Syntheses of pentafulvenes from 4-alkylidenecyclopentenones

Article abstract of DOI:10.1016/S0040-4039(02)01018-3

An efficient synthesis of polysubstituted pentafulvenes from 4-alkylidenecyclopentenones is reported via a two-step procedure consisting of addition of an organometallic reagent (or reduction) followed by dehydration.

Full text of DOI:10.1016/S0040-4039(02)01018-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5029–5031
Syntheses of pentafulvenes from 4-alkylidenecyclopentenones
Fre´de´ric Antras, Mohammed Ahmar and Bernard Cazes*
Laboratoire de Chimie Organique I, associe´ au CNRS, Universite´ Claude Bernard-Lyon, Baˆt. CPE-Lyon,
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Received 24 May 2002; accepted 29 May 2002
Abstract—An efficient synthesis of polysubstituted pentafulvenes from 4-alkylidenecyclopentenones is reported via a two-step
procedure consisting of addition of an organometallic reagent (or reduction) followed by dehydration. © 2002 Elsevier Science
Ltd. All rights reserved.
4-Alkylidene-2-cyclopentenones I are relatively little
known compounds, presumably because of difficult or
unselective preparation.1,2 We recently developed a
straightforward synthesis of these cyclopentenones via
the N-methylmorpholine oxide (NMO) initiated
Pauson–Khand reaction of alkynes with allenic com-
pounds (Scheme 1).3 This route was in most cases
highly regioselective4 and should be considered as a
rather general route to 4-alkylidene-2-cyclopentenones I
as the experimental conditions are compatible with a
large number of functionalities.5,6
hands, because of the easy enolization of the 4-alkyl-
idenecyclopentenones. Indeed, the reaction of ketones
1c with nBuLi (1.2 equiv.) in ether at −78°C followed
by an acidic work-up gave only the recovered ketone
1c. On the other hand a similar addition at −78°C
followed by quenching with diethylchlorophosphate
gave the enol phosphate 3 (20%) and very small
amounts of the phosphate 4 (5%) together with the
recovered ketone 1c (Scheme 2). We report here on
more effective conditions for the 1,2-addition of an
organometallic species to 4-alkylidenecyclopentenones
I, as well as on the reduction of the keto group of these
compounds.
These cyclopentenones I might be appropriate starting
materials for the synthesis of pentafulvenes III via the
dienic alcohols II obtained by the addition of
organometallic reagents or the reduction of ketones I.
This strategy has been shortly described by Martin et
al. who obtained some few pentafulvenes by the slow
addition of an 4-alkylidenecyclopentenone I to an ethe-
real solution of methyl or phenyllithium (1.2 equiv.) at
−70°C, followed by an acidic work-up which realized
the dehydration of the intermediate alcohol II.7
We observed that the reaction of lithium reagents with
the cyclopentenones 1 was more efficient in ether at
0–20°C and gave the very unstable7 tertiary dienic
alcohols 5. Then, these crude alcohols 5 were immedi-
ately treated with 2–4% M p-toluenesulfonic acid or
with ZnBr2 (1 equiv.) in petroleum ether at room
temperature for 15–30 min. Both conditions gave
pentafulvenes 6 in similar yields. The yields depended
dramatically on the number of equivalents of the added
organometallic compound (results summarized in Table
1). Indeed, the addition of butyllithium (1.2 equiv.) to
cyclopentenone 1a gave the pentafulvene 6a with a low
However, the yields of fulvenes III were not clearly
mentioned and the reactions with various lithium com-
pounds turned out to be difficult to reproduce in our
Scheme 1.
Keywords: cyclopentenones; alkyllithium; Grignard reagents; addition reactions; fulvenes.
* Corresponding author. Tel.: +33 4.72.44.85.39; fax: +33 4.72.43.12.14; e-mail: cazes@univ-lyon1.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01018-3

5030
F. Antras et al. / Tetrahedron Letters 43 (2002) 5029–5031
O
O P(OEt)2
O
O
Li
O
O
R1
Bu O P(OEt)2
1) BuLi (1.1 eq)
Ether / -78°C
R1
2)
Cl P(OEt)2
R1
R1
+
1c (R1 = nC5H11
)
3 (20%)
4 (5%)
Scheme 2.
Table 1. Synthesis of pentafulvenes 6 via addition of organometallic reagents to 4-alkylidenecyclopentenone/dehydration
R
R
OH
O
1) R-Met (n eq.)
2-4% pTsOH
or ZnBr2
R1
R1
R2
1a-c
R1
R2
Ether / 0-20°C
R3
R3
R3
R2
Petroleum ether / rt
(- H2O)
2) H2O
R4
R4
R4
5
6
Entry
Cyclopentenone 1
R1
R2
R3
R4
R-Met
No. equiv.
Pentafulvene 6
Yield (%)a
6
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1b
1b
1b
1b
nC3H7
nC3H7
CH3
CH3
CH3
CH3
CH3
nC5H11
nC5H11
nC5H11
CH3
nC3H7 nC6H13
nC3H7 nC6H13
H
H
BuLi
BuLi
BuLi
BuLi
BuLi
PhLi
PhLi
MeMgBr
MeMgBr
BuMgBr
MeMgBr
PhMgBr
PhMgBr
CyMgBr
1.2
2.5
2.5
5
10
5
10
1.2
2.5
2.5
2.5
5
6a
6a
6b
6b
6b
6c
6c
6d
6d
6e
6f
28
38
31
60
77
78
93
35
65
46
72
60
83
86
CH3
CH3
CH3
CH3
CH3
H
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
9
H
H
10
11
12
13
14
CH3
CH3
CH3
CH3
CH3
CH3
CH3
6g
6g
6h
10
10
a Yield of purified products 6 after a short chromatography on alumina.
The reduction of cyclopentenones 1a–e was classically
carried out with 1 equiv. LiAlH4 in ether at 0°C fol-
lowed by quenching with aqueous NaOH (Table 2).
The secondary dienic alcohols 7 were considerably
more stable than the corresponding tertiary ones 5, as
spectroscopic NMR analysis was feasible without the in
situ dehydration to fulvene 8. This last transformation
was easily realized in acidic conditions and gave penta-
fulvenes 8 with satisfactory yields (50–80%).
28% yield (entry 1) while the yield increased to 38% by
using 2.5 equiv. (entry 2). Similar results were observed
with the addition of BuLi and PhLi to ketone 1b
(entries 3–7). Yields up to 77–93% were obtained when
10 equiv. of the organolithium were used (entries 5 and
7). Thus, the use of a large excess of the lithium
reagents is necessary to promote the 1,2-addition to the
carbonyl group of cyclopentenones 1 over the enolate
anion formation. Aggregation phenomena between sol-
vent,8 Lewis bases9 or lithium alkoxides10 and the alkyl-
lithium compounds may be taken into account to
explain this chemoselectivity.11 Indeed, more aggre-
gated reagents have been pointed out to favour the
1,2-addition.9
In summary, we have demonstrated that the 1,2-addi-
tion of organolithium and organomagnesium com-
pounds to 4-alkylidenecyclopentenones requires a large
excess of these reagents to achieve a satisfactory con-
version of these peculiar cyclopentenones, because of
their easy enolization. Thus, the two-step procedure for
addition of an organometallic reagent or reduction
followed by dehydration constitutes an efficient synthe-
sis of polysubstituted pentafulvenes from 4-alkylidene-
cyclopentenones. These methods offer the advantage of
producing regioselectively substituted pentafulvenes
which are versatile synthetic intermediates.13
The addition of organomagnesium compounds to
cyclopentenones 1 were very similar.12 We observed the
same increase of the yields for the overall transforma-
tion when an excess of the Grignard reagent was used
(entries 8–14). Yields as high as 85% were obtained
with the addition of 10 equiv. (entries 13 and 14).

F. Antras et al. / Tetrahedron Letters 43 (2002) 5029–5031
5031
Table 2. Synthesis of pentafulvenes 8 via reduction of 4-alkylidenecyclopentenone/dehydration
OH
O
1) AlLiH4
R1
R1
R2
R1
R2
1a-e
4% pTsOH
Ether / 0°C
R3
R3
R3
R2
Petroleum ether / rt
(- H2O)
2) H2O
R4
R4
R4
8
7
Cyclopentenone 1
R1
R2
R3
nC6H13
R4
Yield (%)a alcohol 7
Yield (%)b pentafulvene 8
1a
1b
1c
1d
1e
nC3H7
CH3
nC3H7
nC3H7
Ph
nC3H7
CH3
H
nC3H7
H
H
97
95
99
99
94
53
68
82
62
48
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
a Yield of crude alcohols.
b Yield of purified products after short chromatography on alumina.
References
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