A new domino autocatalytic reaction leading to polyfunctionalized spiro[5.5]undecanes and dispiro[4.2.5.2]pentadecanes

Article abstract of DOI:10.1039/b822645h

A new domino autocatalytic reaction of imines with Meldrum's acid was described. In this reaction, a series of polycyclic spiro[5.5]undecane-1,5,9- trione and dispiro[4.2.5.2]pentadecane-9,13-dione derivatives, with remarkable diastereoselectivity, were s

Full text of DOI:10.1039/b822645h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new domino autocatalytic reaction leading to polyfunctionalized
spiro[5.5]undecanes and dispiro[4.2.5.2]pentadecanes†
Bo Jiang,a,b Wen-Juan Hao,b Jin-Peng Zhang,c Shu-Jiang Tu*a,b and Feng Shib
Received 17th December 2008, Accepted 13th March 2009
First published as an Advance Article on the web 3rd April 2009
DOI: 10.1039/b822645h
A new domino autocatalytic reaction of imines with Meldrum’s acid was described. In this reaction, a
series of polycyclic spiro[5.5]undecane-1,5,9-trione and dispiro[4.2.5.2]pentadecane-9,13-dione
derivatives, with remarkable diastereoselectivity, were successfully synthesized in acidic condition, and
=
up to six new bonds were formed accompanied by the C N bond cleavage of the imines and the
decomposition of Meldrum’s acid, with by-product of acetohydrazide as a novel autocatalyst.
protocol of Meldrum’s acid that provides one-pot domino syn-
Introduction
thesis of unsymmetrical spiro[5.5]undecanes 1.4 Recently, the
Michael addition approach for the synthesis of symmetrical
spiro[5.5]undecanes 2 has been described by Chande et al.10
Although the diverse synthetic routes to spiro[5.5]undecanes have
been developed, quite surprisingly, utilization of the domino
autocatalytic reaction to build a symmetrical spiro[5.5]undecane
framework and further realize protection of the carbonyl group
to construct a dispiro[4.2.5.2]pentadecane skeleton (3 and 4) in
one-pot has not stimulated much interest so far.
The search for new avenues to molecular complexity from
relatively simple substrates has been one of the major objectives
of organic chemists for the last decade.1 In this regard, the
domino autocatalytic reaction as a unique and fascinating reaction
type has played an important role.2 In addition to the multiple
formation of carbon–carbon bonds in one pot, the domino
autocatalytic reaction intrinsically has the following advantages:
automatic amplification of catalyst, high reaction efficiency, easy
purification of the products, and consecutive reaction pattern.
Therefore, autocatalysis combined with the domino reaction has
made many contributions to modern organic chemistry, both from
academic and industrial points of view. As a result, the continued
development of new domino autocatalytic processes to create
molecular complexity and diversity is becoming an interesting
area for chemists.
Over the past few decades, Meldrum’s acid (2,2-dimethyl-1,3-
dioxane-4,6-dione)3 has been used as a versatile organic reagent4,5
and its derivatives are very useful building blocks in synthetic
organic chemistry.6 Because of its high acidity (pKa 4.83),4 steric
rigidness and notable tendency to regenerate acetone, Meldrum’s
acid is often employed in the design of reactions with multiple
formation of carbon–carbon bonds.7 Spirocyclic compounds
including a Meldrum’s acid unit are attractive intermediates in
the synthesis of natural products and in medicinal chemistry, and
are the starting materials for the synthesis of exotic amino acids
which are used to modify the physical properties and biological
activities of peptides, peptidomimetics, and proteins.8 Thus, the
synthesis of a new highly substituted spiro ring system with a
Meldrum’s acid unit has attracted widespread attention.9 Barbas
III et al. pioneered a new L-proline-catalyzed multi-component
In the literature, Wang et al. have reported the treatment of
imines 5 with Meldrum’s acid 6 unexpectedly generating the
spiro[5.5]undecanes 2 as by-products (Scheme 1).11 This fact and
the results of Barbas III et al. showed that a by-product amine from
=
the reaction of Meldrum’s acid to the imine C N bond may have
served as a self-catalyst to promote the formation of spirotriones
2. The high reactivity of the two nucleophilic centers in imines
5 leads to the benzo[f ]quinolin-3-one 7. Therefore, our concern
is whether the yield of spiro[5.5]undecanes 2 can be improved by
using only one nucleophilic center of the imines.
Scheme 1 The reaction of imines with Meldrum’s acid.
To our delight, we found that the one-pot reaction between
N-arylidene-1-phenylethanamine 5¢ with one nucleophilic center
and Meldrum’s acid 6 efficiently generated sprioheterocycles 2
with remarkable diastereoselectivity at elevated temperature in
moderate yields (Scheme 2 and Table 1). Impressively, when
the symmetric double imines 8 were employed to react with
Meldrum’s acid 6 under acidic conditions, sprioheterocycles 2 as
single diastereomers were obtained in high yields as confirmed
by 1H NMR measurement, together with the acetohydrazide
by-product, which serves as a novel self-catalyst in this reac-
tion (Scheme 3). When the above reaction was performed in
mixed solvent of HOAc and diol such as ethane-1,2-diol and
aCollege of Chemistry, Chemical Engineering, and Materials Science,
Suzhou University, Suzhou, P. R. China. E-mail: laotu@xznu.edu.cn;
Fax: +86(516) 83500065; Tel: +86(516) 83500065
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu, P. R. China
cDepartment of Public Health, Xuzhou Medical College, Xuzhou 221000,
People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental
data. CCDC reference numbers 658845, 658846, 658847 and 700773. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b822645h
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Table 1 The domino autocatalytic synthesis of products 2, 3, and 4
Entry
Product
Ar =
Dialdimines
Time
Yielda/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2a, 4-Chlorophenyl
2b, 4-Bromophenyl
2c, 4-Nitrophenyl
2d, 3,4-Dichlorophenyl
2e, Phenyl
8a
8b
8c
8d
8e
8f
4 h
5 h
18 h
4 h
5 h
4 h
5 h
4 h
4 h
3 h
5 h
9 h
8 h
24 h
10 h
7 h
9 h
8 h
8 h
6 h
8 h
8 h
8 h
10 h
12 h
85 (40)b
89 (38)b
58
84
83 (42)b
87
2f, 4-Tolyl
2g, 4-Methoxyphenyl
2h, Benzo[d][1,3]dioxol-5-yl
2i, 4-Dimethylaminophenyl
2j, 3,4,5-Trimethoxyphenyl
2k, Thien-2-yl
3a, 4-Chlorophenyl
3b, 4-Bromophenyl
3c, 4-Nitrophenyl
3d, 3,4-Dichlorophenyl
3e, 4-Methoxyphenyl
3f, 2-Chlorophenyl
3g, 4-Fluorophenyl
3h, Phenyl
8g
8h
8i
89
84 (36)b
85
2a-2k
8j
81
79
82
84
50
84
85
70
8k
8a
8b
8c
8d
8g
8l
8m
8e
8n
8k
8a
8b
8e
8k
82
83
86
3a-3j
3i, 3,4-Dimethoxyphenyl
3j, Thien-2-yl
78
4a, 4-Chlorophenyl
4b, 4-Bromophenyl
4c, Phenyl
79c
81c
76c
4d, Thien-2-yl
72c
4a-4d
a Reactions are performed with a dialdimines and Meldrum’s acid in a ratio of 1:2.5; the yield is based on the starting dialdimines. b Reaction is performed
with imines 5¢ and Meldrum’s acid in a ratio of 1:2.5; the yield is based on the starting imines. c The yield of two diastereomers.
very cheap; (2) the reaction proceeds smoothly under very mild
conditions without introducing strong acid, base or metal catalyst;
(3) the workup is facile due to the fact that only by-product of
acetohydrazide as an autocatalyst for the Diels–Alder reaction is
released, which is easily isolated because of its water solubility; and
Scheme 2 The reaction of N-arylidene-1-phenylethanamine with Mel-
drum’s acid.
(4) the dispiro[4.2.5.2]pentadecane-9,13-dione systems 3 and 4, to
our best knowledge, represent kind of new two-spiro heterocycles
containing a 1,3-dioxane, a 1,3-dioxolane and a cyclohexane ring,
with the 7,14-cis disposition of substituents. Indeed, the present
protocol provides a novel, straightforward, and effective pathway
to construct spiro heterotricycles of types 2, 3 and 4.
Results and discussion
Scheme 3 The reaction of dialdimines with Meldrum’s acid.
Aldehydes and aldimines are both important electrophiles in
organic synthesis, and addition reactions to these electrophiles
constitute some of the most useful and fundamental organic
transformations. It is generally accepted that aldimines are less
reactive towards nucleophilic addition than their corresponding
aldehydes owing to the difference in electronegativity between
O and N,12 and the steric hindrance present in the aldimines.
Recently, however, an aldimine has been found to be more
reactive than the corresponding aldehyde in many reactions.13
In the present work, symmetric dialdimines 8 as starting ma-
terials were reacted with Meldrum’s acid 6 in a molar ratio of
1:2.5 to yield polyfunctionalized spiro[5.5]undecanes 2 with high
syn-selectivities.
S-propane-1,2-diol, new dispiro[4.2.5.2]pentadecanes 3 and 4 were
provided (Fig. 1).
Fig. 1 The structure of spiro[5.5]undecane derivative.
Next, we devoted our efforts to the study of the reaction of sym-
metric dialdimines 8a with Meldrum’s acid 6 as a model reaction
(Scheme 4). Experiments were carried out in various solvents such
as toluene, THF and EtOH. Unfortunately, the reaction scarcely
Besides a high efficiency in the formation of multiple bonds as
a domino process, this reaction has the following advantages: (1)
the starting materials are readily available and the reagents are
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proceeded in toluene and THF, and an incomplete reaction was
observed in the case of EtOH as solvent. In another case, when
DMF was used as the solvent, the reaction proceeded better and
product 2a as a single diastereomer confirmed by 1H NMR, was
obtained in 46% isolated yield, accompanied with by-products of
acetohydrazide and N¢-(4-chlorophenylidene)acetohydrazide after
purification of the reaction mixture by flash chromatography
(Scheme 4). Subsequently, further optimization of the reaction
conditions, including reaction temperature, reaction time and
more solvents was investigated. Satisfyingly, after a series of
experiments, glacial acetic acid was proved to be the best solvent
and the yield of product 2a reached 85% without the by-product
of N¢-(4-chlorophenylidene)acetohydrazide when the reaction was
performed in HOAc at 80 ◦C for 4 h.
Scheme 5 The synthesis of dispiro[4.2.5.2]pentadecanes 3.
Scheme 6 The synthesis of spiro[5.5]undecanes 4.
1
demonstrated by H NMR integration of the crude mixture (see
the ESI†).
Scheme 4 Optimization of reaction conditions for product 2a.
Proposed reaction mechanism
To extend the scope of this protocol for the synthesis of the
fused spiroheterocycles, substrates 8b–k, with electron-donating
or electron-withdrawing groups on the phenyl rings, were then
examined for their reactions with Meldrum’s acid under the
optimized conditions. As a result, a series of products 2b–k were
obtained in good yields of 79–89% except for the compound 2c
(Table 1, entries 1–11). The substrate 8k, which contained the
heteroaromatic group (2-thienyl), was also allowed to react with
Meldrum’s acid under identical conditions. Accordingly, thienyl-
substituted spriocycle compound 2k was generated.
A reasonable mechanism for the formation of the tricyclic
dispiro[4.2.5.2]pentadecane-9,13-dione 3 was proposed and de-
picted in Scheme 7. First, due to the strong nucleophilicity of
the nitrogen atom of dibenzylidenehydrazine, a Mannich-type
reaction followed by a SNA (nucleophilic acyl substitution) type
reaction14 occurs, leading to the fragmentation of the Meldrum’s
acid, release of acetone, and the formation of intermediate A
To further investigate the synthetic potential of this process,
reaction of Meldrum’s acid with symmetric dialdimines 8a was
carried out in a mixed solvent of HOAc and ethylene glycol.
Interestingly, new dispiro[4.2.5.2]pentadecane 3a was furnished
with ethylene glycol as a protection reagent of the carbonyl group
under these mild reaction conditions. Subsequently, screening of
the solvent ratio in the mixed solvents revealed that a mixture of
glycol and HOAc (2:1, v/v) was the best solvent, affording the
dispirodione 3a as a single diastereomer in good yield. To test
the reaction scope, various symmetric dialdimines 8 were treated
with Meldrum’s acid under the optimized conditions described
above to yield a series of new dispirodiones 3a–j with high syn-
selectivities and concomitant formation of up to two quaternary
carbon centers and six s bonds including two C–O bonds. It
is worth noting that to the best of our knowledge, there has
not yet been any literature precedent for the synthesis of new
polyfunctionalized dispiro[4.2.5.2]pentadecane-9,13-diones 3 via
an autocatalytic reaction (Scheme 5).
To demonstrate the generality of this methodology, the re-
placement of ethylene glycol with chiral 1,2-propanediol (S-)
was examined. To our delight, under the same conditions, the
reaction proceeds stereoselectively also (mixtures of diastereomers
4a–d and 4a¢–d¢ are obtained), with the generation of three
new asymmetric carbons (Scheme 6). The 1H NMR analysis
of the products indicates the presence of a mixture of two
diastereoisomers. The ratio of the isomers was close to 1:1 as
Scheme 7 The reaction mechanism of formation of product 3.
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Table 2 Investigation of reaction mechanism
and were unequivocally confirmed by X-ray diffraction of single
crystals 2h, 3g and 4b (see the ESI†) (Fig. 2–4).
Entry
Solvent
Catalyst
Time/h
Yield of 2e
1
2
3
HOAc
HOAc
HCOOH
Acetohydrazide
—
Acetohydrazide
4
6
7
81
trace
trace
which undergoes retro-Mannich reaction to generate arylidene-
Meldrum’s acid B and intermediate C. The enones D and
acetohydrazide E would be formed by a Mannich and retro-
Mannich reaction of N-arylideneacetohydrazide C with acetone.
The arylidene-Meldrum’s acid B undergoes a Diels–Alder reac-
tion with the soft nucleophilic Barbas dienamine (2-amine-1,3-
butadiene)15 F, generated in situ from enones D and the hydrazide
E, to produce spirotriones G, which further react with diols
in HOAc to dispiro[4.2.5.2]pentadecanes 3. This hypothesis is
supported by the mechanistic investigation of proline-catalyzed
spirotriones’ formation through the reaction of aldehyde and
Meldrum’s acid with enones reported by Barbas III et al.4,9a
In order to further clarify the mechanism for the formation
of 2, a model reaction between benzylidene-Meldrum’s acid, for
example, and 4-phenyl-but-3-en-2-one, was carried out in various
reaction conditions (Table 2). In this reaction, the use of acetohy-
drazide as a catalyst in acetic acid leads to spiro[5.5]undecane
2e in a yield of 81% (Table 2, entry 1) whereas the reaction
scarcely proceeded in HOAc without acetohydrazide or using
formic acid (pKa = 3.77)14 whose pKa value was lower than
that of acetic acid (pKa = 4.76)14 as reaction media in the
presence of acetohydrazide (Table 2, entries 2 and 3). The results
indicated that acetohydrazide might have formed ammonium
salt by reacting with formic acid, losing the catalytic activity.
In addition, the reaction of benzylidene-Meldrum’s acid with
N-benzylideneacetohydrazide (intermediate C) and acetone was
performed in acetic acid to give the spiro[5.5]undecane 2e in high
yield (Scheme 8). Obviously, these experimental results further
supported the mechanism for the products 2. The key step to
spiro[5.5]undecanes 2 was acetohydrazide catalyzed Diels–Alder
reaction between compound B and enones D.
Fig. 2 The ORTEP drawing of 2h.
Fig. 3 The ORTEP drawing of 3g.
Conclusion
In summary, a new and highly efficient autocatalytic domino
reaction constitutes
a good illustration of the potential-
ity of Meldrum’s acid in stereocontrolled multiple s bond
forming reactions and provides a new route to polyfunc-
tionalized spiro[5.5]undecane-1,5,9-triones and dispiro[4.2.5.2]
pentadecane-9,13-diones for the first time. A reaction product,
the acetohydrazide, plays a critical role in the success of the
reaction by serving as a self-catalyst for the Diels–Alder reaction
between arylidene-Meldrum’s acid B and Barbas dienamine F. The
simplicity of manipulation, ready availability of the substrates and
reagents, and the easy access of a significant molecular complexity
make this domino synthetic strategy attractive. An extension of
this work is in progress.
Scheme 8 The investigation of self-catalyst and reaction mechanism.
In most cases, the formation of a single product with concomi-
tant formation of six s bonds in these reactions illustrates the high
efficiency of bond formation and the remarkable chemo-, regio-,
and diastereoselectivity accompanying a remarkable increase in
complexity starting from very simple and easily accessible achiral
substrates. The structural elucidation and the attribution of the
relative stereochemistry of the products rest upon NMR analysis
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was collected by washing with water. The resulting suspension
was neutralized with 10% NaOH. The aqueous layers were then
extracted thoroughly with ethyl ether (3 ¥ 10 mL), and organic
phases were evaporated under reduced pressure to give solid. The
combined solids were purified by flash column chromatography
(silica gel, mixtures of petroleum ether/acetic ester, 10:1, v/v)
to afford the desired pure spirotriones 2a–2k and by-product
acetohydrazide. All organic compounds except 2a–2e, 2g–2h, and
2k are reported in the literature4,9and are fully characterized by
spectral analysis.
General procedure for investigation of autocatalyst. In a 25-mL
flask, benzylidene-Meldrum’s acid (2 mmol), 4-phenyl-but-3-en-
2-one (2 mmol), acetohydrazide(1 mmol), and HOAc (4 mL)
(without HOAc or HCOOH) were mixed and then stirred at
80 ◦C until the disappearance of starting material was confirmed
by TLC. Upon completion, the reaction mixture was cooled to
room temperature. The subsequent work-up was the same as that
of the above preparation of compounds 2e.
General procedure for investigation of reaction mechanism.
In a 25-mL flask, benzylidene-Meldrum’s acid (2 mmol), N¢-
benzylideneacetohydrazide (2 mmol), acetone (5 mmol) and
HOAc (4 mL) were mixed and then stirred at 80 ◦C until the
disappearance of starting material was confirmed by TLC. Upon
completion, the reaction mixture was cooled to room temperature.
The subsequent work-up was the same as that of the above
preparation of compounds 2e.
Fig. 4 The ORTEP drawing of 4b.
Experimental
General
Melting points were determined in open capillaries and were
uncorrected. 1H NMR (13C NMR) spectra were measured on
a Bruker DPX 400 (100) MHz spectrometer in DMSO-d6 with
chemical shift (d) given in ppm relative to TMS as internal
standard. The exact mass measurements were obtained by a
high resolution mass instrument (GCT-TOF instrument). X-Ray
crystallographic analysis was performed with a Siemens SMART
CCD and a Siemens P4 diffractometer.
General procedure for the synthesis of compounds 3a–3j and 4a–4d
In a 25-mL flask, 1,2-diarylidenehydrazine 8 (2 mmol), Meldrum’s
acid 6 (5 mmol), HOAc (4 mL) and ethane-1,2-diol (or S-1,2-
propanediol, 8 mL) were mixed and then stirred at 80 ◦C until the
disappearance of starting material was confirmed by TLC. Upon
completion, the reaction mixture was cooled to room temperature,
and introduced into water. The solid was collected by washing
with water. The aqueous layers were extracted thoroughly with
ethyl ether (3 ¥ 10 mL), and organic phases were evaporated
under reduced pressure to give solid. The combined solids were
purified by flash column chromatography (silica gel, mixtures of
petroleum ether/acetic ester, 10:1, v/v) to afford the desired pure
dispiro[4.2.5.2]pentadecane-9,13-diones 3 and 4.
General procedure for the synthesis of compounds 2a–2k
General procedure for the reaction of ethanamine 5¢ with
Meldrum’s acid 6. In a 25-mL flask, N-arylidene-1-phenyl-
ethanamine 5¢ (2 mmol), Meldrum’s acid 6 (5 mmol), and HOAc
(4.0 mL) were mixed and stirred at 80 ◦C until the disappearance
of starting material was confirmed by TLC. Upon completion, the
reaction mixture was cooled to room temperature, and introduced
into water. The resulting suspension was neutralized with 10%
NaOH. The solid was collected by washing with water. The
aqueous layers were then extracted thoroughly with ethyl ether
(3 ¥ 10 mL), and organic phases were evaporated under reduced
pressure to give solid. The combined solids were purified by
flash column chromatography (silica gel, mixtures of petroleum
ether/acetic ester, 10:1, v/v) to afford the desired pure spirotriones
2a (2b, 2e, and 2h) and by-products acetamides.
7,11-Bis-(4-dimethylaminophenyl)-3,3-dimethyl-2,4-dioxaspiro-
[5.5]undecane-1,5,9-trione (2i)
Pale yellow solid, mp: 229–231 ◦C.
1H NMR (400 MHz) (d, ppm): 6.94 (d, J = 8.8 Hz, 4H, ArH),
6.99 (d, J = 8.8 Hz, 4H, ArH), 3.87 (dd, J1 = 14.2 Hz, J2
=
4.8 Hz, 2H, CH2), 3.48–3.37 (m, 2H, CH), 2.84 (s, 12H, NCH3),
2.39 (dd, J1 = 15.4 Hz, J2 = 4.8 Hz, 2H, CH2), 0.61 (s, 6H, CH3).
13C NMR (100 MHz) (d, ppm): 207.3, 168.0, 156.1, 150.3, 128.6,
124.5, 112.4, 105.8, 60.7, 48.1, 42.8, 27.9. IR (KBr, n, cm-1): 3044,
2992, 2892, 1754, 1726, 1613, 1523, 1450, 1358, 1195, 1167, 1046,
946, 813, 716. ESI-MS: m/z 465.1 [M + H]+ (100%), 497.2 [M +
Na]+.
General procedure for the reaction of diarylidenehydrazine 8 with
Meldrum’s acid 6. In a 25-mL flask, 1,2-diarylidenehydrazine
8 (2 mmol), Meldrum’s acid 6 (5 mmol), and HOAc (4.0 mL)
were mixed and stirred at 80 ◦C until the disappearance of
starting material was confirmed by TLC. Upon completion, the
reaction mixture was cooled to room temperature. The solid
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7,14-Bis-(4-chlorophenyl)-11,11-dimethyl-1,4,10,12-tetraoxa-
dispiro[4.2.5.2]pentadecane-9,13-dione (3a)
˚
O6–C7, O6–C25 are restrained to 1.43 A with an estimated standard
deviation 0.02.
White solid, mp: 270–271 ◦C.
1H NMR (400 MHz) (d, ppm): 7.46 (d, J = 8.0 Hz, 4H, ArH),
7.13 (d, J = 8.0 Hz, 4H, ArH), 3.99-3.96 (m, 4H, CH2), 3.86-3.81
(m, 2H, CH2), 2.76 (t, J = 13.4 Hz, 2H, CH), 1.87-1.83 (m, 2H,
CH2), 0.56 (s, 6H, CH3). 13C NMR (100 MHz) (d, ppm): 168.5,
164.3, 137.2, 133.2, 130.4, 129.2, 107.0, 105.9, 64.3, 60.2, 47.6,
35.5, 28.0. IR (KBr, n, cm-1): 3049, 2983, 1759, 1731, 1599, 1518,
1462, 1403, 1388, 1346, 1286, 1214, 1156, 1101, 1025, 968, 891,
769. Anal. calcd. for C25H24Cl2O6, C, 61.11; H, 4.92; found C,
61.09; H, 4.84.
Acknowledgements
We are grateful for financial support from the National Science
Foundation of China (Nos. 20672090 and 20810102050), Natural
Science Foundation of the Jiangsu Province (No. BK2006033),
and Six Kinds of Professional Elite Foundation of the Jiangsu
Province (No. 06-A-039).
References
1 (a) New Avenues to Efficient Chemical Synthesis. Emerging Technolo-
gies, Eds.: P. H. Seeberger, T. Blume, Springer, Heidelberg, 2007
(Ernst Schering Foundation Symposium Proceedings 2006-3); (b) K. C.
Nicolaou, E. W. Yue, T. Oshima, in The New Chemistry, Ed.: N. Hall,
Cambridge University Press, Cambridge, 2001, pp. 168–198; (c) L. F.
Tietze, F. Hautner, in Stimulating Concepts in Organic Chemistry, Eds:
F. Vgtle, J. F. Stoddart, M. Shibashaki, Wiley-VCH, Weinheim, 2000,
pp. 38–64; (d) D. B. Ramachary, M. Kishor and G. Babul Reddy,
Org. Biomol. Chem., 2006, 4, 1641–1646; (e) D. B. Ramachary and
G. Babul Reddy, Org. Biomol. Chem., 2006, 4, 4463–4468; (f) D. B.
Ramachary and M. Kishor, J. Org. Chem., 2007, 72, 5056–5068;
(g) D. B. Ramachary, K. Ramakumar and V. V. Narayana, J. Org.
Chem., 2007, 72, 1458–1463; (h) D. B. Ramachary and M. Kishor,
Org. Biomol. Chem., 2008, 6, 4176–4187; (i) D. B. Ramachary,
Y. V. Reddy and M. Kishor, Org. Biomol. Chem., 2008, 6, 4188–
4197.
2 (a) H. Hagiwara, S. Endou, M. Fukushima, T. Hoshi and T. Suzuki,
Org. Lett., 2004, 6, 1115–1118; (b) M. Fukushima, A. Morii, T.
Hoshi, T. Suzuki and H. Hagiwara, Tetrahedron, 2007, 63, 7154–7164;
(c) M. Amedjkouh and M. Brandberg, Chem. Commun., 2008, 3043–
3045.
3 (a) L. F. Tietze and U. Beifuss, Angew. Chem. Int. Ed. Engl., 1993, 32,
131–163; (b) L. F. Tietze, T. H. Evers and E. Topken, Angew. Chem.
Int. Ed., 2001, 40, 903–905; (c) S. Ikeda, Angew. Chem. Int. Ed., 2003,
42, 5120–5122; (d) R. J. Linderman, S. Binet and S. R. Petrich, J. Org.
Chem., 1999, 64, 336–337; (e) P. Satymaheshwar, S. Jayakumar and J. J.
Tepe, Org. Lett., 2002, 4, 3533–3535.
4 D. B. Ramachary, N. S. Chowdari and C. F. Barbas III, Angew. Chem.
Int. Ed., 2003, 42, 4233–4237.
5 F. L. Muller, T. Constantieux and J. Rodriguez, J. Am. Chem. Soc.,
2005, 127, 17176–17177.
6 (a) A. N. Meldrum, J. Chem. Soc., 1908, 93, 598–601; (b) D. Davidson
and S. A. Bernhard, J. Am. Chem. Soc., 1948, 70, 3426–3428.
7 H. McNab, Chem. Soc. Rev., 1978, 7, 345–358.
8 (a) D. R. Zitsane, I. T. Ravinya, I. A. Riikure, Z. F. Tetere, E. Y.
Gudrinietse and U. O. Kalei, Russ. J. Org. Chem., 1999, 35, 1457–
1460; (b) D. R. Zitsane, I. T. Ravinya, I. A. Riikure, Z. F. Tetere,
E. Y. Gudrinietse and U. O. Kalei, Russ. J. Org. Chem., 2000, 36, 496–
501; (c) I. Bonnard, M. Rolland, C. Francisco and B. Banaigs, Lett.
Pept. Sci., 1997, 4, 289–292; (d) S. M. Chande and R. R. Khanwelkar,
Tetrahedron Lett., 2005, 46, 7787–7792; (e) A. S. Ivanov, Chem. Soc.
Rev., 2008, 37, 789–811.
2h. The single-crystal growth was carried out in ethanol
at room temperature. Crystal data for C25H22O9, M = 466.43,
˚
monoclinic, space group P2(1)/c, a = 6.8061(8) A, b = 22.230(3)
3
˚
˚
˚
A, c = 14.9656(16) A, V = 2234.9(4) A , Z = 4, T = 298(2) K, m =
0.106 mm-1, 10899 reflections measured, 3836 unique reflections,
R = 0.0943, Rw = 0.1917. In the 1,3-dioxane ring, atoms C7, C8, C10,
and C11 are disordered over two positions. During the refinement
process the disordered atoms C7 and C8 were both refined with
occupancies of 0.58(2) and 0.42(2), respectively, and atoms C10
and C11 were both refined with occupancies of 0.56(2) and 0.44(2),
respectively. In the cyclohexanone ring, atoms O3 and O4 are
disordered over two positions, During the refinement process the
disordered atom O3 was refined with occupancies of 0.502(4) and
0.498(2) whereas atom O4 was refined with occupancies of 0.414(4)
and 0.586(2).
3g. The single-crystal growth was carried out in ethanol at
room temperature. Crystal data for C25H24F2O6, M = 458.44,
¯
˚
˚
triclinic, space group P1, a = 8.146(4) A, b = 10.714(5) A,
3
˚
˚
c = 13.580(7) A, V = 1104.6(9) A , Z = 2, T = 298(2) K,
m = 0.109 mm-1, 5811 reflections measured, 3845 unique reflec-
tions, R = 0.0535, Rw = 0.1330.
4b. The single-crystal growth was carried out in ethanol at
room temperature. Crystal data for C26H26Br2O6, M = 594.29,
¯
˚
˚
triclinic, space group P1, a = 7.356(3) A, b = 12.590(5) A,
3
˚
˚
c = 14.852(6) A, V = 1267.8(8) A , Z = 2, T = 193(2) K,
m = 3.236 mm-1, 6454 reflections measured, 4330 unique re-
flections, R = 0.0728, Rw = 0.1245. In the bromophenyl ring
(C18–C23), atom Br2 was disordered over two positions. During
the refinement process the disordered atom Br2 was refined with
occupancies of 0.51(4) and 0.49(4). In the 1,3-dioxolane ring,
atoms C25 and C26 are disordered over two positions. During
the refinement process the disordered atoms C25 and C26 were
refined with occupancies of 0.320(18) and 0.680(18), 0.320(18) and
0.680(18), respectively. During refinement, atoms C25 and C25¢ are
constrained to have the same x, y and z parameters and anisotropic
9 (a) D. B. Ramachary and C. F. Barbas III, Chem. Eur. J., 2004, 10,
5323–5231; (b) D. B. Ramachary and C. F. Barbas, III, Org. Lett.,
2005, 7, 1577–1580; (c) E. E. Shults, E. A. Semenova, A. A. Johnson,
S. P. Bondarenko, I. Y. Bagryanskaya, Y. V. Gatilov, G. A. Tolstikov
and Y. Pommier, Bioorg. Med. Chem. Lett., 2007, 17, 1362–1368; (d) S.
Lu and H. Chen, Huaxi Yaoxue Zazhi, 1995, 10, 29–31; (e) Q. Zhong,
J. Shao and C. Liu, Youji Huaxue, 1988, 8, 466–469.
displacement parameters. All of the atoms of C, O, Br closer than
2
˚
˚
3.8 A are restrained with an s. u. value of 0.02 A to have the
same Uij components. If (according to the connectivity table,
i.e. ignoring attached hydrogens) one or both of the two atoms
involved is terminal (or not bonded at all), 0.04 is used instead as
0.02. The distance between C24, C26 and C24, C26¢ is restrained to
10 M. S. Chande and R. R. Khanwelkar, Tetrahedron Lett., 2005, 46,
7787–7792.
11 X.-S. Wang, M.-M. Zhang, Z.-S. Zeng, D.-Q. Shi, S.-J. Tu,
X.-Y. Wei and Z.-M. Zong, Tetrahedron Lett., 2005, 46, 7169–
7173.
12 (a) N. B. Ambhaikar, J. P. Snyder and D. C. Liotta, J. Am. Chem. Soc.,
2003, 125, 3690–3691; (b) M. Yamaguchi, in: Comprehensive Organic
Synthesis, (Ed.: B. M. Trost, I. Flem-ing), Pergamon Press, Oxford,
1991, Vol. 1, p. 325.
˚
2.54 A with an estimated standard deviation 0.02. The distances
˚
of C25–C26, C24–C25 and C25–C26¢ are restrained to 1.53 A with an
estimated standard deviation 0.02. The distances of O5–C7, O5–C24,
2200 | Org. Biomol. Chem., 2009, 7, 2195–2201
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13 (a) F. Chemla, V. Hebbe and J. Normant, Synthesis, 2000, 75–85; (b) Y.
Hayashi, T. Urushima, M. Shoji, T. Uchimaru and I. Shiina, Adv. Synth.
Catal, 2005, 347, 1595–1604.
Ramachary, N. S. Chowdari and C. F. Barbas III, Tetrahedron
Lett., 2002, 43, 6743–4746; (c) D. B. Ramachary, N. S. Chow-
dari and C. F. Barbas III, Synlett, 2003, 1910–1914; (d) D. B.
Ramachary, K. Anebouselvy, N. S. Chowdari and C. F. Barbas
III, J. Org. Chem., 2004, 69, 5838–5849; (e) D. B. Ramachary,
Y. V. Reddy and B. V. Prakash, Org. Biomol. Chem., 2008, 6, 719–
726.
14 J. McMurry, Fundamentals of Organic Chemistry, 5th Ed. China
Machine Press, 2003, p. 314.
15 (a) R. Thayumanavan, D. B. Ramachary, K. Sakthivel, F. Tanaka and
C. F. Barbas III, Tetrahedron Lett., 2002, 43, 3817–3820; (b) D. B.
This journal is
The Royal Society of Chemistry 2009
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