Observations on the synthesis and carbocyclisation reactions of 6-oxohexa-2,3-dienoates

Article abstract of DOI:10.1055/s-2008-1078028

6-Oxohexa-2,3-dienoates can be readily prepared via an atom economical Claisen rearrangement of propargyl vinyl ethers formed in situ by the reaction of propargylic alcohols with acetals. Preliminary experiments have demonstrated that these functionalised allenic esters undergo a facile amine-induced carbocyclisation under mild reaction conditions, yielding densely functionalised cyclopentanones containing chiral quaternary carbon centres. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078028

LETTER
2097
Observations on the Synthesis and Carbocyclisation Reactions of
6-Oxohexa-2,3-dienoates
Synthesis and
h
Carbocyclisa
i
tion Re
l
action
i
s
of 6-O
p
xohexa-2,3-dienoa
J
tes . Gray,a William B. Motherwell,*a Tom D. Sheppard,a Andrew J. Whiteheadb
a
Christopher Ingold Laboratories, Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
Fax +44(20)76797524; E-mail: w.b.motherwell@ucl.ac.uk
b
Chemical Development Division, GlaxoSmithKline Research & Development Ltd,
Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
Received 30 June 2008
Dedicated to Professor Sir Jack Baldwin FRS on the occasion of his 70th birthday
R3
O
Nu
R3
R4
Abstract: 6-Oxohexa-2,3-dienoates can be readily prepared via an
Nu–
R1
R2
R1
R2
•
atom economical Claisen rearrangement of propargyl vinyl ethers
formed in situ by the reaction of propargylic alcohols with acetals.
Preliminary experiments have demonstrated that these functiona-
lised allenic esters undergo a facile amine-induced carbocyclisation
under mild reaction conditions, yielding densely functionalised cy-
clopentanones containing chiral quaternary carbon centres.
CO2R5
–
CO2R5
R4
O
1
2
Nu = I, NR2, OR
R1,R2, R3, R4 = alkyl, aryl, H
Key words: acetals, alcohols, allenes, cyclisation, rearrangements
R
5 = alkyl
R3
R1
R2
Nu
CO2R5
R4
R3
R1
R2
Nu
CO2R5
R4
H2O
The presence of two p electron clouds separated by a sin-
gle sp hybridised carbon atom is the identifying structural
characteristic of allenes, and it is this unique structural and
electronic arrangement that is responsible for the extraor-
dinary reactivity profile displayed by allenic compounds.1
The synthetic potential of electron-deficient allenes has
OH
– O
3
4
Scheme 1
been explored extensively in recent years, and this has led We have previously shown that the synthetically versatile
to the development of novel methods for the construction 6-oxo-2-hexenoate moiety can be readily accessed via
of a variety of functionalised heterocyclic and carbocyclic Claisen rearrangement of allyl vinyl ethers, formed in situ
systems.2 As part of our ongoing research programme on through the reaction of substituted allylic alcohols and a-
the application of allenes to the construction of complex disubstituted aldehydes.5 It was envisaged that the analo-
ring systems,3 we envisaged that functionalised allenic es-
gous allenic esters 8 would be obtained by reacting prop-
ters 1 would provide opportunities for the development of
novel cyclisation strategies (Scheme 1). It was anticipated
that allenic esters 1 would undergo cyclisation reactions to
give cyclopentenols 4, via tandem sequences involving
argylic alcohols 6 and aldehydes 5, via intermediate
propargyl vinyl ethers 7 (Scheme 2). It was anticipated
that this protocol would enable a rapid efficient assembly
of a variety of structurally diverse allenic esters 8, allow-
the addition of nucleophiles to the central allenic carbon, ing for a detailed study of their potential to act as precur-
followed by cyclisation of the resulting ester enolates 2 sors to substituted cyclopentenols 4. Precedent exists for
onto the pendant carbonyl. Furthermore, it was expected such an approach to the synthesis of allenic compounds,6
that the electronic properties of the resulting double bond however, to the best of our knowledge, the use of propar-
in the cyclopentenol 4, would depend on the identity of
R4
R3
the added nucleophile and the substituents on the allene,
and in consequence, a range of carbocyclic systems could
be obtained by changing these variables.
CO2R2
R1
R4
R5
O
OH
CO2R2
R5
•
R3
5
R1
O
PTSA, toluene,
reflux
A plethora of methods exists for the construction of allen-
ic esters, including the base-mediated isomerisation of
acetylenic acids and esters, transition-metal-mediated car-
bonylation reactions of propargylic derivatives and the
Wittig or Horner–Wadsworth–Emmons olefination of
ketenes.4
6
8
R1, R2 = alkyl
3 = aryl, alkyl, H
R4
R
R5
R3
O
R1 CO2R2
SYNLETT 2008, No. 14, pp 2097–2100
2
2
.0
8
.2
0
0
8
7
Advanced online publication: 05.08.2008
DOI: 10.1055/s-2008-1078028; Art ID: D24008ST
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

2098
P. J. Gray et al.
LETTER
gylic alcohols bearing an electron-withdrawing group
such as 6, to give the corresponding acceptor-substituted
allenes 8 has not been reported.
Table 2 Synthesis of Allenic Esters 8a–g from Propargylic Alco-
hols 6a–d and Acetals8
Alcohol Acetal
Allene
Yield (%)
In order to assess this approach towards the target allenic
esters 8, a range of propargylic alcohols 6a–e was pre-
pared by the reaction of metallated acetylenes 9 with com-
mercially available pyruvic acid esters 10 (Scheme 3 and
Table 1).7
CO2Me
OMe
•
6e
6a
6c
40
OHC
MeO
MeO
MeO
8a
O
THF
–78 °C to r.t.
CO2Me
OH
R1
R2
X +
CO2R3
R1
OMe
OMe
CO2R3
•
R2
32
44
9
10
OHC
6a–6e
Ph
X = Li, MgBr
8b
Scheme 3
CO2Et
Bn
•
Table 1 Preparation of Propargylic Alcohols 6a–e from Metallated
Acetylenes 9 and Pyruvic Acid Esters 10
OHC
Product
6a
R1
Ph
n-Bu
H
R2
R3
Yield (%)
8c
CO2Et
Me
Me
Me
Et
88
40
62
78
42
•
OMe
OMe
6b
Me
6e
50
24
OHC
6c
CH2Bn
i-Pr
Me
6d
H
Et
8d
CO2Me
Bu
6e
H
Me
•
OMe
6b
OHC
With the required propargylic alcohols in hand, we were
then able to investigate the proposed Claisen rearrange-
ment by condensation with a suitable a,a-disubstituted al-
dehyde. In the first instance a solution of propargylic
alcohol 6e and isobutyraldehyde (11) in toluene was heat-
ed at reflux for 24 hours in the presence of a substoichio-
metric amount of para-toluenesulfonic acid. Disap-
pointingly, after concentration of the crude reaction mix-
ture, no allene was observed in the crude 1H and 13C NMR
spectra. Instead, lactone 14 was identified as the major
product (Scheme 4). A plausible mechanistic rationale to
account for the formation of the lactone 14 is shown in
Scheme 4. Thus, the acid-catalysed condensation of alco-
hol 6e and aldehyde 11 would, in the first instance give the
hemiacetal 13, which upon dehydration would provide the
required intermediate propargyl vinyl ether 7a. However,
in competition with dehydration, cyclisation of hemiace-
tal 13 through an intramolecular transesterification reac-
tion would give the lactone 14. In order to circumvent this
problem, it was anticipated that replacement of isobutyral-
dehyde with its dimethyl acetal would allow the reaction
to proceed via a slightly different pathway, avoiding the
problematic hemiacetal 13. Thus, under acidic conditions,
OMe
8e
CO2Me
•
OMe
OMe
OHC
6e
41
8f
CO2Et
•
OMe
OMe
6d
45
OHC
8g
and consequently allene 8a after [3,3]-sigmatropic rear-
rangement.
Pleasingly, the reaction of acetal 12 with propargylic alco-
acetal 12 would undergo loss of a molar equivalent of hol 6e led to the formation of the expected allenic ester 8a,
methanol to give the oxonium ion, which upon reaction which was isolated in 40% yield after purification by flash
with propargylic alcohol 6e would then provide the corre- column chromatography. The reaction was then extended
sponding mixed acetal 15 which cannot readily undergo to a variety of propargylic alcohols 6a–d and acetals to
give a range of highly functionalised allenic esters 8a–g,
lactonisation. Elimination of methanol from mixed acetal
15 would then proceed to give propargyl vinyl ether 7a,
Synlett 2008, No. 14, 2097–2100 © Thieme Stuttgart · New York

LETTER
Synthesis and Carbocyclisation Reactions of 6-Oxohexa-2,3-dienoates
2099
OH
CO2Me
plane of the molecule and, it is believed, that such steric
constraints inhibit the approach of pyrrolidine to the cen-
tral allenic carbon, preventing the desired cyclisation re-
action from taking place.
OMe
OMe
6e
12
O
11
PTSA, toluene,
reflux
PTSA, toluene,
reflux
R3
NR2
CO2R2
R
R
R3
R1
N
H
16
R4
R5
•
R4
R5
CO2R2
R1
O
O
O
O
15
13
8
17
OMe
CO2Me
OH
CO2Me
– MeOH
NR2
NR2
R3
R4
CO2R2
R1
R3
R4
CO2R2
R1
O
O
O
7a
CO2Me
14
R5
R5
OH
19
OH
18
O
O
H2O
•
Me
8a
CO2Me
R4
OH
CO2R2
R5
R3
Scheme 4
20
R1
all of which were stable towards column chromatography
and storage (Table 2).
O
Scheme 5
With a simple and robust route to the described allenic
substrates in hand, a preliminary study into their synthetic
potential was undertaken. The addition of primary and
secondary amines to the central sp hybridised carbon atom
of allenic esters allows for the regioselective preparation
of synthetically versatile vinylogous urethanes under mild
reaction conditions.3,9 Within this framework, it was ex-
pected that the addition of secondary amines 16 to allenic
esters 8a–g would provide the corresponding vinylogous
urethanes 17 which, upon 5-exo cyclisation onto the pen-
dent carbonyl would give enamines 19 via intermediate
iminium ions 18. Hydrolysis of enamines 19 would then
proceed to give substituted cyclopentanones 20
(Scheme 5).
Table 3 Synthesis of Cyclopentanones 20a–c from Allenic Esters
810
Allene
Cyclopentanone
Yield (%)
45
O
8a
MeO2C
HO
20a
Bn
CO2Et
HO
8c
8f
40
67
O
Pleasingly, the reaction of trisubstituted allenic esters 8a,
8c and 8f with pyrrolidine in acetonitrile at room temper-
ature gave the expected cyclopentanones 20a–c in moder-
ate yields (Table 3). In all cases the cyclopentanones 20a–
c were formed as 1:1 mixtures of diastereoisomers. Disap-
pointingly, the reaction of tetrasubstituted allenic esters
8b and 8e failed to provide the corresponding cyclopen-
tanones. Only starting material was recovered from the re-
action mixtures and attempts to effect the desired
transformations at elevated reaction temperatures also
failed, leading only to degradation of the starting material.
Upon construction of molecular models of these highly
substituted allenic esters it became apparent that a large
level of steric crowding exits both above and below the
20b
OH
CO2Me
O
20c
In conclusion, we have shown that highly functionalised
allenic esters can be readily assembled via an atom eco-
nomical Claisen rearrangement of propargyl vinyl ethers,
themselves obtained from simple acid-catalysed reactions
Synlett 2008, No. 14, 2097–2100 © Thieme Stuttgart · New York

2100
P. J. Gray et al.
LETTER
crude oils were purified by flash column chromatography,
eluting with PE–EtOAc (20:1) to give the described allenes
8a–g as pale yellow oils. Data for 8f: IR (thin film): 2933
(CH), 2804 (CH), 1957 (s, C=C=C), 1716 (C=O), 1450 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.50–1.80 (m, 10 H, CH2),
1.87 (d, J = 2.9 Hz, 3 H, Me), 3.72 (s, 3 H, OMe), 5.27 (q,
J = 2.9 Hz, 1 H, CH), 9.32 (s, 1 H, CHO). 13C NMR (75
MHz, CDCl3): d = 210.7, 201.4, 167.7, 98.2, 95.7, 52.3,
51.5, 30.7, 30.6, 25.5, 22.0, 22.0, 15.0. HRMS: m/z [M + H]
calcd for C16H18O3: 223.13341; found: 223.13276.
of suitably substituted propargylic alcohols and acetals.
Preliminary experiments have clearly demonstrated that
such substrates display significant potential for the syn-
thesis of substituted cyclopentanones under mild reaction
conditions. Reaction optimisation along with the develop-
ment of both catalytic and stereoselective carbocyclisa-
tion reactions using these novel allenic substrates is
currently underway in our laboratory.
(9) (a) Sugita, T.; Eida, M.; Ito, H.; Komatsu, N.; Abe, K.;
Suama, M. J. Org. Chem. 1987, 52, 3789. (b) Sigman, M.
S.; Eaton, B. E. Tetrahedron Lett. 1993, 34, 5367.
(10) General Experimental Procedure for the Preparation of
Cyclopentanones 20a–c: Pyrrolidine (0.45 mmol) was
added to a solution of the allenic ester (0.45 mmol) in MeCN
(8 mL) at r.t. The solution was stirred at r.t. for 12 h and then
concentrated at reduced pressure. The crude oil was
Acknowledgment
We would like to thank GSK for the CASE award provided (P. J.
Gray), and the EPSRC for the provision of a postdoctoral fellowship
(T. D. Sheppard).
References and Notes
dissolved in THF (10 mL) and 10% aq AcOH (10 mL) was
added. The acidic solution was stirred at r.t. for 12 h and then
the mixture was poured into sat. aq NaHCO3 solution (10
mL). The aqueous phase was separated and extracted with
EtOAc (3 × 20 mL). The combined organic extracts were
washed with brine (20 mL), dried (MgSO4), filtered and
concentrated at reduced pressure. The crude oils were
purified by flash column chromatography, eluting with PE–
EtOAc (5:1) to give the title cyclopentanones 20a–c. Data
for 20c: mp 34–36 °C. IR (Nujol): 3496 (br s, OH), 2929,
2856 (CH), 1747 (C=O, ketone), 1728 (C=O, ester), 1452
cm–1. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): d =
1.30–1.74 [m, 10 H, (CH2)5], 1.47 (s, 3 H, Me), 2.27 (d, J =
18.4 Hz, 1 H, CH2CO), 2.53 (br s, 1 H, OH), 2.82 (d, J = 18.4
Hz, 1 H, CH2CO), 3.11 [s, 1 H, CH(OH)], 3.70 (s, 3 H,
OMe). 13C NMR (75 MHz, CDCl3): d = 213.7, 173.6, 77.9,
62.3, 54.2, 49.6, 42.5, 39.0, 29.4, 25.7, 24.3, 22.8, 22.3, 16.4.
Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): d = 1.20–
1.75 [m, 10 H, (CH2)5], 1.33 (s, 3 H, Me), 2.18 (d, J = 5.6 Hz,
1 H, OH), 2.22 (d, J = 17.4 Hz, 1 H, CH2CO), 2.59 (d, J =
17.4 Hz, 1 H, CH2CO), 3.69 (s, 3 H, OMe), 4.39 [d, J = 5.4
Hz, 1 H, CH(OH)]. 13C NMR (75 MHz, CDCl3): d = 212.3,
172.9, 85.9, 60.0, 52.8, 47.3, 42.2, 36.7, 29.0, 25.6, 23.3,
22.1, 15.6. HRMS: m/z [M + H] calcd for C13H20O4:
241.14398; found: 241.14411.
(1) (a) Schuster, H. F.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley: New York, 1984. (b) Zimmer, R.; Dinesh,
C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100,
3067. (c) Ma, S. Chem. Rev. 2005, 105, 2829.
(2) Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004.
(3) Gray, P. J.; Motherwell, W. B.; Whitehead, A. J. Synlett
2007, 431.
(4) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 795.
(5) Freiria, M.; Whitehead, A. J.; Motherwell, W. B. Synlett
2003, 805.
(6) (a) Black, D. K.; Landor, S. R. J. Chem. Soc. 1965, 5225.
(b) Saucy, G.; Marbet, R. Helv. Chim. Acta 1967, 50, 1158.
For a metal-catalysed synthesis of allenes from propargylic
alcohols, see: (c) Sherry, B. D.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 15978.
(7) All pyruvic acid esters were purchased from the Aldrich
chemical company.
(8) General Experimental Procedure for the Synthesis of
Allenic Esters 8a–g: A solution of the propargylic alcohol
(7.00 mmol), acetal (7.70 mmol) and PTSA (30 mg) in
anhyd toluene (30 mL) in a flask fitted with a Dean and Stark
separator was heated to a vigorous reflux for 24 h. The
cooled solution was concentrated at reduced pressure and the
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