Novel routes to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines and 5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines.

Article abstract of DOI:10.1021/jo020371t

Condensation reactions of benzotriazole and 2-(pyrrol-1-yl)-1-ethylamine (1) with formaldehyde and glutaric dialdehyde, respectively, afforded intermediates 2 and 6. Subsequent nucleophilic substitutions of the benzotriazole group in 2 and 6 with Grignard reagents, sodium cyanide, and sodium borohydride gave 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 3a-e, 4, 5 and 5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a-c, 8, 9, respectively, in good yields.

Full text of DOI:10.1021/jo020371t

Novel Rou tes to 1,2,3,4-Tetr a h yd r op yr r olo[1,2-a ]p yr a zin es a n d
5,6,9,10,11,11a -Hexa h yd r o-8H-p yr id o[1,2-a ]p yr r olo[2,1-c]p yr a zin es
Alan R. Katritzky,*,‡ Ritu J ain,‡ Yong-J iang Xu,‡ and Peter J . Steel§
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
katritzky@chem.ufl.edu
Received J une 3, 2002
Condensation reactions of benzotriazole and 2-(pyrrol-1-yl)-1-ethylamine (1) with formaldehyde
and glutaric dialdehyde, respectively, afforded intermediates 2 and 6. Subsequent nucleophilic
substitutions of the benzotriazole group in 2 and 6 with Grignard reagents, sodium cyanide, and
sodium borohydride gave 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 3a -e, 4, 5 and 5,6,9,10,11,11a-
hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a -c, 8, 9, respectively, in good yields.
In tr od u ction
Resu lts a n d Discu ssion
1-[3,4-Dih yd r op yr r olo[1,2-a ]p yr a zin -2(1H )-yl-
m eth yl]-1H-1,2,3-ben zotr ia zole (2). Condensation of
benzotriazole, 2-(pyrrol-1-yl)-1-ethylamine (1),15 and form-
aldehyde in aqueous methanol at 20 °C formed 2 in 74%
yield (Scheme 1). Compound 2 was fully characterized
by 1H, 13C NMR spectra and microanalysis. In the
aliphatic region of the H NMR spectra, signals ascribed
to BtCH2N (δ ) 5.59 ppm) and pyrrole CH2N (δ ) 3.89
ppm), respectively, supported structure 2.
Syn th eses of 1,2,3,4-Tetr a h yd r op yr r olo[1,2-a ]p y-
r a zin es 3a -e, 4 a n d 5 Usin g Gr ign a r d Rea gen ts,
Sod iu m Cya n id e a n d Sod iu m Bor oh yd r id e a s Nu -
cleop h iles. Diverse nucleophiles smoothly substituted
the benzotriazole moiety in compound 2. Reactions of
compound 2 with a variety of Grignard reagents gave
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 3a -e in 70-
92% yields (Scheme 1).
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines are of con-
siderable interest because of their antiamnesic, antihy-
poxic,1 psychotropic,2 antihypersensitive,3 and aldose
reductase inhibitor activities.4 Pyrrolopyrazines also
selectively bind to GABAa receptors5 and are useful
starting materials for the synthesis of octahydropyrrolo-
[1,2-a]pyrazine-based coronary-dilators and neuroleptics.6
1
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines were previ-
ously synthesized via selective hydrogenation or reduc-
tion of 3,4-dihydropyrrolo[1,2-a]pyrazines.3,6-8 However,
5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]-
pyrazines were previously unknown. We now describe
novel and convenient approaches to 1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazines 3a -e, 4, 5 and 5,6,9,10,11,11a-
hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a -
c, 8, 9 using benzotriazole methodology.9-14
Treatment of compound 2 with sodium cyanide and
sodium borohyride at 20 °C afforded 2-[3,4-dihydropyr-
rolo[1,2-a]pyrazin-2(1H)-yl]acetonitrile (4) and the 2-meth-
yl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine boron complex
(5) in 80% and 65% yields, respectively (Scheme 1).
8-Ben zotr ia zolyl-5,6,9,10,11,11a -h exa h yd r o-8H-p y-
r id o[1,2-a ]p yr r olo[2,1-a ]p yr a zin e (6). Condensation
of 2-(pyrrol-1-yl)ethylamine (1), benzotriazole, and glu-
taric dialdehyde formed the fused ring compound 6 as a
mixture of Bt1 (benzotriazol-1-yl) 6a and Bt2 (benzotria-
zol-2-yl) 6b isomers in a 6:1 ratio (determined by 1H NMR
‡ University of Florida.
§ University of Canterbury.
(1) Seredenin, S. B.; Voronina, T. A.; Beshimov, A.; Peresada, V.
P.; Likhosherstov, A. M. RU 2,099,055, 1997; Chem. Abstr. 1998, 128,
290245j.
(2) Seredenin, S. B.; Voronina, T. A.; Likhosherstov, A. M.; Peresada,
V. P.; Molodavkin, G. M.; Halikas, J . A. US 5,378,846, 1995; Chem.
Abstr. 1995, 123, 83350w.
(3) Peresada, V. P.; Medvedev, O. S.; Likhosherstov, A. M.; Skoldi-
nov, A. P.Khim.-Farm. Zh. 1987, 21, 1054; Chem. Abstr. 1988, 108,
68298g.
(4) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya,
A.; Komiya, M.; Suzuki, K.; Matsumoto, J .-i. J . Med. Chem. 1998, 41,
4118.
spectroscopy) in 67% total yield. The H and 13C NMR
(5) Blum, C.; Hutchison, A. US 5,668,283, 1997; Chem. Abstr. 1997,
127, 293247b.
1
data of the major Bt1 isomer 6a are reported in the
Experimental Section. The structure and stereochemistry
(6) Skoldinov, A. P.; Likhosherstov, A. M.; Peresada, V. P. Brit. UK
Pat. Appl. 2,025,936, 1980; Chem Abstr. 1981, 93, 186406k.
(7) Skoldinov, A. P.; Likhosherstov, A. M.; Peresada, V. P. Ger.
Offen. 2,832,488, 1980; Chem. Abstr. 1980, 93, 46720h.
(8) Skoldinov, A. P.; Likhosherstov, A. M.; Peresada, V. P. USSR
798,104, 1981; Chem. Abstr. 1981, 95, 7337k.
(9) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409.
(12) Katritzky, A. R.; Belyakov, S. A. Aldrichimica Acta 1998, 31,
35.
(13) Katritzky, A. R.; Li, J .; Xie, L. Tetrahedron 1999, 55, 8263.
(14) Katritzky, A. R.; Denisko, O. V. Pure Appl. Chem. 2000, 72,
1597.
(15) de Pablo, M. S.; Ganda´segui, T., Vaquero, J . J .; Nav`ıo, J . L. G.;
Alvarez-Builla, J . Tetrahedron 1992, 48, 8793.
(10) Katritzky, A. R.; Qi, M. Tetrahedron Lett. 1998, 54, 2647.
(11) Katritzky, A. R.; Qi, M. Collect. Czech. Chem. Commun. 1998,
63, 599.
10.1021/jo020371t CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
8220
J . Org. Chem. 2002, 67, 8220-8223

Routes to 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
SCHEME 1
SCHEME 2
for 8 and a multiplet in the range of 2.73-2.69 ppm for
7c) was irradiated, no NOE effect was observed for
H(11a) (multiplet in the range of 4.07-3.97 ppm) and
vice versa. When H(11a) in 7a ,b was irradiated, a distinct
positive NOE effect was observed for the phenyl ring.
Thus, H(8) and H(11a) are in a mutually trans orienta-
tion. It is difficult to get a distinct NOE effect between
H(11a) and the ethyl protons in 7c because the protons
of the ethyl group merged with the protons of the six-
membered rings.
of 6a were unambiguously established by single-crystal
X-ray crystallography. Figure 1 (Supporting Information)
shows a perspective view of the structure of 6a , which
shows that the sp3 nitrogen is hybridized such that the
pyridopyrazine ring system has a trans ring fusion. The
adjacent Bt1 substituent occupies an equatorial position
in the chair conformation of its attached six-membered
ring. According to our previous work,9,16,17 Bt1 and Bt2
are both good leaving groups, and removal of benzotria-
zolyl groups from the Bt1 and Bt2 isomers results in the
same iminium cation. Therefore, compound 6 was used
as a mixture of isomers 6a and 6b for the subsequent
reactions.
Syn th eses of 5,6,9,10,11,11a-Hexah ydr o-8H-pyr ido-
[1,2-a ]p yr r olo[2,1-c]p yr a zin es 7a -c, 8 a n d 9 Usin g
Gr ign a r d Rea gen ts, Sod iu m Cya n id e a n d Sod iu m
Bor oh yd r id e a s Nu cleop h iles. Reactions of compound
6 with appropriate Grignard reagents (4-ClC6H4MgCl,
4-CH3C6H4MgBr, and CH3CH2MgBr) in THF at 20 °C
gave products 7a -c in 66-80% yield (Scheme 2).
Treatment of compound 6 with sodium cyanide and
sodium borohydride resulted in substitution of the
benzotriazolyl group (both Bt1 and Bt2) with cyanide
and hydride to give 5,6,9,10,11,11a-hexahydro-8H-
pyrido[1,2-a]pyrrolo[2,1-c]pyrazine-8-carbonitrile (8) and
5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]-
pyrazine (9) in 75% and 63% yields, respectively (Scheme
2).
The structure of 7b was unambiguously confirmed by
X-ray crystallography (Figure 1, Supporting Information).
The single-crystal X-ray structure determination revealed
that, in contrast to the precursor 6, the pyridopyrazine
ring system in 7b has a cis ring fusion. Once again the
adjacent aryl substituent occupies an equatorial position.
This diastereoisomer has H(8) and H(11a) on opposite
sides of the pyridopyrazine ring system, and hence they
would not be expected to show mutual NOE enhance-
ments.
The predominance of the observed isomers can be
explained on the basis of the reaction mechanism.
Compound 6 can easily form the pyrazinium cation since
Bt- is a good leaving group.10-12 Nucleophiles could attack
the iminium cation from either face of the CH2CHdN-
plane. However, attack from above the plane is more
favorable, compared to attack from below the plane,
because of less steric hindrance from the 1,2,3,4-tetra-
hydropyrrolo[1,2-a]pyrazine ring system (Scheme 3).
Thus products 7a -c and 8 are formed by kinetic control.
By contrast, in intermediate 6, easy reversible ionization
leads to the thermodynamically more stable configura-
tion.
Con figu r a tion a l An a lysis of Com p ou n d s 7a -c
a n d 8. Initially, the configurations of 7a -c, 8 were
determined by NOE experiments. For compounds 7a -c
and 8, when H(8) (a broad singlet at 4.41 ppm for 7a ,
4.42 ppm for 7b and a doublet at 3.63 ppm (J ) 11.1 Hz)
To summarize, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyra-
zines 3a -e, 4, 5, and 5,6,9,10,11,11a-hexahydro-8H-
pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a -c, 8, 9 were syn-
thesized via nucleophilic substitutions of the benzotriazolyl
moieties in 2 and 6, themselves readily obtained from
condensations of benzotriazole and 2-pyrrol-1-ylethyl-
amine (1) with formaldehyde and glutaric dialdehyde,
(16) Katritzky, A. R.; Xu, Y.-J .; He, H.-Y.; Mehta, S. J . Org. Chem.
2001, 66, 5590.
(17) Katritzky, A. R.; Xu, Y.-J .; He, H.-Y. J . Chem. Soc., Perkin
Trans. 1 2002, 592.
J . Org. Chem, Vol. 67, No. 23, 2002 8221

Katritzky et al.
Hz, 2H), 2.35 (s, 3H); 13C NMR δ 136.8, 134.7, 128.9, 128.8,
127.0, 118.1, 107.9, 102.5, 62.0, 51.2, 50.2, 44.6, 21.0. Anal.
Calcd for C15H18N2: C, 79.60; H, 8.02; N, 12.38. Found: C,
79.21; H, 8.28; N, 12.38.
SCHEME 3
2-(3-Bu ten yl)-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p yr a zin e
(3d ): yellow oil; yield 70%; 1H NMR δ 6.53 (br s, 1H), 6.13 (t,
J ) 3.1 Hz,1H), 5.91-5.77 (m, 2H), 5.09 (d, J ) 17.1 Hz, 1H),
5.03 (d, J ) 9.9 Hz, 1H), 3.99 (t, J ) 5.6 Hz, 2H), 3.66 (s, 2H),
2.84 (t, J ) 5.9 Hz, 2H), 2.59 (t, J ) 6.9 Hz, 2H), 2.34 (t, J )
7.2 Hz, 2H); 13C NMR δ 136.2, 126.9, 118.3, 115.9, 108.0, 102.7,
57.3, 51.1, 50.9, 44.5, 37.7. Anal. Calcd for C11H16N2: C, 74.96;
H, 9.15; N, 15.89. Found: C, 75.10; H, 9.56; N, 16.14.
2-Allyl-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p yr a zin e (3e):
1
brown oil; yield 75%; H NMR δ 6.55 (br s, 1H), 6.14 (t, J )
3.1 Hz, 1H), 5.93-5.84 (m, 2H), 5.24 (dd, J ) 18.0, 11.1 Hz,
2H), 4.00 (t, J ) 5.6 Hz, 2H), 3.65 (s, 2H), 3.18 (d, J ) 6.6 Hz,
2H), 2.84 (t, J ) 5.6 Hz, 2H); 13C NMR δ 134.8, 126.9, 118.3,
118.2, 108.0, 102.7, 61.0, 51.1, 50.4, 44.6. HRMS calcd for
C
10H15N2 (M + 1) 163.1235, found 163.1212.
2-[3,4-Dih yd r op yr r olo[1,2-a ]p yr a zin -2(1H)-yl]a ceton i-
tr ile (4). Compound 2 (0.5 g, 2 mmol) and sodium cyanide (0.2
g, 4 mmol) were stirred in dimethyl sulfoxide (10 mL) at 20
°C for 12 h. Then the reaction was quenched with water and
extracted with ether. The organic layer was washed with 2 M
NaOH and brine, and then dried over MgSO4. Evaporation of
solvent gave the crude product, which was purified using a
neutral alumina column (eluent: hexanes/EtOAc ) 10/1-5/
1), yellow oil; yield 80%; 1H NMR δ 6.56 (br s, 1H), 6.15 (br s,
1H), 5.88 (br s, 1H), 4.03 (t, J ) 5.4 Hz, 2H), 3.81 (s, 2H), 3.67
(s, 2H), 2.96 (t, J ) 5.3 Hz, 2H); 13C NMR δ 125.0, 118.7, 114.3,
108.4, 103.3, 49.8, 49.6, 45.6, 44.3. Anal. Calcd for C9H11N3:
C, 60.99; H, 6.26; N, 23.71. Found: C, 61.10; H, 6.64; N, 23.64.
2-Meth yl-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p yr a zin e Bo-
r on Com p lex (5). Compound 2 (0.5 g, 2 mmol) and NaBH4
(0.15 g, 4 mmol) were stirred at 20 °C overnight in dry THF
(20 mL). THF was then removed in vacuo. The residue was
dissolved in EtOAc and washed with 2 M NaOH and water
and dried over anhydrous Na2SO4. After the removal of EtOAc
in vacuo, the crude product obtained was purified by column
chromatography (eluent: hexanes/EtOAc ) 9/1-4/1), white
flakes (hexanes/EtOAc); mp 111-112 °C; yield 65%; 1H NMR
δ 6.65 (br s, 1H), 6.21 (t, J ) 3.1 Hz, 1H), 5.96 (br s, 1H), 4.22-
4.14 (m, 2H), 4.10-3.91 (m, 2H), 3.46-3.36 (m, 1H), 3.27-
3.20 (m, 1H), 2.67 (s, 3H); 2.42-1.08 (m, 3H, BH3) 13C NMR δ
122.6, 119.7, 109.3, 105.6, 57.7, 56.3, 47.0, 40.3. Anal. Calcd
for C8H15BN2: C, 64.48; H, 10.15; N, 18.80. Found: C, 64.27;
H, 10.33; N, 18.85.
8-Ben zotr ia zolyl-5,6,9,10,11,11a -h exa h yd r o-8H-p yr id o-
[1,2-a ]p yr r olo[2,1-c]p yr a zin e (6). 2-(Pyrrol-1-yl)ethylamine
(1, 1.1 g, 10 mmol) and benzotriazole (1.19 g, 10 mmol) were
dissolved in methanol (40 mL) at 0 °C. Glutaric dialdehyde
(2.0 g, 10 mmol, 50% aqueous solution) was added dropwise
to the solution during 4 h. Then, the solid obtained was filtered
off, washed with cold Et2O, and dried in vacuo. Brown plates
(hexanes/EtOAc); yield 67%. Data for 6a : mp 104-105 °C; 1H
NMR δ 8.07 (d, J ) 7.8 Hz, 1H), 7.96 (d, J ) 8.0 Hz, 1H),
7.40-7.25 (m, 2H), 6.51 (br s, 1H), 6.18 (t, J ) 2.9 Hz, 1H),
5.97 (br s, 1H), 5.44 (dd, J ) 10.8, 3.4 Hz, 1H), 3.80-3.72 (m,
2H), 3.62 (d, J ) 8.1 Hz, 1H), 2.61 (td, J ) 11.7, 4.6 Hz, 1H),
2.43-2.04 (m, 5H), 1.86-1.80 (m, 2H); 13C NMR δ 146.9, 131.2,
130.3, 127.2, 124.2, 120.0, 118.7, 112.3, 108.3, 102.4, 78.4, 60.1,
47.4, 44.6, 31.5, 29.8, 22.4. Anal. Calcd for C17H19N5: N, 23.87.
Found: N, 23.59. Cr ysta l d a ta for 6a : see Supporting
Information.
Gen er a l P r oced u r e for Syn th eses of 5,6,9,10,11,11a -
Hexa h yd r o-8H-p yr id o[1,2-a ]p yr r olo[2,1-c]p yr a zin es 7a -
c. Compound 6 (0.59 g, 2 mmol) was dissolved in dry THF (15
mL) at 0 °C. The corresponding Grignard reagent (3 mmol,
1.5 equiv) was added dropwise. The mixture was stirred for
12 h at 20 °C. Then, the reaction was quenched with water,
washed with 2 M NaOH, and extracted with ether. The organic
solution was dried over MgSO4, and the solvent was removed
respectively, in good yields. Trans isomers 7a -c and 8
were obtained as the major products.
Exp er im en ta l Section
P r oced u r e for th e Syn th esis of 1-[3,4-Dih yd r op yr r olo-
[1,2-a ]pyr azin -2(1H)-ylm eth yl]-1H-1,2,3-ben zotr iazole (2).
2-(Pyrrol-1-yl)ethylamine (1, 1.1 g, 10 mmol) and benzotriazole
(1.19 g, 10 mmol) were dissolved in methanol/water (v/v ) 4/1)
(50 mL). Formaldehyde (1.7 g, 20 mmol, 37% aqueous solution)
was added dropwise to the solution. The resulting mixture was
stirred at 20 °C for 12 h. Then the precipitate was filtered off,
washed with cold Et2O, and dried in vacuo. Colorless plates
(methanol/water); yield 74%; mp 125-126 °C; 1H NMR δ 8.09
(d, J ) 8.4 Hz, 1H), 7.66 (d, J ) 8.3 Hz, 1H), 7.53 (t, J ) 7.6
Hz, 1H), 7.40 (t, J ) 7.3 Hz, 1H), 6.52 (br s, 1H), 6.11 (t, J )
3.0 Hz, 1H), 5.83 (br s, 1H), 5.59 (s, 2H), 3.99 (t, J ) 5.6 Hz,
2H), 3.89 (s, 2H), 3.06 (t, J ) 5.6 Hz, 2H); 13C NMR δ 145.9,
133.6, 127.7, 125.3, 124.1, 120.0, 118.6, 109.9, 108.3, 103.1,
68.7, 48.3, 48.2, 44.6. Anal. Calcd for C14H15N5: C, 66.38; H,
5.97; N, 27.65. Found: C, 66.49; H, 6.12; N, 27.75.
Gen er al P r ocedu r e for Syn th eses of 1,2,3,4-Tetr ah ydr o-
p yr r olo[1,2-a ]p yr a zin es 3a -e. Compound 2 (0.5 g, 2 mmol)
was dissolved in dry THF (15 mL) at 0 °C. The corresponding
Grignard reagent (3 mmol, 1.5 equiv) was added dropwise. The
mixture was stirred at 20 °C for 12 h. Then, the reaction was
quenched with water, washed with 2 M NaOH, and extracted
with ether. After being dried over MgSO4, the solvent was
removed in vacuo. The product obtained was further purified
by column chromatography (eluent: hexanes/EtOAc ) 8/1-
4/1).
2-(4-Ch lor oben zyl)-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p y-
r a zin e (3a ): colorless plates (EtOAc/hexanes); yield 92%; mp
1
90-91 °C; H NMR δ 7.31 (br s, 4H), 6.55 (br s, 1H), 6.13 (t,
J ) 3.3 Hz, 1H), 5.80 (br s, 1H), 3.98 (t, J ) 5.5 Hz, 2H), 3.63
(s, 2H), 2.82 (t, J ) 5.5 Hz, 2H); 13C NMR δ 136.5, 133.0, 130.2,
128.5, 126.9, 118.4, 108.1, 102.7, 61.6, 51.3, 50.5, 44.7. Anal.
Calcd for C14H15ClN2: C, 68.15; H, 6.13; N, 11.35. Found: C,
68.06; H, 6.26; N, 11.33.
2-P h en eth yl-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p yr a zin e
(3b): yellow crystals (hexanes/EtOAc); yield 80%; mp 49-50
°C; 1H NMR δ 7.32-7.21 (m, 5H), 6.54 (br s, 1H), 6.14 (t, J )
3.1 Hz, 1H), 5.84 (br s, 1H), 4.01 (t, J ) 5.4 Hz, 2H), 3.73 (s,
2H), 2.91-2.85 (m, 4H), 2.80-2.74 (m, 2H); 13C NMR δ 140.1,
128.7, 128.4, 126.8, 126.1, 118.3, 108.1, 102.7, 59.8, 51.2, 51.0,
44.6, 34.0. Anal. Calcd for C15H18N2: C, 79.60; H, 8.02; N,
12.38. Found: C, 79.61; H, 8.44; N, 11.93.
2-(4-Meth ylben zyl)-1,2,3,4-tetr a h yd r op yr r olo[1,2-a ]p y-
r a zin e (3c): orange plates (hexanes/EtOAc); yield 85%; mp
42-43 °C; 1H NMR δ 7.25 (d, J ) 7.8 Hz, 2H), 7.14 (d, J ) 7.8
Hz, 2H), 6.53 (br s, 1H), 6.12 (t, J ) 3.2 Hz, 1H), 5.78 (br s,
1H), 3.97 (t, J ) 5.6 Hz, 2H), 3.63 (br s, 4H), 2.82 (t, J ) 5.6
8222 J . Org. Chem., Vol. 67, No. 23, 2002

Routes to 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
in vacuo. The product obtained was purified using column
chromatography (eluent: hexanes/EtOAc ) 8/1-4/1).
8-(4-Chlor ophen yl)-5,6,9,10,11,11a-h exah ydr o-8H-pyr ido-
[1,2-a ]p yr r olo[2,1-c]p yr a zin e (7a ): colorless needles (hex-
g, 2 mmol) and NaCN (0.2 g, 4 mmol) in dimethyl sulfoxide
(10 mL) was reacted for 12 h at 20 °C, followed by the same
workup procedure as that for 4. The product 8 was obtained
after neutral alumina column chromatography (eluent: hex-
anes/EtOAc ) 10/1-5/1) as white needles (hexanes/EtOAc);
mp 52-53 °C; yield 75%; 1H NMR δ 6.53 (br s, 1H), 6.15 (t, J
) 3.1 Hz, 1H), 5.88 (br s, 1H), 4.08 (td, J ) 11.8, 4.7 Hz, 1H),
4.00 (br s, 1H), 3.95 (dd, J ) 11.7, 4.3 Hz, 1H), 3.63 (d, J )
11.1 Hz, 1H), 3.07 (td, J ) 11.8, 4.7 Hz, 1H), 2.88 (dd, J )
11.7, 4.5 Hz, 1H), 2.21 (d, J ) 13.8 Hz, 1H), 1.99-1.92 (m,
2H), 1.89-1.78 (m, 2H), 1.59-1.49 (m, 1H); 13C NMR 130.1,
118.6, 116.2, 108.4, 102.5, 55.2, 54.5, 50.6, 44.4, 30.2, 28.6, 20.1.
Anal. Calcd for C12H15N3 : C, 71.61; H, 7.51; N, 20.88. Found:
C, 71.31; H, 7.60; N, 20.93.
1
anes/EtOAc); yield 70%; mp 136-137 °C; H NMR δ 7.31 (br
s, 4H), 6.61 (br s, 1H), 6.20 (t, J ) 3.1 Hz, 1H), 5.93 (br s, 1H),
4.41 (br s, 1H), 3.98 (td, J ) 12.4, 5.6 Hz, 1H), 3.59-3.50 (m,
2H), 3.14-2.95 (m, 2H), 2.27 (d, J ) 13.8 Hz, 1H), 2.03-1.90
(m, 1H), 1.66-1.49 (m, 4H); 13C NMR δ 142.6, 132.7, 129.5,
128.8, 128.6, 119.5, 107.6, 103.3, 58.4, 55.1, 46.9, 38.7, 36.0,
27.8, 20.1. Anal. Calcd for C17H19ClN2: C, 71.19; H, 6.68; N,
9.77. Found: C, 71.49; H, 7.01; N, 9.48.
8-(4-Methylphenyl)-5,6,9,10,11,11a-hexahydro-8H-pyrido-
[1,2-a ]p yr r olo[2,1-c]p yr a zin e (7b): colorless needles (hex-
1
anes/EtOAC); yield 66%; mp 106-107 °C; H NMR δ 7.26 (d,
5,6,9,10,11,11a-Hexahydro-8H-pyrido[1,2-a ]pyrrolo[2,1-c]-
p yr a zin e (9). Compound 6 (0.59 g, 2 mmol) and NaBH4 (0.15
g, 4 mmol) were stirred overnight in THF (20 mL) at 20 °C.
Following the same procedure as that for 5, product 9 was
obtained after column chromatography (eluent: hexanes/
J ) 7.4 Hz, 2H), 7.14 (d, J ) 7.8 Hz, 2H), 6.61 (br s, 1H), 6.19
(t, J ) 2.9 Hz, 1H), 5.93 (br s, 1H), 4.42 (br s, 1H), 4.07-3.97
(m, 1H), 3.55-3.48 (m, 2H), 3.08-3.01 (m, 2H), 2.34 (s, 3H),
2.29-2.25 (m, 1H), 2.04-1.97 (m, 1H), 1.66-1.55 (m, 4H); 13
C
1
NMR δ 140.9, 136.8, 129.7, 129.2, 127.2, 119.4, 107.5, 103.2,
EtOAc ) 9/1-4/1) as a brown oil; yield 63%; H NMR δ 6.51
58.7, 55.1, 46.9, 38.8, 35.9, 27.9, 21.1, 20.3. Anal. Calcd for
(br s, 1H), 6.13 (t, J ) 2.9 Hz, 1H), 5.84 (br s, 1H), 4.13 (td, J
) 12.0, 4.6 Hz, 1H), 3.91 (dd, J ) 11.4, 3.9 Hz, 1H), 3.04 (d, J
) 10.5 Hz, 1H), 2.94 (dd, J ) 12.0, 4.2 Hz, 2H), 2.68 (td, J )
12.0, 4.6 Hz, 1H), 2.30-2.13 (m, 2H), 1.84 (d, J ) 4.2 Hz, 1H),
1.71-1.64 (m, 2H), 1.60-1.38 (m, 2H); 13C NMR δ 131.6, 118.4,
108.0, 101.5, 60.7, 55.8, 52.8, 44.6, 30.4, 25.6, 23.9. Anal. Calcd
for C11H16N2: C, 74.96; H, 9.15; N, 15.89. Found: C, 75.30; H,
9.51; N, 16.25.
C
18H22N2: C, 81.16; H, 8.32; N, 10.52. Found: C, 81.45; H,
8.68; N, 10.43. Cr ysta l d a ta for 7b: see Supporting Informa-
tion.
8-Eth yl-5,6,9,10,11,11a -h exa h yd r o-8H-p yr id o[1,2-a ]pyr -
r olo[2,1-c]p yr a zin e (7c): brown oil; yield 80%; 1H NMR δ
6.51 (br s, 1H), 6.13 (t, J ) 3.1 Hz, 1H), 5.84 (br s, 1H), 4.11-
4.02 (m, 1H), 3.92 (dd, J ) 7.5, 3.3 Hz, 1H), 3.83 (dt, J ) 11.5,
2.9 Hz, 1H), 3.10 (dd, J ) 8.2, 3.0 Hz, 2H), 2.73-2.69 (m, 1H),
2.05-1.98 (m, 1H), 1.76-1.48 (m, 6H), 1.28-1.24 (m, 1H), 0.89
(t, J ) 7.2 Hz, 3H); 13C NMR δ 131.5, 118.3, 107.7, 102.2, 58.9,
53.2, 48.1, 43.0, 30.5, 27.8, 19.0 (2), 10.9. HRMS calcd for
Su p p or t in g In for m a t ion Ava ila b le: Crystal data and
structure refinement for compounds 6a and 7b. This material
is available free of charge via the Internet at http://pubs.acs.org.
C
13H21N2 (M + 1) 205.1704, found 205.1723.
5,6,9,10,11,11a-Hexahydro-8H-pyrido[1,2-a ]pyrrolo[2,1-c]-
p yr a zin e-8-ca r bon itr ile (8). A mixture of compound 6 (0.59
J O020371T
J . Org. Chem, Vol. 67, No. 23, 2002 8223