Novel syntheses of indolizines and pyrrolo[2,1-a]isoquinolines via benzotriazole methodology

Article abstract of DOI:10.1021/jo9906936

Indolizines and pyrrolo[2,1-a]isoquinolines are synthesized by 1,3- dipolar cycloadditions of pyridinium benzotriazolylmethylides or isoquinolinium benzotriazolylmethylides with ethylenes and acetylenes.

Full text of DOI:10.1021/jo9906936

7618
J . Org. Chem. 1999, 64, 7618-7621
Novel Syn th eses of In d olizin es a n d P yr r olo[2,1-a ]isoqu in olin es via
Ben zotr ia zole Meth od ology
Alan R. Katritzky,* Guofang Qiu, Baozhen Yang, and Hai-Ying He
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received April 26, 1999
Indolizines and pyrrolo[2,1-a]isoquinolines are synthesized by 1,3-dipolar cycloadditions of pyri-
dinium benzotriazolylmethylides or isoquinolinium benzotriazolylmethylides with ethylenes and
acetylenes.
Sch em e 1
In tr od u ction
Synthetic indolizines are important as potential central
nervous system depressants,1 calcium entry blockers,2
cardiovascular agents,3 spectral sensitizers,4 and novel
dyes.5 They are also used for the treatment of angina
pectoris6 or as testosterone 5R-reductase inhibitors.7
Furthermore, they are key intermediates for the synthe-
ses of cycloazines.8
Typical molecular constructions of indolizines 6 (for a
review, see ref 9) fall into three classes as shown in
Scheme 1: (A) Condensation reactions of a 2-alkylpyri-
dine with acid anhydrides (Scholtz reaction10) or R-halo
ketones (Tschitschibabin reaction11); (B) reactions of an
R-unsubstituted pyridine with a three carbon fragment
such as an acyl- or aryl-substituted allyl halide or ester12
and methyl propiolate;13 (C) reactions of pyridinium
N-methylides, generated from pyridinium salts under
K2CO3,14 pyridine and carbenes,15 or N-(trimethylsilyl-
methyl)pyridinium triflates under fluoride ion,16 with
acetylenes; or reactions of pyridinium N-methylides with
ethylenes in the presence of an oxidant.17 While the third
route has been widely utilized in the syntheses of
indolizines,9 there are some limitations. The reactions of
pyridinium N-methylides with acetylenes require that
the acetylenes bear two electron-withdrawing groups,
e.g., ester groups, and thus limit the substituents (R1,
R2) at the 1,2-positions of indolizines produced; further-
more, most of R3 group are limited to acyl groups14,15 or
hydrogen.16 When pyridinium ylides react with ethylenes,
an oxidant is needed, otherwise di- and tetrahydroin-
dolizines are obtained as byproducts, with correspond-
ingly lower yields of the desired products.17
(1) Harrell, W. B.; Doerge, R. F. J . Pharm. Sci. 1967, 56, 225.
(2) Gubin, J .; Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J .;
Mahaux, J .; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain,
P. J . Med. Chem. 1993, 36, 1425.
(3) Gubin, J .; Descamps, M.; Chatelain, P.; Nisato, D. Eur. Pat. Appl.
EP 235 111, 1987; Chem. Abstr. 1988, 109, 6405b.
(4) Wheeler, J . W. Eur. Pat. Appl. EP 161 789, 1985; Chem. Abstr.
1985, 104, 170108z.
(5) Weidner, C. H.; Wadsworth, D. H.; Bender, S. L.; Beltman, D.
J . J . Org. Chem. 1989, 54, 3660.
(6) Rosseels, G.; Peiren, M.; Inion, H.; Deray, E.; Prost, M.; Des-
camps, M.; Bauthier, J .; Richard, J .; Tornay, C.; Colot, M.; Claviere,
M. Eur. J . Med. Chem. 1982, 17, 581.
(7) Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H.
Eur. Pat. Appl. EP 519 353, 1992; Chem. Abstr. 1993, 118, 212886y.
(8) Dick, J . W.; Gibson, W. K.; Leaver, D.; Roff, J . E. J . Chem. Soc.,
Perkin Trans. 1 1981, 3150.
(9) Uchida, T.; Matsumoto, K. Synthesis 1976, 209.
(10) (a) Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 734. (b)
Boekelheide, V.; Windgassen, R. J ., J r. J . Am. Chem. Soc. 1959, 81,
1456.
(11) (a) Tschitschibabin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607.
(b) Hurst, J .; Melton, T.; Wibberley, D. G. J . Chem. Soc. 1965, 2948.
(c) J ones, G.; Stanyer, J . J . Chem. Soc. C 1969, 901.
(12) Pohjala, E. Tetrahedron Lett. 1972, 2585.
(13) Acheson, R. M.; Robinson, D. A. J . Chem. Soc. C 1968, 1633.
(14) De Bue, G.; Nasielski, J . Bull. Soc. Chim. Belg. 1997, 106, 97.
(15) Padwa, A.; Austin, D. J .; Precedo, L.; Zhi, L. J . Org. Chem. 1993,
58, 1144.
We report here the direct formation of indolizines by
1,3-cycloadditions of pyridinium benzotriazolylmethylides
with ethylenes or acetylenes. No oxidant is needed and
substituents (R2, R3) at the 2,3-positions of the indolizine
ring are not limited to electron-withdrawing groups.
Previous work showed N-bis(benzotriazol-1-ylmethyl)-
hydroxylamine to be an effective 1,3-dipole synthon;
subsequent reactions with dipolarphiles furnished sub-
stituted 2-(benzotriazol-1-ylmethyl)isoxazolidines.18 R-(Ben-
zotriazol-1-yl)arylmethylamines are also convenient
sources of azomethine ylides which readily undergo 1,3-
dipolar cycloaddition with dipolarophiles to produce 2,5-
diarylpyrroles, 3,4-dihydro-2H-pyrroles and c-ring-fused
3,4-dihydro-2H-pyrroles.19 Benzotriazolylmethylaminosi-
lanes as azomethine ylide equivalents undergo stereospe-
cific cycloadditions with dipolarophiles to produce sub-
(16) (a) Miki, Y.; Hachiken, H.; Takemura, S. Heterocycles 1984, 22,
701. (b) Tsuge, O.; Kanemasa, S.; Kuraoka, S.; Takenaka, S. Chem.
Lett. 1984, 279.
(17) Wei, X.; Hu, Y.; Li, T.; Hu, H. J . Chem. Soc., Perkin Trans. 1
1993, 2487.
(18) Katritzky, A. R.; Hitchings, G. J .; Zhao, X. J . Chem. Soc., Perkin
Trans. 1 1990, 2371.
(19) Katritzky, A. R.; Hitchings, G. J .; Zhao, X. Synthesis 1991, 863.
10.1021/jo9906936 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/10/1999

Indolizines and Pyrrolo[2,1-a]isoquinolines
J . Org. Chem., Vol. 64, No. 20, 1999 7619
Sch em e 2
Sch em e 3
stituted pyrrolidines or 2,5-dihydropyrroles.20 The
formation of azomethine ylides in each of these systems
relies on the ability of benzotriazole to stabilize negative
charge at the R-position. In the present work, the
benzotriazolyl group activates the methylene protons for
easy deprotonation, stabilizes the resulting ylide by the
delocalization of the negative charge, and serves as a good
leaving group in the elimination step leading to indoliz-
ines 6.
Sch em e 4
Resu lts a n d Discu ssion
Ta ble 1. P r ep a r a tion of In d olizin es 6a
P r ep a r a tion of N-[r-(Ben zotr ia zol-1-yl)a lk yl]p yr -
id in iu m a n d N-[r-(Ben zotr ia zol-1-yl)a r yl]p yr id in i-
u m Sa lts. An early report for the preparation of N-[R-
(benzotriazol-1-yl)methyl]pyridinium chloride (1a ) in 51%
yield involved refluxing a mixture of pyridine and R-ben-
zotriazol-1-ylmethyl chloride in nitromethane.21 In the
present work, N-[R-(benzotriazol-1-yl)alkyl]pyridinium
and N-[R-(benzotriazol-1-yl)arylmethyl] pyridinium salts
1a -d are readily prepared in 71-87% yield by the
condensation of pyridine, thionyl chloride, benzotriazole,
and the appropriate aldehyde in methylene chloride at
20 °C (Scheme 2). The crude products 1a -d could be used
for the subsequent preparation of indolizines without
further purification.
no.
R
R1
R2
R3
yield (%)b mp (°C)ref
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
COOEt
COOEt
COOEt
CN
H
H
H
H
H
H
H
H
71
74
66c
71
73
66c
82
66
69
69c
78
59
oil22
65
Et
p-tolyl
96
H
53 (5211b
73
)
CN
CN
Et
p-tolyl
107
99
6g Et CN
H
H
6h
6i
6j
H
H
H
COOCH3 COOCH3
COOCH3 COOCH3 Et
COOEt
90 (8923
47
)
COOEt
p-tolyl
94
6k Et COOCH3 COOCH3
6l COOCH3 Ph
H
H
129
H
104 (10624
)
a
6a -g were synthesized from ethylenes 8; 6h -l from acetylenes
b
9. Isolated yield based on 1 except for the preparation of 6c, 6f
and 6j. c Isolated yield based on benzotriazole.
P r ep a r a tion of In d olizin es. On the basis of our
previous work,18-20 the benzotriazolyl group can activate
an R-proton for easy deprotonation and stabilize the
subsequent R-carbanion. Accordingly, dark purple solu-
tions of azomethine ylides 2 are readily formed from 1
with a mild base triethylamine (Scheme 3). Treatment
of 2 with 1 equiv of an electron-deficient alkene 3 gave
indolizines 6 in low yield along with the byproduct
Michael adduct 4, formed by the reaction of benzotriazole
with the dipolarophiles. Therefore, 2 equiv of dipolaro-
phile was used in subsequent reactions. The proposed
mechanism is shown in Scheme 3. Azomethine ylide 2
reacts with electron-deficient alkene 3 to generate 5,
which subsequently eliminates benzotriazole and under-
goes oxidative aromatization to give 6 in moderate yield.
To avoid incomplete oxidation, an R-bromo-R,â-unsatur-
ated ester or nitrile 8 was used instead of 3 (Scheme 3).
The R-bromo-R,â-unsaturated ester and nitrile 8 were
prepared by the bromination of alkene 3 to bromide 7,
followed by the elimination of hydrobromide with sodium
hydroxide (Scheme 4). Treatment of ylides 2 with R-bromo-
R,â-unsaturated esters or nitriles 8, as expected, gave
indolizines 6a -g in good yields (Table 1). However, no
cycloadduct was isolated when styrene was used as the
dipolarophile, and the use of 4-vinylpyridine gave only a
trace amount of the expected product 6.
When an acetylenic dipolarophile, i.e., dimethyl or
diethyl acetylenedicarboxylate (9, R1 ) R2 ) COOCH3
or COOEt), was used, compounds 6h -k were obtained
in 66-78% yields via 1,3-dipolar cycloadditions. Treat-
ment of 1a with ethyl phenylpropiolate produced 6l in
59% yield.
P r ep a r a t ion of 2-(Ben zot r ia zol-1-ylm et h yl)iso-
qu in olin iu m Ch lor id e a n d P yr r olo[2,1-a ]isoqu in o-
lin es. Pyrrolo[2,1-a]isoquinolines were also synthesized
using benzotriazole methodology. 2-(Benzotriazol-1-yl-
methyl)isoquinolinium chloride 10 was prepared in 89%
yield by refluxing isoquinoline and (benzotriazol-1-yl)-
methyl chloride in acetonitrile (Scheme 5). Treatment of
10 with R-bromoacrylonitrile in the presence of triethyl-
amine in acetonitrile gave pyrrolo[2,1-a]isoquinoline-1-
carbonitrile (11) in 51% yield. Similarly, diethyl pyrrolo-
[2,1-a]isoquinoline-1,2-dicarboxylate (12) was obtained in
(20) Katritzky, A. R.; Koditz, J .; Lang, H. Tetrahedron 1994, 50,
12571.
(21) Katritzky, A. R.; Watson, C. H.; Dega-Szafran, Z.; Eyler, J . R.
J . Am. Chem. Soc. 1990, 112, 2471.

7620 J . Org. Chem., Vol. 64, No. 20, 1999
Katritzky et al.
Calcd for C14H15ClN4O4: C, 49.64; H, 4.47; N, 16.54. Found:
C, 49.73; H, 4.26; N, 16.49.
Sch em e 5
1-[Ben zotr ia zol-1-yl(4-m eth ylp h en yl)m eth yl]p yr id in -
iu m ch lor id e (1c): crude intermediate; 1H NMR δ 2.33 (s,
3H), 7.26 (d, J ) 7.6 Hz, 2H), 7.41-7.50 (m, 1H), 7.63-7.67
(m, 1H), 7.68-7.73 (m, 1H), 7.78 (d, J ) 7.6 Hz, 2H), 8.09 (d,
J ) 7.9 Hz, 1H), 8.18 (d, J ) 7.9 Hz, 1H), 8.45 (t, J ) 6.7 Hz,
2H), 8.81 (t, J ) 7.7 Hz, 1H), 9.10 (s, 1H), 9.93 (d, J ) 6.1 Hz,
1H).
1-(Ben zotr ia zol-1-ylm eth yl)-2-eth ylp yr id in iu m ch lo-
1
r id e (1d ): white powder, mp 180-181 °C; (2.39 g, 87%); H
NMR δ 1.29 (t, J ) 7.2 Hz, 3H), 3.57 (q, J ) 7.2 Hz, 2H), 7.54
(t, J ) 7.5 Hz, 1H), 7.74 (t, J ) 7.5 Hz, 1H), 7.99 (s, 2H), 8.10-
8.30 (m, 3H), 8.52 (d, J ) 8.4 Hz, 1H), 8.72 (t, J ) 7.8 Hz,
1H), 9.57 (d, J ) 6.3 Hz, 1H); 13C NMR δ 14.8, 25.3, 64.9, 111.1,
119.7, 125.1, 125.9, 128.4, 129.0, 132.8, 145.0, 145.7, 147.6,
160.6. Anal. Calcd. for C14H15ClN4: C, 61.19; H, 5.51; N, 20.40.
Found: C, 60.79; H, 5.43; N, 20.40.
Gen er a l P r oced u r e for th e P r ep a r a tion of In d olizin es
6a -g. Bromine (0.64 g, 4 mmol) in acetonitrile (5 mL) was
added slowly dropwise to a solution of an ethylene 3 (4 mmol)
in acetonitrile (5 mL). The reaction mixture was stirred at
room temperature until the color of bromine disappeared.
NaOH (0.24 g, 6 mmol) was added, and then a solution of 1a -d
(2 mmol) in acetonitrile (15 mL) was added dropwise. The
mixture was refluxed for 16 h. After cooling, H2O and ethyl
acetate were added. The organic phase was separated, washed
with 1 M HCl and brine, and dried over Na2SO4. After removal
of solvent in vacuo, the residue was separated by a column
(silica gel) with hexanes-ethyl acetate (10:1) as eluent to give
indolizines 6a -g.
67% yield by the reaction of 10 with diethyl acetylene-
dicarboxylate in the presence of sodium hydroxide.
In conclusion, we have described a convenient route
to indolizines and pyrrolo[2,1-a]isoquinolines from readily
prepared N-[(benzotriazol-1-yl)alkyl]pyridinium and
2-(benzotriazol-1-ylmethyl)isoquinolinium salts. Easy
deprotonation by a mild base yields azomethine ylides,
which are the presumed intermediates in 1,3-dipolar
cycloadditions with electron-deficient dipolarophiles. The
advantages of this method include (i) intermediates 1a -d
could be used directly for the next step without further
purification; (ii) no oxidant is needed when 1-bromoeth-
ylenes are used as reactants; (iii) substituents at the 2,3-
positions of the indolizines produced are not limited to
electron-withdrawing groups; and (iv) the yields of in-
dolizines and pyrrolo[2,1-a]isoquinolines are from good
to excellent.
Eth yl 1-in d olizin eca r boxyla te (6a ):22 a pale yellow oil;
1H NMR δ 1.41 (t, J ) 7.1 Hz, 3H), 4.37 (q, J ) 7.1 Hz, 2H),
6.68 (t, J ) 6.6 Hz, 1H), 7.02 (t, J ) 7.9 Hz, 1H), 7.23 (dd, J
) 11.3, 2.8 Hz, 2H), 7.98 (d, J ) 6.9 Hz, 1H), 8.17 (d, J ) 9.1
Hz, 1H); 13C NMR δ 14.6, 59.4, 103.9, 112.3, 113.6, 116.1,
119.9, 122.1, 126.0, 135.7, 165.0.
Eth yl 3-eth yl-1-in d olizin eca r boxyla te (6b): colorless
flake; 1H NMR δ 1.41 (t, J ) 7.4 Hz, 6H), 2.79 (q, J ) 7.4 Hz,
2H), 4.37 (q, J ) 7.1 Hz, 2H), 6.75 (t, J ) 6.7 Hz, 1H), 7.04 (t,
J ) 8.8 Hz, 1H), 7.06 (s, 1H), 7.82 (d, J ) 6.9 Hz, 1H), 8.20 (d,
J ) 9.0 Hz, 1H); 13C NMR δ 11.3, 14.7, 18.9, 59.3, 102.8, 112.1,
112.8, 120.0, 121.1, 122.6, 127.0, 135.7, 165.2. Anal. Calcd for
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of N-[R-(Ben -
zotr ia zol-1-yl)a lk yl]p yr id in iu m or N-[R-(Ben zotr ia zol-1-
yl)a r ylm eth yl]p yr id in iu m Ch lor id es 1a -d . A solution of
thionyl chloride (0.9 mL, 12 mmol) in dry CH2Cl2 (12 mL) was
cooled to 0 °C. Pyridine (1.0 mL, 12 mmol) in dry CH2Cl2 (6
mL) was added dropwise, followed by a solution of an ap-
propriate aldehyde (10 mmol) in dry CH2Cl2 (5 mL). After the
mixture was stirred for 1 h, benzotriazole (1.19 g, 10 mmol)
in CH2Cl2 (50 mL) was added dropwise during 1 h. The mixture
was stirred for another 24 h at room temperature. However,
the time was reduced to 1 h for 1c to avoid formation of
undesired byproducts. The solvent was evaporated in vacuo,
and the crude product could be used directly for the next step.
For the calculation of isolated yield and elemental analysis,
the crude product was recrystallized from acetonitrile or
converted into the pyridinium perchlorate by adding perchloric
acid (70%) to the solution of the crude product in methylene
chloride. However, no pure 1c was obtained by these methods.
1-[(Ben zotr ia zol-1-yl)m eth yl]p yr id in iu m ch lor id e (1a ):
white powder, mp 218-219 °C [lit.21 mp 218-218.5 °C]; (1.75
C
13H15NO2: C, 71.86; H, 6.97; N, 6.45. Found: C, 71.62; H,
7.22; N, 6.75.
Eth yl 3-(4-m eth ylp h en yl)-1-in d olizin eca r boxyla te (6c):
1
colorless needles; H NMR δ 1.41 (t, J ) 7.1 Hz, 3H), 2.39 (s,
3H), 4.38 (q, J ) 6.9 Hz, 2H), 6.63 (t, J ) 6.7 Hz, 1H), 7.01 (t,
J ) 8.4 Hz, 1H), 7.25 (d, J ) 7.7 Hz, 2H), 7.26 (s, 1H), 7.38 (d,
J ) 7.7 Hz, 2H), 8.19-8.29 (m, 2H); 13C NMR δ 14.6, 21.2,
59.3, 104.0, 112.3, 115.7, 120.0, 121.9, 123.2, 126.3, 128.1,
128.4, 129.6, 136.1, 137.7, 164.9. Anal. Calcd for C18H17NO2:
C, 77.39; H, 6.15; N, 5.02. Found: C, 77.01; H, 6.20; N, 5.03.
1-In d olizin eca r bon itr ile (6d ):11b colorless needles; 1H
NMR δ 6.73 (t, J ) 6.8 Hz, 1H), 6.99 (d, J ) 2.5 Hz, 1H), 7.03
(t, J ) 7.3 Hz, 1H), 7.57 (d, J ) 9.0 Hz, 1H), 8.02 (d, J ) 6.9
Hz, 1H); 13C NMR δ 81.2, 112.7, 113.8, 116.6, 116.8, 117.5,
122.2, 126.3, 137.6.
3-Eth yl-1-in d olizin eca r bon itr ile (6e): colorless needles;
1H NMR δ 1.38 (t, J ) 7.4 Hz, 3H), 2.79 (q, J ) 7.5 Hz, 2H),
6.78 (s, 1H), 6.78 (t, J ) 6.5 Hz, 1H), 7.03 (t, J ) 8.5 Hz, 1H),
7.61 (d, J ) 9.1 Hz, 1H), 7.85 (d, J ) 6.9 Hz, 1H); 13C NMR δ
11.2, 18.8, 80.3, 112.5, 113.2, 117.3, 117.8, 121.2, 122.9, 127.6,
137.8. Anal. Calcd for C11H10N2: C, 77.61; H, 5.93; N, 16.46.
Found: C, 77.31; H, 6.27; N, 16.31.
3-(4-Meth ylp h en yl)-1-in d olizin eca r bon itr ile (6f): color-
less needles; 1H NMR δ 2.43 (s, 3H), 6.72 (t, J ) 6.9 Hz, 1H),
7.00 (s, 1H), 7.06 (t, J ) 7.8 Hz, 1H), 7.31 (d, J ) 7.9 Hz, 2H),
7.39 (d, J ) 7.7 Hz, 2H), 7.67 (d, J ) 8.8 Hz, 1H), 8.25 (d, J )
7.1 Hz, 1H); 13C NMR δ 21.3, 82.0, 112.9, 115.9, 117.0, 118.1,
122.1, 123.7, 127.0, 127.2, 128.6, 129.9, 138.2, 138.6; HRMS
calcd for C16H12N2 233.1078 (M + 1), found 233.1004.
1
g, 71%); H NMR (DMSO) δ 7.53 (t, J ) 7.5 Hz, 1H), 7.72 (t,
J ) 7.5 Hz, 1H), 8.02 (s, 2H), 8.17 (d, J ) 8.4 Hz, 1H), 8.31 (t,
J ) 6.9 Hz, 2H), 8.61 (d, J ) 8.4 Hz, 1H), 8.77 (t, J ) 7.8 Hz,
1H), 9.66 (d, J ) 6.3 Hz, 2H); 13C NMR (DMSO) δ 67.3, 111.1,
119.6, 125.2, 128.7, 129.0, 132.7, 144.7, 145.2, 147.9.
1-[1-(Ben zotr ia zol-1-yl)p r op yl]p yr id in iu m p er ch lor a te
(1b): colorless crystal, mp 147-148 °C; (2.47 g, 73%); 1H NMR
(DMSO) δ 0.98 (t, J ) 7.2 Hz, 3H), 2.95-3.08 (m, 1H), 3.10-
3.25 (m, 1H), 7.55 (t, J ) 7.6 Hz, 1H), 7.74 (t, J ) 7.4 Hz, 1H),
7.92 (t, J ) 7.4 Hz, 1H), 8.15 (d, J ) 8.3 Hz, 1H), 8.21 (d, J )
8.3 Hz, 1H), 8.29 (t, J ) 6.7 Hz, 2H), 8.75 (t, J ) 7.7 Hz, 1H),
9.48 (d, J ) 6.1 Hz, 2H); 13C NMR (DMSO) δ 9.3, 27.1, 79.8,
110.3, 119.9, 125.4, 129.1, 132.8, 142.9, 145.2, 148.0. Anal.
(22) Bragg, D. R.; Wibberley, D. G. J . Chem. Soc. 1963, 3277.

Indolizines and Pyrrolo[2,1-a]isoquinolines
J . Org. Chem., Vol. 64, No. 20, 1999 7621
5-Eth yl-1-in d olizin eca r bon itr ile (6g): colorless needles;
1H NMR δ 1.44 (t, J ) 7.4 Hz, 3H), 2.89 (q, J ) 7.3 Hz, 2H),
6.64 (d, J ) 6.7 Hz, 1H), 7.04-7.14 (m, 2H), 7.22 (d, J ) 2.7
Hz, 1H), 7.57 (d, J ) 8.8 Hz, 1H); 13C NMR δ 10.3, 24.8, 81.9,
109.8, 110.6, 115.4, 116.8, 117.2, 122.7, 138.6, 139.8; HRMS
calcd for C11H10N2 171.0922 (M + 1), found 171.0920.
Gen er a l P r oced u r e for th e P r ep a r a tion of In d olizin es
6h -l. A solution of 1a -d (2 mmol), acetylene 9 (4 mmol), and
Et3N (2.3 mL, 16 mmol) in acetonitrile (15 mL) was stirred at
room temperature for 20 h. H2O and ethyl acetate were added
to the mixture. The organic phase was separated, washed with
brine, and dried over Na2SO4. After removal of solvent in
vacuo, the residue was separated by a column (silica gel) with
hexanes-ethyl acetate (10:1) as eluent to give indolizines 6h -
l.
101.6, 112.6, 113.6, 120.3, 122.4, 125.5, 127.0, 127.5, 129.9,
132.7, 134.9, 136.7, 163.0.
Gen er a l P r oced u r e for th e P r ep a r a tion of 11 a n d 12.
To a solution of 1-(chloromethyl)benzotriazole (1.0 g, 6 mmol)
in dry acetonitrile was added isoquinoline (0.77 g, 6 mmol).
The mixture was refluxed with stirring for 20 h. After cooling,
the mixture was diluted with Et2O to give a crude salt, which
was changed to perchlorate 10 (1.93 g, 89%) by addition of 70%
perchloric acid.
A solution of 10 (0.72 g, 2 mmol) and 2,3-dibromopropaneni-
trile (1.28 g, 6 mmol) in dry acetonitrile (15 mL) was refluxed
in the presence of NaOH (0.08 g, 2 mmol) for 16 h. After the
mixture was cooled, H2O and ethyl acetate were added to the
reaction mixture. The organic phase was separated, washed
with 1 M HCl and brine, and dried over Na2SO4. The solvents
were evaporated in vacuo, and the residue was separated by
column chromatography (silica gel) with hexanes-ethyl ac-
etate (10:1) as eluent to give 11 (0.19 g, 51%).
A solution of 10 (0.72 g, 2 mmol) and diethyl acetylene
dicarboxylate (1 mL, 6 mmol) in dry acetonitrile (15 mL) was
stirred in the presence of triethylamine (2.3 mL, 16 mmol) at
room temperature for 20 h. H2O and ethyl acetate were added
to the reaction mixture. The organic phase was separated,
washed with brine, and dried over Na2SO4. The solvents were
evaporated in vacuo, and the residue was separated by column
chromatography (silica gel) with hexanes-ethyl acetate (5:1)
as eluent to give 12 (0.42 g, 67%).
Dim eth yl 1,2-in dolizin edicar boxylate (6h ):23 white solid;
1H NMR δ 3.91 (s, 6H), 6.75 (t, J ) 6.6 Hz, 1H), 7.07 (t, J )
9.2 Hz, 1H), 7.63 (s, 1H), 7.94 (d, J ) 6.9 Hz, 1H), 8.11 (d, J
) 9.3 Hz, 1H); 13C NMR δ 51.2, 52.1, 102.6, 113.6, 116.9, 120.4,
121.5, 123.2, 125.8, 136.0, 164.2, 165.0.
Dim eth yl 3-eth yl-1,2-in dolizin edicar boxylate (6i): white
solid; 1H NMR δ 1.26 (t, J ) 7.4 Hz, 3H), 2.98 (q, J ) 7.6 Hz,
2H), 3.88 (s, 3H), 3.95 (s, 3H), 6.79 (t, J ) 6.8 Hz, 1H), 7.07 (t,
J ) 9.0 Hz, 1H), 7.86 (d, J ) 7.1 Hz, 1H), 8.15 (d, J ) 9.1 Hz,
1H); 13C NMR δ 12.1, 17.8, 51.1, 52.3, 101.3, 113.2, 119.4,
120.5, 122.5, 122.7, 127.8, 135.0, 164.3, 167.0. Anal. Calcd for
C
14H15NO4: C, 64.35; H, 5.80. Found: C, 64.07; H, 6.10.
Dim eth yl 3-(4-m eth ylp h en yl)-1,2-in d olizin ed ica r boxy-
2-(1H-1,2,3-Ben zotr iazol-1-ylm eth yl)isoqu in olin iu m per -
1
1
la te (6j): colorless cube; H NMR δ 1.23 (t, J ) 7.1 Hz, 3H),
1.38 (t, J ) 7.1 Hz, 3H), 2.42 (s, 3H), 4.27 (q, J ) 6.9 Hz, 2H),
4.37 (q, J ) 6.9 Hz, 2H), 6.69 (t, J ) 6.9 Hz, 1H), 7.09 (t, J )
6.9 Hz, 1H), 7.30 (d, J ) 7.7 Hz, 2H), 7.40 (d, J ) 7.9 Hz, 2H),
8.02 (d, J ) 7.1 Hz, 1H), 8.24 (d, J ) 9.1 Hz, 1H); 13C NMR δ
14.0, 14.4, 21.4, 59.8, 61.2, 101.9, 113.2, 120.3, 122.1, 123.2,
123.5, 124.9, 125.9, 129.7, 129.8, 135.1, 138.9, 163.8, 166.4.
Anal. Calcd for C21H21NO4: C, 71.77; H, 6.04; N, 3.99. Found:
C, 71.66; H, 6.04; N, 3.96.
ch lor a te (10): colorless crystal, mp 179-180 °C; H NMR δ
7.54 (t, J ) 7.9 Hz, 1H), 7.70-7.82 (m, 1H), 7.75 (s, 2H), 8.10-
8.21 (m, 2H), 8.28-8.43 (m, 3H), 8.60-8.71 (m, 2H), 9.02 (d,
J ) 6.4 Hz, 1H), 10.47 (s, 1H); 13C NMR δ 67.8, 110.7, 119.7,
125.1, 126.6, 127.2, 127.4, 129.0, 131.3, 131.6, 132.7, 134.0,
137.9, 138.1, 145.4. Anal. Calcd for C16H13N4: C, 53.27; H, 3.64;
N, 15.35. Found: C, 53.44; H, 3.47; N, 15.52.
P yr r olo[2,1-a ]isoqu in olin e-1-ca r bon itr ile (11): colorless
needles, mp 159-160 °C; 1H NMR δ 6.96 (d, J ) 4.3 Hz, 2H),
7.20 (d, J ) 2.5 Hz, 1H), 7.47-7.70 (m, 3H), 7.76 (d, J ) 7.1
Hz, 1H), 8.79 (d, J ) 8.0 Hz, 1H); 13C NMR δ 83.9, 113.8, 115.9,
116.0, 118.5, 123.0, 124.0, 124.8, 127.2, 128.0, 128.1, 128.4,
133.9; HRMS calcd for C13H8N2 (M + 1) 193.0765, found
193.0729.
Dim eth yl 5-eth yl-1,2-in d olizin ed ica r boxyla te (6k ): col-
1
orless needles; H NMR δ 1.43 (t, J ) 7.2 Hz, 3H), 2.88 (q, J
) 7.4 Hz, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 6.64 (d, J ) 6.8 Hz,
1H), 7.10 (t, J ) 7.1 Hz, 1H), 7.64 (s, 1H), 8.07 (d, J ) 9.1 Hz,
1H); 13C NMR δ 10.3, 24.6, 51.2, 52.1, 102.9, 110.5, 113.7,
118.1, 121.4, 123.6, 136.9, 139.1, 164.4, 165.4. Anal. Calcd for
Dieth yl p yr r olo[2,1-a ]isoqu in olin e-1,2-d ica r boxyla te
C
14H15NO4: C, 64.35; H, 5.80; N, 5.36. Found: C, 64.72; H,
1
(12): colorless needles, mp 111-112 °C; H NMR δ 1.36 (t, J
6.17; N, 5.56.
) 7.1 Hz, 3H), 1.44 (t, J ) 7.1 Hz, 3H), 4.34 (q, J ) 7.1 Hz,
2H), 4.52 (q, J ) 7.1 Hz, 2H), 6.76 (d, J ) 7.4 Hz, 1H), 7.36-
7.44 (m, 2H), 7.48 (t, J ) 6.9 Hz, 1H), 7.57 (d, J ) 7.4 Hz,
1H), 7.66 (s, 1H), 8.24 (d, J ) 7.9 Hz, 1H); 13C NMR δ 14.0,
14.2, 60.4, 61.5, 109.7, 114.1, 117.7, 118.7, 123.3, 123.6, 125.0,
127.2, 127.7, 127.8, 128.0, 163.6, 167.4. Anal. Calcd for
Eth yl 2-p h en yl-1-in d olizin eca r boxyla te (6l):24 colorless
1
needles; H NMR δ 1.23 (t, J ) 7.2 Hz, 3H), 4.25 (q, J ) 6.9
Hz, 2H), 6.72 (t, J ) 6.6 Hz, 1H), 7.06 (t, J ) 7.6 Hz, 1H), 7.25
(s, 1H), 7.28-7.41 (m, 3H), 7.51 (d, J ) 6.6 Hz, 2H), 7.98 (d, J
) 6.6 Hz, 1H), 8.24 (d, J ) 9.3 Hz, 1H); 13C NMR δ 14.3, 59.3,
C
18H17N: C, 69.44; H, 5.51; N, 4.50. Found: C, 69.15; H, 5.60;
(23) Kaupp, G.; Hunkler, D.; Zimmermann, I. Chem. Ber. 1982, 115,
2467.
N, 4.62.
(24) Bragg, D. R.; Wibberley, D. G. J . Chem. Soc. 1962, 2627.
J O9906936