(9)-octalone-2 (3) (6.15 g, 40.9 mmol) and
isopropenyl acetate (20 mL, 182 mmol), and the resulting solution
was stirred at room temperature for 15 min. After addition of satu-
rated NaHCO3, the mixture was extracted with EtOAc three times.
The combined extracts were washed with brine, dried, and concen-
trated under reduced pressure to afford the corresponding dienol
acetate, which was used for further reaction without purification.
On a ice-cold solution of the above acetate in 95% EtOH (100 mL)
was added m-CPBA (8.82 g, 80% purity, 40.9 mmol) por-
tionwise, and the resulting mixture was stirred at room temperature
overnight. Methyl sulfide (1 mL, 14 mmol) was added to the mix-
ture, and the mixture was stirred at room temperature for 2 h and
concentrated. Saturated NaHCO3 was added to the residue and
the mixture was extracted with EtOAc repeatedly. The combined
extracts were dried and concentrated to leave alcohol 2 (X ϭ OH)
with a 3:7 ratio of α-/β-OH isomer by 1H NMR spectroscopy.
These stereoisomers were separated by chromatography. The com-
bined stereoisomers (4.74 g) or each of the stereoisomers was used
for the next acetylation. Ϫ II: To an ice-cold stereoisomeric mixture
of the hydroxyoctalenone 2 (X ϭ OH) (4.74 g) in pyridine (6.0 mL,
74.2 mmol) was added Ac2O (3.2 mL, 33.9 mmol). The reaction
mixture was stirred at room temperature overnight and diluted with
EtOAc. The resulting solution was washed with 3  HCl and then
with saturated NaHCO3, dried, and concentrated to give an oil,
which was purified by chromatography to furnish acetate 4 (4.63 g,
54% from octalenone 3) as a mixture of 4α and 4β (3:7). Ϫ Bp 150
°C (Ͻ 1 Torr). III: In a similar way, each of the stereoisomeric
alcohols 2 (X ϭ OH) was transformed into the acetates 4α and 4β,
[a]
A 3:7 ratio of 4α/4β was used; reactions were carried out in the
[b]
presence of NiCl2(dppf) (5Ϫ10 mol-%) at 60 °C for 12Ϫ16 h. Ϫ
[c]
Isolated yield by chromatography. Ϫ
Determined by 1H NMR
spectroscopy.
marized in Table 2, reaction of 4 (4α/4β ϭ 3:7) with borates
10bϪe derived from the corresponding boronate esters
12bϪe and nBuLi afforded the corresponding products
11bϪe in good to moderate yields with high stereoselectiv-
ity (Ͼ 90%).[14] Among them, the substituent of Ar ϭ p-
(NMe2)C6H4 is that used for UR 38 486.[2]
Conclusion
We have succeeded in the installation of aryl groups at
C-8 of the octalenone 4, a model enone for the synthesis of
11-aryl-substituted steroids through the intermediate 1.
High stereoselectivity was observed in the installation of the
five aryl groups and is irrespective of that of acetate 4. We
are now carrying out the full scale synthesis of 11-aryl-sub-
stituted steroids.
Experimental Section
1
General: The H NMR (300 MHz) and 13C NMR (75 MHz) spec-
tra were measured in CDCl3 using SiMe4 (δ ϭ 0) and the center
line of CDCl3 triplet (δ ϭ 77.1) as internal standards, respectively. respectively. Ϫ 4α: IR (neat): ν˜ ϭ 1736, 1676, 1237 cmϪ1. Ϫ 1H
Ϫ The nickel catalysts NiCl2(tpp)2, NiCl2(dppf) were prepared ac-
Eur. J. Org. Chem. 2000, 3393Ϫ3397
NMR δ ϭ 1.29 (dq, J ϭ 4, 13 Hz, 1 H), 1.43Ϫ1.80 (m, 3 H),
3395

Y. Kobayashi, M. Ito
FULL PAPER
1.86Ϫ2.01 (m, 2 H), 2.14 (s, 3 H), 2.12Ϫ2.48 (m, 5 H), 5.31 (ddd,
dried and concentrated to give an oil, which was purified by chro-
J ϭ 11, 6, 2 Hz, 1 H), 5.95 (t, J ϭ 2 Hz, 1 H). Ϫ 13C NMR δ ϭ matography to furnish the coupling product 11a and its stereoiso-
20.9, 23.0, 28.4, 33.2, 33.7, 35.8, 37.0, 72.6, 120.6, 162.9, 170.1,
mer (92 mg, 75%, 11a/isomer ϭ 96:4) and the by-product 3 (13 mg,
1
199.7. Ϫ MS (EI); m/z (%): 208 [Mϩ] (15), 166 (100), 137 (24), 120
16%). Ϫ 11a: IR (neat): ν˜ ϭ 3025, 1671, 1617 cmϪ1. Ϫ H NMR:
(13), 109 (12), 91 (27). Ϫ HRMS (EI) for C12H16O3 [Mϩ]: calcd. δ ϭ 1.32Ϫ1.48 (m, 1 H), 1.62Ϫ1.76 (m, 3 H), 1.82Ϫ1.96 (m, 2 H),
208.1099; found 208.1100. Ϫ 4β: IR (nujol): ν˜ ϭ 1735, 1672, 1236
2.11 (dq, J ϭ 14, 6 Hz, 1 H), 2.30Ϫ2.53 (m, 4 H), 3.80 (t, J ϭ
1
cmϪ1. Ϫ H NMR: δ ϭ 1.29 (dq, J ϭ 4, 13 Hz, 1 H), 1.54Ϫ1.76 3 Hz, 1 H), 6.01 (d, J ϭ 2 Hz, 1 H), 7.19Ϫ7.36 (m, 5 H). Ϫ 13C
(m, 3 H), 1.82 (tt, J ϭ 13, 3 Hz, 1 H), 1.90Ϫ2.02 (m, 1 H), 2.07 (s, NMR: δ ϭ 20.9, 29.1, 30.4, 34.1, 35.1, 36.2, 47.3, 126.5, 127.1,
3 H), 2.04Ϫ2.22 (m, 2 H), 2.28Ϫ2.49 (m, 2 H), 2.56Ϫ2.70 (m, 1
127.4, 128.8, 141.5, 168.7, 200.3. Ϫ MS (EI); m/z (%): 226 [Mϩ]
H), 5.43 (t, J ϭ 3 Hz, 1 H), 5.99 (d, J ϭ 2 Hz, 1 H). Ϫ 13C NMR: (100), 208 (26), 170 (70), 141 (62), 128 (38), 115 (56), 91 (59). Ϫ
δ ϭ 19.8, 21.2, 28.7, 31.6, 33.5, 34.0, 36.1, 73.5, 127.1, 160.6, 170.0, HRMS (FAB) for C16H19O [(M ϩ H)ϩ]: calcd. 227.1436; found
200.3. Ϫ MS (EI); m/z (%): 208 [Mϩ] (15), 166 (100), 148 (34), 138
(25), 137 (25), 120 (44), 91 (56). Ϫ HRMS (EI) for C12H16O3 [Mϩ]:
calcd. 208.1099; found 208.1109.
227.1436.
8-(4-Methylphenyl)-∆1(9)-octalone-2 (11b): IR (nujol): ν˜ ϭ 1660,
1
1614 cmϪ1. Ϫ H NMR: δ ϭ 1.31Ϫ1.47 (m, 1 H), 1.60Ϫ1.75 (m,
2-(4-Biphenylyl)-4,5-dimethyl-1,3,2-dioxaborolane (12d). ؊ I: To a
solution of 4-bromobiphenyl (2.47 g, 10.6 mmol) and bipyridine
(ca. 5 mg) in THF (25 mL) was added nBuLi (4.2 mL, 2.53  in
hexane, 10.6 mmol) slowly at Ϫ78 °C. After 1 h of stirring at Ϫ78
°C, B(OiPr)3 (2.7 mL, 11.7 mmol) was added. The reaction mixture
was stirred at the same temperature for 4 h and warmed up to room
temperature over 2 h. Saturated NH4Cl was added and the re-
sulting mixture was extracted with EtOAc three times. The com-
bined extracts were washed with brine, dried, and concentrated to
give the corresponding boronic acid, which was used for the next
reaction without purification. Ϫ II: To a mixture of the above
boronic acid and MgSO4 (ca. 1 g) in EtOAc (20 mL) was added
2,3-butanediol (0.95 mL, 10.5 mmol, meso/dl isomer ϭ 4:1). The
resulting mixture was stirred at room temperature overnight. After
filtration, the filtrate was concentrated to give a residue, which was
purified by chromatography to furnish the boronate ester 12d
(2.51 g, 94%) as a 92:8 mixture of meso/dl isomers. Ϫ Bp 170 °C
3 H), 1.80Ϫ1.94 (m, 2 H), 2.10 (dq, J ϭ 14, 6 Hz, 1 H), 2.33 (s, 3
H), 2.26Ϫ2.52 (m, 4 H), 3.76 (t, J ϭ 3 Hz, 1 H), 6.00 (d, J ϭ 2 Hz,
1 H), 7.14 (s, 4 H). Ϫ 13C NMR: δ ϭ 20.8, 20.9, 29.0, 30.4, 34.1,
35.0, 36.2, 46.9, 127.0, 127.3, 129.5, 136.1, 138.4, 168.9, 200.4. Ϫ
MS (EI); m/z (%): 240 [Mϩ] (100), 222 (21), 207 (30), 184 (57), 169
(32), 155 (30), 141 (37), 128 (31), 115 (34), 105 (28), 91 (42). Ϫ
HRMS (EI) for C17H20O [Mϩ]: calcd. 240.1514; found 240.1515.
8-(4-Methoxyphenyl)-∆1(9)-octalone-2 (11c): IR (neat): ν˜ ϭ 1670,
1616, 1509, 1250 cmϪ1. Ϫ 1H NMR: δ ϭ 1.32Ϫ2.52 (m, 11 H),
3.74 (t, J ϭ 3 Hz, 1 H), 3.80 (s, 3 H), 5.99 (d, J ϭ 2 Hz, 1 H), 6.86
(d, J ϭ 9 Hz, 2 H), 7.17 (dd, J ϭ 9, 1 Hz, 2 H). Ϫ 13C NMR: δ ϭ
20.8, 29.0, 30.5, 34.1, 34.9, 36.2, 46.5, 55.3, 114.1, 126.8, 128.4,
133.3, 158.2, 169.0, 200.3. Ϫ MS (EI); m/z (%): 256 [Mϩ] (100),
238 (17), 210 (17), 200 (37), 199 (19), 121 (21), 91 (16). Ϫ HRMS
(EI) for C17H20O2 (Mϩ): calcd. 256.1463; found 256.1477.
8-(4-Biphenylyl)-∆1(9)-octalone-2 (11d): IR (neat): ν˜ ϭ 3029, 1670
1
(Ͻ 1 Torr). Ϫ IR (nujol): ν˜ ϭ 1609, 1097 cmϪ1. Ϫ H NMR δ ϭ
1
cmϪ1. Ϫ H NMR: δ ϭ 1.34Ϫ1.50 (m, 1 H), 1.63Ϫ1.79 (m, 3 H),
1.30 and 1.40 (2 d, J ϭ 6 and 6 Hz, 5.52 and 0.48 H), 4.14Ϫ4.24
and 4.66Ϫ4.77 (2 m, 0.16 and 1.84 H), 7.35 (tt, J ϭ 7, 1.5 Hz, 1
H), 7.44 (tt, J ϭ 7, 1.5 Hz, 2 H), 7.62 (d, J ϭ 8 Hz, 4 H), 7.89 (d,
J ϭ 7 Hz, 2 H). Ϫ C16H17BO2 (252.1): calcd. C 76.22, H 6.80;
found C 76.13, H 6.79.
1.85Ϫ2.00 (m, 2 H), 2.13 (dq, J ϭ 14, 6 Hz, 1 H), 2.30Ϫ2.58 (m,
4 H), 3.83 (t, J ϭ 3 Hz, 1 H), 6.04 (d, J ϭ 2 Hz, 1 H), 7.30Ϫ7.61
(m, 9 H). Ϫ 13C NMR: δ ϭ 20.9, 29.1, 30.4, 34.1, 35.1, 36.2, 47.1,
127.1, 127.42, 127.45, 127.9, 128.9, 139.5, 140.5, 140.8, 168.6,
200.3. Ϫ C22H22O (302.4): calcd. C 87.38, H 7.33; found C 87.71,
H 7.33.
2-[4-(Dimethylamino)phenyl]-4,5-dimethyl-1,3,2-dioxaborolane
(12e): According to the procedure described above for the prepara-
tion of the boronate ester 12d, 4-bromo-N,N-dimethylaniline
(2.49 g, 12.4 mmol), nBuLi (5.5 mL, 2.26  in hexane, 12.4 mmol),
B(OiPr)3 (3.2 mL, 13.9 mmol), bipyridine (ca. 5 mg), and THF
(40 mL) afforded the corresponding boronic acid after hydrolysis.
The boronic acid was converted into the boronate ester 12e (1.35 g,
50%, meso/dl isomer ϭ 3:1) by using 2,3-butanediol (1.1 mL,
12.2 mmol, meso/dl isomer ϭ 4:1), MgSO4 (ca. 2 g), and EtOAc
(20 mL). Ϫ Bp 150Ϫ160 °C (Ͻ 1 Torr). Ϫ IR (nujol): ν˜ ϭ 1604,
8-[4-(Dimethylamino)phenyl]-∆1(9)-octalone-2 (11e): IR (neat): ν˜ ϭ
1
1669, 1616, 1521 cmϪ1. Ϫ H NMR: δ ϭ 1.37 (dq, J ϭ 6, 12 Hz,
1 H), 1.59Ϫ1.93 (m, 5 H), 2.09 (dq, J ϭ 14, 6 Hz, 1 H), 2.27Ϫ2.53
(m, 4 H), 2.93 (s, 6 H), 3.71 (t, J ϭ 3.5 Hz, 1 H), 6.00 (d, J ϭ 2 Hz,
1 H), 6.70 (d, J ϭ 9 Hz, 2 H), 7.12 (dd, J ϭ 9, 1 Hz, 2 H). Ϫ 13C
NMR: δ ϭ 20.9, 29.0, 30.4, 34.3, 34.9, 36.2, 40.6, 46.4, 112.8, 126.6,
128.0, 129.0, 149.2, 169.6, 200.5. Ϫ C18H23NO (269.4): calcd. C
80.26, H 8.61; found C 80.42, H 8.54.
1
1094 cmϪ1. Ϫ H NMR δ ϭ 1.27 and 1.37 (2d, J ϭ 6 and 6 Hz,
4.5 and 1.5 H), 2.99 (s, 6 H), 4.07Ϫ4.17 and 4.59Ϫ4.70 (2m, 0.5
and 1.5 H), 6.69 (d, J ϭ 9 Hz, 2 H), 7.69 (d, J ϭ 9 Hz, 2 H).
Ϫ C12H18BNO2 (219.1): calcd. C 65.79, H 8.28; found C 65.94,
H, 8.20.
Acknowledgments
This research was financially supported by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Science, Sports,
and Culture, Government of Japan. The high resolution mass spec-
tra were measured by Mr. Yasumasa Tashiro of Nippon Chemi-
phar.
General Procedure of the Coupling Reaction: Synthesis of 8-phenyl-
∆
1(9)-octalone-2 (11a) is representative. To an ice-cold mixture of
the boronate ester 12a (132 mg, 0.75 mmol) and NiCl2(dppf)
(17 mg, 0.025 mmol) in THF (1.5 mL) was added nBuLi (0.30 mL,
2.53  in hexane, 0.76 mmol) dropwise under argon. The mixture
was stirred at 0 °C for 5 min and then at room temperature for
15 min. Acetate 4 (114 mg, 0.547 mmol, 4α/4β ϭ 3:7) was added to
the mixture, and the resulting solution was stirred at 60 °C for 14 h.
Saturated NaHCO3 was added to the mixture and the product was
extracted with hexane three times. The combined hexanes were
[1]
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A. Belanger, D. Philibert, G. Teutsch, Steroids 1981, 37,
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E.-E. Baulieu, Science 1989, 245, 1351Ϫ1357.
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3396
Eur. J. Org. Chem. 2000, 3393Ϫ3397

Arylation of 8-Acetoxyoctalenone in a Nickel-Catalyzed Coupling Reaction
FULL PAPER
[3e]
[11]
1989, 28, 773Ϫ776. Ϫ
S. Scholz, H. Hofmeister, G. Neef,
The original phenylborate prepared from 12a and MeLi gave
a 57:43 mixture of 11a and 3 under the best conditions (Table
1, Entry 4).
Coupling constants of the proton attached to C-8 for the major
and minor product were almost same as those of acetate 4β
and 4α, respectively (for 1H NMR spectra, see Experimental
Section).
Recently, Trost reported a palladium-catalyzed allylic coupling
reaction involving the palladium enolate: B. M. Trost, F. D.
Toste, J. Am. Chem. Soc. 1999, 121, 3543Ϫ3544.
Stereochemistry of the products 11bϪe was determined by
comparison of the coupling constants for the proton at C-8
with those of 11a. The 1H NMR spectroscopic data of the pro-
tons for α-Ar isomers of 11bϪe were as follows. Ϫ Isomer of
11b: δ ϭ 3.34 (dd, J ϭ 12, 4 Hz, 1 H). Ϫ Isomer of 11c: δ ϭ
3.33 (dd, J ϭ 11, 4 Hz, 1 H). Ϫ Isomer of 11d: δ ϭ 3.42 (dd,
J ϭ 12, 4 Hz, 1 H), Ϫ Isomer of 11e: δ ϭ 3.28 (dd, J ϭ 13,
4 Hz, 1 H).
E. Ottow, C. Scheidges, R. Wiechert, Liebigs Ann. Chem. 1989,
[3f]
151Ϫ158. Ϫ
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A. Cleve, G. Neef, E. Ottow, S. Scholz, W.
[12]
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5464Ϫ5465. Ϫ
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[4c]
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[14]
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2977Ϫ2980. Ϫ
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[5c]
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[8]
[9]
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Y. Kobayashi, R. Mizojiri, E. Ikeda, J. Org. Chem. 1996, 61,
5391Ϫ5399.
To check reactivity of the catalytic system, reaction of acetate
[PhCHϭCHϪCH(OAc)Me] with PhZnCl in the presence of
Pd(tpp)4 (see ref.[6b]) was tested to give the product [PhCHϭ
CHϪCH(Ph)Me] in 86% yield.
[15]
[16]
L. M. Venanzi, J. Chem. Soc. 1958, 719Ϫ724.
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Formation of a reduction product was reported in the at-
tempted palladium-catalyzed coupling reaction of the cepham
acetate and PhSnMe3.[7]
5, 869Ϫ871.
Received March 13, 2000
[O00121]
Eur. J. Org. Chem. 2000, 3393Ϫ3397
3397