A selective solvent-free self-condensation of carbonyl compounds utilizing microwave irradiation

Article abstract of DOI:10.1039/c1gc15164a

An environmentally benign microwave-assisted solvent-free self-condensation of carbonyl compounds was developed using catalytic amounts of triethylamine and lithium perchlorate. Changing the amount of lithium perchlorate helps in controlling the ratio of the single-condensation and double-condensation products. The effect of other additives and microwave activation was also investigated. The optimized conditions were then applied to various cyclic/acyclic ketones and aldehydes, with selectivity observed in many cases.

Full text of DOI:10.1039/c1gc15164a

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Green Chemistry
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PAPER
A selective solvent-free self-condensation of carbonyl compounds utilizing
microwave irradiation†
Lalit Kumar Sharma,a Kyung Bo Kimb and Gregory I. Elliott*a,b
Received 14th February 2011, Accepted 16th March 2011
DOI: 10.1039/c1gc15164a
An environmentally benign microwave-assisted solvent-free self-condensation of carbonyl
compounds was developed using catalytic amounts of triethylamine and lithium perchlorate.
Changing the amount of lithium perchlorate helps in controlling the ratio of the
single-condensation and double-condensation products. The effect of other additives and
microwave activation was also investigated. The optimized conditions were then applied to various
cyclic/acyclic ketones and aldehydes, with selectivity observed in many cases.
known to promote the self-condensation of ketones, but the
Introduction
reaction usually requires 2–3 equivalents of acid. Alternative
The aldol reaction is one of the most powerful tools for the
methods reported for the self-aldol condensation of aromatic
construction of carbon–carbon bonds, both in nature and
and aliphatic ketones require organometallic7,8 or titanium
synthetic chemistry.1 The reaction involves the addition of an
alkoxides,9 while cyclic ketone self-condensation has been
enol or enolate of a carbonyl compound to another aldehyde or
reported using a W(CO)6/CCl4/UV system.11 The cationic
ketone. The product of this reaction is a b-hydroxycarbonyl com-
6
rhodium complex [Cp*Rh(h -C6H6)](BF4)2 is also known to
pound, which, on dehydration, generates the corresponding a,b-
unsaturated carbonyl moiety. This bifunctional moiety is present
in various synthetic intermediates and provides a usefully
functionalized platform, which can be further elaborated.2 The
a,b-unsaturated carbonyl functionality is particularly important
due to its widespread occurrence in biologically important
compounds.3
Self-condensation of aldehydes is a well known process,4
but self-condensation of ketones is limited to a few examples.5
Steric compression accounts for the poor reactivity of ketones.
Special reagents and reaction conditions are required for their
practical conversion, especially for non-activated cyclic and
higher molecular weight ketones.5–10 Ketones being moderate
carbonacids require strong bases, like lithium diisopropylamide
(LDA) and sodium hydride, for their self-condensation.5 These
strong bases are incompatible with protic solvents, therefore
tetrahydrofuran is frequently used as a solvent for these
reactions, which is not preferable from an environmental
perspective.5b Also, the reaction conditions require the complete
exclusion of moisture under an inert atmosphere. Strong acids,
like hydrochloric acid6a and polyphosphoric acid6b are also
promote the self-condensation of ketones.10 While efficient, some
of these methods produce a significant quantity of hazardous
metals and noxious solvents.
The lack of a general strategy for the selective self-
condensation of non-activated ketones under mild conditions
limit its application in organic synthesis.5 Increasing environ-
mental concern around energy efficiency and waste management
provides an opportunity to develop even more powerful and
greener methods for well known organic transformations. This
paper describes a general strategy for the self-condensation of
cyclic/acyclic ketones and aldehydes under mild solvent-free
conditions using microwave irradiation.
Results and discussion
Interestingly, during process development for the synthesis of
arylidene and alkylidene carbonyl compounds, Arnold et al.
observed a very slow self-condensation of cyclopentanone (1)
over a period of 11 days at room temperature.12 The reaction
required two molar equivalents of anhydrous lithium perchlorate
and catalytic triethylamine. Since the application of microwave
irradiation as an alternative heating source provides an efficient
and environment-friendly procedure to accelerate organic trans-
formations, we decided to investigate the microwave–assisted
self-condensation using cyclopentanone as a model substrate
under solvent-free conditions (Scheme 1).
aDepartment of Chemistry, University of Kentucky, Lexington, KY,
40506, USA
bDepartment of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, KY, 40536, USA.
E-mail: gelli3@email.uky.edu; Fax: (+1) 859-257-7564
First, the self-condensation of cyclopentanone was inves-
tigated in the absence of lithium perchlorate. No product
† Electronic supplementary information (ESI) available: experimental
details, 1H and 13C NMR spectra. See DOI: 10.1039/c1gc15164a
1546 | Green Chem., 2011, 13, 1546–1549
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Table 2 Reaction using conventional heatinga
Entry
Time
Ratio (2 : 3)b
Yield of 2 (%)c
1
2
3
4
20 min
1 h
2 h
95 : 5
17
46
68
54
85 : 15
80 : 20
70 : 30
Scheme 1
4 h
a Reactions were carried out with 40 mol% of LiClO4 and 40 mol%
of Et3N at 120 ◦C. b Ratio based on the peak integration of H NMR
1
was obtained, even with an equivalent of triethylamine. In
order to investigate the effect of lithium perchlorate, the self-
condensation was carried out using different amounts of lithium
perchlorate. It was found that as the mol% of lithium perchlorate
increased, more di-condensed product 3 was formed (Fig. 1).
When the effect of triethylamine was investigated, surprisingly,
we observed no effect on the yield or ratio of the two products,
even with the addition of extra equivalents of triethylamine
relative to lithium perchlorate. It is noteworthy that no prod-
uct was obtained when the reaction was performed in the
absence of triethylamine. The best yield for 2-cyclopentylidene-
cyclopentanone (2) was observed when equal molar quantities of
lithium perchlorate and triethylamine were used. We found that
40 mol% of each triethylamine and lithium perchlorate provide
the best yield (80%) with good selectivity (Table 1, entry 5).
Importantly, distillation was used to obtain the enone 2, while
the remaining solid was crystalized to yield 3. Additionally, the
reaction to form compound 2 was accomplished on a 100 mmol
scale without loss in yield or selectivity.
(500 MHz). c Isolated yield.
Table 3 Investigation of other additivesa
Entry
Additive
Ratio (2 : 3)b
Yield of 2 (%)c
1
2
3
4
5
6
Li2SO4
LiCl
LiCF3SO3
LiClO4·3H2O
NaClO4
KClO4
—
—
92 : 8
94 : 6
—
0
0
71
51
0
—
0
a Reactions were carried out with 40 mol% of LiClO4 and 40 mol%
of Et3N at 120 ◦C. b Ratio based on the peak integration of H NMR
1
(500 MHz). c Isolated yield.
To elucidate the importance of microwave irradiation, similar
reactions were performed using conventional heating. When the
reaction was performed in a pre-heated oil bath at 120 0.5 ◦C
using the optimal conditions observed for microwave irradiation
(Table 1, entry 5), only 17% of the desired cyclic enone 2 was
obtained (Table 2, entry 1). An increase in yield was observed
when the reaction was carried out for longer periods of time;
however, selectivity for the monosubstituted enone 2 dropped
4-fold, with a 3-fold increase in reaction time (Table 2, entry2).
In order to investigate the mechanism of self-condensation,
we examined the ability of other additives to catalyze the
reaction. We found that the reaction worked with lithium
trifluoromethanesulfonate in comparable yield (Table 3, entry 3).
The reaction proceeded even in the presence of hydrated lithium
perchlorate (Table 3, entry 4). We also observed that lithium
perchlorate, lithium perchlorate trihydrate, and lithium tri◦fluo-
romethanesulfonate are soluble in cyclopentanone at 120 C.13
The other additives, which are not soluble in cyclopentanone
Fig. 1 The effect of LiClO4 and Et3N on the ratio of mono-condensed
a
(2) and di-condensed (3) products. mol% of LiClO4 was increased,
b
keeping the concentration of Et3N at 20 mol%. mol% of Et3N was
◦
at 120 C, did not work for this reaction. Therefore, it can be
increased, keeping the concentration of LiClO4 at 10 mol%.
concluded that the lithium ion acts as a mild Lewis acid due
to solvation, and that the Lewis acidity of the lithium ion is
a major factor for the reaction to proceed. Also, anhydrous
lithium perchlorate acts as a dehydrating agent, thus helping in
aldol dehydration.
Table 1 Optimization of the self-condensation of 1
Entry LiClO4 (mol%) Et3N (mol%) Ratio (2 : 3)a Yield of 2 (%)b
To explore the substrate scope of this reaction, the self-
condensation of a series of cyclic ketones was attempted under
optimized conditions (Table 4). NOE experiments showed
that the solvent-free condensations of 1-indanone 4 and 5,6-
dimethoxy-1-indanone 7 exclusively gave the E-isomers (Table 4,
entries 2 and 3). The same reaction of 2-indanone 9 afforded the
monoalkylated compound 10 as the major product. Importantly,
the self-condensation of 1,3-indandione was completed in 5 min
giving dione 13 as the major product. An extended reaction
time helped in increasing the yield of truxenequinone 14, an
interesting compound used for the synthesis of compounds
1
2
3
4
5
6
7
8
9
10
20
25
30
40
50
60
70
100
10
20
25
30
40
50
60
70
100
93 : 7
50
69
72
77
80
75
71
75
61
88 : 12
86 : 14
86 : 14
90 : 10
88 : 12
86 : 14
85 : 15
88 : 12
a Ratio based on the peak integration of 1H NMR (500 MHz). Entries
2–6 are the average of two runs. b Isolated yield. Entries 2–6 are the
average of two runs.
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Table 4 Substrate Scopea
Ratiob
(major : minor)
Yield of
Entry
1
Substrate
Major product
Minor product
major (%)c
90 : 10
80
2
99 : 1
73
3d
—
NAe
70
4
75 : 25
99 : 1
71
92
5f
6
7
98 : 2
NA
50
61
—
8
9
50 : 50
40
—
—
NA
No
reaction
a Reactions were carried out with 40 mol% of LiClO4 and 40 mol% of Et3N at 120 ◦C. b Ratio based on the peak integration of 1H NMR (500 MHz).
c Isolated yield. d Reaction temperature was 150 ◦C. e Not applicable. f Reaction time was 5 min.
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Table 5 Self-condensation of acyclic aldehydes and ketones
mode of operation at the specified temperature. All reagents were
obtained from commercial sources and used without further
purification with the exception of triethylamine and aldehydes,
which were distilled under reduced pressure.
Optimized Reaction Procedure
Entry
R1
R2
Yield (%)a
E : Zb
To a 0.2–0.5 mL microwave vial containing substrate (1 mmol)
was added anhydrous LiClO4 (0.043 g, 40 mol%) and Et3N
(0.056 mL, 40 mol%). The vial was sealed and the reaction
mixture was stirred for 20 min at 120 ◦C (or as specified
conditions) in the microwave reactor. After cooling in the
reactor, the microwave vessel was uncapped and 15 mL of
sat. NH4Cl was added. The product was extracted with (2 ¥
20) mL ethyl acetate (diethyl ether was used in the case of
aldehydes). The organic layer was dried over MgSO4, filtered,
and evaporated to dryness under reduced pressure, obtaining an
almost pure product. All liquid products were purified using
distillation, while the solid products were purified either by
crystallization or by silica gel column, as further described in the
ESI.†
1
2
3
4
5
6
7
8
9
C5H11
C4H9
C3H7
C2H5
(CH3)2CHCH2
PhCH2
PhCH2CH2
H
H
H
H
H
H
H
H
95
98 : 2
97 : 3
95 : 5
98 : 2
94 : 6
98 : 2
97 : 3
>99 : 1
50 : 50
93(0)c
90
90
85
92
89
4-Me-C6H4
4-Me-C6H4
15
H
42d
a Isolated yield. b Ratio based on the peak integration of 1H NMR
(500 MHz). c Reaction without LiClO4. d Reaction was done at 200 ◦C
for 4 h.
related to fullerenes.14 Notably, when applying this process to
cyclohexanone 15 and beta-tetralone 18, we obtained the b,g-
unsaturated isomer. It was also possible to apply the reac-
tion to a,b-unsaturated ketone 20. Unlike previous substrates,
larger ring systems, such as cycloheptanone and cyclooctanone
(Table 4, entry 9), did not undergo self-condensation.
To establish the generality and scope of the method, the
procedure was successfully applied to various aldehydes and
afforded the desired self-condensation products in excellent
yields, with high selectivity towards the E-isomer15 (Table 5,
entries 1–7). In addition, we found that the reaction does
not proceed in the absence of lithium perchlorate, even with
aldehydes (Table 5, entry 2). Also, in contrast to aldehydes and
cyclic ketones, which require relatively low temperatures and
shorter reaction times, acyclic ketones require higher tempera-
tures and longer reaction times for their practical conversion to
the required products (Table 5, entries 8–9).
Notes and references
1 (a) C. H. Healthcock, in Comprehensive Organic Synthesis, ed.
B. M. Trost, I. Fleming, Pergamon Press, Oxford, 1991, vol. 2, pp.
133–238; (b) A. T. Nielsen and W. J. Houlihan, Org. React., John
Wiley, New York, 1968, vol 16, p. 1.
2 (a) A. Arcadi, G. Bianchi, M. Chiarini, G. Danniballe and F.
Marinelli, Synlett, 2004, 944; (b) T. P. Clarke, H. A. F. Hoppe, G. C.
Lloyd-Jones, M. Murray, T. M. Peakman, R. A. Stentiford, K. E.
Walsh and P. A. Worthington, Eur. J. Org. Chem., 2000, 963; (c) I. J. S.
Fairlamb, A. R. Kapdi and A. F. Lee, Org. Lett., 2004, 6, 4435.
3 (a) K. B. Adams, E. M. Ferstl, M. C. Davis, M. Herold, S. Kurtkaya,
R. F. Camalier, M. G. Hollingshead, G. Kaur, E. A. Sausville, F. R.
Rickles, J. P. Snyder, D. C. Liotta and M. Shoji, Bioorg. Med. Chem.,
2004, 12, 3871; (b) T. P. Robinson, R. B. Hubbard, T. J. Ehlers, J. L.
Arbiser, D. J. Goldsmith and J. P. Brown, Bioorg. Med. Chem., 2005,
13, 4007.
4 Y. Watanabe, K. Sawada and M. Hayashi, Green Chem., 2010, 12,
384 and references therein.
5 (a) H. O. House, D. S. Crumrine, A. Y. Teranishi and H. D. Olmstead,
J. Am. Chem. Soc., 1973, 95, 3310; (b) S. E. Denmark and W.
Lee, Tetrahedron Lett., 1992, 33, 7729; (c) F. Fringuelli, G. Pani,
O. Piiermatti and F. Pizzo, Tetrahedron, 1994, 39, 11499; (d) R.
Mestres, Green Chem., 2004, 6, 583; (e) C. Capello, U. Fischer and
K. Hungerbuhler, Green Chem., 2007, 9, 927–934.
6 (a) A. T. Nielsen and W. J. Houlihan, Org. React., John Wiley, New
York, 1968, vol 16, p. 1; (b) A. R. Bader, US Patent no. 2769842,
1956; A. R. Bader, Chem. Abstr., 1956, 52, 439.
7 T. Nakano, S. Irefune, S. Umano, A. Inada, Y. Ishii and M. Ogawa,
J. Org. Chem., 1987, 85, 2239.
8 C. Danen and T. T. Kensler, J. Am. Chem. Soc., 1940, 62,
3401.
Conclusion
In summary, we have developed a mild and effective method for
the self-condensation of carbonyl compounds using catalytic
triethylamine and lithium perchlorate. The process takes place
under solvent-free conditions utilizing microwave irradiation.
The present methodology has clear green credentials judging
from the following: (1) the reactions are solvent free, (2) catalytic
amounts of both triethylamine and lithium perchlorate are used,
(3) the reaction time is very short, (4) small amounts of aqueous
waste are produced, (5) distillation or crystallization can be
employed to purify the products in most cases, and (6) it is
possible to scale up the reactions without much loss in yield or
selectivity.
9 Y. G. Yatluk, V. Y. Sosnovskikh and A. L. Suvorov, Russ. J. Org.
Chem., 2004, 40, 763.
10 H. Terai, H. Takaya and T. Naota, Tetrahedron Lett., 2006, 47,
1705.
11 C. Bozkurt, J. Organomet. Chem., 2000, 603, 252.
12 A. Arnold, M. Markert and R. Mahrwald, Synthesis, 2006, 7, 1099.
13 For similar reactions involving solubilities of components see: G.
Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott, J. Am.
Chem. Soc., 2001, 123, 8701.
Experimental
General experimental procedures
14 (a) F. Diederich and Y. Rubin, Angew. Chem., Int. Ed. Engl., 1992,
31, 1101; (b) P. W. Rabideau and A. Sygula, Acc. Chem. Res., 1996,
29, 235.
All microwave reactions were carried out in sealed tubes in a
Biotage InitiatorTM Microwave Synthesizer using the standard
15 The stereochemistry was determined using NOE experiments .
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The Royal Society of Chemistry 2011
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