Iron-catalyzed cross-aldol reactions of ortho-diketones and methyl ketones

Article abstract of DOI:10.1039/b903515j

Iron-catalyzed cross-aldol reactions of ortho-diketones and methyl ketones were developed and the thus formed aldol products were efficiently transformed into cyclohepta-2,4,6-trienone derivatives (tropones) under thermal conditions via ring-expansion.

Full text of DOI:10.1039/b903515j

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Iron-catalyzed cross-aldol reactions of ortho-diketones and methyl
ketonesw
Haijun Li,a Wenjuan Lia and Zhiping Li*ab
Received (in College Park, MD, USA) 18th February 2009, Accepted 14th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b903515j
Iron-catalyzed cross-aldol reactions of ortho-diketones and
methyl ketones were developed and the thus formed aldol products
were efficiently transformed into cyclohepta-2,4,6-trienone deri-
vatives (tropones) under thermal conditions via ring-expansion.
in organic synthesis if other ketones could be applied under the
catalytic and mild reaction conditions. According with our
research,10a,b we investigated the iron-catalyzed reaction of
o-chloranil 1a14,15 and acetophenone. To our delight, the
desired product 3a was obtained in 91% yield using 5 mol%
FeCl3 at room temperature (Table 1, entry 1).z The yield of 3a
depended dramatically on the solvent. Polar solvents led to low
yields of the desired product. Cyclohexane and petroleum ether
(PE) were suitable solvents for this transformation. We chose
PE as a solvent due to its low price. FeCl2 and AlCl3 were much
less effective than FeCl3 in the present aldol reactions. No
product was observed in the absence of a catalyst.
The aldol reaction is a particularly valuable carbon–carbon
bond formation in organic synthesis. The aldol products,
b-hydroxy aldehydes or ketones, are multifunctional products
and versatile intermediates. Extensive studies on the aldol
reaction have produced various efficient methods for the
reactions between aldehydes and ketones. Due to the low
electrophilic reactivity and steric hindrance of ketones,
aldehydes are commonly used as the electrophilic partner in
the aldol reaction. To achieve cross-aldol reactions of two
different ketones is still a great challenge in synthetic chemistry.1
The applications of iron catalysts are attracting much
attention in organic chemistry due to their advantages of being
inexpensive, easily available and nontoxic.2 Some pioneering
works in iron-catalyzed organic reactions have been reported,
which were effectively catalyzed by noble metal catalysts.3–10
To the best of our knowledge, there are no reports on iron-
catalyzed aldol reactions between two ketones.11 Herein, we
report an efficient iron-catalyzed cross-aldol reaction of ortho-
diketones and methyl ketones. Significantly, the cross-aldol
products smoothly transform into multifunctional cyclohepta-
2,4,6-trienone derivatives (tropones) under thermal conditions
via ring-expansion (Scheme 1).
Subsequently, the scope of the aldol reaction was investi-
gated and the representative results are listed in Table 1.
Both electron-donating substituted and electron-withdrawing
substituted acetophenones reacted smoothly with 1a (Table 1,
entries 3–8). Low reaction rates were observed when a- and
b-acetyl naphthalenes were used. Moderate yields of 3h and 3i
were obtained with prolonged reaction time (Table 1, entries 9
and 10). The desired product 3j was obtained with good yield
when 2-acetyl-5-methylfuran was used (Table 1, entry 11).
6 equivalents of acetone had to be used in order to increase the
conversion of 1a (Table 1, entry 12). Importantly, 10 mmol
scale aldol reactions went smoothly under the standard reac-
tion conditions (Table 1, entries 2 and 13). Moreover, the
reactions of 1b and 1c with acetone afforded the corresponding
products in good yields, albeit when excess acetone was used
as a solvent (Scheme 2). Asymmetric ortho-diketone 1b gave
two regioisomeric products 3l and 3l0 with the ratio of 3 : 4.
Due to its unique non-benzenoid aromatic structure and
broad spectrum of biological properties, the synthesis of the
tropone skeleton has attracted great attention.16 With the cross-
aldol products in hand, we explored the generality and selectivity
of thermal ring-expansion.12,17 After countless failures, we found
that the expected seven-membered cyclic compounds 4 were
selectively obtained as single isomers with good yields at 130 1C
for 40 min (Table 2).y The structure of 4b (CCDC 714817) was
unambiguously confirmed by crystal X-ray diffraction.18
These tropone derivatives with multiple functional groups are
potentially useful building blocks for further elaboration.
A tentative mechanism for the formation of the tropone
skeleton is proposed in Scheme 3. Intramolecular aldol
reaction of 3 led to bicyclic intermediate A. A 6p electrocyclic
ring-opening reaction gives seven-membered intermediate B.
Two sequential keto–enol tautomerizations afford the inter-
mediate D via C. Tropone 4 is formed as the final product by
elimination of one chloro atom from D. The relatively high
thermostability of enol form 4 contributes to the isolation of
In 1956, an interesting result of the gas HCl-promoted aldol
reaction of o-chloranil and acetone was reported.12 Acetone
was used as both a reactant and solvent in this transformation.
Unfortunately, there are no further investigations on this
reaction.13 We hypothesized that the reaction would be useful
Scheme 1 FeCl3-catalyzed cross-aldol reactions and ring-expansion.
a Department of Chemistry, Renmin University of China, Beijing
100872, China. E-mail: zhipingli@ruc.edu.cn;
Fax: +86-10-62514226; Tel: +86-10-6251-4226
b State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian 116012, China
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and
13C NMR spectra for isolated compounds, and X-ray data for 4b.
CCDC 714817. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b903515j
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Table 1 Aldol reactions of o-chloranil 1a and ketones 2a
Yield
(%)b
Entry
1
Product
3a
91
Scheme 2 The reactions of 1b and 1c with acetone.
Table 2 Ring-expansion reactions of 3a
2
3
3a
3b
75c
81
4
5
3c
3d
3e
3f
3g
3h
3i
68
66
84
87
71
60d
61d
82
Yield
(%)b
Entry
1
Product
4a
81 (77)
6
2
3
4
5
4b
4c
4d
4e
4f
82 (64)
88 (74)
79 (68)
76 (64)
85 (74)
7
8
9
10
11
12
3j
6
3 (0.2 mmol). NMR yields are determined by 1H NMR spectro-
scopy using mesitylene as an internal standard; isolated yields are
given in parentheses.
a
b
3k
3k
85e
82f
13
only the single isomer.19,20 However, some structurally
uncharacterized solids were obtained when the temperature
of the ring-expansion was above 150 1C.
a
1a (0.5 mmol) and FeCl3 (0.025 mmol), 2 (0.75 mmol); unless otherwise
b
noted. Isolated yield. 1a (10 mmol), 2 (15 mmol), PE (40 mL).
d
c
e
48 h. 2 (3.0 mmol). f 1a (10 mmol), 2 (30 mmol), PE (40 mL).
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¨
In summary, we have demonstrated an efficient iron-catalyzed
cross-aldol reaction between two ketones under mild reaction
conditions. Multifunctional tropones were efficiently and
selectively obtained via ring-expansion of the aldol products
under thermal conditions. Further studies into the applications
of these tropones in synthetic chemistry are in progress.
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Z. L. thanks the program for New Century Excellent
Talents in University. We thank the NSFC (Nos. 20602038
and 20832002) and the State Key Laboratory of Fine
Chemicals (No. KF0704) for financial support. We thank
Prof. Zhenfeng Xi, Peking University, for discussions. We
also thank Prof. Tamotsu Takahashi, Hokkaido University,
for the hospitality during H. L. and Z. L.’s stay in Sapporo,
Japan, and partial works were done in Hokkaido University.
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and H. Li, Angew. Chem., Int. Ed., 2008, 47, 7497; (b) Z. Li, L.
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14 The [4 + 2]-cycloaddition products are generated by the reactions
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(a) T. Bekele, M. H. Shah, J. Wolfer, C. J. Abraham,
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Notes and references
z A typical procedure for the preparation of 3. To a 2.0 mL solution of 1
(0.5 mmol) in petroleum ether (PE) under N2 at room temperature was
added 2 (0.75 mmol, 1.5 equiv.). The resulting mixture was stirred for
24 h at room temperature. The resulting reaction solution was mixed
with silica gel and evaporated in vacuo. The residue was purified
by flash column chromatography using silica gel (ethyl acetate :
PE = 1 : 5) to afford the desired product 3.
y A typical procedure for the preparation of 4. An oven-dried Schlenk
tube was charged with 3 (0.2 mmol) under N2 at room temperature.
The Schlenk tube was put into a pre-heated oil bath at 130 1C for
40 min. The reaction mixture was quenched with saturated NaHCO3
and washed with 10 mL diethyl ether. The resulting aqueous phase was
acidified with 2 mL 3 N HCl and extracted with 15 mL diethyl ether.
The extract was washed with water and dried over Na2SO4. The
solvent was evaporated in vacuo to afford the desired products 4.
17 Two regioisomers were obtained by the reaction of o-chloranil and
triphenylbismuthonium 2-oxoalkylides: M. M. Rahman, Y. Matano
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18 Cryatal data for 4b: C14H7Cl3O3, Mw = 329.55 g molꢁ1, T =
1 (a) S. Samanta and C.-G. Zhao, Tetrahedron Lett., 2006, 47, 3383;
(b) R. Mahrwald, Modern Aldol Reactions, Wiley-VCH, Veinheim,
2004; (c) R. Mahrwald, Chem. Rev., 1999, 99, 1095.
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Chem. Soc. Rev., 2008, 37, 1108; (c) S. Enthaler, K. Junge and
ꢀ
293(2) K, triclinic, space group P1, a = 4.1248(8), b = 18.813(4),
c = 19.845(4) A, a = 62.21(3), b = 89.89(3), g = 89.83(3)1, V =
¨
1362.3(5) A3, Z = 4, rc = 1.607 Mgmꢁ3, m = 0.674 mmꢁ1
reflections collected: 12 452, independent reflections: 6165 (Rint =
,
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¨
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R indices (all data): R1 = 0.1080, wR2 = 0.0780.
3 Carbon–carbon bond formation: (a) A. Furstner, K. Majima,
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Org. Biomol. Chem., 2007, 5, 2114. For a review; (b) Q. Hu and
Z. Xi, Youji Huaxue, 2008, 28, 1864.
20 The steric hindrance prevents the isomerization of b-tropones:
V. I. Minkin, S. M. Aldoshin, V. N. Komissarov, I. V. Dorogan,
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¨
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This journal is The Royal Society of Chemistry 2009
3266 | Chem. Commun., 2009, 3264–3266