Reaction of arynes, N-heteroaromatics and nitriles

Article abstract of DOI:10.1039/b602664h

Various N-heteroaromatic compounds, including pyridines, quinolines and isoquinoline, react with arynes and nitrile-containing solvents to give N-arylated 1,2-dihydro-2-pyridinyl, -2-quinolinyl and -1-isoquinolinyl nitriles in excellent yields. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602664h

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Reaction of arynes, N-heteroaromatics and nitriles{
Masilamani Jeganmohan and Chien-Hong Cheng*
Received (in Cambridge, UK) 22nd February 2006, Accepted 11th April 2006
First published as an Advance Article on the web 3rd May 2006
DOI: 10.1039/b602664h
mechanism is related to that of the Reissert reaction,11 used for
Various N-heteroaromatic compounds, including pyridines,
quinolines and isoquinoline, react with arynes and nitrile-
containing solvents to give N-arylated 1,2-dihydro-2-pyridinyl,
-2-quinolinyl and -1-isoquinolinyl nitriles in excellent yields.
the selective addition of various electrophiles and nucleophiles to
the CLN double bond of pyridine derivatives. Strong support for
the mechanism in Scheme 1 comes from the results of a deuterium-
labelling study of the reaction of 1a and 2a with CD3CN 3b. The
observed product, 4b, contains a CD2CN group and a deuterium
atom at one of the ortho-carbons of the phenyl ring (Table 1, entry
2). Product 4b was characterized by the absence of 1H NMR
signals for the methylene proton, and the absence of 13C NMR
signals for the methylene carbon and one of the ortho-carbons of
the phenyl ring. In addition, the two 13C NMR signals of the two
meta-carbons of the phenyl group can be clearly distinguished. The
parent peak in the mass spectrum of 4b also showed the presence
of three deuterium atoms.
The addition of nucleophiles to benzynes, generating the
corresponding zwitterionic species as intemediates, has played a
crucial role in the development of benzyne chemistry.1 With its
low-lying LUMO, benzyne can readily accept an electron lone pair
from neutral nucleophiles such as pyridines,2 pyrroles,3 aziridines,4
imidazoles,5 amides,1c amines,6 urea,7 isocyanides,1a,b alcohols8
and carboxylic acids.8 Trapping of the resulting zwitterionic species
with various electrophiles such as proton sources,1c,6,8 imines or
aldehydes1a,b gave the final products.
To understand the effect of substituents on the benzyne moiety
in the present reaction, various substituted benzyne precursors 1b–
g were tested (Table 1, entries 3–8). Under similar reaction
conditions, compound 1b, containing 4,5-dimethyl groups, reacted
smoothly with 2a and 3a to give the three-component product 4c
in 89% yield (Table 1, entry 3). Likewise, electron-rich benzyne
precursors 1c and 1d reacted with 2a and 3a to afford 4d and 4e in
excellent yields (Table 1, entries 4 and 5). Nevertheless, benzyne
precursor 1e, with two electron-deficient fluoride groups attached,
gave product 4f in moderate 51% yield (Table 1, entry 6). Thus, the
presence of electron-withdrawing substituents on the benzyne ring
appears less favorable for the present reaction, but the reason for
this is not yet clear.
Although a vast number of reactions involving the addition of
nucleophiles to arynes are known, there is no report of the
trapping of the nucleophile–aryne zwitterions by nitrile-containing
solvents. Our continuous interest in new aryne chemistry9 has led
us to the observation that alkyl nitriles with an a-hydrogen, acting
as both a proton donor and a nucleophile, react with pyridine–
benzyne zwitterions at both the benzyne and the pyridine moieties.
Herein, we report the reaction of arynes, N-heteroaromatics and
nitrile-containing solvents. The observation of the reaction of
CH3CN with aryne-based zwitterionic species is particularly
important to benzyne chemistry in view of the fact that the
generation of arynes from 2-trimethylsilylaryl triflates and CsF are
often carried out in CH3CN.
We next studied the regioselectivity of unsymmetrical benzynes
1f and 1g in the present reaction. When 1-(trimethylsilyl)-2-
naphthyl triflate (1f) was treated with isoquinoline (2a) and
CH3CN (3a), two regioisomeric products, 4g and 4g9, were isolated
in an 85 : 15 ratio in 73% combined yield (Table 1, entry 7).
Clearly, 4g is a steric-controlled product. The regiochemistry of 4g
was further confirmed by NOE experiments. On the other hand,
3-methoxybenzyne (1g) afforded 4h, with the methoxy substituent
meta to the amino group, exclusively in 75% yield (Table 1, entry
8). In this reaction, both steric and electronic effects favor 4h.
When 2-trimethylsilylphenyl triflate (1a) was treated with
isoquinoline (2a) in CH3CN (3a) in the presence of CsF at 50 uC
for 8 h, a three-component assembled product from a molecule of
isoquinoline, benzyne and CH3CN, 4a, was obtained in 85%
isolated yield (Table 1, entry 1). It is noteworthy that CH3CN was
a reagent as well as a solvent in the reaction. The reaction is
completely regioselective, with the cyanomethyl group adding only
to the C-1 position of the isoquinoline ring. Product 4a was
thoroughly characterized by its 1H and 13C NMR, and mass data.
In the reaction, benzyne was generated in situ from 1a and CsF.10
The formation of product 4a can be understood based on the
mechanism shown in Scheme 1. Isoquinoline 2a undergoes
nucleophilic addition to benzyne 5 to give zwitterionic species 6.
The negative charge of the zwitterionic species abstracts a proton
from CH3CN (3a) to give intermediate 7 and acetonitrile anion 8.
The latter undergoes nucleophilic addition to the CLN double
bond of isoquinolinium cation 7 to give product 4a. This proposed
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013 Taiwan. E-mail: chcheng@mx.nthu.edu.tw; Fax: +886 3-5724698;
Tel: +886 3-5721454
{ Electronic supplementary information (ESI) available: Experimental
details, characterisation and NMR spectra. See DOI: 10.1039/b602664h
Scheme 1
2454 | Chem. Commun., 2006, 2454–2456
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Table 1 Results of the reaction of arynes, N-heteroaromatics and nitrilesa
Entry 1
2
3
Product
4
Yield (%)b Entry 1
2
3
Product
4
Yield (%)b
80
1
1a 2a 3a
4a
85
10 1b 2b 3a
4j
2
3
1a 2a 3b
1b 2a 3a
4b
4c
84
89
11 1a 2c 3a
4k
4l
79
12 1a 2a 3cd
45e
4
5
1c 2a 3a
4d
4e
85
83
13 1a 2a 3dd
4m
4n
75e
1d 2a 3a
14 1a 2a 3ed
68e
6
7
1e 2a 3a
1f 2a 3a
4f
51
73
15 1a 2d 3a
4o
4p
70
85
4g, 4g9
16 1a 2e 3a
8
9
1g 2a 3a
4h
4i
75c
17 1a 2f 3a
4q, 4q9
82
80
1a 2b 3a
82
18 1a 2g 3a
4r
a
b
Reaction conditions: Benzyne precursor 1 (1.0 mmol), pyridines 2 (1.2 mmol), nitrile 3a or 3b (3 ml) and CsF (2.0 mmol) at 50 uC for 8 h.
Isolated yields. Reaction was carried out at room temperature for 8 h. For nitriles 3c–e, 1.0 ml was used. 1 : 1 diastereoisomeric ratio.
c
d
e
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determined by NOE experiments.13b It is important to point out
that isoquinuclidines are widely occurring natural products that
show various biological activities.13c
In conclusion, we have observed a new reaction of arynes,
N-heteroaromatic compounds and nitriles. The involvement of
CH3CN in the present reaction, and also the likely role of aryne-
based zwitterionic species, is particularly important in the
development of benzyne chemistry, due to the fact that benzynes
are often generated in this solvent. This method allows the
construction of new C–C and C–N bonds in one pot, and allows
an efficient synthesis of various N-arylated 1,2-dihydro-1-isoqui-
nolinyl, 1,2-dihydro-2-quinolinyl and 1,2-dihydro-2-pyridinyl
nitriles in good to excellent yields. Further studies with other
pronucleophiles and different N-heteroaromatic compounds are in
progress.
Scheme 2
In addition to 2a, quinoline (2b) underwent the three-
component reaction efficiently with acetonitrile and benzyne
precursors 1a and 1b under similar reaction conditions to provide
products 4i and 4j in 82 and 80% yields, respectively (Table 1,
entries 9 and 10). Similarly, 6-methoxyquinoline (2c) reacts with 1a
and 3a to afford 4k in 79% yield (Table 1, entry 11). The present
protocol can be further applied to substituted acetonitriles 3c–e.
Propionitrile (3c) reacted effectively with 1a and 2a to give a pair of
diastereomers 4l, albeit in only 45% yield and a 1 : 1
diastereoisomeric ratio (Table 1, entry 12). The low yield relative
to CH3CN is probably due to the lower acidity of the a-protons in
propionitrile. Likewise, 2-phenylacetonitrile (3d), and 2-(2-thienyl)-
acetonitrile (3e) furnished the corresponding products 4m and 4n
We thank the National Science Council of the Republic of
China (NSC-94-2113-M-007-011) for their support of this
research.
Notes and references
1 (a) H. Yoshida, H. Fukushima, J. Ohshita and A. Kunai, Angew.
Chem., Int. Ed., 2004, 43, 3935; (b) H. Yoshida, H. Fukushima,
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2 (a) E. K. Fields and S. Meyerson, J. Org. Chem., 1966, 31, 3307; (b)
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T. Sambaiah and C.-H. Cheng, J. Org. Chem., 2001, 66, 3646; (d)
E. Ihara, A. Kurokawa, T. Koda, T. Muraki, T. Itoh and K. Inoue,
Macromolecules, 2005, 38, 2167.
3 (a) G. Wittig and W. Behnisch, Chem. Ber., 1958, 91, 2358; (b) G. Wittig
and B. Reichl, Chem. Ber., 1963, 96, 2815; (c) L. A. Carpino and
D. E. Barr, J. Org. Chem., 1966, 31, 764; (d) G. Kaupp, J. Perreten,
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and J. M. Vernon, Adv. Heterocycl. Chem., 1974, 16, 87.
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Int. Ed., 2002, 41, 3247.
8 Z. Liu and R. C. Larock, Org. Lett., 2004, 6, 99.
9 (a) M. Jeganmohan and C.-H. Cheng, Org. Lett., 2004, 6, 2821; (b)
M. Jeganmohan and C.-H. Cheng, Synthesis, 2005, 5, 1693; (c)
T. T. Jayanth, M. Jeganmohan and C.-H. Cheng, Org. Lett., 2005, 7,
2921; (d) T. T. Jayanth and C.-H. Cheng, Chem. Commun., 2006, 894;
(e) T. T. Jayanth, M. Jeganmohan, M.-J. Cheng, S.-Y. Chu and
C.-H. Cheng, J. Am. Chem. Soc., 2006, 128, 2232.
10 (a) Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983,
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in 75 and 68% yields, respectively, both in ca.
1 : 1
diastereoisomeric ratios (Table 1, entries 13 and 14), determined
1
by H NMR experiments. It is noteworthy that 1,2-dihydroiso-
quinoline and 1,2-dihydroquinoline skeletons are found in a large
number of naturally-occurring and synthetic biologically-active
heterocyclic compounds. These substances exhibit psychotropic,
anti-allergenic anti-inflammatory, sedative, anti-depressant, anti-
tumor, and anti-microbial activities.12
The present methodology can be further extended to pyridines
2d–g. Under the standard reaction conditions, the reaction of
pyridine (2d) with 1a and 3a afforded 4o in 70% yield (Table 1,
entry 15). Similarly, 4-phenylpyridine (2e) gave 4p in 85% yield
(Table 1, entry 16). The use of unsymmetrically-substituted
pyridine 2f as a substrate uncovers the regioselectivity of the
reaction. Treatment of 3-phenylpyridine (2f) with 1a and 3a
provided two regioisomeric products 4q and 4q9 with a 55 : 45 ratio
in 82% combined yield (Table 1, entry 17). Products 4q and 4q9
were separated by column chromatography and fully characterized
by spectroscopic techniques. In contrast, 2-phenylpyridine (2g)
reacted with 1a and 2a regioselectively to afford 4r exclusively in
80% yield (Table 1, entry 18). The other regioisomer was not
observed in the 1H NMR spectrum of the crude reaction mixture.
The result of the three-component reaction of pyridine (2d) with 1a
and 3a is surprising in view of the results reported by Ihara et al.,
which showed the formation of pyridine–benzyne polymer at a
slightly lower temperature.2d Therefore, we checked carefully the
reaction mixtures and observed some polymerized product, but in
a very low yield. For the substituted pyridines 2e–g, no
polymerization product was observed.
12 (a) Y. Luo, Z. Li and C. Li, Org. Lett., 2005, 7, 2675 and references
therein; (b) I. N. Nesterova, L. M. Alekseeva, S. M. Golovira and
V. G. Granik, Khim.-Farm. Zh., 1995, 29, 31, Chem. Abs., 1996, 124,
117128t; (c) N. Yamada, S. Kadowaki, K. Takahashi and K. Umezu,
Biochem. Pharmacol., 1992, 44, 1211; (d) K. Faber, H. Stueckler and
T. Kappe, J. Heterocycl. Chem., 1984, 21, 1177; (e) E. Lukevics, I. Segal,
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1173; (g) K. Frisch, A. Landa, S. Saaby and K. A. Jorgensen, Angew.
Chem., Int. Ed., 2005, 44, 6058 and references therein.
To demonstrate the utility of 1,2-dihydropyridine in organic
synthesis, we carried out the [4 + 2] Diels–Alder cycloaddition
reaction of 1,2-dihydropyridine with N-phenyl maleimide (9).13
Treatment of 4o with 9 in toluene at 80 uC for 6 h afforded
2-azabicyclo[2.2.2]octane (isoquinuclidine) derivative 10 in 80%
isolated yield (Scheme 2). The reaction is highly stereospecific and
only one diastereomer was isolated. The stereochemistry was
13 (a) M. Saunders and E. H. Gold, J. Org. Chem., 1962, 27, 1439; (b)
C. Chen and B. Munoz, Tetrahedron Lett., 1999, 40, 3491; (c)
H. Nakano, N. Tsugawa and R. Fujita, Tetrahedron Lett., 2005, 46,
5677 and references therein.
2456 | Chem. Commun., 2006, 2454–2456
This journal is ß The Royal Society of Chemistry 2006