Syntheses and some features of five new cyclohexane-1,3-dicarboxylates with multiple stereogenic centers

Article abstract of DOI:10.1016/j.molstruc.2012.08.006

The condensation of diethyl 4-hydroxy-4-methyl-6-oxo-2-(4- substitutedphenyl)-cyclohexane-1,3-dicarboxylates and N′-(2-chloropropyl) ethane-1,2-diamine leads to diethyl 1-(2-chloropropyl)-9-hydroxy-9-methyl-7- phenyl-1,4-diazaspiro[4.5]decane-6,8-dicarboxylate (2) and its para-substituted methyl (1), chloro (3), bromo (4), and nitro (5) derivatives with a new stereogenic center, which were fully characterized by elemental analysis, ESI-MS, IR, ¹H and ¹³C NMR spectroscopies and X-ray single-crystal analysis (for 2). The condensation reaction is regioselective, only cyclohexanone carbonyl moiety undergoes the transformation, leaving the β-keto ester carbonyls unreacted. Withing the compounds 1-5, the increase in the Hammett's σ_p, related normal σpn, inductive σ_I, negative σp- and positive σp+ polar conjugation and Taft's σpo substituent constants generally leads to the corresponding drift of δ_OH and δ_NH NMR chemical shifts to lower field.

Full text of DOI:10.1016/j.molstruc.2012.08.006

Journal of Molecular Structure 1032 (2013) 83–87
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Syntheses and some features of five new cyclohexane-1,3-dicarboxylates
with multiple stereogenic centers
Arif M. Ismiyev a, Abel M. Maharramov a, Rafiga A. Aliyeva a, Rizvan K. Askerov a,
Kamran T. Mahmudov a,b, , Maximilian N. Kopylovich b, Houcine Naïli c, Armando J.L. Pombeiro b
⇑
a Baku State University, Department of Chemistry, Z. Xalilov Str. 23, Az 1148 Baku, Azerbaijan
b Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Technical University of Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
c Laboratoire de l’Etat Solide, Département de Chimie, Université de Sfax, BP 1171, 3000 Sfax, Tunisia
h i g h l i g h t s
"
"
"
A series of 5 new cyclohexane-1,3-dicarboxylates are synthesized.
A new stereogenic center is introduced to the starting materials upon the synthesis.
Correlations between the substituent constants and dOAH or dNAH NMR chemical shifts are analyzed.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2012
Received in revised form 2 August 2012
Accepted 2 August 2012
Available online 11 August 2012
The condensation of diethyl 4-hydroxy-4-methyl-6-oxo-2-(4-substitutedphenyl)-cyclohexane-1,3-dicar-
boxylates and N0-(2-chloropropyl)ethane-1,2-diamine leads to diethyl 1-(2-chloropropyl)-9-hydroxy-9-
methyl-7-phenyl-1,4-diazaspiro[4.5]decane-6,8-dicarboxylate (2) and its para-substituted methyl (1),
chloro (3), bromo (4), and nitro (5) derivatives with a new stereogenic center, which were fully charac-
terized by elemental analysis, ESI-MS, IR, 1H and 13C NMR spectroscopies and X-ray single-crystal anal-
ysis (for 2). The condensation reaction is regioselective, only cyclohexanone carbonyl moiety undergoes
the transformation, leaving the b-keto ester carbonyls unreacted. Withing the compounds 1–5, the
Keywords:
Stereogenic center creation
Substituted cyclohexane
Correlation analysis
increase in the Hammett’s rp, related normal r r
np, inductive I, negative rpꢀ and positive rþp polar conju-
gation and Taft’s rop substituent constants generally leads to the corresponding drift of dOAH and dNAH
NMR chemical shifts to lower field.
Crown Copyright Ó 2012 Published by Elsevier B.V. All rights reserved.
1. Introduction
Cyclohexanones of the 3-R-2,4-diacetyl(diethoxycarbonyl)-5-
hydroxy-5-methylcyclo-hexanone series are among the products
The development of single-pot reactions which allow the rapid
construction of several new bonds and stereocenters remains a
considerable challenge in modern organic chemistry. The single-
pot multicomponent coupling reactions (MCRs) have proved to
be one of the most powerful and efficient methods for the prepara-
tion of bioactive compounds due to their atom economy, simple
experimentation, and high yields of the products [1–3]. Such reac-
tions offer a wide range of possibilities for the efficient construc-
tion of highly complex molecules in a single procedural step,
usually avoiding the complicate purification operations and allow-
ing savings of both solvents and reagents. Additionally, such MCRs
as tandem or cascade processes provide a wide variety of methods
to synthesize important chiral compounds [4].
which can be synthesized by MCRs, i.e. by condensation of acetyl-
acetone or acetoacetic acid esters with aldehydes. These com-
pounds are known for their important biological activities such as
herbicidal, antibacterial, antifungal, convulsant, anticonvulsant,
antiimplantation and antiasthmone, besides being useful in organic
synthesis and in industry [5–9]. Thus, they are useful synthons
in further synthetic endeavours, as they have multiple keto,
hydroxy and ester functionalities, potentially available for further
transformations.
As was mentioned, usually synthesis of the cyclohexanones of
this type is carried out via one-pot MCRs, where several organic
fragments are coupled in one step with a carbon–carbon formation
and subsequent cyclization [5–8,10–19]. The methods of further
modification of the thus prepared cyclohexanones with mono- or
polyfunctional nucleophiles are also well studied [20–28]. For in-
stance, it was found that reactions of hydroxylamine [9], hydrazine
[23,24], ethylenediamine [27], ethanolamine [8,26,27], ethylene
⇑
Corresponding author at: Baku State University, Department of Chemistry, Z.
Xalilov Str. 23, Az 1148 Baku, Azerbaijan.
E-mail address: kamran_chem@yahoo.com (K.T. Mahmudov).
0022-2860/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.08.006

84
A.M. Ismiyev et al. / Journal of Molecular Structure 1032 (2013) 83–87
glycol [4], substituted aromatic amines [20,21,25], tosylhydrazide
[22] and benzidine [28] with diethyl-4-hydroxy-4-methyl-6-oxo-
2-phenylcyclohexane-1,3-dicarboxylate give isoxazole, imidazole
and 1,3-dioxolane rings, Schiff base condensation products, etc.
Moreover, in some cases the cyclization processes depend on tem-
perature, i.e. the reaction with hydrazine allows to isolate cyclic or
acyclic products at 60 °C and 0 °C, respectively [23].
mass spectra were run with an ion-trap instrument (Varian 500-
MS LC Ion Trap Mass Spectrometer) equipped with an electrospray
(ESI) ion source. For electrospray ionization, the drying gas and
flow rate were optimized according to the particular sample with
35 p.s.i. nebulizer pressure. Scanning was performed from m/z
100–1200 in methanol solution. The compounds were observed
in the positive mode (capillary voltage = 80–105 V).
On the other hand, the creation of new chiral centers is impor-
tant for the synthesis of new drugs [29] or organocatalysts [30].
Concerning the of ethylenediame with diethyl-4-hydroxy-4-
methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate, the num-
ber of the chiral centers does not increase due to the formation
of symmetric cyclic product [27], thus here we fuctionalized the
mentioned cyclohexanone by reacting with an unsymmetric chiral
N0-(2-chloropropyl)ethane-1,2-diamine. Some features of the thus
synthesized compounds, e.g. correlations between the Hammett’s
2.2. Preparation of compounds 1–5
Diethyl 4-hydroxy-4-methyl-6-oxo-2-(4-substitutedphenyl)-
cyclohexane-1,3-dicarboxylates (20 mmol) and N0-(2-chloropro-
pyl)ethane-1,2-diamine (20 mmol) were dissolved in ethanol
(20 ml). The mixture was stirred at 80 °C for 10 h. After cooling
to room temperature the products 1–5 precipitated which then
were filtered off, washed with cold ethanol (50 ml) and recrystal-
lized from hot ethanol to yield colorless block-shaped crystals.
1: yield 79%, white solid soluble in DMSO, methanol, ethanol
and acetone, and insoluble in water. Elemental analysis: C25H37-
ClN2O5 (Mr = 480.24); C 62.42 (calc. 62.12); H 7.75 (7.26); N 5.82
r
p, related normal r r
np, inductive I, negative rpꢀ and positive rþp po-
lar conjugation and Taft’s rop substituent constants and the corre-
sponding dOAH and dNAH NMR chemical shifts also deserve
exploration to predict the corresponding phisico-chemical and
analytical properties of other analogs of this series.
(5.75)%. MS (ESI): m/z: 481 [Mr + H+]. IR (KBr): 3512
(NH), 1731 and 1678
(C@O) cmꢀ1. 1H NMR in DMSO-d6, internal
m(OH), 2993
Hence, taking in mind the above considerations, we focused this
work on the following aims: (i) to synthesize new functionalized
cyclohexanones of the type depicted in Scheme 1 with ACH3 (1),
AH (2), ACl (3), ABr (4) and ANO2 (5) substituents in para-position
of the aromatic ring of the molecule by reaction of diethyl-4-hy-
droxy-4-methyl-6-oxo-2-(4-substitutedphenyl)-cyclohexane-1,3-
dicarboxylates with N0-(2-chloropropyl)ethane-1,2-diamine; (ii) to
study some correlations between the Hammett’s rp and related
substituent constants and the corresponding dOAH or dNAH NMR
chemical shifts of 1–5.
m
m
TMS, d (ppm): 0.83–0.87 (s, 3H, CH3), 0.90–0.95 (s, 3H, CH3), 1.24
(s, 3H, CH3), 2.18 (3H, CH3), 2.33 (3H, CH3), 2.37 (2H, CH2), 2.92
(2H, CH2), 2.95 (2H, CH2), 3.30 (2H, CH2), 3.31 (2H, CH2), 3.77
(2H, CH2), 3.76–3.79 (s, 1H, CH), 3.81–3.85 (s, 1H, CH), 3.88–3.92
(s, 1H, CH), 3.91 (s, 1H, CH), 4.55 (1H, OH), 7.26–7.39 (4H, ArꢀH),
8.59 (H, NH). 13C-{1H} NMR in DMSO-d6, internal TMS, d (ppm):
13.6 (CH3), 13.8 (CH3), 28.4 (CH3), 34.1 (CH3), 49.3 (CH), 51.2
(CH), 52.6 (CH), 55.7 (CH), 56.3 (CH2), 59.6 (CH2), 59.8 (CH2), 60.4
(CH2), 61.7 (CH2), 62.2 (CH2), 68.7 (Cipso), 72.8 (Cipso), 128.1
(2ArꢀH), 128.2 2ArꢀH), 136.3 (ArCꢀCH3), 140.1 (ArCꢀCH), 166.7
and 170.7 (C@O).
2. Experimental
2: yield 75%, white solid soluble in DMSO, methanol, ethanol
and acetone, and insoluble in water. Elemental analysis: C24H35-
ClN2O5 (Mr = 466.99); C 61.73 (calc. 61.46); H 7.55 (7.37); N 6.00
2.1. Materials and methods
Infrared spectra (4000–400 cmꢀ1) were recorded on a BIO-RAD
FTS 3000MX instrument in KBr pellets. 1H and 13C{1H} NMR spec-
tra were recorded on Bruker Avance II + 300 and 400 MHz (Ultra-
Shield™ Magnet) spectrometers at ambient temperature.
Chemical shifts (d) are relative to internal TMS. Carbon, hydrogen,
and nitrogen elemental analyses were carried out by the Microan-
alytical Service of the Technical University of Lisbon. Electrospray
(6.03)%. MS (ESI): m/z: 468 [Mr + H+]. IR (KBr): 3507
m
(OH), 2984
m(NH), 1735 and 1689 m
(C@O) cmꢀ1. 1H NMR in DMSO-d6, internal
TMS, d (ppm): 0.81–0.84 (s, 3H, CH3), 0.91–0.94 (s, 3H, CH3), 1.25
(s, 3H, CH3), 2.32 (3H, CH3), 2.36 (2H, CH2), 2.92 (2H, CH2), 2.96
(2H, CH2), 3.29 (2H, CH2), 3.32 (2H, CH2), 3.76 (2H, CH2), 3.77–
3.79 (s, 1H, CH), 3.80–3.83 (s, 1H, CH), 3.87–3.91 (s, 1H, CH), 3.95
(s, 1H, CH), 4.62 (1H, OH), 7.18–7.31 (5H, ArꢀH), 8.66 (H, NH).
Scheme 1. Preparation of 1–5.

A.M. Ismiyev et al. / Journal of Molecular Structure 1032 (2013) 83–87
85
Table 1
128.1 (2ArꢀH), 128.5 (2ArꢀH), 133.6 (ArCꢀBr), 140.2 (ArCꢀCH),
168.3 and 170.7 (C@O).
Crystallographic data and structure refinement details for 2.
5: yield 81%, white solid soluble in DMSO, methanol, ethanol
and acetone, and insoluble in water. Elemental analysis: C24H34-
ClN3O7 (Mr = 511.99); C 56.30 (calc. 56.15); H 6.69 (6.40); N 8.21
Empirical formula
Fw
k(Å)
Cryst. Syst.
C24H34ClN2O5
465.98
0.71073
Orthorhombic
Pna21
11.0849(4)
17.1049(6)
13.1104(5)
90.00
90.00
90.00
2485.81(16)
4
1.245
(8.14)%. MS (ESI): m/z: 513 [Mr + H+]. IR (KBr): 3523
m
(OH), 2998
Space group
m(NH), 1739 and 1697 m
(C@O) cmꢀ1. 1H NMR in DMSO-d6, internal
a (Å)
b (Å)
c (Å)
a
TMS, d (ppm): 0.83–0.88 (s, 3H, CH3), 0.92–0.96 (s, 3H, CH3), 1.29
(s, 3H, CH3), 2.35 (3H, CH3), 2.37 (2H, CH2), 2.97 (2H, CH2), 2.99
(2H, CH2), 3.34 (2H, CH2), 3.36 (2H, CH2), 3.77 (2H, CH2), 3.80–
3.86 (s, 1H, CH), 3.89–3.93 (s, 1H, CH), 3.96–3.99 (s, 1H, CH), 4.06
(s, 1H, CH), 5.07 (1H, OH), 7.27–7.46 (4H, ArꢀH), 9.25 (H, NH).
13C-{1H} NMR in DMSO-d6, internal TMS, d (ppm): 13.9 (CH3),
14.2 (CH3), 27.3 (CH3), 35.0 (CH3), 49.9 (CH), 51.8 (CH), 52.8 (CH),
55.5 (CH), 56.5 (CH2), 59.9 (CH2), 60.4 (CH2), 61.2 (CH2), 62.4
(CH2), 62.9 (CH2), 69.3 (Cipso), 73.0 (Cipso), 128.8 (2ArꢀH), 129.1
(2ArꢀH), 139.3 (ArCꢀNO2), 140.7 (ArCꢀCH), 168.0 and 171.2
(C@O).
b
c
V (Å3)
Z
Density
GOOF
1.069
0.0689
0.1904
R1a (I P 2
r
)
r
wR2b (I P 2
)
a
R1 =
wR2 ¼ ½
R
||Fo| ꢀ |Fc||/
R |Fo|.
2
2
1=2
½wðF2o ꢀ F2c Þ ꢁ=
R
½wðF2oÞ ꢁꢁ
.
b
R
2.3. X-ray structure determination
13C-{1H} NMR in DMSO-d6, internal TMS, d (ppm): 13.7 (CH3), 14.2
(CH3), 28.3 (CH3), 34.1 (CH3), 49.4 (CH), 51.1 (CH), 52.7 (CH), 55.6
(CH), 56.2 (CH2), 59.5 (CH2), 59.9 (CH2), 60.3 (CH2), 61.9 (CH2),
62.3 (CH2), 68.8 (Cipso), 72.5 (Cipso), 127.0 (ArꢀH), 128.0 (2ArꢀH),
128.4 (2ArꢀH), 140.0 (ArCꢀCH), 167.2 and 170.1 (C@O).
The crystals were prepared from ethanol at room temperature;
the X-ray analysis was performed with a Bruker, 2004 APEX 2 dif-
fractometer using graphite-monochromated Mo K
0.71073 Å) at 293 K. The structure was solved by direct methods
with successive Fourier difference syntheses (SHELXS-97 [31])
and refined by full matrix least square procedure on F2 with aniso-
tropic thermal parameters. All non-hydrogen atoms were refined
(SHELXL-97 [32]) and placed at chemically acceptable positions.
Crystallographic and selected structural details are listed in
Table 1.
a radiation (k
3: yield 73%, white solid soluble in DMSO, methanol, ethanol
and acetone, and insoluble in water. Elemental analysis: C24H34Cl2-
N2O5 (Mr = 501.44); C 57.49 (calc. 57.33); H 6.83 (6.65); N 5.59
(5.42)%. MS (ESI): m/z: 502 [Mr + H+]. IR (KBr): 3503
m
(OH), 2983
m(NH), 1735 and 1691 m
(C@O) cmꢀ1. 1H NMR in DMSO-d6, internal
TMS, d (ppm): 0.85–0.90 (s, 3H, CH3), 0.93–0.95 (s, 3H, CH3), 1.27
(s, 3H, CH3), 2.31 (3H, CH3), 2.37 (2H, CH2), 2.90 (2H, CH2), 2.94
(2H, CH2), 3.30 (2H, CH2), 3.31 (2H, CH2), 3.77 (2H, CH2), 3.77–
3.80 (s, 1H, CH), 3.82–3.86 (s, 1H, CH), 3.88–3.90 (s, 1H, CH), 3.97
(s, 1H, CH), 4.85 (1H, OH), 7.22–7.36 (4H, ArꢀH), 8.93 (H, NH).
13C-{1H} NMR in DMSO-d6, internal TMS, d (ppm): 13.6 (CH3),
13.9 (CH3), 28.4 (CH3), 34.2 (CH3), 49.3 (CH), 51.1 (CH), 52.6 (CH),
55.5 (CH), 56.3 (CH2), 59.6 (CH2), 59.9 (CH2), 60.3 (CH2), 61.7
(CH2), 62.4 (CH2), 68.9 (Cipso), 72.6 (Cipso), 128.2 (2ArꢀH), 128.7
(2ArꢀH), 133.6 (ArCꢀCl), 140.8 (ArCꢀCH), 167.5 and 171.9 (C@O).
4: yield 74%, white solid soluble in DMSO, methanol, ethanol
and acetone, and insoluble in water. Elemental analysis: C24H34-
BrClN2O5 (Mr = 544.89); C 52.80 (calc. 52.67); H 6.28 (6.13); N
3. Results and discussion
3.1. Spectroscopic investigation of 1–5
The synthesis and characterization of the starting diethyl 4-
hydroxy-4-methyl-6-oxo-2-(4-substitutedphenyl)-cyclohexane-1,
3-dicarboxylates were reported earlier [6], and hence will not be
discussed here. For the synthesis of 1–5, the two-components – a
4-hydroxy-4-methyl-6-oxo-2-(4-substitutedphenyl)-cyclohexane-
1,3-dicarboxylate and N0-(2-chloropropyl)ethane-1,2-diamine
–
were stirred in ethanol at 80 °C for 10 h (Scheme 1). Subsequent
cooling of the reaction mixture leads to presipitation of the prod-
ucts 1–5, which were then filtered off and recrystallized giving
73–81% separate yields. The IR spectra of 1–5 uncover two bands
of the C@O groups at 1678–1697 and 1728–1739 cmꢀ1 together
with bands of OH and NH groups at 3503–3523 and 2983–
2998 cmꢀ1, respectively. The peaks on the ESI-MS spectra corre-
spond to the protonated molecular ions, while the 1H NMR spectra
in DMSO-d6 show the characteristic signals of OH and NH groups at
4.55–5.07 and 8.59–9.25 ppm, respectively. On 13C NMR spectra,
the aromatic carbons are observed in the 127–141 ppm region,
methyls of ethoxy groups perform at 13–15 ppm, while carbonyl
5.13 (5.08)%. MS (ESI): m/z: 546 [Mr + H+]. IR (KBr): 3511
2994 (NH), 1728 and 1697
(C@O) cmꢀ1 1H NMR in DMSO-d6,
m(OH),
m
m
.
internal TMS, d (ppm): 0.80–0.84 (s, 3H, CH3), 0.92–0.93 (s, 3H,
CH3), 1.29 (s, 3H, CH3), 2.30 (3H, CH3), 2.37 (2H, CH2), 2.91 (2H,
CH2), 2.97 (2H, CH2), 3.28 (2H, CH2), 3.30 (2H, CH2), 3.77 (2H,
CH2), 3.76–3.79 (s, 1H, CH), 3.81–3.84 (s, 1H, CH), 3.88–3.90 (s,
1H, CH), 3.96 (s, 1H, CH), 4.89 (1H, OH), 7.19–7.30 (4H, ArꢀH),
9.03 (H, NH). 13C–{1H} NMR in DMSO-d6, internal TMS, d (ppm):
13.7 (CH3), 13.8 (CH3), 28.4 (CH3), 34.2 (CH3), 49.3 (CH), 51.2
(CH), 52.6 (CH), 55.7 (CH), 56.2 (CH2), 59.6 (CH2), 60.1 (CH2), 60.5
(CH2), 61.7 (CH2), 62.4 (CH2), 68.9 (Cipso), 72.7 (Cipso), 127.3 (ArꢀH),
Table 2
Substituent constants [33–35] vs. dOAH or dNAH of 1–5, (n = 5).
Constants
Hammett’s
Normal
Inductive
Taft’s
Polar conjugation
Equation
r2
Equation
r2
rp
ꢀ0.17
0
rpn
ꢀ0.13
0
rI
ꢀ0.05
0
rpo
ꢀ0.07
0
rpꢀ
ꢀ0.17
0
r
p = 1.62dOAH ꢀ 7.57
0.91
0.92
r
p = 1.26dNAH ꢀ 11.0
0.91
0.93
rpþ
ꢀ0.31
0
ACH3
rnp ¼ 1:59dOAH ꢀ 7:38
rnp ¼ 1:24dN—H ꢀ 10:8
AH
ACl
r
I = 1.42dOAH ꢀ 6.49
0.96
0.92
r
I = 1.09dNAH ꢀ 9.41
0.94
0.92
0.23
0.24
0.47
0.27
0.19
0.11
rop ¼ 1:61dOAH ꢀ 7:44
rꢀp ¼ 2:37dOAH ꢀ 11:1
rþp ¼ 1:75dOAH ꢀ 8:26
rop ¼ 1:25dNAH ꢀ 10:9
rꢀp ¼ 1:86dNAH ꢀ 16:3
rþp ¼ 1:37dNAH ꢀ 12:0
ABr
0.23
0.78
0.26
0.78
0.45
0.63
0.29
0.83
0.25
1.27
0.15
0.79
0.79
0.85
0.81
0.85
ANO2

86
A.M. Ismiyev et al. / Journal of Molecular Structure 1032 (2013) 83–87
Fig. 1. Correlation between the inductive substituent constant rI and dOAH (a) or dNAH (b) for 1–5.
3.2. Single crystal X-ray structural analysis of 2
The compound crystallizes in orthorombic space group Pna21
with four molecules in the unit cell (Fig. 2). The cyclohexane ring
adopts a chair conformation; the deviations of the C(5) and C(8)
atoms from the rms C(1)C(4)C(6)C(7) plane are ꢀ0.651 and
0.647 Å, respectively. The phenyl ring is in a pseudo-equatorial po-
sition. Torsion angles between the ethoxycarbonyl group and the
phenyl substituent is 54.5(3)° for C15–C5–C4–C9 and ꢀ52.7(2)°
for C12–C6–C5–C15, indicating the pseudo-axial location of hydro-
gen atoms at C4, C5 and C6. The imidazolidine ring has an envelope
conformation. The torsion angle of a N1–C41–C3–N2 fragment of
the ring is 8.6(3)°. The molecules of 2 possess four sterogenic C4,
C5, C6 and C22 carbon atoms which form enantiomeric pairs with
the relative configuration of the centers of rac-1Rꢂ, 4Sꢂ, 5Sꢂ, 6Sꢂ,
7Sꢂ, 22Sꢂ. The five of six stereogenic centers of 2 are of the same
chirality.
The conformation of 2 is stabilized by the intermolecular
CAHꢃ ꢃ ꢃO and intramolecular O(1)AHꢃ ꢃ ꢃN(1) and N(1)AHꢃ ꢃ ꢃO(5)
hydrogen bonding. The six-membered pseudo-rings O(1)C(9)C
(4)C(1)N(1) (I) and N(1)C(1)C(8)C(7)O(5) (II) with the
O(1)AHꢃ ꢃ ꢃN(1) and N(1)AHꢃ ꢃ ꢃO(5) intramolecular hydrogen bond-
ing can be designated [37] as S(6) graph type, where S denotes the
intramolecular hydrogen bonding while the size or degree of the
motif is six. To evaluate the distribution of electrons in the rings,
the Gilli’s method was used (Scheme 2). The O(1)ꢃ ꢃ ꢃN(1) bond
length and the Q value for the pseudo-ring I [2.960 and 0.227 Å,
respectively] are slightly higher than those for the pseudo-ring II
[(2.742 and ꢀ0.028 Å, respectively]. Neverheless, the ring II does
not possess any double bond evidencing the RAHB strengthening.
Fig. 2. Molecular structure of 2. Selected bond lengths (Å) and angles (°): O1AC9
1.210(3), O3AC12 1.200(4), O5AC7 1.434(3), N1AC1 1.468(3), N2AC1 1.475(3),
N2AC3 1.464(4), N2AC21 1.449(4), N1AC1AN2 103.88(19), N1AC1AC8
109.36(19), N2AC1AC8 114.8(2), N1AC1AC4 111.80(18), N2AC1AC4 109.44(18),
C8AC1AC4 107.65(18), C9AC4AC1 111.69(17), C9AC4AC5 109.88(18), C1AC4AC5,
111.91(17), C15AC5AC6 113.58(18), C15AC5AC4 110.15(17), C6AC5AC4
109.07(17), O5AC7AC40 106.8(2), O5AC7AC8 109.9(2), C40AC7AC8 109.7(2),
O5AC7AC6 110.4(2), C40AC7AC6 111.5(2), C8AC7AC6 108.61(19).
carbons are absorbed at the region of 167–172 ppm. The observed
difference in methyl and carbonyl carbon chemical shifts is due to
the intramolecular H-bonding (see below).
The functional groups in para position of the aromatic ring of
the molecule influence the OH and NH chemical shift (dOAH or
dNAH) of 1–5 and possible relations between the Hammett’s rp or
4. Conclusions
related inductive rI, normal r
np, negative rꢀp and positive rþp polar
conjugation and Taft’s rpo substituent constants [33–35] and dOAH
or dNAH were analyzed. The best correlation was found for the
inductive rI substituent constant (Table 2, Fig. 1). The significant
positive slopes of these correlations suggest a surprisingly strong
electronic effect of the para-X group, the 1H chemical shifts of
The reaction of diethyl 4-hydroxy-4-methyl-6-oxo-2-(4-substi-
tutedphenyl)-cyclohexane-1,3-dicarboxylates with N0-(2-chloro-
propyl)ethane-1,2-diamine proceeds regioselectively, the amino
groups of the diamine react with the carbonyl group of the alicycle.
As a result, the substituted cyclohexanes 1–5 with increased num-
ber of stereocenters and effective intramolecular [NAHꢃ ꢃ ꢃO and
OAHꢃ ꢃ ꢃN] hydrogen bonds are formed. The correlations between
1H NMR chemical shifts of OH and NH groups of 1–5 and the Ham-
mett and related constants of the para-substituents in the phenyl
ring were subtracted and analyzed. The obtained correlations can
OAH proton being more sensitive (
NAH (
used to predict and tune some properties of cyclohexanes of this
type such as acidity, coordination ability [36], biological activity
[5,20].
r
I = 1.42dOAH ꢀ 6.49) than
r
I = 1.09dNAH ꢀ 9.41) one. The obtained correlations can be
Scheme 2. Distribution of electrons in the rings according to [37].

A.M. Ismiyev et al. / Journal of Molecular Structure 1032 (2013) 83–87
87
[15] W.H. Correa, J.L. Scott, Green Chem. 3 (2001) 296.
[16] C. Xu, C. Yuan, Tetrahedron 61 (2005) 2169.
[17] T. Sakai, K. Miyata, S. Tsuboi, M. Utaka, Bull. Chem. Soc. Jpn. 62 (1989)
4072.
be used to predict some properties of the 1–5 analogs such as acid-
ity, coordination ability.
[18] D.H. Grayson, M.R.J. Tuite, J. Chem. Soc., Perkin Trans. 1 (1986) 2137.
[19] G.F. Cainelli, M. Panunzio, A. Umani-Ronchi, J. Chem. Soc., Perkin Trans. 1
(1975) 1273.
[20] V.V. Sorokin, A.P. Kriven’ko, N.A. Vinogradova, O.P. Plotnikov, Pharma. Chem. J.
35 (2001) 488.
[21] A.K. Ramazanov, V.V. Sorokin, A.P. Kriven’ko, Chem. Comp. Sim., Butlerov
Commun. 2 (2002) 79.
[22] V.L. Gein, A.S. Prusakova, N.V. Nosova, M.I. Vakhrin, E.V. Voronina, A.P.
Kriven’ko, Pharma. Chem. J. 44 (2010) 427.
[23] E.A. Grigorjeva, V.V. Sorokin, A.P. Krivenko, Chem. Comp. Sim., Butlerov
Commun. 3 (2002) 26.
[24] V.L. Gein, N.V. Gein, K.D. Potemkin, A.P. Kriven’ko, Rus. J. Gen. Chem. 74 (2004)
1564.
Supporting information
CCDC 884786 contains the supplementary crystallographic data
for 2. This data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
References
[25] V.L. Gein, N.V. Gein, A.P. Kriven’ko, Rus. J. Org. Chem. 36 (2000) 781.
[26] A.M. Maharramov, A.I. Ismiyev, B.A. Rashidov, Acta Crystallogr. E 67 (2011)
o187.
[27] A.M. Maharramov, A.I. Ismiyev, B.A. Rashidov, G.M. Rahimova, M.A.
Allahverdiyev, Acta Crystallogr. E 67 (2011) o291.
[28] O.A. Schelochkova, V.V. Sorokin, A.P. Kriven’ko, Chem. Comp. Sim., Butlerov
Commun. 4 (2003) 20.
[29] A.J. Hutf, J. O’Grady, J. Antimic, Chemotherapy 37 (1996) 7.
[30] M.J. Gaunt, C.C.C. Johansson, A. McNally, N.T. Vo, Drug Discovery Today 12
(2007) 8.
[1] A.J. von Wangelin, H. Neumann, D. Gördes, Chem. Eur. J. 9 (2003) 4286.
[2] V.A. Chebanov, E.A. Muravyova, S.M. Desenko, V.I. Musatov, I.V. Knyazeva, S.V.
Shishkina, O.V. Shishkin, C.O. Kappe, J. Comb. Chem. 8 (2006) 427.
[3] A. Dondoni, A. Massi, S. Sabbatini, V. Bertolasi, J. Org. Chem. 67 (2002) 6979.
[4] D.J. Ramón, M. Yus, Angew. Chem. Int. Ed. 44 (2005) 1602.
[5] H. Nitta, K. Takimoto, I. Ueda, Chem. Pharm. Bull. 40 (1992) 858.
[6] M. Srinivasan, S. Perumal, Tetrahedron 62 (2006) 7726.
[7] V.L. Gein, N.V. Gein, A.P. Kriven’ko, Rus. J. Gen. Chem. 73 (2003) 490.
[8] A.P. Kriven’ko, E.A. Kozlova, A.V. Grigor’ev, V.V. Sorokin, Molecules 8 (2003)
251.
[31] G.M. Sheldrick, Acta Crystallogr. 46 (1990) 467.
[32] G.M. Sheldrick, SHELXL 97, University of Gottingen, Gottingen, Germany, 1997.
[33] C. Hansch, A. Leo, W.R. Taft, Chem. Rev. 91 (1991) 165.
[34] C. Laurence, B. Wojtkowiak, Ann. Chim. 5 (1970) 163.
[35] V.A. Pal’m, Rus. Chem. Rev. 30 (1961) 471.
[9] A.I. Ismiyev, A.M. Maharramov, B.A. Rashidov, G.Z. Mammadova, R.K. Askerov,
Acta Crystallogr. E 67 (2011) O3018.
[10] D. Enders, S. Müller, A.S. Demir, Tetrahedron Lett. 29 (1988) 6437.
[11] B. Siebenhaar, B. Casagrande, M. Studer, H.-U. Blaser, Can. J. Chem. 79 (2001)
566.
[36] A.M. Maharramov, A.I. Ismiyev, B.A. Rashidov, Acta Crystallogr. E 67 (2011)
m786.
[37] G. Gilli, F. Bellucci, V. Ferretti, V. Bertolasi, J. Am. Chem. Soc. 111 (1989) 1023.
[12] B. Siebenhaar, B. Casagrande, Inorg. Chem. 10 (2002) 114.
[13] Y.-Q. Cao, Z. Dai, R. Zhang, B.-H. Chen, Synth. Commun. 34 (2004) 2965.
[14] D. Prajapati, J.S. Sandhu, Chem. Lett. 10 (1992) 1945.