Synthesis of semi-calix[4]indoles containing combinations of direct links and methylene linkages

Article abstract of DOI:10.1055/s-0033-1338868

Macrocyclic compounds containing four 3-substituted-4,6-dimethoxyindole units joined through the C2 and C7 positions, by a combination of direct links or methylene bridges, can be prepared by acid-catalyzed reactions of indole methanols and 2,7′-biindolyldimethanols with indoles and 2,7′-biindolyls. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338868

LETTER
▌1497
lSetyternthesis of Semi-Calix[4]indoles Containing Combinations of Direct Links
and Methylene Linkages
Synthesis of Semi-Calix[4]indoles
Rui Chen, Kittiya Somphol, Mohan Bhadbhade, Naresh Kumar, David StC. Black*
School of Chemistry, The University of New South Wales, UNSW, Sydney NSW 2052, Australia
Fax +61(2)93856141; E-mail: d.black@unsw.edu.au
Received: 19.04.2013; Accepted after revision: 02.05.2013
Both C2 and C7′ sites on 2,7′-biindolyls 1–3 are active to-
Abstract: Macrocyclic compounds containing four 3-substituted-
wards electrophilic substitution. Under Vilsmeier–Haack
4,6-dimethoxyindole units joined through the C2 and C7 positions,
formylation conditions,7 2,7′-diformylbiindolyls 4–6 can
by a combination of direct links or methylene bridges, can be pre-
be obtained in good yields from biindolyls 1–3, respec-
tively (Scheme 1). The X-ray crystal structure of 2,7′-bi-
indolyldialdehyde 68 was shown to have formyl groups at
both the C2 and C7′ positions (Figure 1).
pared by acid-catalyzed reactions of indole methanols and 2,7′-bi-
indolyldimethanols with indoles and 2,7′-biindolyls.
Key words: indoles, 2,7′-biindolyls, diindolylmethanes, macrocy-
clic compounds, acid-catalyzed reaction, ipso-substitution reaction,
formaldehyde extrusion
We have previously reported the syntheses of calix[3]-
indoles and calix[4]indoles using one-pot and stepwise
methods via acid-catalyzed addition reactions.1–4 Further-
more, in a more recent paper,5 the synthesis of a second
type of calix[4]indole is described. In the calixindoles, in-
dole units are joined by methylene groups, but related
structures incorporating direct links are also synthetically
feasible using different methodologies. Oxidative reac-
tions of suitably activated indoles can give 2,7′-biindolyls
1–3, and macrocyclic tetraindolyls (including indorphy-
rins), arising from head-to-head and head-to-tail coupling
and containing combinations of direct 2,2-, 2,7- and 7,7-
links.6 We now describe our results on the further func-
tionalization of biindolyls to afford biindolyl dimethanols
which can be subsequently converted to tetraindole con-
taining macrocycles with combinations of methylene and
direct links. These new compounds can loosely be termed
‘semi-calix[4]indoles’.
Figure 1 ORTEP diagram of 2,7′-diformyl biindolyl 6
The 2,7′-diformyl biindolyls 4–6 could also undergo fur-
ther reduction with sodium borohydride in a mixture of
tetrahydrofuran and ethanol (1:1) to afford biindolyl di-
methanols 7–9, respectively as the precursors for the
semi-calix[4]indoles (Scheme 1).
MeO
MeO
MeO
R
R
R
CHO
N
N
N
OH
MeO
R
MeO
R
MeO
R
H
H
H
a
b
NH
NH
NH
OH
MeO
MeO
MeO
CHO
OMe
OMe
R
OMe
R
R
---------------------
---------------------
---------------------
4
5
6
4-ClC6H4
Me
4-BrC6H4
1
2
3
4-ClC6H4
Me
4-BrC6H4
7
8
9
4-ClC6H4
Me
4-BrC6H4
Scheme 1 Reagents and conditions: (a) POCl3, DMF, r.t., 8 h (75–81%); (b) NaBH4, THF, EtOH, r.t., 8 h (90–99%).
SYNLETT 2013, 24, 1497–1500
Advanced online publication: 17.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338868; Art ID: ST-2013-D0363-L
© Georg Thieme Verlag Stuttgart · New York

1498
R. Chen et al.
LETTER
It has been reported previously that hydroxymethyl in- dimethyl sulfoxide to afford semi-calix[4]indoles 18 and
doles can undergo acid-catalyzed addition reactions to 19, respectively in 24–40% yield (Scheme 2). These com-
couple with active sites of indoles.1–5 In a similar manner, pounds represent a new class of indole-containing macro-
semi-calix[4]indoles can be obtained via stepwise synthe- cycles. The acid-catalyzed ring closure is yet another
sis. Diformyl tetraindolyls 12–14 were obtained in 40– example of an ipso-substitution resulting in loss of form-
63% yields from the acid-catalyzed addition of two equiv- aldehyde in the re-aromatization step.5,9
alents of indole-7-carbaldehydes 10 and 11 to one equiv-
The 1H NMR spectrum (DMSO-d6) of the semi-ca-
alent of dihydroxymethyl biindolyls 7 and 8. The diformyl
lix[4]indole 18 displayed six three-proton singlets and a
tetraindolyls 12–14 were reduced by reacting with sodium
six-proton singlet from δ = 3.34–3.90 ppm corresponding
borohydride to give the corresponding dihydroxymethyl
to eight methoxy groups. Two types of methylene groups
can also be identified from the spectrum. Two broad sin-
glets (each with two protons) appear at δ = 3.72 and 4.38
tetraindolyls 15–17, respectively. However, the 3-methyl-
substituted compound 17 was not stable and decomposed
quickly after formation. Thus the 3-aryl-substituted com-
ppm; the remaining methylene group shows an AB pattern
pounds 15 and 16 were treated with trifluoroacetic acid in
at δ = 4.10 and 4.30 ppm, and this phenomenon, which re-
MeO
R1
MeO
OMe
N
OH
R2
MeO
R1
H
R1
MeO
CHO
NH
NH
N
H
MeO
R1
MeO
OH
NH
OMe
R1
H
MeO
______________
CHO
OMe
N
7
8
4-ClC6H4
Me
OMe
R2
a
+
MeO
MeO
R2
R1
R2
_________________________
12
4-ClC6H4
4-ClC6H4
13
14
Me
Me
4-ClC6H4
Me
N
MeO
H
CHO
R2
______________
b
10
11
4-ClC6H4
Me
MeO
R2
OMe
OH
MeO
R1
R1
MeO
R2
NH
OMe
OMe
N
MeO
R1
MeO
N
H
MeO
R1
H
HN
c
NH
NH
HO
H
H
MeO
N
N
OMe
R2
OMe
OMe
R2
OMe
MeO
MeO
R1
R2
R1
R2
4-ClC6H4
Me
Me
_________________________
18
19
_________________________
15
16
17
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
4-ClC6H4
4-ClC6H4
Me
Scheme 2 Reagents and conditions: (a) para-toluenesulfonic acid, isopropanol, 32 h (12, 63%; 13, 56%; 14, 40%); (b) NaBH4, THF, EtOH,
r.t, 8 h (15, 90%; 16, 72%); (c) TFA, DMSO, r.t, 10 min (18, 24%; 19, 40%).
Synlett 2013, 24, 1497–1500
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Semi-Calix[4]indoles
1499
OMe
R1
MeO
MeO
R
R
MeO
OMe
N
N
OH
MeO
R1
N
MeO
R
MeO
R
H
H
H
a or b
HN
R2
NH
+
NH
NH
H
N
OMe
MeO
MeO
MeO
OH
OMe
R
OMe
OMe
R2
OMe
R2
R
R1
______________
______________
____________________________
1
2
7
8
20
21
22
4-ClC6H4
Me
4-ClC6H4
Me
4-ClC6H4
Me
4-ClC6H4
4-ClC6H4
Me
Me
Scheme 3 Reagents and conditions: (a) concd HCl (one drop), isopropanol (20, 30%); (b) TFA, MeCN (21, 43%; 22, 6%).
lates to the rigidity of the linkage, is consistent with obser- ppm which indicated that the two methylene linkages
vations in the case of calix[4]indoles.2,5 Furthermore, four were in the same environment, and this further proved the
separate resonances for indole H5 protons were found at δ structure to have a head-to-tail configuration. Four H5
= 6.35, 6.44, 6.45 and 6.51 ppm. The structure of the semi- proton resonances appeared from δ = 6.49–6.57 ppm.
calix[4]indole 1810 (containing one direct link and three Three singlets at δ = 9.63 (1 H), 9.81 (1 H) and 10.05 (2
methylene links) was further confirmed by the high reso- H) represented four indole NH protons. High resolution
lution mass spectrum which displayed the expected peak mass spectrometry displayed the expected peak at m/z =
at m/z = 1184.2689 [M+].
1169.2538 [M+]. Furthermore the head-to-tail configura-
tion was confirmed by an X-ray crystal structure (Figure
2).
Additionally, semi-calix[4]indoles containing two direct
links and two methylene links can be formed using this
strategy. When biindolyl dimethanol 7 was reacted with In summary, systems of cyclized indole macrocycles with
biindolyl 1 in the presence of hydrochloric acid, the result- different linkages can be synthesized. In these systems,
ing semi-calix[4]indole 2011 was afforded in 30% yield four indole units can be linked with four methylene
(Scheme 3). Similarly, with modified conditions, the groups, three methylene groups and one direct link, two
semi-calix[4]indole 21 was obtained from compounds 8 methylene groups and two direct links, and four direct
and 2 in 43% yield. A hybrid system 22 was also generat- links. The structural differences and capabilities of these
ed from biindolyl dimethanol 8 and biindolyl 1 under the tetraindoles as hosts in supramolecular chemistry will be
same conditions but the yield was only 6%, as there were studied and the results subsequently reported.
many other compounds generated (Scheme 3).
1
The H NMR spectrum (acetone-d6) of compound 20
showed eight singlets from δ = 3.71–3.94 ppm represent-
ing the eight methoxy groups. Two methylene groups
were represented by the singlet of four protons at δ = 4.36
Acknowledgment
Research support from the Australian Research Council (Project
number: DP1095159) and the University of New South Wales is
gratefully acknowledged.
References and Notes
(1) Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R.
J. Chem. Soc., Chem. Commun. 1993, 819.
(2) Black, D. StC.; Craig, D. C.; Kumar, N. Tetrahedron Lett.
1995, 36, 8075.
(3) Black, D. StC.; Craig, D. C.; Kumar, N.; McConnell, D. B.
Tetrahedron Lett. 1996, 37, 241.
(4) Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron
2000, 56, 8513.
(5) Somphol, K.; Chen, R.; Bhadbhade, M.; Kumar, N.; Black,
D. StC. Tetrahedron Lett. 2013, 54, 24.
(6) Chen, R.; Bhadbhade, M.; Kumar, N.; Black, D. StC.
Tetrahedron Lett. 2012, 53, 3337.
(7) Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.;
Kim, M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust.
J. Chem. 1994, 47, 1741.
Figure 2 ORTEP diagram of semi-calix[4]indole 20
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1497–1500

1500
R. Chen et al.
LETTER
(8) To an ice cold solution of phosphoryl chloride (0.37 mL,
4.00 mmol) in anhyd N,N-dimethylformamide (5 mL) was
added a cold solution of biindolyl 3 (1.0 g, 1.5 mmol) in
anhyd N,N-dimethylformamide (1 mL). The mixture was
stirred at r.t. for 30 min, and then at 50–60 °C for an
additional 8 h. After cooling to r.t., the mixture was diluted
with ice-water, basified with 20% aq NaOH and stirred for 1
h. The crude solid was filtered, washed with H2O, dried and
purified by flash chromatography (CH2Cl2–n-hexane, 9:1) to
yield compound 6 (0.86 g, 80%) as a yellow solid; mp 175
°C. 1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H, OMe),
3.80 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.99 (s, 3 H, OMe),
6.18 (s, 1 H, H5), 6.27 (s, 1 H, H5), 7.25 (d, J = 9.5 Hz, 2 H,
ArH), 7.30 (d, J = 9.5 Hz, 4 H, ArH), 7.49 (d, J = 8.5 Hz, 2
H, ArH), 8.75 (s, 1 H, NH), 9.26 (s, 1 H, CHO), 10.24 (s, 1
H, CHO), 10.74 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3):
δ = 55.1, 55.3, 56.2, 56.3 (OMe), 86.6, 89.0 (C5), 96.3 (C7),
104.2, 111.2, 111.6, 115.1, 119.9, 121.8, 126.7, 128.2 (ArC),
130.3, 130.5(ArCH), 131.0, 131.1 (ArC), 131.6, 132.7
(ArCH), 134.3, 137.0, 137.9, 157.4, 158.7, 161.0, 162.8
(ArC), 180.4, 187.9 (CH=O). IR (KBr): 3418, 2936, 2842,
1639, 1583, 1342, 1214, 1136, 1120, 987, 784, 714 cm–1.
UV/Vis (THF): λmax = 226 nm (ε 49,300 cm–1M–1), 267
(43,800), 328 (26,700). HRMS (+ESI): m/z [M + H]+ calcd
for C34H27Br2N2O6: 717.0230; found: 717.0233. Single
crystals were obtained from CDCl3. Crystal data for
compound 6: 2(C34H26Br2N2O6)/5(CDCl3), M = 1906.73,
triclinic, a = 14.7856(11) Å, b = 16.0855(12) Å, c =
19.0647(14) Å, α = 76.490(4)°, β = 78.004(3)°, γ =
ArH), 8.31 (s, 1 H, NH), 8.92 (s, 1 H, NH), 9.08 (s, 1 H, NH),
9.18 (s, 1 H, NH). 13C NMR (75 MHz, acetone-d6): δ = 20.9,
21.7, 23.6 (CH2), 132.8, 133.5, 134.5, 134.9, 135.2, 135.8,
136.6, 136.8, 137.1, 54.5, 54.6, 54.7, 55.4, 55.6, 56.3, 56.5,
56.7 (OMe), 88.9, 89.3, 89.8 (C5), 97.6, 100.1, 102.6, 103.5,
111.5, 111.9, 112.2, 112.2, 112.4, 112.5, 113.4, 114.7 (ArC),
126.5, 126.9, 127.0, 127.1 (ArCH), 127.3, 127.5, 129.6,
129.9, 130.0, 130.6, 130.7, 130.9, 131.0, 131.4 (ArC), 131.5,
131.9, 132.0, 132.4, 132.5 (ArCH), 137.5, 138.3, 152.4,
152.6, 153.3, 153.7, 153.9, 154.0, 154.1, 154.5 (ArC). IR:
3401, 3369, 3323, 2932, 2836, 1595, 1549, 1490, 1334,
1196, 1117, 1088, 997, 817, 788, 740 cm–1. UV/Vis (THF):
λmax = 224 nm (ε 203400 cm–1M–1), 287 (77600). HRMS
(+ESI): m/z [M]+ calcd for C67H54Cl4N4O8: 1184.2666;
found: 1184.2689.
(11) To a solution of biindolyl 1 (0.9 g, 1.57 mmol) and
dihydroxymethyl biindolyl 7 (1.00 g, 1.57 mmol) in a
mixture of isopropanol (100 mL) and CH2Cl2 (100 mL),
concentrated hydrochloric acid (3 drops) was added. The
mixture was stirred at r.t. for 5 min before the addition of
H2O (200 mL). The mixture was then extracted with CH2Cl2
(3 × 100 mL) and the organic phases were combined, washed
with brine and dried over Na2SO4. The solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (CH2Cl2–n-hexane, 1:1) to yield 20
(0.60 g, 30%) as a white solid; mp 262 ºC. 1H NMR (300
MHz, acetone-d6): δ = 3.71 (s, 3 H, OMe), 3.73 (s, 3 H,
OMe), 3.75 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.84 (s, 3 H,
OMe), 3.85 (s, 3 H, OMe), 3.89 (s, 3 H, OMe), 3.94 (s, 3 H,
OMe), 4.36 (s, 4 H, CH2), 6.49 (s, 2 H, H5), 6.54 (s, 1 H, H5),
6.57 (s, 1 H, H5), 7.09–7.63 (m, 16 H, ArH), 9.63 (s, 1 H,
NH), 9.81 (s, 1 H, NH), 10.05 (s, 2 H, NH). 13C NMR (75
MHz, acetone-d6): δ = 18.1, 21.5 (CH2), 54.5, 54.6, 54.7,
54.9, 56.0, 56.1, 56.8, 57.0 (OMe), 89.1, 89.2 (C5), 97.6,
98.1 (C7), 103.6, 103.7, 110.3, 111.2, 112.4, 114.4, 114.5,
114.7, 116.8, 122.2, 126.5 (ArC), 126.6, 126.8, 127.4, 128.9
(ArCH), 127.5, 127.6, 130.3, 130.5, 130.7 (ArC), 130.8
(ArCH), 130.9 (ArC), 131.9 (ArCH), 132.4, 134.5, 135.3,
135.8, 136.3, 137.5, 137.6, 137.9, 151.3, 151.4, 153.2,
153.3, 154.9, 155.0, 155.1 (ArC). IR: 3440, 3330, 2932,
2837, 1595, 1487, 1327, 1207, 1088, 995, 832, 792, 740
cm–1. UV–vis (THF): λmax = 240 nm (ε 113900 cm–1M–1),
291 (55200). HRMS (+ESI): m/z [M + H]+ calcd for
C66H52Cl4N4O8: 1169.2539; found: 1169.2538. Single
crystals were obtained from (CD3)2CO. Crystal data for
compound 20: C40.50H41Cl2N2O6.50, M = 730.65, monoclinic,
a = 21.490(4) Å, b = 10.494(2) Å, c = 33.299(7) Å, α =
90.00°, β = 95.71(3)°, γ = 90.00°, V = 7472(3) Å3, T = 100(2)
K, space group C2/c, Z = 8, μ(Synchrotron) = 0.225 mm–1,
45914 reflections measured, 6568 independent reflections
(Rint = 0.0377). The final R1 values were 0.0736 [I > 2σ(I)].
The final wR(F2) values were 0.1951 [I > 2σ(I)]. The final R1
values were 0.0809 (all data). The final wR(F2) values were
0.2015 (all data). The goodness of fit on F2 was 1.037 (all
data). Crystallographic data for compound 20 has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC 895299. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK [fax:
+44(1223)336033; email: deposit@ccdc.cam.ac.uk].
68.849(3)°, V = 4073.4(5) Å3, T = 150(2) K, space group
P–1, Z = 2, μ(MoKα) = 2.428 mm–1, 42158 reflections
measured, 11460 independent reflections (Rint = 0.1944).
The final R1 values were 0.1769 [I > 2σ(I)]. The final wR(F2)
values were 0.4235 [I > 2σ(I)]. The final R1 values were
0.3679 (all data). The final wR(F2) values were 0.5123 (all
data). The goodness of fit on F2 was 1.362 (all data).
Crystallographic data for compound 6 has been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC 895310. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK [fax:
+44(1223)336033; email: deposit@ccdc.cam.ac.uk].
(9) Black, D. StC.; Bowyer, M. C.; Catalano, M. M.; Ivory, A.
J.; Keller, P. A.; Kumar, N.; Nugent, S. J. Tetrahedron 1994,
50, 10497.
(10) To a solution of tetraindolyl dimethanol 15 (1.00 g, 0.80
mmol) in anhyd dimethyl sulfoxide (100 mL), trifluoroacetic
acid (3 drops) was added. The mixture was allowed to stir at
r.t. for 10 min before the addition of H2O (100 mL). The
mixture was then extracted with CH2Cl2 (3 × 100 mL). The
organic phases were combined, washed with brine and dried
over Na2SO4. The solvent was removed under reduced
pressure and the crude product was purified by flash
chromatography (CH2Cl2–n-hexane, 1:1) to yield 18 (0.23 g,
24%) as a white solid; mp 243 °C. 1H NMR (300 MHz,
acetone-d6): δ = 3.34 (s, 3 H, OMe), 3.72 (s, 6 H, OMe), 3.72
(s, 2 H, CH2), 3.73 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 3.83
(s, 3 H, OMe), 3.89 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.10
(d, J = 16.8 Hz, 1 H, CH2), 4.30 (d, J = 16.8 Hz, 1 H, CH2),
4.38 (br s, 2 H, CH2), 6.35 (s, 1 H, H5), 6.44 (s, 1 H, H5),
6.45 (s, 1 H, H5), 6.51 (s, 1 H, H5), 7.09–7.41 (m, 16 H,
Synlett 2013, 24, 1497–1500
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