Direct anti and regio-specific aldol reactions of cyclododecanone catalyzed by alkali metal hydroxides: Implications for supramolecular helical design

Article abstract of DOI:10.1039/c2nj40499k

The direct aldol condensation of benzaldehyde to cyclododecanone (CDD), catalyzed by NaOH is expected to yield bis-benzylidene cyclododecanone, but we interestingly ended up with novel β-hydroxy carbonyl compounds and monobenzylidene cyclododecanone deriv

Full text of DOI:10.1039/c2nj40499k

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PAPER
Direct anti and regio-specific aldol reactions of cyclododecanone
catalyzed by alkali metal hydroxides: implications for supramolecular
helical designw
Venkatesan Sathesh,a Balijapalli Umamahesh,a Gunasekar Ramachandran,a
Ravindranath S. Rathoreb and Kulathu Iyer Sathiyanarayanan*a
Received (in Montpellier, France) 15th June 2012, Accepted 22nd August 2012
DOI: 10.1039/c2nj40499k
The direct aldol condensation of benzaldehyde to cyclododecanone (CDD), catalyzed by NaOH is
expected to yield bis-benzylidene cyclododecanone, but we interestingly ended up with novel
b-hydroxy carbonyl compounds and monobenzylidene cyclododecanone derivatives in the cases of
2-halo substituted benzaldehydes. This exceptional behaviour is due to the capability of the CDD
ring to exist in the zwitter ionic form. The formation of monobenzylidine derivatives can be due
to less stable hydrogen bonds between –OH and –CQO groups, electrostatic interaction between
aldehyde substituents and metal enolates and the bulkiness of the benzaldehyde ring substituents.
We extensively optimized the reaction conditions using different solvents and alkali metal
hydroxide catalysts and we are getting high yield, regio-specificity and high diastereoselectivity
(anti-aldol) in b-hydroxy carbonyl compounds. The representative crystal structures were
examined and they suggest the tendency of anti-aldol compounds to form supramolecular helical
motifs. The b-hydroxyl carbonyl derivatives form supramolecular helices via O–HÁ Á ÁO hydrogen
bonds with two anti-aldol units per turn and a pitch of B6 A. The cyclododecanone ring adopts
the minimum energy [3333] square conformation. The nucleophile will attack only from the less
hindered side of the carbonyl group in the CDD ring.
to form further derivatives) and monobenzylidene cyclododecanone
Introduction
derivatives in the case of 2-Cl, 2-Br, 2,4-diCl substituted
The synthesis of anti-aldol products has assumed a great deal
benzaldehydes (dehydrated products). Many methods have
of interest in recent times, as many of the synthesis of natural
products require stereospecificity.1a–c The aldol condensation
and cyclic ketones to aldehydes using preformed enolates such
been proposed for aldol reactions, the addition of acyclic
as silyl enol ethers.3a–c Ytterbium triflate (Yb OTf)3,3d lithium
reaction is well known for acyclic and cyclic ketones (5, 6, 7 &
8 member rings) using different metal hydroxides,2a metal
enolate,3e gallium enolates3f and trichlorosilyl triflate3h–i have
complexes2b and polymer supported acid catalyst2c reactions.
been reported to give low yields (16–90%), require higher reaction
However, the previous reports show only the formation of
times (more than 15 hours) and give very low diastereoselectivity
bis-benzylidene cycloalkanones in all the cases so far. In our
case, which is completely different from previous methods,
the reaction has not proceeded after the formation of the
b-hydroxy carbonyl compound (dehydration) due to the unique
conformational property of CDD (Fig. 1). Herein we are
obtaining diastereoselective b-hydroxy carbonyl compounds
(only the anti isomer which is interesting and hence we proceeded
a Chemistry Division, School of Advanced Sciences, VIT University,
Vellore-632014, Tamilnadu, India.
E-mail: sathiya_kuna@hotmail.com; Fax: +91 4162243092
b Department of Biotechnology, School of life sciences, University of
Hyderabad, Hyderabad-500046, India
w Electronic supplementary information (ESI) available: Crystallo-
graphic data and spectral data (H NMR 13C NMR and HPLC).
CCDC numbers 843588–843592. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2nj40499k
Fig. 1 [3333]-2-One conformation of cyclododecanone.
c
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(dr. E 50 : 50), while the anti-selective product was obtained
when MgI2 was used as promoter.4a Several methodologies
have been developed for getting single diastereomers (either
anti or syn isomers), such as boron reagents and metal
complexes in the presence of a tertiary amine, where the amine
was mainly used to convert the ketone into an enol.
Conventionally the selectivity has been achieved in two steps,
for example, the reaction with boron followed by hydrogen
peroxide oxidization. In view of this, ytterbium trifluoro-
methanesulfonate and tertiary amines systems were tried.5
Attempts were also made to obtain anti-aldol products in high
selectivity using dicyclohexylboron chloride and triethylamine.6a,b
High anti-selectivity can be obtained in the case of sterically
hindered aldehyde like trimethylacetaldehyde.7 However, on the
ketone side, the steric hindrance has not been studied extensively
and the sterically hindered ketone was rarely used to get the anti-
selective product in aldol additions. Only one report is available
on using specially modified ketones to obtain high anti-selective
product.4 In all the cases, the reactions proceed smoothly, if the
enolate ion is formed from the ketone. Even after the formation
of the enol, there is no control over the product selectivity. For
instance, the products formed were in ratio of 70 : 30 (anti/syn) in
the reaction between cyclohexanone and benzaldehyde using
MgI2 as the promoter. While considering CDD, there is only
one report available for diastereoselectivity, using a-halocyclodo-
decanone subjected to reduction by TiCl4-n-Bu4NI8 through a
pinacol coupling reaction. However, they achieved only 89%
selectivity and found only parent benzaldehyde. Earlier methods
of aldol condensations suffered from multiple limitations, such
as long reaction times, use of air and moisture-sensitive5,6a,7
reagents, two step reactions that require the enolate to be formed
before the aldehyde can be added, and the random anti/syn
selectivity of products.5,7 Therefore, we have chosen a ketone
which is more sterically hindered and is known for its existence in
the zwitter ionic form.9a
compounds has been reported. Although some reports are
available on aldol additions using NaOH, LiOH and KOH as
catalyst, they also use inclusion complexes with an optically
active compound.2a We studied the effect of catalysts on this
reaction. We chose three different alkali metal hydroxides such
as NaOH, LiOH and KOH. With only 1 mol% the reaction
proceeded smoothly in NaOH and LiOH, but in the case of
KOH, the reaction took slightly longer. Hence, all three alkali
metal hydroxides are able to catalyze the reaction, as shown in
Table 1. All metal hydroxides induce CDD (1) to form the
enolate. When CDD is present in solution, it is in the
W-shaped zwitter ion9a form with a dynamic equilibrium.9b
Further, we studied the reaction with different solvents, such
as non polar, polar, protic aprotic. Out of these solvents, only
methanol was found to be suitable for the reaction to take
place. No product was formed in the case of t-BuOH and PEG
400. The yields are shown in Table 2. In all the metal hydroxide
catalysts and solvents tested, we obtained the b-hydroxyl ketone
Table 1 Screening of metal hydroxide catalysts in the direct anti-aldol
addition of CDD with parent benzaldehydes (product 4a) and o-Cl
benzaldehydes (product 5a), separately, in the presence of metal
hydroxide
Time (h)
Yieldb (%)
Metal hydroxides Cat. loadinga (mol%)
4a
5a
4a
5a
NaOH
LiOH
KOH
0.50
0.75
1
0.50
0.75
1
0.50
0.75
1
60
35
1
60
42
1.5
72
60
24
60
35
3.5 86
60
42
7
72
60
24
—
35
—
20
75
—
20
75
—
10
65
—
30
80
—
30
78
a
The reaction was performed with parent benzaldehyde, o-chlorobenz-
aldehyde (0.01 M) and cyclododecanone (0.01 M) in the presence of
three different metal hydroxide concentrations at room temperature
(28 1C) with vigorous stirring, where methanol was used as solvent.
In the present work, we have developed a direct aldol
addition reaction in cyclododecanone (CDD) with aromatic
benzaldehydes, by using various alkali metal hydroxides to
yield novel b-hydroxy carbonyl compounds. The anti-selective
and regio-specific products were obtained in high yield. In
contrast to earlier methods, the present method does not require
any drastic conditions or any toxic catalysts or promoters. We
designed a supramolecular helix of anti-aldol products.
b
The reported yield is after purification by column chromatography.
Table 2 Screening of different organic solvents
Time (h)
Yieldb (%)
Solventa
4a
5a
3.5
5
8
8
3.5
4
6
6
5.5
4a
5a
Entry
Results and discussion
1
2
3
4
5
6
7
8
CH3OH
C2H5OH
iPrOH
nBuOH
tBuOH
CH2Cl2
CH3CN
CHCl3
1
1.5
3
5
3.5
2
4.5
4.5
4
9
3
86
68
79
60
54
Optimization of the catalyst loading and solvent screening
62
o50
o50
A direct one-pot addition of CDD, benzaldehyde and NaOH
followed by stirring at room temperature is expected to yield
bis-benzylidine substituted cyclododecanone, but interestingly
the reaction yields predominantly anti-b-hydroxy carbonyl
compounds.
—
78
—
65
72
65
65
—
58
58
56
—
9
10
11
THF
PEG 400
n-Hexane
24
5
40
30
Herein we desire to communicate that cyclododecanone can
efficiently generate an anti-aldol product. Whereas the role of
the metal hydroxide enhances the enolate formation in the
zwitter ionic medium of the CDD ring. Even though NaOH is
a known catalyst for aldol condensations, this is the first
time that the exclusive formation of anti-b-hydroxy carbonyl
a
The reaction was performed with different solvents as indicated in
table parent benzaldehyde, o-chlorobenzaldehyde (0.01 M) and cyclo-
dodecanone (0.01 M) in the presence of NaOH (1 mol%) at room
b
temperature (28 1C) with vigorous stirring. % Yield after the column
chromatography.
c
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in the case of parent benzaldehyde (anti-selective) and mono-
benzylidene derivatives in case of o-chlorobenzaldehyde.
The scope of the regio-specific and anti-product formation in the
aldol reaction
The unexpected behaviour of CDD is due to ring strain and
bad transannular interaction observed in higher cyclic ketones
(n 4 7).9a The CDD takes part in the reaction in the form of
a zwitter ion. The Newman projection9c along with the CS-
symmetry show –CO–Ca and –Ca–Cb bonds of the [3333]-2-
one square conformation of CDD, which has a-methylene
groups at either a corner (C) or less hindered side (S) position,
as shown in Fig. 2. One of the two hydrogens (C-12) of the
corner a-CH2 group is eclipsed with the –CQO bond, repre-
sented as a-Hsyn, and the other hydrogen of the corner a-CH2
will be referred to as Hanti. The inner and outer hydrogens
(C-2) of the less hindered side (non-corner) of a-CH2 groups
are represented as a-Hendo and a-Hexo respectively.9d The
corner a-CH2 groups (C) differ from the side a-CH2 (S), since
the projection angle between the p-orbital on the carbonyl
group and two C–H bonds are quite different in the cases of
the corner being 901 and 301.9c So these (C) a-CH2 groups are
affected by torsional angle strain, and there is probably no
large vicinal coupling constants between this a-proton and
either of the two b-protons.
1
Fig. 3 Dynamic H NMR spectra in the solution phase.
À100 1C of CDD shows the dynamic equilibrium (Fig. 3)
associated with a conformational barrier of 7.3–7.6 Kcal molÀ1 9c,d
.
Herein we analyzed the NMR spectra at room temperature
(25 1C), and we also observed a dynamic NMR effect in the
CDD ring. (See ESIw) This consists of two pentets AB and this
will give a different coupling constant and different chemical
shift J = 9.4, 6.4 Hz (A), J = 8.8, 4 Hz (B). The A pentet gave
a large vicinal coupling constant. In the CDD ring, the corner
proton a-Hsyn is more shielded than its germinal counterpart
compared to a-Hanti
.
Hence the corner of the a-Hanti and b-CH2 group (either one
of two b-hydrogens) overlap, and the formation of the carbo-
cation or carbanion is restricted or negligible. Only the less
hindered side (S) a-CH2 groups facilitate the formation of a
carbanion or carbocation, since a-Hexo (outer) and a-Hendo
(inner) protons are at the same angle (301). Hence we conclude
that regio-specificity was present in the CDD ring itself. This
bond angle is steadily increasing for the large ring ketones,
reaching a maximum value above 10-ring cyclic ketones, which
is true for inside-carbonyl-conformation.9e,f
Stereochemical outcome of the reaction aldol molecules
In the CDD ring, out of two hydrogens (C-2) (Fig. 1) at the
less hindered side (S), the exo-hydrogen (trans-enolate) will
be involved in the enolate ion formation in CDD, this
was favourable for anti-aldol product formation via a metal
involving boat-metal-like transition state TS1 (anti isomer up
to 96–100%) Fig. 4a. If the other endo-hydrogen (cis-enolate)
is involved in the enolate ion formation, the syn-aldol product
will be formed through the metal involving boat-metal-like
transition state TS2 (syn isomer up to 4%), which is much
less favourable, as we have shown in Fig. 4a. However, the
syn-aldol adopts a staggered conformation, the phenyl group
(R) is affected by gauche hydrogens on both sides, hence the
aldehydic carbon is away from the keto group of the carbonyl
oxygen, for this reason the dihedral angle increases (more than
601), consequently the transition state will be destabilized.
Obviously we are getting more stable stereoselective anti-aldol
products.
This is quite different from cyclohexanone and other cyclic
ketones (n = 5–8). The previous NMR studies at À140 1C and
The configuration of aldol is associated to the conformation
of the transition state. Previous studies show that proton
transfer from the amine or the carboxylic acid group of proline
to form the alkoxide is essential for charge stabilization and to
facilitate C–C bond formation in the transition state.1c In this
reaction the proton transfer occurs from the solvent. The
oxygen of benzaldehyde forms a hydrogen bond with the
proton (solvent) in the CQO plane along the direction of
the sp2 lone pair of the oxygen atom. When the stereochemistry
at C-2 is inverted from R to S, there is a possibility of C–H–p
interaction between the hydrogen at C-2 and the substituent
(either hydrogen or other substituents) of the aromatic ring of
the benzaldehydes. We proposed a transition state model to
explain the stereochemical outcome of the reaction, which is
shown in Scheme 1.
Fig. 2 Newman projection for the [3333]-2-one conformation of
cyclododecanone.9c
c
2294 New J. Chem., 2012, 36, 2292–2301
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Table 3 anti-Selective and regio-selective aldol addition of cyclodo-
decanone with aldehyde using sodium hydroxide as catalyst
Yield
(%)
Timed
(min.)
Anti/syne,f
(%)
Entry Ra
Aldol productb
1
2
3
H
86
86
87
60
45
30
100
98/2
100
o-CF3
o-CH3
o-
OCH3
4
5
6
84
90
30
45
100
97/3
100
m-CH3
p-CH3
85
97c
Fig. 4 (a) Plausible boat-metal-like transition state for the formation
of aldol products. (b) Plausible transition state for the dehydrated
product.
p-
OC7H7
7
80
120
100
8
9
p-Cl
p-Br
94b
30
45
98/2
100
89c
10
11
p-C2H5
85c
150
180
100
100
C10H7
82
Scheme 1 Synthesis of anti-aldol and monobenzylidene products
4a–o and 5a–c from cyclododecanone catalyzed by sodium hydroxide.
In the case of the monobenzylidene, cyclododecanone derivatives
(dehydrated products in Scheme 1) were formed in the case of 2-Cl,
2-Br and 2,4-Cl benzaldehydes (Table 3 entries 16–18). The
electrostatic attractive force between the electron-withdrawing
halogens (Cl, Br) and the sodium ion of the CDD enolate (e.g.
Na–Cl, Na–Br), in addition to the bulkiness, plays a major
12
13
m-NO2
p-NO2
—
—
2880
2880
+
—
c
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Table 3 (continued )
Entry Ra Aldol productb
Yield
(%)
Timed
(min.)
Anti/syne,f
(%)
m-OH,
p-
OCH3
14
15
16
17
—
—
79
2880
2880
210
—
Fig. 5 Possible conformations of aldol and monobenzylidene
products.
p-OH
—
o-Cl
o-Br
96/4f
75
180
150
98/2f
100f
Scheme 2 L-Proline catalyzed aldol reactions.
though we tried all three alkali metal hydroxides, and at
o-Cl, p-
Cl
18
70c
different temperatures (15 1C and 0 1C).
L-Proline as a catalyst for the aldol reaction
a
The reaction was performed with different benzaldehydes (3a–r)
(0.01 M), and cyclododecanone (0.01 M) in the presence of NaOH
(1 mol%) at room temperature (28 1C) with vigorous stirring and
We also tried to obtain enantioselectivity of the b-hydroxy
carbonyl compounds using L-proline (5–20 mol%) in the
presence of Lewis acid (ZnCl2 and I2) and Lewis base catalysts
(N,N-diisopropyl ethylamine and triethylamine) as shown in
Scheme 2. However, we only achieved the anti isomer, and we
failed to get enantiomeric excess because, in the most stable
conformation of CDD, the carbonyl group (CQO) pointed
inwards of ring showing no room for the incoming L-proline,
as shown in Fig. 2. Hence the enolate formation is restricted or
steric strain is increased when the L-proline moiety is intro-
duced. So this will need to be specially modified for optically
active chiral catalysts.
b
methanol was used as solvent. Isolated yield of 4a–o and 5a–c.
c
d
Crystal structure analysis. All the products are regioselective.
f
The anti/syn ratio of 4a–o. E/Z ratio of 5a–c was determined by
e
1H NMR and chiral column HPLC (see the ESIw).
role in preventing the staggered conformation. Hence, the
dehydrated product is obtained due to the eclipsed conformation
of the intermediate, as shown figure in 4b. The b-carbonyl
compounds were stabilized by hydrogen bond interaction
between the –OH group and –CQO. However, in case of
aldehydes yielding benzylidene derivatives, the hydrogen of the
–OH group is not available to form the hydrogen bond with the
carbonyl group due to the strong interaction between the strong
electron-withdrawing halogen (Cl, Br) and the hydrogen of the
–OH group. As a result, the b-carbonyl compound is destabilized,
leading to the formation of monobenzylidene derivatives.
This forms the well known chair Zimmerman–Traxler transition
state.1a,c These are depicted by a chair-like conformation. This
could be adopted, in which a nucleophilic group should be oriented
gauche to the aldehydic hydrogen for steric reasons.10a,b
Gaudemer, Evans, and Heathcock, suggested that the stiles-
house method1d–f should be carefully used for aldol reactions,
with compounds that have a bulky substituent at the b-position,
where the enhanced gauche interaction destabilizes the hydrogen-
bonded six-membered ring as shown in (Fig. 5) (Table 3,
entries 16–18).
Crystal structure analysis of representative compounds 4f, 4h–4j
and 5c
Crystal structures of the representative compounds were
examined from each category, namely b-hydroxy carbonyl
(4f, 4h–4j) and monobenzylidene derivatives (5c).
The overall structures of 4f and 5c are illustrated in (Fig. 6),
while the ORTEPs of 4h–j are included in Fig. S1, ESI.w In 4f,
and in the reported centro symmetric structures of 4h–4j, the
stereogenic centers, C2 and C13, adopt R and S configurations,
respectively.11a The cyclododecanone ring in all the compounds,
adopts the [3333] square conformation, possessing 422
symmetry.11b,c The numbers in the square brackets indicate
the number of ring bonds between the four corner atoms of the
cyclododecanone ring. The [3333] square conformation is
the most favoured conformation of cyclododecane and is
predominantly observed in the reported structures.11d Based
on theoretical calculations, the other three lowest energy
conformations for the 8-membered ring were found to be –
[2334], [1434], and [2343].11e In all the investigated CDD rings,
the intra-annular bond distances and angles vary in the 1.496(3)–
1.540(2) A and 111.5(1)–120.6(1)1 ranges, respectively. The average
In Table 3, entries 1–11, we get regio-specific and highly
diastereoselective b-hydroxy carbonyl compounds in moderate
to good yield, whereas in the case of 3-NO2, 4-NO2, vanillin
and 4-OH benzaldehydes (Table 3, entries 12–15) we are not
able to obtain the b-hydroxy carbonyl compounds, even
c
2296 New J. Chem., 2012, 36, 2292–2301
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Table 4 Intermolecular interactions observed in 4f, 4h–4j and 5ca
Inter
action D–HÁ Á ÁA
D–H
(A)
HÁ Á ÁA
DÁ Á ÁA
D–HÁ Á ÁA
(A1)
(A)
(A)
4f
4h
4i
4j
O2–H2OÁ Á ÁO1i
0.86 (3) 2.04 (3) 2.8659 (19) 160 (2)
2.40
0.90 (2) 1.99 (2) 2.8621 (16) 166 (2)
C12-H12AÁ Á ÁO2i 0.97
3.367(2)
174
O2–H2OÁ Á ÁO1ii
C12–H12AÁ Á ÁO2ii 0.97
2.43
3.403 (2)
178
O2–H2OÁ Á ÁO1iii 0.81 (2) 2.10 (2) 2.8863 (18) 164 (2)
C12–H12AÁ Á ÁO2iii 0.97
2.46
3.431 (2)
177
O2–H2OÁ Á ÁO1iv 0.91 (5) 2.04 (5) 2.921 (4)
164 (4)
178
157
C12–H12AÁ Á ÁO2iv 0.97
2.50
2.38
3.475 (5)
3.259 (2)
5c
C19–H19Á Á ÁO1v 0.93
a
Symmetry codes: (i) 1 À x, À1/2 + y, 1 À z, (ii) 1/2 À x, À1/2 + y,
1/2 Àz, (iii) 2 À x, 1/2 + y, 1/2 À z, (iv) 1 À x, 1/2 + y, 1/2 À z, (v) 1 À x,
2 À y, 1 À z. An inter-helical C–HÁ Á Áp interaction associated with
methyl hydrogen was observed in 4f, C20–H20AÁ Á ÁCg1 [symmetry
code (vi): Àx, 1/2 + y, 1 À z], HÁ Á ÁA, 2.89 A, DÁ Á ÁA, 3.843(2) A,
D–HÁ Á ÁA 1731. Cg1 is the centroid of the (C14–C19) ring.
Fig. 6 (a) ORTEP for (5c). (b) ORTEP for (4f). A view of 4f and 5c
with non-H atoms shown as probability ellipsoids at 30% levels drawn
with ORTEP (Farrugia, 1997). H atoms radii are on an arbitrary scale.
distance and angle have been observed to be 1.53(2) A and
114(2)1, respectively. The absolute value of the average torsion
angles, corresponding to the synclinal and antiperiplanar
conformations are 69(5)1 and 161(8)1, respectively, for a
cyclodecanone ring. In the present structures, these angles
vary in the absolute 64(1)–75(1)1 and 148(1)1–172(1)1 ranges.
anti-Aldol products forms supramolecular helices
Intermolecular interactions are described in (Table 4). The
b-hydroxy carbonyl compounds (4f, 4h–4j) form supramolecular
helices. In these anti-aldol compounds, (hydroxyl) O–HÁÁÁO
(carbonyl) hydrogen bonds form helices. The helical network is
characterized by a C6 pattern and the direction of the helix is
along the 21-screw axis, as shown in (Fig. 7). The helices are
characterized by two b-hydroxy carbonyl units per turn with an
average pitch (rise per turn) of 6 A (6.0 A in 4f, 4h and 4i, 5.8 A
in 4j). The inner circle axes are approximately 5 A and 2 A,
respectively.
Fig. 7 Top row: Side-on view of hydrogen bonded supramolecular
helices observed in 4f and 4h–j. Only relevant hydrogens have been
shown and the symmetry codes are with respect to (Table 4). Middle
row: Curtailed side-on view of the helices schematically showing
helical chain along the b-axis. Bottom row: Cross-sectional view of
the helices.
The intra-helical O–HÁ Á ÁO interactions are accompanied by
(CDD) C12–H12AÁ Á ÁO2 (hydroxyl) interactions (Table 4).
The O–HÁÁÁO and C–HÁÁÁO interactions together generate a
R22 (12) ring-pattern. The helical outer surface is hydrophobic,
and helices are packed together by hydrophobic forces and also
C–HÁÁÁp and pÁÁÁp interactions (Table 4). Earlier efforts have been
made to design supramolecular architectures, especially helical
motifs, using weak noncovalent interactions. Few examples of the
design of supramolecular helices have been reported.12a–c
These supramolecular architectures have been designed with
a purpose, for use as functional materials such as artificial
ion channels or nonlinear optical (NLO) materials.13a–d The
present O–HÁÁÁO network serves as a supramolecular synthon14a–d
for supramolecular helical design. In monobenzylidene derivative
c
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(5c), the C–HÁ Á ÁO interaction (Table 4) forms a molecular
dimer, as shown in Fig. S2 (ESIw). Significant pÁ Á Áp interac-
tions are also observed in the packing of 5c. Cg1 makes a
stacking interaction with Cg1i [symmetry code (i): 1 À x, 1 À y,
1 À z] with a centroid-to-centroid distance of 3.6776(10) A,
a perpendicular distance of 3.4309(6) A and a slippage of
1.324 A. Cg1 is the centroid of the (C14–C19) ring.
Thin layer chromatography (TLC), was performed on pre-coated
silica gel on alumina plates. Melting points were obtained using
microprocessor digital melting point apparatus and are uncor-
rected. IR spectra were recorded in the range 4000–400 cmÀ1
using the KBr pellet technique. The solution IR spectra were
recorded at 4000–560 cmÀ1 using analytical grade dichloro-
methane as solvent. 1H NMR and 13C NMR spectra were
recorded at 300 and 400 MHz using CDCl3 as the solvent with
TMS as an internal standard. HRMS analysis was obtained
from the double focusing electron impact method. HPLC was
performed using a chromatography equipped with a dual
wavelength UV detector (Deuterium lamp, 192–600 nm) and
the column were used as a CHIRALPAK IC (250 mm Â
4.6 mm) 5 mm HPLC grade acetonitrile and water.
X-Ray diffraction
Suitable single crystals for data collection were grown from a
mixture of ethanol and tetrahydrofuran (1 : 1). Data were obtained
from Oxford Diffraction Xcalibur Eos Gemini diffractometer.15
The structure was solved by applying the direct phase-
determination technique using SHELXS-97, and refined by
full-matrix least square on F2 using SHLEXL-97.16a–c All
structural calculations were performed with WinGX suit of
programs (version 1.85.05).16b Hydrogen atoms were placed in
the geometrically expected positions and refined with the riding
options. Hydroxyl hydrogen atoms were isotropically refined
and methyl hydrogen atoms were fixed with reference to the
local electron density maps. The O–H distances were observed
in 0.81(2)–0.91(5) A range. Distances with the rest of the
hydrogen atoms are: aromatic/sp2 C–H = 0.93 A, methyl
C–H = 0.96 A, methylene C–H = 0.97 A, methine C–H =
0.98 A, and Uiso = 1.2 Ueq (parent) or 1.5 Ueq (for methyl).
Essential crystal data are listed (Table S1 see the ESIw) Crystallo-
graphic data for the structures in this paper (CCDC
843588–843592, for 4f, 4h–4j and 5c, respectively) is provided.w
General procedure for Scheme 1
To a solution of aromatic benzaldehyde (0.01 mol), cyclodo-
decanone (0.01 mol) was added at room temperature (28 1C) in
methanol (10 ml) followed by an aqueous solution of NaOH
(1 mol%) drop wise for a period of 10–15 min. The reaction
mixture was stirred for 1 h at room temperature (28 1C). After
the completion of the reaction, mixture was washed thrice
with water. The white crude solid was subjected to column
chromatography on silica gel (hexane : EtOAc).
HPLC data for all compounds
Analytical high performance liquid chromatography (HPLC)
was performed on a water’s liquid chromatography equipped
with a dual wavelength UV detector (Deuterium lamp,
192–600 nm), using a CHIRALPAK IC (250 mm  4.6 mm)
5 mm HPLC grade acetonitrile and water (80 : 20) were used as
the eluting solvents, flow rate: 1.00 ml minÀ1, injection volume
20 mL column temperature 25 1C, Run time: 12 min.
Conclusions
We have synthesized a new series of anti-aldol addition products
using NaOH as catalyst. The reaction stops half-way due to steric
strain in the ketone, except in the case of three benzaldehydes,
namely o-chloro, o-bromo, o,p-dichloro. Cyclododecanone
(CDD) suffers from ring strain and bad transannular interactions,
unlike ordinary ketones such as cyclohexanone. As a result, the
method yields b-hydroxyl carbonyl compounds because CDD is
already present in the zwitterionic form in the solution phase. We
also observed the dynamic NMR spectra of the cyclododecanone
ring at room temperature (25 1C) in CDCl3 solvent.
We proposed a transition-state model to rationalize the
outcome of the product selectivity. We have established that
these anti-aldol molecules possess the tendency to assemble
into helices. Such molecules could be used for the tailor-made
design of supramolecular helices by altering the C13-side
groups and substituents on CDD. The present study therefore
also serves as an example of a rational design approach14a–d
for assembling interesting supramolecular assemblies. This
concept may be applicable to other metal hydroxides, which
we are investigating, along with the asymmetric catalyst, in our
laboratory.
2-[Hydroxy (phenyl) methyl] cyclododecanone (4a)
The white crude solid was subjected to column chromatography
on silica gel (n-hexane/EtOAc, 4 : 1) to afford the anti-aldol
product 4a (2.48 g, 86% dr = 100 : 0); Rf 0.48 (n-hexane/
1
EtOAc, 4 : 1); Mp: 107–109 1C; H NMR (400 MHz, CDCl3):
d = 7.385–7.258 (m, 5H, CHAr); 4.823–4.783 (dd, J = 8, 3.2
Hz, 1H, CH*(OH)); 2.953–2.897 (td, J = 8.8, 4 Hz, 1H, CHali);
2.804–2.728 (qd, J = 9.6, 3.2 Hz, 1H, CHali); 2.628–2.617
(d, J = 4.4 Hz, 1H, CHali); 2.425–2.353 (qd, J = 8, 3.2 Hz,
1H, CHali); 1.892–1.825 (m, 1H, CHali); 1.606–1.571 (m, 1H,
CHali); 1.531–1.473 (m, 1H, CHali); 1.392–1.160 (m, 15H, CHali).
13C NMR (100 MHz, CDCl3): d = 214.9, 142.1, 128.5, 128.0,
126.6, 75.3, 59.1, 39.5, 27.3, 26.3, 25.9, 24.2, 23.8, 23.8, 22.8, 22.3,
21.5; FTIR (KBr) n = 3418.95, 3058.06, 2934.39, 2858.58,
1688.30, 1460.32, 1282.08, 951.33; HRMS (EI) m/z: Calc. for
C19H28O2 288.2081 [M]+; Found 288.2089.
2-{[2-(Trifluoromethyl) phenyl] (hydroxy) methyl}
cyclododecanone (4b)
Experimental section
The crude residue was then purified by column chromatography
on silica gel (n-hexane/EtOAc, 8 : 2) to afford the anti-aldol product
4b (3.058 g, 86%, dr = 100 : 0) as a white crystalline solid; Mp:
143–145 1C; 1H NMR (400 MHz, CDCl3): d = 7.672–7.654
(d, J = 6.4 Hz, 2H, CHAr); 7.615–7.577 (t, J = 15.2 Hz, 1H,
General information
All chemicals were purchased from commercial sources and they
were used without further purification unless otherwise specified.
c
2298 New J. Chem., 2012, 36, 2292–2301
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CHAr); 7.431–7.393 (t, J = 15.2 Hz, 1H, CHAr); 5.279–5.247
(dd, J = 8, 4.8, 1H, CH*(OH)); 3.080 (t, J = 12H, 1H, CHali);
2.914–2.903 (d, J = 4.4 Hz, 1H, CHali); 2.620–2.558 (m, 2H,
CHali); 1.720, (bs, 1H, OH, CH2ali), 1.308–1.129 (m, 15H,
CHali). 13C NMR (100 MHz, CDCl3): d = 214.7, 141.1, 132.5,
128.0, 127.9, 125.7, 125.7, 70.4, 58.7, 39.2, 27.6, 26.3, 25.8,
24.3, 24.0, 23.9, 23.5, 22.4, 21.6. FTIR n = 3448.25, 3048.06,
2984.29, 2878.38, 1708.20, 1453.42, 1356.45, 1272.08, 957.43,
835.48, 755.34. HRMS (EI) m/z: Calc. for C20H27F3O2
356.1963 [M]+; Found 356.1963.
1H, CH*–CHOH) 2.782–2.708 (qd, J = 8, 3.2 Hz, 1H, CHali);
2.611–2.604 (d, J = 2.8 Hz, 1H, CHali); 2.519–2.454 (qd, J =
8.4, 3.2 Hz, 1H, CHali); 2.356 (s, 3H, CAr–CH3); 1.794–1.759
(m, 1H, OH); 1.698–1.670 (m, 1H, CHali); 1.550–1.490 (m, 1H,
CHali); 1.307–1.117 (m, 15H, CHali). 13C NMR (100 MHz,
CDCl3): d = 215.0, 142.1, 138.2, 128.8, 128.4, 127.3, 123.8,
75.3, 59.2, 39.2, 27.3, 26.4, 26.0, 24.2, 23.8, 23.7, 22.8, 22.3,
21.6. FTIR (KBr) n = 3464.32, 3043.25, 2952.25, 2867.37,
16687.17, 1433.29, 1251.54, 1365.11, 1136.30, 1045.47, 830.58,
725.24. HRMS (EI) m/z: Calc. for C20H30O2; 302.2245 [M]+;
Found 302.2246.
2-[Hydroxy (2-tolyl) methyl] cyclododecanone (4c)
2-[Hydroxy (4-tolyl) methy] cyclododecanone (4f)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 4 : 1) to afford the anti-
aldol product 4c (2.642 g, 87%, dr = 100 : 0) as a white
crystalline solid; Mp: 127–129 1C; 1H NMR (400 MHz,
CDCl3): d = 7.364.7.341 (d, J = 8.2 Hz, 1H, CHAr);
7.213–7.154 (m, 3H, CHAr); 5.083–5.050 (dd, J = 9, 4.4 Hz,
1H, CH*(OH)); 3.102–3.056 (td, J = 4.1, 2.4 Hz, 1H, CHali);
2.740–2.668 (qd, J = 8.4, 3.6 Hz, 1H, CHali); 2.604–2.593
(d, 4.4 Hz, 1H, CHali); 2.589–2.459 (qd, J = 8.4, 3.2 Hz, 1H,
CHali); 2.398 (s, 3H, CAr–CH3); 1.832 (s, 1H, OH);
1.780–1.619 (m, 2H, CH2ali); 1.315–1.135 (m, 15H, CHali).
13C NMR (100 MHz, CDCl3): d = 215.3, 140.2, 135.4, 130.6,
127.7, 126.4, 126.2, 71.7, 58.3, 39.9, 27.3, 26.3, 25.8, 24.3, 24.2,
24.1, 23.4, 22.4, 21.7, 19.4. FTIR (KBr) n = 3452.42, 3052.25,
2942.35, 2857.27, 1675.17, 1435.19, 1255.44, 1375.46, 1124.25,
1041.27, 825.48, 715.34. HRMS (EI) m/z: Calc. for C20H30O2;
302.2245 [M]+; Found 302.2246.
The crude residue was then purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc, 8 : 2) to afford the anti-
aldol product 4f (2.942 g, 97%, dr = 100 : 0) as a white
crystalline solid; Mp: 164–166 1C; 1H NMR (400 MHz,
CDCl3): d = 7.253–7.212 (t, J = 15.2 Hz, 1H, CHAr); 7.155
(s, 1H, CHAr); 7.116–7.098 (d,
J = 7.6 Hz, 2H,
CHAr);4.781–4.736 (dd, J = 9, 3.6 Hz, 1H, CH *(OH));
2.964–2.916 (td, J = 9.6, 3.6 Hz, 1H, CH*–CHOH);
2.805–2.715 (qd, J = 9, 3.6 Hz, 1H, CHali); 2.558–2.547
(d, J = 4.4 Hz, 1H, CHali); 2.523–2.456 (qd, J = 6.7, 3.2
1H, CHali); 2.345 (s, 3H, CAr–CH3); 1.836 (m, 1H, OH);
1.694–1.636 (m, 1H, CHali); 1.552–1.477 (m, 1H, CHali);
1.346–1.165 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3):
d = 214.8, 139.1, 137.6, 129.1, 126.5, 75.1, 59.2, 39.2, 27.3,
26.3, 25.9, 24.2, 23.8, 23.7, 22.8, 22.3, 21.5, 21.0. FTIR (KBr)
n = 3422.35, 3088.15, 2932.45, 2857.67, 1687.87, 1463.49,
1291.54, 1375.91, 1139.40, 1043.57, 819.57, 730.54. HRMS
(EI) m/z: Calc. for C20H30O2; 302.2245 [M]+; Found
302.2246.
2-[Hydroxy (2-methoxy phenyl) methyl] cyclododecanone (4d)
The crude residue was then purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc, 8 : 2) to afford the anti-
aldol product 4d (2.683 g, 84%, dr = 100 : 0) as a white
crystalline solid; Mp: 123–125 1C; 1H NMR (400 MHz,
CDCl3): d = 7.337–7.314 (dd, J = 7.6, 1.6 Hz, 1H, CHAr);
7.263–7.216 (td, 6, 1.2 Hz, 1H, CHAr); 6.960–6.922 (t, J = 14.8
Hz, 1H, CHAr); 6.881–6.860 (d, J = 8.4, 1H, CHAr);
5.058–5.030 (t, J = 11.2 Hz, 1H, CH*(OH)); 3.273–3.134
(m, 1H, CHali); 3.148–3.134 (d, J = 5.6 Hz, 1H, CHali);
2.632–2.559 (qd, 9.2, 3.2 Hz, 1H, CHali); 2.220–2.149 (qd,
J = 8.4, 3.6, 1H, CHali); 1.893 (ms, 1H, OH); 1.667 (s, 3H,
OCH3); 1.298–1.238 (m, 15H, CH2ali). 13C NMR (100 MHz,
CDCl3): d = 215.3, 156.0, 129.7, 128.4, 128.0, 120.7, 110.4,
70.8, 70.7, 55.1, 40.3, 26.1, 25.4, 25.2, 24.6, 24.5, 24.4, 23.5,
22.5, 22.0. FTIR (KBr) n = 3418.93, 3041.28, 2937.42,
2851.54, 1695.28, 1490.27, 1291.54, 1239.26, 1025.42, 761.37.
HRMS (EI) m/z: Calc. for C20H30O3; 318.2194 [M]+; Found
318.2195.
2-{[(4-Benzyloxy) phenyl] (hydroxy) methyl} cyclododecanone
(4g)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 8 : 2) to afford the anti-
aldol product 4g (3.165 g, 80%, dr = 100 : 0) as a white
crystalline solid; Mp: 137–140 1C; 1H NMR (400 MHz,
CDCl3): d = 7.442–7.240 (m, 7H, CHAr); 6.978–6.941 (dt,
J = 11.6, 2.8 Hz, 2H, CHAr); 5.059 (s, 1H, OCH2);
4.790–4.758 (dd,
J = 9.2, 3.6 Hz, 1H, CH*(OH));
2.961–2.906 (td, J = 9.2, 3.6 Hz, 1H, CH*–CHOH);
2.802–2.727 (qd, J = 8.8, 3.6 Hz, 1H, CHali); 2.515–2.417
(m, 2H, CH2ali); 1.807 (m, 1H, OH); 1.674 (m, 1H, CHali);
1.674–1.162 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3):
d = 214.9, 158.6, 136.8, 134.6, 128.6, 128.0, 127.9, 127.4,
114.9, 74.8, 70.0, 59.3, 39.2, 27.3, 26.4, 26.0, 24.2, 23.8, 23.7,
22.7, 22.3, 21.6. FTIR (KBr) n = 3515.72, 3033.39, 2924.34,
2857.33, 1699.07, 1604.36, 1506.40, 1377.38, 1226.07, 1007.30,
819.42, 738.04, 695.95. HRMS (EI) m/z: Calc. for C26H34O3;
394.2507 [M]+; Found 394.2508.
2-[Hydroxy (3-tolyl) methyl] cyclododecanone (4e)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 7 : 3) to afford the anti-
aldol product 4e (2.58 g, 85%, dr = 97 : 3) as a white crystal-
line solid; Mp: 136–138 1C; 1H NMR (400 MHz, CDCl3): d =
7.251–7.213 (t, J = 15.2 Hz, 1H, CHAr); 7.152 (s, 1H, CHAr);
7.118–7.099 (d, J = 7.6 Hz, 2H, CHAr); 4.775–4.743 (dd, J =
9.2, 3.6 Hz, 1H, CH*(OH)); 2.978–2.923 (td, J = 4.1, 3.6 Hz,
2-[(4-Chlorophenyl) (hydroxy) methyl] cyclododecanone (4h)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 8 : 2) to afford the anti-
aldol product 4h (3.165 g, 80%, dr = 98 : 2) ) as a white
crystalline solid; Mp: 146–148 1C; 1H NMR (400 MHz,
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2012
New J. Chem., 2012, 36, 2292–2301 2299

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CDCl3): d = 7.343–7.338 (d, J = 2 Hz, 1H, CHAr);
7.327–7.316 (t, J = 4.4 Hz, 1H, CHAr); 7.286–7.280 (t, J =
2.4 Hz, 1H, CHAr); 7.267–7.262 (d, J = 2 Hz, 1H, CHAr);
4.835–4.802 (dd, J = 9.2, 4 Hz, 1H, CH*(OH)); 2.954–2.896
(td, J = 8.8, 4 Hz, 1H, CHali); 2.814–2.738 (qd, J = 9.6, 3.2
Hz, 1H, CHali); 2.628–2.617 (d, J = 4.4 Hz, 1H, CHali);
2.425–2.353 (qd, J = 8, 3.2 Hz, 1H, CHali); 1.892–1.825
(m, 1H, CHali); 1.606–1.571 (m, 1H, CHali); 1.531–1.473 (m,
1H, CHali); 1.392–1.160 (m, 15H, CHali). 13C NMR (100 MHz,
CDCl3): d = 214.7, 140.6, 133.7, 128.7, 128.0, 74.4, 58.9, 39.7,
27.3, 26.4, 25.9, 24.2, 23.8, 23.7, 22.6, 22.4, 21.5. FTIR (KBr)
n = 3411.89, 3055.80, 2932.90, 2857.00, 1687.46, 1596.64,
1375.43, 1291.41, 1139.02, 822.98, 731.68, 602.81. HRMS
(EI) m/z: Calc. for C19H27ClO2; 322.1699 [M]+; Found
322.1700.
(d, J = 8 Hz, 1H, CHAr); 7.888–7.865 (d, J = 8.8 Hz, 1H,
CHAr); 7.807–7.787 (d, J = 8 Hz, 1H, CHAr); 7.562–7.431
(m, 4H, CHAr); 5.566–5.536 (dd, J = 8, 4 Hz, 1H, CH*(OH));
3.412–3.367 (td, 4.5, 3.2 Hz, 1H, CH*–CHOH); 2.910 (s, 1H,
OH); 2.714–2.640 (qd, J = 8, 3.2 Hz, 1H, CHali); 2.433–2.360
(qd, J = 8.4, 3.2 Hz, 1H, CHali); 1.784–1.606 (m, 3H, CH2ali);
1.299–1.075 (m, 15H, CHali ). 13C NMR (100 MHz, CDCl3):
d = 215.4, 137.7, 134.0, 130.8, 129.0, 128.6, 126.2, 125.6,
125.3, 124.6, 123.4, 73.0, 57.7, 40.4, 28.2, 26.4, 25.8, 24.3, 24.1,
23.4, 22.4, 21.6. FTIR (KBr) n = 3417.40, 3065.26, 2920.95,
2846.49, 1696.30, 1517.53, 1453.65, 1365.83, 1324.23, 1140.69,
1036.67, 830.66, 736.13, HRMS (EI) m/z: Calc. for C23H30O2;
338.2245 [M]+; Found 338.2246.
(E)-1-(2-Chlorobenylidene) cyclododecanone (5a)
The white crude solid was subjected to column chromato-
graphy on silica gel (n-hexane/EtOAc, 7 : 3 ) to afford the
monobenzylidene product 5a (2.42 g, 79% E/Z = 96/4), Rf 0.4
(n-hexane/EtOAc, 4 : 1); white crystalline solid; Mp: 93–95 1C;
1H NMR (400 MHz, CDCl3): d = 7.464 (s, 1H, CHvinylic);
7.445–7.421 (td, 4.4, 1.2 Hz, 1H, CHAr); 7.288–7.256 (m, 3H,
CHAr); 2.873–2.842 (m, 2H, CH2ali); 2.549–2.519 (t, 12 Hz,
2H, CH2ali); 1.866 (bs, 2H, CH2ali); 1.318 (s, 11H, CH2ali);
1.245 (s, 1H, CHali); 1.136–1.110 (t, J = 10.4 Hz, 2H, CH2ali).
13C NMR (100 MHz, CDCl3): d = 205.0, 143.2, 136.0, 134.7,
133.8, 130.3, 129.4, 129.2, 126.4, 38.8, 26.5, 26.4, 25.4, 24.4,
24.2, 24.1, 23.9, 23.1, 22.5. FTIR (KBr) n = 3515.35 [(broad
peak) absence of OH peak], 3066.80, 2939.97, 2855.73,
1661.73, 1465.48, 1361.77, 1239.93, 1157.74, 939.21, 870.34,
767.87, 692.52. HRMS (EI) m/z: Calc. for C19H25ClO;
304.1593 [M]+; Found 304.1594.
2-[(4-Bromophenyl) (hydroxy) methyl] cyclododecanone (4i)
The crude residue was then purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc, 7 : 2) to afford the anti-
aldol product 4i (3.165 g, 89%, dr = 100 : 0) as a white
crystalline solid; Mp: 154–156 1C; 1H NMR (400 MHz,
CDCl3): d = 7.49–7.46 (m, 2H, CHAr); 7.22–7.20 (d, J =
8 Hz, 2H, CHAr); 4.80–4.77 (dd, J = 8, 4 Hz, 1H, CH*(OH));
2.93–2.89 (td, J = 8, 4 Hz, 1H, CHali); 2.80–2.74 (qd, J = 8,
4 Hz, 2H, CH2ali); 2.43–2.36 (qd, J = 12, 4 Hz, 1H, CHali );
1.88–1.81 (m, 1H, CHali); 1.63–1.45 (m, 2H, CH2ali); 1.37–1.20
(m, 15H, CHali). 13C NMR (100 MHz, CDCl3): d = 214.7,
141.1, 131.6, 128.3, 121.8, 74.5, 58.8, 39.7, 27.3, 26.3, 25.9,
24.2, 23.7, 23.7, 22.68, 22.3, 21.5. FTIR (KBr) n = 3408.00,
3056.76, 2931.76, 2856.76, 1686.10, 1589.96, 1373.30, 1290.54,
1139.00, 1043.02, 821.01, 730.46, 599.60. HRMS (EI) m/z:
Calc. for C19H27BrO2; 366.1194 [M] +; Found 366.1194.
(E)-1-(2-Bromobenylidene) cyclododecanone (5b)
2-[(4-Ethylphenyl) (hydroxy) methyl] cyclododecanone (4j)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 8 : 2) to afford the
monobenzylidene product 5b (2.624 g, 75%, E/Z = 98/2) as
a white crystalline solid; Mp: 111–113 1C; 1H NMR (400
MHz, CDCl3): d = 7.635–7.615 (m, 1H, CHAr); 7.288–7.256
(s, 1H, CHvinylic); 7.344–7.168 (m, 3H, CHAr); 2.877–2.846
(m, 2H, CH2ali); 2.539–2.509 (t, J = 12 Hz, 2H, CH2ali); 1.893
(bs, 2H, CH2ali); 1.318 (s, 11H, CH2ali); 1.241 (s, 1H, CHali);
1.132–1.107 (t, J = 10 Hz, 2H, CH2ali). 13C NMR (100 MHz,
CDCl3): d = 205.1, 142.8, 138.0, 136.5, 132.6, 130.5, 129.3,
127.1, 124.0, 38.8, 26.5, 26.5, 25.4, 24.4, 24.2, 24.1, 24.0, 23.1,
22.5. FTIR (KBr) n = 3483.16 [(broad peak) absence of OH
peak], 3064.86, 2938.19, 2860.89, 1661.57, 1464.88, 1358.90,
1239.37, 1113.73, 765.70, 742.36. HRMS (EI) m/z: Calc. for
C19H25BrO 348.1088 [M]+; Found 348.1089.
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 7 : 3) to afford the anti-
aldol product 4j (3.165 g, 85%, dr = 100) as a white crystalline
solid; Mp: 123–125 1C; 1H NMR (400 MHz, CDCl3): d =
7.262–7.242 (d, J = 8 Hz, 2H, CHAr); 7.196–7.176 (d, J = 8
Hz, 2H, CHAr); 4.800–4.771 (dd, J = 9.2, 6.4 Hz, 1H,
CH*(OH)); 2.983–2.928 (td,
J = 9.2, 3.6 Hz, 1H,
CH*–CHOH); 2.797–2.723 (qd, J = 9.2, 3.2 Hz, 1H, CHali);
2.753–2.619 (q, J = 15.2, 7.6 Hz, 2H, CH2ethylic); 2.531–2.458
(qd, J = 8.4, 3.2 Hz, 1H, CHali); 1.801–1.770 (ms, 1H, OH);
1.706–1.651 (m, 1H, CHali); 1.315–1.253 (m, 1H, CHali);
1.235–1.207 (t, J = 11.2 Hz, 3H, CH3ethylic); 1.199–1.182
(m, 16, CH2ali). 13C NMR (100 MHz, CDCl3): d = 214.9,
144.1, 139.4, 128.0, 126.6, 75.2, 59.3, 39.1, 28.5, 27.3, 26.4, 26.0,
24.2, 23.8, 23.7, 22.8, 22.3, 21.6, 15.5. FTIR (KBr) n = 3437.90,
3015.26, 2930.95, 2856.69, 1690.00, 1509.83, 1465.65, 1372.63,
1314.23, 1140.29, 1038.80, 831.36, 732.13. HRMS (EI) m/z:
Calc. for C21H32O2; 316.2402 [M]+; Found 316.2402.
(E)-1-(2,4-Dichlorobenylidene) cyclododecanone (5c)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 8 : 2) to afford themono-
benzylidene product 5c (2.386 g, 70%, E/Z = 100) as a white
crystalline solid; Mp: 140–142 1C; 1H NMR (400 MHz,
CDCl3): d = 7.464–7.459 (d, J = 2 Hz, 1H, CHvinylic); 7.375
(s, 1H, CHAr); 7.284–7.258 (dd, 8, 2 Hz, 1H, CHAr);
7.231–7.210 (d, 8.4 Hz, 1H, CHAr ); 2.862–2.831 (m, 2H,
CH2ali); 2.517–2.831 (t, 12 Hz, 2H, CH2ali);1.859–1.852 (s, 2H,
2-[Hydroxy (napthalen-1-yl) methyl] cyclododecanone (4k)
The crude residue was then purified by column chromato-
graphy on silica gel (n-hexane/EtOAc, 7 : 3) to afford the anti-aldol
product 4k (3.165 g, 82%, dr = 100) as a white crystalline solid;
Mp: 131–133 1C; 1H NMR (400 MHz, CDCl3): d = 8.253–8.233
c
2300 New J. Chem., 2012, 36, 2292–2301
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CH2ali); 1.373–1.236 (m, 12H, CH2ali); 1.117–1.091 (t, 10.4 Hz,
2H, CH2ali). 13C NMR (100 MHz, CDCl3): d = 204.7, 143.8,
134.4, 133.2, 131.1, 129.4, 126.9, 38.8, 26.5, 26.4, 25.5, 24.3,
24.2, 24.1, 24.0, 23.0, 22.5. FTIR (KBr) n = 3429.57 [(broad
peak) absence of OH peak], 3072.08, 2930.28, 2856.31, 1667.90,
1581.91, 1466.23, 1373.53, 1236.79, 1107.15, 854.61, 755.08,
698.29. HRMS (EI) m/z: Calc. for C19H24Cl2O; 338.1204
[M]+; Found 338.1206.
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Acknowledgements
V. S and B. U. M. thank the Vellore Institute of Technology,
Tamilnadu, India, for providing Research Associateship. R. S. R.
acknowledges CSIR, for funding under the scientist’s pool scheme.
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