Synthesis of chiral nonracemic polyimine macrocycles from cyclocondensation reactions of biaryl and terphenyl aromatic dicarboxaldehydes and 1R,2R-diaminocyclohexane

Article abstract of DOI:10.1016/j.tetlet.2005.08.155

The synthesis of biaryl and terphenyl dicarboxaldehydes using Suzuki coupling methodology and their macrocyclisation reactions with 1R,2R-diaminocyclohexane yielding novel polyimine macrocycles derived from the [2+2] and [3+3] cyclocondensation reactions

Full text of DOI:10.1016/j.tetlet.2005.08.155

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7575–7579
Synthesis of chiral nonracemic polyimine macrocycles from
cyclocondensation reactions of biaryl and terphenyl aromatic
dicarboxaldehydes and 1R,2R-diaminocyclohexane
Nikolai Kuhnert,* Chirag Patel and Fatemeh Jami
Supramolecular and Biomolecular Chemistry Laboratory, Chemistry, School of Biomedical and Molecular Sciences,
The University of Surrey, Guildford GU2 7XH, UK
Received 26 May 2005; revised 19 August 2005; accepted 26 August 2005
Available online 16 September 2005
Dedicated to Professor Angela Danil de Namor on the occasion of her 65th birthday
Abstract—The synthesis of biaryl and terphenyl dicarboxaldehydes using Suzuki coupling methodology and their macrocyclisation
reactions with 1R,2R-diaminocyclohexane yielding novel polyimine macrocycles derived from the [2+2] and [3+3] cyclocondensa-
tion reactions is presented. The ratio of products was found to depend on the overall geometry of the dicarboxaldehydes.
Ó 2005 Published by Elsevier Ltd.
The development of supramolecular chemistry has been
mainly driven by the availability of suitable macrocyclic
receptors. Once a class of macrocyclic receptors with a
unique shape, distinct architecture and set of functional
groups becomes widely available from natural or syn-
thetic sources, they start to inspire the imagination of
supramolecular chemists to devise and synthesise novel
sophisticated receptors, molecular machines and de-
vices.1–3 Following initial work by Gawronski et al.,4
we have recently reported the synthesis of large poly-
imine meta- and para-cyclophane type macrocycles
using a [3+3] cyclocondensation strategy, in which six
imine bonds are formed.5–8 We have named these com-
pounds trianglimines due to their characteristic triangu-
lar geometry. In a modular approach, macrocycles of
various ring sizes including different functionalities in
enantiomerically pure form were obtained. Other groups
have also reported on the use of the [3+3] cycloconden-
sation strategy.9–13
ing macrocycles with ring sizes between 30 and 60 in a
highly efficient way. As model substrates, we chose a ser-
ies of differently substituted biaryl dicarboxaldehydes,
which we obtained by the palladium catalysed Suzuki
coupling reactions using formyl boronic acids 1–3 and
aromatic bromobenzaldehydes 4 and 5. All biaryl
dicarboxaldehydes 6a–e could be obtained in good to
excellent yield using a modification of the literature pro-
cedure (Scheme 1)14 with Pd(dppf)Cl2 as the catalyst.
Compounds 6b–e are novel compounds and the yields
are given in Table 1.
We then extended our Suzuki coupling approach by
reacting 2 equiv of 4-formyl boronic acid 2 with a series
of aromatic dibromides 7a–g to obtain a series of substi-
tuted terphenyl dialdehydes 8a–g in moderate to good
yields. For the terphenyl series, slightly modified Suzuki
conditions were required using Pd(PPh3)4 as the catalyst
in toluene (Scheme 2). All compounds, with the excep-
tion of 8g, which has been reported by Gawronski and
co-workers during the course of this investigation13 are
novel and were fully characterised. The yields are sum-
marised in Table 1.
In this communication, we report a detailed and system-
atic study of the [n+n] cyclocondensation concept using
a selection of biaryl and terphenyl dicarboxaldehydes.
Both types of dicarboxaldehyde building blocks should
allow a modular approach for the synthesis of fascinat-
All the dicarboxaldehydes were subjected to the [n+n]
cyclocondensation reaction with 1R,2R-diamino-cyclo-
hexane 9 using the conditions reported by us previously
(Scheme 3).5–8 The crude reaction mixtures were
*
Corresponding author. E-mail: n.kuhnert@surrey.ac.uk
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.155

7576
N. Kuhnert et al. / Tetrahedron Letters 46 (2005) 7575–7579
O
Pd(dppf)Cl2 5 mol%
(HO)2B Ar CHO
+
Br Ar CHO
Ar Ar
Na2CO3/DMF/H2O
O
1-3
4, 5
6a-e
O
O
O
O
S
B(OH)2
O
B(OH)2
Br
3
4
B(OH)2
Br
1
2
5
O
O
O
O
O
S
S
6b
6c
6e
O
O
6a
6d
O
O
O
Scheme 1. Synthesis of biaryl dicarboxaldehydes.
cient was assigned as the [2+2] cyclocondensation
product.15–17
Table 1. Yields of aromatic dicarboxaldehydes 6a–e and 8a–g
Starting materials
Product
Yield (%)
2 and 4
1 and 4 or 2 and 5
1 and 5
3 and 5
3 and 4
1 and 7a
1 and 7b
1 and 7c
1 and 7d
1 and 7e
1 and 7f
1 and 7g
6a
6b
6c
6d
6e
8a
8b
8c
8d
8e
8f
31
12/84
71
As expected mass spectrometry overestimates the forma-
tion of the lower molecular weight product in all cases.
If FAB and ESI mass spectrometry are directly com-
pared, FAB was found to overestimate the amount of
the lower molecular weight compound formed. All com-
pounds with a linear arrangement of the two O@C
carbons and the biaryl axis form trianglimines as the
product of a [3+3] cyclocondensation reaction (see
8a,b,g). In some instances, small amounts of [2+2] cyclo-
condensation products are observed after 12 h of reac-
tion time. In all of these cases, the trianglimine
macrocycles could be isolated in pure form and charac-
terised. Interestingly, the 1H NMR spectra were charac-
terised by broad bands presumably due to rapid rotation
around the C–C biaryl axes. In the case of dicarboxalde-
hydes displaying a nonlinear arrangement of the two
O@C carbons and the biaryl axes mixtures of [2+2]
and [3+3] cyclocondensation products were always ob-
served after 12 h of reaction time. After 48 h of reaction
time it was observed that the reaction mixture had equili-
brated and in case of, for example, compounds 8c,f the
[2+2] cyclocondensation products 12c,f were obtained
exclusively. It appears that in these cases the [2+2] cyclo-
condensation products 12c,f are the products of thermo-
dynamic control as suggested earlier.7 In the case of
dicarboxaldehydes 6b,d and 6e two alternative regioiso-
meric tetraimine macrocycles 10a,d,e are expected to
form in the [2+2] cyclocondensation reaction. Detailed
1H,1H-NOESY experiments showed that in each case,
the regioisomer with a C2-axis along the centre of the
macrocyclic cavity is formed exclusively as the only
product of the [2+2] cyclocondensation reaction (see
Scheme 4 for representative structures). Representative
analytical data are given in reference section.17–20
98
86
81
23
90
75
70
51
8g
48
1
analysed by H NMR spectroscopy and FAB and ESI
mass spectrometry after 12 and 48 h of reaction time
in dichloromethane at room temperature and the ratios
of [2+2] and [3+3] cyclocondensation reaction products
were determined (representative results in Table 2). In
all cases macrocyclic products were observed exclusively
as opposed to alternative polymeric oligoimine prod-
ucts. Both reaction products display, due to their inher-
ent symmetry only one set of NMR signals for the two
or three repeating units but can be unambiguously iden-
tified according to their unique m/z of their molecular
ions. It has to be noted that the ratio of products deter-
mined by integration of the crude 1H NMR spectra and
the mass spectra differ greatly.10 To allow unambiguous
1
assignment of the minor and major products in the H
NMR spectra diffusion, NMR spectra of the crude mix-
tures were obtained. The macrocyclic polyimine com-
pound displaying a smaller diffusion coefficient was
assigned to the [3+3] cyclocondensation product,
whereas the compound with the larger diffusion coeffi-

N. Kuhnert et al. / Tetrahedron Letters 46 (2005) 7575–7579
7577
O
O
Pd(PPh3)4 5 mol%
Ar Ar Ar
+
Br Ar Br
2 eq
Br
toluene/MeOH
Na2CO3
O
8a-g
7a-g
B(OH)2
2
Br
Br
Br
Br
F
F
F
Br
Br
Br
Br
Br
Br
Br
N
Br
F
N
7a
7f
Br
7b
7c
7g
7e
7d
O
O
O
O
O
O
O
F
F
F
N
N
F
8g
8d
8a
8b
8c
8e
8f
O
O
O
O
O
O
O
Scheme 2. Synthesis of terphenyl dicarboxaldehydes.
NH2
O
O
Ar Ar
Ar Ar Ar
NH2
O
O
8a-g
6a-e
(1R, 2R)-9
Ar Ar Ar
Ar Ar
N
N
N
N
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
N
N
N
N
N
N
N
N
Ar
N
Ar
11a-e
13a-g
N
N
N
Ar Ar Ar
Ar Ar
N
N
N
N
12a-g
Ar
Ar
10a-e
Ar Ar Ar
Scheme 3. Synthesis of polyimine macrocycles.
In conclusion, we have shown that extended rigid aro-
matic dicarboxaldehydes can be obtained in good yields
using Suzuki coupling reactions. This class of compound
represent valuable building blocks in polymer chemistry
and macrocyclic chemistry. The [n+n] cyclocondensation
strategy using an aromatic dialdehyde and 1R,2R-diami-
nocyclohexane can be applied to biaryl and terphenyl
dicarboxaldehydes to yield fascinating enantiomerically
pure polyimine macrocycles. The nature of the cyclocon-
densation product depends strongly on the overall geom-
etry of the dicarboxaldehyde building block. For a linear
arrangement of carbonyl–biaryl axes trianglimine [3+3]
cyclocondensation products were obtained exclusively,
whereas in all cases of nonlinear carbonyl biaryl axes
geometries, [2+2] cyclocondensation products were ob-
tained. All novel macrocycles synthesised maybe useful
in organic synthesis, for chiral recognition and applica-
tions in supramolecular chemistry.

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N. Kuhnert et al. / Tetrahedron Letters 46 (2005) 7575–7579
Table 2. Ratio of products formed from the [n+n] cyclocondensation reaction
Starting
materials
Productsa
Ratio after 12 h
by 1H NMRb
Ratio after 12 h
by ESIc
Ratio after 48 h
by 1H NMR
Ratio after 48 h
by ESI
Isolated
yield (%)
6a
6b
6c
6d
6e
8a
8b
8c
8d
8e
8f
10a+11a
10b+11b
10c+11c
10d+11d
10e+11e
12a+13a
12b+13b
12c+13c
12d+13d
12e+13e
12f+13f
12g+13g
6:94
97:3
>98:2
95:5
98:2
2:98
12:88d
95:5
98:2
95:5
98:2
2:98
2:98
70:30e
58:42
75:25
60:40
2:98
>2:98
—
—
—
—
2:98
2:98
95:5
95:5
98:2
90:10
2:98
>2:98
—
—
—
—
2:98
2:98
90:10
88:12
95:5
80:20
2:98
90 (11a)
67 (10b)
72 (10c)
72 (10d)
66 (10e)
66 (13a)
55 (13b)
78 (12c)
81 (12d)
79 (12e)
34 (12f)
71 (13g)
2:98
90:10
78:22
90:10
85:15
>2:98
8g
a Products assigned by diffusion NMR.
b Crude mixture in CDCl3 at 500 MHz using the HC@N signal.
c In MeOH positive ion mode 0.0001 M ratio of intensities of m/z.
d FAB measurement shows 35:65 ratio.
e FAB measurement shows 90:10 ratio.
N
N
N
N
N
N
N
S
N
N
N
N
S
S
S
N
N
N
N
N
N
N
10d
10e
10b
12c
Scheme 4. Selected products of macrocyclisation reaction.
11. Korupoju, S. R.; Zacharias, P. S. Chem. Commun. 1998,
1267–1268.
Acknowledgements
12. Korupoju, S. R.; Mangayarkarasi, N.; Ameerunisha, S.;
Valente, E. J.; Zacharias, P. S. J. Chem. Soc., Dalton
Trans. 2000, 65, 2845–2852.
We acknowledge EPSRC funding for a DTA student-
ship for F.J.
13. Kwit, M.; Skowronek, P.; Kolbon, H.; Gawronski, J.
Chirality 2005, 17, 93–100.
References and notes
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4. Gawronski, J.; Kolbon, H.; Kwit, M.; Katrusiak, A.
J. Org. Chem. 2000, 65, 5768–5773.
5. Kuhnert, N.; Straßnig, C.; Lopez-Periago, A. M. Tetra-
hedron: Asymmetry 2002, 13, 123–128.
6. Kuhnert, N.; Patel, C.; Burzlaff, N.; Lopez-Periago, A. M.
Org. Biomol. Chem. 2005, 3, 1911–1921.
7. Kuhnert, N.; Lopez-Periago, A. M.; Rossignolo, G. M.
Org. Biomol. Chem. 2003, 1, 1157–1170.
17. Analytical data for compound 6c: Mp (98–98.2 °C); IR
mmax (Nujol)/cmꢀ1 1698 (C@O), 1600–1463 (CAr@CAr),
783, 690; 1H NMR (500 MHz; CDCl3) dH 10.12 (2H, s,
CH@O), 8.15 (2H, s, Ar–H), 7.93 (4H, m, Ar–H), 7.68
(2H, d, J 8.1 Hz, Ar–H); 13C NMR (125 MHz, CDCl3): dC
192.9, 140.9, 137.3, 133.2, 130.02, 129.2, 128.2; CHN
calcd: 79.90 C, 4.70 H; found: 79.83 C, 4.72 H; GC–MS
C14H10O2 (m/z 210, M+H).
8. Kuhnert, N.; Lopez-Periago, A. M.; Rossignolo, G. M.
Org. Biomol. Chem. 2005, 3, 524–537.
9. Kwit, M.; Gawronski, J. Tetrahedron: Asymmetry 2003,
14, 1303–1308.
10. Chadim, M.; Budesinsky, M.; Hodacova, J.; Zavada, J.;
Junk, P. C. Tetrahedron: Asymmetry 2001, 12, 127.
18. Analytical data for compound 10c: Mp 197.8–198 °C;
25
½aꢁD ꢀ113.75 (c 0.4, CHCl3); IR mmax (Nujol)/cmꢀ1: 1629
(C@N), 1463–1377, 723 cmꢀ1 1H NMR (500 MHz;
;
CDCl3): dH 8.37 (4H, s, N@CH), 8.15 (4H, s, Ar), 7.66
(12H, m, ArH), 3.74 (4H, m, NCH), 2.17–1.56 (16H, m,
CH2); 13C NMR (125 MHz; CDCl3): dC 162.4, 154.6,

N. Kuhnert et al. / Tetrahedron Letters 46 (2005) 7575–7579
7579
145.9, 141.4, 137.2, 134.2, 131.5, 129.8, 128.6, 126.8, 124.8,
74.8, 72.2, 65.8, 33.1, 32.1, 24.65, 15.29; FAB: C40H40N4
(m/z 576, M+H).
20. Analytical data for compound 12c: Mp over 200 °C;
25
½aꢁD ꢀ182 (c 0.1, CHCl3); IR mmax (Nujol)/cmꢀ1: 1637
(C@N); 1H NMR (500 MHz; CDCl3): dH 8.35 (s, 4H,
HC@N), 7.97 (d, 8H, J 8.1, ArH), 7.61 (d, 8H, J 8.1,
ArH), 7.57 (t, 2H, J 7.9, pyrH), 7.39 (d, 4H, J 7.9, pyrH),
3.39 (m, 4H, NCH), 1.96–1.52 (m, 16H, CH2); 13C NMR
(125 MHz; CDCl3): dC 161.7, 156.5, 141.5, 137.7, 136.9,
128.5, 127.5, 120.1, 74.4, 32.9, 24.7; CHN calcd: 82.16 C,
6.34 H, 11.5 N; found: 82.50 C, 6.05 H, 11.31 N; MS
(LSIMS): C50H46N9 (m/z 731, M+H).
19. Analytical data for compound 8c: Mp over 163–166 °C;
1
IR mmax (Nujol)/cmꢀ1: 1687 (C@O); H NMR (500 MHz;
CDCl3): dH 10.11 (s, 2H, CHO), 8.32 (d, 4H, J 8.1, ArH),
8.03 (d, 4H, J 8.1, ArH), 7.93 (t, 1H, J 7.8, pyrH), 7.84 (d,
2H, J 7.8, pyrH); CHN calcd: 79.43 C, 4.56 H, 4.88 N;
found: 79.6 C, 4.51 H, 4.80 N; MS (CI): C19H13NO2 (m/z
287.1, M+H).