A facile synthesis of new chiral [1 + 1] macrocyclic schiff bases

Article abstract of DOI:10.1246/cl.2007.1332

A series of new chiral [1 + 1] macrocyclic Schiff bases have been synthesized in high yields and short reaction times from cyclocondensation of dialdehydes with long tethers and chiral diamines. The yields of the macrocycles were higher when the dialdehyd

Full text of DOI:10.1246/cl.2007.1332

1332
Chemistry Letters Vol.36, No.11 (2007)
A Facile Synthesis of New Chiral ½1 þ 1ꢀ Macrocyclic Schiff Bases
Paulsamy Suresh, Sankareswaran Srimurugan, and Hari N. Patiꢀ
Department of Process Chemistry, Advinus Therapeutics, Phase-II, Peenya Industrial Area, Bangalore-560058, India
(Received July 12, 2007; CL-070739; E-mail: hari.pati@advinus.com)
CHO
A series of new chiral ½1 þ 1ꢁ macrocyclic Schiff bases have
been synthesized in high yields and short reaction times from
cyclocondensation of dialdehydes with long tethers and chiral
diamines. The yields of the macrocycles were higher when
the dialdehyde component is also chiral. The macrocyclisation
was performed under microwave irradiation and aqueous
reaction conditions employing salts of chiral diamines in con-
trast to free diamines normally employed.
n-BuLi,THF -78 °C, 1 h
DMF, -40 °C, 3 h, 65%
NaH, MOMCl
DMF, 1 h, 92%
OH
OH
OMOM
OMOM
OMOM
OMOM
1
CHO OHC
CHO
DMAP (cat.),
CH2Cl2, 3 h
5% HCl/MeOH,
5 h, 82%
HO
OH
OH
OH
HOOC
COOH + EDCL
+
n
O
O
n
O
O
n = 2, 3, 4
2
3; n = 2; 73 %
4; n = 3; 96 %
5; n = 4; 94 %
The design and study of new macrocyclic species is one of
the most interesting areas in the field of supramolecular
chemistry.1 In particular, chiral macrocyclic compounds have
been studied extensively for their applications in molecular rec-
ognition, host–guest chemistry, supramolecular structures, mate-
rial chemistry, and catalysis. A variety of chiral macrocycles
with different central cavity sizes and tunable functionalities
were synthesized and explored in this regard.2 Chiral macrocy-
clic Schiff bases derived from condensation of diamines and di-
aldehydes allows for easy tuning of the central cavities and they
can be further functionalised.3 These macrocyclic structures are
generally formed under thermodynamic control depending on
the type of dialdehydes employed and hence this method can
be applied for the synthesis of macrocycles with desired central
cavities. Though there are many examples that describe the syn-
Scheme 1.
R
R
CHO OHC
N
N
-X+H3N NH3+X-
K2CO3, EtOH-H2O,
MW, 5 min
HO
O
OH
O
HO
O
+
OH
O
R
R
n
n
O
O
O
O
R = -(CH2)4-, -CH2OBn,
-CH2N(Bn)CH2-
n = 2, 3, 4
(3-5)
n = 2, 3, 4
R = -(CH2)4-, -CH2OBn, -CH2N(Bn)CH2-
(6-8)
Scheme 2.
adipic acid in place of succinic acid.
Microwave irradiation (5 min)10 of a mixture of bisbinaphth-
yl aldehyde 3–5 and chiral diamine 6–8 in presence of potassium
carbonate afforded chiral ½1 þ 1ꢁ macrocyclic imines in good
yields. The cyclocondensation does not require any anhydrous
or dilute reaction conditions for the macrocycle synthesis.
Moreover, salts of chiral diamines were employed instead of
widely employed enantiopure diamines (Scheme 2).
4,5
thesis of ½2 þ 2ꢁ and ½3 þ 3ꢁ chiral macrocyclic Schiff bases,
there are only few papers involving ½1 þ 1ꢁ macrocycles. Li
and co-workers6 reported the synthesis of binol-based ½1 þ 1ꢁ
macrocyclic Schiff bases and explored their possible application
towards enantioselective fluorescence recognition. Martinez and
co-workers7 reported a series of chiral ½1 þ 1ꢁ macrocycles de-
rived from achiral dialdehyde moieties and chiral diamines.
However, the reported methods involve either a longer reaction
time or moderate yields of macrocycle.
The ½1 þ 1ꢁ macrocycle was formed exclusively in higher
yield which was free from linear oligomers or higher macrocy-
cles during the cyclocondensation of 3 with (1R,2R)-cyclohex-
anediammonium mono-(+)-tartrate (6) (Table 1, Entry 1). The
tether length was found to exhibit little effect on the yield
and the nature of macrocyclization. Accordingly, 4 and 5 gave
½1 þ 1ꢁ macrocycle in 94–96% with 6 (Table 1, Entries 4 and
6). Chiral diamines with different dihedral angles namely
(3R,4R)-diamino-1-benzylpyrrolidine dihydrochloride (7) and
(2R,3R)-1,4-bis(benzyloxy)butane-2,3-diamine dihydrochloride
(8) displayed reactivity similar during the condensation with 6
forming ½1 þ 1ꢁ macrocycle in 78–91% yields (Table 1, Entries
2, 3, 5, 7, and 8). In all the cases MALDI-TOF mass spectra re-
vealed a single peak corresponding to the molecular ion of the
macrocycle. Similarly, all the macrocyclic imines displayed
the predicted spectroscopic features, most importantly one set
of NMR signals indicating a highly symmetric structure. The
1H NMR of the ½1 þ 1ꢁ macrocycles derived from 5 and chiral
diamines 6 and 8 displayed interesting features.
As an extension of our earlier works on the synthesis of
chiral macrocyclic Schiff bases with moderate (½2 þ 2ꢁ and
½3 þ 3ꢁ)8 and large (½6 þ 6ꢁ)9 cavity sizes, macrocycles with
small cavities (½1 þ 1ꢁ) were explored. Both the chiral and
achiral dialdehydes were employed for this purpose.
The conformational bias offered by the dialdehydes forms a
key factor in deciding the major macrocycle formed during con-
densation with chiral diamines. On this basis, dialdehydes con-
taining a long tether between the aldehyde moieties can facilitate
½1 þ 1ꢁ macrocyclisation with chiral diamines. As an initial ef-
fort, bisbinaphthyl aldehyde tethered using a diester group was
used for the reaction. The bisbinaphthyl aldehyde 3 was synthe-
sized from the corresponding optically pure (S)-[1,10-binaphth-
yl]-2,20-diol (BINOL) according to the Scheme 1. Condensation
of 2 with succinic acid using EDC as a coupling agent afforded
bisbinaphthyl aldehyde 3 in 73% yield. In order to study the ef-
fect of the tether length of dialdehyde on macrocyclisation, 4 and
5 were synthesized in an analogous manner using glutaric and
The influence of chirality at the aldehyde moiety on macro-
cyclisation was studied by synthesizing achiral dialdehydes pos-
sessing similar long diester tethers. Accordingly, dialdehydes
10–12 were synthesized by condensing 3-tert-butyl-2,5-dihy-
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.11 (2007)
1333
Table 1. ½1 þ 1ꢁ Cyclocondensation of chiral bisbinaphthyl and achiral
OH
aldehydes with chiral diamine salts
DMAP (cat.),
CH2Cl2, 3 h
OHC
O
C
O
C
H2
C
DCC
COOH
+
HO
OHC
O
O
OH
HOOC
+
n
n
Entry
Bis(hydroxy
aldehyde)
CHO OHC
Chiral diamine
[n + n]
m/z
Yield
/%
n = 2, 3, 4
CHO
10; n = 2; 41%
11; n = 3; 75%
12; n = 4; 72%
OH
9
+
-OOC
-OOC
OH
OH
NH3
HO
OH
+
1
[1 + 1]
788
97
NH3
O
O
2
Scheme 3.
O
O
6
3
from the corresponding ½1 þ 1ꢁ macrocycle (Table 1, Entry 9).
The reaction however produced little amounts of higher order
macrocycles as observed in the MALDI-TOF mass spectrum.
Dialdehyde 11 (n ¼ 3), on the other hand formed a mixture
of ½1 þ 1ꢁ and ½2 þ 2ꢁ macrocycles with 6 under identical reac-
tion conditions (Table 1, Entry 10). These macrocycles were an-
alyzed as a mixture and the individual components were not iso-
lated. Unusually cyclocondensation of 11 with acyclic diamine 8
afforded ½1 þ 1ꢁ macrocycle in 58% isolated yield (Table 1,
Entry 11). Dialdehyde 12 with the long tether exclusively
formed ½1 þ 1ꢁ macrocycle upon cyclocondensation with both
cyclic and acyclic diamine 6 and 8 in 65–70% yields (Table 1,
Entries 12 and 13) indicating the role of tether length in macro-
cyclisation.
Cl-
+H3
Cl-
CHO OHC
+
N
NH3
HO
OH
2
O
O
[1 + 1]
866
89
N
2
Bn
O
O
3
7
CHO OHC
Cl-
NH3
Cl-
+H3N
+
HO
OH
O
O
2
3
4
[1 + 1]
[1 + 1]
947
802
78
94
O
O
BnOH2C
CH2OBn
3
8
CHO OHC
+
-OOC
OH
OH
NH3
HO
OH
+
-OOC
NH3
O
O
3
O
O
6
4
Cl-
NH3
CHO OHC
Cl-
+H3N
BnOH2C
+
HO
OH
5
6
[1 + 1]
[1 + 1]
989
816
91
96
O
O
3
CH2OBn
O
O
8
4
CHO OHC
+
-OOC
OH
OH
NH3
In conclusion a facile method for synthesis of ½1 þ 1ꢁ
chiral macrocyclic Schiff base is described. Chiral dialdehydes
afforded ½1 þ 1ꢁ macrocycles in high yields with chiral diamines
when compared to achiral dialdehydes.
HO
OH
+
-OOC
NH3
O
O
4
O
O
6
5
Cl-
+H3
Cl-
NH3
CHO OHC
+
N
HO
OH
O
O
7
8
[1 + 1]
894
84
89
N
References and Notes
4
O
Bn
O
1
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5
7
Cl-
NH3
Cl-
CHO OHC
+H3N
+
HO
OH
O
O
[1 + 1] 1003
[2 + 2] 1097
4
O
BnOH2C
CH2OBn
O
5
8
2
3
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CHO
HO
OHC
O
OH
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OH
OH
NH3
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-OOC
O
O
NH3
9
48
67
2
O
4
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6
10
11
11
12
CHO
+
HO
OHC
OH
-OOC
-OOC
OH
OH
NH3
NH3
[1 + 1]
563,
+
´
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10
+
O
O
O
3
O
6
1125
[2 + 2]
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5
CHO
HO
OHC
OH
Cl-
NH3
Cl-
+H3N
+
ˇ
Hodacova, M. Chadim, J. Zavada, J. Aguilar, E. Garcıa-Espana, S. V. Luis,
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´
´
´
ˇ
11
[1 + 1]
759
58
O
O
O
3
O
BnOH2C
CH2OBn
6
7
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8
CHO
HO
OHC
OH
+
+
-OOC
-OOC
OH
OH
NH3
12
13
O
O
O
[1 + 1]
[1 + 1]
577
763
65
70
NH3
4
O
6
8
9
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Chem. 2007, in press.
Cl-
NH3
Cl-
CHO
HO
OHC
O
OH
+H3N
BnOH2C
+
10 Typical experimental procedure: A mixture of dialdehyde 3 (1.0 equiv.),
chiral diamine 6 (1.5 equiv.), and K2CO3 (2.0 equiv.) in water–ethanol
(1:1) was irradiated in an unmodified domestic oven at low power settings
for 5 min. The reaction mixture was cooled to room temperature and the
solid materials were collected by filtration. It was redissolved in ethyl ace-
tate and filtered. The filterate was dried over sodium sulfate and concentrat-
ed under reduced pressure to afford pure ½1 þ 1ꢁ macrocycle as a yellow
CH2OBn
O
O
4
O
8
12
droxybenzaldehyde (9) with various diacids using DCC accord-
ing to Scheme 3.
solid in good yield. Yield: 94%; [ꢀ]D = ꢂ110 (c 0.1, CH2Cl2); 1H NMR
28
Cyclocondensation of dialdehydes 10–12 with chiral dia-
mines 6 and 8 were performed under microwave irradiation in
aqueous ethanol. The reactivity pattern was different in compar-
ison to the chiral dialdehydes indicating the significance of rigid
conformation in the process of macrocyclisation. In the case of
dialdehyde 10 (n ¼ 2), the cyclocondensation with 6 formed
½2 þ 2ꢁ macrocycle as the major product which was totally free
[400 MHz, CDCl3] ꢁ 12.92 (s, 2H), 8.54 (s, 2H), 7.92–7.86 (m, 6H), 7.77–
7.75 (d, J ¼ 8:4 Hz, 2H), 7.41–7.37 (t, J ¼ 7:6 Hz, 2H), 7.33–7.13 (m,
10H), 6.90–6.88 (d, J ¼ 8:4 Hz, 2H), 3.30–3.28 (d, J ¼ 9:6 Hz, 2H),
1.83–1.80 (m, 4H), 1.40–1.38 (m, 2H), 1.22–1.18 (m, 4H), 1.16–1.13 (m,
2H); 13C NMR [400 MHz, CDCl3] ꢁ 171.2, 164.9, 155.5, 151.5, 135.3,
134.7, 133.5, 130.0, 129.3, 129.2, 129.0, 128.3, 127.8, 126.5, 124.8,
124.6, 123.9, 123.3, 120.6, 117.7, 114.4, 113.5, 72.7, 60.4, 32.7, 24.1;
MALDI-TOF-MS: m=z 789 (½M þ Hꢁþ).
Published on the web (Advance View) October 6, 2007; doi:10.1246/cl.2007.1332