Intramolecular Diels-Alder Reaction of 2-Cyano-1-aza-1,3-butadienes

Article abstract of DOI:10.1021/jo961403d

It has been demonstrated that a 2-cyano substituent is sufficient to activate 1-aza-1,3-butadienes with respect to the intramolecular Diels-Alder reaction. This reaction is successful for the preparation of the indolizidine and quinolizidine ring systems. The stereochemistry of the isomeric products was assigned by a careful analysis of their NMR spectral data.

Full text of DOI:10.1021/jo961403d

J . Org. Chem. 1997, 62, 2093-2097
2093
In tr a m olecu la r Diels-Ald er Rea ction of
2-Cya n o-1-a za -1,3-bu ta d ien es
Nicholas J . Sisti, Emmanuel Zeller, David S. Grierson,*,† and Frank W. Fowler*,‡
Department of Chemistry, State University at New York at Stony Brook, Stony Brook, New York 11794,
and Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received J uly 23, 1996X
It has been demonstrated that a 2-cyano substituent is sufficient to activate 1-aza-1,3-butadienes
with respect to the intramolecular Diels-Alder reaction. This reaction is successful for the
preparation of the indolizidine and quinolizidine ring systems. The stereochemistry of the isomeric
products was assigned by a careful analysis of their NMR spectral data.
The indolizidine and quinolizidine alkaloids1 represent
a relatively large class of natural products whose impor-
tance stems from the potent and useful biological activity
of certain of its members.2-4 The common structural
feature of these compounds is a six-membered nitrogen
heterocycle incorporated into a bicyclic ring system.
Among the heterocyclic ring forming reactions available
for the preparation of indolizidines and quinolizidines,
nitrogen versions of the Diels-Alder reaction are par-
ticularly attractive.5,6 For example, the intramolecular
Diels-Alder reaction (IMDA)7 of 1-aza-1,3-butadienes can
produce, in one step, three stereogenic centers, two
σ-bonds, and two new rings. Clearly, synthetic strategies
for the preparation of quinolizidine and indolizidine
alkaloids incorporating the IMDA reaction of 1-aza-1,3-
butadienes will be extremely efficient8 (Scheme 1).
IMDA reactions of simple alkyl or unsubstituted 1-aza-
1,3-butadienes have not been reported, indicating that
activation is necessary for the success of this reaction.9,10
We have reported that substitution on nitrogen by an
aromatic ring and by a cyano group at C-2 produces
azadienes which react with both electron rich and
Sch em e 1. IMDA Rea ction of 1-Aza -1,3-bu ta d ien es
a s a n Ap p r oa ch to In d olizid in es a n d
Qu in olizid in es
electron deficient dienophiles with equal ease.11 These
studies have led us to explore the possibility of using a
cyano substituent alone to activate 1-aza-1,3-butadienes
with respect to the Diels-Alder reaction. Advantages
of the cyano group in this role are that it suppresses
unwanted side reactions of the imine reactant, stabilizes
the reactive enamine in the product, and can be useful
for further structural elaboration.12,13
Considering that many indolizidines are substituted
on the five-membered ring it was of interest to investigate
the IMDA reaction of 1-aza-1,3-butadienes with substi-
tutents on the connecting chain. The 2-cyano-1-aza-1,3-
butadienes (e.g. 3) employed in our studies (Scheme 2)
were prepared by treatment of the corresponding amides
(e.g. 2) with triflic anhydride at -60 °C in CH2Cl2
containing diisopropylethylamine, followed by reaction
of the in situ generated imidoyl triflates with lithium
cyanide.11 The starting amide 2 was readily obtained by
reduction of the oxime derivative of 5-hexen-2-one (1)
with LAH followed by reaction with acryloyl chloride.14,15
In the crucial Diels-Alder step, heating the racemic
azadiene 3 in benzene at 110 °C for 24 h led to very clean
conversion to product. The desired cycloadducts 4 and
† Institut de Chimie des Substances Naturelles.
‡ State University of New York at Stony Brook.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) (a) Michel, J . P. Nat. Prod. Rep. 1994, 11, 17. (b) Howard, A.
S.; Michael, J . P. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1986; Vol. 28, p 183.
(2) Examples being the swansonine,3 slaframine,3 and the amphib-
ian alkaloids.4
(3) (a) Elbein, A. D.; Molyneux, R. J . In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Springer Verlag: New
York, 1986; Vol. 4, p 1. (b) Fleet, G. W. J .; Fellows, L. E.; Winchester,
B. Bioactive Compounds from Plants; Ciba Foundation Symposium
154; Wiley: Chichester, 1990; p 112.
(4) Daly, J . W.; Spande, T. F. In Alkaloids: Chemical and Biological
Perspectives, Pelletier, S., W., Ed.; Springer Verlag: New York, 1987;
Vol. 5, p 1.
(5) Weinreb and co-workers have applied the intramolecular Diels-
Alder reaction of N-acyl imines to the preparation of piperidine,
indolizidine, and quinolizidine alkaloids. For some examples, see
Chapter 2 in ref 6.
(6) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: San Diego, 1987.
(7) For some selective reviews on the intramolecular Diels-Alder
reaction, see: (a) Roush, W. R. In Comprehensive Organic Synthesis;
Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 513. (b)
Craig, D. J . Chem. Soc. Rev. 1987, 16, 187. (c) Fallis, A. G. Can. J .
Chem. 1984, 62, 183. (d) Ciganek, E. Org. React. 1984, 32, 1.
(8) For an efficient method for the preparation of the quinolizidine
alkaloid deoxynupharidine using the intramolecular Diels-Alder reac-
tion of an N-acyl-1-azadiene, see: Hwang, Y. C.; Fowler, F. W. J . Org.
Chem. 1985, 50, 2719.
(9) For successful intramolecular Diels-Alder reactions of 1-aza-
dienes, see: (a) Teng, M.; Fowler, F. W. J . Org. Chem. 1990, 55, 5646
and work cited therein. (b) J un, M. E.; Choi, Y. M. J . Org. Chem. 1991,
56, 6729. (c) Uyehara, T.; Suzuki, I.; Yamamoto, Y. Tetrahedron Lett.
1990, 31, 3753. (d) Whitesell, M. A.; Kyba, E. P. Tetrahedron Lett.
1984, 25, 2119. (e) See also ref 6, Chapter 9, and ref 10c.
(10) Other nitrogen substituents, such as N,N-dimethylamino and
sulfonyl groups are known to activate azadienes with respect to the
Diels-Alder reaction but are not directly produce indolizidines and
quinolizidines. (a) See ref 6, Chapter 9. (b) Ghosez, L. J . Heterocycl.
Chem. 1985, 22 (Suppl. Issue Lect. Heterocycl. Chem. 8), 69. (c) Boger,
D. L.; Corbett, W. L. J . Org. Chem. 1993, 58, 2068 and work cited
therein.
(11) (a) Sisti, N. J .; Fowler, F. W.; Grierson, D. S. Synlett 1991, 816.
(b) For a comparison of nitrogen activating substituents, see: Trione,
C.; Toledo, L. M.; Kuduk, S. D.; Fowler, F. W.; Grierson, D. S. J . Org.
Chem. 1993, 58, 2075. (c) Sisti, N. J .; Motorina, I. A.; Tran Huu Dau,
M.-E.; Riche, C.; Fowler, F. W.; Grierson, D. J . Org. Chem. 1996, 61,
3715.
(12) (a) Grierson, D. S.; Harris, M.; Husson, H.-P. J . Am. Chem. Soc.
1980, 102, 1064. (b) Albright, J . D. Tetrahedron 1983, 39, 3207. (c)
Shafran, Y. M.; Bakulev, B. A.; Mokrushin, V. S. Russ. Chem. Rev.
1989, 58, 148. (d) Viehe, H. G.; Merenyi, R.; Stella, L.; J anousek, Z.
Angew. Chem., Ind. Ed. Engl. 1979, 18, 917. (e) Zeller, E.; Sajus, H.;
Grierson, D. Synlett 1991, 44. (f) Yue, C.; Royer, J .; Husson, H.-P. J .
Org. Chem. 1992, 57, 4211.
(13) Albrecht, H.; Vonderheid, C. Synthesis 1975, 512.
(14) House, H. O.; Lee, L. F. J . Org. Chem. 1976, 41, 863.
(15) Harding, K. E.; Burks, S. R. J . Org. Chem. 1981, 46, 3920.
S0022-3263(96)01403-X CCC: $14.00 © 1997 American Chemical Society

2094 J . Org. Chem., Vol. 62, No. 7, 1997
Sisti et al.
Sch em e 2. P r ep a r a tion of In d olizid in es by th e
IMDA Rea ction of 2-Cya n o-1-a za -1,3-bu ta d ien es
Sch em e 3. Exo a n d En d o Rea ction P r od u cts of
th e IMDA Rea ction
hydrogen on C-3 to collapse to a doublet of doublets (J )
6.8, 4.3 Hz).
Furthermore, the methyl group at C-3 of the major
isomer 4 is shifted downfield (0.15 ppm) compared to the
minor isomer 5. Molecular modeling shows the methyl
group of 4 more in the plane of the π system and,
consequently, more deshielded than the same methyl
group in compound 5. These assignments were con-
firmed by the results of a 1D NOE experiments in which
a strong NOE was observed between the C-3 methyl
group and C-8a hydrogen in 4, indicating their spatial
proximity. Isomer 5 showed no analogous NOE.
5 were isolated after silica flash column chromatography
as an inseparable mixture of diastereomers [4/5 ) 4:1
(R ) Me)] in 94% yield. Subsequent rate studies with
azadiene 3 showed that cycloaddition is complete after
7-8 h of heating (110 °C sealed tube) in benzene and
acetonitrile, whereas the reaction is three times slower
in either CH2Cl2 or THF.
Because of the presence of the stereocenter on the
connecting chain of 3, there is the possibility of producing
two diastereomeric Diels-Alder adducts, 4 and 5. The
origin of these two stereoisomers is relatively complex
since the faces of both diene and dienophile are diaste-
reotopic. This situation allows for four possible diaster-
eomeric reaction pathways, two passing through exo
transition states and two passing through endo transition
states. Because the nitrogen atom rapidly inverts at
room temperature, cis and trans ring fusions are not
possible and it is not possible to distinguish between the
exo and endo transition states.18
The above described observation is significant for the
following reasons. Simple 1-aza-1,3-butadienes have not
been reported to react in the IMDA. The all-carbon
diene, 1,6,8-nonatriene, is less reactive being reported to
be unreactive upon heating at 140 °C for 10 days.16 Thus,
cyano substitution results in a relatively reactive azadi-
ene (110 °C for 24 h) that undergoes the IMDA to give
the Diels-Alder adduct in high yield. This reaction is
potentially a useful route to fused nitrogen heterocycles.
Separation of the stereoisomers 4 and 5 was ac-
complished by HPLC (reverse phase: Hypersel C-8).
From the NMR spectra it is possible to assign the relative
stereochemistry of the individual stereoisomers with a
high degree of certainty (Scheme 2). The methine
hydrogen adjacent to the methyl group on C-3 in com-
pounds 4 and 5 have different multiplicities in the proton
NMR spectrum. In compound 4 this proton appears as
an undefined multiplet (δ 3.61) whereas the analogous
hydrogen in compound 5 appears as a quintet (δ 3.85),
being coupled to the three hydrogens of the methyl group
and one of the hydrogens on the adjacent methylene
group. Inspection of molecular models17 clearly demon-
strates that the dihedral angle between the methine
hydrogen of compound 5 at the stereogenic center C-3
and one of the adjacent hydrogens on the C-2 methylene
group is approximately 90°, resulting in one of the
coupling constants being nearly zero. This is consistent
with the observation that the quintet collapses to a
doublet (J ) 6.6 Hz) upon irradiation of the methyl
doublet at δ 1.13.
When a substituent is present on the terminal carbon
atom of the diene, then the four diastereomeric pathways
all produce different diastereomers. That is, the exo and
endo reaction pathways lead to different diastereomers.
For this reason it was of interest to study the 4-phenyl-
substituted azadiene 6. Compound 6 was prepared from
5-hex-2-one in an analogous manner as described above
for azadiene 3. Heating azadiene 6 in benzene for 26 h
at 110 °C gave a 3:2 mixture (73%) of only two of the
four possible stereoisomers, 7 and 8 (Scheme 3), that
could be detected by NMR spectroscopy.
Close similarities in the NMR spectra of 4 and 7 as
well as 5 and 8 permit the stereochemical assignments
for C-8a and C-3 shown in Scheme 3. For example, the
13C chemical shifts of C-8a and C-3 for 4 (δ 57.0, 57.2)
and 7 (δ 57.3, 57.4) are nearly identical, whereas the
same peaks in the spectra for 5 (δ 55.1, 57.2) and 8 (δ
52.6, 55.5) are located upfield and split by about 2.5 ppm.
Also, the methyl groups in 4 and 7 (δ 1.28 and 1.33) are
both found downfield with respect to the methyl groups
in 5 and 8 (δ 1.13 and 1.19). A similar correspondence
is observed in the proton spectra, i.e. a larger separation
in the chemical shift for the C-3 and C-8a methine
absorptions in the spectrum for 8 than for 7.
In compound 4 there should be significant coupling of
the methine hydrogen at C-3 to both of the hydrogens of
the adjacent methylene group.17 Irradiation of the meth-
yl doublet at δ 1.28 in this compound caused the methine
As the predominant conformations 7 and 8 have the
hydrogen at C-8a occupying the pseudoaxial position,19
(16) Lin, Y.-T.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2269.
A
Diels-Alder adduct was obtained in 85% yield when the nonatriene
was heated for 35 h at 190 °C.
(18) In the all carbon intramolecular Diels-Alder reaction the endo
reaction pathway leads to the cis-fused product whereas the exo
reaction pathway leads to the trans-fused product. Although cis- and
trans-fused transition states are also involved in the nitrogen analog
of this reaction, nitrogen inversion precludes distinguishing their
products.
(17) These conclusions are supported by MM2 calculations using
MacroModel version 4.0 developed by C. Still, Columbia University.
These calculations predict that the dihedral angle between the cis and
trans C-H bonds of C-2 and C-3 for 4 are 32 and 153°, respectively.
These same bonds for 5 are 39 and 91°.

Diels-Alder Reaction of 2-Cyano-1-aza-1,3-butadienes
J . Org. Chem., Vol. 62, No. 7, 1997 2095
Sch em e 4. P r ep a r a tion of a Qu in olizid in e by th e
IMDA Rea ction of 1-Aza d ien es
the coupling constant of the vinyl hydrogen gives the
stereochemistry of the carbon bearing the phenyl
substituent.9a The larger coupling constant of the vinyl
hydrogen is due to the pseudoequatorial hydrogen, and
the smaller coupling constant is due to the pseudoaxial
hydrogen. The compound with the larger coupling
constant, 8, has a trans relationship of the hydrogens at
C-7 and C-8a and is the product of the reaction proceed-
ing through the exo transition state.
In principle, the use of IMDA reactions with a four-
atom connecting chain can allow for the preparation of
the quinolizidine ring system. In order to explore this
possibility, azadiene 9 was prepared in an analogous
manner to that described for the preparation of 3.
Heating azadiene 9 in benzene at 110 °C for 48 h gave a
1:4 ratio of 10 and 11 in 86% yield (Scheme 4).
The structures of 10 and 11 were again assigned from
an examination of their NMR spectra. The bridgehead
C-9a hydrogen of the minor isomer 10 appeared as a
broadened triplet (J ) 11 Hz), which is consistent with
coupling to two adjacent axial protons. This situation
would exist when the two six-membered rings are in the
half-chair and chair conformations (Figure 1). Irradia-
tion of the C-6 methyl group resulted in collapse of the
C-6 hydrogen multiplet to a doublet (J ) 3.3 Hz), showing
that the methyl group occupies an axial position.
Although the major isomer, 11, is epimeric at C-6 with
the minor isomer, 10, molecular modeling indicates that
the saturated six-membered ring cannot be in a simple
chair conformation and the proton NMR spectrum sup-
ports this view. The C-9a bridgehead hydrogen of the
major isomer (11) appears as a complex multiplet with
a chemical shift nearly identical to that of the minor
isomer20,21 with a half-width w1/2 ) 24 Hz. These data
are consistent with an axial position for the C-9a hydro-
gen anti to two of the adjacent hydrogens. However,
irradiation of the C-6 methyl group resulted in collapse
of the multiplet to a doublet of doublets (J ) 5.6 and 4.5
Hz). This observation is not consistent with the C-6
hydrogen simply occupying an axial position as would be
anticipated if compound 11, like 10, existed in the half-
chair, chair conformation.
F igu r e 1. Most stable conformations calculated for 10 and
11.
in Figure 1. Thus, the NMR spectrum and molecular
modeling are consistent with the conformation, shown
in Figure 1, playing an important role in the ground state
of stereoisomer 11.
There is a significant change in the stereochemistry
of these Diels-Alder reactions as the connecting chain
changes from three to four carbon atoms. The major
product (4) with a three-carbon connecting chain (aza-
diene 3) has a trans relationship of the hydrogen atoms
at the stereogenic centers whereas the major product (11)
with a four-atom connecting chain (azadiene 9) has a cis
relationship of the hydrogen atoms at the stereogenic
centers. This change in stereochemistry reflects a change
in the reaction pathway from predominantly endo, with
azadiene 3, to the exo reaction pathway, with azadiene
9. Changes in exo/endo ratios as a function of connecting
chain length and substituents have been the focus of
much discussion,7 and a “twist asynchronous” model has
been successful for rationalizing the results for all carbon
IMDA reaction. A 2-cyano substituent is an important
group for the Diels-Alder activation of 1-aza-1,3-buta-
dienes. Although kinetic measurements are not avail-
able, cyano activation appears to be comparable to N-acyl
activation.22 Possible roles for N-acyl activation involve
lowering the LUMO of the diene in order to faciliate
HOMO-LUMO interactions and stabilizing the transi-
tion state by partial amide development. The cyano
group lowers the LUMO of the diene11c but it cannot
directly stabilize the developing lone pair of electrons of
the amino substituent. However, the cyano substituent
can stabilize the transition state by stabilizing the newly
developing bonds. In particular, the presence of a
nitrogen atom and an amino substituent on the same
carbon23 can stabilize biradicaloid electronic configura-
tions of the transition state.24
Exp er im en ta l Section
N-[5-(1-Hexen yl)]-cya n o-1-a za bu ta -1,3-d ien e (3). To a
solution of hydroxylamine hydrochloride (11.3 g) and anhy-
drous K2CO3 (22.5 g) in 26 mL of ethanol and 32 mL of water
was added 5-hexene-2-one (1) (17.6 g, 130 mmol) over 5 min.
The mixture was refluxed for 6 h, and after cooling was
extracted with ether (2 × 50 mL). The combined ether layers
were washed once with water (20 mL), dried over sodium
sulfate, and concentrated in vacuo. The 5-hexene-2-one oxime
(13.6 g, 93%) was obtained as a pale yellow oil and used
without further purification.14
In the half-chair, chair conformation, molecule models
indicate that there would be a nonbonded interaction
between the equatorial methyl and the cyano groups. In
agreement with this hypothesis, MM2 calculations17
predict the most stable conformation to be that shown
(19) Supporting this assumption, MM2 calculations predict that the
conformation of 8 with an axial phenyl substituent at C-7 and an axial
hydrogen at C-8a is 2.5 kcal/mol more stable than the conformation of
8 with an equatorial phenyl substituent at C-7 and an equatorial H at
C-8a.
(20) The nearly identical chemical shift indicates that the bridge-
head hydrogen in both isomers is anti to the nitrogen lone pair of
electrons (see ref 21a).
Following the method developed by Harding and Burks,15
the above oxime (3.0 g, 27 mmol) in 20 mL of anhydrous ether
was added dropwise over a period of 5 min to a stirred solution
(21) For references related to the structure and NMR spectroscopy
of indolizidines and quinolizidines, see: (a) Crabb, T. A.; Newton, R.
F. Chem. Rev. 1971, 71, 109. (b) Tourwe, D.; Binst, G. V. Heterocycles
1978, 9, 507. (c) Skvortsov, I. M. Russ. Chem. Rev. 1979, 48, 262. (d)
Crabb, T. A. In Annual Reports in NMR Spectroscopy; Webb, G. A.,
Ed.; Academic Press: London, 1982; p 60.
(22) For example, an analogous N-acyl azadiene requires heating
for 6 h at 110 °C, compared to 24 h at the same temperature for
azadiene 3.
(23) Sustman, R.; Korth, H.-G. Adv. Phys. Org. Chem. 1990, 26, 131.
(24) Houk, K. N.; Li, Y.; Evanseck, J . D. Angew. Chem., Int. Ed.
Engl. 1992, 31, 682.

2096 J . Org. Chem., Vol. 62, No. 7, 1997
Sisti et al.
of LiAlH4 (3.0 g) in 200 mL of anhydrous ether, under argon
at 0 °C. The mixture was refluxed for 23 h and then chilled
in a brine/ice bath, and the excess LiAlH4 destroyed by
dropwise addition of 6 mL of water, 6 mL of a 15% NaOH
solution, and finally 10 mL of water. After being stirred for
an additional 2 h, the mixture was treated with 15 g of 1:1
mixture of anhydrous MgSO4 and anhydrous Na2SO4, placed
under an argon atmosphere, and stirred for 3 h. Acryloyl
chloride (2.4 g) was then added dropwise over a period of 10
min, and the reaction mixture was allowed to stir overnight.
The resulting mixture was filtered, and the filtrate was
concentrated to 50 mL, washed sequentially with 50 mL of
saturated NaHCO3 solution, brine, and water, dried over
Na2SO4, and concentrated under vacuum. Amide 2 was
obtained as a colorless oil (2.6 g, 63%) after flash column
purification (silica gel, 1:1 heptane/ether): IR (neat) 1656 and
1642 cm-1 (CdO); 1H NMR (CDCl3) δ 1.18 (d, J ) 6.6 Hz, 3H),
1.58 (m, 2H), 2.10 (apparent q, J ) 7.0, 7.4 Hz, 2H), 4.09 (m,
1H), 5.01 (m, 2H), 5.65 (m, 1H), 5.80 (m, 1H), 6.18 (m, 2H);
13C NMR (CDCl3) δ 20.9, 30.4, 36.0, 45.0, 114.9, 126.1, 131.3,
138.0, 164.9; MS m/ z 153 (M+), 138, 125, 98; HRMS calcd for
C9H15NO 153.1154, found 153.1154.
cinnamide was obtained as a colorless solid (3.2 g, 80%) after
flash column purification (silica gel, 1:1 heptane/CH2Cl2, then
CH2Cl2): mp 69-71 °C; IR (Nujol) 3276 (NH), 1656 cm-1
1
(CdO); H NMR (CDCl3) δ 1.20 (d, J ) 6.5 Hz, 3H), 1.59 (m,
2H), 2.11 (q, J ) 7.3 Hz, 2H), 4.16 (quintet, J ) 7.0, 7.7 Hz,
1H), 4.97 (m, 2H), 5.79 (m, 1H), 6.31 (N-H), 6.51 (d, J ) 15.5
Hz, 1H), 7.28 (m, 3H), 7.46 (m, 2H), 7.62 (d, J ) 15.7 Hz, 1H);
13C NMR (CDCl3) δ 20.9, 30.4, 36.1, 45.2, 114.9, 121.4, 127.7,
128.7, 129.5, 135.0, 138.0, 140.6, 165.4; MS m/ z 229 (M+), 175,
146, 131, 103, 84, 77.
The derived amide (0.5 g, 2.2 mmol) was treated with triflic
anhydride (0.74 g, 1.2 equiv) in anhydrous CH2Cl2 containing
diisopropylethylamine (0.39 g) at -60 °C and then with LiCN
(0.1 g) and 12-crown-4 (0.05 g). Azadiene 6 was obtained as a
light yellow oil (0.22 g, 43%) after flash column purification
(silica gel, 9:1 heptane/ether): IR (neat) 2221 (CN), 1629
(CdC), 1578 cm-1; (CdN); 1H NMR (CDCl3) δ 1.29 (d, J ) 6.2
Hz, 3H), 1.75 (m, 2H), 2.03 (q, J ) 7.0, 7.9 Hz, 2H), 3.96 (m,
1H), 5.01 (m, 2H), 5.80 (m, 1H), 6.96 (d, J ) 16.3 Hz, 1H),
7.38-7.55 (m, 6H); 13C NMR (CDCl3) δ 21.8, 30.6, 36.9, 63.4,
109.1, 115.1, 126.0, 127.7, 129.0, 130.1, 134.6, 137.7, 140.7,
142.2; MS m/ z 238 (M+), 223, 140, 129, 102, 91, 77; HRMS
calcd for C16H18N2 238.1470, found 238.1463.
1,2,3,7,8,8a -Hexa h yd r o-3-m eth yl-7-p h en ylin d olizin e-5-
ca r bon itr ile (7) a n d 1,2,3,7,8,8a -Hexa h yd r o-3-m eth yl-7-
p h en ylin d olizin e-5-ca r bon itr ile (8). Azadiene 6 (150 mg)
in 2 mL of anhydrous benzene was placed in an argon-flushed
10-mL capacity thick-walled glass tube, equipped with a
Rotoflo tap and a magnetic stirring bar, and heated under
closed conditions at 110 °C for 26 h. (CAUTION: Sealed tube
reactions should always be carried out behind a safety shield,
using thick-walled glass tubes.) After cooling, the solvent was
removed under vacuum and the residue was applied to a flash
column (silica gel, 5:1 heptane/ether). Indolizidines 7 and 8
(a 3:2 mixture of diastereomers) were obtained as a yellow oil
(110 mg, 73%). The mixture of isomers was separated by
HPLC (silica, 97:3.0:0.1 heptane/EtOAc/TEA).
Triflic anhydride (4.9 g, new or freshly distilled) was added
dropwise over 10 min to a cold (-60 °C, argon atmosphere)
solution of amide 2 (2.2 g, 15 mmol) and dry diisopropylethyl-
amine (2.9 g) in 40 mL of anhydrous CH2Cl2, and the resulting
mixture was stirred at -60 °C for 1 h. A suspension of LiCN
(0.7 g, predried for 2 h at 80 °C, 0.01 mmHg) in 40 mL of
anhydrous THF containing 12-crown-4 (0.36 g, 0.1 equiv) was
then added dropwise over a period of 10 min, and stirring was
continued for an additional 1 h at -60 °C. The reaction
mixture was warmed to -20 °C over a period of 15 min and
quenched with 50 mL of water. After the two layers were
separated and the aqueous phase was washed with ether, the
combined organic layers were washed with water, dried over
Na2SO4, and concentrated in vacuo. Purification by flash
chromatography (silica gel, 3:1 pentane/ether) gave azadiene
3 as a volatile yellow liquid (1.0 g, 42%): IR (neat) 2221 (CN),
Spectral data for 7: IR (neat) 2225 (CN), 1602 cm-1 (CdC);
1H NMR (CDCl3) δ 1.33 (d, J ) 6.2 Hz, 3H), 1.54 (m, 2H), 2.12
(m, 4H), 3.65 (m, 3H), 5.33 (s, 1H), 7.26 (m, 5H); 13C NMR
(CDCl3) δ 22.3, 30.9, 32.3, 36.7, 41.0, 57.3, 57.4, 116.6, 126.9,
127.2, 128.9, 144.0; MS m/ z 238 (M+), 223, 140, 115, 91; HRMS
calcd for C16H18N2 238.1470, found 238.1466.
1
1651 and 1623 (CdC), 1588 cm-1 (CdN); H NMR (CDCl3) δ
1.25 (d, J ) 6.2 Hz, 3H), 1.72 (m, 2H), 2.00 (q, J ) 7.5, 7.0 Hz,
2H), 3.90 (q, J ) 6.3 Hz, 1H), 5.01 (m, 2H), 5.79 (m, 1H), 5.98
(d, J ) 10.8 Hz, 1H), 6.16 (d, J ) 18.3 Hz, 1H), 6.57 (dd, J )
10.2, 7.2 Hz, 1H); 13C NMR (CDCl3) δ 21.7, 30.6, 36.7, 63.6,
108.7, 115.2, 127.6, 134.9, 137.7, 141.0; MS m/ z 162 (M+), 147,
107; HRMS calcd for C10H14N2 162.1157, found 162.1168.
1,2,3,7,8,8a -Hexa h yd r o-3-m eth ylin d olizin e-5-ca r bon i-
tr ile (4) a n d 1,2,3,7,8,8a -Hexa h yd r o-3-m eth ylin d olizin e-
5-ca r bon itr ile (5). Azadiene 3 (100 mg, 0.6 mmol) in 4.0 mL
of anhydrous benzene was placed in an argon-flushed 10-mL-
capacity thick-walled glass tube, equipped with a Rotoflo tap
and a stirring bar, and stirred under closed conditions at 110
°C (oil bath temperature) for 24 h. (CAUTION: Sealed tube
reactions should always be carried out behind a safety shield,
using thick-walled glass tubes.) After cooling, the solvent was
removed and the residue applied to a flash column (silica gel,
1:1 heptane/ether). Indolizidines 4 and 5, a 4:1 mixture of
diastereomers, were obtained as a yellow oil (94 mg, 94%
overall). The mixture of isomers was separated by HPLC
(reverse phase: Hypersel C-8; 55:45:0.1 MeOH/H2O/TEA).
Spectral data for 4: IR (neat) 2223 (CN), 1639 cm-1 (CdN);
1H NMR (CDCl3) δ 1.20 (m, 2H), 1.28 (d, J ) 6.2 Hz, 3H), 1.52
(m, 2H), 1.81 (m, 1H), 2.02-2.20 (m, 3H), 3.36 (m, 1H), 3.61
(m, 1H), 5.34 (t, J ) 4.2 Hz, 1H); 13C NMR (CDCl3) δ 22.1,
23.1, 26.0, 30.6, 31.3, 57.0, 57.2, 113.7, 117.0, 119.2; MS m/ z
162 (M+), 147, 138, 119, 93, 80, 67; HRMS calcd for C10H14N2
162.1157, found 162.1159.
Spectral data for 8: IR (neat) 2224 (CN), 1602 cm-1 (CdC).
1H NMR (CDCl3) δ 1.19 (d, J ) 6.4 Hz, 3H), 1.58 (m, 2H), 1.99
(m, 4H), 3.13 (m, 1H), 3.63 (t, J ) 5.6 Hz, 1H), 3.97 (m, 1H),
5.44 (d, J ) 5.5 Hz, 1H), 7.14-7.35 (m, 5H); 13C NMR (CDCl3)
δ 21.8, 30.0, 31.3, 37.4, 39.1, 52.6, 55.5, 112.8, 116.3, 118.8,
126.6, 128.4, 128.5, 146.0; MS m/ z 238 (M+), 223, 199, 161,
140, 115, 91; HRMS calcd for C16H18N2 238.1470, found
238.1471.
N-[6-(1-Hepten yl)]-2-cyan o-1-azabu ta-1,3-dien e (9). Us-
ing the procedure described for the preparation of the azadiene
3, the syn- and anti-6-hepten-2-one oximes (1.7 g, 13.9 mmol)
prepared from 6-hepten-2-one15 were reacted with acryloyl
chloride. The derived amide was obtained as a colorless oil
(1.6 g, 70%) after flash column purification (silica gel, 1:1 hep-
tane/ether): IR (neat) 3276 and 3077 (NH), 1629 cm-1 (CdO);
1H NMR (CDCl3) δ 1.16 (d, J ) 6.4 Hz, 3H), 1.45 (m, 4H), 2.05
(q, J ) 6.5, 7.0 Hz, 2H), 4.06 (quintet, J ) 7.0, 8.1 Hz, 1H),
4.98 (m, 2H), 5.60 (dd, J ) 2.2, 8.0 Hz, 1H), 5.78 (m, 1H), 5.92
(NH), 6.16 (m, 2H); 13C NMR (CDCl3) δ 20.9, 25.4, 33.6, 35.4,
45.3, 114.8, 126.0, 131.3, 138.5, 164.9; MS m/ z 167 (M+), 152,
143, 134, 126; HRMS calcd for C10H17NO 167.1309, found
167.1309.
The above amide (1.5 g, 9.0 mmol) was treated with triflic
anhydride (3.0 g, 1.2 equiv) in anhydrous CH2Cl2 containing
diisopropylethylamine (1.7 g, 1.5 equiv) at -60 °C and then
with LiCN (0.4 g, 1.4 equiv) and 12-crown-4 (0.2 g, 0.1 equiv).
Azadiene 9 was obtained as a light oil (0.7 g, 43%) after flash
column purification (silica gel, 3:1 heptane/ether): IR (neat)
2221 (CN), 1588 cm-1 (CdN); 1H NMR (CDCl3) δ 1.24 (d, J )
6.2 Hz, 3H), 1.33 (m, 2H), 1.63 (m, 2H), 2.06 (q, J ) 7.0 Hz,
2H), 3.87 (q, J ) 6.3 Hz, 1H), 4.99 (m, 2H), 5.78 (m, 1H), 5.95
(d, J ) 10.6 Hz, 1H), 6.15 (d, J ) 17.6 Hz, 1H), 6.56 (dd, J )
10.6, 6.9 Hz, 1H); 13C NMR (CDCl3) δ 21.8, 33.6, 37.1, 64.1,
Spectra data for 5: IR (neat) 2223 (CN), 1639 cm-1 (CdN);
1H NMR (CDCl3) δ 1.13 (d, J ) 6.5 Hz, 3H), 1.22 (m, 2H), 1.61
(m, 2H), 2.08 (m, 4H), 3.22 (m, 1H), 3.85 (quintet, J ) 6.6 Hz,
1H), 5.32 (m, 1H); 13C NMR (CDCl3) δ 21.4, 23.7, 29.0, 30.3,
31.2, 55.1, 57.2, 113.4, 116.4, 117.8; MS m/ z 162 (M+), 147,
138; HRMS calcd for C10H14N2 162.1157, found 162.1155.
N-[5-(1-H exen yl)]-2-cya n o-4-p h en yl-1-a za b u t a -1,3-d i-
en e (6). Following the procedure described for the preparation
of azadiene 3, 5-hexene-2-one oxime (2.0 g, 17 mmol) was
reduced using LiAlH4 in anhydrous ether. N-[5-(1-Hexenyl)]-

Diels-Alder Reaction of 2-Cyano-1-aza-1,3-butadienes
J . Org. Chem., Vol. 62, No. 7, 1997 2097
108.8, 114.9, 127.6, 134.9, 138.4, 140.8; MS m/ z 176 (M+), 161,
107; HRMS calcd for C11H16N2 176.1313, found 176.1307.
1,6,7,8,9,9a -Hexa h yd r o-6-m eth yl-2H-qu in olizin e-4-ca r -
bon itr ile (10) a n d 1,6,7,8,9,9a -Hexa h yd r o-6-m eth yl-2H-
qu in olizin e-4-ca r bon itr ile (11). Azadiene 9 (100 mg) in 2
mL of anhydrous benzene was placed in an argon-flushed 10-
mL capacity thick-walled glass tube, equipped with a Rotoflo
tap and a magnetic stirring bar, and heated under closed
conditions at 110 °C for 48 h. (CAUTION: Sealed tube
reactions should always be carried out behind a safety shield,
and using thick-walled glass tubes.) After cooling, the solvent
was removed under vacuum and the residue was applied to a
flash column (silica gel, 20:1 heptane/ether). Quinolizidines
10 and 11 were obtained as a yellow oil in a 1:4 ratio (86 mg,
86%). The mixture of isomers were separated by HPLC
(reverse phase: Hypersel C-8; 55:45:0.1 MeOH/H2O/TEA).
Spectral data for 10: IR (neat) 2223 (CN), 1614 cm-1 (CdC);
1H NMR (CDCl3) δ 1.12 (d, J ) 6.8 Hz, 3H), 1.41-1.83 (m,
8H), 2.10 (m, 2H), 2.92 (broad triplet, J ) 11 Hz, 1H), 3.90
(m, 1H), 5.40 (m, 1H); 13C NMR (CDCl3) δ 13.8, 18.8, 22.3, 29.4,
30.5, 32.6, 49.6, 51.6, 116.0, 116.4, 122.6; MS m/ z 176 (M+),
161, 133, 107; HRMS calcd for C11H16N2 176.1313, found
176.1313.
Spectral data for 11: IR (neat) 2223 (CN), 1614 cm-1 (CdC);
1H NMR (CDCl3) δ 1.32 (d, J ) 6.8 Hz, 3H), 1.44-1.85 (m,
8H), 2.16 (m, 2H), 3.00 (m, 1H), 3.45 (m, 1H), 5.55 (t, J ) 4.2
Hz, 1H); 13C NMR (CDCl3) δ 19.2, 22.0, 23.0, 28.9, 29.2, 31.0,
53.5, 55.2, 117.3, 119.6, 121.7; MS m/z 176 (M+), 161, 133, 107;
HRMS calcd for C11H16N2 176.1313, found 176.1307.
Ack n ow led gm en t. The authors thank Dr. Charles
DeBrosse of SmithKline Beecham for his assistance with
the NOE experiments. This work was supported by
grants from NATO (900305) and NIH (GM3972903) and
a Chateaubriand scholarship for N.J .S.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for compounds 2-11, as well as the amide precursors
to azadienes 6 and 9 (23 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O961403D