Synthesis and molecular structure of new macro acyclic mannich derivatives: Symmetrical and unsymmetrical 2-[(E)-(Benzylideneamino)(aryl)methyl] cyclododecanone

Article abstract of DOI:10.1080/00397911.2011.584023

In an effort to provide a green synthetic route for heterocyclic scaffolds, new macro analogs of acyclic Mannich derivatives have been synthesized in good yields in a one-pot, efficient fashion. The acyclic symmetrical and unsymmetrical 2-[(E)-(benzylideneamino)(aryl)methyl]cyclododecanones have been synthesized by condensation of cyclododecanone, aromatic aldehyde, and ammonium acetate in ethanolic media. By infrared, NMR, and mass spectral analyses, their structures were determined. Examination of crystal structure of a p-Cl and o-Br analogs reveals the minimum energy [3333] square conformation of cyclododecanone ring. In the crystal, molecules aggregate in dimeric subunits formed by C-Cl π and C-H.π interactions. The reported one-pot, multichain reaction of macrocycles is the first synthetic attempt of acyclic compounds in this type of Mannich reaction involving ketones containing active methylene groups. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.584023

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Synthesis and Molecular Structure of
New Macro Acyclic Mannich Derivatives:
Symmetrical and Unsymmetrical
2-[(E)-(Benzylideneamino)
(aryl)methyl]cyclododecanone
Natesan Sundaramoorthy Karthikeyan a , Ramachandran Gunasekar a
, Kulathu Iyer Sathiyanarayanan a & Rathore Ravindaranath b
a Chemistry Division, School of Advanced Sciences, VIT University,
Vellore, India
b Bioinformatics Infrastructure Facility, Department of
Biotechnology, School of Life Science, University of Hyderabad,
Hyderabad, India
Accepted author version posted online: 11 Nov 2011.Published
online: 02 Aug 2012.
To cite this article: Natesan Sundaramoorthy Karthikeyan , Ramachandran Gunasekar , Kulathu
Iyer Sathiyanarayanan & Rathore Ravindaranath (2012): Synthesis and Molecular Structure of New
Macro Acyclic Mannich Derivatives: Symmetrical and Unsymmetrical 2-[(E)-(Benzylideneamino)
(aryl)methyl]cyclododecanone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:23, 3429-3440
To link to this article: http://dx.doi.org/10.1080/00397911.2011.584023
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Synthetic Communications1, 42: 3429–3440, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.584023
SYNTHESIS AND MOLECULAR STRUCTURE OF
NEW MACRO ACYCLIC MANNICH DERIVATIVES:
SYMMETRICAL AND UNSYMMETRICAL
2-[(E)-(BENZYLIDENEAMINO)(ARYL)METHYL]
CYCLODODECANONE
Natesan Sundaramoorthy Karthikeyan,1
Ramachandran Gunasekar,1 Kulathu Iyer Sathiyanarayanan,1
and Rathore Ravindaranath2
1Chemistry Division, School of Advanced Sciences, VIT University,
Vellore, India
2Bioinformatics Infrastructure Facility, Department of Biotechnology,
School of Life Science, University of Hyderabad, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract In an effort to provide a green synthetic route for heterocyclic scaffolds, new
macro analogs of acyclic Mannich derivatives have been synthesized in good yields in a
one-pot, efficient fashion. The acyclic symmetrical and unsymmetrical 2-[(E)-
(benzylideneamino)(aryl)methyl]cyclododecanones have been synthesized by condensation
of cyclododecanone, aromatic aldehyde, and ammonium acetate in ethanolic media. By
infrared, NMR, and mass spectral analyses, their structures were determined. Examination
of crystal structure of a p-Cl and o-Br analogs reveals the minimum energy [3333] square
conformation of cyclododecanone ring. In the crystal, molecules aggregate in dimeric
subunits formed by C-Cl . . . p and C-H..p interactions. The reported one-pot, multichain
reaction of macrocycles is the first synthetic attempt of acyclic compounds in this type of
Mannich reaction involving ketones containing active methylene groups.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Received January 7, 2011.
The current affiliation for N.S.K. is Center for Plastic Information Systems (CPIS), Department of
Chemistry Education, Pusan National University, Pusan, South Korea.
Address correspondence to Kulathu Iyer Sathiyanarayanan, Chemistry Division, School of
Advanced Sciences, VIT University, Vellore 632014, India. E-mail: sathiya_kuna@hotmail.com
3429

3430
N. S. KARTHIKEYAN ET AL.
Keywords Ammonium acetate; cyclododecanone; Mannich reaction; MCR
INTRODUCTION
The concept of ideal synthesis was first put forth by Wender et al.[1] Multicom-
ponent reactions (MCRs) are efficient synthetic routes to perform near-ideal
synthesis. MCRs are now being tailored and fine-tuned for synthesizing various com-
pounds including many heterocyclic scaffolds.[2] The one-pot MCR has emerged as an
attractive tool for atom-economical and benign synthesis by virtue of convergence,
productivity, facile execution, and generation of diverse compounds from easily avail-
able starting materials in a single operation.[3–8] Our goal is to provide a rapid and
green synthetic route for new representative title compounds. We had earlier reported
efficient synthesis of several such compounds in a one-pot fashion using ammonium
acetate.[9–13] Here, we report the Mannich synthesis of macro analogs of acyclic sym-
metrical (R1 ¼ R2) and unsymmetrical (R1 ¼ R2) 2-[(E)-(benzylidene amino)(aryl)-
methyl]cyclododecanones. Our interest in compounds containing medium to large
alicyclic rings (in the C10–C20 range) began with the discovery of their importance
in many natural products and biologically active compounds. Macromolecules
containing hetero-atoms have gained considerable interest in recent years, and parti-
cularly the ligands containing N or O macro systems are of special interest as natural
products. Moreover, they also demonstrate a broad spectrum of biological activities
with unusual pharmacological properties.[14–17]
The development of synthetic methods for the formation of acyclic compounds
has increased enormously. However, the construction of a large ring with appropri-
ately situated functional groups poses a great synthetic challenge. Various piperi-
dones and bicyclic analogs were synthesized earlier by Noller, Jeyaraman, and
coworkers.[18,19] Although the Mannich procedure for the preparation of such
azabicyclic system was published more than a half-century ago, the applications of
this versatile skeleton of acyclic derivatives have not been investigated. To the best
of our knowledge, despite the intensive chemical and pharmacological investigations
of various acyclic symmetrical Mannich dervatives, studies on unsymmetrical
Mannich compounds remain scarce. In this article, we report successful synthesis
of libraries of acyclic symmetrical and unsymmetrical 2-[(E)-(benzylideneamino)
(aryl)methyl]cyclododecanone in good purity and good yield, targeting the diversity
of Mannich derivatives for further activity screening.
RESULTS AND DISCUSSION
The title compounds were readily synthesized in good yields by the reaction
of cyclododecaone (1) and aromatic aldehdye (2) in the presence of ethanolic
ammonium acetate (3), and the strategy is depicted in the Scheme 1. Surprisingly,
the condensation reaction does not lead to the cyclic Mannich adduct, but the C-C
and C-N bond formation gave the acyclic adduct. We got only the acyclic product.
Presumably, formation of the quaternary center is avoided in this case because of ring
strain in the large annulated ring of cyclododecanone (absence of planarity). Even
though the expected product is a six-membered ring, we are getting acyclic product.

MACRO ACYCLIC MANNICH DERIVATIVES
3431
Scheme 1. General synthesis of 2-[(E)-(benzylideneamino)(aryl)methyl]cyclododecanone (4a–g).
This may be due to the prevention of the formation of six-membered ring by ring stain
already present in cyclododecanone ring. This is very clear from the formation of
six-membered ring in the case of cyclohexanone instead of cyclododecanone.
Because it is a new product, this method can be applied to higher cyclic ketones
to test whether we are getting the six-membered ring product. We were excited to
learn that the method was applicable to a broad spectrum of substrates on various
substituted benzaldehydes (2), even though we are not getting a cyclic Mannich
product. In this way, we used two different aromatic aldehydes for the synthesis
of unsymmetrical acyclic analogs without the protection of a-carbon in ketone.
This protocol can be applied not only to electron-withdrawing groups (such as
halide groups) but also to electron-donating groups (such as alkyl groups) under the
same conditions. In most of the cases, the reaction proceeded smoothly and gave the
products in good yields. However, we failed to get the products in a few aromatic
aldehydes, such as p-ethyl, p-ethoxy, o-methyl, and o-methoxy. Presumably, the long
carbon chain in para-substituted benzaldehydes (p-ethyl, p-ethoxy) decreases the elec-
trophilicity of the imine carbon. The reduced reactivity diminishes the product forma-
tion. Similarly the electron-donating group on the ortho position (o-methyl, o-
methoxy, o-ethyl, o-ethoxy) fails in the product formation because of the steric effect.
This principle was also successfully applied to two different aldehydes (R1 ¼ R2). We
are getting unsymmetrical product only in the case of the electron-donating group
(Me ¼ MeO) on the para position of benzaldehyde. The reaction is stopped halfway
without leading to ring closure. The results are summarized in Table 1.
The products obtained through this protocol had the inherent advantage of
precipitating out the insoluble product. Thus, the reaction could be monitored

3432
N. S. KARTHIKEYAN ET AL.
Table 1. Three-component reaction of cyclododecanone (1), aromatic aldehyde (2),
and ammonium acetate (3)
Entry
RCHO (R1)
RCHO (R2)
Product
Yield (%)
Mp (ꢁC)
1
2
H
p-F
H
p-F
4a
4b
4c
4d
4e
4f
67
86
77
74
68
84
82
74
69
70
–
118–120
116–118
3
p-Cl
p-Cl
p-Br
114–116
242–244
4
p-Br
m-Br
o-F
5
m-Br
o-F
o-Br
150–152
158–160
6
7
o-Br
p-MeO
p-Me
p-Me
p-OEt
p-Et
4g
4h
4i
142–144
132–134
8
p-MeO
p-Me
p-MeO
p-OEt
p-Et
9
142–144
110–112
10
11
12
13
14
15
16
17
18
19
4j
4k
4l
–
–
–
–
–
–
–
–
–
–
o-OMe
o-Me
o-OEt
o-Et
o-MeO
o-Me
o-OEt
o-Et
4m
4n
4o
4p
4q
4r
4s
–
–
–
–
o-Br
o-Br
o-Br
p-Br
p-Cl
–
–
p-MeO
–
visually by the formation of pale white precipitate, indicating the completion of the
reaction. Therefore, the purity of the obtained product was consistently better.
Spectroscopic Characterization
The structures of synthesized compounds were unequivocally identified with
the aid of spectroscopic means. The Fourier transform–infrared (FT-IR) spectrum
of the compounds, 4a–j had a sharp band at 1695–1711 cmꢀ1 (C O stretch);
=
1618–1646 cmꢀ1 (N CH stretch), clearly indicating the formation of acyclic (open)
=
1
structure. In the H NMR spectrum of the compounds 4a–j, the N CH protons
=
occur as singlets, ranging from d 8.11–8.75 ppm. The mass spectrum of the com-
pounds 4a–j showed their respective peaks (spectra available in the supplementary
data). The structures of crystalline compounds 4c and 4g were also confirmed by
single-crystal x-ray analysis (Figs. 1a and 1b, respectively).
Based on IR, 1H NMR, 13C NMR, and mass spectrometry, it can be concluded
that the reaction affords a sole product. The selectivity of the desired products thus
obtained was consistently high, probably because the reaction took place under mild
conditions. These structures were further validated by x-ray crystallographic studies.
Crystal Structure Analyses of Representative Compounds 4c and 4g
These compounds are noncrystalline in nature, and diffraction data for only 4c
and 4g could be obtained. The overall structures of 4c and 4g are illustrated in Fig. 1a
and 1b, respectively. In the reported structures of the centrosymmetric crystal of 4b,
the stereogenic centers (C2 and C13) adopt R and S configurations, respectively. In
4g, C13 adopts S configuration. C2 possess S configuration in the major component,

MACRO ACYCLIC MANNICH DERIVATIVES
3433
Figure 1. (a) Molecular structure of 4c; (b) molecular structure of 4g. (Figure is provided in color online.)
whereas in minor component it assumes R configuration.[20] The molecules 4c and 4g
=
adopt an E configuration with respect to the imine C N, with C13—N1—C20—C21
torsion angles of 175.5(2)ꢁ and ꢀ178.4(3)ꢁ, respectively.
The cyclododecanone ring adopts [3333] square conformation in both compounds
possessing 422 symmetry.[21,22] The numbers in the square brackets indicate the number
of ring bonds between the four corner atoms of cyclododecanone ring. The [3333] square
conformation is the most favored conformation of cyclododecanone. Based on theoreti-
cal calculations, the other three lowest energy conformations for the 12-membered ring
were [2334], [1434], and [2343].[23] Upon examination of the structures of cyclododeca-
none ring in Cambridge Structural Database (version 5.31), 38 structures were retrieved.
Their refcodes are as follows: BRDECO, DESNUL, DESPAT, DIFJEH, EJEJEI,
ETIBAK, EVIPEE, FEYYEO, FOMYAH, FOMYEL, FONBAL, GEFMAG,
HABWUC, HABXAJ, HABXOX, HABYIS, HABYUE, HABZUF, HIBLIN,
HIHPOD, IJUTIQ, KOQHON, NILMOK, NIVROZ, OMIWUC, QAYKAD,
QIXFUY, QIXFUY01, TOCFAS, UNOCEF, VASDAU, VASKUV, VASLOQ,
VASQAH, VASQEL, XEXYAA, ZOGRIW, and ZUMLIC. In all, the cyclododeca-
none ring assumes the lowest energy [3333] square conformation with very few excep-
tions (in the cases of ETIBAK, IJUTIQ, NILMOK, and QAYKAD), where the
additionally fused cyclic ring imposes severe restraints, leading to preference for other
minimum-energy conformations. To calculate the average geometry of the cyclododeca-
none ring, we selected only those structures having a cyclododecanone ring without any
associated fused cyclic ring (refcodes: BRDECO, DESNUL, EJEJEI, EJEJEI, GEF-
MAG, HABXAJ, HABXOX, HABYIS, HABYUE, HABZUF, HIBLIN, HIHPOD,
XEXYAA, and ZOGRIW). The average intra-annular bond distance and angles are
ꢁ
ꢁ
˚
˚
1.53(2) A and 114 (2) , respectively. The observed values in 4c [1.52(1) A and 115(2) ]
ꢁ
˚
and 4g [1.51(1)A and 114(3) ] are in agreement with the mean values. The absolute
value of average torsion angles corresponding to the synclinal and antiperiplanar con-
formations are 69(5)ꢁ and 161(8)ꢁ, respectively, for a cyclododecanone ring. In the
present case, out of 12 torsion angles, eight are in -synclinal conformations having aver-
age values of 68.1ꢁ and 68.1 ꢁ, in 4c and 4g. The other four torsion angels are in

3434
N. S. KARTHIKEYAN ET AL.
Figure 2. (a) Crystal packing in 4c; (b) C-H. . .p bonded dimer in 4g. (Figure is provided in color online.)
antiperiplanar conformations with average values of 161.0ꢁ and 158.7 ꢁ (in 4c and 4g).
The internal torsion angles of the cyclododecanone ring are listed in Fig. 1.
Crystal packing in 4c is characterized by two kinds of adjacent dimers (Fig. 2a).
Short intermolecular C10–H10B . . . p(Cg2)i [symmetry code (i):ꢁ1-x, 1-y, 2-z] contacts
˚
stabilize the dimeric subunit (H . . . p ¼ 2.98 A; C-H . . . p ¼ 137 ). An adjacent dimer
is also formed by a C24–Cl2. . .p(Cg1)ii [symmetry code (ii): 2-x, -y, 2-z] contact.
Cg1 and Cg2 are the centroids of (C14–C19) and (C21–C26) rings, respectively.
ꢁ
˚
The Cl . . . p distance and C-Cl . . . p angle are 3.368(2) A and 157.3(1) , respectively,
˚
whereas the minimum atomic distance, in Cl . . . p, is 3.569(3) A. These dimeric sub-
units in tandem generate a one-dimensional chain along crystal [1-1 0]-direction.
The C-Hal . . . p–dimer interactions, which have also been referred to as PHD
(p-halogen–dimer) interactions, have recently been shown to play an important role
in host–guest chemistry.[24,25] Aromatic–aromatic stacking interactions are also
observed in the packing with Cg2 . . . Cg2i [symmetry code (i): 2-x, -y, 2-z] centroid . . .
˚
˚
centroid distance of 3.892(2) A, an interplanar distance of 3.608(1) A, and a slippage
˚
of 1.457 A. Cg2 is the center of the (C21–C26) ring. In the crystal of 4g, intermolecular
C23-H23 . . . p(Cg1)i [symmetry code (i): 1-x, 1-y, 1-z] short contact stabilizes the
dimeric subunit (H . . . p ¼ 2.97 A; C-H . . . p ¼ 133 ). Cg1 is the center of the
ꢁ
˚
(C14–C19) ring (Fig. 2b).
CONCLUSION
A multicomponent Mannich reaction has been successfully used as the key step
for the synthesis of the first representatives of the new class of stable macro acyclic
analogs. These structures were established by spectroscopic and x-ray crystallo-
graphic methods. The proposed one-pot synthetic method is green, efficient, and
rapid. The starting materials are easily available, and the chemical diversity of
products can be conveniently manipulated. The reported one-pot synthesis serves
as an interesting example of efficient and rapid green synthetic route for designing
other macro molecules.

MACRO ACYCLIC MANNICH DERIVATIVES
3435
EXPERIMENTAL
All chemicals purchased were of reagent grade and were used without further
purification. Melting points were determined in open capillary tubes with a Dalal
melting-point apparatus (100 watts) and are uncorrected. IR spectra were recorded
in the range 4000–400 cmꢀ1 on a Thermo Nicolet Avatar 330 FT-IR spectrometer
in KBr pellets. 1H NMR and 13C NMR spectra were recorded in chloroform-d using
a Bruker AMX 500 FT, while the mass spectrum was obtained with an Agilent instru-
ment. Chemical shifts are reported as parts per million (ppm) relative to tetramethyl-
silane (TMS). LC-MS (liquid chromatography–mass spectrometry) data were
obtained using an Agilent 1200 series LC and Micromass zQ 4000 spectrometer.
Spectral data are reported as supplementary data.
General Procedure for the Preparation of Synthesis of Products 4a–j
A mixture of cyclododecanone (0.01 mol) and the respective aldehyde (0.02 mol)
was added to a warm solution of ammonium acetate (0.01 mol) in absolute ethanol
(15 ml). The mixture was gently warmed on a water bath for 2–3 min and was stirred
at room temperature. The completion of the reaction was identified with thin-layer
chromatography (TLC). The solid obtained was separated, and the crude compound
was purified by silica-gel column chromatography (hexane and ethyl acetate as
elutant). The desired product precipitated out in the reaction mixture because of
the poor solubility in ethanol at room temperature. Hence, the reaction could also
be monitored for its completeness by the visual inspection of the formation of pale
white precipitates.
2-[(E)-(Benzylideneamino)(aryl)methyl]cyclododecanone (4a)
ꢁ
=
Pale white solꢀid1; mp 118–120 C; yield 67%; IR (KBr): 2930, 2857, 1706 (C O),
1
=
1632 (N CH) cm
=
; H NMR (CDCl3, 400 MHz): d 8.30–8.18 (1H, N CH),
7.77–7.20 (10H, ArH), 4.46–4.36 (1H, Ali-CH), 3.60–3.43 (1H, Ali-CH), 3.60–1.14
13
=
=
(20H, CH2); C NMR (CDCl3, 100 MHz): d 213.63 (C O), 160.64 (N CH),
142.41, 141.79, 141.50, 136.20, 130.72, 130.64, 128.58, 128.52, 128.49, 128.43,
128.36, 128.32, 127.89, 127.74, 127.42, 127.34, 126.84, 70.64, 59.66, 58.22, 41.18,
28.21, 27.62, 26.45, 26.28, 25.95, 25.86, 24.55, 23.20, 23.03, 22.31; MS: m=z ¼ 376
(M þ 1); HRMS: calculated 375.5463; found 375.5462.
2-[(E)-(4-Fluorobenzylideneamino)(4-fluorophenyl)methyl]
cyclododecanone (4b)
ꢁ
=
White solid; mp 116–118 C; yield 86%; IR (KBr): 2937, 2850, 1711 (C O),
ꢀ1
1
=
1642 (N CH) cm
=
; H NMR (CDCl3, 400 MHz): d 8.24–8.12 (1H, N CH),
7.68–6.97 (8H, ArH), 4.44–4.42 (1H, Ali-CH), 3.37–3.35 (1H, Ali-CH), 2.27–1.14
(20H, Ali-CH2); C NMR (CDCl3, 100 MHz) d 213.97 (C O), 165.60, 163.29,
13
=
=
163.11, 160.85 (N CH), 159.58, 137.50, 137.47, 132.34, 132.31, 130.24, 130.16,
129.32, 129.24, 115.69, 115.57, 115.47, 115.36, 57.72, 41.59, 27.45, 26.27, 25.85,
24.57, 24.40, 22.95, 22.22, 21.89; HRMS: calculated 411.5272; found 411.5271.

3436
N. S. KARTHIKEYAN ET AL.
2-[(E)-(4-Chlorobenzylideneamino)(4-chlorophenyl)methyl]
cyclododecanone (4c)
Crystalline solid; mp 114–116 ꢁC; yield 77%; IR (KBr): 2930, 2857, 1710
ꢀ1
1
=
=
=
(C O), 1638 (N CH) cm ; H NMR (CDCl3, 400 MHz): d 8.23 (1H, N CH),
7.69–7.24 (8H, ArH), 4.45–4.43 (1H, Ali-CH), 3.40–3.34 (1H, Ali-CH), 2.77–1.15
13
=
=
(20H, Ali-CH2); C NMR (CDCl3, 100 MHz) d 213.69 (C O), 159.92 (N CH),
140.09, 136.80, 134.46, 133.21, 129.50, 129.16, 128.80, 128.79, 58.20, 57.54, 41.61,
27.91, 27.41, 26.43, 26.28, 25.89, 24.53, 24.37, 24.34, 22.89, 22.59, 22.24, 21.87;
HRMS: calculated 444.4364; found 444.4362.
2-[(E)-(4-Bromobenzylideneamino)(4-bromophenyl)methyl]
cyclododecanone (4d)
ꢁ
=
White solid; mp ꢀ2142–244 C; yield 74%; IR (KBr): 2926, 2855, 1701 (C O),
1
=
=
1638 (N CH), 639 cm ; H NMR (CDCl3, 400 MHz): d 8.22–8.11 (1H, N CH),
7.62–7.25 (m, 8H, Ar-H), 4.43–4.36 (1H, Ali-CH), 3.39–2.69 (1H, Ali-CH), 2.44–
1.26 (20H, Ali-CH2); C NMR (CDCl3, 100 MHz) d 213.65 (C O), 160.08
13
=
=
(N CH), 141.31, 140.56, 134.85, 131.84, 131.76, 129.76, 129.72, 129.53, 125.38,
125.28, 121.35, 121.26, 58,14, 57.46, 41.62, 41.10, 27.40, 26.28, 25.89, 24.52, 24.36,
24.33, 24.29, 22.27, 22.24, 21.86, 21.80; HRMS: calculated 533.3384; found 533.3381.
2-[(E)-(3-Bromobenzylideneamino)(3-bromophenyl)methyl]
cyclododecanone (4e)
ꢁ
=
White solid; mp 150–152 C; yield 68%; IR (KBr): 2935, 2864, 1700 (C O), 1620
ꢀ1
1
=
=
(N CH) cm ; H NMR (DMSO-d6, 500 MHz): d 8.25 (1H, N CH), 7.97–7.26 (8H,
ArH), 4.04–4.02 (2H, Ali-CH), 2.82–1.04 (20H, Ali-CH2); 13C NMR (DMSO-d6,
=
=
125 MHz) d 212.97 (C O), 162.95 (N CH), 134.46, 131.08, 130.89, 130.78, 130.60,
127.07, 56.19, 26.45, 24.08, 22.37, 21.65; MS: HRMS: calculated 533.3384; found
533.3179.
2-[(E)-(2-Fluorobenzylideneamino)(2-fluorophenyl)methyl]
cyclododecanone (4f)
ꢁ
=
White solid; mp 158–160 C; yield 84%; IR (KBr): 2930, 2859, 1705 (C O), 1639
ꢀ1
1
=
=
(N CH) cm ; H NMR (DMSO-d6, 400 MHz): d 8.53 (1H, N CH), 7.97–7.00 (8H,
ArH), 4.98–4.96 (1H, Ali-CH), 3.49–3.47 (1H, Ali-CH), 2.43–1.17 (20H, Ali-CH2); 13
C
=
=
NMR (CDCl3, 100 MHz) d 213.32 (C O), 155.16 (N CH), 132.32, 129.31, 128.87,
128.79, 127.84, 124.47, 124.18, 115.73, 115.60, 115.50, 69.06, 40.67, 27.26, 26.30,
25.90, 24.35, 24.29, 23.01, 22.27, 21.92; HRMS: calculated 411.5272; found 411.5269.
2-[(E)-(2-Bromobenzylideneamino)(2-bromophenyl)methyl]
cyclododecanone (4g)
ꢁ
=
White solid; ꢀm1p 142–144 C; yield 82%; IR (KBr): 2935, 2856, 1700 (C O), 1638
1
=
(N CH), 678 cm
=
;
H NMR(CDCl3, 400 MHz): d 8.75–8.65 (1H, N CH),

MACRO ACYCLIC MANNICH DERIVATIVES
3437
7.98–7.07 (8H, ArH), 5.24–5.13 (1H, Ali-CH), 3.52–3.47 (1H, Ali-CH), 2.41–1.24
13
=
=
(20H, Ali-CH2); C NMR (CDCl3, 100 MHz) d 212.85 (C O), 160.91 (N CH),
140.07, 134.59, 133.14, 132.96, 131.96, 129.85, 129.10, 128.83, 127.73, 127.53,
125.20, 123.84, 72.59, 56.90, 38.97, 26.59, 26.15, 25.78, 24.15, 24.12, 24.04, 22.66,
22.32, 22.03; MS: m=z ¼ 534 (Mþ þ 1); HRMS: calculated 533.3384; found 533.3382.
2-[(E)-(4-Methoxybenzylideneamino)(4-methoxyphenyl)methyl]
cyclododecanone (4h)
ꢁ
=
White solid; mp 132–134 C; yield 74%; IR (KBr): 2927, 2855, 1700 (C O),
ꢀ1
=
3420, 1636 (N CH) cm
;
1H NMR (DMSO-d6, 400 MHz): d 8.24–8.11 (1H,
N CH), 7.57–7.13 (8H, ArH), 4.38–4.36 (1H, Ali-CH), 3.44–3.39 (1H, Ali-CH),
=
2.36–2.28(6H, OCH3), 2.75–1.12 (20H, Ali-CH2); 13C NMR (CDCl3, 100 MHz) d
=
=
214.57 (C O), 160.53 (N CH), 140.83, 138.90, 136.96, 133.69, 129.24, 129.12,
128.28, 127.75, 57.69, 41.67, 27.70, 26.26, 25.83, 24.87, 24.62, 24.48, 23.33, 22.29,
22.00, 21.47, 21.11; HRMS: calculated 435.5983; found 435.5981.
2-[(E)-(4-Methylbenzylideneamino)(4-methylphenyl)methyl]
cyclododecanone (4i)
ꢁ
=
White solid; mp 142–144 C; yield 69%; IR (KBr): 2929, 2858, 1695 (C O), 1627
ꢀ1
1
=
=
(N CH) cm ; H NMR (CDCl3, 400 MHz): d 8.11 (1H, N CH), 7.57–7.13 (8H,
ArH), 4.39–4.36 (1H, Ali-CH), 3.45–3.39 (1H, Ali-CH), 2.36–2.28(6H, OCH3),
2.75–1.12 (20H, Ali-CH2); C NMR (CDCl3, 100 MHz) d 214.56 (C O), 160.54
13
=
=
(N CH), 140.83, 138.90, 136.96, 133.69, 129.24, 129.13, 128.28, 127.76, 57.70,
41.67, 27.71, 26.27, 25.84, 24.87, 24.62, 24.49, 23.34, 22.29, 22.00, 21.47, 21.11; MS:
m=z ¼ 404 (Mþ þ 1); HRMS: calculated 403.5995; found 403.5992.
2-[(E)-(4-Methoxybenzylideneamino)(4-methylphenyl)methyl]
cyclododecanone (4j)
ꢁ
=
White solid; mp 110–112 C; yield 70%; IR (KBr): 2931, 2858, 1707 (C O), 1646
ꢀ1
1
=
=
(N CH) cm ; H NMR (CDCl3, 400 MHz): d 8.11–8.07 (1H, N CH), 7.61–6.84
(8H, ArH), 4.36–4.33 (1H, Ali-CH), 3.78–3.75 (3H, OCH3), 3.41–3.38 (1H, Ali-CH),
2.36–2.28(6H, CH3), 2.74–1.11 (20H, Ali-CH2); 13C NMR (CDCl3, 100 MHz) d
=
=
214.67 (C O), 161.58 (N CH), 159.90, 158.79, 140.84, 139.00, 138.88, 136.93,
133.66, 129.85, 129.25, 128.84, 128.28, 127.74, 113.79, 57.72, 41.62, 27.69, 26.25,
25.82, 24.84, 24.61, 24.47, 23.31, 22.25, 22.00, 21.09; HRMS: calculated 419.5989;
found 419.5981.
X-Ray Diffraction
Suitable single crystals for data collection were grown from a mixture of ethanol
and tetrahydrofuran in a 1:1 ratio. Data were obtained from a Bruker SMART and
Oxford Diffraction Xcalibur Eos Gemini diffractometers.[26] Crystals were stable
during data collection. The structure was solved by applying the direct phase-
determination technique using SHELXS-97 and refined by full-matrix least square

3438
N. S. KARTHIKEYAN ET AL.
on F2 using SHLEXL-97.[27] All structural calculations were performed with the
WinGX suit of programs (version 1.70.01).[28] These compounds are mostly noncrys-
talline, and suitable crystals for 4c and 4g could be grown. The cyclododecanone
ring in 4g had a conformational disorder with contribution of major and minor com-
ponents of 0.79(1) and 0.21(3), respectively. Ring atoms (excluding oxygen O1 and
anchor atom C2) were refined isotropically and their equivalent distances and dis-
placement parameters were restrained to be the same using SADI and EADP options
in SHELX-97. Distance restraints were also applied to C7–C8 and C6–C7 distances.
The hydrogens were placed in the geometrically expected positions and refined
Table 2. Crystal data for 4c and 4g
Parameter
4c
4g
Crystal data
Empirical formula
Molecular weight
Morphology
C26H31Cl2NO
444.42
C26H31Br2NO
533.34
Colorless, block
Colorless, rectangular
0.42 ꢂ 0.22 ꢂ 0.20
Crystal size (mm)
Cell parameters
0.38 ꢂ 0.35 ꢂ 0.35
˚
a (A)
13.5193(13)
5.5858(5)
31.994(3)
90.0, 98.268(5), 90.0
2390.9(4)
2532
7.9961(5)
9.6617(7)
˚
b (A)
˚
c (A)
16.890(1)
102.312(6), 91.493(5), 106.857(6)
a, b, c (ꢁ)
3
˚
V (A )
1214.7(1)
12186
Cell measuring reflection
h range (ꢁ)
Crystal system
2.6–21.8
Monoclinic
P21=n
2.7–29.2
Triclinic
P1 bar
2=1
Space group
Z=Z0
Dx(cal.) (g=cm3)
m (mmꢀ1
Absorption correction
4=1
1.235
1.455
3.354
)
0.289
Multiscan
944
Multiscan
542
F (000)
Data collection
Radiation
MoKa
298(2)
2.3–28.4
MoKa
295(2)
2.7–29.3
Temperature (K)
h range (ꢁ)
Index ranges
ꢀ18 <¼ h <¼ 16
ꢀ6 <¼ k <¼ 6
ꢀ37 <¼ l <¼ 42
u and x scans
5586
ꢀ10 <¼ h<¼ 10
ꢀ13 <¼ k<¼ 12
ꢀ23 <¼ l<¼ 22
u and x scans
6082
Scan type
Independent reflections
Observed [I > 2r (I)]
Refinement
Final R [F2 > 2(F2)]
wR(F2)_all
2379
2995
0.0578
0.1716
0.0510
0.1428
Goodness of fit (S)
(D=r)max
Dqmax and Dqmin(e A
Data=restraints=parameter
0.998
0.002
1.103
0.001
ꢀ3
˚
)
0.413 and ꢀ0.286
5586=0=271
0.767 and ꢀ0.440
6082=12=241
2
Note: w ¼ 1=½r2ðF02Þ þ ðaPÞ þ bPꢃ where P ¼ ðFo2 þ 2Fc2Þ=3; parameters a and b are 0.0701, 0.3657
(4c), and 0.0651, 0.000 (4g), respectively.

MACRO ACYCLIC MANNICH DERIVATIVES
3439
with the riding options. The distances with hydrogen atoms are aromatic=sp2
˚
˚
˚
C—H ¼ 0.93 A, methylene C—H ¼ 0.97 A, methine C—H ¼ 0.98 A, and Uiso ¼ 1.2
Ueq (parent). Essential crystal data are listed in Table 2. Crystallographic data for
the structures in this article have been deposited with the Cambridge Crystallographic
Data Centre with the following accession numbers: CCDC 801979 (4c) and CCDC
801980 (4g). Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
Database Study
Cambridge Structural Database (version 5.31) searches were carried out using
Conquest (version 1.12) and analyzed with VISTA (version 2.1).
ACKNOWLEDGMENTS
N. S. K. thanks the Council of Scientific and Industrial Research (CSIR), New
Delhi, for the Senior research fellowship. R. S. R. acknowledges CSIR for funding
under the scientist’s pool scheme.
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