Synthesis of spirocyclic carbazole- and acridine-lactams

Article abstract of DOI:10.1039/b922827f

Spirocyclic carbazole- and acridine-lactams were prepared by Fischer-indole or Friedlaender-quinoline synthesis starting from spirocyclic ketones with a lactam ring. All annulation products were obtained as mixtures of separable regioisomers, which differ only in the position of one methyl group. The starting materials were prepared from 2-pyrrolidone and 2-piperidone by a sequence of protection (by N-allylation), α-acylation, iron-catalyzed Michael reaction followed by Robinson-annulation, palladium-catalyzed N-deprotection and catalytic hydrogenation. The overall yields of this six-step sequence are 13 and 17%, respectively, and the racemic ketones are obtained as single diastereoisomers.

Full text of DOI:10.1039/b922827f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of spirocyclic carbazole- and acridine-lactams†
Martina Wu¨rdemann and Jens Christoffers*
Received 2nd November 2009, Accepted 9th February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b922827f
Spirocyclic carbazole- and acridine-lactams were prepared by Fischer-indole or Friedla¨nder-quinoline
synthesis starting from spirocyclic ketones with a lactam ring. All annulation products were obtained as
mixtures of separable regioisomers, which differ only in the position of one methyl group. The starting
materials were prepared from 2-pyrrolidone and 2-piperidone by a sequence of protection (by
N-allylation), a-acylation, iron-catalyzed Michael reaction followed by Robinson-annulation,
palladium-catalyzed N-deprotection and catalytic hydrogenation. The overall yields of this six-step
sequence are 13 and 17%, respectively, and the racemic ketones are obtained as single diastereoisomers.
Introduction
Results and discussion
Spirocyclic compounds are challenging synthetic targets in organic
chemistry.1 Because of their conformational rigidity they are often
used as scaffolds in medicinal chemistry.2 Whereas spirocyclic
structures with an indole moiety are often reported in the
literature,3 respective quinoline derivatives are less frequently
precedented.4 Most prominent examples of such spirocyclic
indoles with an additional lactam moiety are probably the
spirotryprostatins, which exhibit very potent antitumor activity.5
In this work, we wish to report on the synthesis of spirocyclic
carbazole-lactams 1 and acridine-lactams 3 from ketones 2 by
Fischer-indole6 and Friedla¨nder-quinoline synthesis (Scheme 1).7
Spirocyclic ketones 2 would be accessible by Robinson annulation
of N-protected a-acetyl lactams8 4 followed by hydrogenation.
They are useful scaffolds for combinatorial chemistry with a high
degree of novelty.
Based on our previous work with a-acetyl lactams 49 we had
initially chosen the benzyl group as a protective group PG in the
synthesis of spirocyclic ketones 2. However, we had to recognize
that this group is very difficult to remove from N-benzyl lactams
and therefore made the decision to use the N-allyl group for
the protection of our lactams. N-Allylation of butyrolactam and
valerolactam with allyl bromide proceeded in DMF in the presence
of KOH. Both compounds 5a10 and 5b11 were isolated in 49%
yield after distillation. The spirocyclic ketones 7a and 7b were
then prepared in five steps starting with deprotonation (LDA)
and a-acetylation with MeOAc (Scheme 2). The use of EtOAc,
Ac2O, AcCl or AcCN as acetylating reagents gave lower yields.
The Michael reaction of b-oxolactams 4 was performed with
an excess of methyl vinyl ketone (MVK) according to an iron-
catalyzed protocol developed in our group.12 Experiments with
acrolein as a Michael acceptor were unfortunately not successful.
For this reason, an additional methyl group is retained as a
structural difference to the lactams of our initial plan. The next
step was the intramolecular Robinson-type aldol reaction of
1,5-diketones 6 mediated by pyrrolidinium acetate giving spiro-
cyclic enones 9 with correct regiochemistry.13 The cleavage of the
Scheme 1 Synthetic plan for spiro-indole-lactams 1 and spiro-quino-
line-lactams 3 from a-acetyl lactams 4 via spirocyclic keto-lactams 2.
Institut fu¨r Reine und Angewandte Chemie, Carl von Ossietzky-Universita¨t
Oldenburg, D-26111, Oldenburg, Germany. E-mail: jens.christoffers@
uni-oldenburg.de; Fax: +49 441 798 3873; Tel: +49 441 798 4744
† Electronic supplementary information (ESI) available: Synthetic pro-
cedures for and characterization data of compounds 4b, 5b, 6b,7b, 8b,
9b, 10b, 11b, 12b, and 13b. CCDC reference number 748342. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b922827f
Scheme 2 Synthesis of spirocyclic keto-lactams 7 from N-allyl lactams 5.
Reagents and conditions: (a) 1. 1.2 eq. LDA soln., THF, -78 ◦C, 0.5 h, 2.
3 eq. MeOAc, 23 ◦C, 0.5 h; (b) 0.1 eq. FeCl3·6 H2O, 2 eq. MVK, CH2Cl2,
23 ◦C, 16 h; (c) 1 eq. pyrrolidine, 1 eq. HOAc, CH2Cl2, 23 ◦C, 16 h; (d)
0.05 eq. Pd(OAc)2, H2O, TFA, 80 ◦C, 16 h; (e) Pd/C, 1 atm H2, i-PrOH,
50 ◦C, 16 h.
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N-allyl group was then first attempted by isomerization-hydrolysis
with Pd(tfa)2–DPPP according to a recent literature report.14 We
were, however, only able to achieve double bond isomerization
under the reported conditions. After tedious optimization of
reaction parameters, it turned out that allyl-cleavage can be
achieved with 5 mol% Pd(OAc)2 in TFA–water without any
phosphane ligand. Yields up to 75% were achieved for products
8a and 8b on a 5 g-scale. On larger scales, lower conversions
limit the yields and results sometimes become irreproducible.
Finally, catalytic hydrogenation proceeded smoothly and should
be performed in isopropanol as solvent in order to prevent acetal
formation (if EtOH or MeOH are used).15 The racemic products 7a
and 7b now have an additional stereocenter, but they are obtained
as single diastereoisomers as evidenced by NMR. Attempts to
elucidate the relative configuration by ROESY experiments were
not successful, but the relative configuration was established at a
later stage by X-ray crystallography (vide infra) to be cis (methyl
and lactam-carbonyl group).
Fig. 1 ORTEP representation of the structure of racemic compound 10b
in the solid state.
The Fischer indolization of racemic spiroketones 7 was per-
formed under standard conditions16 (Scheme 3) and yielded a
mixture of regioisomeric products 10 and 11 with overall yields
of 76% (five-membered lactam, ratio 10a : 11a ca. 2 : 1) and 78%
(six-membered lactam, ratio 10b : 11b ca. 1 : 2). In each case, both
isomers actually differ only in the position of the methyl group
on the carbazole part (either at C-2 or C-4). They were separable
by column chromatography and are obtained in about the same
amounts. All four compounds are crystalline materials, which
are hardly soluble in CDCl3, so NMR spectra were obtained
in a mixture of CDCl3–CD3OD. All the proton and carbon
resonances of all four products, 10a, 10b, 11a and 11b, were
unequivocally assigned by 2D-NMR techniques (H,H-COSY,
HMBC and HMQC experiments).
Scheme 4 Synthesis of regioisomeric quinoline-lactams.
Their separation by column chromatography was challenging due
to their low solubility in common solvents, but finally succeeded
with toluene–acetone–NEt3 as the mobile phase. NMR spectra
were obtained in a mixture of CDCl3–CD3OD. All the proton
and carbon resonances of all four products, 12a, 12b, 13a and
13b, were unequivocally assigned by 2D-NMR techniques (H,H-
COSY, HMBC, HMQC experiments).
Experimental
General methods
Preparative column chromatography was carried out using Merck
SiO2 (0.035–0.070 mm, type 60 A) with ethyl acetate (EA),
tert-butyl methyl ether (MTBE), toluene or methanol (MeOH)
as eluents. TLC was performed on Merck SiO2 F254 plates on
aluminium sheets. H- and 13C-NMR spectra were recorded on
1
Scheme 3 Synthesis of regioisomeric indole-lactams.
a Bruker Avance DRX 500 and Avance DPX 300 at 23 ◦C.
Multiplicities in 13C-NMR were determined with DEPT experi-
ments. EI-MS, CI-MS and HR-MS spectra were obtained with
a Finnigan MAT 95 spectrometer, GC-MS (EI) spectra with a
Focus GC and a DSQ MS-detector (Thermo-Fisher). IR spectra
were recorded on a Bruker Tensor 27 spectrometer equipped with
a “GoldenGate” diamond-ATR unit. ortho-Aminobenzaldehyde
was always freshly prepared by reduction of nitrobenzaldehyde
with iron-powder as reported previously.18 All other starting
materials were commercially available.
From compound 10b, single crystals were obtained for an X-ray
structure determination.17 An ORTEP-representation is given in
Fig. 1. First of all, the constitution of compound 10b (methyl group
at position 2) was confirmed. Secondly, the relative configuration
of all compounds was established to be cis (methyl and lactam-
carbonyl group). Therefore, the syn-hydrogenation of enones 8a
and 8b had proceeded anti with respect to the lactam-carbonyl
groups. This relative configuration is given in the formula of
compounds 7a and 7b in Scheme 4, but omitted in all other
structures for simplicity.
1-Allyl-2-pyrrolidone (5a)
The synthesis of spiro-acridine-lactams was accomplished in
glacial acetic acid at 100 ◦C. 2-Aminobenzaldehyde always had to
be freshly prepared by reduction of 2-nitrobenzaldehyde with iron-
powder.18 As observed for indole formation, again a mixture of
regioisomeric products 12 and 13 with overall yields of 77% (five-
membered lactam) and 71% (six-membered lactam) was obtained.
The ratio of 3-methyl- (12) and 1-methyl-isomers (13) was ca. 2 : 1.
Allyl bromide (30.6 ml, 42.6 g, 352 mmol) was added dropwise to
a stirred suspension of 2-pyrrolidone (30.0 g, 352 mmol) and
KOH powder (19.8 g, 352 mmol) in DMF (110 ml). The
mixture was further stirred at 60 ◦C for 16 h, then diluted with
water (150 ml) and extracted with CH2Cl2 (3 ¥ 150 ml). The
combined organic extracts were dried (MgSO4). After filtration
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1
5.71 (ddt, J = 17 Hz, J = 10 Hz, J = 6 Hz, 1H) ppm. 13C{ H}-
and evaporation of the solvent the residue was submitted to
vacuum distillation through a 10 cm Vigreux co◦lumn. The product
5a was obtained as the main fraction (bp. 80 C at 5 mbar) and
as a colorless liquid (21.8 g, 174 mmol, 49%). 1H-NMR (CDCl3,
500 MHz): d = 2.03 (pentet, J = 7.6 Hz, 2H), 2.42 (t, J = 8.1 Hz,
2H), 3.36 (t, J = 7.0 Hz, 2H), 3.89 (d, J = 6 Hz, 2H), 5.18 (d,
br, J = 16 Hz, 1H), 5.19 (d, br, J = 11 Hz, 1H), 5.73 (ddt, br,
NMR (CDCl3, 125 MHz): d = 26.15 (CH3), 26.45 (CH2), 27.57
(CH2), 29.89 (CH3), 38.56 (CH2), 43.81 (CH2), 45.55 (CH2), 61.56
(C), 118.20 (CH2), 131.72 (CH), 171.86 (C), 205.60 (C), 207.16
(C) ppm. MS (EI, 70 eV): m/z (%) = 237 (5) [M+], 195 (28), 167
(17), 138 (100). IR (ATR): 3080 (w), 2925 (m), 1708 (m), 1677
(vs), 1494 (s), 1417 (s), 1356 (s), 1270 (s), 1164 (s), 931 (s) cm-1.
HRMS: calcd. 237.1365 (for C13H19NO3), found 237.1361 [M+].
C13H19NO3 (237.30).
1
J = 16 Hz, J = 11 Hz, J = 6 Hz, 1H) ppm. 13C{ H}-NMR
(CDCl3, 125 MHz): d = 17.52 (CH2), 30.72 (CH2), 44.90 (CH2),
46.46 (CH2), 117.46 (CH2), 132.21 (CH), 174.44 (C) ppm. MS (EI,
70 eV): m/z (%) = 125 (79) [M+], 70 (100), 41 (56). IR (ATR): n =
3082 (w), 2978 (m), 2948 (m), 2994 (m), 1676 (vs), 1494 (m), 1462
(m), 1438 (m), 1416 (s), 1281 (m), 1264 (s), 1199 (m), 993 (m), 923
(s) cm-1. HRMS: calcd. 125.0841 (for C7H11NO), found 125.0839
[M+]. C7H11NO (125.17).
2-Allyl-6-methyl-2-azaspiro[4.5]dec-6-ene-1,8-dione (9a)
Pyrrolidine (8.4 ml, 7.2 g, 101 mmol) was added to a cooled (ice
water bath) and stirred solution of lactam 6a (24.0 g, 101 mmol)
in CH2Cl2 (50 ml). Subsequently, glacial acetic acid (5.8 ml,
6.1 g, 101 mmol) was added, the cooling bath was removed
and the mixture stirred for 16 h at ambient temperature. After
concentrating the reaction mixture to half of its volume, it was
transferred directly on top of a SiO2 column and chromatographed
(MTBE, Rf 0.11) to give the title compound 9a (17.9 g, 81.6 mmol,
81%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz): d = 1.93 (s,
3H), 1.93–1.96 (m, 1H), 2.13–2.23 (m, 2H), 2.33–2.44 (m, 2H),
2.56–2.62 (m, 1H), 3.37–3.45 (m, 2H), 3.88 (dd, J = 15.1 Hz, J =
6.3 Hz, 1H), 4.01 (dd, J = 15.1 Hz, J = 6.0 Hz, 1H), 5.23 (d, br,
J = 17 Hz, 1H), 5.24 (d, br, J = 10 Hz, 1H), 5.75 (ddt, br, J =
3-Acetyl-1-allyl-2-pyrrolidone (4a)
LDA (198 mmol, 110 ml of a 1.8 mol dm-3 solution in THF–
heptane–ethylbenzene) was added dropwise over a period of
30 min to a stirred and cooled (dry ice–acetone bath) solution of
lactam 5a (21.1 g, 169 mmol) in abs. THF (170 ml). Subsequently,
MeOAc (40.3 ml, 37.6 g, 507 mmol) was added in one portion,
and the mixture was stirred and warmed to ambient temperature
(30 min). Half concentrated hydrochloric acid (100 ml) was added,
the layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 ¥ 100 ml). The combined organic layers were
dried (MgSO4). After filtration, the solvent was evaporated and
the residue submitted to chromatography (SiO2, MTBE, Rf 0.38)
to give the title compound 4a as a colorless oil (19.0 g, 114 mmol,
67%). Alternatively, the product can be purified by vacuum
distillation (bp. 92 ◦C at 1.3 mbar). 1H-NMR (CDCl3, 500 MHz):
d = 2.05 (ddt, J = 13.4 Hz, J = 5.4 Hz, J = 9.0 Hz, 1H), 2.44 (s,
3H), 2.55 (ddt, J = 13.4 Hz, J = 8.4 Hz, J = 5.6 Hz, 1H), 3.29
(dt, J = 5.3 Hz, J = 9.4 Hz, 1H), 3.39 (dt, J = 3.6 Hz, J = 9.2 Hz,
1H), 3.61 (dd, J = 9.2 Hz, J = 6.0 Hz, 1H), 3.84–3.91 (m, 2H),
5.17 (d, br, J = 16 Hz, 1H), 5.19 (d, J = 10 Hz, 1H), 5.70 (ddt, J =
1
17 Hz, J = 10 Hz, J = 6 Hz, 1H), 5.96 (s, br, 1H) ppm. 13C{ H}-
NMR (CDCl3, 125 MHz): d = 20.58 (CH3), 28.30 (CH2), 31.07
(CH2), 33.79 (CH2), 44.39 (CH2), 46.07 (CH2), 50.43 (C), 118.96
(CH2), 129.37 (CH), 132.28 (CH), 161.46 (C), 175.19 (C), 198.34
(C) ppm. MS (EI, 70 eV): m/z (%) = 219 (19) [M+], 218 (18), 204
(19), 191 (100), 176 (8), 163 (56), 150 (5), 135 (33), 122 (17). IR
(ATR): 3081 (w), 2949 (m), 1669 (vs), 1439 (s), 1417 (s), 1377 (m),
1343 (m), 1326 (m), 1268 (s), 1232 (m), 1187 (m), 1167 (m), 993
(m), 954 (m), 929 (m), 858 (m) cm-1. HRMS: calcd. 219.1259 (for
C13H17NO2), found 219.1257 [M+]. C13H17NO2 (219.28).
6-Methyl-2-azaspiro[4.5]dec-6-en-1,8-dione (8a)
1
16 Hz, J = 10 Hz, J = 6 Hz, 1H) ppm. 13C{ H}-NMR (CDCl3,
Pd(OAc)2 (344 mg, 1.5 mmol, 0.05 eq) was added to a solution of
lactam 9a (6.72 g, 30.6 mmol) in H2O (15 ml) and TFA (15 ml). The
resulting mixture was stirred for 16 h at 80 ◦C. All volatile materials
were removed in vacuo and the residue dissolved in MeOH (5 ml)
and chromatographed on SiO2 (MTBE–MeOH 5 : 1, Rf 0.24) to
give the title compound 8a (4.04 g, 22.5 mmol, 74%) as a colorless
oil. 1H-NMR (CDCl3, 500 MHz): d = 1.98 (d, J = 1.3 Hz, 3H),
2.00–2.03 (m, 1H), 2.28–2.44 (m, 4H), 2.58–2.63 (m, 1H), 3.47 (t,
J = 7.0 Hz, 2H), 5.98 (q, J = 1.1 Hz, 1H), 6.59 (s, br, 1H) ppm.
125 MHz): d = 19.30 (CH2), 29.74 (CH3), 44.84 (CH2), 45.27
(CH2), 55.47 (CH), 117.84 (CH2), 131.61 (CH), 169.29 (C), 203.52
(C) ppm. MS (EI, 70 eV): m/z (%) = 167 (54) [M+], 124 (100), 96
(47). IR (ATR): 3083 (w), 2985 (m), 2893 (m), 1714 (s), 1675 (vs),
1644 (m), 1493 (m), 1418 (s), 1357 (m), 1263 (s), 1164 (m), 993
(m), 928 (s) cm-1. HRMS: calcd. 167.0946 (for C9H13NO2), found
167.0950 [M+]. C9H13NO2 (167.21).
13C{ H}-NMR (CDCl3, 125 MHz): d = 20.14 (CH3), 30.38 (CH2),
1
3-Acetyl-1-allyl-3-(3-oxobutyl)-2-pyrrolidone (6a)
30.50 (CH2), 33.42 (CH2), 39.60 (CH2), 49.10 (C), 129.15 (CH),
160.46 (C), 179.06 (C), 197.73 (C) ppm. MS (EI, 70 eV): m/z
(%) = 179 (16) [M+], 178 (18), 164 (36), 151 (100), 123 (87). IR
(ATR): 3335 (m), 3086 (w), 2927 (m), 2900 (m), 1693 (vs), 1651
(vs), 1445 (m), 1430 (s), 1372 (s), 1267 (s), 1190 (s), 1064 (m), 884
(m), 711 (s), 687 (s), 666 (s), 619 (s) cm-1. HRMS: calcd. 179.0946
(for C10H13NO2), found 179.0950 [M+]. C10H13NO2 (179.22).
FeCl3·6 H2O (1.10 g, 4.07 mmol) and MVK (6.6 ml, 5.71 g,
81.4 mmol) were subsequently added to a stirred solution of lactam
4a (6.80 g, 40.7 mmol) in CH2Cl2 (40 ml). After stirring the mixture
for 16 h at 23 ◦C, all volatile materials were removed in vacuo and
the residue chromatographed on SiO2 (MTBE, Rf 0.23) to yield
the title compound 6a (9.16 g, 38.6 mmol, 95%) as a colorless oil.
1H-NMR (CDCl3, 500 MHz): d = 1.75 (ddd, J = 13.1 Hz, J =
8.5 Hz, J = 7.1 Hz, 1H), 2.08–2.16 (m, 1H), 2.14 (s, 3H), 2.20–2.26
(m, 1H), 2.29 (s, 3H), 2.41–2.45 (m, 2H), 2.58 (ddd, J = 13.2 Hz,
J = 7.8 H, J = 4.2 Hz, 1H), 3.22–3.32 (m, 2H), 3.87–3.89 (m,
2H), 5.17 (d, br, J = 17 Hz, 1H), 5.20 (d, br, J = 10 Hz, 1H),
cis-6-Methyl-2-azaspiro[4.5]decane-1,8-dione (7a)
A mixture of lactam 8a (7.62 g, 42.5 mmol), Pd/C (425 mg, 10%
w/w Pd), and iPrOH (65 ml) was degassed (three cycles of freeze,
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pump, thaw) and stirred at 50 ◦C for 2 d under an atmosphere of
H2 (balloon). The solvent was removed in vacuo and the residue
chromatographed on SiO2 (MTBE–MeOH 5 : 1, Rf 0.40) to give
the title compound 7a (5.49 g, 30.3 mmol, 71%) as a colorless solid,
m.p 142–143 ◦C. 1H-NMR (CDCl3, 500 MHz): d = 1.08 (d, J =
6.7 Hz, 3H), 1.75–1.81 (m, 1H), 1.92–2.01 (m, 2H), 2.23–2.28 (m,
4H), 2.97 (t, J = 13.4 Hz, 1H), 3.01–3.08 (m, 1H), 3.33–3.42 (m,
7.08 (m, 1H; 7-H), 7.28–7.30 (m, 1H; 8-H), 7.43–7.45 (m, 1H;
1
5-H) ppm. 13C{ H}-NMR (CDCl3–CD3OD 1 : 1, 125 MHz): d =
18.64 (CH3; 4-Me), 20.23 (CH2; C-1), 26.06 (CH2; C-2), 32.21 (CH;
C-4), 34.06 (CH2; C-4¢), 39.46 (CH2; C-5¢), 47.30 (C; C-3), 111.36
(CH; C-8), 113.09 (C; C-4a), 117.84 (CH; C-5), 119.01 (CH; C-6),
121.17 (CH; C-7), 127.84 (C; C-4b), 132.84 (C; C-9a), 137.17 (C;
C-8a), 182.94 (C; C-2¢) ppm. MS (EI, 70 eV): m/z (%) = 254 (42)
[M+], 167 (12), 157 (100), 108 (20), 77 (9), 43 (10). IR (ATR): 3390
(s), 3249 (m), 3053 (w), 2987 (w), 1696 (vs), 1650 (vs), 1466 (s),
1430 (s), 1329 (m), 1273 (s), 1202 (s), 1140 (m), 1068 (m), 1037 (m),
747 (vs), 732 (vs) cm-1. HRMS calcd. 254.1419 (for C16H18N2O),
found 254.1412 [M+]. C16H18N2O (254.33).
1
2H), 6.31 (s, 1H) ppm. 13C{ H}-NMR (CDCl3, 125 MHz): d =
16.75 (CH3), 33.30 (CH2), 34.61 (CH2), 37.80 (CH2), 39.11 (CH),
39.16 (CH2), 44.61 (C), 45.80 (CH2), 180.09 (C), 211.61 (C) ppm.
MS (EI, 70 eV): m/z (%) = 181 (60) [M+], 139 (23), 138 (28), 112
(34), 98 (100). IR (ATR): 3184 (m), 3081 (w), 2876 (m), 1711 (vs),
1674 (vs), 1457 (m), 1416 (m), 1347 (m), 1285 (s), 1130 (m), 803
(s), 771 (s), 707 (s), 670 (s), 620 (s) cm-1. HRMS calcd. 181.1103
(for C10H15NO2), found 181.1099 [M+]. C10H15NO2 (181.23).
Friedla¨nder-synthesis with lactam 7a
2-Aminobenzaldehyde (225 mg, 1.86 mmol) was added to a
solution of ketone 7a (260 mg, 1.43 mmol) in glacial◦acetic acid
(3.6 ml) and the mixture was stirred for 16 h at 100 C. MTBE
(30 ml) and 10% aqueous NaOH (15 ml) were added, and the
layers separated. The aqueous layer was further extracted with
MTBE (2 ¥ 20 ml) and the combined organic layers were dried over
MgSO4. After filtration and evaporation of the solvent the residue
was chromatographed on SiO2 (toluene–acetone–NEt3 50 : 50 : 1)
to yield acridine 12a (213 mg, 0.80 mmol, 56%) in the first fraction
(Rf 0.21) and acridine 13a (102 mg, 0.30 mmol, 21%) as the second
fraction (Rf 0.14), both as colorless solids.
Fischer-indolization of lactam 7a
A mixture of ketone 7a (207 mg, 1.14 mmol), glacial AcOH
(2.8 ml), TFA (1.0 ml) and PhNHNH2 (136 mg, 1.26 mmol) was
stirred for 16 h at 100 ◦C in a tightly closed reaction vial. The
mixture was poured onto ice water (ca. 20 g) and the resulting
emulsion extracted with CH2Cl2 (3 ¥ 10 ml). The combined organic
layers were dried (MgSO4) and the solvent removed under reduced
pressure. The residue was chromatographed on SiO2 (EtOAc) to
yield carbazole 10a (130 mg, 0.51 mmol, 45%) in the first fraction
(Rf 0.30) and carbazole 11a (91 mg, 0.36 mmol, 31%) in the second
fraction (Rf 0.17).
1,2,3,4-Tetrahydro-3-methylspiro[acridine-2,3¢-pyrrolidine]-2¢-one
(12a)
cis-1,2,3,4-Tetrahydro-2-methylspiro[carbazole-3,3¢-pyrrolidine]-
2¢-one (10a)
Colorless solid, mp. 244–245 ◦C. 1H-NMR (CDCl3–CD3OD 1 : 1,
500 MHz): d = 1.15 (d, J = 6.9 Hz, 3H; 3-Me), 1.99 (td, J =
13.3 Hz, J = 8.2 Hz, 1H; 4¢-H), 2.11–2.21 (m, 2H; 3-H, 4¢-H), 2.85
(d, J = 16.9 Hz, 1H; 1-H), 3.05 (dd, J = 17.8 Hz, 8.3 Hz, 1H; 4-H),
3.13 (dd, J = 17.8 Hz, 5.8 Hz, 1H; 4-H), 3.23–3.25 (m, 1H; 1-H),
3.26–3.30 (m, 2H; 2 ¥ 5¢-H), 7.36–7.40 (m, 1H; 7-H), 7.53–7.57 (m,
1H; 6-H), 7.67 (d, J = 8.2 Hz, 1H; 8-H), 7.83 (d, J = 8.6 Hz, 1H; 5-
Colorless solid, mp. 235–236 ◦C. 1H-NMR (CDCl3–CD3OD 1 : 1,
500 MHz): d = 1.22 (d, J = 6.9 Hz, 3H; 2-Me), 1.96–2.05 (m,
1H; 4¢-H), 2.14–2.22 (m, 2H; 2-H, 4¢-H), 2.55–2.63 (m, 2H; 1-
H, 4-H), 3.02 (dd, J = 16.7 Hz, J = 5.3 Hz, 1H; 1-H), 3.10 (d,
J = 15.7 Hz, 1H; 4-H), 3.28–3.36 (m, 2H; 2 ¥ 5¢-H), 7.01–7.04
(m, 1H; 6-H), 7.06–7.10 (m, 1H; 7-H), 7.30 (d, J = 7.9 Hz, 1H;
1
H), 7.85 (s, 1H; 9-H) ppm. 13C{ H}-NMR (CDCl3–CD3OD 1 : 1,
1
8-H), 7.42 (d, J = 7.7 Hz, 1H; 5-H) ppm. 13C{ H}-NMR (CDCl3–
125 MHz): d = 15.22 (CH3; 3-Me), 33.39 (CH2; C-4¢), 34.34 (CH;
C-3), 35.98 (CH2; C-1), 37.60 (CH2; C-4); 38.27 (CH2; C-5¢), 44.43
(C; C-2), 125.12 (CH; C-7), 126.06 (CH; C-5), 126.36 (CH; C-8),
126.74 (C; C-8a), 128.27 (CH; C-6), 128.37 (C; C-9a), 134.96 (CH;
C-9), 145.29 (C; C-10a), 157.55 (C; C-4a), 179.79 (C; C-2¢) ppm.
MS (EI, 70 eV): m/z (%) = 266 (100) [M+], 251 (90), 238 (32), 209
(33), 194 (55), 181 (40), 168 (23). IR (ATR): 3208 (m), 3086 (w),
2967 (m), 2872 (m), 1674 (vs), 1493 (s), 1288 (s), 1258 (s), 1142 (m),
924 (m), 786 (vs), 762 (vs), 696 (s) cm-1. HRMS calcd. 266.1419
(for C17H18N2O), found 266.1422 [M+]. C17H18N2O (266.34).
CD3OD 1 : 1, 125 MHz): d = 15.85 (CH3; 2-Me), 26.73 (CH2; C-4),
29.14 (CH2; C-1), 33.43 (CH; C-2), 34.50 (CH2; C-4¢), 39.00 (CH2;
C-5¢), 46.23 (C; C-3), 106.33 (C; C-4a), 110.94 (CH; C-8), 117.62
(CH; C-5), 118.92 (CH; C-6), 120.96 (CH; C-7), 127.94 (C; C-4b),
132.22 (C; C-9a), 136.79 (C; C-8a), 182.63 (C; C-2¢) ppm. MS (EI,
70 eV): m/z (%) = 254 (85) [M+], 180 (8), 167 (10), 157 (96), 143
(100), 130 (20). IR (ATR): 3364 (m), 3187 (m), 3075 (w), 2971 (w),
2870 (m), 1677 (vs), 1463 (s), 1433 (m), 1285 (s), 1257 (m), 1234
(m), 796 (m), 734 (vs), 625 (s) cm-1. HRMS calcd. 254.1419 (for
C16H18N2O), found 254.1412 [M+]. C16H18N2O (254.33).
1,2,3,4-Tetrahydro-1-methylspiro[acridine-2,3¢-pyrrolidine]-2¢-one
(13a)
cis-1,2,3,4-Tetrahydro-4-methylspiro[carbazole-3,3¢-pyrrolidine]-
2¢-one (11a)
Colorless solid, mp. 190–191 ◦C. 1H-NMR (CDCl3–CD3OD 1 : 1,
500 MHz): d = 1.33 (d, J = 7.3 Hz, 3H; 1-Me), 1.73 (ddd, J =
13.6 Hz, J = 6.3 Hz, J = 4.2 Hz, 1H; 3-H), 1.90 (ddd, J = 12.8 Hz,
J = 7.2 Hz, J = 3.0 Hz, 1H; 4¢-H), 2.01 (td, J = 12.8 Hz, J = 8.4 Hz,
1H, 4¢-H), 2.38 (ddd, J = 13.6 Hz, J = 10.8 Hz, J = 6.5 Hz, 1H;
3-H), 2.94–3.01 (m, 1H; 4-H), 3.09 (q, J = 7.3 Hz, 1H; 1-H), 3.20–
3.29 (m, 2H; 4-H, 5¢-H), 3.31–3.37 (m, 1H; 5¢-H), 7.37–7.41 (m,
1H; 7-H), 7.54–7.58 (m, 1H; 6-H), 7.70 (d, J = 8.1 Hz, 1H; 8-H),
Colorless solid, mp. 206–208 ◦C. 1H-NMR (CDCl3–CD3OD 1 : 1,
500 MHz): d = 1.34 (d, J = 6.9 Hz, 3H; 4-Me), 1.57–1.62 (m,
1H; 2-H), 1.96–2.04 (m, 2H; 2 ¥ 4¢-H), 2.38 (ddd, J = 13.3 Hz,
J = 11.9 Hz, J = 6.2 Hz, 1H; 2-H), 2.67–2.75 (m, 1H; 1-H), 2.83
(ddd, J = 16.7 Hz, J = 6.2 Hz, J = 1.8 Hz, 1H; 1-H), 3.16 (q, J =
6.9 Hz, 1H; 4-H), 3.26 (ddd, J = 10.2 Hz, J = 7.7 Hz, J = 2.6 Hz,
1H; 5¢-H), 3.40–3.46 (m, 1H; 5¢-H), 7.00–7.03 (m, 1H; 6-H), 7.05–
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1
7.84 (d, J = 8.5 Hz, 1H; 5-H), 7.96 (s, 1H; 9-H) ppm. 13C{ H}-
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NMR (CDCl3–CD3OD 1 : 1, 125 MHz): d = 18.55 (CH3; 1-Me),
25.39 (CH2; C-3), 28.25 (CH2; C-4), 33.10 (CH2; C-4¢), 37.57 (CH;
C-1), 37.92 (CH2; C-5¢), 44.82 (C; C-2), 125.38 (CH; C-7), 126.19
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(100) [M+], 251 (57), 237 (9), 223 (11), 209 (44), 194 (51), 180
(26), 168 (71). IR (ATR): 3191 (m), 3089 (w), 2922 (s), 2890 (m),
2853 (m), 1697 (vs), 1675 (vs), 1488 (s), 1377 (m), 1273 (s), 1080
(m), 908 (m), 786 (s), 753 (vs) cm-1. HRMS calcd. 266.1419 (for
C17H18N2O), found 266.1424 [M+]. C17H18N2O (266.34).
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Acknowledgements
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We gratefully acknowledge support from Boehringer-Ingelheim,
Biberach. We are furthermore grateful to Ludmila Hermann
and Elisabeth Jaskulska for assistance, to Irina Profir for initial
experiments, to Detlev Haase for X-ray crystallography and Dr
Herbert Frey for helping us with this manuscript. We acknowledge
a generous donation of solvents from Dr Burkard Kreidler, Evonik
Oxeno GmbH, Marl.
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1898 | Org. Biomol. Chem., 2010, 8, 1894–1898
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