Synthesis of 1,3-diketones through ring-opening of ketoketene dimer β-lactones

Article abstract of DOI:10.1016/j.tetlet.2009.09.158

The reaction of ketoketene dimers with organolithium reagents afforded 1,3-diketones in good to excellent yields, and with good diastereoselectivity in some cases.

Full text of DOI:10.1016/j.tetlet.2009.09.158

Tetrahedron Letters 50 (2009) 6919–6922
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,3-diketones through ring-opening of ketoketene dimer
b-lactones
*
Ahmad A. Ibrahim, Stephen M. Smith, Sarah Henson, Nessan J. Kerrigan
Department of Chemistry, Oakland University, 2200 N. Squirrel Rd, Rochester, MI 48309-4477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of ketoketene dimers with organolithium reagents afforded 1,3-diketones in good to excel-
lent yields, and with good diastereoselectivity in some cases.
Received 12 August 2009
Revised 25 September 2009
Accepted 25 September 2009
Available online 1 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Diketones
Ketoketene dimers
b-Lactones
Organolithiums
Alkyllithiums
Diastereoselectivity
The single step conversion of esters to ketones is a potentially
useful reaction in complex molecule synthesis. However, there
are few examples of such one-step transformations in the litera-
ture.1–5 Typically, the reactions of organolithium and Grignard re-
agents with esters form ketones initially, which being more
electrophilic than esters, undergo a second nucleophilic addition
to give tertiary alcohols.1,2 While a few dimethylketene dimer
ring-openings are known, ring-openings of ketoketene dimers de-
rived from unsymmetrical ketoketenes have not been studied
due to a paucity of general methods for their preparation.3–12 Inter-
estingly, the reaction of dimethylketene dimer 1a with simple
Grignard reagents (EtMgX, i-PrMgX, t-BuMgX, and PhMgBr) was
reported to provide 1,3-diketones in modest yields (5–50%), while
a single example involving PhLi as the nucleophile favored retro-
aldol product 5a (80%) after double addition.4,5 Retro-aldol prod-
ucts presumably arise from decomposition of the intermediate 3a
during the reaction (Scheme 1) or alternatively through decompo-
sition of the derived b-hydroxyketone during aqueous work-up.4,10
In addition, a handful of modest yielding ketone forming reac-
tions (21–71%) from the reaction of b-lactones (derived from alde-
hydes) with organometallics are known.13–16
diketone synthesis rely on the use of a modification of the Claisen
condensation (acylation of a ketone by an ester in the presence of
an alkoxide or metal hydride base) or on the use of LDA to preform
an enolate from a ketone followed by C-acylation through reaction
with an acyl chloride.17–21 More recently a milder soft enolization
protocol has been introduced.19 However most of these methods
have disadvantages with respect to competing side reactions
(e.g., O-acylation or bis-acylation) or limited substrate scope (e.g.,
tetrasubstituted enolates not being tolerated).18
Our group has recently developed a general method for the ster-
eoselective dimerizationofketoketenesto givearangeofketoketene
dimer b-lactone products in good to excellent yields and with excel-
lent diastereoselectivity favoring the Z-isomer (Scheme 2).3,22
With the aim of utilizing our ketoketene dimers in the synthesis
of interesting molecules possessing a quaternary stereogenic cen-
ter, we initiated the development of organometallic-mediated
ring-opening reactions of our b-lactones.3 We initially investigated
the reaction of methylphenylketene dimer 1b with excess n-BuLi
(2 equiv) in THF at À78 °C and were surprised to find that 1,3-dike-
tone 6b (88%, dr = 86:14), derived from single addition, was ob-
tained as the major product rather than retro-aldol product 5b
(Scheme 3).4,5 Interestingly, relatively few studies have investi-
gated diastereoselectivity in 1,3-diketone formation.23
Access to 1,3-diketones from ketoketene dimers would be a
desirable reaction as 1,3-diketones are important organic com-
pounds and are found in many natural products and pharmacolog-
ically active compounds, and moreover have been widely used as
intermediates in synthesis.17 The most popular method for 1,3-
Although quenching the reaction with excess water after warm-
ingfrom–78 °Ctoroomtemperatureledtogooddiastereoselectivity
(dr = 86:14), we subsequently found that slightly higher diastere-
oselectivity could be obtained when the reaction was quenchedwith
water (93%, dr = 89:11) or acetic acid (72%, dr = 90:10) at À78 °C.24
* Corresponding author. Tel.: +1 2483702085.
E-mail address: kerrigan@oakland.edu (N.J. Kerrigan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.158

6920
A. A. Ibrahim et al. / Tetrahedron Letters 50 (2009) 6919–6922
M
O
M
O
O
O
O
OM
RM
RM
R
R
Me
Me
Me
Me
Me
Me
R
Me Me
Me Me
Me
Me
1a
3a
2a
O
OM
M+
O
H+
O
_
Me
Me
Me
Me
+
+
R
R
R
R
Me Me
Me Me
5a
4a
Scheme 1. Formation of retro-aldol products from dimer 1a.
Table 1
O
O
•
0.1 equiv PBu3 or PMe3
Ring-opening of 1b with various RLi to afford 6b–ha
O
R1
R2
O
R1
O
O
R1
R2
0.3 equiv LiI
CH2Cl2/Et2O
0° C
O
1. RLi, -78 °C
R2
Ph
Me
R
Ph
Me
Ph
Ph Me
2. H2O or AcOH
60-90% yield
d.r. ≥ 16:1
Me
1b
6b-6h
8 examples
Entry
R
Yield % of 6
drb of 6
Compound
Scheme 2. Phosphine-catalyzed dimerization of ketoketenes.
1
2
3
4
5
6
7
n-Bu
t-Bu
s-Bu
Et
Me
Ph
93
80
72
89:11 (90:10)c
85:15c
6b
6c
6d
6e
6f
87:13c
O
O
O
O
>99d
21e
70e
99
77:23
80:20
58:42
62:38
O
1. n-BuLi, -78 °C
Ph
Ph
Ph
+
Ph
Me
n-Bu
Ph
6g
6h
2. H O at rt
2
Ph Me
Me
Me Me
MeO
Me
5b
<5%
1b
6b
88%
d.r. = 6:1
a
b
c
Yields are isolated yields.
Diastereomeric ratio (dr) as determined by GC–MS or 1H NMR analysis.
Quenched with AcOH (2 equiv).
d
e
Contains 10% 5b.
Scheme 3. Reaction of n-BuLi with ketoketene dimer 1b.
Conversion to 6 as determined by GC–MS analysis. The rest of the product
mixture was accounted for by 5b.
Employing our optimized conditions (2 equiv RLi, À78 °C, and
H2O or acetic acid quench at À78 °C) we then investigated the reac-
tion of methylphenylketene dimer 1b with a variety of commercially
available and in situ-prepared organolithium reagents (Table 1).25 A
THF solution of MeOLi was generated in situ, through the reaction of
n-BuLi with methanol in THF (Table 1, entry 7). In most cases, single
addition of the organolithium reagent occurred to give the corre-
sponding 1,3-dicarbonyl compounds 6b–h cleanly with moderate
to good diastereoselectivity (dr up to 90:10). The poor conversion
of 1b to 1,3-diketone 6f when MeLi is the nucleophile is presumably
due to intermediate 2 (Scheme 4) readily undergoing a second addi-
tion of MeLi. We speculate that the transition state for equilibration
of 7 to 2 is of lower energy when R = Me than when R = n-Bu or t-Bu,
dueto reducedsteric interactionsin thetransitionstate leadingto 2f,
andconsequentlythiswouldmeanthat 2fratherthan7f is favoredat
equilibrium. Therefore in reactions involving MeLi, the formation of
double addition-derived retro-aldol product 5b, rather than 1,3-
diketone 6, is favored.
The reaction of other ketoketene dimers (1c–e) with various
alkyllithium reagents was also investigated (Table 2). While ring-
opening of ethylphenylketene dimer 1c proceeded less cleanly,
ring-opening reactions of methyl-4-tolylketene dimer 1d and
methyl-6-methoxy-2-naphthylketene dimer 1e gave similar yields
to those of 1b. In some cases, the crude products obtained from
alkyllithium ring-opening of 1d contained 5–10% retro-aldol prod-
uct 5d, as determined by GC–MS and 1H NMR analysis, most likely
formed through the mechanism outlined in Scheme 1.
On the basis of the results obtained in these experiments we pos-
tulate that the reaction involves a stabilized lithium lactol tetrahe-
dral intermediate 7 (Scheme 4). 7 is stable at À78 °C and only
collapses to give 1,3-diketone 6 when water (or another proton
source) is added at À78 °C and the reaction is allowed to warm to
ambient temperature. Good diastereoselectivity (Table 1, entries
1–3, and Table 2, entry 2) in 1,3-diketone formation presumably
arises from protonation of the less sterically hindered
p-face of 8
(the face not blocked by the 4° center Ph substituent) to give the
anti-diastereomer as the major diastereomer (see Scheme 4 for a
plausible stereochemical model).26 In those cases where lower dia-
stereoselectivity (Table 1, entries 6 and 7) is obtained we presume
that tetrahedral intermediate 7 is less stable (due to the R = MeO
or Ph substituent) than 2 and hence that the acyclic enolate interme-
diate 2 is favored under the reaction conditions. Protonation of acy-
clic lithium enolate 2 would be expected to proceed with poor
diastereoselectivity due to reduceddiastereocontrol associated with
the conformational flexibility of 2 and the similar sizes of the Ph and
RC@O substituents at the 4° center, in comparison with that ex-
pected from the conformationally rigid cyclic intermediate 8.27
Tentative support for the intermediacy of 7 was obtained from
the following control experiments: Firstly, reaction of 1b with
1 equiv of MeOLi, followed by 2 equiv n-BuLi, led to the formation
of ca. 30% double addition-derived retro-aldol product 5b (Scheme
4). This implies that the non-cyclic lithium enolate intermediate 2
from this reaction does not significantly contribute to 1,3-diketone

A. A. Ibrahim et al. / Tetrahedron Letters 50 (2009) 6919–6922
6921
O
O
O
O
O
1. RLi, -78 °C
Ph
Me
Ph
Ph
Ph
Me
R
Ph
2. H2O or AcOH
Ph Me
Me Me
Me
1b
6
5b
OH
R
Ph
O
1. RLi
2. H2O or AcOH
via
RLi, -78 °C
H2O
Ph
Me
Me
Li
LiO
R
HO
R
O
O
H2O
O
H2O or AcOH
-78 °C -rt
O
Ph
R
Ph
Me
Ph
Me
Ph
Me
Ph
Ph Me
Me
Me
2
7
8
Scheme 4. Proposed mechanism for the formation of 1,3-diketone 6.
Table 2
Supplementary data
Ring-opening of 1c–e with various RLi to afford 6i–na
O
O
O
2
Supplementary data (Detailed experimental procedures and
characterization data for 6b–n) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.09.158.
O
1. RLi, -78 °C
1
R
1
R
1
R
R
1
2
2
R
R
R
2. H O or AcOH
R
2
2
R
References and notes
1c-1e
6i-6n
Yield % of 6 drb of 6 Compound
Entry R1
R2
Et
R
1. Fernández-Megía, E.; Iglesias-Pintos, J. M.; Sardina, F. J. J. Org. Chem. 1997, 62,
4770–4779.
1
2
Ph
n-
Bu
73c
n.d.
6i
6j
2. Avenoza, A.; Busto, J. H.; Peregrina, J. M. Tetrahedron 2002, 58, 10167–10171.
3. (a) Kerrigan, N. J.; Ibrahim, A. A.; Harzmann, G. D. Abstracts of Papers, 236th
National Meeting of the American Chemical Society, Philadelphia, PA;
American Chemical Society: Washington, DC, 2008; ORGN 531.; (b) Ibrahim,
A. A.; Harzmann, G. D.; Kerrigan, N. J. J. Org. Chem. 2009, 74, 1777–1780; (c) Lv,
H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal. 2008, 350, 2715–2718.
4. Berlin, K. D.; Cooper, M. H. J. Org. Chem. 1964, 29, 2057–2058.
5. Combret, J. C. C.R. Acad. Sci., Ser. C 1967, 264, 622–624.
4-MePh
Me n-
78d
85:15
Bu
3
4
5
4-MePh
4-MePh
6-MeO-2-
Naphthyl
6-MeO-2-
Naphthyl
Me t-Bu 83
76:24
60:40
70:30
6k
6l
6m
Me s-Bu 90d
Me n-
96
Bu
6. Hasek, R. H.; Clark, R. D.; Elam, E. U.; Martin, J. C. J. Org. Chem. 1962, 27, 60–64.
7. Hasek, R. H.; Clark, R. D.; Elam, E. U.; Nations, R. G. J. Org. Chem. 1962, 27, 3106–
3111.
6
Me t-Bu 94
67:33
6n
a
b
c
8. Martin, J. C.; Burpitt, R. D.; Hostettler, H. U. J. Org. Chem. 1967, 32, 210–213.
9. Clark, R. D. J. Org. Chem. 1967, 32, 1237–1238.
Yields are isolated yields.
Diastereomeric ratio (dr) as determined by GC–MS or 1H NMR analysis.
Conversion as determined by GC–MS analysis.
10. Berlin, K. D.; Hanson, R. B. J. Org. Chem. 1967, 32, 1763–1769.
11. For examples of reactions of the related aldoketene dimers see: (a) Calter, M.
A.; Guo, X. J. Org. Chem. 1998, 63, 5308–5309; (b) Calter, M. A.; Song, W.; Zhou,
J. J. Org. Chem. 2004, 69, 1270–1275; (c) Duffy, R. J.; Morris, K. A.; Romo, D. J.
Am. Chem. Soc. 2005, 127, 16754–16755; (d) Purohit, V. C.; Richardson, R. D.;
Smith, J. W.; Romo, D. J. Org. Chem. 2006, 71, 4549–4558; (e) Ma, G.; Nguyen,
H.; Romo, D. Org. Lett. 2007, 9, 2143–2146.
d
Contains 5–10% retro-aldol product 5d.
formation. Secondly, when 6b was exposed to 4 equiv n-BuLi, ca.
25% 5b was obtained after quenching with water. This again sug-
gests that the 1,3-diketone forming reaction primarily involves 7
as opposed to the lithium enolate 2. Finally, reaction of 1b with
MeOLi provided b-ketoester 6h (Table 1, entry 7) in excellent yield,
but with poor diastereoselectivity (dr = 62:38) after an aqueous
quench, and so it must involve quenching of a significantly differ-
ent intermediate to that for 6b, which was obtained in a dr of
90:10.
When toluene was used as the solvent, lower conversion to 6b
(ca. 25%) was obtained and an elevated level of 5b was obtained
(ca. 20%). This suggests that the polarity of the solvent is critical
to stabilization of the intermediate 7, and hence formation of 6.
In conclusion, we have described an efficient method for the
conversion of ketoketene dimers to 1,3-diketones with moderate
to good diastereoselectivity. We are currently carrying out further
mechanistic investigations of this reaction and exploring its appli-
cation in drug molecule synthesis.
12. For an illustration of the divergent reactivity of b-lactones see: Yokota, Y.;
Cortez, G. S.; Romo, D. Tetrahedron 2002, 58, 7075–7080.
13. Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Bankert, R. A. J. Am. Chem. Soc. 1949,
71, 2807–2808.
14. Stuckwisch, C. G.; Bailey, J. W. J. Org. Chem. 1963, 28, 2362–2363.
15. Smith, N. D.; Wohlrab, A. M.; Goodman, M. Org. Lett. 2005, 7, 255–258.
16. Fujisawa, T.; Ito, T.; Nishiura, S.; Shimizu, M. Tetrahedron Lett. 1998, 39, 9735–
9738.
17. Kel’in, A. V. Curr. Org. Chem. 2003, 7, 1691–1711.
18. Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed.; Wiley & Sons: NY, 2001. Chapter 10.
19. Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Org. Lett. 2007, 9, 4139–4142.
20. Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679–3682.
21. Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron Lett. 2002, 43,
2945–2948.
22. The olefin geometry of our ketoketene dimers was determined to be Z by
agreement of 1H and 13C NMR data with those for ketoketene dimers prepared
by Ye and co-workers, which were determined to possess Z geometry on the
basis of NOE studies (see Ref. 3).
23. Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem. Soc. 1984,
106, 1154–1156.
24. The dr’s for 6b were determined by GC–MS analysis and were found to be
reproducible over three injections.
25. A typical procedure for the reaction of ketoketene dimers 1 with alkyllithiums
is as follows: Ketoketene dimer 1 (0.61 mmol) was dissolved in THF (4.8 mL),
and n-butyllithium (2.5 M in hexane, 0.48 mL, 1.20 mmol) was added dropwise
over 5 min at À78 °C. After 15 min the reaction was quenched by adding water
(2 mL) at À78 °C. The quenched reaction was then warmed up to room
temperature, brine (8 mL) and CH2Cl2 (5 mL) were added, and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (2 Â 5 mL) and the
Acknowledgments
We thank the National Science Foundation (Grant CHE-
0911483), and Oakland University (startup funds and Research
Excellence Award, N.J.K.) for financial support of this work.

6922
A. A. Ibrahim et al. / Tetrahedron Letters 50 (2009) 6919–6922
combined organics were dried over anhydrous Na2SO4. The solvent was
27. For examples of stereoselectivities obtained in kinetic protonations of cyclic
and acyclic enols/enolates see: (a) Zimmerman, H. E. Acc. Chem. Res. 1987, 20,
263–268; (b) Zimmerman, H. E.; Chang, W.-H. J. Am. Chem. Soc. 1959, 81, 3634–
3643; (c) Williams, T. M.; Crumbie, R.; Mosher, H. S. J. Org. Chem. 1985, 50,
91–97.
removed under reduced pressure to afford the desired 1,3-diketone 6 as a
colorless oil in the yields given in Tables 1 and 2. All 1,3-diketones were
characterized by GC–MS, IR, 1H NMR, 13C NMR and HRMS analyses.
26. The relative stereochemistry of 1,3-diketones 6 remains to be determined and
this is the subject of current studies.