Novel cycloaddition of nitriles with monolithio- and dilithiobutadienes

Article abstract of DOI:10.1021/ja0262176

Two novel and synthetically useful reaction patterns of organolithium compounds with nitriles are reported to afford pyridine derivatives as the final products. Both 1-lithio-1,3-dienes and 1,4-dilithio-1,3-dienes, which can be easily generated in situ by lithiation of their corresponding iodo compounds, react with nitriles in the presence of HMPA to form substituted pyridines including 2,2′-bipyridines and tetrahydroisoquinolines in high yields. Copyright

Full text of DOI:10.1021/ja0262176

Published on Web 05/09/2002
Novel Cycloaddition of Nitriles with Monolithio- and Dilithiobutadienes
Jinglong Chen, Qiuling Song, Congyang Wang, and Zhenfeng Xi*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing 100871 China
Received March 18, 2002
The addition of organolithium compounds to nitriles predomi-
nately forms N-lithioketimines,1 which afford ketones or imines
upon hydrolysis, and may be used as reactive intermediates for
synthesis of N-substituted imines.2,3 Although intramolecular trap-
ping of the N-lithioketimines is very attractive for constructing
important N-containing heterocycles such as pyridine derivatives,
with <5% of the pyridine derivative 2a. With temperature increas-
ing, 3a decreased while 2a increased (Table 2). Finally, 3a
disappeared completely, and 2a was formed as the only final product
in 98% yield. On the basis of these observations, a possible reaction
mechanism is given in eq 5. The N-lithioketimines 4 are formed as
few useful reports have appeared. The conventional way to achieve
such syntheses is via subsequent intramolecular nucleophilic
substitution of organohalides (eq 1, X ) F, Cl, or Br).4 Herein we
would like to report two novel and synthetically useful reaction
patterns of organolithium compounds with nitriles affording pyridine
derivatives as the final products (eq 2, X ) H or Li).
the first intermediates, which undergo intramolecular lithiation-
cyclization to afford 5. Elimination of LiH or LiSiMe3 (R′ ) SiMe3)
gives rise to the final pyridine derivatives 2.
Very interestingly, when 1,4-dilithio-1,3-dienes 6, generated in
situ by lithiation of their corresponding 1,4-diiodo-1,3-dienes,6,7
were treated with nitriles in the presence of HMPA, pyridine
Lithiation of 1-iodo-1,3-dienes with 2 equivalents of t-BuLi gave
their corresponding 1-lithio-1,3-dienes 1 in quantitative yields as
monitored by GC.5 Addition of 1 equiv of HMPA (hexameth-
ylphosphoramide) and 1.5 equiv of a nitrile to the above in situ-
generated monolithium reagent caused an immediate reaction to
afford the pyridine derivatives 2 in high yields (eq 3). Representative
Table 1. Formation of Pyridine Derivatives from
1-Lithio-1,3-dienes and Nitriles
examples of pyridines 2 thus prepared are given in Table 1. 1,2,3,4-
Tetrasubstituted 1-lithio-1,3-diene 1a reacted with nitriles (A:
p-tolunitrile, B: 4-methoxybenzonitrile, C: benzonitrile) to afford
pyridines 2a-c in high isolated yields. Tetrahydroisoquinolines 2d
and 2e could be readily prepared in 85 and 75% isolated yields,
respectively, from the reactions of 1b and 1c with benzonitrile. It
is interesting to note that the pyridine derivative 2a and the
desilylated product 2e are formed in the reaction mixtures without
hydrolysis, as demonstrated by NMR.
To investigate the reaction mechanism, an experiment demon-
strated in eq 4 was carried out from -78 °C to room temperature.
After the reaction mixture was stirred at -78 °C for 15 min,
hydrolysis afforded the linear imine 3a in 64% isolated yield along
a GC yields. Isolated yields are given in parentheses. b p-Tolunitrile. c 4-
* To whom correspondence should be addressed. E-mail: zfxi@pku.edu.cn.
Methoxybenzonitrile. d Benzonitrile.
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J. AM. CHEM. SOC. 2002, 124, 6238-6239
10.1021/ja0262176 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Formation of Linear Imine 3a and Pyridine 2a
as determined by NMR. In fact, NMR spectra show that the pyridine
derivatives have been already formed in the reaction mixture. When
the reaction of 6a with 2-cyanopyridine was carried out at -60 °C
in the presence of HMPA, cyclopentadienylamine 8a was isolated
in 29% yield, along with 34% yield of 7a (eq 7). Unlike the case
T/°C
t/min
yield of 3a/%
yield of 2a/%
-78
-60
-60
0
15
30
60
30
30
70 (64)
<5
54
86
95
98
23
10
<3
0
rt
Table 3. Formation of Pyridine Derivatives from
1,4-Dilithio-1,3-dienes and Nitriles
of monolithio compounds 1, no linear imines were observed in cases
of dilithio compounds 6 even at lower temperatures. All these
observations suggest that, although the same pyridines are formed
as the final products, the reaction mechanisms for the formation of
2 from 1 might be different from those for the formation of 2 from
6. Further investigation to elucidate the reaction mechanisms and
further applications of these novel and synthetically useful reactions
are in progress.
Acknowledgment. This work was partially supported by the
Natural Science Foundation of China and the Major State Basic
Research Development Program (G2000077502-D). Cheung Kong
Scholars Program and Qiu Shi Science and Technologies Founda-
tion are gratefully acknowledged. Mr. Yuxing Zhao, Mr. Zhuo Gao,
and Miss Jun Yan carried out some experimental work.
Supporting Information Available: Experimental details, char-
acterization data, copies of H and 13C NMR spectra for all isolated
compounds and IR spectra of 3a (PDF). This material is available free
of charge via the Internet at http//pubs.acs.org.
1
a GC yields. Isolated yields are given in parentheses. b Desilylation took
place in the workup procedure.
derivatives 2 were also formed as the final products in high isolated
yields (eq 6). Both the monolithio compounds 1 and the dilithio
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It is noteworthy that substituted 1,3,5-triazines,1,2 the self-
cyclotrimerization products of nitriles, were formed as byproducts
in these reactions. Therefore, at least 3 equiv of nitriles should be
used to ensure high-yield formation of pyridines 2 from 6. On the
contrary, formation of substituted 1,3,5-triazines was not observed
in cases of 1-lithio-1,3-dienes 1. No dihydropyridines or related
intermediates were observed in the reaction mixtures before workup
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