Lithium-liquid ammonia mediated carbocyclisation of δ,ε- unsaturated esters: Annulation of cyclopentanones

Article abstract of DOI:10.1016/j.tetlet.2003.10.164

Lithium-liquid ammonia mediated carbanion cyclisation of δ,ε-unsaturated esters leading to cyclopentanes, fused as well as spiro, via annulation is described.

Full text of DOI:10.1016/j.tetlet.2003.10.164

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 379–382
Lithium–liquid ammonia mediated carbocyclisation
of d,e-unsaturated esters: annulation of cyclopentanones
A. Srikrishna* and S. S. V. Ramasastry
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 10 September 2003; revised 25 September 2003; accepted 24 October 2003
Abstract—Lithium–liquid ammonia mediated carbanion cyclisation of d,e-unsaturated esters leading to cyclopentanes, fused as well
as spiro, via annulation is described.
Ó 2003 Elsevier Ltd. All rights reserved.
The synthetic potential of cyclisation of 5-hexenyl-
lithium, generated from the corresponding iodide or
arylselenide by treatment with butyllithium, to generate
cyclopentylmethyllithium (Eq. 1) has been exploited
recently by several research groups.1 In a similar manner
the utility of samarium iodide for the generation of
dianions from aldehydes/ketones and their cyclisation
(Eq. 2) has also been well studied.2 It is well known that
electron transfer (e.g., alkali metal in liquid ammonia) to
esters results in the formation of either acyloin products
(Eq. 3) or the Bouveault–Blanc reduction to primary
alcohols (Eq. 4).3
However, cyclisation of esters via generation of carba-
nions (at the carbonyl carbon) and their addition to
unactivated double bonds has not been properly
explored.4 Herein, we report the cyclisation of d,e-unsat-
urated esters leading to cyclopentanols under alkali
metal in liquid ammonia reduction conditions.
M/NH3
COOR
O
OR
X
1
2
X = O or H,OH
It was contemplated that reaction of an ester with an
alkali metal in liquid ammonia would form a dianion 1,
which could add to an appropriately located olefin
resulting in the formation of a cyclic compound 2. To test
the validity of the hypothesis, the reaction of the, d,e-
unsaturated ester 4a, obtained from cyclohexylidene-
ethanol5 3a via an ortho ester Claisen rearrangement and
a one carbon homologation, was investigated. Addition
of a THF solution of the ester 4a to a suspension of
lithium (10–15 equiv) in liquid ammonia followed by
workup with ammonium chloride furnished a mixture of
the secondary and primary alcohols 5a and 6a (along
with a small amount of the corresponding aldehyde 7a),
which on oxidation with PCC–silica gel furnished a 3:1
mixture of the cyclopentanone 8a and the aldehyde 7a in
84% yield, which were separated on a silica gel column.6
On the other hand, slow addition of lithium (6 equiv)
to a solution of the ester 4a in liquid ammonia and dry
THF followed by workup, oxidation and separation on a
silica gel column furnished predominantly the cyclo-
pentanone 8a in 90% yield along with 6% of the alde-
hyde 7a. In order to probe the possibility of the aldehyde
Li
Li
ð1Þ
SmI2
OH
R
O
ð2Þ
R
OH
COOR
COOR
M/NH3
M/NH3
( )n
ð3Þ
ð4Þ
( )n
O
RCH2OH
RCOOR'
Keywords: Lithium in liquid ammonia; Carbanion cyclisation; Cyclo-
pentane annulation.
* Corresponding author. Tel.: +91-80-2932215; fax: +91-80-3600683/
3600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.164

380
A. Srikrishna, S. S. V. Ramasastry / Tetrahedron Letters 45 (2004) 379–382
Table 1. Cyclisation of d,e-unsaturated esters6;7
Entry
Ester/aldehyde
Methoda
Products (8+7)
% Yieldb (ratio 8:7)
O
R
O
aa
ab
ac
4a R ¼ OMe
4a R ¼ OMe
7a R ¼ H
A
B
84 (3:1)
96 (15:1)
74 (2:1)
Me
Me
Me
+ 7a
8a
A
O
R
O
O
ba
bb
bc
4b R ¼ OMe
4b R ¼ OMe
7b R ¼ H
A
B
73 (3:2)
94 (15:2)
66 (4:3)
+ 7b
8b
A
O
R
ca
cb
cc
4c R ¼ OMe
4c R ¼ OMe
7c R ¼ H
A
B
85 (3:1)
96 (10:1)
72 (3:2)
A
+ 7c
8c
O
O
R
da
db
dc
dd
4d R ¼ OMe
4d R ¼ OMe
7d R ¼ H
A
B
A
B
81 (6:1)
98 (24:1)
73 (3:2)
94 (4:3)
Me
+ 7d
7d R ¼ H
()7
()7
8d
O
ea
eb
ec
ed
ee
4e R ¼ OMe
4e R ¼ OMe
4e R ¼ OMe
4e0 R ¼ OiPr
7e R ¼ H
A
B
84 (9:2)
93 (1:0)
92 (1:0)
92 (1:0)
91 (1:2)
O
R
+ 7e
Bc
α:β
1:14
8e
B
Ph
B
O
R
O
fa
fb
fc
fd
4f R ¼ OMe
4f R ¼ OMe
7f R ¼ H
A
B
A
B
86 (1:0)
96 (1:0)
75 (2:1)
88 (4:7)
+ 7f
α:β
1:12
7f R ¼ H
8f
O
R
O
H
ga
gb
gc
4g R ¼ OMe
4g R ¼ OMe
7g R ¼ H
A
B
95 (5:6)
93 (11:5)
96 (2:7)
+ 7g
A
8g
O
R
O
H
ha
hb
hc
4h R ¼ OMe
4h R ¼ OMe
7h R ¼ H
A
B
95 (2:1)
92 (7:2)
90 (5:11)
+ 7h
A
8h
O
H
O
MeO
i
4i
B
95 (8:3)
+ 7i
8i
O
ja
jb
jc
4j R ¼ OMe
4j R ¼ OMe
7j R ¼ H
A
B
B
88 (7:2)
96 (11:1)
94 (2:3)
5:1
O
+ 7j
R
8j

A. Srikrishna, S. S. V. Ramasastry / Tetrahedron Letters 45 (2004) 379–382
381
Table 1 (continued)
Entry
Ester/aldehyde
Methoda
Products (8+7)
% Yieldb (ratio 8:7)
ka
kb
kc
kd
A
75 (3:1)
88 (4:1)
70 (5:2)
62 (7:2)
O
2:1
O
B
OEt
Ad
Ae
+ 7k
4k
8k
la
lb
lc
4l R ¼ OMe
4l R ¼ OMe
7l R ¼ H
A
B
90 (4:1)
94 (5:1)
70 (5:2)
+ 7l
R
A
8l
O
O
a Method A: addition of a THF solution of 4 or 7 to a suspension of Li in liquid NH3; Method B: addition of Li to a solution of 4 or 7 in liquid NH3
and THF; in both the methods the alcohol mixture 5 and 6 obtained was oxidised with PCC–silica gel and separated on silica gel.
b Yield for two steps (cyclisation and oxidation).
c In the presence of tert-butanol.
d Sodium is used instead of lithium.
e Potassium is used instead of lithium.
R' R"
R' R"
R'
7a as an intermediate in the conversion of the ester 4a
into the secondary alcohol 5a, the reaction was carried
out with the aldehyde 7a. However, reaction of the
aldehyde 7a in liquid ammonia with lithium followed by
oxidation furnished a 2:1 mixture of the cyclopentanone
8a and the aldehyde 7a, in 74% yield, which suggests that
the aldehyde 7a may not be the intermediate (or more
than one pathway is involved) in the conversion of the
ester 4a into the secondary alcohol 5a.
a
b-e
55-65%
R"
60-75%
COOEt
R
4a-j
COOMe
R
R
OH
3a-j
9a-j
HO
a
60%
COOEt
4k
HO
MeOOC
HOH2C
OH
b-e
Li /
liq. NH3
Me
56%
COOMe
MeOOC
4l
+
9l
3a
4a
5a
6a
O
Scheme 1. Reagents and conditions: (a) MeC(OEt)3, EtCOOH, sealed
tube, 180 °C, 60 h; (b) 5% NaOH, MeOH–H2O (1:1), reflux, 8 h;
(c) (COCl)2, C6H6, rt, 1 h; (d) CH2N2, Et2O, 0 °C ! rt, 3 h; (e) hm,
MeOH, 1 h.
OHC
PCC
Me
+
(15 : 1)
8a
7a
Li
5-exo
R
R
O-
OMe
R
R
O-
OMe
liq.NH3
R
R
trig
COOMe
To establish the generality of the reaction, a series of
olefinic esters 4b–l were subjected to it and the results
are summarised in Table 1. Esters 4a–l were prepared by
conventional methods7 as depicted in Scheme 1. Reac-
tions using both methods were carried out. In all the
cases, the mixture of the alcohols 5 and 6, obtained in
the reaction with lithium and liquid ammonia of the
esters 4, was oxidised with PCC–silica gel in methylene
chloride and the ketone 8 and aldehyde 7 separated by
silica gel column chromatography. It was found that in
all the cases, addition of lithium to a solution of the ester
4 in liquid ammonia and THF (method B) led to efficient
cyclisation as compared to the addition of the ester 4 to
a suspension of lithium in liquid ammonia (method A).
It is worth noting, that there is only a marginal influence
of the metal among lithium, sodium and potassium
(entries kc and kd) on the course of the reaction. Simi-
larly, no significant change was observed by the presence
of an external proton donor such as tert-butanol (entry
4
5
11
8
12
NH3
O-
R
R
Li
R
R
OH
-OMe
O
liq.NH3
OMe
R
R
13
Scheme 2.
ec), and no change was observed by changing the methyl
to ethyl or isopropyl esters. For comparison, the cor-
responding aldehydes 7b–l were also subjected to the
reaction with lithium–liquid ammonia followed by oxi-
dation. Cyclisation was found to be more facile with the
esters 4 than the aldehydes 7. Even a bridged compound,
such as brendane 8l was found to form efficiently. It is
worth mentioning that the cyclopentanone 8f, obtained

382
A. Srikrishna, S. S. V. Ramasastry / Tetrahedron Letters 45 (2004) 379–382
as a 12:1 diastereomeric mixture, is a well-established
precursor for the sesquiterpenes, laurene and epilau-
renes, a-cuparenone and cuparene.6
tricyclic compound in the present reaction also suggests
that the reaction is proceeding via a dianion.9
In conclusion, intramolecular addition of carbanions,
generated from esters under lithium–liquid ammonia
reduction conditions, to unactivated olefins is described,
which resulted in the development of an efficient cyclo-
pentane annulation methodology. Contrary to the gen-
eral reactivity pattern, the cyclisation is found to be
more facile with esters than with the corresponding
aldehydes. The synthetic utility of this reaction in the
construction of simple, fused, spiro and bridged cyclo-
pentanoid systems has been demonstrated. Currently,
we are investigating the application of this methodology
to natural product synthesis.
OH
4-exo
or
CH2OH
COOEt
Li
6-exo
X
OH
or
liq. NH3
9j
9l
10j
10l
4-exo
or
5-endo
X
Li
liq. NH3
COOMe
or
CH2OH
OH
OH
To test the feasibility of cyclisation leading to either six-
or four-membered rings, reaction of the diene ester 9j
was carried out. However, no product from cyclisation
was noticed in the reaction of the ester 9j in liquid
ammonia with lithium; this only generated the Bouveault–
Blanc reduction product, the primary alcohol 10j, which
clearly indicated that the reaction is proceeding via the
dianion (if the reaction was proceeding via the radical
anion, then 6-exo cyclisation would have been noticed)
and is highly suitable only for the generation of cyclo-
pentane rings. In a similar manner, the bicyclic ester 9l
also failed to cyclise and generated only the primary
alcohol 10l. On the basis of these results a tentative
mechanism is depicted in Scheme 2. The ester 4 forms
the dianion 11, which undergoes a 5-exo-trig cyclisation
to generate the alkyllithium 12, which is rapidly pro-
tonated by ammonia analogous to the 1,4-reduction of
conjugated ketones. The resulting alkoxide 13 eliminates
the methoxy group to form the cyclopentanone 8, which
under the reaction conditions is reduced to the corre-
sponding alcohol 5.
References and Notes
1. Krief, A.; Bousbaa, J. Tetrahedron Lett. 1997, 38, 6291;
Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002,
4, 791; Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4,
787, and references cited therein.
2. Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745;
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
3. Kaiser, E. M. Synthesis 1972, 391, and references cited
therein.
4. To the best of our knowledge there is only one report on
the intramolecular addition of esters to olefins under alkali
metal in liquid ammonia conditions assisted by an a-
hydroxy group (claimed as radical anion mediated addi-
tion), see: Cossy, J.; Gille, B.; Bellosta, V. J. Org. Chem.
1998, 63, 3141–3146.
5. Srikrishna, A.; Nagaraju, S. J. Chem. Soc., Perkin Trans. 1
1992, 311.
6. Yields (unoptimised) refer to isolated and chromatograph-
ically pure compounds. All the compounds described in
this manuscript exhibited spectral data (IR, 1H and 13C
NMR and mass) consistent with their structures. Spectral
data for the ketone 8a: IR (neat): mmax/cmÀ1 1739. 1H NMR
(300 MHz, CDCl3+CCl4): d 2.30–2.00 (3H, m), 1.88 (1H, q,
J 6.9 Hz), 1.75–1.30 (8H, m), 1.30–1.10 (3H, m), 0.92 (3H,
d, J 6.9 Hz). 13C NMR (75 MHz, CDCl3+CCl4): d 218.9
(C), 55.1 (CH), 42.3 (C), 37.6 (CH2), 34.2 (CH2), 29.7
(CH2), 28.5 (CH2), 26.0 (CH2), 22.4 (CH2), 22.1 (CH2), 8.0
(CH3). HRMS: m=z for C11H19ONa (Mþ+Na+1): Calcd
190.1333. Found 190.1331.
7. For 8a: Eilbracht, P.; Acker, N.; Haedrich, I. Chem. Ber
1988, 121, 519; for 8b: Wender, P. A.; White, A. W. J. Am.
Chem. Soc. 1988, 110, 2218; for 8e: Dygutsch, D. P.;
Eilbracht, P. Tetrahedron 1996, 52, 5461; for 8f: Chavan,
S. P.; Patil, S. S.; Ravindranathan, T. Tetrahedron 1999,
55, 13417; for 8i: Jung, M. E.; Johnson, T. W. Tetrahedron
2001, 57, 1449; for 8l: Majerski, Z.; Hamersak, Z. J. Org.
Chem. 1984, 49, 1182.
O-
MeO
MeOOC
X
Li
liq. NH3
H
14
15a X = Li
15b X = H
OH
O
H
OH
H
H
PCC
H
H
16
A tandem carbanion cyclisation was also attempted for
the generation of a tricyclic system starting from diene
ester 14, obtained from 6-(3-butenyl)-3-methylcyclohex-
2-enone. The reaction of the diene ester 14 in liquid
ammonia with lithium followed by oxidation, however,
generated only the bicyclic compound 16 in 76% yield,8
indicating that the protonation of the intermediate
alkyllithium 15a by ammonia is much faster than the
second cyclisation. Since tandem reactions are very
facile with radicals, the failure of the generation of the
8. In addition 16% of the corresponding aldehyde was also
obtained.
9. In addition, the 6-endo cyclisation, a dominant reaction
with the 5-substituted-5-hexenyl radicals, with d-substi-
tuted esters was not observed, which also further supports
the absence of a radical intermediate in these cyclisations.
See: Srikrishna, A.; Kumar, P. R.; Ramasastry, S. S. V.
Tetrahedron Lett. 2003, 44, See: doi:10.1016/j.tetlet.2003.
10.165.