One-pot method for α-phenylation of ketones using isoxazolidine and triphenylaluminum

Article abstract of DOI:10.1016/j.tetlet.2012.05.146

The efficient one-pot umpolung α-phenylation of ketones via N-alkenylisoxazolidine is described. When the various ketones are treated with triphenylaluminum prepared from phenylmagnesium chloride and AlCl₃ in the presence of isoxazolidine, the desired products are obtained in good to moderate yield. This method is equivalent to a direct α-arylation reaction of carbonyl groups.

Full text of DOI:10.1016/j.tetlet.2012.05.146

Tetrahedron Letters 53 (2012) 4188–4191
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot method for a-phenylation of ketones using isoxazolidine
and triphenylaluminum
⇑
Tetsuya Miyoshi, Shohei Sato, Hiroya Tanaka, Chihiro Hasegawa, Masafumi Ueda, Okiko Miyata
Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient one-pot umpolung
the various ketones are treated with triphenylaluminum prepared from phenylmagnesium chloride and
AlCl3 in the presence of isoxazolidine, the desired products are obtained in good to moderate yield. This
a
-phenylation of ketones via N-alkenylisoxazolidine is described. When
Received 11 April 2012
Revised 25 May 2012
Accepted 30 May 2012
Available online 7 June 2012
method is equivalent to a direct
a
-arylation reaction of carbonyl groups.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Umpolung
Ketone
One-pot reaction
Enamine
Phenylmagnesium chloride
The direct introduction of an aryl group at a nucleophilic
bon of a carbonyl compound is a challenging problem in organic
synthesis. It is known that -arylation proceeds via the nucleo-
philic aromatic substitution (SNAr) of an enolate and an aryl halide,
but the scope of these reactions has been limited to electron-with-
drawing substituted aryl halides.1 Over the last decade, the transi-
a
-car-
that could be applied not only to nonanone but also to various
other ketones.
a
In this one-pot method, we considered that the bulky triarylalu-
minum reagents would not react with ketone 1 due to steric
hindrance, and the reaction with in situ-derived N-alkenylisoxaz
olidines 2 from the ketone and isoxazolidine would preferentially
proceed (Scheme 1). Furthermore, the excess amount of triarylalu-
minum reagents would trap H2O which was generated by the con-
densation reaction of the ketone and isoxazolidine.
tion metal-catalyzed
a-arylation reaction of carbonyl compounds
has been developed.2 Buchwald,3 Hartwig,4 Miura,5 and others6
have shown that the transformation is effective for coupling of var-
ious aryl halides with ketones, esters, amides, aldehydes, and eno-
lates. However, these procedures suffer from the use of costly
transition metals, exotic and/or expensive ligands, or an elevated
reaction temperature. More recently, Coltart and his co-worker re-
We firstly examined in more detail the reaction with nonanone
under the same conditions as the previous report (Table 1, entry
1).9 To a solution of 5-nonanone (1a) and isoxazolidine was added
triphenylaluminum reagent prepared from AlCl3 and phenylmag-
nesium bromide in THF. The desired product 3a was obtained in
73% yield similar to the previous report. When we researched the
ported the construction of
arylation of N-sulfonyl azoalkenes.7 However, this did not achieve
the direct transformation of ketone into -arylketone, and only one
a-phenylketones by using umpolung
a
by-products in detail, a
-alkoxylated ketone 4a was observed.10
example of arylation was provided while the others were alkyl-
ation reactions. We previously reported the umpolung alkylation
We thought that the by-product was obtained from THF and the
bromide ion of the phenylmagnesium bromide that were used in
the preparation of the triphenylaluminum reagent.11 Therefore,
we examined the reaction in the absence of THF or bromide ion
to suppress the generation of the by-product. Using a solution of
triphenylaluminum in Et2O resulted in lower yields of the desired
product (Table 1, entry 2). When phenylmagnesium chloride was
employed instead of phenylmagnesium bromide to prepare the tri-
phenylaluminum, this umpolung phenylation proceeded without
the generation of by-product 4a to afford phenylnonanone 3a in
78% yield (Table 1, entry 3). Thus, the yield of the one-pot reaction
could be increased by using phenylmagnesium chloride instead of
phenylmagnesium bromide to prepare triphenylaluminum.
and arylation of N-alkenylisoxazolidines to afford various
a-aryl
ketones.8 In this previous report, we primarily described the step-
wise reaction of enamine formation and the umpolung reaction,
and additionally reported part of a one-pot reaction with nona-
none. The one-pot reaction was suitable for the construction of
a-arylketones, however, the
a-arylation of the ketones expect for
nonanone diminished the yield of the desired product. In this con-
text, we developed a general one-pot method for
a-phenylation
⇑
Corresponding author. Tel.: +81 78 441 7554; fax: +81 78 441 7556.
E-mail address: miyata@kobepharma-u.ac.jp (O. Miyata).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.146

T. Miyoshi et al. / Tetrahedron Letters 53 (2012) 4188–4191
4189
O
O
O
N
H
O
N
Ar3Al
Ar
R1
R1
R1
R2
R2
R2
1
3
2
Ar3Al
Ar3Al
H2O
Ar2Al(OH)
+
ArH
Ar
R2
HO
R1
Scheme 1. One-pot strategy of umpolung
a-arylation of ketones.
Table 1
Optimization of one-pot phenylation of 5-nonanone
AlCl3
+
PhMgX in solvent
O
O
O
O
N
H
Ph3Al
,
Ph
O
Br
n
Bu
n
Bu
( )4
n
Bu
CH2Cl2
Pr
n
Pr
n
n
Pr
3a
4a
1a
Entry
X
Solvent
Yielda (%)
3a
4a
1
2
3
Br
Br
Cl
THF
Et2O
THF
73
38
78
8
NDb
NDb
a
Isolated yield.
ND = not detected.
b
AlCl3
+
PhMgX in THF
O
O
O
O
N
O
Br
Ph
nBu
( )4
H
Me
Ph3Al
Me
(1)
CH2Cl2
1b
3b
4b
X=Br
X=Cl
56%
81%
21%
--
AlCl3
+
O
PhMgX in THF
O
O
O
O
Br
( )4
Ph
N
H
Ph3Al
(2)
CH2Cl2
Ph
Ph
1c
Ph
3c
4c
X=Br
X=Cl
31%
58%
16%
--
Scheme 2. One-pot
a
-phenylation of ketones with phenyl magnesium bromide and chloride.
These results in hand, we next investigated the reaction of other
ketones 1b and 1c with triphenylaluminum prepared from phenyl-
magnesium bromide and chloride. In the case of 5-hexen-2-one 1b,
the use of phenylmagnesium bromide gave the desired product 3b
in moderate yield (56%) and the by-product 4b in 21% yield. In-
stead, the use of phenylmagnesium chloride greatly improved

4190
T. Miyoshi et al. / Tetrahedron Letters 53 (2012) 4188–4191
Table 2
a
-Phenylation of various ketones
AlCl3
+
PhMgCl in THF
O
N
O
O
Ph3Al
CH2Cl2
,
H
Ph
R1
R1
R2
R2
1
3
Entry
1
Substrate
Product
Yielda (%)
79 (73)b
O
O
Ph
Et
Et
3d
1d
Me
O
Me
O
Ph
2
3
70 (68)b
n
C7H15
O
n
C7H15
O
n
C6H13
3e
n
C6H13
1e
Ph
Me
76
Me
n
Pr
n
Pr
3f
1f
O
O
O
O
Ph
4
5
6
76
Me
Me
Me
Me
1g
3g
CN
CN
78 (73)b
Ph
1h
3h
Bn
Bn
O
O
O
Ph
63c
Ph
1i
Ph
Me
Ph
Ph
3i'
Me
Ph
3i
Me
Ph
O
O
Ph
7
8
51
1j
3j
Me
O
Me
Ph
O
O
63 (60)b
3k
1k
O
Me
Me
Ph
9
61
60
3l
1l
O
O
Ph
10
3m
1m
a
Isolated yield.
b
Values in parentheses indicated the yield of isolated product in a stepwise procedure.
Reaction produced a 2:1 mixture of regioisomers 3i and 3i0.
c
the yield of 3b (81%) (Eq. 1). A similar result was obtained for the
cyclic ketone 1c (Eq. 2). The yield of 3c also increased to 58% from
31% when phenylmagnesium chloride was used. These results indi-
cated that the low yield of the desired product 3 was caused by the
generation of 4, and the use of phenylmagnesium chloride im-
proved the yield by suppressing the formation of 4.
To explore the scope of the reaction, we examined various ke-
tones. As shown in Table 2, the symmetric linear ketones 1d and
1e gave the desired a-phenylated products in good yields (entries
1 and 2). To examine the regioselectivity of this reaction, asymmet-
ric linear ketones were also investigated. The reaction using ke-
tones bearing a methyl group as R1 proceeded regioselectively at

T. Miyoshi et al. / Tetrahedron Letters 53 (2012) 4188–4191
4191
5. (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997,
36, 1740; (b) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002,
43, 101.
6. (a) Iwama, T.; Rawal, V. H. Org. Lett. 2006, 8, 5725; (b) Guo, Y.; Twamley, B.;
Shreeve, J. M. Org. Biomol. Chem. 2009, 7, 1716; (c) Desai, L. V.; Ren, D. T.;
Rosner, T. Org. Chem. 2010, 12, 1032; (d) Allen, A. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2011, 133, 4260.
7. Hatcher, J. M.; Coltart, D. M. J. Am. Chem. Soc. 2010, 132, 4546.
8. Miyoshi, T.; Miyakawa, T.; Ueda, M.; Miyata, O. Angew. Chem., Int. Ed. 2011, 50,
928.
the secondary carbon to afford 3f–h (entries 3–5). On the other
hand, 1-phenyl-2-butanone (1i), an asymmetric ketone bearing a
secondary carbon at both
a
- and a0-positions gave a 2:1 mixture
of regioisomers 3i and 3i0 (entry 6). While propiophenone (1j)
underwent the desired reaction with a slightly diminished yield,
it was improved over that of the stepwise reaction using propio-
phenone and (4-MeOC6H4)3Al (29%) (entry 7).8 The cyclic ketone,
cyclohexanone (1k), gave the desired product 3k in 63% yield
(entry 8). To test the substituent effect of cyclohexanone, cyclohex-
anone derivatives 1l was employed. Interestingly, 2-methylcyclo-
hexanone gave only the trans-isomer 3l in a diastereoselective
manner (entry 9), whereas 4-phenylcyclohexanone gave the cis-
isomer 3c (Scheme 2). Furthermore, seven-membered cyclohepta-
9. Experimental procedure: To
a
solution of ketone
1
(0.50 mmol) and
added
isoxazolidine (0.75 mmol) in dry
CH2Cl2 (5.0 mL) was
triphenylaluminum (1.0 mmol) dropwise at 0 °C. After stirring at room
temperature for 8–16 h, the reaction was quenched by the addition of water.
The resulting suspension was filtered and the filtrate was extracted with CHCl3.
The combined organic layers were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by either flash column
chromatography or PTLC to give 3.
none also gave
a-phenylketone 3m in 60% yield (entry 10).
10. NMR and HRMS data for compound 4a: 1H NMR (300 MHz) d: 3.65 (1H, dd,
J = 7.0, 5.0 Hz, 4-H), 3.48 (1H, dt, J = 9.0, 6.5 Hz, 10-H), 3.46 (2H, t, J = 6.5 Hz, 40-
H), 3.36 (1H, dt, J = 9.0, 6.0 Hz, 10-H), 2.90 (2H, td, J = 7.0, 3.0 Hz, 6-H), 2.03–1.93
(2H, m), 1.78–1.70 (2H, m), 1.62–1.28 (8H, m), 0.92 (3H, t, J = 7.5 Hz, 1-H or 9-
H), 0.91 (3H, t, J = 7.5 Hz, 1-H or 9-H); 13C NMR (75 MHz) d: 213.5, 85.7, 69.5,
37.2, 34.2, 33.6, 29.6, 28.5, 25.3, 22.4, 18.6, 13.9, 13.9; HRMS m/z: Calcd for
In summary, we describe a general one-pot method for the
a
-
phenylation of ketones using isoxazolidine and triphenylaluminum
reagents. We found that the use of phenylmagnesium chloride for
the preparation of aluminum reagents was able to increase the
13H26O281Br (M+H+) 295.1090. Found: 295.1090.
yield of the one-pot reaction. This reaction allows direct a-pheny-
C
11. Possible reaction pathway for bromobutoxylated compound 4a: The bromide ion
attacked the 2-position of THF which was activated by aluminum reagents to
give bromobutoxyaluminum A. Then, the N-alkoxyenamine 2a was reacted
lation without the use of transition metal catalyst under mild con-
ditions. By comparison with a two step procedure, the one pot
reaction simplifies the method, and minimizes the use of solvents.
with A to afford the a-bromobutoxylated ketone 4a. The production of A might
occur in the presence of free isoxazolidine or hydroxyaluminum species, since
the by-product 4a was not isolated in a stepwise procedure.
Acknowledgments
The Grant-in-Aid for Scientific Research (C) and Young Scien-
tists (B) from the Japan Society for the promotion of Science are
gratefully acknowledged.
AlY3
Br
Br
( )4
O
Y2Al
O
Y = Ar, OH
A
References and notes
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O
O
O
O
N
H
N
A
1)
O
Br
3. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108; (b) Fox, J. M.;
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nBu
( )4
nBu
nBu
nPr
2)H2O
nPr
nPr
1a
4a
2a