Synthesis of a benzannulated pyrrolizidine by a copper-catalyzed intramolecular α-Arylation reaction

Article abstract of DOI:10.1002/hlca.201300313

A synthetic route to the pyrrolo[1,2-a]indole ring system (benzannulated pyrrolizidine) involving a base-induced intramolecular aza-Michael reaction as the key C-N bond-forming penultimate step, followed by a Cu-catalyzed intramolecular α-arylation reacti

Full text of DOI:10.1002/hlca.201300313

Helvetica Chimica Acta – Vol. 97 (2014)
569
Synthesis of a Benzannulated Pyrrolizidine by a Copper-Catalyzed
Intramolecular a-Arylation Reaction
by Flavia Magalhaes Araujo, Wellington Martins Ventura, and Jason Guy Taylor*
´
Departamento de Quꢀmica, ICEB, Universidade Federal de Ouro Preto, Campus Universitario Morro do
Cruzeiro, 35400-000, Ouro Preto-MG, Brasil (phone: þ 553135591233; e-mail: jason@iceb.ufop.br)
A synthetic route to the pyrrolo[1,2-a]indole ring system (benzannulated pyrrolizidine) involving a
base-induced intramolecular aza-Michael reaction as the key CꢀN bond-forming penultimate step,
followed by a Cu-catalyzed intramolecular a-arylation reaction, to provide the tricyclic framework over
six steps is described.
Introduction. – Tricyclic heterocycles are pervasive structural frameworks in nature
and have a broad profile of biological features, such as antibiotic, anthelmintic,
antifungal, antitumor, antiviral, anti-inflammatory, and cytotoxic activities. Examples
of natural products with O- or N-containing tricyclic structures include gynunone,
neuchromenin, citreoindole, and fumiquinazoline (Fig. 1) [1 – 3].
Their biological activities render this family of organic compounds interesting
structural scaffolds for the development of new drug candidates. Notably, these
structural motifs are rarely reported in medicinal-chemistry publications, indicating
that there still exists a need to develop more efficient procedures, particularly those
that allow the synthesis of complex azapolycyclic ring systems.
Heterocyclic structures pertinent to this communication involve the pyrrolo[1,2-
a]indole ring system which has been employed in the stereocontrolled synthesis of the
mitosane skeleton (Fig. 2) [4].
As part of our research program aimed at developing new methodologies for the
synthesis of heterocyclic compounds [5], we directed our focus towards preparation of
Fig. 1. Examples of O- or N-containing natural products
ꢁ 2014 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Fig. 2. Pyrrolo[1,2-a]indole ring system and mitosane
tricyclic structures for future applications in total syntheses. Herein, we report an
efficient and simple synthetic route to a ꢃbenzannulated pyrrolizidineꢄ derivative via a
base-induced intramolecular aza-Michael reaction as the key CꢀN bond forming step,
followed by a Cu-catalyzed intramolecular a-arylation.
Results and Discussion. – Synthesis of the target tricyclic molecule started with
tetrahydrofuran-2-ol (2), which was obtained by an acid-catalysed hydrolysis of 2,3-
dihydrofuran 1 [6]. Tetrahydrofuran-2-ol (2) exists in a tautomeric equilibrium with 4-
hydroxybutanal 3 and thus enables the synthesis of a a,b-unsaturated ester substrate via
a HornerꢀWadsworthꢀEmmons (HWE) reaction with the appropriate phosphonium
ylide 4 (Scheme 1). Synthesis of 5 proceeded smoothly to afford the hydroxy a,b-
unsaturated ester 5 in good yield and with predominately (E)-selectivity (> 96%) as
determined by 1H-NMR spectroscopy: evidenced by the presence of two signals
exhibiting a splitting pattern of double triplets at 6.95 (J ¼ 7.2 and 15.6) and 5.85 ppm
1
(J ¼ 1.6 and 15.6) . All H- and 13C-NMR signals were unambiguously assigned and
correlated well with literature values [7][8].
Scheme 1. Synthesis of Hydroxy a,b-Unsaturated Ester 5
The hydroxy ester 5 was converted to the corresponding formyl ester 6 by
pyridinium chlorochromate (PCC) oxidation in good yields. Compound 6 was used
immediately in the next step (Scheme 2). We envisaged a base-induced intramolecular
aza-Michael reaction to install the pyrrolidine moiety. Hence, to prepare target
molecule 8, a reductive amination was carried out between 6 and 2-bromoaniline with
NaBH(OAc)3 as reducing agent. The expected product 7 was obtained in good yield,
with the incorporation of Br that could be exploited in the last key bond-forming step of
the synthesis. After extensive optimizations studies, we found that the intramolcular
aza-Michael reaction could be effected in the presence of a strong base, such as tBuOLi,
to afford the N-substituted pyrrolidine derivative 8 in good yield.

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Scheme 2. Synthesis of Pyrrolidine Derivative 8
So, with compound 8 in hand, the stage for the evaluation of the intramolecular Cu-
catalyzed a-arylation reaction was set (Scheme 3). Precedence for this type of
cyclization had been established in a similar substrate in which CuI catalyzed a remote
amide-assisted intramolecular arylation, followed by alkylation, in the synthesis of
hexahydropyrroloindole alkaloids [9]. We applied a modification of the intermolecular
protocol reported by Kwong and co-workers in 2007 [10]; employing a catalytic amount
of 2-picolinic acid (L) and CuI, and 1 equiv. of lithium bis(trimethylsilyl)amide
(LiHMDS) as base was successful in providing the target molecule 9 in modest yield.
Interestingly, the formation of the trans-isomer of 9 was favored which we were able to
isolate by column chromatography, and the cis-isomer was not detected during
purification. Of the trans-isomer, the NꢀCH H-atom in the 1H-NMR spectrum
displayed a characteristic ddd signal at ca. 3.9 ppm and coupling constants indicative of
a trans-isomer.
Scheme 3. Synthesis of Pyrrolidine 9
Conclusions. – In summary, we have developed a synthetic protocol for the
preparation of a pyrrolo[1,2-a]indole ring system, utilizing a Cu-catalyzed intra-
molecular a-arylation reaction as the key CꢀC bond-forming step, to afford the target
molecule in 15.4% overall yield over six steps.
`
This work was supported by the Brazilian funding agency FundaÅa˜o de Amparo a Pesquisa do Estado
de Minas Gerais (FAPEMIG) under research grant project code APQ-00307-12. The authors gratefully

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acknowledge the generous financial support from Conselho Nacional de Desenvolvimento Cientꢀfico e
´
Tecnologico (CNPq) for graduate research studentships and bursaries.
Experimental Part
General. All commercial reagents were used as received. Anh. THF and 1,4-dioxane were purchased
from SigmaꢀAldrich. Column chromatography (CC): silica gel (200 – 400 mesh). TLC: silica-gel plates,
UV light (254 nm) or vanillin soln. for visualization. M.p.: uncorrected. IR Spectra: either a liquid film
between NaCl plates, or pressed in to KBr discs. NMR spectra: in d [ppm] referenced to residual 1H- and
13C-signals in CDCl3; the coupling constants (J) expressed in Hz. HR-EI-MS: in m/z.
Ethyl (2E)-6-Hydroxyhex-2-enoate (5). Ethyl(triphenylphosphonyliden)acetate (22.2 mmol) and
tetrahydrofuran-2-ol (17.1 mmol), were refluxed in toluene for 18 h. Upon completion, the mixture was
cooled to r.t., washed with brine, extracted three times with CH2Cl2, and worked up in the usual way to
provide an oily residue, which was purified by CC by afford 5 (74%). Transparent oil. Rf (hexane/AcOEt
3 :2) 0.2. IR: 3384, 2939, 1710, 1656, 1445, 1369, 1274, 1197, 1097, 1044, 981, 917, 711. 1H-NMR (400 MHz,
CDCl3): 6.97 (dt, J ¼ 7.2, 15.6, 1 H), 5.88 (dt, J ¼ 1.6, 15, 1 H); 4.23 (q, J ¼ 6.8, 2 H); 3.70 (t, J ¼ 6.0, 2 H);
2.34 (q, J ¼ 7.2, 2 H); 1.74 – 1.79 (br. m, 3 H); 1.32 (t, J ¼ 6.8, 3 H). 13C-NMR (100 MHz, CDCl3): 166.7;
148.5; 121.8; 61.9; 60.2; 30.9; 28.5; 14.3. NMR data were in accordance with those reported in [7].
Ethyl (2E)-6-Oxohex-2-enoate (6). To a soln. of 5 (10 mmol) in 100 ml of dry CH2Cl2 was added PCC
(12 mmol). The resulting mixture was stirred at r.t. for 3 h and dried (MgSO4). The filtrate was
concentrated under reduced pressure, and the residual material was purified by CC to give 6 (78%).
1
Transparent oil. Rf (CH2Cl2) 0.2. IR: 2982, 2938, 1720, 1654, 1312, 1268, 1193, 1043, 984, 852. H-NMR
(400 MHz, CDCl3): 9.78 (s, 1 H); 6.95 (dt, J ¼ 7.2, 15.6, 1 H); 5.85 (dt, J ¼ 1.6, 15.6, 1 H); 4.21 (q, J ¼ 6.8,
2 H); 2.51 (t, J ¼ 7.2, 2 H); 2.28 (q, J ¼ 7.2, 2 H); 1.84 (quint., J ¼ 7.2, 2 H); 1.30 (t, J ¼ 6.8, 3 H). 13C-NMR
(100 MHz, CDCl3): 201.6; 166.4; 147.5; 122.3; 60.2; 43.2; 31.2; 20.3; 14.2 (OCH2Me). NMR Data are in
accordance with those reported in [11].
Ethyl (2E)-6-[(2-Bromophenyl)amino]hex-2-enoate (7). In a two-neck 150-ml round-bottom flask,
equipped with stirring bar and reflux condenser, 2-bromoaniline (8 mmol), 6 (4 mmol) and MgSO4 (5 g)
were dissolved in THF (80 ml), and the mixture was stirred at r.t. for 1.0 h. NaBH(OAc)3 (5.5 mmol) was
added, and the mixture was heated to 658 for 20 h. Upon completion of the reaction, the solvent was
removed under reduced pressure, and the residue was dissolved in 1m HCl (50 ml), and then carefully
neutralized with aq. sat. NaHCO3 soln., and finally extracted with AcOEt (3 ꢁ 40 ml). The combined org.
layers were washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure to
yield 7 (71%). Transparent oil. Rf (hexane/CH2Cl2 3 :2) 0.2. IR: 3404, 2933, 2861, 1720, 1656, 1593, 1511,
1459, 1317, 1273, 1201, 1169, 1042, 1018, 980, 743, 657. 1H-NMR (400 MHz, CDCl3): 7.44 (t, J ¼ 8.0, 2 H);
7.23 (dt, J ¼ 1.2, 8.4, 1 H); 7.03 (dt, J ¼ 6.8, 15.6, 1 H); 6.64 (d, J ¼ 8.4, 2 H); 6.61 (dt, J ¼ 1.6, 8.0, 1 H);
5.89 (dt, J ¼ 1.6, 15.6, 1 H); 4.30 (br. s, 1 H); 4.24 (q, J ¼ 6.8, 2 H); 3.23 (br. m, 2 H); 2.40 (q, J ¼ 6.8, 2 H);
1.90 (quint., J ¼ 7.2, 2 H); 1.33 (t, J ¼ 6.8, 3 H). 13C-NMR (100 MHz, CDCl3): 166.5; 148.2; 144.8; 132.4;
128.5; 122.2; 117.7; 111.2; 109.7; 60.3; 43.1; 29.6; 27.6; 14.3. HR-EI-MS: 311.0525 (C14H18BrNOþ2 ; calc.
311.0521).
Ethyl 2-[1-(2-Bromophenyl)pyrrolidin-2-yl]acetate (8). An oven-dried Schlenk tube containing a
stirring bar and a rubber septum was evacuated and filled with N2 four times. A soln. of 7 (2 mmol in anh.
THF (4 ml)) was placed in the tube via syringe, and the soln. was cooled to ꢀ 108 using an ice-salt bath.
tBuOLi (1.0m soln. in THF, 20 mmol) was added to the soln., which was left to stir for 1 h. The mixture
was then allowed to warm to r.t., the reaction was quenched with sat. NH4Cl (aq.; 2 ml), and the mixture
was extracted with CH2Cl2 (2 ꢁ 10 ml). The org. extract was dried (Na2SO4), concentrated under
vacuum, and the residue was purified by CC to afford 9 (67%). Pale-yellow oil. Rf (hexane/CH2Cl2, 6 :4)
0.1. IR: 3376, 3060, 2975, 2874, 2360, 1897, 1731, 1585, 1474, 1436, 1372, 1314, 1245, 1193, 1155, 1101, 1026,
976, 849, 752, 720, 669. 1H-NMR (400 MHz, CDCl3): 7.56 (d, J ¼ 8.4, 1 H); 7.26 (t, J ¼ 6.8, 1 H); 7.08 (d,
J ¼ 8.4, 1 H); 6.87 (t, J ¼ 6.8, 1 H); 4.22 – 4.25 (m, 1 H); 4.10 (q, J ¼ 7.2, 2 H); 3.88 (dd, J ¼ 1.6, 6.4, 1 H);
2.89 – 2.90 (m, 1 H); 2.59 (dd, J ¼ 4.0, 15.2, 1 H); 2.31 – 2.33 (m, 1 H); 2.23 (dd, J ¼ 9.2, 15.2, 1 H); 1.98 –
2.02 (m, 1 H); 1.88 – 1.91 (m, 1 H); 1.72 – 1.73 (m, 1 H); 1.24 (t, J ¼ 7.2, 3 H). 13C-NMR (100 MHz,

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CDCl3): 172.5; 147.4; 134.2; 127.8; 123.2; 120.9; 118.5; 60.3; 56.4; 53.0; 38.8; 31.6; 23.8; 14.2. HR-EI-MS:
311.0517 (C14H18BrNOþ2 ; calc. 311.0521).
Ethyl 2,3,9,9a-Tetrahydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (9). A Schlenk tube equipped with
magnetic stirring bar was charged with CuI (5.0 mol-%) and 2-picolinic acid (10.0 mol-%). The tube was
evacuated and filled with N2 (3 cycles). Next, a soln. of 8 (0.80 mmol) in anh. 1,4-dioxane (1.0 ml) was
added by syringe, followed by LiHMDS (1 equiv., 1.0m soln. in THF) at ꢀ 108. This mixture was stirred at
ꢀ 108 for 10 min, then the resulting soln. was allowed to warm to r.t. and heated to 508 for 3 h. The
mixture was cooled to r.t., and the reaction was quenched with sat. aq. NH4Cl (1.0 ml). H2O (10.0 ml) was
added, and the resulting mixture was extracted with AcOEt (2 ꢁ 10 ml). The combined extracts were
washed with brine (10 ml), dried (Na2SO4), and concentrated under reduced pressure. The crude
material was purified by CC to afford 9 (52%). Pale-yellow oil. Rf (hexane/CH2Cl2, 6 :4) 0.2. IR: 2984.5,
1741.4, 1731, 1585, 1474, 1436, 1373.7, 1239.8, 1047.1. 1H-NMR (400 MHz, CDCl3): 7.10 (t, J ¼ 8.5, 1 H);
7.05 (d, J ¼ 7.9, 1 H); 6.74 (d, J ¼ 7.9, 1 H); 6.53 (d, J ¼ 7.9, 1 H); 4.12 (q, J ¼ 7.2, 2 H); 3.96 (ddd, J ¼ 9.7,
8.4, 5.3, 1 H); 3.70 (ddd, J ¼ 9.6, 8.5, 6.1, 1 H); 3.45 (ddd, J ¼ 10.7, 8.8, 3.7, 1 H); 3.10 (ddd, J ¼ 10.5, 8.5,
7.6, 1 H); 1.80 – 1.96 (m, 2 H); 1.68 (m, 1 H); 1.36 – 1.30 (m, 1 H); 1.24 (t, J ¼ 7.2, 3 H). 13C-NMR
(100 MHz, CDCl3): 172.5; 154.81; 128.98; 128;41; 124.03; 119.35; 110.76; 68.6; 60.3; 51.8; 44.6; 27.2; 25.1;
14.2. HR-EI-MS: 231.1265 (C14H17NOþ2 ; calc. 231.1259).
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Received August 10, 2013