Inter- and intramolecular Mitsunobu reaction and metal complexation study: Synthesis of S-amino acids derived chiral 1,2,3,4-tetrahydroquinoxaline, benzo-annulated [9]-N3 peraza, [12]-N4 peraza-macrocycles

Article abstract of DOI:10.1039/c1ob06304a

Substituted 1,2,3,4-tetrahydroquinoxaline, benzo-annulated unsymmetrical chiral [9]-N₃ peraza, and [12]-N₄ peraza-macrocycles have been synthesized employing an inter- and intramolecular Mitsunobu reaction from an amino acid derived

Full text of DOI:10.1039/c1ob06304a

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PAPER
Inter- and intramolecular Mitsunobu reaction and metal complexation study:
synthesis of S-amino acids derived chiral 1,2,3,4-tetrahydroquinoxaline,
benzo-annulated [9]-N3 peraza, [12]-N4 peraza-macrocycles†
Krishnananda Samanta,a Nitin Srivastava,b Satyen Sahab and Gautam Panda*a
Received 1st August 2011, Accepted 27th October 2011
DOI: 10.1039/c1ob06304a
Substituted 1,2,3,4-tetrahydroquinoxaline, benzo-annulated unsymmetrical chiral [9]-N3 peraza, and [12]-
N4 peraza-macrocycles have been synthesized employing an inter- and intramolecular Mitsunobu reaction
from an amino acid derived common synthetic intermediate 3. The metal complexation study of these
macrocycles has been investigated by UV-visible spectroscopic technique with binding constant (Kb)
value 1.84 × 103 dm3 mol−1 using the Benesi–Hildebrand equation and a Gibbs free energy (ΔG)
−19.4 kJ mol−1 at 35 °C for 14d with Co2+. The binding properties of the metal were dependent on the
structure of polyaza-macrocycles that were confirmed by the DFT optimized structure of two macrocycles.
A detailed investigaton of UV-visible spectra of macrocycles and their complete interpretation with the
help of TD-DFT along with the frontier molecular orbital calculations are presented.
Design and synthesis of chiral macrocycles are important
Introduction
areas of research because of their diverse range of applications
such as enantiomeric recognition,11 asymmetric catalysis12 and
Substituted 1,2,3,4-tetrahydroquinoxaline core is very a impor-
complex formation with transition metal ions.13 The azamacro-
tant structural unit, exhibiting a wide range of biological activi-
ties such as prostaglandin D2 receptor1 and vasopressin V2
cycles 1,4,7-triazacyclononanes have drawn much attention,
receptor antagonists.2 A common method to synthesize tetrahy-
droquinoxalines involves the reduction of quinoxalines,3 giving
a mixture of diastereoisomers. Asymmetric hydrogenation of
quinoxalines in the presence of a chiral catalyst or ligand is also
important for the synthesis of optically active tetrahydro-quinox-
alines.4 An alternatative strategy involves the Pd catalyzed reac-
tion of 1,4-butenediols and acetates with 1,2-diaminobenzene
furnishing 2-vinyl-1,2,3,4- tetrahydroquinoxalines.5 However
one of the major drawbacks of this strategy is that it is only
applicable to symmetrically substituted 1,2-diaminobenzene.
Furthermore, other methods involved intermolecular Michael
additions,6 the reduction of nitroarenes and SN2 cyclization with
leaving groups,7,8 tandem reduction-reductive amination reac-
tions.9 Eary and co-workers have described the Cp*Ir-complex
mediated hydrogen transfer N-heterocyclization of anilino alco-
hols.10 High temperature and long reaction time are generally
required in these methods.
because of their ability to bind with transition metal ions.14 Due
to the ability to bind with high oxidation state metal ions, 1,4,7-
triazacyclononanes are used as redox metalloenzyme mimic,15
oxidative catalysts for organic transformations,16 hydrolytic
agents for the non-oxidative cleavage of DNA17 and RNA.18
Thus, an efficient synthetic route is highly desirable for acces-
sing these chiral 1,4,7-triazacyclononanes. Careful literature
search reveals that there are only few synthetic approaches for
chiral symmetrical and unsymmetrical 1,4,7-triazacyclono-
nanes19 and other peraza-macrocycles.20 Most of the reported
procedures used Richman–Atkins cyclization21 strategy to syn-
thesize chiral 1,4,7-macrocycles. The yield of the reaction is
not satisfactory and also high temperature is required. In some
cases, ring cyclization has failed.19a Similarly, 12-membered
1,4,7,10-tetraaza-macrocycles also have the ability to stabilize
high oxidation state metal ions22,23 The metal complexes of
these macrocycles are known to catalyze alkene epoxidation,
electrochemical epoxide carboxylation and intramolecular reduc-
tive cyclization.24
aMedicinal and Process Chemistry Division, CSIR-Central Drug
Research Institute, Lucknow, 226001 UP, India. Fax: 91-522-2623405;
Tel: 91-522-2612411-18, Ext. 4385, 4603
We have been working on the synthesis and biology of S-
amino acids-based chiral heterocycles and natural product-like
molecules.25 From our previous knowledge,25k the Mitsunobu
approach has been utilized for the construction of enatiomeri-
cally pure amino acids-derived tetrahydroquinoxaline deriva-
tives. Moreover, the Mitsunobu reaction offers the advantage of
bDepartment of Chemistry, Banaras Hindu University, Varanasi, 221
005 UP, India. E-mail: gautam.panda@gmail.com, gautam_panda@
cdri.res.in
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06304a
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Scheme 2 Synthesis of (S)-3-s-1-tosyl-1,2,3,4-tetrahydroquinoxalines
6a–g.
Scheme 1 Retro synthetic analysis of substituted-1,2,3,4-tetrahydro-
quinoxalines, benzo-annulated chiral [9]-N3 peraza- and [12]-N4 peraza-
macrocycles.
Synthesis of (S)-3-substituted-1-tosyl-1,2,3,4-tetrahydro-
quinoxalines
S-Amino acids and substituted benzene derivatives were used as
building blocks for the synthesis of substituted tetrahydroquinox-
alines, (Scheme 2). S-Amino acids 2a–g were reacted with
ortho-nitrofluorobenzene via a SNAr pathway in the presence of
K2CO3 and DMF at 90 °C to afford 2-nitrobenzene protected
amino acids. These amino acid derivatives were converted to
their methyl esters 3a–g in the presence of SOCl2 and MeOH.
In addition, it was interesting to know whether any racemization
of the amino acids occurred upon nucleophilic aromatic sub-
stitution. The chiral HPLC of 3b and 3f showed that the
nucleophilic aromatic substitution of amino acids on ortho-
nitrofluorobenzene occurred without any racemization (see
ESI).† We used reference compounds {mixture of S-3b and its
enantiomer R-3b} to prove the condition that was appropriate for
the separation of racemic compounds. The lithium aluminum
hydride reduction of 3a–g was interesting.
When 1 equiv of LAH was used at 0 °C in dry THF, the ester
was reduced to carbinol along with formation of anilino carbi-
nols in 5 min (10–15% yield). Use of 3 equiv of LAH from 0 °C
to room temperature in dry THF for half an hour furnished
desired anilino carbinols in 20–45% yield. Alternatively, anilino
carbinols could be synthesized from ester reduction of 3a–g fol-
lowed by hydrogenolysis (10% Pd/C) of the nitro group. It is
noted, a successful Mitsunobu reaction is dependent on the pKa
associated with the incoming nucleophile and is independent of
the nucleophilicity of the nucleophile.26 Thus, the amine func-
tionality of anilino carbinol was selectively converted to its tosyl
derivative by treatment with TsCl in pyridine at 0 °C for 12 h
(kept in refrigerator) in order to make its proton acidic for Mitsu-
nobu reaction. Interestingly, the tosylated product of the primary
carbinol was not detected although primary carbinol was very
reactive, indicating selectivity on aromatic amine functionality.
The intramolecular Mitsunobu27 cyclization between the acti-
vated sulfonamide and primary carbinol of 5a–g in the presence
of diethylazodicarboxylate (DEAD), triphenylphosphine (PPh3)
mild reaction conditions with a short reaction time giving rise to
products with excellent yields. Herein, we report the utility of
the Mitsunobu approach for the synthesis of tetrahydroquinoxa-
lines and its versatility for accessing new types of unsymmetrical
chiral benzo-annulated triaza- and tetraaza-macrocycles derived
from S-amino acids and the metal complexation study of these
macrocycles towards transition and alkaline-earth metal ions by
a UV-vis technique with binding constant Kb and Gibbs free
energy ΔG values.
Results and discussion
Retrosynthetic analysis and strategy
From a retrosynthetic point of view (Scheme 1), amino acids-
based chiral polycycles could be synthesized from a common
intermediate E. The substituted-1,2,3,4-tetrahydroquinoxalines
G could be obtained from N-Ts-anilino carbinol F through intra-
molecular Mitsunobu cyclization. The anilino carbinol F can be
obtained from LAH reduction of a common intermediate E fol-
lowed by tosylation. Benzo-annulated triaza-macrocycles I could
be prepared through an intramolecular Mitsunobu cyclization
from an intermediate H which could be easily prepared again
through an intermolecular Mitsunobu reaction between inter-
mediate D and N-Ts-amino ester followed by selective ester
reduction. Benzo-annulated tetraaza-macrocycles A can be easily
constructed from B through intramolecular Mitsunobu cycliza-
tion. B could be easily prepared through intermolecular Mitsu-
nobu cyclization of C with Boc-protected amino alcohol
followed by Boc-deprotection, tosylation and LAH reduction of
the ester group. The intermediate C can be synthesized easily
from D through intermolecular Mitsunobu cyclization with N-
Ts-amino esters. The common intermediate E could be easily
prepared from SNAr reaction between commercially available
ortho-nitrofluorobenzene and amino acids.
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at 0 °C furnished enatiomerically pure substituted 1,2,3,4-tetra-
hydroquinoxalines 6a–g (70–85%) along with 8–16% overall
yield. The tosyl group of the selected molecules 6a–b were
deprotected (Scheme 3) by using sodium naphthalenide 28 in dry
THF with 60–70% yield and the overall yield was 10–11%.
tosyl groups of the final molecules 13b–f were deprotected by
using sodium naphthalenide in dry THF with 60–70% yield and
the overall yield was 6–10% (Scheme 5).
Synthesis of benzo-annulated [12]-N4 peraza-macrocycles 20a–b
Synthesis of benzo-annulated chiral [9]-N3 peraza-macrocycles
Next, a synthesis of enantiomerically pure benzo-annulated [12]-
N4 peraza-macrocycle was undertaken (Scheme 6). The
advanced synthetic intermediate 11b–c and Boc-protected amino
carbinol 15 were used for the synthesis of tetraaza-macrocycles.
Boc-protected amino carbinol 15 was synthesized in three steps
from our previous reported procedure.25d Treatment of 11b–c
with 15 under the Mitsunobu conditions furnished ester deriva-
tives 16a–b in 60–70% yield. Next, 16a–b was treated with
TFA, instead of Boc-deprotection, salt formation took place.
After the neutralization of salt, the starting material was recov-
ered. We circumvented the problem using SOCl2 and MeOH to
deprotect29 the Boc-group, affording free amine hydrochlorides
17a–b which were again converted to their tosyl derivatives
18a–b by treatment with tosyl chloride and pyridine at 0 °C in
50–60% yield. The reduction of the ester group of 18a–b by
LAH gave carbinols 19a–b in 60–70% yield. The intramolecular
Mitsunobu cyclization between the sulfonamide and primary car-
binol in 19a–b furnished enantiomerically pure benzo-annulated
tetraaza-macrocycles 20a–b in 50–60% yield along with recov-
ery of 20–30% starting material. The tosyl groups of 20a were
deprotected by using sodium naphthalenide protocol with 66%
yield and the overall yield was 1.69% (Scheme 7).
After a successful synthesis of enantiomerically pure 3-substi-
tuted-1-(toluene-4-tosyl-1,2,3,4-tetrahydro quinoxalines via Mit-
sunobu cyclization, the advanced synthetic intermediate 7a–c
used in (Scheme 4), was utilized for the construction of benzo-
annulated chiral [9]-N3 peraza-macrocycles. Tosyl derivatives of
amino acids methyl ester 9a–d were synthesized25d following
two steps: amino acids were transformed to their methyl esters
by treatment with SOCl2 and MeOH, followed by treatment with
p-toluenesulfonyl chloride, triethyl amine in dry DCM. The
treatment of 9a–d with 7a–c under DEAD/PPh3 conditions furn-
ished 10a–f in 70–80% yield. The nitro groups in 10a–f were
converted into its amine by hydrogenolysis and the activated sul-
fonamides 11a–f were synthesized by treatment with TsCl in
pyridine at 0 °C to make its proton acidic for Mitsunobu reac-
tion. The reduction of the ester group in 11a–f by LAH gave car-
binol 12a–f in 60–68% yield. The intramolecular Mitsunobu
cyclization between the activated sulfonamide and primary carbi-
nol in 12a–f afforded enantiomerically pure benzo-annulated
chiral [9]-N3 peraza- macrocycles 13a–f in 70–80% yield. Both
Scheme 3 Deprotection of the tosyl group of 6a–b.
Scheme 5 Deprotection of both tosyl groups of 13b–f.
Scheme 4 Synthesis of benzo-annulated chiral [9]-N3 peraza-macro
cycles 13a–f.
Scheme 6 Synthesis of benzo-annulated [12]-N4 peraza-macrocycles
20a–b.
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Scheme 7 Deprotection of the tosyl groups of 20a.
Fig. 2 UV-Visible spectra of different compounds in acetonitrile
recorded at laboratory temperature (35 °C).
Table 1 Molar extinction coeffcient (ε) at the lowest energy band
maxima for various compounds at laboratory temperature.
Fig. 1 Metal complexation studies of these macrocycles.
Compound
(λmax nm)
ε (M−1 cm−1, at λmax
)
UV-Visible spectroscopic study
14a
14b
14c
14d
14e
296
293
275
296
295
3009
2414
2586
2269
1344
The objective of synthesizing these amino acids derived chiral
macrocycles is to study their complexation with metal ions. The
metal complexation studies have been reported by various spec-
troscopic techniques, such as ultraviolet visible (UV-Vis.),
NMR, fluorescence, and infrared (IR).30 UV-Vis spectroscopy is
the most popular tool for examination of binding phenomena.31
The UV-visible spectrum of some of these novel chiral macro-
cyle derivatives (Fig. 1) have been recorded in dry acetonitrile
and are presented in Fig. 2. Among triaza-macrocycles, except
the diphenyl substituted derivative 14c, all derivatives show a
broad band in the wavelength region of 275–325 nm having
wavelength maxima at 295 nm, which is assigned to π–π* tran-
sition in benzene moiety with a considerable overlap from amino
groups, along with a sharp band at 222 nm. The absorption peak
maxima and the corresponding molar extinction coefficients (ε)
are presented in Table 1. The highest ε value is observed for 14a
while the lowest is observed for 14e. Similar values are obtained
for 14b, 14c and 14d. No specific relationship could be observed
between the strength of transition and the subsituation in the
macrocycle. In case of 14c derivatives this sharp band is blue
shifted to below 210 nm. Since in this low wavelength region
(below 190 nm) acetonitrile also absorbs, it was not possible to
detect exactly its peak position. In addition, for 14c the broad
band is blue shifted and became structured. This hypsochromic
effect is due to the phenyl substitutions which changes the elec-
tronic properties as will be discussed in detail in the section
‘Quantum chemical calculations: DFT and TD-DFT’.
spectrum of tetraaza-macrocycle derivatives is red shifted (e.g.,
to 305 nm for 21, see ESI, S-162)† as compared to that of the
triaza-macrocycles discussed above, the high energy band in
these derivatives appears as a hump. It is probably due to the
inclusion of one amino group which increases the number of
electronic energy levels thereby making the electronic energy
levels closer. The molar extinction coefficient as tabulated in
Table 1 shows no definite trend with substitution. However, the
derivatives without any phenyl ring substitution have the lowest
molar extinction coefficients (14e and 14d). Due to poor solubi-
lity, metal complexation studies could not be performed for tetra-
aza-macrocycle derivatives.
Studies of complexation with metal salts
As reported elsewhere, on addition of a cation, the low energy
absorption band increases with increase in concentration of the
cation in solution.32 During our studies with the synthesized
novel macrocycles (Fig. 1), we have found that in some cases
there are some significant changes in absorbance at the peak
maximum, while in other cases, only a minor change in absor-
bance followed by a change in the position was observed (see
ESI, S-154 to S-161).† Fig. 3 shows a typical enhancement of
absorbance of the characteristic band when it binds with the
cation. It is interesting to note the appearance of isosbestic points
due to complexation, which is generally either not observed or
not given importance. The appearance of isosbestic points is far
more confirmative of the complex formation than enhancement
of absorbance since we found that few of the cations (e.g. Ni2+)
themselves absorb in the same wavelength range in which the
In fact, an in-depth investigation on the absorption spectra of
14c and 14d has been performed with the help of TD-DFT and
described in the same section. The solvent polarity sensitivity of
these derivatives has also been studied. No noticeable sensitivity
is observed (see Fig. S-167 and S-168 in the ESI).† We also
have not observed any change in the UV-visible spectrum for
any compound due to the change of concentration. Hence the
possibility of intermolecular complexation or dimerization can
be ruled out. While the low energy band in the UV-visible
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Fig. 3 Change of UV-visible spectra of 14d with gradual addition of
Ca2+ in acetonitrile. The concentration of 14d was 2.8 × 10−4 M while
the concentration of Ca2+ was varied from 2.8 × 10−5 M to 2.8 × 10−4
M. Isosbestic points are marked on the x-axis.
Fig. 4 Bensei-Hildebrand plot for 14d with Co2+, considering the 1 : 1
complexation. The goodness of the fit is shown by the R2 value. The
equation is also mentioned in the graph.
ligand absorbs. Fig. 3 also shows an appearance of a broad band
above 320 nm which increases gradually with the increase in
addition of metal salts. This broad band is due to a complex
which is evident from the fact that the metal salt has no absorp-
tion in these wavelength ranges (see ESI, Fig. S-153).† In
general, the appearance of an isosbestic point indicates that two
species involved in the complexation are related linearly by stoi-
chiometry, such that the absorbance is invariant for one particu-
lar wavelength. The complexation properties of these
macrocycles (Fig. 1) have been studied by an UV-visible spectro-
scopic technique with transition metal ions Co2+, Ni2+, Cu2+ and
Zn2+ and an alkaline earth metal ion Ca2+.
Fig. 3 shows representative spectra of the change of absorp-
tion spectra on addition of Ca2+ solution of various concen-
trations. It has been observed that a response to the addition of a
particular metal ion is different for the different triaza-macro-
cycles (ESI, Fig. S-154-161).† In some cases there are clear iso-
sbestic points with the in absorbance of the longest wavelength
band (e.g., 14e with Co2+, S-155) while for others the absence of
any isosbestic point with enhancement of absorbance are noticed
(e.g. 14e with Ni2+, S-160 ESI),† though no definite trend could
be established in the structure of the macromolecules. While a
slight increase in absorbance of the longest wavelength peak is
observed for 14d and 14e with gradual addition of Co2+ salt sol-
ution, the presence of sharp isosbestic points is clearly indicative
of complex formation. For both compounds slight blue shifts
were observed on complexation. On the other hand, for 14a and
14b, no substantial increase in absorbance at peak maxima is
observed. Insignificant change of absorbance may be due to the
similar values of molar absorptivity of the complexes with that
of host molecules alone. The different response of different com-
pounds to the Co2+ is due to the different structure of the host
molecules. Since the compound containing a phenyl group is
found to be less sensitive to the cations, it must be the structure
of the host molecule which inhibits proper interaction which is
discussed in detail in the section ‘Quantum chemial calculation’.
Among all the macrocycles studied, the complexation behavior
is clearly depicted by 14e with Co2+ which shows a considerable
increase in absorbance as well as these isosbestic points (at 274,
298 and 329 nm) (Fig. S-155).† Since there is no clear peak at
295 nm regions (due to overlapping of a low energy peak with
high energy) for 14c, the formation of a complex is evident from
the appearance of isosbestic points at 282 and 313 nm
(Fig. S-158).† Interestingly, isosbestic points different from that
appeared in other derivatives (appear approximately at 295 and
325 nm). This further indicates that the complexation for 14c is
clearly different than that of others and has been explained in the
following section taking into consideration the different
structure.
The Benesi–Hildebrand equation33 for a 1 : 1 complex was
employed for the cases where a significant change in absorbance
is observed. Fig. 4 represents a case where we could successfully
use the above mentioned equation. The binding constant value
as determined from the figure was found to be 1.84 × 103 dm3
mol−1 which corresponds to the Gibbs energy change (ΔG) of
−19.4 kJ mol−1 at 35 °C. This binding constant is found to be
less by an order of magnitude as compared to the tetraaza deriva-
tives reported in literature.32 The highest binding capability is
shown by 14b with Co2+ (9.6 × 103) while the lowest was
obtained for 14a with Ni2+ (1.7 × 103). The binding constants
for Ni2+ and Ca2+ with various derivatives are found to vary
between 1.8–6.2 × 103 and 1.7–8.0 × 103, respectively. An inter-
esting fact that came out particularly from these two cations with
various macromolecules is that symmetrically substituted deriva-
tives like 14d (dimethyl substituted) and 14c (dibenzyl substi-
tuted) have relatively higher binding constants as compared to
others. However, the difference of strength of binding for
various derivatives does not vary significantly, therefore no
definite conclusion is made. In general, the binding constants for
different metal–ligand complexes here vary between 1.7–9.6 ×
103 dm3 mol−1
.
Quantum chemical calculations: DFT and TD-DFT
In this section the ground state molecular, electronic structure
and optical spectra of two of the macrocycles (14c and 14d) are
computed in the solution phase (acetonitrile as bulk solvent)
using DFT and TD-DFT methods. These studies, as will be seen
from the following discussions, lead to an unambiguous
interpretation of their optical spectra and to rationalization of the
different complexation behaviour of 14c as compared to the
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Fig. 5 DFT optimized structures of 14d (left) and 14c (right) mol-
ecules. The optimizations were done using the polarizable continuum
model (PCM) with acetonitrile as the dielectric continuum. Blue spheres
indicate nitrogens while the gray stands for carbon atoms.
other macrocycles studied. The solution phase DFT (polarizable
continuum model, PCM using acetonitrile as dielectric conti-
nuum, see ESI, Fig. S-163 to S-166)† optimized structures of
14d and 14c are presented in Fig. 5. While 14d represents the
basic unit of the all the macromolecules studied for the com-
plexation and 14c is studied due to its different complexation be-
havior as discussed in the preceding section. It is found that the
replacement of a methyl group by phenyl has significantly stabil-
ized 14c over 14d, (as is evident from the total energy of the
system, −687219 vs. −397223 kcal mol−1) which is presumably
due to the electronegative nature of phenyl ring.
The main purpose of performing the TD-DFT calculation is to
analyse the UV-visible spectra of different compounds and more-
over to know the reason for the difference in the spectrum of 14c
with respect to 14d (which represents other derivatives as well).
An overall excellent agreement can be seen between the theoreti-
cal and experimental UV-visible spectral data which are shown
in Fig. 6 (a and b). The HOMO of 14c and 14d are strickingly
similar, in both cases this higest occupied molecular orbital is
situated mainly on the benzene ring along with the adjacent two
nitrogens in spite of the fact that 14c has two phenyl groups. The
main differences are noticed on LUMOs. While the LUMO of
14c is mainly on the two phenyl groups attached to two aza
nitrogens, the same for the 14d is mainly on the parent benzene
ring with minor contributions from adjacent methyl groups. The
groups of predicted transitions in 14c within the wavelength
region of 225 nm to 325 nm appear at 287, 277, and 248 nm
(indicated in Fig. 6(a), as 1, 2, and 3 respectively). These tran-
sitions match reasonably well with experimental values (284,
276 and 253 nm respectively). Similar good agreements, though
to a lesser extent have been observed for 14d as well. While
experimental band positions are observed at 296, 249 and
221 nm, the calculated corresponding band positions are 284,
244 and 234 nm. The longest wavelength band (284 nm) is
clearly the n–π* transition (HOMO to LUMO). The involvement
of a phenyl ring in LUMO is clearly seen in the Frontier Mol-
ecular Orbital pictures, emboided in the Fig. 6 (a and b). Hence,
it is clear that the difference in nature of the band and peak pos-
itions in 14c as compared to others is because of the presence of
phenyl rings in 14c.
Fig. 6 Experimental UV-visible spectra in acetonitrile along with the
TD-DFT calculated spectra of (a) 14c and (b) 14d. Frontier Molecular
Orbitals involved in predominant transitions are also shown in respectve
diagrams. Smooth lines correspond to experimental while vertical lines
correspond to calculated transitions with their respective oscillator
strength shown on the right axis. The difference in nature of the band
and peak positions in 14c as compared to others is because of the pres-
ence of phenyl rings in 14c.
derivatives were unhindered or exposed for the complexation.
On the other hand, one N–H of 14c was sandwiched between
two phenyl rings making it difficult to be accessible for the guest
molecules to bind. This initial structural difference might be the
reason for a different response of 14c to the cation. It is necess-
ary to mention here that the observed complexation differences
are explained here considering the initial structure of macromol-
ecule as the initial structure will guide the complexation.
Another approach of examining the final complex structures is
also possible. Since at present, convincing information (like
single crystal X-ray diffraction data) on the type of complex for-
mation is unavailable, intution based calculations on the final
To know the reason for the different types of complexation for
14c and others, we have optimized the structures of 14c and 14d
as already mentioned. Though the 14c molecule containing a
phenyl substituent was found to be more symmetrical as com-
pared to 14d, the binding sites (amino nitrogens) of 14d
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complex structure may not produce trustworthy or convincing
results.
that a concentration range of host : guest, starting from 1 : 0 to
1 : 2 was prepared. UV-Visible spectra of these solutions were
recorded at laboratory temperature (35 °C) keeping acetonitrile
as reference.
Conclusion
We have synthesized enantiomerically pure amino acids derived
substituted 1,2,3,4-tetrahydroquinoxalines, new types of benzo-
annulated unsymmetrical chiral [9]-N3 peraza- and [12]-N4
peraza-macrocycles employing an inter- and intramolecular Mit-
sunobu reaction. The binding phenomena of the macrocycles
with metal ion have been investigated by an UV-visible spectro-
scopic technique. The binding constant (Kb) value 1.84 ×
103dm3 mol−1 using the Benesi–Hildebrand equation and the
Gibbs free energy (ΔG) −19.4 kJ mol−1 at 35 °C were deter-
mined for 14d with Co2+. UV-Visible along with DFT study
reveal that the responses of polyazamacrocycles towards metal
ions greatly depend on molecular conformation and substitution.
The presence of clear isosbestic points and the increase (in some
cases) of absorbance of the longest wavelength peak maxima
confirm the formation of 1 : 1 complex with the metal ions.
Computational method
The Gaussian 03 program34 was used for the density functional
theory (DFT) calculation for two derivatives. The basis
set already implemented in the program was used for the differ-
ent types of calculations. The geometry of the molecule was
optimized with 6-31G++(d,p) basis set at the Becke’s three para-
meter hybrid method with LYP correlation (B3LYP) using the
PCM model (solvent : acetonitrile). In addition to optimization, a
frequency calculation was also performed at the B3LYP level of
calculation. The absence of imaginary vibrational frequencies in
the vibrational spectrum ensures the presence of a true
minimum. The TD-DFT method (time-dependent density func-
tional theory) is also used for calculating transitions. The elec-
tronic spectrum is calculated in the polarizable continuum model
(PCM) using acetonitrile as dielectric continuum. We have used
the same basis set and geometry as we used for optimization.
Experimental
General remarks
Experimental procedures and characterization data of the
selected examples
IR spectra were recorded on 55 a Perkin-Elmer FT-IR RXI spec-
1
trometer. H NMR and 13C NMR spectra were recorded on a
General experimental procedure for the synthesis of
(3a–g). To a stirred solution of S-amino acids 2 (1 equiv) in
30 mL of anhydrous DMF was added K2CO3 (1.5 equiv) at
25 °C followed by addition of ortho-nitrofluorobenzene
(1equiv). The mixture was stirred for 4 h at 90 °C, K2CO3 was
filtered off, and DMF was removed under vacuum. The residue
was diluted with 30 mL MeOH and followed by addition of
SOCl2 at 0 °C, and then the reaction mixture was stirred for
3–4 h. After completion of the reaction, the solvent was removed
under vacuum, the reaction mixture was diluted with water and
then was added excess NaHCO3 to neutralize the HCl and
aqueous layer was extracted with ethyl acetate (3 × 50 mL).
Removal of the solvent under vacuum and column chromato-
graphy of the crude product on silica gel with hexane-ethyl-
acetate (8.5 : 1.5) as eluent furnished 3.
Brucker DPX-200 or DPX- 300 spectrometer using CDCl3 as
solvent. Tetramethylsilane (0.00 ppm) served as an internal stan-
dard in 1H NMR and CDCl3 (77.0 ppm) in 13C NMR. Chemical
shifts are expressed in parts per million (ppm). Mass spectra
were recorded on JEOL SX 102 spectrometer. Elemental ana-
lyses were done on Varian EL-III CH N analyzer (Germany).
The enantiomeric excess was determined by Lichro CART Chir-
adex column (250 × 4 mm, 5 μm) using 10–100 acetonitrile,
water, gradient method, flow rate 1 mL min−1 as eluent at 20 °C.
The ee value was determined for the compounds 3b and 3f
(using CHIRAL 1C, hexane/propanol 95 : 5, flow rate 0.50 mL
min−1), for 6f (using CHIRAL 1C, hexane/propanol 95 : 5, flow
rate 0.80 mL min−1) and for 13b (using CHIRAL 1C, hexane/
propanol 50 : 50, flow rate 0.60 mL min−1) as eluent at 20 °C.
All complexation studies were performed at 35 °C ( 0.2 °C)
using the Peltier thermostat. UV-Visible spectra were recorded
by CARY 100 BIO UV-Visible spectrophotometer (in the range
of 200–800 nm) attached with the Peltier temperature controller,
which has photometric linearity till absorbance 3.5 and wave-
length resolution of 0.2 nm. A pair of Spectrosil quartz cuvette
with Teflon stopper was used for the measurements.
(2S)-2-(2-Nitrophenylamino) propionic acid methyl ester
(3a). Yellow oil; yield, 67% (based on two steps); Rf 0.51 (8.5/
1.5, hexane/EtOAc); IR νmax (neat, cm−1) 3456, 2926, 2858,
2370, 1744, 1620, 1267, 1163, 744; 1H NMR (300 MHz,
CDCl3) δ 8.32–8.30 (bs, 1H), 8.22 (dd, 1H, J1 = 1.9, J2 = 8.8),
7.48–7.42 (m, 1H), 6.76–6.70 (m, 2H), 4.37–4.28 (m, 1H), 3.79
(s, 3H), 1.63 (d, 3H, J = 6.7); 13C NMR (75 MHz, CDCl3) δ
173.0, 143.7, 136.1, 132.5, 126.9, 116.1, 113.6, 52.5, 51.1, 18.5;
MS (ESI): m/z 225 [M + H]+; Anal. calcd. (%) for C10H12N2O4:
C 53.57; H 5.39; N 12.49; Found: C 53.61; H 5.49; N 12.53.
Appropriate concentrations of chloride salts of different metal
ions in acetonitrile have been prepared as follows
Due to the limited solubility of chloride salts in acetonitrile,
initially salts were dissolved in a minimum amount of triple
water (less than 7% of the total solution volume). Then an appro-
priate amount of acetonitrile was added to the water solution to
prepare a salt solution of required concentration. This solution of
the host molecule was added in the guest solution in such a way
(2S)-3-Methyl-2-(2-nitrophenylamino)butyric acid methyl
ester (3f). Yellow oil; yield, 68% (based on two steps); Rf 0.52
(8.5/1.5, hexane/EtOAc); IR νmax (neat, cm−1) 3387, 2964,
2366, 1743, 1619, 1512, 1160, 745; 1H NMR (300 MHz,
CDCl3) δ 8.38 (d, 1H, J = 7.3), 8.20 (dd, 1H, J1 = 1.5, J2 = 8.6),
7.46–7.40 (m, 1H), 6.75–6.67 (m, 2H), 4.08–4.04 (m, 1H), 3.76
This journal is © The Royal Society of Chemistry 2012
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General experimental procedure for the synthesis of (6a–g).
To a stirred solution of 5 (1equiv), and triphenylphosphine (1.2
equiv) in anhydrous THF (10 mL) under N2 atmosphere, DEAD
(1.2 equiv in THF) was added dropwise at 0 °C. The reaction
mixture was stirred at the same temperature for additional 1 h.
The organic solvent was removed under vacuum and the column
chromatography (eluent = hexane-ethylacetate, 8.5 : 1.5) of crude
product over silica gel furnished 6.
(s, 3H), 2.38–2.26 (m, 1H), 1.12 (d, 3H, J = 6.8), 1.07 (d, 3H,
J = 6.8); 13C NMR (50 MHz, CDCl3) δ 172.6, 144.9, 136.7,
133.1, 127.4, 116.5, 114.1, 62.1, 52.6, 31.8, 19.5, 18.9; MS
(ESI): m/z 253 [M + H]+; Anal. calcd. (%) for C12H16N2O4: C,
57.13; H, 6.39; N, 11.10; Found: C, 57.23; H, 6.43; N, 11.15.
General experimental procedure for the synthesis of (4a–g).
Compound 3 (1 equiv) in anhydrous THF (15 mL) was added to
a suspension of LAH (1 M) soln (3 equiv) in THF (15 mL) at
RT. The reaction mixture was stirred at RT for 30 min. The reac-
tion was quenched by addition of ethyl acetate (30 mL) followed
by water (30 mL) at 0 °C. The aqueous layer was extracted with
ethyl acetate (3 × 50 mL) and the organic layer was dried over
anhydrous Na2SO4. After concentration under vacuum, the crude
product was chromatographed on silica gel with hexane-ethyl-
acetate (6 : 4) as eluent to furnish 4.
(3S)-3-Methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline
(6a).
Yellow solid; mp 162–164 °C; yield, 77%; overall yield, 16.3%;
Rf 0.52 (8.0/2.0, hexane/EtOAc); [α]3D0 −47.3 (c 0.11, MeOH),
HPLC analysis: ee > 99 (tR = 5.2 min, CH3CN/H2O); IR νmax
(KBr, cm−1) 3407, 2930, 2374, 1602, 1344, 1162, 573; 1H
NMR (300 MHz, CDCl3) δ 7.68 (dd, 1H, J1 = 1.3, J2 = 8.2),
7.49–7.46 (m, 2H), 7.22–7.19 (m, 2H), 7.01–6.96 (m, 1H),
6.73–6.67 (m, 1H), 6.47 (dd, 1H, J1 = 1.4, J2 = 8.0), 4.26–4.23
(m, 1H), 2.90–2.87 (m, 2H), 2.39 (s, 3H), 1.05 (d, 3H, J = 5.7);
13C NMR (75 MHz, CDCl3) δ 143.5, 137.8, 136.3, 129.5,
127.0, 126.2, 125.4, 121.2, 116.8, 114.4, 50.1, 43.2, 21.4, 19.1;
MS (ESI): m/z 302.9 [M + H]+; Anal. calcd. (%) for
C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26; Found: C, 63.61; H,
6.10; N, 9.30.
(2S)-2-(2-Aminophenylamino)propan-1-ol (4a). Brown oil;
yield, 41%; Rf 0.51 (6.5/3.5, hexane/EtOAc); IR νmax (neat,
1
cm−1) 3653, 3437, 2926, 1633, 1458, 746; H NMR (200 MHz,
CDCl3) δ 6.83–6.70 (m, 4H), 3.76–3.70 (m, 1H), 3.63–3.45 (m,
2H), 2.94–2.87 (m, 4H), 1.19 (d, 3H, J = 6.1); 13C NMR
(75 MHz, CDCl3) δ 136.2, 135.0, 120.6, 119.4, 117.0, 113.8,
65.9, 50.5, 17.4; MS (ESI): m/z 167 [M + H]+; Anal. calcd. (%)
for C9H14N2O: C, 65.03; H, 8.49; N, 16.85; Found: C, 65.11; H,
8.46; N, 16.91.
(3S)-3-Benzyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline
(6b).
Light yellow semi-solid; yield, 75%; overall yield, 15.9%; Rf
0.53 (8.0/2.0, hexane/EtOAc); [α]3D0 −93.3 (c 0.13, MeOH),
HPLC analysis: ee > 99 (tR = 12.4 min, CH3CN/H2O); IR νmax
(KBr, cm−1) 3399, 2926, 1601, 1497, 1349, 1163, 752; 1H
NMR (300 MHz, CDCl3) δ 7.69 (dd, 1H, J1 = 1.1, J2 = 8.2),
7.42–7.28 (m, 5H), 7.22–7.19 (m, 2H), 7.07–7.04 (m, 2H),
7.00–6.94 (m, 1H), 6.74–6.68 (m, 1H), 6.43 (dd, 1H, J1 = 1.3,
J2 = 8.1), 4.24 (dd, 1H, J1 = 2.4, J2 = 13. 9), 3.71 (bs, 1H), 3.06
(dd, 1H, J1 = 10.1, J2 = 13.9), 2.86–2.78 (m, 1H), 2.69 (dd, 1H,
J1 = 5.6, J2 = 13.4), 2.49 (dd, 1H, J1 = 8.4, J2 = 13.4), 2.41 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 143.6, 137.5, 136.4, 136.1,
129.6, 129.0, 128.7, 127.3, 126.9, 126.3 125.6, 121.9, 117.3,
114.6, 48.9, 48.3, 40.0, 21.5; MS (ESI): m/z 379 [M + H]+;
Anal. calcd. (%) for C22H22N2O2S: C, 69.81; H, 5.86; N, 7.40;
Found: C, 69.88; H, 5.92; N, 7.45.
(2S)-2-(2-Aminophenylamino)-3-phenylpropan-1-ol
(4b).
Brown oil; yield, 43%; Rf 0.48 (6.5/3.5, hexane/EtOAc); IR νmax
(neat, cm−1) 3652, 3446, 2929, 2372, 1600, 1514, 747; 1H
NMR (300 MHz, CDCl3) δ 7.37–7.23 (m, 5H), 6.89–6.73 (m,
4H), 3.78–3.68 (m, 2H), 3.56–3.50 (m, 1H), 3.16 (bs, 4H), 2.99
(dd, 1H, J1 = 5.6, J2 = 13.6), 2.87 (dd, 1H, J1 = 7.5, J2 = 13.6);
13C NMR (50 MHz, CDCl3) δ 138.3, 136.1, 135.2, 129.3,
128.5, 126.4, 120.7, 119.6, 117.2, 114.1, 62.9, 56.1, 37.6; MS
(ESI): m/z 243 [M + H]+; Anal. calcd. (%) for C15H18N2O: C,
74.35; H, 7.49; N, 11.56; Found: C, 74.33; H, 7.57; N, 11.62.
General experimental procedure for the synthesis of (5a–g).
Compound 4 (1 equiv) was dissolved in 5 mL anhydrous pyri-
dine, and then was cooled at 0 °C, followed by addition of
p-toluenesulfonylchloride (1.2 equiv). Then it was kept in a
refrigerator for 12 h. The pyridine was removed under vacuum
and diluted with 30 mL water. The aqueous layer was extracted
with ethyl acetate (3 × 50 mL) and dried over anhydrous sodium
sulfate. The solvent was removed under vacuum and the crude
product was then chromatographed over silica gel with eluent
MeOH-CHCl3 (0.3 : 9.7) to afford the title compound 5.
General experimental procedure for the synthesis of (7a–c).
Compound 3a–b, 3f (1 equiv) in anhydrous THF (15 mL) was
added to a suspension of LAH (1 M) soln (1 equiv) in THF
(15 mL) at 0 °C. The reaction mixture was stirred at RT for
5 min and was quenched by addition of ethyl acetate (30 mL)
followed by water (30 mL) at 0 °C. The same work-up procedure
was followed as described for 4 and the product was chromato-
graphed on silica gel with hexane-ethylacetate (7 : 3) as eluent to
furnish 7a–c.
(S)-N-[2-(2-Hydroxy-1-methylethylamino)phenyl]-4-methylben-
zenesulfonamide (5a). Brown oil; yield, 77%; Rf 0.51 (6.0/4.0,
hexane/EtOAc); IR νmax (neat, cm−1) 3652, 3417, 2927, 2366,
1602, 1326, 1159, 750; 1H NMR (300 MHz, CDCl3) δ 7.61
(d, 2H, J = 8.2), 7.24 (d, 2H, J = 8.1), 7.12–7.06 (m, 1H), 6.71
(d, 1H, J = 8.2), 6.43–6.41 (m, 2H), 6.38 (bs, 1H), 3.74 (dd, 1H,
J1 = 3.6, J2 = 11.1), 3.67–3.61 (m, 1H), 3.46 (dd, 1H, J1 = 3.5,
J2 = 11.0), 2.41 (s, 3H), 1.16 (d, 3H, J = 6.5); 13C NMR
(75 MHz, CDCl3) δ 144.7, 143.6, 135.9, 129.4, 128.8, 128.5,
127.4, 120.9, 116.4, 112.4, 65.3, 49.9, 21.4, 16.9; MS (ESI): m/z
321 [M + H]+; Anal. calcd. (%) for C16H20N2O3S: C, 59.98;
H, 6.29; N, 8.74; Found: C. 59.93; H, 6.32; N, 8.79.
(S)-2-(2-Nitro-phenylamino)-propan-1-ol (7a). This product
was isolated as yellow oil. yield, 64%, Rf 0.49 (7.olour, hexane/
EtOAc); IR νmax (neat, cm−1) 3366, 2924, 2366, 1616, 1507,
1
1227, 770; H NMR (300 MHz, CDCl3) δ 8.07 (dd, 1H, J1 =
1.2, J2 = 8.5), 7.99–7.97 (m, 1H), 7.34–7.29 (m, 1H), 6.84 (d,
1H, J = 8.7), 6.57–6.52 (m, 1H), 3.84–3.74 (m, 1H), 3.70–3.59
(m, 2H), 1.27 (d, 3H, J = 6.4); 13C NMR (50 MHz, CDCl3) δ
145.0, 135.9, 127.3, 115.4, 114.1, 66.2, 49.9, 17.6; MS (ESI):
1560 | Org. Biomol. Chem., 2012, 10, 1553–1564
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m/z 197 [M + H]+; Anal. calcd. (%) for C9H12N2O3: C, 55.09;
H, 6.16; N,14.28; Found: C, 55.14; H, 6.23; N, 14.34.
(s, 3H), 2.32 (s, 3H), 2.16–2.08 (m, 2H), 1.05 (d, 3H, J = 7.0),
0.98–0.90 (m, 9H); 13C NMR (50 MHz, CDCl3) δ 171.1, 145.0,
143.3, 137.0, 135.7, 129.5, 129.2, 127.1, 126.9, 114.9, 114.1,
66.3, 55.6, 51.6, 45.5, 29.1, 28.9, 21.4, 19.6, 19.3, 18.1, 17.1;
MS (ESI): m/z 492 [M
C24H33N3O6S: C, 58.64; H, 6.77; N, 8.55; Found: C, 58.68; H,
6.81; N, 8.59.
General experimental procedure for the synthesis of (8a–b).
Finely chopped sodium metal (10 equiv) and naphthalene (12
equiv) were dissolved in 10 mL dry THF. The reaction mixture
was stirred for 2 h, until dark green color appeared. The desired
THF solution of 6a–b was cooled to −78 °C and then Na-
napthalenide solution was added dropwise to the reaction
mixture via a syringe, until dark green color persisted. The reac-
tion mixture was stirred for 10 min at −78 °C and then was
quenched by adding 1–2 drops water to discharge the green
color. The reaction mixture was diluted with water and then
extracted with Et2O (3 × 50 mL) and the organic layer was dried
over anhydrous Na2SO4, concentrated under vacuum and the
column chromatography (eluent = hexane/ethylacetate, 7.5 : 2.5)
of crude product over silica gel furnished 8.
+
H]+; Anal. calcd. (%) for
General experimental procedure for the synthesis of (11a–f).
Compound 10 dissolved in MeOH and added Pd (10% on
carbon) in a bottle under nitrogen atmosphere. Then the nitrogen
was completely replaced by hydrogen in parr assembly. The
reaction was allowed to run for 1 h under pressure of 50 psi of
H2. After completion of the reaction (1 h, TLC monitoring), the
catalyst was removed by filtration through celite, the solvent was
removed under vacuum, the crude which was directly used for
next step. The procedure was followed as described in the syn-
thesis of 5a–g.
(S)-2-Methyl-1,2,3,4-tetrahydroquinoxaline (8a). Brown oil;
yield, 65%; overall yield, 10.6%; Rf 0.51 (8.0/2.0, hexane/
(S)-Methyl-2-(4-methyl-N-((S)-2-(2-(4-methylphenylsulfonamido)
phenylamino)-3-phenylpropyl)phenylsulfonamido) propanoate
(11a). Brown oil; yield, 63% (based on two steps); Rf 0.52 (7.5/
2.5, hexane/EtOAc); IR νmax (neat, cm−1) 3021, 2361, 1737,
EtOAc); [α]D30 −47.3 (c 0.14, MeOH); IR νmax (neat, cm−1
)
1
3441, 2362, 1640, 1217, 767; H NMR (200 MHz, CDCl3) δ
6.61–6.47 (m, 4H), 3.58–3.43 (m, 1H), 3.31 (dd, 1H, J1 = 2.9,
J2 = 10.7), 3.03 (dd, 1H, J1 = 8.1, J2 = 10.7), 1.18 (d, 3H, J =
6.3); 13C NMR (75 MHz, CDCl3) δ 133.4, 133.0, 118.6, 114.4,
114.3, 48.1, 45.6, 19.8; MS (ESI): m/z 149 [M + H]+; Anal.
calcd. (%) for C9H12N2: C, 72.94; H, 8.16; N, 18.90; Found: C,
72.91; H, 8.27; N, 18.96.
1
1215, 761; H NMR (300 MHz, CDCl3) δ 7.72–7.69 (m, 2H),
7.51–7.48 (m, 2H), 7.30–7.15 (m, 10H), 7.09–7.04 (m, 1H),
6.93 (d, 1H, J = 8.1), 6.59–6.53 (m, 2H), 4.65–4.62 (m, 2H),
4.13 (dd, 1H, J1 = 7.2, J2 = 14.2), 3.88–3.86 (m, 1H), 3.41 (s,
3H), 3.30 (dd, 1H, J1 = 4.3, J2 = 15.3), 3.10 (dd, 1H, J1 = 9.0,
J2 = 15.3), 2.73 (dd, 1H, J1 = 5.5, J2 =, 14.2), 2.41 (s, 3H), 2.38
(s, 3H), 1.29 (d, 3H, J = 7.2); 13C NMR (75 MHz, CDCl3) δ
172.3, 143.5, 143.4, 143.0, 137.9, 137.1, 136.2, 129.45, 129.39,
129.2, 129.1, 129.0, 128.5, 128.3, 128.0, 127.5, 127.3, 127.2,
126.4, 121.6, 117.0, 111.6, 55.6, 54.2, 52.3, 48.4, 39.2, 21.5,
21.4, 16.1; MS (ESI): m/z 636 [M + H]+, 658 [M + Na]+; Anal.
calcd. (%) for C33H37N3O6S2: C, 62.34; H, 5.87; N, 6.61;
Found: C, 62.37; H, 5.82; N, 6.65.
General experimental procedure for the synthesis of (10a–f).
To a stirred solution of 7a–c (1 equiv), 9a–d (1.1 equiv) and tri-
phenylphosphine (1.3 equiv) in anhydrous THF (15 mL) under
atmosphere of N2, DEAD (1.3 equiv) in THF was added drop-
wise at 0 °C. The same reaction condition and worked-up pro-
cedure followed as described in the synthesis of 6a–g. The
column chromatography (eluent = hexane-ethylacetate, 8.5 : 1.5)
of crude product over silica gel furnished 10a–f.
(S)-Methyl-2-(4-methyl-N-((S)-2-(2-nitrophenylamino)-3-phenyl-
propyl)phenylsulfonamido)propanoate (10a). Yellow oil; yield,
(S)-Methyl-3-methyl-2-(4-methyl-N-((S)-2-(2-(4-methyl phenyl-
sulfonamido)phenylamino)-3-phenylpropyl)phenyl-sulfonamido)
butanoate (11b). Brown oil; yield, 64%, (based on two steps); Rf
0.54 (7.5/2.5, hexane/EtOAc); IR νmax (neat, cm−1) 3023, 2361,
1742, 1602, 1216, 762; 1H NMR (300 MHz, CDCl3) δ
7.77–7.74 (m, 2H), 7.55–7.53 (m, 2H), 7.33–7.11 (m, 10H),
7.08–7.02 (m, 1H), 6.63–6.58 (m, 1H), 6.52 (bs, 1H), 6.43 (d,
1H, J = 7.8), 4.60–4.58 (m, 1H), 4.01–3.98 (m, 1H), 3.74–3.73
(m, 1H), 3.64 (dd, 1H, J1 = 3.7, J2 = 15.4), 3.36 (s, 3H), 3.12
(dd, 1H, J1 = 10.3, J2 = 15.5), 2.69 (dd, 1H, J1 = 4.2, J2 = 13.9),
2.43 (s, 3H), 2.37 (s, 3H), 2.05 (dd, 1H, J1 = 8.4, J2 = 13.9),
1.85–1.75 (m, 1H), 0.80 (d, 3H, J = 6.4), 0.78 (d, 3H, J = 6.5);
13C NMR (75 MHz, CDCl3) δ 171.7, 143.6, 143.4, 142.3,
137.8, 137.5, 136.4, 129.42, 129.38, 129.0, 128.6. 128.2, 127.6,
127.4, 126.6, 121.4, 116.8, 110.8, 65.9, 53.6, 51.6, 48.0, 39.2,
28.8, 21.6, 21.5, 19.7, 19.4; MS (ESI): m/z 664 [M + H]+, 686
[M + Na]+; Anal. calcd. (%) for C35H41N3O6S2: C, 63.32; H,
6.23; N, 6.33; Found: C, 63.36; H, 6.28; N, 6.43.
75%; Rf 0.54 (8.5/1.5, hexane/EtOAc); IR νmax (neat, cm−1
)
3022, 2361, 1741, 1509, 1216, 760; 1H NMR (300 MHz,
CDCl3) δ 8.12–8.08 (m, 2H), 7.65–7.62 (m, 2H), 7.45–7.38 (m,
1H), 7.30–7.20 (m, 7H), 7.06 (d, 1H, J = 8.6), 6.65–6.59 (m,
1H), 4.73–4.65 (m, 1H), 4.37–4.30 (m, 1H), 3.58–3.50 (m, 1H),
3.43 (s, 3H), 3.29–3.20 (m, 2H), 2.68 (dd, 1H, J1 = 8.9, J2 =
13.8), 2.40 (s, 3H), 1.42 (d, 3H, J = 7.2); 13C NMR (75 MHz,
CDCl3) δ 171.5, 144.8, 143.9, 137.4, 136.2, 135.8, 132.2, 129.7,
129.5, 129.1, 128.7, 128.6, 127.4, 127.2, 126.9, 126.7, 115.6,
114.3, 56.1, 54.3, 52.2, 49.0, 39.4, 21.5, 16.7; MS (ESI): m/z
512 [M + H]+, 534 [M + Na]+; Anal. calcd. (%) for
C26H29N3O6S: C, 61.04; H, 5.71; N, 8.21; Found: C, 61.12; H,
5.74; N, 8.28.
(S)-Methyl-3-methyl-2-(4-methyl-N-((S)-3-methyl-2-(2-nitro
phenylamino)butyl)-phenylsulfonamido)butanoate(10f). Yellow
oil; yield, 75%; Rf 0.50 (8.0/2.0, hexane/EtOAc); IR νmax (neat,
cm−1) 3343, 3021, 2361, 1739, 1509, 1216, 761; 1H NMR
(300 MHz, CDCl3) δ 8.16–8.10 (m, 2H), 7.64–7.61 (m, 2H),
7.36–7.27 (m, 2H), 7.14–7.11 (m, 2H), 6.62–6.56 (m, 1H),
4.09–4.06 (m, 2H), 3.76–3.62 (m, 1H), 3.57–3.50 (m, 1H), 3.52
General experimental procedure for the synthesis of (12a–f)
The procedure was followed as described for 4a–g.
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N-((S)-1-Hydroxy-3-methylbutan-2-yl)-4-methyl-N-((S)-2-(2-(4-
methylphenylsulfonamido)phenylamino)-3-phenyl propyl) ben-
zenesulfonamide (12b). Brown oil; yield, 64%; Rf 0.52 (7.0/3.0,
hexane/EtOAc); IR νmax (neat, cm−1) 3681, 3021, 2359, 1603,
2.68–2.64 (m, 1H), 1.76–1.69 (m, 1H), 1.53–1.45 (m, 2H),
0.95–0.93 (m, 6H); MS (ESI): m/z 324 [M + H]+; Anal. calcd.
(%) for C21H29N3: C, 77.97; H, 9.04; N, 12.99; Found: C,
77.91; H, 9.11; N, 12.95.
1
1216, 761; H NMR (300 MHz, CDCl3) δ 7.67–7.64 (m, 2H),
General experimental procedure for the synthesis of (16a–b).
To a stirred solution of 11b–c (1 equiv), Boc-protected amino
alcohol 15 (1.2 equiv) and triphenylphosphine (1.5 equiv) in
anhydrous THF (15 mL) under atmosphere of N2, DEAD (1.5
equiv) in THF) was added dropwise at 0 °C. The same reaction
condition and worked-up procedure followed as described in the
synthesis of 6a–g. The column chromatography (eluent =
hexane-ethylacetate, 8.5 : 1.5) of crude product over silica gel
furnished 16a–b.
7.51–7.48 (m, 2H), 7.34–7.26 (m, 6H), 7.19–7.17 (m, 2H),
7.02–6.99 (m, 3H), 6.62–6.60 (m, 1H), 6.52–6.44 (m, 2H),
4.10–4.04 (m, 1H), 3.85–3.82 (m, 1H), 3.70–3.56 (m, 2H), 3.49
(dd, 1H, J1 = 2.7, J2 = 15.0), 2.95 (dd, 1H, J1 = 10.8, J2 = 14.9),
2.89–2.83 (m, 1H), 2.42 (s, 3H), 2.38–2.30 (m, 4H), 1.80–1.73
(m, 1H), 0.92 (d, 3H, J = 6.5), 0.69 (d, 3H, J = 6.5); 13C NMR
(75 MHz, CDCl3) δ 143.8, 143.3, 142.9, 139.2, 138.2, 137.7,
136.5, 129.7, 129.6, 129.3, 129.1, 128.6, 128.4, 127.65, 127.57,
127.1, 126.6, 126.4, 122.4, 117.9, 112.9, 67.0, 62.3, 53.2, 47.4,
39.1, 27.6, 21.6, 21.4, 20.7, 20.2; MS (ESI): m/z 636 [M + H]+,
658 [M + Na]+.; Anal. calcd. (%) for C34H41N3O5S2: C, 64.22;
H, 6.50; N, 6.61; Found: C, 64.28; H, 6.54; N, 6.71.
(S)-Methyl-2-(N-((S)-2-(2-(N-((S)-2-(tert-butoxycarbonyl amino)-
3-phenylpropyl)-4-methylphenylsulfonamido) phenyl amino)-3-
phenylpropyl)-4-methylphenylsulfonamido)-3-methylbutanoate
(16a). Colorless oil; 65%; Rf 0.54, (7.5/2.5, hexane/EtOAc); IR
νmax (neat, cm−1) 3403, 3022, 2977, 1737, 1703, 1513, 1342,
1216, 765; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 1H, J = 8.1),
7.67 (d, 1H, J = 8.1), 7.54–7.49 (m, 2H), 7.32–7.16 (m, 14H),
6.94 (d, 1H, J = 8.1), 6.81 (bs, 1H), 6.47–6.40 (m, 2H), 5.18
(bs, 1H), 4.67–4.64 (m, 1H), 4.48 (bs, 1H), 4.37–4.30 (m, 1H),
4.19–4.06 (m, 2H), 3.96–3.87 (m, 1H), 3.74–3.67 (m, 1H),
3.57–3.51 (m, 2H), 3.45 (s, 3H), 3.32–3.26 (m, 1H), 3.21 (bs,
1H), 2.95–2.90 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.64–1.55
(m, 1H), 1.34 (s, 9H), 0.98 (d, 3H, J = 5.8), 0.93 (d, 3H, J =
6.6); 13C NMR (75 MHz, CDCl3) δ 171.0, 170.6, 145.8, 143.7,
143.6, 143.4, 138.0, 135.8, 129.5, 129.45, 129.36, 129.3, 128.5,
128.3, 128.2, 128.0, 127.8, 126.3, 126.1, 116.3, 111.9, 66.4,
53.1, 52.5, 51.5, 51.2, 48.8, 39.1, 28.4, 21.5, 20.3, 19.5, 19.4;
MS(ESI): m/z 797 [M − Boc]+, 897 [M + H]+, 919 [M + Na]+;
Anal. calcd. (%) for C49H60N4O8S2: C, 65.60; H, 6.74; N, 6.24;
Found: C, 65.68; H, 6.73; N, 6.35.
General experimental procedure for the synthesis of (13a–f)
The procedure was followed as described for 6a–g.
(3S,6S)-6-Benzyl-3-methyl-1,4-ditosyl-2,3,4,5,6,7-hexahydro-1H-
benzo[b] [1,4,7]triazonine (13a). Colorless semi-solid; yield,
66%, (based on two steps); overall yield, 13.8%; Rf 0.51 (8.0/
2.0, hexane/EtOAc); [α]3D0 +105.2 (c 0.11, MeOH), HPLC analy-
sis: ee > 99 (tR = 14.5 min, CH3CN/H2O); IR νmax (KBr, cm−1
)
3024, 2926, 2363, 1218, 1160, 762; 1H NMR (300 MHz,
CDCl3) δ 8.13 (bs, 1H), 7.72–7.67 (m, 3H), 7.57–7.54 (m, 2H),
7.30–7.17 (m, 8H), 7.06–7.04 (m, 2H), 6.86–6.84 (m, 2H),
4.17–4.12 (m, 1H), 3.62–3.58 (m, 1H), 2.99–2.84 (m, 2H), 2.78
(dd, 1H, J1 = 3.5, J2 = 11.9), 2.46 (s, 3H), 2.36–2.33 (m, 1H),
2.30 (s, 3H), 2.18 (dd, 1H, J1 = 1.1, J2 = 11.8), 1.85–1.77 (m,
1H), 1.25 (d, 3H, J = 6.7); 13C NMR (75 MHz, CDCl3) δ 144.2,
143.4, 138.2, 137.3, 136.6, 136.5, 134.8, 129.7, 129.6, 128.6,
128.5, 127.2, 127.0, 126.9, 126.7, 124.3, 123.2, 117.8, 60.7,
59.5, 48.7, 44.7, 36.8, 21.5, 21.4, 14.7; MS (ESI): m/z 590 [M +
H]+; Anal. calcd. (%) for C32H35N3O4S2: C, 65.17; H, 5.98; N,
7.12; Found: C, 65.21; H, 6.02; N, 7.21.
General experimental procedure for the synthesis of (18a–b).
Compound 16 (1 equiv) was dissolved in 20 mL MeOH and fol-
lowed by addition of SOCl2 (3 equiv) at RT for 5 min. Removal
of the solvent under vacuum and the crude were directly used for
next step. The procedure was followed as described in the syn-
thesis of 5a–g.
General experimental procedure for the synthesis of (14a–e)
The procedure was followed as described for 8a–b.
(S)-Methyl-3-methyl-2-(4-methyl-N-((S)-2-(2-(4-methyl-N-((S)-
2-(4-methylphenylsulfonamido)-3-phenylpropyl)phenyl sulfona-
(2S,5S)-2-Benzyl-5-isopropyl-2,3,4,5,6,7-hexahydro-1H-benzo[b]
[1,4,7] triazonine (14a). Brown oil; yield 68%; overall yield,
mido)phenylamino)-3-phenylpropyl)phenylsulfona
mido)
10.1%; Rf 0.51 (0.8/9.2, MeOH/CHCl3); IR νmax (neat, cm−1
)
butanoate (18a). Brown oil; yield, 55%, (based on two steps); Rf
1
3022, 2369, 1432, 1217, 767; H NMR (300 MHz, CDCl3) δ
7.23–7.13 (m, 3H), 7.08–6.95 (m, 4H), 6.82–6.77 (m, 2H),
3.42–3.37 (m, 1H), 3.21–3.15 (m, 1H), 3.05–2.85 (m, 4H),
2.68–2.55 (m, 2H), 1.94–1.89 (m, 1H), 1.04 (d, 3H, J = 6.7),
1.00 (d, 3H, J = 6.7); MS (ESI): m/z 310 [M + H]+; Anal. calcd.
(%) for C20H27N3: C, 77.63; H, 8.79; N, 13.58; Found: C,
77.68; H, 8.72; N, 13.54.
0.52 (7.0/3.0, hexane/EtOAc); IR νmax (neat, cm−1) 3390, 3024,
1
1738, 1343, 1217, 1160, 758; H NMR (300 MHz, CDCl3): δ
7.73 (d, 1H, J = 8.1), 7.67 (d, 1H, J = 8.1), 7.56–7.47 (m, 3H),
7.39 (d, 1H, J = 8.2), 7.32–7.04 (m, 15H), 6.92 (d, 1H, J = 8.2),
6.84–6.80 (m, 1H), 6.57–6.47 (m, 3H), 6.37–6.21 (m, 1H),
5.15–5.10 (m, 1H), 4.33–4.25 (m, 1H), 4.24–4.22 (m, 1H),
4.19–4.10 (m, 1H), 4.02–3.89 (m, 1H), 3.60 (dd, 1H, J1 = 7.8,
J2 = 13.2), 3.54–3.52 (m, 1H), 3.41 (s, 3H), 3.30 (dd, 1H, J1 =
3.2, J2 = 13.4), 3.22 (bs, 1H), 3.16–3.12 (m, 1H), 2.88–2.83 (m,
1H), 2.75–2.69 (m, 1H), 2.63–2.56 (m, 1H), 2.44 (s, 3H), 2.38
(s, 3H), 2.33 (s, 3H), 1.66–1.51 (m, 1H), 0.91–0.88 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 170.9, 146.0, 143.9, 143.3,
142.9, 138.4, 136.7, 136.4, 136.1, 135.9, 134.1, 129.4, 129.34,
(2S,5S)-2-Benzyl-5-isobutyl-2,3,4,5,6,7-hexahydro-1H-benzo[b]
[1,4,7]triazonine (14b). Brown oil; yield 65%; overall yield,
16.6%; Rf 0.58 (0.8/9.2, MeOH/CHCl3); IR νmax (neat, cm−1
3372, 2925, 2361, 1592, 771; H NMR (300 MHz, CDCl3) δ
7.22–7.13 (m, 4H), 7.06–6.98 (m, 3H), 6.81–6.77 (m, 2H),
3.79–3.67 (m, 1H), 3.44–3.41 (m, 1H), 3.08–2.84 (m, 5H),
)
1
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129.27, 129.0, 128.5, 128.4, 128.3, 128.2, 127.8, 127.1, 126.22,
126.16, 125.5, 116.3, 112.2, 66.1, 54.2, 53.3, 52.9, 51.4, 48.3,
38.9, 38.1, 29.0, 21.5, 21.4, 21.3, 20.1, 19.3; MS (ESI): m/z 951
[M + H]+, 973 [M + Na]+; Anal. calcd. (%) for C51H58N4O8S3:
C 64.40; H, 6.15; N, 5.89; Found: C, 64.48; H, 6.21; N, 5.91
Brown oil; yield, 66%; overall yield, 1.7%; Rf 0.51 (1.5/8.5,
MeOH/CHCl3); IR νmax (neat, cm−1) 3430, 3023, 2953, 1610,
1218, 765; H NMR (300 MHz, CDCl3) δ 7.35–7.00 (m, 14H),
3.41–3.28 (m, 3H), 2.98–2.89 (m, 5H), 2.66–2.59 (m, 5H),
1.76–1.61 (m, 1H), 1.05 (d, 3H, J = 6.4), 0.99 (d, 3H, J = 6.4);
13C NMR (75 MHz, CDCl3) δ 137.3, 136.3, 129.6, 129.25,
129.16, 128.6, 128.2, 126.8, 117.1, 54.1, 39.0, 29.6, 19.4, 19.1;
MS (ESI): m/z 443 [M + H]+; Anal. calcd. (%) for C29H38N4: C,
78.69; H, 8.65; N, 12.66; Found: C, 78.76; H, 8.61; N, 12.72.
1
General experimental procedure for the synthesis of (19a–b)
The procedure was followed as described for 4a–g.
N-((S)-1-Hydroxy-3-methylbutan-2-yl)-4-methyl-N-((S)-2-(2-(4-
methyl-N-((S)-2-(4-methylphenyl-sulfonamido)-3-phenyl propyl)
phenylsulfonamido)phenylamino)-3-phenylpropyl) benzenesulfo-
namide (19a). Brown oil; yield, 63%; Rf 0.45 (7.0/3.0, hexane/
EtOAc); IR νmax (neat, cm−1) 3657, 3424, 3022, 2361, 1642,
1216, 762; 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H, J = 8.1),
7.63–7.57 (m, 1H), 7.51–7.49 (m, 2H), 7.32–7.05 (m, 18H),
6.93 (d, 1H, J = 6.3), 6.75–6.64 (m, 2H), 6.59–6.54 (m, 1H),
6.31–6.20 (m, 1H), 5.12–5.10 (m, 1H), 4.22–4.12 (m, 1H), 3.94
(bs, 1H), 3.77–3.70 (m, 1H), 3.62 (bs, 1H), 3.56–3.48 (m, 1H),
3.37–3.27 (m, 1H), 3.22–3.15 (m, 1H), 3.06–2.96 (m, 2H),
2.89–2.80 (m, 1H), 2.75–2.66 (m, 1H), 2.47–2.42 (m, 1H), 2.37
(s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 1.67–1.51 (m, 1H), 0.93–0.89
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 146.4, 143.2, 142.7,
138.5, 137.0, 136.3, 135.7, 133.4, 129.6, 129.5, 129.4, 129.3,
129.1, 128.9, 128.6, 128.5, 128.4, 128.3, 127.8, 127.4, 127.3,
126.8, 126.5, 126.3, 125.8, 116.3, 112.3, 63.1, 54.9, 52.6, 52.4,
38.9, 38.4, 30.9, 21.6, 21.4, 21.3, 20.9, 20.1; MS (ESI): m/z 923
[M + H]+; Anal. calcd. (%) for C50H58N4O7S3: C, 65.05; H,
6.33; N, 6.07; Found: C 65.13; H 6.39; N 6.18.
Acknowledgements
This research project was supported by the Department of
Science and Technology, New Delhi, India. K.S. thanks CSIR
for providing fellowship grant (NET-SRF). S.S. acknowledges
funding received under the Fast Track scheme (SR/FTP/CS-70/
2006). Instrumental facilities from SAIF, CDRI are acknowl-
edged. This is CDRI communication number 7884.
References
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General experimental procedure for the synthesis of (20a–b)
The procedure was followed as described for 6a–g.
(3S,6S,9S)-3,9-Dibenzyl-6-isopropyl-1,4,7-tritosyl-1,2,3,4,5,6,7,
8,9,10-decahydrobenzo[b][1,4,7,10] tetraaza-cyclododecine (20a).
Light brown, semi-solid; yield, 56%; Rf 0.51 (8.0/2.0, hexane/
EtOAc); [α]3D0 −201.9 (c 0.11, MeOH), HPLC analysis: ee > 99
(tR = 17.1 min, CH3CN/H2O); IR νmax (KBr, cm−1) 3021, 2360,
1
1595, 1216, 761; H NMR (300 MHz, CDCl3) δ 7.53–7.50 (m,
2H), 7.46–7.37 (m, 4H), 7.34–7.17 (m, 11H), 7.10–7.00 (m,
4H), 6.97–6.94 (m, 2H), 6.86–6.84 (m, 2H), 6.58 (d, 1H, J =
7.2), 5.11–5.09 (m, 1H), 4.17–4.10 (m, 1H), 3.84–3.73 (m, 2H),
3.63–3.47 (m, 3H), 3.42–3.34 (m, 1H), 3.11 (dd, 1H, J1 = 4.8,
J2 = 14.2), 2.97 (dd, 1H, J1 = 10.7, J2 = 14.4), 2.74–2.62 (m,
2H), 2.46 (s, 6H), 2.41–2.35 (m, 1H), 2.26 (s, 3H), 2.18–2.14
(m, 1H), 1.64–1.54 (m, 1H), 0.99 (d, 3H, J = 6.6), 0.89 (d, 3H, J
= 7.0); 13C NMR (75 MHz, CDCl3) δ 150.3, 144.1, 143.5,
142.7, 138.7, 138.1, 137.6, 136.5, 135.8, 134.9, 129.6, 129.5,
129.4, 129.0, 128.9, 128.7, 128.5, 128.4, 127.1, 127.0, 126.9,
126.6, 126.1, 125.4, 60.4, 60.3, 60.2, 55.4, 55.3, 52.0, 38.1,
36.6, 29.6, 21.5, 21.4, 21.3, 21.2, 21.1; MS (ESI): m/z 905 [M +
H]+; Anal. calcd. (%) for C50H56N4O6S3: C, 66.34; H, 6.24; N,
6.19; Found: C, 66.58; H, 6.19; N, 6.25.
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General experimental procedure for the synthesis of (2S,5S,8S)-
2,8-Dibenzyl-5-isopropyl-1,2,3,4,5,6,7,8,9,10-decahydrobenzo[b]
[1,4,7,10]tetraazacyclodod-ecine (21)
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The procedure was followed as described for 8a–b.
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