Stereoselective synthesis of 4-substituted 1,2,3,4,10,10a- hexahydropyrazino[1,2-a]indoles

Article abstract of DOI:10.1007/s11172-005-0241-4

4-Substituted 1,2,3,4-tetrahydropyrazino[1,2-a]indoles were synthesized from 2-cyanoindole. (R)-4-Methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole was obtained by the Mitsunobu reaction. Stereoselective reduction of 4-substituted 1,2,3,4-tetrahydropyrazino[

Full text of DOI:10.1007/s11172-005-0241-4

226
Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 226—230, January, 2005
Stereoselective synthesis of 4ꢀsubstituted
1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indoles
N. E. Golantsov,a A. V. Karchava,a V. M. Nosova,b and M. A. Yurovskayaa
ꢀ
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Eꢀmail: yumar@org.chem.msu.ru
bState Scientific Center of the Russian Federation
"State Research Institute of Chemical Technology of Organoelement Compounds",
38 sh. Entuziastov, 111123 Moscow, Russian Federation
4ꢀSubstituted 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indoles were synthesized from 2ꢀcyanoꢀ
indole. (R)ꢀ4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole was obtained by the Mitsunobu
reaction. Stereoselective reduction of 4ꢀsubstituted 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indoles
gave 4ꢀsubstituted 1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indoles. (4R,10aR)ꢀ4ꢀMethylꢀ
1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indole was synthesized.
Key words: 1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indoles; 1,2,3,4ꢀtetrahydropyraziꢀ
no[1,2ꢀa]indoles; Nꢀsubstituted indoles; reduction of nitriles; 2ꢀcyanoindole; Mitsunobu reꢀ
action.
Scheme 1
Derivatives of 1,2,3,4,10,10aꢀhexahydropyraziꢀ
no[1,2ꢀa]indole and 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]inꢀ
dole exhibit a broad spectrum of biological activity.1,2 In
this study, 4ꢀsubstituted 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀ
a]indoles were obtained and stereoselectively reduced into
the corresponding 1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀ
a]indoles. The starting 2ꢀcyanoindole for the synthesis of
1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indoles was prepared
according to a known procedure.3 Having an increased
acidity of the NH proton, 2ꢀcyanoindole (1) reacts with
alkylating agents and K2CO3 under mild conditions to
give Nꢀsubstituted indoles 3a,b in high yields (Scheme 1).
Nonꢀracemic indole derivatives with a chiral substituent
at the N atom are most expediently obtained by the
Mitsunobu reaction with secondary alcohols as alkylating
agents and a redox PPh3—dialkyl azodicarboxylate (e.g.,
diisopropyl azodicarboxylate, DIAD) system as a conꢀ
densing agent. The use of optically active secondary alcoꢀ
hol Sꢀ2a made it possible to obtain derivative Rꢀ3a conꢀ
taining a chiral substituent at the N atom (Mitsunobu
reaction proceeds stereospecifically and inverts the conꢀ
figuration of the asymmetric atom of the starting alcoꢀ
hol4).
2a: R1 = Me, R2 = Et, X = Br;
Sꢀ2a: R1 = Me, R2 = Et, X = OH;
2b: R1 = Ph, R2 = Me, X = OMs;
3a: R1 = Me, R2 = Et;
3b: R1 = Ph, R2 = Me
Reagents and conditions: (a) DIAD, PPh3, THF or
(b) K2CO3, DMF.
Note that the reported syntheses of similar individual
indole stereoisomers are few;5—8 a chiral substituent was
directly introduced at the N atom of indole by the
Mitsunobu reaction only in two documented cases.7,8
Catalytic reduction of the cyano group in compound 3
with NaBH4 at nickel boride9 prepared in situ from
NiCl2•6H2O and NaBH4 is accompanied by intramoꢀ
lecular acylation to give cyclic amides 4 in 60 to 65%
yields (Scheme 2). The analogous reduction of compound
3a in the presence of Boc2O10 affords a NꢀBoc derivative
5 in 74% yield and, on elimination of the protective group
with CF3COOH, amide 4a in total 68% yield.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 221—225, January, 2005.
1066ꢀ5285/05/5401ꢀ0226 © 2005 Springer Science+Business Media, Inc.

Hexahydropyrazino[1,2ꢀa]indoles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
227
Scheme 2
3a: R1 = Me, R2 = Et; 5: R1 = Me, R2 = Et; 3b: R1 = Ph, R2 = Me;
4a: R1 = Me; 4b: R1 = Ph; 6a, 7a: R1 = Me; 6b, 7b: R1 = Ph
Reagents and conditions: a. NaBH4, MeOH, NiCl2; b. NaBH4, MeOH, NiCl2, Boc2O; c. TFA, CH2Cl2; d. LiAlH4, THF;
e. BH3, THF; f. BH3 (excess), THF; g. NaBH3CN.
Amides 4a,b were reduced with LiAlH4 in THF into
the corresponding 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]inꢀ
doles 6a,b in 72 and 87% yields, respectively (see
Scheme 2). The optically active amide Rꢀ4a was reduced
with a BH3—THF complex. The reduction of amide 4a
with a large excess of the borane complex unexpectedly
gave the corresponding 4ꢀmethylꢀ1,2,3,4,10,10aꢀhexaꢀ
hydropyrazino[1,2ꢀa]indole (7a), although these reagents
were reported11 to reduce indoles into indolines only in
acidic media. For instance, the reaction of amide 4a with
5 equiv. of BH3•Me2S in boiling THF for 12 h yielded a
mixture of compounds 6a (25%) and 7a (75%, 1 : 2 mixꢀ
ture of diastereomers) (1H NMR and GCꢀMS data).
1,2,3,4ꢀTetrahydropyrazino[1,2ꢀa]indoles 6a,b and
Rꢀ6a were reduced into the corresponding indolines 7a,b
and (4R,10aR)ꢀ7a with NaBH3CN (see Scheme 2) used
earlier5 for asymmetric reduction of indoles into indolines.
The reduction was carried out under different condiꢀ
tions (temperature, solvent, and the amount of the reducꢀ
ing agent); the results obtained are summarized in Table 1.
The ratio of the diastereomers and the degree of converꢀ
sion were determined from 1H NMR data.
In all cases, one of the diastereomers was obtained
in a large excess. A virtually complete conversion of
1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indoles 6a,b into the
corresponding indolines 7a,b was achieved by the roomꢀ
temperature reaction in AcOH; for compound 6a, the
content of the minor diastereomer was ~9%, while for
compound 6b containing the Ph group in position 4, its
content was 14%. In the reduction of compound 6a at
–70 °C, the content of the minor diastereomer was no
higher than 3%; however, the total yield was poor. Neverꢀ
theless, the yield was increased by elevating the reaction
temperature to –10 °C, dr remaining virtually the same.
The spatial structures of the major diastereomers 7a,b
were determined in NOE experiments. Irradiation of a
solution of indoline 7a in DMSOꢀd6 at the resonance
frequency of the methyl protons revealed the NOE for the
Table 1. Stereoselective reduction of 1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indoles 6a (R1 = Me) and 6b (R1 = Ph)
R1
Conditions
T/°C
Substrate :
NaBH3CN
dr (%)
Converꢀ
sion (%)
Solvent
t/h
Me
Ph
Me
Me
Me
AcOH
AcOH
MeOH—dioxane—HCl
MeOH—dioxane—HCl
MeOH—dioxane—HCl
25
25
–70
–50
–10
4
7
4
10
24
1 : 4
1 : 4
1 : 4
1 : 7
1 : 7
91
86
>97
>97
>97
>99
83
59
71
82

228
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Golantsov et al.
1.76 (d, 3 H, CH3CH, J = 7.4 Hz); 4.40 (m, 2 H, CH3CH2);
5.80 (q, 1 H, CH3CH, J = 7.4 Hz); 7.20 (t, 1 H, J = 7.65 Hz);
7.41 (t, 1 H, J = 7.8 Hz); 7.47 (s, 1 H, C(3)H); 7.62 (d, 1 H, J =
8.5 Hz); 7.66 (d, 1 H, J = 8.1 Hz). MS, m/z (Irel (%)): 242 [M]+
(23), 169 [M – CO2Et]+ (100), 142 (6), 115 (8).
C(4)H (3.9%), C(10a)H (2.2%), C(3)Ha (1.2%), and
C(6)H protons (0.7%). A similar pattern was obtained for
its solution in C6D6. These data suggest that the C(10a)H
proton is spatially closer to the methyl group than to the
C(4)H proton. Irradiation at the resonance frequency of
the C(3)Hb proton brought about the NOE for the gemiꢀ
nal C(3)Ha proton (15.4%) and the C(4)H proton (3.3%).
For compound 7b in DMSOꢀd6, the NOE for the C(4)H
proton (4.3%) was observed upon irradiation at the resoꢀ
nance frequency of the C(10a)H proton, thus indicatꢀ
ing their spatial vicinity. These data suggest that the
reduction of compound 6a predominantly gives the
(4R*,10aR*)ꢀisomer, while the reduction of compound
6b yields the (4R*,10aS*)ꢀisomer.
Methyl (2ꢀcyanoindolꢀ1ꢀyl)phenylacetate (3b) was obtained
analogously with methyl mesyloxy(phenyl)acetate as an alkylatꢀ
ing agent. The yield of compound 3b was 69%. Found (%):
C, 74.23; H, 4.80; N, 9.59. C18H14N2O2. Calculated (%):
C, 74.47; H, 4.86; N, 9.65. IR, ν/cm–1: 705 (Ph); 1750 (C=O);
1
2235 (C≡N). H NMR, δ: 3.83 (s, 3 H, OMe); 7.12 (s, 1 H,
CHPh); 7.23 (t, 1 H, J = 7.5 Hz); 7.29—7.45 (m, 6 H); 7.57 (s,
1 H, C(3)H); 7.72 (d, 2 H, J = 8.1 Hz). MS, m/z (Irel (%)):
290 [M]+ (4), 231 [M – CO2Me]+ (4), 121 (10), 89 (14), 77
(13), 59 (100).
Ethyl (R)ꢀ2ꢀ(2ꢀcyanoindolꢀ1ꢀyl)propionate (Rꢀ3a). A soluꢀ
tion of diisopropyl azodicarboxylate (4.44 g, 22 mmol) in anꢀ
hydrous THF (5 mL) was added dropwise at 0 to 5 °C under
argon to a solution of triphenylphosphine (5.87 g), 2ꢀcyanoindole
(2.11 g, 15 mmol), and ethyl (S)ꢀ2ꢀhydroxypropionate (2.61 mL,
22 mmol) in anhydrous THF (50 mL). The reaction mixture was
left at ~20 °C for 48 h, whereupon the solvent was removed
in vacuo and the residue was chromatographed on silica gel with
AcOEt—light petroleum (1 : 25) as the eluent. The yield of comꢀ
pound Rꢀ3a was 2.54 g (71%), [α]D20 –18.0 (c 2.0, CHCl3). Its
spectra are in agreement with the data for racemic ethyl
2ꢀ(2ꢀcyanoindolꢀ1ꢀyl)propionate (3a).
Ethyl 2ꢀ(2ꢀ(tertꢀbutoxycarbonylaminomethyl)indolꢀ1ꢀyl)proꢀ
pionate (5). Nickel dichloride hexahydrate (5 mg, 0.2 mmol)
was added to a solution of ethyl 2ꢀ(2ꢀcyanoindolꢀ1ꢀyl)propionate
(3a) (0.5 g, 2 mmol) and Boc2O (0.87 g, 4 mmol) in anhydrous
MeOH (15 mL). Then NaBH4 (0.53 g, 14 mmol) was added in
portions at 0 to 5 °C. The reaction mixture was stirred at ~20 °C
for 1 h, whereupon the solvent was removed in vacuo. The resiꢀ
due was dissolved in AcOEt (50 mL), washed with a solution of
NaHCO3 (2×20 mL) and brine, and dried with anhydrous
Na2SO4. The extract was concentrated in vacuo and the residue
was chromatographed on silica gel with light petroleum—EtOAc
(10 : 1) as an eluent. The yield of compound 5 was 0.51 g (74%).
Found (%): C, 65.26; H, 7.54; N, 7.79. C19H26N2O4. Calcuꢀ
lated (%): C, 65.87; H, 7.56; N, 8.09. IR, ν/cm–1: 1710
(NHC=O); 1735 (C=O); 3390 (N—H). MS, m/z (Irel (%)): 346
[M]+ (36), 290 [M – H2C=C(CH3)2]+ (68), 245 (23), 230 (15),
200 (27), 171 (32), 156 (100), 144 (38), 130 (54), 57 (83).
1H NMR, δ: 1.09 (t, 3 H, CH3CH2, J = 7.1 Hz); 1.39 (s, 9 H,
CMe3); 1.62 (d, 3 H, CH3CH, J = 7.4 Hz); 4.11 (m, 2 H,
CH3CH2); 4.30 (m, 2 H, CH2NH); 5.80 (q, 1 H, CH3CH, J =
7.4 Hz); 6.31 (s, 1 H, C(3)H); 6.99 (t, 1 H, J = 6.9 Hz); 7.06 (t,
1 H, J = 7.7 Hz); 7.17 (d, 1 H, J = 8.3 Hz); 7.38 (br.s, 1 H, NH);
7.49 (d, 1 H, J = 7.5 Hz).
The reduction of optically active indole Rꢀ6a in
the MeOH—HCl system at –10 °C afforded indoline
(4R,10aR)ꢀ7a, [α]D –35.0 (c 2.0, MeOH). The other
enantiomer was not detected by HPLC with a chiral staꢀ
tionary phase.
23
Experimental
IR spectra were recorded on a URꢀ20 instrument (Nujol or
neat compounds). Rotation values were measured on a Jasco
DIPꢀ360 polarimeter (589 nm). GCꢀMS studies were performed
with a Carlo Erba/Kratos Fractovap Series 4200 gasꢀliquid chroꢀ
matograph (Ultraꢀ1 column, Hewlett Packard, 25 m × 0.2 mm,
phase layer thickness 0.33 µm, helium as a carrier gas
(1 mL min–1), flow separator 1 : 10, evaporator temperature
280 °C, temperature gradient 150—280 °C (5 deg min–1),
ITDꢀ700 MS detector (Finnigan MAT), EI, 70 eV, mass range
m/z 45—400). The enantiomeric excess was determined by HPLC
(column 280 × 4 mm, Vancomycinꢀimmobilized silica gel, flow
rate 0.7 mL min–1). 1H NMR spectra were recorded on a Bruker
AMXꢀ400 spectrometer (400.13 MHz) in DMSOꢀd6 (unless othꢀ
erwise specified) with Me4Si as the internal standard. 2D COSY
and HMBC NMR spectra were recorded on a Bruker DRXꢀ500
spectrometer (500.13 (1H) and 125.76 MHz (13C)). NOE exꢀ
periments were performed on a Bruker AMꢀ360 spectrometer.
Melting points were measured in open capillaries and are given
uncorrected. Compounds were purified by chromatography
on silica gel 60 (0.040—0.063 mm, Merck Co.). The course
of the reactions was monitored and the purity of the comꢀ
pounds obtained was checked by TLC on Silufol UVꢀ254 plates
and GCꢀMS.
Ethyl 2ꢀ(2ꢀcyanoindolꢀ1ꢀyl)propionate (3a). Ethyl 2ꢀbromoꢀ
propionate (4.2 g, 23 mmol) and K2CO3 (3.2 g, 23 mmol) were
added to a solution of 2ꢀcyanoindole3 (3 g, 21 mmol) in DMF
(20 mL). The reaction mixture was stirred at 50 °C for 6 h and
then water (150 mL) was added. The products were extracted
with ether (4×50 mL). The extract was washed with water
(5×50 mL) and brine (100 mL) and dried with anhydrous
Na2SO4. The solvent was removed in vacuo and the residue was
chromatographed on silica gel with AcOEt—light petroleum
(1 : 25) as an eluent. The yield of compound 3a was 4.8 g (94%).
Found (%): C, 68.96; H, 5.89; N, 11.12. C14H14N2O4. Calcuꢀ
lated (%): C, 69.41; H, 5.82; N, 11.56. IR, ν/cm–1: 1740 (C=O);
4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ3ꢀone
(4a). A. Trifluoroacetic acid (0.33 mL, 4.3 mmol) was added to a
solution of ethyl 2ꢀ(2ꢀ(tertꢀbutoxycarbonylaminomethyl)indolꢀ
1ꢀyl)propionate (5) (0.15 g, 0.43 mmol) in 2 mL of CH2Cl2. The
reaction mixture was kept at room temperature for 2 h and then
diluted with CH2Cl2 to 10 mL, washed with a solution of
NaHCO3 (2×5 mL), and dried with anhydrous Na2SO4. The
solvent was removed in vacuo and the residue was recrystallized
from EtOH to give compound 4a (80 mg, 92%).
B. Nickel dichloride hexahydrate (0.25 g, 1 mmol) was added
to a solution of ethyl 2ꢀ(2ꢀcyanoindolꢀ1ꢀyl)propionate (3a)
1
2240 (C≡N). H NMR, δ: 1.15 (t, 3 H, CH3CH2, J = 7.1 Hz);

Hexahydropyrazino[1,2ꢀa]indoles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
229
(2.5 g, 10.3 mmol) in 75 mL of anhydrous methanol. Then
NaBH4 (2.74 g, 72 mmol) was added in portions at 0 to 5 °C.
The reaction mixture was stirred at room temperature for 2 h,
whereupon the solvent was removed in vacuo. The residue was
dissolved in 200 mL of AcOEt, washed with a solution of
NaHCO3 (2×100 mL) and brine, and dried with anhydrous
Na2SO4. The extract was concentrated in vacuo and the residue
was recrystallized from EtOH to give compound 4a (1.4 g, 63%),
m.p. 220—222 °C (from ethanol). Found (%): C, 71.46; H, 5.92;
N, 13.55. C12H12N2O. Calculated (%): C, 71.98; H, 6.04;
10.00 (br.s, 2 H, NH2+). MS (for the free base), m/z (Irel (%)):
186 [M[+ (47), 157 (62), 130 (100), 117 (49), 102 (30), 89
(48), 63 (55).
(R)ꢀ4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole
hydrochloride (Rꢀ6a). (R)ꢀ4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyraziꢀ
no[1,2ꢀa]indolꢀ3ꢀone (Rꢀ4a) (0.1 g, 5 mmol) was added to a 1 M
solution of a borane—THF complex (1.1 mL, ~1.1 mmol). The
reaction mixture was left for 24 h, whereupon methanol (1 mL)
was added dropwise. Volatile compounds were removed in vacuo.
The residue was dissolved in 2 mL of dilute HCl (1 : 1). The
mixture was heated with stirring for 1 h, cooled to 0 °C, and
alkalified with 30% KOH to pH ~12. The product was extracted
with CHCl3 (5×10 mL). The extract was washed with brine and
dried with anhydrous Na2SO4. The solvent was removed in vacuo;
the residue was dissolved in anhydrous ether and 4 M HCl (in
dioxane, 0.13 mL, ~5 mmol) was added with cooling. The preꢀ
cipitate that formed was filtered off, washed with anhydrous
ether, and dried to give compound Rꢀ6a (0.87 g, 78%), m.p.
1
N, 13.99. IR, ν/cm–1: 1670 (C=O); 3200 (N—H). H NMR, δ:
1.52 (d, 3 H, CH3, J = 6.8 Hz); 4.53 (dd, 1 H, C(1)Ha, J =
16.3 Hz, J = 4.4 Hz); 4.69 (d, 1 H, C(1)Hb, J = 16.3 Hz); 5.02
(q, 1 H, CH3CH, J = 6.8 Hz); 6.33 (s, 1 H, C(10)H); 7.04 (t,
1 H, J = 7.4 Hz); 7.11 (t, 1 H, J = 7.4 Hz); 7.51 (t, 2 H); 8.39
(br.d, 1 H, NH). MS, m/z (Irel (%)): 200 [M]+ (82), 185
[M – Me]+ (60), 156 (58), 130 (100), 115 (71), 77 (91), 63 (72).
(R)ꢀ4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ3ꢀone
(Rꢀ4a) was obtained as described for 4ꢀmethylꢀ1,2,3,4ꢀtetraꢀ
hydropyrazino[1,2ꢀa]indolꢀ3ꢀone (4a) in procedure B. The
yield of compound Rꢀ4a was 0.5 g (65%), m.p. 221—222 °C;
20
249—251 °C (from ethanol); [α]D –40.2 (c 0.8, MeOH). Its
spectral characteristics agree with the data for the racemate.
4ꢀPhenylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole (6b).
4ꢀPhenylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ3ꢀone (4b)
(0.71 g, 2.7 mmol) was added in portions (to prevent very vigorꢀ
ous boiling) to a suspension of LiAlH4 (0.26 g, 6.8 mmol) in
15 mL of anhydrous THF. The reaction mixture was refluxed for
16 h and cooled to room temperature. Water (0.3 mL) was
carefully added; then 15% KOH (0.3 mL) and an additional
portion of water (0.3 mL) were added. The mixture was stirred
at room temperature for 30 min. The precipitate was filtered off
and washed with THF (50 mL). The filtrate was concentrated
in vacuo and the residue was dissolved in CH2Cl2 (50 mL),
washed with brine, and dried with anhydrous Na2SO4. The solꢀ
vent was removed in vacuo and the residue was chromatographed
on silica gel with CHCl3 as an eluent to give compound 6b
(0.58 g, 87%), m.p. 139—140 °C (from heptane). Found (%):
C, 82.08; H, 6.47; N, 11.05. C17H16N2. Calculated (%): C, 82.22;
H, 6.49; N, 11.28. IR, ν/cm–1: 715 (Ph), 760, 3325 (N—H).
1H NMR, δ: 2.59 (br.s, 1 H, NH); 3.05 (dd, 1 H, C(3)Ha, J =
13.2 Hz, J = 4.6 Hz); 3.49 (dd, 1 H, C(3)Hb, J = 13.0 Hz, J =
4.8 Hz); 4.11 (d, 1 H, C(1)Ha, J = 16.0 Hz); 4.20 (d, 1 H,
C(1)Hb, J = 16.0 Hz); 5.43 (t, 1 H, PhCH, J = 4.8 Hz); 6.24 (s,
1 H, C(10)H); 6.72 (d, 1 H, J = 8.0 Hz); 6.83 (t, 1 H, J =
7.5 Hz); 6.92 (d, 1 H, J = 7.4 Hz); 7.02 (d, 2 H, J = 6.8 Hz);
7.20—7.31 (m, 3 H); 7.45 (d, 1 H, J = 6.8 Hz). MS, m/z (Irel (%)):
248 [M]+ (38), 218 (36), 204 (31), 130 (18), 116 (31), 103 (94),
89 (100), 77 (77), 63 (49).
4ꢀMethylꢀ1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indole
(7a). A. Sodium cyanoborohydride (0.23 g, 3.6 mmol) was
added to a solution of 4ꢀmethylꢀ1,2,3,4ꢀtetrahydropyraziꢀ
no[1,2ꢀa]indole hydrochloride (6a) (0.2 g, 0.9 mmol) in glacial
AcOH (10 mL). The reaction mixture was stirred at ~20 °C for
4 h and then water (15 mL) was added. The mixture was stirred
for an additional 30 min and alkalified with 30% KOH to pH ~12.
The product was extracted with CHCl3 (5×15 mL). The extract
was washed with brine and dried with Na2SO4. The solvent was
removed in vacuo to give a mixture of diastereomers (0.15 g,
90%); the ratio of the diastereomers was 1 : 10 (1H NMR data).
B. A 4 M solution of HCl (1 mL) in dioxane was added to a
solution of 4ꢀmethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole
hydrochloride (6a) (0.1 g, 0.45 mmol) in 5 mL of anhydrous
MeOH. The reaction mixture was cooled to –20 °C and
23
[α]D –91.5 (c 1.3, MeOH). Its spectral characteristics agree
with the data for the racemate.
4ꢀPhenylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ3ꢀone (4b)
was obtained as described for 4ꢀmethylꢀ1,2,3,4ꢀtetrahydroꢀ
pyrazino[1,2ꢀa]indolꢀ3ꢀone (4a) in procedure B. The yield of
compound 4b was 65%. Found (%): C, 77.50; H, 5.18; N, 10.35.
C17H14N2O. Calculated (%): C, 77.84; H, 5.38; N, 10.68. IR,
ν/cm–1: 710 (Ph), 1775 (C=O), 3330 (N—H). 1H NMR, δ:
4.64—4.75 (m, 2 H, CH2); 6.18 (s, 1 H, PhCH); 6.47 (s, 1 H,
C(10)H); 6.98—7.06 (m, 2 H); 7.11 (d, 2 H, J = 6.3 Hz);
7.25—7.35 (m, 4 H); 7.55 (d, 1 H, J = 6.6 Hz); 8.51 (br.s, 1 H,
NH). MS, m/z (Irel (%)): 262 [M]+ (27), 218 (62), 128 (21),
115 (28), 103 (28), 89 (90), 77 (100), 62 (47), 51 (56), 44
(55), 39 (81).
4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole hydroꢀ
chloride (6a). 4ꢀMethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ
3ꢀone (4a) (0.95 g, 4.75 mmol) was added in portions (to preꢀ
vent very vigorous boiling) to a suspension of LiAlH4 (0.45 g,
11.9 mmol) in anhydrous THF (12 mL). The reaction mixture
was refluxed for 10 h and cooled to room temperature. Water
(0.5 mL) was carefully added; then 15% KOH (0.5 mL) and an
additional 0.5 mL of water were added. Then the mixture was
stirred at ~20 °C for 30 min. The precipitate was filtered off and
washed with THF (50 mL). The filtrate was concentrated in vacuo
and the residue was dissolved in CH2Cl2 (50 mL), washed with
brine, and dried with anhydrous Na2SO4. The solvent was reꢀ
moved in vacuo and the residue was dissolved in a small amount
of anhydrous ether; 4 M HCl (1.2 mL, ~4.75 mmol) in dioxane
was added with cooling. The precipitate that formed was filtered
off, washed with anhydrous ether, dried, and recrystallized from
ethanol. The yield of salt 6a was 0.76 g (72%), m.p. 251—252 °C
(from ethanol). Found (%): C, 64.42; H, 6.83; N, 12.44.
C12H14N2·HCl. Calculated (%): C, 64.71; H, 6.79; N, 12.58.
IR, ν/cm–1 (for the free base): 760, 780, 3060, 3390 (N—H).
1H NMR, δ: 1.52 (d, 3 H, CH3, J = 6.6 Hz); 3.57 (dd, 1 H,
C(3)Ha, J = 13.2 Hz, J = 3.5 Hz); 3.69 (dd, 1 H, C(3)Hb, J =
16.3 Hz, J = 4.9 Hz); 4.44 (d, 1 H, C(1)Ha, J = 15.7 Hz); 4.52
(d, 1 H, C(1)Hb, J = 15.7 Hz); 4.81—4.90 (m, 1 H, CH3CH);
6.40 (s, 1 H, C(10)H); 7.06 (t, 1 H, J = 7.4 Hz); 7.15 (t, 1 H, J =
7.6 Hz); 7.49 (d, 1 H, J = 8.0 Hz); 7.54 (d, 1 H, J = 7.8 Hz);

230
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Golantsov et al.
NaBH3CN (0.2 g, 3.1 mmol) was added. The mixture was stirred
at –10 to –5 °C for 9 h, diluted with water (10 mL), stirred for
an additional 30 min, and alkalified with 30% KOH to pH ~12.
The product was extracted with CHCl3 (5×15 mL). The extract
was washed with brine and dried with Na2SO4. The solvent was
removed in vacuo. The conversion was 82% and the content of
the minor diastereomer did not exceed 3% (1H NMR data). The
starting compound was separated by column chromatography
on silica gel with CHCl3—MeOH (100 : 1) as the eluent. The
product was isolated as dihydrochloride and recrystallized from
ethanol—ether to give the individual major diastereomer (86 mg,
73%). Found (%): C, 76.08; H, 8.52; N, 14.57. C12H16N2. Calꢀ
culated (%): C, 76.55; H, 8.57; N, 14.88. IR, ν/cm–1 (for the
free base): 755 (Ar), 1610 (Ar), 3320 (N—H). 1H NMR (CDCl3),
δ: 1.23 (d, 3 H, CH3, J = 6.8 Hz); 2.16 (br.s, 1 H, NH); 2.50 (dd,
1 H, C(10)Ha, J = 14.9 Hz, J = 9.5 Hz); 2.71 (t, 1 H, C(1)Ha,
J = 11.3 Hz); 2.80 (d, 1 H, C(3)Ha, J = 12.2 Hz); 2.91 (dd, 1 H,
C(10)Hb, J = 14.9 Hz, J = 7.9 Hz); 3.00—3.10 (m, 2 H, C(1)Hb,
C(3)Hb); 3.69—3.75 (m, 2 H, C(4)H, C(10a)H); 6.36 (d, 1 H,
C(6)H, J = 8.0 Hz); 6.59 (t, 1 H, C(8)H, J = 7.3 Hz); 7.03—7.06
(m, 2 H, C(7)H, C(9)H). 13C NMR (CDCl3), δ: 11.98 (CH3);
32.81 (C(10)); 46.52 (C(4)); 49.34 (C(3)); 50.84 (C(1)); 57.31
(C(10a)); 105.36 (C(6)); 116.88 (C(8)); 124.57 (C(9)); 127.34
Reduction of 4ꢀmethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]inꢀ
dolꢀ3ꢀone (4a) with the dimethyl sulfide—borane complex. The
complex BH3•Me2S (0.38 g, 5 mmol) was added to a solution of
4ꢀmethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indolꢀ3ꢀone (4a)
(0.2 g, 1 mmol) in anhydrous THF (10 mL) and Me2S was
removed. The reaction mixture was refluxed for 12 h and MeOH
(5 mL) was added with cooling. The solvent was removed in vacuo
and the residue was dissolved in 12% HCl (10 mL), refluxed for
1 h, and alkalified with 30% KOH to pH ~12. The product was
extracted with dichloromethane (5×20 mL). The extract was
washed with brine and dried with anhydrous Na2SO4. Volatile
compounds were removed in vacuo to give a mixture (0.33 g) of
4ꢀmethylꢀ1,2,3,4ꢀtetrahydropyrazino[1,2ꢀa]indole (6a) (25%)
and 4ꢀmethylꢀ1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indole
(7a) (75%). Compound 7a was a 1 : 2 mixture of diastereomers
(1H NMR data).
References
1. A. R. Katritzky, A. K. Verma, H.ꢀY. He, and R. Chandra,
J. Org. Chem., 2003, 68, 4938.
2. Ger. Offen. 2 162 422, Chem. Abstr., 1973, 79, 66402.
3. F. P. Doyle, W. Ferrier, D. O. Holland, M. D. Mehta, and
J. H. C. Nayler, J. Chem. Soc., 1956, 8, 2854.
4. O. Mitsunobu, Synthesis, 1981, 1.
5. A. V. Karchava, M. A. Yurovskaya, T. R. Wagner, B. L.
Zybailov, and Y. G. Bundel, Tetrahedron: Asymmetry, 1995,
6, 2895.
6. A. V. Kurkin, V. V. Nesterov, A. V. Karchava, and M. A.
Yurovskaya, Khim. Geterotsikl. Soedin., 2003, 1665 [Chem.
Heterocycl. Compd., 2003 (Engl. Transl.)].
1
(C(7)); 128.56 (C(9a)); 150.02 (C(5a)). The signals in the H
and 13C NMR spectra were assigned from the COSY and HMBC
data. MS, m/z (Irel (%)): 188 [M]+ (6), 144 (35), 130 (14), 117
(29), 89 (37), 77 (16), 43 (100).
(4R,10aR)ꢀ4ꢀMethylꢀ1,2,3,4,10,10aꢀhexahydropyraziꢀ
no[1,2ꢀa]indole ((4R,10aR)ꢀ7a) was obtained in 76% yield as
20
described for racemate 7a in procedure B; [α]D –35.0 (c 2.0,
MeOH). Its spectral characteristics agree with the data for the
racemate.
7. S. S. Bhagwat and C. Gude, Tetrahedron Lett., 1994,
35, 1848.
4ꢀPhenylꢀ1,2,3,4,10,10aꢀhexahydropyrazino[1,2ꢀa]indole
(7b) was obtained as described for 4ꢀmethylꢀ1,2,3,4,10,10aꢀ
hexahydropyrazino[1,2ꢀa]indole (7a) in procedure A. The yield
of compound 7b was 79% (de 86%). Found (%): C, 81.29;
H, 6.93; N, 11.02. C17H18N2. Calculated (%): C, 81.56; H, 7.25;
N, 11.19. IR, ν/cm–1: 715 (Ph), 765, 1610, 3320 (N—H).
1H NMR (C6D6), δ: 2.43—2.57 (m, 2 H); 2.61—2.75 (m, 2 H);
2.78—2.88 (m, 2 H); 3.01—3.13 (m, 1 H); 3.73 (dd, 1 H,
C(10a)H, J = 10.01 Hz, J = 3.5 Hz); 5.88 (d, 1 H, PhCH, J =
7.3 Hz); 6.67—6.75 (m, 2 H); 6.95—7.24 (m); 7.35 (d, 2 H, J =
6.6 Hz). MS, m/z (Irel (%)): 250 [M]+ (4), 206 (42), 118 (22),
104 (30), 89 (37), 77 (35), 44 (100).
8. A. Bombrun and G. Casi, Tetrahedron Lett., 2002, 43, 2187.
9. C. A. Brown, J. Org. Chem., 1970, 35, 1900.
10. S. Caddick, D. B. Judd, A. K. d. K. Lewis, M. T. Reich, and
M. R. V. Williams, Tetrahedron, 2003, 59, 5420.
11. R. J. Sundberg, Indoles, Academic Press, London—San
Diego—New York—Boston, 1966, 145.
Received October 27, 2004