Synthesis of 2-Aza[6]helicene and attempts to synthesize 2,14-diaza[6]helicene utilizing metal-catalyzed cycloisomerization

Article abstract of DOI:10.1021/jo100252a

A modular synthetic approach leading to 2-aza[6]helicene is reported. It involves assembly of key hetero biphenylylnaphthalenes from functionalized building blocks and study of their metal catalyzed cycloisomerization.

Full text of DOI:10.1021/jo100252a

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silver(I),5 and chiroptical properties controlled by metal co-
Synthesis of 2-Aza[6]helicene and Attempts
To Synthesize 2,14-Diaza[6]helicene Utilizing
Metal-Catalyzed Cycloisomerization
ordination6 have been performed. During the past few years,
besides photochemical procedures,7 only two examples of
nonphotochemical synthesis of aza[6]helicenes have been
elaborated, [2 þ 2 þ 2] cycloisomerization of triynes5a,8 and
Stille-Kelly reaction of dihalogenated cis-stilbene-type
precursors.9 To our best knowledge only one study of diaza-
[6]helicene synthesis utilizing unsuccessful photocyclode-
hydrogenation of pyridine containing stilbene-type precursor
and effective Stille-Kelly reaction of 2,7-bis(2-(pyridin-3-yl)-
vinyl)naphthalene3b has been described up to now. Promising
applications of azahelicenes in various branches of chemistry
and material science might be envisaged, therefore, further
research in the field and a larger scale preparation by simple
methods is required.
ꢀ
Jan Storch,* Jan Cermak, Jindrich Karban, Ivana Cısarova,
ꢁ
and Jan Sykora
ꢀ
ꢀ ꢁ
ꢁ
Institute of Chemical Process Fundamentals of the AS CR, v.v.i.,
ꢁ
Rozvojova 135, CZ-16502 Prague 6, Czech Republic
storchj@icpf.cas.cz
Received February 15, 2010
Recently, we have developed an alternative approach to
[6]helicene synthesis, which involves platinum-catalyzed double
cycloisomerization of biphenylylnaphthalene derivatives.10
We decided to continue exploring its potential to prepare
aza[6]helicene and diaza[6]helicenes. Herein, we report on the
synthesis of two nitrogen-containing biphenylylnaphthalenes,
which were subjected to metal-catalyzed cycloisomerization.
This modular method is again based on assembling from
functionalized building blocks with final atom economic
transformation.
3-Bromo-4-iodopyridine 1 prepared from commercially
available 3-bromopyridine according to the literature pro-
cedure11 was converted into 2 by Sonogashira coupling with
propyne. Boronic acid 3 was obtained from 2 by lithiation
in diethyl ether and subsequent reaction with B(OMe)3
(Scheme 1).
A modular synthetic approach leading to 2-aza[6]helicene
is reported. It involves assembly of key hetero bipheny-
lylnaphthalenes from functionalized building blocks and
study of their metal catalyzed cycloisomerization.
SCHEME 1. Synthesis of Pyridine Building Block
Azahelicenes are a subgroup of helicenes, a fascinating class
of compounds which possess a unique screw-shaped π-con-
jugated aromatic systems consisting of all ortho-annelated
aromatic and heteroaromatic rings. Despite their chiralityand
possibility of coordination of the heteroatoms with metals,
there are only scattered examples of using azahelicene deriva-
tives in asymmetric catalysis.1 Studies focused on their self-
assembly,2 basicities,3 proton affinities,4 complexation with
(1) (a) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem., Int.
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Ed. 2008, 47, 9708. (b) Samal, M.; Mısek, J.; Stara, I. G.; Stary, I. Collect.
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Czech. Chem. Commun. 2009, 74, 1151.
ꢀ
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(2) (a) Tanaka, K.; Kitahara, Y.; Suzuki, H.; Osuga, H. Tetrahedron Lett.
1996, 37, 5925. (b) Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett.
2000, 2, 3169.
(3) (a) Staab, H. A.; Zirnstein, M. A.; Krieger, C. Angew. Chem., Int. Ed.
Engl. 1989, 28, 86. (b) Staab, H. A.; Diehm, M.; Krieger, C. Tetrahedron Lett.
1994, 35, 8357.
Suzuki coupling of the triflate 410 with the boronic acid 3
under standard conditions afforded azabiphenylylnaphtha-
lene 5 in 35% yield (Scheme 2). This racemic diastereomers
ꢁ
€
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(4) Roithova, J.; Schroder, D.; Mısek, J.; Stara, I. G.; Stary, I. J. Mass
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Spectrom. 2007, 42, 1233.
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(5) (a) Mısek, J.; Teply, F.; Stara, I. G.; Tichy, M.; Saman, D.; Cısarova,
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I.; Vojtısek, P.; Stary, I. Angew. Chem., Int. Ed. 2008, 47, 3188. (b) Mısek, J.;
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(8) Andronova, A.; Szydlo, F.; Teply, F.; Tobrmanova, M.; Volot, A.;
Tichy, M.; Stara, I. G.; Stary, I.; Schroder, D. Collect. Czech. Chem.
Commun. 2009, 74, 323.
(6) Graule, S.; Rudolph, M.; Vanthuyne, N.; Autschbach, J.; Roussel,
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Stara, I. G.; Stary, I.; Rulısek, L.; Saman, D.; Cvacka, J.; Fiedler, P.;
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Vojtisek, P. Collect. Czech. Chem. Commun. 2009, 74, 189.
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Ch.; Crassous, J.; Reau, R. J. Am. Chem. Soc. 2009, 131, 3183.
(9) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem., Int. Ed.
2008, 47, 9708.
(7) (a) Staab, H. A.; Diehm, M.; Krieger, C. Tetrahedron Let. 1994, 35,
8357. (b) Aloui, F.; Abed, R. E.; Hassine, B. B. Tetrahedron Lett. 2008, 49,
1455. (c) Aloui, F.; Abed, R. E.; Marinetti, A.; Hassine, B. B. Tetrahedron
Lett. 2008, 49, 4092.
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(10) Storch, J.; Sykora, J.; Cermak, J.; Karban, J.; Cısarova, I.; Ruzicka,
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A. J. Org. Chem. 2009, 74, 3090.
(11) Baxter, P. N. W. Chem.;Eur. J. 2003, 9, 2531.
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DOI: 10.1021/jo100252a
r
Published on Web 04/14/2010
J. Org. Chem. 2010, 75, 3137–3140 3137
2010 American Chemical Society

Storch et al.
JOCNote
SCHEME 2. Construction of Azabiphenylylnaphthalene
behaves similarly as their carbo-analogue.10 The free energy of
activation of hindered rotation in 5 is slightly lower than that
FIGURE 1. ORTEP projection of the crystal structure 9.
inthecarbo-analogue10 -ΔGq300 =14.5and15.0kcal mol-1
,
3
respectively (for the variable-temperature 1H NMR analysis
see Figures S6 and S7 in the Supporting Information), and
thus, rapid rotation around the pyridine-phenyl bond at
ambient temperature makes it impossible to separate the
two diastereomers.
both conformational isomers. The structure of 9 proposed by
NMR spectroscopy was later confirmed by X-ray crystallo-
graphy. The crystal lattice of 9 contains both enantiomers
(space group P-1) (Figure 1).
Having 5 and 9 in hand, we could investigate their ability to
undergocycloisomerizationtoformaza- anddiaza[6]helicenes
(Table 1). Previously, we found that carbo-analogues were
appropriate substrates for fast isomerization to [6]helicenes
under platinum catalysis.10 In the case of 5, attempts for
cycloisomerization by PtCl2 or PtCl4 failed (entries 1 and 2).
Partial success was achieved with InCl3 (entry 3) yielding half-
cyclized molecule isolated as an addition product with HCl 12,
which could be formed during the reaction. Finally, we found
that when the isomerization reaction was carried out with the
catalyst mixture composed of InCl3 and PtCl4 (entry 4) the
desired product 10 was successfully obtained in 80% yield.
Unfortunately, the attempts for cycloisomerisation of azabi-
phenylylisoquinoline 9 using the same reaction conditions as
for 5 (entries 4-7) did not work. The use of AuI and AuIII
catalysts14 also did not bring any success (entries 8-17). Also,
Hg(OTf)2-catalyzed15 enyne cycloizomerization gave no reac-
tion. Attempts for electrophilic cyclization using iodonium
chloride16 provided only addition product 13. Conversion of 9
into bis(pyridinium) dichloride by HCl leading to neglecting
of potential coordination properties and subsequent attempts
for cycloizomerization catalyzed by PtCl2, PtCl4, or InCl3 also
failed.
The multistep synthesis of isoquinoline building block
started from isoquinolin-5-ylboronic acid12 6 prepared from
5-bromoisoquinoline13 and 2-bromo-1-methoxy-3-(propyn-
1-yl)benzene10 7 (Scheme 3). Suzuki coupling provided
5-(2-methoxy-6-(propyn-1-yl)phenyl)isoquinoline 8a which
was converted via ether cleavage into desired triflate 8c.
SCHEME 3. Synthesis of Isoquinoline Building Block
Then, we could assemble the pyridylphenylisoquinoline
backbone by the Suzuki coupling of boronic acid 3 and
triflate 8c under analogous conditions resulting in the for-
mation of desired diastereomeric mixture of 9 in 41% yield
(Scheme 4).
In conclusion, we have explored metal-catalyzed cyclo-
isomerization of nitrogen-containing byphenylylnaphtha-
lenes prepared by Suzuki coupling of functionalized building
blocks. Our approach was successfully applied to the synth-
esis of 2-aza[6]helicene. Further efforts directed at achieving
so far unsuccessful cycloisomerization of 9 yielding 2,14-
diaza[6]helicene continue in our laboratories.
SCHEME 4. Synthesis of Azabiphenylylisoquinoline
Experimental Section
3-(2-(Naphth-1-yl)-3-(propyn-1-yl)phenyl)-4-(propyn-1-yl)-
pyridine (5). A mixture of Pd(PPh3)4 (200 mg, 0.17 mmol, 10 mol %)
and triflate 4 (0.7 g, 1.8 mmol) in toluene (9 mL) was stirred for
5 min at room temperature under argon. Aqueous Na2CO3 (2 M,
4.5 mL, 9 mmol, 5 equiv) was added to the mixture, followed by
the boronicacid3 (0.36 g, 2.24 mmol, 1.2equiv) inethanol(9mL).
In this case, the rotation barrier is much lower compared to
5, and at ambient temperature, we can see average spectrum of
~ ~
(14) (a) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402.
(12) Lee, I. Y. C.; Jung, M. H.; Lim, H. J.; Lee, H. W. Heterocycles 2005,
65, 2505.
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€
(13) Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner,
R. J.; Didomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.; Drizin, I.;
Hannick, S. M.; Macri, B. S.; McDonald, H. A.; Honore, P.; Wismer, C. T.;
Marsh, K. C.; Wetter, J.; Stewart, K. D.; Oie, T.; Jarvis, M. F.; Surowy, C. S.;
Faltynek, C. R.; Lee, C. H. J. Med. Chem. 2005, 48, 744.
(b) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(c) Nevado, C.; Echavarren, A. M. Chem.;Eur. J. 2005, 11, 3155.
(15) Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T.
Org. Lett. 2003, 5, 4563.
(16) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
3138 J. Org. Chem. Vol. 75, No. 9, 2010

Storch et al.
JOCNote
TABLE 1. Cycloisomerization Reaction Experiments
entry
substrate, X
catalyst (mol %), solvent
PtCl2 (10), toluene
PtCl4 (10), toluene
temp, °C
GC, %
1
2
3
4
5
CH
CH
CH
CH
N
90
90
90
90
90
90
0
0
InCl3 (10), toluene
40a
80
0
InCl3 (5), PtCl4 (5), toluene
PtCl2 (10), toluene
PtCl4 (10), toluene
6
N
0
7
8
9
N
N
N
InCl3 (10), toluene
AuCl (10), MeCN
AuCl (10), toluene
90
70
90
0
0
0
10
11
12
13
14
15
16
17
18
19
20
N
N
N
N
N
N
N
N
AuCl(PPh3) (10), DCM
AuCl(PPh3) (10), AgOTf (10), MeNO2
AuCl(PPh3) (10), AgOTf (10), DCM
AuCl(PPh3) (10), AgBF4 (10), DCM
AuCl3 (10), toluene
AuCl3 (10), PPh3 (10), DCM
AuCl3 (10), AgOTf (10), DCM
AuCl3 (10), AgBF4 (10), DCM
Hg(OTf)2 (6), MeCN
rt
80
rt
rt
90
rt
rt
rt
60
0
0
0
0
0
0
0
0
N
N
N
0
Hg(OTf)2 (10), tetramethylurea (30), MeCN
ICl (3 equiv), DCM
rt
0
-78 to rt
80b
aIsolated product.
bIsolated product.
The mixture was heated at 75 °C for 20 h and then cooled to room
temperature, diluted with water, and extracted with ethyl acetate
(3ꢀ 30 mL). Combined organic extracts were dried and evaporated
in vacuo. The residue was purified by column chromatography
(ethyl acetate/petroleum ether, 2:1). Product was obtained as color-
less oil (0.23 g, 35%): 1H NMR (500 MHz; C2D2Cl4, 75 °C) δ 8.10
(d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.72 (d,
J = 8.1 Hz, 1H), 7.68-7.64 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.48-7.47 (m, 2H), 7.43- 7.35 (m, 3H), 7.32 (d, J = 6.8 Hz, 1H),
7.08 (d, J = 5.1 Hz, 1H), 1.99 (s, 3H), 1.56 (s, 3H); 13C NMR
(125 MHz; C2D2Cl4, 75 °C) δ 149.6 (d), 146.9 (d), 141.7 (s), 133.0
(s), 132.0 (s), 131.9 (d), 131.1 (s), 130.1 (d), 128.9 (s), 128.2 (d), 128.1
(s), 127.7 (d), 127.3 (d), 126.7 (d), 126.3 (d), 125.5 (d), 125.4 (s),
125.18 (d), 125.17 (s), 125.1 (d), 124.5 (d), 94.5 (s), 90.0 (s), 79.0 (s),
77.2 (s), 4.3 (q), 3.7 (q); EI-MS m/z357 (84, Mþ), 342, 327, 317, 171,
163, 150. Anal. Calcd for C27H19N: C, 90.72; H, 5.36; N, 3.92.
Found: C, 90.52; H, 5.33; N, 3.87.
5-(2-(Propyn-1-yl)-6-(4-(propyn-1-yl)pyridin-3-yl)phenyl)-
isoquinoline (9). A mixture of Pd(PPh3)4 (224 mg, 0.19 mmol,
10 mol %), LiCl (90 mg, 2.13 mmol, 1.1 equiv), and triflate 8c
(0.76 g, 1.94 mmol) in toluene (9.7 mL) was stirred for 5 min
at room temperature under argon. Aqueous Na2CO3 (2 M,
4.85 mL, 44 mmol, 5 equiv) was added to the mixture,
followed by the boronic acid 3 (1.39 g, 8.73 mmol, 4.5 equiv)
in ethanol (9.7 mL). The mixture was heated at 75 °C for 20 h
and then cooled to room temperature, diluted with water, and
extracted with ethyl acetate (3 ꢀ 30 mL). Combined organic
extracts were dried and evaporated in vacuo. The residue was
purified by column chromatography (ethyl acetate/petroleum
ether/acetone, 2:1:1 þ 5% i-Pr2NH). The product was obtained
as a colorless oil (0.29 g, 41%) which solidified upon standing: 1H
NMR (500 MHz; CDCl3) δ 9.17 (bs, 1H), 8.13 (d, J = 4.3 Hz, 1H),
8.1-7.9 (bm, 1H), 7.81 (bm, 1H), 7.63 (dd, J = 1.1, 7.6 Hz, 1H),
7.55-7.37 (bm, 4H), 7.47 (t, J = 7.7 Hz, 1H), 7.42 (dd, J = 1.3 7.8
Hz, 1H), 7.04 (bm, 1H), 1.93 (s, 3H), 1.53 (s, 3H); 13C NMR (125
MHz; CDCl3) δ 154.9 (d), 152.5 (d), 147.6 (d), 142.4 (d), 140.0 (s),
137.9 (s), 137.5 (s), 136.1 (s), 134.6 (s), 132.3 (d), 132.2 (d), 131.2 (s),
130.3 (d), 128.2 (s), 127.5 (d), 127.3 (d), 126.2 (d), 125.8 (d), 125.3
(s), 119.2 (d), 94.7 (s), 90.4 (s), 78.6 (s), 77.0 (s), 4.6 (q), 4.0 (q); MS
(EI) m/z 358 (100, Mþ), 343, 228, 315, 301, 288, 274, 264, 250, 238,
224, 213, 200, 187, 178, 157, 151, 143, 137, 124, 112. Anal. Calcd for
C26H18N2: C, 87.12; H, 5.06; N, 7.82. Found: C, 87.04; H, 5.23; N,
7.79.
2-Aza-6,10-dimethyl[6]helicene (10). A solution of 5 (0.4 g,
1.12 mmol), PtCl4 (18.9 mg, 0.056 mmol, 5 mol %), and InCl3
(13 mg, 0.056 mmol, 5 mol %) in toluene (10 mL) was stirred for
20 h at 90 °C. The solvent was evaporated. Purification of the
residue by column chromatography (ethyl acetate/petroleum
ether, 50:50 - 67:33) gave 0.31 g (78%) of 10 as a colorless oil.
1H NMR (500 MHz; CDCl3) δ 8.71 (s, 1H), 8.18 (d, J = 8.5 Hz,
1H), 8.15 (d, J = 5.4 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (d,
J = 8.5 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.84 (d,
J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.49 (d,
J = 8.8 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 6.70 (t, J = 7.4 Hz,
1H), 2.95 (s, 3H), 2.92 (s, 3H); 13C NMR (125 MHz; CDCl3) δ
150.0 (d), 142.5 (d), 137.7 (s), 134.7 (s), 134.3 (s), 132.8 (s), 131.9
(s), 131.1 (s), 130.1 (s), 129.1 (s), 128.4 (s), 128.3 (d), 128.2 (d),
128.0 (d), 127.3 (s), 127.2 (d), 126.9 (d), 125.7 (d), 125.1 (d), 124.7
J. Org. Chem. Vol. 75, No. 9, 2010 3139

Storch et al.
JOCNote
(d), 124.1 (s), 123.0 (d), 122.5 (s), 122.0 (d), 119.3 (d), 20.7 (q),
20.0 (q); MS (EI) m/z 357 (91, Mþ), 342, 327, 317, 171, 163, 150,
137. Anal. Calcd for C27H19N: C, 90.72; H, 5.36; N, 3.92.
Found: C, 90.68; H, 5.41; N, 3.89.
Education (Grant No. MSM0021620857). NMR measure-
ments were supported by the Grant Agency of ASCR (Grant
No. IAA400720706). All of the financial support is gratefully
acknowledged.
Acknowledgment. The synthetic work was supported by
the Ministry of Education, Youth and Sport of the Czech
Republic (Grant No. LC06070) and the Grant Agency of the
Czech Republic (Grant No. P207/10/1124). The service of
the X-ray diffractometer was supported by the Ministry of
Supporting Information Available: Experimental procedures
1
and spectroscopic details for 2, 3, 8a-c; H and 13C NMR
spectra for all compounds; X-ray diffraction data for 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3140 J. Org. Chem. Vol. 75, No. 9, 2010