First intramolecular geminal acylation: Synthesis of bridged bicyclic diketones

Article abstract of DOI:10.1016/S0040-4039(01)00852-8

Bicyclic diketones have been produced by Lewis acid-promoted geminal acylations involving cyclic acyloins tethered to an acetal. This intramolecular process must proceed via a mode of reaction which, due to steric hindrance, is not seen in the intermolecu

Full text of DOI:10.1016/S0040-4039(01)00852-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4779–4781
First intramolecular geminal acylation: synthesis of bridged
bicyclic diketones
Angela N. Blanchard and D. Jean Burnell*
Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3X7
Received 23 February 2001; accepted 18 May 2001
Abstract—Bicyclic diketones have been produced by Lewis acid-promoted geminal acylations involving cyclic acyloins tethered to
an acetal. This intramolecular process must proceed via a mode of reaction which, due to steric hindrance, is not seen in the
intermolecular version of the geminal acylation. © 2001 Elsevier Science Ltd. All rights reserved.
Considerable effort has gone into the development of
procedures for the conversion of acetals1–3 and ketones4
into cyclic 1,3-diketones by geminal acylation with a
cyclic acyloin such as 1,2-bis(trimethyl-silyloxy)-
cyclobutene (1),5 its methylated analogues (e.g. 2)6,7 and
1,2-bis(trimethylsilyloxy)cyclopent-ene (3).8 Geminal
acylation has been used as a key-step in syntheses of
natural products and other structurally interesting com-
pounds.9 The two-step process to generate a 1,3-
cyclopentanedione with 1 is illustrated in Scheme 1. In
many instances, both steps can take place in the same
vessel, without the addition of trifluoroacetic acid
(TFA), if many equivalents of BF3·Et2O are used ini-
tially. However, in the presence of a high concentration
of the Lewis acid, 1, 2 and 3 also decompose quite
quickly to leave intractable polar material, so the one-
pot procedure often requires an excess of the acyloin in
order to give a good yield of the cyclic diketone.2,3
Steric hindrance greatly affects the yields, so the
efficacy of the overall process ranges from zero to
quantitative. Reactions with 3 are slower than with 1,
but some 1,3-cyclohexanediones can be obtained in
excellent yields by the one-pot procedure.8
acylation might be strongly disfavored for two reasons.
Firstly, unless the tether were long, the initial carbon–
carbon bond-forming reaction would involve reaction
at the carbon of the acyloin adjacent to the tether and
onto the face of the acyloin syn to the tether. However,
in reactions of 2, the one mode of addition that is never
seen is onto the carbon adjacent to, and syn to, its
methyl substituent.6 This is certainly due to a severe
steric interaction. Secondly, bridged bicyclic diketones
such as those expected by the acid-promoted geminal
acylation, are susceptible to acid-promoted ring-
opening.10,11
We set out to assess the feasibility intramolecular gemi-
nal acylation with acetals derived from both a ketone
and an aldehyde and with four- and five-membered
acyloins. Tethers of three carbons were employed. The
preparation of the substrates 7a–c is outlined in Scheme
2. Alkylation of diethyl malonate, first with 5-bromo-
pentene and then with a halo-ester, yielded the triesters
4a,b. Decarboxylation of one of the geminal car-
boxyethyl groups using sodium bromide and water in
DMSO12 gave 5a,b. Wacker oxidation13 provided
methyl ketones that were converted to the acetals 6a,b.
Acyloin reactions with sodium metal in toluene gave
The intramolecular reaction of an acetal tethered to
an acyloin has never been reported. Such a geminal
TMSO
OTMS
OTMS
TMSO
Me
OTMS TMSO
OTMS
O
1
=
acid
O
R
O
O
R
O
O
OTMS
BF3·Et20
R'
R'
R
R'
2
3
Scheme 1. Geminal acylation reaction.
* Corresponding author. Tel.: (709) 737-8535; fax: (709) 737-3702; e-mail: jburnell@mun.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00852-8

4780
A. N. Blanchard, D. J. Burnell / Tetrahedron Letters 42 (2001) 4779–4781
1. NaOEt, EtOH
2. 5-bromopentene
CO2Et NaBr, H2O,
CO2Et
CO2Et
( )n
( )n
DMSO, ∆
EtO2CCH2CO2Et
CO2Et
3. NaOEt, EtOH
4. X(CH2)nCO2Et
CO2Et
4a
4b
5a
5b
n = 1 (76%)
n = 2 (82%)
n = 1 (77%)
n = 2 (98%)
(n = 1, X = Br
n = 2, X = Cl)
Na0, toluene,
TMS-Cl, ∆
TMSO
OTMS
( )n
1. PdCl2, CuCl, O2,
CO2Et
( )n
H2O, DMF
O
O
O
O
2. (CH2OH)2,
CO2Et
p-TsOH, C6H6, ∆
6a
6b
7a
7b
n = 1 (52%)
n = 2 (36%)
n = 1 (97%)
n = 2 (63%)
TMSO
OTMS
Na0, toluene,
TMS-Cl, ∆
CO2Et
1. O3, (CH2OH)2, CHCl3
O
O
O
O
5b
H
H
2. p-TsOH, S(CH3)2
CO2Et
6c
(75%)
7c (82%)
Scheme 2. Synthesis of substrates for intramolecular geminal acylation.
7a,b. Attempts to purify 7a,b by distillation were com-
promised by their thermal instability, and their sensitiv-
ity to moisture precluded other methods of purification.
some by-products appeared to be formed by attack on
the solvent (toluene). With much less BF3·Et2O, 9 still
produced, but diketone 8 was not detected. In order to
effect the rearrangement of 9 to 8, TFA was added. The
overall yield of 8 was not improved, but 10b was an
additional minor product. A problem with ring-opening
had been seen with 1,3-cyclopentane-dione products
formed by geminal acylation from more hindered
acyclic ketones.3 (Ring-opening can be greatly encour-
aged by the use of SnCl4 as the Lewis acid.1,14) Never-
theless, when the substrate for the geminal acylation
was an acetal derived from 2,3-butanediol, ring opening
was suppressed.3 Therefore, acyloin 11a was prepared
as for 7a (acyloin estimated at 82% yield). Two equiva-
1
Nevertheless, the H NMR spectra of the crude reac-
tion products indicated that the ester functions were
gone and each product had two trimethylsilyl groups.
The yields for the acyloin steps were estimated from
these 1H NMR spectra. Diester 5b was treated with
ozone in the presence of ethanediol, and, after 20
minutes, a small amount of p-TsOH was added with
dimethylsulfide. This provided the acetal 6c, and an
acyloin reaction gave 7c, which could also not be
purified rigorously.
A dilute toluene solution of 7a was cooled to −78°C
before 15 equivalents of BF3·Et2O were added. After
stirring for 7.5 h, the mixture was allowed to warm
slowly to room temperature. Aqueous work-up pro-
vided 16% of the bicyclo[3.2.1]octanedione 8,15 along
with small amounts of 9 (as a single isomer) and 10a.
lents of BF3·Et2O were added slowly to
a
dichloromethane solution of 11a at −78°C. When the
last of the BF3·Et2O was added, the solution was
warmed to room temperature and TFA (10 equiv.) was
introduced. Work-up after one hour provided 8 in an
improved yield of 36% following chromatography.
There was no evidence of any ring-opened product by
1H NMR.
Compound
9 was an intermediate, unrearranged
molecule, and 10a arose by acid-induced ring-opening
of 8. The initial aldol process took place to a modest
O
OH
O
TMSO
OTMS
( )n
O
OH
O
O
R
O
R
O
O
O
O
8
9
R = H
R = COCF
10a
10b
11a R = CH3, n = 1
11b R = CH3, n = 2
11c R = H, n = 2
3
O
F
F
R1
OH
O
B
O
O
O
O
O
O
O
OH
OH
R2
12 R1 = CH3, R2 = H
15 R1 = H, R2 = CH3
16 R1 = H, R2 = H
13
14
17
In the presence of 15 equivalents of BF3·Et2O, the
acyloin 7b (in toluene, −78°C warming to room temper-
ature overnight) provided the bicyclo[3.3.1]nonanedione
extent, but the production of a considerable amount of
polar material indicated that the acyloin moiety was
also being destroyed relatively quickly. Furthermore,

A. N. Blanchard, D. J. Burnell / Tetrahedron Letters 42 (2001) 4779–4781
4781
1216 in a yield of 23%. (None of the unrearranged aldol
product 13 was detected.) The only isolated by-product
(25%) was the ring-opened compound 14 (as a 2:1
mixture of isomers), but the use of the more substituted
acetal 11b did not lead to a better yield of 12. Butkus
and Bielinyte–Williams11 had shown that 12 can also be
produced by the reaction of the enamine of 2-methyl-
cyclohexanone with acryloyl chloride, but this unavoid-
ably leads to the production of an equal amount of 15.
(Furthermore, it appears from their 13C NMR data that
their assignment of structures to the isomers 12 and 15
might be reversed.)
6. Crane, S. N.; Jenkins, T. J.; Burnell, D. J. J. Org. Chem.
1997, 62, 8722.
7. (a) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63,
1352; (b) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998,
63, 5708.
8. Wu, Y.-J.; Burnell, D. J. Tetrahedron Lett. 1989, 30,
1021.
9. For instance: (a) Parker, K. A.; Koziski, K. A.; Breau, G.
Tetrahedron Lett. 1985, 26, 2181; (b) Bunnelle, W. H.;
Shangraw, W. R. Tetrahedron 1987, 43, 2005; (c) Burnell,
D. J.; Wu, Y.-J. Can. J. Chem. 1989, 67, 816; (d) Burnell,
D. J.; Wu, Y.-J. Can. J. Chem. 1990, 68, 804; (e) Hyuga,
S.; Shoji, H.; Suzuki, A. Bull. Chem. Soc. Jpn. 1992, 65,
2303; (f) Julia, M.; Saint-Jalmes, L.; Lila, C.; Xu, J. Z.;
Moreau, L.; Pfeiffer, B.; Eck, G.; Pelsez, L.; Rolando, C.
Bull. Soc. Chim. Fr. 1993, 130, 447; (g) Pandey, B.;
Reddy, R. S.; Kumar, P. J. Chem. Soc., Chem. Commun.
1993, 870; (h) Wu, Y.-J.; Zhu, Y.-Y.; Burnell, D. J. J.
Org. Chem. 1994, 59, 104; (i) Wendt, J. A.; Gauvreau, P.
J.; Bach, R. D. J. Am. Chem. Soc. 1994, 116, 9921; (j)
Liu, P.-Y.; Burnell, D. J. J. Chem. Soc., Chem. Commun.
1994, 1183; (k) Balog, A.; Curran, D. P. J. Org. Chem.
1995, 60, 337; (l) Balog, A.; Geib, S. J.; Curran, D. P. J.
Org. Chem. 1995, 60, 345; (m) Zhu, Y.-Y.; Burnell, D. J.
Tetrahedron: Asymmetry 1996, 7, 3295; (n) Lin, X.;
Kavash, R. W.; Mariano, P. S. J. Org. Chem. 1996, 61,
7335; (o) Liu, P.-Y.; Wu, Y.-J.; Burnell, D. J. Can. J.
Chem. 1997, 75, 656; (p) Kanada, R. M.; Taniguchi, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1998,
1755.
The addition of BF3·Et2O to a dilute solution of 7c, in
which the acetal was produced from an aldehyde, did
not give any of the desired bicyclic ketone 16. The
unusual fused tricyclic compound 17,17 in which a
boron from the Lewis acid was captured in one ring,
was isolated in low yield (18%).
In summary, intramolecular geminal acylation can take
place when a four- or a five-membered acyloin is
attached by a three-carbon tether to the acetal derived
from a methyl ketone. This is in spite of the initial step
involving a mode of reaction (carbonꢀcarbon bond-for-
mation adjacent to, and syn to, the point of attachment
of the tether onto the acyloin) that is highly disfavored
in the analogous, intermolecular reactions of 2.
Although the yields of the bicyclic diketones were mod-
est, the positions of the methyl groups on the bridge-
heads were assured by the intramolecular geminal
acylation process, in contrast with the enamine route.
10. Hickmott, P. W.; Hargreaves, J. R. Tetrahedron 1967, 23,
3151.
11. Butkus, E.; Bielinyte-Williams, B. Collect. Czech. Chem.
Commun. 1995, 60, 1343.
12. Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 957.
13. Tsuiji, J.; Masaoka, K.; Takahashi, T. Tetrahedron Lett.
1977, 26, 2267.
Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada for financial support.
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15. For 8: white solid, mp 65–66°C; 1H NMR (300 MHz,
CDCl3) l 2.95 (1H, m), 2.66 (2H, m), 2.20 (2H, m), 1.88
(4H, m), 1.06 (3H, s); 13C NMR (75 MHz, CDCl3) l
217.7, 212.3, 59.3, 45.7, 44.9, 42.9, 35.7, 18.2, 12.1.
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1
16. For 12: white solid, H NMR (500 MHz, CDCl3) l 2.90
(1H, m), 2.64 (1H, m), 2.38 (1H, m), 2.27 (1H, m), 2.20
(1H, m), 2.07 (2H, m), 1.81 (1H, m), 1.75–1.60 (3H, m),
1.15 (3H, s); 13C NMR (125 MHz, CDCl3) l 213.4, 212.6,
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1
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CDCl3) l 2.91 (2H, m), 2.55 (3H, m), 2.13 (2H, m), 1.72
(2H, m), 1.30–0.80 (2H, m); 13C NMR (75 MHz, CDCl3)
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