Photochemical synthesis and properties of axially chiral naphthylpyridines

Article abstract of DOI:10.1016/j.jphotochem.2011.06.006

Five alkynyl pyridines were prepared and cyclized to naphthylpyridines as the main products in the course of a Photo-Dehydro-Diels-Alder reaction. Four of the final products are axially chiral and the determination of the rotational barrier by DFT calculations, dynamic NMR and HPLC experiments is demonstrated.

Full text of DOI:10.1016/j.jphotochem.2011.06.006

Journal of Photochemistry and Photobiology A: Chemistry 222 (2011) 263–265
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Journal of Photochemistry and Photobiology A:
Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Photochemical synthesis and properties of axially chiral naphthylpyridines
Pablo Wessig∗, Charlotte Pick
Institut für Chemie Universität Potsdam Karl-Liebknecht-Str. 24-25 D-14476 Potsdam, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Five alkynyl pyridines were prepared and cyclized to naphthylpyridines as the main products in the course
of a Photo-Dehydro-Diels-Alder reaction. Four of the final products are axially chiral and the determination
of the rotational barrier by DFT calculations, dynamic NMR and HPLC experiments is demonstrated.
© 2011 Elsevier B.V. All rights reserved.
Received 19 April 2011
Received in revised form 2 June 2011
Accepted 4 June 2011
Available online 12 June 2011
Keywords:
Photochemistry
Axial chirality
Photo-Dehydro-Diels-Alder reaction
Dynamic NMR
Dynamic HPLC
Molecular modeling
1. Introduction
culations, DNMR and DHPLC experiments are presented in the
Electronic Supplementary Information (ESI).
Heterocyclic biaryls play an important role as ligands in count-
less metal complexes. Especially, pyridyl moieties are part of many
mono- and polydentate ligands. The ligands are closely associated
with catalytic activity, which hallmark many of the metal com-
plexes, in particular those of transition metals [1]. Therefore, there
is a great demand for new synthetic methods for the preparation
of structurally complex ligands.
Synthetic methods for the preparation of biaryls were sum-
marized in several reviews and books and here we refer to this
literature [2]. Most methods for the preparation of heterocyclic
biaryls are based on coupling of already existing rings and in only
few cases one or both aryl moieties are built up in the key step of the
synthesis [3]. One of the latter methods is the Dehydro-Diels-Alder
reaction [4]. Its photochemical version (the Photo-Dehydro-Diels-
Alder reaction, PDDA) has been intensively investigated in our
group in recent years [5]. Herein, we report on the PDDA synthe-
sis of some naphthylpyridines as well as on the conformational
flexibility of the biaryl axis.
3. Results and discussion
The PDDA reaction has proved its worth for the preparation
of highly substituted naphthalenes. The cycloaddition takes place
between an alkyne A and an alkynyl-arene B, giving substituted
naphthalenes C (Scheme 1). If both reactants are alkynyl-arenes
and/or the arenes are not monosubstituted, several regioisomers
are possible [4]. To investigate whether alkynyl-pyridines undergo
the PDDA reaction and how the nitrogen atom influences regiose-
lectivity, we first prepared the three isomeric 3-pyridyl-2-propynyl
3-phenylpropynoates 3a–c. Commencing with commercially avail-
able iodopyridines 1a–c, the 2-propyn-1-ols 2a–c were prepared
by Sonogashira coupling in excellent yields [5]. Esterification with
3-phenyl-propynoic acid provided the target compounds 3a–c
(Scheme 1).
In accordance with previously reported findings [6b], the 3-
phenylpropynoates 3 are unreactive upon direct irradiation. This
phenomenon was attributed to an inefficient intersystem crossing
(ISC) to the triplet state, which is necessary for a successful PDDA
reaction [6]. The problem can be circumvented by irradiation of
such compounds in acetone as triplet sensitizer [7].
2. Materials and methods
Experimental procedures, spectroscopic data, X-ray structure
analysis of compounds 4 and 6, and the details of the DFT cal-
The irradiation of alkynyl pyridines 3a–c in acetone afforded
in all three cases products of a PDDA reaction, even though the
overall yields were rather low in the range of 20–30%. Furthermore,
we found that in each case, both the pyridyl and the phenyl ring
were attacked in the course of the cycloaddition, albeit with a clear
∗
Corresponding author. Tel.: +49 331 977 5401; fax: +49 331 977 5065.
E-mail address: wessig@uni-potsdam.de (P. Wessig).
1010-6030/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jphotochem.2011.06.006

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P. Wessig, C. Pick / Journal of Photochemistry and Photobiology A: Chemistry 222 (2011) 263–265
R3
OH
R1
R3
PDDA
I
OMe
OMe
OMe
R1
iii, iv
i
N
N
N
R2
R2
C
A
B
10
13
11
O
O
Cl
OH
OH
O
vi
v
ii
I
COOH
O
O
OH
Ph
O
O
N
Ph
Ph
PdCl2(PPh3)2
CuI, Et3N
DCC, DMAP
O
15
14
N
N
Ph
OMe
OMe
N
1a ortho
1b meta
1c para
2a 96%
2b 91%
2c 96%
3a 73%
3b 72%
3c 61%
Ph
N
16
12
Scheme 1. Preparation of alkynyl pyridines 3a–c.
Scheme 3. Synthesis of compounds 12 and 16 (i: PdCl2(PPh3)2/CuI/Et3N,
82%, ii: 3-phenylpropynoic acid, DCC, DMAP, 75%, iii trimethyl-silylethyne,
PdCl2(PPh3)2/CuI/Et3N, 70%, iv: K2CO3/MeOH, 97%, v: phosgene, vi: 1. n-BuLi, 2. 15,
10%).
preference for the phenyl ring. X-ray crystal structure analysis of
compounds 4 and 6 permitted an unambiguous assignment of the
structures of heterocyclic biaryls 4–9 (Scheme 2) [8].
The most important conclusion from these first-cut experiments
was that both ortho-positions of one of the two arene moieties must
be interlocked to avoid attack and increase the selectivity. Because
the irradiation of compounds 3 furnished no evidence at all that
the nitrogen atom is attacked, we focused in the second part of this
work on 2-alkynyl pyridines, supplied with a second substituent in
the 3-position of the pyridine moiety.
Starting with 2-iodo-3-methoxy-pyridine 10 [9], we prepared
two 2-alkynyl pyridines 12 and 16 according to the routes depicted
in Scheme 3. Whereas 12 was accessible by the same route
described above for compounds 3, 16 needed another approach. 2-
Ethynyl-3-methoxypyridine 13 was prepared from 10 in two steps
and treated with the chloro formate 15 after lithiation with BuLi
giving 16. 15 was obtained from 3-phenyl-propyn-1-ol and phos-
gene and was used without further purification (Scheme 3).
Upon irradiationof compounds12 and 16 in acetone, we isolated
only one product in each case (17 and 18, respectively, Scheme 4).
Naphthylpyridines 5, 7, 17, and 18 are axially chiral and we
were interested in the rotational barrier ER of the aryl-aryl-bond
to evaluate the usability of such compounds as chiral ligands. First,
we calculated ER by means of two different density functional
methods (B3LYP [10] and M06-2X [11]). The B3LYP functional,
which is very often used in routine calculations [12], results in
consistently lower activation barriers (1–2 kcal/mol) compared
with the M06-2X functional (Table 1). These results indicate the
well-known underestimation of weak non-bonding interactions by
N
O
N
hν
3a
3b
3c
+
+
+
O
[acetone]
O
O
O
O
O
4 (8 %)
5 (11 %)
hν
hν
16
12
O
MeO
MeO
N
N
N
O
hν
N
O
[acetone]
17 (34%)
18 (18%)
O
Scheme 4. Irradiation of compounds 12 and 16 (solvent: acetone).
O
6 (5 %)
7 (25 %)
Table 1
Rotational barriers of compounds 5, 7, 17, 18.
N
a
b
O
Compound
Ecalc
Ecalc
Eexp
N
hν
5
7
17
18
7.5
17.0
16.5
24.4
8.6
18.0
18.5
26.0
–
O
16.0c
19.0c
25.8d
[acetone]
O
a
B3LYP/6-31G* in kcal/mol.
M06-2X/TZVP in kcal/mol.
DNMR.
DHPLC. For details, see ESI.
O
8 (3 %)
9 (24 %)
b
c
d
Scheme 2. Photochemical behavior of compounds 3a–c.

P. Wessig, C. Pick / Journal of Photochemistry and Photobiology A: Chemistry 222 (2011) 263–265
265
B3LYP, which should be important for an accurate calculation of the
rotational barrier of biaryls [13].
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[3] Due to lack of space, only the asymmetric reactions are cited. With respect to
achiral variants, we refer to the references cited therein:
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8382–8383;
To evaluate the calculated Ecalc values, we decided to deter-
mine the rotational barriers experimentally, if possible. Depending
on the height of the rotational barrier, two different meth-
ods are appropriate for this problem. If the barrier amounts
to 15–20 kcal/mol, dynamic NMR (DNMR) [8,14] is the method
of choice, whereas barriers between 20 and 30 kcal/mol are
accessible by dynamic HPL chromatography (DHPLC) [8,15]. The
experimentally determined rotational barriers are summarized
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in Table
values.
1 and are in good agreement with the calculated
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[4] P. Wessig, G. Müller, Chem. Rev. 108 (2008) 2051–2063.
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17 (2006) 1238–1252 (2a);
4. Conclusion
In summary, we reported on the synthesis of eight heterocyclic
biaryls 4–9, 17, 18 with the Photo-Dehydro-Diels-Alder (PDDA) reac-
tion as a key step. Half of these compounds are axially chiral and
we calculated the rotational barriers by means of DFT methods.
Furthermore, we succeeded in the experimental determination of
these barriers with DNMR (7 and 17) and DHPLC (18), respec-
tively. The values calculated with the M06-2X/TZVP method are in
excellent accordance with experimental values and we therefore
emphatically recommend this method for such problems.
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(c) P. Wessig, G. Müller, R. Herre, A. Kühn, Helv. Chim. Acta 89 (2006)
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jphotochem.2011.06.006.
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