Synthesis of β,γ-unsaturated ketones by allylation of pentamethylcyclopentadienyl ketones followed by removal of pentamethylcyclopentadiene

Article abstract of DOI:10.1055/s-2006-956455

A new route to β,γ-unsaturated ketones is disclosed. Aryl pentamethylcyclopentadienyl ketones underwent allylation with allyldimethylaluminum to yield the corresponding alcohols. Heating the alcohols in boiling toluene resulted in removal of pentamethylcy

Full text of DOI:10.1055/s-2006-956455

LETTER
167
Synthesis of b,g-Unsaturated Ketones by Allylation of Pentamethylcyclopenta-
dienyl Ketones Followed by Removal of Pentamethylcyclopentadiene
Synthesis of
b
,
g
-Unsat
a
urated
K
eto
s
nes ayuki Iwasaki, Eiji Morita, Minoru Uemura, Hideki Yorimitsu,* Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan
Fax +81(75)3832438; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp; E-mail: oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received 20 September 2006
magnesium chloride (Cp*MgCl) took place to form 4a.
Abstract: A new route to b,g-unsaturated ketones is disclosed. Aryl
The ketone 4a, having a less hindered, and thus more
reactive carbonyl group compared to that of 2a, immedi-
ately reacted with the Grignard reagent. The elimination
pentamethylcyclopentadienyl ketones underwent allylation with al-
lyldimethylaluminum to yield the corresponding alcohols. Heating
the alcohols in boiling toluene resulted in removal of pentamethyl-
cyclopentadiene to provide b,g-unsaturated ketones. The removal of Cp*MgCl took place due to the weaker oxophilicity of
would proceed via a retro-carbonyl–ene process. Synthesis of an
alkyl allyl ketone is also described.
magnesium than that of aluminum. Higher reaction
temperatures such as 0 °C in the allylation step also led to
Key words: allylation, cleavage, pentamethylcyclopentadiene, ke-
tones
the formation of 6, even when the allylaluminum reagent
was used.
Among compounds 2, only ortho-iodophenyl ketone 2e
resisted the allylation (entry 5). When the allylation reac-
tion of 2e was performed at 0 °C, the reaction resulted in
recovery of 2e (78%), and formation of a small amount of
4e (<10%) and the iodinated analogue of 6 (<10%).
The b,g-unsaturated carbonyl moiety is an interesting
building block in organic synthesis. However, synthesis
of b,g-unsaturated ketones1 is often complicated since the
ketones are prone to isomerization into the corresponding
a,b-unsaturated ketones under basic or acidic conditions.
Here we report a new route to b,g-unsaturated ketones.
The route involves allylation of aryl pentamethylcyclo-
pentadienyl ketones (ArCOCp*) and the subsequent re-
moval of pentamethylcyclopentadiene (Cp*H)2 from the
tertiary alcohols under neutral conditions. The neutral
conditions can prevent the undesirable isomerization.
Table 1 Synthesis of b,g-Unsaturated Ketones via ArCOCp*
AlMe2
(1.5 equiv)
O
O
Cp*Li (1.1 equiv)
THF, 0 °C, 30 min
THF, –20 °C, 1 h
Ar
Cl
Ar
Cp*
1
2
OH
O
toluene
reflux,15 min
Ar
Ar
3
4
Cp*
Aryl pentamethylcyclopentadienyl ketones were prepared
by the reactions of acid chlorides with lithium penta-
methylcyclopentadienide (Cp*Li) in high yields
(Table 1). Ketones 2 underwent allylation by reacting
with allyl-dimethylaluminum, prepared from allyl-
magnesium chloride and chlorodimethylaluminum. The
allylation afforded the corresponding tertiary alcohols 3.
Even though alcohols 3 were stable in a refrigerator in the
absence of acid or base, heating 3 in boiling toluene for 15
minutes resulted in removal of Cp*H to yield the allyl aryl
ketones 4a–4g.3 The removal most probably proceeded
via a retro-carbonyl–ene process.2a,c We could isolate the
intermediate 3 conveniently. For instance, usual silica gel
column chromatographic purification of a crude oil
derived from 2a provided 92% of 3a.
Entry
Ar
2 (%)
4 (%)
1
2
3
4
5
6
7
Ph
2a (90)
2b (92)
2c (61)
2d (89)
2e (78)
2f (93)
2g (91)
4a (82)
4b (95)
4c (90)
4d (93)
4e –
p-CF3C6H4
p-CF3C6H4
p-BrC6H4
o-IC6H4
m-ClC6H4
2-Thienyl
4f (70)
4g (62)
MgCl
OMgCl
Ph
– Cp*MgCl
(1.2 equiv)
The use of allylmagnesium chloride instead of the allyl-
aluminum reagent provided 6 selectively and an un-
changed 2a (Scheme 1). No formation of 3a was
observed. Magnesium alkoxide 5 was so unstable that
an in situ elimination of pentamethylcyclopentadienyl-
2a
THF, –20 °C
Cp*
5
1.0 mmol
OH
MgCl
Ph
4a
6
0.56 mmol
SYNLETT 2007, No. 1, pp 0167–0169
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-956455; Art ID: U10906ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

168
M. Iwasaki et al.
LETTER
5 mol% Pd(OAc)2
15 mol% PPh3
1.2 equiv Na2CO3
Preparation and allylation of aliphatic ketone 2h were per-
formed in a similar fashion (Scheme 2). However, at-
tempted removal of Cp*H under thermal conditions
resulted in recovery of 3h. Instead, treatment of 3h with a
catalytic amount of trichloroacetic acid at 25 °C yielded
allyl heptyl ketone (4h) in 99% yield.2a,c Fortunately, the
acidic conditions did not promote the isomerization of 4h
into the corresponding a,b-unsaturated ketone.
O
2d
2.0 mmol
+
PhB(OH)2
1.2 equiv
Cp*
iPrOH–H2O (8 mL + 4 mL)
100 °C, 3 h
9a 98%
Ph
O
AlMe2
(1.5 equiv)
THF, –20 °C
toluene, reflux
15 min
Ph
10a 84%
Methallylation of 2a followed by removal of Cp*H yield-
ed the corresponding ketone 8 in good yields (Scheme 3).
However, the reactions of 2a with dimethylprenylalu-
minum and crotyldimethylaluminum at –20 °C, or even at
0 °C, did not proceed. The reactions of 2a with prenyl-
and crotylmagnesium chloride resulted in the formation of
complex mixtures containing the corresponding ana-
logues of 6.
5 mol% Pd2(dba)3
O
15 mol% PtBu3
2f
0.50 mmol
+
PhB(OH)2
1.2 equiv
Ph
3.3 equiv KF
Cp*
9b 73%
dioxane (1 mL)
100 °C, 72 h
O
AlMe2
(1.5 equiv)
THF, –20 °C
Ph
toluene, reflux
15 min
10b 86%
AlMe2
(1.5 equiv)
O
O
5 mol% Pd(OAc)2
15 mol% PPh3
2.4 equiv CsF
Cp*Li (1.05 equiv)
THF, 0 °C, 1 h
O
2d
1.0 mmol
+
ArB(OH)2
1.2 equiv
nC7H15
Cl
nC7H15
2h 73%
Cp*
THF, –20 °C, 1 h
Cp*
1h
DME (10 mL)
100 °C, 13 h
Ar = p-(MeOCO)C6H4
9c 94%
Ar
OH
O
10 mol% CCl3COOH
O
AlMe2
(1.5 equiv)
THF, –20 °C
nC7H15
nC7H15
CH2Cl2
25 °C, 2 h
Cp*
3h 85%
4h 99%
toluene, reflux
15 min
10c 49%
Ar
Scheme 2
Scheme 4
(1.5 equiv)
AlMe2
OH
O
References and Notes
Ph
2a
Cp*
toluene
reflux
15 min
THF, –20 °C
Ph
(1) (a) Gohain, M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S. New
J. Chem. 2003, 27, 1038. (b) Yasuda, M.; Tsuchida, M.;
Baba, A. Chem. Commun. 1998, 563. (c) Inaba, S.; Rieke,
R. D. J. Org. Chem. 1985, 50, 1374. (d) Onaka, M.; Goto,
T.; Mukaiyama, T. Chem. Lett. 1979, 1438. (e) Yadav, J. S.;
Reddy, B. V. S.; Reddy, M. S.; Parimala, G. Synthesis 2003,
2390. (f) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2004, 45,
1295. (g) Lee, A. S.-Y.; Lin, L.-S. Tetrahedron Lett. 2000,
41, 8803. (h) Baruah, B.; Boruah, A.; Prajapati, D.; Sandhu,
J. S. Tetrahedron Lett. 1996, 37, 9087. (i) Marceau, P.;
Gautreau, L.; Béguin, F.; Guillaumet, G. J. Organomet.
Chem. 1991, 403, 21. (j) Calas, R.; Dunogues, J.; Pillot, J.-
P.; Biran, C.; Pisciotti, F.; Arreguy, B. J. Organomet. Chem.
1975, 85, 149.
(2) (a) Yagi, K.; Yorimitsu, H.; Oshima, K. Tetrahedron Lett.
2005, 46, 4831. (b) Uemura, M.; Yorimitsu, H.; Oshima, K.
Tetrahedron Lett. 2006, 47, 163. (c) Uemura, M.; Yagi, K.;
Iwasaki, M.; Nomura, K.; Yorimitsu, H.; Oshima, K.
Tetrahedron 2006, 62, 3523. (d) Uemura, M.; Yorimitsu,
H.; Oshima, K. Chem. Lett. 2006, 35, 408.
(3) General Procedure (Table 1, Entry 2): BuLi (1.7 M
hexane solution, 6.5 mL, 11 mmol) was added to a solution
of 1,2,3,4,5-pentamethyl-1,3-cyclopentadiene (1.9 mL, 12
mmol) in THF (30 mL) at 0 °C. The resulting white
suspension was stirred for 40 min. p-Trifluoromethyl-
benzoyl chloride (1.49 mL, 10.0 mmol) was then added to
the suspension at 0 °C. After being stirred for 30 min, the
mixture was poured into water and extracted with EtOAc.
The organic layer was dried over Na2SO4. Evaporation
followed by silica gel column chromatographic purification
(hexane–EtOAc = 80:1) provided 2b (2.84 g, 9.2 mmol) in
92% yield. Allylmagnesium bromide (0.94 M ethereal
7
8 100%
Scheme 3
The pentamethylcyclopentadienylcarbonyl groups in 2
were compatible under basic conditions. Hence 2 can be
more useful intermediates than acid chlorides. For in-
stance, 2d and 2f underwent the cross-coupling reactions
with arylboronic acids under palladium catalysis to yield
biaryls 9 in good yields (Scheme 4). The biaryls 9 having
a Cp*CO moiety were transformed into the corresponding
b,g-unsaturated ketones 10. The ketones 10 would not be
accessible from 4d and 4f since 4d and 4f would isomer-
ize under such basic conditions during the cross-coupling
reactions.
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology, Government of Japan.
Synlett 2007, No. 1, 167–169 © Thieme Stuttgart · New York

LETTER
solution, 2.4 mL, 2.3 mmol) was placed in a 20-mL reaction
Synthesis of b,g-Unsaturated Ketones
169
silica gel (hexane–EtOAc = 10:1) afforded 4b (0.31 g, 1.4
mmol) in 95% yield. Ketone 2b: colorless oil. IR (neat):
2921, 1674, 1325, 1169, 1130, 1068 cm–1. 1H NMR (500
MHz, CDCl3): d = 1.26 (s, 3 H), 1.69 (s, 6 H), 1.83 (s, 6 H),
7.49 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H). 13C NMR
(125.7 MHz, CDCl3): d = 10.77, 11.61, 18.84, 70.60, 123.91
(q, J = 273 Hz), 125.11 (q, J = 4 Hz), 127.67, 133.29 (q, J =
32 Hz), 139.19, 139.56, 141.30, 201.94. Anal. Calcd for
C18H19F3O: C, 70.12; H, 6.21. Found: C, 69.88; H, 6.33.
Ketone 4b showed spectra identical to the reported data:
Toy, P. H.; Dhanabalasingam, B.; Newcomb, M.; Hanna, I.
H.; Hollenberg, P. F. J. Org. Chem. 1997, 62, 9114.
flask under argon. Chlorodimethylaluminum (1.04 M
hexane solution, 2.2 mL, 2.3 mmol) was added at –20 °C.
After the mixture was stirred for 10 min, ketone 2b (0.46 g,
1.5 mmol in 6 mL of THF) was added dropwise. The whole
mixture was stirred for 1 h at –20 °C. The reaction was
quenched with 1 M HCl. Extractive workup yielded a crude
oil. The oil was passed through a pad of silica gel with
EtOAc to remove polar impurities. The filtrate was
concentrated in vacuo. The resulting oil was dissolved in
toluene (13 mL) and heated at reflux for 15 min under an
atmosphere of argon. Concentration and purification on
Synlett 2007, No. 1, 167–169 © Thieme Stuttgart · New York

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