Cycloaddition reactions of 1-lithio-1,3-dienes with aromatic nitriles affording multiply substituted pyridines, pyrroles, and linear butadienylimines

Article abstract of DOI:10.1021/jo061574a

Fully or partially substituted 1-iodo- or 1-bromo-1,3-dienes could be readily lithiated using t-BuLi or n-BuLi to afford their corresponding 1-lithio-1,3-diene derivatives in quantitative yields. When these in situ generated lithium reagents were treated

Full text of DOI:10.1021/jo061574a

Cycloaddition Reactions of 1-Lithio-1,3-dienes with Aromatic
Nitriles Affording Multiply Substituted Pyridines, Pyrroles, and
Linear Butadienylimines
Congyang Wang,† Zhihui Wang,† Lantao Liu,‡ Chao Wang,† Guangzhen Liu,† and
Zhenfeng Xi*,†,§
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College of Chemistry, Peking UniVersity, Beijing
100871, China, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China, and State
Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
zfxi@pku.edu.cn
ReceiVed July 29, 2006
Fully or partially substituted 1-iodo- or 1-bromo-1,3-dienes could be readily lithiated using t-BuLi or
n-BuLi to afford their corresponding 1-lithio-1,3-diene derivatives in quantitative yields. When these in
situ generated lithium reagents were treated with organonitriles, depending on the substitution patterns
of the butadienyl skeletons, substituted pyridines, pyrroles, and/or linear butadienyl imines were formed
in good to excellent yields via N-lithioketimine intermediates. In the cases of 1,2,3,4-tetrasubstituted and
2,3-disubstituted 1-lithio-1,3-dienes, pyridine derivatives or linear butadienyl imines were generally formed
depending on the reaction temperatures. When 1,2,3,4-tetrasubstituted 4-halo-1-lithio-1,3-dienes and 1,2-
disubstituted 1-lithio-1,3-dienes were treated with organonitriles, pyrrole derivatives or linear butadienyl
imines were obtained. Competition between 5-exo and 6-endo cyclization was found to be responsible
for the formation of either pyrroles or pyridines. Selective elimination of RLi from the lithiated cyclic
N-containing intermediates was observed. The order of elimination was found to be LiCl > Me3SiLi >
LiH.
Introduction
pyrrole derivatives has continuously been a major research topic
in synthetic chemistry,1,2 because these N-containing hetero-
cycles, especially pyridine and pyrrole derivatives, are of great
importance in many areas including natural products synthesis,
materials chemistry, coordination chemistry, pharmaceutical
chemistry, and the agrochemical industry.1-4 Among the many
synthetic methods for pyridine and pyrrole derivatives with a
The development of synthetically useful methods for the
preparation of N-containing heterocycles such as pyridine and
† Peking University.
‡ Institute of Chemistry, Chinese Academy of Sciences.
§ State Key Laboratory of Organometallic Chemistry, Chinese Academy of
Sciences.
10.1021/jo061574a CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/30/2006
J. Org. Chem. 2006, 71, 8565-8571
8565

Wang et al.
wide diverse of substitution patterns,1-4 the addition reaction
of organolithium reagents to organonitriles, which is funda-
mental in organometallic chemistry,5-7 provides an alternative
synthetic method.5-9
SCHEME 1. Generation and Reaction of
1,2,3,4-Tetrasubstituted 1-Lithio-1,3-dienes with
Organonitriles Affording Multiply Substituted Pyridine
Derivatives
Conventionally, the addition intermediates, N-lithioketimines,
are intramolecularly trapped by organohalides via nucleophilic
substitution to generate N-containing heterocycles such as
pyridines.8,9 We have recently communicated a novel synthetic
method for the preparation of pyridines from the cycloaddition
of organonitriles with 1-lithio-1,3-dienes (Scheme 1).10 On the
basis of the experimental observations, we have proposed a
reaction mechanism for this addition reaction leading to pyridine
SCHEME 2. A Proposed Reaction Mechanism for the
Reaction of 1-Lithio-1,3-dienes with Organonitriles Leading
to Pyridine Derivatives
(1) For recent reviews on the synthesis of pyridine derivatives, see: (a)
Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787-3901. (b) Jones, G. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, V. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, pp 167-243. (c)
Grotjahn, D. B. Transition Metal Alkyne Complexes: Transition Metal-
Catalyzed Cyclotrimerization. In ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Hegedus, L. S., Vol.
Ed.; Pergamon: Oxford, 1995; Vol. 12, p 741. (d) Henry, G. D. Tetrahedron
2004, 60, 6043-6061. (e) Newkome, G. R.; Patri, A. K.; Holder, F.;
Schubert, U. S. Eur. J. Org. Chem. 2004, 235-254. (f) Xi, Z.; Li, Z. Top.
Organomet. Chem. 2004, 8, 27-56.
(2) For recent reviews on the synthesis of pyrrole derivatives, see: (a)
Luh, T. Y.; Lee, C. F. Eur. J. Org. Chem. 2005, 3875-3885. (b) Sundberg,
R. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Scriven, V. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 119. (c)
Gribble, G. W. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2,
p 207. (d) Jones, R. A. Pyrroles, Part II, The Synthesis, Reactivity and
Physical Properties of Substituted Pyrroles; Wiley: New York, 1992. See
also: (e) Mathew, P.; Asokan, C. V. Tetrahedron 2006, 62, 1708-1716.
(f) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8, 835-838 and references
therein.
(3) Sainz, Y. F.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem. 2005, 70,
10086-10095 and references therein.
(4) For reviews on the bioactivity and physical properties of pyrrole
derivatives, see: (a) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-
3603. (b) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783. (c) Balme,
G. Angew. Chem., Int. Ed. 2004, 43, 6238-6241. (d) Yamaguchi, S.; Tamao,
K. J. Organomet. Chem. 2002, 653, 223-228. (e) Guernion, N. J. L.; Hayes,
W. Curr. Org. Chem. 2004, 8, 637-651.
SCHEME 3. 6-Endo-trig versus 5-Exo-trig
(5) Wakefield, B. J. Organolithium Methods; Academic Press: San
Diego, CA, 1988; p 62.
(6) For recent reviews on the reaction of organolithium reagents with
organonitriles affording pyridine derivatives and related compounds, see:
(a) Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459-490. (b) Langer,
P.; Freiberg, W. Chem. ReV. 2004, 104, 4125-4149. (c) Xi, Z. Eur. J. Org.
Chem. 2004, 2773-2781. (d) Najera, C.; Sansano, J. M.; Yus, M.
Tetrahedron 2003, 59, 9255-9303.
(7) Reactions of mono organolithium compounds with nitriles: (a) Anker,
R. M.; Cook, A. H. J. Chem. Soc. 1941, 323-331. (b) Scala, A. A.; Bikales,
N. M.; Becker, E. I. J. Org. Chem. 1965, 30, 303-304. (c) Berry, D. J.;
Wakefield, B. J. J. Chem. Soc. C 1971, 642-645. (d) Berry, D. J.; Cook,
J. D.; Wakefield, B. J. J. Chem. Soc., Perkin Trans. 1 1972, 2190-2192.
(e) Cook, L. S.; Wakefield, B. J. Tetrahedron Lett. 1976, 147-150. (f)
Cook, L. S.; Wakefield, B. J. J. Chem. Soc., Perkin Trans. 1 1980, 2392-
2397. (g) Seyferth, D.; Hui, R. C.; Wang, W. J. Org. Chem. 1993, 58,
5843-5845. (h) Armstrong, D. R.; Clegg, W.; MacGregor, M.; Mulvey,
R. E.; O’Neil, P. A. J. Chem. Soc., Chem. Commun. 1993, 608-610. (i)
Armstrong, D. R.; Henderson, K. W.; MacGregor, M.; Mulvey, R. E.; Ross,
M. J.; Clegg, W.; O’Neil, P. A. J. Organomet. Chem. 1995, 486, 79-93.
(j) Ball, S. C.; Davies, R. P.; Raithby, P. R.; Shields, G. P.; Snaith, R. J.
Organomet. Chem. 1998, 550, 457-461. (k) Coleman, C. M.; O’Shea, D.
F. J. Am. Chem. Soc. 2003, 125, 5054-5055.
derivatives. As illustrated in Scheme 2, the N-lithioketimines 4
must be formed as the reactive addition intermediates at -78
°C, because hydrolysis of the reaction mixture at -78 °C
afforded the linear imines 5 in high yields.10 With reaction
temperature increasing, intramolecular lithiation-cyclization took
place to form cyclic intermediates 6-8, which afforded pyridine
derivatives via elimination of LiH.
As described above, the reaction of 1,2,3,4-tetrasubstituted
1-lithio-1,3-dienes 2 with organonitriles afforded pyridine
derivatives exclusively as the final products at room tempera-
ture.10 However, in principle, a five-membered N-containing
heterocycle such as a pyrrole derivative 9 might be also formed
(Scheme 3). In addition, aromatization via elimination of a
lithium salt from 8 is the driving force. It could be expected
that, as illustrated in Scheme 4, either LiR4 or LiR5 might be
(8) Recent references on the reaction of organolithium reagents with
organonitriles leading to pyridine formation, see: (a) Hansen, H. M.; Lysen,
M.; Begtrup, M.; Kristensen, J. K. Tetrahedron 2005, 61, 9955-9960. (b)
Kristensen, J. K.; Vedso, P.; Begtrup, M. J. Org. Chem. 2003, 68, 4091-
4092. (c) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4, 2687-2690. (d) Lysen,
M.; Kristensen, J. L.; Vedso, P.; Begtrup, M. Org. Lett. 2002, 4, 257-259.
(e) Pawlas, J.; Vedso, P.; Jakobsen, P.; Huusfeldt, P. O.; Begtrup, M. J.
Org. Chem. 2001, 66, 4214-4219.
(9) Jakiela, D. J.; Helquist, P.; Jones, L. D. Org. Synth. 1984, 62, 74-
85.
(10) Chen, J.; Song, Q.; Wang, C.; Xi, Z. J. Am. Chem. Soc. 2002, 124,
6238-6239.
8566 J. Org. Chem., Vol. 71, No. 22, 2006

Reactions of 1-Lithio-1,3-dienes with Aromatic Nitriles
SCHEME 4. Elimination of R4Li versus Elimination of
R5Li
SCHEME 6. Elimination of LiSiMe3 versus Elimination of
LiH
With the above results in hand, we tried to investigate
reactions of other types of 1-lithio-1,3-dienes with organonitriles.
First, 1,2,3,4-tetraethyl 1-iodo-4-chloro-1,3-diene 10a was pre-
pared.11,12 Selective lithiation of 10a afforded 1-lithio-1,3-diene
11a in a quantitative yield as followed by GC measurement.
Reactions of 11a with organonitriles afforded the linear imines
12 in high isolated yields upon hydrolysis at -78 °C after the
reaction mixture was stirred at -78 °C for 1 h, as expected
(Scheme 7). It is noteworthy that these linear imines were stable
in air and could tolerate the normal workup procedures and
purification process using column chromatography. The reaction
temperature was then increased. After 3 h at 0 °C, the linear
imine 12a decreased to 50% yield, while the pyridine derivative
3d appeared and was obtained in 39% isolated yield. The linear
imines disappeared completely after 3 h at room temperature.
Hydrolysis of the reaction mixtures afforded the pyridine
derivatives 3d and 3e in 47% and 56% isolated yields,
respectively. Surprisingly, along with formation of the expected
pyridines derivatives 3d and 3e, unexpected pyrrole derivatives
13a and 13b were also obtained. If the reaction temperature
was increased to 50 °C immediately from -78 °C, the pyridines
derivatives 3 were not obtained at all in most cases, while the
pyrrole derivatives 13 were obtained as the only final products
in high isolated yields. To further study the reaction mechanism,
we treated the isolated linear imine 12a with n-BuLi. At this
treatment, the N-lithioketimine 14a should be formed. As
expected, a mixture of 3d and 13a was obtained (Scheme 8).
As shown in Scheme 9, a competition between path a and
path b is operating in this reaction. The involvement of path b
in this reaction may be due to the steric hindrance of the
chlorinated carbon center and the electro-withdrawing effect of
the chlorine atom. These results show that path b is thermody-
namically favored, affording the five-membered intermediates
9. For the formation of pyrrole derivatives, although we were
not successful in trapping the intermediates 9, a carbene-like
intermediate 16 must be generated and followed by a 1,2-H
shift (Scheme 9) to afford the pyrrole derivatives 13.13
SCHEME 5. Elimination of LiH To Afford Pyridine
Derivatives
eliminated from 8 and both types of elimination could lead to
the formation of pyridine derivatives 3 or 3′. Therefore, during
our systematic investigation into this synthetically useful
reaction, we envisioned that not only pyridine derivatives but
also pyrrole derivatives of diversified structures could be
prepared following the above novel cycloaddition reaction. In
this paper, we report the scope and limitations of the cycload-
dition reactions of substituted 1-lithio-1,3-dienes with organo-
nitriles. A wide variety of pyridine derivatives, pyrrole deriva-
tives, and linear butadienyl imines of diversified substitution
patterns could be prepared following this method.
Results and Discussion
Reaction of 1,2,3,4-Tetrasubstituted 1-Lithio-1,3-dienes 2
with Organonitriles. Formation of Multi-Substituted Py-
ridines and/or Pyrroles. 1,2,3,4-Tetrasubstituted 1-lithio-1,3-
dienes reacted cleanly with aromatic organonitriles (ArCN) to
afford multiply substituted pyridines and tetrahydroisoquinolines
in high isolated yields.10 For example (Scheme 5), 1,2,3,4-
tetrapropyl 1-lithio-1,3-diene 2a reacted with PhCN affording
the pyridine derivative 3a in 77% isolated yield, and the
tetrahydroisoquinoline 3b was obtained in 85% isolated yield
from 2b and PhCN. When aliphatic organonitriles were used,
messy mixtures were obtained probably due to the relatively
acidic nature of R-hydrogen of aliphatic organonitriles.
In the above-mentioned reactions,10 elimination of LiH rather
than PrLi or BuLi took place, leading to the aromatic rings of
pyridine derivatives (Scheme 5). However, interestingly, when
trimethylsilyl-substituted 1-lithio-1,3-diene 2c was used, unlike
the reaction of 2a,b, elimination of LiSiMe3 rather than LiH
took place (Scheme 6). The tetrahydroisoquinoline 3c was
obtained solely in 75% isolated yield, obviously via elimination
of LiSiMe3. The product 3c′ via elimination of LiH was not
formed at all.
It is interesting to note that the intermediate 8 underwent
elimination of LiCl rather than EtLi (Scheme 9) to afford pyri-
dine derivatives 3. Product 15 via elimination of EtLi was not
(11) Preparative methods for 1-iodo-1,3-diene derivatives, see: (a)
Takahashi, T.; Kondakov, D. Y.; Xi, Z.; Suzuki, N. J. Am. Chem. Soc.
1995, 117, 5871-5872. (b) Takahashi, T.; Sun, W.; Xi, C.; Ubayama, H.;
Xi, Z. Tetrahedron 1998, 54, 715-726. (c) Ubayama, H.; Sun, W.; Xi, Z.;
Takahashi, T. Chem. Commun. 1998, 1931-1932. (d) Xi, Z.; Liu, X.; Lu,
J.; Bao, F.; Fan, H.; Li, Z.; Takahashi, T. J. Org. Chem. 2004, 69, 8547-
8549.
(12) Reactions of 1-lithio-1,3-dienes with unsaturated organic substrates,
see: (a) Song, Q.; Li, Z.; Chen, J.; Wang, C.; Xi, Z. Org. Lett. 2002, 4,
4627-4629. (b) Fang, H.; Song, Q.; Wang, Z.; Xi, Z. Tetrahedron Lett.
2004, 45, 5159-5162. (c) Wang, C.; Song, Q.; Xi, Z. Tetrahedron 2004,
60, 5207-5214. (d) Wang, C.; Lu, J.; Mao, G.; Xi, Z. J. Org. Chem. 2005,
70, 5150-5156. See also: (e) Shirley, D. A.; Cameron, M. D. J. Am. Chem.
Soc. 1952, 74, 664-665. (f) Fitt, J. J.; Gschwend, H. W. J. Org. Chem.
1979, 44, 303-305.
(13) Dolbier, W. R., Jr.; Chen, Y. J. Org. Chem. 1992, 57, 1947-1947.
J. Org. Chem, Vol. 71, No. 22, 2006 8567

Wang et al.
SCHEME 7. Reaction of 4-Chloro-1-lithio-1,3-diene 11a with Organonitriles Affording Pyridines and Pyrroles
SCHEME 8. Treatment of Linear Imine 12a with n-BuLi
SCHEME 9. Proposed Reaction Mechanisms for the
Formation of Pyridines and Pyrroles from
4-Chloro-1-lithio-1,3-dienes and Organonitriles
observed. Further, to know whether LiSiMe3 or LiCl is elim-
inated when both are present in the intermediate, we prepared
the monolithio reagent 11b. Interestingly, as shown in Scheme
10, LiCl was selectively eliminated, affording the pyridine
derivative 3f in 68% isolated yield as the only final product.
We also prepared the lithium reagents 17 possessing a methyl
group at position 4 (Scheme 11). We found the procedure
reported recently by Hudrilik was very effective for preparation
of this type of monolithium reagent.14 However, no intramo-
lecular lithiation-cyclization of 18 took place even at elevated
reaction temperatures. The linear butadienyl imines were not
stable in these cases. Trap of 18 with PhCOCl gave a stable
product 19 in 74% yield.
Reaction of Disubstituted 1-Lithio-1,3-dienes with Orga-
nonitriles. To further investigate the effect of substitution
patterns on the butadienyl skeletons of these mono lithium
reagents, we prepared the 1,2-dibutyl monoiodobutadiene 20,11a
which could be also readily lithiated to afford its corresponding
1,2-dibutyl 1-lithio-1,3-butadiene 21. Reaction of 21 with
organonitriles at -78 °C generated the linear butadienyl imines
22 upon quenching with aqueous NaHCO3 (Scheme 12). When
the temperature was increased to a higher temperature, in
addition to linear butadienyl imines 22, the pyrrole derivatives
23 appeared. If the reaction was carried out at reflux, the pyrrole
(14) Hudrilik, P. F.; Dai, D.; Hudrilik, A. M. Tetrahedron Lett. 2006,
47, 3427-3430.
8568 J. Org. Chem., Vol. 71, No. 22, 2006

Reactions of 1-Lithio-1,3-dienes with Aromatic Nitriles
SCHEME 10. Elimination of LiCl versus Elimination of
LiSiMe3
SCHEME 13. Proposed Mechanism for the Formation of 23
from 21
SCHEME 11. Reaction of 4-Methyl-Substituted Mono
Lithio Reagents with ArCN
SCHEME 14. Reaction of 2,3-Disubstituted 1-Lithio
Reagents with Organonitriles
SCHEME 12. Reaction of 1,2-Disubstituted 1-Lithio
Reagents with Organonitriles
tuted patterns, for example, 2,3-dihexyl-1-lithio-1,3-diene 29,15
its reaction with organonitriles afforded pyridine derivatives 30
as the only products (Scheme 14). No pyrrole derivatives were
formed in these cases.
Conclusions
The above results clearly demonstrate that the substitution
patterns on the butadienyl skeletons of the monolithio reagents
remarkably influence the reactivity of these lithium reagents.
Substituents at positions 3 and 4 of the skeleton of 1-lithio-
1,3-butadienes play an important role in the reaction paths,
leading to either 5-exo or 6-endo cyclization. As summarized
in Figure 1, N-lithioketimines Type I (from 1,2,3,4-tetrasubsti-
tuted lithium reagents) and Type II (from 2,3-disubstituted
lithium reagents) undergo 6-endo cyclization to give pyridine
derivatives, while N-lithioketimines Type III (with a chlorine
atom at position 4) and Type IV (from 1,2-disubstituted lithium
reagents) undergo 6-endo and 5-exo competitive cyclization to
give either pyridine derivatives or pyrrole derivatives, depending
on the reaction conditions. The order of elimination of RLi from
derivatives 23 were obtained as the sole products in high isolated
yields. No pyridines were formed, except in the case of PyCN.
When PyCN was used, the bipyridine derivative 3g was obtained
in 64% isolated yield even at -78 °C (Scheme 12). No linear
imine 22d was observed. The coordination of the nitrogen atom
to the Li atom (intermediate 24) is assumed to be essential for
this special reactivity.
A proposed mechanism for the formation of pyrrole deriva-
tives 23 from 21 is given in Scheme 13. The 5-exo intramo-
lecular lithiation-cyclization of 25 took place to afford the lithio
pyrrole intermediates 26. Indeed, when the reaction mixture was
further trapped with PhCOCl, acylated product 27 was formed
in 41% isolated yield (Scheme 13).
Interestingly, when the substitution pattern on the butadienyl
skeletons of monolithio reagents was changed to 2,3-disubsti-
(15) Xi, Z.; Song, Z.; Liu, G.; Liu, X.; Takahashi, T. J. Org. Chem.
2006, 71, 3154-3158.
J. Org. Chem, Vol. 71, No. 22, 2006 8569

Wang et al.
1
13a. Colorless liquid, isolated yield 56% (157 mg). H NMR
(CDCl3, TMS): δ 0.58 (t, J ) 7.5 Hz, 3H), 0.93 (t, J ) 7.5 Hz,
3H), 1.11 (t, J ) 7.5 Hz, 3H), 1.68 (dd, J ) 6.3, 1.5 Hz, 3H),
1.77-2.47 (m, 9H), 5.28 (dq, J ) 15.6, 1.5 Hz, 1H), 5.69 (dq, J )
15.6, 6.3 Hz, 1H), 7.19-7.56 (m, 4H). 13C NMR (CDCl3, TMS):
δ 7.5, 13.2, 14.3, 18.1, 18.6, 19.5, 21.3, 27.1, 83.9, 124.3, 127.6,
128.8, 131.1, 133.4, 137.1, 138.8, 166.0, 174.4. HRMS calcd for
C20H27N 281.2144, found 281.2147.
Typical Procedure for the Preparation of Pyridine 3f. To a
diethyl ether (5 mL) solution of 2,3-dihexyl-1,4-di(trimethylsilyl)
1-iodo-4-chloro-1,3-diene (1.0 mmol) at -78 °C was added t-BuLi
(2.0 mmol, 1.5 M in pentane). The above reaction mixture was
then stirred at -78 °C for 1 h to generate its corresponding 1-lithio-
1,3-diene 11b, which was monitored by GC analysis or by TLC.
After addition of PhCN (1.2 mmol) at -78 °C, the mixture was
stirred at -78 °C for 1 h. The mixture was then stirred at room
temperature for 3 h. The above reaction mixture was then quenched
with saturated aqueous NaHCO3 and extracted with diethyl ether.
The extract was washed with brine and dried over MgSO4. The
solvent was evaporated in vacuo to give a yellow oil, which was
purified by column chromatography (silica, hexane:Et2O ) 30:1)
to afford 3f.
3f. Colorless liquid, isolated yield 68% (318 mg). 1H NMR
(CDCl3, TMS): δ -0.01 (s, 9H), 0.45 (s, 9H), 0.85-0.92 (m, 6H),
1.28-2.91 (m, 20H), 7.35-7.47 (m, 5H). 13C NMR (CDCl3,
TMS): δ 2.8, 3.7, 14.0, 14.0, 22.5, 22.6, 29.5, 29.6, 30.7, 31.9,
32.0, 35.7, 37.8, 39.4, 127.4, 127.8, 127.9, 128.0, 129.8, 145.0,
165.1, 166.3, 167.3. HRMS calcd for C29H49NSi2 467.3404, found
467.3401.
FIGURE 1. Summary of reactivities of cycloaddition intermediates
Typical Procedure for the Preparation of Compound 19. To
a diethyl ether (5 mL) solution of 1,2,3,4-tetraethyl 1-iodo-4-methyl-
1,3-diene (1.0 mmol) at -78 °C was added t-BuLi (2.0 mmol,
1.5 M in pentane). The above reaction mixture was then stirred at
-78 °C for 1 h to generate its corresponding 1-lithio-1,3-diene 17,
which was monitored by GC analysis or by TLC. After addition of
PhCN (1.2 mmol) at -78 °C, the mixture was stirred at -50 °C
for 1 h. PhCOCl (1.5 mmol) was added at -50 °C, and the mixture
was stirred at room temperature for 1 h. The above reaction mixture
was then quenched with saturated aqueous NaHCO3 and extracted
with diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give a yellow
oil, which was purified by column chromatography (silica, hexane:
Et2O ) 30:1) to afford 19.
of 1-lithio-1,3-dienes with organonitriles.
the lithiated cyclic N-containing intermediates was found to be
LiCl > LiSiMe3 > LiH. No elimination of alkyllithium salts
was observed.
Experimental Section
Typical Procedure for the Preparation of Linear Butadienyl
Imines 12a-c, Pyridine 3d-e, and Pyrroles 13a-d from 1,2,3,4-
Tetraethyl 1-Iodo-4-chloro-1,3-diene 10a. To a diethyl ether
(5 mL) solution of 1,2,3,4-tetraethyl 1-iodo-4-chloro-1,3-diene 10a
(1.0 mmol) at -78 °C was added t-BuLi (2.0 mmol, 1.5 M in
pentane). The above reaction mixture was then stirred at -78 °C
for 1 h to generate 1-lithio-1,3-diene 11a, which was monitored
by GC analysis or by TLC. After addition of organonitriles
(1.2 mmol) at -78 °C, the mixture was stirred at -78 °C for 1 h.
If the mixture was not quenched at -78 °C, then it was stirred at
0 °C, room temperature, or 50 °C for 3 h, respectively. The above
reaction mixture was then quenched with saturated aqueous
NaHCO3 at -78 °C and extracted with diethyl ether. The extract
was washed with brine and dried over MgSO4. The solvent was
evaporated in vacuo to give a yellow oil, which was purified by
column chromatography to afford 12a-c (silica, treated by Et3N,
hexane:Et2O ) 10:1), pyridines 3d,e (silica, hexane:Et2O ) 30:1),
and pyrroles 13a-d (silica, hexane:Et2O ) 10:1), respectively.
1
19. Colorless liquid, isolated yield 74% (286 mg). H NMR
(CDCl3, TMS): δ 0.47-0.57 (m, 3H), 0.72-0.78 (m, 3H), 0.84-
1.01 (m, 6H), 1.51 (s, 1.85H), 1.66 (s, 1.15H), 1.79-2.34 (m, 8H),
7.37-7.55 (m, 6H), 7.96-8.07 (m, 4H). 13C NMR (CDCl3, TMS):
δ 11.0, 11.5, 12.1, 12.2, 12.3, 12.9, 13.2, 13.6, 15.7, 19.4, 23.6,
24.6, 26.0, 26.4, 26.6, 27.08, 27.13, 28.3, 128.3, 128.6, 128.76,
128.79, 129.2, 131.5, 131.6, 131.7, 132.1, 132.2, 132.7, 133.1,
134.1, 134.3, 134.3, 137.4, 137.5, 141.3, 141.6, 170.3, 170.4, 179.8,
180.0. HRMS calcd for C27H33NO 387.2562, found 387.2556.
Typical Procedure for the Preparation of Linear Butadienyl
Imines 22a-c, Pyridine 3g, and Pyrroles 23a-c from 1,2-
Dibutyl 1-Iodo-1,3-diene 20. To a diethyl ether (5 mL) solution
of 1,2-dibutyl 1-iodo-1,3-diene 20 (1.0 mmol) at -78 °C was added
t-BuLi (2.0 mmol, 1.5 M in pentane). The above reaction mixture
was then stirred at -78 °C for 1 h to generate its corresponding
1-lithio-1,3-diene 21, which was monitored by GC analysis or by
TLC. HMPA (1.0 mmol) was then added, and the reaction mixture
was stirred at room temperature for 15 min. After addition of
organonitriles (1.2 mmol) at -78 °C, the mixture was stirred at
-78 °C for 1 h. If the mixture was not quenched at -78 °C, it was
then stirred at -5 °C or refluxed for 1 h, respectively. The above
reaction mixture was then quenched with saturated aqueous
NaHCO3 and extracted with diethyl ether. The extract was washed
with brine and dried over MgSO4. The solvent was evaporated in
vacuo to give a yellow oil, which was purified by column
chromatography to afford 22a-c (silica, treated by Et3N before
1
12a. Colorless liquid, isolated yield 74% (235 mg). H NMR
(C6D6, TMS): δ 0.80 (t, J ) 7.5 Hz, 3H), 0.91-0.97 (m, 6H),
1.09 (t, J ) 7.8 Hz, 3H), 1.84-2.40 (m, 11H), 6.99-7.02 (m, 2H),
7.16 (s, 1H), 7.92-7.95 (m, 2H). 13C NMR (C6D6, TMS): δ 12.6,
13.1, 13.3, 13.9, 21.3, 24.1, 25.6, 27.2, 28.8, 128.5, 129.1, 133.8,
136.4, 138.0, 138.9, 140.3, 140.5, 177.06. HRMS calcd for
C20H28N35Cl 317.1910, found 317.1911.
1
3d. Colorless liquid, isolated yield 47% (132 mg). H NMR
(CDCl3, TMS): δ 1.00 (t, J ) 7.5 Hz, 3H), 1.18-1.31 (m, 9H),
2.38 (s, 3H), 2.58 (q, J ) 7.5 Hz, 2H), 2.67-2.75 (m, 4H), 2.82
(q, J ) 7.5 Hz, 2H), 7.18-7.31 (m, 4H). 13C NMR (CDCl3,
TMS): δ 14.6, 15.3, 15.4, 15.6, 21.2, 21.3, 21.7, 22.0, 28.3, 128.6,
128.7, 132.4, 133.1, 136.6, 139.5, 149.1, 156.6, 158.1. HRMS calcd
for C20H27N 281.2143, found 281.2132.
8570 J. Org. Chem., Vol. 71, No. 22, 2006

Reactions of 1-Lithio-1,3-dienes with Aromatic Nitriles
used, hexane:Et2O ) 10:1), pyridines 3g (silica, treated by Et3N,
hexane: Et2O ) 30:1), and pyrroles 23a-c (silica, treated by Et3N,
hexane:Et2O ) 30:1), respectively.
3H), 1.22-1.57 (m, 8H), 2.24 (s, 3H), 2.34-2.47 (m, 4H), 6.96-
7.48 (m, 10H). 13C NMR (CDCl3, TMS): δ 11.9, 13.9, 14.1, 22.8,
22.9, 24.2, 24.2, 33.5, 33.7, 123.2, 125.0, 126.1, 127.7, 127.75,
127.83, 129.5, 123.0, 130.2, 132.4, 133.7, 136.0, 171.2. HRMS
calcd for C26H31NO 373.2406, found 373.2406.
1
22a. Colorless liquid, isolated yield 56% (151 mg). H NMR
(CDCl3, TMS): δ 0.82-1.01 (m, 6H), 1.29-1.52 (m, 8H), 2.22-
2.40 (m, 4H), 4.96-5.00 (m, 1H), 5.22-5.28 (m, 1H), 6.30-6.39
(m, 1H), 7.37-7.44 (m, 3H), 7.75-7.77 (m, 2H), 9.20 (br, 1H).
13C NMR (CDCl3, TMS): δ 13.9, 14.0, 22.8, 23.2, 26.7, 30.8, 30.9,
31.6, 113.8, 127.9, 128.5, 130.8, 135.5, 136.2, 137.4, 141.2, 179.4.
HRMS calcd for C19H27N 269.2144, found 269.2137.
Typical Procedure for the Preparation of Pyridines 30a-d.
To a THF (5 mL) solution of 2,3-dihexyl 1-bromo-1,3-diene 28
(1.0 mmol) at -78 °C was added t-BuLi (2.0 mmol, 1.5 M in
pentane). The above reaction mixture was then stirred at -78 °C
for 1 h to generate its corresponding 1-lithio-1,3-diene 29, which
was monitored by GC analysis or by TLC. HMPA (1.0 mmol) was
then added, and the reaction mixture was stirred at room temperature
for 15 min. After addition of organonitriles (1.2 mmol), the mixture
was stirred at room temperature for 3 h. The above reaction mixture
was then quenched with saturated aqueous NaHCO3 and extracted
with diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give a yellow
oil, which was purified by column chromatography (silica, hexane:
Et2O ) 30:1) to afford 30a-d.
1
3g. Colorless liquid, isolated yield 64% (172 mg). H NMR
(CDCl3, TMS): δ 0.76 (t, J ) 7.2 Hz, 3H), 0.97 (t, J ) 7.2 Hz,
3H), 1.15-1.68 (m, 8H), 2.66-2.83 (m, 4H), 7.11 (d, J ) 4.8 Hz,
1H), 7.26-7.30 (m, 1H), 7.60-7.63 (m, 1H), 7.76-7.82 (m, 1H),
8.39 (d, J ) 4.8 Hz, 1H), 8.64-8.66 (m, 1H). 13C NMR (CDCl3,
TMS): δ 13.6, 14.0, 22.8, 22.9, 27.5, 32.0, 32.7, 32.8, 122.4, 124.0,
124.3, 135.1, 136.5, 146.2, 148.4, 151.0, 157.3, 159.9. HRMS calcd
for C18H24N2 268.1940, found 268.1937.
1
23a. Colorless liquid, isolated yield 69% (186 mg). H NMR
1
(CDCl3, TMS): δ 0.89-0.97 (m, 6H), 1.34-1.58 (m, 8H), 2.19
(s, 3H), 2.37-2.42 (m, 2H), 2.52-2.58 (m, 2H), 7.13-7.58 (m,
6H). 13C NMR (CDCl3, TMS): δ 11.4, 14.0, 14.1, 23.0, 23.1, 24.3,
24.7, 34.0, 34.0, 120.7, 120.8, 124.0, 125.4, 125.7, 126.2, 128.6,
134.3. HRMS calcd for C19H27N 269.2144, found 269.2141.
Typical Procedure for the Preparation of Acylated Pyrrole
27. To a diethyl ether (5 mL) solution of 1,2-dibutyl 1-iodo-1,3-
diene 20 (1.0 mmol) at -78 °C was added t-BuLi (2.0 mmol, 1.5
M in pentane). The above reaction mixture was then stirred at -78
°C for 1 h to generate 1-lithio-1,3-diene 21, which was monitored
by GC analysis or by TLC. HMPA (1.0 mmol) was then added,
and the reaction mixture was stirred at room temperature for 15
min. After addition of organonitriles (1.2 mmol) at -78 °C, the
mixture was stirred at -78 °C for 1 h. It was then stirred refluxing
for 1 h. PhCOCl (1.5 mmol) was added, and the reaction mixture
was stirred at room temperature for 1 h. The above reaction mixture
was then quenched with saturated aqueous NaHCO3 and extracted
with diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give a yellow
oil, which was purified by column chromatography (silica, hexane:
Et2O ) 10:1) to afford 27.
30a. Colorless liquid, isolated yield 60% (194 mg). H NMR
(CDCl3, TMS): δ 0.88-0.92 (m, 6H), 1.32-1.67 (m, 16H), 2.60-
2.66 (m, 4H), 7.24-7.49 (m, 4H), 7.94-7.98 (m, 2H), 8.42 (s,
1H). 13C NMR (CDCl3, TMS): δ 14.1, 22.61, 22.64, 29.3, 29.4,
29.8, 30.4, 31.0, 31.7, 32.2, 120.7, 126.7, 128.4, 128.6, 134.6, 139.7,
150.0, 150.3, 155.0. HRMS calcd for C23H33N 323.2613, found
323.2608.
Acknowledgment. This work was supported by the Natural
Science Foundation of China (29825105, 20172003, 20232010)
and the Major State Basic Research Development Program
(G2000077502-D). Co.W. is thankful for financial support from
the Postdoctorate Research Fund of China (2005038003). The
Cheung Kong Scholars Program, Qiu Shi Science & Technolo-
gies Foundation, and Dow Corning Corp. are gratefully ac-
knowledged.
Supporting Information Available: Characterization data for
1
all products except for an illustrative example; copies of H and
13C NMR spectra for all isolated compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
27. Colorless liquid, isolated yield 41% (153 mg). H NMR
(CDCl3, TMS): δ 0.83 (t, J ) 7.2 Hz, 3H), 0.97 (t, J ) 7.2 Hz,
JO061574A
J. Org. Chem, Vol. 71, No. 22, 2006 8571