An efficient approach to pyrroles and N-bridgehead pyrroles by propargylation/cycloamination of 4-amino-1-azabutadiene derivatives

Article abstract of DOI:10.1021/jo951887y

The thermal cycloamination of several propargyl-substituted 4-amino-1-azabutadienes 2 leading to 3-functionalized pyrroles 4-6 is described. Derivatives of pyrrolizidines 9 and indolizidines and azaazulenes 11-13 are synthesized directly from cyclic imines 7 and 10, respectively, in a multistep process that involves metalation with LDA, addition of a nitrile, carbanion trapping with propargyl bromide, and cycloamination. In all cases the more substituted imine nitrogen is involved in the cyclization reaction; such an experimental finding is supported by theoretical calculations.

Full text of DOI:10.1021/jo951887y

J . Org. Chem. 1996, 61, 2185-2190
2185
An Efficien t Ap p r oa ch to P yr r oles a n d N-Br id geh ea d P yr r oles by
P r op a r gyla tion /Cycloa m in a tion of 4-Am in o-1-a za bu ta d ien e
Der iva tives
J ose´ Barluenga,* Miguel Toma´s, Vladimir Kouznetsov, Angel Sua´rez-Sobrino, and
Eduardo Rubio
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”, Unidad Asociada al CSIC,
Universidad de Oviedo, J ulia´n Claverı´a 8, 33071 Oviedo, Spain
Received October 23, 1995X
The thermal cycloamination of several propargyl-substituted 4-amino-1-azabutadienes 2 leading
to 3-functionalized pyrroles 4-6 is described. Derivatives of pyrrolizidines 9 and indolizidines and
azaazulenes 11-13 are synthesized directly from cyclic imines 7 and 10, respectively, in a multistep
process that involves metalation with LDA, addition of a nitrile, carbanion trapping with propargyl
bromide, and cycloamination. In all cases the more substituted imine nitrogen is involved in the
cyclization reaction; such an experimental finding is supported by theoretical calculations.
Pyrrole derivatives represent a class of heterocycles of
great importance, as many reviews, monographs, and
reports have been released. Compounds containing the
pyrrole ring are widely spread in nature1 and substituted
pyrroles very frequently display biological activity;2
moreover, polymers derived from pyrrole have found
applications as conducting and nonlinear optics materi-
als.3 On the other hand, N-bridgehead pyrroles, for
instance pyrrolizidines and indolizidines, encompass one
of the most intriguing fused pyrrole derivatives; they
constitute the basic skeleton of many alkaloids with well
recognized pharmacological properties.4
to the synthesis of (()-monomorine10 reported by Living-
house is remarkable. Obviously, the potential of this
simple cycloamination methodology would become greatly
enhanced if its application to fused pyrroles would be
feasible.
Continuing our interest in the regioselective prepara-
tion of heterocycles from readily available starting ma-
terials,11 we report herein the synthesis of functionalized
pyrroles, pyrrolizidines, indolizidines, and azaazulenes,
which is based on the intramolecular amination of
3-propargyl-4-(alkyl(aryl)amino)-1-azabutadienes.12
Syn th esis of P yr r oles 4-6. First, the required
propargyl azadienes 2 were obtained in multigram
quantities by metalation of azadienes 113 with n-butyl-
lithium followed by C-alkylation with propargyl bromide
(R4 ) H) or 2-butynyl p-toluenesulfonate (R4 ) Me), as
previously reported.14 Then, heating compounds 2a -d in
toluene at 60 °C for 4 h followed by work-up with 1N
HCl resulted in the formation of 3-acylpyrroles 4 in
excellent yields after column chromatographic purifica-
tion (Scheme 1; Table 1, compounds 4a -d , entries 1-4).
When using azadiene 2e having a more nucleophilic,
unhindered nitrogen (R1 ) n-Bu, entry 5, Table 1) the
process was found to occur in 2 h at room temperature;
conversely, the cyclization of the azadiene 2f derived from
an internal alkyne (R4 ) Me) into the pyrrole 4f (entry
6, Table 1) required more drastic reaction conditions (120
°C, EtOH, sealed tube, 24 h).
Of the many efficient pyrrole synthesis reported to
date,5 the cyclization of aminoalkynes has not been
extensively exploited.6 Thus, functionalized amino and
amido alkynes have been cyclized in the presence of
palladium(II)7 and silver(I)8 salts, respectively. The
intramolecular [2 + 2] cycloaddition between group IV
metal-imido complexes and alkynes9 and its application
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) Pinder, A. R. In The Alkaloids; Grundon, M. F., Ed.; Chemical
Society: London, 1982; Vol. 12.
(2) (a) Korostova, S. E.; Sobenina, L. N.; Nesterenko, R. N.; Aliev,
I. A.; Mikhaleva, A. I. Zh. Org. Khim. 1984, 1960; Chem Abstr. 1985,
102, 131860. (b) Itoh, S.; Fukui, Y.; Haranou, S.; Ogino, M.; Komatsu,
M.; Ohshiro, Y. J . Org. Chem. 1992, 57, 4452. (c) Woo, J .; Sigurdsson,
S. T.; Hopkins, P. B. J . Am. Chem. Soc. 1993, 115, 3407. (d) Lainton,
J . A. H.; Huffman, J . W.; Martin, B. R.; Compton, D. R. Tetrahedron
Lett. 1995, 36, 1401.
(3) (a) Niziurski-Mann, R. E.; Cava, M. P. Heterocycles 1992, 34,
2003. (b) Naarmann, H.; Theophilou, N. In Electroresponsive Molecular
and Polymeric Systems; Marcel Dekker Inc.: New York, 1988; Vol. 1.
(c) Bauerle, P. Adv. Mater. 1993, 5, 879.
Although the primary cycloamination products 3 were
not isolated in pure form because of their easy hydrolysis
when subjected to column chromatography purification,
the imine function of 3 could be acylated or reduced in
situ (Scheme 2, Table 1). Thus, azadiene 2a was cyclized,
and the resulting toluene solution was cooled back to
room temperature and treated with benzoyl chloride in
the presence of pyridine to furnish the 3-(benzoylimino)-
(4) For the biological activity of indolizidine alkaloids, see: (a)
Takohata, H.; Momose, T. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1993; Vol. 44. (b) Nishimura, Y., In Studies
in Natural Products Chemistry; Rahman, A.-U., Ed.; Elsevier: Am-
sterdam, 1988; Vol. 1, p 227. (c) Elbein, A. D.; Molineux, R. J . In
Alkaloids: Chemical, Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1987; Vol. 5, p 1. For the biological activity of
pyrrolizidine derivatives, see: (d) Iyer, V. N.; Szybalski, W. Science
1964, 145, 55. (e) Anderson, K. W.; Corey, P. F. J . Med. Chem. 1977,
20, 812. (f) Weidner, M. F.; Sigurdsson, S. T.; Hopkins, P. B.
Biochemistry 1990, 29, 9225.
(9) McGrane, P. L.; J ensen, M.; Livinghouse, T. J . Am. Chem. Soc.
1992, 114, 5459.
(5) Sundberg, R. J . In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1984;
Vol. 4, p 313.
(6) For syntheses of five-membered heterocycles by cycloamination
under neutral or basic conditions, see: (a) Overman, L. E.; Tsuboi, S.;
Angle, S. J . Org. Chem. 1979, 44, 2323. (b) J acobi, P. A.; Brielmann,
H. L.; Hauck, S. I. Tetrahedron Lett. 1995, 36, 1193.
(7) (a) Utimoto, K.; Miwa, H. and Nozaki, H. Tetrahedron Lett., 1981,
22, 4277. (b) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H. Tetrahedron
Lett. 1985, 26, 5963.
(10) McGrane, P. L.; Livinghouse, T. J . Org. Chem. 1992, 57, 1323.
(11) (a) Barluenga, J .; Aznar, F.; Fustero, S.; Toma´s, M. Pure Appl.
Chem. 1990, 62, 1957. (b) Barluenga, J .; Toma´s, M. Adv. Heterocycl.
Chem. 1993, 57, 1.
(12) Preliminary communications: (a) Barluenga, J .; Toma´s, M.;
Sua´rez-Sobrino, A. Synlett 1990, 351. (b) Barluenga, J .; Toma´s, M.;
Kouznetsov, V.; Rubio, E. J . Chem. Soc., Chem. Commun. 1993, 1419.
(13) (a) Hoberg, H.; Barluenga, J . Synthesis 1970, 142. (b) Wittig,
G.; Fischer, S.; Tanaka, M. Liebigs Ann. Chem. 1973, 1075.
(14) Barluenga, J .; J ardo´n, J .; Gotor, V. J . Org. Chem. 1985, 50,
802.
(8) Prasad, J . S.; Liebiskind, L. S. Tetrahedron Lett. 1988, 29, 4253.
0022-3263/96/1961-2185$12.00/0 © 1996 American Chemical Society

2186 J . Org. Chem., Vol. 61, No. 6, 1996
Ta ble 1. P yr r ole Der iva tives 4-6 P r ep a r ed fr om Aza d ien es 2
Barluenga et al.
yield (%)a,b
entry
azadienes 2
R1
R2
R3
R4
compounds
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2a
2a
2d
2e
2g
p-Me-C6H4
Ph
c-C6H11
p-Me-C6H4
n-Bu
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
n-Bu
Ph
Ph
H
Ph
Ph
H
H
H
H
H
Me
H
H
H
H
H
4a
4b
4c
4d
4e
4f
5
6a
6b
6c
6d
96
95
80
95
91
79
93
93
91
91
96
p-Me-C6H4
c-C6H11
Ph
Ph
Ph
Ph
c-C6H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
p-Me-C6H4
p-Me-C6H4
a
b
Isolated yields from azadienes 2. Yields of purified compounds.
Sch em e 1
Sch em e 2
F igu r e 1.
results, semiempirical calculations using the Gaussian
92 series of programs17 and the AM1 hamiltonian18 were
performed. All the structures located were fully opti-
mized and characterized by the corresponding frequency
calculations. On the basis of these calculations we can
infer that the s-cis conformer A, wherein the carbon-
carbon triple bond was found to be nearly coplanar with
the substituted nitrogen, is responsible for the cyclization
rather than the s-trans conformer B (Figure 1).
pyrrole 5 (entry 7, Table 1). Alternatively, this benzoyl-
ated derivative 5 is readily available in two steps by
N-benzoylation of azadiene 2a (benzoyl chloride, toluene-
Et3N, 25 °C)14 followed by heating in toluene at 110 °C.
Similarly, the preparation of 3-(R-aminoalkyl)pyrrole
derivatives 6 (entries 8-11) could be achieved in high
yields in a one-pot procedure that involves heating of
azadienes 2 in THF and treatment of the resulting
3-iminopyrrole intermediates 3 with NaBH4 (molar ratio
1:1) in THF/MeOH at room temperature.
The most stable conformations located for a simple
4-amino-1-azabutadiene 2 (R1 ) Me, R2 ) R4 ) H, R3 )
Ph) are shown in Figure 1. The AM1 calculations
indicate that the s-cis conformer A (∆Hf° ) 107.2 kcal
mol-1) is more stable than the s-trans conformer B (∆Hf°
) 108.4 kcal mol-1) by 1.2 kcal mol-1
. This result is
consistent with the steric requirements of the phenyl
group. Accordingly, it can reasonably be expected that
the cycloamination reaction proceeds through the sub-
stituted nitrogen (conformation A). We have not found
any stationary point corresponding to a conformation
having the alkyne function close to the unsubstituted
imine nitrogen. In addition, the analysis of the Mulliken
The process shown is an example of a favorable exo-
dig cyclization,15 in which two unexpected features have
to be mentioned. Firstly, the reaction takes place with
complete chemoselectivity, and secondly, the more sub-
stituted nitrogen is surprisingly involved in the cycliza-
tion.16 In order to gain some evidence regarding these
(17) Gaussian 92 Revision A. Frisch, M. J .; Trucks, J . W.; Head-
Gordon, M.; Gill, P. M. W.; Wong, M.W.; Foresman, J . B.; J ohnson, B.
G.; Schlegel, H. E.; Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andre´s,
J . L.; Raghavachari, K.; Binkley, J . S.; Gonza´lez, C.; Martin, R. L.;
Fox, D. J .; Defrees, D. J .; Baker, J .; Stewart, J . J . P.; Pople, J . A.,
Gaussian Inc.: Pittsburgh, PA, 1992.
(15) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 735.
(16) The general behavior of 4-amino-1-azadienes 1 and 2 toward
electrophilic reagents implies the initial attack of the unsubstituted
imine nitrogen, see reference 11.
(18) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.

Propargylation/Cycloamination of 4-Amino-1-azabutadiene
J . Org. Chem., Vol. 61, No. 6, 1996 2187
Ta ble 2. N-Br id geh ea d P yr r oles 9-13
Sch em e 3
cmpd
n
R
yielda (%)
9a
9b
-
-
1
1
1
2
2
2
1
1
1
2
2
2
1
2
Ph
c-C6H11
Ph
55
71
82
75
71
78
70
77
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
12e
12f
13a
13b
c-C3H5
2-thienyl
2-furyl
Ph
2-thienyl
c-C3H5
2-thienyl
2-furyl
Ph
88b
92b
87b
96b
82b
76b
83
2-thienyl
3,4-dimethoxyphenyl
2-thienyl
2-furyl
72
charges shows that the nitrogen actually involved in the
cyclization is the most negatively charged (0.16 e vs 0.12
e).
a
b
Yields of purified products. Overall yields from imine 10.
Sch em e 4
The process shown here provides access to 3-function-
alized pyrroles, e.g. 3-acylpyrroles, in a simple and
efficient fashion. While the synthesis of 2-acylpyrroles
is easily achieved by direct acylation of pyrroles, the
approaches to 3-acylpyrroles are relatively few in num-
ber. For instance, the directed electrophilic acylation of
the pyrrole ring has been achieved by the introduction
of appropriate, removable substituents either at nitro-
gen19 or at C-2 positions;20 the [4 + 1] annulation of
2-acyl-3-sulfonylbutadienes with primary aliphatic
amines21 also gives access to some pyrroles of this type.
Syn t h esis of N-Br id geh ea d P yr r oles. Next, this
methodology was extended to the synthesis of N-bridge-
head heterocycles containing a pyrrole unit, including not
only the classical pyrrolizidine22 and indolizidine23 sys-
tems, but also the quite rare azaazulene derivatives.24
First, the monocyclic azadienes 8 required for the
preparation of pyrrolizidines 9 were generated in one-
pot from the corresponding 2-methyl-1-pyrroline 725
following the procedure for acyclic azadienes 214 (Scheme
3). To this end, azadienes 8 were formed by successive
treatment of imines 7 in THF with one equiv of LDA (-78
°C), an aliphatic or aromatic nitrile (1 equiv, -78 °C),
and propargyl bromide (1 equiv, -78 °C to 25 °C).26 The
use of equimolecular amounts of base implies that the
addition of the azaenolate to the nitrile function giving
the species C is followed by tautomerization to form the
1,5-diazapentadienyl anion D, which finally undergoes
C-propargylation (Scheme 3). The corresponding ami-
noazabutadienes 8 were isolated after aqueous workup
of the reaction mixture and used without purification.
Furthermore, heating a solution of 8 in a mixture of
EtOH-Et3N (100 °C, sealed tube, 6 h) resulted in pyrrole
annulation and hydrolysis of the imine group affording
didehydropyrrolizidines 9 in moderate yields after col-
umn chromatographic purification (Table 2).
On the other hand, when six- and seven-membered
cyclic imines 10 (n ) 1,2) were subjected to the same
protocol as described above for five-membered imines 7,
the corresponding azadiene derivatives could not be
isolated. Gratifyingly, the cyclization of the latter oc-
curred at room temperature, giving rise directly to
indolizidine and azaazulene derivatives 11 (n ) 1,2) in
good yields (70-82% from imine 10) (Scheme 4, Table
2). Unlike their monocyclic analogues 3, compounds 11
could be easily purified by column chromatography
without observed hydrolysis of the unsubstituted imine
function. Heterocycles 11 were further hydrolyzed with
dilute HCl giving 12 or reduced with NaBH4/MeOH to
yield R-aminoalkyl derivatives 13.
It should be noted that this cycloamination process
works well for alkyl, aryl, and heteroaryl nitriles, provid-
ing potentially useful compounds. For instance, deriva-
tives 13a and 13b can be envisaged as masked non-
natural R-amino acids,27 whereas the incorporation of the
synthetically useful cyclopropyl group (compounds 11b
and 12a ) should permit further manipulations.28 On the
other hand, these fused aromatic pyrroles are a highly
uncommon type of N-bridgehead heterocycles. Besides,
the biological activity of compounds of this sort, e.g.
didehydropyrrolizidines, is well recognized.29
(19) (a) Rokarch, J .; Hamel, P.; Kakushima, M. Tetrahedron Lett.
1981, 22, 4901. (b) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach,
J . J . Org. Chem. 1983, 48, 3214. (c) Bray, B. L.; Muchowski, J . M. J .
Org. Chem. 1988, 53, 6115.
(20) Anderson, H. J .; Loader, C. E. Synthesis 1985, 353.
(21) Chou, S.-S. P.; Yuan, T.-M. Synthesis 1991, 171.
(22) (a) Hall, G.; Sugden, J . K.; Waghela, M. B. Synthesis 1987, 10.
(b) Robine, D. J . Nat. Prod. Rep. 1994, 11, 613. For recent syntheses,
see: (c) Ogawa T.; Niwa, H.; Yamada, K. Tetrahedron Lett. 1993, 34,
1571. (d) Eguchi, M.; Zeng, Q.; Korda, A.; Ojima, I. Tetrahedron Lett.
1993, 34, 915. (e) Murray, A.; Proctor, G. R. Tetrahedron Lett. 1995,
36, 291.
(23) (a) Michael, J . P. Nat. Prod. Rep. 1994, 11, 639. For recent
syntheses, see: (b) Barton, D. H. R.; Arau´jo Pereira, M. M. M.; Taylor,
D. K. Tetrahedron Lett. 1994, 35, 9157. (c) Momose, T.; Toyooka, N. J .
Org. Chem. 1994, 59, 943. (d) Pilli, R. A.; Dias, L. C.; Maldaner, A. O.
J . Org. Chem., 1995, 60, 717.
Con clu sion s
(24) (a) Flitsch, W. Adv. Heterocycl. Chem. 1988, 43, 35. (b) Nitta,
M.; Mori, S.; Iino, Y. Heterocycles 1991, 32, 2247.
(25) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo,
A. A. J . Org. Chem. 1990, 55, 3682.
(26) Barluenga, J .; Toma´s, M.; Kouznetsov, V.; Rubio, E. Synlett
1992, 563.
The work described here represents an efficient and
simple entry into 3-functionalized pyrroles. The method
is based on the uncatalyzed cyclization of propargyl-
substituted 4-amino-1-azabutadienes and is applied to

2188 J . Org. Chem., Vol. 61, No. 6, 1996
Barluenga et al.
C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.21; H,
8.28; N, 4.87.
both monocyclic and N-bridgehead pyrroles; in the case
of the latter, the process starts from conventional cyclic
imines and is run in one-pot in most instances, though
it comprises as many as four steps (metalation of an
imine, addition to a nitrile, propynylation, and cycloami-
nation).
3-(Cycloh exylca r bon yl)-2-p h en yl-5-m eth yl-1-(p-tolyl)-
p yr r ole (4d ): mp 148-149 °C; 1H NMR δ 1.0-1.7 (m, 10H),
2.1 (s, 3H), 2.3 (s, 3H), 2.6 (m, 1H), 6.5 (s, 1H), 6.9 (d, J ) 8.4
Hz, 2H), 7.1 (d, J ) 8.4 Hz, 2H), 7.2 (m, 5H); 13C NMR δ 12.8
(CH3), 21.0 (CH3), 25.8 (CH2), 29.3 (CH2), 47.4 (CH), 107.9
(CH), 121.5 (C), 127.4 (CH), 127.5 (CH), 128.0 (CH), 129.2
(CH), 130.2 (C), 130.9 (CH), 132.6 (C), 135.0 (C), 137.6 (C),
200.4 (C); MS m/ e 357 (M+, 13), 274 (100). Anal. Calcd for
C25H27NO: C, 83.99; H, 7.61; N, 3.92. Found: C, 83.98; H,
7.67; N, 3.85.
3-Ben zoyl-1-bu tyl-5-m eth yl-2-p h en ylp yr r ole (4e): oil;
1H NMR δ 0.6 (t, J ) 7.3 Hz, 3H), 1.1 (m, 2H), 1.4 (m, 2H), 2.2
(s, 3H), 3.7 (m, 2H), 6.3 (s, 1H), 7.1-7.3 (m, 8H), 7.6 (d, J )
7.6 Hz, 2H); 13C NMR δ 12.3 (CH3), 13.4 (CH3), 19.6 (CH2),
32.7 (CH2), 43.8 (CH2), 110.2 (CH), 120.9 (C), 127.4 (CH), 127.7
(CH), 127.8 (CH), 128.4 (C), 129.1 (CH), 130.6 (CH), 130.7
(CH), 132.4 (C), 140.0 (C), 141.0 (C), 191.6 (C); MS m/ e 317
(M+, 79), 105 (100). Anal. Calcd for C22H23NO: C, 83.24; H,
7.30; N, 4.41. Found: C, 83.58; H, 7.67; N, 4.15.
P r ep a r a tion of 3-Ben zoyl-5-eth yl-2-p h en yl-1-(p-tolyl)-
p yr r ole (4f). Azadiene 2f (5 mM, 1.8 g) was dissolved in 10
mL of EtOH and heated in a sealed tube at 120 °C for 12 h.
The mixture was cooled back to rt, treated with 1 N HCl (20
mL), extracted with ether (3 × 10 mL), washed with brine,
and dried over anhydrous sodium sulfate. Removal of solvents
under vacuum and purification as above resulted in pyrrole
4f (1.4 g, 79%): mp 135-136 °C; 1H NMR δ 1.0 (t, J ) 7.4 Hz,
3H), 2.3 (s, 3H), 2.4 (q, J ) 7.4 Hz, 2H), 6.4 (s, 1H), 6.9-7.4
(m, 12H), 7.7 (d, J ) 7.9 Hz, 2H); 13C NMR δ 12.6 (CH3), 20.2
(CH3), 21.0 (CH2), 108.3 (CH), 121.4 (C), 127.0 (CH), 127.2
(CH), 127.4 (CH), 128.2 (CH), 129.3 (CH), 129.4 (CH), 130.9
(CH), 131.0 (CH), 131.6 (C), 135.0 (C), 136.8 (C), 137.8 (C),
138.6 (C), 139.6 (C), 192.3 (C); MS m/ e 365 (M+, 40), 105 (100),
77 (56). Anal. Calcd for C26H23NO: C, 85.45; H, 6.34; N, 3.83.
Found: C, 85.26; H, 6.47; N, 3.76.
Exp er im en ta l Section
Gen er a l Meth od s. Mp’s are uncorrected. General spec-
troscopic techniques have been previously reported.30 NMR
experiments were run in CDCl3. Column chromatography was
performed with silica gel (230-400 mesh) and florisil (100-
200 mesh) by standard flash chromatographic techniques.31
Ma ter ia ls. Toluene was distilled from sodium benzophe-
none ketyl under nitrogen prior to use. Ether and THF were
treated with sodium and distilled over sodium. Triethylamine
was distilled from KOH pellets. Ethanol was distilled from
calcium hydride. n-BuLi was used as a 2.5 M solution in
hexane. The preparations of the starting azadienes 1,13 their
alkylated derivatives 2,14 and imines 7 and 1025 have been
previously described.
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr r oles
4a -e. Azadienes 2 (5 mM) were dissolved in 15 mL of toluene
and stirred (60 °C, 4 h for 4a -d ; 25 °C, 2 h for 4e). The
solution was then cooled to rt and treated with 1 N HCl (25
mL). After extraction with ether (3 × 20 mL), the combined
organic layers were washed with water and dried over
anhydrous sodium sulfate and the solvents removed at vacuum.
The residue was then subjected to column chromatography
(SiO2, hexane/ether, 2:1) to yield compounds 4a -e which were
recrystallized from hexane-CHCl3.
3-Ben zoyl-5-m eth yl-2-ph en yl-1-(p-tolyl)pyr r ole (4a): mp
152-153 °C; 1H NMR δ 2.1 (s, 3H), 2.3 (s, 3H), 6.4 (s, 1H),
6.9-7.4 (m, 12H), 7.7 (d, J ) 7.1Hz, 2H); 13C NMR δ 12.8
(CH3), 20.9 (CH3), 110.12 (CH), 121.3 (C), 126.9 (CH), 127.2
(CH), 127.4 (CH), 127.9 (CH), 129.2 (CH), 129.3 (CH), 130.2
(C), 130.7 (CH), 130.9 (CH), 131.6 (C), 135.0 (C), 137.6 (C),
138.6 (C), 139.5 (C), 192.0 (C); MS m/ e 351 (M+, 100), 274
(87), 105 (48), 77 (65). Anal. Calcd for C25H21NO: C, 85.44;
H, 6.02; N, 3.98. Found: C, 85.28; H, 5.89; N, 4.21.
P r ep a r a t ion of 3-[(Ben zoylim in o)p h en ylm et h yl]-2-
p h en yl-5-m eth yl-1-(p-tolyl)p yr r ole (5). Meth od A.
A
solution of azadiene 2a (5 mM, 1.75 g) in 15 mL of toluene
was heated at 60 °C for 4 h under N2; after cooling the solution
to rt, Et3N (5 mM, 0.7 mL) and benzoyl chloride (5 mM, 700
mg) were added. The mixture was stirred for 6 h at rt and
then treated with 1 N HCl (20 mL) and extracted with ether
(3 × 20 mL). The combined organic layers were washed with
aqueous saturated solution of NaHCO3 (2 × 20 mL) and water
(2 × 20 mL) and dried over anhydrous sodium sulfate. After
removal of solvents at vacuum, the residue was subjected to
column chromatography (SiO2, hexane/ether, 2:1) to yield
compound 5 (1.9 g, 84%) which was further recrystallized from
hexane-CHCl3.
Meth od B. Azadiene 2a was acylated following the method
described.14 The resulting acylazadiene was heated at 110 °C
in toluene for 12 h. Removal of toluene gave a residue which
was purified as above to afford 5 in 93% yield: mp 192-193
°C; 1H NMR δ 2.0 (s, 3H), 2.3 (s, 3H), 6.2 (s, 1H), 6.8-7.5 (m,
15H), 7.6 (d, J ) 9.2 Hz, 2H), 7.9 (d, J ) 9.2 Hz, 2H); 13C NMR
δ 12.9 (CH3), 20.9 (CH3), 109.3 (CH), 118.7 (C), 126.5 (CH),
127.2 (CH), 127.4 (CH), 128.0 (CH), 128.1 (CH), 129.1 (CH),
129.3 (CH), 129.4 (CH), 130.1 (CH), 130.5 (CH), 131.5 (C),
132.0 (CH), 134.3 (C), 135.4 (C), 135.9 (C), 137.5 (C), 137.8
(C), 164.9 (C), 179.4 (C); MS m/ e 454 (M+, 20), 349 (32), 105
(100), 77 (95). Anal. Calcd for C32H26N2O: C, 84.55; H, 5.76;
N, 6.16. Found: C, 84.80; H, 5.67; N, 6.31.
3-Ben zoyl-5-m eth yl-1,2-d ip h en ylp yr r ole (4b): mp 136-
1
137 °C; H NMR δ 2.1 (s, 3H), 6.4 (s, 1H), 6.9-7.7 (m, 15H);
13C NMR δ 12.8 (CH3), 110.2 (CH), 121.4 (C), 127.0 (CH), 127.1
(CH), 127.4 (CH), 127.8 (CH), 128.3 (CH), 128.7 (CH), 129.3
(CH), 130.1 (C), 130.7 (CH), 131.0 (CH), 131.5 (C), 137.7 (C),
138.2 (C), 139.5(C), 192.0 (C); MS m/ e 337 (M+, 100), 260 (83),
105 (30), 77 (92). Anal. Calcd for C24H19NO: C, 85.43; H, 5.67;
N, 4.15. Found: C, 85.49; H, 5.47; N, 4.31.
1-Cycloh exyl-5-m eth yl-3-(p-tolylca r bon yl)p yr r ole (4c):
1
oil; H NMR δ 1.2-2.1 (m, 10H), 2.3 (s, 3H), 2.4 (s, 3H), 3.8
(m, 1H), 6.4 (s, 1H), 7.2 (s, 1H), 7.3 (d, J ) 7.6 Hz, 2H), 7.7 (d,
J ) 7.6 Hz, 2H); 13C NMR δ 11.9 (CH3), 21.4 (CH3), 25.2 (CH2),
25.7 (CH2), 35.1 (CH2), 55.6 (CH), 108.6 (CH), 123.0 (C), 124.1
(CH), 128.6 (CH), 128.9 (CH), 129.7 (C), 137.5 (C), 141.3 (C),
190.3 (C); MS m/ e 281 (M+, 100), 119 (100). Anal. Calcd for
(27) The transformation of the 2-furyl group into the carboxylic acid
function is a quite common process in synthetic strategies. See, for
instance: (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J . Org. Chem. 1981, 46, 3936. (b) Martin, S. F.; Zinke, P. W. J .
Org. Chem. 1991, 56, 6600. (c) Adger, B. M.; Barrett, C.; Brennan, J .;
McKervey, M. A.; Murray, R. W. J . Chem. Soc., Chem. Commun. 1991,
1553.
(28) (a) Reissig, H. U. In The Chemistry of the Cyclopropyl Group;
Patai, S., Ed.; Wiley: New York, 1987; p 383. (b) Hudlicky, T.; Reed,
J . W. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Perga-
mon: New York, 1991; Vol. 5, p 899.
(29) (a) Mann, J . In Secondary Metabolism, 2nd ed.; OUP: New
York, 1987; p 205. (b) Anderson, W. K.; Mach, R. H. J . Heterocycl.
Chem. 1990, 27, 1025. (c) Mattocks, A. R. In Chemistry and Toxicology
of Pyrrolizidine Alkaloids; Academic Press: London, 1986. (d) Daly,
J . W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier S. W., Ed.; Wiley: New York, 1986; Vol 4, p 1-102.
(30) Barluenga, J .; Aguilar, E.; Olano, B.; Fustero, S. J . Org. Chem.
1988, 53, 1741.
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr r oles 6.
Azadienes 2 (5 mM) were disolved in 15 mL of THF and heated
at 60 °C under N2 for 6 h. After cooling to 0 °C, MeOH (7 mL)
and portionwise sodium borohydride (15 mM) were added and
the mixture was stirred for 12 h at rt. Conventional aqueous
workup gave a residue which was subjected to column chro-
matography (SiO2, hexane/ether/diethylamine, 4:4:1) to yield
the pure compounds 6.
3-(r-Am in ob en zyl)-5-m et h yl-2-p h en yl-1-(p -t olyl)p yr -
1
r ole (6a ): oil; H NMR δ 2.1 (s, 3H), 2.4 (s, 3H), 5.2 (s, 1H),
6.1 (s, 1H), 7.0-7.6 (m, 16H); 13C NMR δ 13.1 (CH3), 20.8
(31) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(CH3), 52.0 (CH), 105.4 (CH), 126.2 (CH), 126.6 (CH), 127.2

Propargylation/Cycloamination of 4-Amino-1-azabutadiene
J . Org. Chem., Vol. 61, No. 6, 1996 2189
(C), 127.6 (CH), 128.0 (CH), 128.1 (CH), 128.5 (C), 129.6 (CH),
130.0 (CH), 130.2 (C), 130.3 (CH), 130.5 (C), 132.6 (C), 136.1
(C), 136.4 (C); MS m/ e 352 (M+, 58), 275 (100). Anal. Calcd
for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.32; H,
6.67; N, 7.84.
added. The reaction mixture was then allowed to slowly reach
rt, treated with H2O (50 mL), and extracted with ether (3 ×
20 mL). The combined organic layers were dried over anhy-
drous sodium sulfate and the solvents removed at vacuum.
The oily residue was then subjected to column chromatography
(florisil, CH2Cl2/MeOH, 5:1) to yield pure compounds 11.
1-(Im in op h en ylm eth yl)-3-m eth yl-5,6,7,8-tetr a h yd r oin -
3-(Am in ocycloh exylm et h yl)-5-m et h yl-2-p h en yl-1-(p -
1
tolyl)p yr r ole (6b): oil; H NMR δ 0.8-2.1 (m, 11H), 2.2 (s,
1
3H), 2.3 (s, 3H), 3.5 (d, J ) 8.1 Hz, 1H), 6.1 (s, 1H), 6.9-7.3
(m, 11H); 13C NMR δ 13.1 (CH3), 20.8 (CH3), 26.1 (CH2), 26.2
(CH2), 26.3 (CH2), 29.8 (CH2), 30.2 (CH2), 45.1 (CH), 53.1 (CH),
104.7 (CH), 125.9 (CH), 127.4 (CH), 127.9 (CH), 128.9 (CH),
129.7 (C), 130.5 (CH), 130.8 (C), 130.9 (C), 132.9 (C), 136.2(C),
136.8 (C); MS m/ e 358 (M+, 26), 275 (100). Anal. Calcd for
C25H30N2: C, 83.75; H, 8.43; N, 7.81. Found: C, 83.98; H, 8.47;
N, 7.61.
d olizin e (11a ): oil; H NMR δ 1.8-2.0 (m, 4H), 2.2 (s, 3H),
2.8 (t, 2H), 3.8 (t, 2H), 6.0 (s, 1H), 7.4-7.7 (m, 5H); 13C NMR
δ: 11.5 (CH3), 20.0 (CH2), 22.8 (CH2), 24.5 (CH2), 42.9 (CH2),
107.8 (CH), 127.4 (C), 128.0 (CH), 128.6 (CH), 129.6 (CH),
130.4 (C), 132.5 (C), 140.8 (C), 174.2 (C); MS m/ e 238 (M+,
12), 162 (7), 134 (15), 104 (21), 77 (100). Anal. Calcd for
C16H18N2: C, 80.63; H, 7.61; N, 11.75. Found: C, 80.77; H,
7.88; N, 11.65.
3-(r-Am in ob en zyl)-1-b u t yl-5-m et h yl-2-p h en ylp yr r ole
1-(Im in ocyclop r op ylm eth yl)-3-m eth yl-5,6,7,8-tetr a h y-
d r oin d olizin e (11b): oil; 1H NMR δ 0.8-1.0 (m, 4H), 1.5-
2.1 (m, 5H), 2.1 (s, 3H), 3.0 (t, J ) 7.5 Hz, 2H), 3.7 (t, J ) 6.6
Hz, 2H), 6.1 (s, 1H); 13C NMR δ 7.9 (CH2), 11.6 (CH), 14.0
(CH3), 20.3 (CH2), 22.8 (CH2), 24.6 (CH2), 42.8 (CH2), 106.9
(CH), 119.0 (C), 128.1 (C), 130.2 (C), 176.0 (C). Anal. Calcd
for C13H18N2: C, 77.18; H, 8.97; N, 13.85. Found: C, 77.19;
H, 9.04; N, 13.77.
1
(6c): oil; H NMR δ 0.7 (t, J ) 7.5 Hz, 3H), 1.2 (m, 2H), 1.5
(m, 2H), 2.3 (s, 3H), 3.7 (m, 2H), 4.9 (s, 1H), 5.9 (s, 1H), 7.1-
7.6 (m, 12H); 13C NMR δ 12.4 (CH3), 13.4 (CH3), 19.6 (CH2),
33.0 (CH2), 43.5 (CH2), 52.0 (CH), 104.4 (CH), 125.2 (C), 126.0
(CH), 126.4 (CH), 127.2 (CH), 127.9 (CH), 128.0 (CH), 128.6
(C), 129.5 (C), 130.9 (CH), 133.0 (C), 146.8 (C); MS m/ e 318
(M+, 48), 241 (100), 104(15). Anal. Calcd for C22H26N2: C,
82.97; H, 8.23; N, 8.80. Found: C, 83.00; H, 8.27; N, 8.71.
3-[Am in o(p-tolyl)m eth yl]-5-m eth yl-2-ph en yl-1-(p-tolyl)-
p yr r ole (6d ): oil; 1H NMR δ 2.1 (s, 3H), 2.2 (s, 3H), 2.3 (s,
3H), 5.1 (s, 1H), 6.1 (s, 1H), 6.8-7.3 (m, 15H); 13C NMR δ 13.1
(CH3), 20.8 (2CH3), 51.7 (CH), 105.4 (CH), 115.0 (C), 126.1
(CH), 126.4 (CH), 127.6 (CH), 128.0 (CH), 128.7 (CH), 129.0
(CH), 130.0 (C), 130.1 (C), 130.3 (CH), 132.6 (C), 135.6 (C),
136.2 (C), 136.4 (C), 143.7 (C); MS m/ e 366 (M+, 55), 275(83),
91(100). Anal. Calcd for C26H26N2: C, 85.21; H, 7.15; N, 7.64.
Found: C, 85.28; H, 7.27; N, 7.71.
P r ep a r a tion of Aza d ien es 8. To a freshly prepared
solution of LDA (10 mM) in THF (20 mL) was slowly added at
-78 °C a solution of imine 7 (10 mM) in THF (25 mL). The
mixture was stirred for 1 h at the same temperature, and then
a solution of the corresponding nitrile (10 mM) in THF (10
mL) was added. After stirring at this temperature for 1 h the
mixture was quenched with water, extracted with ether (3 ×
10 mL), and dried over anhydrous sodium sulfate. Removal
of solvents under vacuum resulted in azadienes 8 which were
used without further purification. 8a : 1H NMR δ 1.7-1.9 (m,
4H), 2.7-2.9 (m, 3H), 3.9 (t, J ) 6.5 Hz, 2H), 7.4-7.7 (m, 6H).
P r ep a r a tion of P yr r olizid in es 9. A solution of freshly
prepared azadiene 8 (5 mM) in a 1:1 mixture of EtOH/Et3N
(20 mL) was heated at 100 °C in a sealed tube for 6 h. After
cooling to rt, the mixture was treated with 1 N HCl and
extracted with ether (3 × 10 mL). The combined organic layers
were washed with water and dried over anhydrous sodium
sulfate, and the solvents were removed under vacuum. The
oily residue thus obtained was subjected to column chroma-
tography (florisil, CH2Cl2/MeOH, 5:1) to yield pure pyrrolizi-
dine derivatives 9.
1-[Im in o(2-t h ien yl)m et h yl]-3-m et h yl-5,6,7,8-t et r a h y-
1
d r oin d olizin e (11c): oil; H NMR δ 1.6-1.9 (m, 4H), 2.0 (s,
3H), 2.6 (t, J ) 7.6 Hz, 2H), 3.7 (t, J ) 6.6 Hz, 2H), 6.1 (s, 1H),
7.2-7.6 (m, 3H); 13C NMR δ 12.3 (CH3), 20.9 (CH2), 23.6 (CH2),
24.6 (CH2), 43.6 (CH2), 107.7 (CH), 117.6 (C), 127.8 (C), 127.9
(CH), 129.6 (CH), 131.1 (CH), 131.4 (C), 146.0 (C) 167.3 (C).
Anal. Calcd for C14H16N2S: C, 68.82; H, 6.60; N, 11.46.
Found: C, 68.74; H, 6.78; N, 11.42.
1-[Im in o(2-fu r yl)m et h yl]-3-m et h ylp yr r olo[1,2-a ]a ze-
p a n e (11d ): oil; 1H NMR δ 1.5-1.8 (m, 6H), 2.2 (s, 3H), 2.9 (t,
J ) 7.6 Hz, 2H), 3.9 (t, J ) 6.6 Hz, 2H), 6.0 (s, 1H), 6.5 (m,
1H), 6.9 (m, 1H), 7.6 (m, 1H); 13C NMR δ 11.7 (CH3), 25.2
(CH2), 26.8 (CH2), 28.0 (CH2), 30.3 (CH2), 44.8 (CH2), 106.0
(CH), 111.3 (C), 114.7 (CH), 115.3 (CH), 126.6 (CH), 136.3 (C),
144.4 (C), 151.0 (C), 161.5 (C); MS m/ e 242 (M+, 100), 213
(82), 199 (90), 95 (25). Anal. Calcd for C15H18N2O: C, 74.35;
H, 7.49; N, 11.56. Found: C, 74.41; H, 7.55; N, 11.67.
1-(Im in op h e n ylm e t h yl)-3-m e t h ylp yr r olo[1,2-a ]a ze -
p a n e (11e): oil; 1H NMR δ 1.5-1.7 (m, 6H), 2.1 (s, 3H), 2.6 (t,
J ) 7.6 Hz, 2H), 3.8 (t, J ) 6.7 Hz, 2H), 5.8 (s, 1H), 7.2-7.6
(m, 5H); 13C NMR δ 12.1 (CH3), 25.8 (CH2), 27.1 (CH2), 28.6
(CH2), 30.8 (CH2), 45.2 (CH2), 106.5 (CH), 118.5 (C), 127.7 (CH),
128.0 (CH), 129.5 (CH), 132.2 (C), 135.8 (C), 141.1 (C), 174.7
(C); MS m/ e 252 (M+, 18), 199 (90), 105 (24), 95 (25), 77 (100).
Anal. Calcd for C17H20N2: C, 80.91; H, 7.99; N, 11.10.
Found: C, 81.08; H, 7.92; N, 11.23.
1-[Im in o(2-t h ie n yl)m e t h yl]-3-m e t h ylp yr r olo[1,2-a ]-
a zep a n e (11f): oil; 1H NMR δ 1.5-1.8 (m, 6H), 2.0 (s, 3H),
2.7 (t, J ) 7.4 Hz, 2H), 3.9 (t, J ) 6.7 Hz, 2H), 5.9 (s, 1H),
7.0-7.6 (m, 3H); 13C NMR δ 12.2 (CH3), 25.9 (CH2), 27.6 (CH2),
28.6 (CH2), 30.8 (CH2), 45.3 (CH2), 106.0 (CH), 118.7 (C), 126.8
(CH), 129.0 (CH), 130.7 (CH), 132.4 (C), 137.2 (C), 145.3 (C),
167.7 (C). Anal. Calcd for C15H18N2S: C, 69.73; H, 7.02; N,
10.84. Found: C, 69.84; H, 7.09; N, 10.52.
7-Ben zoyl-5-m eth yl-2,3-dih ydr o-1H-pyr r olizin e (9a): oil;
1H NMR δ 2.1 (s, 3H), 2.4 (m, 2H), 2.9 (t, J ) 7.5 Hz, 2H), 3.8
(t, J ) 6.5 Hz, 2H), 6.2 (s, 1H), 7.3-7.7 (m, 5H); 13C NMR δ
11.3 (CH3), 26.3 (CH2), 26.5 (CH2), 44.5 (CH2), 111.5 (CH),
116.0 (C), 128.6 (CH), 129.0 (CH), 129.3 (CH), 131.3 (C), 141.4
(C), 144.5 (C), 191.6 (C). Anal. Calcd for C15H15NO: C, 79.97;
H, 6.71; N, 6.22. Found: C, 79.72; H, 6.63; N, 6.39.
Hyd r olysis of Im in e Der iva tives 11. A solution of
heterocycle 11 (5 mM) in THF (20 mL) was treated with 1 N
HCl (10 mL) at rt for 2 h. The mixture was then extracted
with ether (2 × 15 mL); the combined organic layers were
washed with water and dried over anhydrous sodium sulfate
and the solvents eliminated under vacuum. The oily residue
thus obtained was subjected to column chromatography (flo-
risil, CH2Cl2/MeOH, 9:1) to yield pure carbonyl derivatives 12.
1-(Cyclopr opylcar bon yl)-3-m eth yl-5,6,7,8-tetr ah ydr oin -
d olizin e (12a ): oil; 1H NMR δ 0.8 (m, 2H), 1.2 (m, 2H), 1.7-
2.1 (m, 4H), 2.2 (s, 3H), 2.4 (m, 1H), 3.1 (t, J ) 7.5 Hz, 2H),
3.8 (t, J ) 6.6 Hz, 2H), 6.4 (s, 1H); 13C NMR δ 9.4 (CH2), 11.4
(CH3), 17.7 (CH2), 19.5 (CH), 22.6 (CH2), 24.4 (CH2), 42.6 (CH2),
106.7 (CH), 119.0 (C), 127.0 (C), 136.6 (C), 195.8 (C); MS m/ e
203 (M+, 100), 188 (91), 162 (80). Anal. Calcd for C13H17NO:
C, 76.81; H, 8.43; N, 6.89. Found: C, 76.73; H, 8.55; N, 6.69.
3-Met h yl-1-(2-t h ien ylca r b on yl)-5,6,7,8-t et r a h yd r oin -
7-(Cycloh exylca r bon yl)-5-m eth yl-2,3-d ih yd r o-1H-p yr -
1
r olizin e (9b): oil; H NMR δ 1.1-1.8 (m, 10H), 2.1 (s, 3H),
2.5 (m, 2H), 2.9 (m, 1H), 3.0 (t, J ) 7.4 Hz, 2H), 3.8 (t, J ) 6.5
Hz, 2H), 6.2 (s, 1H); 13C NMR δ 12.5, 22.3, 24.2, 26.3, 26.9,
27.4, 27.8, 30.2, 45.5, 48.0, 110.5, 125.0, 131.5, 143.1, 200.3.
Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.06.
Found: C, 77.70; H, 9.23; N, 5.98.
Gen er a l P r oced u r e for th e P r ep a r a tion of Im in e
Der iva tives 11. To a freshly prepared solution of LDA (10
mM) in THF (20 mL) was slowly added at -78 °C a solution
of imine 10 (n ) 1, 2) (10 mM) in THF (25 mL). The mixture
was stirred for 1 h at the same temperature, and then a
solution of the corresponding nitrile (10 mM) in THF (10 mL)
was added. After stirring at this temperature for 1 h, a
solution of propargyl bromide (10 mM) in THF (10 mL) was
1
d olizin e (12b): oil; H NMR δ 1.8 (m, 2H), 2.0 (m, 2H), 2.2
(s, 3H), 3.1 (t, J ) 7.6 Hz, 2H), 3.8 (t, J ) 6.6 Hz, 2H), 6.4 (s,

2190 J . Org. Chem., Vol. 61, No. 6, 1996
Barluenga et al.
1H), 7.0 (m, 1H), 7.5 (m, 1H), 7.7 (m, 1H); 13C NMR δ 11.4
(CH3), 19.5 (CH2), 22.6 (CH2), 24.4 (CH2), 42.7 (CH2), 107.9
(CH), 117.0 (C), 127.1 (CH), 130.7 (CH), 131.0 (CH), 138.1 (C),
146.0 (C), 181.6 (C); MS m/ e 245 (M+, 100), 134 (90), 111 (78).
Anal. Calcd for C14H15NOS: C, 68.54; H, 6.16; N, 5.71.
Found: C, 68.33; H, 5.95; N, 5.90.
1-(2-Fu r ylcar bon yl)-3-m eth yl-5,6,7,8-tetr ah ydr oin doliz-
in e (12c): oil; 1H NMR δ 1.8 (m, 2H), 1.9 (m, 2H), 2.2 (s, 3H),
3.2 (t, J ) 7.5 Hz, 2H), 3.8 (t, J ) 6.7 Hz, 2H), 6.5 (m, 1H), 6.6
(s, 1H), 7.2 (m, 1H), 7.6 (m, 1H); 13C NMR δ 11.6 (CH3), 19.6
(CH2), 22.7 (CH2), 24.7 (CH2), 42.8 (CH2), 107.8 (CH), 111.5
(CH), 116.1 (CH), 116.4 (C), 127.4 (C), 139.0 (C), 144.7 (CH),
154.5 (C), 176.9 (C); MS m/ e 229 (M+, 100), 214 (19), 134 (92).
Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.25; H, 6.61; N, 6.05.
(CH2), 45.1 (CH2), 55.6 (CH3), 55.7 (CH3), 108.8 (CH), 109.3
(CH), 111.5 (CH), 118.9 (C), 123.4 (CH), 133.2 (C), 141.8 (C),
148.1 (C), 148.7 (C), 152.5 (C), 190.9 (C); MS m/ e 313 (M+,
100), 298 (32), 165 (70). Anal. Calcd for C19H23NO3: C, 72.82;
H, 7.40; N, 4.47. Found: C, 72.99; H, 7.31; N, 4.69.
Red u ction of Im in e Der iva tives 11. To a solution of
heterocycle 11 (5 mM) in MeOH (20 mL) at 0 °C was carefully
added NaBH4 (10 mM) in small portions. The mixture was
then stirred at room temperature for 6 h, treated with water
(20 mL), and extracted with ether (3 × 10 mL). The combined
organic layers were washed with water and dried over
anhydrous sodium sulfate and the solvents removed under
vacuum. The oily residue thus obtained was subjected to
column chromatography (florisil, CH2Cl2/MeOH, 9:1) to yield
pure amino derivatives 13.
1-Ben zoyl-3-m eth ylp yr r olo[1,2-a ]a zep a n e (12d ): oil; 1H
NMR δ 1.4-1.7 (m, 6H), 2.1 (s, 3H), 3.1 (t, J ) 7.5 Hz, 2H),
3.8 (t, J ) 6.7 Hz, 2H), 5.9 (s, 1H), 7.2-7.8 (m, 5H); 13C NMR
δ 11.7 (CH3), 25.0 (CH2), 26.2 (CH2), 27.6 (CH2), 30.5 (CH2),
44.8 (CH2), 108.9 (CH), 117.4 (C), 126.3 (C), 127.2 (CH), 130.3
(CH), 131.4 (CH), 140.4 (C), 142.0 (C), 191.9 (C); MS m/ e 253
(M+, 100), 238 (38), 195 (42), 148 (45), 105 (40). Anal. Calcd
for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.47;
H, 6.52; N, 5.49.
1-[Am in o(2-t h ien yl)m et h yl]-3-m et h yl-5,6,7,8-t et r a h y-
d r oin d olizin e (13a ): oil; H NMR δ 1.7-1.9 (m, 4H), 2.1 (s,
3H), 2.7 (m, 2H), 3.7 (m, 2H), 5.5 (s, 1H), 5.8 (s, 1H), 6.8-7.5
(m, 3H); 13C NMR δ 11.4, 20.3, 21.8, 23.2, 42.2, 55.8, 104.1,
105.5, 115.5, 123.4, 127.3, 132.4, 136.5, 144.2. Anal. Calcd
for C14H18N2S : C, 68.25; H, 7.36; N, 11.37. Found: C, 68.34;
H, 7.31; N, 11.49.
1
1-[Am in o (2-fu r y l)m e t h y l]-3-m e t h y lp y r r o lo [1,2-a ]-
1
a zep a n e (13b): oil; H NMR δ 1.5-1.8 (m, 6H), 2.1 (s, 3H),
3-Meth yl-1-(2-th ien ylca r bon yl)p yr r olo[1,2-a ]a zep a n e
2.7 (m, 2H), 3.8 (m, 2H), 5.1 (s, 1H), 5.7 (s, 1H), 6.1 (m, 1H),
6.3 (m, 1H), 7.3 (m, 1H); 13C NMR δ 12.3 (CH3), 25.3 (CH2),
28.5 (CH2), 29.5 (CH2), 31.6 (CH2), 45.1 (CH2), 47.6 (CH), 103.4
(CH), 104.8 (CH), 110.0 (CH), 119.3 (C), 126.6 (C), 131.3 (C),
141.4 (CH), 160.5 (C); MS m/ e 244 (M+, 12), 227 (100), 198
(29). Anal. Calcd for C15H20N2O : C, 73.74; H, 8.25; N, 11.46.
Found: C, 73.77; H, 8.31; N, 11.69.
1
(12e): oil; H NMR δ 1.7-1.9 (m, 6H), 2.2 (s, 3H), 3.2 (t, J )
7.4 Hz, 2H), 3.9 (t, J ) 6.7 Hz, 2H), 6.3 (s, 1H), 7.1-7.9 (m,
3H); 13C NMR δ 12.3 (CH3), 25.5 (CH2), 26.7 (CH2), 28.4 (CH2),
31.1 (CH2), 45.4 (CH2), 108.3 (CH), 115.6 (C), 127.0 (C), 127.9
(CH), 129.6 (CH), 131.1 (CH), 131.4 (C), 146.0 (C) 183.1 (C);
MS m/ e 259 (M+, 85), 111 (100). Anal. Calcd for C15H17
-
NOS: C, 69.46; H, 6.61; N, 5.40. Found: C, 69.31; H, 6.44;
N, 5.52.
Ack n ow led gm en t. We acknowledge the financial
support (DGICYT PB88-0500 and PB92-1005) and
fellowships (to A.S.-S. and E.R.) received from the
Ministerio de Educacio´n y Ciencia.
1-[(3,4-Dim eth oxyp h en yl)ca r bon yl]-3-m eth ylp yr r olo-
[1,2-a ]a zep a n e (12f): oil; 1H NMR δ 1.6-1.8 (m, 6H), 2.1 (s,
3H), 3.1 (t, J ) 7.5 Hz, 2H), 3.8 (s, 3H), 3.9 (s, 3H), 3.9 (t, J )
6.7 Hz, 2H), 5.9 (s, 1H), 6.8 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H);
13C NMR δ 12.0 (CH3), 25.4 (CH2), 26.6 (CH2), 28.2 (CH2), 30.8
J O951887Y